PL154878B1 - Method of obtaining novel phosphorus containing derivatives of 3-hydroxybutanic acid - Google Patents

Description

PATENT DESCRIPTION

154 870

Additional patent to patent no. Pending: ⁸⁸ 05 21

Priority 87 05 22 / P. 272598 /

United States of America

Int. Cl. ⁵ C07C 9/30 C07F 9/547 // A61K 31/66

OFFICE

PATENT

RP

READING 0 G D Lh

Application announced: 89 05 16

Patent description published: 1992 04 30

Creators of the invention: Dornald S. Karanewsky, Michel Ch. Badia, Scott A. Biller, Erie M. Gordon, Michel J. Sofia

Covered by patent: E.R. Sąuibb and Sons, Inc.,

Princeton / United States Amenry! /

METHOD OF PLAYING NEW PHOSPHORES OF KWSU DERIVATIVES

3-HYDROXYBUTAU

The subject of the invention is the method of tytraurania, containing phosphorus, 3-hydroxybutane karst derivatives, inhibiting the activity of 3-hydroxy-3-eethylglutarylene reductase A, useful for inhibiting the biosynthesis of cholesterol, influencing the effects of hypocholesterolization, and of intermediates in the synthesis of these compounds.

F.M.Singer et al., Prrc. Soc. E: R. Biol.Med. 102, 370 (1959) and P. H. HiHcher, Arch. Biochee. Biophys., 146, 422 (1971) discloses that certain eoraloncwegc acid derivatives initiate cholesterol biosynthesis.

In U.S. Patents Ae. Nos. 4,049,495, 4,137,322 and 3,983,140 Endo et al. disclose a fereenation product titrating activity in cholesterol biosynthesis. This product was named Cceeacjin, C. Brown et al., J.Chee.Soc. Porkin P 1165/1976 / reported that it differs in the structure of the eraaaonic karst lactone.

In British specification pate ^ salty No. 1586152 discloses a group of synthetic compounds of general formula 23a in which E represents a direct bond, C ₁ eootek _3cl0ieenooy or ro ^ ttek oieylrncwy, and different syrnbole R ^ are different bases path.

The activity of the compounds described in the British description pcaentooye ^ n> si below 1% aOayonoCci coeeaaCie.

In the patent description of St. Zjein.Ae. No. 4375475 JLord WI ^ et ^ l disclose compounds acting yypocholesteΓoOremjzeye and hypolipeeicznye of general formula 24 in which A is hydrogen or atoe eeeyl, E is a direct bond, the group -CT ^ - »-CHh- -CH ₂ - -CC2 _CH2-CH2- or -CH = CH-, R, _R2 and R ^ are rene atoeu of hydrogen atoeów halo, Cj ^ alkyl, H __ ^ chyorowoccal01ooej, phenyl, phenyl substituted with halogen atoeee group, CJj_ _Buy ClkoOsylooą, H2_gClOanoylOsylowa, C ₁ _ _clay aΓoylooą or C ₁ _ ^ chlc154 373

154 878 rowcoalkilową and a group wherein R represents a hydrogen ator, a C2_g3lkanoilową, benzoyl, phenyl, halophenyl, phenyl-Cc_ ₃ alkyl C_galkilc ^ group, cinnamyl, C ^ haloalkyl, aHHinią cycloalkyl-CL - ^ - alkioową, adamantylOo -c_ ₃ alkyl group or a substituted phenyl-C --alkilową, wherein each substituent is selected from halogen atoms, groups CF-Lalkoksylowej Cf ^ alkyl or C ^ chiorowccolkilowej; and the corresponding ia dihydroxy-lactate ring-opening repeating acid, and the farraakilogically acceptable salts of these acids and the C6-6alkyl- and phenyl-, dimethylaaine or acetylaaine or acetylaaine substituted C1-4alkyl esters of the dihydroxy acids, all of which these compounds are enantiomaeraai of the 4r configuration in the tetrahydropyran part of the trans raceate shown in the general formula above.

In International Publication No. WO 84/02131 of the PCT / PCT / EP 83/00308 patent application / / based on US patent applications, AA. no. 443668, works 22 liiso ^^ and ^ da 1382 and no. 548850, November 4, 1983 / Sandos AG discloses heterocyclic analogs of aoloaclolactons and their derivatives of general formula 25, in which one of the symbols R and R _o is a group of formula 26 and the other is primary or secondary pieiwszorzędowy glkU C, C - ^ ^^^ οβ ίΐ group or a phenyl-Cc ^ / a-, has combined with R 26 in the formula ATOA is hydrogen, C alkyl, C ₁ -C -lkkoksyl / z wyjątkiea III rzęd.bu1t <ltsy ^ J ^ ^ l ^ /, trójfluorGaetyl, ATOA fluoro, chloro, phenoxy or benzyloxy, R represents a hydrogen ATOA, Ο ^^ - ΙΙϊΙ, C1_ ₃ ^ alkoxycarbonyl; ^^ ₁ triph ^ c ^ i ^ i ^^^ i ^ y ^ l ^, fluorine, chlorine, phenoxy or benzyloxy group,

Ra is hydrogen, Cc_2alkyl, Cc_2ackoxyl ator of fluorine or chlorine, anda is the number 1, 2 or 3, so that when R- is hydrogen then both R- and R- _a substituents are hydrogen when R- is hydrogen Ra or be hydrogen, not more than one of R- and R- is trifluoroethyl, not more than one of R- and R- is phenoxy and not more than One of Ri R- is benzyloxy group; R ₂ is a hydrogen atom, ^ - βΒϋ, Cj_gccyiooakill C · --al-cooxy! / with exception III row. butoxyl /, toojflιl5Γoaethyll atoa of fluorine, chlorine, phenoxy or benzyloxy; Rj is hydrogen, Ci-uckl, Cy-alkoxy, trifluoroethylene fluorine, chlorine, phenoxy or benzyloxy group, however, when Rg is hydrogen, then Rj must be hydrogen, no more than one of R2 and Rj is to tfSuOΓmethyl no more than one of R2 and R- is phenoxy, and no more than one of Rg and Rj is benzyloxy and Z is a group of formula 27 wherein Rg is hydrogen or C 1-6kyl; in free acid form or in the form of physiologically hydrolyzable and physiologically dopuszczatoego esrtu ^l with ^b <hMonu Hu ¹ in the form of salted.

British Patent No. 2162-Γ79-Α discloses naphthyl molololactane analogs useful as inhibitors of cholesterol biosynthesis having the general formula 28, wherein R2 is -lik !, Z is a group of formula 29, or of formula 30, wherein R? is a hydrogen atom, a hydrated ester group or a cation.

EP 164-698-A discloses lactones useful as anti-hyptrcholesterocltail agents by treating an organic sulfonyl halide aaid of the formula R SOgX and removing the protecting group Pr as shown in Scheat 1, which X stands for a halogen aton, Po stands for a carbinol dependence group, R stands for a hydrogen atom, R and R stands for a hydrogen aton, Cj-jaUkllul feπdlo-Cjjjjaakil with a phenyl group eoenttuιanit substituted with C - j-akilea ^l C T-alkoxy ylea tob ^ ^yk lΓlwca atoaea ^c, R ^- represents ru ^{g PE} formula Toti 31 3 ^{2 and Q} oz rmcza group of formula 33 or 34; where in these formulas R represents a hydrogen atom or a hydroxyl group; R is hydrogen lul meeyl; a, b, c and d are optionally double bonds; R is a lul 1-tinsyl xyl group having a ring optionally substituted with a C 1-6 alkyl group or a halogen atom; R and R are C ^ -alkyl or halogen and ^R is C ^ alkyl, phenyl, February) single dwuu ^{B A} dz / CC-yl ^ uL / phenyl.

154 878

In the published German Patent Application No. 3525256 discloses naphthyl analogs of prayers lactones of formula ³ 5 wk tórym ^R ^ ^and ozneiczii lkil, Z ozracw group of the "Decision of ^{an 36} ltib

37, in which R formulas? is hydrogen lu ^b crosslinkable ^h ydro ^of Iza ester group; useful as cholesterol inhibitors and in the treatment of atherosclerosis.

In International Publication No. WC 8402-903 of PCT Application, which is based on US Patent Application. No. 460,600, filed January 24, 1983 nS noun firay Sandoz AS discloses analogs mot 'lonollktoou useful as agents with hydroxypropyl] poly] X) proteOtomiconym of the general formula 38, wherein the two groups R _Q together form the radical of a "plow 39 or C - (CH ₂ ) A - in which the value 38 - R 2 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy) except II! row. butoxyl /, trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy group, Rj is hydrogen atom, C1-4alkyl, C1-4aakyl, trifluoromethyl, fluorine, chlorine, phenoxy or gasoline atom, but not more than one podstawin.ków of R 2 and R trójfuiorometyl is no more than one of R2 and R is phenoxy and not more than one of R ₂ and R represents a benzyloxy; Rj is hydrogen, CC-jaakyl, fluoro, chloro or benzyloxy; Rj is hydrogen, Cjalkyl, Rajalktxyl) with a 3rd order. butoxy /, trifluoromeeyl, fluoro, chloro, phenoxy or benzyloxy; R is hydrogen, ^and Cj_j lkil, C ₁ _jalkoksyl, tróafluorometyl »fluoro, chloro, fenoisylooą or benzyloxy; Rj is a hydrogen atom, R ₂ i ^ S ··! Cj ^ alkoxy, fluoro or chloro, with the proviso that no more than one of Rj and Rj is trifluoromethyl, and no more than one of Rj and Rg is a group phenoxy and no more than one of Rj and Rj is a lenzylthisyl group; X is a group of formula - / CH ₂ / _n ~ ^lu b grupj 0 formula 40, in which formula o is 0, 1, 2 or 3, and both symbols q are 0 or one is 0 and the second number 1; Z is a group of phenyl group 41, where Rg is hydrogen or ^ ^ ^ ^, with the proviso that the group -Χ-Ζ and Rj with the phenyl group are ortho to each other; in free form or in the form of the physiologically hydrosable and physiologically acceptable ester or lactone thereof, or in the form of a salt.

In the StZ patent specification, j ^ nAm. No. 4,613,610 discloses a series of 6-pi CoazoleO22,4-dihydrohikton-5-pha-carboxylic acid redoxase inhibitors of the general number 42, wherein Rj is C CgaUk1 not containing an asymmetric carbon atom, each of R2 and R6 independently is an atom hydrogen, n-butyl, i-butyl, 3rd order. butyl,

C. ^ a_alkoxy, n-butoxy, isobutoxy, trifluoromethyl, fluoro, chloro, phenyl, fentisyl or benzyltxyl group, each of Rj and Rg is independently hydrogen, ^ ^ ^ ^, Cl_allStxyl, troafltoromethyl, fluorine, chlorine , a pheothisylooa or lenzylthisylooa group; each of Rj and R? independently represents hydrogen, C _1-2 i1kil, CŁ_2llktksyl, fluoro or chloro, with the proviso that no more than one of R 2 and R tróafluorometyl is no more than one of R2 and R is a group fentSsylaoą, no more than one of R2 and Rj is benzylthSsylooa, no more than one of Rj and Rg is trinornomethyl, no more than one of Rj and Rg is phenoxy, and no more than one of Rj and Rg is benzyloxy; X represents groups of the formulas - / CR / -, -CH-CH-CR- or -CH2-CH-CH- where o is 0, 1, 2 or 3, and Z is a group of formula 43 or 44, wherein R _1Q and R'iq is hydrogen or ^^, ^ ^, and Rn is hydrogen, Rj2 or N, wherein Rj is a physiologically acceptable and hydrolysable ester group and M is a cation, with the proviso that / a / the -Χ-Ζ group is in the 4- or 5-position of the piΓlztlooegt 1 ring / i / the Rj group and the -Χ-Ζ group are in the ortho position.

International Publication No. WG 36O7-O54A of the PCT Application discloses imidazole analogs of mo.-alonolactone useful for the treatment of hyperploproteinemia and atherosclerosis, represented by the general formula 45 where R 1 is alkyl, cynloalkyl, adarannyl-1 or R 1, R, R 5 phenyl / group A '; R ₂ is alkyl, cycloalkyl, adamntyl-1 or R ', R _g , R _c . AND

154 378

- substituted phenyl (group B); Rj is hydrogen, alkyl, cycloalkyl, adatranty-1, styryl or Rj, Rj, Rj - substituted phenyl (C) group; X is a group of the formula - / CR / -CH-CH-, -CH-CH-CHg- or CR-CH-CH-; n is 0-3, Z is a group of formula

-CH / OH / -CH ₂ -C / R 11 / 70H / CH ₂ -COOR 10 (n group); -Q CH2- (C) Rij / OH / CM2-COORiz / group c / or group of formula 46 (group b) in which Q is CO or -C / ORu / 2 -; R 15 is a primary or secondary alkyl, wherein each R is the same or R + R is a group / CH ₂ / g or / CIG / g; R <1> is hydrogen or Ci-alkyl; Rj is hydrogen, Rjg is an ester group and M is a cation, with the proviso that Z may be c) only when X is CH-CH or CR-CH-CH and / or when Ru is R__allyl; R ^, R? and R ^ q is <R ^ alkyl, η-, iso- or tertiary butyl, R ^ or isobutoxy, CFj, fluoro, chloro, bromo, phenyl, phenoxy or benzyloxy; Rj, Rg and Rj are hydrogen, C 1-6 alkoxy, tri (nuoromethyl, fluoro, chloro, bromo, COORy, N / R ^ / ₂ , fetoisyl or benzyloxy); R.,? is hydrogen, Rjg or K; Rj- is R 1- alkyl, η-, iso- or tertiary-butyl or benzyl; Rjg is alkyl; Rg, Rg and R4 are hydrogen, Ci_2i1 ^^ 1, Rrialkoxyl, fluoro, with the proviso that (1) not more than one substituent from each of A, B and C groups is trifluoro; and , no more than one of each of A, B, and C is phenoisylic and no more than one of each of A, B, and C is benzyl, oxy, ^ ^ t; (2) when Z is the group c / 0 is C / ORr /// J, the compound is in the free base form and either / and / Rj is Rj and each of Rj is independently CRC, or / 11 / R / is M, and each of Rjy ₈ is independently R or M; and (3) when Rz and / or therein one of Rjy is M, the compound is in the form of a free base.

Unless otherwise stated, all alkyl groups are groups with 1-6 carbon atoms and no asymmetric carbon atom, and cycloalkyl groups are groups with 3-7 carbon atoms.

In International Publication No. WO 8603-499-A of the PCT patent application, unique indene analogs of mova-lactote are useful as anti-hypoliproteinemic and anti-atherosclerotic agents, in the free acid, ester, β-lactome or salt form, of general formula 47, in which R is hydrogen or Cj-g-aakH primary or secondary; Rj is primary or secondary Cg8-alkyl; or R + Rj are the group / CHR / n or / z / -CR-CH-CH-CR; n is from 2 to 6; R _Q is Ο __- 11ϊ1, Cj-yCyckoolkyl or Rj Rj »Rg and substituted phenyl; R2 and Rj are hydrogen, CRjalkyl, CRjalkoxy and except for the 3rd order. butoxyl /, trifluoromethyl, fluoro, chloro, phyltoisyl or bitzyloxy; Rj and Rj are hydrogen, Ri6alkyl, Ci ^ alkoxy, trifluoroethyl, fluoro, chloro, phtoisylocyl or benzene; Rg is R_ ₂ alkyl, C-IIR ^s 2al yl, fluoro or chloro, with the proviso that each of the rings of the phenyl and indene may be only one of the substituents forming yrójfluoΓImetyl, phenoxy or benzyloxy; X is a group of formula / CR / n or -OR / 6 -CHaCH / CR / R 2 -; n is 1 to 3; the symbols q are both zero or one of them is zero, the other 1; Z is a group of the formula -Q-CH ₂ -C / Rrq / CH / CH ₂ CQOH, in the form of a coltiglqh, ester, j-1a1-4 or a salt; Q is a CO, aC / OR /, ^^ or CHOH group; R 'substituents? are in the same majority or secondary alkyl, or together form a group of formula (CH2 / 2 or / CR / j); R _1o is hydrogen or R_j / alkyl, with the proviso that -Q may MEC CHOH other than when X is CH or CR-CH-CH-CH and / HR is C1 ^ _ / - alkyl.

In the patent description, i.e. the United States, No. 4,647,576 discloses new C- and H- substituted pyrroles useful as hypolipidaenic agents and hyx:> choOesterIloaenic agents in general voids 48 and 49, wherein X is -CR-, -CR-CR- or -CH / CHj / CR- ; R is 1- or 2-naphthyl, cyclohexyl, norbornenyl, phenyl ewentiulnie substituted by fluorine, chlorine, hydroxyl, trójfloroornetylem, C, _zalkilea, R_ ^ al.koksylem or _C2 _galkanoiloksylea groups ,. 2-, 3- or 4-pyridinyl, or the l, '- oxides thereof, or a group of formula 50 wherein

154 873

R _alkil and hal is ATOA chlorine, bromine or one of R ₂ and R 3 are hydrogen, chlorine, bromine, CN, CFG, phenyl, ^ _ ^ 11 <ϊ1, C ₂ _ _s kartx> alkoxy, CH ₂ ORg or -CH6OCC-HHfR, wherein Rg is hydrogen or C1-6alkanoylia R is alkyl or phenyl ewenttulnie substituted by chlorine, bromine or Cg_galkilem, or R2 and R together represent a group of formula -CO ^ / n -CHgOCHg- "-COH / R / CO- or C0N / _R9 / n / r ₁₀ / C0-, in which n is the number 3 or 4, Ηθ is hydrogen, C1-8gakyl, phenyl or benzyl, Rg and Riq are hydrogen, C1-6alkyl or benzyl; and Rg is C1-6alkyl, cyclopropyl, cyclobutyl, or trifluonomistyl.

In European Patent Application No. 0221025 Al discloses heterocyclic analogs mowaaonolaktonu and their derivatives of the general formula 51, wherein Ro is a -Χ-Ζ, _Rc is R2, Rc is R_, R is R and Y is a group of formula -MR.J, or Ra is R_, R b is -Χ-Ζ, Rc is _R2, Rd is R and Y is oxygen, sulfur or a group -M / R / -; wherein R-, R2, R_ and R_ are independently Ci_alkyl containing no asymmetric carbon atom, C8_cykyl or a ring of general formula 52, or in the case of Rj and Rg additionally a hydrogen atom, or in the case of Rg when Y is oxygen or sulfur, a group of general formula 53, wherein R. is hydrogen or a Cj__alkil _# R_g and Rig are independently hydrogen, ^ ___ ϋ1 or phenyl; each R 5 is independently hydrogen, C 1-6 alkyl, n-butyl, isobutyl, tertiary butyl, C 1-6 alkoxy, n-butoxy, isobutoxy, trinoromethyl, fluoro, chloro, bromo, phenyl, pheolkyl, or benzyloxy; each of R &lt; 1 &gt; independently is hydrogen, Ci_alkyl, ^ ^ ^ ^ ^, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy, and each R &lt; is independently hydrogen, C1-2alkyl, C1-2alkoxy, fluoro or chloro, with the proviso that there may be only one trinoromethyl, one phenoxy or benzyloxy group in each ring A; X is / CH ₂ / _b or / CH ₂ / qCH-CH / CH2 / q, m is 0, 1, 2 or 3, and q is both zero or one of them is zero and the other is 1; Z is a group of formula 54, wherein Rg is hydrogen or Cfj_alkyl in the form of the free acid or its ester

-lactone, or in the form of a salt, depending on which of these compounds is indicated for use as a hipllipoprotein and anti-atherosclerotic agent.

In Tetrlhedrlo Letters, 29, 929, 1988, the synthesis of the 3-hydroxy-3-methylglulayinineonine reductase A reductase inhibitor of formula 55 is disclosed where R is atoa Ha or C2H3 group.

European Patent Application No. 127848-A discloses acid derivatives

2 -hydΓOxy-5-thio-vailyl-carboxy of general formula 56, where Z is a group of formula 57 or formula 58, n is 0, 1 or 2, Z is -CH2-, -CH ₂ -CH2, -CH ₂ -CH ₂ -CH ₂ -, -CH-Ch-CH ₂ - or -CH ₁ -CH-CH-; R, R _2, and R? are, for example, hydrogen, chlorine, bromine, fluoro, C1-alkyl, phenyl, substituted phenyl or a group of the formula CR ', wherein R is, for example. hydrogen, C ₂ galkanoH, benzoyl, phenyl, substituted phenyl, C__alk ^ l cynamml, Cj_zchloeowccllkil, allyl, tick Uo N, N-C ^ -alkyl, -C ₁ adaimanylo omicron -alkyl or phenyl-Ci__ -alkyl; R, R, and R 8 are hydrogen, chlorine, bromine, fluoro, or C 8-12 kk1; and X is, for example, a hydrogen atom, a C 1-8 ack1, an alkali metal cation or an ammonium cation.

These compounds have antifungal activity due to the ability to inhibit 3-hydroisy-3-methylcglulrllineonyymlA / HKC-Co a reductase and antifungal activity.

In the description of French Patent Application No. 2,596,393, Aljlinilol acid derivatives

3-carblxy-2-hydroxyprlplOlflsphonoiegl and salts thereof, useful as hypolipasmic agents of general formula 59 wherein R and R2 are hydrogen, lower alkyl, or optionally substituted aralkyl and Rg and R are hydro, lower alkyl or optionally substituted aryl or aralkyl. ^! Jg ^ w] oooo that these compounds provide a greater reduction in the content of cholesterol, triglycerides and phospholppids in the blood than mogluuoi.

154 878

In European Patent Application No. 142 146 - A discloses compounds mowikolinowe oo ^g olny formula 60, wherein R is, for example. Hydrogen or C _ ^ - alkyl, Z is a group -CHoCHo, -CH = CH- or - / CH, / _- and Z means: / l / group with general sea 61, where * 5 9 7

X represents the -O- group or the -NR group, where R is hydrogen or C1 -alkyl; R is C 1-alkyl; and R is hydrogen or mmtyl; / 2 / group of general sea 62 in which

R, R ¹ and R are independently, for example · hydrogen, halogen or C / alkyl; Ia Dec14 is general sea 63, where n is 0-2 and R is halogen or C 1-6 alkyl; or / 4 / general sea 64 group. These compounds are inhibitors of HM-Co A reductase

Phosphorus-containing compounds which inhibit the enzyme 3-hydroxy-3-methylglutate enzyme A / HM-Co a / 1 reductase / 1 are therefore useful as hypocholesterolomic agents. These compounds contain moieties of general formula 65, wherein X is -C1C- and Z is a hydrophobic anchor.

The term hydrophobic anchor as used herein refers to a lipo / yl group which, when linked to the upper HO-like side chain of a molecule via an appropriate binding group / x /, binds to a hydrophobic enzyme pocket not used in the bonding of the HMC-Co A substrate, resulting in increased potency compared to compounds where Z is hydrogen.

According to the invention, the method of boiling phosphorus derivatives of butanoic acid at sea

Wherein R is a hydroxy group or a lower alkoxy group, Z is a group having the secondary 7, 8 ^ 9, 10, 11, 12 13 ^ 12 15 ^ 16 ^ 17 ^ 18 ^ where r, R ^ R ^2a and R ^2b s ^a same or different and are each independently hydrogen, halogen, lower alkyl, chlorowic-alkll · phenyl, substituted phenyl, or a guano 0R1, wherein R "is hydrogen, alkanoH, benzoyl, phenyl, halophenyl, phenyl -lower alkyl, lower alkyl, tinir, halogen, lower alkyl, allyl, cycloalkyl lower alkyl, or substituted 5 'phenyl lower alkyl, and when Z is a group of 18, R and R are the same l.ub y ^oz ne ^l ^ represent Μάοη than ^that s ^{k y} al yl or ^g roups ^ę OH, R 'represents ru ^{g PE} of formula ¹ 9 ^t I ^k and ^each of the formula ²⁰ or ao ^r ^ ^H lo-- ^{-, R 'a} represents than ^f s ^y alky ^l · ^g ru ^PE b ^ raks ^ on ^ ^£ 7 keto group or halogen, q is zero 1, 2 or 3 and R is hydrogen or lower alkyl, where Z denotes a group of sea 9, 10, 11, 12, 13, 14 and 16, one of subs tawniJtów R 'LR' means grap ^E with formula 21, and the other is a lower ^y alkyl, C ^y kloaakil, lu ^b phenyl-ZCI ^ / p - wherein p is zero, 1, 2, 3 or 4, R is hydrogen , lower alkyl, lower alloxyl (except the 3rd order) - butoxy /, halogen, phenoxy 14 or benzoyl, R is hydrogen, lower alkyl, lower alkoxy, halogen,

14a a pheilyl or benzyl group, R is hydrogen, lower alkyl, lower alkoxy 13 14 14a xyl or halogen, but if R is hydrogen, both R LR must

14 hydrogen atoms if R is hydrogen R must be hydrogen, not ^{learn more,} n ^L one of R ^{1 'L R 1 Z} represents trójduorometyl no more than j ^ en R ^{1' L} R ^1Z 13, 14 is a fenoksyrlową L no more than one of R LR is beisrlilsyl;

Q

R is hydrogen, C ^ aH ^ H CJ_gcyrloilkil - ₁ _ «- allilsrl / except iii row .- ^ buatom fluoro, chloro, C ^ Fenot words or beizyliks ^y group, R" is hydrogen, -. ' __alkil, C.trójfuuorometyl, fluoro, chloro, fen ^ s ^ words or benz ^ o ^^ words zt ^{y y,} if. ® ^R is ^hydrogen, R "mini iziacza ^{a C} atom of hydrogen, not more than one of R LR is trójfuuorometyl no more nLż one

9 8 9 R LR is a feiilsylową L is not more than one of RLR is a benzyls sylową ^{L, 10} R ^L R ^{L 1} AZD ^R is independently hydrogen, alkyl, ο Ιαθ ^ ^ ί! adaϊmniyl-1 13 14 14a or a group o 22, in which R, R LR have the meaning given above, and q is zero ^ 1 2 ^, 3 or 4 ^, Y is an atom ^ βη ^ si ^ arc or ^b group ^N -R ^{10 in} a spinning ^ u ^ ^g d ^y Z is a group of the formula 15, ^and R is hydrogen or a primary or secondary alkyl group -'_ ^C "group, ^{R '3} is secondary or ptorwszorzędowa grap ^E C" gaHLlow ^a or R ^and ♦ R ¹ represent a group - / CH? / - or cis-CH. _? - ^-H = ^-H - ^-H · _:) - · r is 2 ^, 3, 4 ^, 5 or 6 ^, R ¹² is _r 8 ° 13 14 14 _and lower alkyl, cycloalkyl, or a group of formula 21 and R, R ', R, R LR are higher than 154 878

16, R ³ and R are both hydrogen, chlorine, bromine, CN, CF, phenyl, C, alkyl, C? "Alkoxycarbonyl, -CHOR

IR ^£ 17 18 ^'O ~ or -CHgOCOHHR, R is hydrogen or C ggami, R is alkyl or phenyl ewenalkiitawą, lu ^Rig and ^{b. R1} ® ratualnie substituted by fluorine, chlorine, bromine or a C ^^ alkyl ZEM form group - / CTł ^ »- ^{/ H} 2- ^O ^ H2 ^-, - ^ ΟΝ / Η ^ / Μ- l.uh ^- CdN ^ ^R θ // n / r ²¹ / coa means they form a group

1C l ^l l 20 21, or 4, R is hydrogen, C, _t alkyl, phenyl or benzyl, R and R represent Vol-22 hydrogen, C, .alkil or benzyl, when Z is' eagle 17, R l 22 * niżl- lower alkyl, cycloalkyl, adamintyl of formula 17, R is lower alkyl, cycloalkyl, ^adamant-1-y l or ^{g PE} ru 'eagle 2 ^3, όιη ° ^ ^t is 1, 2 ³ lu ^b 4, R ^{2g and R2g8 are} Ta ^k e ^s ame l.ub different and each independently represents hydrogen, lower alkyl, lower alkoxy / except pa

Tertiary-butoxy /, halogen, phenoxy or benzyloxy group, except that if R - - 23a

23 _and 23 is hydrogen, R must be hydrogen, no more than One of R is trifluoromethyl, no more than one of R and R is phenoxy and not

_And * more than one of R and R is benzyloxy. R represents a hydrogen atom or a lower alkyl group in the form of a free acid or in the form of a physiologically acceptable and hydrolysable ester in the form of a salt, which consists in the fact that in the acetylenephosphinate of the formula II In a known manner, especially glacial acetic acid and n-butylamyl fluoride, the alkyl ether group is cleaved off to give the two string of formula III and, if necessary, it is converted to munoster of formula 4, basic salt of number 5, dibasic salt with a pound 6 or a corresponding biconvex of formula 1.

Preferred compounds according to the invention are compounds of general formula I in which R is hydroxy or lower alkoxy, R * is hydrogen or lower alkyl, and Z is a hydrophobic anchor as defined hereinbefore and in the form of pharmaceutically acceptable salts.

The term salt or salts refers to basic salts formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts such as kilois, sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as salts with amines, e.g. dibsyloxylaminooyl salt, benzothiazine salt, N-mesyl-D-gltklyin salt, hydrabamine salts, amino acid salts such as argititol, lysine and the like. The non-toxic, cat, c, c, and all acceptable salts are preferred, although other salts are also suitable, e.g. for deburring or cleaning the product.

Examples of hydrophobic anchors that are found in the compounds to be folded according to the invention are those with general "7, 8,"

9, 10, 11, 2, 13, 14, 15, 16, 17 uuh 18, with the zzyme in the formula 18 linee prse oznacziΊase denote possible double bonds, e.g. groups of 66, 67, 68, 69, 70, 71 and 72. the 1 2 2 R 2b these formulas, R, R, R and R may be the same or different and are each independently hydrogen, halogen, lower alkyl, chloroiccolk01, phenyl, substituted phenyl or a 0 ^R \ wherein R represents hydrogen, aloanoyl, benzoyl, phenyl, halophenyl, tert-yl-lower alkyl, lower alkyl, cinnamyl, chloro-lower alkyl, allyl, cycloalkyl-lower alkyl, adayali-lower alkyl, or substituted phenyl-lower alkyl.

the same or different, oria5 5

When Z is a group of general iznlcrl "plows 18 wiwzas lurk and R is hydrogen, lower aliil or a hydroxyl group, R ° is a group of the" plow 19, the I ^kg roup of a "plow ^20] .u ^g roup ^ę aryl- - ^C H ^{5, and R} is a lower ® ^from alkyl, ru ^{g u} re wodorot enoią ^k, £

Oeto or halogen, q is 0, 1, 2 or 3 and R is hydrogen or lower alkyl.

When Z denotes a group of 9, 10, 11, 12, 13, 14 or 16, one of the symbols of R and R is a group of general formula 21 and the other is a lower alkyl, cycloalkyl or group phenyl- (CH2 / p-, where the sweat is 0, 1, 2, 3 or 4; where in "0rze ² 1 ^r1Z means hydrogen atoms, lower al ⁰ !!., lower ^y 1 ^l OiOsyl ^, chkirowisc ^{, g} roup phenox ^

Iowa or Usnzylixic, R is hydrogen, lower alkyl, lower alkoxy or chloro

154 878

- 14 14a, rhe, except that when R is hydrogen then R and R m are hydrogen atoms, and when R: is hydrogen then R must be hydrogen, not more than one of R 3 and r trójfuuorometyl is no more than one of R ¹ and R ^1Z represents ru ^{g PE k} sylową phenol and not more than ^that one of the padstawni- ^ and ^{R 1.} R ^1Z represents a benzyloxy group; R ¹³ is hydrogen, C 1-6 alkyl, C 1-6 cycloalkyl, C 1- alkoxy (except tert-butoxy), trifuromethyl, fluoro, chloro, phenoxy or benzyloxy; R is hydrogen, C amil, C. ^ .__ _and alliOiyl, trójfuuorometyl atom, a fluorine ^{with chlorine,} ru ^{g PE} phenoxy ^k s ^y phenylsulfonyloxy or nzylo ^ ^ yl group, m of ^{the back,} that ^when R B represents a- hydrogen volume wΛ OQ R 'muui time to be a hydrogen atom, not more than one of R and R is trifluoromethyl, not more than one of R and R is phenoxy and not more than one of R and R is benzyloxy; R and R are independently hydrogen, alkyl, cycloalkyl, adarantyl-1 or a group of general formula 28, wherein ^R1 \, R ^{1 C} and R ^1Select Raja the above ^zraczenie, q is liczt) ^{ę □,} 1, ^2, 3 or ^{b 4;} Y is oxygen, ^sulfur or NR ¹⁰ .

When Z is a group of raorze 15 wówzas In this formula R1 is hydrogen or a primary or secondary ^Ed mid-R ^- is Herwszorzędtowy lu ^b secondary row ^Ed mid-C ^ alkyl, or R1 and R together form a group of the formula / CH ₉ / _y where r is the number 2, 3, 4, 5, or 6, or the group of formula (cis) -CH ₃ -CH-CH-CH ₉ ; R 6 is lower alkyl, cycloalkyl or a group of 8 9 * 13 14 * 14 _{in the} formula 21, wherein R, R, R, R and R are as defined above.

When Z is a group of general sack 17 wówwzas R is lower alkyl, cycloalkyl, a ^d-lMntyl .l or ru ^{g PE} of formula 10 ^{2, kt} órym ^t is 1, ^{2, 3, 4} lu ^b, and ^2- and ^2- \ same or different, are each independently hydrogen, lower alkyl, lower alkoxy / z ^ ^ exception III rzęd.butokayl, halo, phenoxy or benzyloxy, with the proviso that ^when R ² is hydrogen wówwzas ^{2- 3} mnui lznlcza ^{a C} atom of hydrogen, not more than 23, 23a one of R and R is trójfh ^ (^ ^^^^ and 1 ^ y ^^, no more than one of the bases of 23 _and 23, 23 _a speaker R and R a phenoxy group, and no more than one of R and R is benzyloxy.

The term lower alkyl or alkyl as used herein alone or as part of another group will include both straight and branched chain hydrocarbon chains containing up to 12 carbon atoms in the normal chain, preferably 1-7 carbon atoms, such as meeyl, ethyl, propyl, isopropyl, butyl, Tertiary butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4 _J 4-dimethylolentyl, octyl, 2,2,24-trimethylpentyl, nomyl, decyl, undecyl, dodecyl, their various branched isomers and similar chains hydrocarbyl, as well as mentioned groups containing a halogen substituent, such as fluorine, bromine, chlorine or iodine, threefh ^^ R ^ ^ ^ ^ ^]., alkoisyl substituent, aryl substituent, alkylaryl substituent, haloaryl substituent, cycloaliyl substituent , alkylcycloalkyl, hydroxy, alkylamino, alkanoylamino, arylcarbonylamino, nitro, cyano, thiol or 11kylthio.

The term cycloalkyl as used alone or as part of another group includes saturated cyclic hydrocarbon groups of 3-12 carbon atoms, preferably 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyylheptyl, cyclooctyl and cyilldldecyl, each these groups are to be substituted with 1 or 2 halogens, 1 or 2 lower alkoxy groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxyl groups, 1 or 2 alkoxyl groups, 1 or 2 aliatoamino groups, or 2 arylcarbotoaminooy groups, 1 or with 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups, and / or 1 or 2 allylthio groups.

The term aryl or ar as used herein refers to monocyclic or bicyclic aroratic groups having 6-10 carbon atoms in the ring portion, such as phenyl, kerosene !, substituted phenyl or substituted naphthyl, in which groups the substituents of the phenyl or naphthyl group can be 1, 2 or 3 lower alkyl groups, halogen atoms

154 878 (Cl, Br, or F), 1, 2 or 3 lower alkoxy groups, 1, 2 or 3 hydroxyl groups, 1, 2 or 3 phenyl groups, 1,2 or 3 alkanoyloxy groups, 1, 2 or 3 benzoyloxy groups, 1, 2 or 3 haloalkyl groups, 1, -2 or 3 halophenyl groups, 1, 2 or 3 allio groups, 1, 2 or 3 cycloalkyloxy groups, 1, 2 or 3 adamntyloolkyl groups, 1, 2 or 3 αlkiOcaminoot groups, 1, 2 or 3 alkaioiOaamlnaoe groups, 1, 2 or 3 arylcarbonylamino groups, 1, 2 or 3 amino groups, 1, 2 or 3 nitro groups, 1, 2 or 3 cyano groups, 1, 2 or 3 yloo groups and / or 1, 2 or 3 alkylthio groups, with aryl groups having 3 substituents being preferred.

The term aralkyl, aryl-alkyl, or aryl-lower alkyl, as used herein, alone or as part of another group, refers to lower alkyl groups previously having an aryl substituent, such as benzyl.

The term lower alkoxy, alkoxy, or aryloxy, or aralkoxy as used herein alone or as part of another group, means any of the previously described lower alkyl, alliU, aralkyl, or aryls bonded to an oxygen atom.

The term lower alkylthio, alkylthio, arylthio, or aralkylthio, alone or as part of another group, as used herein, includes any of the previously described lower alkyl, allyl, aralkyl or aryl groups linked to a sulfur atom.

As used herein, lower alkyl, alliH, aryl or arylalkyl groups linked to a nitrogen atom are included in the term α lower alkyl, aryl or arylalkyl group, alone or as part of another group, as used herein.

The term alkanoH as used herein as part of another group means lower alkyl attached to a carbonyl group.

The term halogen as used herein denotes chlorine, bromine, iodine or fluorine, with chlorine and fluorine being preferred. The term also includes trifluoromethyl.

Preferred are compounds of the "plow 1, wherein R is OH, OLi or CRO, R * is hydrogen or lithium, and Z is ^g rupa of general" plows ⁷³ to ^k TORAM ^R1 is phenyl, ^lu b phenyl substituted by alkyl or halogen / including OTomety trifluoro ^! /, or R 1 is cycloalkylalkyl such as cyclohexylmethyl, or R is a benzyloxy group that is substituted by halogen ^{± /} on when wireless ^{± ±} cw -ttójfluorome to-back / and ^r2 and ^R2c are the ^s ame Dad and represent hydrogen atoms, halogen (including the tri-C ^ C ^ and ^ C ^ ^ ^ ^ ^ ^ 1) or lower alkyl, or Z may preferably represent a group of general formula 74, wherein R and R pass as previously defined for a group of formula Z 73, or Z may preferably be a group of the formula ^75, the ^angle órym R ⁵ is substituted phenyl, lower alhil, cycloalkyl 1 .ub ^l ^^ l ^ a loslki

R is a substituted phenyl, lower alkyl such as isopropyl, cycloalkyl or phenylalkyl, Z i.Iio Mze Dad toorzystnie aznacza ^Æ ru ^{g PE} of the general formula 76, wherein R ⁵ is a hydrogen atom £ 7, meeyl or hydroxy and R is a group of general formula 77, wherein R is hydrogen, methyl ^l previous atóo ^R5 is ^ dstawi-ones tónylometyl.

Z may also preferably represent 10, 11 or 12 groups, wherein at least one of R and R is phenyl or paistavi! phenyl and the other 3 4 substituent

R or R is lower alkyl.

Compounds of formula 2 are prepared according to the process as outlined in Scheirae 2.

As shown in Scheme 2, the compound of formula 2 can be prepared by subjecting an iodide of formula II to a Arbuzov reaction by heating an iodide of formula II with a phosphoyl of formula P / O-alkyl / j under the conditions of Arbuzov's reaction to give a c-phosphate of IV, which is new intermediate product.

The phosphate of formula IV is then subjected to cleavage of the ester group of the phosphoric ester by treating a solution of foifonia of formula IV in an organic solvent such as methylene chloride, successively with trismethylsilyl (-trifluoroacttamide (BSTFA) and triethyloyl bromide in an inert atmosphere such as methylene chloride. argon,

154 878

WT to form phosphonic acid of formula V which is a new intermediate.

The phosphonic acid of formula V is esterified by treating it in anhydrous pyridine with a lower allto-alcohol (such as methanol) and dicylhexylcarbodiimide and then combing the resulting reaction mixture under an inert gas such as argon. Thus, the monoalkyl phosphoric acid ester of formula VI is obtained, which is a novel intermediate.

The phosphoric ester of roor VI is then dissolved in an inert organic solvent such as methylene chloride, benzene or tethiaahydrofuran (tw) by treatment with trimethylsilylvumethylamine and stirred under an inert gas such as argon and the mixture is then dissolved in methylene chloride / or in another suitable inert organic solvent /. Poawtały solution is cooled to a temperature of from about ^-10 C to about 0 ° C, treated with chloride okseUlu and catalytically acting lwumtyCoformtπddlie evaporated ^ u ^ ^e, to yield the crude chlorophosphonate of formula VII, which is a new intermediate product.

Clhorophosphonate of formula VII is dissolved in an inert organic solvent such as triton chloride, benzene, pyridine or TH ¹ , the solution is cooled to about -90 ^° C to about 0 ° C, preferably from about -85 ° C to about -30 ° C and will cover an acetylene compound of formula 10, formed by treatment with a lithium source such as n-buCyCoOit in hexane or other inert solvent, using a lithium anion solution cooled to the same limits, using a compound of formula X in ranging from about 3: 1, preferably from about 1.5: 1 to about 2: 1, including acetylenephosphinate of formula XI as a novel intermediate.

The compounds according to the invention can be prepared as racemic mixtures and subsequently separated to isolate the S isomer, which is preferred. However, these compounds can also be produced directly as B-isomers as described in the description and in the examples.

The compounds of the formula I are inhibitors of 3-hclrix-3-methylgutacillin [mu] ^{l [} alpha] (HMC-Co [alpha]) and are therefore useful for inhibiting cholesterol biosynthesis as demonstrated in the following tests.

1. Rat hepatic reductase HMC-Co A

Rat hepatic HHC-CO A reductase activity was measured using a modified method described by Edwrds / Edwrds, P.A. et al., J. Lipid Res. 20:40, 1979 /. Rat liver micrites were used as the source of the enzyme, and the activity of the enzyme was determined by measuring the conversion of C-HCC-Co A medium to - volonoic acid.

a / Preparation of micro-rooms. From 2-4 Spraque Dwley rats, fed with cholastyramine, decapitated livers were collected and homogenized in phish A / potassium phosphonate buffer, 0.04 m, pH 7.2; DCI 0.05m; sucrose 0.1 m; EDTA 0.03m; aprotinin, 500 k / col / units. The homooetizing product was centrifuged at 16,000 g for 15 minutes at 4 ° C. The superratant was removed and centrifuged again under the same conditions. The supernatant from the second centrifugation was centrifuged for 70 minutes at 4 ° C at 100,000 g. The microscopic tablet was resuspended in a minimum volume of buffer A (3-5 ml per liver) and homogenized in a glass / glass filter. Dithiothreitol (10 rolls) was added and the formulation was divided into young portions, which were quickly frozen in an acetene / dry ice mixture and stored at -80 ° C. The specific activity of the first micrithimioegaly preparation in donkeys is 0.68 m 3. moioaonioegi acid / mg protein / minute.

b / Arnlitic enzyme determination. The reductase was determined analytically in 0.25 m samples, containing the following components at the indicated final concentration: 0.04 m potassium phosphate, pH 7.0; 0.05 m KCl; 0.10 m of sucrose; 0.03 m EDTA; 0.01 m of dwiUiotreitol; 3.5 moles of NaCl; 1% ά ^ -ΜίθΐγΙο ^ Ι, ίοΙΙθη ¹ : ^ ⁵⁰ - ² ° C> ^/ U ^g microsomal protein ^; 10 ° ydg 1 ^Zc - / ^, "DLHHMC-C ^and A / 0.05 / uCl, 30-60 £ l / mreo / j 2.7 mn / oi? NA) PH / adonine nicotinamide nicotinamide diphthate phosphate /.

154 878

Reaction mixtures were incubated at 37 ° C. Under the conditions described, the enzyme activity increased linearly to 300 µg microsomal protein per reaction mixture and remained linear with an incubation time of up to 30 minutes. The standard incubation time selected for drug testing is 20 minutes followed by a 12-1% conversion of KMC-Co A medium to mooolonoic acid. The 100 µm 2d, L-7 HMC-Co A medium was 100 µm, which was a fold greater than that required to saturate the enzyme under the conditions described. NADPH was used in excess of 2.7 times the concentration needed to achieve the maximum enzyme rate.

Standard assays for evaluating inhibitors were carried out in the following manner. The microsoral enzyme was incubated in the presence of NADPH for 15 minutes at 37 ° C. Added as liquid^y DMSO medium including^y or without test compound^ekand the mixture was further incubated at temperature³⁷° C within¹⁵ minutes. Prdtika^enwith^ymu aktyroowa Well,^dhare^pput aside^1CC-MC-CoA. After^twenty minute^h ir ^ ulation. in temperature³⁷° C resection by rival accessory²5 µl 33% KOH. - 2 - Mowlonic acid (0.05 pCC) was added^and reaction mixture the liquid was allowed to stand for 30 minutes at room temperature. For the lactonization of the monovalonic acid, 50 µl of 5 N-Cl was added. Bromophenol blue was added as an indicator of p- for slowing the corresponding decrease in pH. The lactonization was allowed to proceed at room temperature for 30 minutes, the reaction mixture was centrifuged for 15 minutes at 2800 rpm.

The supernatants were layered on 2 g of AO 1-ΧΒ anion exchange resin (Biorad, formatted form), loaded into 0.7 cm diameter glass columns and eluted with 2.0 m KgO. The first 0.5 ml was discarded and the next 1.5 ml were collected and the content of both tritium and ^1Z * C carbon in 100 ml of Optifluor scintillation liquid was counted. The results were calculated as the amount of moles of rovonic acid produced in 20 minutes and corrected for 100% tritium recovery. Drug efficacy was expressed as the value (µg) of the drug concentration inducing 50% inhibition of enzyme activity (obtained from the combined dose responses) with the 95% confidence interval indicated.

The conversion of the lactone drugs to their sodium salts was achieved by dissolving the lactone in DMSO, adding a 10 fold molar excess of NaCH and allowing the mixture to stand for 15 minutes at room temperature. The mixture was then neutralized (pH 7.5-8.0) with 1N HCl and diluted to obtain an enzyme reaction mixture.

2. Cholesterol synthesis in freshly w / soluble rat hepatocytes

Compounds ^manhole O .i ^and .ce activity as inhibitors of HMC-Co A were evaluated for their ability to turn on December inhibiloorania ^p y ^ C-acetate into cholesterol in freshly isolated rat suspended hepatocytes, by using the method originally described by Capuzzi DM and Margo, s, S., Lipide, 6: 602, 1971).

2. Rat hepatocyte isolation. Spraque Dawley rats / 180-220 g / were anesthetized with ^ ιΟ ^^ Ιθο / 50 mg / kg /, after which their abdominal cavities were opened and portal veins pressed. Heparin / 100-200 units / was injected directly into the main vein of the abdominal cavity. A single clamping surgical suture was placed on the distal segment of the vein and the portal vein was catheterized between the clamping suture and the first branching vein. Liver perfusion was performed with 20 st ^b bone iml / min heated support nio ^d of ^d ternperatur ^y 3 ⁷ ° C ftleni.nyjm buffer A / HBSSS without calcium or magnesium has jącym 0.5 mimla EDTA / after removing the vena cava to allow drainage of the outflow. The liver was additionally perfused with 200 ml of pre-warmed B buffer (hBSS containing 0.0% Bacterial Colbagmaase). After perfusion of the liver buffer 5 ^'c l · RLL and degreased in 60 ml of medium Weyyraottia, plzo ^ aając the free diffusion of free cells in the medium. Inventive was hrpatocntn by slow centrifugation for 3 m.: Batch at room temperature under 50 g overload. The hepatocyte tablet was washed once with Weyπ.ooth medium, scored, alalylated by removal of the tr / red blue. Such suspensions of enriched hepatocyte cells routinely visualize a viability of 70 - 90%.

154 878

b. Incorporation of ^1Z C-acetate group into cholesterol. Hepatocytes flat ribbon suspended in ^p ożywce hftZ at a concentration of 5.10 ° cells per 2 ml of medium 2 ~ rn Tris 0.02 - Ml / p ^H 7.4 / 0.1 m KCl, 3.3 maooa sodium citrate 6 7 mmol of nicotinic acid amide, 0.23 mole of NADP, 1.7 mole of glucose-6 J phosphate.

Test compounds were routinely dissolved in DMSO or in a mixture of DMSOsHgO (1: 3) and added to the JM. Final DMSO concentration in 1 M was <1, (¾ and had no significant effect on cholesterol synthesis.

Incubation was initiated by adding ^1Z C-acetate (58 m Ci / mmol, 2 µCi / ml) and placing the cell suspensions (2.0 O.) for 2 hours at 37 ° C in 35 mm diameter tissue culture vessels. . After incutbation, the cell suspensions were transferred to glass centrifuge tubes and centrifuged at room temperature for 3 minutes at 5O.g. Cell pellets were resuspended and lysed in 1.0 OH ₂ O and then placed in an ice bath.

Lipids were extracted essentially as described in Bligh, B.C. and W.J.Dyer, Can.

J. Biochem. and Physioo., 37: 911, 1959. The lower organic phase was removed and dried under a stream of nitrogen and the residue was resuspended in 100 [deg.] L of chloroform: motanol (2: 1). The entire sample was spotted onto siliconised gel plates (1KGD) into the layer layer and the chromatogram was developed with the hexane: ethyl ether: acetic acid mixture (75: 25: 1). Plates were examined and counted using a Bio Scan automated screening system. The level of radiolabeled groups in the cholesterol peak (Rf 0.28) was determined and trailed as the total number of counts per peak and as the percentage of the groups labeled in total lipid extract. The cholesterol peaks in the control cultures routinely amount to 800-1000 ppm and contain 9-2% labeled groups present in the total lipid extract; Results obtained by the method of Cayzzi et al. show 9% extracted groups labeled in cholesterol.

The action of drugs (% inhibition of cholesterol synthesis) was determined by comparing the% cholesterol labeled groups of the control and drug treated cultures. From two or more compound dose trials, daWtifactivity response curves were plotted as ratios / ° / with 95% confidence interval /.

3. Cholesterol synthesis in human skin fibroblasts.

The selectivity of a compound favoring greater inhibitory activity in hepatic tissue would be a hallmark of a cholesterol synthesis inhibitor. Therefore, in addition to evaluating inhibitors in hepa Scythians, these compounds were also tested for their activity as inhibitors of cholesterol synthesis in cultured fibroblasts.

a. Cultures of human skin fibroblasts. The human skin filrsblasts (passage 7-27) were grown in miml.Mi Eagle's Basal Medium (Em) containing 10% fetal calf serum. In each trial, stock cultures were trypsonized to disperse cell monolayers, counted, and plated in tissue culture wells 35 mm in diameter ⁽⁵ × 10 ° cells / ^2.0 °). IRL cultures of ^{k l} c ^ ślanś iągu ¹⁸ gocteró at ³ 7 ° C in air zawatości 5% _CO2 and 95% humidity. Cholesterol biosynthesis enzymes were induced by removing serum-containing medium, washing with m 2, 3, and more cells, and adding 1.0O EM containing 1% fatty acid-free bovine serum albumin, and incubating the cultures for an additional 24 hours. hours.

b. Incorporation of C-octcnśwsjh groups into cholesterol. Induced fibroHast cultures were washed with ΕΜΗΜ ^ θθ (Eagle's Minimum Medium Medium). The test compounds were dissolved in DMSO or in the DMSO: EM mixture (3: 1) final concentration of DMSO in the cells of U 1.0% /, added to the culture, and the cultures Ιο ^ Ι ^^ initially at 37 ° C for 30 minutes in a room atmosphere with a COj content of 5% and a humidity of 95%. After the initial incubacc! with the drug, ethyl ^1- C ⁴ C / ^2, 0 ^y u Ci ^/ ml. 5 and ^{8 ° C} / MTM ^S / inkutowino again ^{and the} cultures of pregnant ^ in ^{4 g} odzii. After incubation, the culture medium was removed and the cellularity (200 µg of the cork protein ca culture) / was scraped into 1.0 ml of H ₂ O. The lipids contained in the cell suspension to be Lysed were extracted with chloroform: metam as described for hepato suspensions. 878 citations. The organic phase was dried under nitrogen and the residue was resuspended in chloroform: methanol (2: 1/100 µU) and the entire sample was dotted onto silica gel / LKGDD thin layer chromatography plates and then analyzed as described for hepstocytes.

The inhibition of cholesterol synthesis was determined by comparing the content of radiolabeled groups in the cholesterol peak with the control and drug treated cultures. Results are expressed as / ^ θ values and are derived from plots of composite dose response curves for two or more trials. The 95% confidence interval was also calculated from these curves.

The compounds of the present invention can be used in the form of pharmacological commands, consisting of at least one compound of Formula I in combination with an acceptable carrier or diluent. These compositions may be formulated using known solid or liquid carriers and pharmaceutical additives appropriate to the desired mode of administration. They can be administered orally, e.g. in the form of tablets, capsules, granules or powders, or by parenteral administration in the form of injectables, with dosage forms containing 1 - 2000 mg of active ingredient per donor being used for treatment. The administered dose depends on the unit dose, symptoms, age and weight of the patient.

Compounds of formula I can be administered in a similar manner to known compounds suggested for use in inhibiting cholesterol biosynthesis such as lovastatin to mammals such as dogs, cats and the like, and to humans. Thus, the compounds of formula I may be administered in an amount of from about 4 - 2000 mg in a single dose or in the form of individual doses 1-4 times daily, preferably in an amount of 4 - 200 mg in partial doses of 1 - 100 ml, suitably in unit doses. 0.5 - 50 mm 2 - 4 times a day, or in the form of prolonged release of the active ingredient.

The following examples show preferred embodiments of the process according to the invention. Unless otherwise indicated, all temperatures are expressed in ° C. Flashing Cluromatorraia was carried out on either Merck 60 or Whatronn LPS-1 silica gel. The reversed-phase Claroιrαozraaia was run on a CHP-20 MI resin gel, manufactured by Mitsubishi, Ltd.

The abbreviations used in the examples for EtOAc, MeOH, and EtOH * represent diethyl ether, ethyl acetate, methanol and ethanol, respectively.

Example I. (s) -4- [2-C 4'-fluoro-3,3z, 5-taireiyCo0l, 11-biphenyl) -2-o <e7 etadylmethoxyiosilnyl J / -3-hcdΓoxybutanoviro acid methyl ester

A. N- (2,4-dimetyZbbenzyiidizoibinzeπorriia) (see U.S. Patent No. No. 4 375 475, p. 39 //.

A solution of 6.97 ml / 50 Mlimooi / freshly oazidistyZowaniro 2,4-dimethylbenzredehyeu / Aldrich / and 4.56 m / 50 rilirrZί / distilled aniline / Aldrich / in 80.0 ml of dry toluene was heated under reflux for 3.0 hours in an atmosphere argon, in the flask in the DeannaS-grater adapter. The mixture was cooled and then cooked under reduced pressure to yield a yellow oil. The crude oil was purified by distillation on a Kuuglrchr rotary evaporator at 160-180 ° C under a 0.5 mm column of mercury to yield 8.172 g (78.1%) of the desired title binomial as a light yellow oil that left aside. forming a solid with a low melting point. Chnoimatogafia trierkowowa / TCL / hexane-acetone 4: 1, Ri = 0.67 and 0.77 / geometric isomers, ultraviolet / uv / i J ₂

B. The Palladium Coim / Plex of the Compound of Part A (U.S. Patent Zjdin.Am. No. 4 375 475, page 39 /

A mixture of 6.0 g (28.7 mmole) of part A in 144 ml of glacial acetic acid was treated with 6.44 g (23.7 mmole) of palladium acetate (Ii), and then a homogeneous, red-colored solution was treated. boiling in rtroziiazi argon for 1 hour. The resulting cloudy mesh was filtered warm through a 1.27 cm thick cement bed into 900 ml of water. The orange-colored precipitate was filtered off and

Dryed under reduced Ηήηΐθηΐϋ at 65 ° C over 16 hours, yielding

10.6 g (5.1%) of the desired title Iddo complex as an orange colored solid, mp 194-196 ° C (melting point of recrystallized analytical wool sample 203-205 ° C).

C. 4'-fluoro-3,3 *, 5-trimethyl- / 1,1'-biphenol-2-OrCarboxyildehyl

1. BΓOEoO / - toro-3- [retylίenyl (magnesium) see U.S. Patent Zjdin.Am. No. 4 375 475. pp. 37 and 38 /

The title Grignard reagent was obtained by adding 22.5 g (60.9 mmole) of 5-bromine of --- om torotoluene / Fairfield Chemical. dropwise at a rate so as to maintain the mixture at reflux, up to 1.35 g (55.4 mL of mdi), 8.0 eq. of shavings mixed in 70.0 mL of dry diethyl ether. The reaction was irinitiated in a sound system.

After all the bromide had been added, the reaction mixture was stirred for 1 hour at room temperature, heated under vacuum for 15 minutes and allowed to cool to room temperature.

2. 4'-fluoro-3,3 ', 5-trimethyl / 1,1'-blphenyl-2-2-carboxaaldhhydrate

In a separate flask, a mixture of 3.0 g (6.92 milimoi) of Part B tetulliadium complex and 14.52 g (55.4 mMOI, 8.0 equiv) in 100 ml of dry benzene was stirred at room temperature for 30 minutes in rymodferzd argon. The freshly prepared and filtered Grignard reagent from Part C-1 was then added in one portion via a catheter to this solution, and the resulting mixture was stirred for 1.5 hours at room temperature under argon. 35 ml of 6.0 N HCl were added and the mixture was continued for 1 hour at room temperature, then the mixture was filtered through a 1.27 cm thick Celite packet. The filtrate was extracted with 250 ml of ether, then the extract was washed twice with 100 ml of brine, dried over anhydrous MgSO 4 and evaporated under reduced pressure to give 13.35 g of a viscous oil which crystallized over time. The crude solid was purified by flash chromatography on 700 g of silica gel with hexane and then hexane-diethyl ether 95: 5. Product containing fractions were combined and evaporated to yield 1.507 g (89.9%) of the desired title aldehyde as a pale yellow solid, mp 72-75 ° C (Lidcite reported mp 73-74 ° C).

TLC: hexane-diethyl ether OoI 95: 5, Rf = 0.40; UV and PMA.

D. 2- (2,2-libromootyyylo-4'-fiuoco-3,3 ', 5-yrimeeySlO) .l, 1'-biphenyl /

For a solution chilled to -10 ^O C in a salt and ice bath solution of 242 mg / 1.0 mmoles / biphenylaldehyde from part C and 787 mg / 3.0 ιΜΙ ^ Ηί, 3.0 equals of dizhnin / iΓiffdySl0osfins in 10 m dry 1H ₂ C1 ₂ a solution of 497 mg / 1.5 milimodi, 1.5 eq / CBr C in 5 mL of CH2C1 ₂ for 5 minutes. After 30 minutes at 0 ° C, the red-orange solution was extracted with a mixture of CH2Cl2 and saturated NaCHHo solution.

The organic phase was washed with saturated NaHCO- and brine, dried over anhydrous NagSO4, and evaporated to give 1.478 g of a light brown solid. The crude solid was purified by flash chromatography on silica gel (50: 1 ratio), eluting with 9: 1 hexane-CH ₂ Cl ₂ . The product fractions were combined and evaporated to give 392 mg (99%) of pure title ΙΙΛΛΛ μ ^ ^ of the title vinyl as a pale yellow oil. TLC, 95: 5 hexane-ethyl acetate, Rf 0.51, UV and PMA.

E. 2-eysnylo-4'-fltOΓOo3'3 ', 5-tcimitylod-i, l · ibiphenyl /

A solution of 336 mg / 0.844 milrooi / dw / vinyl broiler in 5 ml of dry yetrahslrofuran / thf / cooled to -78 ^o 1 in a dry ice and acetone bath was injected with a syringe of 1.06 ml / 1.7 ίl.imdί 2.0 tbsp / 1.6 molar n-butyllithium fruit in hexane and the mixture was stirred at -73 ° C under an argon atmosphere for 1 hour. The color changed from colorless to through on addition of the n-butyiolite

154 87S pale yellow and intense yellow to dark blue-red. Reaction at -78 ° ^C was quenched by dropwise addition of 4 ml of a saturated solution of M ^ d the mixture was allowed to warm to pokojowj in ^ kstrahowano diethyl ether and the ether wirstwę washed with brine, dried over anhydrous MgSO- and evaporated to give an oil 191 mm with zieonnjra in color. The crude oil was purified by flash chromotography on L.KS-1 silicide gel (60: 1 ratio), eluting with hexanes. Product containing fractions were combined and evaporated to afford 185 mg (92%) of the desired title acetylene compound as a colorless oil which turned dark blue over time when stored at -20 ^° C under argon.

TLC, hexane, Rf <0.18, UV and PMA.

F. Mety ester of acid / s / -3- / [l'y., Zm.ti! S ^ d.yłeedyJl.oZl ^^^ ey'Jł / si.Xlł - /:> d._y] - ^| 'h-ϋcar.oτot-tlksyfosfiyylQ7butane.

/ l / Acid methyl ester / s - 4-bΓOπo --- yyroo / dbbutanoate / l // a / Stern acid salt hydrate / r- / r ^x , -R ^x /.7-2,3,4- tΓihydrokSbbuaanoitgl Reference: Carbohydrate Research 77, 301-304 (1979). 50 g of stem carbonate was added to a solution of 44.0 g (250 mM) of Da karst / koabincwtgo in 625 ml of HgO, then the suspension was cooled to 0 ° C in an ice bath and 100 ml of 30% was added thereto in portions. HgOj · The reaction mixture was stirred at 30-4O ° C in an oil bath for 30 minutes. 10 g of Darco activated charcoal was added and the black suspension was heated in an oil bath until the evolution of O 2 ceased. The suspension was filtered through celite and evaporated in vacuo from a 40 ° C bath. The residue was dissolved in 50 m HgO, heated on a steam bath and CH-OH was added until the solution turned cloudy. The substantial gummy precipitate was filtered off and air-dried to provide 30.836 g (75%) of the desired stock salt as a white-colored soft solid.

TLC (7: 2: 1) iso-propanol-tffi40H-H20, Rf = 0.19, PMA.

/ l // b / Karst methyl ester [S- / r ^x S ^X / _7-2, ^{4-dibromo-3-hydroxybutanoic} Reference: Brücke K. et al, Acta Scandinayict / b / 37, 341-344 / 1983 /. 30 g of calcium srli component / l // a / dissolved by 210 ml of a ^3: 0 ~ ³ 2-prrc. ffl3r of ^k "August acid, and stirred ^at the eraturze ^ room temperature for 24 hours. The solution was browned to 990 ml of methanol and stirring was continued overnight. The mixture was evaporated to give an orange color which was dissolved in 75 ml of CH-OH, refluxed for 2.0 hours and evaporated. The residue was extracted with a mixture of 100 mL of ethyl acetate and radium, then the organic layer was washed two times with water, then brine, then dried over anhydrous NagSO 4 and evaporated to give 22.83 g (90.5%) of the crude dibromide as a light orange oil. tinted. TLC (l: l) ethyl acetate-hexane, Rf = 0.69, UV and PMA.

/ l // c / ^E st ^er methyl ester / s ^- 4-bromo-3-yydooksybuaaoowego reference the same as the synthesis / l // b /. Purged with argon, a solution of 20.90 g / ^d 75.4 wu romka ^{b u 2} 1 ⁰ g of ethyl Sa ^d pink ^g of Ezra ^{b <g} ine head 370 ml ^of ethyl acetate and the back and 37 ml of glacial acetic kwisu added 1.30 g 5% Pd / c and the black slurry was stirred under a hydrogen atmosphere (0.1 M) to monitor the hydrogen uptake. After 2.0 hours, the hydrogen uptake had ceased. The mixture was filtered through celite and the filtrate was washed with saturated NaHCO- and brine, dried over anhydrous MgSO 4 and evaporated to give the crude dibromoester as a brown oil. The crude oil was combined with another batch / Fnd N, ^36.77 g ^of the dibromide / ^{p, and the} distillation of ^d reduced to give 2 ciśnienieai ^{5. 77} g / 61.3% / p ^of żądtneg ° tytutawego bromoestru as a colorless oil, bp ⁷⁹ - ⁸ 0 ° C / 1.0 mm Hg /. TLC (1: 1) ethyl acetate-hexane Rf = 0.44, PMA.

Analysis: for C-HO.Br 5 9 3 Calculated: C 30.48; H 4.60; Br AO.56 Found: C 29.76; H 4.50; Br 39.86. / 2 / Methyl ester of / s / --- boorno-3-Z - [/l,1-d.ϊmeyZ0c-eyZo/ diphenylsilyl/oxy J butanoic acid

154 878

For a solution of 4.0 g / 20.4 mmol / bromohydrin from the F part / l /, 6.94 g / 5.0 eq / imdazol and 12 mg / 0.005 eq / 4-diraety.loarainopyridine / 4-DMAP / in 40 ml of dry dimethylamld (DMF), 5.85 ml (1.1 eq. Virel) of chlorine tert-butyl-diphenylsilyl was added and the resulting homogeneous mixture was stirred overnight in an argon atmosphere at room temperature. The mixture was extracted with a 5% blend. And ethyl acetate, then the organic layer was washed with water and brine, dried over anhydrous NagSOi and evaporated to give 9.32 g (100%) of crude siluic ether as colorless viscous oil. TLC (3: 1) hexane-ethyl acetate, RO Bruinous ether? 0.75, UV and BW.

(3) K "su / sA-iodine2-4 [1,1-dimethyloltyloldiphenylolylJ0> xy] butane methyl ester

To a solution of 9.32 g (201 mmH) of crude bromide from part f (2) in 60 ml of methyl ethyl ketone, which was dried over 4A sieves, 15.06 g (100.5 mmH), 5.0 equiv. Of sodium iodide were added and the resulting suspension was the yellow color was heated for 5.0 hours under argon. The mixture was cooled, diluted with ethyl acetate and filtered, the filtrate washed with dilute NaHSO3 until decolorization followed by brine, then dried over anhydrous NagSO3 and evaporated in vacuo to give 10.17 g of a yellow oil. The crude oil was purified by flash over 600g silica gel, eluting with 3: 1 hexane-CH6Cl3. Product containing fractions were combined and evaporated to give 7.691 g (74.%, total yield for both steps) / the desired title iodide as a clear, colorless, viscous oil. TLC (3: 1 (hexane-ethyl acetate, product - RO = 0.75, UV and PMA) (Note: The product iodide forms a common spot with the <RTI ID = 0.0> almbromide).

(4) (5) -4- (detoxyphosphino) ester (33 H - [(1,1-dimethylethyl) diphenylsUl-7oxy] -butanoic acid.

A solution of 7.691 g iodide in 20 m triethylphosphite was heated at 155 ° C in an oil bath for 3.5 hours under argon. The mixture was cooled and an excess of ohosphite under reduced pressure, 0.5 mm mercury, 75 ° C to give about 8.0 g of a yellow oil. The crude oil was purified by flash chromatography over 400 g of silica gel using 4: 1 hexane-acetone as smelting. Product fractions were evaporated to yield 3.222 g (41.1%) of the desired 0ltuO carbon phosphate as a clear viscous oil, TLC (1: 1) hexane-acetone, RF = 0.51.

UV and PMA. In addition, oyd (itloio) 2.519 g of starting iodide from the (-L) oligo-yield - 61.1%).

/ 5 / Acid methyl ester / s / -3- / Z / 1,1 / demethylethyl / -d0tenlllsilyl. Oxy J-4-Oo & Oonobutai! Otgl

To a solution of 9.85 g / 20.0 millimH / O-phosphonate from part f / 4 / in 20 m dry CRClj was successively 5.31 ml / 32.0 mli ^ m ^ oe, 1.6 eq. / BisOrieetylεilylthoFlO.oactamide / BSTFA (i 6.60 ml) (50.0 ml) of: 1.25 equiv. of (dimethylolyl bromide (TNSBr)) and the clear mixture was stirred overnight under argon at room temperature. Up to / anl 80 ml 5% KHSOj and the mixture was extracted with ethyl acetate. The aqueous phase was saturated with NaCl and re-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous ItiCL / parloal and evaporated to give the crude title O-phosphonic acid as a viscous oil. TLC / 7: 2: 1 / isopropanol · NH ₄ 0H-H ₂ 0, RO> 0.30, UV, X PMA.

/ 6 / Ester ^^ IiiL ^^ w ^ 'acid / s / -3-, z 2 / Π l / dieth0llot0ylo / ci0tinylosllilloklyJ - 4- / ly / roksyeetoksy0ls0inyl // bttaoiwtgl

About 20.0 ml of crude Olsfonootgo acid from part F / 5 / in 25 ml of dry pirldyil was treated with 1.62 ml / 40.0 m.]. And. 2.20 eq. 3 A and 4.54 g (22.0 ml) 0.10 equiv. (Ic10hexylcarbo) (ui (DCC) and the resulting white suspension was stirred under argon overnight at room temperature. Pyridine was removed under low pressure and then performed

Azeotropic distillation with two 15 m portions of benzene. The resulting oil was dissolved in ethyl acetate, filtered, washed with 1.0 N HCl and brine, dried over anhydrous NagSO 4, and evaporated under reduced pressure to yield an oil containing a small amount of precipitated

154 878

Example II. Dulite salt of the cross / s / -U- [[2 ~ £ 4'-11οατο-3,3 ', 5-trlmethyl 2 1, r'-biphenyls ^ -2-yl-ilethynyl / hydroxyphosphinyl _7-3-hydroxybutane

D 1 of the mixture of 203 mg / 0.469 mmol / of diester from Example 1 H in 6 ml. didani dioxane

1.6 ml / 1.6 mmoles 3.5 equiv / l.0 N LiOH and solution at temperature

55 ° C in an oil bath and the atmsfetze atgin for 30 minutes. The mixture was cooled, diluted with water, mixed with water, and dissolved in 30 mL of water and dried by freeze-drying. The product of drying and a white color of the thistle in a minimum amount of water was chrimaographed on a column of 25 mm diameter with a 10 cm bed of HP-20 resin by eluting with water followed by a 50:50 wda-methanol mixture. The fractions containing the product were combined and laparlron, and the remainder was dissolved in 30 ml of water and dried by freeze drying, yielding 199% / 9% in the ratio of dihydrate and having a molecular weight of 435.36% of the title silica in the form of a solid and white color. TLC / 8: 1: 1 (CH 2 Cl 2 -methanol-cyanite, R f = 0.13, UV and PMA.

Mikroaniaiz- for C21H2OO5FPL12. 1.06 HgO / molecular bowl 435.36 /:

Wyyichini: C 57.93! H 5.12; F 4.36; P 7.11 Found: C 57.91; H 4.89; F 4.22; P, 6.89 ¹ H ^- NMR / 400 fflz, CD-° O / ^J / ppm /: 1,76-1, ^82/2 H, m /, ^2, 3 ² / 3H, ^d, J _HF = l . ^{8 H} with /,

2.34 (3H, s), 2.37 (H, dd, J s 8.4 Hz), 2.41 (H, dd, J? 4.1 Hz), 2.49 (3H, s),

4.27 (1H, m /, 6.89-7.37 (5H, m).

Example III. Kros dulite salt / s / -Uj C 2- / l- / 4-liioro-phenyll / -3 - / - πlttyto ^ y ^ Z-H-indol ^ -ili ^ ethynyl J7hyrolssyosphininyl J / ^ - hydroxybutamic

A. Milky ester of the crossover (s / -4- Z2 - / "1- (4-fluoro-liphenyl) -3 - / - methylttyll) -M-indol-2-yl, 7'ethynyl &lt; 7-meetlzsyolfiiyll -hydroxybutanivegi.

Di riztvir 987 mg / 1.39 mi ^^ liwegi krosu / s> / - 4z * Z2-Z 1- / 4-fluoriftnyl / -l - / - methyllethyll / -M-inaol-2-illJetynyli. 7metolzyfolf- nnyo / -3-2 / l, 4aremttyllttyll / aiphenyl8il / lZsysb / bu tellwegl in 12 mL dry THF dld-il another 320 yul / 5.6 miimoii / 4 tówi> corner / lidlaategl of ictiwegi and 3.8 ml / 4 , 17 mmoles, 3 mmoles / 1.1 mm riztvir Z / n -? Hg / N in THF and the resulting mixture was stirred for nothing under argon at room temperature. The mixture was diluted with 10 ml of water cooled in a lid and extracted with ethyl acetate. The organic phase was smuggled 5%. KHSO- (three times), saturated with NaHCO- and sllαaZA, was dried over Na2SO4 and idparivani to give 1.0 g of yellow and yellow color. TLC showed the pouring of a full amount of monocrosis which was converted with the pivrot into a melting ester with an ethereal C CNg riztvir. The excess CHNi was decomposed with glacial ictic acid, and the lap-tla-yl mixture under a varying pressure of 2 to 3 m 2 to give 1.012 g of il and a brown color. The crude il was purified with a ktzeeioiZlOlm Merck flash eetide eluting with a mixture of 8: 2 hexane-acetone in an amount of 600 L followed by a 1: 1 mixture of hexane-acetone. The product fractions and the parivani yielded 516 g (78%) of the free title alcohol in an il form and a light brown color.

TLC (9: 1 CH 2 Cl 2 - 6 - ³ nn), R - = 0.41, UV + PMA. Mass spectra: zaibseiwuwani M + H + = 472 *

B. (S) -4-Z C 2 -1- (4-fluorophenyl) -3- (1-methylethyl) -1H-indol-2-yl-eeynyl-7-hydroxyphosphinyl) -3-hydroxybutanoic acid diethyl salt.

10 ml of a solution of 516 mg / 1.09 ml of diester from part A. didani dioxane 3.8 ml / 3.8 milli, 3.5 ^ ίίοί-γ η / 1.0 N LiOH solution and the clear mixture was heated in an oil bath and 60 ° C for 1.5 hours under argon. The mixture was diluted with water, filtered and the laparoronl under pressure, and the residue in the oil company was dissolved in a minimum amount of rhodium and chrimtigrated in a column 25 mm in diameter with a 15 cm bed of G? -20 resin, first with only water / neutral reaction. , /, a i zastiit eieszαiiią 1: 1 woia-mittnal. Fractions of the product lapαtlwai.l under lower pressure, dissolved in 50 ml of water, filtered and lyophilized to give 447 mg, 182.3% L of the desired title salt as a white lyophilate. TLC: 1: 1 CHCl-methane-coacetate), Rf = 0.39, UV + PMA.

Analysis for CgjHg.iO/PN^Li. i, i7 Hi0 / partial mass 496,191:

Found: C 55.69; H 5.19; N i, 8i; F 3.83; P 6.24 Found: C 55.69; H 5.37; N i, 8i; F 3.85; P 6.19

Example IV. Acid / s / -4- / | '' 2i2i4-dimethyl-6 - // 4-fluorophenyl / eeeokky _phennlto7etinyl yhylroxyspinyl | d33-hdagsklyllaenic salt

A. 1- (eethoxyeeeoxy) -3,5-dl.eethylbenzee

A solution of 10.42 g (85.3 eool) 3,5-dimethylphenol in 12 m THF was trapped within 10 minutes into a suspension of 85.3 mMol NaH pre-washed with pentane in 150 ml THF in argon afmsferae with cooling to 0 ° C. After the addition of phenol was complete, the reaction mixture was stirred at 0 ° C for 10 minutes, warmed to room temperature and stirred for 20 minutes. 42 mL of dry DW was added to the alkoxide solution, followed by the slow addition of a solution of 11.19 g (89.6 mmol) of bromolyl ethyl raatyium ether in 10 mL of THF ¹ . A white precipitate formed. After stirring for 2.5 hours at room temperature, the reaction was quenched with 25 ml of 1N NaOH. The THF was removed from the reaction mixture using a rotary evaporator and the resulting solution was diluted with saturated NaCl solution and extracted three times with ether. The combined ether extracts were dried over NagSO 4 and filtered. After removal of the solvent, an orange oil was obtained. As a result of flash chroiratggaai purification with elution

5% ether in hexanes afforded 12.0 g (≤ 5% vl) (ngsi) of the title mmeoxymethyl ether (MOM) as a clear oil. TLC: Ri = 0.45 µS-percent. ethyl ether in hexane, silica gel / MS spectrum: mle 166 lM + l, 165 lM + - H ~ l.

B. 2 (eeeoks) lleetgsy (d4,6ddimetllobeezrldehyde)

7.70 g (79.45 mmoles) of retramethylthylenediaein was added slowly to 26.5 M of a 2.5 molar solution of ι - ^^ ΙοΙΙ ^ in heRsane at 30 ώ. cyclohexane under an argon atmosphere. The solution was cooled to 0 ° C and 11.0 g (66.21 mmol) of MOM ether from part of the solution was added dropwise over 20 minutes.

A. After completion of water, the mixture was stirred at 0 ° C for 30 minutes, warmed to room temperature, and stirred for an additional 10 minutes. The Arnlon was then added via a drip funnel to a dry 100 µm cyclohexae solution containing 5.81 g (79.45 mMool / DMF) under argon at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then quenched by the addition of eeenneO · Roopulsor, the mixture was removed on a spinner, and the orange-colored oil residue was dissolved in 1: 1 ether / water. The bottom layer was extracted three times with ether and the combined ether extracts were dried over MgSO4. After filtration and removal of the solvent, a pommon oil was obtained. As a result of oil purification using the chromatograph method! projection with elution 20 ^^ 0. ether in hexane yielded 7.7 g (%) of the desired aldehyde as a clear oil. TLC: Rf = 0.14 (1S-% ethyl ether in hexane, silica gel). MS spectrum: m / e 195 / M + H / *, 179 / M-CCg / ' ¹ ', 163 / m - ΟΟΗ ^ / *, 149 / μ - ΟΟ / Η, / Λ.

C. 2dhldΓOxy-4,6-dimethylbenzaidehyd

35.5 ml of 1M HCl was added to a solution of 6.89 g (35.5 mmol) of MOM ether from Part B in 130 ml of dioxane at room temperature. The reaction mixture was warmed to a gentle reflux and stirred for 30 minutes. The mixture was cooled to room temperature, then the dioxane was removed by a rotor. The resulting aqueous solution was diluted with water and extracted with ether. The aqueous layer was saturated with NaCl and twice back-extracted with ether. The ether extracts were combined and dried over MSOg. After filtration and removal of the solvent, a solid was obtained which was purified by recrystallization from hexane to give 4.01 g (75%) of the product. TLC: Rf "0.48 (25% ethyl ether in hexane, silica gel). Melting point 46-48 ° C. MS spectrum: m / e 151 / M + H / +, 135

154 878

D. Z-C (4-fuuoro-phenyl) -methoxy N-4-dimethylbutyl-smallhehydrate

A solution of 4.0 g (26.7 mmol) of Part C phenol in 30 ° C dry DMF was stirred under argon. At room temperature, the phenol-o-ano solution was 4.43 g (32 mmol) of K ₂ COj and the mixture was heated to 60 ° C for 35 minutes. The resulting orange-colored solution was cooled to room temperature and then 5.55 g (29.3 M lymol) of p-fluorobenzyl bromide. The mixture was heated to 60 ° C and stirred for 2 hours, then poured into 50 ml of water / ice and the resulting mixture was extracted several times with ether. The combined ether extracts were dried over MgSO 4 and filtered to yield a yellow solid after removal of the solvent. Filtration with flash chromatography eluting with 15% ether in hexane afforded 4.48 g (60%) of the title benzyl ether as a white solid. TLC: Rf = 0.34 / 25%. ethyl ether-hexane, silica gel). Racial Wi-mo: m / e 259 / m + h / +,

231 (M-CHC //, 109 (M-C6H7F) +.

E. l- / 2, - iLiboonoethynyl-22,4- <iimttyO - 6iefer ', oloetOoksyber'Lzeπ

A solution of 4.42 g (17.13 mmol) al-ehy from part D in 170 mL dry CRCR under argon was cooled in a salt and ice bath. To a cooled solution of 14.4 g (55.0 milimol) triphenylphosphine, and the resulting mixture was stirred until the solids were completely dissolved. Within 12 minutes, a solution of 8.52 g / 25.7 mmol of CC3R in 50 ml of CRgC6 was carried out with a scrubber. After the addition was complete, the orange-colored reaction solution was stirred at 0 ° C for 1 hour 15 minutes. The reaction was quenched by adding 60 M of saturated aqueous NaHCO3 solution with vigorous stirring. The aqueous layer is green and extracted twice with CH ₂ Cl ₂ . The combined CHgCl3 solutions were washed once with saturated aqueous NaHCO3, dried over MgSO4 and filtered to give the title bromide as a brown solid, 13 g. The title bromide was purified by flash chromatography eluting with 2% . ether in hexane to give 5-49 g ITT & product yield. TLC:

Rf = 0.28 (2%, ethyl ether in hexane, silica gel). Pure breed: m / e 413 / M + H / +

- 333, 335 / M-Br / ⁺ , 317 / M-CgRCF *, 109 / M-CuROBr / *

F. 1-ethyl-2-2 / 4-fluoro / methoxs. / 4,6-methylbenzene

The ml of the THF solution containing 5 → 48 g (13.3 mMH) -bromide from part E was cooled under argon at -78 ° C. To the -bromide -o-ano solution over 10 minutes 10.6 ML / 26.5 mmol / H / 2.5 molar n-butyllithium solution in hetman. The reaction mixture was triturated at -78 ° C for 1 hour then quenched at -78 ° C with the addition of saturated aqueous WRCC. After the reaction mixture was warmed to room temperature, it was diluted with water and the aqueous layer was extracted with ether. All organic layers were combined and dried over MgSO4. After filtration and removal of the solvent, 3.8 g of the title berzyllxyacetienl was obtained as a yellow solid. The title benzene / acetylene was purified by flash chromatography eluting with 3%. ether in hexane. 2.76 g (8% of Satin) of the title acetylene was obtained as a white solid.

TLC: Rf = 0.17 / 2%. ethyl ether in hexane, silica gel), m / e 255 (M + H) +, 159 (M-C 6 H 4 P) +, 109 (M-C 2 Hg)) *.

G. Acid acid salt / s / -4- / [C 2,4-1 / eeySo-6-Z '/ 4-fluorophenyl / methoxy / phenyl-7-acetyl-hySroOsySosphinyio -3- / tert-bltyl-ifenslosillloxy / Uutaoiwego.

Ml of a THF solution containing 2.76 g / l millimeter / acetylene from the F part in the molten argon temperature was cooled at -78 ° C. At -78 DEG C. for 8 minutes, 4.4 mL of a 2.5 molar solution of n-butyl lithium in hexane. The mixture was stirred at -78 ° C for 40 minutes.

17.4 ιΜΙϊ / ο ^ phosphonochloridar from the base in 60 ML of THF at M ^^ L ^ era of argon cooled down to -78 ° C. -O-cyano Naatępnie for 8 minutes ^ anion prepared above acetylenes · After stirring at -78 ° C for 1 hour the reaction was quenched at -78 ° ^C a saturated aqueous solution -odając ΝΗ ^ Ι, the mixture was allowed to warm o - about room temperature. The aqueous layer was diluted with water and extracted with ether. THF was removed from the reaction layer containing this solvent, and the resulting amber oil was dissolved in

154,878 with ether. All the ethereal solutions were combined and washed once with saturated aqueous NaHCO 3 solution and once with saturated aqueous NaCl solution. fer ^ TIE organic ws ^sus bride, MgSO ₄ and filtered to give, after removal of the solvent 9.4 g of the acetylenic tytuoowego kwsu Oosfenowego in the form of an orange gum. The title actylphosphinic acid was purified by flash chromatography eluting with 5: 1: 4 hexantoluene-ethyl acetate. The title acetenoic phosphonic acid was obtained in the amount of 4.23 g (a yield of 56%) as a clear gum.

TLC: Rf = 0.28 / 5: 1: 4 hexane-toluene-ethyl acetate gel krzemionkowi · spectrum race ra / e: 609 / MLE-C / ^1, 255 / C ^{i4 H} 9 S ^and O / ^+.

H. Esrór meth low ^{yk y} Vasu A / - ⁴ - / ^"[C ^^^-O-methyl / ^{4-fluorophenyl} ~ / ^y JimylsJ methoxy rtyrylo ^7-yl and mtoksyfosfin ^ -tydrnksybutenowefro.

0.455 g (0.66 mmol) of the acltyeen phosphinate part G was stirred in 10 m THF under an argon atmosphere. 0.16 g (2.66 µl of acetic acid) was added at room temperature, followed by the dropwise addition of 1.8 ml of a 1.1 M solution of NH 4 HgNF in THF over 5 minutes. After stirring for 24 hours at room temperature, the reaction was quenched by adding 30 ml of ice-cold water. The aqueous layer was separated and extracted twice with total / ethyl. The THF was removed from the organic post-reaction layer and the resulting oil was dissolved in ethyl acetate and combined with the aqueous layer extracts. The ethyl acetate solution was washed twice with saturated aqueous NaHCO 3 solution and once with saturated aqueous NaCl solution then dried over Na 2 SO 4. After filtration and removal of solvent afforded 0, ⁴ 0 g of hydroxyl ethyl ^^ tyttuoowego acid phosphinate as an oil. The title hydroxyacetylene phosphinate was purified by 100% Break Flash Chromium. ethyl acetate. The title compound was achieved at 79%. TLC: ro = 0.56 / 7: 3 acetone-hexane, silica gel. ^The racial idmo: mle ⁴⁴⁹ / M + H / + ⁴³¹ / ^m, h / ^{+ 417} / m-OCH ^j / ^+.

J. salt dwtLitowa kwisu / ^S / - ~ ^{4 / /} C2, ⁴ -dimet ln ^{y-6-2 [4} - ^f j luorofen ^{yl 7} m / ^{l oxy} Jien ^yl Jetym yl-7-hydroxy ns ^{f f} in ^y lo .7- ³ -h ^{s of} dΓOxybutene.

6 m dioksanoolgn solution containing 0.191 g / 0.43 miimola / jcetylenowegn phosphinate of Part H was added ^1, 4 ml of 1 N solution of ^L and H. ^The Meszaninę reakce o ^ ^y jna been shown to 55 ° C and stirred for 2 hours. The mixture was cooled to room temperature and evaporated to dryness to give the title compound. The title compound was purified to 130 x 30 mm ^ Ιιι / πΙι with HF-20, eluting first with 100 mL of water and then with 1: 1 methanol water. 0.170 g (91%) of the title compound was obtained as a white lyophilisate. TLC: Rf = 0.37 / : 2: 1 n-projasnol / HlOW / water, silica gel. Race spectrum / FAB /: // i 421 / M + H / + ⁷ 427 / M + Li / ⁺ , ⁴ 33 / M + 2Li / ⁺ .

Analysis for C2 ^ (^ 2Q0g ^ P '^^ ^L 2 · 1.4 ^ O calculated: C 55.09; H 288; F 4.55; P 6.88 found: C 55 »13; H 5 ^ 5; F; P 6 / ^ 1 ..

EXAMPLE ^S <51 dwuli accom-kwisu ^/ 5 / - * - C ^[2- [C1, l-b ^f f .7-2 ^{yl en-i} q7et ^y n ^y and LA7 hydroksyfosf boronic ^ -hydroksybutanowego.

A. Bifeeylo ^{karboksyαldehyd-2-2} 7.64 ^g / mile 632 / Ola / ^s perjod diisocyanate essa- ^{D M} Artina mixed under argon with 150 ml of CHgClg · To the stirred solution was added 8.0 ml of dry tert-butanol and the resulting mixture was After stirring for 10 minutes at room temperature, a solution of 10 g (54.3 mlIrali) of biphenyl &lt; RTI ID = 0.0 > -methanol in 20L Cl &lt; Clg &gt; After completion of the dropwise addition, the mixture was stirred at room temperature. After stirring for 1 hour at room temperature, 600 ml of anhydrous diethyl ether were added to the reaction mixture, followed by 225 ml of NaOH. After 10 minutes, the recovered suspension was filtered and the filter cake was washed with diethyl ether. The filtrate was washed twice with 250 ml of IN NaOH each. The organic layer was dried over MgSO 4 and filtered to give 10 g of a yellow oil after removal of the solvent. As a result of flash purification on silicon gel with za22

Using a 1:10 mixture of diethyl ether-hexane afforded 9.58 g (97%) of the title aldehyde as a colorless oil.

TLC / 1: 9 / ethyl acetate-hexane, silica gel Rf 0.29 IR / film / 3065, 3025, 2850,

2760, 1685, 1700, 1600, 1470, 1450, 1395 cm ¹ . 'H NHR ^1/2 70 Mz- CDCCj / ^<8, 00' d, 1H, J = 70.0 Hz / 7.60 'm, H /, 7.40 / m, 7H /.

Race spectrum m / e: 183 (M + + h).

B. 2- / 2,2-dibroπ »ethynyl / s / '1,1'-biphenyl

A solution of 2.0 g (11 mimoyl) aldehyde from part A o 60®. CHCC / * argon was cooled to -10 ° C. Codano 9.21 g / 35 milimooi / l trifenyiofosfiny szanlnę resulting writing was stirred until dissolution of the components stałych.- What the resulting solution at -10 ° ^C was added over 15 minutes a solution of 5.5 g / 16.5 ®.iioooi / CBr ^ at 40 m O / dg. The reaction mixture was stirred at -10 ° ^C for 1 hour 15 mirnit, the reaction was quenched -10 ° ^C with 50 O. saturated aqueous NaHCO. The ₁ H ₂ dg and aqueous layers were separated and the aqueous layer was extracted once with CH ₂ Cl ₂ . The combined CH2Ig extracts were washed once with saturated visible NaHCO3 solution and once with saturated visible NaHCO3 solution. The C21HC extract was dried over NagSO4 and evaporated to dryness. The crude product was purified by flash chromatography, eluting with hexane. The title dibromide was obtained as a biatine-colored solid in an amount of 2.45 g (66%).

TLC / 5: 95 ethyl acetate / hexane, silica gel, Rf = 0.47.

IR / CDdj / 3064, 3011, 1596, 1473 ^, 145O ^, 1435 ^, 889 ^, 860 ^, 701 cm ¹ .

¹ H NMR ^{/ 2} 70 Mz, OCCj / CT ^7, 75 Z® ^7, 35 Z® 8ha ^7, 20 ^/ s, H /.

^{13 C-NMR / 67,} 0 ^Mz, CDDJ / CT ^141.06, 140.08, 137.49, 133.83, 129.81, 129.45, 129.17, 128.61, 128.22, 127 , 50, 127.08, 90.78.

Race spectrum: m / e 337/339/341 / m ⁺ + h /.

C. 2-ethin ^ 1 <^^ - / 1, and '-biphenya7

A solution of 2.31 g / 6.9 miiimooi / vinyl dibromide from part B in 35 mL of THF was cooled to -78 ° ^C in atmospheres of ^ and ^ jrerze argon. What vinyl dibromide stirred at -78 ° ^C for 10 minutes, 5.52 ml of 2,5-molooe2S solution of n-butyllithium in hexane. After the addition of n-butyllithium was complete, the reaction mixture turned a dark red color. After stirring at -78 ° C ^for 2 hours 45 minutes the reaction was quenched with a saturated aqueous solution of N-d. After quenching the mixture was warmed to room temperature, it usmięto ¹ THF and the resulting raaeeiał diluted with water and extracted three times with a mixture of ether and hexane dietySowe2S. The organic extract was dried over MgSO and filtered to give 1.3 g of a yellow oil. In the cleaning method of the flash chromοatocaiii from zrsto5owrniοο to elusoaeir 1%. diethyl ether in hexane afforded 1.04 g (88%) of the desired title acetylene compound.

TLC / 10% hexane, silica gel, Rf = 0.16 IR / mO0 / 3287, 3061, 3026, 1474, 1449, 143 ^2, 1008, 775 ^, 756 ^, 738 cm ¹ .

¹ H NMR ^/ 70 Μϋ ^2, C d ^// c 'is ^7, 68 / 3H ® ^{/, 7,} 35' of, 6h / ^3, 00 / s, 1H /.

¹⁵ C NMR '67, 8 1MHz dCCj / c ^ ^T 144.44 ^140.22, 133.8 ³ 129.56, 129, 0 ^{2, 128.92,} 127.95, 127.49, 126, 94, 120.44, 83.08, 80.15.

Mass spectrum: m / e 179 (M + + H).

C. (s (-4-) [2- [[-1, i'-biphenyl 7-2-10o / ethyl.7mοttSεyphosphinyl7-3- (tert-butyldiphenylsilSiloxy) -butyric acid ester.

0.332 g / 1.86 of Part C acetyl was stirred at -78 ° C in 10 1 THF under argon. 0.75 O was added to the solution of the acetylene compound over 5 minutes.

2,5-οolooe2o n-butyllithium solution in hexane. The reaction mixture was stirred at -78 ° C ^for 1 hour, warmed to room temperature, and mish ^ for 10 minutes and then cooled to -78 ° C. The acetylene anion solution was then fused over 8 minutes into a solution of 2.98 mmoles of phosphonochloridate from Example 1, Part F, in 10 m THF cooled to -78 ° C under argon. After completion of the dropwise addition, the reaction mixture was stirred at -78 ° C for 1 hour then quenched by the addition of saturated aqueous NH4C2 solution. The mixture was warmed to room temperature, diluted with half-saturated aq. NaCl solution and extracted three times with diethyl ether. The combined ether extracts were washed with saturated aq. NaHCO- and saturated aq. NaCl. The ethereal vegetable was dried over MgSO, and evaporated to give 1.5 g of a yellow oil. Purification by flash chromium eluting with 5: 1: 4 hex4 in-toluene-ethyl acetate afforded 0.543 g (48%) of the title acetylene phosphinate.

TLC (5: 1: 4 hexane-toluene-ethyl acetate), silica gel), Rf = 0.20.

1429 cm-1 ¹ H NMR ^/ 270 Miz, ODCj / ^{c 7 6} 5 / m, 3H / ^{7, 6} 5-7,28 / a 16h / ^4, 55 / 'm, 1H / 3 ⁵⁵ 3h /.

3.40 (dd, 3H), 2.80 (m, 1H), 2.55 (m, 1H), 2.35 (m, 1H), 2.80 (m, 1H), 1.00 / s , 9H /.

13 _C-NMR / 67.8 Mz, CDC1- / 0170.83, 145.29, 145.19, 139.22, 135.95, 135.59, 133.86,

133.75, 133.16, 132.86, 130.57, 129.56, 129.34, 128.81, 127.92, 127.75, 127.44,

127.39 126.94, 117.90, 100.91, 100.38, 100.18, 84.51, 81.60, 65.53, 65.42, 60.06,

51.61, 51.50, 51.11, 42.07, 41.90, 38.86, 37.16, 26.56, 20.75, 18.98, 13.97.

Irns spectrum, m / e 611 (M + + H).

E. (s) -4- [2- [[1,1'-bHenyl-7-2-yl] -nto-hhyiolrithiolfinyl-3-hydroxybutyric carbon acid methyl ester.

0.985 g (1.61 mmol) of Phosphenate from Part D was stirred under argcin at room temperature with 19.6 ml dry TH. 0.386 g / 0.368 m3 was bought into this solution,

6.44 mmol / l of glacial acetic acid followed by the dropwise addition of 4.40 ml (4.84 mmol) of [/ n- < cH 6 / N_7F in THF] dropwise over 8 minutes. After stirring at room temperature for 18 hours, the reaction was quenched by adding 30 ml of ice water. The light layer was extracted with ethyl acetate. The organic extracts were combined, washed with dianol saturated aqueous NaHCO-, once with brine, dried over MSO4, filtered and evaporated. The product was issued by the οΗ / ιμ ^^ οΙ method !! flash on a 50 mm diameter Merck silica column, 40% eluting with a. acetone in hexane at 2 m / min. The product fractions were concentrated, roped with toluene and evaporated under reduced pressure to give 0.369 g (0.991 mmol, 62% yield of the title alcohol as a viscous yellow oil). Also, 0.098 g (0.263 mmL, 16%) of a slightly impure product was obtained. TLC: silica gel, Rf = 0.35 / 50%. acetone in hexane /. Mass Spectrum: Ci ml and 373 (M + H / +).

F. Karst diethyl salt (s) (-4-) [2 - C 1,1'-biphenyl-2-ylq7et> non-hyyrolytosphinyl J-3-hydroxy-butane.

0.275 g (0.739 mmol) of the E part diester was stirred under argon with 7.57 ml of dioxane, followed by the addition of 2.22 ml (2.22 mmol / 1 N LiOH). The cloudy reaction mixture was heated to 55 ° C in an oil bath for 45 minutes and then cooled to room temperature. The resulting yellow foam was dissolved in 4 ml of distilled water and electrostatic column with dimensions of 2.5 x 19 cm with H-20. The obtained yellow foam was removed by means of a rotary distillation. The iIu column (first until 15 fractions were collected (until the saline has disappeared) and then the 45:55 meeanol (ooda) mixture. After two lyophilization and drying over PJO for 16 hours by typing pump ^rs oropΓÓżniłwej afford 0.231 g / 0.649 mmol, 88% wydirnełśi / title diacid as a white color liofilżzatu. TLC: silica gel, Rf s 0.55 (7: 2: 1 e-polypropyl-4-OH-bovine). Mass spectrum: FAB a / e 345 / M ♦ H / +, 351 / M + Li / +, 357 / M + 2111 / +.

Aralization for ^c igHi5 ° 5 ^i> Lj- ₂ · 1.42 H2 ° / particle mass 381.75 / _:

Found: C, 56.63; HA, 7Xs P 8.07. Found :. C 56.62; H 4.70; P 8.07.

Example VI. (S) (-4 - / ") 2- (5- (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-1H-pyrazol-4-yl-7-ethynyl-methoxyphosphinyl acid methyl ester. 3-hydroxybutane

A. 4-fluoro-9k _O ethyl ester of xobemenoroopnoic acid

17.4 g / 0.43 millium / 60 oroc. The sodium hydride in the mineral oil is washed twice with dry hexane, dried under reduced pressure. 44.3 µm (0.36 mmol) diethylate was added, followed by 22 µm (0.18 µm) (0.18 µmol) and (0.18 µm) acid, and "Acet" (0.36 mmol). After about 10% of the ketone had been added, 4 drops of ethanol were added to initiate the drug, and the remainder of the p-fluoroacetophenone was added dropwise over 1.0 hour at a rate to maintain the drug. The resulting yellow precipitate was dispersed in 250 ml of dry ether and heated in a gas for an additional 3.0 hours under argon.

The reaction mixture was cooled in an ice bath, diluted with 200 ml of ether, then onssOi 1.3 liters of water were added until all solids had dissolved. The aqueous phase was separated from the organic phase, quenched by adding 32 ml of 12 N HCl to pH 1.0 and extracted with two 500 m. Ether portions. The combined organic extracts were washed with 200 ml of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness. The crude product in the amount of 44.0 g destyOswann. under reduced pressure, 3.5 mm of mercury to give 24.88 g (65.8%) of the title compound as a homogeneous oil. TLC: Rf = 0.46 / silica gel, CRgCg:

: hexane 4: 1 /.

B. 4-flunrn- (5- (2-methyl-1-oxopropyl) - / 3-oxobenzene triangular acid ethyl ester

10.3 g / 0.26 mmol / 60% sodium chloride in mineral oil was washed with two dry hexanes, dried under reduced pressure, dispersed in 245 tilts. dry tetrachloridate and cooled to 0 ° C in an ice-water bath under argon. 24.5 g / 0.12 of Part A compound was added dropwise to the suspension over 20 minutes, warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled back to 0 ° C in an ice-water bath, then 18.62 g (0.17 mol) of isobutyryl chloride was dripped and the mixture was warmed to room temperature and stirred for 3.0 hours. The mixture was cooled once more to 0 ° C in an ice-water bath, quenched with 200 ml of water, and the resulting homogeneous solution was evaporated on a rotary hammer to remove most of the tetranydrodsuflran. The aqueous phase was acidified by adding 37 ml of 10%. HCl to pH 1.0 and then extracted with three 100 ml portions of ether. The combined organic extracts were washed with 50 mL of brine, v / v / ml over anhydrous MgSO 4, filtered, and evaporated to dryness to give 36.85 g of an oil that was a mixture of the starting material and two other products. TLC: Rf = 0.46, 0.33, 0.20 (silica gel, CRCl3 ^: hexane 4: 1, UV).

C. 5- (4-Fluoro-phenyl) -3 - / - elethylethyl) -1-pheyn-Hί-4-pyrazole-4-cboxitic acid ethyl ester

36.85 g (about 0.12 m) of the crude compound from Part B was dissolved in 151 ml of glacial nctnsegn acid followed by the addition of 18.1 ml (0.18 m / 97%) portionwise. phenylhydrazine under nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was taken up in 350 ml of water and extracted with three 100 ml portions of ether, then the combined organic extracts were washed with saturated NaHCO3 until the aqueous phase was basic, then with brine, dried over anhydrous MgSO3, filtered and evaporated to dryness.

The dark orange oil was evaporated once with 300 ml of petroleum ether to give a yellow solid. The crude product was triturated with 100 ml of petroleum ether to give 15.3 g of the product, which was chromatographed on a LPS-1 silica gel column, eluting with 2: 1 CH 6 CO 3 -hexane. 11.53 g of pure product was obtained. The mother liquor in the amount of 26.4 g of chrnmtogrid on a column with LPS-1 silica gel, and then triturated to obtain an additional 7.12 g of the desired product (total yield 18.65 g, 44.1%).

154 878

A small sample of the title compound was recrystallized from ether-hexane to give a homogeneous solid, mp 92-93 ° C. TLC: Rf "0.35 (silica gel, CHCl-hexane 4: 1).

Araliza includes: C 71.57; H 6.01; N 7.95; F 5.39 Found: C 71.62; H 5.99; N 7.91; F 5.54.

D. 5- / 4-fluoΓzfeoylz / -0- / l-mιrtyletletZo / -leOenyl-1H-pyraooOo-4-mjtknzl

A solution of 11.53 g (3.27 mH 3 Calcium) of the compound from Part C in 142 ml of anhydrous ether was scraped over 1.5 hours in an ice-salt bath, cooled to 0 ° C, and a suspension of 3.67 g / 96.7 millimoles / liO-glycine hydride in 70 ml. anhydrous ether in an argon atmosphere. The slurry with a color of z ^ ^ oonk ^ iy ^ m was allowed to warm to room temperature for 1.5 hours, cooled again to 0 ° C in an ice-salt bath and the reaction was quenched with 20 ml of water until the water disappeared. - gas leak. The thick suspension was diluted with 100 ml of ether and filtered, washing the precipitate thoroughly with three 150 ml. Portions of ethyl acetate. The combined organic extracts were washed with 50 ml of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness to give 10.3 g / 10% of a crude product / cream solid. 100 mm of the crude product was recrystallized from ethyl ether-hexane to give 58 mg of the title compound as white crystals, m.p. 138-140 ° C. TLC: Rf = 0.01 (silica gel, CHHCO ₂ ).

Analysis: Included: C 73.52; H 6.17; F 6.22; N 9.03. Found: C 73.16; H 6.15; F 6.22; N 89 90.

Race spectrum / MS /: / m ♦ H / + = 311.

E. 5- / 4-ηυθΓοίenylo / -3- / l-mtty0etty0ol-l-0enz- ^o --H-pkz · azo-o-kkkarZokSkaZdehyde

A solution of 10.2 g (about 32.7 mmol) of crude Part D compound in 85 ml of dry dichloromethane was quickly added to a solution of 21.23 g (98.4 mmol) of pyridine chlorochromate in 125 ml of dry dichloromethane and the resulting solution was dark The brown color was stirred at room temperature in a nitrogen atmosphere for 4.0 hours. The mixture was quenched with 750 ml of ether and stirred for 10 minutes. A solution of Zekkotookoo above the brown-colored residue, the residue was triturated twice with 100 ml portions of dichloromethane. The dichloromethane extracts were diluted with 750 mL of ether and the combined extracts were filtered through a pad of silica gel. The clear filtrate was evaporated to dryness to give 10.0 g of crude product.

The crude product was chrroratograph-eyed on a column containing 400 ml of 60-200 mesh Baker silica gel, eluting the column with 4: 1 CH ₂ Cl ₂ -Hjksko mixture. The yield was 9.6 g (952%) of the throttle compound. 72 mg of a] Oίlitic sample with a melting point was obtained after recrystallization of 100 mg of the substance from hexane. TLC: Rf = 0.58 / silica gel, CH ₂ CC ₂ UV /.

ΑηθΙΟι: included: C'74.01; H 5.56; N 9.09; F 6.16 Found: C 77.1 °; H 5.52; N 99 12; F 6.29.

MS: / K + H / + = 309.

F. 4- / 5,2-dibromoet ^ ΊyOo / z5- / 4 - luoooOenoloO - o / 1-meyyl-ethyl / -1-tert-yl-1H-ρlrkzole

To a mixture of 2.0 g (6.48 mmol) of Part E compound and 5.10 g (19.2 mmol) of triphenylphosphine in 30 ml of dry dichloromethane cooled to -5 ° -10 ° C in an ice-salt bath, under argon atmosphere, a solution of 3.22 g of quaternary carbon (9.61 mmol) in 10 ml of dry dichloromethane was added dropwise over 5 minutes. The reaction mixture was stirred at 15-20 ¹ ¾ for 15 minutes, then poured into 10 ml of saturated NaHCO3 and extracted with three 50 ml portions of dichloromethane. The combined organic extracts were washed with 10 ml of saturated NaHCO 3, ml of brine, concentrated over anhydrous MgSO 4, filtered and evaporated to dryness.

9.33 g of a crude chlorine gas mixture on a silica gel LP3-1 column, eluting the column with 1: 9, 1: 1 and 4: 1 C 1 -HCl 3 -hexane mixtures. The yield was 2.75 g of the title of the compound. After recrystallization of a small sample of the title compound, white crystals were obtained, mp 88-9O ° C.

TLC: Rf = 0.85 / silica gel, CH ₂ Cl ₂ chekn 4-1I.

154 878

Aieliza: w-icioil: ^c 51.75; H 3.69; N 6.04; F 4.09; Br 34.43 Found: C 51.06; H 35.51; N 5.079; p 4.22; Br 34.77.

MS: (w + H F) &gt; 465.

G. 4-ethynyl-5 ~ (4-fluorophenyl) -3- (1-methylethyl) -1-phenyl-M-pyrazole

To a solution of 2.64 g / 5.67 milirooi / of Part F compound in 10.5 ml of dry tetrahydrofuraeu, schłcdzoeego in a dry ice-acetone bath to -78 ° ^C under an atmosphere of argoeu, wkroploeo 7.16 ml / 11.37 milimoyl / 1.6 molar e-butyllithium in hexane. The resulting suspension was stirred at -78 ° C for 1 hour and then quenched with 10 M. 25%. NRCl and the mixture allowed to warm to room temperature. The reaction mixture was extracted with three 50M portions of ether, then the combined organic extracts were washed with 20M of sodium, dried over anhydrous MgSO, filtered and evaporated to dryness to give

1.70 g of the title compound as a light-colored solid.

The crude product was purified by chromatography on a silica gel column, eluting the column with 5:05 ethyl ether-ether. 1.08 g (07.0%) of the title compound were obtained in the form of a golden solid. After recitation of a sample from hexae, white fluffy crystals with a temperature of 106-108 ° C were obtained. TLC:

Rf = 0.70 (silica gel, diethyl ether-hexane 1: 0, develop two-column).

Analysis:

calcd: C 78.92; H 56 63; N 9 ^^ 1; F 6.24 found cmo: C 70.22; H, 55 ^ 39; Ń 9.28; F 6223.

H. N - 3- [1 ₁ 1-Dimeeallotallotallo-diphenyl-methyl / oxy 7-4- [[5- (N-fluoro-pheyl) -3- (1-methylethyl) -1-phenyl-H-pyrazol-4 acid methyl ester -yl (ethylloyl) / raethoxyphosphinyl / butane

A mixture of 2.77 g (5.55 mmole) of the crude monomethyl phosphorus ester from Part F of Example 1 and 2.1 M (11.05 mmole) of triethylotiliOodttlyOfeeiey in 10 M dry dichloro ^ ^ eLaHu is stirred under argoeu at room temperature for 1 0 hours. The mixture was evaporated to dryness, azeotroped with 20 ML of dry benzene and dried under reduced pressure using a vacuum pump for 15 hours. The sticky oil was poroused in 10 M dry dichloromethane, 1 drop of DM was added, cooled to -10 ° C in an ice-salt bath and bought in 530 µu (6.08 mmol) of oxaail chloride. Vigorous bleaching of the gas was observed and the dark yellow solution was stirred at -10 ° C for 15 minutes and then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, azeotroped with 20 ml of benzene and under reduced Μέηϊε ^ ^.

To a solution of 1.12 g / 3.67 milimU / compound of part G in 0.0 el dry tetrahydrofuran cooled in a dry ice-acetone to -78 ° ^C in ΜΟ ^ ^ ^ θη argon was added 2.3 mL / 3, 67 eilimola / a 1.6 molar n-butyyclitu in hexane and stirred at -78 ° C for 30 minutes, the above-described • fosfochloridae dissolved in 6.5 M of dry tetrahydrofuran, cooled in a dry ice-acetone to ^-78 C fam> s-argon nitrogen and a solution of acetylene anion infiltrated into it via a catheter, both solutions during imprinting at -78 ° C. The reaction mixture was stirred at -78 ° C ^for 30 minutes, then quenched by dropwise addition of 6.0 M. 25 percent. NRCl and the mixture was warmed to room temperature. The mixture was extracted with three 100M portions of ether, then the combined organic extracts were washed with 10 ml of 25%. NRCC and 25 gels of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness.

4.2 g of the crude chΓOMaogIaff extract was poured onto a silica gel column, eluting the column with 0: 1 hexane-acetone. 1.54 g (70%) of the title compound was obtained as a light brown oil. TLC: Rf? 0.33 (kaitmilnklwy gel, htksai-fcttli 7: 3).

I. Methyl ester (S) (-4- [Z - [5-74-flulletnyl) -3- (1-methylethyl) -lphthenyl-Wpirazol-1-yl 7-tytinyl 7m3 mt Rt 4-1 ttl- ^ l-ii.yio 7-3hlydl0klybufan carbon

For a solution of 5935.0 M! (0.81 mmol) of the compound from part of H in 8.0 M. of dry tetrahydropyran, 190 [mu] l (3.24 mmol) of glacial acetic acid and 2.54 - (2.54 mmol) [mu] mol / C4 were added successively. Hg / 4NF and the resulting mixture was stirred overnight at room temperature under argon. The mixture was cooled to 0 ° C in an ice / water bath, 8.5 ml of 5% were added. KHSO4 and extracted with three 75 mL portions of ethyl acetate. The combined organic extracts were washed with 10 ml of 5%. KHSOo., 10 -. brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness.

The crude product was dissolved in a mixture of 14 ml of ether and 10 - dry tetra hydrophilic cod liver oil, cooled to 0 ° C in an ice and salt, dim ^es been shown with an excess of diazomethane in ether and stirred at 0 ° C for 3.0 hours. The reaction was quenched by dropwise addition of glacial acetic acid, then the mixture was evaporated to dryness and dried under reduced pressure. The crude product was chromatographed on a silica gel column, eluting the column with 1: 1 acetone-hexal. 325.6 mg (80.6% yield) of the title compound was obtained as a semi-solid

Example VII. Hwilitoro krosu salt / s / 44- Z "2- /" 5 - / - 4-fluorophenyl / -3 - / - nethylethyl / -fnnyl-H-pyrazol-4-yl, 7-ethynyl. / Hydroxyphosphinyl ^ Q ^ -3-hd <rio ^ lcsybu ^ i ^ <^ w ^ go

A solution of 325 mg (0.65 -ilimda) of the compound from Example 6 in 7.7 ml of dioxane was added 2.25-. (2.25 milliard) 1 N LiOH and heated in an oil bath at 55 ° C under nitrogen for 1.5 hours and then at room temperature for 16 hours. The reaction mixture was evaporated to dryness and dried under reduced pressure. The crude product was chromitographed on a 25 x 125 µm HP-20 column, eluting the column with 400 -. distilled water and 500 ml of 50% degenerate methanol. The desired fractions were combined, evaporated to dryness and dried under reduced pressure. The solid product was dissolved in distilled water and lyophilized to give 317.1- (96%) of the title product as a fluffy solid lyophilisate. TLC: Rf 0.33 (silica gel, isopanol-HHoOH-equine 8: 1: 1). Analysis for Cg ^ i ^ HggFNOO '· ^! ^! · · 1.3 H ₂ 0 / real - there are particles 505.861 /.

Viscilno: C 56.99; H 2.90; N 5.54; F 3.75; P 6.12 Found: C 56.98; Η 2 »17; N ^> 4 ^; F 3.90; P 6.26.

¹ H-NMR ⁽ 400 MH, CD-OD): rf 1.4 (4 (d, 6H, J = 7 Hz? 1.81-1.98 (rn, 2h), 2.3 5 1H, J = 2,

152), 2.48 (dd, 1H, J = 4.15 Hz), 3.35 (septet, 4H (J? 7 Hz), 4.42 (m, 1H), 7.08-7 (4L) , 9H /.

IR / 'KBr /: 2173 c ^{--1 /} CC /.

Example VIII. -Itylowy acid ester / S / -4-Z "[2- / 3- / 4-fluorofenyll / -5 - / - metsioethlo / eonylo -l-H-pyrazine ^ ol-4-yl h-etyoΊylo _- / metlxyphosphoyloylo- 7-3-hydroxyutanoic acid

A. 2-phenyohydΓaihH of 4-fluolobenzGesowegl

To a mixture of 25 ml (0.25-yl-ol) phenylhydrazine and 35 -1 / 0.25-ylmol / triethyl alcohol in 500 ml anhydrous ether, cooled in a bath of IoHe and Ho -5 + -10 ^O C under a nitrogen atmosphere was added over 30 ° -1 / 0.25-da / 9-fluobenzenecaryonyl chloride. The reaction mixture was warmed to room temperature, stirred for 3 hours and filtered, then the solid was washed thoroughly with 200 ml of ether. The solid component was dissolved at 600 -. dichloromethane, stripped to near dryness, dispersed in 600 mL of hexane and filtered. The clear filtrate is evaporated to dryness, triturated with 700 - tetrahydrofuran and filtered, washing the precipitate thoroughly with 10O ml of tetrahydrofuran. The filtrate was evaporated to dryness and dried under lower shadow, yielding 34.6 g of crude product contaminated with two other ingredients.

The crude product, recrystallilorone from acetone, gave the title compound (22.36 g (38.8%) as white crystals, mp 18-184 ° C.

The filtrate and lye were combined - the chafflower and the chromium (I graph on a column of 400 - Baker 60-200 -esh silica gel, eluting the column with ethyl acetate-CH ₂ Cl ₂ 1: 9). An additional 9.78 g was obtained. 55.8% in total of the title compound TLC: Rf 7, 0.63 (silica-octal gel, ethyl acetate -CH 3 O 2 1: 4).

Analysis for Ο -, - Η, ^ ΕΝ-, Ο:

154 878

Included: C 67.81; H 4.82; N 12.17; F 8.25

Found: C 67.86; H 4.88; N 12.14; F 8.10.

ra: / m + h / * = 231.

B. 4-fluooo-N-enlyloennenookartκ) hldazonoyl chloride

To a solution of 6.16 g (26.8 mmol) of Part A compound in 46 ml of anhydrous ether was added

6.6 g (3.17 mmol) of phosphorus pentahydrate and the reaction mixture refluxed under nitrogen for 16.0 hours. The reaction mixture was cooled to room temperature, a solution of 11.5 g (122.2 mmol) of Senoiu in 15 m of ether was added, let it sit for 5 minutes and then 11.4 mL. The mixture was concentrated at about 75 ° C at rotary evaporator and the resulting oil was cooled to 5 ° C. The resulting solid was triturated with 20 mL of 5% of aqueous acetone, filtered, and the precipitate was washed thoroughly with 30 mL of 5-percent. hydrated acetone. The precipitate was dried in vacuo to give 2.2 g of the title compound as a solid, m.p. 118-120 ° C.

The clear filtrate was evaporated to dryness and the resulting product mixture was chromatographed twice in a column containing 400 ml Baker 60-200 mesh silica gel, eluting the column with 1: 3 and 1: 1 CH.Cl.-hexane mixtures. A total of 5.66 g (85%) of the title compound was obtained.

TLC: RS = 0.90 (µL silica, C 1 -H 8 -hexane 4: 1).

Anaaiza for C ^^ g ^ Ng!

Learned: C 62.78; H 4.05; N 11.77; F 7.64; Cl 14.26

Found: C 62.77; H 3.77; N 11.47; F 7.14; Cl 13.95.

ra: / M + H / * «249.

C. 3- (4-Fluoro-Seaylo) -O- (1-methyl-nitro) -lseany0Oltt, -pyrazII-4-carboxylic acid ethyl ester

To the solution of sodium ethanol obtained from 0.28 g / 12 millimels / sodium metallic and 40 m. Of absolute ethanol, 2.0 ml / 12 milliOU / l-isobutyol of ethanol acetate was fused in room j, for 15 minutes, then 3.0 g (12 ml mdi) of Part B compound was added. The mixture was stirred at room temperature for 4.0 hours, quenched with an additional 10 ml. 10%. HCl, the mixture was evaporated to dryness and the resulting solid was triturated with three 100 m portions of ether. The combined organic extracts were washed with a 25 ml bath, dried over anhydrous MgSO 4, filtered and evaporated to dryness.

4.3 g of the crude product of chromatography on a silica column, eluting the column with 1: 1 C1C8C6-hexane. 3.27 g (77%) of the title compound was obtained in the form of a reddish-blue syrup.

TLC: RS at 0.42 (silica gel, .alpha. 2 CO.sub.2 CO.sub.2 -hirsan 4: 1).

D. 3- (4-fluorophenyl) -5- (1-melylitol) -Sialll-o-1H-pyrallol 064-methanol

A solution of 3.26 g (9.25 mmoleH) of Part C compound in 22 ml of dry ether was added to a 0 ° C ice-brine suspension of 0.71 g (18.7 mMOi) of aluminum aluminum hydride in 22 ml. 32m of dry ether and the resulting reaction mixture was stirred at 0 ° C under a nitrogen atmosphere for 3.0 hours. The reaction was quenched at 0 ° C with 5.0 mL of ethyl acetate followed by 11 mL of 10%. HCl, the mixture was decanted and the residue was decanted twice with 100 mL of ether. The combined organic extracts were washed with 20 mL of brine, dried over anhydrous MgSO, filtered and evaporated to dryness to yield 2.87 g (94.4%) of the title compound.

100 ml of the title compound was recrystallized from ether to give 57 µg of an analytical sample, mp 145-147 ° C. TLC: RS = 0.17 (silica gel, CH2gl2-hexa? 4: 1, developed twice).

Analysis for ^ g ^ gF ^ O:

Found: Found: MS: / Μ + H / *

C 73.52; C 73226; 311.

F 6.12 F 6.09.

N 9.03; N 8 ^ 6;

H 6.17; H ^ 1 ^ 1;

154 878

E. 3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-1H-pLrazole-4-card »keyaldehyde

A solution of 2.59 g (8.34 mmol) of Part D compound in 22 ml of dry lichloophthane was quickly poured into a stirred suspension of 5.41 g (25.1 ml) of phenyl chlorothromate in 32 ml of dry dichloromethane. After it was stirred, the mixture was stirred at room temperature under a nitrogen atmosphere for 4.0 hours. The reaction mixture was diluted with 190 M of ether, washed for 20 M, notes and decanted. The turbid residue was triturated with 100 M of ether and 30 mL of dichloromethane and the combined organic extracts were filtered through a silica gel system. The clear filtrate was evaporated to dryness and the crude product was graphed on a 300M Baker 60-200 mesh silica gel column, eluting the column with 4: 1 CHgClg. 2.40 g (93.4%) of the title compound was obtained as a solid product.

100 mg of the title compound rdkrystelZoo * afa from hexane to give 50 mg of an analytical sample, mp 1O3-1O5 ° C. TLC: Rf = 0.67 (klzdemiafkawy gel, C gC).

Analysis for

Found C 74.11; H 5.66; N 9.09; F 6.16

Found: C Τ ^ ΐβ; H 5.35; N 9.11; F 6 ^^ 2 ..

MS: / M + H / ⁺ > 309.

F. 4- / 2,2-diaramooeedfloa --- / 4o-fluoro-phenyloo-5- / 1-methyl-ethyl / -1-phenyl-ΙΗ-pyrazole

To a mixture of 2.296 g / 7.45 M.lieoai / of Part E compound and 5.86 g / 22.1 milimooi / trifdn lafasfin ^{y y 3} L of 5 ^M of dry ^leaves c ^h yl] romdtafu, cooled by -5 * ^{d 10} ° ^C in an salt-Ιο »dem wkoplono under argon for 5 minutes a solution of 3.70 g / M.lim 11.0> oi / czterobrom k ^of carbon in ¹² ml of dry ^g of ^{di chlorometafu,} part of the ^{p y} m ca & down were mixed at - ¹⁰ ° ^C for ²⁰ min. The reaction mixture was warmed to temperature, poured into 12 mL of saturated BaHCOo and extracted with three 50M portions of dichloromethane. The combined organic extracts were washed with 12 M saturated NaHCOO and 10 M solariki, dried over anhydrous MgSO 4, filtered and evaporated to dryness.

11.0 of the crude solid product was chromatographed on a silica gel column, eluting the column with 1: 1 and 4: 1 mixtures of CHgCl8 with hexane. The obtained was 2.96 g / 96, (% of corrected W ^Γ 11noaśi / and 250.6 mg of unreacted baseline sutasannia).

100 mg of the compound tltuOowega rdkrystaliaowana from ether-hexane u ^s s ^k uj c ^{36 ±} 5 mg ^p V ^a sponge at an analytical tanienia ^93, 5 ° ^C.

TLC: Rf = 0.57 (silica gel, H 4 Cl 2 -hexane 4: 1).

Analysis for Czj / łjjBrgFNg!

Found C 51.75; H 35.69; N 6 ^ 4; Br 34.43; F 4.09

Found: C 51.78; H; N £> 0 ^ * 7; Br; F 3.22.

MS: / M + H / ⁺ = 465.

C. 4-ethynyl-3- / O-fluorophenfloO-53-1-eedylatylO-1-phenyl-ΙΗ -pyrazole

A solution of 2.87 g / 6.18 M.3.im> oLy4 of Part F compound in 11.44 M dry cooled tetasbydrofuranu ^d of -78 ° ^C in a mixture of dry ice uz ^{d acetonde,} part .mu.m wkroH.ono ¹¹ 7 ^M -1 · ^8.6 mMooL / ⁶ -mol n-butyllithium in hexane under argon and the mixture was stirred at -78 ° C for 2 hours 20 minutes. The reaction was quenched at ^-78 C by addition of 16.5 M-23 Hroj. the mixture was warmed to room temperature and extracted with 60M portions of ether. The combined organic extracts were washed with 22 ml of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness. 1.5 g of the crude product was chroratographed on a Ηϊ ^ ζμπι0ι ^ ι ^^ (^ »1 kolumnie gel column, eluting the column with a 5:95 mixture of ethyl ether and hexane. The desired fractions were combined and evaporated to dryness to give 1.88 g / 10 (% o > llj ^f ° ASJ / tytuoowego compound as a solid product.

100 mg of the compound tltuOowega rdkrlStalZaowana from hexane to give 645 mg of analytical 3 ^H r ^crib hand a melting point of ¹¹ 7- ¹¹ 8 ° ^C. TLC: R ^f = 0 ^ 7 (silica gel ⁵ ethyl ether, hexane 1: 9). Analysis for C2QCjyCN2 ^:

Calculated: C H 5.63; F N 9.21

Found: C 79.12; H 5> 6O; F 6.02; N 9 ^ 2.

154 878

MS / + η / * &quot; 305.

Η. Isl-3-C [(1,1-dimethylethyl) diphenylsilyl 7oxy] -k- [[C 3- (4-fluorophenyl) -5- (1-methylethyl) -1-phenyl-m-pyrazole- 4-yl 7-methoxy-phosphine-butane.

To the solution of karst methyl ester (S) (-3-ZL) 1, L, 3, 3-ethyl (difeaylsilio) (oxy (i4i) (hyroxymeeoxoxyosyl) butene, 2.77 g (5.55 millimooa), obtained in Part F of Example 1, in 10 ml of dry dichloromethane, 2.1 ml of trimethyl-ethylthiminium were added and the mixture was stirred at room temperature for 1.0 hour under argon. The reaction mixture was evaporated to dryness, azeotroped with 20 ^{ml of} dry benzene and ^dried under pressure. The syrup was redissolved in 10m of dry dichloromethane, cooled to -10 ° C in an ice-salt bath, 1 drop of DM was added, then 530 µH of oxalite chloride was added dropwise, then cooled to -10 ° C for 15 minutes. and at room temperature for 1.0 hour. The mixture was evaporated to dryness, azeotozed with 20 ml of benzene and dried under reduced pressure.

1.12 g (3.67 mmol) of Part G compound was dissolved in 9.0 m of dry tetral of m-uranium, cooled in a dry ice acetone bath to -78 ° C, then 2.3 ml was added. 3.68 mMooa / 1.6 mole nbut 2 3 lithium in hexane and troweled at -78 ° C for 45 minutes. The above -phosphonochloridate was dissolved in 6.5m of dry Uetahldrl-uranium, cooled to -78 ° C, and a solution of the tciUyien anion was dripped into the resulting solution via a catheter, both solutions being kept at -78 ° C throughout the addition. The reaction mixture was stirred at -78 ^° C for 30% until quenched by the dropwise addition of 6.0 mL of 25%. NH4Cl and the mixture was allowed to warm to room temperature. The mixture was extracted with three 100 ml portions of ether, then the combined organic extracts were washed with 10 ml of 25%. NH 4 Cl and 25 M brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness.

4.0 g of the crude product was chromatographed on a silica gel column, eluting the column with acetone-hexane 1: 9 and 3: 7 mixtures. 1.76 g (65%) of the title compound was obtained as an oil. TLC: Rf = 0.40 (silica gel, hexane-acetone 7: 3).

I. Methoyl / S ---- / acid ester [2 .- [3--4-llloro-enylol-5-l '- m & Uli.oetliol -'-- inΐlJl <:> - lH-pyrazol-4 -yl / ethynyl-7-methoxyphos. phenyl-7-3-dihydroxybutanoic

For 100 mg / 0.95 ml solution. mole / of a compound from the H 9 m portion of dry tetrahydrofuran, 22 µl (3.62 mmol) of glacial acetic acid and 7.0 m (7.0 mmol) 1.0 molar (CH 3 Hg) NF are added successively, the mixture was then stirred overnight at room temperature under an argon atmosphere. A solution of ³ schiłodzono of about 0 ° C in a bath of ice and salt, were sealed into 10 mL 5- ^p roc. KHSO4 and extracted with ζΙ'ζμβ with 15 ml portions of ethyl acetate. The combined organic extracts were washed with 10 ml and 5%. KHSO ° C and 25 ml of brine, in ^su 3zono over anhydrous magnesium sulphate, filtered and evaporated to dryness.

890 mg of crude product was dissolved in a mixture of 16 ml of ether and 12 ml of tetrahydrofuran, cooled in an ice-salt <io 0 ° C ^and treated with excess ^d iazometanu in ether. The mixture rea ^k c ^y jna was stirred at 0 ° C ^p slaughter olcoło ⁷ hours rea ^k cj ^ę quenched by the dropwise addition of lo ^d ^ t; ^e acetic acid, then the mixture was evaporated to dryness. 16- mg of the crude chromium product was trapped on a gel column; silica, eluting the collimine with 1: 1, -: 1, and 9: 1 ethyl acetate-hexane mixtures. 7-1 mg (77.2%) of the title compound were obtained as a semi-solid. TLC: Rf = 0.28 (silica gel, ethyl acetate-hexane -: 1).

Example IX. 3w.LLitoor acid salt / s / 4- / / 2/7 - / - lfluoΓOfenylo / -5l / L metyloetel ^and / -l-ffnylo- ^H ^ ^{-pirrιzol-4-i} o / s ^and ynyl ^ ^f in hydroksylos of ^7-3-yl hydroksybutaoowego

To a solution of 7-1 mg / 0.7 mmol / the compound from Example VIII in 8.7 mL of dioxane was added 2.4 mL / 2.4 mmol / 1.0 N-IdOH, and makes the mixture was stirred at 55 ° C to ^L and ^Z oil bath under nitrogen for -5 minutes. The reaction mixture was evaporated to dryness and dried under reduced pressure. The obtained chroMtografoorno semisolid was in a 25 x 15 mm column with H-20, eluting the column with 750 ml of distilled water and 250 ml of 50%. hydrated methanol. The desired fractions were combined, evaporated to dryness and dried under reduced pressure. The product was dissolved in distilled water and lyophilized to give the title compound (338 mg) (97.5%) as a white solid lyophilisate. TLC:

Rf s 0.50 / silica gel, isopopanol-NH 2 OH-water 7: 2: 1 /,

Analysis for 1.95 HgO:

Learned: C 55.11; H 5.04; l 5.22; F 3.67; P 5.99

Found: C 55.01; H 5.4.1; l 5.00; F 3.95; P 5.96.

¹ H 1MR / 400 Mz, CDDCD /: ^{j 1,} 45 GH, J = 7 Hz /, 1,89- ² »05 / m, 2H /, 2.38 / d ^ 1 H, J" ⁹

Hz /, 2.52 (dd, 1H, J? 4.15 Hz), 3.06 (septet, 1H, J? 7 Hz), 4.48 - 1H), 7.16-8.11 (m, 9H).

Example X. Acid methyl ester (s) -4-j- ['[4- (4-fluorophenyl) -1- (1-methylethyl) -3-phenyl-JH-pyrazoo-5-yl. ^ i ^ ylo [methokkyfoafinyl / 3i_yddrkxybutane].

A. 2- (44 fluoro-enyl) -loeeny-oaanone) suspension of 928 mg (38 millimeter) -gnesium-turnings in 38 -l dry ether under argon, 5.3 ml (42 µl-Λβ) of 4-fluorobenzyl bromide was added dropwise over 45 minutes with at a speed that ensures a steady, moderate take. After complete fusion, the mixture was refluxed for 30 minutes, cooled to room temperature, and 2.96-1 (29 mmoles) of beiisonitrile in 5-dry ether was added. The mixture was stirred at room temperature for 4.5 hours, poured onto 40 µL of cold 10%. HCl. and the resulting suspension was extracted with 5 portions of 50L of ether and two portions of 100L of ethyl acetate. The combined organic extracts were washed first with 50L of saturated 1HCOo, then with 50L of brine, dried over anhydrous-MSOi, filtered and evaporated to dryness.

9.8 g of the crude product was chromatographed on a 400 µL column of Baker 60-200 mesh gel, eluting the column with 1: 4 and 1: 2 CRCR-hexane mixes. The desired fractions were combined and evaporated to dryness to give 3.29 g of the compound as a white solid, mp 106-108 ° C. In addition, 2.60 g was obtained from the other fractions containing a trace of starting material so that the overall yield was 94.1%. TLC: Rf = 0.60 (CRCR silica gel-hexane 1: 1).

Analysis for CHF:

Calculated: C 78.99; H 5118; F 8.87

Found: C 78.21; H 5.21; F 9.2i.

MS: / M + H / + = 215.

B. l4oethyltyl / hr, 2i (4-fluorophenyl) il-filyl-telicon) solution of 4.45 g (21-li-di) of Part A compound in Oeszanine 34 -l 95%. ethaneLu and 0.74L glacial acetic acid 3.63L (about 42 milliL) is added and the resulting mixture was heated in an 80 ° C oil bath with nitrogen for 1.4 hours. C ^ h-oπolokgal'il thie] ktooarsOwooa indicated that the mixture still contained some starting material so ₍ that a further 2.0-1 (about 23%) of isopropylhydrazine was added to the reaction mixture and heating at 80 ° C to The oil bath was continued for one hour, the reaction mixture was cooled to room temperature, the kdparoolnk was rotated to remove most of the solvent, then diluted with 200 µl of dichloromethane, the organic solution was washed with 25 µl of brine, dried over anhydrous 4 SO 4, filtered and evaporated to dryness Obtained yellow-colored lztotropoolnk oil once with 150 -L toluene to obtain 5.63 g of the title compound in the form of a crude product contaminated with some substance in the ^Γ oil and a trace of two other components. TLC: Rf = 0.28 / ' silica gel OZ2C424htkyan 1: 1 /.

Isopropyl chloride was obtained as follows: 10.3 L / 90.10 Iodicpropyl was added over 2.0 hours to 48.1 L ml / 1.0 mg hydrazine hydrate in the offer R The mixture was cooled at 60 ° C in a booth bath under R atmosphere for 3 hours, cooled and extracted with 250 -L of ether for 20 hours in a liquid extraction device. The ether extract was evaporated to yield 5.63-1 (5.3 g) of i.zkprkpyL.khydrlzyil.

154 878

C. 2-Z2- (4-fluoro-phenyl) -l -ienylethylidene ⁷ -l- (1-ii) ethyl ethyl hydrazide of acetic acid 5.63 g - about 21 mmol / crude compound from Part E and 5.85 ml / 42 mllimol ^e / treeyyo ^and mmiri ^{y 2} 10 ml of dry toluenes Schlo unto ^ ^d of about 0 ° C in an 1o ^(ui salt under a nitrogen atmosphere ioiano 1.86 ml / 26.3 mmol / acetyl chloride. the reaction was stirred With gradual heating at room temperature for 1.5 hours, it was diluted with 700 ml of ether and filtered The clear filtrate was dried with anhydrous tegSO 3, filtered, evaporated and dry and evaporated again after adding 300 ml of toluene. 7.1 g was obtained. a semi-solid substance that was chromotogrifovino on a column of 400 ml Baker 60-200 mesh silica gel, eluting the column with mixtures of CH ₂ Cl ₂ with hexane 1: 1 and 2: 1, CH-Rlg and a mixture of CH2C12-Eethanol 9: 1. 11 g of the title compound as a crude product. The crude product was again chromatographed on another silica gel column, eluting the column with <4: 1 ethyl acetate-hexane mixture. The desired fractions were combined and evaporated and dried to give 3.89 g of the title compound as a viscous yellow oil. TLC: Rf = 0.47 (silica gel, ethyl acetate-hexane 1: 1).

D. 4- (4-fluorophenyl) -5-methyl-1- (1-methylethyl) -3-phenyl-1H-pyrazole

To a solution of 1.50 g / 4.80 mmol / of Part C compound in 48 mL of bis / 2-methoxyethyl / ether was added 615 / 10.96 milimooi / solid potassium hydroxide, the mixture was heated in an oil bath & ^O 0 C. nitrogen atmos ^{f p} slaughter age of ^2, 0 ^g odziny. To the reaction mixture (tocteno second portion of 700 mg / 12.5 mmol / potassium hydroxide and the mixture was heated at 80 ° C, ^{2 g of p} slaughter odziny and stirred at the position yo temperature for ^{16 g} odzin. Mieszanj.n ^ę poured into 300 ml of water and extracted successively with three 150 ml portions of ether and once with 200 ml of ethyl acetate The organic solutions were combined, washed with 500 ml of cold 3% HCl, two 100 ml portions of brine, ^dried over anhydrous MgSO 3, filtered and evaporated to The crude product in an amount of 3.5 g was chromatographed on a 500 ml column of Baker 60-200 mesh silica gel, eluting with a 1: 4 ethyl acetate-hexane mixture to give 1.33 g (94%) of the title compound as a solid. ^b Arwi of a cream at a temperature of topmenia ^{13 13} 7 5 ^o C. TLC:

R f = 0.63 (silica gel, ethyl acetate, hexane 1: 4).

E. 4- (4-fl ^ .. oιrophenyl) -1- (1-methyleethyl) -3-phenyl-3H-piΓalol-5-k.aroksyaidehyd

A mixture of 2.21 g (8.85 mmol) CuSO 3. 5 ^ 0 and 9.53 g / 35.3 mmol / potassium persulfate in ⁶ ml of acetonitrile and 5. ³ 9 rnl water was heated to łatoi. Oil ^d of 65 ° C under atmospheric ^f era of nitrogen, was added 2.6 g / 8.83 mmol / compound of Part D. Tempeeaturę bath powli the oyższano ^{and d} 75 ° ^C "temperature was 75 ° C utrz ^p-yrnywano 40 slaughter Procedure of ^ ^p wherein mieszmin ^ę cooled to room temperature in a water bath. The reaction mixture was diluted with 45 mL of dichloromethane, picked for 10 minutes, and rinsed and the aqueous suspension was extracted with three 45 mL portions of dichloromethane. The combined organic extracts were washed with two 30 ml portions of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness. The crude product amounting to 2.75 g of chromitographooιino on a column of LPS-1 silica gel, eluting the column with ethyl acetate-h.exane 1: 9. 1.57 g (57.5%) of the trivalent compound was obtained as a solid. TLC: Rf = 0.72 (silica gel, ethyl acetate-hexane 1: 4).

F. 5- (2,2-iibromooteeyl) -4 - / - fluOΓoOennZo0-1- (1-methyl-ethyl) -3-fenzlo-1H-eirirol

A mixture of 1.75 g (5.68 mmol) of Part E compound and 4.6 g (16.8 mmol) of triphenylphosphine in 27 ml of dry dichloromethane was cooled to -5 + -1C ° C in an ice-salt bath under an atmosphere of under argon was added dropwise over 5 minutes 2.82 g / 8.42 mmol / czteroboomku atoms in ⁹ ml suc ^h ^ ego chloromethane and the mixture was stirred at -10 ° C ²⁰ minutes slaughter. The reaction mixture was warmed to room temperature, poured into 9.0 m of saturated NaHCO 3, and extracted with three 50 ml portions of dichloromethane. The combined organic extracts were washed first with 10 ml of saturated NaHCO 3, then with 10 ml of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness.

The crude product was chrroratographed on a keralone gel eluting with 1: 0 and 1: 4 CH2Cl2-hekSin mixtures. The desired fractions were combined to yield 2.35 g (91.4%) of the title compound as an oil. TLC: Rf? = 0.32 (silica gel, CH1 Cl2 -hexane 1: 1).

154 878

G. 5-ethyl-4- (4-fluorophenyl) -1- (1-methyl-ethyl) -3-phenylc -% - pyrazole

Cool a solution of 1.89 g (4.08 mmol) of Part F compound in 7.6 ml of dry tetrahydrofurar in a bath with dry sodium and acetone to -78 ° C, then 5.2 ml (8.18 mmoles) was added dropwise. 2 equally / aanykk / wt -molowego butyllithium in hexane ATMS-era argon and the mixture was stirred at -78 ° C for 1 hour 20 quenched at ^-78 C by addition of 11.0 ml of 25 percent.

NH / CC, the mixture was warmed to room temperature and extracted with three 50 ml portions of dichloromethane. The combined organic extracts were washed with 15 vol. Brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness. The crude product, 1.77 g of Chloro-Tetrahydrate, was washed on a silica / calcane gel column, eluting the column with 1: 4 and 1: 1 Cf / C12 -hexane mixtures. 648 mg of the title compound was obtained together with the mixed fractions containing the title compound and the compound from Part F. The mixed fractions were combined with 490 mg of the product obtained in another synthesis from 1.1-millimoOa of the compound from Part F, and then chromatographed in the second column. eluting the column with 1: 9 Cl 4 Cl 2 -hexane. The desired fractions were combined and evaporated to dryness to give 1.02 g of an oil, 71.5% skin and lower yield relative to the outlet material.

H. Acid, methyl ester (S) -3-, -1,1-dimethyl (difeyylsiOi77oxy] U- [CC 4- (4-fluoro-eyyl // -1 // 1-methylOoethyl / 8-eyyy / Oom-) pyraz / l-5-O / o / ethyl / o / -πletoxy-os-inyl / but new

A solution of 2.41 g / 5.01 of the compound from Part F of Example 1, sheath monomethyl ester and 1.90 m. (10 mMool) trimethylsiloelylamine in 9.5 ml of dry dichloromethane was stirred at room temperature under argon for 1 hour. The mixture was evaporated to dryness, azeotroped with 15 ml of dry benzene and dried in vacuo. Ponowiie viscous oil was dissolved in 9.5 mL of dichloromethane was added one drop of DM, cooled to -10 -0 ° ^C in an ice-salt was added dropwise 480 yul / 5.47 ιΜΙ ο ^ ^ / lithium chloride window. Vigorous and bleaching of the gas was observed, with the dark yellow solution stirred at -10 ° C to 0 ° C for 15 minutes and then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, evaporated from 18 ml of benzene, and concentrated under reduced pressure.

A solution of 1.016 g (8.34 millimoles) of part G compound in 8 ml of dry tetahydao: furayu cooled (y) to -78 ^O C in a bath of dry Ood and acetone in an argon atmosphere and then additions of / 2.1 mL (8.36 mmol / l) 1.6-m (loweg) n-butyllithium in hexane and the resulting mixture was cooled to -78 ° C for 1 hour. The above-obtained -sphoyochloaiday was dissolved in 8 mL of dry tetrahydro-uranium, cooled in a bath with dry sodium and acetone to -78 ° C under argon, and then a solution of acetylene nitrate was fused into it using a catheter. both solutions were kept at -78 ° C during the dropwise addition. The reaction mixture was stirred at -78 ° C for 1.0 hour, quenched by the dropwise addition of 9 mL of 25%. M / Cl and the mixture was warmed to room temperature. The mixture was extracted with three 100 mO portions of ether, then the combined organic extracts were washed with 10 mL of 25%. NH (CC) and 25 ml of brine, dried over anhydrous MgSO, filtered and evaporated to dryness.

The crude product cha / raιt / gaafowayo on a silica gel column, eluting the column with acetone-hexane 1: 9 and 1: 4 mixtures. 1.595 g (64.8%) of the title compound was obtained in the form of an oil. TLC: Rf = 0.48 (silica gel, jcetoyhersay 8: 7).

I. Acid methyl ester / s / -4-ZC L 4- / 4-flu / a / pheyyl / -O - / - methyl oethyl // - 3-ethyl-1H-pyrazol-5-yl / elyny / oT'metoksyί'osf iyyło78 - ydd / rklbbutanowego

For a solution of 1.0 g / 1.36 of the compound of H part in 18 ml of dry tetΓahydΓoίurayt

The mixture was mixed / overnight at room temperature in cpm / argon choke from (dj) 820 µl (5.46 mmol) of glacial acetic acid and 4.26 w (4.26 mmol) of 1-moic acid. The reaction mixture is cooled to 0 ° C in an ice-salt bath, d / d 15 ml 5%. KHSOc and extracted with three 125M portions of ethyl acetate. The combined organic extracts were washed twice with 25 ml of 5-aoc. KGSO (25 mO brine), stood out over anhydrous MgSO, filtered and (Zpaa) to dryness.

The crude product in the amount of 1.06 g of roiltsici / n / in a mixture of 28 ml of ether and 18 m of tetrahy34

Drofuran, cooled to 0 ° C in an ice-salt bath, then an excess of diazomethane in ether was added and stirred at 0 ° C for 4 hours. The reaction was quenched by dropwise addition of an iceberg acetic patch, then the mixture was evaporated to dryness and dried under reduced pressure. The crude product was chroratografted on a silica gel column, eluting the column with acetone-hexane 1: 2. Desired fractions were combined and evaporated to dryness to yield 330 mg (48%) of the title compound as an oil. TLC: Rf 0.23 (silica gel, ethyl acetate-hexane 4: 1).

Example XI. Kros diethyl salt / S / -4- [[4- (4-fluoropheoyl) -1-11-methylethyl) -phenyl-phenylH-pyrazol-S-ooo.-eetnyoy / hhddroxyphinyl / -3-hydroxybutane

A solution of 330 mg (0.66 mMUa) of the compound from Example 10 in 0.8 ml of dioxane, to which 2.29 m / 2.29 mMUa / 1 n LiOl was added, was stirred at 55 ° C in an oil bath under argon. for 1.5 hours and then at room temperature for 16 hours. The reaction mixture was evaporated to dryness and dried under reduced pressure. The crude product chromtografowano in a column atm ch ^ara 25 x 250 mm, 1P-20, eluting the column successively with 050 m of distilled water, 500 m 10 percent. of hydrated ^^ e ^ i ^ c ^ LLu, 500 d 20% of hydrated methanol and 500 d. 50% The desired fractions were combined, evaporated to dryness and dried in vacuo. The solid product was dissolved in distilled water and lyophilized to give 205 mg (99.5%) of the title compound as a fluffy solid lyophilisate. TLC: Rf "0.50 (silica gel, azoprppino-H {, Ol-water 8: 1: 1).

AnaUza for CjH ^ PLi ^ NgOjP.2,281.0 / actual molecular msa /:

Learned: C 55.08; l 5.11; N 5.35; F 3.63; P 5.92

Found: C 55.08; H 4.98; N 5.47; F 3.66; P 5.99.

IR (KBr): 2102 cm ^-1/0 C).

¹ L NMR ^/ 400 Miz, CDOOD: S 1.57 (d, 6H, J = 7Hz), 1.86-2.01 (-, 2h), 2.37 (dd, 1H, J-8Hz),

2.50 (dd, 11, J = 4.1z), 4.40 (m, 1H), 5.01 (septet, 11, J &lt; 1z), 7.04-7.39 (m, 9H).

Example XII. (S) -k-f [[1 ----- Fluorophenyl / -4-(1-methylethyl) -2-phenyl-1H-imidzlol-5-yl.i-eiynyd7moroxyphoaihly-o.3-3-hydroxy-uaine acid methyl ester

A. N-benzoylvaline

To a solution of 20 g / 0.10 mol / rol in 20 ml of tetrahydrofuran and 111 ml of 2 N NaOH, cooled to -10 ° C in an ice-salt bath under nitrogen, 23.8-1 / 0.21 mol / chloride was added dropwise. benzoyl. The reaction mixture was warmed to room temperature, stirred for 3.0 hours, and cooled back to 0 ° C in an ice-salt bath, then adding 8.0 mL of concentrated sulfur cossum. The mixture was extracted with three 200 ml portions of ethyl acetate. The combined organic extracts were washed with 100 mL of water and 50 mL of brine, dried over anhydrous MgSO 4, filtered, and evaporated to dryness to give 41.90 g of the title compound / title compound as a solid 41.90 g.

A small sample of 260 mg of the product rerr ^, hstalyloroio from ethyl acetate and petroleum ether to give 205 mg of an analytical sample of the title compound, m.p. 132-133 ° C. TLC: Rf = 0.10 (silica gel, acetone-hirsane 1: 1).

Analysis:

Calculated: C 65.14; N 6.83; N 6333

Found: C 64, © 1; N 6.79); N 6.29

MS: / M + H / ' ⁺ - 222.

B.. ^ '- / l-αcetyl --- d.e'tyOopoopyl // biizaiid

To a mixture of 41.0 g (about 0.10 mole) of the compound from Part A and 40.3 ml (0.34 mole) of triethylamine in 48 mole of acetic anhydride was added in two portions, 2.00 g (0.010 mole) of 4-dimethloamiilpyridine. then the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to 0 ° C in an ice / salt bath, quenched with ϋϋϋϋΐΐ, then stirred for 30 minutes. Precipitate a light brown color, ^yellow r ^k t ^y wyyrącił si.ę, filtered, zemyto ^ syntax fo ⁵ in ^1.1> d ^y, and then spread on ^p uszczono

154 878

750 nl of dichloromethane. The resulting solution was dried over anhydrous MgSO 4, filtered and evaporated to dryness to give 35.9 g of crude product.

Crude dissolution product^smerged in 1.3 dm⁹ ether, filtered to remove^ęCi.a of insoluble solids, and the clear filtrate was concentrated to a volume of about 300 mL and cooled in an ice bath. The title compound is precipitated in the form of a cream-colored solid, temperature t^ptemperature 88-9 ° C, drained from^yhissing²¹, 55^g related^andzku.^S.this eyes^yThe filtrate was evaporated by evaporation on a column containing 600 ML of Baker 60-200 eesh silica gel, eluting the column with 1: 7 and 1: 4 ethyl acetate-hexane mixtures. An additional 4.77 g of the title compound was obtained. A small sample of the title compound was recrystallized from ether to give a product, mp S5-89 ° C. TLC: RF = 0.75 / silica gel,^actoken-hek san 1: 1 /.

Analysis:

Found: C 70.20; H 7.81; N 6.99

Found: C 70.99; H 7.88; N 6.31.

MS: (M + H f) = 220.

C. N-f 1- f 1-Z / 4-fluoro-phenyl / imino / ethyl-7-2-methylfume O. / Benzamide

To a solution of 25.0 g (0.114 mol) of Part B compound in 250 ml of dry toluene was added 12 ml (0.127 mol, 1.11 eq.) And 125 mg of p-toluene sulfuric acid hydrate, and the mesanine was refluxed under a nitrogen atmosphere with a Dearni-Stark distillation cap for ²⁰ hours. A solution of ^b Arwi czerwoliawOłbπ.matnej cooled to -10 ° C in La ^Ni. with ice and salt and used as obtained in the next reaction step.

D. l · - / 4-llłOłfeinylo - 5-methyl-4- / l-methylethyl met ^y - 2-ίinylo-Hi-imidazłl

For a cooled solution about ^0.1 l. ⁴ moles of connection with parts. C diluted at -10 ° ^C in an ice-salt bath in 200 ml of dry dichloromethane, 47.4 g (0.228 mol) of phosphorus pentachloride were added portionwise. The cream-colored suspension was warmed, refluxed for 2.5 hours under nitrogen atmosphere, cooled to room temperature and poured slowly into a mixture of 400 g of ice and 105 ml of 50%. NaOH. The organic phase was separated and the w / ^e aqueous phase was extracted with two 200 ml portions of dichloromethane. The combined organic extracts were washed with two 100M portions of brine, dried over anhydrous MgSO4, filtered and evaporated to dryness.

The crude product in an amount of 35.0 g was photographed on a column containing 600 M Baker 60-200 mesh silica gel, eluting with 1: 9 and 1: 4 ethyl acetate-hexane mixtures. Was obtained 29.24 g / 87% / tytuoowego compound as white needles, at a temperature of the melting-down 14 ⁶ -ł.48 ° ^C. TLC: ^Rf = 0.4 ⁰ (demionic gel, ethyl acetate-hexane I .: ⁴ ).

Analysis:

Calculated C 77.52; H 6.51; N 9.52; F 6.45

Found: C 77.48; H 6.69; N 9.40; F 6.45

MS: / M * H / * = 295

E. 1- (4-fluorophenyl) -4- (1-methylethyl) -2-phenyl-1H-ieidazole-5-carboxaldehyde

A mixture of 8.50 g / 34.0 mmol / hydrate of cupric sulfate and 36.8 g / 0.136 mole / of potassium persulfate rozpuszczalnkków in a mixture of 250 ml of acetonitrile and 150 ml of water was heated La ^Ni oLLejowej ⁶ to 5 ° ^{C and} TMOS ^f era of nitrogen, to which ^{10 g} / 3 ⁴ 0 mmol orga ^k // in D. Meszaninę re ^k c ^s p ^o jna will ogre been shown to ^7-5 ° C, ltrly ¢ ^l wail at this temperature for 40 ^p slaughter minutes and cooled to room temperature. The solution was decanted from the precipitate, then the aqueous phase and the precipitate were extracted with three 200 ml portions of dichloromethane. The combined organic extracts were washed with two portions and 100 ml each of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness. 17.0 g of the crude product was chilled on a column containing 600 ML of Baker 60-200 eesh silica gel, eluting the column with ethyl acetate-hexane 5:95 1 1: 7. 6.27 g (59.8%) of the title compound were obtained as a solid.

154 878

200 mg of the title compound was recrystallized from ethyl ether-hexane to give 76 mg of an analytical sample, mp 16O-161 ° C. TLC: Rf = 0.34 (silica gel, ethyl acetate-hexane 1: 4).

Analysis:

Calculated: C 74.01; H 5.56; N 9.09; F 6.16

Found: C 73.98; H 5.68; N 9.04; F 6.09.

MS: / M ♦ H / * - 30 ¹⁹ .

F. 5- (2,2-dibromoethnyl) -1-α-loorophenyl) -4- (1-meeyyethyl) -2-phenyl-ΙΗ-imidazole

To a solution of 1.75 g (5.68 mmole) of the compound from Part E and 4.46 g (16.8 mmole) of triphenylphosphine in 27 ml of dry dichloromethane, cooled to -5 ♦ -10 ^O C in an ice bath and salt, a solution of 2.82 g (8.42 mmol) of tetrabated carbon in 9 ml of dry dichloromethane was embedded in an argon atmosphere within 5 minutes. The mixture was stirred at -10 ° C for 20 minutes, then poured into 9.0 mL of saturated sodium bicarbonate and extracted with three 50 mL portions of dichloromethane. The combined organic extracts were 10 ml. saturated NaHCO 3 and 10 ml of brine, dried over anhydrous 2 SO 4 and evaporated to dryness. The crude product, 8.07 g, was chromatographed on a silica gel column, eluting the column with 1: 7 and 1: 4 CHgCl6-hexane mixtures. 2.35 g (91.4%) of the title compound were obtained as a solid.

100 mg of the compound from the F ecrystalZzooeaz portion from the ethyl ether-hexane mixture to give 49 mg of the analytical sample, mp 164-165 °. TLC: Rf - 0.32 (silica gel, CH 2 O 1: 1 hexane).

Analysis:

Found: C 51.75; H 3.69; N 6.4; F 4.09); Br 34.43

Found: C 51.00; H 3> 71; N ^ O ^; F 4.08); Br 34.25.

MS: (J + H) &lt; + &gt; 465.

G. 5-etylz-1- (4-lluorophenoyl) -4- / l-: w! Ty0oethyl / -2feayy0OlM-0midazzl

A solution of 3.065 g / 6.60 milimoi / of Part F compound in 12.5 mL of dry tetrahydrofuran was cooled to -78 ° ^C in a dry ice-acetone, was added 8.4 mL / 13.4 mile ^ ^^ ^ oo 8-molar α-bullolithium in hexane at? m??:? the argon era. The reaction mixture was stirred at -78 ° C for 1 hour 20 mimt, then quenched by a pour of 18 mL of 25-percent. In 1 ° C, the mixture was warmed to room temperature and extracted with three 100 mL portions of ether. The combined ethereal extracts were washed with 25 ml of brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness. The crude product, 2.08 g, was chrroratographed on a 400 ml Baker 60-200 mesh silica gel column, eluting the column with 1: 9 and 1: 4 ethyl acetate-hexane mixtures. Desired fractions were combined and evaporated to Dry to yield 1.97 g (978%) of the title compound as a solid.

mg of Part G compound was recrystallized from hexane to give 59 mg of analytical sample, mp 148-15O ° C. TLC: Rf? = 0.60 (silica gel, ethyl acetate-hexane 1: 4).

Analysis:

Learned: C 78.92; H 50 ^ 31; N 9.21; F 6.24

Found: C 78.95; H 5.83; N £>, 07; F 6.63.

MS: / M - H / ′ = 303.

H. Ester moLiIowi kwsu / s / -3-CC / 1,1-dioethylethyl / diphenylsili] Zokly / -4- [[1- / 4-fluoro-phenyl / -4- / 1-methylethylZo ---- falyZ - 1HiO Inidazzl -5-iZo / etJanllo ./- oetzksy-zs-lnylz7bltane

A mixture of 3.54 g (7.86 mmoles) of the crude O.Z. nitrous phosphoric ester from Part F of Example 1 and 2.70 ml (14.21 mmoles) of trioethylsίliZo ^d itl ^y Zaaoinl in dry dichloromethane was stirred at room temperature under argon for 1 .0 hour. The mixture was evaporated to dryness, the azeztzopooanz with 26 ml of dry benzene and dried over reduced pressure. The sticky oil was redissolved in 14 ml of dry dichloromethane, 2 drops of DM were added, cooled to -10 ^° C in an ice-salt bath and then taken up with 0.68 ml (7.79 mmol) of chloride.

154 878 oxalyl. Vigorous gas evolution was observed and the yellowish brown solution was stirred at -10 ° C for 15 minutes then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, azeotroped with 26 M dry benzene and dried under reduced pressure.

A solution of 1.43 g (4.7 mmol) of Part G compound in 11.5 ml of dry tetrahydrofuran was cooled to -78 ° C in m ^^^; ^ r ^ i. Not dry flight with acetone, under argon, by adding to it was 2.94 M / 4.7 1.6 mol n-butyolite in hexane, then stirred at -78 ° C for 30 minutes. The above-described phosphonochloridate was dissolved in 11.5 ml of dry tetrahydrofuran, cooled to -78 ° C in a mixture of dry ice and acetone under argon, and a solution of acetyl anion was added dropwise via a catheter, both solutions being kept at the same time during the addition. -78 ° C. The reaction mixture was meshed at -78 ° C for 30 minutes, then quenched by dropwise addition of 13 M 25%. N ° C, the mixture was allowed to warm to room temperature and then extracted with three 130 M portions of ether. The combined organic extracts were washed with 15 ml of 25%. NRCl and 30 M brine, dried over anhydrous MgSO 4, filtered and evaporated to dryness.

The crude product in the amount of 4.3 g of chlorobutyltoxide on a silica gel column, eluting the column with acetone-hexane 5:95 and 1: 4 mixtures. The desired fractions were combined and evaporated to dryness to yield 2.18 g (62.9%) of the title compound as a light brown syrup. TLC: Rf = 0.13 (silica gel, hexane-acetone 7: 3).

I. Acid, methyl ester (s) -4-C Z 1/4-fflloropheyl) -4- (1-methylethyl) -2-phinyO-M-imidaiol-5-10 (ethynylmethoxyfosinyl) -3-hydroysibutil

310 µl (5.29 mmol) of glacial acetic acid and 4.14 M. (4.14 mmol) of dry tetrahydrofuran were added successively to a solution of 974 mg of the compound from the H part (1.32 mmol) in 13.0 M dry tetrahydrofuran. (1 M solution) CcR) cHF and the resulting mixture was stirred overnight at room temperature under argon. The reaction mixture was cooled to 0 ° C in an ice bath and water, 14 M 5% was added. KHSOc and extracted with three 125M portions of ethyl acetate. The combined organic extracts were washed with 16M 5%. KHSOc and 35M brine, dried over anhydrous MS, filtered and evaporated to dryness.

The crude product of 1.48 g was dissolved in a mixture of 22 mL of ether and 17 M dry tetrahydrofuran, cooled to 0 ° C in an ice-water bath, then excess diazomethane in ether was added and stirred at 0 ° C for 4. 0 hours. The reaction was quenched by spraying with glacial acetic acid, then the mixture was evaporated to dryness and dried under reduced pressure. The crude product was chromatographed on a silica gel column, eluting the column with 1: 1 and 4: 1 ethyl acetate-hexane mixtures. Desired fractions were combined to yield 304 mg (46%) of the title compound as a solid. TLC: Rf = 0.33 (silica gel, ethyl acetate-hexane 4: 1).

Example XIII. Qutsu / s / -4_ [[2- (cyclohexylmethyl) -4,6-dimethylphenyloyetinyl / hydroxyphosphinyl Thio-hd-hydroxybutane diethyl salt

A. N- (2,4-dimethloberzylidil (ybiizintamiia) (see StZj ^^ dnJl ^^ r, No. 4,375,475, p. 39-).

The title compound was prepared as described in Part A of Example I.

B. Palladium comoxide of the compound of Part A (see US Pat. Amer. no. 4 375 475, p. 39 /.

The title Pd line was prepared as described in Part B of Example I.

C. 2-C / cyclohekshloeetyll / -4, / zdemeyy0ybinzaZdehhd

1.44 g (59.45 mmol) of magnesium turnings were covered with 15 M dry diethyl ether under argon and sonicated for 5 minutes. 1.5 ml of chklohexylmethyl bromide was added to the Mg turnings and the ultrasound treatment was continued so that for a few min. the mixture began to boil. From the dropping funnel, 60 M of dry diethyl ether and a solution of the rest of the cyclo-ethyl bromide in 5 g of diethyl ether were added under continuous ultrasound. A total of 9.12 g / 65.3 g / 65.3 chloroexyl ethyl bromide was added. After completion of the dropwise addition, the sonication treatment was continued for 15 and the mixture was reacted 38

The solution was heated to room temperature and then added via a catheter to a solution of 5.55 g (7.43 mmol / Pd complex from Part B and 15.59 g (59.45 mmol) of triphenylphosphine mixed with previously for 30 minutes under argon at room temperature. After the addition of the Grignard reagent, the mixture turned green and a precipitate formed. The reaction mixture was stirred at room temperature for 2 hours, then 37 ml of 6N HCl were added. The mixture was stirred for an additional 1 hour then filtered through a pad of celite on a sintered funnel to remove solids. The precipitate was washed with ethylene ether and the filtrate was evaporated on a rotary dish to remove volatiles. The resulting residue was wm ^es been shown with diethyl ether and filtered as in the above ^ · The filtrate was washed once with saturated NaCl solution, then wrstwę organic phase was dried over magnesium sulfate. The yield was 14.5 g of a brushed oil. The flash mitode purification screen with 4% elution. etylinym ether in hexane gave 1.70 g / 99% S ^{and Γ} t bile ⁿ / a clear oil. TLC: Rf - 0.30 / 5%. ethyl ether in hexane, silica gel /.

IR (CHCl ³ ): 3030 ^, 3008, 2926, 2853, 1679 ^, 1606, 1448 ^, 1147 cm ¹ .

¹ H NMR ⁽² 70 Mir, CCDCl 2): < 10.51 ^/ s, 1 /, 6.90 / s, l /, 6.85 / s, l /, 2.80 / d, 2, 1 = 6 ^ 2 ^

2.55 / s, 3 /, 2.30 / s, 3 /, 1.80-1.55 / m, 5 /, 1.55-1.30 / m, 1 /, 1.30-0, 80 / m, 5 /.

Mass spectrum / Cl /: m / e s 231 / M ♦ H / *.

D. l- / cy ^k 0ohexylmethyl / -2-22,2-diblomletenyll / 33, - dlmety0oberzen

1.68 / 7.30 milimU / aldehyde from part C in 65 m. Dry GCG CT ^ under argon was cooled to 0 ^o C. To this solution was added 6.13 g / 23.4 Mund / triphenylphosphine, and the solution was stirred until dissolving the solids. A solution of 3.63 g (11.0 mMU) was added at 0 ° C.

CBr 5 in 20 ml of C 2 C 3. The reaction solution turned tan. The reaction mixture was stirred at 0 ° C for 1.5 hours, then quenched with saturated NaHCO 3 solution while stirring vigorously. The councilman was separated and extracted 2 times with CH 2 Cl 2. The organic solutions were combined, washed once with saturated sodium bicarbonate solution and dried over M ^s · ° ± Filtration and removal of solvent gave 9.6 g of solid bruratnej.

Purification by flash chromator with pure hexane eluent gave 2.52 g (9C% yield) of a clear oil. TLC: Rf - 0.62 (5% ethyl acetate) in hexane, silica gel / PMA.

IR 2 H 11: 292 ^7, 2852 ^, 1608 ^, 1472, 869 cm ¹ .

¹ H NMR ^{/ 2} 70 Mir CDDCj /: ^{J = 7,} 39 / s, 1s 6.87 / s, ^1/6, 80 / s ^ 2 ^1, 37 / d, ^2, Je ^ HZA

2.27 / s, 3 /, 2.24 / s, 3 /, 1.70 / m, 5 /, 1.45 / m, 1 /, 1.38-1.10 / m, 3 /, 0 , 90 / m, 2 /.

Mass spectrum (Cl / m / e 387 (M + H / ⁺⁾ .

E. 1- (cyclhexyllEetlo) -2-ethynyl-3,5-dimethylbenzene

2.51 g (6.5 mmol) of Part D vinyl dibromide under argon was mixed with 30 m THF and cooled to -78 ° C. To a solution of dibromide at -78 ° ^C was added over 3 minutes 5.20 m. 2.5 moIowego solution of n-butyllithium in hexane. The resulting pink reaction mixture was stirred at -78 °. After 1.5 hours at -78 ° ^C the reaction was quenched with saturated aqueous ΝΗ ^ Ι and the mixture was warmed to room temperature <^^^^^^. The aqueous vegetable was separated and extracted twice with ether and once with hexane. All the organic layers were combined and dried over MSO 4 to yield 1.65 g of a cloudy oil after filtration and removal of the solvent. After purification of the young chaomat and flasher eluting with hexane, 1.39 g of the title acetylene compound of the title acetylene compound (^> 5% ^ 8 ^ 0 ^ 1) was obtained. TLC: Rf 0.50 / 5%. toluene in hexane, RiA silica gel).

IR / CHCj 3305, 300-7, 2924, 2852, 2096, 1607, 1470, 1448 cm ¹ .

¹ H NMR ^{/ 2} 70 Mir, CIDC ^ / cf ^6, 86 / s, ^1/6, 79 / s, 1 /, 3.39 / s 1A 2.63 / d, ^{2, J} = 6. ⁹ Hertz

2.63 (m, 6), 1.20 (m, 3), 1.00 (n, 2).

Race spectrum / Cl /: m / e 227 / M + H./+

154 878

F. KKisu (S (-4-) ^[[ 2- (cyclohexylmethyl) -4,6-dimethylphenyl-7-methoxyphosphinyl) -3-7C (1,1-imethylethyl) -phtnylsilyl) xxy-7-butane methyl ester.

1.36 g (6.0 mMU) of the actithene compound from part E in 30 m of dry THF in an argon atmosphere cooled at -78 ° C. To a solution of mp-o-aeo 2.4 ml of a 2.5 molar solution of e-butyllithium in htxanite. The mercury mixture of the burgundy color is reduced for 1 hour at -78 ° C. 4.68 g (9.6 mmol) of phosphonochloride Uieu from Part F of Example 1 was mixed with 30 ml of dry THF and cooled to -78 ° C. A solution of acetylene prztcewnikowano -o-phospho solution of ⁿ oc ^h lori- of pregnant ^anu ^ 15 m.nut, part of ^{p y} m ^k cyano mixture rta ⁿ ± miessraro at ^-7 8 ^O C ^p y ^{1 t} h of ^it, the reaction prztrwano -odając saturated with aqueous NH 4 Cl, and the mixture was warmed to room temperature. The THF was removed from the reaction mixture and the resulting carbon dioxide was dissolved in a mp. The aqueous vial was extracted 3 times with ttyloyl ether. The tertiary extracts were combined and washed once with saturated NaHCO3 solution and once with brine, then dried over MgSO4. After filtration and removal of the solvent, an olive oil was obtained, which was obtained in a 3M gradient, which was purified by means of a method of flash chromatograph, with tluoronium with a mixture of ttyluheSan-tolute 3.5: 5.5: 1. 2.80 g / 70% of the title phosphinate was obtained as a clarifier. TLC: Rf? 0.37 (htSstn-toluee-octtn ttylu 5: 1: 4, Tmtmic, PIM).

IR: (CHCCj) 3025, 3001, 2929, 2856, 2164, 1736, 1607, 1240, 1112, 1039, 823 cm.

^{1 H} NMR / 2 ⁷ 0 ^Mh CDDCj / ^{cf 7 6} 6 / m, ^4/7, 30 ^/ m, 6 /, ^{6.87 / s, 2/6,} 81 ^{/ s} V ⁴ , ^{66 / m} , V »

3.70 - 3.66 / -s, 3, J-14.3Hz /, 3.56 / s, 3 /, 2.95 / m, 1 /, 2.69 / m, 1 /, 2.50 / m, 3 / 2.32 / m, 2 /,

2.30 / s, 3 /, 2.27 / s, 3 /, 1.60 / m, 6 /, 1.03 / m, 3 /, 1.02 / s, 9 /, 0.95 / m , 2 /.

Racial Wi-mo / ci /: m / t: 659 / M + H / ⁺

G. (S) -4-Z acid methyl ester [[2- (cySlohtSsylmethyl) 4,6-dimethylphenyl-7-tinyl 7 mm -toxylphosphinyl 7-3-hydroxybutanoic acid

0.633 g (0.96 m. Lime). Acetylene phosphine from part F, a mucilage in an argon atmosphere at room temperature with 14.0 m3. Dry THF. Into the phosphinine-o-ano solution 0.22 ml / 3.84 mmol / l ^ ^^^ o ^ - ^ tth acetic stack, and then add 2.62 ml of a 1.1 molar solution to the solution for 5 minutes. 0 / ^ // NF in TKF. After stirring for 19 hours at room temperature, the reaction mixture was added to ice-water, and the aqueous layer was extracted 3 times with ttyl acetate. Combine the or / ant solutions with 2 times saturated aqueous NaHCO3 solution and once with saturated NaCl solution. The organic layer was dried with Na ₂ SO NA- / and filtered to give, after removal of the solvent 0.658 g of resin Barwite żółttj. After purification with flash chromatography, elution with ethyl acetate and ethyl acetate afforded 0.23 g (65%) of the title alcohol as Sltrowee. TLC: Rf = 0.51 / 6: 4 tcetoe-heSste, ζβΐ Srzemileklwy, PM /.

IR / CHClj /: 3450 / εϋηΚΐ®, 3005, 2926, 2852, 2164, 1733, 1607, 1448, 1439, 1039 cm'1.

¹ HW® / 270 times, ^CDClj /: ^ά 6.89 / s, 1 /, 6.82 / s, l /, 4.63 Λ, 1 /, 3.88 + 3.87 / 2 xd, ³ ,

J = 12Hz /, 3.69 / s, 3 / .2.70 / s, 2 /, 2.62 / d, 2, J = 6.3Hz /, 2.43 / s, 3 /, 2.31 / s, 3 /, 2.27 / m, 2 /, ^1.65 / m, ⁶ /, 1.19 / m, 3 /, 1 ^{, 0} 0 / ną 2 /.

Race spectrum: / II /: m / s 421 / μ + h / +.

H. Sól -wlitowa krosu / S / -4-Z "/ 2- / cycllheSsylonΘ'tslo / -4, —z (jii '_< et, ylphenyloyetyesll7 hydroxyphosphinyl7-3-h-rosysbbuailowe / l

0.212 g (0.51 mmol) of -grastru from part G was stirred in 7 ml of -oxane and -1-tel at room temperature 1.5 ml / 1.5 mmol / 1 N LiOH. The mixture was heated to 55 ° C, and after 20 minutes the precipitated solid was dissolved, giving 5 ml of ioxane and 4 ml of water. After 2.5 go-zines at ⁵⁵ ° ^C rniesz RAE ^rtaSc ^ s ^ hL ^ ^jna zoro tiemperatu ^-o ^ en ojlwej ^s, rozpuszczaldS of deleted ^ro-PO- pressure, and the resulting solid was dried of Barwite białtj PO- high vacuum prztz 15 minutes. The pro-uSt was purified in Solumr.it, 3.0 x 19 cn with a? -? 10 resin, by triturating first with 100 ml of water and then with a 1: 1 methanol-water mixture. After lyophilization, 0.145 g (71%) of the lyophilitate was obtained with a white color.

154 878

Rf = 0.39 (n-pooparo-HH4OH-water 7: 2: 1, silica gel, PM).

IR (KBr): 3700-3100 (sherol), 2922, 2850, 2167, 1590, 1447, 1179, 1076 cm ^-1 .

¹ H -MR / 400 MH ^z, Pr0 ^/ : ₁ f6 ^, 99 ^/ s, l /, 6 ^, 94 / s, l /, 4.53 ^{/ b,} _ l /, 2.64 / m, lĄ 6 ^, 22 / d. 2 "

The room was stirred for 18 hours. The reaction mixture was filtered and the precipitate washed 0Η ₂ 01 ₂ and the filtrate was evaporated under reduced pressure. The residue was dissolved in 350 mL of ethyl acetate and washed sequentially with 250 mL of water, 250 mL of 5-percent. HCl, 250 ml 5% NaOH and 250 ml of brine. Each of the aqueous extracts was extracted with ethyl acetate. The organic extracts were combined, dried over MgSO 4, filtered and evaporated in vacuo to give an orange oil which was azeotroped with 250 ml of toluene, then dried under high vacuum for 8 hours at 55 ° C to give 38.2 g / 139.76 ml. -limli, 90% yield of the title naphthalenamide as a light yellow solid.

TLC: Rf at 0.65 / 100%. ethyl acetate, tertiary gel ( ¹ H NMR (270 MHz, CDCC ₃ ): J 8.19 ('bs, 1 h), 8.14 (m, Lz), 8.03 ⁽ d, 1H, J <8) 7 Hz /, 7.83 / m, 1H /, 7.66 / d, 1H, J88.7Hz /, 7.55 / m, 2h /, 4.00 / s, 3H /, 3.74 / a, 2h /, 1.47 (s, 6h).

MSow spectrum;: CIm / e 274 / M + H / +.

IR (CHHC6 solution): 3365, 3063, 3024, 3005, 2971, 2938, 2873, 1641, 1597, 1540, 1456, 1446, 1387, 1371, 1344, 1291, 1256, 1238, 1223, 1210, 1199, 1183, 1168, 1145, 1079, 981, 833 μΛ

C. 4,5-dihydro-O-2- (1-methoxy-2-naphthaleeyl) -4,4-dimethyloxazole

6 (5.15 g / 40.56 ml, 0.556 mole / thionyl chloride) was added dropwise to every 38.2 g (139 milimol) of Part B naphthaasmide, stirred under argon and cooled to 0 ° C. The resulting dark brown oil was stirred with water. at room temperature for 45 minutes. 500 mL of dry diethyl ether was added and the reaction mixture was stirred idly for 2.5 hours. The yellow crystalline precipitate was filtered, washed with ethyl ether and suspended in 250 mL of diethyl ether. The slurry was cooled to 0 ° C and zrlkαlilewαeo by adding about 200 ml of 10 per cent. NaOH. the aqueous layer was at ^rθ kstrαhoernl three times with ether etyowwym and once with ethyl acetate. the organic extracts were combined, washed once with brine, concentrated, ^ dried over MgSOg and filtered. the filtrate was αzeotroIl> Erel with toluene under reduced pressure, and the residue was dried under low vacuum at 55 ° C for 8 hours to give 32.10 g (0.126 moles) (90%) of the title oxazoline in the form of a golden powder. TLC: Rf = 0, 37/50% ethyl acetate, gel kr zemionko w / · ¹ H NMR ^/ 270 Mh, CDCCg / ^J 8, ² 5 / M, H /, 7.84 ^/ d, 1 J ^- 8.8 Hz /, 7.84 ^/ m in / 7 .60 / d,

1H, J = 8.7 Hz /, 7.54 (m, 2h), 4.19 (s, 2H), 4.04 (s, 3H), 1.46 (s, 6h).

Race spectrum: CI m / e 256 / m + H / ⁺ .

IR: 2969, 2939, 2896, 1642, 1465, 1447, 1386, 1372, 1349, 1255, 1109, 1074, 991 cm- ¹ .

C. Z-C L .- (4-fluoro-enyl) -2erftraeeyoyO7-4, --dihddro-4,4-dimethyloxazole.

30.0 g (117.52 mmol) of Part C oxazoline was stirred under argon in TH 352.5 ml dry. This solution was heated to 45 ° C in an oil bath. The heat source was removed and 158.65 mmoles (79.33 ml) of a 2-molar solution of 4-fluoro-phenylmagnesium bromide in ethyl ether (Aldrich) were embedded within 30 minutes at such a rate as to maintain the reaction temperature at about 45 ° C. After completion of the dropwise addition, the reaction mixture was stirred for 18 hours while maintaining the temperature at 45 ° C. The mixture was cooled to 0 ° C, the reaction was quenched with 200 mL saturated with ^ox-N-c C and then diluted with 200 ml of water and 200 ml of ethyl acetate. The aqueous layer was extracted 4 times with ethyl acetate. The organic extracts were combined, concentrated, chilled over MgSO 4 and filtered. The filtrate was evaporated under reduced pressure to give 39 g of a dark gold solid. The product was purified by flash chrome tografii in a column having a diameter of 95 mm Merck silica gel K ^s head ° oci bed 175 mm, eluting with 25 percent. ethyl acetate in hexane at a linear flow rate of 50 µm min. 30.42 g (95.25 mmol, 81% yield) of the title 4-fluorophenyl substituted naphthalene were obtained as a pale yellow solid, m.p.

Also, 3.38 g (10.58 mmol, 9%) of a slightly impure product was obtained.

TLC: Rf = 0.45 / 50%. ethyl acetate in hexane, silica gel /.

¹ H NMR / 270 Mz, CDClg /: 7,93-7,13 ^yellow / 'aromatic 10ha 3.77 / s, 2H ^/, 1.27 / s, St /.

154 878

Mass spectrum: CI m / e 320 / Μ + H / *

IR (KBr): 3060, 2966, 2927, 2884, 1667, 1603, 1508, 1462, 1383, 1354, 1335, 1293, 1219, 1185, 1160, 1190, 1083, 978, 8 ⁴ 2, 830 cm ^-1 .

E. 2- ^ 1-44-fluorophenes O H -3-methylOo-2-naphthalenyl-7-4,5-dihd < lro-4,4-dimethyloxanol "g (87.67 mmol) of Compound 1-4-fliP ] i-phennlo-2-oxy-2-oxy-raifnylvig from part D was mixed in a togoe atmosphere with 585 ml of dry ethyl ether. This solution was cooled to -25 ° C, and was then horrified for 1 hour with 140.27 milliMtli (56.1 M), 5-molool solution of n-buynolite in hexane. Over the course of this hour, the reaction mixture transformed from Jldnooldnlgo ooztwoou with a yellow bait, after an ooztoo with a yellow bait, up to an ooztooou with an orange-green bait with sediment. The reaction mixture was stirred at -25 ° C for 2.5 hours before adding 37.33 g / 16.4 μm, 263.01 mmol / iodomethal-I over 15 minutes. The resulting dark blue solution was stirred at ~ 25 ° C for 4.5 hours, cooled to 0 ° C and stirred for 16 hours, then warmed to room temperature and stirred for 7 hours. The resulting clear, yellowish ooztoo was diluted by adding 500 ml of ice-cold brine. The aqueous layer was about 4 ^Γe kstoahootno oases with ethyl acetate. The ooganic extracts were combined, concentrated, dried over MgSO 4, and placed through a sintered glass funnel with a capacity of 300 µm and 2/3 of a Florosil preptotte. Florosil was removed from C ^ CCg. The filtrate was concentrated, azeotrolized with toluene and evaporated under reduced pressure, then dried under high vacuum for 3 hours at 55 ° C, yielding 30.32 g (90.94 mmol, 100% of i-tn-Oci) of the title isolated na-talene. as a yellow solid. TLC: R0 &lt; 0.50 / 50%. ethyl acetate / hexane, Sozi ^^ and ^ ^ gel.

¹ H NMR ⁽² 70 MHz, (OCR): ^J 7.79-7.07 ⁽ ao, 9h? 3.80 (s, 2H ⁾ , 2.54 / s, 3h? 1.13 (s, 6h). Spectrum racial: CI m / e 334 / M + H / ⁺

IR (CHCl ₃ , solution): 3013, 2967, 2931, 2895, 2870, 1667, 1605, 1513, 1497, 1461, 1299, 1280, 1235 ^, 1190 ^, 1158 ^, 1041, 965 ^, 841 c ^m_1 .

F. Iodide 2-C l ^ - / - i ^ l.lrl-ee n'l0o / -> ml ^ tnί'l ^, --2e ^ α- £ aae-yy0o // - 4, - d.ihylo ~ 3,4,4trimenyooctil.

29.23 g (87.68 mmL) of the E part oxazoliene was mixed under a trgonl atmosphere in 140.28 ml of nitromethane. Each solution of this solution in one portion is 112 g (49.2 ml), 0.789 mio / iodine. The resulting bruteine reaction mixture was heated at 60 ° C in an oil bath for 1 hour 20 minutes protected from light. Jo-omette was removed by simple distillation. The nitromethane was removed on a rotary evaporator and then dried under high vacuum for 45 minutes. The resulting solid was mixed in a blend of melt-coke with 250 M. of ethyl ether for 1 hour. The filtrate was red-z-ekaetooaeo and the precipitate po-oo-ii was triturated with ethylene ether as it was. The resulting solid with a yellow Barcie filtered and dried under vacuum for oSi® ^s pozez 4 · godziey the absence of light, to give 44 g / 9-, δ3 mural 100% It asked ⁿ -O-t ^c, and / okΞazolinioolgo of title iodide as a substance mulzZtfd-lo-yellow constant. The title compound is unaffected by light at -30 ^° C for 18 hours, then used directly to prepare the compound from Part C. TLC:

Rf = 0.30 ZlO% netanol / CRClg, silica gel /

0.l- / 4-flurroeeyyoo / -3-eeyylo-2-aaftalenkaarbkkyyaldehyde

41.67 g (87.67-yl-ol) oxazolinium iodide from the F part Mesano under argon at-oser in 5-6 -1 dry THF and -10 ML absolute ethanol dried over molecular sieves / A. The resuspension was cooled to -15 ° C and NaSH 3 was added portionwise over 1 hour. After the addition was complete, the solution was stirred at -10 * - -15 ° C for -5 hours, then it was diluted with -10 -L absolute ethanol and initially very slowly, 438 ml (6 /76 -ΙΗ-Ηι / -n HCl) was added dropwise over 45 minutes while stirring at -15 ^° C. After completion of the dropwise addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. After dilution with 500 M water, the aqueous phase was extracted with ethyl ether. The organic extracts were combined, concentrated, with ^EuS o

154,878 over MgSO 4, filtered, concentrated, azeotroped 2 times with 120 mL of toluene and stripped in vacuo to yield 12.9 g (48.81 mmol, 56% vodka / the title aldehyde as a pale yellow solid). TLC: Rf = 0.66 / 50%. ethyl acetate / hexane, silica gel.

H NMR ^{/ 2} 70 Miz, CDCly: 10.0 ^J / s, 1H /, ^{7, 83-7,} 18 / Ai ·, 9HA ^2, 81 / s, 3H /.

Race spectrum: 11 m / e 265 / Μ + H / +.

IR (OK1 solution): 1685, 1512, 1422, 1237, 862 cm1.

H. 2- (2,2-dibromoethenyl) -1 / 4-fluorophenyl) -3-methylnaphthalene

3.0 g (11.35 mmol) of Part G aldehyde was stirred under argon in 113.5 mL of dry OH ₂ O 2 ₂ . R ° ^from this material was cooled to 0 ° and added to. of it in one portion 9.53 g (36.32 mmol) of triphenylphosphine. The reaction mixture was stirred at 0 ° L for 20 minutes, then a solution of 6.02 g (18.16 mMooa) of carbon tetrabromide in 41 mL of dry ₁ HhCl _{2 was} added dropwise thereto over 20 minutes. The resulting dark orange solution turned dark burgundy in color when stirred at 0 ° L for 1 L / 4 hours. The reaction was quenched with 150m of sat. Aq. NaHCOO. The aqueous layer was extracted 4 times with (3) (3) * The organic extracts were combined, concentrated under reduced pressure, washed once with brine, dried over MgSO 4, and filtered. The filtrate was adsorbed onto approximately 28 g of Merck silica gel, and then loaded onto a 50 mm diameter flash column containing a 15 cm layer of Merck silica gel, eluting with 7-paoc ethyl acetate in hexane at a linear flow rate of 5 amine. 4.23 g of the title dibromo-oefin was obtained as a slightly impure yellow solid. Recrritellation from hexane gave 3.68 g (8.77 mmol (77% yield) of the title dibromo-oefin as a white solid powder, m.p. 134.5-135.5 ° O. TLO: Rf = 0.60 / 20% ethyl acetate (hexane, silica gel).

H NMR ^{/ 270} Wiz, ° Χ ° - / ^J Aromtyczne about ^{l ef new} ° 1 h / ^2, 48 JJH /.

Race spectrum: CI m / e 419 / 42.1 / 423 ^/ M + H / *

IR (1) ΟΗΗΟ- / solution: 3016, 1604, 15 1496 ^, 1234 ^, 1220 ^, 1208, 1158, 886, 858 c ^m_1 .

I. 2-ethyl ^^]. O-1- / 4fflorophyll-33-methylnaphthalene

3.69 g (8.7 milliMl) of the H part dibromoefin was stirred under argon in 47.9m dry DIM '. This solution was cooled to -78 ° C and then poured into it for 15 minutes 6.96 m (17.4 mmol) of 2.5 molar n-bulb lithium in hexane (Aldrich). The reaction mixture was stirred at -78 ° L for 1 hour then quenched by adding 40 µL of saturated aqueous WHCl. After warming to 0 ° L, the reaction mixture was diluted with 40 L of water and 40 M of diethyl ether. The aqueous phase was extracted twice with ethyl ether and once with ethyl acetate. The organic extracts were combined, dried over MgSO 4, filtered and evaporated under reduced shadow. As a result of preliminary purification, a young chromatograph! flash on a 50 mm diameter column containing 15 cm Merck silica gel bed eluting with T-percent. Ethyl acetate in hexane at a linear rate of 5 cm / min flow gave 2.32 g of a green oily solid.

H NMR analysis (270 ffz) showed it was an impure product. As a result of repeated purification, the young flash chaoma in a column 75 mm in diameter containing 15 cm of Merck silica gel, soldered with 1%. ethyl acetate in hexane at a linear flow rate of 5 cm / min gave 2.11 g (8.11 ml) of the title acetylene compound, 925% ^as a pale blue solid, m.p. high vacuum for 8 hours / 91.5-94.5 ° ¾. TLO: Rf = 0.56 (20-paoc * ethyl acetate / hexane, silica gel).

¹ H NMR ⁽² 70 MHz, UDO- (:? 7 ^, 77-7 ^, 13 Ar, 9H), 3.18 (s, 1H ^? 2.62 (s, 3H).

MS spectrum: Ol m / e 260 M *

154 878

IR / movie with CH ₂ C1 ₂ /: 3291, 1604, 1512, 1494, 1383, 1222, 1158, 1150, 1092, 884, 871, 853,

825 c ^i_1 .

J. Acid methyl ester / S / -3-TC / 1,1-dlmethylethyl / d.ifenylsilyl / oxy) -4-, L Ct-1b-fluoro-phenyl / -3-methyl-2-naphthalenyloyethynyl / etc ) osyiosfinyl / butane.

5.57 g (8.82 mmol) of the dicyclohexylammonium salt from Example 13 was dissolved in a 1: 1 mixture of ethyl acetate with 5%. KHSO (150 L each) and vigorously shaken. The layers were separated and the ethyl acetate layer was washed twice with 100 ml of fresh 5% KHSOa. Finally, the organic phase is dried over MgSO 4, filtered and the solvent is evaporated off under reduced pressure. The resulting azeltlopowanl residue, with 2 portions of 120 µl of benzene, was evaporated and dried under high vacuum for 2 hours to give 4.33 g (10% yield) of the phosphono ether as a pale yellow viscous oil. The oil was stirred under an argon atmosphere in 24.8 m of dry CH ₂ Cl ₂ and then cropped into it for 8 minutes with 2.56 g (3.34 ml, 17.64 mmol) of distilled alitylmitylsilylmins. This solution was stirred at room temperature for 2 hours, then the volatiles were removed in a rotary jug (under gassing to argon) and the resulting residue was anthinated once with 60 ml of benzene, evaporated in vacuo and dried under high vacuum for 45 minutes. Wymiesn residue "in an argon atmosphere in 24.8 ml of dry CH ₂ C1 ₂ · ² toople DMF was added and the solution was cooled · ^d of about ⁰ ° C 3 in the ^y-m WTA oplono for 1 ⁰ minutes 1.34 g / 0.923 ul , 10.58 mmol / of oxalyl chloride. The resulting amber solution was stirred at 0 ° C for 30 minutes, warmed to room temperature, and stirred for 2 hours. Volatiles were removed and the residue was aziltoopowanl and dried under high vacuum as in AL®J. Finally, the residue was stirred under an argon atmosphere in 27.7 ml of dry THF. The solution was cooled ^d of -78 ° C and wlkoplono ^d for it in ci.ągu ¹ 5 minutes cooled ^{to -} 78 ° ^C of the acetylenic anion solution in THF, and added to the obtained fosfonochloridanu as follows.

1.35 g / 5.19 mmol / jcityienowegl compound of Part I wsmleszano under argon at ^27, 7 ml of dry THF ^and cooled - ⁷⁸ ° C. To this solution ^{and a} cyano l ^{P k} ropli cis ^ 10 minutes at 2.08 mL / 5.19 mJ.imni.a / 2,5-llllowigl solution of n-butyllithium in hexane. The resulting green colored solution was stirred at -78 ° ^C 1.5 ^{g of p} slaughter odzin ^s, warmed ^d of about ⁰ ° C for ¹ 5 minutes and cooled onownie ^{d p} of 78 ° ^C · While maintaining this roztwiśr at -78 ° ^C was transferred it purcjami ^d of the link and a dropping funnel, ^p wkraplarn ^d utry ^^ - ^ of a valid at -7 ° C the obtained solution harness ^f ^ n and o ls ^f oelchllridanu in THF. After the dropwise addition, a ^ nozeniu mesrjein ^ę rea ^k c ^y jna was stirred at -78 ° C for 1 hour, interrupting then quenched by adding 50 ml of saturated aqueous NHhCC, the mixture was warmed to 0 ° C. The reaction mixture was diluted by adding 40 H of water and 40 ml of diethyl ether. The aqueous layer was extracted with 4 portions of 50 ml of diethyl ether. The organic extracts were combined, concentrated, dried over MgSO 4, filtered, and the solvent was evaporated under reduced pressure. Product ^'R Sarellel chromaoggafii by flash column having a diameter of 75 mm containing 15 cm bed of silica gel krzemoi-kiowego Merck using the elrnwania hexane-ethyl acetate-toluene 5: 4: 1 at a linear flow rate of 5 cm / min. The yield was 1.53 g (2.21 mmol, 43% of the avenge of the title acetine phosphinate in the form of a yellow foam. 0.589 g of the organic w / oinner was also recovered. TLC: Rf = O ²⁶ / hexane-ethyl etyto-toluene 5: 4: 1, gel zemionkowy ^ ^p MAA.

¹ H NMR (270 MHz, CDCl):? 7.82-7.09 (Ar, 19K), 4.52 (m, 1H) 3.60 + 3.59 (2xs, 3ϋ) ^,

3.36-3.31 / 2 xd, 3H, J 11.5Hz /, 2.54-2.49 / 2xs, 3H /, 2.87-2.73 Im, 1H /, 2.61- 2.56 / m,

1H), 2.39-2.22 (rn, 1H), 2.12-2.00 (m, 1h), 1.02 (s, 9H).

MS spectrum: CI m / e 693 / M + H / +.

IR (CHCC solution): 3004, 2951, 2932, 2858, 2164, 1735, 1605, 1512, 1494, 1472, 1437, 1427,

U _1

1237, 1197, 1182, 1158, 1151, 1138, 1110, 1105, 1093, ^1038, 1017, ¹ 95, 885, S3 ^{A 4} cm.

K. Methyl / s / 4-C C ^- l- / 4-fluoro-phenyl / -3-myths ^II - ² -on ^{e f} talenylo./ety YLQVNSLQTV / metoksyfosfiny0o7 --- Sddnoksybutanowego.

To a solution of 0.60 g (0.866 mmol) acetinine phosphinate from part J in 10.5 ml dry THF, m.isrjnegl under argon was added 0.208 g (0.198 ml, 3.46 mmol) of ice cold.

Acetic acid, then 2.36 ml (2.60 mmol) of a 1.1 M solution of tetrabutylammonium fluoride in THF was added dropwise. The reaction mixture was stirred at room temperature for 24 hours, then quenched with 25 mL of ice water and the mixture was diluted with ethyl acetate. The aquatic vegetable was extracted 3 times with ethyl acetate. The organic extracts were combined, washed once with saturated aqueous NaHCO- and once with brine, dried over MgSO 4, filtered, and evaporated under reduced pressure. The product was purified by flash chromatography using a 30 mm diameter column with a bed of Merck 35: 1 silica gel, eluting with ethyl acetate at a linear flow rate of 5 cm / min. The yield was 0.267 g (0.588 millimoles, 68% ^^ Ο ^ ι ^ ι) of the title β-hydroxy fossil in the form of a pale yellow barrn.e foam. TLC: Rf a 0.28 (ethyl acetate, silica gel, PM).

¹ H NMR ^/ 270 MH ODCj / ^ 7,81-7,18 ^/ / r, 9H /, 4.33 / b, 1H / ^3, 71 ^/ s 3HA ^{3,59-3, 58/2} xd, 3H, J = 12Hh), 2.66-2.65 (2xs, 3h), 2.62-2.52 (m, 2h), 2.19-1.92 (s, 2h).

Usual spectrum: CI i / e 455 / Μ + H / +.

IR / film /: 3380 / wide /, 3065, 3048, 2993, 2951, 2166, 1738, 1604, 1513, 1495, 1457, 1438, 1423 ^, 1401, 1385 ^, 1378 ^, 1334, 1299, 1222 ^, 1179 ^, 1160, 1138, 1095, 1035 ^, 951, 887 ^, 836 cm ^-1 .

L. Acid salt / s-4- [[[l-faiίt \ lΌriiinf \ l> - ~ --li ^J tf'LO / 2-i &ftaL..eny'lo]etfJi.f'Lo] hydroxypofinyl / -3-yydroxybutane p.

0.265 g (0.583 ml) of the diester from part K was mixed in an argon atomizer in 6 g of dioxane, followed by the addition of 1.75 H (1.75 mmol / ln LiOH). The reaction mixture was heated to 70 ° C in an oil bath for 45 minutes and then cooled to room temperature. The solvents were removed on a rotary evaporator and the residue was dried under high vacuum for 1 hour. The resulting white solid was dissolved in 4 H of deitized water and applied to a 2.5 x 17.0 cc column with HP-20 saturated with water. The column was eluted with 250 H of water followed by 45:55 methanol-water. Fractions at approximately 10H were pooled every 1.3 limits. The product fractions were evaporated under a pressure of

35 ° C, freeze-dried and dried over P 2 Og under high vacuum for 8 hours to give 0.257 g (541 µl, 93% in equilibrium) of the title phosphinic acid diethium salt as a white lyophilisate.

TLC: Rf 0.40 (n-pooallol-HHOHOH-equa 7: 2: 1, silica gel, Pm).

¹ H NMR ^/ 400 MHz, D ₂ 0 ^{/ f} 7.88 M, 1H, J = 8.43 ΗζΛ 7.80 ^/ s, 1H ^/, 7,58-7,29 pharmaceutical · 7 hectares 4.14 -4.05 (m, 1H), 2.61 (s, 3H), 2.43 (dd, 1H, J = 3.67 Hz, J-15.39 Hz), 2.21 (dd, 1H, J = 9.16 Hz, J = 15.39 Hz /, 1-84-1-67 / m, 2h /,

User video: F / B i / e 439 / m + 2Li / ⁺ .

IR (KBr) 344 --- 260 (wide), 3066, 2164, 1594, 1512, 1495, 1434, 1222, 1183, 1160, 1071, ⁸³⁴ cm ^-1 .

/ analysis for C23H., gOjPLig + 0.66 R0; usa cząs ^ - ^^ zk ^ i ^ wa 450.14.

Wyiczmo: C 61.38; H 4.33; F 4+, 2: 2; P 6.88

Found: C 61.3S; H 2.07; F 4.42; P δ ^ Ο.

Example XV. (3) (44-) ^- [[3 '- (4-phthalophenyl) ypirl) cyclopeitoyl-1- 1' - / H // inder J4 --- yOoyetinyl./hydroxyphosphinflo) --- phydoxybutanoic acid salt, salt.

/. - (4-ft10rofenflo) -HH-indei

A solution of 6.61 g was added dropwise to the solution of broine 4 / fluoroiphyliragnesium - obtained from 6.4 + 3 gel 4 - ^^^ 06 roeobenzene and 1.71 g of Mg in 50 H of ether at room temperature, under argon atmosphere, a solution of 6.61 g was added dropwise within 40 minutes. / 50 eilieooi / 1 / indent in 20 H of dry ether. After stirring at room temperature for 1 hour, the reaction was quenched by dropwise addition of 15 µl of saturated NRCC solution. The mixture was diluted with ethyl ether and washed with saturated NaCl solution, dried over MgSO 4 and evaporated.

The residue was dissolved in 15 µl of glacial acetic acid and refluxed under argon through the acetic acid evaporated and the residue was wasotroped twice with toluene. The residue, 9.45 g, was purified by flash chromatography

154,878 silica gel, eluting with hexane to give 8.174 g (78%) of the title compound as a colorless oil which crystallizes over time to form a material, mp 38-4O ° C. TLC: (hexane): Rf = 0.21.

B. 3 '- / ^ 4ł- ^ jm ^ c ^ ro> phenyl / spiro / cy ^^ op ^ nnar ^ nol, l' - ^ lH / in ^ d.en /

To a solution of 10.676 g (50.8 mmol) of Part A compound at 90 ° C. of dry THF at 0 ° C under argon, 12.2 g (109 mMol) of solid potassium tert-butoxide were added portionwise.

After stirring at 0 ° C for 30 minutes, 6.50 ml / 101 ml of 1, 4-dibromobutane was added dropwise. The resulting mixture was warmed to room temperature, washed for 2 hours, then 150 ml of ethyl acetate and 5% of ethyl acetate were added each time. KHHO ^. The organic phase was washed with saturated NaCl solution, dried over NaSO 4 and evaporated to dryness. The crude product was purified by silica gel flash chromatography eluting with hexane to give 9.43 g (70%) of the title compound as a colorless oil. TLC (diethyl ether-hexane 1: 9): Rf 0.69. Rf of the compound of part A = 0.63.

C. 3 '- / 4-fluorophenyls / sleeping / cyclopennannsl, 1'-1m / iIdien 7-2'-carboxS5raldehyde

To a solution of 9.30 g (35.2 mmole) of Part B compound in 50 ml of dry CR6C6 at 0 ° C under argon was added 70 ml (70 mmIoL) 1.0 M solution of TiCl 3 in (C 2 g 3 To the resulting dark green solution was added dropwise 3.50 mL (38.7 mmol) of 1,1-dichloromethyl methyl ether After stirring at 0 ° C for 1 hour and at room temperature for 1 hour, the mixture was poured into a cold, saturated NaHCOo solution. The organic phase was separated, dried over NagSO 4 and evaporated to dryness The crude product was purified by flash chromatography on silica gel eluting with 5:95 ethyl ether-hexane to give 8.233 g (80%) of the title compound as a yellow oil. Crystallization of the oil from hexane gave 6.778 g (6%) of pure title compound as yellow crystals, m.p. 116-117 ° C. TLC: Rf 0.56 (ethyl ether hexane 15: 85?).

Analysis for C20H170F:

Found C 82.77; H 5.86; F £ 5.50

Found: C 83.33; H 5882; F 6.29.

D. 8'-etynlls-3, - / 4-fluoΓOphenyl / splro- / clklopenntkn-1, l '- / H / irdlen /

To a solution of 0.672 g / 6.00 milimooi / potassium t-butoxide in 8 ml of dry THF at ^-78 C under argon was added dropwise a solution of 0.960 g / 6.40 milimoSa / diazomeeylofosfonianu dimethylsulfoxide / otnymanego according to J. Org. 36, 1379, 1971: / in 4 ml THF. After stirring at -78 ° C for 5 minutes, a solution of 1.163 g / 4.00 of the compound from a portion was added dropwise over 10 minutes.

C in 8 ml THF. After being stirred at -78 ° C for 3 hours, at -45 ° C for 1.5 hours and at room temperature for 1 hour, the mixture was diluted with 50 mL of hexane and washed with 5%. KHSO4 solution. The organic phase was washed with saturated NaCO solution, dried over NagSO 4 and concentrated to low volume (not to dry). The yellow solution was flash chromatographed on silica gel eluted with hexane. The product containing fractions were combined, treated with 0.080 g (0.36 µmol) butylated hydroxytoluene (BHT) and concentrated to a low volume (5-10 m 3), which solution was used immediately in the next step. TLC:

Rf = 0.57 (diethyl ether-hexane 1: 9).

^ ^{H NMR / 270} ffih, ^{O Oi} DC / ^using BHT I ^k of the pattern wewętrznego / 1.45 p ^{p m,} LBH s /, was the presence of 3.10 mmol / 77.5% wll ^and knęSśi / desired compound acetylnnowego (3.32 ppm, 1H, s).

E. Karst mitis ester (s) / -4-Cci-Sosoyethoxyfoεfiilio / -3- / C / 1,1-dimethylsilyl / diphenylsilyl /oxy /--uaanovegs.

The title fosfoęochisridaę prepared from 3.44 g / 54.4 miHiMla / j dicyclohexylamine salt Part B of the method described in Part J of Example, starting from the following quantities: 1.36 mL / 10.85 yl.iy) 0 ^ / ^/ ariyetylosiliOo- dialyOαimine, 15 ml CH2C12 »

0.50 µ (5.73 mmol) of oxalyl chloride, 1 drop of DMF, 15 mL of CH22C2.

154 878

F. Acid methyl ester (S) (-3-CC) 1,1-dimethylethyl / diphenylsilyl / oxy) -4- [C fluoro / feyy0o / spaocycycopentyl-1,1 * -IhIindene] -Z6-yl] tl-yy0 .o. 7raetoxyf (sfinyl) butane.

A solution of the tetylene compound from Part D in hexane (3.10 millimolts - 0.36 millimolts of Bffi) was diluted with 15 mL of dry HF and cooled to -78 ° C under argon. To this solution was added dropwise using a syringe - 16 ml (3.46 mmol) of a 1.6 M solution of n-butyllithium in hexane. After miesztniu at -78 ° C for 45 minutes, the solution was transferred TNJ ^^ nu zt with cewnikt to a cooled -78 ° ^C solution of 54.4 milimolt fosfonochloridayu of Part E in 15 mL of dry / HF. After mieszeniu at -78 ° C for 1 hour retkcję przelotno wkraplLając 15 m. Nasycoytgo ^N-C H C, and m.esztninę / lawn / to room temperature. Methyl ethyl acetate, extracts washed sequentially with 5%. KHSO6 and saturated solutions of NaHCO3 and NaCl, wetted with NagSOc and dry. The crude product (purified) by flash chromatography is silica gel, eluting with ethyl acetate-cexm -5: 75 to give 1.781 g / 8% based on the compound in the DI part of the title compound as a pale yellow glass. / LC. Rf = 0.46 (tcetone-hexy 1: l).

G. Isl-hC acid methyl ester [C 3 '- (4-ftuo] rofeyyl / splro / -cycl) pental-1,1' - / H / / indene / -2-yl7eelny / o / methoxyphosphinyl / 4 - yddoxybutane

To a solution of 1.00 g / 1.39 ΕίχΟσ] !! / Part F compound in 5 ml dry / HF at room temperature, under argoy, 0.3 ml / 5.59 mmol / glacial acetic acid and 3 , 80 m (4.18 mmol) 1.1 M solution (nC? H 8)? NF w / HF. After stirring at room temperature for 18 hours, the mixture was diluted with 50 mL of ethyl acetate, washed successively 3 times with 30 mL of 1 N HCl and once with saturated NaCl solution, dried with radium NaCl, and stripped to dryness. The residue was dissolved in -0 m. Of diethyl ether, cooled in an ice bath and an excess of ethereal ditzomethane solution. After evaporation of the ether, the residue was purified by chrome-10 / flash to silicate gel with gel. 3: 7 aceto-hexane to give 0.595 g / 89 µl of the title compound as a colorless glass. / LC: Rf = 0.19 / lcet / n-hexn 1: 1 /.

H. Acid diglite salt / 3 / -4- / ^- Z'Z''3 '- / 4-Ot / orophenyl // spiΓo / cycle / pentanool, l'-0-H / iralene / --- yl // ethyoylo 7hyda / xyphosphinyl / 733-hydoxybutane.

To a solution of 0.580 g (1.0 mmole) of Part G compound in 6 ml of dioxstne at room temperature in tmosphease trgoyu d / don (4.m) / 4.Z mmole / ln LiOH. After stirring at room temperature for 3 hours, the mixture was diluted with -0 ml of tcttonitrile, the precipitated tritonitrile was filtered, washed with tcetitrile and dried under reduced pressure to give 0.670 g of the crude title product as a white solid. The crude product was suspended in 10 ml of water and put into a short head of a 35 mm diameter column with a 15 ml HP-20 bed, using first 300 ml of water and then 300 ml of eeeanolt for the oxygenation. Product containing fractions were combined and drained. The solid residue was triturated with acet (nitrile) to give 0.550 g (90% of the title) compound as a white solid, mp (nitrile 3O1-3O3 ° C and decomposition). (LC: Rf = 0.48 (isopa (panol-concentrated NHGOO-aqua 7: -: 1)).

Claims (2)

Patent claims I. The method for the preparation of new phosphorus-containing 3-hydro acids (kSl-butane) of formula 1, in which R is a hydroxyl group or a lower oxy group, Z is a 1 - 2a -h group of formulas 7, 8, 9, 18, in which R, R, R and R are of the same or different type and are each non-oxygenated to hydrogen, halogen, lower elkyl, chlo (aowcc) -lkyl, phenyl, substituted phenyl, or the group OR, where r0 / zntcza ttom of hydrogen, aOkano / l, benzoyl, phenyl, halophenyl, phenyl / -lower tlkyl, lower tlkyl, cinntmyl, 01 ^ 1 ^^ 0 ^ -1 ^ 1, tllyl, cycloaOkil / -lowszl ιΙΠΟ, ldaιMltylO / lower thkyl, or substituted phenyl-lower tlkil, and przyCC * '^ p where Z ozticzi to a group of the formula 18, R and plants are STME or different and represent ttom wo ^{d / au,} lower tics ^y! ° .ub an ^O H ^rO ozticzi December ^EP Formula 19 ^j such tk of formula ^{E -} 0 l ^u b 154 878 aryl-CH -, -, R ^-a is lower alkyl, hydroxy, keto or halogen, q is zero, 1, 2 or 3 and R is hydrogen or lower alkyl, and when Z is 3 Z a group of formula 9, in which one of R and R is a group of formula 21, in which R 1 - is hydrogen, lower alkyl, lower alkoxy (except 1-tert-butoxy), halogen, phenoxy or benzyloxy group, R is hydrogen, lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy, R is hydrogen, lower 13 alkyl, lower alkoxy or halogen, provided that if R is hydrogen both R and 1 For 1A 1Zq R must be hydrogen if R is hydrogen, R must represent hydrogen wo ^d orw no more than one of R ^{and R 1 Z} represents ^1j 'triójfLtuorometyl no more ^that jióen n with ^R1 and. 14 1314 R is phenoxy and no more than one of R and R is benzyloxy and the other is lower alkyl, cycloalkyl or phenyl- / α · Η / _η where p is zero, 1,2,3,1bb 4, R is m 2 hydro, C 1-6 alkyl, C 1-6 cycloalkyl, C 1-4 alkoxy with the form of tertiary butoxy /, tri-l, c, r, r, f, f, f, fluoro. , chlorine, phenoxy or benzyloxy group, R- is hydrogen atom, C1-4alkyl, C1- yloxy, trifluoromethyl, fluorine, chlorine X>Χ> QQ or a phenoxy or benzyloxy group, except that if R is a hydrogen atom, R must be a hydrogen atom, not more than one of R and R is trifluoromethyl, not more than DQ 8 9 one of R and R represents a phenoxy group and no more than one of R and R represents a benzyloxy group, R ^X represents a hydrogen atom or a lower alkyl group in the form of a free patch or in the form of a physiologically acceptable and hydrolysable ester or in the form of a salt, characterized in that the acetylene phosphine of formula II, in which Z is defined above, in a manner known per se, in particular by the action of ice-acetic acetic cross and z-butylaoonium fluoride, to form a silyl ether group with the formation of a divider of formula III and, if necessary, to convert it to a ratio of 4, a basic salt of formula 5, a general salt of formula 6 or the corresponding dihydrogen salt of formula 1. 2. A method for the preparation of new phosphorus-containing derivatives of the looms 3 - ^^ dok ^ y ^ - ^ l ^ i ^ '^^ and ^ o ^^ g ^ o with formula 1, where R is a hydroxyl group or a lower coxy group, Z is a group of formulas 10, 11, 12, 13, 14, 15, 16 and 17, where when Z is a group of formula 11 12 ¹ 3 ¹⁴ and ^16, one of R ^{- and} R is ^{a group} of formula And the second is lower alkyl, cycloalkyl, or a phenyl-OJ / C 1-6 H - / - group in which p is zero, 13, 1, 2, 3 or 4, R is hydrogen, lower alkyl, lower alkoxy (except ΙΙΙ-γό). ^b utoxys /, c ^hl orlwiec ^, group fino ^k s ^y looą tob ^b izzyll ^k s ^yI ow ^ą , R ^1ił means atoo w> doru ^{, then} 14a Lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy, R represents a volume-wodon than ¹ s ^{f s} al ¹ !! n-st altoltsyl ^{l b} c u ^{hI orowiec,} zt ^Y, if. R ^1j is atom 14 14 ₁₄ 14 are both hydrogen and R euszą be hydrogen, when R is hydrogen, R 13, 14 must be a hydrogen atom, not more than one of R and R is trifluoromethyl, not more than j ^ en R ^1j and ^{R 1 Z} 'semitraile ^g ru ^{PE f} ene ^k s ^y lowa i. No more than one of R ^{1j and} R ^1Z 10 11 represents a benzyloxy group, R and R are each independently hydrogen, alkyl, cyklo13 14 ₁₄ alkyl, N Mantua, or R 22, wherein R, R and R Oja in ^ above defined znacze10 not aq is zero, 1, 2, 3 or 4, Y is oxygen, sulfur or NR group when Z is a chip 15, R is vol, H -alkyl, C1-6Cycloaalkyl, alkoxy / z except for III tertiary-butoxy /, trifluoromethyl, fluorine, chlorine, phenoxy or bezzyloxy group, R is hydrogen, // - ^ ΖΧϊΙ, C1-alkoxy, trifluoromethyl, fluorine, chlorine or phenoxy or benzyloxy group with with the proviso that when R @ is 9 8 9 atoo wdiori, the R axes are not more than one of R and R 7 is tri-fluoroethyl, no more than one of R and R is phenoxy, and no more than 8 9 with one of R and R ^J is a benzyloxy group, R is hydrogen or pierwrszorzędową or secondary Ci / omicron alkyl, R b is a primary or secondary Ci / _- ^lo alkyl hose tob ^RZ + ^Rb "are grnpę - ^{// H} ? ^/ _- ^l u ^b ci - CH -> - ^H H ^ ^/ H-CH ⁰ - ^, γ is 2 3 ^{, 4} 5 l ^u b 6, R1 is lower alkyl, cycloalkyl, or a group of R 21, R, R and R ¹ in Imja ^ given above ^refers, in Γoy ^{p p} u and ^dk when Z ^ racra ^of guano in ^ (^ .-- ¹⁶ with ^{R 1 j} r ¹ ® obydro racra ^ ^ hydrogen, chlorine, bromine , CN, CF-, phenyl // - allyl / ₂ _galkoksykarbozyIową. 154 378 17 18 17 1R -CHgOR or -CHgOCONHR, R 'is a hydrogen atom or a C 1-8 aUk1, R is an alkyl or phenyl optionally substituted with a fluorine, chlorine, bromine or C-, -alkyl group, or 1R IA 1Q I R ⁵ and R ⁶ together form the group - / CH ³ /, -, -CHo-O-CH? -, -CON / R ^{9 /} CO- or -C0N / R ^2U / n / r / C0-, s 19 eccc 20 21 is 3 or 4, R is hydrogen, C, Uk1, phenyl or benzyl, R and R are xo 22 hydrogen, or benzyl, when Z is a group of formula 17, R is lower alkyl, cycloaakyl, adamatyl -1 or a group of formula 23 in which t is 1, 2, 3 or ⁴ , ^R2a f. R ^2aa S ^{a t} a ^k e same rfone and soldered. ^{Eac h} each independently ^^ e is hydrogen, lower alkyl, lower alkoxy / z wjątkiem tert.-butoxy /, halogen, or fer.oksylową ^ ^^ words nzylo ^with the proviso that when R ^2a is hydrogen, R ^2A8 MMSI hydrogen, not more than one of R and R is trifluoromethyl, not more than one of R, and 23a 23 23a R is phenoxy and no more than one of R and R is benzyl xyl, R is hydrogen or lower alkyl as a free cross or in the form of a physiologically acceptable and hydrohzing ester or in the form of a salt, characterized in that the acetylene The silH ether group is split off in a known manner, especially by the action of glacial acetic acid and n-butyooammonium fluoride, to give the diuretic of the formula III, in which Z is as defined above, and, if necessary, it is converted to a moltoether of Formula 4, a basic salt of Formula 5, a dibasic salt of Formula 6 or the corresponding dicrosal of Formula 1. ABOUT H. R-P-Hjf-OI -OHrCCj R * - ^OH c 2 Formula 1 1) Cleavage of the silyl ether (n-C ^ Hgl ^ NF, ObGOOH, THF HO 2) Hydrolysis (LiOH, dioxane) o P-CH ₂ CH CH ₂ every ₂ hours oh c I z Formula 1a O alki l - O - P - - ^ - -H - GH ₂ - -O2 alkylc = c δ. and Sr-CtCH ^ cX \ h ₅ Formula 2 154 878 Ο Ρ - CHj CH - - CR-CO2alkyl C OH 1 c AND 2 0 Formula 3 II C ^ CH CH ₂ CO ₂ H alkyl- O-P | C. ^About H. 0 m C. AND WITH PATTERN 4 alkyl - O - P - CR- CH - CR- CO ₂ - R ^w C OH m C i Z Formula 5 o R * a opg ^ -cH -Cty-COjR * ^{0 O} H n c i Formula 6 154 878 Formula 13 R6 I ii lower alkyl - C - Pattern 19 sts CH3— QL-C-C / \ CHj R ^ł Formula 20 Formula 17 - (CHj) t- <O> = r Rs Pattern 26 Pattern 23 154 878 * 6 S 4 31 2 1 CH OI C CH COOH I and OH OH R ⁶ - C r * -ch I <^ ₂ chch ₂ coor ₇ OH OH CH, CHj 8 7 6 5 c = c-c = c I and R ₂ R3 Pattern 39 - (CH ₂ fy (CH 2, q = c H. Pattern 40 154 878 H. ABOUT Pattern 46 17 19 Pattern 53 154 878 CH-CH ₂ -C-CH ₂ -COOH I and OH OH Pattern 54 Tuesday 63 ^ 2 0 AD I SI 7 ^ * 1 r, ooc-ch ₂ -c-ch ₂ -p. OH OR Pattern 59 II PCRCHCRCO ch ₃ ź AND OH Pattern 65 E i WITH Pattern 60 154 878 R * Scheme 1 154 878 C 'H _S OSi - 00,), j ( ^C C »H _s alkyl- O - P -C, - CH - OH, -CQ, oll <and! ^P (0- alkiO, ^Ó atkj, oh, ciC ^ łj 1. (0,1, SiBr, CH, Cl, 2. H, 0__ The soap is not a phosphorous ester QH _S c ₆ h ₅ Formula IV HOP-Wj-CH-CH, -COjalkllOH Oolkyl-O-pCH-αHcO3cCOjalkite OH O Si-C (CH,), X \ ^C e ^H s ° H ₅ Secondary VI ^ ClOS2, (HS OHs Formula V olkanol-tCC pyridine Scheme 2 1) (CH ₃ ^ SN (C2H ₅ ) ₂ (rMSNEt2) 2) (COCl fc; CH ₂ C! ₂ acid formation VI O alkyl-0 ~ ^p I a CHO AND WITH VIII CB ^{4 ph} 3 ^p # Declarative Wlttg IX t | nB 2) H ₂ O BuLi ch ₂ -ch 4 i O ^ h-00HA C * H _$ CjHs VII C -ch of x 1 pharmaceutical ion Li (n BuLi, THF) 2) candensation from VII --— alkyl- O - P -CH ₂ CH - CH ₂ - CO2alkyl C = C AND From "Sr-CiCH ^ Scheme 2 .2 CjH ₅ XI Department of Publishing of the UP RP. Circulation 100 copies Price: PLN 3,000