DE2528070A1 - 9-THIA-, 9-OXOTHIA- AND 9-DIOXOTHIA- 11,12-SECOPROSTAGLANDINE - Google Patents

Description

The invention relates to new 9-thia, 9-oxothia and 9-dioxothia -11,12-secoprostaglandins of the general formula I

^ -CH-CH ₂ -Y-CHg-A-CH ₂ -R (I)

CH ₉ -ZCC (R ^) ₉ -R ⁵ R ^

in which R is a carboxyl group, a carboxy salt group (where the salt-forming counterion is a pharmacologically acceptable cation, e.g. a metal, such as an alkali or alkaline earth ion, an ammonium ion or one of amines, such as primary or secondary amines, e.g. methylamine or di-methylamine, or quaternary represents ammonium hydroxides such as tetramethyl or tetraethylammonium hydroxide, cation derived), a carbalkoxy (-COOR), wherein R is a Cj_ ₁₀ alkyl radical, a carbamoyl group (-CONH _2). a substituted carbamoyl group (-CONR R), where R and R are each a hydrogen atom, a C - ^ - alkyl radical or a di-

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-lower-alkylaininoalkyl radical having 4 to 7 carbon atoms, or a Garbazoylgruppe (-CONHNH ₂ ), A represents a methylene group (-CHp-) or an oxygen atom (-O-),. _HH

Y is an ethylene group (-CH ₂ -CH ₂ -), a cis-vinylene group (-C = C-) or an ethynylene group (-C ^ C-), η has the value 0, 1 or 2,

R is a methyl, ethyl, 2-hydroxyethyl, 2- (lower alkyloxy) - means ethyl or vinyl group,

Z represents an ethylene, vinylene or ethynylene group,

ρ
R is a hydrogen atom or a methyl group, R is a hydrogen atom or a C ₁ , - alkanoyl radical,

4th
R represents a hydrogen atom or a methyl group and

5
R is a C, g-alkyl radical or branched alkyl radical.

With regard to the general formula I, the following should also be noted:

5 2

If R is a straight-chain alkyl radical and R is a methyl group, can be the terminal carbon atom of R with R (if one hydrogen atom is omitted) to form a carbocyclic Be linked to a ring having 6 to 9 carbon atoms;

5 2

if R is a straight-chain alkyl radical and R is a hydrogen atom

5 can represent the terminal carbon atom of R with the the radical OR bearing carbon atom to form a carbocyclic Be linked to a ring with 5 to 8 carbon atoms.

5 5a 5a

Furthermore, R can represent a radical OR, where R is an alkyl radical, a branched C ₂ _, - alkyl radical, a substituted alkyl radical, for example a 3,3,3-trifluoropropyl group, or a nitrogen- or oxygen-containing 5- or O-membered heterocyclic ring, for example a pyridyl, puryl or purfuryl group or a phenyl group which can have one or two substituents in the form of halogen atoms or methyl, methoxy or trifluoromethyl groups.

The 11,12-secoprostaglandins are preferred according to the invention general formula II

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^> 252807Q

.CH ^ / CH ₉ / COOH ^A ^ ^UyiU

¹ ^ Y-CHj ^ CHg (II)

Hp-Z - ^ - C (R ⁴ ) _? -R ⁵
R ^ OH

in which Z represents an ethylene, vinylene or ethynylene group, R and R have the meaning given above, Y is an ethylene, cis-vinylene or ethynylene group and R is an alkyl radical, a branched C ^ ^ -alkyl radical, a vinyl or

5a 5a

4,4,4-trifluorobutyl group or OR where R is the above

has given meaning.

It should be noted that the carbon atom bearing ^{the radicals R and OR J is asymmetric.} The invention includes the stereoisomers in which this asymmetric center is present exclusively in one or the other of the two possible configurations (R and S).

The compounds of general formula I are because of their structural relationship to the naturally occurring prostaglandins referred to as 11,12 secoprostaglandins.

The compounds according to the invention represent active pharmaceutical ingredients When administered orally, they are effective against diseases which also affect naturally occurring Address prostaglandins. The compounds of the invention are useful for the treatment of various skin diseases such as Psoriasis, atopic dermatitis, non-specific dermatitis Irritant effects can be attributed to the forms of dermatitis, externally caused, allergic Dermatitis, scaly skin cell carcinoma, lamella, ichthyosis, epidermolytic hyperkeratosis, sun exposure premalignant keratosis, non-malignant keratosis, acne and seborrheic dermatitis in human medicine as well as atopic Dermatitis and Mange in Pets.

Certain compounds of the invention have a particular one Efficacy to inhibit collagen-stimulated platelet agglomeration and are therefore suitable for preventing the

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Thrombus formation. Furthermore, certain compounds of the invention - both for in-vivo and in-vitro tests - a special one Demonstrated effectiveness in promoting pituitary growth hormone secretion. Compounds that result from the said tests Prove to be active, are suitable for stimulating the release of growth hormone in hypophyseal hypofunction.

The compounds of the invention can be used either topically or systemically, i.e. intravenously, subcutaneously, intramuscularly, orally, rectally or administered by aerosol therapy or in the form of sterile implants with long-term effects.

The medicinal preparations can be as sterile, injectable suspensions or solutions or as solid, orally administrable, pharmaceutical compatible tablets or capsules are present; the preparations can also be for sublingual administration or in the form of Have suppositories. To ensure easy and convenient administration and uniformity of the dosage, it is particularly advantageous to prepare the drugs in unit doses. Under "unit doses" are for veterinary and Human medicine to understand physically separate units suitable for human medicine, each containing a certain amount of active ingredient, which is dimensioned in such a way that it leads to the desired biological effect in the context of the respective therapy.

The medicinal preparations (aqueous or oil based) are preferred made at concentrations ranging from 2 to 50 mg / ml. Lesser ones Concentrations require unnecessary amounts of fluid, while concentrations higher than 50 mg / ml are difficult to maintain are better avoided.

Because of their gR-ringpn Hfirrr ^ 11imgpT <nKteri and Iprinhtm ifoffirglirJhVmt recommend the compounds according to the invention are especially suitable for use in veterinary medicine, where their possible applications are those are comparable in human medicine.

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Process for the preparation of the compounds according to the invention A preferred group of the compounds according to the invention has the general formula Ia

R ¹ -S (O) _n -CH-CH ₂ -Y-CH ₂ -A-CH ₂ CO ₂ H

CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵ (Ia)

R ^ OH

in which R, n, Y, A, Z, R, R and R each have the above Have meaning. This general class of compounds is synthesized by three main methods.

The first synthetic method is suitable for making a preferred one Subgroup of compounds which have the general formula II

R ⁹ -S (0) -CH-CHoCHoCHoCHo-A-CHo-COoH

CH ₂ OH ₂ -CH ₂ -CH-C (R ⁴ ) ₂ -R ¹⁰ (II) OH

in which A, R and η each have the meaning given above

α
have, R ^{y represents} a methyl, ethyl, 2-hydroxyethyl or 2-methoxyethyl group and R is an optionally branched C-, g-alkyl radical or a 4,4,4-trifluorobutyl group. This process consists in principle in that di-tert-butylmalonate in any order in the presence of sodium hydroxide with a halogen-substituted ester of the general formula III

X-CH ₂ -CH ₂ -CH ₂ -CH ₂ -A-CH ₂ -Co ₂ R ¹¹ (III)

in which X represents a halogen atom and R represents an ethyl or TIethyl group means, as well as with a compound of the general formula V

X-CH ₂ -CH ₂ -CH ₂ -CH-C (R ⁴ ) ₂ -R ¹⁰ (V)

OCOCH ₃

alkylated and the resulting appropriately substituted malonic acid ester of the general formula VI

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(tert-C ₄ H ₉ O ₂ C) ₂ - ^ r ⁴ , ₄ χ 10 ^(VI)

⁴ * * ^ ( ⁴ ) R ^υ

₂₂₉

OCOCH ₃

in the presence of a strong acid (p-toluenesulfonic acid or sulfuric acid in an inert solvent) heated, with Elimination of isobutene and carbon dioxide is the key intermediate of the general formula VII

HO ₂ C-CH- (CH ₂ ) ₄ -A-CH ₂ -CO ₂ -R ¹¹ (VII)

CH ₂ -CH ₂ -CH ₂ -OH-C- (R ⁴ ) ₂ -R ¹⁰ OCOCH.

forms. The carboxydiester VII is then reacted with red mercury (II) oxide and bromine in order to replace the carboxyl group with a bromine atom. The bromine derivative obtained is then reacted with a lower alkyl mercaptan in methanol or ethanol to split off the bromine substituent, a derivative of compound II being formed, the hydroxyl and carboxyl functions of which are protected by esterification. The alkylthio derivative is then subjected to alkaline saponification (with dilute NaOH or KOH in methanol, ethanol or tetrahydrofuran), a compound according to the invention from the preferred subgroup having the formula II (n = 0) being obtained. This thia derivative II is then converted into the corresponding oxothia derivative II according to the invention (n = 1) by oxidation with sodium metaperiodate in dilute sodium bicarbonate solution or with hydrogen peroxide (30 percent aqueous H ₉ O ₉ ) in a solvent, e.g. ethanol, isopropanol or acetic acid, into the dioxothia derivative II ( n = 2) transferred.

The second synthesis method is particularly suitable for production another preferred subgroup of compounds, i.e. those having the general formula XIII

R ¹² -SO ₂ -CH- (CH ₂ ) 5CO ₂ H

CH ₂ -ZPC (R ⁴ ) ₂ -R ⁵ (XIII)

2 *

R ^ OH

6 -

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in which Z, R, R and R each have the meaning given above

12th
have direction and R represents a methyl or ethyl group.

In these processes, an alkylsulfonyl derivative of an azelaic acid diester is alkylated under alkaline conditions with a substituted halogen ester or ether and the alkylation product is decarbalkoxylated by heating, giving a derivative of compound XIII whose hydroxyl substituent is protected by an alkanoyl or benzyl group and whose carboxyl group is protected by esterification . By mild alkaline hydrolysis and / or
Hydrogenolysis of the benzyl group (if present) gives the compounds of subgroup XIII. The synthesis can be achieved through the
The following reaction scheme is illustrated:

R ⁹ SH in alcohol sodium methylate R ⁹ SNa

_w / GO ₂ CH. R ^y -S-CH ^{ά ό} (XIV)

/ CO ₂ CH H

₆ CO ₂ CH ₃

(XIV) HpO ₉ j > R SOp-CH ^J Nail \ Anion

'"" ^ (CH ₂ ) g CO ₂ CH. in a '

/ if necessary (NH ₄ ) MoO _A as catalyst / ^J aprotic

^{4 4} (XV) solvent

'i ₂ -R ⁵ (XVIa)

R ^c Ö-lower alkanoyl
or
⁴ ) _O -R ⁵ (XVIb)

X-CH ₂ -ZCC (R ⁴ ) 2-

R ² OCH
(X = halogen atom) I.

CO ₀ CH.
ι ² 3

R ¹² SO ₂ -C- (CH ₂ ) 5CO ₂ CH ₃ (XVII)

CH ₂ ZCC (R ⁴ ) ₂ -R ⁵

R o (lower alkanoyl or benzyl)

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3-10 hrs. X R SO ₀ -CH- (CHg) ₆ CO ₂ CH ₃

! jh _o z- £ -c (r ⁴ ) _o -r ⁵

NaCl in ' i \

Diraethyl sulfoxide R ^ OCOCH ₃ (or

130 to 16O ⁰ C (XVIII)

when XVIII has an acetoxy group:

XVIII NaOH, H ₀ OR ¹² SO ₂ CH- (CH ₂ ) gCOgH

in alcohol or ' l " zC-CfR ⁴ ") -R ^ tetrahydrofuran 2 "^ ~ ° ^ ^K > 2. ^Ά

R "OH (XIII)

when XVIII has a benzyl group:

XVIII NaOH, H ₃ OR ¹² SO ₂ CH- (CH ₂ ) 5CO ₂ H

λιττ «7 Π H f Ό · \ Ό-2

ΐ / ίΐηώ-ν-υ \, ϊί) 2 ~ λ

R ² OCH CH (XIX) ^{2 6 5}

XIX H ₂ (Pd) R ¹² SO ₂ CH- (CH ₂ ) ₆ CO ₂ H

CH ₀ ZPC (R ⁴ ) _O -R ⁵

(XIII)

R ² I) H

The hydrogenolysis of the benzyl group leads to reduction at the same time any unsaturation in Z or R.

The third synthesis method according to the invention is particularly suitable for the preparation of a further preferred subgroup, i.e. the compounds of the general formula XX

R ¹² -SO ₂ -CH-CH ₂ -Y-CH ₂ -A-CH ₂ CO ₂ H (XX)

CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵ R ^d OH

in which all symbols have the meanings given above. This process uses an alkylsulfonyl derivative of ethyl acetate successively alkylated in the presence of a strong base with two specific bromo esters and the reaction product by heating in

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decarbalkoxylated in a solvent. The compounds according to the invention are obtained by mildly alkaline saponification: E ¹² —SO2 — CH ₂ —GOOC ₂ H ₅ NaH anion

in an aprotic solvent

_{% R} _ _so _ ^

* ^ CH ₀ -Y-CH ₀ -A-CH ₀ COOR

^{l l ά}

₀ (XXI) (XXII) ^l

R ² O-acetyl

NaH χ anion X-CH ₂ -Z ^ CC (R ⁴ ) ₂ -R ⁵

in a * ■

aprotic
solvent

ϊς 2 H ₉ O

1 ο I * 11 + NaCl

R SOo-C-CHp-Y-CHp-A-CHp-COpR in dimethyl sulfoxide _s

¹ _ώ 4λ _d 5 130 - 160 ° '

(R ² OCOCH

_R 5 130-160C

₂ -R ₃ _ ₅

(XXIII)

R ¹² SO ₀ -CH-GH ₀ -Y-CH ₀ -A-CHo-CO ₀ R ¹¹ NaOH or KOH

j ί ς ⁱⁿ alcohol or

CH ₂ -ZCC (R ⁴ ) ₂ -R ° tetrahydrofuran

S V _nnrT T 25 - 65 ⁰ C

(XXIV) ³ 24-64 hours

R ^{1 2} SO ₂ -CH-CH ₂ -Y-CH ₂ -A-CH ₂ -Co ₂ H
CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵

A \

R ^ OH
(XX)

Therapeutic considerations often make it appropriate to to produce compounds according to the invention (formula I),

2 λ

in which the asymmetric carbon atom carrying the radicals R and OR is only available in the R or S configuration. The corresponding center of asymmetry of the naturally occurring Prostaglandins are known to have the S configuration; its inversion usually leads to a decrease in biological Effectiveness, although at times a pronounced increase in

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biological specificity.

Regarding the mentioned asymmetry center exclusively in the R- or S-configuration present 9-thia-, 9-oxothia- and 9-dioxothia-11,12-seeoprostaglandins can be produced thereby any of the three basic synthetic methods of optically active (i.e. into their stereoisomers R- or S-form split) intermediate compounds V, XVIa or XVIb emanates.

It has proven to be particularly advantageous to use an optically active Use compound of the general formula XVIac

⁴ ) R ⁵

^ C (R ⁴ ) ₂ _R ⁵ (XVIac)

R OCOCH ₃

2 4. 5

in which R, R and R each have the meaning given above and the labeled carbon atom is exclusively in either the R or S configuration.

When using a compound XVIac in the third method, an intermediate of the general formula XXIIIa is obtained

CO ₂ C ₂ H ₅ R ¹² SO ₀ -C-CH ₀ -Y-CH ₀ -A-CH ₀ CO ₀ R ¹¹ (XXIIIa)

C. I £ L C. C-C.

() ₂ r OCOCH ₃

which by decarbalkoxylation and subsequent saponification in an inventive optically active compound of the general Formula XXa is transferred

R ¹² SO ₂ CH-CH ₂ -Y-CH ₂ -A-CH ₂ Co ₂ H (XXa)

I * / As CC (R ^) ₂ -R ^J

CCC

Ah

in which the labeled carbon atom is exclusively in either the R or the S configuration.

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Catalytic hydrogenation of the compounds XXa gives more Compounds according to the invention with the general formula XXb

R ¹² SO ₂ CH- (CH ₂ ) ₄ -A- _{CO 2} H (XJCb)

CH ₀ CH ₀ CHo-CC (F. ⁴ "} .-, - R ^{5 2 2} % \
p / OH

the marked carbon atom exclusively in either the R or S configuration is available.

Preparation of derivatives of the products of the basic synthetic methods The compounds obtained directly from the three synthetic methods described above can be converted into derivatives which also fall under the general formula I in various ways according to conventional practice.

example 1 Manufacture; of 8- ^T .! ethylthio-12-hydroxyl; ptadecanoic acid Stage At production of di-tert-butyl- (6-ethoxycarbonylhexyl) -

-malonate

A suspension of 57 percent sodium hydride in mineral oil (5.05 g net weight, 0.21 mole) in a mixed solvent from 95 ml of benzene and 95 ml of dimethylformamide, 41.09 g (0.19 mol) of di-tert-butyl malonate are added dropwise over a period of 30 minutes offset. The batch is stirred for a further 30 minutes, then 49.8 g (0.21 mol) of ethyl 7-bromoheptanoate are added dropwise over the course of 30 minutes and the mixture is heated to 100 ° C. for 4 1/2 hours.

380 ml of water are added to the cooled reaction mixture and the mixture is separated remove the organic layer and extract the aqueous layer with ether. The combined ether extracts are washed with saturated sodium chloride solution washed and then dried over anhydrous sodium sulfate. The one after solvent evaporation The oily residue remaining in vacuo is the desired compound; Yield 70.78g.

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Level B; Preparation of i-chloro-4-acetoxynonane Stage B-1; Preparation of 1-chloro-4-nonanone The Grignard reagent prepared from a mixture of 226.59 g (1.5 mol) of amyl bromide and 36.48 g (1.5 mol) of magnesium in 100 ml of ether is added dropwise over 1 hour 155.34 g (1.5 mol) of 4-chlorobutyronitrile were added. Stirring is continued for an additional hour. The reaction mixture is then poured into a mixture of 1000 g of finely crushed ice and 750 ml of concentrated hydrochloric acid. The ether layer is quickly separated and discarded. The aqueous layer is heated in a steam bath for 1 hour, during which the imine formed as an intermediate product is hydrolyzed and the ketone is deposited in the form of an oil. After cooling, the oil is extracted with ether and the combined extracts are washed with saturated sodium chloride solution. Then it is dried over anhydrous sodium sulfate, the solvent is evaporated off in vacuo and the oily residue is distilled. This gives 69 g (26 $>) of a colorless oil with a boiling point of 115 to 117 ° C./14 mm; Proton resonance (pmr) (CDClO £ o.9O (3H, t) 3.56 (2H, t, CH ₂ Cl).

Level B-2; Production of 1-chloro-4-nonanol

61.4 g (0.349 mol) of 1-chloro-4-nonanone are added dropwise to a suspension of 6.62 g (0.175 mol) of sodium borohydride and 1.3 g of sodium hydroxide in 310 ml of ethanol. The temperature is kept at 45 to 5O ⁰ C. Stirring is continued for a further hour without external cooling. The reaction mixture is then acidified against Congo red with concentrated hydrochloric acid. The ethanol is then evaporated off under reduced pressure. The residue is treated with 200 ml of water and the oil obtained is extracted with ether. The combined extracts are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After the solvent has been evaporated off in vacuo, 1-chloro-4-nonanol is obtained as a pale yellow, oily residue (58.85 g); IR (pure or undiluted) 3400 cm ".

Level B-3; Preparation of 1-chloro-4-acetoxynonane A mixture of 111.99 g (0.627 mol) 1-chloro-4-nonanol and 128 g (1.254 mol) acetic anhydride is heated for 1 1/2 hours

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at the steam bath. The volatile components are then evaporated off under reduced pressure and the oil remaining as residue is distilled. This gives 88.6 g (64 $>) of a colorless oil with a boiling point of 130 to 133 ° C./14 mm; pmr (CDCl ₃ ) £ 0.89 (3H, t)., 2.02 (3H, s CH ₃ COO), 3.53 (2H, t CH ₂ Cl), 4.89 (1H, m).

Stage C; Production of di-tert-butyl-2- (4-acetoxynonyl) - 2-

- (6-ethoxycarbonylhexyl) malonate

A suspension of 57prosentigem sodium hydride in mineral oil (5.05 g net weight, 0.21 mol) in a solvent mixture of 95 ml benzene and 95 ml dimethylformamide is added dropwise within 30 minutes with 69.7 g (0.187 mol) di-tert.- butyl- (6-ethoxycarbonylhexyl) malonate added. The mixture is stirred an additional 2 hours, then added within 30 minutes dropwise 46.35 g (0.21 mol) of 1-chloro-4-acetoxynonan added and the mixture heated 42 hours at 100 ⁰ C.

380 ml of water are added to the cooled reaction mixture, the organic layer is separated off and the aqueous layer is extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The oily residue remaining after the solvent has been evaporated off in vacuo is the desired compound; Yield 104.12 g; pmr (CDCl ₃ ) <ίθ, 88 (3H, t), 1.45 (18H, s), 2.00 (3H, s CH ₃ COO), 4.12 (2H, q).

Stage D: Preparation of ethyl S-carboxy - ^ - acetoxyheptadecanoate A mixture of 104.12 g (0.187 mol) of di-tert.-butyl-2- (4-acetoxynonyl) -2- (6-ethoxycarbonylhexyl) -raalonate, 3.3 g of p-toluenesulfonic acid monohydrate and 330 ml of toluene are refluxed for 9 1/2 hours. The cooled reaction equipment is washed well with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent is evaporated off in vacuo. The desired compound remains as a residue in the form of an oil; Yield 74.9 g. The oil is purified by column chromatography on silica gel with 2 % methanol in chloroform as the eluent; pmr (CDCl ₃ ) S 0.88 (3H, t), 2.02 (3H, s

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CH ₃ COO), 4.12 (2H, q), 10.97 (1H, s COOH). 2528070

Level E; Preparation of ethyl 8-bromo-12-acetoxyheptadecanoate A mixture of 31 _f 5 g (0.079 mol) ethyl S-carboxy - ^ - acetoxyheptadecanoate, 12.8 g (0.059 mol) red mercury (II) oxide and 200 ml Carbon tetrachloride is added dropwise with stirring at room temperature within one hour with 12.6 g (0.079 mol) of bromine. The mixture obtained is refluxed for 1 hour and, after cooling, filtered. The piltrate is washed with dilute hydrochloric acid, water and sodium chloride solution and dried over sodium sulfate. When the solution is evaporated in vacuo, 24.5 g of product remain in the form of a yellow oily residue. The product is purified by chromatography on a column containing 250 g of silica gel using chloroform as the eluent. This gives 14.4 g of pure ethyl -S-bromo - ^ - aeetoxyheptadecanoate, which is a yellow oil and _{gives an R f} value of 0.49 on silica gel thin-layer chromatography with chloroform elution; pmr (CDCl.) 00.90 (3H, t), 2.03 (3H, s CH ₃ CO), 4.07 (1H, m HCBr), 4.13 (2H, q), 4.92 (1H , m HCO).

Level F; Preparation of 8-methylthio-12-hydroxyheptadecanoic acid . Methyl mercaptan gas is introduced into a solution of 3-7 g (0.16 mol) of sodium in 150 ml of methanol until 7.7 g (0.16 mol) of the gas have been absorbed. 17.8 g (0.041 mol) of ethyl 8-bromo-12-acetoxyheptadecanoate are then added and the resulting solution is refluxed for 4 hours. A solution of 5 g of sodium hydroxide in 50 ml of water is then added and refluxing is continued for a further hour. The solution is then cooled, diluted with 500 ml of water and extracted with ether. The aqueous solution is acidified with concentrated hydrochloric acid. The oily acid which separates out is taken up in ether. It is then washed with water, dried over sodium sulphate and the ether is evaporated off. This leaves 12.5 g of crude product in the form of a yellow, viscous oil. The purification is carried out by chromatography on a column containing 250 g of silica gel using 2 # methanol in chloroform as the eluent. Receives

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7 g (51 #) e-methylthio - ^ - hydroxyheptadecanoic acid in the form of a pale yellow, viscous oil; pmr (CDCl.) Jo, 90 (3H, t), 2.07 (3H, s CH ₃ S), 3.64 (1H, m HCO).

If you use ethyl mercaptan instead of methyl mercaptan in stage F or 2-mercaptoethanol is used, 3-ethylthio-12-hydroxyheptadecanoic acid is obtained or 8- (2-hydroxyethylthio) -12-hydroxyheptadecanoic acid.

Example 2

Preparation of 8-meth.ylsulfonyl-12-iiydroxyheptadecanoic acid A mixture of 3 g (0.009 mol) of S-methylthio-12-iiydroxyheptadecanoic acid (Example 1) and 0.1 g of ammonium molybdate in 10 ml of isopropanol is added dropwise with stirring and ice bath cooling with a so 5 ml (0.044 mol) of 30 percent aqueous hydrogen peroxide are added at the measured rate so that the temperature is kept below 20 ^° C. The mixture is then stirred for 16 hours at 25 ^° C., diluted with 75 ml of water, the product is extracted in chloroform and the extract is washed with sodium chloride solution. After drying over sodium sulfate, the chloroform is evaporated off in vacuo and the crude product obtained is purified by chromatography on silica gel, eluting with benzene / dioxane / acetic acid (90: 30: 1). The desired compound is obtained in the form of a yellowish, viscous oil (1.85 gi yield 56 %) .

Example 3

Preparation of 8-methylsulfonyl-12-hydroxyheptadecanoic acid, step A; Preparation of dimethyl 2-methylthioazelate Excess methylraercaptan is introduced into a rapidly stirred solution of 13.5 g (0.25 mol) of sodium methylate in 200 ml of anhydrous methanol at ⁰ ° C. in order to produce sodiumraethyl mercaptide. 55 g (0.186 mol) of dimethyl 2-bromoazelate are added to the resulting solution and the mixture is then refluxed for 5 hours with stirring in a nitrogen atmosphere. The reaction solution is then concentrated in vacuo, diluted with ether and filtered. The filtrate is washed with water (until the washing water reacts neutral) and dried over sodium sulfate. The distillation

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produce the desired compound in the form of a colorless liquid (28.4 g; 58 $>) from Ep. 128 to 138 ° C / O, 2 mm; pmr (CDCl ₃ ) 32.10 (s, 3H), 2.31 (t, 2H), 3.20 (t, H), 3.63 (s, 3H) and 3.71 (s, 3H).

Step B-1t (g 28; about 0.25 moles) Preparation of dimethyl 2-methylsulfonylazelat 30prozentiges hydrogen peroxide with stirring to a cooled to about 1O ⁰ C mixture of 26.2 g (0.01 mol) of dimethyl ~ 2- mercaptoazelate and 0.3 g of ammonium molybdate (catalyst) in 20 ml of methanol are added dropwise at a rate such that the temperature of the mixture is kept below 30 ^° C. The batch is then stirred for 16 hours at room temperature, diluted with 150 ml of water and filtered. To obtain the desired compound as white crystals (26.2 g j $ 89), mp. 47-48 ⁰ C. Recrystallization from ether at -10 ⁰ C gives the analytical sample as colorless needles, mp. 50 to 5O, 5 ° C; pmr (CDCl ₃ ) ί 3.0 (s, 3H), 3.63 (s, 3H), 3.72 (t, H) and 3.82 (s, 3H).

Stage B-2z Preparation of 1-iodo-4-acetoxynonane A mixture of 35 »3 g (0.16 mol) 1-chloro-4-acetoxynonane (Example 1, Stage B-3) and 120 g (0.8 mol ) Sodium iodide in 350 ml of acetone is refluxed for 10 hours with stirring and with exclusion of light. The suspension obtained is filtered and the sodium chloride retained on the filter is washed out with acetone. The filtrate combined with the washing water is evaporated in vacuo and the mass remaining as residue is divided between ether and water. The organic extract is washed with dilute aqueous sodium thiosulfate solution and water, dried over sodium sulfate and evaporated in vacuo. The desired compound is obtained in the form of a colorless liquid; (48.7 g, 98 #); pmr (CDCl ₃ ) S 2.0 (s, 3H), 3.18 (t, 2H) and 4.98 (m, H).

Stage C; Manufacture; of methyl-8-methoxycarbonyl-8-methylsulfonyl-

-12-acetoxyheptadecanoate

A 57 percent sodium hydride suspension in mineral oil (3.84 g,

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0.091 mol) is freed from mineral oil by washing with petroleum ether. The pesticide remaining when the liquid parts are decanted is suspended in 100 ml of anhydrous dimethylformamide. A solution of 23.5 g (0.08 mol) of dimethyl 2-methylsulfonylazelate in 60 ml of anhydrous dimethylformamide is added dropwise to the suspension at room temperature in a nitrogen atmosphere. The resulting solution is stirred for 1 hour at room temperature, cooled to about 10 ⁰ C and 1-iodo-4-acetoxynonan added so dimensioned speed with 30 g (0.096 mol) of that their temperature is kept below 35 ⁰ C. After standing at room temperature for 19 hours, the reaction mixture is filtered. The sodium iodide (17.1 g) retained on the filter is washed out with ether. Evaporate the combined filtrate with the washings then in vacuum at about 100 ⁰ C and distributes the remaining oil as a residue between ether and dilute hydrochloric acid. The organic extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The desired compound remains as a residue in the form of a viscous oil (37.7 g, 98 j>) j pmr (CDCl.) ^ 2.0 (s, 3H), 3.0 (s, 3H), 3.65 ( s, 3H), 3.81 (s, 3H) and 4.9 (b, H).

Stage D: Production of methyl-8-methylsulfonyl-12-acetoxy-

heptadecanoate

A mixture of 36.7 g (0.077 mol) of methyl 8-methoxycarbonyl-S-methylsulfonyl-12-acetoxyheptadecanoate, 4.68 g (0.08 mol) of sodium chloride, 1 ml of water and 60 ml of dimethyl sulfoxide is added for 5 hours under nitrogen heated in a kept at 185 ⁰ C bath. The reaction mixture obtained is ^{evaporated at 100 °} C. in vacuo and the oily residue is diluted with water. The aqueous mixture is acidified with 6 η hydrochloric acid against Congo red and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate and filtered. When the filtrate is evaporated in vacuo, the desired compound remains as a viscous oil (31 ei 95 $>)% pmr (CDCl ₃ ) i 2.0 (s, 3H), 2.82 (s, 3H), 3.63 (s, 3H) and 4.9 (b, H).

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Step E: Preparation of 8-methylsulfonyl-12-hydroxyheptadecanoic acid. A solution of 29.4 g (0.07 mol) of methyl 8-methylsulfonyl-12-acetoxyheptadecanoate and 70 ml of 20% aqueous NaOH in 70 ml of methanol is stirred for 17 hours at room temperature . The solution obtained ^{in this way was evaporated in vacuo at about 100 °} C. and the oily residue was dissolved in water. The aqueous solution is extracted with ether and the organic extract is discarded. The aqueous phase is then acidified with 6 η hydrochloric acid against Congo red and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and filtered. The filtrate is ^{evaporated at about 100 0} C in a vacuum; the crude desired compound is obtained in the form of a viscous oil (23.6 g $ 93 #)

The viscous oil is poured onto a silica gel column (700 gj 0.063 to 0.2 mmj E. Merck, Darmstadt) with benzene / dioxane / acetic acid (volume ratio 90: 15: 1). Elution with the same solvent mixture gives the pure desired compound in the form a colorless, viscous oil; (16.5; $ 65) J pmr. (CDCl ^) S2.82 (s, 3H), 2.82 (b, H), 3.63 (b, H) and 7.2 (s, 2H, interchangeable); pK 5.20 (water).

Example 4

Preparation of 8-methylsulfinyl-12-hydroxyheptadecanoic acid. 6.7 g (0.0202 mol) of 8-methylthio-12-hydroxyheptadecanoic acid (Example 1) are dissolved in a solution of 1 g (0.025 mol) of NaOH in 80 ml of water ", 7 g (0.022 mol) of sodium metaperiodate are added and the resulting mixture is stirred overnight (17 hours) at room temperature. The solid components are then filtered off and the filtrate is acidified with dilute hydrochloric acid in order to liberate the oily acid product Oil in ether, washed with water and dried over sodium sulfate. When the ether is evaporated off in vacuo, the crude 8-methylsulfinyl-12-hydroxyheptadecanoic acid remains in the form of a viscous, yellowish oil (5.8 g). The product is purified by chromatography on a 125 g column containing silica gel using 4 ° methanol in chloroform as the eluent, 2.2 g of pure 8-methylsulfinyl-12-hydroxyheptadecanoic acid are obtained in the form of a colorless, viscous oil, which in the

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Silica gel thin layer chromatography with chloroform / methanol / acetic acid (96: 3: 1) as eluant shows an R ^ value of 0.14; pmr (GDCl ₃ ) S 0.90 (3H, t); 2.50 (3H, s CH ₃ SO); 3.64 (1H, m HCO).

Example 5

Preparation of 8- (2-hydroxyethylsulfonyl) -12-hydroxyheptadecanoic acid ^{Left to stand 0} C and then diluted with 140 ml of water. The oily product is taken up in ether, washed with water and dried over sodium sulfate. When the ether evaporates, 6.8 g of crude product remain in the form of a viscous, yellow oil. The product is purified by chromatography on a column containing 125 g of silica gel using 3 % methanol in chloroform as the eluent. This gives 2.4 g of 8- (2-hydroxyethylsulfonyl) -12-hydroxyheptadecanoic acid in the form of a colorless, viscous oil, which in silica gel thin-layer chromatography with chloroform / methanol / acetic acid (95: 4: 1) as the eluent has an R _f Shows value of 0.18; pmr (CDCl ₃ ) <Fo, O90 (3H, t), 2.37 (2H, t CH ₂ CO ₂ H), 3.21 (2H, t CH ₂ SO ₂ ), 3.66 (1H, m HCO ), 4.14 (2H, t CH ₂ OH), 5.52 (3H, s COOH and OH).

Example 6

Production of 8-vinylsulfonyl-12-hydroxyheptadecanoic acid Level A; Production of ethyl-8- (2-hydroxyäthylthio) -12- -ac etoxyheptadekano at

31.2 g (0.4 mol) of 2-mercaptoethanol are in a solution of 9.2 g (0.4 mol) of sodium dissolved in 300 ml of methanol. Then add 43.5 g (0.1 mol) of ethyl 8-bromo-12-acetoxyheptadecanoate (Example 1, stage E) and the resulting solution boils for 5 hours under reflux. The bulk of the methanol is then evaporated off in vacuo. 350 ml of water are added to the residue, the oily product is taken up in ether and washed with water and sodium chloride solution and dried over sodium sulfate. At the Evaporation of the ether leaves the desired compound in the form of a yellow oil, which can be used in the next without further purification

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Stage is used.

Level B; Production of ethyl-8- (2-chloroethylthio) -12-acetoxy-

heptadecanoate

A solution of 43.2 g (0.1 mol) of ethyl-8 - (. 2-hydroxyäthylthio) -12- Acetoxyheptadecanoate in 150 ml of benzene is added dropwise with stirring with 13.1 g (0.11 mol) of thionyl chloride and then Boiled under reflux for 2 hours. The solvent and the excess thionyl chloride are then evaporated off in vacuo, with the desired compound remains in the form of an orange-yellow, oily residue.

Stage Ct Production of ethyl-8- (2-chloroethylsulfonyl) -12-

acetoxyheptadecanoate

A solution of 45.1 g (0.1 mol) of ethyl-8- (2-chloroethylthio) -12- acetoxyheptadecanoate and 50 ml of 30% aqueous hydrogen peroxide in 225 ml of acetic acid is left to stand for 20 hours at 25 ° C and then diluted with 600 ml of water. You take the oily one Product in ether, washed with dilute sodium bicarbonate solution and four portions of water and then dried over sodium sulfate. When the ether evaporates in vacuo, the desired compound remains in the form of a light yellow, viscous oil.

Stage D; Preparation of S-vinylsulfonyl - ^ - hydroxyheptadecanoic acid A mixture of 43.5 g (0.09 mol) ethyl 8- (2-chloroethylsulfonyl) - -12-acetoxyheptadecanoate, 14.4 g (0.36 mol) sodium hydroxide, 150 ml of water and 600 ml of tetrahydrofuran is ^{stirred at 25 °} C. for 24 hours. The majority of the tetrahydrofuran is then evaporated off in vacuo, the temperature of the solution being kept at 30 ^° C. or below. The residue is diluted with 300 ml of water. It is extracted with ether, the aqueous solution is acidified with dilute hydrochloric acid and the oily product is taken up in ether. Then it is washed with water, dried over sodium sulfate and the ether is evaporated. The product remains in the form of a yellowish, very viscous oil. This is purified by column chromatography on silica gel with a benzene / dioxane mixture as the eluent. The desired compound is obtained in the form of a colorless, viscous oil.

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-U

Example 7 2528070

Production of S-methylsulfonyl-g-hydroxytetradecyloxyacetic acid Stage A: ethyl 4 "bromo" butoxyacetate

9 g (0.375 mol) of sodium hydride are suspended in 1,2-diraethoxyethane and the suspension is added with stirring and ice bath cooling within 1 hour with 39 g (0.375 mol) of ethyl glycolate dropwise. 108 g (0.5 mol) of 1,4-dibromobutane are then added to the viscous suspension obtained in one shot. Then warmed up the mixture is mild, a strongly exothermic reaction commencing. The mixture is then on the steam bath for 3 hours heated and then poured into cold water. The heavy layer of oil is absorbed in ether and washed with three servings Water, dry over sodium sulfate and evaporate the ether. When the oily residue is distilled, 21.3 g are obtained ($ 24) ethyl 4-bromobutoxyacetate in the form of a colorless oil from Bp. 99 to 103 ° C / 0.2 mm.

Stage B: Production of di-tert-butyl- / 4- (ethoxycarbonylmethoxy) -

-butylT-malonate

Example 1, step A is repeated, but using ethyl 4-bromobutoxyacetate instead of ethyl 7-bromoheptanoate is used. You get the desired compound in the form of an oily residue.

Steps C, D, E, F and G: Making 5-methylsulfonyl-9-

-hydroxytetradecyloxyacetic acid

The compound is analogous to Example 1, stages C, D, E and F as well Example 2, except that in Example 1, stage C, instead of di-tert-butyl (6-ethoxycarbonylhexyl) malonate, di-tert-butyl- / 4- ( ethoxycarbonylmethoxy) butyl / malonate is used; di-tert-butyl-2- (4-acetoxynonyl) -2- / 4- (ethoxycarbonylmethoxy) butyl / malonate, ethyl 5-carboxy-9- are obtained as intermediates -acetoxytetradecyloxyacetate, ethyl 5-bromo-9-acetoxytetradecyloxyacetate and S-methylthio-g-hydroxytetradecyloxy acetic acid. The wished The product is purified by chromatography on silica gel and is obtained as a very viscous, yellowish oil.

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Production of B-methylsulfonyl - ^ - hydroxy - ^ - heptadecinic acid Stage A: ethyl 2- (6-methoxycarbonyl-2-hexrn-1 -yl) -2- (methylsulfo nyl) acetate

A suspension of 57 percent sodium hydride in mineral oil (5.05 g net weight; 0.21 mol) in a solvent mixture of 95 ml benzene and 95 ml dimethylformamide is treated dropwise over 30 minutes with 33.2 g (0.2 mol) ethylmethylsulfonyl acetate. The mixture is stirred an additional 30 minutes, then added dropwise within 30 minutes 43.8 g (0.2 mol) Meth.yl-7-bromo-5-h.eptinoat added and the mixture heated 90 minutes 80 ⁰ C. After After cooling, the mixture is treated with water and the organic layer is separated off, washed with water and sodium chloride solution and dried over sodium sulfate. When the solvent is evaporated off in vacuo, the desired compound remains in the form of a yellow, oily residue.

Stage B: Production of ethyl 2- (6-methoxycarbonyl-2-hexin-1-yl) -

-2- (4-acetoxynonyl) -2- (methylsulfonyl) acetate

The compound is prepared analogously to Example 1, stage C, wherein however, ethyl 2- (6-methoxycarbonyl-2-hexin-1-yl) -2- (methylsulfonyl) acetate instead of di-tert-butyl (6-ethoxycarbonylhexyl) malonate is used.

Step C: Preparation of methyl-8-methylsulfonyl-12-acetoxy-5-

-hept ad e c ino at

A solution of 48.8 g (0.1 mol) of ethyl 2- (6-methoxyearbonyl-2- -hexin-1-yl) -2- (4-acetoxynonyl) -2- (methylsulfonyl) acetate, 3, 6 g (0.2 mol) of water and 6.5 g (0.11 mol) of sodium chloride in 120 ml of dimethyl sulfoxide are ^{heated to 130 to 150 °} C. for 6 hours (until the evolution of carbon dioxide has ceased). The mixture is then cooled, 400 ml of water are added, the oily product is taken up in ether, washed with water and dried over sodium sulfate. When the ether is evaporated in vacuo, the desired compound remains in the form of a yellow, viscous oil.

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Stage D; Production of 8-methylsulfonyl-12-hydroxy-5-hepta-

decinic acid

A solution of 12 g (0.3 mol) of NaOH in 120 ml of water and 600 ml of methanol is mixed with 41.6 g (0.1 mol) of methyl 8-methylsulfonyl-12-acetoxy-5-heptadecinoate. The solution obtained is heated for 24 hours 55 to 6O ⁰ C. The majority of the methanol is then evaporated off in vacuo, the residue is diluted with water, extracted with ether and the aqueous solution is acidified with concentrated hydrochloric acid. The product that is deposited is absorbed in ether. It is washed with water / water, dried over sodium sulfate and the ether is evaporated off in vacuo. The desired compound remains in the form of a viscous, yellow oil. This is purified by column chromatography on silica gel with 2% methanol in chloroform as the eluent. The desired compound is obtained as an almost colorless, viscous oil.

Example9

Preparation of 8-methylsulfonyl-12-hydroxy-5-cis-heptadecenoic acid. 3.6 g (0.01 mol) of 8-methylsulfonyl-12-hydroxy-5-heptadecinic acid (Example 10) are dissolved in 50 ml of ethyl acetate, 1 g is added Lindlar catalyst is added and the mixture is hydrogenated at 25 ^° C. and 1 atm. After taking up 0.01 mol of hydrogen, the catalyst is filtered off and the solvent is evaporated off in vacuo. The oily residue represents the crude product, which is purified by column chromatography on silica gel with 2 io methanol in chloroform as the eluent. 8-Methylsulfonyl-12-hydroxy-5-cis-heptadecenoic acid is obtained in the form of a colorless, viscous oil.

Example 10

Preparation of 8-methylsulfonyl-12-hydroxy-10-heptadecenoic acid, step A; Preparation of 1-bromo-4-acetoxy-2-nonene A mixture of 73.5 g (0.4 mol) of 4-acetoxy-2-nonene, 80 g (0.45 mol) of N-bromosuccinic acid imide and 500 ml of carbon tetrachloride is used Boiled under reflux for 3 hours and then cooled. The suspended succinic acid imide is filtered off, the carbon tetrachloride solution is washed with dilute sodium bicarbonate solution and water and dried over sodium sulfate. Then you steam the

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Carbon tetrachloride is removed in vacuo and the oil-like one is distilled off Residue. This gives 62 g (59 #) 1-bromo-4-acetoxy-2-nonene in the form of a light yellow oil with a boiling point of 110 to 112 ° C / 0.1 mm.

Steps B, C and Dt production of 8-methylsulfonyl-12-hydroxy-

-10-heptadecenoic acid

Example 3 is repeated with steps C, D and E, however instead of 1-iodine-4-acetoxynonane the equivalent amount of 1-bromine -4 — acetoxynonan uses; methyl- -S-methoxycarbonyl-δ-methylsulfonyl-12-acetoxy-10-heptadecenoate and methyl 8-methylsulfonyl-12-acetoxy-1O-heptadecenoate.

Example 11

Preparation of 8-methylsulfonyl-12 (S) -hydroxy-10-heptadecinic acid Step A-1; Preparation of 3 (S) -acetoxy-1-octyne Dissolve 100 "g (0.794 mol) of (S) -1-octyn-3-ol in 79 g (1 mol) of pyridine and then add 81 dropwise with stirring over the course of one hour 6 g (0.8 mol) of acetic anhydride are added, the temperature rises to 45 ° C. The solution is then heated to 55 ° C. for 1 hour, then cooled and poured into 200 ml of ice-cold 5% hydrochloric acid the oily product is washed up in ether, washed with water and sodium chloride solution and dried over sodium sulphate. The ether is then evaporated off and the oily residue is distilled. This gives 106.4 g (80 #) 3 (S) -acetoxy- -1- octyne from ep. 91 to 92 ° C / 15 mm; / ö / p ⁶ -79 ° (C 3.0, CHCl ₃ ).

Level A-2; Preparation of 1-diethylamino-4 (S) -acetoxy-2-nonyne A mixture of 58.5 g (0.35 mol) 3 (S) -acetoxy-1-octyne, 28.5 g (0.39 mol) Diethylamine, 13.8 g (0.46 mol) of paraformaldehyde and 60 ml of p-dioxane are refluxed on a steam bath for 17 hours. The resulting solution is cooled and diluted with 250 ml of ether. Then it is extracted with 300 ml of 5 percent hydrochloric acid, the acidic aqueous extract is made alkaline with 10 percent sodium hydroxide solution, the amine released is taken up in ether, washed with water and sodium chloride solution and dried over sodium sulfate. The oily residue obtained on evaporation of ether yields 73.1 g ($ 89) of 1-diethylamino-4 (S) -acetoxy-2-nonyne on distillation

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from bp 103 to 109 ° C / 0.3 mm; / Ö 7 ^ ⁶ -80 ° (C 3.3, CHCl ₃ ).

Level A-3; Preparation of 1-bromo-4 (S) -acetoxy-2-nonine A solution of 50.6 g (0.2 mol) 1-diethylamino-4 (S) -aeetoxy-2-nonine and 21.2 g ( 0.2 mol) of cyanogen bromide in 250 ml of ether for 18 hours at 25 to 27 ⁰ C allowed to stand and then with hydrochloric acid of 5 per cent, water and sodium chloride solution and dried over sodium sulfate. The oily residue obtained in the evaporation of ether is distilled. After a first run of diethyl cyanamide, 34.1 g (65 %) of 1-bromo-4 (S) -acetoxy-2-nonyne with a boiling point of 97 to 105 ° C./0.2 mm are collected; / ä / p ⁶ -83 ° (C 3.7, CHCl ₃ ).

Levels 3, C and D; Preparation of 8-methylsulfonyl-12 (S) -hydroxy-

-10-heptadecinic acid

The compound according to Example 3, stages C, D and E, is obtained, with however, instead of i-iodo-4-acetoxynonane, the equivalent amount of 1-bromo-4 (S) -aeetoxynonine is used; arise as intermediate products Methyl 8-methoxycarbonyl-8-methylsulfonyl-12 (S) -acetoxy-10-heptadeinoate and methyl 8-methylsulfonyl-12 (S) -acetoxy-10-heptadecinoate.

Example 12

According to one or more of the procedures described in the preceding description and examples or according to the Modifications of these methods which are readily apparent to those skilled in the art are obtained from the starting compounds below via the likewise mentioned intermediates the following compounds: 1) 8-methylsulfonyl-12 (R) -hydroxy-10-heptadecinic acid from R-1- -Octin-3-ol as the starting compound via the following intermediates in the order given:

a) 3 (R) -acetoxy-1-octyne; / W ^ + IO ⁰ (C 3.1, CHCl.)

b) 1-diethylamino-4 (R) -acetoxy-2-nonyne; / 0 / ^ + 74 (C 3.2, CHCl ₃ )

c) 1-bromo-4 (R) -acetoxy-2-nonyne; / ö / p ⁶ + 75 ° (C 3.2, CHCl ₃ )

d) methyl-S-methoxycarbonyl-S-methylsulfonyl-12 (R) -acetoxy-10- -hept ad e c ino at

e) methyl 8-methylsulfonyl-12 (R) -acetoxy-10-heptadecinoate;

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2. 8-Methylsulfonyl-12 (S) -hydroxyheptadecanoic acid from 8-methylsulf onyl-1 2 (S) -hydroxy-10-heptadecinic acid as starting compound;

3. 8-Methylsulfonyl-12 (R) -hydroxyheptadecanoic acid from 8-methylsulf onyl-1 2 (R) -hydroxy-IO-heptadecinic acid as starting compound;

4. S-methylsulfonyl - ^ - hydroxy - ^ - methylheptadecanoic acid from 8-methylsulf onyl-12-hydroxyheptadecanoic acid as the starting compound the following intermediates in the order given:

a) 8-methylsulfonyl-12-oxoheptadecanoic acid

b) 8-methylsulfonyl-12-hydroxy-12-methylheptadecanoic acid;

5. 8-Methylsulfonyl-12-hydroxy-13-13-Ä.imethylheptadkansäure from Lithium acetylide-ethylenediamine complex as a starting connection over the following intermediates in the order given:

a) 3-acetoxy-4,4-dimethyl-1-octyne

b) 1-diethylamino ^ -acetoxy-S, 5-dimethyl-2-nonyne

c) 1-Bromo-4-acetoxy-5,5-dimethyl-2-nonyne

d) methyl-8-methoxycarbonyl-8-methylsulfonyl-12-acetoxy- -13,13-dimethyl-10-heptadecinoate

e) methyl-8-methylsulfonyl-i 2-acetoxy-13,13-dimethyl-1O- -heptadecinoate

f) 8-methylsulfonyl-12-hydroxy-13,13-dimethyl-10-heptadecic acid;

6. 8-methylsulfonyl-11 - (1-hydroxycyclohexyl) -10-undecinic acid 1-Ethynylcyclohexan-i-ol as a starting compound via the following Intermediate products in the order given:

a) i-acetoxy-i-ethinylcyclohexane

b) 1-acetoxy-1- (3-diethylamino-1-propynyl) cyclohexane

c) 1-acetoxy-1- (3-bromo-1-propynyl) cyclohexane

d) methyl-e-methoxycarbonyl-e-methylsulfonyl-11 - (1 -acetoxy-

cyclohexyl) -1O-undecinoate

e) methyl-8-methylsulfonyl-11- (1-acetoxycyclohexyl) -10-

undecinoate;

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7. 8-methylsulfonyl-11 - (1-hydroxycyclohexyl) undecanoic acid 8-methylsulfonyl-11 - (1-hydroxycyclohexyl) -1O-undecinic acid as Output compound j

8. S-methylsulfonyl - ^ - hydroxy-iö-heptadecenoic acid from 5-bromo-1- -pentene as the starting compound via the following intermediates in the order given:

a) 1-chloro-8-nonen-4-one

b) 1-chloro-8-nonen-4-ol

c) i-chloro-A-acetoxy-S-nonene

d) 1-iodo-4-acetoxy-8-nonene

e) methyl-S-methoxycarbonyl-S-methylsulfonyl-12-acetoxy-16- -heptadecenoate

f) methyl 8-methylsulfonyl-12-acetoxy-16-heptadecenoate;

9. 8-Methylsulfonyl-12-hydroxy-17,17,17-trifluoroheptadecanoic acid from 1,1, i-trifluoro-5-bromopentane as the starting compound via the the following intermediates in the order given:

a) Di-tert. butyl (6-ethoxycarbonylhexyl) malonate

b) 1-chloro-9,9,9-trifluoro-4-nonanone

c) 1-chloro-9,9,9-trifluoro-4-nonanol

d) 1-chloro-9,9,9-trifluoro-4-acetoxynonane

e) Di-tert-butyl-2- (4-acetoxy-9,9,9-trifluoronyl) -2- - (6-ethoxycarbonylhexyl) malonate

f) ethyl 8-carboxy-12-acetoxy-17,17,17-trifluoroheptadecanoate

g) ethyl 8-bromo-12-acetoxy-17,17,17-trifluoroheptadecanoate

h) 8-methylthio-12-hydroxy-17,17,17-trifluoroheptadecanoic acid;

10. 8-methyl sulfonyl-12-hydroxy-16,16-dimethylheptadecanoic acid 1-Bromo-4,4-dimethylpentane as the starting compound via the following Intermediate products in the order given:

a) 1-chloro-8,8-dimethyl-4-nonanone

b) 1 -ChIo r-8,8-dimethyl-4-nonanol

c) 1-chloro-8,8-dimethyl-4-acetoxynonane

d) Di-tert-butyl 2- (4-acetoxy-8,8-dimethylnonyl) -2- (6-ethoxycarbonylhexyl) malonate

e) ethyl 8-carboxy-12-acetoxy-16,16-dimethylheptadecanoate

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♦ λ? -

f) ethyl 8-bromo-12-acetoxy-16,16-dimethylheptadecanoate g) 8-methylthio-1 2-hydroxy-16,16-dimethylleptadecanoic acid;

11. 8-Methylsulfonyl-12-hydroxy-13- (4-fluorophenoxy) -tridecanoic acid from p-fluorophenol as the starting compound via the following Intermediate products in the order given:

a) 4-fluorophenoxyacetaldehyde diethyl acetal

b) 4-fluorophenoxyacetaldehyde

c) 5 - (4-fluorophenoxy) -1-pentene-4-o 1

d) 4-Benzyloxy-5- (4-fluorophenoxy) -1-pentene

e) 4-Benzyloxy-5- (4-fluorophenoxy) -1-pentanol

f) 4-Benzyloxy-5- (4-fluorophenoxy) -1-pentanol tosylate

g) 4-Benzyloxy-5- (4-fluorophenoxy) -1-iodopentane

h) methyl-8-methylsulfonyl-8-methoxycarbonyl-i2-benzyloxy-

-13- (4-fluorophenoxy) tridecanoate
i) methyl-8-methylsulfonyl-12-benzyloxy-13- (4-fluorophenoxy) -

-tridecanoate
3) 8-methylsulfonyl-12-benzyloxy-13- (4-fluorophenoxy) tridecanoic acid;

12. 8-Methylsulfonyl-12-hydroxy-13- (4-methylphenoxy) -tridecanoic acid from p-cresol as the starting compound via the intermediate products below in the order given:

a) 4-methylphenoxyacetaldehyde diethyl acetal

b) 4-methylphenoxyacetaldehyde

c) 5- (4-methylphenoxy) -1-pentene-4 - <) l

d) 4-benzyloxy-5- (4-methylphenoxy) -1-pentene

e) 4-Benzyloxy-5- (4-Hiethylphenoxy) -1-pentanol

f) 4-Benzyloxy-5- (4-methylphenoxy) -1 -pentanol-tosylate

g) 4-Benzyloxy-5- (4-methylphenoxy) -1 -iodopentane

h) methyl-8-ynethylsulfonyl-8-methoxycarbonyl-i 2-benzyloxy-13- - (4-methylphenoxy) tridecanoate

i) methyl 8- ^ aethylsulfonyl-12-benzyloxy-13- (4-methylphenoxy) tridecanoate

j) 8-methylsulfonyl-12-benzyloxy-13- (4-methylphenoxy) tridecanoic acid ;

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13. 8-Methylsulfonyl-12-hydroxy-1 3- (3-trifluoromethylphenoxy) -tridecanoic acid from 3-trifluoromethylphenol as the starting compound via the following intermediates in the order given :

a) 3-Trifluoromethylphenoxyacetaldehyde diethylacetal

b) 3-trifluoromethylphenoxyac etaid ehyd

c) 1 - (2-Tetrahydropyranyloxy) -4-acetoxy-5- (3-trifluoromethylphenoxy) -2-pentine

d) 1 - (2-Tetrahydropyranyloxy) -4-acetoxy-5- (3-trifluoromethylphenoxy) -pentane

e) 4-acetoxy-5- (3-trifluoromethylphenoxy) -1 -pentanol

f) 1 - (p-Toluenesulfonyloxy) -4-acetoxy-5- (3-trifluoromethylphenoxy) pentane

g) 1-iodo-4-acetoxy-5- (3-trifluoromethylphenoxy) pentane

h) methyl-8-methylsulfonyl-8-methoxycarbonyl-12-acetoxy-13- - (3-trifluoromethylphenoxy) tridecanoate

i) methyl-8-methylsulfonyl-12-acetoxy-13- (3-trifluoromethylphenoxy ) -tridekano at;

14 · 8-methylsulfonyl-12-hydroxy-13-phenoxytridecanoic acid from phenol as the starting compound via the following intermediates in the order given:

a) Phenoxyacetaldehyde diethyl acetal

b) phenoxyacetaldehyde

c) 5-phenoxy-1-penten-4-ol

d) 4-benzyloxy-5-phenoxy-1-pentene

e) 4-Benzyloxy-5-phenoxy-1-pentanol

f) 4-Benzyloxy-5-phenoxy-1-pentanol tosylate

g) 4-Benzyloxy-5-phenoxy-1-iodopentane

h) methyl 8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13-phenoxytridecanoate

i) methyl 8-methylsulfonyl-12-benzyloxy-13-phenoxytridecanoate j) 8-methylsulfonyl-12-benzyloxy-13-phenoxytridecanoic acid k) 8-methylsulfonyl-12-hydroxy-13-phenoxytridecanoic acid;

15. 8-Methylsulfonyl-12-hydroxy-13- (2,4-dichlorophenoxy) -tridecanoic acid from 2,4-dichlorophenol as the starting compound via the

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standing intermediates in the order given:

a) 2,4-dichlorophenoxyacetaldehyde diethyl acetal

b) 2,4-dichlorophenoxyacetaldehyde

c) 5- (2,4-DiChIoJTPhOnOXy) -I-penten-4-ol.

d) 4-benzyloxy-5- (2,4-dichlorophenoxy) -1-pentene

e) 4-Benzyloxy-5- (2,4-dichlorophenoxy) -1-pentanol

f) 4-Benzyloxy-5- (2,4-dichlorophenoxy) -1-pentanol tosylate

g) 4-Benzyloxy-5- (2,4-dichlorophenoxy) -1-iodopentane

h) methyl-8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13-

- (2,4-dichlorophenoxy) tridecanoate
i) methyl-8-methylsulfonyl-12-benzyloxy-13- (2,4-dichlorophenoxy) -

-tridecanoate
j) 8-methylsulfonyl-12-benzyloxy-13- (2,4-dichlorophenoxy) -tri-

decanoic acid
k) 8-methyl sulfonyl-12-hydroxy-13- (2,4-dichlorophenoxy) -tridecanoic acid j

16. 8-methylsulfonyl-12-hydroxy-13- (4-methylphenoxy) tridecanoic acid from 4-methoxyphenol as a starting compound via the following Intermediate products in the order given:

a) 4-iiethoxyphenoxyacetaldehyde diethylacetal

b) 4-methoxyphenoxyacetaldehyde

c) 5- (4-methoxyphenpxy) -1-penten-4-ol

d) 4-benzyloxy-5- (4-methoxyphenoxy) -1-pentene

e) 4-Benzyloxy-5- (4-methoxyphenoxy) -1 -pentanol

f) 4-Benzyloxy-5- (4-methoxyphenoxy) -1 -pentanol tosylate - g) 4-Benzyloxy-5- (4-methoxyphenoxy) -1-iodopentane

h) methyl-8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13- - (4-methoxyphenoxy) tri-decanoate

i) methyl 8-methylsulfonyl-12-benzyloxy-13- (4-methoxyphenoxy) tridecanoate

j) 8-methylsulfonyl-12-benzyloxy-13- (4-methoxyphenoxy) -tridecanoic acid

k) 8-ethylsulfonyl-12-hydroxy-13- (4-methoxyphenoxy) -tridecanoic acid;

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17. 8-Methylsulfonyl-12-hydroxy-13- (3-pyridyloxy) -tridecanoic acid from 3-hydroxypyridine as a starting compound via the following Intermediate products in the order given:

a) 3-pyridyloxyaeetaldehyde diethylacetal "b) 3-pyridyloxyacetaldehyde

c) 5- (3-pyridyloxy) -1-penten-4-ol

d) 4-benzyloxy-5- (3-pyridyloxy) -1-pentene

e) 4-Benzyloxy-5- (3-pyridyloxy) -1-pentanol

f) 4-Benzyloxy-5- (3-pyridyloxy) -1-pentanol tosylate

g) 4-3enzyloxy-5- (3-pyridyloxy) -1-iodopentane

h) methyl-8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13- - (3-pyridyloxy) tridecanoate

i) methyl-8-methylsulfonyl-12-benzyloxy-13- (3-pyridyloxy) -tridekano at

j) 8-methylsulfonyl-12-benzyloxy-13- (3-pyridyloxy) -tridecanoic acid

k) 8-methylsulfonyl-12-hydroxy-13- (3-pyridyloxy) -tridecanoic acid;

18. 8-Methylsulfonyl-12-hydroxy-13-propoxytridecanoic acid from 1-propanol as the starting compound via the following intermediates in the order given:

a) Propoxyacetaldehyde diethylacetal

b) propoxyacetaldehyde

c) 5-propoxy-1-penten-4-ol

d) 4-benzyloxy-5-propoxy-1-pentene

e) 4-Benzyloxy-5-propoxy-1-pentanol

f) 4-Benzyloxy-5-propoxy-1-pentanol tosylate

g) 4-benzyloxy-5-propoxy-1-iodopentane

h) methyl-8-methylsulfonyl-8-methoxycarbonyl-12-benzyloxy-13- propoxytridecanoate

i) methyl 8-methylsulfonyl-12-benzyloxy-13-propoxytridecanoate 3) 8-methylsulfonyl-12-benzyloxy-13-propoxytridecanoic acid k) 8-methylsulfonyl-12-hydroxy-13-propoxytridecanoic acid;

19 "methyl 8-methylsulfonyl-12-hydroxyheptadecanoate.

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.si.

Example 13

8-methylsulfonyl-12-acetoxyheptadecanoic acid A unit of 9.1 g (0.025 mol) of 8-itfethylsulfonyl-12-hydroxyheptadecanoic acid and 0.1 g (0.06 mol) of acetic anhydride is heated to 60 ° C for 18 hours and, after cooling, in 80 ml of diethyl ether dissolved. The solution is then extracted with an ice-cold solution of 8 g of NaOH in 150 ml of water. The alkaline extract is acidified with concentrated hydrochloric acid and the oily acid which separates out is taken up in ether. After washing with water and subsequent drying over sodium sulfate, the ether is evaporated. This leaves 9 g of the oily crude product. This is purified by chromatography on a column containing 150 g of silica gel using methanol in chloroform as the eluent. 8-Methylsulfonyl-12-acetoxyheptadecanoic acid is obtained in the form of a colorless, viscous oil.

Analogous to Example 13, but instead of acetic anhydride in each case the equivalent amount of propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride or If pivalic anhydride is used, 8-methylsulfonyl-12-propionyloxyheptadecanoic acid is obtained, 8-methylsulfonyl-12-butyryloxyheptadecanoic acid, 8-methylsuflonyl-12-isobutyryloxyheptadecanoic acid, 8-methylsulfonyl-12-valeryloxyheptadecanoic acid or 8-methylsulfonyl-12-pivaloyloxyheptadecanoic acid.

Example 14

Production of N- (2-dimethylaminoethyl) -8-methylsulfonyl-12- -hydroxyheptadecanamide

A solution of 3.6 g (10 mmol) of 8-methylsulfonyl-12-hydroxyheptadecanoic acid (Example 2), 1.74 ml (12.5 mmol) of triethylamine and 18 ml (1 mol) of distilled water in 100 ml of acetonitrile is mixed with 3 g (12.5 mmol) of N-tert-butyl-5-methylisoxazolium perchlorate are added. The solution obtained is evaporated in vacuo (water jet pump) for 4 hours at 20 to 23 ^° C. A sticky residue is obtained, which is rubbed in for 15 minutes at 0 to 5 ° C. with 150 ml of water. After the aqueous phase has been decanted off, the oil

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like residue in 200 ml benzene / ether (1: 1). The organic extract is dried over sodium sulfate and filtered. Evaporation in vacuo at 35 to 40 ^° C. gives the desired "active ester", ie N-tert-butyl-3- (8-methylsulfonyl-12-hydroxyheptadekanoyloxy) crotonamide, in the form of a pale yellow oil.

A solution of 0.88 g (10 mmol) of 2-dimethylaminoethylamine in 25 ml of acetonitrile is then added to a solution of the "active ester" in 25 ml of acetonitrile. The resulting clear solution is stirred at 25 ° C. for 17 hours. The solvent is then evaporated off in vacuo at 40 to 50 ^° C. and the remaining oily residue is divided between ether (200 ml) and water (2 × 100 ml). The organic extract is washed with saturated sodium chloride solution (2 × 100 ml), dried over sodium sulfate and filtered. The Piltrat is evaporated at 40 to 5O ⁰ C in vacuum; a yellow-brown, oily crude product is obtained. This oil is divided between 5 percent hydrochloric acid (100 ml) and ether (2 χ 100 ml). The aqueous acid phase is first slowly made alkaline with 16.8 g (0.2 mol) of sodium bicarbonate and then with 10 ml of 40 percent aqueous sodium hydroxide solution. The resulting heterogeneous mixture is extracted with 100 ml of ether. The ether extract is washed with water and sodium chloride solution, dried over sodium sulphate and the ether is evaporated in vacuo. The desired compound remains in the form of a light yellow, viscous oil.

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Claims (1)

663 Y Patent claims 1. Process for the preparation of the compounds of the general formula below R ⁹ -S (O) _n -CH-CH ₂ GH ₂ CH ₂ CH ₂ -A-CH ₂ -CO ₂ H CH ₂ -CH ₂ -CH ₂ -CH-C (R ⁴ ) ₂ -R ¹⁰ OH in the A represents a methylene group or an oxygen atom, R represents a hydrogen atom or a methyl group, η has the value 0, 1 or 2, R is a methyl, ethyl or 2-hydroxyethyl group and R is an alkyl radical or branched alkyl radical having 3 to 6 carbon atoms or represents a 4,4,4-trifluorobutyl group, characterized in that one di- -tert-butylmalonate one after the other in any order with a halogen ester of the general formula below in the A has the meaning given above, X is a halogen atom (chlorine, bromine or iodine atom) and R is a straight-chain Represents lower alkyl (an ethyl or methyl group), and a halogen ester represented by the following general formula X-CH ₂ -CH ₂ -CH ₂ -CH-C (R ⁴ ) ₂ -R ¹ ° in which X, R ⁴ and R each have the meaning given above, to a disubstituted malonic ester of the following general formula (tert-C ₄ H _g O ₂ C) ₂ C- (CH ₂ ) ₄ ACH ₂ CO ₂ R ¹¹ CH ₂ CH ₂ CH ₂ CH-C (R ⁴ ) ₂ R ¹⁰ OCOCH- - 34 - 509882/1013 252807Q 663 Y in which R, R and A each have the meaning given above and R is a straight-chain lower-alkyl radical (a Ethyl or methyl group) represents, alkylated, by heating the disubstituted malonic ester in the presence a strong acid, a substituted decarboxylated malonic acid derivative the general formula below HO ₂ C-CH- (CH ₂ ) ₄ ACH ₂ CO ₂ R ¹¹ CH ₂ CH ₂ CH ₂ CH-C (R ⁴ ) ₂ -R ¹⁰ OCOCH ₃ in which R, R, R and A each have the above Have meaning, generates, the decarboxylated malonic acid derivative in the presence of mercury (II) oxide reacts with bromine, a substituted bromine ester with replacement of the carboxyl group by a bromine atom the general formula below Br-CH- (CH ₂ ) ₄ ACH ₂ CO ₂ R ¹¹
CH ₂ CH ₂ CH ₂ CH-C (R ⁴ ) ₂ -R ¹⁰ OCOCH ₃ in which R, R, R and A each have the meaning given above, arises, the substituted bromine ester reacts with an alkali metal salt of a mercaptan and then the ester functions with saponified dilute aqueous alkali, with a thia-11,12- -secoprostaglandin compound of the following general formula R ⁹ S-CH- (CH ₀ ) .ACH ₀ CO ₀ H CH ₂ CH ₂ CH ₂ CH-C (R ⁴ ) ₂ -R ¹ ° OH in which R, R, R and A each have the meaning given above, arises, and the thia-11,12-s ecopro st aglandin compound to an oxo- or dioxothia-11,12-secoprostaglandin compound with a of the general formulas below - 35 509882/1013 663 Y R ⁹ SO-CH- (CH ₂ ) ₄ -A-CH ₂ CO ₂ H OH
or R ⁹ SO ₂ CH- (CH ₂ ) ₄ -A-CH ₂ CO ₂ H CH ₂ CH ₂ CH ₂ CH-C (R ⁴ ) ₂ -R ¹⁰ OH in which R, R, R and A are each given the above Have meaning oxidized. 2. Process for the preparation of the compounds of the general formula below R ¹² -SO ₂ -CH- (CH ₂ ) ₆ CO ₂ H CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵ A \ R ^ OH 2
in which R is a hydrogen atom or a methyl group, R ^{4 is} a hydrogen atom or a methyl group, R is an alkyl radical, a branched alkyl radical having 3 to 6 carbon atoms, a vinyl group, a 4,4,4-trifluorobutyl group or a radical OR, where R is an alkyl radical, a branched alkyl radical with 2 to 5 carbon atoms, a substituted alkyl radical (e.g. a 3,3,3-trifluoropropyl group), a nitrogen or oxygen-containing 5- or 6-membered heterocyclic ring (e.g. a pyridyl or furfuryl group) or a phenyl group represented by one or two substituents in Form of halogen atoms, methyl or methoxy groups substitutes can be, is, and furthermore, if R is a straight chain 2
gen lower-alkyl radical and R represent a methyl group, the 5 2 terminal carbon atom of R with R to form a carbocyclic ring with 6 to 9 carbon atoms linked 5 2 can be, or if R is a straight-chain alkyl radical and R - 36 509882/1013 663 Y represent a hydroxyl group, the terminal carbon atom 5 3 of R with the carbon atom bearing the radical OR below Formation of a carbocyclic ring with 5 to 8 carbon atoms can be linked, R is a methyl or ethyl group and Z is an ethylene, vinylene or ethynylene group, characterized in that an alkylsulfonyl derivative of an azelaic acid diester of the general formula below -j R ' I ₆ CO ₂ CH ₃ 12th
in which R has the meaning given above, alkylated by reacting an anion of the abovementioned azelaic acid diester with a lower alkanoyl ester or benzyl ether of a compound of the general formula below X-CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵ in which R, R, R and Z each have the meaning given above and X represents a halogen atom, to a substituted sulfonylazelaic acid diester derivative of the following implements the general formula CO ₂ CH ₃ R ¹² -SO ₂ -C- (CH ₂ ) ₆ -CO ₂ -CH ₃ CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵ R ^ OH where R, R, R, R, and Z are each as given above Have meaning and the hydroxyl group is in the form of its lower alkanoyl ester or benzyl ether derivative, decarbalkoxylated the sulfonylazelic acid diester by heating to give a compound of the general formula below R ¹² SO ₂ -CH- (CH ₂ ) ₆ -CO ₂ -CH ₃ CH ₀ -ZCC (R ⁴ ) ₉ -R ⁵ R OH - 37 -509882/1013 663 Y . it. 2 4 5 12
where R, R, R, R and Z each have the meaning given above and the hydroxyl group is protected in the form of its lower alkanoyl ester or benzyl ether derivative, then the protective ester groups are split off by mild alkaline saponification and then a compound is formed by hydrogenolysis of any benzyl ether groups present the general formula below R ¹² -SO ₂ -CH- (CH ₂ ) ₆ CO ₂ H CH ₉ -ZCC (R ⁴ ) ₉ -R ⁵ R ^ OH in which R, R, R, R and Z each have the meaning given above, generated. 3. Process for the preparation of the compounds of the general formula below R ¹² -SO ₂ -CH-CH ₂ -Y-CH ₂ -A-CH ₂ -CO ₂ -H CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵ R ^ OH in which R is a hydrogen atom or a methyl group, R is a hydrogen atom or a methyl group, R is an alkyl radical, a branched alkyl radical with 3 to 6 carbon atoms, is a vinyl group, a 4,4,4-trifluorobutyl group or a radical OR, where R is an alkyl radical, a branched one An alkyl group of 2 to 5 carbon atoms, a substituted alkyl group (e.g. a 3,3,3-trifluoropropyl group), a nitrogen or oxygen-containing 5- or 6-membered heterocyclic Ring (e.g. a pyridyl or furfuryl group) or a phenyl group substituted by one or two substituents in Form of halogen atoms, methyl or methoxy groups can be iert, and also if R is a straight chain gen lower-alkyl radical and R represent a methyl group, the 5 2 terminal carbon atom of R ^ with R to form a carbocyclic ring with 6 to 9 carbon atoms linked - 38 509082/1013 663 Y 5. ■ * · can be, or if Ir is a straight-chain alkyl radical and R represent a hydroxyl group, the terminal carbon atom 5 "\ of R with the carbon atom bearing the radical OR below Formation of a carbocyclic ring with 5 "to 8 carbon atoms can be linked, 12th
R is a methyl or ethyl group, A is a methylene group or an oxygen atom, Z is an ethylene, vinylene or ethynylene group and Y is an ethylene, vinylene or ethynylene group, characterized in that an alkylsulfonylacetic acid-lower alkyl ester stepwise alkylated, where it is with a halogen ester of the general formula below X-CH ₂ -Y-CH ₂ -A-CH ₂ -CO ₂ -R ¹¹ in which Y and A each have the meaning given above 11 ben, X represents a halogen atom and R a straight-chain lower alkyl radical (an ethyl or methyl group) is reacted and the substituted alkylsulfonyl acetate derivative obtained the general formula below R ^y S0 _o CH in which A and Y each have the meaning given above ben, R is a hydrogen atom, a lower-alkyl radical with 1 to Carbon atoms, a di-lower-alkylaminoalkyl radical with 4 to 7 is carbon atoms or a carbazoyl group and R is Means methyl, ethyl or 2-hydroxyethyl group, with a compound of the general formula below X-CH ₉ -ZCC (R ⁴ ) ₉ -R ⁵ R ^ OCOCH ₃ 2 4 5
in which R, R, R, X and Z each have the meanings given above, to a compound of the general formula below - 39 509882/1013 663 Y ν *. CO ₂ C ₂ H ₅ ι ' ² ^ O ₉ -C-CH ₉ -Y-CH ₉ -A-CH ₉ -OO ₉ -R ¹¹ CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵ R ² OCOCH ₃ in which R ² , R ⁴ , R ⁵ , R ¹¹ , R ¹² , A, Y and Z each have the meanings given above, the aforementioned compound is alkylated by heating to give an alkylsulfonyl ester of the general formula below R ¹² So ₂ -CH-CH ₂ -Y-CH ₂ -A-CH ₂ -CO ₂ R ¹¹ CH ₂ -ZCC (R ⁴ ) ₂ -R ⁵
R OCOCH ₃ in which R, R ⁴ , R ⁵ , R, R, A, Y and Z each have the meanings given above, decarboxalkylated and the alkylsulfonyl ester saponified. f Ay compounds of the general formula below R ¹ S (O) _n -CH-CH ₂ -Y-CH ₂ -A-CH ₂ -R CH ₉ -ZCC (R ⁴ ) ₉ -R ⁵ A 3 Xt UJl in which R is a carboxyl group, a carboxyl salt group or a derivative of a carboxyl group, A represents a methylene group or an oxygen atom, Y is an ethylene, vinylene or ethynylene group, R is a methyl, ethyl, 2-hydroxyethyl, 2- (lower alkoxy) - means ethyl or vinyl group, η has the value 0, 1 or 2, Z is an ethylene, vinylene or ethynylene group, R represents a hydrogen atom or a methyl group, R is a hydrogen atom or a lower alkanoyl radical having 1 to 5 carbon atoms, R is a hydrogen atom or a methyl group, and R- * is an alkyl radical, a branched alkyl radical with 3 to 6 carbon atoms, a vinyl group, a 4,4,4-trifluorobutyl group - 40 509882/1013 663 Y or a radical OR, where R is an alkyl radical, a branched one An alkyl group of 2 to 5 carbon atoms, a substituted alkyl group (e.g. a 3,3,3-trifluoropropyl group), a nitrogen or oxygen-containing 5- or 6-membered heterocyclic ring (e.g. a pyridyl or pururfuryl group) or a phenyl group which is substituted by one or two substituents in the form of halogen atoms or methyl, metboxy or trifluoromethyl groups can be, as well as if R is a straight chain 2
gen lower-alkyl radical and R represent a methyl group, the 5 2 terminal carbon atom of R with R to form a carbocyclic ring with 6 to 9 carbon atoms linked 5 2 or, when R is a straight-chain alkyl radical and R is a hydroxyl group, the terminal carbon atom of R can be linked to the ^{carbon atom bearing the radical OR J to} form a carbocyclic ring having 5 to 8 carbon atoms. 5. 8-methylthio-12-hydroxyheptadecanoic acid. 6. 8- (2-Hydroxyethylthio) -12-hydroxyheptadecanoic acid. 7. 8-methylsulfinyl-12-hydroxyheptadecanoic acid. 8. 8-Ethylsulfonyl-12-hydroxyheptadecanoic acid. 9. 8- (2-Hydroxyethylsulfonyl) -12-hydroxyheptadecanoic acid. 10. 8-vinylsulfonyl-12-hydroxyheptadecanoic acid. 11. 5-methylsulfonyl-9-hydroxytetradecyloxyacetic acid. 12. 8-methylsulfonyl-12-hydroxy-5-heptadecic acid. 13. 8-methylsulfonyl-12-hydroxy-5-cis-heptadecenoic acid. 14. 8-methylsulfonyl-12-hydroxy-10-heptadecenoic acid. - 41 509882/1013 15 663 Y . η. 15. 8-methylsulfonyl-12 (S) -hydroxy-10-heptadecic acid. 16. S-methylsulfonyl- ^ iRj-hydroxy-IO-heptadecinic acid. 17. 8-Methylsulfonyl-11- (1-hydroxycyclohexyl) -1O- undecic acid. 18. Methyl 8-methylsulfonyl-12-hydroxyheptadecanoate. 19 · N- (2-dimethylaminoethyl) -8-methylsulfonyl-12-hydroxyheptadecanamide. 20. 8-methylsulfonyl-12-hydroxy-12-methylheptadecanoic acid. 21. 8-Methylsulfonyl-11- (1-hydroxycyclohexyl) undecanoic acid. 22. e-Methylsulfonyl - ^ - acetoxyheptadecanoic acid. 23. e-Methylsulfonyl - ^ - hydroxy- ^ f ^ -dimethylheptadecenoic acid. 24. 8-methylsulfonyl-12-hydroxyheptadecanoic acid. 25. 8-Methylsulfonyl-12 (S) -hydroxyheptadecanoic acid. 26. 8-Methylsulfonyl-12 (R) -hydroxyheptadecanoic acid. 27. 8-Methylsulfonyl-12-hydroxy-16-heptadecenoic acid. 28. 8-Methylsulfonyl-12-hydroxy-17,17,17-trifluoroheptadecanoic acid. 29. 8-methylsulfonyl-12-hydroxy-16,16-dimethylheptadecanoic acid. 30. 8-Methylsulfonyl-12-hydroxy-13- (4-fluorophenoxy) -tridecanoic acid. 31. 8-methylsulfonyl-12-hydroxy-13- (4-methylphenoxy) -tridecanoic acid, 32. 8-methylsulfonyl-12-hydroxy-13-phenoxytridecanoic acid. - 42 -5Ö98Ö2 / 1013 252807Q 15 663 Y 33. 8-methylsulfonyl-12-hydroxy-13- (2,4-dichloroplienoxy) -tridekan acidic. 34. 8-Methylsulfonyl-12-hydroxy-13- (4-methoxyphenoxy) -tridecanoic acid. 35.8-Meth.ylsulfonyl-12-hydroxy-13- (3-pyridyloxy) -tridecanoic acid. 36. 8-methylsulfonyl-12-hydroxy-13-propoxytridecanoic acid. 37. 8-Methylsulfonyl-12-hydroxy-13- (3-trifluoroethylphenoxy) -tridecanoic acid. 509882/1013