DE1643325A1 - 3-Aminoacylamino-thiophenes and process for their preparation - Google Patents

Description

R is hydrogen, a straight-chain or branched alkyl radical with 1-6 C atoms, which is optionally through Hydroxy groups or by alkoxy groups with 1 ~ 3 carbon atoms substituted r.cdn can,

R, a straight-chain or verses-waved alkyl radical with 1-6 C-Atoincij-, the gc _i; . vb ^ iaii Ta J Jw can be substituted by IlydroJcygruppeu or Alkoxygrupjjen with 1 "3 C-atoms, a CycJoalkyJ cc st with 5-6 C-atoms or an A3 knny I ro": t ni. t 2.-h ^r - -Ai.orc-sr), where "i. ... H vncl Ii ₀ gemeji · n ^ * i'.i with the N-i also atoi (ι, η *> ί f ·, ϊ *:;., I + ^f i '..... ; ■. C · η h. · T'.rroöVcU ::. H <: i;

Neue Unte ^^ i- ^ i ^ 7 ι q <7 · ό '· · * · ·' · runüHgoe v.

BATH ORIGINAL

Can form a ring with 5-7 ring members, if necessary still contain oxygen, or the methylitnino group,

R, R, and R are each hydrogen, an alkyl radical having 1-4 C atoms or a carbalkoxy group, and

A is a straight-chain or branched alkylene chain mean with 1-4 carbon atoms.

The invention also relates to a method for production the called-n connections, which is characterized is that one

a) 3-HalQgenacylaminothiopheire of the formula R _o -ir NH-CO-AX

J Ί

I I-

in the X halogen, e.g. D. is chlorine, bromine or iodine or an alkoxy, aralkoxy or aryloxy group, with primary or secondary amines of the formula

/ ^R l
HN III

implements, or

b) 3-Aüii jiothri ophniic. ' r.-ΊΊ;. t ..κ-i ι · - "■ .. · Porin oil

10: M / 187

BATH

¹ S; ~

Il iv

or their salts or Grignard compounds with Aminocarboxylic acids, of the formula

HOOC - A - K 'V

or realcti onsabileix derivatives of the same acylated, c) 3 ~ Ämino-4, 5- or -2.5- ~ dih> 'drothioplicno' "of the formulas

^ or

^E 4 ¹ V

Via

l ~ i TfH- CO- AN

S R VIb

dehydrated ₄ or d) 3 ~ Aminoacylaminothiophf: ne der R ί,

Jt

⁸ ■ ■ να

Jt

10. 1 Ί / 1 R 7

1843315

allcylated in a manner known per se or e) _; Vc? Γφ indications of the formula

^H 2

R. NH-CO-A-K '

-3- -—r- j

VIII

R, -

• Κ ι. ti ._

wherein R 1 represents an ester group, saponified; or f) to unsaturated acyl & tninoMiipphene of the formula

R ₃ ~ f— -r NK-CO - A · -U-

/ X

wherein A ^{f is} a straight or branched alkenyl radical with 2-4 carbon atoms, amines of

"^" R
Formula HN 1 attaches; or

g) Thioplien-i soni trile of Foniiöl

^R 31: r ^NC χ

ii i!

«4 S R

with amines of the formula HN _v

in the presence of eil iphati. multiple aldehydes with i ~ k carbon dioxide fatomcii i-inset v, t,

109-1 37,187 3

BATH ORIGINAL

g-ogcbenen £ all in R "-, R ₁ " and / or R -SteLUmg existing ^l

Carbalkoxy groups saponified and decarboxylated uad / odei · j

converted, where appropriate, the resulting compounds with acids in, \ pharmaceutically acceptable salts. _;

a) The 3-IIalogeii-acylaminothlophene aar Forme3 used in the method according to variant α). II preferably contain chlorine or brons in the acyl radical. For the reaction with the 3-i'itlogeriacylaminoth.iophenes, for example, the following amines of formula ΧΪΙ are possible: {|

Alkylamine irio methylamine, ethylamine, n-propylamine, isopropylamine, n-butylaniln, isobxitylamiii, sec. Butylaraisi; tert. Butylamine; Hydroxyalkylcunines such as hydroxypropylamine and diethanolamine, alkoxyalkyl amines such as methoxyethylamine; Dialkylamines such as diethylamine and di-nbittylamine, and also alkyleneimines such as pipei'idine, pyrrolidine or N-methylpiperazine. The reaction of the haloecyiamiiiothiophenes with the amines can be carried out both in the presence and in the absence of solvents. As a solvent. come in Beti-eight: ether, dioxane, alcohols such. B. methanol, ethanol, propanol, saturated cyclic liohlenwassei-ijtoffe such as λ

Cyclohexane and Methylcyclohcxan, aromatic hydrocarbons such as BenKO1, toluene, xylene and chlorinated hydrocarbons such as chlorobenzene, chloroform and carbon tetrachloride. The reaction temperatures are between room temperature and the boiling temperature of the respective solvent; During the reaction, pressure can optionally also be applied. "To neutralize the acid formed during the reaction, it is preferred to work with a small excess of the amine used and V * -., .. uic"; L ,, f. Tdeston.h.-2 parts- Λυύη to 1 part 3-iialogenMcylaiii.i.iio ihi ophon. The Rea-ktio-na-. Depending on the reaction temperature, the duration is about k -12 hours. This is used as a cleaning product

109813/187 3 BAD ORiGiNAl.

Amine hydrohaloganide dissolved out with water, solvent and; excess "Am in distilled off and that remaining process product distilled or by dissolving in mineral seeds and precipitating with diluted Caustic soda purified

To illustrate the halogeriacylaminothiophene used as starting materials, rtv & n proceeds in a manner known per se. Example sx-Reise, aminothiophenes or aminothiophtmearboxylic acid esters are reacted with Iialogenacylhalogeniden and optionally saponified the products obtained. The Arninothiophone and Aminothiophencciirbonsaureestcr is likewise obtained in a known manner, the latter, for example, by the process of DBP 1055 ?, 00 1 O88 507 / and 1,083,830, ersterc by saponification and decarboxylation of the Aminothiophencarbonsäureester. If the starting materials used are amino thiophenes which carry a girbaloxy radical in the h position, these can be converted according to the method of Cheney and Piening "Journal of the American Chemical Society." Vol. 67 Si 729, 731 (19 ^ 5) from the corresponding thiophanone- (3) -carboxylic acid esters and hydroxylamine. Instead of the halogenacylaini no thiophenes, one can also start with alkoxy-, aralkoxy- or aryloxyacylaminothiophenes. For example, methoxy is used -, ethoxycarbonyl-, BenKylo ^ y or phenoxy substituted Äcylatninothiophene * they are obtained, for example, by reacting ,. Aminothi-ophehen hzvr Aininothiophcri'carbonsäureostern with · alkoxy, aralkoxy "or aryloxycarboxylic and Chlorameisnnsäuröester IMCH the method of getniijeilten. .Anhydrides.

1038 13/1873

ORIGfKlAL BATHROOM

1843325

b) The process products are also used in accordance with variant b) by reacting 3-aniinothiophone of the formula IV with an aniinoearboxylic acid of the formula V or, preferably, a reactive derivative of such an acid , Ethyl ami na ossigsäiir _e , n ^ Propyltimiiiocssigsäure, let :. Butylitinocssigsaure, Cyc.l olf xylahu noes yi ~ .sciur. ^v c, Biäthy.1 amino ο sin Ag. acid and Fxperidyliiiuj koesaetic acid. Instead of the mentioned. Ami »ο e. ^c .: si sr κ ä UJ-c η also leave the corresponding subs ti Uli. er t en ζ: ^ - and ß-Aniiiiicpropionsäurcri ,, the various ifioiKcren A'üinobnttersätjreii and / utiinovalerian " μ acids venrcncloR" as reactive derivatives of the ajuinocarboiiiiÄure Ivominen z. D. Acid chlorides, acid esters, acid amides, acid aides and acid aihydrides iii. Instead of the 3-ainothiophenes, their salts, e.g. B. Use allvcili or alkaline earth salts or Grignard compounds (halogen-magne- sium compounds). The reaction is expediently carried out in inert solvents, for example in ether, benzene, toluene or xylene.

c) The dehydrogenation of the starting materials of the formulas Vl a and "b" becomes known per se with usual

Dehydrating agents carried out. As particularly good \

suitable dehydrating agent has been Chlorani.l

proven; it is tel Lösungstnit as an aromatic hydrocarbon, such as ζ * as toluene, xylene or mesitylene, used, and preferably 5-15 hours »heated to Öiedcn. At Verviendunf; of bromine as a dehydrogenating agent works unnecessarily under cooling, before urri.aise. -10 to ■; 10. As a solvent,; /. ' , · Fs: ^ s (isbej «jevorvvagt halogRiiicr ie

1 0 O r: 13/1873

BATH

• - 8th -

Hydrocarbons, such as ζ. B. Kethylenchloi-id, chloroform, carbon tetrachloride. Catalysis of the halogenated hydrogen cleavage with basic agents is not necessary. The ones used as raw materials. 3- (sub. Amino) acylatin, o ~ 2, 5- or ~ k , 5-dihydric thiophenes are obtained analogously to the corresponding thiophenes (cf. variant a)) using "" of appropriately substituted aniirio-dihydric thiophenes . The latter can be prepared from appropriately substituted thiophanones by introducing ammonium gas or by heating with ammonium acetate.

d) The alkylation of starting materials of the formula VIl is carried out by known methods, for. B. with aldehydes or ketones in the presence of reducing agents such as

• ζ. B. formic acid. As an alkylation smi.tteJ. permit

also mineral acid esters, such as. B. Use alkyl halides, sulfuric acid or phosphoric acid esters. Aryl sulfonic acid esters are also suitable. The starting materials of the formula VII are according to the under a). . . general methods of preparation described; accessible from aminoacylotninothiophenes. -, -. ·. .- ■■, ■

e) In the compounds d & v formula VIII, IL- denotes an ester residue, as is generally used in peptide chemistry for the protection of amino groups. Examples are carbobenzoxy, mercaptocarbonyl, tosyl, trifluoroacetyl, tort. Butyl, oxycarbonyl, and -Ni l.ropheny.1 -.si'lf euyli'ps t . The cleavage also takes place according to the methods customary in peptide chemistry, for example with sodium in liquid ammonia or with a compound in glacial acetic acid. In some i'äilon er.Cc .1 ^; i. D i -'- Sj> ril t ung with dilute hydrochloric acid * r> when standing. on

TOSiM 3 / 1-873

BATH

1843325

these ^{: In} one embodiment, compounds are obtained in which R represents hydrogen.

f) The procedure is also carried out in the Voise that acylamino thiophane or "acylamino thiophane" carboxylic acid esters which have a double bond in the acyl chain are thai, with a corresponding primary or . sec \ mdaren amine converts acyl radicals containing double bonds, tO inf come rage: acrylic acid -, - methacrylic acid, Tiglinsaure- _t <([

Crotorisäuve «or IsoGX'otoiiöäurereste, '

The yniseti5un, s with the amines can take place both at itauro temperature as well as at higher temperature with or without the application of pressure, uiid / or * solution atnxtt .Mol per mole of acyl derivative. The preparation of the starting materials of formula IX is carried out, for example, by ^{transesterification:} reduction of the unsaturated acid chlorides with aminothiophene or Aminothiophencarbonsäureestern. However, no Λ is obtained using the method of variant f)

oC-Aniinöacylaminothiophenes.

g) The thiophore isonitriles of the formula X are prepared by methods known per se (Heuere methods dor prep. org. Chemistry Vol. IV, S, hy ff) by reacting the corresponding formylamino thiophenes with water-splitting agents. The reaction with aldehyde and antioxidants in the precursor products is carried out at room temperature in an aqueous medium; by Z ·:, ",:, ^: · ·? ί.> ϊ \ SH ^ s ν ·, virct the pü-lCr-rf. to about 5 to 8 einjjes tcl J 1 .. The reaction time is

1098 13/18 73

between a few minutes and 100 hours. If primary amines are used, it is expedient to work with an excess. Included after the '3. metho-dim)' bis- dj illustrated process products' still Carbalkaxygruppcn in R ", Ti ₁ <* and / or ß _r ~ position so Can ta-ls getreinschtenfaJ removed by hydrolysis and decarboxylation of this The hydrolysis is carried out in a manner known per se with alkali metal or alkaline earth metal dihydroxides. The process can be carried out either at the construction rate or at an elevated temperature ,, For example Chi «οIiη or diethylaniline in the presence of lvupf erpulver, excellent viaise just below the boiling point of the organic bases.

According to the method of the present invention The connections established are in Kor in their Salts easily soluble in water »Organic and inorganic acids are used for salt formation, for example Acetic acid, lactic acid, maleic acid, citric acid, tartaric acid, aceturic acid, arnidosulfonic acid, oxyethane sulf onic acid, phosphoric acid, hydrochloric and hydrochloric acid under consideration »". "" ■ -

The salts crystallize gtvfc and are very persistent. Their aqueous solutions can be kept well, can be easily sterilized and do not cause tissue irritation. The compounds are valuable therapeutic agents with interesting pharmacological properties, both in free form and in the form of their salts. On the basis of their potency and their low value . .1 does;: ijid they are suitable for ex la local anesthetics alone.

1098 13/1873 _v BAD oSSi

The following table gives an overview of dje Toxi ity and the aesthetic effect some?! * in advance of "the well-known Lolcalanaesthotika Xylocaine and Butan.il icain.

In the table:

RA: relative filtration aiiaeiithesies (During their determination, the fourth in the column dvti * eh-- dividing the column 3) «

RLi relative Leituii <Ti ~. ~ R <a. <: «I? Thcsie

(For their investigation "" -urdeii · the values in column 7 divided by that of column 3)

MAY mean anaostlietic index
(arithmetic mean of RA and RL)

The following connections were investigated:

me t liylt hi phenbydr ο chloride,

2) 3-i ¹ -utylaminoacetylaniino-4-methylthiophene hydrochloride,

3) 3-Diiithylamino-ß "propionylaniino-2-carbonietlioxy - ^ -" never thylthiophene hydrochloride

k) 3-n-I3utyla! nino ~ ß-propionylamino-2-carboinethoxy - ^ -

methylthiophene hydrochloride
5) 3-n ~ Butylam.inoacetyla ⁱ ! Tino-S-carbonjethoxy-2,4-diethyl · ·

thiophene hydrochloride,
^] Butanilica
"? J xylocaine

From the juxtaposition der ■ ^r 'inz ⁿ li lind RclatiwrertR related to the Toxi? i "t; ^r . ~ \"il' · ■ ·: "■:. 'f.' . th: ·> - · ■■ H'uttaeiiP superiority of erfintlv-.vgs ^ iuiaiSe.n new i ^x ERL> iafl-un £ cu over known Lol <aliinaos-th3ßt-i:>; a cni-Ksb!

■ 109ST3 / 1873
BATH ORIGINAL

- ■ 12 r-

1
verb

No.

toxicity
DL ₅₀ iV

/ "" mg / kg 7

relative toxicity

(Hostacain =!)

Inf i1trati on? -
anesthesia
1% solution
/ min. 7

relative s amk ei t

! 6th

Lei t "OJ

anesthesia 0.25 %

/ Z, 4 _, "7

-s-

Effective

kei.t. (Hq s ta-. caiti-1)

RA

9 i

RL ί I-iAI ■

IR A + RL

χ »·

37 40

CO
33.1

.ν i>. 6th

0.9 0.8

Oi 7 0.7 0, 'i 1.0

45.0
39.0
<* 3.0
21.3
37.7
38.3

0.9

1 * 2

i _f o

111

0.6 1.0 1.0

27.0 38.5 36.0 46.0 21.9 23, c

1.2

1.2

1.6

2.0

0.3.

! 1.0 1.5

1.6

1.3

1.5

1.2

1.5

2.3 y 1.9

a,

2.3

, 1.1 1.3 1.0 1.0 I 1.0 0.3 0.4 j 0.6

- 13 Example 1

3 "ii-butyl-afn.ino-ace tylaiitino-2- carbome thoxy-4-methylthiaphene

24.7 S 3-Cb.loroacetylamino-2-t.carboniGthoxy-4 »methylth: ± phen (made from 3 ~ amino ~ 2-cm * bome ^- thox.y ~ 4 - iHethylth.ioph-en (mp 84 -85 ° C) and chloroacetyl chloride; mp, Il8 ° (from methanol)) are dissolved in 200 ml of toluene, then 22 g of n-butyl chloride are added and the mixture is heated to the boil for 6-7 hours. After cooling, the butylamine hydrochloride formed is washed out with water, the toluene phase is dried with sodium sulfate, and the solvent and excess butylamine are then distilled off. The oily residue is taken up in ether. Passing in hydrogen chloride gas or methanolic hydrochloric acid gives 3-n-butylnmino-acetylamino-2-carbomefchoxy-4-ynethylthiophene hydrochloride, yield 92 %. For purification, the substance is recrystallized from water, it melts at 154 - 156 ° C.

In an analogous manner, using appropriate amines - -.

the 3-diethylaminoacetylamino-2-carbomethoxy-4-methylthio-

phen hydrochloride, pp. 157-158 ° i the 3-piperidino-acetylamino-2-carbomethoxy-4-methylthio-

phen of m.p. 110-111 ° (llydrochloridi p. 188 °); the 3-pyrrolidino-acetylaiiilno-2-carbomethoxy ~ 4-methylthio-

phen hydrochloride, m.p. 182-183 ° ^ the 3 ~ isopropylamino-acetylamino-2 ~ carbomethoxy-4 ~ methyl-

thiophene hydrochloride, m.p. 98-99 ° |

from 3 "chloroacetylaniiiiu- · '; ·· vn mp 137-13δ °

109813/1873 BAD ORIGfNAL

- I ¹ I -

the 3-11 "butylamino-acetyllamino ^ i-carbornethoxy- · 2-methyl-. thiophene hydrochloride, which when recrystallized Water and 1 mole of crystal water crystallizes; Fp,

3-diethylaniinoacetylamiuo-'i-carboniethoxy-2-ynethylthiophene hydrochloride, melting point 163 ° -164 °; from 3-Chlorace tylamino-5-carboniethoxy-2, 4- dimethyl thiophene mp l42 ₄ - °

3-n-Butylainino ~ aoetyla! iiino-5-ca-rboniethoX3 ^r -2, 4-diinethylthiophene hydrochloride, melting point 23Ί (with decomposition);

3-E ^> iäthylaniinoacetylaniino-5-carbomethoxy-2 t 4-diethylthiophene hydrochloride, mp 112-114; from 3 ° (-chloropropionylamino-2-carbomethoxy - ^ - methylr thiophene, melting point 99-101 °;

3-n-Propylainino _i -P ( "propionylamina-2-carboinethoxy-" 4-methyl-rthiophen hydrochloride, m.p. 177-170 ° (Kp j of the base 162 - L67 ° / O.3 mm)..;

the 3 ~ nB ^u tyl.amino CC propioiiylamino-2-carbomethoxy-4-methylthiophene-hydrochloride, mp. 178 - 180 {

the 3-diet hylainino- ^! ^ rpropionylamino-2-carbomethoxy-4-methylthiophene hydrochloride, mp 178 - LSSO.

the 3-Py- £ Tolidi ⁿ or - (\ - propiany.l amino ~ 2-carbomethoxy-4-methylthiophenchlorid a melting point of 19O - 195 j from 3-ß "~ Cblorpropionylainino-2-carboxylic} eth0xy-4-5HGthyl-. thiophene, m.p. 108-110 °

10 98 13/1873 BAD ORfQfNAt,

the ^ -n-Biitylauino-ß-propionylainino-S-carbonicthoxy ^^ -mnethyl- · tliiopheiJ-hydrochloride of melting point 174 - if 5 ° 5

das 3 ~ ⁿ ~ ^ ^ro Pyla> u ^: ino ~ ß ~ | uu}? ioiiylafrtiticr-2-Ctirbi> ei.etboxy- ^/ t-raelhy.l · thiophene hydroehlorid, Vp * 2ÜÖ - 202 °;

das 3 - diethj'laiwJLttö-ß-propicmylarHino-S-carbomethoxy - ^ »metiivithiophan-hydx-o chlorine: · d, m.p. ICf 1-102 j

the 3 ~ Py

Ihiopben-hydrnChlorid, Vp * 13? Ί -

from 3 - Ch 1 or ac e ty lanii πο ■ »2- * c: affjä t-lioxy ■ * 4 *> me thy 1 thi opiien Fp. 103 ■ - luk °

das- 3-n-Btitylanrxiioacety.T aiüiiio ~ 2 * carbäthQXy-'ί-roethylthiiyphen-hydrachlorid, Pp ,. 130 - 134 ° \

das 3-I> iäthylataino-aeetylainiiT6-2-earbäthpxy-4-ittethylthiophen vent Kp, ^ _Λί . 160-162 ^G (hydrochlorideί m.p. 130-

Example 2 a

17 * 6 g of 3-Chloi'acetylaininothiophene, which is obtained by decarboxylation of 3-Aiuiiio-2-carboxythiophens and subsequent reaction of the 3 "amino-thiophenes of boiling point 50 ° / 6 mm with chloroacetyl chloride, are with 300 ml Benzene and 23 ml of II-butylamine are heated to the boil for 7 hours. After cooling, the butyl amine hydride formed is washed out with water, the benzene phases are dried with sodium sulfate and then the solvent and excess butylamine are distilled off

1098 13/1873

BATH

- i6 - ■ -; '■■■

oily residue, some of which is ki-.tstallis.xert, becomes in ether added and by introducing hydrogen chloride gas. or the hydrochloride by means of methanolic hydrochloric acid of the 3-n - "* butylamino-a.cetylaminothiophene. precipitated". Yield 19-K The hydrochloride melts after the urine crystal

yaw from i-propornol at 219 ~ 220.

In an analogous manner, one obtains using appropriate amines

from 3-chloroacetyläiiiino- (l-methylthioplien (mp. 95-96), which is obtained by decarboxylation of the 3-amino-2-carboxy-'i-methyl-thiophenes (mp. IZJ) and subsequent reaction of the dal .'ei. obtained "3 ~ amin.o" ^ - methy! thiophenes (Sp. k'j / 0.05 mm) with chloroacetyl chloride,

3-n-Butylamiitoace tylamino-4-i-diethylthiophene, Sp. ΐ'ϊ5 150 ° / O.O5 now (melting point of the hydrochloric acid: 219 ° -220 °);

the 3-n-propylaminoacetyiamirio- ⁷ i-methylthioi) hen, Sp. ikk / 0.15 mm (mp. of the hydrochloride 218-219 °);

das 3 ~ l) iäthylam: i noacetylarnino- ^ l-niethyl i hiophene, m.p. 52 (melting point of the hydrochloride: 18-120 °);

the 3 ~ Cyciohexylaniinoacetylämi'j) o - '{- methylthiophene hydrochloride, Mp 250 ° (dec.);

from 3-chloroacetylamino-2, / j-djfieihyltliiop) ien (mp. 120-2 °), which is obtained in the reaction by saponification and decarboxylation from the 3-Auu no-5-carbomethoxy-2, k- ' dimethyl thiophen (Fp. 81! - 8'j) .entatandenen 3 ~ aniino'2, 4-dimc ^v Lhylthio}) means:, 11 CiI υ . .jcc ΐ. . ·. iclilor.if, ..rhalL,

I ^:; 13/1873 BAD ORiGJNAi. ..

the 3 ~ * i "i ^ tylamino-acetylön} ± iio-2, ^ -dimethylthiophene hydrochloride, Mp 230-223 °;

the 3 ~ r>iäthylami.noacetyrami'no-2, ^ - dimethyl.thiophene hydrochloride, melting point Ijk - 176 °;

from S-OC-chloropropionylaraiAo-it-methylthiophene. (Mp. 7 ^l- 75 °), which can be prepared from 3 ~ Amxiio- ^/ i - raethylthiapheii (Sp. K5 ° / 0.Q5 mm) and "(- chloropropionyl chloride,

the 3 "n-Propylarairio ~ 0i-propionylaniino- ^/ i-niethylth.iophene,

Sp. 1Λ0-1 '^ Jt ⁰ ZOrI mm (m.p. of the hydrochloride 219 ° -219 °);

the 3 ~ n-butylamino-o (~ propionylamino ^/ i-metliylthiophen, mp 66 ° (m.p. of the hydrochloride: 130-13 ^ ^0);..

from 3 ~ ß-chloropropionylamino- * t-methylthiophene (melting point 108-109 ° C), obtained from 3-amino-4-raothylthipphen and ß-chloropropionyl chloride

3-n-butylamino-ß-propionylaraino-4-methylthiophene-hydrochloride, Pp 170-171 °.

4 ·· Sn-propylamino-β-propionylamino - ^ - methylthiophene hydrochloride, m.p. 159-5-160.g ° j

dae 3 -Pyrr <> Ii dylamino "-ß-propioiiyl ami no- 4-m et ethylthiophene hydrochloride, pp. 169 - ^

Example 3

3-diethy.latninoaco tylant .inu "- ^ - cv _3t rboi; iu h_l> o -ry-4-inf thyJ Lliiophon

S 3-amino-2-carbomethoxy ~ 'i ~ ineihyl thiophane ■ (mp. Ö'i-ß3 °) are cooked in portions while stirring and cooling

109813/4 ti3.

BAD OFAD ^ ^{i: AB}

added to a suspension of 15 g of diethylarninoacetic acid chloride in 100 ml of acetone and then heated to boiling for 30 minutes. After cooling, the 3-diethy3 - ■ amino-acetylaniino-S-cnrbomethoxy-'i-methylthio'pheii hydrochloride is filtered off. To clean it, the hydrochloride is dissolved in water, shaken out with ether and the rabbit is precipitated with potassium carbonate solution. The base is then taken up in ether, dried, iv.lt sodium sulfate and, after chasing off the ether, the residue is distilled in a high vacuum. This gives 6 g of 3 ″ Wiäthylam: Liioacetylaniino-2-carboinethoxy-4-methylthiophene with a bp 16-165 / OI mm. The hydrochloride melts from isopropanol / diisopropyl ether at 157-158 °.

Example k

3-diethylan) inoacctylamino-2-carbomethoxy-4-methylthiophene

1 ^ S i3 3- äthylaminoacetylamino ^{Di-2-carbomethoxy-4-methyl-} ^, 5-dihydrothidphen (Sp 156 -. L6L ° / O.O5 torr) in 50 nl of methylene chloride, "" load, and with stirring at -5 bie -10 ° drop white with a solution of 8 g of bromine in 25 «1 of methylene chloride. The mixture is then allowed to continue for 1 hour at the same temperature, the excess of bronchi which has formed is removed by sucking air through the solution, and the methylene chloride is then expelled in a water jet. The residue is dissolved in water and the aqueous solution is extracted with ether. After separating the ether, the base is precipitated from the hydrobromic acid solution with sodium carbonate solution, it is taken up in ether and the ethereal solution is dried in it 1ΐί \ Lriviusu '.. at ... After Abdesti. liieren des

10 9 8 13/187 3 BAD ORtGINAt

- 19 -

Ether, the residue is distilled in a high vacuum at i6.1-165 and 0.1 mm. 7.7 g of 3-diethylaminoacctylamino ~ 2-carboinethoxy-4-riethylthiophene are obtained (melting point of the hydrochloride 157-158 °)

The starting material is obtained by unsctimg of 3-chloroacetylauiino-2-carboniethoxy-4-methyl-4,5-dihydrothiopheri '(mp. 84 ~ B5 ⁰ ; prepared by reaction of 2-carboraethoxy-4-methyl-thiophanou- (3 ), Sp. 75 /0.05 torr) tind

Chloroeotyl chloride). and diethylamine.

■ - ■ "

Example 5

3 ~ diethylamino-a cctylamino-S- carboniethoxy - ^ - methylthiophen .

36 g of 3-isocyan-2-carbomethoxy- ^/ i-methylthiophene (melting point 107 108 °), which is obtained from 3-PormyJenvino-2-cnrbomethoxy-4-methylthiophene (melting point 13Ο -1) by known methods (s. New methods of preparative organic chemistry, Vol. IV, p. 43), 25.8 ml of diethylamine, 25 ml of 30% formaldehyde solution, 100 ml of acetone and 50 ml of water are added. and under .cooling with 25 ml conc. . Hydrochloric acid added. The mixture is left to stand for 60 hours at room temperature and then distributed between water and ether. The aqueous phase is made alkaline with sodium carbonate solution and extracted several times with ether. After drying with sodium sulfate, the ether is stripped off and the residue is dissolved in vacuo. M-in receives 42 g of diethylamino-acetylamino-4 ~ methylthiophene with a boiling point of 161-165 ° / ol mm. Hydrochloride m.p. 157 "- 158 °.

1 0 i? ^r M 3/1 8 7 3

- 20 Example 6

^ -Difithylaiiiino-fi-butyrylamLno - ^ - inethylth iophen

10.5 g of 3-crotonylamino-4-methylthiophene (p. 99-100 °), which was obtained from 3-amino-4-methylthiophene and crotonic acid ^{chloride, will «dissolved in 3 '1} '" -T-diethylamine and 20 hours, im autoclave l'4O - VjO heated After cooling, the excess of diethylamine is abdestilliex't, the residue is dissolved in ether and extracted with 2N hydrochloric acid After separation <ler ether layer is precipitated from the aqueous Shicht the Bane with sodium carbonate solution of.. takes it up in ether and dries the ethereal solution with sodium sulfate. The addition of ethereal hydrochloric acid precipitates the hydrochloric!

■ * ■ r 1 / ~ O

■ Aether uncrystallized at 164 - I65 melts. Yield: Example 7

3-n - B utylani j.ito "c- c e tyl anil no - ¹ I -iüc t hyl thi opii en

9> 5 £ N - Bonzyl "oxycarbonyl-n-butylamine.ossig.Äure and 5 nil triethylamine are poured into 50 ml of Toi rahydrofuran" with. -5 drops.v7cise under Rülu * nn nil 3 »^ '» 1 ethyl chloroformate added and 15 minutes? stirred at this temperature. Then a solution, cooled down to ~ 5, of ¹ g of 3-amino ~ 'f-methylthiophene in 20 ml of tetrahydrofuran is added and the mixture is stirred for 2 hours. During this time one leaves there ;; 'GtMnisr.h slowly come to a temperature. Pm'i) ui .tu \ Λι : ir . ·, (; ■: (■ tc !! n , tu <i di ·.

10 ' 3I 1 R 7 3

Dissolve triethylamine hydrochloride, shake out the aqueous phase again with ether and dry the pre-cleaned organic solutions with sodium sulfate. The residue v. Remaining after the solvent has been distilled off. ^r ir'd with kO ml of a solution of ■ hydrogen bromide in glacial acetic acid (approx. 37 %) left to stand for 1 hour. It falls; the hydrobromide of the 3-tt-Butylamirtoacetylamino ^"/ i" -niethy3 thiophene cius suctioned uncliiiit Athci washed *, yield: 7 g, mp 200-202 ° is void added in sodium carbonate with stirring, the liberated base in Äthei.... After the ethereal solution has dried, the hydrochloride of 3-n-butyla? ai.no.-acetylamino-4 "inethylthiophene is precipitated with ethereal hydrochloric acid (219 ° -220 °).

In an analogous way one obtains:

from N-benzyloxycarbonyl-n. "hut ylamino acetic acid and 3-Amino-5-carbomethoxy-2,4-dimethyltbiophen

the 3-n-Butylami.no-acetyla ^ τιino-5-carboιπet.h'-χy-2, 4 ~ dimethylthiophene hydrochloride, Fp-. 23 ^ (with decomposition)

109813/1873

EAD

Claims (1)

R is hydrogen, a straight-chain or branched one Alkyl radical with 1-6 carbon atoms, which is optionally through Hydroxyl groups or can be substituted by alkoxy groups with 1 - 3 carbon atoms, R is a straight-chain or branched alkyl radical with 1-6 carbon atoms, which can optionally be substituted by hydroxyl groups or alkoxy groups with 1-3 carbon atoms, a cycloalkyl radical with 5-6 carbon atoms or an alkenyl radical with 2- k carbon atoms , where R. and R together with the N atom also form a saturated heterocyclic ring with 5-7 ring members,. can, which may optionally also contain oxygen or the methylimino group, R, R /. and R is in each case hydrogen *, an alkyl radical with 1 - * i C-Atoinon or a lower carba 1 koxy group, A a straight-chain or branched alkylene group with t - h. Mean carbon atoms. 2. Process for the manufacture of .substituier uen 3'-AiHiivo ~ ■ acylaminothiophenes of the formula UnterlagBiI (Ail '' .j 1 '.--. Κ- ι ■.,' -. _S j «ÄiK-pruresgea. Ν. 109B13 / 1873 BAD R, -C -G-KH-CO-A-K il G-IL characterized in that one a) 3 - Ha .1 ο se ϊΐ ε \ c 3 ^r 1 ami η ο t hx ο ρ 1> υ η. c the P rnie 1 - KH-CO-A-X ■ Κ Ι I in the X halogen, ζ. B. chlorine, bromine or iodine or, a Alkoxy-aralkoxy or aryloxygi-uppc means with one primary or selcundäx'en Ainin. the formula HN III implements, or b) 3- Amine thiophenes of the al "lf \ rni a formula , .. _K " ₂ or their salts odc-r C ^; ri i ,; ^! .; - j-fi->»t>rbiji..iv> n / rcri 10 ^f 13VT87? BATH • - 2k -. with an aminocarboxylic acid of the formula HOOC »A-N V or «, acylated a reactive derivative of the same, c) 3 ~ amino-4, 5- or, -2, 5 ~ dihyc3rothiophenes of the formula / ^R l R -γ ___ - NH-CO- Λ ~ Ν IJ "^ P or ■ R /. ' ^{S Χ} R _r -2 Via ^R l NH-CO-A-N VIb dehydrated, or d) 3-Aminoacylaminothiophei3.e of the formula J-NiI-CO-A-NH ₂ ^R alkylated in lieiso known per se, or 10 33 1 3/1873 e) compounds of the formula R- ——7Γ NH-CO-AK ' ^J j! ! j I VIII VS ^ R ₅ ^R 6 ■ *. ■ wherein Rr shares an ester group, saponified; or f) to unsaturated acylaminothiophenes of the formula R T jj - NH-CO- «A * -H J ' ^R 5 in which A ¹ denotes a straight or branched alkyl radical having 2- k carbon atoms, amines of the formula - ^ R 1 attaches; or g) thiophene isonitriles of the formula ¹ V NC - ^R 5 formula V " ^s ' ^v the with amines in the presence of aliphatic aldehydes with Converts carbon atoms, 10981371873 any carbalkoxy groups present in the R "- _f R ^ - and / or R ^ -position are saponified and docarboxylated and / or, if appropriate, the compounds obtained are converted with acids into pharmaceutically acceptable salts. 109813/1873 ORIGINAL·