DE1643325B2 - 3-AMINOACYLAMINOTHIOPHENA AND THE METHOD FOR THEIR PRODUCTION - Google Patents

Description

/ R ³ NH-C-A-N

XX °

R ⁴ SR ⁵
characterized in that one

(X)

R ⁴ 'SR ⁵
with amines of the general formula so

R ¹

HN

\ as

R ²

in the presence of aliphatic C _{1 -C 4} aldehydes, optionally ^{saponified and decarboxylated carbalkoxy groups present in the R 3} , R ⁴ and / or R ^s position and / or optionally converting the compounds obtained into pharmaceutically acceptable salts with acids, wherein the symbols R ¹ , R ^a , R ³ , R ⁴ and R ^s each have the meanings given in spoke 1 3s.

a) 3-Halogenacylaminothiophenes of the general formula

in the X halogen, e.g. B. chlorine, bromine or iodine, or an alkoxy, aralkoxy or aryloxy group means with a primary or secondary amine of the general formula

R ¹

HN

(HD

implements or
b) 3-aminothiophenes of the general formula

The invention relates to substituted 3-aminoacylaminothiophenes the general formula

R ¹

NH-C-A-N

SR ⁵

(IV)

or their salts or Grignard compounds with an aminocarboxylic acid of the formula

(D R '

HOOC-A —N (V)

R ²

in which R ¹ is hydrogen, a linear or branched C ₁ - Q-alkyl, R ² is a linear or branched C ₁ -Ce alkyl group, a C ₆ -C ₆ cycloalkyl radical or a C ₂ -C ₄ alkenyl, wherein R ¹ and R ⁸ together with the N atom can also mean a pyrrolidino, morpholino or piperidino radical, R ^s hydrogen, a C ₁ -C ₄ -AUCyI radical, the carbomethoxy or carboethoxy group, R ⁴ hydrogen, a C ₁ -C ₄ alkyl or the carbomethoxy group, R ^{6 is} hydrogen, a C ₁ -C ₄ alkyl or a lower carbalkoxy group and A is a straight-chain or branched alkylene group having 1 to 4 carbon atoms.
The invention also relates to a process or a reactive derivative thereof acylated,

c) 3-Amino-4,5- or -2,5-dihydrothiophenes of the formula

R ³

NH-C-A-N

(Via)

R ¹

NH-C-A-N

(VIb)

R-

dehydrated or

d) 3-Aininoacylaininothiophenes of the formula

R ³ ^ NH-CA-NH ₂

> / \ O (VII)

R ⁴ SR ⁵

or alkylated in a manner known per se

e) compounds of the formula

R ² / R ³ NH-C — A —N (VIII)

V / Ii i

XX ° ^R "

R ⁴ SR ⁵

in which R ^{e represents} an ester group, saponified or f) to unsaturated acylaminothiophenes of the formula

(IX)

in which A 'denotes a straight or branched C ₂ -C ₄ -alkenyl radical, amines of the general formula

R ¹

HN

attaches or
g) Thiophene isonitriles of the general formula

with amines of the general formula

in the presence of aliphatic C ₁ -C aldehydes, optionally ^{saponified and decarboxylated carbalkoxy groups present in the R 3} , R ⁴ and / or R ^s position and / or optionally converts the compounds obtained into pharmaceutically acceptable salts with acids, the Symbols R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the meanings given in claim 1.

a) Those used in the method according to variant a) 3-halo-acylaminothOphene of the formula II preferably contain chlorine or bromine in the acyl radical. For the reaction with the 3-haloacylaminothiophenes come z. B. the following amines of the formula III in question: alkylamines, such as methylamine, Ethylamine, n-propylamine, isopropylamine, n-butylamine Isobutylene, sec-butylamine; tert-butylamine; Dialkylamines, such as diethylamine and di-n-butylamine, also alkylenimines, such as piperidine, or pyrrolidine. The implementation of the Halogenacylaminothiophenes with ao the amines can be carried out either in the presence or in the absence of solvents. Possible solvents are: ether, dioxane. Alcohols such as B. methanol, ethanol, propanol, saturated cyclic hydrocarbons such as cyclohexane * 5 and methylcyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene, and chlorinated hydrocarbons, such as chlorobenzene, chloroform and carbon tetrachloride. The reaction temperatures are between room temperature and the boiling temperature the respective solvent; pressure can optionally also be used during the reaction. In order to neutralize the acid formed during the reaction, an excess is preferably used of the amine used and uses at least 2 parts of amine to 1 part of 3-haloacylaminothiophene. The reaction time is about 4 to 12 hours, depending on the reaction temperature. For cleaning the aminohydrohalide formed as a by-product is dissolved out with water, solvent and Excess amine is distilled off and the remaining process product is distilled or through Dissolving in mineral acid and precipitating cleaned with dilute sodium hydroxide solution.

For the preparation of the haloacylaminothiophenes used as starting materials one proceeds in per se known way. For example, aminothiophenes or aminothiophenecarboxylic acid esters are used with haloacyl halides and optionally saponify the products obtained. The aminothiophenes and Aminothiophenecarboxylic acid esters are also obtained in a manner known per se, the latter for example after the process of DT-PS 10 55 007, 10 88 507 and 10 83 830, the former by saponification and decarboxylation the aminothiophenecarboxylic acid ester. If aminothiophenes are used as starting materials, which are found in 4-position carry a carbaloxy radical, this can be done according to the method of Cheney and Piening, "Journal of the American Chemical Society ", Vol. 67, p. 729, 731 (1945), from the corresponding thiophanone- (3) -carboxylic acid esters and hydroxylamine obtain. Instead of the haloacylaminothiophenes, one can also use alkoxy-, aralkoxy- or aryloxyacylaminothiophenes run out. For example, methoxy, Ätlioxy, benzyloxy are used as or phenoxy substituted acylaminothiophenes. Mim she receives z. B. by Umset / .iüig of aminothiopheies or Aminothiophenaubcmsäureestern with Alkoxy, aralkoxy or aryloxycarboxylic acids and

7 8

Chloroformic acid ester by the method of using dilute hydrochloric acid on standing. On top of these mixed anhydrides. Compounds are obtained in which R ¹

b) The process products are also obtained according to represents hydrogen.

Variant b) by using 3-aminothiophenes of the form f) One can (Jas method also in the manner mel IV carry out with an aminocarboxylic acid of the formula V 5, since acylaminothiophenes or or preferably a reactive derivative Acylaminothiophencarbonsäureester, which in the Acyleiner converts such acid. As an aminocarboxylic acid chain, contain a double bond, with a broken one named for example: methylaminoacetic acid, speaking substituted primary or secondary Ethylaminoacetic acid, n-propylaminoacetic acid, secondary amine. As acyl residues, the double bonds Butylaminoacetic acid, cyclohexylaminoacetic acid, Di- i ° contain, come z. B. in question: acrylic acid, methylaminoacetic acid and piperidylaminoacetic acid. acrylic acid, tiglic acid, crotonic acid or isocrotonic acid Acid residues can be found in place of the aminoacetic acids mentioned.

also the correspondingly substituted «- and / 5-amino- The reaction; with the amines can be both at propionic acids, the various isomeric amino- room temperature as well as at higher temperature with Use butyric and aminovaleric acids. 15 or without the application of pressure and / or solution ais reactive derivatives of aminocarboxylic acids take place in the middle. This usually comes with an overcoming z. B. acid chlorides, acid esters, acid amides, shot of the amine worked, preferably used Acid azides and acid anhydrides into consideration. Instead of using about 3 moles per mole of acyl derivative. The Herder 3-Aminothiophenes can also be their salts, if the starting materials of the formula IX are made z. B. alkali or alkaline earth salts, or Grignard ao, for example, by reacting the unsaturated compounds (halogen-magnesium compounds) with acid chlorides with aminothiophene or aminothio ends. The reaction is expediently carried out in inert phencarboxylic acid esters. According to the procedure of Solvents, for example in ether, benzene, To variant f), however, no-aminoacylluol is increased or xylene. aminothiophenes.

c) The dehydrogenation of the starting materials of the formula »5 g) The preparation of the thiophene isonitriles of the formulas VIa and VIb is carried out in a manner known per se using conventional dehydrogenating agents according to methods known per se. (Newer methods of preparative organic chemistry, Vol. IV, particularly well-suited dehydrogenating agent has been found on p. 43 ff.) By reacting the corresponding for-chloranil; a mylaminothiophene with dehydrating agent, aromatic hydrocarbon, such as. B. Toluene, 30 The reaction with aldehyde and amine to the ver-xylene or mesitylene, used and preferably 5 vehicle products is heated to the boil at room temperature in up to 15 hours. Carried out when using an aqueous organic medium; by adding bromine as the dehydrogenating agent, adding acid, the pH is set to about 5 to 8, advantageously with cooling, preferably at. The reaction time is between a few - 10 to + 1O ⁰ C. The solvents used 35 minutes and lOOStundsn. When using primary, preferably halogenated hydrocarbons, such as amines, it is expedient to use an excess z. B. methylene chloride, chloroform, carbon tetrachloride worked. Contain the substances according to methods a) to. A catalysis of the hydrogen halide cleavage d) shown process products nor carbalkoxy with basic agents is not necessary. The 3- (sub.Amino) -acylamino used as groups in R ^s , R ⁴ and / or R ⁵ position can be used as starting materials, if desired by saponification and 2,5- or 4,5-dihydrothiophenes obtained analogous to remove decarboxylation. The saponification is carried out in the corresponding thiophenes [cf. Variant a)] carried out in a manner known per se with alkali or alkaline earth metals using appropriately substituted hydroxides. This can be done with amino-dihydrothiophenes. The latter can be worked with appropriately substituted thiophanones from room temperature or at elevated temperature by incorporating them. The decarboxylation is carried out, for. B. pass ammonia gas or by heating with by heating with suitable organic bases, represent ammonium acetate. for example quinoline or diethylaniline in opposition

d) The alkylation of starting materials in the form of copper powder, preferably just below mel VII, is carried out by known methods, e.g. B. with the boiling point of the organic bases.
Aldehydes or ketones, in the presence of Reduk- 50 The tion agents according to the method according to the present, such as. B. formic acid. Compounds prepared as the alkylation invention are in the form of medium can also be mineral acid esters, such as. B. their salts readily soluble in water. For salt formation, alkyl halides, sulfuric acid or -phosphoric acid come organic and inorganic acids, use with esters. Arylsulfonic acid esters are, for example, acetic acid, lactic acid, maleic acid, and Zi as well. The starting materials of the formula VII are troöenic acid, tartaric acid, aceturic acid, amidosulfone according to the general process acid described under a), oxyethanesulfonic acid, phosphoric acid, chlorine ren for the preparation of aminoacylaminothiophenes hydrochloric and hydrobromic acid, available. The salts crystallize well and are very stable.

e) In the compounds of formula VIII is your aqueous solutions are well preserved, can call and no tissue is my used to protect amino groups without R ^e a Esterrest as are general sterilized in peptide chemistry 60 further. irritation. The compounds represent valuable captocarbonyl, tosyl, trifluoroacetyl, tert-butyloxy therapeutics with interesting pharmacological carbonyl and -nitrophenyl-sulfenyl groups in the form of carbobenzoxy and mer-free as well as in the form of their salts. The splitting properties dat. Due to their strength of action, they are also based on those in peptide chemistry and their low toxicity, and they are primarily suitable as customary methods, for example with sodium in local anesthetics

liquid ammonia or with hydrogen bromide in the following table gives an overview of the glacial acetic acid. In some cases the split is already taking place. Toxicity and the anesthetic effect of some ver

bonds according to the invention compared to the known local anesthetics butanilicain (Hostacain®) No. 6 and lidocaine (Xylocain®) No.

The table contains under column

2) the toxicity in mg / kg mouse,

3) the relative toxicity based on hostacaine = 1,

4) the duration of infiltration anesthesia in minutes, caused by a 1% solution,

5) the relative effect of infiltration anesthesia, based on hostacaine = 1,

6) the conduction & anesthesia in minutes, caused by a 0.25% solution,

7) the relative effect of central anesthesia, based on hostacaine = 1,

8) RA = relative infiltration anesthesia, quotient from the values in columns 5 and 3,

9) RL = relative central anesthesia, quotient from the values in columns 7 and 3,

10) MAI = mean anesthetic index, the arithmetic Funds from RA and RL.

The table below contains the following compounds:

1) S-n-Propylamino-Ä-propionylamino ^ -carbomethoxy-4-methylthiophene hydrochloride,

2) S-n-ButylaminoacetylamineG ^ -methylthiophene hydrochloride,

3) S-diethylamino-ß-propionylamino ^ -carbomethoxy-4-methethylthiophene hydrochloride,

4) S-n-Butylamino-zI-propionylamino ^ -carbomethoxy-4-methylthiophene hydrochloride,

5) S-n-Butylaminoacetylamino-S-carbomethoxy-2,4-dimethylthiophene hydrochloride,

6) butanilica,

7) lidocaine,

8) S-n-Propylamino-öi-propionylamino ^ -carbo-

butoxy-4-methylthiophene hydrochloride, 9) 3-pyrrolidino-acetylamino-2-carbomethoxy-4-methylthiophene hydrochloride,

10) S-diethylamino-acetylamino ^ -carbomethoxy-2-methylthiophene hydrochloride,

11) S-n-propylamino-acetylamino ^ -methylthiophene hydrochloride,

12) S-diethylamino-acetylamino ^ -methylthiophene hydrochloride,

13) j-n-butylamino-acetylamino ^ -dimethylthiophene hydrochloride,

14) S-Allylamino-a-propionylamino ^ -carbomethoxy-4-methylthiophene hydrochloride,

15) S-n-Propylamino-a-propionylamino ^ -carboao methoxythiophene hydrochloride,

16) S-n-propylamino-a-propionylamino ^ -carbomethoxythiophene hydrochloride,

17) S-n-propylamino-a-propionylamino ^ .S-dimethylthiophene hydrochloride,

18) S-n-Propylamino-a-propionylamino-S-methyl-2-carbomethoxythiophene hydrochloride.

By comparing the individual and relative values related to toxicity, the therapeutic Superiority of the new compounds according to the invention over known local anesthetics remove.

Connection no.

toxicity
DL ₁₀ iv

3 4 5

Relative infiltration Relative line toxicity anesthesia effect anesthesia

Relative
effect

8 RA

9 RL

10TH OF MAY

37

40

50.5

45

80

33.1

28.6

12.7

58

45

44

61

43.5

38.9

45.3

57.2

54.3

91.0

0.9

0.8

0.7

0.7

0.4

1.0

1.2

2.6

0.6

0.7

0.8

0.5

0.8

0.85

0.7

0.6

0.6

0.4

34.9 45.0 39.0 43.0 21.3 37.7 38.3 31.7 26.4 35.8 34.4 44.6 20.1 41.1 25.8 7.4 20, 7 13.8

0.9

1.2

1.0

1.1

0.6

1.0

1.0

0.85

0.7

1.0

0.9

1.2

0.5

1.1 0.7 0.2 0.5 0.4

27.0 38.5 36.0 46.0 21.9 23.0 24.2 115.8

18.7 25.7 22.9

20.8 13.8 18.6 18.2

1.2 1.0 1.7 1.5 1.6 1.4 2.0 1.6 0.95 1.5 1.0 1.0 1.1 0.8 5.0 0.3 - 1.2 - 1.4 0.8 1.1 1.1 2.4 1.0 0.6 - 1.3 0.9 1.0 0.7 0.3 0.8 0.8 0.8 1.0

1.3 2.1 2.3 2.9 2.3 1.0 1.1 1.9

1.0 2.2 1.2

1.3 1.2 1.3 2.0

1.2 1.8 1.9 2.3 1.9 1.0 1.0 1.1

1.05

2.3

0.9

1.15 0.8 1.1 1.5

example 1

S-n-butyl-ammo-acetylamino ^ -carbomethoxy-4-methylthiophene

24.7 g of 3-C-Moracetylammo-2- arboinethoxy-4-ynethylthiophene (prepared from 3-amino-2-carbomethoxy-4-methylthiophene [mp 84 to 85 ° C] and chloroacetyl chloride; mp 118 ° C [from methanol ]) are in ml of toluene dissolved; 22 g of n-butylamine are then added added and heated to the boil for 6 to 7 hours. After cooling, the butylamine hydrochloride formed is washed out with water, the toluene phase dried with sodium sulfate and then the solvent and excess butylamine are distilled off. The oily residue is taken up in ether. 6s By introducing hydrogen chloride gas or by methanolic hydrochloric acid gives 3-n-butylamino-acerylamino ^ -caÄomethoxy- ^ methylthiophene hydrochloride; Yield 92%. The

11 12

Substance recrystallized from water, it melts when obtained with chloroacetyl chloride, with 300 ml

154 to 156 ° C. Benzene and 23 ml of n-butylamine to boil for 7 hours

In an analogous manner, one obtains heated using. After cooling down, the

butylamine hydrochloride formed by corresponding amines washed out,

the S-diethylaminoacetylamino ^ -carbomethoxy- 5 dried the benzene phases with sodium sulfate and

4-methylthiophene hydrochloride, mp 157-158 ° C; then the solvent and excess

the S-piperidino-acelylamino ^ -carbomethoxy ^ -me-butylamine distilled off. The oily residue that led to the

ethylthiophene from 110 to Hl ⁰ C (hydrochloride: part crystallizes, is taken up in ether and

Mp 188 ° C); by introducing hydrogen chloride gas or by means of

the 3-pyrrolidino-acetylamino ^ -carbomethoxy- io methanolic hydrochloric acid the hydrochloride of the 3-n-

4-methylthiophene hydrochloride, mp 182-183 ° C; Butylamino-acetylaminothiophene precipitated. Yield

the S-isopropylamino-acetylamino ^ -carbomethoxy- 19 g. The hydrochloride melts after the recrystallization

4-methyltb.iophene hydrochloride, m.p. 98 to 99 ° C, lize from i-propanol at 219 to 220 ° C.

from S-chloroacetylamino ^ -carbomethoxy ^ -methyl- is obtained in an analogous manner using

thiophene mp 137-138 ° C; 15 corresponding amines

3-n-Butylamino-acetylamino-4-carbomethoxy from 3-chloroacetylamino-4-methylthiophene (F. 95

2-methylthiophene hydrochloride, which in the case of Umkristall- up to 96 ⁰ C), which is obtained by decaiboxylation of the

lize from water and 1 mol of water of crystallization crystalline S-Amino-i-carboxy - ^ - methyl-thiophens (F. 123 ⁰ C) and

siert; M.p. 142 to 143 ° C; subsequent implementation of the 3-amine thus obtained

the S-diethylaminoacetylamino ^ -carbomethoxy- 20 no-4-methylthiophene (bp 45 ° C / 0.05 mm) with chlorine

2-methylthiophene hydrochloride, mp 163 to 164 ° C, acetyl chloride is obtained,

from 3-chloroacetylamino-5-carbomethoxy-2,4-dime- the S-n-butylaminoacetylamino ^ -methylthiophene,

ethylthiophene, m.p. 142-143 ° C; Bp. 145 to 150 ° C / O, O5mm (F. of the hydrochloride:

the Sn-butylamino-acetylamino-S-carbomethoxy 219 to 22O ⁰ C);

2,4-dimethylthiophene hydrochloride, mp 234 ⁰ C (dec.); 25 the Sn-Propylaminoacetylamino ^ -methylthiophene,

the S-diethylaminoacetylamino-S-carbomethoxy- boiling point 144 ° C / 0.15 mm (F. des hydrochloride 218 bis

2,4-dimethylthiophene hydrochloride, mp 112 to 114 ⁰ C, 219 ° C);

from 3- <x-chloropropionylamino-2-carbomethoxy- 3-diethylaminoacetylamino-4-methylthiophene,

4-methylthiophene, m.p. 99 to 101 ⁰ C; Mp 52 to 55 ° C (mp of the hydrochloride: 118 to 120 ⁰ C);

the S-n-propylamino-a-propionylamino ^ -carbo- 30 the S-cyclohexylaminoacetylamino ^ -methylthio-

methoxy-4-methyl-thiophen-hydrochloride, m.p. 177 to phen hydrochloride, mp 250 ⁰ C (dec.);

178 ° C (bp of the base: 162 to 167 ° C / 0.3 mm); from S-chloroacetylamino - ^ - dimethylthiophene (F.

the S-n-butylamino-a-propionylamino-i-carbo-120 to 122 ° C), which one in the implementation of by

methoxy- ^ methylthiophene hydrochloride, F. 178 to saponification and decarboxylation from the 3-amino

180 ⁰ C; 35 5-carbome & oxy-2,4-dimetoylthiophene (m.p. 82 to 84 ° C)

the 3-diethylamino-a-propionylamino-2-carbo- formed 3-amino-2,4-dimethylthiophene with

methoxy-4-methylthiophene hydrochloride, F. 178 to obtain chloroacetyl chloride,

180 ⁰ C; the 3 -n-Buty lamino-acetylamino - ^^ - dimethylthio-

the S-pyrrolidino-ft-propionylamino - ^ - carbometh-phen-hydrochloride, mp 230 to 223 ° C;

oxy-4-methyllhiophenchlorid of melting point 190 40 the S-diethylaminoacetylamino-i ^ dimethylthio-

up to 195 ° C, phen-hydrochloride, mp 174 to 176 ° C;

from 3 - /? - chloropropionylamino-2-carbomethoxy from 3 - «- chloropropionylamino-4-methylthiophene (F.

4-methylthiophene, m.p. 108 to 110 ^° C; 74 to 75 ^° C.), which is obtained from 3-amino-4-methylthiophene (bp.

the 3-n-butylamino / 3-propionylamino-2-carbo- 45 ° C / 0.05mm) and «-chloropropionyl chloride shown

methoxy- ^ methylthiophene-hydrochloridvornSchmelz- 45 can be provided,

point 174 to 175 ° C; the S-n-propylamino-a-prcpionylamino- ^ methyl-

the S-n-Propylammo-ß-propionylamino ^ -carbothiophene, b.p. 140 to 144 ° C / 0.1 mm (F. des Hydro-

methoxy-4-methylthiophene hydrochloride, m.p. 200 to chloride 218 to 219 ° C);

202 ^c C; the Sn-Butylamino-a-propionylamino ^ -methyl-

the S-Diathylamiao-zS-propionylammo ^ -carbo- 50 thiophene, F. 66 ⁰ C (F. of the hydrochloride: 130 to

methoxy-4-methylÜiiopb.en-hydrochloride, m.p. 101 to 134 ° C);

102 ° C; from S - ^ - chloropropionylamino- ^ methylthiophene (F.

the 3-pyrrou'dino- / I-propionyiamino-2-carbo- 108 to 109 ° C), obtained from S-amino- ^ methylthio-

methoxy-4-methylthiophene hydrochloride, F. 138 bis phen and ^ -chloropropionyl chloride,

139 ° C, 55 the S-n-Butylamino - ^ - propionylamino ^ methyl-

from S-chloroacetylamino ^ carbethoxy ^ methylthiophene hydrochloride, mp 170 to 171 ° C;

phen, m.p. 103 to 104 ^° C; the 3-n-propylamino - ^ - propionylamino-4-methyl

3-n-Butylaminoacetylamino-2-carbethoxy-4-thiophen-hydrochloride, m.p. 159.5 to 160.5 ⁰ C;

methylthiophene hydrochloride, m.p. 130 to 134 ⁰ C; the 3-pyrroHdylamino- / S-propionylamino-4-methyl

the S-diethylamino-acetylamino-l-carbäthoxy- 60 thiophene hydrochloride, F. 169 to 170 ⁰ C.
4-methylthiophene, bp _o, os 160-162 ⁰ C (hydrochloride: mp 130 to 132 ° C).

_. . , _ Example 3
Example 2

"_,", _,,.,., ,, S-diethylaminoacetylamino ^ -carbomethoxy-

17.6 g of 3-chloroacetylammothiophene, which is replaced by 65 '4-methylthiophene
Decarboxylation of 3-amino-2-carboxythiophene

and subsequent reaction of the 9 g of 3-amino-2-carbomethoxy-4-methylthiophei obtained in this way

3-aminothiophene ° C / 0.06 mm (F- 84-85 ⁰ C) in portions of boiling point 50 under stirring

13 14

and cooling with ice water in a suspension of between water and ether. The aqueous phase is gsmicht 15 g of diethylaminoacetic acid chloride in 100 ml of acetone with sodium carbonate solution and introduced and then shaken out several times with ether for 30 minutes to boil. After heating to dry. After cooling, the 3-diethylamine with sodium sulfate, the ether is stripped off and acetylamino ^ -carbomethoxy ^ -methylthiophene-hydro- 5 the residue is distilled in vacuo. 42 g of chloride are obtained with suction. For purification, the hydro-diethylamino-acetylamino-4-m2thylthiophene is dissolved from the sieve chloride in water, shaken out with ether and falls from 161 to 165 ° C / 0.1 mm. Hydrochloride: F. 157 the base with potassium carbonate solution. One takes up to 158 ⁰ C.
then the base in ether, dries with sodium sulphate and, after chasing off the ether, distills the io
Residue in a high vacuum. 6 g of 3-di-example 6 are obtained in this way

äthylaminoacetylamino-Z-carbo ^ thoxy ^ -methylthio- 3-diethylamino - /? - butyrylamino-4-methylthioph _e n

phen from bp 161 to 165 ° C / 0.1 mm. The hydro rj ι jv

Chloride melts from isopropanol / diisopropyl ether by 10.5 g of 3-crotonylamino-4-mithylthiophene (F. 99

crystallizes at 157 to 158 ° C. 15 to 100 ⁰ C), which consists of 3-amino-4-methylthiophene and

Crotonic obtained are dissolved in 34 ml of diethylamine and heated for 20 hours in autoclave at 140 to 15O ⁰ C. After cooling down, this will be

Example 4 excess diethylamine distilled off, the residue

ao dissolved in ether and extracted with 2N hydrochloric acid.

S-diethylaminoacetylamino ^ -carbomethoxy- After the ether layer has been separated off, it is precipitated

4-methylthiophene of the aqueous layer the base with sodium carbonate

solution, absorbs it in ether and dries it

14.3 g of S-diethylaminoacetylamino ^ -carbomethoxy- ethereal solution with sodium sulfate. The hydrochloride 0.05 torr is precipitated by adding 4-methyl-4,5-dihydrothiophene (boiling point 156 to 161 ° C / »5 of ethereal hydrochloric acid) in 50 ml of methylene chloride, des3-diethylamino- / 3-butyrylamino is dissolved -4-methylthiophene and with stirring at -5 to -10 ⁰ C, which, recrystallized from ethanol / ether, melts at 164 to 165 ⁰ C with a solution of 8 g of bromine in 25 ml of methylene. Yield: 5 g.
chloride added. The mixture is then allowed to stir for a further 1 hour at the same temperature, removed for more than 30 minutes
excess bromine and hydrogen bromide formed,

by sucking air through the solution, and driving it away,

the methylene chloride then in the water jet example 7

vacuum. The residue is dissolved in water and 3-n-butylamino-acetylamino-4-methylthiophene

the aqueous solution extracted with ether. After 35

Separation of the ether is precipitated from the bromine solution 9.5 g of N-benzyloxycarbonyl-n-butylaminoacetic acid

acidic solution the base with sodium carbonate and 5 ml of triethylamine are dissolved in 50 ml of tetrahydro solution, taken up in ether and dried, the furan is dissolved, at -5 ° C. ethereal solution with sodium sulfate is added dropwise with stirring. After distillation, 3.4 ml of ethyl chloroformate are added and the ether is removed, and the residue is stirred in a high vacuum of 4 ° for 15 minutes at this temperature. Then distilled at 161 to 165 ° C and 0.1 mm. Is obtained is a likewise cooled to -5 ⁰ C solution of 7.7 g of S-Diäthylaminoacetylamino ^ -carbomethoxy- 4 g of 3-amino-4-methylthiophene in 20 ml of tetrahydro-4-methylthiophene (melting point of the Hydrochloride was added furan and 2 hours stirred. During 157 to 158 ° C). During this time, the mixture is allowed to slowly dissolve

The starting material is obtained by reacting 45 to room temperature. Then it becomes water of j-chloroacetylamino ^ -carbomethoxy ^ -methyl- added to the trietbylamine hydrochloride out-4,5-dihydrothiophene (M.p. 84 to 85 ° C; produced by dissolving, the aqueous phase again with ether out-reaction of 2-carbomethoxy-4-methyl-thiopha- shakes and the combined organic solutions non- (3), bp. 75 ° C / O, 0.5 Torr, and chloroacetyl chloride) dried with sodium sulfate. After leaving and diethylamine. 5 ° distill the solvent remaining back

stand is left to stand for 1 hour with 40 ml of a solution of hydrogen bromide in glacial acetic acid (about 37%). The hydrobromide of the 3-n-butylamino-

Example 5 from acetyJamino-4-methylthiophens, which is sucked off and

55 is washed with ether. Yield: 7 g. F. 200 to

S-diethylamino-acetylamino ^ -carbomethoxy- 202 ⁰ C. It is stirred in sodium carbonate

4-methylthiophene solution entered and the released base in ether

recorded. After the essential

36 g of 3-isocyano-2- <arbomethoxy-4-methylthiophene solution is treated with ethereal hydrochloric acid, the hydro (F. 107-108 ⁰ C), which is from 3-60 FormyIamino- chloride of the 3-n-Butykmino-acetylamino ^ metliyltbJo-2-carbomethoxy-4-methyltbiophen (mp 130 to 131 ° C) phens precipitated, mp 219 to 220 ⁰ C.
according to known methods (see New Methods

der preparative organic chemistry, Vol. IV, p. 43) _f In an analogous way one obtains:

25.8 ml of diethylamine, 25 ml of 30% formaldehyde solution, 100 ml of acetone and 50 ml of water are obtained from N-benzyloxycarbonyl-n-butylamraoacetic acid combined and with cooling with 25 ml kon- uni 3-Aimno-5 <^ bomethoxy-2,4-dimethylthiophene centered hydrochloric acid added. The S-n-butylamino-acetylamino-S-carbomethoxy-

stand at room temperature and then partitioned 2,4-dimethylthiophene-faydrochloride, mp 234 ° C (decomp.).

Examples 8a to 8g
Process a) continues to produce:

a) S-Allylamino-a-propionylamino-l-carbomethoxy-4-methylthiophene hydrochloride, Mp 170-171 ° C;

b) 3-Μθφ ^ 1ώο - / ^ ρΓορϊο ^ ΐ3πΰηο-2-ι ^ Γΐ> οΐηεΛοχ} '- 4-methylthiophene hydrochloride, M.p. 152 to 153 ° C;

c) S-diethylamino-acetylamino-thiophene hydrochloride, F. 93 to 95 ° C (boiling point of the base 145 ° C at 0.3 mm Hg);

d) 3-Piperidino-a (^ lamino-2-carbomethoxy-4-methylthiophene hydrochloride, 198 ° C .;

e) 3-bis (2-hydroxyethyl) -amino-acetylamino-4-methylthiophene-hydrochloride, mp 204-205 ⁰ C;

T) 3- (piperidine- / i-proFionylamino) -2-carbomethoxy-4-methyItfaiophen-hydrochloride, mp 195 to 196 ° C;

g) 3- [a- (n-Penrylamino) -a-propionylamino] -

^ methyl ^ -carbomethoxy-thiophene hydrochloride, F. 175 to 176 ° C.

Example 9
Method d)

S-diethylamino-acetylamino- ^ methyUhiophen

1.7 g 3-AnünoacetylaTnino-4-methylthiophene (F. 73 up to 74 ° C) with 3.9 g of diethyl sulfate and 3.4 g

ίο Sodium hydrogen carbonate in 50 ml Tolnol heated to boiling for 5 hours. After cooling, it is extracted with 2N hydrochloric acid. The hydrochloric acid phase is extracted again with methylene chloride, filtered with activated charcoal and made alkaline with 2N sodium hydroxide solution. The 3-diethylamino-acetylamino-4-methylthiophene which precipitates is filtered off with suction, washed with ice water and dried (melting point 53 ° C.). ^{The hydrochloride, which melts at 118 to 120 °} C., is obtained therefrom with ethereal hydrochloric acid

Claims (2)

Patent claims: 1. Substituted 3-aminoacylaminothiophenes of the general formula R ¹ R ³ NH-C-A-N (D 10 SR ⁵ jn where R ^{1 is} hydrogen, a straight-chain or branched C ₁ -C _e -alkyl radical, R ^{a is} a straight-chain or branched C ₁ -C _e -alkyl radical, a C ₆ -Ce cycloalkyl radical or a C ₂ -C ₄ -alkenyl ao test, where R ¹ and R * together with the N atom • cloth can mean a pyrrolidino, morpholino or piperiidino radical, R ³ hydrogen, a C _{1 -C 4} -AlkViTeSt, the carbomethoxy or carbo-ethoxy group, R * is hydrogen, a C ₁ -C ₄ -AIlCyI- as radical or the carbomethoxy group, R ^{5 is} hydrogen, a C ₁ -C ₄ -AUCyIrCSt or a lower carbalkoxy group and A is a straight-chain or branched alkylene group with 1 to 4 carbon atoms. 2. Process for the preparation of substituted 3-amino-acylaminothiophenes of the general formula R ¹ 35 NH-C-A-N (D R ² 45 R ⁴ SR ⁵ characterized in that one a) 3-Halogenacylaminothiophenes of the general formula R ³ NH-C-A-X O (II) R ⁴ SR ⁵ in the X halogen, e.g. B. chlorine, bromine or iodine, or an alkoxy, aralkoxy or aryloxy group, with a primary or secondary amine of the general formula 55 60 R ¹ HN (III) implements: or b) 3-aminothiophenes of the general formula (IV) R ⁴ SR ⁵ or their salts or Grignard compounds with an aminocarboxylic acid of the formula HOOC-A-N R ² or a reactive derivative the same! acylated, c) 3-Amino-4,5- or -2,5-dihydrothiophenes dei formula R ³ NH-C — A —N (VIa) OR ² R ⁴ SR ' or R ³ NH-C-A-N R ¹ (VIb) R ² R ⁴ SR ⁵ dehydrated or
d) 3-Aminoacylaminothiophenes of the formula NH-CA-NH ₂ (VII) R ⁴ SR ⁵ or alkylated in a manner known per se e) compounds of the formula R ² R ³ NH-C — A —N (VIII) OR ⁶ R ⁴ SR ^s in which R 'represents an ester group, versei or f) to unsaturated acylaminothiophenes of the form R ¹ NH-C-A '-H / \ XR ⁴ SR ⁵ (IX) in which A 'denotes a straight or branched C ₂ -C ₄ alkenyl radical, amines of the general "formula for the preparation of substituted 3-amino-acylaminothiophenes the general formula R ¹ HN attaches or
g) Thiophene isonitriles of the general formula R ³ NC 2i IO R '