GB1598518A - Alpha-(acetylamino)acetic acid derivatives - Google Patents

Description

PATENT SPECIFICATION

( 11) 1 598 518 ( 21) Application No 2431 ( 62) Divided out of No.

( 31) Convention Applicat ( 32) Filed 10 March 1977 ( 31) Convention Applicat ( 32) Filed 21 April 1977 ( 33) United States of Am ( 44) Complete Specificati ( 51) INT CL 3 C 07 C 103 ( 52) Index at acceptance 01/80 ( 22) Filed 10 March 1978 1598517 tion No 776400 tion No 789467 in lerica (US) on published 23 Sept 1981 /30 C 07 D 307/54 333/24 ( 19) C 2 C 1470 1510 215 220 226 227 22 Y 246 247 253 254 25 Y 270 282 30 Y 313 316 31 Y 326 339 342 34 Y 366 367 368 440 586 58 Y 596 601 62 X 638 63 X 658 65 X 699 AA KK KW ( 72) Inventors UWE D TREUNER and HERMANN BREUER ( 54) a-(ACETYLAMINO)ACETIC ACID DERIVATIVES ( 71) We, E R SQUIBB & SC INC, a corporation organised and exisi under the laws of the State of Delaw United States of America, of Lawrencevi Princeton Road, Princeton, New Jer 08540, United States of America, do her.

declare the invention for which we pray t a patent may be granted to us, and method by which it is to be performed, tc particularly described in and by following statement:-

This invention provides lIl(cyanoalkyl)aminol oxoacetyll ami acetic acid derivatives More particularl provides a compound of the formula R 1-CH-COOH R 4 l 1 l NH-C-C-N-C-C=N 11 I 1 1 1 0 O R 3 R 5 wherein R 1 is hydrogen, lower all saturated or unsaturated cycloalkyl, herein defined), phenyl, phenyl-lower all substituted phenyl wherein said phenyl substituted by one or two radicals selec from halogen, lower alkyl, lower alko and hydroxy or heterocyclic group selec from 2-thienyl, 3-thienyl, 2-furyl, 3-furyl pyridyl, 3-pyridyl, and 4-pyridyl; R 3 hydrogen, lower alkyl, phenyl-lower alky cyloalkyl; and R 4 and R 5 each is hydrol or lower alkyl.

The carbon atom next to the carbo group is asymmetric (when (R, is hydrogen) so the compound can exist ir and L forms A further centre of asymme occurs when R 4 and R 5 are different.

The compounds of this invention may used as intermediates in the preparation )NS cephalosporin derivatives as described in ting our related copending patent application are, No 9580/78 Serial No 1598517.

lle The lower alkyl groups referred to rsey throughout this specification are straight or eby branched chain hydrocarbon groups containing that 1 to 7 carbon atoms, preferably I to 4 the carbons, and especially I or 2 carbons.

be Examples of the type of groups the contemplated are methyl, ethyl, propyl, isopropyl, butyl and t-butyl The lower alkoxy and lower alkylthio groups are such nol lower alkyl groups attached to an oxygen or y it sulfur, respectively, e g, methoxy, ethoxy, propoxy, methylthio, ethylthio and propylthio The phenyl-lower alkyl and diphenyl-lower alkyl groups are such lower alkyl groups attached to one or two phenyl (I) rings, preferably benzyl, phenethyl and diphenylmethyl.

The saturated and unsaturated cycloalkyl groups are the alicyclic groups having up to 7 carbons and up to 2 double bonds in the kyl, ring, i e the cycloalkyl groups cyclopropyl, (as cyclobutyl, cyclopentyl, cyclohexyl and kyl, cycloheptyl, the cycloalkenyl groups having 1 is up to 7 carbons with one double bond, ted cyclobutenyl, cyclopentenyl, cyclohexenyl xy, and cycloheptenyl and the cycloalkadienyl ted groups having up to 7 carbons with two 2 double bonds located at various positions is such as 1,4-cyclohexadienyl which is l or especially preferred.

gen The substituted phenyl groups include one or two substituents selected from xyl halogen (preferably chlorine or bromine), not lower alkyl (preferably having I to 4 a D carbons, especially methyl or ethyl), lower -try alkoxy (preferably having I to 4 carbons especially methoxy or ethoxy), and hydroxy, be e g, 2-, 3-, or 4-chlorophenyl, 2-, 3-, or 4of bromophenyl, 2-, 3-, or 4-hydroxyphenyl, 0 o L 3,5-dichlorophenyl, 2-, 3-, or 4methylphenyl, and 2-, 3 or 4-ethoxyphenyl.

The halogens are the four common halogens, of which chlorine and bromine are preferred.

The compound of the invention of formula (I) is produced from an a-amino acid ester having the formula R 1-CH-COOY ( 11) I NH 2 wherein R 1 has the same meaning as defined above and Y is a readily removable group, e.g, diphenylmethyl, nitrophenyl, dinitrophenyl, t-butyl or trimethylsilyl, which is reacted with an oxalyl halide such as oxalyl chloride to form an intermediate having the formula R 1-CH-COOY I NH C=O I C=O hal wherein hal represents halogen, preferably chlorine, in a solvent such as dioxane This intermediate is then reacted with a compound having the formula R 4 N=-C-C-NH-R 3 (IV) I R 5 e.g, in an organic solvent such as dioxane in the presence of an organic base such as dimethylaniline at a reduced temperature, e.g, about -20 C, and treatment of this intermediate with an acid, e g, trifluoroacetic acid and anisole, yields the free acid of formula (I).

Alternatively, the compound of formula (I) can be produced from starting material of formula RCH(NH 2)COOY where Y is as defined above by reacting the latter with a compound having the formula R 4 Ra I t N=-C-C N-C-C-hal 1 11 11 Rs O O Preferred compounds of this invention are the acids of formula I wherein R 1 is cyclohexadienyl, phenyl or heterocyclic selected from 2-thienyl 3-thienvl 2-furvl 3furyl, 2-pyridyl, 3-pyridyl and 4-pyridyl; and R 3, R 4 and Rs each is hydrogen or lower alkyl, especially hydrogen, and especially the D-isomers thereof.

The most preferred compounds are the acids of formula I wherein R 1 is 2-thienyl, or phenyl most especially 2-thienyl; and R 2, R 3, R 4 and Rs each is hydrogen.

Example 1 l(Cyanomethyl)aminoloxoacetyl chloride m M of cyanomethylamine hydrochloride and 25 m M of oxalyl chloride in 100 m M of absolute dioxane are heated at 60-70 while passing through a stream of nitrogen After one hour a clear solution results and there is no evidence of hydrogen chloride in the nitrogen stream The solvent is evaporated under vacuum and the residual, light brown oil is taken up in methylene chloride, filtered over charcoal and stored at-30 until it is to be used.

Example 2

D a lll(Cyanomethyl)aminoloxoacetyllaminol 2 thiophenacetic acid, diphenylmethyl ester m M of 2 D thienylglycine, diphenylmethyl ester are dissolved in 20 ml.

of methylene chloride, 10 m M of dimethylaniline are added and half the product of Example 1 is added dropwise with stirring at -20 After thirty minutes, the reaction solution is washed first with 50 ml of I N hydrochloric acid and then with 50 ml of water After drying over sodium sulfate, it is concentrated by evaporation A viscous yellow mass is obtained which solidifies upon treatment with ether This is crystallized from a little ethanol to obtain Da lll(cyanomethyl)aminol oxoacetyllaminol-2-thiopheneacetic acid, diphenylmethyl ester in the form of white crystals, yield 63 %, m p 160-161 .

Example 3

D alll(Cyanomethyl)aminoloxoacetyl J aminol 2 thiopheneacetic acid By treating the diphenylmethyl ester obtained in Example 2 with trifluoroacetic acid and anisole ( 4:1) D-a-lll(cyanomethyl)aminoloxoacetyllaminol 2 thiopheneacetic acid is obtained in 74 % yield.

The product is recrystallized from absolute ethanol to obtain white crystals, m p 1992000.

Examples 4-39

The following Examples illustrate compounds of formula I which may be prepared by the method of Example 3.

1.598 518 1,598,518 R, Ri H H H H Example R,

4 M 11 "-, c 7 8 r - i 9 s j1 1 12 C L i i 13 -31 o H CH, H H -C H 2 H CH CH, H H C Hr, H H H H C^ H CH H C^ H H CH, -CH, H -( H 2 ( H CH, H H H -CH,, H H H 14 1 i 16 31 o 17 1 (_) 1 H CH, H H H 1.598,518 R, H R, H Example R,

19 Ny H H 21 -CH, 22 23 c24 C Gir 26 _)_ 27 IF 11 , 5 "28 D_ 29 H 7) CY(C11 Y 31 c32 HO-33 14 j C-(cl 34 cl H H -C^ H H H H H -CH, H H H H H H H CH, H _( 3 -0 H H -CH, H H CH, H H H H H H H H H H H H H M -C,,H H H H H 1,598518 5 Example R,

R 3 H H CH 3 H CH 3 H CH 2 ( H H

Claims (8)

WHAT WE CLAIM IS:-

1 A compound of the formula R 1-CH-COOH R 4 I I' NH-C-C-N-C-C-N 11 11 1 1 0 O R:, R, wherein R, is hydrogen, lower al saturated or unsaturated cycloalkyl herein defined), phenyl phenyl-lower al substituted phenyl wherein said phen 3 substituted by one or two radicals selei from halogen, lower alkyl, lower alkt and hydroxy, or a heterocyclic gr selected from 2-thienyl, 3-thienyl, 2-fury furyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl is hydrogen, lower alkyl, phenyl-lower a or cycloalkyl; and R 4 and R 5 each hydrogen or lower alkyl.

2 A compound as in Claim I whereir is thienyl.

3 A compound as in Claim I wherein is phenyl.

H H H H -CH 3 -CH 3

4 A compound as in Claim I wherein R, is furyl.

A compound as in Claim 1 wherein R, R 3, R 4 and R

5 each is hydrogen.

6 A compound as in Claim 1 wherein R, (I) is cyclohexadienyl, phenyl, thienyl, furyl or pyridyl; and R 3, R 4 and R 5 each is hydrogen or lower alkyl.

7 A compound as in Claim I wherein R, is phenyl or thienyl; R 3 is hydrogen or kyl, methyl; and R 4 and R 5 each is hydrogen.

(as 8 A compound as in Claim 1 wherein R, kyl, is 2-thienyl and R 3, R 4 and Rs each is yl is hydrogen.

cted 9 The D-isomer of a compound as in oxy, Claim 1.

oup 10 The D-isomer of the compound as in _ 3 Claim

8.

R, 11 A compound as in claim 1, as named ikyl or shown in any of Examples 3-39.

h is n R, n R, For the Applicants, D YOUNG & CO, Chartered Patent Agents, 9 & 10 Staple Inn, London WCIV 7RD.

Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

M 3 C O 36 J 37 A 7 L 38 Ho 39 e 1,598,518