CS195683B2 - Process for the production of non-phenylglycine derivatives - Google Patents

Abstract

The present invention relates to methods for the production of novel amino acids. It relates in particular to amino acids which are suitable for introducing side chains into the 7-position of cephalosporin antibiotics and to methods for their preparation.

Description

i CZECHOSLOVAK SOCIALIST E PU MIKA(18)

TO PATENT 95683 (82)

ŮAAD FOR INVENTIONS AND DISCOVERIES (22) Filed 05 07 74(21) (PV 4978-77) {40) Published 31 05 79 (45) Issued 15 03 83 (5%) Isnt. Cl.3 C 07 C 101/00 AUTHOR OF THE INVENTION TANÁRA KUNTHIKŮ, NAKAI YOSMIIiARU, RISHIMOTQ TRI JI, TAKAIKEÍjl, ΚΑΜΓΫΑ TARASWL,. - SAÍTO ÝOSHIHISA and TĚŘAJI TSUTOMÚ, OSAKA (Japan)

Patent holder .fujisawa pharmaceuticae, g0„ ltd., gakka (japan) (54) Process for producing novel phenylglycine derivatives '1 The present invention relates to a process for producing novel amino acids. It relates in particular to amino acids which are suitable for introducing side chains into the 7-position of cephalosporin antibiotics and a process for their preparation. Up to now, a large number of cephalosporin compounds have been produced. However, only a few of these compounds are practically used and there is a constant need to find new, practically usable cephalosporin antibiotics. .

After extensive study, it has now been found that cephalosporin compounds which contain an acylamino group of the general formula at position 7-

2 R'2 represents a lower C1-C6 alkyl group (for example methyl, ethyl, propyl, isopropyl, butyl, pentyl),

R 5 represents hydrogen or a C 1 -C 5 alkane sulfo group (e.g. methanesulfonyl, ethanesulfonyl) and Y represents a group of the formula —SO 2 — or — NHSO 2 —, wherein R 3 represents hydrogen when Y represents a group of the formula —-NHSO 2 —, . .... · exhibit a strong antimicrobial effect against a wide range of microorganisms, including gram-positive and gram-negative bacteria. It is particularly noteworthy that in the case of some types of pathogenic microorganisms, their antimicrobial activity is higher than that of celaxin, which is one of the well-known cephalosporin antibiotics.

It is also noteworthy that when administered orally to mammals, their antibiotic effect is maintained at a high level for a long time. For this reason, they are useful as long-acting antibiotics that can be administered orally.

Amino acids of general formula 1, which are used for the introduction of an acylamino group

of the general formula A to position 7 of the ceálosporin nucleus, can be represented by the general formula

cem I 195883 where

R 1 represents a hydrogen atom or a hydroxy group, 1 9S8 8 3

’ J^/Vch-coóH rj : where

R 1 , R 2 , R 5 and Y have the meanings given above.

When the symbol R3 represents a lower alkane-sulfonyl group, it has the meaning of a group of the formula R2—Y—. The subject of the invention is a process for the preparation of amino acids of the general formula I and their derivatives.

The term "derivative" is used here in a broader sense. "Derivatives" include any modified forms of the amino acid general formula 1, which are used to increase the reactivity of the carboxyl group (so-called reactive derivatives), or which are used to protect the carboxyl group and/or the α-amino group of these substances from the effects of some reaction (so-called protected derivatives). Examples of derivatives with a modified carboxyl group include salts, esters, halides, amides, anhydrides, etc. Examples of derivatives with a modified α-amino group include salts, acylamino compounds, Schiff bases, etc.

The subject of the invention is a process for the production of new phenylglycine derivatives of the general formula I and their derivatives with a modified carboxy group, for example salts, characterized in that the compound of the general formula VI is hydrolyzed

where

R 1 , R 2 , R 5 and X have the meanings given above.

Compounds of general formula VI can be obtained by allowing a compound of general formula IV to react with

CHO Z represents halogen and R a and Y have the meanings given above, then

the resulting product of the general formula V '^3”ch°

Where is the

R1, R2, R3 and Y have the meanings given above, is reacted with hydrogen cyanide in the presence of ammonia to form a compound of general formula VI.

The reaction between the compound of the general formula IV and the acylating agent of the general formula III can be carried out simply by treating the compound of the general formula IV with the acylating agent of the general formula III in an inert solvent (e.g. water, dioxane, tetrahydrofuran, ether), if necessary, optionally in the presence of a base (e.g. pyridine, triethylamine, dimethylaniline). The starting material of the general formula IV is in some cases commercially available in polymer form. It can be used in the reaction directly in polymer form in the same way as the monomeric material is used.

The reaction of a compound of the general formula V with hydrogen cyanide in the presence of ammonia is the so-called Strecker synthesis of amino acids and can be carried out in a manner known per se. It can be carried out, for example, by treating a compound of the general formula V with an alkali metal cyanide (for example sodium cyanide, potassium cyanide) and an ammonium halide (for example ammonium chloride, ammonium bromide) in aqueous ammonia. -

The hydrolysis of the compound of formula VI according to the invention can also be carried out in a manner known to the person, for example by treating the compound of formula VI with an acid (for example hydrochloric acid, nitric acid and sulfuric acid) in an aqueous medium. When the reaction is carried out under relatively harsh conditions, for example using a higher acid concentration and/or at a higher temperature, the cyano group is hydrolyzed to the carboxy group in one step. On the other hand, when working under relatively mild conditions, for example using a lower acid concentration and/or at a lower temperature, the cyano group is hydrolyzed only to the carbamoyl group, whereby the compound of formula VII, where "R1 has the meaning given above, is obtained as the main product, reacting with

acylating agent, of general formula III R2—Y—z . (IIIJ, s 8 19S6 8 3

where

R1, R2, R3 and Y are as defined above. In the latter case, the carbamoyl group can be readily hydrolyzed to the carboxyl group under the more stringent conditions as described above. The hydrolysis can therefore be carried out in two stages.

The amino acid of formula I may be present in the form of the D-isomer or L-isomers or in racemic form. When obtained in racemic form, the racemate may be resolved at any stage of the preparation. For example, in the preparation of the amino acid of formula I by a three-step process which comprises acylation of a compound of formula IV, reaction of a compound of formula V with hydrogen cyanide and hydrolysis of a compound of formula VI, the final product is usually obtained in the form of a racemic mixture. The resolution of the racemate may be carried out before hydrolysis (i.e., on the compound of formula VI) or after hydrolysis (i.e., on the compound of formula I). However, the resolution of the racemate is usually carried out after the Ctrecker synthesis before hydrolysis because better results are obtained. The following examples serve to further illustrate the invention, but do not limit the scope of the invention in any way. Example 1 (1) 3-Aminobenzaldehyde (in polymer form, water content 3% by weight, 5.16 g) and water (3.3 ml) were added to tetrahydrofuran (80 ml) and the resulting mixture was cooled to 5 to 10°C. Pyridine (8.9 g) was added, and then methanesulfonyl chloride (11.45 g) was added dropwise at the same temperature over a period of fifteen minutes. Stirring of the mixture was continued for three and a half hours at room temperature. The reaction mixture concentrated under reduced pressure, 5% hydrochloric acid (120 ml), ethyl acetate (60 ml) and sodium chloride were added. The precipitate was filtered off and recrystallized from ethyl acetate. 3-mesylaminobenzaldehyde (1.8 g) was obtained in crystalline form with a melting point of 142-144 °C. The ethyl acetate layer was separated, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the same product as above (4.36 g). The same product was also obtained from the ethyl acetate mother liquor (0.83 grams). Total yield 6.99 g. IR (Nujol) in cm-1: 3120, 1670, 1600, 1580, 1320, 1242, 1160, 1143, 997, 970, 890, 788, 753, 670.

NMR (DMSO-dsj <5 ppm: 3.03 (3H, s), 7.4-7.8 (4H, m), 9.95 (1H, s), 10.07 (1H, broad s). (2)

To a mixture of sodium cyanide (2.18 g), ammonium chloride (2.19 g) and 28% aqueous ammonia (17 ml), cooled to 10°C, was added 3-mesylaminobenzaldehyde (3.98 g) at 10 to 15°C over four hours with stirring. Excess ammonia was removed from the reaction mixture at 15°C under reduced pressure, the pH of the residue was adjusted to pH 7 with concentrated hydrochloric acid, and the residue was extracted five times with ethyl acetate (30 ml each time). The extract was washed with saturated aqueous sodium chloride solution (30 ml), dried over anhydrous magnesium sulfate, and concentrated to give DL-α-amino-α-(3-mesylaminophenyl)acetonitrile (4.19 g) as an oil. IR (film) in cm-1: 3270, 1608, 1595, 1477, 1400, 1327, 1148,972, 890, 795, 768, 697.

NMR (DMSO-d 6 ) δ ppm: . 3.00'(3H,s), 5.01 (1H,s), 7.0-7.7 (4H,m). (3) Glacial acetic acid (7 ml) was added to DL-α-amino-α-(3-mesylaminophenyl)acetonitrile (2.10 g), and L(-j-)tartaric acid (1.56 g) in the form of a fine powder was added to the mixture. Ethyl acetate (4.7 ml) was added to the resulting solution with stirring in portions, and stirring was continued at room temperature overnight. The precipitated crystals were filtered off, washed successively with a mixture of ethyl acetate and acetic acid and ethyl acetate, and dried. D-α-amino-α-(3-mesylaminophenyl)acetanitrile-L.(-j-)-tartrate (containing one molecule of acetic acid) is obtained (3.25 g), melting point 97 to 98 °C. " : .

IC (nujol) in cm-1: 3220, 3670, 1735, 1692, 1593, 1542, 1520, 1422, 1405, 1310, 1262, 1237, 1220, 1165, 1133, 1070, 978, 903, 800, 782, 663, 602.

NMR (DaO-DCl) 5 ppm: 3.12 (3H, s), 3.20 (3H, s), 4.78 (2H, s), 5.87 (1H, s), 7.3-7.7 (4H, m). 1!ef]j3 = +310 (1 N hydrochloric acid, c=1). (4)

A solution of D-α-amino-α-(3-mesylaminophenyl)-acetonitrile-L(—j-)-tertrate (containing one molecule of acetic acid) 434 mg) in 22.2% hydrochloric acid (1.9 ml) is refluxed for four hours. The hydrochloric acid is removed under reduced pressure and methanol (about 5 ml) is added to the residue. The pH of the resulting solution is adjusted to 6 with methanolic ammonia and the solution is left to stand overnight in the refrigerator. The precipitated crystals are filtered off. The separated crystals (132 mg) are dissolved in hot water (0.5 ml), methanol (2 ml) is added to the solution and the resulting mixture is left to stand overnight in the refrigerator. The precipitated crystals are filtered off and washed with methanol. D-[3-mesylaminophenyl]glycine (54.3 mg) is obtained. Melting point 193-194 °C (decomposition).

IC (nujol) in cm-1: 3230, 2720, .2550, 1610, 1508, 1400, 1330, 1310, 1260, 1145, 985, 783, 695, 662.

NMR (D2O-HCl) S ppm: 2.20 (3H,s), 6.38 (1H,s), 7.3-7.7 (4.H,m).

[:®3D— —100® (1 N hydrochloric acid, c=1). (5) To a solution of sodium cyanide (purity 90%, 1.08 g) and ammonium chloride (purity 98.5 percent, 1.18 g) in 30% aqueous ammonia (17 ml) was added m-mesylaminobenzaldehyde (1.99 g) at 15 °C and the resulting mixture was stirred at the same temperature for four and a half hours. The excess ammonia was distilled off at 35 °C under reduced pressure and the pH of the resulting solution was adjusted to 7 with 10% hydrochloric acid. The mixture was extracted four times with ethyl acetate (15 ml each time): The extract was washed with aqueous saturated sodium chloride solution and concentrated under reduced pressure to about 10 ml. The concentrated solution was extracted four times with 10% hydrochloric acid (5 ml each time). The extract was washed with ethyl acetate (5 ml), mixed with 35% hydrochloric acid (8.6 ml) and refluxed for three hours. The reaction mixture was purified with activated charcoal, concentrated under reduced pressure to remove hydrochloric acid, mixed with ethanol (5 ml) and then concentrated to dryness under reduced pressure. The residue was dissolved in methanol (20 ml) with heating and the pH of the solution was adjusted to 5 with methanolic ammonia. The precipitated crystals were left overnight in the refrigerator, then filtered off, washed with methanol and dried by filtration. The resulting crystals (1.93 g) were dissolved in water (4 ml) with heating, ethanol (8 ml) was added to the solution, and the resulting mixture was left to stand overnight in a refrigerator. The precipitated crystals were filtered off and dried. D-α*(3-mesyl-aminomethyl)glycine 40.98 g was obtained;

íC (nujol) υ cm-1: 3260, 1895, 1605, 1590, 1477, 1400, 1330, 1250, 1150, 973, 890, 790, 760.

NMR (D2O+DCI) <5 ppm: 3.18 (3H, s), 5.38 (1H, S), 7.2-7.6 (4H, m). Example 2 (1) D -α-Amino- o- (3-mesylaminophenyl)acetonitrile-L(+)-tartrate (containing one molecule of acetic acid) (435 mg) was dissolved in concentrated hydrochloric acid (1.5 ml) and the resulting solution was refluxed. Hydrochloric acid was distilled off from the reaction mixture under reduced pressure. The residue was applied to a column of ion exchange resin ("Amberlite IR-120B" type H+, manufactured by Rohm and Haas Co.) (10 ml). The column was washed with water until the washings were neutral. Then 7% aqueous ammonia was passed through the column. The eluate is collected

Claims (4)

195883 and then concentrated under reduced pressure. The residue was crystallized from methanol. D-α-(3-mesylaminophenyl)-glycine (220 mg) was obtained in the form of crystals. Melting point 207°C (decomposition). [iof]D = -100° (1 N hydrochloric acid, c = 1). (2) To a suspension of the thus prepared D-α-(3-mesylaminophenyl)glycine (3.0 g) in anhydrous methanol (60 ml), cooled with ice water, dry hydrogen chloride is added until saturation. The resulting mixture is left to stand at 4 to 5°C for forty hours. After distilling off the ethanol under reduced pressure, the precipitate is filtered off, dried under reduced pressure, washed with acetone and dried again. D-α-(3-mesylaminophenyl)glycine methyl ester hydrochloride (containing 1/2 molecule of acetone) (3.8 g) is obtained. NMR (CD3OD-D3O) in ppm: 2.16 (3H, s), 3.05 (3H, s), 3.81 (3H, s), 5.23 (1H, s), 7.16-7.5 (4H, m). Example 3 A solution of D-α-amino-α-(3-mesylaminophenyl)-acetonitrile-L-(-j-)-tartrate (containing one molecule of acetic acid) (1.3 g) in concentrated hydrochloric acid (10 ml) was allowed to stand at room temperature for one and a half hours. The reaction mixture was concentrated under reduced pressure and then dried in vacuo. The yellow viscous solid obtained was washed with acetone (10 ml) and separated. D-α-(3-mesylaminophenyl)glycinamide hydrochloride (580 mg) was obtained as a greenish-white powder. Melting point 236-240°C. IC (nujolj in cm"1): 3450—3350, 3240, 3180, 1695, 1605, 1590, 1150. Example 4 To a methanolic solution saturated with hydrogen chloride (10 ml) were added water (1 drop) and •D-α-amino-φ-(3-mesylaminophenyl)-acetonitrile-L-(=)-tartrate (containing one molecule of acetic acid) (435 mg) and the resulting mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, water (20 ml) was added and the resulting solution was neutralized with aqueous sodium bicarbonate. The neutralized solution was then extracted with chloroform. The chloroform extract was concentrated under reduced pressure. D-(3-mesylaminophenyl)glycine methyl ester (230 mg) is obtained, melting point 101 to 153 °C. C (nulol) in cm-1: 3370, 3300, 1740, 1605, 1590. SUBJECT OF THE INVENTION A method for the preparation of new phenylglycine derivatives of the general formula I <í)CV.CH’G00H Y represents the group —SO2— or —NH—SOz—, wherein R3 represents hydrogen, when Y represents the group —NHSO2— and their derivatives with a modified carboxy group, for example salts, characterized in that the compound of the general formula VI S£Y-N Arí,% is hydrolyzed R^ HCfl NH, where R1 represents hydrogen or a hydroxy group, R2 represents a C1-C6 alkyl group, R3 represents hydrogen or a C1-C6 alkanesulfonyl group and - '(V1/ where R1, R2, R3 and Y have the above meanings. Severografla, a. p., plant 7, Most