JPS5912661B2 - Intermediate manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a new method for preparing a useful acylating agent of the formula Ho□CIH-Π-Cl 15NH2HCl.

The above acid chloride hydrochloride is a novel 3-thiolated salt.
-Acylamidocephalosporanic acid derivatives and other active penicillins and cephalosporins, such as p-hydroxyampinrin, are preferred acylating agents.

The novel Cef25 allosporin derivatives obtained using the compounds of the invention consist of the compound represented by the structural formula and its easily cleavable esters and pharmaceutically usable salts.

The pharmaceutically usable salts mentioned above include salts of non-toxic carboxylic acids, such as non-toxic metal salts such as sodium, potassium, calcium and aluminum, ammonium salts and non-toxic amines such as trialkylamines, procaine, etc. , dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N-N'
- Includes salts with dibenzylethylenediamine, N-alkylpiperidine and other amines used to form salts of penicillin.

Within the definition of pharmaceutically usable salts are non-toxic acid addition salts (salts of amines), such as salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric and maleic acids. acids, acetic acid, citric acid, oxalic acid, succinic acid, benzoic acid,
Also included are salts with organic acids such as tartaric acid, fumaric acid, mandelic acid, ascorbic acid and malic acid. The easily cleavable esters mentioned above include ester groups that can be removed by methods that do not result in appreciable degradation of the remainder of the cephalosporin molecule, such as chemical or enzymatic hydrolysis.

Examples of suitable esters include those disclosed in US Pat. Esters of particular mention are pivalyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters. There is extensive literature regarding cephalosporin antibiotics. Relatively relevant prior art in this field will be discussed below. Various 7-[d-amino-arylacetamido]cephalosporanic acids and the corresponding desacetoxy compounds, where aryl represents unsubstituted or substituted phenyl or 2- or 3-thienyl, are
For example British patent specification 985747:1017624:
1054806 and 1123333, Pelkey Patent 6
96026; US Patent 3311621; 3352858
;3489750:3489751:3489752 and 35182601 Japanese Patent 16871/66, Spencer et al., J. Med. Chem. 9(5), 746~
750 (1966) and Kurita et al., J. Antibl
Otics (TOkyO) (A) 19, 243-249
(1966) as well as US Pat. No. 3,485,891.

Dutch patents 68/11676 and 68/12382 and US patent 3489750;3
489751 and 3489752 disclose current substituted cephaloglycines.

A 71[alpha-amino-arylacetamido]cephalosporin in which one hydrogen of the alpha-amino group is replaced by a carbonyl group bonded to another moiety has been reported.

The earliest are cephaloglycine and cephalexy, where common peptide protecting groups such as carbobenzyloxy are used as exemplified by US Pat. It was the first time. Related compounds are described in U.S. Pat. No. 3,303,19
3; 3311621 and 3518260. Various cephalosporins, sometimes including cephalosporin C, have been reacted with nucleophilic aromatic mercaptans to produce compounds having the structure.

In US Pat. No. 3,278,531, Ar is phenyl or some substituted phenyl or some aromatic heterocycle. Similar nucleophiles, such as 2-mercaptopyridines, are described in US Pat. No. 3,261,832 and 1 and UK Pat.
101422 and US Pat. No. 3,479,350 and 3
No. 502,665.

This type of nucleophile is further described in Pelkey Patent No. 714,518;
Disclosed in Canadian Patent 818501, British Patent 1187323 and US Patent 35169975. This US patent describes the compound named cefazoline, which has a tetrazolylacetyl group on the amino group and a 5-methyl-thiadiazolylthiomethyl group in the 3-position, and is based on scientific literature such as An
tibiOtic Agents and ChemOthe
rapy'1969, Bethesda, Maryland, American Society. Fuoa. Microbiology 1 pages 236-243 and J. AntibiOtics (
Japan) 23(3), 131-148 (1970)
It includes the following which are described in some detail. Substitution of the 3-acetoxy group of cephalosporin with various heterocyclic thiols is disclosed in US Pat. A typical heterocyclic thiol is 2-methyl-1.
They were 3,4-thiadiazole-5-thiol and 1-methyl-1,2,3,4-tetrazole-5-thiol.

Because of the asymmetric carbon atoms in the side chains of the compounds of formula 1, these compounds can exist in optically active forms, and such forms as well as racemic mixtures thereof are encompassed within the scope of the present invention. It is intended that

Preferred and most active compounds of formula 1 are those with a D configuration at the d carbon atom in the 7 side chain, i.e. D-(-)
-α-amino-p-hydroxyphenylacetic acid or its functional equivalent. In the present invention, amino groups include t-butoxycarbonyl, carpobenzyloxy, formyl, o-nitrophenylsulfenyl, β●
Compounds that are "protected" by substituents such as β●β-trichloroethoxycarbonyl, 4-oxo-2-pentenyl-2, 1-carbomethoxy-1-propenyl2, etc. (either as an intermediate or as a metabolic precursor) ) are also included.

In particular, such protecting groups are described, for example, in U.S. Pat.
Ketones (especially acetone) and aldehydes (especially formaldehyde and acetaldehyde) as disclosed in US Pat.
Included are ketoamides. The object of the present invention is to use a compound of formula (4) or an easily cleavable ester or salt thereof as an intermediate in the process for producing a novel cephalosporin derivative comprising the following steps. representing an amino protecting group) to produce, after removal of the amino protecting group B, a compound of formula 1 or a readily cleavable ester or pharmaceutically usable salt thereof; If desired, before or after removal of the protecting group, (a) the product in the form of the free acid or its salt is converted by methods known per se into the corresponding readily cleavable ester or its pharmaceutical form; or (b) converting the product in the form of an ester or salt which can be easily cleaved by methods known per se into the corresponding free acid compound or its pharmaceutically usable salt. Convert; or (F3)
A compound of formula I or a readily cleavable ester or salt thereof is reacted with a thiol of formula or a salt thereof to form a compound of formula I or a readily cleavable ester or salt thereof, if desired. (a) converting or (converting) the free acid or the product in the form of its salt into the corresponding easily cleavable ester or its pharmaceutically usable salt by methods known per se; Compounds having the formula and their It is useful as an intermediate in the preparation of easily cleavable esters and pharmaceutically usable salts.

In one method of preparing the novel cephalosporin compounds described above, a 3-thiolated-J[aminocephalosporanic acid compound of the formula or a readily cleavable ester or a salt of said acid or ester is combined with a suitable p-hydroxy compound of the formula Acylated with phenylglycine derivatives.

The 7-amino-3-cephem-4-carboxylic acid intermediate is
It can be produced by displacement of the 3-acetoxy group of 7-aminocephalosporanic acid with 5-mercapto-1.2.3-triazole or a salt thereof.

Displacement of ester groups by thiol groups is a known reaction and is preferably accomplished in aqueous solution under heating. The compound can then be obtained by acylation of the 7-amino group of the 3-thiolated-J[aminocephalosporanic acid intermediate with an acylating agent.

The above intermediates may, if desired, be converted into easily cleavable esters or salts prior to acylation. Procedures for making esters are disclosed in the literature and are well known to those skilled in the art of penicillin and cephalosporin chemistry. One suitable process particularly useful for making pivalyloxymethyl, acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters is disclosed in US Pat. No. 3,284,451. This cited document is
Esterification of cephalothin sodium with a suitable active chloro or bromo compound (e.g. phenacyl bromide, chloroacetone, chloromethyl ether, pivaroyloxymethyl chloride, acetoxymethyl chloride) followed by enzymatic oxidation of the thienyl acetate side chain. Describe the removal. In another good method, as in British Patent No. 1229453
- directly reacting the triethylamine salt of aminocephalosporanic acid with an active halogen compound. Compounds of formula may also be converted to silyl esters, such as by methods described in the literature, for example US Pat. No. 3,249,622.

The silyl ester group can be removed by hydrolysis or alcoholysis after the acylation reaction. Before the acylation reaction, the amino group of the p-hydroxyphenylglycine acylating agent is protected with a commonly used amino protecting group B,
This material can be easily removed at the end of the reaction.

Examples of suitable protecting groups are t-butoxycarbonyl, carbobenzyloxy, 2hydroxy-1-naphthocarbonyl, trichloroethoxycarbonyl, 2-ethoxycarbonyl-1-methylvinyl and 2-methoxycarbonyl-1-
Includes methylvinyl. Particularly valuable protecting groups are protons, as in formula, or British Patent No. 112333
3 or U.S. Patents 3,325,479 and 3,316,247
β-diketone or β-ketoester, as in
For example, methyl acetoacetate or Japanese patent 71/24
The acid, which is a β-ketoamide as in 714, in which case it contains a protected amino group, is preferably mixed, e.g. by treatment with an alkyl chloroformate, before reaction with the compound or its ester or salt. Converted to anhydride.

After the acylation coupling reaction, the amino protecting group B can be removed by methods known per se to form the desired product of formula 1. Thus, for example, t-butoxycarbonyl groups can be prepared by using formic acid, carbobenzyloxy groups by catalytic hydrogenation, 2-hydroxy 1-naphthocarbonyl groups by acid hydrolysis, and trichloroethoxycarbonyl groups by using zinc dust in glacial acetic acid. Depending on the treatment used, protons can be removed, such as by neutralization. If desired, the phenolic hydroxyl group of the acylating agent can also be added, e.g.
Protection of this group is generally not necessary, although it can be protected during the acylation step, such as by using easily removable protecting groups such as -benzyl, o-benzyloxycarbonyl or trimethylsilyl. Obviously other functionally equivalent protecting groups for amino or hydroxyl groups can be used and such groups are considered within the scope of this invention. Acylation of the 7-amino group of cephalosporin is a well known reaction, and any functional equivalent of the formula commonly used as an acylating agent for primary amino groups may be used.

Examples of suitable acylated derivatives of free acids include the corresponding acid anhydrides, mixed anhydrides such as alkoxyformic anhydrides, acid halides, acid azides, active esters and active thioesters. The free acid can be prepared by first reacting the free acid with N·N chloride and dimethylchloroforminium, or by reacting with an enzyme or an N-N'-carbonyldiimidazole or N-N5 carbonylditriazole or carbodiimide reagent, e.g. N・N'-diisopropylcarbodiimide, N-N'-dicyclohexylcarbodiimide or N-cyclohexyl-N'-(2-
morpholinoethyl) carbodiimide or by the use of alkylamine reagents or isoxazolium salt reagents. Another equivalent of the free acid is the corresponding azolade, i.e. a quasi-aromatic five-membered ring in which the amide nitrogen contains at least two nitrogen atoms, i.e.
Amides of the corresponding acids that are members of the imidazoles, pyrazoles, triazoles, benzimidazoles, benzotriazoles and substituted derivatives thereof. p-
Another monoreactive derivative of hydroxyphenylglycine is
Leuch anhydrous.

In this structure, the group that activates the carboxyl group also serves to protect the amino group. A particularly preferred acylating agent is p-hydroxyphenylglycine chloride hydrochloride, which also serves the dual function of carboxyl activation and amino protection. The use of enzymes to conflate free acids with compounds with protected amino groups was mentioned. Within such methods, enzymes provided by various microorganisms, such as T. Takahashi et al., J. Am. Che
m. SOc. , 94(L1), 4035-4037(1
972) and T. Nara et al., J. AntiblOtic
s (Japan) 24 (5), 321-323 (197
The use of esters of this free acid according to those described under 1), such as the methyl ester, is included. The particular processing conditions chosen for the coupling reaction, such as temperature, solvent, reaction time, etc., will be determined by the type of acylation method and are known to those skilled in the art.

Organic tertiary amines, such as tritylamine, N.
-N'-dimethylaniline, ethylpiperidine, 2.6
- It is useful to add lutidine or quinoline. The compound can be isolated in a manner conventionally used for the isolation of similar cephalosporins.

The product can thus be obtained as a neutral molecule (perhaps more accurately expressed as a zwitterion) or isolated as a salt. The formation of the desired pharmaceutically usable carboxylic acid or acid addition salts is carried out in known manner, for example by reaction of this acid with a suitable base or acid. The product obtained at the end of the acylation reaction (before or after removal of the amino protecting group) can be converted into other desired products of formula 1 by methods known per se.

Thus, a compound of formula 1 in the form of the free acid or its salt can be converted into the corresponding easily cleavable ester or its pharmaceutically usable salt by methods known per se. Similarly, products of formula 1 in easily cleavable ester or salt form can be prepared by, for example, aqueous or enzymatic hydrolysis (such as with human or animal serum) or acidic or alkaline hydrolysis or catalytic hydrogenation or The free acid product or its pharmaceutically usable salts can be converted to the free acid product or its pharmaceutically usable salts by removal of the esterification group by treatment with sodium thiophenoxide as taught in US Pat. In another method of preparing the above compound, 7-aminocephalosporanic acid or a salt thereof is acylated with p-hydroxyphenylglycine or an acylated derivative thereof to form a 7-acylated cephalosporin starting material of formula.

The preparation of this starting material is described, for example, in US Pat. No. 3,489,752.
It is disclosed inside. The free acid or the compound in its easily cleavable ester or salt form is then reacted according to the method of the invention with a thiol of the formula or a salt thereof, most preferably the sodium or potassium salt.

This displacement reaction is preferably carried out in aqueous solution in the presence of a mild base, such as sodium bicarbonate. The reaction mixture is preferably heated in an inert atmosphere, for example under a stream of nitrogen, for at least 50 min.
heated to a temperature of °C. The products of the displacement reaction can be converted into pharmaceutically usable salts, if desired. As in the case of the above-mentioned alternative preparations of compounds of formula 1, the product in the form of the free acid or its salts can be converted into easily cleavable esters or pharmaceutically usable salts, or alternatively As such, the easily cleavable ester or salt form of the product can be converted into the free acid or its pharmaceutically usable salt. Easily cleavable esters of compounds of Formula 1 are useful as intermediates in the production of free acid products.

Pivaloyloxymethyl, acetoxymethyl, and methoxymethyl esters are also useful as active antimicrobial agents because they are rapidly hydrolyzed to active metabolites upon oral administration. These esters are of interest because they differ in the rate and amount of absorption upon oral administration and differ in the concentration of active antimicrobial agent in the blood and tissues. The pharmaceutically active compounds described herein exhibit highly desirable solubility in water, are efficiently absorbed upon oral administration, resulting in relatively high and sustained blood concentrations, and are widely used in poultry and animals (including humans). It is a potent antibacterial agent that is useful in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria.

The active compounds are also valuable as nutritional supplements in animal feed and as agents for the treatment of mastitis in cattle. The novel medicaments described herein can be formulated as pharmaceutical compositions comprising, in addition to the active ingredient, a pharmaceutically acceptable carrier or diluent. These compounds can be administered both orally and parenterally. Pharmaceutical preparations may be in solid form, such as capsules, tablets or dragees, or in liquid form, such as solutions, suspensions or emulsions. For the treatment of bacterial infections in humans, the compounds of the invention may be administered parenterally, e.g., 3 to 4 times a day, in doses of about 5 to 200 η per day, preferably about 5 to 20 η per day. can be administered. They can be used, for example, at 125, 250 or 50%, together with suitable physiologically acceptable carriers or excipients.
It is administered in dosage units containing exactly 0.00 active ingredients. The compounds obtained here have surprisingly been found to have strong antibacterial properties upon oral administration and at the same time exhibit excellent absorption. The combination of a specific p-hydroxyphenylglycine side chain on the 7-amino group of the cephalosporin molecule with a specific 1,2,3 triazol-5-ylthiomethyl group in the 3-position unexpectedly It brings about favorable characteristics. The present invention provides a new method for making useful acylating agents of the formula.

The above acid chloride hydrochloride is a suitable acylating agent for the preparation of compounds of formula 1 and is also useful as an intermediate for the preparation of other active penicillins and cephalosporins, such as p-hydroxyampinrin. It is. The preparation of acid chlorides from 2-phenylglycine and phenyl-substituted phenylglycine by the use of reagents such as phosphorus pentachloride and thionyl chloride has been reported in the literature.

Such 2-phenylglycyl chloride hydrochloride is used in the production of semi-synthetic penicillins and cephalosporins having a 2-phenylglycine side chain.
It is of considerable value as an acylating agent for -amino or 7-amino groups. However, when the above prior art procedure was attempted on 2-phenylglycines with hydroxy substitution in the phenyl ring, this chloride hydrochloride product was found to be produced in low yield and purity. It's being served. Furthermore, it has been found that the products produced have very poor physical crystallinity and are therefore unsuitable for use in the commercial production of penicillins and cephalosporins. It is an object of the present invention to provide a new and improved method for producing 2-phenylglycyl chloride hydrochloride having a hydroxyl substituent on the phenyl ring, particularly a new and improved method for producing D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride. It was the purpose of the invention.

The present invention provides a practical method for producing the desired chloride hydrochloride in high yield and purity.

Furthermore, the crystalline products produced by this method are suitable for efficient recovery from reaction mixtures, good storage stability and for use on a commercial scale in the production of semi-synthetic penicillins and cephalosporins. It has been found that it has physical properties. More specifically, the present invention provides a method for preparing D-(-)-2-(p-hydroxyphenyl)glycidyl chloride hydrochloride 1;
) in a suitable substantially anhydrous inert organic solvent under heating.
-(-)-2-(p-hydroxyphenyl)glycine is reacted with excess phosgene to form an anhydride of the formula in solution: (2) removing excess phosgene from the reaction mixture; (3) Adding excess HCl gas to the cooled reaction mixture (4) recovering the desired D-(1)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride.

A preferred embodiment of the present invention comprises: (1) D-(-)-2-(p-hydroxyphenyl)glycine having a particle size of less than 200 mesh by heating in substantially anhydrous dioxane; reacting with at least 1.6 moles per mole of phosgene for a period sufficient to form an anhydride of the formula; (2) removing excess phosgene from the reaction mixture as quickly as possible after the formation of the anhydride; (3) reacting. Approximately 0~
D-(1)-2-(p-chloride) at a temperature in the range of 5°C.
D chloride consisting of a continuous step of adding a large excess of HCl gas for a time sufficient to form hydroxyphenyl)glycyl hydrochloride; and (4) recovering the product from the reaction mixture.
This is a method for producing -(1)-2-(p-hydroxydiphenyl)glycyl hydrochloride.

The method of the invention can be represented by the following flowchart. From the diagram above, the method consists of the reaction of p-hydroxyphenylglycine with phosgene to form N-carboxy anhydride (Rorke's anhydride), followed by treatment with gaseous hydrogen chloride to form the acid chloride of the anhydride. It can be seen that this includes conversion to hydrochloride.

Rourke's anhydride intermediate was found to decompose gradually in the presence of phosgene, and therefore phosgene and p-
In order to obtain the highest yields, it is advantageous for the reaction of hydroxyphenylglycine to proceed as quickly as possible and to remove excess phosgene from the reaction mixture as soon as possible after the formation of the anhydride intermediate.

The amino acid, D-(-)-2-(p-hydroxyphenyl)glycine, and phosgene are reacted in an anhydrous inert organic solvent.

Suitable solvents are (1) substantially chemically inert towards p-hydroxyphenylglycine and phosgene; (2)
and (3) an anhydrous organic solvent that is a substantial non-solvent for the acid chloride hydrochloride final product. Examples of suitable solvents are dioxane,
Includes acetonitrile and tetrahydrofuran.
The preferred solvent for highest yields is dioxane. This is because dioxane has a boiling point sufficient to heat the reaction mixture to a suitable temperature as described below. Since phosgene is sensitive to moisture, a substantially anhydrous solvent is used. The inventors have determined that <0.0
It is preferred to use a solvent with 2% moisture, most preferably <0.01% moisture. To obtain the highest yields, the reaction rate of the phosgene addition step can be maximized by appropriate adjustment of factors such as the particle size and concentration of p-hydroxyphenylglycine, the temperature of the reaction mixture, and the rate of phosgene addition. do.

The D-(-)-2-(p-hydroxyphenyl)glycine is preferably ground and sieved to a finely divided state to increase surface area. When the p-hydroxyphenylglycine has a particle size smaller than 200 meshes, i.e. 2
Best results have been achieved when this amino acid is ground so that less than 3% remains on the sieve of 0.00 mesh. Use excess phosgene to reduce reaction time. Preferably an amount of phosgene of at least 1.6 to 2.0 moles per mole of amino acid is used. Addition of phosgene to p-hydroxyphenylglycine results in an exothermic reaction. However, to increase the reaction rate and minimize decomposition,
The reaction mixture is preferably stirred and heat is applied. The best results have been obtained when the phosgene is added as rapidly as possible while heating to about 60 DEG -80 DEG C. for the minimum time necessary to form anhydride. Rapid addition of phosgene and the use of relatively high temperatures of about 60-80° C. for short periods of time, e.g. 5 minutes, have been found to be particularly advantageous for obtaining good yields when carrying out the reaction on a large scale. ing. Best results have been obtained when using fairly concentrated suspensions of amino acids, most preferably a concentration of about 10 t of amino acid per 80-100 ml of solvent. Complete dissolution of the amino acid indicates completion of the reaction in the phosgene addition step. The reaction can also be monitored by a suitable technique, such as thin layer chromatography, to indicate the minimum reaction time required to form the anhydride. By using the suitable reaction conditions discussed above, virtually quantitative yields of anhydride can be produced. Since, as mentioned above, it has been found that the anhydride of Roque decomposes gradually in the presence of phosgene, the excess phosgene is preferably removed as quickly as possible after the completion of the phosgene addition step.

Suitable methods for phosgene removal include purge with dry nitrogen gas and vacuum stripping. gaseous HC
It has been found to be advantageous, but not essential, to remove a portion of the organic solvent, preferably by concentration in vacuo, before the addition of 1.

The solvent may be concentrated to remove preferably up to about 50-60% of the original solvent volume. Since the chloride hydrochloride product is generally at least partially soluble in the reaction solvent, it is advisable to add an antisolvent (AntisOluent) before the HCl addition step to maximize recovery of crystalline product. It has been found desirable. Suitable anti-solvents include hydrogen chloride such as methylene chloride, chloroform or ethylene dichloride and inert organic solvents such as aromatic hydrocarbons such as benzene, xylene or toluene. The most preferred antisolvents are toluene and methylene chloride. Most advantageously, the dioxane reaction mixture is concentrated to a volume of about 50-60% of the original volume and sufficient toluene or methylene chloride is added to yield a solution having a dioxane:antisolvent volume ratio of about 7:3. Results are being obtained. To convert Roque's anhydride intermediate to the desired chloride hydrochloride, excess gaseous hydrogen chloride is added. Cool the anhydride solution until HCl solubility.
Large excess of HC to completely protonate dioxane
The best results have been obtained using dioxane solvent when using l. If insufficient HCl is used, acid chloride hydrochloride solvates may form. Using this solvate to generate penicillin or cephalosporin core 6
Although the -amino or 7-amino groups can be acylated in situ, they have been found to have poor storage stability. Therefore, any solvate that forms may be subjected to operations such as (1) further gas treatment with additional HCl or (2) stripping of the solvate and reslurry in dry methylene chloride. It is then preferably converted into the unsolvated acid chloride hydrochloride. Recovery of (p-hydroxyphenyl)glycyl chloride hydrochloride is carried out according to conventional procedures.

During or after the HCl addition, seed crystals of the desired product are preferably added to induce crystallization. The progress of the HCl addition step can be followed by periodic testing by thin layer chromatography until conversion to the acid chloride hydrochloride is demonstrated. After sufficient HCl has been added, the solution is slowly warmed to room temperature to cause gradual crystallization and formation of the desired heavy dense crystalline product. Cooling of the crystal slurry should be avoided to prevent solvate formation. The crystalline product is filtered, washed, for example with toluene, dioxane, methylene chloride, and dried to give excellent product yields of up to about 95% when suitable reaction conditions are followed.

D-(1)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride is a 6-aminopenicillanic acid or 7-aminopenicillanic acid or derivatives thereof, e.g. 6 of a derivative of 7-aminocephalosporanic acid substituted by a nucleophile of
It can be used to acylate -amino or 7-amino groups.

Synthesis of starting material 1,2,3-triazole-5-thiolpotassium The synthesis of thiols is described in the literature [J. G.G.G. and G.
Gunado, Chem. Ber. 99, 1618 (1966
)] was accomplished by essentially the same procedure as described in [2009].

5-Benzamide-1,2,3-thiadiazole was added to a solution of benzoyl isocyanate (50.6r1310 mmol) in commercially available anhydrous ether (400d) under stirring.
0.685N ethereal diazomethane (1310 mmol of 453TI) was added with vigorous stirring under a nitrogen stream.

When the addition was complete, the mixture was stirred for 1 hour at 0°C, and the solids were collected by filtration and dried in vacuo. The Mp of the thus obtained crude product (23.3f7) was observed around the area of 232-257. Geldra reported his opinion of Mp267 regarding pure products. A small amount of second crop (2.11) was obtained by vacuum evaporation of the mother liquor. The total yield was therefore 40%. 1●2,3-triazole-5-
A solution of the benzamide compound (8.2P, 40 mmol) in thiol 2N-caustic soda (80 mL, 1160 mmol) was heated at reflux temperature in a stream of nitrogen for 24 hours.

The solution was cooled to 0 nitrogen in ice while a continuous stream of nitrogen was passed through the solution and concentrated hydrochloric acid (26ml) was added. Collect the precipitated benzoic acid by filtering. The slurry was saturated with sodium chloride, and the separated benzoic acid was removed by filtration. The filtrate was immediately extracted with ethyl acetate, the extract was washed with saturated salt solution, dried over magnesium sulphate and then evaporated in vacuo. The remaining viscous oil was immediately evaporatively distilled under vacuum (70-75 t/0.001 m0) to obtain an oil (2.84 t 170%), which solidified spontaneously (Mp 52-59: Geldra-1). is Mp
6O conversion was reported). 1,2,3-triazole-5-
Potassium Thiol To a solution of the above thiol (2.84 V 128.1 mmol) in absolute ethanol (28 ml) was added 1.
A 93N alcoholic caustic solution (14.5d) was added.

The solution was then diluted with anhydrous ether until crystallization of the salt was complete. The solid was collected by filtering, washed with ether, and dried in vacuo. The salt thus obtained (3.6
5P193%) had Mp225 et al. (degraded).
Conversion of benzamidothiadiazole to triazolethiol proceeds via 5-amino-1,2,3-thiadiazole [G. G.G.G. and G. Kunado, Ch.
em. Ber. 99, 16187-amino-3-(1.
2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (I) The reaction was carried out under a nitrogen atmosphere in a reaction vessel protected from light.

Water and phosphate buffer were heavily gassed with nitrogen to drive out oxygen before use. 5-amino-1,2,3-thiadiazole (10.3f7, 0.102 mol) in 1 mol of water
It was added to a solution of caustic soda 8167 in 00d.

The mixture was rapidly heated to reflux and then refluxed for 10 minutes to rearrange the 5-amino-1,2,3-thiadiazole to 5-mercapto-1,2,3-triazole. It is important to note that the reaction mixture containing the 5-mercapto-1.2.3 triazole was cooled in an ice bath. 5-amino-1,2,3-thiadiazole can be produced by a different route that does not include diazomethane [P. L. Behn and R. Slutsk, J. Chem. SOc. 5l66 (1965)
] Washed with o-Nol and dried under vacuum over phosphorus pentoxide; 1
1.47.

IR and NMR were completely consistent with the desired product. Analysis Calculated value as ClOHl, N5O3N2: Cl
38.42; Hl 3.55; Nl 22.4O.

Experimental value: Cl38.27:38.26:Hl3.76,
3.40:Nl2l. O2, 21.00: H2Oll.
7O. 7-Amino-3-(1,2,3-triazole-
Purification of crude 7-amino-3-(1.
2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (16.1 t) was dissolved in methanol 6
00ml and concentrated HCl4Oa.

After charcoal treatment, the solution was diluted with 1.5 liters of ice water and extracted once with ethyl acetate. The aqueous phase was concentrated under reduced pressure to remove methanol. The cold aqueous concentrate was then diluted with 20% caustic soda to adjust the pH to 4, and the product was crystallized. The product was collected by filtration, washed with water and methanol, and dried under vacuum over phosphorus pentoxide; 11.4r0
The NMR spectrum showed that the product contained about 7 mol% of 7-aminocefrosporanic acid as an impurity. The above purification procedure was repeated with 11.4 V of product using 425 dl of methanol, 28 WLl of concentrated HCl and 1 liter of ice water to yield 8.0 t of product.

The NMR spectrum was completely consistent with the desired product and showed no trace of 7-aminocephalosporanic acid as an impurity. Analysis ClOHl5N5O3S2
Calculated value: C) 38.42; Hl 3.55; Nl2
2.4O.

Experimental value: Cl39. O6, 38.53; Hl3.56,
3.51;Nl22. O5, 21.60; H2Oll.
78.7-amino-3-[S-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-4-
Carboxylic acid (n) 5-merkabuto-1,2,3-triazole potassium salt 10f7 (0.07 mol) at 0.1 M
7 purified in 350 d of phosphate buffer (PH6.4)
-Aminocephalosporanic acid 19r (0.07 mol) and NaHCO, 5.9V (0.07 mol) were added to a slurry, and the mixture was heated and stirred at 55° C. for 3.5 hours in a nitrogen stream.

The resulting solution was cooled to 22° C. and the pH was adjusted to 5.5 with 40% H3PO4. Separate the obtained precipitate,
Washed with cold water (50a) and air dried. 7-Amino-1-3-
The yield of [S-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid was 8r.
1 decomposition point was 230°C.

IR analysis showed some decomposition of the β-lactam ring, but
It was used as it was in the next step. Analysis ClOHl,N5
Calculated value as O3S2: Cl38.39; Hl3.54
.

Experimental value: Cl38,36; H13.78.7-Amino-
3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3) 7-aminocephalosporinic acid 272r (1.0 mol) was added to 0.1M phosphate buffer ( pH 6.4) 3000d and 150ml of methyl in butyl ketone were then suspended in sodium bicarbonate 841 (1.0 mol) (note: baking soda was added little by little).

Next, 5-mercapto-1(H)-1,2,3-triazole potassium salt 143f (1.0 mol) was added, and the mixture was stirred at 55°C±1°C in a nitrogen stream for 4 hours.
After 1 hour the pH was readjusted to 6.4 by addition of a small amount of 40% H3PO4.

At the end of the 4 hour heating period, after stirring for 15 minutes at 55° C., it was filtered hot through a pad of diatomaceous earth (“Celite”).

1000TLI of Patsudo! The solution was washed three times with water, the hot sap was combined and the pH was adjusted to 4.5 by addition of 6N HCl. After cooling for 30 minutes at 0° C., the crude product was collected by filtering, washed twice with 200 ml of cold water, then twice with 1000 ml of methanol and air-dried.

The crude product was suspended in 3000 d of 50% methanol and water,
300 V (1.5 mol) of p-toluenesulfonic acid was added.

Stirred for 15 minutes and then added 50 tons of "Darco KB" decolorizing charcoal.

After stirring for 15 minutes at 22° C., the slurry was filtered through a Celite pad and the pad was washed twice with 100 ml of 50% methanol and water.

The filtrate was combined and the pH was adjusted to 4.0 by addition of about 210 d of triethylamine. After cooling for 1 hour at 0° C., the product was collected by P filtration and washed twice with 400 d of 50% methanol in water and then twice with 1000 ml of methanol.

I let it air dry. This was suspended in 2000 TILI3 of water and 84 V (1 mol) of sodium bicarbonate was added.

After stirring for 10 minutes at 22°C, "Darco 50" Charcoal 5
After adding Oy and stirring for 15 minutes at 22°C, the slurry was filtered through a pad of "Celite".

Wash it twice with 100ml of water, and combine the filtrate with 6NH.
The pH was adjusted to 3.5 by slow addition to C1. After stirring for 10 minutes at 22°C, it was cooled to 0°C for 1 hour.

The product was collected by filtering and washed twice with 200 ml of cold water and twice with 1000 ml of acetone. After drying in a vacuum desiccator with P2O5 for 14 hours at room temperature, the yield was 1.
00y; decomposition point 230°C. IR and NMR were consistent with the desired structure. Analysis ClOHllN5O
3S2. Calculated value as l/2H20: Cl37.5l:
Hl3.75; Nl2l. 68OKF (H2O). 2.
8.

Experimental values: C, 37.78; H, 3.69; Nl2O. 4
2. KF(H2O), 2.4607-amino-3-(1
・2,3-triazol-5-ylthiomethyl)-3-
Cefem-4-carboxylic acid pivalyloxymethyl Method A1 Hydrochloric acid 7 prepared from 7-aminocephalosporanic acid according to Example 2 of UK Patent 1229453 instead of the 7-aminocephalosporanic acid used immediately before. The title compound is prepared by using equimolar amounts of pivalyloxymethyl-aminocephalosporanate.

Method B - Instead of the 0.025 mol (6.8 V) of 7-aminocephalosporanic acid used during the procedure of Example 2 of GB 1229453, an equimolar amount of 7-amino-3-(1.
The title compound is prepared by using 2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid.

German patent 1904585 (FarnldOc3944
5) corresponds to British Patent No. 1229453.

In Method B above, 7-amino-3-( 1
・2,3-triazol-5-ylthiomethyl)-3-
Acetoxymethyl, methoxymethyl, acetonyl and phenacyl esters of cefem-4-carboxylic acid are prepared.

Reference example 1 7-[D-α-amino-α-(p-hydroxyphenyl)acetamide]-3-[S-(1,2,3-triazol-5-yl)thiomethyl]-3-cephem-4 -carboxylic acid 93.9 t (0.3
mol) of triethylamine 81a (0. mol) under stirring.
58 mol), then 50 ml of N.N-dimethylaniline (
0.39 mol) is added.

After cooling to 12°C, 76.2 TL of trimethylchlorosilane
1 (0.6 mol) over a period of 15 minutes.

After a further 15 minutes the mixture was brought to gentle reflux and after 45 minutes of reflux the almost clear solution was cooled to 5°C and added with D chloride.
0.354 mol of -(-)-α-amino-α-(p-hydroxyphenyl)-acetyl hydrochloride is added in portions over 30 minutes. The mixture is stirred for 1 hour at 5° C., with the ice bath removed (temperature max. 18° C.) for 1 hour. Add 1 liter of water and slowly adjust the pH to 2.2 with 20% NaOH while stirring well. Separate the aqueous phase and
Discard H2Cl2 and gummy precipitate. Adjust the pH to 2 with good stirring under a layer of ether (1 liter). The aqueous phase is stirred with "Darco KB" (charcoal) 207 for 15 minutes, filtered and under a fresh layer of ether (1 liter), the pH is adjusted to 4. After seeding and stirring for 1 hour at 20 °C. , the crystals are separated, thoroughly washed with water, then washed with acetone, and air-dried. After vacuum drying over P2O5, solid 71 [
D-α-amino-α-(p-hydroxyphenyl)acetamide]-3-[R-(1,2,3-triazole-
5-yl)-thiomethyl]-3-cephem-4 carboxylic acid is obtained. Reference example 2 7-[D-(α-amino-d-p-hydroxyphenylacetamide)]-3-[s-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem-1 4-
Sodium carboxylate JyokD-(α-amino-α-p
-Hydroxyphenylacetamide)]-3-[s-(
1,2,3-triazol-5-yl)-methyl]-3
A clear solution (PHlO
．． Add 1N aqueous caustic soda at room temperature until 8) is obtained.

This solution was immediately lyophilized to form an impure solid 71 [D-
(d-amino-α-p-hydroxyphenylacetamide)]-3-[s-(1,2,3-triazole-5-
yl)thiomethyl]-3-cephem-4-carboxylic acid sodium is obtained. Reference example 3 7-[D-(-)-α-amino-α-(p-hydroxyphenyl)acetamide]-3-[s-(1・2・3-
7-Amino-3-[s-(1,2,3-triazol-5-yl)-thiomethyl]-3-cephem in 150 ml of methylene chloride. -4-carboxylic acid 16
r (0.05 mol) with stirring, add 13.51 ml of triethylamine! Ll (0.092 mol), N-N-dimethylaniline 15d (0.118 mol) and, under cooling (7°C to 15°C), trimethylchlorosilane 19.17
Add n1 (0.15 mol).

After cooling for 15 minutes, the mixture is refluxed for 25 minutes, cooled to 5° C. and 0.061 mol of D-(−)-d-amino-α-(p-hydroxyphenyl)-acetyl chloride is added.

The mixture was stirred for 1 hour at 10°C to 12°C, then 150 TLI of water was added and after 15 minutes of stirring the mixture was
The aqueous phase was separated and the pH was adjusted to 2 using 20% NaOHVC.
charcoal (“Darco JB” 10t) was added,
After stirring for minutes, filter the mixture. The pale yellow solution was layered with ether (150a), and while stirring well, 2
Adjust pH to 4 with 0% NaOH. The aqueous phase is separated and 50 ml of acetonitrile are added to it. Scratching or seeding induces crystallization, forming a solid 7-[D-(1)-d-amino-α-(p-hydroxyphenyl)-acetamide]-3-[s-(1.2・3.Triazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid is obtained. Reference example 4 7-[D-α-amino-α-(p-hydroxyphenyl)acetamide]-3-(1,2,3-triazole-
Purification of 5-ylthiomethyl)-3-cephem-4-carboxylic acid (methanol crystallization) Amorphous 7-[D-α-amino-d-(p-hydroxyphenyl)acetamide]
400 TfIf of -3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was dissolved in warm 95% methanol H2O (20a), filtered and scratched.

After 4 hours, the white crystalline material was collected by filtering, washed with methanol, and air dried.

After further drying over P2O5, 100η was obtained; decomposition point 190-220°C infinite. The NMR spectrum was consistent with the desired structure and indicated the presence of approximately 1 mole of methanol. Analysis Calculated value as Cl8H, 8N6O5S2: Cl46.65: Hl3.9l; Nll8. l4.

Experimental value: Cl44.25: Hl4.64: Nll5.3
5. (5.9 found by Karl Fischer method)
(Uncorrected for 9% and uncorrected for methanol)
. Reference example 5 Via acid chloride hydrochloride 71 [D-α-amino-α1 (p-
hydroxyphenyl)acetamide]-3-(1.2.
Preparation of 3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid 7-amino-3-(1,2,3-triazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid 6 in CH2Cl2l5Oml .2
61 (0.02 mol) with stirring, triethylamine 5.6a (0.04 mol) and N-N-dimethylaniline 5 ml! and 7.62 ml of chlorotrimethylsilane
(0.06 mol) was added dropwise and the mixture was then slowly refluxed for about 1.5 hours.

An almost clear solution was obtained. Next, D-(-)-2
-(4-Hydroxyphenyl)glycinate chloride hydrochloride 4.44f (0.02 mol) was added in small portions over 30 minutes at 22°C. After stirring for 2 hours at 22° C., 20 d of methanol was added, and after 30 minutes, 5071 L1 of water was added with good stirring.

The pH was then adjusted to 2.1 with 20% NaOH, and the solids were separated. Next, separate the aqueous layer and use decolorizing charcoal (“Darco KB”)
) Stir for 10 minutes with 2t, filter, and add ether
The pH was adjusted to 4 with 20% NaOH under a layer of 0 ml. The aqueous phase was separated and an equal volume of methanol was added to seed the solution. 71 [D-
400 mg of α-amino-d-(p-hydroxyphenyl)acetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was obtained. Reference example 67-[D-α-amino-p-hydroxyphenylacetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4
- Acetoxymethyl carboxylate 7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-13-cephem-4-acetoxymethyl carboxylate in 30 ml of ethyl acetate (regenerated from 0.009 mol of its hydrochloride) Add 0.20 mol of pyridine to the solution.

The mixture is cooled in ice and stirred while adding 30 d1 of ethyl acetate: 0.010 mol of D-(1)-2-p-hydroxyphenylglycine chloride hydrochloride over a period of 10 minutes. After a further 20 minutes under cooling, stirring is continued for 1 hour at room temperature. The mixture was then washed successively with aqueous baking soda, 0.1N hydrochloric acid and water, dried and evaporated under vacuum to give the desired 7
[D-α-amino-p-hydroxyphenylacetamide]-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid acetoxymethyl remains as an oil, which is triturated in cyclohexane. crystallize. The 7-amino-3-(1.2.
7-amino-3-(1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in place of acetoxymethyl)-3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylate - pivaloyloxymethyl, methoxymethyl, acetonyl and phenacyl esters corresponding to the earth acetoxymethyl esters by using 0.009 mol of pivaloyloxymethyl, methoxymethyl, acetonyl and phenacyl esters of carboxylic acids are manufactured respectively. Example 1 Preparation of D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride D-(-)-2-(p-hydroxyphenyl)glycine 10.07 (~0.06 mol) was made into a slurry in 100 ml of dioxane.

COCl2 (phosgene) was introduced while stirring the slurry and maintaining the temperature of the slurry at 50-58<0>C. A yellow solution was obtained. ) Purge the solution with nitrogen to remove excess COCl2.
kicked out.

HCl gas was bubbled through the solution for 2.5 hours. The solution was stirred and a small amount was diluted with some ether to give some crystals which were added to the batch as seeds. 20~
Stirred at 25°C for 16 hours. Crystalline chloride D-(-
)-2-p-Hydroxyphenylglucyl hydrochloride slurry was filtered to collect the product. The filter cake was washed with dioxane and methylene chloride and then dried over P2O5 in a vacuum desiccator. The yield of the title compound is 7.
It was 37. IR spectrum showed that an excellent compound was obtained. Elemental analysis Theoretical value: Cl. 3l.
93;C, 43.14:Hl4. O9;Nl6.37O
Experimental value: Cll3l. 96:Cl42.46; H14.
22; Nl 6.56O Acid Chloride Determination Acid Chloride 986% No free COOH No free HCl Example 2 Mono-dioxane solvate of D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride Manufacturing D-(-
)-2-(p-hydroxyphenyl)glycine 207 was slurried in 200 ml of dioxane.

Introduce phosgene gas for 3.75 hours, during which time the temperature is about 50℃.
The reaction mixture was heated to a temperature of .

The presence of a yellow solution and a single band by thin layer chromatography (TLC) indicated that the reaction had reached completion. The solution was purged with N2 and cooled to approximately 6°C. HCl gas was added for approximately 130 minutes and the temperature was maintained between -3°C and 6°C. Seed crystals were added to the solution approximately 90 minutes after the start of the HCl addition. The solution was warmed to approximately 15° C. and stirred overnight. A slurry of heavy crystals formed. The HCl was removed by slowly applying vacuum to the system. The slurry was stirred at room temperature for several hours, filtered, washed with dioxane and methylene chloride, and dried over P2O5 in a vacuum dessicator to yield 26.4t of white product. The product is D-(-)-2 chloride
-(p-hydroxyphenyl)glycyl hydrochloride. Determination of acid chloride = 62% COOH = 4.5% Free HCl = 0.4% Dioxane = 29.5% Example 3 Acetonitrile of D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride Production of solvate 10.0t
f) D-(-)-2-(P-hydroxyphenyl)glycine was slurried in 100 d of acetonitrile.

The suspension was stirred and phosgene was added for approximately 25 minutes. The reaction mixture was then heated to about 46°C, during which time the reaction mixture was heated for an additional 2 hours at C.
OCl was added continuously. The solution was cooled to about 1° C. and stirred for about 15 minutes. The solution was then allowed to warm up to room temperature and more COCl2 was added while heating to 46°C until a total of 193 Pf) COCl2 was used. Excess COCl2 was removed by purging with N2 and the solution was cooled. Seed with HCl. 5.75 at about 4-6°C
After adding HCl for an hour, 257! When / of acetonitrile was added, the crystals that had formed began to dissolve. The reaction mixture was stirred for several hours and seeded to form crystals. The mixture was stirred overnight, filtered, washed with acetonitrile and methylene chloride, and dried to yield 4.2t. IR showed the product to be an acetonitrile solvate of D-(1)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride. Gas-liquid chromatography (GLC) analysis showed an acetonitrile content of 15.6%, which is a theoretical % of the solvate.
It is in good agreement with Example 4 D-(-)-2-(p-chloride) using fine amino acids
Preparation of hydroxyphenyl)glycyl hydrochloride 10.0f of D-(-)-2-(p-hydroxyphenyl)glycine having a particle size of less than 200 mesh was mixed with 10.0f of dioxane.
07111 was made into a slurry.

Phosgene was introduced for 10 minutes and the reaction mixture was then heated at 64° C. with further phosgene addition until a total of 18 moles of COCl2 were used per mole of amino acid. After completion of the reaction and expulsion of excess COCl2, the solution was concentrated under vacuum. Toluene (25 d) was added and the solution was made up to a volume of 80 d with dioxane. Cool the solution to approx.
Gently gassed with HCl for an hour. Add seed crystals,
The reaction mixture was stirred and allowed to warm to room temperature. After several hours of continuous stirring, the crystals were filtered off, washed and dried over P,O to give the title product 11.65' (87.5%). Quantified acid chloride = 101.9% No free COOH Example 5 D chloride using 20 moles of phosgene per mole of amino acid
-(-)-2-(p-HydroxyJ-glycyl)glycide heptahydrochloride preparation D-(
-)-2-(p-hydroxyphenylglycine 100f
was made into a slurry in dioxane 10007n1.

COCl2 was added for about 15 minutes (123y), and the reaction reached T.
The mixture was heated to approximately 62° C. until LC showed it to be essentially complete. Excess COCl2 was removed with N2 and the solution was concentrated under vacuum to a volume of approximately 550ml. Toluene 250a was added to this concentrated solution. The solution was cooled to 5°C and incubated at about 0-5°C for 2 hours with HC.
1 gas (190 t) was bubbled.

After stirring for 20 minutes at 3°C, the reaction mixture was seeded and stirred for an additional few hours to form a heavy slurry.

The slurry was filtered, washed with dioxane-toluene and methylene chloride, and dried over PO to give the title product 112.
f7 (84.2%) was produced. Quantified acid chloride = 100.3% No free COOH Free HCl = 0.7% Infrared spectrum (Cl!L-1) 3370 (phenolic OH), 1770 (acid chloride physical C=O) Example 6 Chloride D -Preparation of -(-)-2-(p-hydroxyphenyl)glycyl hydrochloride A. Preparation of Rourke's anhydride of D-(-)-2-(p-hydroxyphenyl)glycine D-(1)-2-(p-hydroxyphenyl)glycine (200
The mesh was sieved so that less than 3% remained on the sieve.100r was slurried in dioxane 100d.

Phosgene was added for 25 minutes under heating to about 80° C., resulting in an orange solution. Excess phosgene was removed using a 5 house vacuum and the reaction mixture was concentrated under vacuum to a volume of approximately 420 d.

Dioxane was added to bring the volume to 500 WLI. T.L.C.
showed that only Roque's anhydride was present in the reaction mixture. B. Rourke's anhydride 1 from chloride hydrochloride production process A using methylene chloride-dioxane mixed solvent
25 ml of methylene chloride 62 ml and dioxane 13
m1 was added.

The solution was stirred and cooled to 5°C, and 50y of HCl gas was added to the
Addition was made over 0 minutes at 0-6°C. After stirring and seeding, a slurry of crystals formed. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The crystals were washed twice with 200 ml of dioxane-methylene chloride and 300 ml of methylene chloride and dried over P2O5 in a vacuum desiccator to give 28.47 (85.5% yield) of the title product. Quantified acid chloride - 92.9% Free COOH - 2.6% Free HCl = 0.6% Dioxane - 1.06% Infrared spectrum (Cm-1) 3370 (phenolic 0H), 1770 (acid chloride physical C =O) C. Methylene chloride 627n1 used in Part B of production of chloride hydrochloride using toluene-dioxane mixed solvent
The procedure in part B was repeated except that 65 ml of toluene was used instead of .

28-7t (86.7% yield) of dry product was produced and characterized by IR to be the desired chloride hydrochloride salt.

Quantified acid chloride = 93.9% Free COOH = 3.6% Free HCl = 0.5% D. Production process A of chloride hydrochloride via dioxane solvate
to 125 ml of Rourke's anhydride solution and 12 ml of dioxane.
1 and 65 TL of toluene were added.

The solution was cooled to 0°C and incubated with HC at 2°C for 30 min.
126t was added. After stirring and allowing the solution to warm up to room temperature, a slurry of heavy crystals formed, which was determined by microscopic examination to be a dioxane solvate of D-1-2-(p-hydroxyphenyl)glycyl chloride hydrochloride. Crystals of matter were seen collapsing. Upon seeding, the desired chloride hydrochloride crystals form and after filtration, washing and drying the product 29.7
y (89.5% yield). R showed little or no COOH and good C-Cl. Quantitative acid chloride = 90.4% COOH-4.4% HCl = 1.4% Dioxane = 1.49% Infrared spectrum (CTn-ri 3370 (phenolic 0H), 1770 (acid chloride physical property C=O) Example 7 Preparation of D-(-)-2(p-hydroxyphenyl)glycyl chloride hydrochloride using slow HCl addition and dioxane-toluene mixed solvent Roque's anhydride solution 125WL1 prepared according to Example 6A Dioxane 13
ml and 70 ml of toluene were added.

The solution was stirred, cooled to 0°C and gassed with HCl5O7 at 0-3°C for 70 minutes. After stirring and seeding the cooled solution, a heavy slurry of crystals forms;
When filtered, washed and dried, excellent chloride hydrochloride 3
1.37 (95.5% yield) was obtained. Quantitative acid chloride = 92.3% COOH = 5.9% HCl - 1.6% Dioxane = 1.12% Example 8 D-(-)-2(p-hydroxyphenyl) chloride using dioxane solvent Preparation of glycyl hydrochloride (1) add 10 ml of dioxane instead of the mixture of dioxane and toluene, (2) use 70 t of HCl gas instead of 50 f7, and (3) gasse the solution for about 3 hours instead of 75 minutes. The procedure of Example 7 was repeated except for the following points.

22.7 t (68.5% yield) of dry product was obtained, which was identified by IR as the desired chloride hydrochloride salt. Quantified acid chloride = 95.7% COOH = 4.0% Free HCl = 0.1% Dioxane = 1.06% Infrared spectrum ((Tn-Li3370 (phenolic 0
H), 1770 (acid chloride physical property C=0) The embodiments of the present invention are as follows.

(1) D-(-)-2-(p-hydroxyphenyl)
A method according to the claims for producing D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride from glycine.

Claims (1)

[Scope of Claims] 1. A method for producing 2-(p-hydroxyphenyl)glycyl chloride hydrochloride (1) in which 2-(p-hydroxyphenyl)glycine is added in excess under heating in a substantially anhydrous inert organic solvent. React with phosgene to form an anhydride with the formula ▲Mathematical formula, chemical formula, table, etc.▼ in a solution state: (2) Remove excess phosgene from the reaction mixture; (3)
Add excess HCl gas to the cooled reaction mixture; (4
) A process characterized in that the desired 2-(p-hydroxyphenyl)glycyl chloride hydrochloride is recovered.