IL50774A - Preparation of d-(-)-2-(p-hydroxyphenyl)-glycyl chloride hydrochloride - Google Patents

Abstract

1460914 Cephalosporin derivatives BRISTOL-MYERS CO 21 Dec 1973 [26 Dec 1972] 59332/73 Heading C2C The novel compound I having the D-(-)-configuration in the 7-side chain and salts and esters thereof are prepared by reacting a compound II or an ester or salt thereof with an acylating derivative of an acid III which is in the D-(-)-form (B is an amino-protecting group) followed by removal of the protecting group and optional esterification or salt formation. Potassium 1,2,3-triazole-5-thiolate is prepared by reaction of benzoyl isothiocyanate with diazomethane under nitrogen to give 5-benzamido- 1,2,3-thiadiazole, refluxing this with sodium hydroxide to give 1,2,3-triazole-5-thiol and reaction of this with alcoholic potassium hydroxide. 7-Amino-3-(1,2,3-triazol-5-yl-thio-methyl) - 3 - cephem - 4 - carboxylic acid is prepared by reaction of 7-aminocephalosporanic acid with 5-mercapto-1,2,3-triazole or its potassium salt. Salts and esters of the 7-amino-3-(1,2,3- triazol - 5 - ylthiomethyl) - 3 - cephem - 4 - carboxylic acid are prepared similarly. Sodium D - (-) - N - (2 - methoxycarbonyl - 1 - methylvinyl) - α - amino - α - (4 - hydroxyphenyl)- acetate is prepared by reaction of D-(-)-2-(phydroxyphenyl)glycine with sodium hydroxide followed by methyl acetoacetate. D-α-t-Butoxycarbonylamino - α - (p - hydroxyphenyl)acetic acid is prepared by reaction of D-(-)-p-hydroxyphenylglycine with magnesium oxide, then with t-butoxycarbonyl azide. Pharmaceutical compositions used as antibiotics contain a compound I together with a suitable carrier or diluent . Reference has been directed by the Comptroller to Specification 1,363,833. [GB1460914A]

Description

ν»»» *-(V3D»opiK*n»n- p)-^ -)-D nisn γ~ The preparation of D-(-)-2-(p-hydroxyphenyl)- glyoyl chloride hydrochloride BRISTOL-MYERS COMPAHY C; 47991 .- .The present invention provides a novel process for preparing the useful acylating agent of the formula * The D-(-)epimer of the above acid chloride hydrochloride is a preferred acylating agent for preparing 7-acylamido- cephalosporanic acid derivatives and is also useful as an intermediate for preparing other active penicillins and cephalosporins, e.g. p-hydroxyampicillin. One such process, for preparing 7-[D-(-)-a-a&i&o-a-(p-hydroxyphenyl) acetamido] -3-[s- (1,2,3-triazole - 5 - yl)-thiomethylJ-3-cephem-4carboxylic acid, is described and claimed in Israel Patent Specification No. 43913 (from which the present application was divided out).

The preparation of acid chloride hydrochlorides from 2-phenylglycine and phenyl-substituted 2-phenylglycines by use of such reagents as phosphorous pentachloride and thionyl chloride has been reported in the literature. Such 2-phenylglycyl chloride hydrochlorides are of considerable value as acylating agents for the 6-amino or 7-amino group of 6-aminopenicillanic acid or 7 aminopenicillanic acid or derivatives thereof in producing semisynthetic penicillins and cephalosporins having 2-phenylglycine side chains. When the above-mentioned prior art procedures have been attempted with 2-phenylglycines having a hydroxy substituent in the phenyl ring, however, the chloride hydrochloride products are found to be produced in low yields and with low purities. The products produced,, moreover, are found to have such poor physical crystalline properties that they are not suitable for use in the 1 It was an object of the present invention to provide a new ^ 2 and improved process for the preparation of 2-phenylglycyl 3 chloride hydrochlorides having a hydroxy substituent in the phenyl 4 ring and in particular a new and improved process for the 5 preparation of D- (-) -2- (p-hydroxyphenyl) glycyl chloride hydro- 6 chloride. 7 This invention provides a practical method for preparing 8 the desired chloride hydrochlorides in high yield and in high 9 purity. Additionally, the crystalline products prepared by the 0 present method are found to have the physical properties necessary 1 for efficient recovery from the reaction mixture, for good 12 storage stability and for use on a commercial scale in preparing 13 semisynthetic penicillins and cephalosporins.

I* More particularly, the present invention provides a process 15 for the preparation of D- (-) -2- (p-hydroxyphenyl) glycyl chloride 16 hydrochloride; which process comprises the consecutive steps of 17 (1) reacting D- (-) -2- (p-hydroxyphenyl) glycine with an excess 18 of phosgene with heating in a suitable substantially anhydrous 19 inert organic solvent as defined herein to form in solution the 20 anhydride of the formula 21 26 (2 ) removing excess phosgene from the reaction mixture; 28 (3) adding an excess of HCl gas to the cooled reaction mixture (4) recovering the desired D- (-) -2- (p-hydroxypehnyl) glycyl chloride hydrochloride.

A preferred embodiment of the present invention is the process for preparing D- (-) -2- (p-hydroxyphenyl) glycyl chloride 5 hydrochloride which process comprises the consecutive steps of 6 (1) reacting D- (-) -2- (p-hydroxyphenyl) glycine having a particle Y size of less than 200 mesh with at least 1.6 moles of phosgene 8 per mole of D- (-) -2- (p-hydroxyphenyl) glycine in substantially 9 anhydrous dioxane with heating for the minimum time necessary 0 to form the anhydride of the formula 1 6 (2) removing excess phosgene from the reaction mixture as rapidly 7 as possible after formation of the anhydride; 8 (3) adding a large excess of HCl gas to the reaction mixture 9 at a temperature in the range of about 0-5°C. for a period of 0 time sufficient to form D- (-) -2- (p-hydroxyphenyl) glycyl chloride 1 hydrochloride; and 2 (4) recovering the product from the reaction mixture. 3 The process of the invention may be represented by the follow- ^ ing flow diagram. 5 6 7 8 9 0 1° 11 it can be seen from the above diagram that the process involves 12 formation of an N-carboxyanhydride (Leuch's anhydride) by 13 reaction of the p-hydroxyphenylglycine with phosgene and then 14 conversion of the anhydride to the desired acid chloride 15 hydrochloride by treatment with gaseous hydrogen chloride. 16 The Leuch's anhydride intermediate is found to gradually 17 decompose in the presence of phosgene and. hence it is 18 advantageous for maximum yields to have the reaction between 19 the phosgene and p-hydroxyphenylglycine proceed as rapidly as possible and to remove excess phosgene from the reaction ^ mixture as soon as possible after formation of the anhydride 22 intermediate. 23 The amino acid, i.e. D- (-) -2- (p-hydroxyphenyl) glycine, and 24 phosgene are reacted in an anhydrous inert organic solvent. 25 Suitable solvents are those anhydrous organic solvents which 26 are (1) substantially chemically inert toward the p-hydroxy¬ 27 phenylglycine and phosgene, (2) solvents for the Leuch's 28 anhydride intermediate and (3) substantially non-solvents for 29 the acid chloride hydrochloride end-product. Examples of 30 1 suitable solvents include dioxane, 2 furan. The solvent preferred for 3 since in addition to the above properties it has a boiling point sufficient to enable the reaction mixture to be heated 5 to the preferred temperatures as described below. A 6 substantially anhydrous solvent is used as the phosgene is 7 sensitive to moisture. We prefer to use solvents having a 8 moisture content of £ 0.02% water, most preferably those 9 having a moisture content of ■ 0.01%. 10 For maximum yields, the reaction rate of the phosgene 11 addition step is maximized by proper adjustment of such factors 12 as particle size and concentration of the p-hydroxyphenyl- 13 glycine, temperature of the reaction mixture and concentration l^ and rate of addition of phosgene. The D- (-) -2- (p-hydroxyphenyl) 15 glycine is preferably ground and screened to a finely divided ^ state so as to increase the surface area. Best results have ^ been achieved when the p-hydroxyphenylglycine has a particle l8 size of less than 200 mesh, i.e. the amino acid is ground so 19 that less than 3% is retained on a 200 mesh screen. An excess 20 of phosgene is used to decrease reaction time. The phosgene 21 is preferably used in an amount of at least 1.6 to 2.0 moles pp per mole of amino acid. The addition of phosgene to the p-p , . hydroxyphenylglycine results m an exothermic reaction. To 24 increase the reaction rate and minimize decomposition, however, 25 the reaction mixture is preferably stirred and heat is added. 26 The most advantageous results have been obtained when the 27 phosgene is added as rapidly as possible with heating to about 28 60-80° C. for the minimum time necessary to form the anhydride. 29 Use of rapid phosgene addition and higher temperatures of about 30 60-80° C. for short time periods, e.g. 5 minutes, is found to be particularly advantageous for obtaining good yields when the reaction is conducted on a large scale. Best. results have been obtained when a fairly concentrated suspension of amino acid is employed, most preferably a concentration of about 10 g. amino acid per 80 - 100 ml. solvent.

Complete solubility of the amino acid is indicative of a complete reaction in the phosgene addition step. The reaction may also be monitored by appropriate techniques, e.g. thin layer chromatography, so as to indicate the minimum reaction time required for formation of the anhydride. By use of the preferred reaction conditions discussed above, practically quantitative yields of anhydride may be produced.

Since the Leuch's anhydride is found to gradually decompos in the presence of phosgene as mentioned previously, excess phosgene is preferably removed as rapidly as possible after completion of the phosgene addition step. Suitable methods for phosgene removal include purging with dry nitrogen gas and vacuum withdrawal.

Prior to addition of the gaseous HCl, it is found advantageous but not essential to remove a portion of the organic solvent, preferably by vacuum concentration. The solution may be concentrated so as to preferably remove up to a maximum of about 50-60% of the original solvent volume.

Since the chloride hydrochloride product generally is at least partially soluble in the reaction solvent, it has been found desirable to add an antisolvent prior to the HCl addition step so as to maximize recovery of the crystalline product.

Suitable antisolvents include such inert organic solvents as chlorinated hydrocarbons, e.g. methylene chloride, chloroform or ethylene dichloride and aromatic hydrocarbons, e.g. benzene^ I xylene or toluene. The most preferred antisolvents are toluene and methylene chloride. Most advantageous results have been obtained when the dioxane reaction mixture is concentrated to a volume of up to about 50-60% of the original volume and sufficient toluene or methylene chloride antisolvent added so as to result in a solution having a dioxane :antisolvent volume-volume ratio of about 7:3.

To convert the Leuch ' s anhydride intermediate to the desired chloride hydrochloride product, an excess of gaseous hydrogen chloride is added. To increase the solubility of the HCl, the anhydride solution is cooled, preferably to a temperature in the range of about 0-5° C. Best results have been obtained with a dioxane solvent when a large excess of HCl is used so as to completely protonate the dioxane. If insufficient HCl is used, a solvate of the acid chloride hydrochloride may form. This solvate may be used to acylate in situ the 6-amino or 7-amino group of a penicillin or cephalosporin nucleus but has been found to have poor storage . stability. Accordingly, any solvate which forms is preferably converted to the unsolvated acid chloride hydrochloride by such procedures as (1) further gassing with additional HCl or (2) filtering out the solvate and reslurrying in dry methylene chloride.

Recovery of the (p-hydroxyphenyl) glycyl chloride hydro-chloride is carried out according to conventional procedures. During or following HCl addition, seed crystals of the desired product are preferably added to induce crystallization.

Progress of the HCl addition step may be followed by periodic 1 testing with thin layer chromatography until conversion to the./") 2 3 has been added, the solution is allowed to gradually warm to k room temperature so as to allow slow crystallization and forma- 5 tion of the desired heavy dense crystalline product. Chilling 6 of the crystal slurry should be avoided so as to prevent solvate 7 formation. 8 The crystalline product is filtered, washed, e.g. with 9 toluene, dioxane, methylene chloride, and dried to give yields 10 of up to about 95% of excellent product when the preferred 11 reaction conditions are followed. 12 The D- (-) -2- (p-hydroxyphenyl) glycyl chloride hydrochloride 13 may be used to acylate the 6-amino or 7-amino-groups of 6-l^ aminopenicillanic acid or 7-aminopenicillanic acid or derivatives 15 thereof, e.g. derivatives of 7-aminocephalosporanic acid in 16 which the acetoxy group is replaced by other nucleophiles by 1? methods known in the literature. 18 19 20 1 2 3 5 6 7 8 9 0 Example 1 Preparation of D- (-) -2- (p-hydroxyphenyl) lycyl chloride hydrochloride 10.0 g. («^ 0.06 mole) of D- (-) -2- (p-hydroxyphenyl) glycine was slurried in 100 ml. of dioxane. The slurry was stirred and COClj (phosgene) was passed in while the slurry temperature was held at 50-58° C. The COC^ was passed in for a total time of 3.5 hours. A yellow solution was obtained.

The solution was purged with nitrogen to expel the excess COClj. 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 obtain some crystals which were added to the batch as seed. The solution was stirred at 20-25° C. for 16 hours. The resulting slurry of crystalline D-(-)-2- p-hydroyxphenyl glycyl chloride hydrochloride was filtered to collect the product. The filter-cake was washed with dioxane and methylene chloride and then dried in a vacuum desiccator over P2°5* Tne ^e^d of tne title product was 7.3 g. The IR spectrum indicated that excellent product was obtained.

Elemental Analysis: Cl C H N Theory 31.93 43.14 4.09 6.37 Found 31.96 42.46 4.22 6.56 Acid Chloride Assay Acid Chloride - 98.6% Free COOH - None Free HCl - None Example 2 j Preparation of Mono-Dioxane Solvate of D- (-) -2- (p-hydroxyphenyl) · qlycyl chloride hydrochloride 20 g. of D- (-) -2- (p-hydroxyphenyl) glycine was slurried in 200 ml. dioxane. Phosgene gas was passed in for a period of 3.75 hours and the reaction mixture was heated up during this period to a temperature of about 50° C. The yellow solution and the presence of a single zone by thin layer chromatography (TLC) indicated that the reaction had reached completion. The solution was purged with and cooled to about 6° C. HCl gas was added for about 130 minutes and the temperature was maintained at between -3° C. and 6° C.

Seed crystals were added to the solution approximately 90 minutes after the start of HCl addition. The solution was allowed to warm up to about 15° C. and stirred overnight. A heavy slurry of crystals formed. The system was slowly placed under vacuum whereupon HCl was removed. The slurry was stirred at room temperature for several hours, filtered, washed with dioxane and methylene chloride and dried in a vacuum desiccator over P2°5 to yie d 26.4 g. of white product. The product was found to be the monodioxane solvate of D- (-) -2- (p-hydroxyphenyl) glycyl chloride hydrochloride.

Assay Acid Chloride COOH Free HCl Dioxane Example 3 Preparation of Acetonitrile Solvate of D- (-) -2- (p-hydroxyphenyl)-qlycyl chloride hydrochloride 10.0 g. D-(-) -2-(p-hydroxyphenyl) glycine was slurried in 100 ml. acetonitrile. The suspension was stirred and phosgene was added for a period of about 25 minutes. The reaction mixture was then heated to about 46° C. with continued addition of COClj for another ί hours. 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 additional COClj was added with heating to 46° C. until a total of 193 g.

COCI2 bad been used. Excess COClj was removed by purging with and the solution was chilled. HCl gas was added and the solution was seeded with crystals of p-hydroxyphenylglycyl chloride HCl. After HCl addition for 5.75 hours at about 4-6° C, there was added 25 ml. acetonitrile and the crystals which had formed began to dissolve. The reaction mixture The mixture was stirred overnight, filtered, washed with acetonitrile and methylene chloride and dried to yield 4.2 g.

The IR indicated the product was the acetonitrile solvate of D- (-) -2- (p-hydroxyphenyl) glycyl chloride hydrochloride. Analysis by gas liquid chromatography (G.L.C.) showed 15.6% acetonitrile content which is in excellent agreement with the theoretical percentage of 15.6 for the solvate.

Example 4 Preparation of D- (-) -2- (p-hydroxyphenyl) lycyl chloride hydrochloride using finely divided amino acid 10.0 g. of D- (-) -2- (p-hydroxyphenyl) glycine haying a particle size of less than 200 mesh was slurried in 100 ml. dioxane. Phosgene was passed in for 10 minutes and then the reaction mixture was heated up to 64° C. with additional phosgene addition until a total of 1.8 moles C0Cl2 had been used per mole of amino acid. After completion of the reaction and expulsion of the excess COCl2, the solution was concentrated under vacuum. Toluene (25 ml.) was added and the solution was brought to a volume of 80 ml. with dioxane. The solution was chilled and slowly gassed with HC1 for approximately 1 hour. Seed crystals were added and the reaction mixture was stirred and allowed to warm to room temperature. After continued stirring for several hours, the crystals were filtered, washed and dried over P205 to yield 11.65 g. (87.5%) of the title product.

Example 5 ; Preparation of D- (-) -2- (p-hydroxyphenyl) glycyl chloride hydrochloride using 2.0 moles phosgene per mole amino acid 100 g. D- (-) -2- (p-hydroxyphenyl) glycine screened to 200 mesh was slurried in 1000 ml. dioxane. C0C12 was added for about 15 minutes (123 g.) and the mixture heated to about 62° C. until the reaction was shown by TLC to be essentially complete Excess COCl2 was removed with N2 and the solution was concentrated under vacuum to a volume of about 550 ml. To this concentrated solution was added 250 ml. toluene.

The solution was cooled to 5° C. and HCl gas (190 g.) bubbled ^ in slowly at 0-5°C. for 2 hours. After stirring at 3° C. for 20 minutes, the reaction mixture was seeded and stirred for several more hours to form a heavy slurry. The slurry was filtered, washed with dioxane-toluene and methylene chloride and dried over ?205 to form 112 g* (84·2%) of t¾e title product. 1 Example 6 2 Preparation of D- (-) -2- (p-hydroxyphenyl) glycyl chloride 3 hydrochloride A. Preparation of Touch's Anhydr-i riP nf n- ( - ) -2- (p-hvdroxv- 5 phenyl) glycine 6 100 g. of D- (-) -2- (p-hydroxyphenyl) glycine (screened so that 7 less than 3% was retained on a 200 mesh screen) was slurried 8 in 1000 ml. dioxane. Phosgene was added for 25 minutes 9 with heating up to about 80° C. whereupon an orange solution 10 was produced. Excess phosgene was removed by house vacuum and 1 the reaction mixture concentrated under vacuum to a volume 12 of approximately 420 ml. Dioxane was added to give a volume 13 of 500 ml. TLC indicated the presence of only Leuch ' s ^ anhydride in the reaction mixture. 5 B. Preparation of chloride hydrochloride using methylene l chloride - dioxane mixed solvent To 125 ml. of the Leuch 1 s anhydride solution from Step A was added 62 ml. methylene chloride and 13 ml. dioxane. The solution 9 Was stirred, chilled to 5° C. and 50 g. HCl gas added over a 40 20 minute period at 0 - 6° C. After stirring and seeding, a slurry 21 of crystals formed. The reaction mixture was allowed to warm to 2 room temperature and stirred overnight. The crystals were washed 3 twice with 200 ml. dioxane-methylene chloride and 300 ml. ^- methylene chloride and dried in a vacuum desiccator over P2O5 25 to give 28.4 g. of title product (85.5% yield). 26 Assay 27 Acid chloride = 92.9% 28 Free COOH = 2.6% 29 Free HCl = 0.6% 3° Dioxane = 1.06% 1 C. Preparation of chloride hydrochloride using toluene- . 2 dioxane mixed solvent 3 The procedure of Part B was repeated except that 65 ml. 4 toluene was substituted for the 62 ml. methylene chloride used 5 therein. There was produced 28.7 g. (86.7% yield) of dried 6 product which was characterized by IR as being the desired 7 chloride hydrochloride. 8 Assay 9 Acid chloride = 93.9% 0 Free COOH = 3.6% 1 Free HC1 = 0.5% 2 D. Preparation of chloride hydrochloride via dioxane solvate 3 To 125 ml. of the Leuch ' s anhydride solution from Step A was 14 added 12 ml. dioxane and 65 ml. toluene. The solution was 15 chilled to 0° C. and 26 g. HCl added over a 30 minute period 16 at 2° C. After stirring and allowing the solution to warm ? to room temperature, a heavy slurry of crystals formed which A were found by microscopic examination to be needles of the 19 dioxane solvate of D- (-) -2- (p-hydroxyphenyl) glycyl chloride HCl. 20 An additional 60 g. HCl gas was added as the temperature was 21 gradually lowered to 7° C. and the solvate crystals were 22 seen to break up. Upon seeding, the desired chloride hydrochlor¬ 23 ide crystals formed and after filtering, washing and drying, 24 there was produced 29.7 g. (89.5% yield) of product. IR 25 0 ind-icated littl-e or no COOH and- good It C - CI.

Assay Acid chloride COOH HCL Dioxane 1 Example 7 2 Preparation of D- (-) -2- (p-hydroxyphenyl) lycyl chloride 3 hydrochloride using slower HCl addition and dioxane- toluene mixed solvent 5 To 125 ml. of Leuch's anhydride solution prepared according to 6 6 Example 2ϋ¥ was added 13 ml. dioxane and 70 ml. toluene. The 7 solution was stirred, chilled to 0°C. and gassed at 0-3° C. 8 with 50 g. HCl over a 75 minute period. After stirring and 9 seeding the chilled solution, a heavy slurry of crystals 0 formed which when filtered, washed and dried gave 31.3 g. 1 (95.5% yield) of excellent chloride hydrochloride product. 2 Assay 3 Acid chloride = 92«-3% COOH = 5.9% 5 HCl = 1.6% 1 Dioxane = 1.12% 17 18 19 Example 8 20 preparation of D- (-) -2- (p-hydroxyphenyl) lycyl chloride 21 hydrochloride using dioxane solvent 22 The procedure of Example ' \ was repeated except that (1) 3 10 ml. dioxane was added instead of the mixture of dioxane *^ and toluene, (2) 70 g. HCl gas was used instead of 50 g. ^5 and ( 3 ) the solution was gassed for about 3 hours instead 26 of 75 minutes. There was produced 22.7 g. (68.5% yield) of 27 dried product which was identified by IR as being the desired 28 chloride hydrochloride. 29 30

Claims (3)

CLAIMS :

1. A process for the preparation of D- (-) -2- (p-hydroxyphenyl) -glycyl chloride hydrochloride; which process compri the consecutive steps of 1) reacting D- (-) -2- (p-hydroxyphenyl) glycine with an excess of phosgene with heating in a suitable substantially anhydrous inert organic solvent as defined herein to form in solution the anhydride of the formula 2) removing excess phoijgene from the reaction1 mixture ; 3) adding an excess of HCl cas to the cooled reaction mixtur? i 4) recovering the desired D- (-) -2- (p-hydroxyphenyl) glycyl chloride hydrochloride.

2. The process according to Claim 1 which comprises the consecutive steps of (1) reacting D- (-) -2- (p-hydroxyphenyl) glycine having a particl size of less than 200 mesh with at least 1.6 moles of phosgene per mole of D-(-) -2- (p-hydroxyphenyl) glycine in substantially anhydrous dioxane with heating from about 60-80°C. for the minimum time necessary to form the anhydride of the formula (2) removing excess phosgene from the reaction mixture as (3) adding a large excess of HCl gas to the reaction mixture at a temperature in the range of. about 0 - 5° C. for a period of time sufficient to form D- (-) -2- (p-hydroxyphenyl)glycyl chloride hydrochloride; and .(4) recovering the product from the reaction mixture. . « ■ .

3. p- (- ) -2- (p-hydroxyphejliyl) glycyl chloride hydrochloride whenever prepared according to a process of any of Claims 1 and 2.