DE2127225A1 - New process for making cephalexin - Google Patents

Description

DR. WALTER NiELSCH Potent attorney

2 Himburg 70 · P.O. Box 10914

Long distance call; 6529707

Yamanouchi Pharmaceutical Co., Ltd. Chuo-ku, Tokyo / Japan

New process for making cephalexin

This invention relates to a new process for the preparation of 7- (D-α-aminophenylacetamido) desacetoxycephalosporanic acid, commonly called "Cephalexin", which is carried out on an industrial scale with commercial success can be.

More specifically, the invention relates to a new process for the preparation of cephalexin, characterized in that a 7-acylaminodesacetoxycephalosporanic acid ester with the general formula I.

R ₁ CONH

10OR ₂ *
in which R 1 denotes a benzyl group, a phenoxymethyl group, a p-hydroxybenzyl group, a penteny group, an amyl group, a heptyl group and the like, and R p denotes a triphenylmethyl group, a bis (p-methoxyphenyDmethyl group, a 3,5-di-tert. -Butyl-4-hydroxybenzyl group and the like is reacted with a phosphorus halide, the iminohalide compound thus obtained

109851/1959

reacts with a lower alcohol, the imino ether compound obtained reacted with phenylglycyl chloride hydrochloride, then the product obtained with water or a treated lower alcohol and finally the protective group for the carboxyl group under mild conditions without Opening of the desacetoxycephalosporanic acid ring removed.

In the present invention, the term "means desacetoxycephalosporanic acid

4-carboxylic acid with the formula

"Desacetoxycephalosporanäureririg" the 3-methyl-A -cephem

OOH

Cephalexin is one of the typical so-called cephalosporins and is suitable for oral administration Antibiotic.

As a method of industrially producing cephalexin from the 7-acylaminodeacetoxycephalosporanic acid ester, there is known a procedure in which the ester is reacted with phosphorus halide to obtain an iminohalide compound. The imino halide is reacted with a lower alcohol in order to obtain an imino ether compound, the imino ether is then hydrolyzed to the 7-aminodeacetoxycephalosporanic acid ester, the ester is then reacted with phenylglycine or its reactive derivative and then the ester group is split off, see, for example, Belgian patent 717 7 ¹ H.

However, it is difficult in the known method to obtain the intermediate compound 7-aminodeacetoxycephalosporanic acid ester to isolate and so in practice the known method is accompanied by such difficulties, that the ester can only be used as a salt of a sulphonic acid, such as p-Toluenesulfonic acid is isolated and then after over-

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leading of the sulfonate to a free 7-aminodeacetoxycephalosporanic acid ester, the acylation (introduction of a phenylglycyl group) is carried out.

The inventors have the economical industrial production of cephalexin from 7-acylaminodesacetoxycephalosporanic acid ester investigated and found that when converting dos 7-acylaminodesacetoxycephalosporanic acid ester with the formula I already shown with a phosphorus halide, by reacting the imino halide compound thus obtained an imino ether compound with a lower alcohol is obtained; by reacting the imino ether compound with phenyl glycyl chloride hydrochloride, treatment of the product with water or a lower alcohol and finally, lastly, by removing the protective group of the carboxyl group under mild conditions, high-purity cephalexin is unexpectedly obtained in a high yield the direct reaction of the imino ether compound and the phenylglycyl chloride hydrochloride produced without the To split the imino ether bond during the reaction; that is, without transferring the 7-position of the desacetoxycephalosporanic acid ring to a free amino group (7 ~ aminodeacetoxycephalosporanic acid ester).

about examples for the implementation of iminoether-type compounds and carbonic acid chlorides have been sparsely reported. It's just a report about

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-If-

described by HL Wheeler and PT Waiden in J. ACS, 19 , 129-139 (1897). On the other hand, it is actually most surprising that the monoacylamide compound is obtained by the present invention contrary to the above expectation that a diacylamide should be formed.

Since, according to the process of this invention, cephalexins are obtained in actually the same reaction kettle can, without the need, the 7-aminodeacetoxycephalosporanic acid ester as an intermediate product and also without separating intermediate products in the reaction processes, The operation of this invention is very simple and can be compared in a shorter working time be carried out with the already mentioned known method. Furthermore, high-purity cephalexin can be used in in high yield, taking into account that the intermediates are not isolated and purified during the reactions, making the process of this invention very economical industrially is.

When using, for example, a 7- (phenylacetamido) desacetoxycephalosporanic acid ester as 7-acyiaminodesacetoxycephalosporanic acid ester can the reaction sequence of this Invention can be accepted as formulated as follows:

CH ₂ CONH

2
Phosphorus halide

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II

III

COOR

(1)

/ ~ "\ cH

CHCOCl

/ HCOCl Y- / NH ₂ -HCl

(2) Treatment with water or a lower alcohol

IV

(Cephalexin)

COOH

In the above formulas, X represents a halogen atom and R represents a methyl group, an ethyl group or represents a propyl group.

The starting compound of this invention is the 7-acylaminodeacetoxycephalosporanic acid ester with the general formula I can be obtained by oxidation of an ester of natural penecillin to give a sulfoxide therefrom making and heating the product in the presence of a

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ken acid to enlarge the ring or by esterification of T-acylaminodesacetoxycephalosporanic acid according to the known ones Processes such as those in US Pat. No. 3,275,626 and Dutch Patents No. 68 065 32 and 68 O65 33 are described.

The acyl group (R.Co) of the 7-acylaminodesacetoxycephalosporanic acid ester I is an organic acyl group, which has natural penicillin and this is to be Clarification / τ \

/ % CH ₂ CO- of penicillin G,

OrCH _n CO- from penicillin V,

fA->

CH ₃ CH ₂ CH = CHCH ₂ CO-from penicillin P, CH ₃ (CH ₂ ) ^ CO - from dihydro penicillin F, CH ₃ (CH ₂ ) gCO - from penicillin K and

CH ₂ CO - from penicillin X

called,

Suitable protective groups (R ₃ ) for the carboxyl group are those groups which can be removed chemically under mild conditions without opening the deacetoxycephalosporanic acid ring. Examples of such groups are the groups capable of being released by hydrolysis such as a triphenylmethyl group, a bis (p-methoxyphenyl) methyl group and a trimethylsilyl group; the groups capable of being set free by a basic material such as thiophenol ^{sodium salt are such as a 35 5-di-tert-butyl-1-} hydroxybenayl group, a phenacyl group and a p-nitrophenacy group; ·

1G9851 / 1S59

Groups capable of being released by zinc dust treatment in acetic acid are, for example a trichloroethyl group; and the groups capable of treatment with trifluoroacetic acid To be released is, for example, a p-methoxybenzyl group. The method of this invention will now be practically explained.

First, the step for preparing the iminohalide compound II by the reaction of the 7-acylaminodeacetoxycephalosporanic acid ester can be carried out I with a phosphorus halide according to a known method, as for example in the Belgian 717,741 and in the South African patent 672 927 is to be carried out. For example, the 7-acylaminodeacetoxycephalosporanic acid ester is used I with a slight excess of a phosphorus halide, such as phosphorus pentachloride, in an inert organic solvent such as chloroform, dichloromethane, dichloroethane, trichloroethylene and the like reacted in the presence of a tertiary amine such as pyridine and dimethylaniline with cooling. The response time is usually about an hour.

Then the step for the preparation of the iminoether compound III is carried out by reacting the iminohalide compound II thus obtained with a lower alcohol by a known method, as indicated, for example, in the Belgian patent 717 74l and the South African patent 672 927. For example, the iminohalide compound II obtained above, without being isolated from the reaction product mixture, can be reacted with an excess amount of a lower alcohol such as methanol, ethanol or propanol with cooling. The reaction time is usually about 2 to 5 hours. If the triphenyl methyl ester or the trimethyl

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BATH ORIGINAL

silyl ester is used as a starting material must be taken into account be that the protecting group for the CarboxjzL group to be removed at this stage.

It is unnecessary to use the obtained imino ether compound III to isolate from the reaction product mixture.

The step for preparing the final intermediate IV is carried out by adding phenylglycyl chloride hydrochloride in an equimolar or excess molar amount to the amount of the starting material I to the imino ether compound III obtained above. The reaction is usually under cooling, preferably at temperatures from -15 ⁰ C to -25 ° C with stirring for several hours. In this case it is preferred, in order to continue the reaction mildly, to add an amine such as pyridine or dimethyl aniline or a basic material such as ammonium acetate or potassium 2-ethylhexanate as an acid-binding agent to the reaction mixture.

Then if the addition compound obtained above is treated with water or a lower alcohol, the 7- (a-aminophenylacetamido) desacetoxycephalosporan becomes acid ester IV formed.

This treatment is carried out by adding water or a lower alcohol to an organic solvent solution, which contains the above product and while vigorously stirring the batch with ice cooling for one carried out for a short period of time. Likewise, if there is an excess amount of the lower alcohol in the already mentioned Imino etherification is used, it is believed that the addition product formed above into the 7- (a-aminophenylacetamido) desacetoxycephalosporanic acid ester IV by the alcohol remaining in the reaction mixture

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hol is convicted. However, when triphenylmethyl _{ester 5} bis (p-methoxyphenyl) methyl ester or trimethylsilyl ester is used as the starting material, an aqueous dilute solution of an acid having a pH of 2 to 3 is added to the organic solvent solution containing the aforementioned addition product with stirring. The protective group for the carboxyl group is removed and the objective end product cephalexin is obtained at the same time through the water treatment.

Finally, the step of removing the protective group of the obtained 7 ~ (ct-aminophenylacetamido) desacetoxycephalosporanic acid ester can be carried out IV can be carried out by a known method. For example, if triphenyl methyl ester, Bis (p-methoxyphenyl) methyl ester or trimethylsilyl ester is used as the starting material, becomes a aqueous dilute acid solution to the organic solvent solution containing the aforementioned compound IV, added with subsequent vigorous stirring for a few hours, preferably with ice cooling. If 3,5-di-tert-butyl-4-hydroxybenzyl ester, Phenacyl ester or p-nitrophenacy! Ester is used as the starting material, becomes at least an amount equivalent to the starting material of a basic material such as a sodium salt of thiophenol, potassium 2-ethylhexanate, methylamine, ethylamine, Diethylamine, cyclohexylamine or triethylamine to the organic solvent solution that has already been mentioned Compound IV contains, added with subsequent stirring for 1 to 2 hours, preferably below Ice cooling. In this case, it is preferred to use a mild nucleophilic agent such as to continue the reaction Add ethyl mercaptan or triethyl phosphite.

The separation of cephalexin from the reaction product liquid is made according to known chemical methods

for the carboxyl group

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such as precipitation at the isoelectric point.

Reference example 1

In 450 ml of dimethylformamide 37 ₃ 0 g of potassium 7- (phenylacetamido) are dissolved desacetoxycephalosporanat and 4.1 g of 2,6-di-tert-butylphenol and then added 10 g potassium bicarbonate to the solution.

The suspension obtained in this way was cooled to -15 ° C. and then 48 g of 3,5-di-tert-butyl-4-hydroxybenzyl bromide were added added with stirring in portions over 3.5 hours. After further stirring at the same temperature the liquid reaction product batch was dispersed in 1 liter of ice water and the product was dispersed over a period of 30 minutes extracted three times with 250 ml of ethyl acetate each time. The ethyl acetate extracts were combined and mixed with 250 ml of 3% solution aqueous sodium bicarbonate solution, then twice washed with 200 ml of water and then dried over anhydrous sodium sulfate.

The ethyl acetate solution obtained was concentrated to 50 ml under reduced pressure at low temperature. After adding 400 ml of petroleum ether to the concentrated liquid, crystals were deposited. The crystals were separated off by filtration and washed twice with 100 ml of petroleum ether each time. After drying, 46.8 g of pale yellow powdery crystals from 7 ~ (Phenylacetamidojdesacetoxycephalosporansäure ^ ^1, 5 '-di-tert-butyl-4'-hydroxybenzyl ester in a yield of 85 $ having a melting point 101-104 ° C obtain.

Elemental analysis as C ₅₁ H-ZgNpO ₁ -S: C (? 5) H (SS) N (Ji)
Calculated: 67.61 6.96 5.09
Found: 68.20 7, i »8 4.72

109851/1959 ORIGINAL BATHROOM

Reference example 2

In 93 ml of dimethylformamide, 18.5 g of potassium 7- (phenylacetamido) desacetoxycephalosporanate and 1.1 g of potassium bicarbonate and then 13.9 g of triphenylmethyl chloride were added over 2.5 hours to the suspension with stirring. After stirring for an additional two hours, the reaction product liquid was dispersed in 5/6 aqueous sodium bicarbonate solution and then the product was extracted three times with 300 ml of ethyl acetate. The ethyl acetate extracts were combined and washed twice with 140 ml of water each time and dried over anhydrous sodium sulfate. The ethyl acetate solution was concentrated to 50 ml at low temperature under reduced pressure, and then 70 ml of ether was added to the solution to form crystals. The crystals formed were separated off by filtration, washed twice with 50 ml of ether each time and dried. 25 »2 g of the white powdery crystals of 7 (-phenylacetamido) desacetoxycephalosporanic acid triphenylmethyl ester with a melting point of 112-113.5 ° C. were obtained in a yield of 88% .

Elementary analysis as C H(*) 35 ^H 3O ^N 2 ° 4 S: S (Ji) ~ V ι-. 5.26 N (Z) 5.58 Calculated: T5.15 5.29 4.87 5.54 Found: 73.00 5.20

Reference example 3

26 g of potassium 7- (phenylacetamido) deacetoxycephalosporanate were added to 200 ml of dichloroethane suspended. Then 3.5 g of pyridine and 18.5 g of bis (p-methoxyphenyl) -methyIchlordd added to the suspension over 1.5 hours with stirring. After another 2.5 hours With stirring, the reaction product liquid became twice with 60 ml each of cold water and 50 ml of cold 5% aqueous

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Washed sodium bicarbonate solution, then washed with water and dried over anhydrous sodium sulfate. The dichloroethane solution thus obtained was concentrated to 50 ml under reduced pressure at low temperature. Then 100 ml of ether were added to induce crystallization. The crystals formed were separated off by filtration, washed twice with 50 ml of ether each time and dried. There were 33 "3 g of pale yellow powdery crystals from 7 ~ (phenylacetamido) desacetoxycephalosporanic acid" bis (p-methoxyphenyl) methylester having a melting point of 130-132 ⁰ C in a yield of

Received $ 85. Elemental analysis as C ₃₁ H ₃₀ N ₂ OgS: C (5O H (JS) N (50 S (SO 66.65 5.41 5, oi 5.74 Calculated: 66.13 5.59 5.30 5.67 Found :

example 1

5.74 g of 7- (phenylacetamido) -desacetoxycephalosporanic acid triphenylmethyl ester were dissolved in 57 ml of dichloroethane. 4.12 ml of dimethylaniline was added. The solution was cooled to -15 ° C to -20 ⁰ C. Then, 2.3 g of phosphorus pentachloride was added and the mixture stirred at -15 ° C to -20 ⁰ C for 1.5 hours. Then 40 ml of methanol were added dropwise while keeping the mixture in the same temperature range and stirring was continued for 2 hours for a further two hours.

Then, 9.6 ml Dimethylsnilin was added to the solution and the mixture was kept by cooling to -15 ° C to -20 ⁰ C. A total of 2.5 g of D (-) - ct-phenylglycyl chloride hydrochloride were then added in small portions over the course of two hours with stirring. Thereafter, the mixture was stirred for a further two hours at the same temperature. Then 20 ml of water was added and the mixture

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30 minutes intensive at temperatures between 0 to ~ 5 ° C touched.

Perlite (see Römpp, Chemie Lexikon, 6th edition, column 4764) was added and then filtered. The filtered off Perlite was washed with 10 ml dichloroethane. Wash liquid and filtrate were combined, which thereby formed The aqueous layer and the dichloroethane layer were separated from one another. The dichloroethane layer was used twice extracted with 10 ml of water each time. The extracts were combined with the above aqueous layer and the mixture was washed with 20 ml of isobutyl methyl ketone to obtain a colorless and transparent aqueous solution with a pH of about 2.5. By using a qualitative analysis by the plate method of Bacterium subtilis, the aqueous solution was confirmed to contain 2.72 g of cephalexin, the yield being 78,552.

The aqueous solution obtained above was mixed with 105 ml of ligroin, which contains 35 ml of a liquid ion exchanger, Amberlite LA-2 (containing Acetic acid type Organo CoJ) with sufficient shaking of the mixture. The ligroin solution was then removed and the resulting aqueous solution had a pH of about 4. After adjusting the pH of the aqueous solution was adjusted to 4.5-5.0 with sodium bicarbonate, the solution was made with 50 ml of isobutyl methyl ketone washed. Then the solution was concentrated to about 10 ml under reduced pressure at low temperature Crystals to form. After the batch was left to stand in a refrigerator overnight, the deposited ones were deposited The crystals were separated by filtration. The crystals were washed with a small amount of isobutyl methyl ketone, washed in cold water and then acetone and dried. 2.1 g of the white powdery crystals from Cepha-

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Lexin hydrate with a decomposition point of 18-190 ° C. was obtained in a yield of 57 »5% .

The product was suspended in acetone which contained 10 l of water in 20 times the volume of the product, and while stirring the suspension at ⁰ ° C., the product was dissolved by acidifying the mixture with hydrochloric acid. A small amount of activated charcoal was then added to the solution and the mixture was filtered. When the pH of the filtrate einge- to about 5 with triethylamine with stirring W was assumed crystals were deposited. The deposited crystals were separated off by filtration, washed with acetone and washed with cold water. After drying, cephalexin hydrate with a decomposition temperature of 190-193 ° C. was obtained.

Elemental analysis as C ₁ ^ H ₁ "N ^ O ^ S · H ₃ O

C (SS) H (Ji) N (JO S (JO Calculated: 52.59 5.24 11.50 8.77 Found: 52.67 4.63 11.15 8.24

Example 2:

^ 74 g of 7- (phenylacetamido) desacetoxycephalosporanic acid triphenylmethyl ester were suspended in 80 ml of toluene and, after adding 3.4 ml of pyridine, the mixture was cooled to temperatures between -5 ° C and -10 ° C , 6 g of phosphorus pentachloride were added and the mixture was kept for one hour at temperatures between ⁰ ° C. and -5 ° C. with stirring. 40 ml of ethanol was added dropwise to the mixture with stirring and then the mixture for another 3 hours at temperatures between -15 ⁰ C to -20 ° C was stirred. Thereafter, 3.6 ml of pyridine was added to the mixture and after cooling to temperatures between -15 ° C to -20 ⁰ C 2.5 g of di-yes-Phenylglycylehlorid hydrochloride was added in small portions in total. That

1Ö9861 / 19S9

The mixture was kept at the same temperature for a further 2 hours. Then 20 ml of water were added and the mixture was ^{stirred intensively for 30 minutes at temperatures between 0} ° C. and -5 ° C. By treating the reaction product liquid thus obtained as described in Example 1, 1.75 g of cephalexin hydrate was obtained in a yield of 48%. The product had a decomposition point of 187-190 ° C.

Example 3:

In 20 ml of dichloroethane was 1.44 g of 7- (phenylacetamido) -desacetoxycephalosporansäure "triphenylmethylester dissolved and, after addition of 1 ml of N-ethylaniline the mixture to -20 ⁰ C + _ 5 ⁰ C was cooled. It was 0.58 g of phosphorus pentachloride was added to the solution un <i the mixture 1 _S 5 hours at temperatures between -20 ⁰ C ± 5 ° C stirred. Then, 10 ml of methanol was added to the mixture at the same temperature, and the mixture was further stirred for 3.5 hours. Thereafter, 1.9 ml of N-ethylaniline was added to the mixture. The mixture was cooled to -20 ⁰ C ± 5 ⁰ C. Then, a total of 0.63 g of D (-) - ct-phenylglycyl chloride hydrochloride was added to the mixture in small portions over the course of one hour with stirring. The mixture was then stirred for a further 3 hours at the same temperature. The mixture was then ^{cooled to 0} ° C. and, after 10 ml of water had been added while stirring, the mixture was stirred for a further 30 minutes. The piltering aid perlite was added to the reaction mixture. Then it was filtered. The perlite was washed with 5 ml of water. The wash water was combined with the filtrate and the aqueous layer formed in the process and the dichloroethane layer were separated from one another. The dichloroethane layer was extracted twice with 5 ml of water each time. The extract was washed with the aqueous solution obtained above

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Layer united. After washing the aqueous solution twice with 10 ml of isobutyl methyl ketone each time an almost colorless and transparent aqueous solution with a pH of about 2.5 is obtained. The aqueous solution was Made up to 50 ml with water and then the solution checked by means of high-voltage filter paper electrophoresis. At the point that corresponds to the cephalexin, one stain was positively detected by means of ninhydrin. Likewise, in the analysis by the plate method under Use of Bacterium subtilis confirms that the solution contained 10.9 mg / ml cephalexin. The total amount of the product was 5 ^ 5 mg and the yield therefor was $ 62.8.

Example 4:

5-58 g of 7- (phenylacetamido) -desacetoxycephalosporanic acid bisCp-methoxyphenyDmethyl ester were dissolved in 56 ml of dichloroethane. After addition of 4.12 ml of dimethylaniline to the solution, the mixture to -25 ⁰ C _ + 5 ° C was cooled. Then 2.5 g of phosphorus pentachloride was added to the solution. The mixture was stirred for 1.5 hours at -25 ° C Hh 5 ⁰ C, ¹ JO ml of methanol was added dropwise to the mixture at the same temperature. The mixture was stirred for an additional 2.5 hours. Then 9 »6 ml of dimethylaniline was added to the mixture. The mixture was cooled to -25 ° C + 5 ° C and 2.5 g of D (-) - ot-phenylglycyl chloride hydrochloride was added in small portions to the mixture with stirring. The mixture was gerüfcrt then further 1 hour at the same temperature and kept for 16 hours in a refrigerator at -20 ⁰ C. To the reaction product fluid 150 ml 0.1 N hydrochloric hydrochloric acid solution while stirring and maintaining the temperature between 0 _ + 5 ⁰ C was added. The mixture was then vigorously stirred for Ί hours at the same temperature. The aqueous layer thus formed and

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the dichloroethane layers were separated from one another. The Dichloroäthanschicht was twice with 20 ml of water extracted. The extracts were combined with the separated aqueous layer and perlite became the Solution added as filter aid. It was filtered. The Piltrat was twice with 50 ml of isobutyl methyl ketone washed to obtain an almost colorless solution. By quantitative analysis by the plate method under Use of Bacterium subtilis was made in the aqueous Solution determined the content of cephalexin to be 2.55 g, which represents a yield of $ 73.6.

The aqueous solution thus obtained was washed with 120 ml of ligroin containing 42 ml of an acetic acid type Amberlite LA-2 liquid ion exchanger with sufficient shaking. The aqueous solution obtained after separating the ligroin had a pH of about 4. After adjusting the pH of the aqueous solution to 4.5-5.0 with sodium bicarbonate, the solution was washed with 50 ml of isobutyl methyl ketone and then taken up under reduced pressure at a low temperature concentrated about 10 ml to allow the solution to crystallize out. After the batch was left to stand in the refrigerator overnight, the deposited crystals were separated by filtration and the crystals were washed with a small amount of isobutyl methyl ketone, cold water and then acetone. It was dried. 2.04 g of the white powdery crystals of cephalexin hydrate with a decomposition point of 186-191 ° C. were obtained in a yield of 55.8 % .

Example 5:

1.4 g of 7- (phenylacetamido) desacetoxycephalosporanic acid bis (p-methoxyphenyl) methyl ester was added to 20 ml of toluene dissolved. After adding 0.85 ml of pyridine to the solution was

109851 / 19B9

the mixture to -2O ⁰ C + _ 5 ⁰ C cooled. Ilach adding O365 g of phosphorus pentachloride and stirring the mixture for 1.5 hours at -2O ⁰ C + _ 5 ° C 10 ml of methanol was added dropwise to the mixture with stirring at the same temperature given. Then 0.9 ml of pyridine was added to the mixture. The mixture was maintained at -20 ° C + _ 5 ⁰ C by cooling. A-Phenylglycylchlorid hydrochloride was added at -20 ⁰ C + _ 5 ° C - in the course of 30 minutes was added with stirring in portions a total of 0.63 g of D (-). The mixture was then stirred for a further 2 hours at the same temperature. The reaction product liquid was washed with 25 ml of cold 55% sodium bicarbonate aqueous solution, and then the aqueous solution and the toluene solution were separated from each other. To the toluene solution 50 ml of water was added and acidified by dropwise addition of lO ^ hydrochloric acid solution with stirring at 0 ⁰ C + _ 5 ⁰ C, the pH of the aqueous layer was adjusted to about 2 and the mixture stirred for 4 hours at the same temperature.

The aqueous layer and the toluene layer were separated from each other, and the toluene layer was made twice extracted with 10 ml of water each time. The extracts were combined with the resulting aqueous layer and the mixture was washed twice with 15 ml of isobutyl methyl ketone each time to obtain an almost colorless and transparent aqueous Get solution. The aqueous solution was made up to a total volume of 100 ml with water. The solution was examined by means of high voltage filter paper electrophoresis. At the point corresponding to the cephalexin with the positive ninhydrin reaction, the cephalexin was detected. Using an analysis with the plate test of Bacterium subtilis showed that 6 mg / nü.Cephalexin was included in the solution. The total amount of the product was 600 mg and the yield was 69.25?.

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Example 6:

(a) as described in Example 4 With the same procedure, was added 5 ₉ 58 g of 7- (phenylacetamido) desacetoxycephalosporanic acid · bis (p-methoxyphenyl) methyl ester with D! a-Phenylglycylchlorid hydrochloride umgeßetzt - (-). The reaction product liquid was mixed with 100 ml of cold 5% aqueous sodium bicarbonate solution, and the mixture was stirred at 0 C ± 5 ° C for one hour. Perlite was added to the mixture as a filter aid. It was filtered and the aqueous layer formed and the dichloroethane layer were separated from each other. The aqueous layer was extracted with 25 ml of dichloroethane, the extract was combined with the dichloroethane layer obtained above, and the mixture was washed twice each time with 50 ml of water. After drying the dichloroethane solution over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure and at low temperature to a total volume of about 50 ml. After adding about 100 ml of ether to the concentrate and subsequent stirring treatment, a small amount of crystals separated out, which were filtered off. After 150 ml of ligroin was added to the filtrate, crystals were deposited. These were separated by filtration and dried. 4.0 g of the slightly yellowish powdery crystals of 7- (D (-) - a-aminophenylacetamido) desacetoxycephalosporanic acid bis (p-methoxyphenyl) methyl ester with a melting point of 96-98 ° C. were obtained. The yield was 70%.

Elemental analysis as ^C 3i ^H 3i ^N 3 ° 6 ^S:

C (Ji) H (X) N (X) S (X) Calculated: 64.91 5.45 7.32 5.59 Found: 64.30 5.41 7.53 5.4l

109851/1959

(b) In a mixture of 1 N hydrochloric acid and ¹ acetone (ratio 1: 4), 0.57 g of 7- (D (-) - ot-aminophenylacetamidojdesacetoxycephalosporanic acid · bis (p-methoxyphenyl) methyl ester was dissolved to make a total volume of 5 ml The solution was allowed to stand at room temperature for 3 hours, and it was confirmed that the aqueous solution contained 0.33 g of cephalexin by quantitative analysis by plate test using Bacterium subtilis, and the yield was 90%.

Example 7:

To a solution of 5.5 g of 7- (phenylacetamido) desacetoxycephalosporanic acid · 3 '»5'-di-tert-butyl-4'-hydroxybenzyl ester in 55 ml of dichloroethane, 4.12 ml of N, N-dimethylaniline was added and the mixture was brought to -25 ° C + 5 ° C cooled down. Then 2.3 g of phosphorus pentachloride was added to the mixture. It was then an hour at -25 ° C +. Stirred at 5 ° C. There was 40 ml of ethanol dropwise added to the solution while maintaining the batch at the above temperature and the mixture was still Stirred for a further 2.5 hours. To the reaction product liquid was added 6.86 ml of Ν, Ν-dimethylaniline and then 2.5 g * D (-) - a-phenylglycyl chloride hydrochloride in small proportions to the mixture kept with stirring and cooling to -25 C + _ 5 ° C for 2 hours. After additional Stirring the mixture for an additional 2 hours at the same temperature became the product liquid approximately 200 g of ice water acidified with hydrochloric acid with a pH of 2-3 emptied. After shaking enough of the mixture, the resulting aqueous layer and the dichloroethane layer were separated from one another. the aqueous layer was extracted twice with 20 ml of dichloroethane each time and the extract was mixed with the dichloroethane solution united. After washing the mixture with

109851/1959

50 ml of hydrochloric acid acidified water having a pH of 2-3 and further washing with 50 ml of 5% aqueous sodium bicarbonate solution, the mixture was further washed twice with 50 ml of water each time and dried over anhydrous magnesium sulfate. The dichloroethane solution thus obtained was ^{cooled to 0} ° C. and then 3 ml of diethylamine were added with stirring. The mixture was stirred for one hour at ⁰ ° C., mixed with 20 ml of water, and the pH of the aqueous layer thus formed was adjusted to 4.0-4.5 with acetic acid. The aqueous layer thus formed and the dichloroethane layer were each separated. The dichloroethane layer was extracted twice with 10 ml of water each time. The extracts were combined with the aqueous layer and washed twice with 20 ml of isobutyl methyl ketori each time. The solution was then made up to a total volume of 50 ml with water. When the aqueous solution was examined by high-voltage filter paper electrophoresis, the cephalexin was detected at the site corresponding to the cephalexin with the positive ninhydrin reaction. Also, it was confirmed from the result of quantitative analysis by the plate test using Bacterium subtilis that the solution contained 2.63 g of cephalexin.
The yield was 76 $ S.

The aqueous solution was concentrated to about 10 ml, operating under reduced pressure and low temperature. 20 ml of acetone were added to the concentrate and stored in the refrigerator. Crystals were deposited and separated by filtration. The crystals were washed with a small amount of cold water and then with acetone. It was dried. 2.4 g of the white powdery crystals of cephalexin hydrate with a melting point of 187-19O ⁰ C (with decomposition)

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obtain.

The yield was 65.8%.

When 1 g of the product was suspended in 20 ml of a 9: 1 mixture of acetone and water and the pH of the suspension was ^{adjusted to about 1 by the dropwise addition of concentrated hydrochloric acid with stirring at 0} ° C., a solution was formed. Then a small amount of activated charcoal was added to the solution and then filtered. The pH of the Piltrats was adjusted to about 5 by addition of triethylamine under stirring and cooling to 0 ⁰ C. Crystals were deposited. These were separated off by filtration, washed with 10 ml of acetone and rewashed with a small amount of water. It was dried. Cephalexin hydrate with a melting point of 190-193 ° C. (with decomposition) was obtained.

Elemental analysis H (JO as C., 5 ^H 17 ^N 3 C (JS) 5.24 N (JS) S (%) Calculated: 52.59 5.03 11.50 8.77 Found : 52.71 11.25 8.37 Example 8:

To a solution of 5.5 g of 7- (phenylacetamido) desacetoxycephalosporanic acid 3 ', 5'-di-tert-butyl-4'-hydroxybenzyl ester in 80 ml of dichloroethane was added 31 ml of pyridine. The mixture was increased to -10 ° C cooled. Then, 2.5 g of phosphorus pentachloride was added to the solution and the mixture was stirred for 1.5 hours at a temperature between ⁰ C to -5 ⁰ C. Thereafter, 40 ml of methanol was added thereto dropwise, the solution between -20 ° C was maintained for 5 i ⁰ C. Then, the mixture was kept for one hour at temperatures from -10 ⁰ C to -15 ° C and stirred. 4.4 ml of triethylamine were added to the reaction product liquid while the mixture was stirred at -25 ° C ± 5 ° C

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given. Thereafter, 2.1 g of D (-) - α-phenylglycyl chloride hydrochloride was added in small portions to the mixture over the course of one hour. The mixture was stirred at the same temperature for 2 hours. The batch was then poured into 200 g of water acidified with hydrochloric acid and having a pH of 2-3. The mixture was shaken thoroughly, the aqueous layer formed and the dichloroethane layer were separated from one another. The aqueous layer was extracted twice with 15 ml dichloroethane each time. The extract thus obtained was combined with the dichloroethane layer. After washing the mixture with 50 ml of aqueous hydrochloric acid solution having a pH of 3, it was then washed with 50 ml of 5% aqueous sodium bicarbonate solution. The mixture was then washed twice more with 50 ml of water each time. It was then dried over anhydrous magnesium sulfate. The Dichloroäthanlösung thus obtained was cooled to ⁰ ° C. Then 3.5 ml of cyclohexylamine was added with stirring and the mixture was ^{stirred at 0 °} C. for one hour.

By treating the reaction product liquid thus obtained According to the information in Example 7, 2.22 g of cephalexin hydrate were obtained obtained with a melting point of 187-19O ° C (with decomposition) in a yield of 61%.

Example 9 *

(a) To a solution of 5.5 g of 7- (phenylacetamido) desacetoxycephalosporanic acid'3 ¹ , S'-di-tert-butyl- ¹ ! '- hydroxybenzyl ester in 55 ml of dichloroethane was added 4.12 ml of Ν, Ν-dimethylaniline added. The mixture was cooled to -25 ⁰ C ⁰ C + 5. Then, 2.3 g of phosphorus pentachloride was added to the solution and the mixture was stirred at -25 ° C + 5 ° C for one hour, 40 ml of methanol was added dropwise to the mixture at the same temperature, and the mixture became

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stirred for a further 2.5 hours. To the Reäktionsproduktflüssigkeit was 6.86 ml N, N-dimethylaniline and 2.5 g of D (-) - a-Phenylglycylchlorid hydrochloride in small portions to the mixture with stirring and cooling to -25 ° C + _ 5 ⁰ C in the course of 2 hours added. After further stirring the mixture at the same temperature for 2 hours, the product liquid was poured into 200 g of ice water acidified with hydrochloric acid to pH 2-3. After the mixture had been thoroughly shaken, the aqueous layer formed and the dichloroethane layer were separated from one another. The aqueous layer was extracted twice with 20 ml of dichloroethane each time. The extract thus obtained was combined with the dichloroethane layer. The mixture was washed with 50 ml of aqueous hydrochloric acid solution with a pH of 3, 50 ml of 5% aqueous sodium bicarbonate solution and then twice with 50 ml of water each time. The mixture was dried over anhydrous magnesium sulfate. The chloroethane solution thus obtained was concentrated at low temperature. 100 ml of petroleum ether was added to the residue and the mixture was stirred. The insoluble precipitates thereby formed were separated by filtration and dissolved in 20 ml of ethyl acetate. 200 ml of petroleum ether were added to the solution, and white precipitates were formed which were separated off by filtration. The separated precipitates were washed with a small amount of petroleum ether and then dried. 3> 9 g of the white powdery crystals of 7- (D (-) - a-aminophenylacetamidojdesacetoxycephalosporanic ^{acid · 3 ', 5 f} di-tert-butyl-i'-hydroxybenzyl ester with a melting point of 106-108 ° C. were obtained obtain.
The yield was £ 68.7 -

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Elemental analysis as C,

C (Ji) H (Ji) N (Ji)
Calculated: 65.82 6.95 7.43 5.67 Found: 66.24 7.12 6.89 5.41

Then 0.5 g of the product was dissolved in 10 ml of ether and 0.17 g of p-toluenesulfonic acid monohydrate was added and the mixture was stirred at room temperature. The crystals thereby formed were separated by filtration, washed with a small amount of ether and dried. It was 0.64 g of white crystals of 7- {D (-) - a-aminophenylacetamido) desacetoxycephalosporanic acid · 3 ', 5'-di-tert-buty1-4 ^f -hydroxybenzylester with a melting point of 165-166 ⁰ C. (with decomposition) obtained in a yield of $ 98.

Elemental analysis as 0, QH ₁ J ₇ N ^ OqS ₂ :

C (Jt) H (Jt) N (Si) S (JS) Calculated: 61.85 6.42 5.69 8.69 Found: 61.36 6.40 5.35 8.47

b) In 3 ml of dichloroethane, 0.56 g of 7- (D (-) - a-aminophenylacetamido) desacetoxycephalosporanic acid 3 * »5'-di-tert-butyl-4'-hydroxybenzyl ester and dissolved 0.12 g of ethyl mercaptan. After adding 1 ml of a dichloroethane solution of 0.21 g of triethylamine under While cooling with ice, the mixture was stirred for 1 hour. Then, 3 ml of water became the reaction product liquid was added and the pH of the liquid was increased to 4.0 4.5 by adding 10% hydrogen chloride solution set. The aqueous layer thus formed and the dichloroethane layer were separated from each other and the dichloroethane layer was extracted twice with 2 ml of water each time. The extracts were made with the aqueous layer combined. Then the mixture became

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washed twice with 5 ml of ethyl acetate each time. The mixture was then made up to a total volume of 10 ml with water. The aqueous solution was electrophoresed by means of high voltage filter paper electrophoresis checked. A positive ninhydrin reaction spot appeared on the site found that corresponds to the Cephalexin. In quantitative analysis using Bacterium subtilis was confirmed that the solution contained 0.33 g of cephalexin in a yield of 91%.

Example 10:

In 3 ml of dichloroethane, 0.56 g of 7- (D (-) - a-aminophenylacetamidojdesacetoxycephalosporanic ^{acid ^ 1} , 5 * -di-tert-butyl-4'-hydroxybenzyl ester was prepared by carrying out the same reaction as in Example 9 (a) indicated, but using 7- (phenylacetoamido) -desacetoxycephalosporanic acid · 3 ' _S 5 ^f -di-tert-butyl- * i ^f hydroxybenzyl ester. The solution was ^{cooled to 0} ° C. 3 ml of dichloroethane solution of 0 ° was added to the solution , 21 g of triethyl phosphite and 0.21 g of triethylamine were added with stirring. The mixture was stirred for 1.5 hours at the same temperature. After adding 3 ml of water to the reaction product liquid, the pH of the solution was adjusted to H ₉ O 4.5 by adding The aqueous layer thus formed and the dichloroethane layer were extracted twice with 2 ml of water each time. The extracts were combined with the aqueous layer. After the mixture was washed twice with 5 ml of ethyl acetate each time, it was mixed t water made up to a total volume of 10 ml.

When the aqueous solution using high-voltage filter paper electrophoresis was checked, the positive ninhydrin reaction spot was found at the point that the Position of the cephalexin corresponds. In the quantitative

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A plate method analysis using Bacterium subtilis confirmed that the aqueous solution contained 0.32 g of cephalexin in a yield of 69% .

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Claims (2)

Claims Process for the preparation of cephalexin, characterized in that a T-acylaminodesacetoxycephalosporanic acid ester with the formula R ₁ CONH 'COOR ₂ t R _{1 is} a benzyl group, a phenoxymethyl group, a pentenyl group, an amyl group, a heptyl group or a p-hydroxybenzyl group and Rp is a triphenylmethyl group, a bis (n-methoxyphenyl) methyl group, a trimethylsilyici group, a 3,5-di tert-butyl-4-hydroxybenzyl group, a phenacyl group, a p-nitrophenacyl group, a trichloroethyl group or a p-methoxybenzyl group _{f is} reacted with a phosphorus halide, the iminohalide compound thus obtained is reacted with a lower alcohol, the iminoether compound thus obtained is reacted with phenylglycyl chloride Hydrochloride is reacted and the product obtained is treated with water or a lower alcohol and finally the ester group is split off. 2. The method according to claim 1, characterized in that as T-acylaminodesacetoxycephalosporanic acid esters-i · the 7- (Pheny! acetamido) desacetoxycephalosporanic acid ester is used. 1 09851/1959