FI74017C - FOERFARANDE FOER OEVERFOERING AV 6-AMINOPENICILLANSYRA ELLER DESS ESTER TILL ETT LAETT HYDROLYSERBART DERIVAT. - Google Patents

Description

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SUOMI FINLAND

(FI) (21) Patent application - Patentansökning 802286 (22) Application date - Ansökningsdag 18.07.80

National Board of Patents and Registration (23) Start date - Giltighetsdeg 18.07.8 0

Patent-OCh reQfeteretyreleen (41) Date of publication - Blivit offentlig 21.01.81 (44) Date of dispatch and of publication. - -j 1 q8 87

Ansökan utlagd och utl.skriften publicarad ^ "(86) International application - Int. Ansökan (32) (33) (31) Privilege claimed - Begärd priority 20.07-79 USA (US) 59 *» 01 Toteennäytetty-Styrkt (71) Bristol-Myers Company, 3 ^ 5 Park Avenue, New York, New York, USA (72) Derek Walker, Jamesville, New York,

Herbert H. Silvestri, Dewitt, New York,

Chester Sapino, East Syracuse, New York,

David A. Johnson, Fayetteville, New York, USA (US) (7 * 0 Oy Kolster Ab (5 * 0 Process for the conversion of 6-aminopenicillanic acid or its ester into a readily hydrolysable derivative - Preparation of 6-aminopenicillanic acid or its ester to an ester thereof) hydrolyserbart der ivat

The invention relates to a process for the preparation of 6-aminopenicillanic acid of the formula I or an ester thereof

H H s CH

H2N-f — Y ^ <CH3 ch3 i Λ-N-- cr c

^ O-B

2 74017 wherein B is hydrogen or a readily cleavable conventional ester protecting group to convert the compound of formula II to 0-5L

(CH3) 3Si-O-C-NH-f-Y P ^ CH

I 3 II

Wherein B 'is a trimethylsilyl group or a readily cleavable, conventional ester protecting group by mixing a compound of formula I and at least a small stoichiometric excess of trimethylsilyl chloride in an anhydrous, inert organic solvent, and a slight amount of said trimethylsilylating agent a subordinate amount of a solvent-soluble, strong organic base that acts as a hydrogen chloride acceptor, followed by treatment with carbon dioxide.

Urea is used as a catalyst in the process according to the invention. Urea acts as a transsilylating agent, i.e. the amino group of the 6-amino-penicillan molecule is silylated more rapidly in the presence of urea. Under the influence of trimethylsilyl chloride alone, the silylation reaction does not complete. Thus, the yield of silyl carbonate is greatly improved by the action of urea.

The process according to the invention for the preparation of the compound of the formula I is characterized in that, after silylation and before the carbon dioxide treatment, an amount of urea is added which is just sufficient to convert all the free organic base after silylation to the hydrochloride.

The use of amino acid chloride hydrochlorides to prepare penicillins under anhydrous conditions is known, for example, from GB Patent No. 938,321 and GB Patent No. 959,853 (to protect the carboxyl group of 6-aminopenicillanic acid during acylation, the latter used a silyl group, as is also known from GB-8). U.S. Patent No. 3,249,622). GB Patent No. 962,719 discloses a process for 3,701017 preparation of penicillins in cold aqueous acetone. The penicillins thus obtained are amphoteric amino acids and were therefore isolated (e.g., U.S. Patent Nos. 3,157,640 and 3,271,389) using certain aliphatic asymmetric side chain secondary amines (often referred to as liquid amine resins) previously used to isolate 6-amino acids. which is also an amphoteric amino acid (U.S. Patent No. 3,008,956). Improved methods for isolating and purifying such penicillins are known, e.g., from U.S. Patent No. 3,180,862 to β-naphthalenesulfonates and from U.S. Patent No. 3,198,804 to the isolation of an intermediate and subsequent easy hydrolysis of hetacillin.

The use of a silyl group to protect the carboxyl group of natural penicillin during chemical cleavage to 6-aminopenicillanic acid is known from U.S. Patent No. 3,499,909. , 3,595,855, 3,654,266, 3,479,338 and 3,487,073. Some of these patents also mention the use of liquid amine resins; see. see also U.S. Patent Nos. 3,912,719, 3,980,637 and 4,128,547.

GB Patent No. 1,339,605 provides various specific and detailed examples for the preparation of amoxicillin by reacting a silylated derivative of 6-aminopenicillanic acid with a reactive derivative of D - (-) - α-amino-p-hydroxyphenylacetic acid (including chloride-hydrochloride protecting group) wherein the amino group is after which the silyl group or groups are removed by hydrolysis or alcoholysis, after which, where possible, amoxicillin is recovered, usually as a crystalline trihydrate. Thus, crystalline amoxicillin was obtained in Example 1 by isoelectric precipitation from aqueous solution, e.g. at pH 4.7. Purification is performed in this example by dissolving the crude product (before isoelectric precipitation) in an acidic aqueous solution (e.g., aqueous hydrochloric acid, pH = 1.0) in the presence of a water-immiscible organic solvent such as methyl isobutyl ketone (4-methylpentan-2-one); cf.. see also U.S. Patent No. 3,674,776.

4 74017

The present invention relates to a process for the preparation of penicillins by converting 6-aminopenicillanic acid or an ester thereof into a compound of formula II wherein B 'is a trimethylsilyl group or a readily cleavable ester protecting group, namely benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroacetyl, trichloroethyl, trichloro methoxymethyl, 5-indanyl, 3-phthalidyl, 1 - ((ethoxycarbonyl) oxy) ethyl, pivaloyloxymethyl or acetoxymethyl. The reaction is carried out in a dry inert organic solvent, especially methylene chloride, preferably in the presence of a weak base such as propylene oxide, and at a temperature above -10 ° C, most preferably -8 ° C to + 20 ° C, and most preferably 0-20 ° C, and in particular about 20 ° C.

It can be assumed that all of the urea spontaneously reacts with an unused trimethylsilylating agent, e.g., trimethylchlorosilane, to form hydrochloric acid and, as a by-product, ineffective bis-trimethylsilylurea. Thus, no urea remains to remove trimethylsilyl groups from the silylated core, e.g., trimethylsilyl-6-trimethylsilyloxycarbonylaminopenicillanate.

A specific example is the case where compound B of formula I contains hydrogen and the system is completely anhydrous. In this case, the silylation of one mole of the compound consumes two moles of triethylamine and 0.5 moles of urea must be added for each mole of triethylamine initially present in addition to the two moles of triethylamine mentioned above.

5 74017

Example

reaction scheme

Methylene chloride

MH / S ^ CH3! CS ™

2 “1 f + P ·. TF A 1 - N-cOOH 3: Urea (25 ° -28 ° C) 7 (Molecular Weight 216) S 2 H 2 Cl 2 (CH 5) 5 -Si-NH - f * Yv.CH + TEA'HCl

J-N C003i (CH 2)., + BSU

0 3'3 (I) 0

Il ς ^ CH

I + CO 2> (CH 2 -Si-O-C-NH -, -> CcH

N COOSi (CH3) 3 (II) 0 A— \ || Propylene oxide II + HO - // 7-CH-C-C1 ^ ---> \ - / | CH, -CH-OHo NH2-HCl JV / 2 (T = 0-3 ° C) 6 74017 CH3 (CH3) 3-Si-O-CH-CH2-Cl + CO2 / ΓΛ N s / CH3 + HO- ^ CH-C-NH j ^ SNCcH5 NH2 * HCl COOSi (CH ^ (III) // '~ \\ | l CH ^ 111 + © ~ -1> HO-fV CH-C-NH -pY' S vCc „* 3 „0

NH2 O- ^ N ^ COOH

(Molecular Weight 419) BSU is bis-trimethylsilylurea TMCS is trimethylchlorosilane TEA is triethylamine LA-1 is a mixture of secondary amines (liquid anion exchange resin);

The formula for secondary amines is R 1 CH 3 C (CH 3) 2 CH 2 C (CH 3) 2 CH 2 CH = CH-CH 2 NHC-R 2 R 3 12 3 wherein R, R and R are each an aliphatic hydrocarbon group and wherein 12, 12 are R, R and R in a group of 11 to 14 carbon atoms, this special mixture of secondary amines, sometimes called "7 74017" Liquid Amine Mixture No. I ", is a clear golden brown liquid with the following physical properties: viscosity at 25 ° C 70 centipoise; specific gravity at 20 ° C 0.845; refractive index at 25 ° C 1.467; distillation range under 10 mm vacuum: not more than 160 ° C to 4%, 160 to 210 ° C to 5%, 210 to 220 ° C to 74%, more than 220 ° C to 17%.

Materials The amounts are based on the starting material, 1.0 kg of recrystallized 6-aminopenicillanic acid, which is assumed to be 100% pure.

Reagent Amount of reagent _2_1_mol 6-APA 1000.0 4.63 D - (-) - p-hydroxyphenylglycyl chloride hydrochloride hemidioxane solvate (US 3,925,418, purity 79.0%) 1305.6 4.63

Trimethylchlorosilane 1173.0 1.370 10.80

Triethylamine (dry) 1075.6 1.482 10.63

Urea 38.9 0.651

Propylene oxide 323.0 0.389 5.56

50% aqueous solution of the tetrasodium salt of ethylenediaminetetraacetic acid 0.092

Sodium bisulphite 11.5 0.11

Dry methylene chloride (less than 0.02% water) ca.0.30

Non-ionic and gas-free water as required

Isopropyl alcohol n.10 LA-1 resin (100%) 3.0-3.05

Urea is added in an amount calculated to react in an equivalent ratio with the excess triethylamine (after first reacting with the remaining trimethylchlorosilane to liberate hydrogen chloride to form triethylamine hydrochloride and bis-trimethylsilylurea.)

8 74017

Safety 6-APA Toxicity unknown, allergen.

Handle with care, eg on a factory scale. Avoid contact with skin or eyes and inhalation of dust.

Trimethylchlorosilane Toxic, flammable. Reacts with moisture to release HCl.

D - (-) - p-hydroxyphenyl- Toxic. The same precautions as for glycyl chloride. HCl- when binding D - (-) - phenylglycylcholemidioxane solvate ridi.HCl.

Triethylamine Toxic. Precautions as above.

Propylene oxide Toxic. Take precautions.

Methylene chloride Use factory precautions.

Method 1. 1.0 kg (4.63 moles) of 6-aminopenicillanic acid was added to 10.0 liters of dry methylene chloride (less than 0.02% water). Stirred moderately vigorously. The vessel walls were rinsed with 1.0 L of dry methylene chloride to remove trapped 6-aminopenicillanic acid. 1.371 liters (10.80 moles) of trimethylchlorosilane was added. Quantitative transfer of trimethylchlorosilane was confirmed by rinsing the beaker with 0.5 liters of dry methylene chloride. Stirred for 5 minutes and the reaction mixture was protected with dry nitrogen. The temperature was maintained at about 25 ° C.

2. 1.482 liters (10.63 moles) of dry triethylamine was added over 20-30 minutes. The temperature was maintained at 25-30 ° C. Quantitative transfer was confirmed by rinsing the beaker and addition funnel twice with dry methylene chloride. The total amount of rinsing liquid was about 1.0 liters.

3. After the addition of triethylamine was complete, the suspension was stirred for an additional hour to complete the silylation. A sample was taken and allowed to settle. If 6-aminopenicillanic acid had remained insoluble, this settled to the bottom. Triethylamine hydrochloride surfaced.

4. 38.9 g (0.65 moles) of ground urea was added. The suspension was stirred moderately vigorously (nitrogen blanket gas).

9 74017

Stirring of the suspension was continued for 1.5 hours. At the end of this time, no solid urea could be detected. The temperature was 25 ° C.

5. The suspension was stirred and carbon dioxide was introduced. Gas was bubbled into the suspension for 3 hours. A condenser was used to avoid evaporation loss of methylene chloride.

6. 0.389 L (5.56 moles) of propylene oxide was added to the suspension. The beaker was rinsed with 100 mL of methylene chloride to ensure quantitative transfer. The reaction was protected with nitrogen. Cooled to 0 ° C.

7. 4.63 moles of D - (-) - p-hydroxyphenylglycyl chloride. HCl hemidioxane solvate were added in about five equal portions (1306 g, purity 79%). The addition took place every 25-30 minutes. The temperature was maintained at 0-3 ° C. The reaction suspension was stirred for 2 hours at 0-3 ° C. A sample was taken for thin layer chromatography. The reaction produced carbon dioxide gas which was discharged. Stirred moderately vigorously.

8. The stirring speed was increased and 5.6 liters of deionized and degassed water (5 ° C) was added. The mixture was stirred and the temperature of the mixture was adjusted to 7-8 ° C. Stirred for 10 minutes. After the addition of water was complete and the solution formed, stirring was moderate (reduced emulsion formation). The separation into two phases took place rapidly.

9. Crystallized immediately by adding 1.0 liter of 100% LA-1 resin to the cooled solution over 5 minutes. Mixed and inoculated. The temperature was allowed to rise to about 12 ° C. Stirring was continued and an additional 0.5 liters of LA-1 resin was added. (Crystallization must occur during this time; the addition time was about 5 minutes.) Stirring was continued and about 1.0 liter of LA-1 resin was added over another 10 minutes. During this addition, the temperature was slowly raised to about 18 ° C (pH about 4.0). 0.092 liters (92 ml) of a 50% aqueous solution of the tetrasodium salt of ethylenediaminetetraacetic acid was added and stirred. Additional LA-1 resin was added slowly over 30 minutes. A total of 2700 ml of LA-1 resin was added, these additions took place in 50 ml portions; The total need for LA-1 resin is 3.0-3.05 liters. Temperature 011 18 ° C and pH 5.4.

10 7401 7 10. 11.5 g of sodium bisulfite dissolved in about 200 meters of deionized and degassed water was added to the suspension.

11. The two-phase suspension was stirred and 8.0 liters of methylene chloride was added. Stirred for 1 hour at 18-20 ° C.

12. The suspension was cooled to 0-5 ° C and allowed to stand for 2 hours.

13. The solid in the suspension was isolated by filtration. The filter cake was washed with 10.0 liters of methylene chloride to remove LA-1-methylene chloride.

14. The filter cake was washed with 4.0 liters of cold (0-5 ° C), deionized and degassed water. The mother liquor and the combined washings were collected (the following washings should not be mixed with the above).

15. The filter cake was washed with 6.5 liters of cold isopropanol solution (80% isopropanol and 20% water, i.e. 5.2 liters of isopropanol and 1.3 liters of water).

16. The filter cake was washed with 4.0 liters of isopropanol.

17. The filter cake was washed with 5.0 liters of methylene chloride.

18. The filter cake was dried at 40-45 ° C.

19. The yield was about 1.65 kg (85% of the stoichiometric yield). Using 1.05 moles of hemidioxane solvate per mole of 6-aminopenicillanic acid, the yield was 86.5%, the Klett color of the product was less than 50. Only an amoxicillin band was observed in the thin layer chromatogram of the 10% solution. The product is suitable for formulation as such.

Claims (2)

A process for the preparation of 6-aminopenicillanic acid of the formula I or an ester thereof! Vs ^ / ch3 H2N] Vch3 i! J I # -N-1 O! c 1 O-B wherein B is hydrogen or a readily cleavable, conventional ester protecting group to convert to a compound of formula II 0. H (CH-j) «Si-O-C-NH —-J CH J II * -N-- 0 c. OB 1 wherein B 'is trimethylsilyl or a readily cleavable conventional ester protecting group by mixing a compound of formula I and at least a small stoichiometric excess of trimethylsilyl chloride in an anhydrous, inert organic solvent and a slightly equimolar amount of said trimethylsilylating agent which acts as a hydrogen chloride acceptor, followed by treatment with carbon dioxide, characterized in that an amount of urea is added after the silylation and before the carbon dioxide treatment that is just sufficient to convert the entire free organic base after silylation to the hydrochloride.