SE448630B - PROCEDURE FOR PENICILLIN PREPARATION - Google Patents

Description

The use of amino acid chloride hydrochlorides for the preparation of such penicillins has been disclosed in the patent literature, for example in British Patent Specification 938 321, in British Patent Specification 959 853 under anhydrous conditions (in the latter patent the possibility is used that during the acylation protect the carboxyl group of the 6-aminopenicillanic acid with a silyl group, which has also been disclosed in British Patent Specification 1,008,468 and U.S. Pat. No. 3,249,622) and in British Patent Specification 962,719 in a cold aqueous solution of acetone. These penicillins are amphoteric amino acids, and in isolating them (as disclosed, for example, in U.S. Pat. Nos. 3,157,640 and 3,271,389), certain aliphatic, asymmetric, branched chain secondary amines have been used (often referred to as liquid amine resins). which has previously been used in the isolation of 6-aminopenicillanic acid, which is also an amphoteric amino acid (see U.S. Pat. No. 3,008,956). Improved methods for isolating and purifying such penicillins are disclosed, for example, in U.S. Pat. No. 3,180,862 via [B] -naphthalene sulfonates and in U.S. Pat. No. 3,198,804 via isolation and subsequent hydrolysis of the intermediate hetacillin.

The use of a silyl group to protect the carboxyl group of a natural penicillin during chemical cleavage to 6-aminopenicillanic acid is disclosed in U.S. Patent No. 3,499,909. The use of silylated 6-aminopenicillanic acid during anhydrous acylation with amino acid chloride hydrochlorides is disclosed in numerous patents, for example in U.S. Patents 3,479,018, 3,595,855, 3,654,266, 3,479,338 and 3,487,073. Some of these patents also disclose the use of liquid amine resins. Reference is also made to U.S. Pat. Nos. 3,912,719, 3,980,637 and 4,128,547.

British Patent Specification 1,339,605 contains various specific and detailed examples of the preparation of amoxycillin by reacting a silylated derivative of 6-aminopenicillanic acid with a reactive derivative (including the chloride hydrochloride) of D- ( -) - so-amino-p-hydroxyphenylacetic acid, wherein the amino group is protected, then removes the silyl group or groups by hydrolysis or alcoholysis and, if possible, extracts the amoxycillin, usually as the crystalline trihydrate. Thus, according to Example 1, crystalline amoxycillin is obtained by isoelectric precipitation from an aqueous solution, for example at pH 4.7. It can be assumed that the purification according to the said example has been effected by dissolving the crude product (before isoelectric precipitation) in water at an acidic pH value, such as lÅbf (for example in an aqueous solution of hydrochloric acid), in the presence of a water not miscible organic solvent such as methyl isobutyl ketone (4-methylpentan-2-one). Substantially the same procedure is used in U.S. Pat. No. 3,674,776.

According to the invention there is provided a process for the preparation of penicillins of the formula § H R_g_NH E.š CH3 N. CH 3 O 2 - α 2 O 3 wherein R-α- constitutes the residue after removal of the hydroxyl group from an organic carboxylic acid containing 2-20 carbon atoms, by acylating with the acid chloride of said organic carboxylic acid a silylated core having wherein B is a readily cleavable ester protecting group, and then the group B is converted to hydrogen, the process being characterized in that, prior to acylation, said silylated core is converted to a molar in CH3 (en) sin 3 3 cH - 3 0 440 448 ÖÉÛ 4 wherein B a compound of the formula OH (cH3) 3s1-oc-NH '' N cH3 O% O \ ø_ß wherein B has the meaning given above, by adding dry carbon monoxide to a solution of a compound of the formula 5 H 5 E CH3 ( ca) its CH 3 0 4; wherein B is as defined above, in an anhydrous, inert organic solvent at a temperature in the range of 0 ° -100 ° C until the reaction is complete.

As a preferred embodiment, the present invention provides a process for the preparation of a 6fl- -aminoarylacetamidopenicillanic acid, preferably ampicillin or amoxycillin, reacting a compound of the formula II / S \ / C (CH2) 3s1-oc-NH-one. in an anhydrous inert organic solvent, preferably methylene chloride and preferably in the presence of a weak base, which is preferably propylene oxide, and preferably at a temperature above -10 ° C, especially in the range from -8 ° C to 20 ° C, especially in the range from 0 ° C to 20 ° C and especially preferably at about 20 ° C, with approximately an equimolar amount of D - (-) - WPaminoarylacetyl chloride hydrochloride, preferably D - (-) - 2-phenylglycyl chloride hydrochloride and D - (-) - 2-p-hydroxyphenylglycyl chloride hydrochloride, respectively, the latter reactant is preferably added portionwise to the solution of the former reactant; this embodiment is characterized in that for the preparation of the compound of the formula o HS (cnjësi-oc-NH-CH-g fl / \ <|: <3 JN cH oh: Lo-si (cr-ä) ä 3 is added dry carbon dioxide as a gas to a solution of trimethyl-6-trimethylsilylaminopenicillanate in an anhydrous inert organic solvent, preferably methylene chloride, at room temperature or at a temperature in the range of 0-100 ° C until the reaction is complete.

According to the present invention there are provided compounds of the formula 0 ä * š (czääsl-o-ö-Nníšfs (m3 N cH3 O ççg \ oB 448 650 6 wherein B is preferably trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichloroethyl, phenaxyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1-β-ethoxycarbon-Y1) oxyethyl, pivaloyloxymethyl or acetoxymethyl.

In particular, there is provided the compound of the formula cs '(cnyjsi-o-Icl-NH-cn-cn / \ c / ° H3 k; lya O' cl-o-si (sig) g 3 In the following, various trivial names are used for this compound , such as bissilylated carbamate of 6-APA, SCA, 6-trimethylsilyloxycarbonylpenicillan TMS ester and TMSO C.APA.TMS.2 The mere existence of this compound is surprising given the well-known fact that the reaction of 64APA with carbon dioxide destroys 6-APA and produces 8-hydroxypenicillanic acid, as disclosed, for example, in U.S. Patent No. 3,225,033. 448,630 The key solution to obtaining quantitative yields of 6-trimethylsilyloxycarbonylaminopenicillanic acid trimethylsilyl ester (TMS02C.APMSTA.TMS completely produce the 6-APA-bis-TMS precursor compound in the first stage.

This is achieved by reacting 6-APA with hexamethyldisilazane (HMDS) as schematically illustrated below: 6-APA + HMDS + imidazole reflux. complete catalyst 6-8 hours carboxyl "silylation" 1 mOl 1.1 mOl 3-5 111013: and about 40-653; 6-NH 2 - "silylation" Add 5 mol% TMSNH _______________ .S TMcs and reflux overnight N / f / 0 O CO 2 TMS_ (δ-.arAfbis-trns) The completion of the bis-trimethylsilylation reaction can be easily monitored using NMR. The 3-trimethylsilyloxycarbonyl group exhibits a methylsilyl singlet at 0.31 ppm (tetramethylsilane = 0), while the 6-trimethylsilyylamine group exhibits a methylsilyl singlet at 0.09 ppm. The 6-APA trimethylsilylation reaction is preferably carried out in methylene chloride. However, other solvents can be used, for example acetonitrile, dimethylformamide and even HMDS itself.

Conversion of the trimethylsilylamino group to the trimethylsilyloxycarbonylamino group is easily accomplished by bubbling dry CO 2 through the reaction solution. The conversion is easily monitored by NMR, since the trimethylsilylamino isletlet at 0.09 ppm disappears as a new singlet for the trimethylsilyloxycarbonylamino group appears at 0.27 ppm. 448 650 When the process of the present invention is used for the preparation of ampicillin, ampicillin anhydrate, ampicillin trihydrate, amoxycillin and amoxycillin trihydrate, the final products are isolated and purified according to conventional methods well known in the art, as illustrated in U.S. Pat. 980,637 and 4,128,547 and the other patents and publications referred to therein.

The acid chlorides used in the working examples below can be replaced by a variety of other acid chlorides for the preparation of conventional penicillins. Thus, the acyl halide can be selected to introduce any desired acyl group into the 6-amino position, as is well known in the art, e.g. U.S. Pat. No. 3,741,959. It is thus possible to introduce specific acyl groups which include, but are not limited to, the acyl groups listed below: (i) RuCnH2nCO-, wherein Ru is aryl (carboxylic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl or a non-aromatic or mesoionic heterocyclic group and n is an integer 1-4. Examples of this group include phenylacetyl, substituted phenylacetyl, for example fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, metphenylacetyl and hydroxyphenylacetyl, N, N-chlorophenyl (3-n-propyl) -3-acetyl, 4-isooxazolyl and substituted 4'iSOXa2QlYl "acetyl, pyridylacetyl, tetrazolylacetyl or a sydnonacetyl group. The substituted 4-isoxazolyl group may be a 3-aryl-5-methyl-isoxazol-4-yl-group the aryl group is, for example, phenyl or halophenyl, such as chloro- or bromophenyl, An acyl group of this type is 3-o-chlorophenyl-5-methyl-isoxazol-4-yl-acetyl. integer 1- 7. The alkyl group may n 2n + 1 be straight or branched and may, if desired, contain a 448,650 oxygen or sulfur atom or be substituted by, for example, a cyano group Examples of such groups include cyanoacetyl, hexanoyl , heptanoyl, octanoyl and butylthioacetyl. (iii) CnH2n_lCO-, wherein n is an integer 2 -7. The group may be straight or branched and may, if desired, contain an oxygen or sulfur atom. An example of such a group is al1Yl thioacetyl. (lv) lív Rus-cš-co- RW wherein Ru has the meaning given under (i) and in addition may be benzyl and RV and RW, which may be the same or different, each being hydrogen, phenyl, benzyl, phenethyl or lower alkyl. Examples of such groups include phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybutyryl, benzyloxycarbonyl, 2-methyl-2-phenoxypropionyl, p-cresoxyacetyl and p-methylthiophenoxyacetyl. (v) wherein Ru has the meaning given under (i) and may also be benzyl and Rv and RW have the meanings given under (iv). Examples of such groups include S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl. 448 650 10 (vi) R "z (cH2) mco-, where R" has the meaning given under (1) and may also be benzyl, Z is an oxygen or sulfur atom and n is an integer 2-5. An example of such a group is S-benzylthiopropionyl. (vii) RuCO-, where Ru has the meaning given in (i).

Examples of such groups include benzoyl, substituted benzoyl (for example aminobenzoyl), 4-isoxazolyl and substituted 4-isoxazolylcarbonyl, cyclopentanecarbonyl, sydonecarbonyl, naphthoyl and substituted naphthoyl (for example 2-ethoxynaphthoyl) or quinoxylalkylalkinoalkylcarbonyl -carboxy-2-quinoxalinyl-carbonyl). Other possible substituents for benzoyl include alkyl, alkoxy, phenyl or phenyl substituted with carboxy, alkylamido, cycloalkylamido, allylamido, phenyl- (lower alkyl) amido, morpholinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, tetrahydropyridino, furfurylamido N-anilino or derivatives thereof and such substituents may be present in the 2- or 2- and 6-positions. Examples of such substituted benzoyl groups are 2,6-dimethoxybenzoyl, 2-biphenylcarbonyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. In case Ru is a substituted 4-isoxazolyl group, the substituents may be those listed above under (i). Examples of such 4-isoxazole groups are 3-phenyl-5-methylisoxazol-4-yl-carbonyl, 3-o-chlorophenyl-5-methylisoxazol-4-yl-carbonyl and 3- (2,6-dichlorophenyl) -5- methyl-isoxazol-4-yl-carbonyl. (viii) Ru- H-co- i where Ru has the meaning given in (i) and X is amino, substituted amino (for example acylamido or a group obtained by reacting the amino group and / or groups). in the 7-side chain with an aldehyde or ketone (for example acetone, methyl ethyl ketone or ethyl acetoacetate), hydroxy, carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halogen, acyloxy (eg formyloxy or lower alkanoyloxy) or etherified hydroxy group. Examples of such acyl groups are G 1 -aminphenylacetyl, GL-carboxyphenylacetyl and 2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl. (ix) wherein Rx, Ry and Rz, which may be the same or different; each is lower alkyl, phenyl or substituted phenyl. An example of such an acyl group is triphenylcarbonyl.

(X) - ä n “-Nn-c- wherein Ru has the meaning given in (i) and may also be hydrogen, lower alkyl or halogen-substituted lower alkyl and Y is oxygen or sulfur. An example of such a group is Cl (CI-Iz) 2NHCO.

('). »*' / CH xi (CH2 r1j: É:;> f_C0_ X _ c fl z wherein X has the meaning given under (viii) and n is an integer 1-4. An example of such an acyl group is 1- amino-cyclohexanecarbonyl. (xii) Aminoacyl, for example RwCH (NH 2). (CH 2) n CO, wherein n is an integer 1-10, or NH 2 .CnH 2 nAr (CH 2) m CO, wherein m is 0 or an integer 1-10 een n is 0, 1 or 2, RW is a hydrogen atom or an alkyl, aralkyl or carboxy group or a group of the type defined above for Ru and Ar is an arylene group, for example p- Phenylene or 1,4-naphthylene Examples of such groups are disclosed in British Patent Specification 1,054,806. One group of this type is the p-aminophenylacetyl group Other acyl groups of this type include those, for example 6-aminoadipoyl, derived from naturally occurring amino acids and derivatives thereof, for example N-benzoyl-5-aminoadipoyl.7 (xiii) Substituted glyoxylyl groups of the formula RY.CO.CO-, wherein Ry is an aliphatic, araliphatic or aromatic group, e.g. for example a thienyl group, a phenyl group or a mono-, di- or tri-substituted phenyl group, the substituents being, for example, one or more halogen atoms (F, Cl, Br or I), methoxy groups, methyl groups or amino groups, or a fused benzene ring.

When the acyl group introduced contains an amino group, it may be necessary to protect it during the various reaction steps. The protecting group is suitably one which can be removed by hydrolysis without affecting the remainder of the molecule, especially the lactam and 7-amido bonds. The amine protecting group and the esterifying group in the 4-COOH position can be removed using the same reagent. An advantageous procedure involves removing both groups in the last step of the reaction sequence. Protected amino groups include those of the urethane, arylmethyl (e.g. trityl) amino, arylmethyleneamino, sulphenylamino or enamine type. Enamine blocking groups are especially useful for o-aminomethylphenylacetic acid. Such groups can generally be removed by one or more reagents consisting of dilute mineral acids, for example dilute hydrochloric acid, concentrated organic acids, for example concentrated acetic acid, trifluoroacetic acid or liquid hydrobromide at very low temperatures, for example -80 ° C. A suitable protecting group is the t-butoxycarbonyl group, which is easily removed by hydrolysis with dilute mineral acid, for example dilute hydrochloric acid, or preferably with a strong organic acid (for example formic acid or trifluoroacetic acid), for example at a temperature of 0-40 ° C, preferably preferably at room temperature (15-25 ° C). Another suitable protecting group is the 2,2,2-trichloroethoxycarbonyl group, which can be cleaved with an agent such as zinc / acetic acid, zinc / formic acid, zinc / lower alcohols or zinc / pyridine.

The NH 2 group can also be protected as NH 3 + by using the amino acid halide as the acid addition salt under conditions in which the amino group remains protonated.

The acid used to form the acid addition salt is preferably one having a pKa value (in water at 25 ° C) of greater than X + 1, where X is the pKa value (in water at 25 ° C) for the carboxy groups of the amino acid; the acid is preferably monovalent. In practice, the acid HQ (see below) has a pKa value below 3, preferably below 1.

Particularly advantageous results are obtained in the process according to the invention if the acyl halide is a salt of an amino acid halide. Amino acid halides have the formula HZN-R1-COHal where R1 is a divalent organic group and Hal is chloride or bromide. Salts of such amino acid halides have the formula ßen-R1-conaifg 'wherein R1 and Hal have the meanings given above and Q- is the anion of the acid HQ with the pKa value defined above. The acid HQ is preferably a strong mineral acid, such as, for example, a halide hydrochloric acid such as hydrochloric acid or hydrobromic acid. An important amino acid halide, due to the valuable penicillin antibiotics that contain the group derived therefrom, is DL- (el-chlorocarbonyl-out-phenyl) -methylammonium chloride, 448 650 l4 n-¿PhcH (NH3) coc; 7+ c1 ', in the following, for the sake of simplicity, D-O1-phenylglycyl chloride hydrochloride is drawn.

Penicillins obtained by the process of the invention and containing the acylamido group RuCH (NH 2) -CONH-, wherein Ru has the meanings given above, can be reacted with a ketone R 2, R 3 CO, wherein R 2 and R 3 to give compounds which are believed to contain the group are lower alkyl groups (C 1 -C 4), for Compounds of this type include hetacillin, sarpicillin, p-hydroxyhetacillin and sarmoxicillin.

Also within the scope of the present invention are the acyl groups disclosed in U.S. Patent 4,013,648 in columns 7-20.

In the case where the acylation process of the present invention is used for the preparation of penicillins, the final products are isolated and purified by conventional methods well known in the art.

Preferred acyl chlorides used in the present invention for acylating a compound of the formula O H 3 (CH 3) 3s1-O-3-NH 5 5 S CH 3 N CH 3 O '6.0 448 630 wherein A is (CH 3) 3 Si or a readily cleavable ester protecting group includes the following compounds: O 'N a) A-CH 2 Cl -Cl, wherein A is HZNHR' - CH R or sign 'e-ner II: arma' - s wherein R is hydrogen, hydroxy or methoxy and R 'is hydrogen or methyl and the amino group is optionally blocked by conventional blocking groups, in particular by protonation; U b) B-? HC-CL'HCl, wherein B is NH 2 H 2 NH 2 R 1 or or s 2 - wherein R is hydrogen, hydroxy or acetoxy and R 2 is hydrogen, chlorine or hydroxy, in case R 1 is hydroxy , and R 2 is hydrogen, in case R 1 is hydrogen or acetoxy; I e) h 11 ä? - S CH 2 Cl-Cl; O d) K C-g-Cl; Q H N-ocH3 H u II) / \ -Na-oH-c-cl e. Wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexa-1,4-dien-1-yl; wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexa-1,4-dien-1-yl; _ ä, 's) © - çn-c-cl; 0 .. _. wherein H is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl; wherein R 1 is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl and R 2 is hydrogen or hydroxy; 448 eso ~ '17 u J) F30-s-cH2c-cl; = \ ~ R) Å = Ny-cxzg-cl; o 1) Nc-cgzä-cl; __ 0, _ u H H) Br-CH 2 C-cl; "2f7 == n 0) s \ == L?; I C520-Cl = H P) N-c-caz-s-cx2-C_Cl.

I NH SQ) är, IQ HN - »3-c-cl = N- OCH3 I 'r' _" “l O r) LO Ü C¿ = NN \ ïf, N-É-NH-c fl- ä-cl Wherein R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl; 448 650 18 gas) AN / N -g-NrMfH-c-cl \ __ / R wherein A is hydrogen or alkyl with 1-4 carbon atoms or CH 3 SO 2 -, X is oxygen or sulfur and R is phenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexa-1,4-dien-1-yl; R vt) -. -EITC-Cl 3 - wherein R is hydrogen or methyl; OCd 3 u) u C-Cl, O CH 3 v) wherein R 1 and R 2 are x) B-â fi- g-Cl'HCl, wherein B is §H ç Wherein NH 1 is hydrogen, hydroxy or acetoxy and R 2 is hydrogen, chlorine or hydrexy, in case nl is hydroxy, and az is hydrogen, in case R 1 is hydrogen or acetoxy; ouy) <::::> _ §Hc-cl; N3 _ .v) H2N3 Z cxzï-c1. o fi == ° CN-CH u ß bb) o Cl CH2-C-Cl I dä) N 'i Ee) B-QH-g-Cl, wherein B is I; 1H § = ° NHR R 2 2 wherein R 1 is hydrogen, hydroxy or acetoxy and R is hydrogen, chlorine or hydroxy, in case R 1 is hydroxy, and R 2 is hydrogen, i - in case R1 is hydrogen or acetoxy, and R is hydrogen or cyanomethyl; '__ o ff) I N-cnàä-cl' u ss) cH2 = cH-cH2-s-cna-0-01 un) '> <° 6H5 _ c-cl no O' vari B är 11) B ~ § H-3-cl NH 1 - NH * \ N fi é.

R 2 H 1 - <::} - f _ H Ü i or or S or or S / - 448 630 21 wherein R 1 is hydrogen, hydroxy or acetoxy and R 2 is hydrogen, chlorine or hyarexi, 1 ae: case nl is hydrexi, een az is hydrogen, in case R1 is hydrogen or acetoxy; O 'JJ) en-c-cl H ffMOR 0 3 me) Hc-cl I o = co c-cl 1 ”CX NH2 and the amino group are blocked, if desired, by means of conventions wherein R is hydrogen or methyl thionic blocking groups, in particular by protonation; mm) Cl n CH-És-cl m; cl nn) HO ou ena-cl ¥ HR NH o = c-cH2-NH-c-rn-c ° ”\ * NH 448 650 22 oo) H0 ïf cIJH-c-cl Ifzi OH o = c-NH / N \ N pp) (CH)) 2CHCH2CHC-Cl å- fi- U. h) o qq) Q-çn-c-cl Iiï-CHB _ NH - such as hydrochloride, if 2 is desired OH rr) B-clzn-c-cl, å "0 = C where B is% - I in S H2 R 11 or or S wherein R 1 is hydrogen, hydroxy or acetoxy and R 2 is hydrogen, chlorine or hydroxy, in case R 1 is hydroxy, and R 2 is hydrogen, in case R 1 is hydrogen or acetoxy; 448 630 23 N ss) B-CH-C-Cl, _ u I varl B ar lm llH \ H2 _ eller. or ES 1- wherein R 1 is hydrogen, hydroxy or acetoxy and R 2 is hydrogen, chlorine or hydroxy, in case R 1 is hydroaci, and R 2 is hydrogen, in case R 1 is hydrogen or acetoxy; Wherein b1 is hydrogen, hydroxy or acetoxy and R2 is hydrogen, chlorine or hydroxy, i bt - b-cH-c-cl) wherein B is l, on o = c X \ ll / \ \ NN / N N-cHo wherein R the fan R1 is hydroxy, and RZ is hydrogen, in case R1 is hydrogen or acetoxy; Cl Cl nl ll ll or or S 24 VV) H: -: H -? H§_C1 l ÄÉÉÉIR is hydrogen or s ff = ° 0 R Il - ww) B-? HC-Cl, '- ~ where B is ¥ H _ <. == ° H_C- - p (f CH: O Cl 9 H- R1. Or or ES EL- - wherein R1 is hydrogen, hydroxy or acetoxy and R2 is hydrogen, chlorine or hydroxy, in case R1 acid hydroxy, and R 2 is hydrogen, in case R 1 is hydrogen or acetoxy; The invention is further illustrated by the following exemplary embodiments, in which the temperature indications refer to degrees Celsius.

Example 1 To a mixture of αV6-aminopenicillanic acid (6-APA) and 10 ml of CD2Cl1 and 1.13 ml of trimethylchlorosilane at a temperature of 25-27 was added dropwise 1.23 ml of triethylamine over a period of 30 minutes. Stirring was continued for another two hours. Dry carbon dioxide gas was then bubbled through the mixture for an additional three hours. Towards the end of said period, NMR (nuclear magnetic resonance) showed the presence of 60% silylated carboxy-6-APA (SCA) with the structure o (CH3 Esi-og-HN M5 ~ I NI en; 'o S ñ-o-si (cgš) The mixture was allowed to stand in a refrigerator overnight, the following morning 0.77 ml of N, N-dimethylaniline was added and the mixture was cooled: in -s °, but then added 1.2 g of D- (fl-p-hyarexi-z- -phenylglycyl chloride-hydrochloride (79% purity) portionwise as follows: Time minutes Temperature C Added amount in grams 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +8 220 '+15 310 +20 Towards the end of the 310 minute reaction time, thin layer chromatography (TLC) indicated the presence of amoxycillin. The thin layer chromatography was performed on a sample of the reaction mixture using a solvent system consisting of 60% ethyl acetate. , 20% acetic acid and 20% water.

To a cold sample and 2 ml of the final reaction mixture was added 1.0 ml of D 2 O. After separation by centrifugation, the aqueous phase was found by NMR analysis to contain 78% amoxicillin and 20% 6-APA. The presence of amoxycillin was also confirmed by TLC analysis. Example 2 A mixture of 5.4 g (0.025 mol) of 6-aminopenicillanic acid and 6.2 ml of 93% hexarnetylisilazane (HMDS: 0.27 mol) and 0.7 g (about 0.001 mol) of imidazole in 40 ml of CH 2 Cl 2 At the end of this time period, 0.13 ml (about 0.001 mol) of trimethylchlorosilane (TMCS) was added, the solution becoming cloudy, the reflux was continued for a further 7 hours; At this stage, NMR analysis showed about 100% silylation of both the amino and carboxyl groups in 6-APA, then 0.2 ml of Hmns (0.0125 moi; about 5 mois) were added and 0.06 ml 'mcs (about 0, o05 mol) and refluxing under a nitrogen atmosphere was continued for a further 17 hours, at which point the NMR spectrum was the same as before with the addition of small amounts of HMDS and TMCS. Dry carbon dioxide was then bubbled through the reaction mixture for 75 minutes at room temperature, then NMR analysis showed no presence of HMDS and more than 92% silylated carboxy-6-APA (SCA). Then 4.45 ml of N, N-dimethylaniline (DMA) (0.035 mol) were added and the mixture was cooled to -30. At this stage, 5.65 g of D - (-) - 2-phenylglycyl chloride (95% purity; 0.026 mol) were added portionwise as follows: 27 448 630 Time, minutes Temg. C Amount added in grams 0 -3 ~ 1.05 20 0 1.30 40 0 1.30 50 0 1.00 60 0 1.00 The reaction was monitored by NMR, which showed very little change about 5 hours after the start of the reaction. ; the temperature was then 30. The reaction mixture was then kept in ice for the following 16 hours. The mixture was then removed from the ice and stirred for 3.5 hours at room temperature (about 20-240). A large amount of solid material was still present. The reaction mixture was stirred at room temperature (22-240) for about 63 hours. Towards the end of this time period, only slight turbidity could be observed. Upon D20 extraction of a sample, NMR analysis showed ampicillin and 6-APA.

The reaction mixture was cooled to about 0 DEG C. and stirred for 5 minutes in the cold after the addition of 35 ml of ice water. After clear filtration, the mixture was washed with cold water and CH 2 Cl 2.

After separation, the aqueous phase on TLC analysis showed a large zone, which moved more slowly than ampicillin and 6-APA and which represented the new intermediate X.

The aqueous phase was adjusted to pH 3.0 with NH 4 OH and seeded with ampicillin crystals. Methyl isobutyl ketone (MIBK; 35 ml was added and the mixture was stirred, adjusted to pH 5.2 with additional NH 4 OH, stirred at 20 ° for one hour, stirred in an ice bath for another hour and stored in a refrigerator overnight. of ampicillin was collected by filtration, washed first with 25 ml of cold water and then with 40 ml of MIBK and finally with 40 ml of a mixture of 85 parts of isopropyl alcohol and 15 parts of water, dried at 500 and found to weigh 4.5 g. 448 630 28 Example 44 A mixture of 5.4 g of 6-APA, 6.2 ml of HMDS (93%) and 0.06 g of imidazole in 50 ml of CH 2 Cl 2 was refluxed under a nitrogen atmosphere for 18 hours. Then 0.1 ml of TMCS was added, which gave rise to turbidity. Refluxing for a further 2 hours gave a clear solution of NH4Cl in the condenser. An additional 0.1 ml of TMCS was added, whereby only very slight turbidity was obtained. The refluxing was continued under a nitrogen atmosphere. further 65 hours and the mixture was then cooled to about 22 °, after which the addition of dry carbon dioxide was started. After 75 minutes, NMR analysis showed the formation of over 99% bis-silylated carbamate (SCA). 4.45 ml of DMA were then added and further 5.6 g of D - (-) - 2-phenylglycyl chloride hydrochloride (97% purity) portionwise as follows: Time, minutes Theme E ° C Added amount in grams 0 20 1 After stirring this mixture for an additional 17 hours, TLC analysis was performed on a sample of the reaction mixture and on a dilute reaction mixture ( 1 ml of reaction mixture was diluted with 2 ml of CH 2 Cl 2). In both cases, a small zone of ampicillin and a large zone of the new intermediate X were obtained.

The reaction mixture was then cooled to 0 DEG, 40 ml of ice water were added and the mixture was stirred for 5 minutes, filtered clear and washed with water and with CH2 Cl2. The aqueous phase was separated, 10% was removed for sampling and the residue was adjusted to pH 3.0 with NH 4 OH, seeded with ampicillin crystals and stirred. After adding another 40 ml of 448 630 29, MIBK, the mixture was stirred and the pH was adjusted to 5.2 with NH 4 OH and then stirred at room temperature for 1 hour and then in an ice bath for a further 1 hour. Crystals precipitated. After storage in a refrigerator overnight, the crystalline product was collected by filtration, washed successively with MIBK, water and MIBK and then with 40 ml of a mixture of isopropanol and water in the ratio as = 15 one terkedee at 4s ° to obtain 6.25 g of ampicillin (6.8 g after correction for sampling corresponding to a yield of 68%).

Example 4 To a mixture of 1.0 g of 6-APA and 1.3 ml of TMCS in 10 ml of CD 2 Cl 2 was added dropwise 1.23 ml of TEA over 30 minutes and the mixture was stirred for a further 2 hours. Dry carbon dioxide was then allowed to bubble through the solution for 4 hours.

At this stage, NMR analysis showed about 55-600 carboxysilylation.

The mixture was then allowed to stand in the refrigerator overnight. The following morning 0.77 ml of DMA was added, the mixture was stirred and cooled to -80, after which 1.2 g of D - (-) - p-hydroxy-2-phenylglycyl chloride hydrochloride was added portionwise as follows: Time, minutes Temp. ° C Added amount in grams 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4. 0.30 120 8 220 15 310 20 Towards the end of the 310 minute reaction period, NMR analysis showed about 78% amoxycillin and about 20% δ-APA. Example 5 10.0 g (46.24 mmol; 1.0 equivalents) of 6-aminopenicillanic acid were suspended in 175 ml of anhydrous methylene chloride with stirring at 2 °. 10.7 g (10.0, 3e mmol; 2.30 equivalents) of triethylamine were added at 2.5 ° C, followed by the addition of 11.70 g (107.75 mmol; 2.33 equivalents) of trimethylchlorosilane over a period of 10 15 minutes, keeping the temperature below about 320 by controlling the rate at which the trimethylchlorosilane was added. After stirring for 20-30 minutes, the mixture containing precipitated triethylamine hydrochloride was analyzed by 80 MHz NMR analysis, which showed complete silylation. The mixture was then charged with carbon dioxide at 200 for about 2 hours and analyzed by 80 MHz NMR analysis, which showed complete carboxylation. Further introduction of carbon dioxide gas could possibly be required.

The volume of the carboxylation mixture was adjusted, if necessary, to about 175 ml with dry methylene chloride. After complete carboxylation, the slurry was treated with 2.95 g (3.56 mL; 50.87 mmol; 1.1 equivalents) of propylene oxide and cooled to 0 ° C. n - (-) - 2- (p-nyaroxyphenyl) glycyl chloride hydrochloride hemidioxane solvate was added in 5 portions of 2.71 g each at about 2 ° (total 13.54 g; 50.87 mmol; 1.1 equivalents were added ). It was ensured that each portion of the acid chloride was dissolved before the next portion was added (stirring was stopped and the mixture was examined for any solids on the bottom of the flask; in this test the slurry was not allowed to warm to a temperature above 50, otherwise the results became incorrect). This required about 20 minutes per serving. This portionwise addition was very significant. The final acylation mixture was examined for any undissolved acid chloride hydrochloride. The mixture was kept at 0-50 for 30 minutes and treated with cold (0-50) deionized water (100 ml) with high speed stirring for 10 minutes. The mixture was allowed to separate and the lower methylene chloride phase was removed. The enriched aqueous phase was clearly filtered (very small amount of solid) through a thin (Dicalite) filter of diatomaceous earth and the filter cake was washed with cold (0-SO) deionized water (15 ml). Any lower organic phase present was removed prior to crystallization. The clear, light yellow aqueous solution (pH 2-2.5) is adjusted to pH 3.5 at o-s ° and fitted with frog crystals, if required. The slurry was maintained at 0-50 for 40 minutes and the pH was adjusted to 4.8-5.0 with 6N ammonium hydroxide and crystallized for 2 hours. The slurry was filtered and the solid amoxycillin thus obtained was washed with a cold (0-SO) mixture of isopropanol and water in a ratio of 1: 1 and the filter cake was washed with 30 ml of methylene chloride to give about 13.5 g ( about 70%) snow white amoxycillin trihydrate.

Example 6 108 g (0.5 mol) of 6-aminopenicillanic acid, 1.0 g (0.07 mol) of imidazole, 800 ml of dry methylene chloride and 120 ml (0.56 mol) of HMDS (about 98% purity) were stirred and refluxed under 3.3 hours. In the reaction vessel, dry nitrogen gas was introduced during the reflux to remove the ammonia formed in the reaction. Then 2.0 ml (0.016 mol) of trimethylchlorosilane (TMCS) was added. Refluxing was continued under nitrogen purge for an additional 19 hours and then the ammonium chloride sublimed in the condenser was removed and 2.6 ml (0.0206 mol) of TMCS was added to the reaction mixture. The reflux under nitrogen purge was continued for another 34 hours. The volume of the reaction mixture was adjusted to 1000 ml with dry methylene chloride. NMR analysis showed 100% silylation of the amino and carboxyl groups in the 6-aminopenicillanic acid. The solution was stored for 9 days under a nitrogen atmosphere. NMR analysis confirmed the product and the stability. The solution was stirred and carbon dioxide was allowed to bubble through the solution for 90 minutes.

The temperature was 20-220. NMR analysis showed 100% conversion of the bis-trimethylsilyl-6-aminopenicillanic acid to bis-trimethylsilylcarboxy-6-aminopenicillanic acid (SCA). 448 630 32 This main mixture was used for the acylation experiments described below. The compound in this solution had the formula O ((395 .êi-o-c- fl j / j / i. 'N. Z - 0.

NMR analysis (CH3) 3 NMR analysis showed that the bis-trimethylsilylcarboxy-6-aminopenicillanic acid was stable after 9 days. 100 ml of the main mixture (SCA equivalent to 10.8 g of 6-aminopenicillanic acid; 0.05 mol) were stirred at 220 and 8.0 g (0.058 mol) of TEA.HCl and 4.2 ml of propylene oxide (0.06 mol) (see U.S. Pat. No. 3,741,959) was added. Some amount of TEA.HCl precipitated. The mixture was stirred and cooled to +30. 15.5 g of D - (-) - p-hydroxyphenylglycyl chloride hydrochloride-hemidioxane solvate (79% purity; 0.055 mol) were added to the reaction mixture portionwise as follows: peace, minutes, remEPc added amount in grams o + 3 in 3 .0 7 +2 3.0 2o +2 3.0 33 + z _ & §_ 15.5 After a further 70 minutes, about 50 ml of dry methylene chloride was added to the reaction mixture to reduce the viscosity.

After an additional 160 minutes, a 2 mL sample was removed and added to 1.0 mL of D 2 O. After centrifugation, 448 630 NMR analysis of the aqueous phase indicated about 6% non-acylated 6-aminopenicillanic acid. 10 minutes later, the reaction mixture was transferred to a 600 ml beaker and the whole was supplemented with a wash with 50 ml of methylene chloride. While stirring in an ice bath, 60 ml of cold deionized ice water was added to provide a two-phase solution which did not contain any solid material and a pH of 1.0. 15.0 ml of liquid ion exchange resin ("LA-1") was added to the two-phase system with stirring and addition of seed crystals at pH 2.0. Crystallization occurred. An additional 10.0 mL of LA-1 was added slowly over about 5 minutes. The pH was 3.0.

Then 0.15 g of NaBH 4 was added. At this stage, 5.0 ml of LA-1 was now added; The pH was 4.5. Stirring was continued and 1.0 g of NaHSO 3 (sodium bisulfite) in 4.0 ml of water was added dropwise. Then 10.0 ml of LA-1 was added; PH'Vär “it continued to rise. A total of 40 ml of LA-1 was added and the final pH was 5.6. Now 5 ml of acetone were added.

At this stage, 1.5 g of NaHSO 3, dissolved in 6.0 ml of water, were added over a period of 30 minutes. Stirring in the ice bath continued. The precipitated product was collected by filtration and the filter cake was washed successively with 50 ml of methylene chloride, 40 ml of water, 100 ml of isopropyl alcohol water in a ratio of 80:20 and 100 ml of methylene chloride.

The filter cake was then washed at atmospheric pressure at 45 ° to give 18.2 g of amoxycillin trihydrate, which corresponded to a yield of 87%, calculated on 6-aminopenicillanic acid; after correction for 1% sampling, the total yield was about 88%.

"LA-1" liquid anion exchange resin is a mixture of secondary amines, wherein each secondary amine has the formula R1 - (C3) (CH3) 2CH2c (C115) 2cH2cH = cH-c1f12NH <': - R2 3 R 448 630 34 wherein var and one of the substituents R 1, R 2 and R 3 is an ali 1, R 2 and R 3 together in-phatic hydrocarbon group and wherein R contains 11-14 carbon atoms, this particular mixture of secondary amines, sometimes referred to as "liquid amine mixture no. I ", is a clear amber liquid having the following physical properties: viscosity 7o eps at zs °; specific gravity 0,845 at 2o °; refractive index 1,467 at zs °; aeeeii- iaeieasiaservaii via 10 mm; up to 1eo ° - 4%, 160 to 21o ° - 5%, 21o to 22o ° - 74%, above 22o ° - 17%.

Example 7 5.0 ml of a methylene chloride solution of 0.54 g (2.497 mmol) of trimethylsilyl-6-trimethylsilyloxycarbonylaminopenicillinate was treated with 0.20 g (1.45 mmol) of triethylamine hydrochloride, followed by 0.162 g (2.75 mmol) of prepyienexia, at 2s °. The bianan was stirred at 250 for 20 minutes to facilitate the dissolution of most of the triethylamine hydrochloride. 0.43 g (2.75 mmol) of phenoxyacetyl chloride was added dropwise at 250 and the mixture was stirred for 30 minutes at 250. A sample was removed and analyzed by CMR at 20.0 MHz. CMR (carbon-13 nuclear magnetic resonance spectroscopy) data showed complete absence of phenoxyacetyl chloride and APA carbamate and presence of penicillin V-trimethylsilyl ester.

The presence of penicillin V-trimethylsilyl ester was confirmed by spectral comparison with an identical sample prepared by silylation of penicillin V in the form of the free acid with triethylamine and trimethylchlorosilane. The yield calculated on the basis of the CMR spectrum was 85-90%.

In a similar manner, cloxacillin, dicloxacillin, staphcillin and nafcillin were prepared using the same molar ratios of the reagents and the appropriate acid chloride. CMR data for these acylation mixtures showed an extremely pure acylation mixture with estimated yields of at least 85%. Example 8 Reaction according to the above procedures of a compound of the formula e wherein H is a readily cleavable ester protecting group, which B is a readily cleavable ester protecting group, which consists of trimethylsilyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, trichlorethyl, phenacyl, acetonyl, methoxymethyl, 5-indanyl, 3-phthalidyl, 1-α-ethoxycarbonyl) oxy7ethyl, pivalovoyloxymethylene methyl, - was made from the appropriate acid chloride or acid chloride hydrochloride in question and which optionally contained blocking groups, followed by removal of any blocking groups present, gave the following compounds: almecillin; armecillin, azidocillin; azlocillin; bacampicillin; The compound Bay K4999 of the formula HO CH3 S TH-CONH '' T CH --N 3 NH 0 / ä COOH 0 5G \ N / “fw-Maxim \ __ f 448 630 36 The compound BL-Pl654 of the formula <í ::> > \ * ïH _ coNH ;; l :: š: í:] <: fE3 ffs NH 0 coon H = c -NH-cáN Xmxa The compound BL-P1908 with the formula.f NHOHO -L \ .ø_ J Nfï:; ° carfecillin; carindacillin; cyclacillin; clometocillin; cloxacillin; dicloxacillin; The compound EMD-32412 of the formula HO-K :: ;; L_ CH3 cH-coNH-í-f S _ _ Jm 02- * | on coon o = c-NH i / f N; ~ \ N, / 448 650 37 epicillin; floxacillin (flucloxacillin); furbucillin; hetacillin; The compound I.S.F.-2664 of the formula O. V CH.

CH - com: S 3 PII ~ CH3 o; NÅ- CH3 ff. I u. . Qa'C "ÜCH2QC..C (CH3. M2 isopropicillin; methicillin; mezlocillin; nafcillin; oxacillin; phenbenicillin; Compound PC-455 of the formula Y MW * NH N - 0 ° cooH ) with the formula C213 '(i: kcn-coxm-fl / s | cH --N NH 0 /' 3 448 630 38 piperacillin; 3,4-dihydroxypiperacillin; pirbenicillin; pivampicillin; Compound PL-385 with the formula HO CH cin- The compound of the present invention can be used industrially.

Claims (4)

10 15 20 25 30 448 630 PATENT CLAIMS Process for the preparation of penicillins of the formula H H 1 O:: u a a ° H3 R-C-NH 0 ¿0. In which RC- constitutes the residue after removal of the hydroxyl group from an organic carboxylic acid containing 2-20 carbon atoms, by acylating with the acid chloride of said organic carboxylic acid a silylated core of the formula II 11 aa CH3 wherein B is a readily cleavable ester protecting group, and then the group B is converted to hydrogen, characterized in that said acylated core is converted to acylation before acylation. a compound of the formula E15 wherein: CH3 (CH) S1-OC-NH _ 3 3 2 CH N 3 O ¿; O \ 10 15 20 25 30 448 630 40 wherein B has the meaning given above, by add dry carbon dioxide to a solution of a compound of the formula fi. fg .__- j CHB (cH3) 3s1NH _ - C113 -o temperature within the range o ° -1oo ° c to the aeee reaction has fuliberaete. 2. A process according to claim 1 for the preparation of 6-Nk aminoarylacetamidopenicillanic acid, characterized in that reacting a compound of the formula n S CHB (cH3) 3si-O-c-NH-cH-c 1 μm: C. 3. A process according to claim 1 for the preparation of amoxicillin, characterized in that reacting a compound of the formula 10 "20 448 630 41 / * š ~ \ /" C33 _ H (cH3) 3s1- oc-NH-cn-en ï_ \ CH3 '- f N CH in ° Å-o-si (ca) Q hydroxyphenyl glycyl chloride hydrochloride, preferably at a temperature above -1 ° C. A process according to claim 1 for the preparation of ampicillin, characterized in that a compound of the formula // 5 ~ \ / 'CHÉ CH C NH; CH C-O-oi (CH3) 3 H O H m% ë fi w4mmw_ ÄJ 'O in an anhydrous, inert organic solvent with approximately an equimolar amount of D - (-) - 2-phenylglycylchlorohydrochloride, preferably at a temperature above -10 ° C.