JPS6183188A - Manufacture of penicillin - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The method of the invention utilizes a class of antibacterial agents commonly referred to as semi-synthetic penicillins, preferably α on the acyl side chain at the 6-position, such as ampicillin and amoxicillin.
- A novel method for producing a group of antibacterial agents characterized by an amino group.

The first commercial penicillin with an α-amino group on the 6-acylamino side chain was 6-(D-α-amino-α-phenylacetamido)penicillanic acid or ampicillin (U.S. Pat. No. 2,985,648 (see issue).

Amoxicillin is also an antibacterial agent used in human therapy and is commercially available as the trihydrate of the free acid (i.e., zwitterion). This is, for example, disclosed in British Patent No. 978.178 J, Chem, Soc.

(London) pp. 1920-1922 1971, “Fungicides and Chemotherapy-1970” pp. 407-430 (1
971). Its chemical name is 6-[D-
α-Amino-α-(p-hydroxyphenyl)acetamide] penicillanic acid.

The use of amino acid chloride hydrochloride to make the above-mentioned penicillins1, under anhydrous conditions, is disclosed in the patent literature, such as GB 938,321 and GB 959,853 (the latter being GB 938,321 and GB 959,853). 1.008.
No. 468, U.S. Pat. No. 3,249,622 utilizes protection by a silyl group during acylation of the carboxyl group of 6-aminopenicillanic acid),
In cold acetone, it is disclosed in British Patent No. 962.779. These penicillins are amphoteric amino acids, so their isolation (e.g., U.S. Pat. No. 3,157,640; U.S. Pat. No. 3,271,3
89) using certain aliphatic asymmetric side-chain secondary amines (often referred to as liquid amine resins); It was used to isolate acids (see U.S. Pat. No. 3,008,956). Improved methods for isolating and purifying these penicillins are described, for example, in U.S. Pat. No. 3,180,862 using β-naphthalene sulfonate, and in US Pat. As disclosed in US Pat. No. 3,198,804.

The use of silyl groups for protection of the carboxyl group of natural penicillin during chemical cleavage to 6-aminopenicillanic acid is disclosed in US Pat. No. 3,499,909. The use of silylated 6-aminopenicillanic acid during anhydrous acylation with amino acid chloride hydrochloride has been described in numerous patents such as U.S. Pat. No. 3.479.018;
, 595.855, U.S. Patent No. 3,654,266, U.S. Patent No. 3.479,338, U.S. Patent No. 3,4
This is disclosed in No. 87,073. Some of these patents also disclose the use of liquid amine resins. See also U.S. Pat. No. 3.912.719, U.S. Pat.

British Patent No. 1,339,605 discloses a silylated derivative of 6-aminopenicillanic acid and a D-
Reaction with reactive derivatives (including chloride hydrochloride) of (-)-α-amino-p-hydroxyphenylacetic acid, followed by removal of the silyl group by hydrolysis or alcoholysis, followed by crystallization, if possible. The present invention includes various specific detailed examples of producing amoxicillin by recovering amoxicillin as a trihydrate. Thus, in Example 1, isoelectric precipitate isoelectric IE5i (isoelectric precipitate
crystalline amoxicillin was obtained. Perhaps in this example, the crude product (before isoelectricity)
Water with an acidic pH such as 1.0 (e.g. hydrochloric acid aqueous solution)
Methyl isobutyl ketone (4-methylpentane-2-
Purification was carried out by dissolution in the presence of water-immiscible organic solvents such as The same procedure was used in US Pat. No. 3.674.7'76.

Further, a compound of the following structural formula (wherein B is a trialkylsilyl group) is prepared in an anhydrous inert organic solvent, preferably in methylene chloride, preferably in the presence of a weak base, preferably propylene oxide. is a temperature of -10°C or higher, more preferably in the range of -8 to 20°C, even more preferably in the range of 0 to 20°C.
in the range of 20° C., most preferably at about 20° C., with about an equivalent amount of acid chloride or chloride hydrochloride (preferably the latter added in portions to the solution of the former) and then, if desired, , a conventional process for the production of penicillin consisting of converting the B group to hydrogen has been provided by the inventors.

The conventional penicillins defined herein are those already described in patents or literature (including abstracts thereof).

Also in accordance with the invention, a solution of the compound in an anhydrous inert organic solvent, preferably methylene chloride, with dry carbon dioxide as gas (where B is a trialkylsilyl group) at room temperature or at a temperature in the range from 0°C to 100°C A method is provided for the preparation of a compound of the formula (where B is the same as above), comprising adding until the reaction is complete.

I in an anhydrous inert organic solvent, preferably methylene chloride, preferably in the presence of a weak base, preferably propylene oxide, preferably above -10°C, more preferably in the range -8°C to 20°C, More preferably 0°C~
at a temperature in the range of 20°C, most preferably about 20°C, about equimolar amounts of D-(-)-α-ruaminoarylacetyl chloride, preferably D-(-)-2-phenylglycyl. Chloride hydrochloride or D-(-)-2-p-
6-α-aminoarylacetamidopenicillanic acid as a preferred embodiment of the invention, consisting of reacting with each of hydroxyphenylglycyl chloride hydrochloride, the latter preferably being added in portions to the solution of the former;
Preferably, a method for producing ampicillin or amoxicillin is provided.

One of the surprising features of this new method is the stability of the anhydrous acylation solution. This can be maintained for long periods of time even at room temperature without appreciable decomposition of the penicillin molecule. This is in contrast to the behavior of the acylation solution in previously described methods. This stability advantage is usually below 0°C, typically around -
This allows the acylation reaction to be carried out at a much higher temperature (we used room temperature) than the temperature normally used for ampicillin production, which is 10°C.

Dry as a gas, carbon dioxide is added to a solution of trimethylsilyl 6-drimethylsilylaminobenicillanate in an anhydrous inert organic solvent, preferably methylene chloride, at room temperature or in the range 0 to IO θ C until reaction completion. Also provided as a preferred embodiment is a method for preparing a compound of the formula:

Also provided as embodiments of the invention are compounds having B, where B is a trialkylsilyl group.

Compounds having the following are provided as preferred embodiments. This compound has the bissilylation power of 6-APA/L/ha?
-t, SCA, 6-drimethylsilyloxycarbonylpenicillanic acid TMS ester, TMSO□C-APA・
It is referred to by various common names such as TMS.

For example, as disclosed in U.S. Pat. No. 3,225,033, the reaction of 6-APA with carbon dioxide
The existence of said compound is surprising in view of the well-known fact that it destroys -APA and produces 8-hydroxypenicillanic acid.

6-Dolimethylsilyloxycarbonylaminobenicilanic acid trimethylsilyl ester (TMS(hC・AP^
・The key to quantitatively obtaining 6-AP
The aim is to completely synthesize the AbisTMS precursor. This is achieved by reacting 6-APA with hexamethyldisilazane (HMDS) as shown in the following schematic outline.

1 mole 1. tmol 3-5 mol% 6-8 hours Completion of the bistrimethylsilylation reaction can be easily followed using NMR. 3-trimethylcy! J-ruoxycarbonyl group is 0.31 ppm (tetramethylsilane = 0)
shows a methylsilyl single line at 0.09pp+*, while the 6-trimethylsilylamine group shows a methylsilyl single line at 0.09pp+*.

The 6-APA) remethylsilylation reaction has hitherto only been carried out in methylene chloride. The conversion of the trimethylsilylamino group to the trimethylsilyloxycarbonylamino group is easily accomplished by adding other solvents such as acetonitrile, dimethylformamide and dry Cot into the reaction solution. A new single line of trimethylsilyloxycarbonylamino group is 0
．． The conversion can be easily traced as the 0.09 ppm trimethylsilylamino single line fades as it increases to 27 ppm.

When used in the production of ampicillin, ampicillin anhydride, ampicillin trihydrate, amoxicillin, amoxicillin trihydrate, U.S. Pat.
No. 3,980.637, No. 4,128.547, and other patents and publications cited therein, by conventional methods well known in the art, the final product can be prepared. Isolated and purified.

The acid chlorides used in the following examples can be replaced with various other acid chlorides to produce conventional penicillins.

Thus, the acid chloride may be selected to introduce any desired acyl group at the 6-amino position, as is known in the art, eg, US Pat. No. 3,741,959. Alternatively, specific acyl groups can be introduced, including (but not limited to) those specified in the general formula below.

(i) R'C. H. , CO-, where Ru is ryol (carboxylic or heterocyclic), cycloalkyl, substituted aryl, substituted cycloalkyl, or non-aromatic or mesoionic heterocyclic group, and n is an integer from 1 to 4. . Examples of this group are phenylacetyl, substituted phenylacetyl Jv, such as fluorophenylacetyl, nitrophenylacetyl, aminophenylacetyl, acetoxyphenylacetyl, methoxyphenylacetyl, methylphenylacetyl, or hydroxyphenylacetyl; N,N-bis(210 loethyl)aminophenylpropionyl; Cheso 3-acetyl; 4-isoxasilyl and substituted 4-isoxacylylacetyl: pyridylacetyl; tetrazolylacetyl or cytononeacetyl groups. A substituted 4-isoxasilyl group may be a 3-aryl-5-methylisoxazol-4-yl group, where aryl is, for example, fenino-1 or halophenyl, such as chlorophenyl or bromophenyl. An acyl group of this type is 3-o-chlorophenyl-5-methylisoxazol-4-yl-acetyl.

(II) CnHzn*+ C O-, where n is an integer from 1 to 7. The alkyl group may be straight-chain or grouped and may be substituted, if desired, via an oxygen or sulfur atom or, for example, by a cyano group. Examples of such groups are cyanoacetyl, hexanoyl, heptanoyl,
Includes octanoyl and butylthioacetyl.

(iii) C, lHz□1C〇-where n is an integer from 2 to 7. This group may be straight-chain or segmented and may contain intervening oxygen or sulfur atoms if desired. An example of such a group is allylthioacetyl.

(iv) v R'S - C - CO - R' However, R' has the meaning defined in (i) and may also be benzyl, Rv and R' may be the same or different, and each hydrogen , phenyl, hensyl, phenethyl or lower alkyl. Examples of such groups are phenoxyacetyl, 2-phenoxy-2-phenylacetyl, 2-phenoxypropionyl, 2-phenoxybutyryl, hensyloxycarbonyl, 2-methyl-2
-phenoxypropionyl, p-talezixyacetyl and p-methylthiophenoxyacetyl.

(v) Rv ■ -Ru5-C-C0 R' However, R'' has the meaning defined in (i), and may also be benzyl, and Rv and R' have the meaning defined in (iv). Examples of such groups include S-phenylthioacetyl, S-chlorophenylthioacetyl, S-fluorophenylthioacetyl, pyridylthioacetyl and S-benzylthioacetyl.

(vi) R'Z (CHI), CO-However, R.
has the meaning defined in (1), and may also be benzyl, Z is oxygen or sulfur atom, and m is 2
It is an integer of ~5. An example of such a group is S-hensylthiopropionyl.

(vi) R' C○- where R' has the meaning defined in (i). Examples of such groups are benzoyl, substituted benzoyl (e.g. aminobenzoyl), 4-isoxasilyl and substituted 4-isoxasilylcarbonyl, cyclopencunecarbonyl,
Includes sidonecarbonyl, naphthoyl and substituted naphthoyl (e.g. 2-ethoxynaphthoyl), quinozalinylcarbonyl and substituted quinozalinylcarbonyl (e.g. 3-carboxy-2-quinozalinylcarbonyl).

Other possible substituents for benzoyl are alkyl, alkoxy, phenyl or carboxy, alkylamido,
Cycloalkylamide, allylamide, phenyl(lower)-alkylamide, morpholinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, tetrahydropyrrolidino, furfurylamide or N-alkyl-N-
phenyl substituted with anilino, or derivatives thereof, such substituents include 2- or 2- and 6-
It may be a rank. Examples of such substituted benzoyl groups are 2,6-simethoxybenzoyl, 2-biphenylcarbonyl, 2-methylamidobenzoyl and 2-carboxybenzoyl. When the R' group represents a substituted 4-isoxazoyl group, it may be as described above for substitution % (i). Examples of such 4-isoxasilyl groups are 3-phenyl-5-methyl-isoxazole-4-isocarbonyl, 3-o-chlorophenyl-5
-methyl-isoxazol-4-ylcarbonyl and 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-isocarbonyl.

(viii) R'CH-Co-? where Ru has the meaning defined in (i), and X is amino, substituted amino (e.g. acylamide or 7-side chain amino group and/or group reacted with aldehyde or ketone, e.g. acetone, methyl ethyl ketone or ethyl acetoacetate) hydroxy, carboxy, esterified carboxy, triazolyl, tetrazolyl, cyano, halogeno, acyloxy (for example formyloxy or lower alkanoyloxy) or etherified hydroxy groups. Examples of such acyl groups are α-aminophenylacetyl, α-carboxyphenylacetyl and 2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl.

(ix) RX R'-C-CO- R madashi RX, R' 1. and R'' may be the same or different and each represents lower alkyl, phenyl or substituted phenyl. An example of such an acyl group is triphenylcarbonyl.

(x) '/R'-NH-C- However, R'' has the meaning defined in (i), and hydrogen,
It may be lower alkyl or halogen-substituted lower alkyl, and Y represents oxygen or sulfur. An example of such a group is CI (C1h) tNIICO.

(xi) However, X has the meaning defined in (vii), and n is 1
It is an integer of ~4. An example of such an acyl group is l-amino-cyclohexanecarbonyl.

(xii) 7-minoacyl, e.g. R'CH(Nu,)
-(CI(2)nCO- (where n is an integer from 1 to 1o) or NHzC, 1llzJr(C1lz)+
++CO- (where m is 0 or an integer from 1 to 10, n is 0.l or 2, R' is a hydrogen atom or an alkyl, aralkyl or carboxyl group, or
' and Ar is an arylene group, such as p-phenylene or 1,4-naphthalene. ) Examples of such groups are UK Patent No. 1.054.80.
It is disclosed in No. 6. A group of this type is the p-aminophenylacetyl group. Other acyl groups of this type include δ-aminoadipoyl and derivatives thereof derived from naturally occurring amino acids, such as N-hencyyl-δ-aminoadipoyl.

(xiii) a substituted glyoxylyl group of the formula R'-CO.CO-, where R' is an aliphatic, aralphatic or aromatic group, such as a chenyl group, a phenyl group, or a mono-, di- or tri-substituted phenyl group; , substituents include, for example, one or more halogen atoms (F, Cf,
Br, or ■), a methoxy group, a methyl group, an amino group, 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. Conveniently, the protecting group is one that can be removed by hydrolysis without affecting the rest of the molecule, especially the lactam and 7-amide bonds. The amine protecting group and the esterifying group at the 4-COOH position can be removed using the same reagent. An advantageous operation is to remove both at the final stage of the process. Protected amino groups include urethane, arylmethyl (eg trityl)amino, arylmethyleneamino, sulfenylamino or enamine types. Enamine blocking groups are particularly useful in the case of 0-aminomethylphenylacetic acid. Such groups can generally be removed by one or more reagents selected from dilute mineral acids, such as dilute hydrochloric acid, concentrated organic acids, such as concentrated acetic acid, trifluoroacetic acid, and liquid hydrogen bromide at cryogenic temperatures, such as -80°C. . A convenient protecting group is the t-phthoxycarbonyl group, which is protected with a dilute mineral acid, such as dilute hydrochloric acid, or preferably with a strong organic acid, such as formic acid or trifluoroacetic acid, for example at a temperature of 0 to 4°C, preferably is easily removed by hydrolysis at room temperature (15-25°C). Another convenient protecting group is 2,2
．． 2-1-lichloroethoxy carbonyl group, which can be cleaved with reagents such as zinc/acetic acid, zinc/formic acid, zinc/lower alcohol or zinc/pyridine.

By using an amino acid chloride as an acid addition salt under conditions where the amino group remains protonated, the NH group can be converted to N
H3”.

The acid used to form the acid addition salt is preferably X
It has a pka (in water at 25°C) of +l (where X is the pka value of the carboxyl group of the amino acid (25°C
(in water), the acid is preferably monovalent. Actual acid H
Q (see below) generally has a pka of less than 3, preferably less than 1.

It has been found that particularly advantageous results are obtained from the process according to the invention when the acid chloride is a salt of an amino acid chloride. Amino acid chlorides have the formula IIJ -R+ -C0Fla1 where R2 is a divalent organic group and Hal is chlorine or bromine. Such amino acid chloride salts are
- (However, R' and Hal are the same as above,
Q- is the anion of the acid and HQ has the pka described above). The acid HQ is preferably a strong mineral acid, for example a hydrohalic acid such as hydrochloric acid or hydrobromic acid. Important acyl chlorides are D-N~(α-chlorocarbonyl-α-phenyl)-methylammonium chloride, D-(PhCH(NHi ) COCl) ” C1
-te, which is conveniently referred to herein as D-α-phenylglycyl chloride hydrochloride.

obtained by the final method, and the acylamido group R'CI(N)
lz) Penicillins with CONII- (R, Ru, same as above; theal) can react with the ketone R"COR5 (wherein R2 and R3 are lower alkyl groups (c, ~Ca)), and the group Compounds of this type include hetacillin, salpicillin, P-hydroxyhetalycin and salpicillin.

The acyl groups described in US Pat. No. 4,813,648 7-20 frA are also included herein and fully incorporated by reference.

When the terminal acylation process is used to produce penicillin, the final product is isolated and purified according to conventional methods known in the industry.

Preferred acyl chlorides used in the process to acylate compounds having the formula % where A is a trialkylsilyl group include the following.

fa) Q A-C) 12C-(1! where A represents , R is hydrogen, hydroxy or methoxy, R' is hydrogen or methyl, the amino group in particular includes protonation if necessary (b) 0 B-CH-C-CIl-HC (! NH.

(However, B represents, R1 is hydrogen, hydroxy or acetoxy, Rz is hydrogen, chloro or hydroxy when R' is hydroxy, R2 is hydrogen when R1 is hydrogen or acetoxy); , R is phenyl, 4-
hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohex-1,4-dien-1-yl) (wherein R is phenyl, 4-hydroxyphenyl, 3
, 4-dihydroxyphenyl or cyclohex-1,
4-dien-1-yl); 1-position (where R is phenyl, 4-hydroxyphenyl, 3
,4-dihydroxyphenyl or cyclohexadien-1-yl); (wherein R' is phenyl, 4-dihydroxyphenyl or cyclohexadien-1-yl);
-hydroxyphenyl, 3,4-dihydroxyphenyl or cyclohexadien-1-yl- and R2 is hydrogen or hydroxy); fj) Ff
fc S CHzCC1; (ρ ++) NC-CH2C-cl iH,N N=CCHz S CHz CC1! HN
OCHz (where R is phenyl, 4-hydroxyphenyl, 3
．． 4-dihydroxyphenyl or cyclohexadien-1-yl); (wherein A is hydrogen or alkyl of 1 to 4 carbon atoms or CIh5O□-, X is oxygen or sulfur, and R is Phenyl, 4-hydroxyphenyl, 3.4
-dihydroxyphenyl or cyclohexa-1゜4-
dien-1-yl); (wherein R is hydrogen or methyl); (wherein,
each of R1 and R2 is hydrogen, chloro or fluoro); ChangC=NH H2 (wherein B is, R1 is hydrogen, hydroxy or acetoxy, and R2 is hydrogen, chloro or hydroxy when R1 is hydroxy); and R2 is hydrogen when R1 is hydrogen or acetoxy); B-CH-C-C1 (ee) NH C=0 ■ IIR (where B represents and R1 is hydrogen, hydroxy or acetoxy, R2 is hydrogen, chloro or hydroxy when R1 is hydroxy; hydrogen is hydrogen when R1 is hydrogen or acetoxy; R is hydrogen or cyanomethyl): (gg) Cf1z=CHCHz
S CHI CC1B-CH-C-CI (ii) l N1( (where B represents , R1 is hydrogen, hydroxy or acetoxy, and R2 is hydrogen, chloro or acetoxy when R1 is hydroxy) R2 is hydrogen when R1 is hydrogen or acetoquine); (wherein R is hydrogen or methyl) and the amino group is, if desired, protected with conventional blocking groups, including inter alia protonation; NH.

(as a salt if desired) (where B is, R1 is hydrogen, hydroxy or acetoxy and R2 is hydrogen, chloro or hydroxy when R' is hydroxy and R2 is hydrogen when R1 is hydrogen or acetoxy) ); I B -Cl1-C-CI (where B represents , R1 is hydrogen, hydroxy or acetoxy, R2 is hydrogen, chloro or hydroxy when R1 is hydroxy, and R2 is when R1 is hydrogen or acetoxy); (wherein B represents, R1 is hydrogen, hydroxy or acetoxy, Rt is hydrogen, chloro or hydroxy when R1 is hydroxy and R2 is hydrogen when R1 is hydrogen or acetoxy); (ww) B-CI-C-CCH C=0 薯HsCCC1l:I (However, B represents , R1 is hydrogen, hydroxy or acetoxy, and R2 is hydrogen, chloro or hydroxy when R1 is hydroxy, and R2 is hydrogen when R1 is hydrogen or acetoxy): Acid chlorides are usually prepared under harsh conditions, such as by treatment of acid with thionyl chloride at reflux, but are sensitive to the inclusion of sensitive protecting groups. When the group is present, the acid chloride can be prepared under virtually neutral conditions by reaction of oxalyl chloride with a salt of the acid.

Example 1 6-aminopenicillanic acid (6-APA) and CDZC
To a mixture of 10 ml of N z and 1.13 ml of trimethylchlorosilane was added dropwise 1.23 mj+ of triethylamine over 30 minutes at 25-27°C.

Stirring was continued for another 2 hours. Dry carbon dioxide gas was then bubbled through the mixture for about 3 hours. At the end of this time, NMR (nuclear magnetic resonance) shows the following structure 0
The presence of 60% silylated carboxy 6-APA (SCA) with C-0-5i (C113)3 was found.

This mixture was kept in the refrigerator for two nights. The next day, 0.11 ml of N,N-dimethylaniline was added, and the mixture was cooled to 8°C. Then, I)-(-)-p-hydroxy-2-phenylglycylhydrochloride ('4@
4l 9%) was added.

Omi-dara” stand Muhin unishi Sokai uni tile 0
-8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +3 220 +15 310 +20 At the end of the 310 minute reaction, add 60% ethyl acetate,
Thin layer chromatography (TI, C) performed on a sample of Reaction 1 using a solvent system of 0% and 20% water showed the presence of amoxicillin.

A cold sample of the final reaction mixture in 1 ml is 0□01. Added Omf. After separation by centrifugation, the aqueous phase was found to contain 78% amoxicillin and approximately 20% 6-APA by NMR. The presence of amoxicillin was also confirmed by TLC.

Example 2 5.4 g (0.025 mol) of 6-amitubenicilanic acid in 40 ml of CIl□C (lz) and 2 ml of 93% hexamethyldisilazane (HMDS, 0.0275
A mixture of 0.07 g (about o, oot moles) of imidazole and imidazole was refluxed for about 17.5 hours under a nitrogen purge.

At the end of this time, trimethylchlorosilane (TMCS)
) 0.13 mft (approximately 0.001 mole) was added. The solution became cloudy. Reflux was continued for another 7 hours, and the su4
Precipitation of cg was observed. At this point, if NMR is 6-APA
It showed about 100% silylation of both amino and carboxyl groups. Then HMDS0.2m/(0,001
25 mol, about 5 mol%) and TMCSo, 06ml! (approximately 0.05 moles of OQ) was added and reflux was continued for an additional 17 hours with nitrogen purge. At this time, the NMR spectrum was the same as before the addition of small amounts of HMDS and TMCS.

Dry carbon dioxide was then bubbled into the reaction mixture for 75 minutes at room temperature, then NMR showed no HMDS and >92% silylated carboxy 6-APA (SCA).

Then 4.45 m of N,N-dimethylaniline (DMA)
1 (0,035 mol) was added and the mixture was cooled to -3°C. Then, 5.65 g (purity 95%, 0.026 mol) of D-(-')-2-phenylglycyl chloride was added in the following proportions.

Todoroki: r (L) LLO-3
1,05 2001,30 4001,30 5001,00 6001,00 The reaction was followed by NMR and showed almost no change after about 5 hours from the start of the reaction. The temperature was 3°C. The reaction mixture was then kept on ice for the next 16 hours. It was then removed from refrigeration and stirred at room temperature (approximately 20-24°C) for 3.5 hours. A large amount of solid material was still present. The reaction mixture was then stirred at room temperature (22-24°C) for about 63 hours.

At the end of this time there was a slight haze. Sample 02
NMR showed ampicillin and 6-APA.

The reaction mixture was cooled to about 0° C. and stirred for 5 minutes in the cold after addition of 35 ml of ice water. After polish filtration, mix the mixture with cold water and CIl□CI! , washed with 2. After separation, the aqueous phase was subjected to TLC
showed a large band slower than ampicillin and 6-APA, representing a new intermediate X.

The aqueous phase was adjusted to p) 13.0 with NH,OH and seeded with ampicillin. Methyl isobutyl keto 7 (MIBK,
Add 35 ml of NH, stir the mixture, and add NH,
The pH was adjusted to 5.2 with OR, stirred at 20°C for 1 hour, stirred for another hour in a water bath, and then cooled with acid overnight. The ampicillin precipitate was collected by filtration, washed first with 25 ml of cold water, then with 49 ml of MIBK, and finally with 40 ml of a mixture of 85 parts of isopropyl alcohol and 15 parts of water.
Dry at ℃ and identified as ampicillin by TLC4
．． It was found that 5g was obtained.

6-APA 5.4 g in 50 mg,
HMDS (93%) 6.2ml, imidazole 0.06
The mixture of g was refluxed for 18 hours under nitrogen purge. Then, when 1rrl of TMCSo was added, turbidity occurred. The mixture was further refluxed for 2 hours to obtain a clear solution, and NH4Ce was deposited in the condenser. Then, 1 m/m of TMCSo was further added, and a very slight turbidity remained. Reflux was continued for the next 65 hours without nitrogen purge. The mixture was then cooled to about 22°C and the addition of dry carbon dioxide began.

After 75 minutes, NMR showed >90% bissilylated carbamate (SCA) formation.

Next, add DMA4.45m/ and D-(-
)-2-phenylglycyl chloride hydrochloride (purity 97%
) 5.6g was added.

Time (min) Temperature (℃) Addition (g) 0
20 1.35 20 20 1.3032
20 1.0048 20
1.0075 20 1.00 After stirring the mixture for a further 17 hours, TLC was performed on a sample of the reaction mixture and on the diluted reaction mixture (1 mff1 of reaction mixture diluted with CII (Jl, 2 m7!), each showing a small band of ampicillin and A large band of folded intermediate X was shown.

The reaction mixture was then cooled to 0°C and 40ml of ice water was added.
Stir the mixture for 5 minutes, polish filter, add water and C.
H, +1. I washed it with The aqueous phase was separated, 10% was sampled and the remainder was adjusted to pH 3.0 with NH4OH, seeded with ampicillin and stirred.

After adding another 40 ml of MIBK, stir the mixture.
N)1. The pH was adjusted to 5.2 with an OR, stirred for 1 hour at room temperature, and further stirred for 1 hour in a water bath. Crystals precipitated. - After night refrigeration, the crystalline product is collected by filtration and MIBK
, water, MIBK, isopropanol-water (85:15)
Wash with 40 ml of water, dry at 45°C, and add ampicillin 6.
, 25 g was obtained. (Corrected for sample use: 6.8 g, 6
8% yield).

L Shishi ↓ CDzClz TEAl, 23r to a mixture of 6-APAl, 0g and TMC51,13ml in 10ml
nj! was added dropwise over 30 minutes and the mixture was stirred for a further 2 hours. Dry carbon dioxide was then bubbled in for 4 hours. At this time NMR showed about 55-60% carboxysilylation. The mixture was then refrigerated overnight. Morning DMA
0.77 ml was added, the mixture was stirred, cooled to -8°C and 1.2 g of D-(-)-p-hydroxy-2-phenylglycyl chloride hydrochloride was added in the following proportions:

Seed layer" light A1: Ω low normal force LΩO-0-80
, 30 20-40, 30 40-40, 30 60-40, 30 At the end of 310 minutes, NMR showed about 78% amoxicillin and about 20% 6-APA.

Example 5 Dry 6-amitubenicilanic acid (10.0 g, 46,24
millimoles, 1.0 equivalents) in anhydrous methylene chloride (175 m
The mixture was stirred and suspended at 25°C.

Triethylamine (10.76 g, 36 mmol IO, 2.30 eq.) was stirred at 25°C, then the temperature was increased to about 32°C depending on the rate of addition of trimethylchlorosilane.
Trimethylchlorosilane (I 1.7
0 g, 107.75 mmol, 2.33 equivalents) from 10 to
Added over 15 minutes. After stirring for 20-30 minutes, the mixture containing precipitated triethyl hydrochloride was 80 MlllNMR.
The complete silylation was analyzed by The mixture was then bubbled with carbon dioxide gas for about 2 hours at 20°C to give a concentration of 80 M
Complete carboxylation was analyzed by Hz NMR. Sometimes it was necessary to introduce additional carbon dioxide gas.

If necessary, the volume of the carboxylation mixture was readjusted to about 175 ml with dry methylene chloride. After the carboxylation is complete, the slurry is treated with propylene oxide (2.95 g,
3, 56 ml, 50.87 mmol, 1.1 eq)
and cooled to 0-5°C. D-(-)'-2-(
Midioxane solvate was added to p-hydroxyphenyl)glycyl chloride hydrochloride at approximately 2° C. in 5×2.71 g portions [total 13.54 g (50.87 mmol, 1
．． 1 equivalent) was added]. Each portion of the above acid chloride was dissolved to the point where the next portion was added. This is about 2 per portion
It took 0 minutes. This stepwise addition was of great importance.

The final acylation mixture was checked for undissolved acid chloride hydrochloride. The mixture was kept at 0-5 °C for 30 minutes and cooled (0-5 °C).
Treated with deionized (Dl) water (100 mJ with high speed agitation for 10 minutes). The mixture was separated to remove the underlying methylene chloride. The aqueous mixture was polished through a thin precoat of diatomaceous earth. (no solids) and soak the cake in cold (0-5°C) DI water (15°C).
mJ). The underlying organic layer was removed before crystallization. A clear pale yellow aqueous solution (p112~2.5) was heated at 0~5°C.
The temperature was adjusted to H3.5, and seeds were added if necessary. The slurry was kept at 0-5° C. for 40 minutes, 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 amoxicillin thus collected was cooled (
The cake was washed with methylene chloride (30 ml) to give about 13.5 g (about 70%) of snow-white amoxicillin trihydrate.

*) Stop stirring and check the mixture for solids at the bottom of the flask. For this sample, the slurry must not be heated above 5°C or the results will be erroneous.

Example 6 108 g (0.5 mol) of rhoaminopenicillanic acid, 1.0 g (0.017 mol) of imidazole, dry methychloride L/7800 mp, HMDS (approx. 8% purity) 12
0 ml (0.56 mol) was stirred and heated under reflux for 3.3 hours. The reaction was purged with dry nitrogen gas at reflux to scavenge the NH produced in the reaction.

Then, 2.0mj of trimethylchlorosilane (TMC3)
! (0,016 mol) was added. Reflux was continued for an additional 19 hours while purging with N2, and then the sublimated N was placed in a condenser.
Cleanly remove H, C1, 7MC32,6m1 (0,0
206 mol) was added to the reaction. Refluxing was continued for an additional 34 hours while purging with SZ. The reaction mixture volume was made up to lOOml with dry methylene chloride. Then NMR is 6-
It showed 100% silylation of the amino and carboxyl groups of aminopenicillanic acid. The solution was covered with a N2 atmosphere and kept for 9 days. The above stability was confirmed by NMR. The solution was stirred and CO2 was bubbled through for approximately 90 minutes. The temperature was 20-22°C. NMR showed that bistrimethylsilyl 6-7 minopenicillanic acid was 100% converted to bistrimethylsilylcarboxy 6-aminopenicillanic acid (SCA).

This master mixture was used for the acylation experiments described below. The chemical in the solution had the following structural formula:

NMR showed that bistrimethylsilylcarboxyne 6-aminopenicillanic acid was stable after 9 days.

100 m of this master mixture/(0.05 mol of SCA equivalent to 10.8 g of 6-aminopenicillanic acid) was added to 22
Stir at ℃, TEA-HCI 8.0 g (
0,058 mol) and 4.2 mI of propylene oxide!
(0.06 mol) (see US Pat. No. 3,741,959) was added.

Some TEA-H1! was precipitated. Stir the mixture;
Cooled to +3°C. 15.5 g of D-(-)-p-hydroxyphenylglycyl chloride hydrochloride heminoxane solvate (79% purity, 0.055 mol) was added to the reaction in the following proportions.

To Asahi "Kou L One leg" Bunhong 1 skin uni and 3, 0
0 + 33.0 7
+2 3, 0 20 + 26.5
33 +2 15.5 After a further 70 minutes approximately 50 ml of dry methylene chloride was added to the reaction mixture to reduce the viscosity.

After another 160 minutes, 2 ml of sample was taken out, D201,
After centrifugation, NMR analysis of the aqueous phase showed approximately 6% unacylated 6-aminopenicillanic acid.

After 10 minutes, the reaction mixture was transferred to a 60 Oml beaker and washed with 50ml of methylene chloride to complete the transfer. Cool deionized ice water while stirring in a water bath 5 Qmj!
was added to obtain a two-phase solution containing no solids and having a pH of 1.0.

15.0 ml of liquid anion exchange resin (LA-1) was stirred and added to the two-phase system and seeded with I)) 12.0 ml. Crystallization has begun. Furthermore LA-110, 0m/
1 was gradually added over about 5 minutes. The pH was 3.0. Then, 0.15 g of Na8L was added.

Then LA l 5. Added Oml. pl+ is 4
．． It was 5. Continue stirring and add water 4. NaHSOs (sodium bisulfite) in Q ml 1. Og was added dropwise. Then, 0ml of LA-110 was added. The pH continued to rise. Total LA-140m/, final pH 5.
It was 6. Then 5 ml of acetone was added. Water 5. Na)ISO31 dissolved in Qml,
5g was added over 30 minutes. I continued stirring in the water bath.

The precipitated product was collected by filtration and the cake was dissolved in methylene chloride 5
0m6, water 40ml, isopropyl alcohol-
Water (80:20) 10 Oml, methylene chloride 10
Washed sequentially with Oml. The cake was then dried at 45° C. under normal pressure to obtain 18.2 g of amoxicillin trihydrate, which was a yield of 87% based on 6-aminopenicillanic acid.
The overall yield was approximately 88% when corrected for % sampling.

LA-1 liquid anion exchange resin has the following structural formula: It is a mixture of secondary amines having 5 carbon atoms). This particular mixture of secondary amines, sometimes referred to as Liquid Amine Mixture NIIIJ, is a clear amber liquid with the following physical properties: Viscosity at 25℃ 70cp
s, specific gravity at 20°C 0.845. Refractive index at 25°C 1.46
7. Distillation range at 101■, up to 160℃ is 4%, 16
0-210℃ 5%, 210-220℃ 74%, 220℃
More than 17%.

Daisenukinitrimethylsilyl 6-trimethyldilyloxycarponylaminopenicillinate (0.54 g, 2.497 mmol) was dissolved in methylene chloride (5.0 ml) with triethylamine hydrochloride (0.20 g, 1.45 mmol). treatment followed by propylene oxide (0,162 g, 2
．． 75 mmol) at 25°C. The mixture was stirred at 25° C. for 20 minutes to facilitate dissolution of most of the triethylamine hydrochloride. Phenoxyacetyl chloride (0.43 g, 2.75 mmol) was added dropwise at 25°C and the mixture was stirred at 25°C for 30 minutes. Take out the sample and CM
The analysis was performed at 20.0 MHz with R. CMR (CI3 nuclear magnetic resonance spectroscopy) data showed complete disappearance of phenoxyacetyl chloride and APA carbamate as well as appearance of penicillin trimethylsilyl ester. Penicillin■ The presence of trimethylsilyl ester indicates that penicillin with triethylamine and trimethylchlorosilane■
This was demonstrated by spectral comparison with the same sample prepared by silylation of the free acid. The yield estimated from the CMR spectrum was 85-90%.

Cloxacillin, dicloxacillin, stafcillin and nafcillin were similarly prepared using the same molar reagents and the appropriate acid chlorides. These acylated mixed C
MR data showed a very clean acylation mixture with a yield estimated to be at least 85%.

A compound having the formula B (where B is a trialkylsilyl group) is reacted with a suitable acid chloride or acid chloride hydrochloride reagent (containing a blocking group if necessary) according to the procedure described above. The following compounds were generated by subsequent removal of the blocking group desired to be removed: almecillin, armecillin, azid
ocillin), azlocillin (azlocillin)
in), bacampicillin
), 4999 in Bay with 2, BL-P1908 with formula % formula % formula ■, calfecillin (carf
ecillin), carinda cillin (carinda)
cillin), cyclacillin
in ), clomethocillin
in ), cloxacillin
), dicloxacillin (dicloxacilli
n), EMD-32412 with 2, epicillin (epicillin)
llin), floxacillin (floxacilli
n), (flucloxacillin (flucloxacillin)
llin)), flubucillin (furbuccales 1i
n), hetacillin, 1,S,F,-2664, isopropicillin (with the formula
isopropicillin), methicillin (met
hicillin), mezlocillin (mezloci
llin), nafcillin
, Oxactllin, Phenbenicillin, Formula% Formula% Aparcillin, (
PC-904), piperagiline (piperacill)
in ), 3°4-dihydroxypiperacillin (3,4
-dihydroxypiperacillin)
, pirbenicillin
, pivampicillin
, PL-385, Brassylin (prazo-c
illin), sarpicillin (sarmoxicil)
lin ), salpicillin (5arpicillin
), ticarcillin resin sodium (ticarc
illin cresyl sodium), ticarcillin, carbenicillin, carfe-cillin, fibrasillin (
fibracillin) and Bay-e-
6905° The present invention can be applied industrially.

Claims (5)

[Claims] (1) A silylation nucleus having the formula ▲ Numerical formula, chemical formula, table, etc.▼ (where B is a trialkylsilyl group) is acylated with an acid chloride of an organic carboxylic acid containing 2 to 20 carbon atoms. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, ▲There are mathematical formulas, chemical formulas, tables, etc.▼) consists of the continuous process of converting group B into hydrogen. In a conventional method for producing penicillin having a group), the silylated nucleus is heated at 0°C to 0°C in an anhydrous inert organic solvent before acylation.
By adding dry carbon dioxide at a temperature in the range of 100°C until the reaction is complete, the above is converted into a compound with the formula ▲ Mathematical formula, chemical formula, table, etc. ▼ (where B is the same as above) Production method. (2) The compound of formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is added in an approximately equimolar amount of D-(
-)-A method for producing 6-α-aminoarylacetamidopenicillanic acid, which comprises reacting it with α-aminoarylacetyl chloride hydrochloride. (3) The compound of formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ is added in approximately equimolar amounts of D-(
-)-2-p-hydroxyphenylglycyl chloride hydrochloride.
A method for producing amoxicillin as described in Section 1. (4) The compound of formula ▲ includes mathematical formulas, chemical formulas, tables, etc.
-)-2-Phenylglycyl chloride hydrochloride.The method for producing anpinrin as claimed in claim (2). (5) The manufacturing method according to any one of claims (2) to (4), wherein the reaction is carried out at a temperature of -10°C or higher.