JPH0137395B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [INDUSTRIAL APPLICATION] The method of the present invention applies to a class of antibacterial agents commonly referred to as semi-synthetic penicillins, preferably on the acyl side chain at position 61, such as ampicillin and amoxicillin. The present invention relates to a method for producing a group of antibacterial agents characterized by an α-amino group.

[Conventional technology]

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.
(See No. 2985648).

Amoxicillin is also an antibacterial agent used in human therapy and is commercially available as the trihydrate of the free acid (i.e., zwitterion). However, for example, J.Chem.Soc (London) 1920-1922
p. 1971, "Fungicides and Chemotherapy - 1970" 407
~430 (1971), U.S. Pat. No. 3,674,776 (see also U.S. Pat. No. 3,192,198).
Its chemical name is 6-[D-α-amino-α-(p-hydroxyphenyl)acetamido]penicillanic acid.

The use of amino acid chloride hydrochloride to make the above penicillins has been demonstrated in patent documents such as British Patent No. 938327 and British Patent No. 959853 under anhydrous conditions.
(the latter being disclosed in British Patent No.
1008468 and U.S. Pat. No. 3,249,622 (utilizing protection by the silyl group during acylation of the carboxyl group of 6-aminopenicillanic acid), and in cold aqueous acetone as disclosed in British Patent No.
It is disclosed in No. 962719. These penicillins are amphoteric amino acids, so their isolation involves certain aliphatic asymmetric side chains (as disclosed, for example, in U.S. Pat. No. 3,157,640, U.S. Pat. No. 3,271,389). amines (often referred to as liquid amine resins), which have previously been used to isolate the amphoteric amino acid 6-aminopenicillanic acid (see US 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 U.S. Pat. No. 3,198,804, which involves isolation of intermediates and easy hydrolysis of hetacillin. It is revealed in the issue.

The use of silyl groups for protection of the carboxyl groups of natural penicillins 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 reported in numerous patents such as U.S. Pat.
3479018, U.S. Patent No. 3595855, U.S. Patent No.
3654266, U.S. Patent No. 3479338, U.S. Patent No.
This is disclosed in No. 3487073. Some of these patents also disclose the use of liquid amine resins. U.S. Patent No. 3912719, No. 3980637, No.
See also issue 4128547.

British Patent No. 1339605 discloses a silylated derivative of 6-aminopenicillanic acid and a reactive derivative of D-(-)-α-amino-p-hydroxyphenylacetic acid with a protected amino group (chloride hydrochloride). various specific details of the preparation of amoxicillin by reacting the silyl group with the silyl group (containing ), followed by removal of the silyl group by hydrolysis or alcoholysis, and subsequent recovery of the amoxicillin, usually as a crystalline trihydrate, if possible. Contains examples. Thus, in Example 1, crystalline amoxicillin was obtained from an aqueous solution by isoelectric precipitation at, for example, pH 4.7. Perhaps in this example, the crude product (before isoelectric precipitation)
Water with an acidic pH like 1.0 (e.g. hydrochloric acid solution)
Purification was carried out by dissolving in the presence of a water-immiscible organic solvent such as methyl isobutyl ketone (4-methylpentan-2-one). The same procedure was used in US Pat. No. 3,674,776.

A search of Volumes 58 to 87 of the Chemical Abstracts Formulation Index revealed that the compound of general formula () was not indexed.

Siloxycarbonylamino derivatives are indexed as N-carboxy derivatives of compounds such as silanols, carbamic acids, and trimethylsilyl esters.

However, the following paper seems to be of some interest.

(1) Breederherdt, H., Interaction of dialkylaminosilanes and carbon dioxide. New reactions in organosilicon chemistry. Recueil, vol. 79, p. 1126 (1960
Year).

(2) Club, RH, Rapert, MF, amino derivatives of metals and metalloids. Aminosilylation and phosphination of some unsaturated substrates. J.
Chem.Soc.(A), pp. 82-85 (1966).

(3) Production of Kricheldorf, HR, N-silyloxycarbonyl amino acid derivatives.
Synthesis, pp. 259-60 (1970), CA, vol. 73,
45820r (1970).

(4) Production of amino acid N-carboxy anhydrides (NCAs) from Kricheldorf, HR, N-silyloxycarbonylamino acid trimethylsilyl ester. Chem.Ber., vol. 104, 87-91
Page (1971), CA, vol. 74, 54156b (1971).

(5) Mironov, VF, Kozyukov, VP, Kirillin, AD, et al. Synthesis and reaction of silyl carbamate. A new method for producing organic isocyanates that does not use phosgene. Zh.Obshch Khim, 45 volumes, 1971
~73 pages, (1975).

(6) Sierdeyakov, VD, Kirillin, AD,
Mironov, VF, a new manufacturing method for (carbamoyloxy)silane. Zh.Obshch Khim, vol. 45, 471
Page (1975).

(7) Mironov, VF, Sierdeiakov, VD,
Siloxycarbonylation of Kirillin, AD, and amines. Zh. Obshch Khim, vol. 46, pp. 2297-98 (1976).

(8) Falbenfabriken Bayer A-G
(Ester. G. et al.) Organosilicon compounds. Chem.
Abs., Vol. 60, 6868b (German Published Patent No. 1157226).

[Contents of the invention]

The following structural formula in an anhydrous inert organic solvent, preferably in methylene chloride, in the presence of a weak base, preferably dimethylaniline, preferably at a temperature above -10°C, more preferably in the range -8 to 20°C. in,
D-(-)-α-aminoarylacetyl chloride hydrochloride, preferably each D-(-)
-2-phenylglycyl chloride hydrochloride or D
-(-)-2-A 6-α-aminoarylacetamide formed by reacting with approximately equimolar weights of p-hydroxyphenylglycyl chloride hydrochloride, preferably adding the latter in portions to a solution of the former. A method for producing penicillanic acid, preferably ampicillin or amoxicillin, is provided by the present invention.

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. The advantage of this stability is that
This allows the acylation reaction to be carried out at temperatures much higher than those normally used for ampicillin production (we used room temperature), which are usually below 0°C, typically about -10°C.

When this method is used to produce ampicillin, ampicillin anhydride, ampicillin trihydrate, amoxicillin, amoxicillin trihydrate, U.S. Pat.
3912719, 3980637, 4128547 and other patents and publications cited therein, the final product can be isolated, Refined.

〔Example〕

Reference example 1 6-aminopenicillanic acid (6-APA) and
_{10ml CO2Cl2} and 1.13ml trimethylchlorosilane
1.23 ml of triethylamine was added dropwise to the mixture 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) following structure Silylated carboxy 6-APA (SCA) with 60
I found out the existence of %.

Example 1 The mixture prepared in Reference Example 1 was kept in the refrigerator overnight. The next day 0.77 ml of N,N-dimethylaniline was added and the mixture was cooled to -8°C. Then, 1.2 g of D-(-)-p-hydroxy-2-phenylglycyl chloride hydrochloride (79% purity) was added in the following proportions.

Time (min) Temperature (℃) Addition (g) 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 +8 220 +15 310 +20 At the end of the 310 minute reaction, ethyl acetate 60%, acetic acid
Thin layer chromatography (TLC) performed on a sample of the reaction mixture using a solvent system of 20% and 20% water showed the presence of amoxicillin.

1.0 ml of D ₂ O was added to a 2 ml cold sample of the final reaction mixture. After separation by centrifugation, the aqueous phase was found by NMR to contain 78% amoxicillin and approximately 20% 6-APA. TLC for the presence of amoxicillin
It was also confirmed by.

Reference example 2 5.4 g of 6-aminopenicillanic acid in 40 ml of CH ₂ Cl ₂
(0.025 mol) and 93% hexamethyldisilazane
A mixture of 6.2 ml (HMDS, 0.0275 moles) and 0.07 g (about 0.001 moles) of imidazole was refluxed for about 17.5 hours under a nitrogen purge. At the end of this time, 0.13 ml of trimethylchlorosilane (TMCS) (approximately 0.001
mol) was added. The solution became cloudy. Refluxing was continued for an additional 7 hours, and NH ₄ Cl was observed to be deposited in the condenser.
At this point, NMR showed approximately 100% silylation of both the amino and carboxyl groups of 6-APA. Then add 0.2 ml of HMDS (0.00125 mol, about 5 mol%) and
0.06 ml (approximately 0.0005 mol) of TMCS was added and reflux was continued for an additional 17 hours with a nitrogen purge. At this time,
The NMR spectrum was the same before addition of small amounts of HMDS and TMCS. Dry carbon dioxide was then bubbled into the reaction mixture for 75 min at room temperature, followed by NMR analysis.
No HMDS was present, showing >92% silylated carboxy 6-APA (SCA).

Example 2 4.45 ml (0.035 mol) of N,N-dimethylaniline (DMA) was added to the solution prepared in Reference Example 2, and the mixture was cooled to -3°C. Then D- at the following rate
5.65 g (-)-2-phenylglycyl chloride (95% purity, 0.026 mol) was added.

Time (minutes) Temperature (°C) Addition (g) 0 -3 1.05 20 0 1.30 40 0 1.30 50 0 1.00 60 0 1.00 The reaction was followed by NMR, and showed almost no change approximately 5 hours after the start of the reaction. The temperature was 3°C. The reaction mixture was then kept on ice for the next 16 hours. It is then removed from refrigeration and brought to room temperature (approx.
℃) for 3.5 hours. A large amount of solid material was still present. The reaction mixture was then brought to room temperature (22-24
℃) for approximately 63 hours. At the end of this time,
It was slightly cloudy. Extract the sample with _D2O ,
NMR showed ampicillin and 6-APA.

The reaction mixture was cooled to about 0° C. and stirred for 5 minutes while cold after addition of 35 ml of ice water. After polish filtration, the mixture was washed with cold water and CH ₂ Cl ₂ . After separation, the aqueous phase is
TLC showed a large band slower than ampicillin and 6-APA, indicating that the new intermediate X
It represents. The aqueous phase was adjusted to PH 3.0 with NH ₄ OH and seeded with ampicillin. Methyl isobutyl ketone (MIBK, 35 ml) was added, the mixture was stirred and the pH was adjusted to 5.2 with NH ₄ OH, stirred for 1 hour at 20°C, further stirred for 1 hour in an ice bath and refrigerated overnight. The ampicillin precipitate was collected by filtration, washed first with 25 ml of cold water, 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 50°C, and yielded 4.5 g of ampicillin, identified by TLC. I found out what I got.

Reference example 3 5.4 g of 6-APA in 50 ml of CH ₂ Cl ₂ , HMDS (93
%) and 0.06 g of imidazole was refluxed for 18 hours under nitrogen purge. Then add 0.1ml of TMCS. Turbidity arose. The mixture was refluxed for an additional 2 hours to obtain a clear solution, and NH ₄ Cl was deposited on the condenser. Then, 0.1 ml of TMCS was 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 was begun. After 75 minutes, NMR showed >90% bis-silylated carbamate (SCA) formation.

Example 3 Add 4.45ml of DMA to the solution prepared in Reference Example 3,
5.6 g of D-(-)-2-phenylglycyl chloride hydrochloride (purity 97%) was added in the following proportions.

Time (min) Temperature (°C) Addition (g) 0 20 1.35 20 20 1.30 32 20 1.00 48 20 1.00 75 20 1.00 After stirring this mixture for a further 17 hours, the reaction mixture sample and the diluted reaction mixture (CH ₂ Cl _{2 2} ml TLC was performed on 1 ml of the reaction mixture diluted with
Each showed a small band of ampicillin and a large band of new intermediate X.

The reaction mixture was then cooled to 0°C, 40 ml of ice water was added, the mixture was stirred for 5 minutes, filtered through a polisher,
Washed _with water and _CH2Cl2 . Separate the aqueous phase and 10%
was removed as a sample, and the remainder was adjusted to pH 3.0 with NH ₄ OH, and ampicillin seeds were added and stirred. After adding 40ml of MIBK, stir the mixture.
The pH was adjusted to 5.2 with NH ₄ OH and stirred at room temperature for 1 hour and in an ice bath for an additional hour. Crystals precipitated. After overnight refrigeration, the crystalline product was collected by filtration, washed sequentially with 40 ml of MIBK, water, MIBK, isopropanol-water (85:15), and dried at 45°C to yield 6.25 g of ampicillin. (6.8 corrected for sample use)
g, 68% yield).

Reference example 4 1.0g of 6-APA in 10ml of CD ₂ Cl ₂ and
1.23 ml of TEA was added dropwise to the 1.13 ml TMCS mixture over 30 minutes and the mixture was stirred for an additional 2 hours. Dry carbon dioxide was then bubbled in for 4 hours. At this time NMR showed about 55-60% carboxysilylation.

Example 4 The mixture prepared in Reference Example 4 was refrigerated overnight. morning
Add 0.77 ml of DMA, stir the mixture, cool to -8°C and add D-(-)-p-hydroxy-2 in the following proportions.
- 1.2 g of phenylglycyl chloride hydrochloride was added.

Time (min) Temperature (℃) Addition (g) 0 -8 0.30 20 -4 0.30 40 -4 0.30 60 -4 0.30 120 8 220 15 310 20 3 At the end of 310 minutes, NMR of amoxicillin approx.
% and 6-APA about 20%.

Reference example 5 Dry 6-aminopenicillanic acid (10.0g, 46.24
mmol, 1.0 eq) in anhydrous methylene chloride (175
ml) at 25°C. Triethylamine (10.76 g, 106.36 mmol, 2.30 equivalents) at 25°C
and then add trimethylchlorosilane (11.70 g, 107.75 mmol,
2.33 eq.) was added over 10-15 minutes. After stirring for 20-30 minutes, the mixture containing precipitated triethyl hydrochloride was analyzed by 80MHz NMR for complete silylation. Carbon dioxide gas was then passed through the mixture at 20° C. for about 2 hours, and complete carboxylation was analyzed by 80 MHz NMR. Sometimes it was necessary to introduce additional carbon dioxide gas. If necessary, the volume of the carboxylation mixture was readjusted to approximately 175 ml with dry methylene chloride.

Example 5 After completing the carboxylation of the solution prepared in Reference Example 5, the slurry was diluted with propylene oxide (2.95
g, 3.56 ml, 50.87 mmol, 1.1 eq),
Cooled to 0-5°C. D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride hemidioxane solvate was added at about 2°C in 5 x 2.71 g portions [total 13.54 g (50.87 mmol, 1.1 eq.) ]. Each portion of the acid chloride was allowed to dissolve ^*) before adding the next portion. This is approximately per portion
It took 20 minutes. This stepwise addition was of significant importance. The final acylation mixture was checked for undissolved acid chloride hydrochloride. The mixture was kept at 0-5 °C for 30 min and then diluted with cold (0-5 °C) deionized (DI) water (100 ml).
The mixture was stirred at high speed for 10 minutes and processed. The mixture was separated and the lower layer of methylene chloride was removed. Polish filter the aqueous mixture through a thin (guicharite) precoat of diatomaceous earth (almost no solids)
The cake was then washed with cold (0-5°C) DI water (15ml). The underlying organic layer was removed before crystallization. A clear pale yellow aqueous solution (PH 2-2.5) was adjusted to PH 3.5 at 0-5°C, and seeds were added if necessary. This slurry is 0
It was kept at ~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 washed with a cold (0-5°C) 1:1 isopropanol/water mixture and caked with methylene chloride (30 ml) to give about 13.5 g of snow-white amoxicillin trihydrate.
(approximately 70%).

* Stop stirring and examine the mixture for solids at the bottom of the flask. The slurry must not be heated above 5°C in this test or the results will be erroneous.

The present invention can be applied industrially.

Reference Example 6 108 g (0.5 mol) of 6-aminopenicillanic acid, 1.0 g (0.017 mol) of imidazole, 800 ml of dry methylene chloride, and 120 ml (0.56 mol) of HMDS (approximately 98% purity) were stirred and heated under reflux for 3.3 hours. The reaction was purged with dry nitrogen gas at reflux to sweep away the NH ₃ produced in the reaction. Then 2.0 ml (0.016 mol) of trimethylchlorosilane (TMCS) was added. Refluxing was continued for an additional 19 hours while purging with N ₂ , then the sublimed NH ₄ Cl was removed in a condenser, and 2.6 ml (0.0206 mol) of TMCS was added to the reaction. Refluxing was continued for an additional 34 hours while purging with _N2 . Bring up the reaction mixture volume with dry methylene chloride.
The volume was set to 1000ml. Next, NMR detected 100% of the amino and carboxyl groups of 6-aminopenicillanic acid.
showed the silylation of This solution was blanketed with _N2 gas,
I kept it 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 revealed that bistrimethylsilyl 6-aminopenicillanic acid was 100% converted to bistrimethylsilylcarboxy 6-aminopenicillanic acid (SCA).

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

NMR is bistrimethylsilylcarboxy 6-
Aminopenicillanic acid was shown to be stable after 9 days.

Example 6 100 ml of the master mixture prepared in Reference Example 6 (6
- SCA equivalent to 10.8 g of aminopenicillanic acid, 0.05
mol) at 22℃, TEA・HCl8.0g
(0.058 mol) and 4.2 ml (0.06 mol) of propylene oxide (see US Pat. No. 3,741,959). Some TEA·HCl precipitated. Stir the mixture;
Cooled to +3°C. 15.5 g (79% purity, 0.055 mol) of D-(-)-p-hydroxyphenylglycyl chloride hydrochloride hemidioxane solvate in the following proportions:
was added to the reaction.

Addition (g) Time (min) Temperature (°C) 3.0 0 +3 3.0 7 +2 3.0 20 +2 6.5 35 +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 and D ₂ O1.0
Added to ml. After centrifugation, NMR analysis of the aqueous phase showed approximately 6% unacylated 6-aminopenicillanic acid.

After 10 minutes, transfer the reaction mixture to a 600 ml beaker and
The transfer was completed by washing with 50 ml of methylene chloride. 60 ml of cold deionized ice water while stirring in an ice bath.
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 this two-phase system, and the seeds were added at pH 2.0.
Crystallization has begun. Furthermore, 10.0 ml of LA-1 was gradually added over about 5 minutes. The pH was 3.0.
Then 0.15 g of NaBH ₄ was added. Then LA-1
Added 5.0ml. The pH was 4.5. Continue stirring and add NaHSO ₃ (sodium bisulfite) in 4.0 ml of water.
1.0 g was added dropwise. Then, 10.0 ml of LA-1 was added. PH continued to rise. Total LA-1 40ml,
The final pH was 5.6. Then 5 ml of acetone was added. At this point 1.5 g of NaHSO ₃ dissolved in 6.0 ml of water
was added over 30 minutes. Stirring was continued in the ice bath. The precipitated product was collected by filtration and the cake was washed sequentially with 50 ml of methylene chloride, 40 ml of water, 100 ml of isopropyl alcohol-water (80:20), and 100 ml of methylene chloride. The cake was then dried at normal pressure at 45°C to obtain 18.2 g of amoxicillin trihydrate, an 87% yield based on 6-aminopenicillanic acid, and a total yield corrected for 1% sampling. The rate was approximately 88%.

In LA-1 liquid anion exchange resin, each secondary amine has the following structural formula: (However, each of R ¹ , R ² , R ³ is an aliphatic hydrocarbon group, and R ¹ , R ² , R ³ as a whole contains 11 to 14 carbon atoms.) It is a mixture of amines. Sometimes “Liquid Amine Mixture No.
This particular mixture of secondary amines, designated ``1'', is a clear amber liquid with the following physical properties: Viscosity at 25℃ 70cps, specific gravity at 20℃ 0.845, refractive index at 25℃ 1.467, distillation range at 10mm, up to 160℃ 4
%, 160-210℃ 5%, 210-220℃ 74%, 220℃ or higher 17%.

The present invention can of course be applied industrially.

(Effects of the Invention) As is clear from the above examples, this acylation reaction is usually achieved with a yield of 85% or more, and since the reaction is not exothermic, it can be carried out in a factory without the need for a special cooling device. It can be applied in

Moreover, bistrimethylsilylcarboxy-6-aminopenicillanic acid used as a raw material in this acylation is stable and can be stored for a long period of time after being prepared in an anhydrous solvent, so that this acylation can be widely applied. Furthermore, it is noteworthy that the acylation solution is stable over a long period of time without causing any decomposition of the penicillin produced, so that the acylation reaction can be carried out at much higher temperatures than in conventional methods.

Claims (1)

[Claims] First-order structural formula D-α-aminoarylacetyl chloride hydrochloride having the structural formula in approximately equimolar amounts in an anhydrous inert organic solvent. (In the structural formula, Ar represents an aryl group.) A method for producing 6-α-aminoarylacetamidopenicillanic acid, which comprises reacting with 6-α-aminoarylacetamidopenicillanic acid. 2. The manufacturing method according to claim 1, wherein the reaction temperature is -10°C or higher. 3. The production method according to claim 2, wherein the reaction is carried out in the presence of a weak base. 4. The manufacturing method according to claim 1, wherein the reaction is carried out in anhydrous methylene chloride in the presence of dimethylaniline at a temperature of -10°C or higher. 5. The method according to claim 1, wherein the compound of structural formula is added little by little to a solution of structural formula in anhydrous methylene chloride in the presence of dimethylaniline at a temperature in the range of 0 to 20°C. 6. The method for producing amoxicillin according to any one of claims 1 to 5, wherein Ar is p-hydroxyphenyl. 7 Claim 1 in which Ar is a phenyl group
The method for producing ampicillin according to any one of Items 5 to 5.