JPS6124595A - Manufacture of ester compound of alpha-aminobenzylpenicillin - 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 present invention relates to a method for producing an ester compound of α-aminobenzylpenicillin having the structural formula (1), which is a penicillin derivative.

Hz The compound of structural formula (I), which is the object of the present invention, is a known compound that maintains a higher blood concentration than ampicillin when administered orally, and therefore has a strong effect on Gram-positive and Gram-negative bacteria. It is a compound that exhibits extremely effective antibacterial activity.

The method for producing the compound of the above structural formula (1) is described in U.S. Patent Nos. 3.873.521 and 3,939,270
British Patent No. 1,363,506, Belgian Patent No. 77
No. 2.723, French Patent No. 2.106,578,
It is described in Swiss Patent No. 577.513 and the like. These methods can be roughly divided into two.

The first method involves producing an ester compound by reacting the sodium salt of 6-[α-)-α-azidophenylacetamide] penicillanic acid with α-chlorodiethyl carbonate, and then converting the azide group into an ester compound under a palladium catalyst. The second method is to react penicillin G potassium salt and α-chlorodiethyl carbonate in water and an organic solvent/medium for a long time to obtain the target compound. This was then deacylated to obtain ]-ethoxycarbonyloxy-ethyl-6-aminopenicillanate, which was reacted with D(-)-α-aminophenyl acetyl chloride hydrochloride to form the above structural formula (I). It is a method of manufacturing a compound.

However, among these production methods, if the first method is used, the production cost increases because expensive and unstable α-azidophenyl aceto acids must be used, and after producing the ester compound, the azide When hydrogenating groups, it is not only uneconomical because an expensive palladium catalyst must be used, but also the yield of the reaction is quite low. In addition, if the second method is used, it will take a long time for the reaction to esterify penicillin G-potassium salt, and a mixed solvent of water and an organic solvent will be used. α−
Since the chlorodiethyl carbonate was decomposed, the reaction yield would be low.

Therefore, an object of the present invention is to produce a target compound in high yield by a simple method that eliminates the disadvantages of the conventional methods.

That is, the feature of the present invention is to react the known compound ampicillin (II) with the known compound alkyl acetoacetate in the presence of an inorganic base in an organic solvent.
Known inorganic salts of ampicillin with protected amino groups α)
and without separating it, in an organic solvent,
Phase Transfer Catalyst
alyst), completes the reaction with α-chlorodiethyl carbonate (b) within a short time to prevent decomposition of the β-lactam ring, amino group protecting group, α-chlorodiethyl carbonate, etc. Therefore, the ester compound (
Vl), which is then hydrolyzed to give 11-ethoxy-carbonyloxy-ethyl-6-(D
←) -α-Aminophenylacetamide] penicillanate hydrochloride is produced.

C13-CH-0-C-0-CzH5(V)Hz M represents an alkali metal. ) The phase transfer catalyst used in the present invention can be used to perform reactions that were previously impossible in the field of organic synthesis, as well as reactions between organic compounds and inorganic reagents that were possible but had extremely poor yields. For example, it is a catalyst suitable for use in the oxidation of alkenes with potassium permanganate, the alkylation reaction of carbonyl compounds with alkylno-lides, etc. By using this catalyst, the target compound can be obtained in high yield. .

That is, the phase transfer catalyst reacts with an inorganic reagent that is difficult to dissolve in an organic solvent to form a salt that is soluble in the organic solvent, thereby allowing the inorganic reagent to react effectively in the organic solvent. In the present invention, the phase transfer catalyst acts to increase the solubility of the reactant in the organic solvent by reacting with the inorganic salt of ampicillin in which the amine group is protected. The inorganic metal cation that has a strong ionic bond with the ampicillin anion is substituted with the cation of the phase transfer catalyst, weakening the bonding force of that ion, thereby facilitating the desired substitution reaction. do.

The phase transfer catalyst that can be used in the present invention includes:
These include quaternary ammonium halides, quaternary ammonium hydrogen sulfates, crown ethers, cryptands, and the like.

Of course, compounds having the structural formula can be produced by known methods in addition to the production method of the present invention.

That is, a salt of α-aminophenyl acetoic acid is reacted with a total β-dicarbonyl compound to produce a dine salt with a protected amine group (Dane 5olt), and this is converted into a reaction derivative with an activated carboxyl group. It is produced by reacting with a salt of 6-aminopenicillanic acid (Che
Ampicillin can also be produced by making an ampicillin salt and then reacting it with a β-dicarbonyl compound (Ch.
em, PharM', Bull, 29 (
7), 1986 (198D)).

Organic solvents that can be used in the present invention include chloroform, aliphatic hydrocarbons such as methylene chloride, alcohols having 1 to 10 carbon atoms, acetonitrile, N,N-dimethylbormamide, N , N-dimethylacetamide.

'Aprotic polar solvents such as dimethyl sulfoxide and hexamethylphosphoramide, or mixed solvents thereof.

The following examples will specifically explain the present invention.

Example 1: Preparation of potassium salt of 6-[D(=)-α-(1-methyl-2-methoxycarbonyl)-vinylaminophenyl acetamide] penicillanic acid 6-[α-aminophenyl acetamide] ] Penicillanic acid 17.5ft (0,
0.05 mol), 2.8 g (0.05 mol) of potassium hydroxide, and 5.6 rd (0.052 mol) of methyl acetoacetate were added and stirred at room temperature for 4 hours. The solvent was distilled under reduced pressure to form an oily residue. 22.6 # (yield 93 #) is obtained.

1. I knew that R, N, M, and R were the same as standard products.

Example 2: Preparation of 6-(D(-)-α-(Vmethyl-2-methoxycarbonyl)-vinylaminophenylacetamide) penicillanic acid sodium salt: Preparation of Improvil alcohol 100!Ll! and dimethyl sulfoxide 50.d 6-(D(-)-α-
Aminophenylacetamide] penicillanic acid 17.5
# (0.05 mol), sodium carbonate 5.3 no (0,
05 mol), methyl acetoacetate 5.6 d (0.05 mol), methyl acetoacetate 5.6 d (0,05
2 mol) and stirred at room temperature for 4 hours.

The solvent was distilled under reduced pressure to leave an oily residue of 21.611 g (yield: 9
0chi) is obtained.

1. I knew that R, N, M, and R were the same as standard products.

Example 3: 11-ethoxycarbonyloxy-ethyl-6-(D
Preparation of (-)-α-aminophenyl acetamide peninranate hydrochloride: 6-CD(-)-α-(1-methyl-2-methoxycarbonyl) in 150 d of N,N-dimethylformamide cooled at 5°C. -Vinylaminophenylacetamide]
Add 22.5 g (0.05 mol) of penicillanic acid potassium salt and 8.4 f of α-nichlorodiethyl carbonate.
(0,055 mol) and 0.6 f (0,0018 mol) of tetra-n-butylammonium bromide were added, and the mixture was allowed to react at room temperature for 4 hours.

After the reaction is completed, add mild hydrochloric acid at 5℃ to adjust the pH to 2.
, 0 and stir for (9) minutes.

After distilling the reaction solution under reduced pressure to obtain an oily residue, add 100 g of water to dissolve it, wash impurities three times with 80 g of ethyl acetate, and chloride.) Add IJium to make a saturated solution. Afterwards, it is extracted twice with 100 d of methylene chloride.

After the Glauber's salt treatment, the solvent was removed through vacuum distillation, normal hexane was added and stirred, and the white powder crystals produced were filtered and dried.I
I-c) oxycarbonylxy-ethyl-6-[D(-)
19 g (yield: 76%) of -α-aminophenylacetamide] Benicilla, *-to hydrochloride was obtained.

m, P,: 171-176°C (decomposition) [α) f:
+161.5 (C=1, chloroporum)・K
Br t ■, R0Vmaxcm- 1780 (β-lactam carbonyl) 1750 (ester carbonyl) Example 4: The same method as Example 3 was carried out except for the following points.

Acetoni+1 instead of N,N-dimethylformamide
was used as the solvent and 18-crown-6 was used instead of tetra-n-butylammonium bromide as the phase transfer catalyst. 17.5 # of target compounds (yield: 70%) were obtained.

Example 5: 11-ethoxycarbonyloxy-ethyl-6-CD (
-)-α-Aminophenylacetamide] Preparation of penicillanate hydrochloride 160 units of dimethyl sulfoxide are added to 6-(D(-)-α-
Aminophenylacetamide] penicillanic acid 17.5
# (0,05 mol), potassium hydroxide 2,8 # (
0.05 mol), methylacetoacetate) 5.6 m
1 (0,052 mol) and stirred at room temperature for 4 hours. After removing unreacted methyl acetoacetate by distillation under reduced pressure, the reaction solution was cooled to 5°C, and 8.4 f (0,055 mol) of α-chlorodiethylcarboide and 0 of tetra-n-butylammonium bromide were added. .6
After adding f (0°0018 mol), the mixture was allowed to react at room temperature for 4 hours.

After the reaction is completed, add mild hydrochloric acid at 5℃ to adjust the pH to 2.
, 0, and stir for several minutes.

The reaction solution was distilled under reduced pressure to obtain an oily residue, to which 10% of water was added.
After washing impurities three times with 80 d of ethyl acetate, adding sodium chloride to make a saturated solution, the solution was extracted twice with 100 d of methylene chloride.

After the treatment with Glauber's salt, the solvent was removed by distillation under reduced pressure, normal hegysan was added, and after stirring, the white powder crystals formed were filtered and dried to give 11-ethoxycarbonyloxy-
Ethyl-6=CD(-”)-α-aminophenyl acetamide] penicillanate hydrochloride 15.8# (yield 63%
)was gotten.

m, P, , 1. I knew that R, N, M, and R were the same as standard products.

Example 6: It was carried out in the same manner as in Example 5 except for the following points.

As a phase transfer catalyst, 18-crown-6 was used in place of tetra-n-butyl-ammonium bromide. 14.3 # of target compounds (yield 57 #) were obtained.

Claims (2)

[Claims] (1) After adding alkyl acetoacetate of structural formula (III) to ampicillin of structural formula (II) to create a compound of structural formula (IV) with a protected amino group, the compound is aprotic without being separated. After reacting with α-chlorodiethyl carbonate of structural formula (V) in a polar solvent in the presence of a phase transfer catalyst to produce an ester compound of structural formula (VI), acid hydrolysis is performed by a known method. A method for producing an ester compound of α-aminobenzylpenicillin having the structural formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (In the above structural formula, R represents a methyl group or an ethyl group, and M represents an alkali metal. show.) (2) The method according to claim (1), wherein the compound of structural formula (IV) is prepared at room temperature by adding ampicillin, potassium hydroxide, and alkyl acetoacetate to an organic solvent.