JPS609756B2 - Method for producing phthalidyl ester of aminobenzylpenicillanic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing the hydrochloride of the phthalidyl ester of 6-[D(1)-Q-aminophenyl acetamido]benicillanic acid represented by the following formula:

Processes for producing phthalidyl esters of aminobenzylbenicilanic acid are known, for example as described in British Patent No. 13646.
No. 72, German Patent Publication No. 2228012, No. 236474, No. 236475, No. 24210
No. 30, No. 222514, etc.

In these known production methods, the esterification reaction is generally carried out after the amino group of the starting material is protected with an appropriate reactant. Specifically, it is protected with phenamine, reacted with benzaldehyde to protect it in the form of a Schiff base, or reacted with acetone in a basic medium to form hetacillin, and then esterified. There is. However, these methods generally have drawbacks such as extremely strict reaction conditions that are difficult to achieve, long reaction times, and the need to separate synthetic intermediates.

This increases the cost required for manufacturing, which increases the manufacturing cost. An object of the present invention is to overcome these drawbacks and provide a method for easily producing phthalidyl ester of aminobenzylbenicilanic acid. In the present invention, a new derivative of penicillin, the salt of methylene bis(Q-aminophenylacetamidobenicillanic acid) of the formula 2, is used as a starting material. Here, M represents an alkali metal Na+, K+ or an organic amine N'R3 (R is an alkyl group having 2 to 5 carbon atoms).

A compound of formula B is reacted with 3-furomophthalide of formula: to form a compound of structural formula W.

This can be hydrolyzed and recovered as a compound of formula 1', or
Alternatively, it is recovered in the form of the hydrochloride of formula 1. Formula 1' is represented by the following structural formula. To explain the present invention in more detail, first, ampicillin trihydrate is reacted with an organic salt in a halogenated hydrocarbon solvent to prepare a compound of formula (B).

Separately, Q-bromobenzyl chloroformate was subjected to a Friedel-Craftacylation reaction in the presence of a Lewis catalyst.
Alternatively, 3-furomophthalide of formula m is produced by a known method. A compound of formula D and a compound of formula m are reacted in an organic solvent in the presence of a catalyst to form a phthalidyl ester of formula W, and this ester is hydrolyzed with dilute hydrochloric acid in an acetonitrile solvent to form a compound of formula Obtain the hydrochloride of ester 1. Next, an example of producing a starting material and an example of producing a target product will be shown.

Example 1 Preparation of triethylamine salt of ethylene bis(Q-aminophenyl acetamidobenicillanic acid) 20.15 ml of ampicillin trihydrate (0.05 mol) was suspended in 200 methylene chloride, and 7 units of triethylamine (
0.05 mol) was added thereto, 15 mol of anhydrous potassium carbonate was added, and the mixture was reacted at room temperature for 1 hour.

After the reaction was completed, 2.5% of formalin aqueous solution (35%, 0.025 mol) was added to the reaction mixture, and an exothermic reaction occurred and the temperature of the reaction mixture increased.

After the reaction mixture was cooled to room temperature, it was heated to this temperature for an additional 1
The reaction was carried out for a certain period of time. The hydrated potassium carbonate was then removed by filtration. After that, the solvent is distilled off under reduced pressure. Adding petroleum ether to the obtained oily substance
After stirring for an hour, the target compound was obtained for 22 hours (yield 96.4%).
I got it. When this compound was analyzed, the elemental analysis values were S6.8% and N12.1%, and [Q] color. =
It was 1150 (1% methyl alcohol). Further, it was confirmed by iodometric analysis that the purity was 95% or more.
The infrared absorption spectrum (KBr) of this compound is shown in FIG.

Absorption band max = 2660 k-1 (amine salt), 17
Characteristic peaks such as 65 Hada-1 (6-lactam), 1670 Kay-1 (amide), and 1600 Hada-1 (carboxyl salt) all appeared. [B} Production of 3-bromophthalide Add 50 parts of carbon disulfide to 14.6 parts of anhydrous aluminum chloride (
0.11 mol) was added and the mixture was cooled and maintained at 5°C.

To this mixture with stirring was slowly added 25 g (0.1 mole) of Q-promo-penzyl chloroformate over about 30 minutes. During this time, aluminum chloride adhering to the reactor wall was peeled off and mixed into the reaction mixture. The temperature of the reaction mixture was raised to room temperature, refluxed for 1 hour, and then cooled again to 0-5°C. After adding 30 g of ice while stirring and adding 100 g of cold water, carbon disulfide was removed by steam distillation. After distilling off the solvent, 450 ml of carbon tetrachloride was added to perform heating extraction. The carbon tetrachloride extract was distilled off under reduced pressure, and the residue was recrystallized from petroleum ether to obtain the desired product 12 (yield 56.3%). Analysis of this compound revealed that the melting point was 79°C and the Br content was 3.
It was confirmed that the purity was 9.6% by halogen elemental analysis. This compound was analyzed by infrared absorption spectrum (KBr). Absorption band max=1790
( ), 1600, 1465 1340, 1300, 128
All characteristic peaks such as 0 and 1220 skin-1 appeared.

■ Methylenebis(Q-aminobenylacetamidobenicillanic acid) obtained from the production of phthalidyl ester of methylenebis(〇-aminophylacetamidobenicillanic acid)
22 hours of triethylamine salt was dissolved in 60 minutes of N.N-dimethylformamide, 5 hours of potassium carbonate was added thereto, and the solution was cooled to 0-500 degrees.

To this solution was added 10.7 g of 3-bromophthalide obtained from the base, and the mixture was allowed to react at room temperature for more than 2 hours.

After the reaction was complete, the reaction mixture was dispersed in one glass of cold water and extracted twice with 200 g of methylene chloride (each time). This methylene chloride extract was distilled under reduced pressure to remove methylene chloride. The remaining oily substance was dispersed in cold water and then dried in an oven to obtain the desired product (yield: 82%). When this compound was analyzed, the elemental analysis values were S6.3% and N8.5%, and [Q] color.

: +45.6 (1% methyl alcohol). It was confirmed that the purity was 95% or more using the iodine satisfactorily analytical method. The infrared absorption spectrum (KBr) of this compound is
As shown in the figure.

Absorption band max = 1780 (8-lactam, lactone, ester), 1685 (amide), 1500, 129
Peaks such as 0, 1155, 980, 755, and 703 skin-1 all appeared. In NMR, 6 = 4.3 (-NH-CH2-NH), 1.3-1.7 (-CH3), 5.5
All the signals in () appeared.

Blood 6-Production of hydrochloride of phthalidyl ester of [D(1)-1Q-aminophenyl acetamide]benicillanic acid'
20 parts of the phthalidyl ester of methylene bis(Q-aminophenylacetamidobenicillanic acid) obtained in step C} was dissolved in 40 parts of acetonitrile, and 6 parts of 15% hydrochloric acid was added and stirred at room temperature for 3 minutes. .

The concentrate obtained by distillation under reduced pressure was suspended in 200 ml of water,
Substances that were not hydrolyzed were dissolved and separated by adding 100 g of ethyl acetate.

The aqueous phase was foamed with sodium chloride and the separated oily phase was extracted twice with 200 g of methylene chloride (each time). The separated methylene chloride phase was dehydrated with anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and then Zenal was added for crystallization. After filtration, the crystals were washed with ether, dried,
The target product 14 (yield 65.8%) was obtained. Four days of hydrolyzed material was recovered from the ethyl acetate phase. When this recovered amount is converted and added, the corrected yield of the target product is 82%. The product is a nearly white crystalline powder with a melting point of 156~
158℃, elemental analysis values S6.0% and CI6.5%
and [Q] Ministry 0 = 1154 (1% methyl alcohol).

Chemical analysis showed 105-110%, purity by iodometric titration was 92-94%. The infrared absorption spectrum (KBr) of this compound is shown in FIG. Absorption band max=1
778 (8-lactam, lactone, ester), 163
2 (amide), 150 stop 128 fu 1149 97 & 7
All characteristic peaks such as 52 and 697 skin-1 appeared.

[Brief explanation of the drawing]

Figure 1 shows the IR of the triethylamine salt of methylenebis(Q-aminophenylacetamidobenicillanic acid) obtained in A.
Figure 2 shows the IR spectrum of the phthalidyl ester of methylenebis(Q-aminophenyl acetamidobenicillanic acid) obtained in step C, and Figure 3 shows the IR spectrum of the phthalidyl ester of methylene bis(Q-aminophenyl acetamidobenicillanic acid) obtained in step D. FIG. 2 is an IR spectrum diagram of the hydrochloride of benicillanic acid phthalidyl ester (Q-aminophenyl acetamide). Hata/Okamaku 2 town dormitory 3 laps

Claims (1)

[Claims] Primary formula: ▲ Numerical formulas, chemical formulas, tables, etc. ▼ , the following formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (M in the formula is an alkali metal Na^+, K^+ or an organic amine H^+NR_3 (R is an alkyl group having 2 to 5 carbon atoms) methylene bis (α-
A salt of aminophenylacetamidopenicillanic acid) is reacted with 3-bromophthalide represented by the following formula: ▲Mathematical formula, chemical formula, table, etc.▼ to form the following formula: ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ Forms the phthalidyl ester of methylene bis (α-aminophenyl acetamidopenicillanic acid),
A method for producing a hydrochloride of phthalidyl ester of 6-[D(-)-α-aminophenyl acetamide] penicillanic acid, which comprises hydrolyzing the same and recovering the compound of formula I in the form of a hydrochloride. .