JPS6015636B2 - Production method of heterocyclic carboxylic acid ester - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a polycyclic carboxylic acid ester.

More specifically, the present invention relates to penicillin-1-oxide or a salt thereof represented by the general formula (wherein A means an acylamine/group), which is represented by the following formula (wherein each symbol has the same meaning as above): The present invention relates to a method for producing a heterocyclic carboxylic acid ester, which is characterized by obtaining 1-oxide of a penicillin ester.

Unless the ester form of penicillin is used as a medicine itself, deesterification is always carried out at an appropriate stage after carrying out the necessary chemical reaction and forming the penicillin or cephalosporin derivative.

Since the deesterification must be carried out mildly under conditions that do not cause splitting of the 8-lactam ring, the types of ester groups are extremely limited. In particular, in the case of cephalosporin esters after ring conversion from penicillin esters, the deesterification conditions involve movement of double bonds, so in order to obtain △3, which is useful as an antibiotic, the deesterification reaction must be completed to the utmost. I've been under a lot of restrictions. The inventor of this invention ``Considered such a deesterification reaction, discovered a new ester group suitable for carrying out the desired reaction and deesterification reaction, and which was industrially valuable, and created this invention. As the acylamido group at the 6-position of the penicillin-1-oxide of the general formula (1), any group can be used.

For example, ~phenylacetamide group ~ phenoxyacetamide group "Acetamide group, propionamide group ~ penzoylamino group, phthalic group [wherein the father is a halogen atom, RI is a lower alkyl group ~ or phenyl group ~ R2 is a lower alkoxycarbonyl group, Lower alkylcarbonyl group or formula -C
A halogen compound represented by the following formula is reacted: ON Examples include the imido group, the 2-trichloroethoxycarbonylamino group, and the benzyloxycarbonylamino group, but from industrial knowledge, the phenylacetamide group and phenoxyacetamide group are preferable.

Salts of penicillin 1-oxide of general formula (X) include potassium salt, sodium salt, triethylamine salt, etc.
Cyclohexylamine salt "Dicyclohexylamine salt"
Examples of N-methyl-morpholine salts include morpholine salt, piberidine salt, tN-ethylpiveridine salt, N-methylpiberidine salt, etc., but usually potassium salt and sodium salt are preferable. As preferred specific examples of 3-promo204-bentanedione, Q-bromo-Q-benzoylacetate, 1-bromo-1-benzoylacetone, -bromoacetoacetic acid methyl, -bromoacetoacetate, Q-bromoacetoacetate, Q-bromoacetoacetate, Examples include acetic acid N·N-dimethylamide, bromoacetoacetic acid N·N-diethylamide, Q-bromoacetoacetic acid N·N-dipropylamide, tN-(Q-bromoacetoacetyl)morpholine, and their chlorides.

The esterification reaction of the present invention is usually carried out by reacting penicillin-1-oxide of general formula (m) or a salt thereof with a halogen compound of general formula (m) using an inert solvent.

When using the penicillin itself of the general formula (0), prepare in advance a strongly basic tertiary organic salt such as triethylamine, tribupylamine, trialkylamine such as diethylbenzylamine, dimethylbenzylamine, or dialkylaralkylamine. It is preferable to add an N-alkyl conversion heterocyclic base such as N-methylmorpholine, N-ethylmorpholine, or N-methylpiveridine to the reaction system and react penicillin in the form of a salt.The inert solvent used is Methanol/Ethanol, Butanol, Methyl Cellsolve, Ethyl Cellsolve, Acetone, Methyl Ethyl Ketone, Methyl Isopropyl Ketone, Methyl Propyl Ketone, Methyl Isoptyl Ketone, Acetonitrile, Dimethyl Formamide, Dimethyl Acetamide, Dimethyl Sulfoxide, Tetrahydrofuran, Dioxane, Methylene Chloride, Chloroform, Carbon chloride, ethylene chloride, trichlorethylene, trichloroethane, propylene chloride, ethylene glycol dimethyl ether, methyl acetate,
Examples include ethyl acetate, propyl acetate, butyl acetate, etc. Among these, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, methyl isobutyl ketone, methyl isopropyl ketone, methyl ethyl ketone, methylene chloride - trichloroethylene, ethylene chloride. etc. are preferred examples.

The reaction is carried out at 0-100°C, usually 10-60°C.

The reaction time varies depending on the reaction temperature, type of solvent, type of halogen in the compound of general formula (melon), etc. When a chlorine compound is used as the halogen in the halogen compound (air), the reaction can be accelerated by adding a catalytic amount of sodium iodide or potassium iodide to the reaction system, if necessary. The progress of the reaction can be tracked by TLC (thin layer chromatography) (e.g., developed with benzene:ethyl acetate=2:1 and colored with azide iodide). After the reaction is completed, the solvent is removed from the reaction solution if necessary, ice water is added to the residue, and the product is extracted with the solvent. Extraction solvents include methyl acetate, ethyl acetate, butyl acetate, methylene chloride, chloroform, ethylene chloride, benzene, toluene, xylene, ethyl ether, isopropyl ether, isobutyl ether, methyl isobutyl ketone, methyl isopropyl ketone, butanol, and isopropyl ether. Tanol, etc. can be used.The product obtained by removing the solvent from the extract is generally difficult to crystallize because it is a mixture of keto-type and phenol-type tautomers. Since the purpose of use is as a synthetic intermediate, there is no particular problem.
The object of the present invention (1) is particularly useful as an intermediate for the synthesis of penicillin and cephalosporin, and after the desired reaction, the ester moiety and the S-oxide moiety can be removed very easily and in high yield. The ester moiety can be removed very easily and in high yield by using, for example, a method discovered by the present inventors in which nitrite or nitrite ester is reacted.Next, this invention will be explained with examples. This invention is not limited by this.

In the following description, IR, UV, NMR, and TLC represent infrared absorption spectrum, ultraviolet absorption spectrum, nuclear magnetic resonance spectrum, and thin layer chromatography, respectively. Reference Example 6 - Phenoxyacetamide Benam-3-carboxylic acid diacetyl methyl ester 1-oxide 4.64 to 7
0% acetone 30 [in addition to Kagi Azusa's figure of sodium nitrate 2.
An aqueous solution containing 1 ml of water was gradually added dropwise.

It will soon generate heat and react, so cool it down with water. After the dropwise addition was completed, 1.2 hours of acetic acid was added in several portions, and the reaction was then allowed to proceed at 40 to 50° C. for 30 minutes. TLC (benzene: ethyl acetate = 2
:1. Follow up with heating color development after azide iodide treatment). After confirming the completion of the reaction, the pressure was adjusted to 7.5 with sodium bicarbonate water, and acetone was distilled off under reduced pressure. The aqueous layer was washed several times with methylene chloride, fresh methylene chloride was added to the aqueous layer, and the feed was adjusted to 2.0 with 20% hydrochloric acid while cooling on ice.The methylene chloride layer was separated and extracted several times with methylene chloride. do.

The methylene chloride layers were combined, washed three times with brine, dried, and the solvent was distilled off under reduced pressure.

Qianzumi will be treated with oil. 6-Phenoxyacetamidobenamoo 3-carboxylic acid-1-oxide (phenoxymethylbenicillin-sulfoxide) 3.44 min (9
4%). Melting point: 157°C (decomposed), IR: 179
5-1 (B-lactam), structure confirmed by NMR and IR,
It matched the standard. When 1'-methoxycarbonyl-2-oxopropyru(1') ester 1-oxide was used instead of diacetylmethylester 1-oxide, the yield was 95%. Example 1 Anhydrous 6-phenylacetamide-benam-3-carboxylic acid 1-1-oxide (benzyl-penicillin sulfoxide) 3.50 hours, N-methylmorpholine 1.11 hours, potassium bicarbonate 0.3 hours N ．． Add 10 ml of N-dimethylformamide and cool on ice.

3-brome-2.4-bentanedione 1.
Gradually drip 97 yen. After incubating for 30 minutes, the mixture was gradually warmed to room temperature and the reaction was monitored by TLC (benzene:ethyl acetate = 2:1, azide iodide solution was sprayed and heated to develop color). 3-5
The reaction ends in time.

Add 20 parts of methylene chloride and 20 parts of ice water to the reaction solution, and adjust the pH to 7.0 while condensing. Separate the organic layer, extract the aqueous layer several times with methylene chloride, combine the methylene chloride solutions,
Wash with a small amount of salt water and dry with magnesium sulfate. The solvent is distilled off under reduced pressure, and the remaining bamboo is treated with isoprobal/n-hexane to solidify. Melting point 65-80℃ 6-phenylacetamidobenam-3-carboxylic acid 1
- diacetyl methyl ester of oxide at 4.31 pm (
96%).

Purify by silica gel chromatography (benzene + ethyl acetate). Melon (KBr): 1800 imitation-1 (8-lactam), which matched the separately synthesized standard. According to NMR, the ratio of keto type to phenol type was 1:5. Elemental analysis;
C2, day 24N207S Calculated value; C56. 24th day 5.39N625 Analysis value: C5
6.38 days 5.31N6.32 Example 2 Anhydrous 6-phenylacetamide-benam-3-carboxylic acid 1-1-oxide 3.50 hours, triethylamine 1.11 hours, potassium hydrogen carbonate 0.3 hours Add 5 parts of acetone and 10 parts of dimethyl sulfoxide.

While cooling on ice, 1.40 g of 3-chloro-2,4-pentanedione and 5 g of sodium iodide were added, and after 30 minutes, the temperature was raised to room temperature and the reaction was monitored by TLC. Let it react for about 1 hour. Acetone is removed from the reaction solution under reduced pressure, and the subsequent treatment is carried out in accordance with Example 1. Melting point 65-8 p0 6-phenylacetamide-benam-3-carboxylic acid-1
- diacetyl methyl ester of oxide at 4.26 pm (
95%) was obtained.

TLC, the melon was consistent with the standard product. Example 3 In place of 3-chloro-2,4-bentanedione in Example 2, Q-chloroacetoacetic acid methyl ester was used, and the reaction and treatment were carried out according to Example 2.

6-phenylacetamide-benamoo 3-carboxylic acid 1
1'-methoxycarponyl-2'-oxoprobyl-(1') ester of -oxide was obtained in a yield of 94%.

Recrystallized from ethanol and isopropyl ether, melting point 1
24-125℃ m1795-1 (8-lactam),
UV^max25 elemental analysis of enemy: C2, day 24N208
S Calculated value; C I. 30th day 5.21N6.03 analysis value; C5
4.04 days 5.20N5.89 Example 4-8 Example 2
The following chloro compound (CIR) was used in place of 3-chloro-2,4-pentanedione, and the reaction was carried out according to Example 2.

6-phenylacetamidobenam-3-carboxylic acid ester-1-oxide was obtained as shown in the table below.

[A: phenylacetamide: R = ester residue] Examples 9 to 15 6-phenylacetamide benam-3-carboxylic acid-1-oxide (benzylbenicillin-sulfoxide) in Example 2 was replaced with 6 Example 2 using monophenoxyacetamide-benam-3-carboxylic acid-1-oxide (phenoxymethyl-penicillin-sulfoxide) and using various chloro compounds (CIR) in place of 3-chloro-2,4-pentanedione. React and process according to the following.

6-Phenoxyacetamide-benamoo 3-carboxylic acid ester 1-oxide was obtained as shown in the table below.

Claims (1)

[Claims] 1 Penicillin-1-oxide or its salt represented by the general formula ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ (A in the formula means an acylamino group) A method for producing a heterocyclic carboxylic acid ester, which is characterized by obtaining a 1-oxide of a penicillin ester represented by ▼ (in the formula, each symbol has the same meaning as above). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X is a halogen atom, R^1 is a lower alkyl group or phenyl group, R^2 is lower alkoxycarbonyl,
Lower alkylcarbonyl group or formula ▲ Numerical formula, chemical formula,
There are tables, etc. ▼ (In the formula, R^3 and R^4 are the same or different lower alkyl groups, however, R^3 and R^4 may be ring-closed with an oxygen atom to form a morpholino group)] The general formula is obtained by reacting the halogen compounds