JPH02273685A - Production of diester compound - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the subject compound useful as a synthetic intermediate for penicillin-based antimicrobial agents in good yield without forming by-products by reacting specific two kinds of compound in the presence of a urea-based solvent. CONSTITUTION:A compound expressed by formula I (R<1> is H, phenylacetylamino or phenyoxyacetylamino; Y<1> is S or sufonyl; X is Cl, Br or I) is reacted with a compound expressed by formula II (R<2> is H, phenylacetylamino or phenoxyacetylamino; Y<2> is S or sulfonyl; M is alkali metal) in the presence of a urea-based solvent (e.g. tetramethylurea or 1,3-dimethyl-2-imidazolidione), preferably at 30 to 250 deg.C for 1 to 24hr to afford the objective compound expressed by formula III (R is phenylacetylamino or phenoxyacetylamino).

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an improved method for producing diester compounds useful as intermediates for the synthesis of penicillin antibacterial agents.

[Conventional technology]

Penicillanic acid 1,1-dioxide (sulbactam) is known as a useful β-lactamase inhibitor. It contains phenoxyacetylamino, Y2 is sulfur, and it is also a mutual protrangyl compound in which sulbactam and ampicillin are ester bonded. 1,1-Dioxopenicilanoyloxymethyl 6-CD-(2-amino-2-phenylacetylamino)]penicillinate (sultamicillin) is a drug that increases blood and tissue concentrations of ampicillin and sulbactam. It is an oral antibacterial agent developed with the aim of exhibiting a mutually cooperative effect on ampicillin-resistant bacteria and β-lactamase production in vivo.

And, as an important synthetic intermediate for the synthesis of sultamicillin, 1,1-dioxopenicilanoyloxymethyl-6-(2-phenyl or phenoxyacetylamino)penicillate (hereinafter referred to as compound A or B)
Diester compounds such as

JP-A-55157589 discloses a method for obtaining a diester compound of Compound A by reacting potassium penicillin G with chloromethyl penicillanate 1,1-dioxide in dimethyl sulfoxide.

Further, JP-A-59-98090 discloses a method for producing sultamicillin from compound A or B, in which, as Example 1, sodium penicillin G and chloromethyl penicillinate in dimethyl sulfoxide are disclosed. The method for obtaining the diester compound of compound A by reacting 1.1-dioxide is further described in Example 2 (b
) discloses a method for obtaining a diester compound of Compound A by reacting chloromethyl 6-(2-phenylacetylamino)penicylanate and tetrabutylammonium penicylanate 1,1-dioxide in acetone.

[Problem to be solved by the invention]

These conventional methods for producing diester compounds have low yields in -a. For example, according to the method disclosed in JP-A-55-157589, chloromethyl penicillanate 1.1
-The yield of the diester compound is very low at about 12% based on chloromethyl penicylate 1,1-dioxide in the method of Example 1 of JP-A-59-9809G. In the method of Example 2(b), the yield of the diester compound was 25.6%, and the yield was 45% in the method of Example 2(b), both of which were not industrially satisfactory.

Furthermore, all of the diester compounds obtained by the above methods are obtained as foamy substances, making separation and purification of the target products complicated.

Furthermore, in the presence of conventional solvents such as dimethyl sulfoxide, the inventors conducted additional tests and found that the yield was low and the desired product was obtained only in the form of foam, and that it was thought to be a decomposition product. A considerable amount of by-products of unknown structure were produced, making separation and purification of the target product more difficult.

Therefore, it has been desired to develop an industrial production method that can efficiently separate and purify these diester compounds in good yields and without producing by-products.

(Means for Solving the Problems) Therefore, as a result of intensive studies to solve the above problems, the present inventors found that by using a urea-based solvent as a solvent during the above reaction, by-products can be produced in good yield. The present inventors have discovered that a diester compound represented by the general formula (wherein R represents phenylacetylamine or phenoxyacetylamino) can be obtained without the formation of The invention was completed.

That is, the present invention relates to the general formula (n) (wherein, R1 is hydrogen, phenylacetylamino, phenoxyacetylamine, y+ is sulfur, sulfonyl,
X represents chlorine, bromine, or iodine. ) and a compound represented by the general formula (III) (wherein R1 represents hydrogen, phenylacetylamino, or phenoxyacetylamino, Y2 represents sulfur or sulfonyl, and M represents an alkali metal) as urea. The present invention relates to a method for producing a diester compound represented by the general formula (RI), which is characterized by carrying out the reaction in the presence of a system solvent.

To explain the production method of the present invention in more detail, the starting material, the compound of general formula (II), is prepared using penicillin G, penicillin II, or penicillanic acid 1,1-dioxide, which are available at low cost as industrial raw materials. can be easily synthesized by reacting with methylene chloride, chloroiodomethane, bromochloromethane, etc., using conventional methods or the method described in Japanese Patent Application No. 62-298083.

As the compound of general formula (1), which is the other starting material, any water-soluble compound can be used, and the alkali metal salts include preferably sodium salts, potassium salts, and the like.

The reaction solvent that is a feature of the present invention is a urea-based solvent such as tetramethylurea, 1,3-dimethyl-2-imidazolidinone, 1,3-diethyl-2-imidazolidinone, .1,
Examples include 3-dipropyl-2-imidazolidinone, which can be used alone or as a mixed solvent.

Furthermore, the urea-based solvent of the present invention can be easily recovered and reused.

Furthermore, by adding sodium iodide or potassium iodide to the reaction, the reaction can proceed smoothly. The amount used is approximately 0.1 times mole to equimole relative to compound (III).

Furthermore, by simultaneously adding sodium thiosulfur to the reaction system, effects such as preventing coloring of the reaction solution, stabilizing the reaction solution, and preventing the production of by-products are observed. Its usage is
The amount is approximately 0.1 times mole to equimole relative to the compound (In).

The reaction temperature ranges from room temperature to 60°C, preferably 30 to 250°C with heating.The reaction time may vary depending on the amount of additives used, the reaction temperature, etc., but is usually 1 to 250°C.
It will be done in 24 hours.

Wear. Moreover, the quantitative ratio of the raw material compounds is preferably equimolar.

After completion of the reaction, the diester compound of general formula (1) thus obtained can be isolated and purified by conventional methods such as precipitation, distillation, filtration, recrystallization, and column chromatography.

For example, when the reaction solution is compound A, after the reaction is completed,
The desired product can be easily isolated as crystals by cold pouring into excess water.

[Action and effect of the invention]

According to the method of the present invention, (1) the target product can be obtained in high yield and high purity; (2) the product can be isolated as crystals, and the obtained product is also highly pure; There is no need for further purification, and the purification operation can be shortened. (3) No by-products with unknown structure are generated, the reaction can proceed smoothly, and at the same time, the reaction time can be shortened. Yield, purity, etc. It is possible to advantageously produce a diester compound which has advantages in terms of reaction operation and is useful as a synthetic intermediate for penicillin antibacterial agents, particularly sultamicillin.

〔Example〕

Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto. It should be noted that the obtained compounds were analyzed by means such as IR spectrum, NMR spectrum, HPLC, elemental analysis, etc. It was confirmed that it was a compound.

Reference Example 1: Chloromethyl 6-(2-phenylacetylamino)penicylanate bromochloromethane 300 aw, water 10 g and 50.
A mixture of 1.3 g of 9% tetrabutylammonium bromide kept at 45°C was added with a solution of 45 g of potassium 6-(2-phenylacetylamino)penicillane door, 40 g of water and 0.2 g of potassium bicarbonate (7). Added. After the reaction was completed at 45°C for 8 hours with vigorous stirring, the composition of the reaction solution was potassium 6-(2-phenylacetylamino))penicylanate: chloromethyl 6-(2-phenylacetylamino)penicylanate. : Methylenebis(6-(2-phenylacetylamino)
penicillanate) -6,5: 85.6: 7.9
The reaction solution (HPLC area ratio) was 0, and the organic layer was separated, washed with water, and concentrated under reduced pressure to obtain 7.4 g of a pale brown oil. The composition of this oil is potassium 6-(
2-phenylacetylamino)penicylanate: chloromethyl 6-(2-phenylacetylamino)penicylanate: methylenebis[6-(2-phenylacetylamino)penicylanate)-0,23:85.63:9.
87 ( ) (PLC area ratio).

Reference Example 2z Chloromethyl penicillanate 1,1-dioxide 300 g of bromochloromethane, 5 g of water and 50,9
g A mixture of 0.65 g of tetrabutylammonium bromide was kept at 50°C, and 1 part of sodium penicillanate was added to it.
, 2.55 g of 1-dioxide.

A solution of 20 g of water and 0.67 g of potassium carbonate was added. The reaction was carried out at 50° C. for 200 hours with vigorous stirring.

After the organic layer was separated and washed with water, bromochloromethane was distilled off. The composition of the residue is chloromethyl penicillate 1
．． 1-dioxide: methylene bis[1,1-dioxopenicillanate]-93,18: 6.82 (HPL
C area ratio).

A portion of the residue crystallized when left in the refrigerator.

The crystals were collected by filtration and washed with a small amount of ether-petroleum ether mixed solvent to obtain target crystals with a melting point of 94 to 96°C.

Example 1 Composition obtained by the same operation as in Reference Example 1 Lolomethyl 6-(2-phenylacetylamino)penicylanate: methylenebis(6-(2-phenylacetylamino)
penicillanate)-97,81,2 (HPLC area ratio)
Dissolve 7.6g of oil in 25g of 1,3-dimethyl-2-imidazolidinone, add 5g of potassium iodide, 5.1g of sodium penicillanate 1,1-dioxide and 0.6g of sodium thiosulfate. The reaction was carried out at 40°C.

After confirming the completion of the reaction by HPLC, the reaction solution was poured into 150 g of cold water. The precipitated result is aged by water cooling, collected by filtration, washed with water, and dried over phosphorus pentoxide.
10.8 g of light brown crystalline powder was obtained. The composition of this crystalline powder is 1.1 dioxopenicilanoyloxymethyl 6-(2-phenylacetylamino)penicillane: methylenebis(6-(2-phenylacetylamino)penicillane)): 1,3-dimethyl -2-imidazolidinone: water-88,8: 3.4: 6.8
: 1.0 (HPLC area ratio), and no other structurally unknown by-products were detected.

Example 2 Composition obtained by the same operation as in Reference Example 2 Lolomethyl penicillate 1,1-dioxide: methylenebis[1,1-dioxopenicilanato)-96,3F 3
．． 7 (HPLC area ratio) 5.6 g of viscous oil was added to 1.
Dissolved in 25 g of 3-dimethyl-2-imidazolidinone,
5 g of potassium iodide, 7.4 g of potassium 6-(2-phenylacetylamino)penicylanate and 0.6 g of sodium thiosulfate were added and reacted at 40°C. HPLC
After confirming that the reaction was completed, the mixture was poured into 150 g of cold water. After the precipitated crystals mature during water cooling, they are collected by filtration,
After washing with water and drying over phosphorus pentoxide, 10.5 g of light brown crystalline powder was obtained. The composition of this crystalline powder is 1
．． 1-Dioxopenicilanoyloxymethyl 6-(2
-phenylacetylamino)penicylanate: methylenebis[1,1-dioxopenicylanate)il, 3-dimethyl-2-imidazolidinone: water-87,8: 3.
The ratio was 8:7.2:1.2 (HPLC area ratio), and no other by-products of unknown structure were detected.

Example 3 Composition obtained by the same operation as Reference Example 1 Lolomethyl 6-(2-phenylacetylamino)penicylanate: Methylenebis(6-(2-phenylacetylamino)
penicillanate) -90,21,8 (HPLC area ratio)
Dissolve 7.6g of the oil in 30g of tetramethylurea,
Potassium iodide 3.3g, sodium penicillanate 1.
5.1 g of 1-dioxide was added and reacted at 45° C. for 13 hours. After cooling, the reaction solution was poured into 150 g of cold water.

The precipitated crystals were aged during cooling with water and then collected by filtration. After washing with water,
Light brown crystalline powder when dried over phosphorus pentoxide 10.6
g is obtained. The composition of this crystalline powder is 1.1-dioxopenicilanoyloxymethyl 6-(2-phenylacetylamino)penicylanate: methylenebis(6-
(2-phenylacetylamine) penicillate]:
Tetramethylurea: water - 83.1: 8.2: 7
．． 2:1.5 (HPLC area ratio), and no other structurally unknown by-products were detected.

Example 4 Composition obtained by the same operation as in Reference Example 1 Lolomethyl 6-(2-phenylacetylamino)penicylanate: Methylenebis(6-(2-phenylacetylamino)
penicillanate) -97,71,3 (HPLC area ratio)
Dissolve 7.6 g of the oil in 25 g of 1,3-dimethyl-2-imidazolidinone, add 5 g of potassium iodide, 5.1 g of sodium penicillanate 1,1-dioxide, and 1.6 g of sodium thiosulfate. The composition of the crystalline powder obtained by treating the 0 reaction solution reacted at 45°C for 6 hours in the same manner as in Example 1 is 1.1-dioxopenicilanoyloxymethyl 6-(2-phenylacetylamino). Penicylanate: Methylenebis[6-(2-phenylacetylamino)penicylanate]-95,6: 4.4 (H
(PLC area ratio), and no other structurally unknown by-products were detected.

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is hydrogen, phenylacetylamino, phenoxyacetylamino, Y^1 is sulfur, sulfonyl, and X is chlorine, bromine, iodine. ) and general formulas ▲ mathematical formulas, chemical formulas, tables, etc. represents an alkali metal) in the presence of a urea-based solvent ▲ There are mathematical formulas, chemical formulas, tables, etc. A method for producing a diester compound represented by (representing acetylamino).