KR20020063383A - New manufacturing process of sulbactam - Google Patents

Abstract

PURPOSE: A process for producing sulbactam is provided, thereby a halogenation process and a high pressure hydrogenation process during the total process can be removed, so that the sulbactam can be rapidly and simply produced in higher yield. CONSTITUTION: The process for producing sulbactam comprises the steps of: reacting 6-APA(aminopenicillanic acid) of formula 2 with sodium nitrate and hypophosphorous acid to produce penicillanic acid of formula 3; and reacting the penicillanic acid with potassium permanganate to produce the sulbactam of formula 1, in which the amount of the sodium nitrate used is 1 to 5 equivalent; and the amount of the hypophosphorous acid used is 0.1 to 3 equivalent.

Description

New manufacturing process of sulbactam

The present invention relates to a method for producing sulbactam having the structure of formula (1).

Among the beta-lactam antibiotics, sulbactam is an antibiotic that is synthesized through various reactions such as halogenation, oxidation, and hydrogenation using 6-APA (6-aminophenicylic acid) as a starting material.

To date, methods for preparing commercial sulbactam antibiotics have been mentioned in several patents (USP 4234579, USP 4244951, USP 4420426). US Patent No. 4234579 describes a method for preparing sulbactam according to Scheme (1) below.

However, when manufacturing sulbactam according to the above method, there are various difficulties in the manufacturing process. First, in order to remove the amine substituent at position 6 in the reaction process, a halogenation reaction and a high-pressure hydrogenation reaction are essential. As a result, the reaction process is complicated, industrial application is difficult, and the yield is low.

Accordingly, the present inventors have solved the problems of the prior art, and simplifies the process and researches to produce sulbactam with high yields. As a result, the present inventors have found that the above object can be satisfied by using sodium nitrite and hypophosphite. It was.

It is therefore an object of the present invention to provide a method which is simple and easy to apply industrially and which can produce sulbactam in high yield.

The present invention removes the amine group at position 6 using sodium nitrite and hypophosphorous acid in the starting material 6-APA (6-aminophenic silane) to prepare penicilanic acid, and then further adds potassium permanganate. Oxidation reaction is used to produce sulbactam.

Sulbactam preparation method according to the invention is shown in the following scheme (2).

The sodium nitrite used for the deamine reaction of 6-APA is preferably used in an amount of 1 to 5 equivalents, more preferably 2 to 3 equivalents. At this time, the reaction temperature is -20 ~ 10 ℃ is more suitable -5 ~ 0 ℃.

The amount of hypophosphorous acid used is preferably 0.1 to 3 equivalents, more preferably 0.3 to 0.7 equivalents.

As a reaction solvent, an organic solvent which can be mixed with water or water was used, and as the organic solvent, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, methanol, isopropyl alcohol, butanol, and the like can be used. The ratio of preferably contains 1 to 40% of an organic solvent, more preferably 10 to 20%.

Hereinafter, preferred examples and comparative examples are presented to help understand the present invention. However, the following examples are provided only to more easily understand the present invention, and the present invention is not limited to the following examples.

Analysis method

NMR Spectroscope: JNM LA 400 (400MHz)

Example 1 Preparation of Penicillanic Acid

21.6 g of 6-APA (6-aminophenicylanic acid) was suspended in 90 ml of water and 10 ml of dimethylformamide mixed solvent and dissolved by adding 50 ml of hydrochloric acid. The solution was lowered to -5 to 0 DEG C and 7.3 g of sodium nitrite (20 mL aqueous solution) was added dropwise for 1 hour. 50% hypochlorous acid solution, previously cooled, was added dropwise for 30 minutes. After completion of the dropwise addition, the reaction temperature was raised to room temperature and stirred at the same temperature for 2 hours. After completion of the reaction, the mixture was extracted with 50 ml of dichloromethane, washed twice with purified water, and concentrated under reduced pressure to obtain crystals. The crystals were purified by silica gel column chromatography (mobile phase; acetonitrile: water = 3: 1) to obtain 16.4 g of peniclanic acid (yield 82%).

NMR (D ₂ O) 1.29 (3H, s), 1.45 (3H, s), 3.31 (1H, dd), 3.63 (1H, dd),

4.1 (1 H, s), 5.33 (1 H, m).

Example 2 Preparation of Peniccillanic Acid 1,1-dioxide (Sulbactam)

20.1 g of peniclanic acid was suspended in 200 ml of purified water, and then the temperature was lowered to 0-5 ° C. The solution was adjusted to pH 4.0 with 3N-sodium hydroxide solution. 23.7 g of potassium permanganate was dividedly administered 5 times for 1 period and stirred at the same temperature for 5 hours. After completion of the reaction, 200 ml of ethyl acetate was added, the pH was lowered to 1.1-1.2 with concentrated hydrochloric acid, and further stirred at 10 ° C. for 30 minutes. An excess of sodium persulfate solution was added to remove excess potassium permanganate, the organic solvent layer was taken up, distilled under reduced pressure, and then suspended in purified water and filtered. The resulting solid was washed twice with purified water and dried to give 32.3 g (81% yield) of peniclanic acid 1,1-dioxide.

NMR (DMSO-D6) 1.36 (3H, s), 1.46 (3H, s), 3.28 (1H, dd), 3.63 (1H, dd),

4.24 (1H, s), 5.10 (1H, m)

Comparative Example 1. Preparation of 6,6-Dibromo penicillanic acid

40 g of bromine was added to 50 ml of 2.5 M sulfuric acid solution, and 17.3 g of sodium nitrite was added to the solution to dissolve it. 21.6 g of 6-APA (6-aminophenicsilane acid) was suspended in 90 ml of water and added dropwise while lowering the temperature so that the reaction temperature was -5 to 0 ° C. After completion of the dropwise addition, the mixture was stirred at 0˜5 ° C. for 5 hours. After completion of the reaction, bromine was removed with an aqueous sodium hydrogen sulfite solution and crystallized by adjusting the pH to 0.8 with concentrated hydrochloric acid. The crystals were filtered, washed three times with purified water and dried to obtain 31.9 g (yield 98%) of 6,6-dibromo peniclanic acid.

NMR (DMSO-D6) 1.45 (3H, s), 1.53 (3H, s), 4.62 (1H, s), 5.82 (1H, s)

Comparative Example 2. 6,6-Dibromophenic silane acid 1,1-dioxide (6,6-Dibromo penicil

-preparation of lanic acid 1,1-dioxide)

52.5 g of 6,6-dibromophenic silane acid was suspended in 200 ml of purified water, and then the temperature was lowered to 0-5 ° C. The solution was adjusted to pH 4.0 with 3N-sodium hydroxide solution. 23.7 g of potassium permanganate was dividedly administered 5 times for 1 period and stirred at the same temperature for 5 hours. After completion of the reaction, 200 ml of ethyl acetate was added, the pH was lowered to 1.1-1.2 with concentrated hydrochloric acid, and further stirred at 10 ° C. for 30 minutes. An excess of sodium persulfate solution was added to remove excess potassium permanganate. The organic solvent layer was taken up, distilled under reduced pressure, and then suspended in purified water and filtered. The resulting solid was washed twice with purified water and dried to give 42.4 g (76% yield) of 6,6-dibromophenic silane acid 1,1-dioxide.

NMR (DMSO-D6) 1.19 (3H, s), 1.54 (3H, s), 4.64 (1H, s), 5.27 (1H.s)

Comparative Example 3 Preparation of Penicillanic Acid 1,1-Dioxide

55.7 g of 6,6-dibromophenicylanic acid 1,1-dioxide was dissolved in 250 ml of ethyl acetate. An aqueous solution of 33.6 g of sodium bicarbonate was added to this solution, followed by the addition of 8.11 g of 10% palladium carbon. This mixed solution was subjected to pressurized hydrogenation for 8 hours. After completion of the reaction, the organic layer was removed and washed twice with 100 ml of ethyl acetate. The pH of the aqueous solution was adjusted to 3 and extracted with dichloromethane solvent. The extraction solvent was concentrated under reduced pressure to obtain crystals. The crystals were purified by silica gel column chromatography (mobile phase; acetonitrile: water = 3: 1) to obtain 33.1 g of a peniclanic acid 1,1-dioxide (83% yield).

NMR (DMSO-D6) 1.36 (3H, s), 1.46 (3H, s), 3.28 (1H, dd), 3.63 (1H, dd),

4.24 (1H, s), 5.10 (1H, m)

The present invention relates to a method for producing sulbactam, and by using sodium nitrite and hypophosphorous acid, it is possible to omit the halogenation reaction and the high-pressure hydrogenation reaction in the reaction process, thereby simultaneously improving the side reaction problem of carboxylic acid formation at the 3 position derived therefrom. . In addition, by simplifying the reaction step, industrial application is easy, and sulbactam can be obtained in high yield.

Claims (3)

6-APA of formula (2) using sodium nitrite and hypophosphorous acid to produce peniclanic acid of formula (3), and further comprising the step of oxidation reaction using potassium permanganate (1) Method for producing sulbactam. Formula 2 Formula 3 Formula 1 The method according to claim 1, wherein sodium nitrite is used in an amount of 1 to 5 equivalents. The method according to claim 1, wherein hypophosphorous acid is used in an amount of 0.1 to 3 equivalents.