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Preparation method of 1-(4, 5-dihydro-2-thiazolinyl)-3-mercaptoazetidine hydrochloride

A technology based on mercaptoazetidine hydrochloride and thiazoline, applied in the new preparation field of 1--3-mercaptoazetidine hydrochloride, can solve the problems of long route, harsh reaction conditions, high cost, etc. The route is simple, the raw materials are easy to obtain, and the effect of increasing the yield

Active Publication Date: 2015-06-03
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] (1) In the patent JP8053453 applied by Wyeth Rieter Corporation of Japan, Abe, T. et al. used 2-methylthio-2-thiazoline as the starting material to prepare 1-(4,5-di Hydrogen-2-thiazolinyl)-3-mercaptoazetidine, the resulting reaction intermediates in each step will be purified by silica gel chromatography, which is very difficult for industrial production
[0008] (2) Hayashi, K. et al. (Hayashi, K. et al., Tetrahedron Lett.1999, 40, 3761-3764.) developed a method for preparing 1-(4,5-dihydro-2-thiazolinyl)-3 -A new method for mercaptoazetidine hydrochloride, the route uses allylamine as a starting material and prepares 1-(4,5-dihydro-2-thiazolinyl)-3-mercaptoazetidine through 5 steps of reaction Ding hydrochloride, the reaction intermediate needs to be purified by distillation or purified by silica gel column, which is expensive in industry and difficult to produce
Although this route can crystallize and purify the intermediates in each step, there are many steps, resulting in low yield and harsh reaction conditions, so the industrial production cost is high, and there are certain risk factors
[0010] (4) Isoda, T. et al. (Isoda, T. et al., Heterocycles, 2006, 68 (9), 1821-1824) take epichlorohydrin as a starting material, and obtain 1-(4, 5-dihydro-2-thiazolinyl)-3-mercaptoazetidine, this method route is longer, and productive rate is lower, and wherein used reagent is sensitive to moisture or has very strong pungent smell, and industrial application is very difficult. difficulty

Method used

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Embodiment 1

[0032] The first step: the preparation of 1-(4,5-dihydro-2-thiazolinyl)-3-hydroxyazetidin (II)

[0033] Add 3-hydroxyazetidine hydrochloride (103.68g) in dry there-necked flask, KHCO 3 (124.50g) and methanol, stirred at room temperature, then added 2-methylthio-2-thiazoline (120.00g), reacted at 80°C for 10h, cooled to room temperature, filtered, the filtrate was concentrated, and chloroform (600ml) was added to the residue , the filtered solid was dissolved in water (600ml), the two were mixed and then separated, the aqueous phase was extracted with chloroform, the combined filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain a white solid, and dried in vacuo to obtain intermediate 94.31 g of 1-(4,5-dihydro-2-thiazolinyl)-3-hydroxyazetidin (II), with a yield of 66%, was directly put into the next reaction.

[0034] 1 H NMR (400MHz, CDCl 3 )δ: 7.28(s, 1H), 4.67-4.61(m, 1H), 4.18(dd, J=6.88, 8.20Hz, 2...

Embodiment 2

[0036] The first step: the preparation of 1-(4,5-dihydro-2-thiazolinyl)-3-hydroxyazetidin (II)

[0037] In dry there-necked flask, add 3-hydroxyazetidine hydrochloride (108.64g), K 2 C0 3 (137.00g) and ethanol, stirred at room temperature, then added 2-methylthio-2-thiazoline (120.00g), reacted and refluxed at 100°C for 8h, cooled to room temperature, filtered, the filtrate was concentrated, and chloroform (600ml ), the filtered solid was dissolved in water (600ml), the two were mixed and then separated, the aqueous phase was extracted with chloroform, the combined filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain a white solid, and dried in vacuo 131.55 g of the intermediate 1-(4,5-dihydro-2-thiazolinyl)-3-hydroxyazetidin (II) was obtained with a yield of 92%.

Embodiment 3

[0039] The second step: the preparation of 1-(4,5-dihydro-2-thiazolinyl)-3-methanesulfonate group azetidine (III)

[0040] Get 1-(4,5-dihydro-2-thiazolinyl)-3-hydroxy azetidin (II) (40.00g) and Et 3 N (38.38g) was added into dichloromethane (250ml), MsCl (37.69g) was added dropwise at 0°C, then stirred at the same temperature for 8h, filtered, the filtrate was washed with saturated sodium bicarbonate solution, and the aqueous phase was reused Back extraction with dichloromethane, the combined filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, recrystallized in a mixed solution of ethyl acetate and n-hexane (10:1), filtered the solid, washed, and dried in vacuo to obtain White solid 39.07g, yield 66%.

[0041] 1 H NMR (400MHz, CDCl 3 )δ: 5.31-5.28(m, 1H), 4.37-4.32(m, 2H), 4.19-4.15(m, 2H), 4.03(t, J=7.56, 2H), 3.39(t, J=7.52Hz, 2H), 3.06(s, 3H);

[0042] MS(EI):m / z[M] + calcd for C 7 h 12 N 2 o 3 S ...

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Abstract

The invention discloses a method for synthesis of 1-(4, 5-dihydro-2-thiazolinyl)-3-mercaptoazetidine hydrochloride. With 2-methylthio-2-thiazoline (I) as the raw material, the method of the invention comprises the steps of: in the presence of alkali, reacting 2-methylthio-2-thiazoline (I) with 3-hydroxyazetidine hydrochloride so as to obtain 1-(4, 5-dihydro-2-thiazolinyl)-3-hydroxyazetidine (II), and reacting (II) with methyl sulfonylchloride in the presence of alkali so as to obtain 1-(4, 5-dihydro-2-thiazolinyl)-3-methane sulfonate group azetidine (III), subjecting (III) to a reaction with potassium thioacetate so as to obtain 1-(4, 5-dihydro-2-thiazolinyl)-3-thioacetic acid ester group azetidine (IV), in the presence of alkali, subjecting (IV) to hydrolysis and then to acidification with dilute hydrochloric acid, thus obtaining the 1-(4, 5-dihydro-2-thiazolinyl)-3-mercaptoazetidine hydrochloride (V). With easily available and inexpensive starting material, the method of the invention simplifies the synthesis route, improves the raw material utilization ratio and the overall yield. An intermediate obtained in the reaction can be subjected to refinement by a recrystallization method or to a next reaction directly, so that the yield is high and the "three wastes" produced during the reaction process are few. In addition, with low cost, the method of the invention is beneficial for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new preparation method of 1-(4,5-dihydro-2-thiazolinyl)-3-mercaptoazetidine hydrochloride. Background technique [0002] The present invention relates to the synthesis of the key intermediate 1-(4,5-dihydro-2-thiazolinyl)-3-mercaptoazetidine hydrochloride (V) of the novel antibacterial drug tipipenem pivate (VI) , the structural formula is as follows: [0003] [0004] Tebipenem pivoxil (Tebipenem pivoxil) is a new broad-spectrum antibiotic (VI) of oral penem class, originally developed by Wyeth Rieter Co., Ltd. of Japan, and then transferred to Meiji Seika Pharmaceutical Co., Ltd. of Japan in March 2002. In 2009 It was approved by the Ministry of Health and Welfare in Japan in April, and was first listed in Japan on August 26, 2009. Tipipenem pivoxil has a broad antibacterial spectrum. For most clinically isolated strains, tipipenem pivoxil has shown stronge...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/04
Inventor 黄小光黄冰娥朱少璇
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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