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Method for preparing ceftaroline side-chain acid

A hydrochloric acid aqueous solution, ethoxyiminoacetic acid technology, applied in the direction of organic chemistry, etc., can solve the problems of low yield of amino deprotection reaction, harsh process reaction conditions, low total yield, etc., and achieves great implementation value and social economy. Benefit, good stereo selection, high stereo selectivity

Inactive Publication Date: 2012-07-11
ZHEJIANG UNIV OF TECH +1
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] 2. JP62205066 and J.Antibiot., 2000, 53(10): 1053-1070 reported the use of cyanoacetamide as a raw material with o-hydroxybenzaldehyde, 1-chloropyrrole-2,5-dione, thiocyanate Potassium reaction to generate 3-(5-amino-1,2,4-thiadiazol-3 base) coumarin, and then undergo alkaline ring opening, ozone oxidation, and condensation to obtain cefazolam side chain acid---- (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetic acid, the process reaction conditions are relatively harsh, and the total yield is not high
[0015] 3. Chinese patent 200910155299.7 reports a method for preparing 5-amino-1,2,4-thiadiazole-3-acetamide derivatives using malononitrile as a raw material; Chinese patent 201010505564.2 further reports that 5-amino-1, 2,4-thiadiazole-3-acetamide derivatives as raw materials to prepare cefbutorol side chain acid: (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl) -The route of 2-trityl iminoacetic acid, wherein when the amino group at the 5-position of the thiadiazole ring is protected with a benzoyl group, the selectivity of the reaction is higher, but the yield of the amino group deprotection reaction is lower

Method used

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  • Method for preparing ceftaroline side-chain acid
  • Method for preparing ceftaroline side-chain acid
  • Method for preparing ceftaroline side-chain acid

Examples

Experimental program
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Embodiment 1

[0051] (1) In a 500mL three-necked flask, mix 5-pivalylamino-1,2,4-thiadiazole-3-acetyl-N-acetamide (50.0g, 0.176mol), 31% hydrochloric acid aqueous solution (2.1 g, 0.0176mol) were mixed in tetrahydrofuran (150g), and isopropyl nitrite (46g, 0.528mol) was added dropwise at -15°C. Add bromoethane (152g, 1.41mol) dropwise, keep the temperature for 5 hours, filter with suction, take the filter cake, and dry it in vacuum to obtain (Z)-5-pivalylamino-1,2,4-thiadiazole- 42.0 g of 3-(1-ethoxyimino-acetyl-N-acetamide), the crude product yield is 70%; white solid, melting point: 182.0-184.2°C.

[0052] 1 H-NMR (DMSO, 400MHz): δ (ppm) 1.26 (3H, t, J=8.0Hz, OCH 2 CH 3 ), 1.28 (9H, s, C (CH 3 ) 3 ), 2.24 (3H, s, COCH 3 ), 4.29 (2H, q, J 7.0Hz, OCH 2 CH 3 ), 10.94(H, s, 1H, NH-C=N), 12.94(1H, s, J=11.2Hz, NHCOCH 3 ).

[0053] (2) 42.0 g (0.123 mol) of the crude product obtained in step (1) is mixed with 0.5% NaOH solution (1968 g, 0.246 mol) in a 3L bottle, and incubated for 20 ...

Embodiment 2

[0055] (1) In a 2L three-necked flask, mix 5-pivalylamino-1,2,4-thiadiazole-3-acetyl-N-acetamide (50.0g, 0.176mol), 31% hydrochloric acid aqueous solution (20.7 g, 0.176mol) were mixed in dichloromethane (1000mL), and isopropyl nitrite (76.0g, 0.88mol) was added dropwise at -30°C. ), bromoethane (152g, 1.41mol) was added dropwise at 0°C, and after 10 hours of heat preservation reaction, suction filtration was taken, and the filter cake was taken to obtain 36g of crude product (Z)-5-pivalylamino-1,2,4- Thiadiazole-3-(1-ethoxyimino-acetyl-N-acetamide), crude product yield 60%; white solid, melting point: 181.3-183.5°C.

[0056] (2) Mix 36g (0.105mol) of the crude product obtained in step (1) and 2.5% KOH solution (470.4g, 0.21mol) in a 1L bottle, keep the reaction at 90°C for 20h, cool to 5°C, and wash with 5% dilute hydrochloric acid Adjust the pH to 2-3, filter with suction, and take the filter cake to obtain 13.3 g of ceftaroline side-chain acid, with a total yield of 35%, a...

Embodiment 3

[0058] (1) In a 1L three-necked flask, mix 5-pivalylamino-1,2,4-thiadiazole-3-acetyl-N-acetamide (50.0g, 0.176mol), 31% hydrochloric acid aqueous solution (10.4 g, 0.088mol) were mixed in acetonitrile (50g), and isopropyl nitrite (92.0g, 1.05mol) was added dropwise at 0°C. After 15 hours of insulation reaction, pyridine (69.5g, 0.88mol) was added, Diethyl sulfate (27g, 0.176mol) was added dropwise, and after 1 hour of heat preservation reaction, suction filtration was taken, and the filter cake was taken to obtain 39g of crude product (Z)-5-pivalylamino-1,2,4-thiadiazole- 3-(1-Ethoxyimino-acetyl-N-acetamide), crude product yield 65%; white solid, melting point: 182.4-183.2°C.

[0059] (2) 39g (0.114mol) of the crude product obtained in step (1) and 5% Ba (OH) 2 solution (1949g, 0.57mol) were mixed in a 3L bottle, kept at 100°C for 24h, cooled to 5°C, and heated with 10 % dilute hydrochloric acid to adjust pH to 2-3, suction filtration, take filter cake to obtain 19.8g of ceft...

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Abstract

The invention discloses a method for preparing ceftaroline side-chain acid shown as a formula (I). The method comprises the following steps of: performing oximation reaction on 5-amino-1,2,4-thiadiazole-3-acetamide derivative and nitrite under catalysis of concentrated hydrochloric acid, performing esterification reaction with an ethylation reagent in the presence of organic alkali, dissolving in an aqueous solution of inorganic alkali, and thus obtaining the ceftaroline side-chain acid. The method has the advantages of mild reaction conditions, simplicity and convenience in operation, good reaction selectivity, high yield, short production period, low 'three-waste' quantity, easiness in industrialization and high implementation value and social and economic benefits.

Description

(1) Technical field [0001] The invention relates to a preparation method of ceftaroline side chain acid. (2) Technical background [0002] In recent years, the problem of antibiotic resistance has become increasingly serious. With the increasing drug resistance of bacteria, especially the strong drug resistance of methicillin-resistant Staphylococcus aureus (MRSA), the development of new antibiotics is challenged. Currently, the commonly used antibiotics against MRSA are vancomycin and Linezolid, but both antibiotics are relatively weak against Gram-negative bacteria. [0003] Ceftaroline Fosamil, developed by Japan's Takeda Pharmaceutical Company, the US Forest Laboratories (Cerexa) company obtained market authorization, and was approved for marketing by the US Food and Drug Administration on October 29, 2010. It belongs to the fifth generation A cephalosporin antibiotic that has antibacterial activity against Staphylococcus aureus (MRSA), multidrug-resistant Streptococcu...

Claims

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Application Information

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IPC IPC(8): C07D285/08
Inventor 钟为慧苏为科姚奕王光明顾士崇
Owner ZHEJIANG UNIV OF TECH
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