A kind of Florfenicol intermediate, its preparation method and the preparation method of Florfenicol

A technology for florfenicol and intermediates, which is applied in the field of intermediates for preparing florfenicol, can solve the problems of long process, difficult industrial production, low yield and the like, and achieves high environmental protection pressure, easy operation and high yield. high effect

Active Publication Date: 2020-03-20
HEADING NANJING PHARMTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This process route has the disadvantages of low yield and long process, and it is difficult to apply to industrial production (Tetrahedron: Asymmetry 22(2011) 1337-1341)

Method used

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  • A kind of Florfenicol intermediate, its preparation method and the preparation method of Florfenicol
  • A kind of Florfenicol intermediate, its preparation method and the preparation method of Florfenicol
  • A kind of Florfenicol intermediate, its preparation method and the preparation method of Florfenicol

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Experimental program
Comparison scheme
Effect test

Embodiment I

[0062]

[0063]KCN (307 g, 4.71 mol) was added into a buffer solution prepared with citric acid (400 mL, pH=5.0), cooled to 0° C., and set aside. Dissolve p-methyl sulfide benzaldehyde (71.6 g, 0.471 mol) in TBME (400 mL), add to the reaction solution, maintain 0 °C, add (R)-HNL (40 mL), stir for 1.5 hours, and HPLC detects that the reaction is complete. 5M HCl (50 mL) was added to quench the reaction, the catalyst precipitated, filtered, the filtrate was extracted with DCM (3×50 mL), the organic phases were combined, dried and concentrated to give compound I (83.1 g, 98.6%).

[0064] 1 H NMR (CDCl 3 300MHz): δ2.5(s, 3H), 3.0(br, s, 1H), 5.49(s, 1H), 7.29-7.43(AB, J=8.5Hz, 4H).

Embodiment II

[0066]

[0067] Compound I (10 g, 55.8 mmol) was dissolved in CH 3 CN (150mL), add methylal (12.5g, 167.4mmol), add P 2 o 5 (23.5g, 167.4mmol), TLC detection until the end of the reaction. Pour the reaction solution into water, remove acetonitrile under reduced pressure, add TBME (100mL×2) for extraction, combine the organic phases, and wash with saturated NaHCO 3 (100ml×1), washed with saturated NaCl solution (500mL×1), dried over anhydrous sodium sulfate, concentrated by suction filtration to obtain compound IIa (12.4g, 83.2%).

[0068] Dissolve p-methyl sulfide benzaldehyde (10g, 65.7mmol) in THF (70mL), add zinc bromide (1.5g, 6.57mmol), drop the temperature to 0-5°C under the protection of nitrogen, then add dropwise TMSCN (6.5 g, 6.57mmol), reacted for 25hs, and HPLC detected the end of the reaction. Pour the reaction solution into water, add TBME (100mL×2) for extraction, combine the organic phases, and wash with saturated NaHSO 3 (100ml×1), washed with saturate...

Embodiment III

[0071]

[0072] Compound IIa (5.0g, 22.4mmol) was dissolved in 100mL ether, cooled to 0°C, vinylmagnesium bromide (24mL, 67.2mmol) was added dropwise, stirred at this temperature for 1 hour, and methanol was added after the disappearance of the raw material was detected by HPLC (70mL), added sodium borohydride (3.4g, 89.6mmol) in batches, stirred for 1.5 hours, HPLC detected that the reaction was over, added ice water to quench, extracted with TBME (50mL×2), after combining the organic phases, washed with water (50mL ×2), washed with saturated sodium chloride (50mL×2), dried and concentrated to obtain a crude product (6.8g), which was recrystallized by EA / PE system to obtain compound IIIa (5.4g, 95%) as a white solid.

[0073] 1,3-Dithiane (0.48g, 3.99mmol) was added into ether (20mL), cooled to -78°C, n-butyllithium (2.5mL, 3.99mmol) was added dropwise, and after stirring for 30min, compound IIb (0.5 g, 1.98mmol) in ether solution, reacted at -78°C for 1.5hs, added methano...

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Abstract

The invention discloses a florfenicol midbody, a preparation method thereof and a preparation method of florfenicol, and belongs to the field of veterinary drug preparation. The invention provides the florfenicol midbody shown in a formula IV, wherein R1 is dimethyl sulfide or methylene sulphonyl or methyl sulphonyl, R2 is TBS- or TMS- or MOM- or THP-, R3 is shown in the description, and R4 is dichloroacetyl or benzoyl or t-butyloxycarboryl. The invention further provides a preparation of the florfenicol midbody shown in the formula IV and a preparation method of florfenicol. The obtained florfenicol is low in cost, simple in technology and high in yield, and the product chirality purity reaches up to 98%.

Description

Technical field: [0001] The invention relates to the field of veterinary drug preparation, in particular to an intermediate for preparing florfenicol and a method for preparing florfenicol. Background technique: [0002] Florfenicol, also known as florfenicol and florfenicol, is a class of chemically synthesized antibiotics developed for the animal health market as a new type of anti-Gram-positive bacteria. It is a broad-spectrum antibacterial drug for animals. Its structure Similar to thiamphenicol, it has two chiral centers and four enantiomers, but only one of them is pharmacologically active. [0003] At present, the relatively mature technical routes for the synthesis of florfenicol in China mostly adopt the route of p-thiamphenicol benzaldehyde (Tobibiki Hisao; Ger Offen, DE2349496), all of which are raw materials such as chloramphenicol and thiamphenicol or their related intermediates. As a starting material, it can be prepared by reduction, protection, fluorination,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C315/04C07C317/32C12P13/00C07F7/18C07C319/20C07C323/32
CPCC07C315/02C07C315/04C07C319/20C07F7/1804C12P13/00C07C317/32C07C323/62C07C323/32
Inventor 李文森
Owner HEADING NANJING PHARMTECH CO LTD
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