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Preparation method of posaconazole intermediate

A technology for posaconazole and intermediates, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of expensive, complicated product separation, and low yield, and achieve the effects of low production cost, high reaction yield, and simple operation

Inactive Publication Date: 2012-08-22
FUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although there are few steps in this process, expensive target catalysts are used, and propadiene is extremely active and produces many impurities, which makes the separation of products extremely complicated and the yield is low

Method used

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  • Preparation method of posaconazole intermediate

Examples

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Effect test

example 1

[0058] Example 1 2-(2'-chloropropenyl)-synthesis of diethyl malonate (structural formula III, wherein R=C 2 h 5 )

[0059] Diethyl malonate (115 g, 715 mmol) and potassium iodide (30 mg) were added dropwise to ethanol (250 mL) containing 49.0 g (720 mmol) sodium ethoxide at room temperature. After refluxing for 10 min, 2,3-dichloropropene (78.0 g, 706 mmol) was added dropwise to the reaction solution, and the addition was completed within 2 h. Continue to reflux for 2 h and cool to room temperature. The solvent was distilled off under reduced pressure to obtain the residual oil, which was added with 300 mL of water and extracted with ethyl acetate (2?? 500 mL). The extracts were combined, washed with saturated sodium chloride (300 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the remaining oil was distilled under reduced pressure (bp: 94-100 °C / 3-4 mmHg) to obtain 2-(2'-chloropropenyl)-diethyl malonate ( (147 g, 89.1%...

example 2

[0060] Example 2 Synthesis of 2-(2'-chloropropenyl)-1,3-propanediol (structural formula IV)

[0061] At 0??C, add 2-(2'-chloropropenyl)-diethyl malonate (30.0 g, 128 mmol) to a mixture containing 73 mL of tetrahydrofuran and 7.30 g (190 mmol) of lithium aluminum hydride ) in tetrahydrofuran (50 mL), dropwise over 30 min, stirred at this temperature for 10 min, and then refluxed for 8 h. After cooling with ice water, the reaction solution was slowly added to dilute hydrochloric acid (200 mL, prepared by mixing 170 mL ice water and 35 mL concentrated hydrochloric acid) while stirring. Diethyl ether (100 mL) was added to extract (2?? 100 mL), the combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The diethyl ether solvent was distilled off under reduced pressure to obtain a light yellow solid (17.6 g, 91.7%), which is the crude product of 2-(2′-chloropropenyl)-1,3-propanediol, which was directly used in the next step without fu...

example 3

[0062] Example 3 Synthesis of 2-(2'-chloropropenyl)-1,3-propanediol diacetate (structural formula V, wherein R 1 =CH 3 )

[0063] At room temperature, add dropwise Acetic anhydride (14.0 g, 138 mmol), stirred at room temperature for 4 h, then carefully added saturated sodium bicarbonate solution (150 mL). The layers were separated, and the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to obtain the pale yellow title compound (15.1 g, 97.0%). 1 H NMR (500 MHz, CDCl 3 ) δ 5.24 (d, J = 1.3 Hz, 1 H), 5.18 (d, J = 1.1 Hz, 1 H), 4.10 (dd, J = 11.2, 4.6 Hz, 2 H), 4.05 (dd, J = 11.2, 5.6 Hz, 2 H), 2.46–2.40 (m, 3 H), 2.05 (s, 6 H); IR (KBr) = 3110, 2960, 1745, 1637, 1435, 1368, 1232, 1158, 1043, 890, 635 cm -1 ; MS (ESI + ) m / z : 235 [M+1] + , 257 [M+Na] + . Anal. Calcd for C 10 h 15 ClO 4 (234.68): C 51.18, H 6.44; Found: C 51.11, H 6.27.

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Abstract

The invention belongs to the technical field of pharmacochemistry and in particular relates to a preparation method of a posaconazole intermediate. The method comprises four steps of alkylation, reduction, acylation and cross-coupling, so that a target compound (I) is obtained. Compared with the existing synthetic method, the synthetic method provided by the invention has the characteristics of low price and easiness in obtainment of raw materials, simple and convenient technology, high yield and the like.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to the preparation of a posaconazole intermediate. Background technique [0002] Posaconazole (chemical name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-tri Azol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3 -base]-1,2,4-triazol-3-one, posaconazole), the specific structural formula is shown in formula VI: [0003] . [0004] Posaconazole has a broad antibacterial spectrum, good safety and tolerability, and provides a new treatment option for the prevention and treatment of deep fungal infections. The drug is a broad-spectrum triazole antifungal drug approved by the U.S. FDA on September 15, 2006, and is used for refractory diseases or fungal infections caused by other drugs. [0005] The sulfonate represented by formula VII is a key intermediate of posaconazole, which can be used to further synthesi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/007C07C67/333
Inventor 唐凤翔孟春李小虎
Owner FUZHOU UNIV
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