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Chemical process

A quinazoline and compound technology, applied in the chemical field of preparing quinazoline derivatives, can solve problems such as low total yield, achieve significant time and cost advantages, reduce the number, high quality and yield effects

Active Publication Date: 2012-06-20
GENZYME CORP
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Problems solved by technology

However, these pathways involve linear rather than pooled synthesis, require the use of multiple purification steps, and require the isolation of large numbers of intermediates
Therefore, the overall yield of the synthesis is not high

Method used

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[0076] The routes disclosed in the prior art literature for the preparation of compounds of formula VI are suitable for the synthesis of relatively small quantities of compounds. However, they all require isolation and / or purification of intermediate compounds. This resulted in a satisfactory but not high overall yield of the compound of formula VI.

[0077] Therefore, there is a need for more efficient synthetic methods of compounds of formula VI suitable for the preparation of larger quantities of compounds. Preferably, new syntheses should not involve costly and time-consuming isolation and / or purification procedures. Therefore, the new synthetic method should reduce the number of isolation and / or purification steps required, and thereby reduce the cost and time of preparation. The new synthesis should also allow efficient isolation of the compound of formula VI in high purity and yield, in crystalline form, which should have good filtration properties.

[0078] Accordin...

Embodiment 1

[0306] Preparation of 1-(tert-butoxycarbonyl)-4-(4-methylbenzenesulfonyloxymethyl)-piperidine (compound of formula II)

[0307] A solution of di-tert-butyldicarbonate (88.63 g) in toluene (296 mL) was added to a stirred solution of ethyl hexahydroisonicotinate (62.88 g) in toluene (317 mL). The reaction mixture was then distilled at atmospheric pressure, removing approximately 130 ml of distillate, with a final distillation temperature of 112°C. Sodium bis(2-methoxyethoxy)aluminum hydride (Red-A1, 65% w / w solution in toluene, 161 g) in toluene (220 mL) was then added to in the reaction mixture. A 0.5 molar solution of Rochelle's salt (191 mL) was added to the reaction mixture, and the aqueous phase was separated at 40°C. The organic phase was washed with 15% w / v brine (3x136 mL) and water (136 mL). The solution was distilled at normal temperature, and about 400 ml of distillate was removed, and the final distillation temperature was 112°C. Triethylenediamine (51.62 g) wa...

Embodiment 2

[0309] Preparation of hydrochloride (hydrochloride of formula VI compound) of 7-benzyloxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline

[0310] 7-Benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (20.00 g) was mixed with anisole (190 ml) and N,N-diisopropylethylamine ( 13.74 g) mixed. The reaction mixture was inert with nitrogen and cooled to 15°C. Phosphorus oxychloride (14.12 g) was added to the reaction mixture over 15 minutes, followed by anisole (10 mL) as a wash. The reaction mixture was stirred at 15°C for 15 minutes, then heated to 80°C over 90 minutes, and the resulting reaction mixture was then stirred at 80°C for one hour. A solution of 4-bromo-2-fluoroaniline (16.8 g) in anisole (20 mL) was added to the reaction mixture over 40 minutes. The reaction mixture was stirred at 80°C for 90 minutes. The reaction mixture was then cooled to 25°C and the product was isolated by filtration. Yield: 26.9 g, 84%; NMR spectrum (DMSOd 6 , CD 3 COOD) 4.0 (s, 3H), 5.37 (...

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Abstract

The present invention relates to chemical processes for the manufacture of certain quinazoline derivatives, or pharmaceutically acceptable salts thereof. The invention also relates to processes for the manufacture of certain intermediates useful in the manufacture of the quinazoline derivatives and to processes for the manufacture of the quinazoline derivatives utilising said intermediates. In particular, the present invention relates to chemical processes and intermediates useful in the manufacture of the compound 4-(4- bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline.

Description

[0001] 本申请是申请号为200680036468.X(国际申请号为PCT / GB2006 / 003587)、申请日为2006年9月27日、发明名称为“化学方法”的中国专利申请的分案申请。 field of invention [0002] The present invention relates to chemical processes for the preparation of certain quinazoline derivatives or pharmaceutically acceptable salts thereof. The invention also relates to processes for the preparation of certain intermediates useful in the preparation of quinazoline derivatives, and to methods of using said intermediates to prepare quinazoline derivatives. [0003] In particular, the present invention relates to the preparation of the compound 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline chemical methods and intermediates. 该化合物落入了WO 98 / 13354的宽的公开范围,并且在WO 01 / 32651中的实施例2a、2b和2c中进行了举例说明。 Background technique [0004] 化合物4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)喹唑啉在本文中通过式I描述: [0005] [0006] Also described as ZD6474, the known code for this compound. Compound ZD6474 also known as Vandetanib and Zactima...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D211/16C07D239/94
CPCC07D211/16C07D401/12C07D239/94A61P17/06A61P19/08A61P27/02A61P29/00A61P35/00A61P9/10
Inventor J·布利克斯特M·D·戈尔登P·J·霍根D·M·G·马丁F·J·蒙哥马利Z·帕特尔J·D·皮塔姆G·J·塞彭达C·J·斯奎尔N·C·A·赖特
Owner GENZYME CORP
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