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Simple synthetic method of 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine

A synthesis method and 3-d technology, applied in the field of medicine and biochemical industry, can solve problems such as unfavorable industrialization implementation, unfavorable cost reduction, low atom economy, etc., and achieve the effects of stable and controllable reaction, low cost and high reaction selectivity.

Active Publication Date: 2019-04-19
XINFA PHARMA
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  • Claims
  • Application Information

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Problems solved by technology

[0012] In summary, the compound of formula X, i.e. 7-protecting group-4-(1-hydrogen-pyrazol-4-yl)pyrrole[2,3-d]pyrimidine is the most important compound of ruxolitinib and bazone in the existing synthetic route. The key intermediate of ricitinib, but its preparation method in the prior art has the following deficiencies: the preparation process is loaded down with trivial details, and the amount of waste water is big, and atom economy is low; Required Wittig reaction, tetrakis (triphenylphosphine) palladium catalyzed coupling reaction, Grignard reagent or metal lithiation requires high operation requirements; the raw materials used are 4-chloro-7-hydropyrrole[2,3-d]pyrimidine, 1-(1-ethoxyethyl)-1-hydropyrrole-4- Borate esters and tetrakis(triphenylphosphine) palladium are expensive, and the preparation process is long, which is not conducive to cost reduction, and requires multiple column chromatography separations, which is not conducive to industrial implementation

Method used

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  • Simple synthetic method of 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine
  • Simple synthetic method of 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine
  • Simple synthetic method of 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: 2-(7-hydropyrrole [2,3-d] pyrimidin-4-yl) methyl acetate (V 1 ) preparation

[0056] In a 500 ml four-neck flask, add 150 g of N,N-dimethylformamide, 15.5 g (0.11 mole) of methyl cyanoacetoacetate, 24.0 g (0.12 mole) of 27% sodium methoxide in methanol, 20-25 Between ℃, 17.0 g (0.1 mole) bromoacetaldehyde dimethyl acetal was added dropwise, and the dropwise addition was completed in about 30 minutes. After that, it was reacted at 20-25 ℃ for 6 hours, and the reaction of bromoacetaldehyde dimethyl acetal was completed by gas phase detection, and 1,1 -Dimethoxy-3-cyano-4-oxo-n-hexanoic acid methyl ester (Ⅳ 1 ). Add 10.0 grams (0.12 moles) of formamidine hydrochloride, 24.0 grams (0.12 moles) of 27% sodium methoxide methanol solution, react at 40-45 ° C for 4 hours, add 20 grams of saturated ammonium chloride aqueous solution, adjust the pH value to 3-4, 40 Stir at -45°C for 2 hours. The reaction liquid was added to 500 g of ice water, filtered, and the filt...

Embodiment 2

[0057] Example 2: 2-(7-hydropyrrole [2,3-d] pyrimidin-4-yl) ethyl acetate (V 2 ) preparation

[0058] Into a 500 ml four-necked flask, add 150 g of N,N-dimethylformamide, 15.5 g (0.1 mole) of ethyl cyanoacetoacetate, 27.5 g (0.12 mole) of 30% sodium ethylate ethanol solution, 20-25 Between ℃, 19.5 grams (0.1 mole) of bromoacetaldehyde diethyl acetal was added dropwise, and the dropwise addition was completed in about 30 minutes. After that, the reaction was carried out at 20-25°C for 6 hours. -diethoxy-3-cyano-4-oxo-n-hexanoate (IV 2 ). Add 10.0 grams (0.12 moles) of formamidine hydrochloride, 27.5 grams (0.12 moles) of 30% sodium ethylate ethanol solution, react at 40-45 ° C for 4 hours, add 20 grams of saturated ammonium chloride aqueous solution, adjust the pH value to 3-4, 30 Stir at -35°C for 3 hours. The reaction liquid was added to 500 g of ice water, filtered, and the filter cake was recrystallized with 80 g of isopropanol to obtain 18.6 g of 2-(7-hydropyrrole[2,3-...

Embodiment 3

[0059] Example 3: tert-butyl 2-(7-hydropyrrole [2,3-d] pyrimidin-4-yl) acetate (V 3 ) preparation

[0060] Into a 500ml four-neck flask, add 150g of N,N-dimethylformamide, 18.5g (0.10mol) of tert-butyl cyanoacetoacetate, 6.5g (0.12mol) of solid sodium methoxide, at 30-35°C During this period, 15.5 grams (0.1 mole) of chloroacetaldehyde diethyl acetal was added dropwise, and the dropwise addition was completed in about 30 minutes. After that, it was reacted at 30-35°C for 6 hours. Ethoxy-3-cyano-4-oxo-n-butyl hexanoate (IV 3 ). Add 10.0 grams (0.12 moles) of formamidine hydrochloride, 24.0 grams (0.12 moles) of 27% sodium methoxide methanol solution, react at 40-45 ° C for 4 hours, add 20 grams of saturated ammonium chloride aqueous solution, adjust the pH value to 3-4, 40 Stir at -45°C for 2 hours. The reaction liquid was added to 500 g of ice water, filtered, and the filter cake was recrystallized with 90 g of isopropanol to obtain 19.8 g of tert-butyl 2-(7-hydropyrrole[2...

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Abstract

The invention discloses a simple synthetic method of 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine. The method comprises the following steps: preparing compound (IV) by a dehydrohalogenation reaction between cyanoacetoacetate and haloacetaldehyde glycol, and then preparing a compound (V) by condensation between the compound (V) and formamidine hydrochloride and alkali; preparing a compound (VIII) by amino group protection through a protecting group reagent, methylation of DMFDMA and hydrazine hydrate condensation; preparing a compound (IX) by reacting with a chlorination reagent; and carrying out catalytic hydrodechlorination to obtain 7-protecting group-4-(1-hydrogen-pyrazole-4-yl)pyrrole[2,3-d]pyrimidine. The raw materials used in the invention are cheap and easily available; by using the ''one-pot method'' operation twice, the environmental protection property is high, and the process route is simple; the reaction operation is convenient, and the reaction selectivity is high; the obtained product has high purity, high yield and low cost; and the method is beneficial to green industrial production.

Description

technical field [0001] The present invention relates to a synthetic method of the key intermediate pyrrolopyrimidine heterocyclic compound required for the preparation of ruxolitinib and baricitinib, in particular to a 7-protecting group-4-(1-hydrogen-pyrazole- The invention discloses a convenient synthesis method of 4-yl)pyrrole[2,3-d]pyrimidine (X), which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Ruxolitinib, also known as Ruxolitinib, is an antineoplastic drug developed by Novartis, mainly used for the treatment of myelofibrosis (MF). Myelofibrosis is a hematopoietic stem cell clonal disorder characterized by myeloid proliferation, including primary myelofibrosis (PMF), polycythemia vera (PV), post-polycythemia vera myelofibrosis (post-PV MF) , Myelofibrosis after essential thrombocythemia (post-ET MF), the Janus kinase (JAK) / signal transducer and activator of transcription (STAT) signaling pathway plays an important role ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/10
CPCC07F7/10Y02P20/55
Inventor 戚聿新孟鲁波杨玉梅张明峰鞠立柱
Owner XINFA PHARMA
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