Preparation method for Baricitinib intermediate

A compound and alkyl technology, applied in the field of preparation of baricitinib intermediates, can solve the problems of long reaction route, high production cost, discomfort and industrialized production, etc.

Active Publication Date: 2017-04-05
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Application Information

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Problems solved by technology

[0009] Both method 1 and method 2 need to combine compound 2 and compound 3 in Pd(PPh 3 ) 4 Reaction in the presence of intermediate 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl base)-7H-pyrrolo[2,3-d]pyrimidine (compound 6), and then remove the 1-ethoxyethyl protecting group to obtain the intermediate 4-(1H-pyrazol-4-yl)-7- ((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (compound 5), and then carry out subsequent reactions through this intermediate; since compound 3 is By connecting "1-ethoxyethyl" and "4,4,5,5-tetramethyl-1,3,2-dioxaborolane respectively at the corresponding positions of the 1H-pyrazole structure Alkyl-2-base" structural fragments (such as Qiyan Lin et al., Enantioselective Synthesis of Janus Kinase Inhibitor INCB018424via an Organocatalytic Aza-Michael Reaction, Organic Letters, 2009, 11(9), pp 1999-2002), so method 1 and The reaction route of method 2 has two steps of connection and removal of the "1-ethoxyethyl" protecting group. The reaction route is long, the production cost is high, and it is not suitable for industrial production. Therefore, a new preparation method is still needed to adapt to industrialization. production needs

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  • Preparation method for Baricitinib intermediate
  • Preparation method for Baricitinib intermediate
  • Preparation method for Baricitinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] Example 1 Preparation of 4-chloro-7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrole[2,3-d]pyrimidine (compound of formula IX)

[0124]

[0125] In a 2-liter three-necked flask, add 4-chloropyrrolopyrimidine (280g, 1.83mol) and N,N-dimethylacetamide (500mL), cool down to -10°C, add NaH (84g) three times, and the addition is complete. Keep stirring for 0.5 hours. Add 2-(trimethylsilyl)ethoxymethyl chloride (385mL, 1.98mol). After the addition is complete, react at room temperature for 2 hours, pour the reaction solution into 1L of water, add 500mL of ethyl acetate, stir and extract to separate the ester layer, washed once with 300 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 390 g of a red product with a yield of 75%.

Embodiment 2

[0126] Example 2 2-[1-Ethylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1H- Preparation of pyrazol-1-yl]azetidin-3-yl]acetonitrile (compound of formula V)

[0127]

[0128] Add 4-pyrazoleboronic acid pinacol ester (14g, 72.1mmol) to 100mL acetonitrile at room temperature, add 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile (18g, 96.7mmol ) and DBU (20mL), stirred and reacted at room temperature for 2 hours, added ethyl acetate (500mL) and water (500mL), extracted and separated, the aqueous layer was extracted once with 50mL ethyl acetate, the organic layer was combined, and then washed with 50mL saturated chlorine Wash once with sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 23 g of a yellow solid. Yield 85%. 1 H-NMR (300MHz, CDCl 3 ), δ (ppm): 1.32 (12H, s, 4×CH 3 ), 1.37~1.41 (3H,t,J=7.4Hz,CH 3 ),3.02~3.09(2H,q,J=7.3Hz,CH 2 ),3.33(2H,s,CNCH 2 ),4.15~4.18(2H,d,J=9.1Hz,NCH 2 ),4.50~4.53...

Embodiment 3

[0129] Example 3 2-[1-Ethylsulfonyl-3-[4-(7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrolo[2,3-d ]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl]acetonitrile (compound of formula XI)

[0130]

[0131]4-Chloro-7-[(2-(trimethylsilyl)ethoxy)methyl]-7H-pyrrole[2,3-d]pyrimidine (50g, 0.176mol) and 2-[1 -Ethylsulfonyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1H-pyrazol-1-yl] Azetidin-3-yl]acetonitrile (67g, 0.176mol) was added to a 2L eggplant-shaped bottle, and n-butanol (500mL), potassium carbonate (50g, 0.352mol), and tetrakis(triphenylphosphine)palladium were added successively (0)(Pd(PPh 3 ) 4 , 10g) and water (100mL), heat up to reflux for 2 hours, add 500mL ethyl acetate and 500mL water to the reaction solution, extract and separate the liquid, separate the organic layer, then wash once with 200mL saturated sodium chloride solution, Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 78 g of light yellow solid with a yiel...

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Abstract

The invention belongs to the field of pharmaceutical and chemical industry, and particularly relates to a preparation method for a Baricitinib intermediate. The preparation method is characterized in that a key intermediate 2-[1-ethyl sulfonyl-3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-parazole-1-ethyl] azacyclobutyl-3-yl) acetonitrile is prepared through reaction of a 4-parazole boride and 2-[1-(ethyl sulfonyl-3-azacyclobutaneylidene) acetonitrile, and nitrogen on a pyrazolone ring of 4- parazole boride does not need to be protected, so that a follow-up step of removing a corresponding a protective group is avoided, and therefore, the whole reaction route is short, raw materials are obtained easier, the production cost is low, and the preparation method is especially suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a baricitinib intermediate. Background technique [0002] Baricitinib, chemical name {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azepine Cyclobutan-3-yl}acetonitrile is a small molecule JAK-1 and JAK2 kinase inhibitor developed by Eli Lilly and Incyte for oral treatment of rheumatoid arthritis, psoriasis and other inflammatory diseases, as well as diabetic nephropathy. [0003] [0004] CN102026999A discloses Baricitinib and its intermediate 2-[1-ethanesulfonyl-3-[4-(7-[(2-(trimethylsilyl) ethoxy) methyl]-7H-pyrrolo[ 2,3-d] pyrimidin-4-yl)-1H-pyrazol-1-yl] azetidin-3-yl] the preparation method of acetonitrile (formula I), the intermediate preparation method is as follows: [0005] method 1: [0006] [0007] Method 2: [0008] [0009] Both method 1 and method 2 need to combine compound 2 ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02C07D487/04C07F7/10
CPCY02P20/55
Inventor 甘宗捷刘飞顾红梅张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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