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Synthetic method of tofacitinib intermediate (3r, 4r)-n, 4-dimethyl-1-benzyl-3-piperidinamine

A picoline and amino technology, applied in the field of medicinal chemistry, can solve the problems of poor stereoselectivity, poor atom economy, and low overall yield, and achieve the effects of high reaction yield, high optical purity, and cheap and easy-to-obtain raw materials

Active Publication Date: 2022-03-25
内蒙古京东药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] After investigating various routes, in order to overcome the deficiencies in the preparation of compound I in the prior art (such as the poor stereoselectivity in the preparation of (3R, 4R-rel-) isomers in the process of (II-c) in route one and Cause total yield is not high, atom economy is poor; Need to use very dangerous and expensive aluminum tetrahydrogen lithium or relatively safe some but equally expensive Red-Al) in the route two, the present invention provides a kind of each reaction raw material is cheap and easy Obtaining, the reaction method is simple and safe, especially suitable for industrial production of compound II-c, and then using L-tartaric acid or its O-acyl derivatives to resolve to obtain 3R, 4R-isomers, which are then converted into more suitable subsequent reactions The preparation method of free base and other salts (I-x)

Method used

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  • Synthetic method of tofacitinib intermediate (3r, 4r)-n, 4-dimethyl-1-benzyl-3-piperidinamine
  • Synthetic method of tofacitinib intermediate (3r, 4r)-n, 4-dimethyl-1-benzyl-3-piperidinamine
  • Synthetic method of tofacitinib intermediate (3r, 4r)-n, 4-dimethyl-1-benzyl-3-piperidinamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1: Synthesis of N-Boc-N,4-dimethyl-3-aminopyridine (Compound C)

[0048] 3-Amino-4-methylpyridine (100 g, 924.7 mmol) was added to the reaction flask, then triethyl orthoformate (400 g, 2.699 mol) was added, and the reaction was heated to 130-145° C. for about 8-12 hr. After the reaction was completed, the temperature was lowered to about 100° C., and the triethyl orthoformate was concentrated under reduced pressure. The obtained residue was distilled under reduced pressure with a high vacuum oil pump to obtain 129 g (785.6 mmol) of a pale yellow to colorless liquid (compound A-x, R=Et) with a yield of 85.0%.

[0049] The above-obtained compound A-x (R=Et) (120g, 730.8mmol) was dissolved in 600g absolute ethanol, cooled to between 5 and 10°C, and 32g (845.9mmol) of sodium borohydride was added in batches to control the temperature not to exceed 20°C. After adding, return the temperature to 25-30°C and stir for about 30-60min, then slowly heat to reflux and cont...

Embodiment 2

[0051] Example 2: Synthesis of N-Boc-N,4-dimethyl-3-aminopyridine (Compound C)

[0052] Add 3-amino-4-methylpyridine (120g, 1.110mol) to the reaction flask, then add trimethyl orthoformate (450g, 3.036mol), heat to 120~130℃ and react for about 10~16hrs. After the reaction was completed, the temperature was lowered to about 100° C., and the trimethyl orthoformate was concentrated under reduced pressure. The obtained residue (compound A-x, R=Me) (182.2 g based on theoretical amount) was directly used in the next reaction.

[0053] The above-obtained compound A-x (R=Me) was dissolved in 1080 g isopropanol, cooled to between 5 and 10 ° C, and 45 g (1.190 mol) of sodium borohydride was added in batches to control the temperature not to exceed 20 ° C. Warm to 25-30°C, stir for about 1-1.5 hr, then slowly heat to reflux, and continue the reaction for about 2-4 hr. After the reaction, the isopropanol was concentrated under reduced pressure, water (1000g) was added to the residue, an...

Embodiment 3

[0055] Example 3: Synthesis of 1-benzyl-N-Boc-N,4-dimethyl-1,2,5,6-tetrahydropyridin-3-amine (compound E)

[0056] The obtained compound C (150 g, 674.8 mmol) was added to 600 g of toluene, then benzyl chloride (94 g, 742.6 mmol) was added, heated to between 100 and 110 ° C, and reacted for 10 to 16 hr; after the reaction was completed, cooled to 20 to 20 30°C, add 600 g of water, stir evenly, let stand, and separate the liquid to separate the lower water phase (aqueous solution of compound D-x, X - =Cl - ),spare.

[0057] Dissolve 0.1 g of sodium hydroxide in 100 g of water, then add sodium borohydride (26 g, 687.3 mmol) to dissolve in the aqueous sodium hydroxide solution; slowly add the aqueous sodium borohydride solution dropwise to the above-mentioned quaternary ammonium salt aqueous solution, add dropwise The process temperature was controlled between 15 and 25 ° C. After the dropwise addition, the reaction was continued for 2 to 4 hr. After the reaction was completed,...

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Abstract

The invention relates to a synthesis method of tofacitinib intermediate (3R, 4R)-N,4-dimethyl-1-benzyl-3-piperidinamine. Using 3-amino-4-picoline as the starting material, its amino group reacts with orthoformate to form iminocarbamate, and after simple concentration, it is reduced with metal borohydride to obtain N-methyl derivatives; After Boc protection, form a quaternary ammonium salt with a halobenzyl, reduce it with a metal borohydride, and then selectively hydrogenate it with a Rh catalyst to form a compound with an enriched (3R, 4R-rel-) configuration, and then undergo hydrochloric acid / The alcohol system is deprotected and separated by salt formation to remove the (3R, 4S‑rel‑) isomer pair, and the obtained (3R, 4R‑rel‑) configuration product is separated and then resolved by L‑DTTA to obtain 3R, 4R‑ configuration product.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing a key intermediate of Tofacitinib (3R, 4R)-N, 4-dimethyl-1-benzyl-3-piperidinamine and salts thereof . The general structure of the intermediate (I) and its salt (I-x) is as follows: [0002] [0003] Wherein compound K is (3R,4R)-N,4-dimethyl-1-benzyl-3-piperidinamine monooxalate monohydrate. Background technique [0004] Tofacitinib citrate, a Janus kinases inhibitor developed by Pfizer, affects DNA transcription by interfering with the JAK-STAT signaling pathway. It was first approved by the U.S. Food and Drug Administration (FDA) on November 6, 2012, and subsequently approved by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) on March 25, 2013, and was marketed by Pfizer in the United States and Japan. , the trade name is In China, tofacitinib citrate was approved for marketing by CFDA on March 10, 2017. [0005] Tofacitinib ci...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/56
CPCC07D211/56
Inventor 吕关锋郭荣耀
Owner 内蒙古京东药业有限公司