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Synthetic method of piperidine derivative

A synthesis method and derivative technology, applied in bulk chemical production, carboxylate preparation, organic chemistry, etc., to achieve the effect of improving yield and simple operation

Active Publication Date: 2014-04-30
SHANGHAI BOC CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The yield of this reaction is only less than 15% to 18%.

Method used

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  • Synthetic method of piperidine derivative
  • Synthetic method of piperidine derivative
  • Synthetic method of piperidine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Take 1mol of 4-methyl-3-hydroxypyridine and 1.1mol of di-tert-butyl dicarbonate (Boc 2 O), heated to reflux for 10 hours, TLC showed that the reaction of the raw materials was complete, the reaction system was cooled to room temperature and diluted with ethanol, after cooling to 0°C, 0.9mol sodium borohydride was added, after the addition was completed, stirred at 0°C for 2 hours, TLC showed that the reaction was complete, Add 1mol / L hydrochloric acid aqueous solution, extract with methyl tert-butyl ether, and purify to obtain 1-tert-butoxycarbonyl-4-methyl-3-pyridone (0.86mol), yield 86%, structural formula:

[0029] 1 H NMR (300MHz, CDCl 3 ) 4.12(q,2H), 3.03-2.92(m,2H), 2.40(m,1H), 1.96-1.80(m,2H), 1.38(s,9H), 1.12(d,3H). MS:m / z=214(M+H) + .

Embodiment 2

[0031] 1.0mol of 1-tert-butoxycarbonyl-4-methyl-3-pyridone and 1.1mol of (S)-N-methyl-1-phenylethylamine (cas: 19131-99-8, ) was dissolved in 10 times the volume of dichloromethane (DCM). After stirring at 10°C for 1 hour, 3.2 mol of sodium acetate borohydride was added in batches and reacted for 4 hours. TLC showed that the reaction was complete. Water was added to separate layers and the organic phase was collected. , the obtained 1-tert-butoxycarbonyl-3-[(S)-N-methyl-1-phenylethylamino]-4-methyl-pyridine, structural formula: Ph represents a phenyl group. The purity of the product in the organic phase detected by high performance liquid chromatography is 91%, and the product yield is 95%. The collected organic phase does not need to be purified, and can be directly used for the next step reaction, LC-MS: m / z=333 (M+ h) + .

Embodiment 3

[0033] The ethanol solution containing the L-tartaric acid of 0.49mol is added dropwise in the organic phase adopting the method gain of embodiment 2 (1-tert-butoxycarbonyl-3-[(S)-N-methyl-1-benzene containing 1mol ethylamino]-4-methyl-pyridine), heated to reflux until all the solids were dissolved, cooled to 0°C, crystallized, and recrystallized twice to obtain (3R,4R)-1-tert-butoxycarbonyl-3- [(S)-N-methyl-1-phenylethylamino]-4-methyl-pyridine-L-tartrate, the yield is 78.3% Structural formula:

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Abstract

The invention discloses a synthetic method of a piperidine derivative. The piperidine derivative is tartrate of a compound with a structural formula (I) shown in the specification, wherein R1 is an amino-protecting group; R2 is a phenyl group or alkyl-substituted phenyl group; R3 is C1-C6 alkyl. The piperidine derivative is obtained by reaction of a compound with a structural formula (II) shown in the specification and L-tartaric acid and separation. After an S-substituent group is introduced to the amino group at the third position of a piperidine ring, the effect of splitting out a compound shown in the specification from a compound shown in the specification by using L-tartaric acid can be obviously improved. The method can be applied to synthesis of drug Tofacitinib, so as to improve the yield of the drug Tofacitinib.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of piperidine derivatives. Background technique [0002] Tofacitinib is a new drug developed by Pfizer for the treatment of rheumatoid arthritis (RA), which belongs to a class of oral drugs with a new mechanism of action called JAK inhibitors. Its structural formula is as follows: [0003] CAS number: 477600-75-2, molecular formula: C 16 h 20 N 6 O, molecular weight 312.37. in, It is an important intermediate for the synthesis of Tofacitinib, which is then combined with key, you can get Tofacitinib. [0004] The above intermediates are usually synthesized first Then by chiral separation with enantiomers separate to obtain pure [0005] U.S. Patent US8309716B2 discloses a method of using L-di-p-toluoyl tartaric acid (di-p-tolu oyl-L-tartaric acid, L-DPTT) for the above A method for chiral separation, such as L-DPTT a...

Claims

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Application Information

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IPC IPC(8): C07D211/56C07D487/04C07C51/41C07C59/255
CPCY02P20/55C07D211/56C07D487/04
Inventor 李尚立李建东詹智年张永亮
Owner SHANGHAI BOC CHEM CO LTD
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