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Preparation method of 5,5-difluoro-3-substituted piperidine derivative

A technology of derivatives and piperidine, which is applied in the field of synthesis of organic compounds, can solve problems such as inability to realize industrialized production, difficulty in product purification, and single product, and achieve the effects of avoiding difficult product separation, mild reaction conditions, and single product

Active Publication Date: 2014-07-23
SHANGHAI AQ BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The purpose of the present invention is to overcome the disadvantages of high cost of preparing 5,5-difluoro-3-substituted piperidine compounds in the prior art, difficult purification of the product, and inability to realize industrial production, and provide a relatively mild reaction condition, the product The method for preparing the compound is single, high in yield, and can be easily scaled up for industrial production

Method used

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  • Preparation method of 5,5-difluoro-3-substituted piperidine derivative
  • Preparation method of 5,5-difluoro-3-substituted piperidine derivative
  • Preparation method of 5,5-difluoro-3-substituted piperidine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Embodiment 1: Preparation of ethyl N-benzyl-5,5-difluoro-4-hydroxyl-3-piperidinecarboxylate (3)

[0074]

[0075] 55 g of ethyl N-benzyl-5,5-difluoro-4-carbonyl-3-piperidinecarboxylate (2) was dissolved in 1 L of toluene, 10.5 g of sodium borohydride was added at room temperature, and stirred at room temperature for 72 hours under nitrogen protection. After the reaction, add 300ml of water, adjust the pH value to 8 with 1N dilute hydrochloric acid, separate the liquids, extract the aqueous phase with ethyl acetate (500ml*2), combine the organic phases, dry and concentrate with sodium sulfate, and recrystallize with ethyl acetate petroleum ether , to obtain ethyl N-benzyl-5,5-difluoro-4-hydroxy-3-piperidinecarboxylate (3) cis-trans isomerism mixture 39.6g, yield 72%.

[0076] cis-N-benzyl-5,5-difluoro-4-hydroxy-3-piperidinecarboxylic acid ethyl ester (3-1): 1 HNMR(300MHzCDCl3)δ(ppm)7.34~7.26(br,5H),4.30~4.23(br,1H),4.23~4.16(dd,2H),3.74~3.57(dd,2H),3.01~2.89(br, 4H)...

Embodiment 2

[0079] Example 2: Preparation of ethyl N-benzyl-5,5-difluoro-4-methylsulfonyloxy-3-piperidinecarboxylate (3a)

[0080]

[0081] N-benzyl-5,5-difluoro-4-hydroxy-3-piperidinecarboxylic acid ethyl ester (3) 20g was dissolved in 150ml dry tetrahydrofuran, added 16.8g triethylamine, 0.1g DMAP, cooled to 5 °C, 9.5 g of methanesulfonyl chloride was added dropwise. After the drop, the reaction liquid naturally rose to room temperature and reacted at room temperature for 15 hours. After the reaction, the reaction solution was poured into 100ml of ice water, separated, the aqueous layer was extracted with ethyl acetate (100ml*2), the organic layers were combined, dried and concentrated over sodium sulfate to obtain N-benzyl-5,5-difluoro- Ethyl 4-methylsulfonyloxy-3-piperidinecarboxylate (3a) 21 g of crude product.

Embodiment 3

[0082] Example 3: Preparation of N-benzyl-5,5-difluoro-3-ethoxycarbonyl-1,2,5,6-tetrahydropyridine (4)

[0083]

[0084] Ethyl N-benzyl-5,5-difluoro-4-methylsulfonyloxy-3-piperidinecarboxylate (3a) 21 g of the crude product was dissolved in 100 ml of dry pyridine, followed by the addition of 6.3 g of potassium tert-butoxide, nitrogen Heated to reflux under protection for 8 hours. After the reaction was cooled to room temperature, it was poured into 100ml of ice water, extracted with ethyl acetate (100ml*3), the organic layer was dried and concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether) to obtain N-benzyl-5, 10.2 g of 5-difluoro-3-ethoxycarbonyl-1,2,5,6-tetrahydropyridine (4), yield 65%.

[0085] 1 HNMR (300MHz CDCl 3 )δ(ppm)7.35~7.26(m,5H),6.78(s,1H),4.28~4.22(dd,2H),3.75(s,2H),3.36~3.32(m,2H),2.91~2.86( t,2H),1.33~1.29(t,3H);

[0086] MS-ESI:cal.281;found:282(M+H + ).

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Abstract

The method of the present invention relates to a preparation method of 5,5-difluoro-3-substituted piperidine derivatives, the method comprising the following steps: (1) using compound 2 as the starting material, at 0°C to 80°C , compound 3 was generated by reduction; (2) compound 3 was dehydrated to generate compound 4; (3) compound 4 was catalyzed by Pd-C at 0°C to 70°C, and compound 5 was reduced by H2; (4) compound 5 After further reaction, 5,5-difluoro-3-substituted piperidine derivative 1 was generated. The reaction formula is: where R1 is an ester group, carboxyl, hydroxymethyl, amino, acetamido, trifluoroacetamido, benzylamine or R3 is C1-C9 alkyl, aryl or benzyl; R2 is hydrogen, C1 -C9 alkyl, aryl, hydroxymethyl, benzyl or R4 is C1-C9 alkyl, aryl or benzyl; each of the above groups is unsubstituted or replaced by one or more selected from alkyl, haloalkane Substituents consisting of radical, hydroxyalkyl, halogen, alkoxy or hydroxyl.

Description

technical field [0001] The present invention relates to a synthesis of organic compounds, more specifically to a preparation method of 5,5-difluoro-3-substituted piperidine derivatives. Background technique [0002] Due to the uniqueness of fluorine atoms, the introduction of organic molecules can bring dramatic changes to the molecular activity and its pharmacological properties, especially in the development of safe and selective drug molecules. As a result, more and more pharmacologists and pharmaceutical companies have been attracted to join the ranks of fluorine-containing drug research and development (Klaus Müller, Christoph Faeh, Diederich, Sceience, 2007, 317, 1881; O'Hagan, D., Chem. Soc. Rev., 2008, 37, 308; Purser, S.; Moore, P.R.; Swallow, S.; Gouverneur, V,. .Rev.,2008,37,320;Kirk,K.L.,Org.Process Res.Dev.,2008,12,305;Isanbor,C.;O'Hagan,D.,J.Fluorine Chem.,2006,127,992;Krik,K.L, J. Fluorine Chem., 2006, 127, 992). [0003] The piperidine structure is a very...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/56C07D211/60
Inventor 张会利何运强施成进卢寿福
Owner SHANGHAI AQ BIOPHARMA CO LTD