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Intermediates for synthesizing (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, preparation method and applications of the intermediates

A technology of diphenylhexane and intermediates, applied in the field of organic synthesis, can solve the problems of being unsuitable for large-scale industrial production, harsh reaction conditions, difficult post-processing, etc., and achieve easy-to-operate post-processing, mild reaction conditions, and excellent preparation methods simple effect

Inactive Publication Date: 2015-02-25
SHANGHAI DESANO CHEM PHARMA
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0013] This route is an improvement on the basis of route 1. Compared with route 1, the yield has been improved, but lithium reagents are still used in the synthesis, and there are also defects such as harsh reaction conditions, difficult post-processing, and dangerous operation. It is not suitable for The need for large-scale industrial production

Method used

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  • Intermediates for synthesizing (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, preparation method and applications of the intermediates
  • Intermediates for synthesizing (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, preparation method and applications of the intermediates
  • Intermediates for synthesizing (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, preparation method and applications of the intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 (2S, 3S, 5S)-5-(tert-butoxycarbonylamino)-2-(dibenzylamino)-1,6-diphenyl-3-hexyl methylsulfonate (IIa) synthesis

[0041] The compound of formula I (10g, 17.7mmol) was dissolved in 50g of dichloromethane, triethylamine (1.88g, 18.6mmol) was added, cooled to 0-10°C, methanesulfonyl chloride (2.18g, 19.0mol) was added dropwise, React at room temperature until the compound of formula I disappears (TLC detection, n-hexane / ethyl acetate=5 / 1, V / V); cool to 0-10°C, wash the reaction solution with saturated sodium bicarbonate solution (50mL×3), separate liquid, concentrated under reduced pressure to obtain 10.4 g of the compound of formula IIa, the molar yield was 91%, and the HPLC purity was 98.1%.

[0042] MS(ESI)m / z:M+1=643.3;

[0043] 1 H NMR (CDCl 3 400MHz) δ1.42(m, 9H), 1.68(t, 2H), 2.80~2.92(m, 4H), 3.05(s, 3H), 3.21(s, 4H), 4.25(m, 1H), 4.93( m, 1H), 7.26-7.55 (m, 20H).

Embodiment 2

[0044] Example 2 (2S, 3S, 5S)-5-(tert-butoxycarbonylamino)-2-(dibenzylamino)-1,6-diphenyl-3-hexylethylsulfonate (IIb) synthesis

[0045] The compound of formula I (10g, 17.7mmol) was dissolved in 50g of tetrahydrofuran, diisopropylethylamine (2.4g, 18.6mmol) was added, cooled to 0-10°C, and ethanesulfonyl chloride (2.44g, 19.0 mol), react at room temperature until the compound of formula I disappears (TLC detection, n-hexane / ethyl acetate=5 / 1, V / V); cool to 0-10°C, and use saturated sodium bicarbonate solution (50mL×3) Washing, liquid separation, and concentration under reduced pressure gave 10.2 g of the compound of formula IIb with a molar yield of 88% and an HPLC purity of 96.9%.

[0046] MS(ESI)m / z:M+1=657.6;

[0047] 1 H NMR (CDCl 3 400MHz) δ1.29(t, 3H), 1.43(m, 9H), 1.69(t, 2H), 2.80~2.92(m, 4H), 3.08(s, 2H), 3.24(s, 4H), 4.23( m, 1H), 4.95 (m, 1H), 7.24-7.58 (m, 20H).

Embodiment 3

[0048]Example 3 (2S, 3S, 5S)-5-(tert-butoxycarbonylamino)-2-(dibenzylamino)-1,6-diphenyl-3-hexyl p-toluenesulfonate (IIc) synthesis

[0049] Dissolve the compound of formula I (10g, 17.7mmol) in 100g toluene, add a 20% aqueous solution made of sodium carbonate (2.0g, 19mmol), cool to -5~0°C, add p-toluenesulfonyl chloride (3.8g, 20.0mol) in 10g of toluene solution, react at room temperature until the compound of formula I disappears (TLC detection, n-hexane / ethyl acetate=5 / 1, V / V); cool to 10-15°C, and use saturated sodium bicarbonate solution for the reaction solution (50mL×3) washed, separated, and concentrated the organic phase under reduced pressure to obtain 11.4g of the compound of formula IIc, with a molar yield of 90% and an HPLC purity of 95.8%.

[0050] MS(ESI)m / z:M+1=720.0;

[0051] 1 H NMR (CDCl 3 400MHz) δ1.43(m, 9H), 2.80~2.92(m, 4H), 3.08(s, 2H), 3.24(s, 4H), 4.23(m, 1H), 4.95(m, 1H), 7.22~ 7.61 (m, 24H).

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Abstract

The invention discloses intermediates for synthesizing (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, a preparation method and applications of the intermediates. The intermediates are compounds represented by the structural formula II and the structural formula III. (2R,5R)-1,6-diphenylhexyl-2,5-diamine and salts thereof, which are prepared from the provided intermediates, can reach a HPLC purity of 99% or more without any complicated post-treatment, and the total mole yield can reach 80% or more. Furthermore, the preparation method of the intermediates is simple, the reaction conditions are mild, the post treatment is simple and easy to operate, the raw materials are cheap and easily-available, the mole yield in each step can reach 80% or more, the purity of reaction products in each step can reach 90% or more, and the provided intermediates have a very important meaning and practical value for carry out low cost and massive production of high purity cobicistat.

Description

technical field [0001] The invention relates to an intermediate for synthesizing (2R,5R)-1,6-diphenylhexane-2,5-diamine and a salt thereof, a preparation method and an application of the intermediate, and belongs to the technical field of organic synthesis. Background technique [0002] Cobicistat developed by Gilead Sciences is a new type of synergist that can improve the pharmacokinetic parameters of anti-HIV drugs, thereby increasing the drug efficacy. The drug itself has no anti-HIV activity, but it can increase the blood concentration of anti-HIV drugs by inhibiting CYP3A, the main enzyme that metabolizes drugs in the human body. Gilead has submitted a new drug application to the FDA on June 28, 2012, and is now in the pre-registration stage. [0003] In the international application PCT / US2007 / 015604, the publication number WO2008010921 discloses the following chemical structure of Cobicistat: [0004] [0005] From the chemical structure analysis of Cobicistat, i...

Claims

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Application Information

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IPC IPC(8): C07C303/28C07C309/66C07C309/73C07C309/76C07C309/67C07C309/65C07D295/26C07C271/20C07C269/06C07C211/27C07C209/62
Inventor 李金亮赵楠罗光顺
Owner SHANGHAI DESANO CHEM PHARMA
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