CN103420865B

CN103420865B - A kind of generation and synthesis method of chiral amide crystal compound

Info

Publication number: CN103420865B
Application number: CN201310377949.9A
Authority: CN
Inventors: 罗梅
Original assignee: Individual
Current assignee: Individual
Priority date: 2013-08-27
Filing date: 2013-08-27
Publication date: 2015-08-26
Anticipated expiration: 2033-08-27
Also published as: CN103420865A

Abstract

A kind of chiral amide crystal compound (I), its chemical formula is as follows: the synthetic method of this chiral amide crystal compound (I) in chlorobenzene, has Cu (OAc) with 3-[1-(2-carbonyl) pyrrolidyl]-propionitrile and chiral D-benzene glycinol ₂h ₂when O exists under anhydrous and oxygen-free condition back flow reaction 50 hours, Cu (OAc) ₂h ₂o consumption is the 59.4mol%(molar percentage of material quantity); Reduce pressure with except desolventizing, by residuum water dissolution, and use CHCl ₃(20mLx2) extract, organic phase anhydrous sodium sulfate drying, rotate except desolventizing, by thick product sherwood oil/methylene dichloride (1:100) column chromatography, volatilize last component point naturally, obtains clear crystal.

Description

A kind of generation and synthesis method of chiral amide crystal compound

One, technical field

The present invention relates to a kind of new compound and preparation method thereof, particularly a kind of chipal compounds and preparation method thereof, the preparation of (2R)-2-acetylaminohydroxyphenylarsonic acid 2-ethyl phenylacetate and synthetic method thereof.

Two, background technology

(2R)-2-acetylaminohydroxyphenylarsonic acid 2-ethyl phenylacetate is important medicine intermediate, and its synthetic method has lot of documents report [1-4]:

Reference:

1.Microwave-Assisted Synthesis of Amide under Solvent-free Conditions,Wang,Xiao-Jian；Yang,Qian；Liu,Fei；You,Qi-Dong，Synthetic Communications(2008),38(7),1028-1035.

2.Highly efficient deacetylation by use of the neutral organotin catalyst[tBu2SnOH(Cl)]2,Orita,Akihiro；Hamada,Yuuki；Nakano,Takehiko；Toyoshima,Shinji；Otera,Junzo Chemistry-AEuropean Journal(2001),7(15),3321-3327.

3.[tBu2SnOH(Cl)]2as a highly efficient catalyst for deacetylation,Orita,Akihiro；Sakamoto,Katsumasa；Hamada,Yuuki；Otera,Junzo，Synlett(2000),(1),140-142.

4.Study of the resolution of amino acids and amino alcohols in organic solvents,Orsini,F.；Pelizzoni,F.；Ghioni,C.,Amino Acids(1995),9(2),135-140。

Three, summary of the invention

The present invention is intended to particularly to prepare chiral drug for asymmetric synthesis field provides chipal compounds part needed for a kind of efficient chiral catalyst, and technical problem to be solved is selected corresponding raw material and sets up corresponding method synthesis of chiral catalyst ligand.

(1) chipal compounds alleged by the present invention is the compound shown in following chemical formula I:

Its chemical name: (2R)-2-acetylaminohydroxyphenylarsonic acid 2-ethyl phenylacetate, is called for short compound (I).

The synthetic method of chipal compounds (I) is that 3-[1-(2-carbonyl) pyrrolidyl]-propionitrile and chiral D-benzene glycinol synthesize in organic solvent under catalyzer copper acetate dihydrate 59.4mol% existence condition, and chemical equation is as follows:

This chipal compounds (I) synthetic method comprises synthesis, abstraction and purification, and described synthesis is that 3-[1-(2-carbonyl) pyrrolidyl]-propionitrile and chiral D-benzene glycinol have Cu (OAc) in chlorobenzene ₂h ₂when O exists under anhydrous and oxygen-free condition back flow reaction 50 hours, Cu (OAc) ₂h ₂o consumption is the 59.4mol% (molar percentage, lower same) of material quantity; Reduce pressure with except desolventizing, by residuum water dissolution, and use CHCl ₃(20mLx2) extract, organic phase anhydrous sodium sulfate drying, rotate except desolventizing, by thick product sherwood oil/methylene dichloride (1:100) column chromatography, volatilize last component point naturally, obtains clear crystal,

The reaction mechanism of this reaction can be presumed as follows:

3-[1-(2-carbonyl) pyrrolidyl]-propionitrile and the effect of a large amount of Lewis acid copper acetate dihydrate, discharge two molecule acetic acid, again with chirality (S)-benzene glycinol effect, intramolecular condensation sloughs two molecular waters, forms target compound I.

The preparation of this chipal compounds, adopts simple and easy, efficient methodology of organic synthesis, one-step synthesis chipal compounds, and through X-diffraction, its structure is determined in NMR, IR and ultimate analysis.

Four, accompanying drawing explanation

Fig. 1 is the single crystal diffraction figure of compound (I).

Five, embodiment

1. the preparation of (2R)-2-acetylaminohydroxyphenylarsonic acid 2-ethyl phenylacetate

In 100mL two-mouth bottle, under anhydrous and oxygen-free condition, add Cu (OAc) ₂h ₂o1.7852g (8.97mmol), 40ml chlorobenzene, 3-[1-(2-carbonyl) pyrrolidyl]-propionitrile 2.833g (15.1mmol), D-benzene glycinol 2.0g, at high temperature reflux mixture 50h, stopped reaction, reduces pressure to remove desolventizing, by residuum water dissolution, and use CHCl ₃(20mLx2) extract, organic phase anhydrous sodium sulfate drying, rotate except desolventizing, by thick product sherwood oil/methylene dichloride (1:100) column chromatography, volatilize last component point naturally, obtains clear crystal, productive rate: 40%; M.p.:115-117, [a] ⁵ _d=+69.8 ° of (c=0.082, CH ₃oH); ¹hNMR (500MHz, CDCl ₃, 27 DEG C), δ (ppm)=7.25 ~ 7.37 (m, 5H), 6.02 (s, 1H), 5.30 (dt, 1H), 4.24 ~ 4.27 (m, 2H), 2.03 ~ 2.05 (d, J=15Hz, 6H), HRMS (EI): m/z (%): calcd for C ₁₂h ₁₅nO ₃: 221.1046; Found:221.1043, this match crystal volume data is as follows:

The typical bond distance's data of crystal

The typical bond angle data of crystal:

(2), nitrile silicification reaction application

0.20mmol chipal compounds (I), 2-tolyl aldehyde 0.1mL, TMSCN 0.3ml (3.3mmol) add, after 3d in succession at 20 ~ 30 DEG C, add shrend and go out after post layer that (sherwood oil/methylene dichloride: 5/1), obtains colourless oil liquid.Transformation efficiency: 52%, ee%:20%; ¹h NMR (300MHz, CDCl ₃) 7.52 – 7.53 (d, 7.5Hz, 1H), 7.20 – 7.30 (m, 3H), 5.57 (s, 1H), 2.44 (s, 3H), 0.22 (s, 9H). ¹³c NMR (75MHz, CDCl ₃) 135.8,134.2,131.2,129.5,127.1,126.6,118.9,62.1,18.9 ,-0.2 (X3).

Claims

1. one kind has the chiral amide crystal compound (I) of following structural formula synthetic method, comprise synthesis and be separated, it is characterized in that: described synthesis 3-[1-(2-carbonyl) pyrrolidyl]-propionitrile and chiral D-benzene glycinol have Cu (OAc) in chlorobenzene ₂h ₂when O exists under anhydrous and oxygen-free condition back flow reaction 50 hours, Cu (OAc) ₂h ₂o consumption is the 59.4mol% molar percentage of material quantity; Reduce pressure with except desolventizing, by residuum water dissolution, and use CHCl ₃20mLx2 extracts, organic phase anhydrous sodium sulfate drying, rotates except desolventizing, and by thick product sherwood oil/methylene dichloride 1:100 column chromatography by volume, volatilize last component point naturally, obtains clear crystal.