CN103570578B - Synthetic method for chiral amide crystal compound - Google Patents
Synthetic method for chiral amide crystal compound Download PDFInfo
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- CN103570578B CN103570578B CN201310570691.4A CN201310570691A CN103570578B CN 103570578 B CN103570578 B CN 103570578B CN 201310570691 A CN201310570691 A CN 201310570691A CN 103570578 B CN103570578 B CN 103570578B
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- Prior art keywords
- chiral
- methyl
- oac
- crystal compound
- synthetic method
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 17
- 239000013078 crystal Substances 0.000 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- 150000001408 amides Chemical class 0.000 title claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 4
- 238000004440 column chromatography Methods 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims abstract description 4
- 239000012074 organic phase Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 5
- QMXOFBXZEKTJIK-UHFFFAOYSA-N Glycinol Natural products C1=C(O)C=C2OCC3(O)C4=CC=C(O)C=C4OC3C2=C1 QMXOFBXZEKTJIK-UHFFFAOYSA-N 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000010992 reflux Methods 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 4
- FIMGYEKEYXUTGD-UHFFFAOYSA-N 6-methyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound CC1=CC=C(C#N)C(O)=N1 FIMGYEKEYXUTGD-UHFFFAOYSA-N 0.000 abstract 2
- 239000003208 petroleum Substances 0.000 abstract 2
- IJXJGQCXFSSHNL-QMMMGPOBSA-N (R)-(-)-2-Phenylglycinol Chemical compound OC[C@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-QMMMGPOBSA-N 0.000 abstract 1
- 239000012043 crude product Substances 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- VERVERDPMMBDSS-UHFFFAOYSA-N (2-ethylphenyl) acetate Chemical compound CCC1=CC=CC=C1OC(C)=O VERVERDPMMBDSS-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 2
- 230000006196 deacetylation Effects 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229940078487 nickel acetate tetrahydrate Drugs 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 1
- -1 Lewis acid nickel acetate tetrahydrate Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- OINIXPNQKAZCRL-UHFFFAOYSA-L nickel(2+);diacetate;tetrahydrate Chemical compound O.O.O.O.[Ni+2].CC([O-])=O.CC([O-])=O OINIXPNQKAZCRL-UHFFFAOYSA-L 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The chemical formula of a chiral amide crystal compound (I) is shown in the specification. A synthetic method for the chiral amide crystal compound comprises the following steps: carrying out the reflux reaction for 40 hours on 10.13 mmol of 3-cyano-6-methyl-2-hydroxypyridine and 2.3063 g of chiral D-phenylglycinol in chlorobenzene with Ni(OAc)2.4H2O under the anhydrous and anaerobic condition, wherein the use amount of Ni(OAc)2.4H2O is 98.0 mol% of that of raw material 3-cyano-6-methyl-2-hydroxypyridine, stopping the reaction, reducing the pressure to remove a solvent, dissolving residue with water, extracting with CHC13(20mL*2), drying the organic phase with anhydrous sodium sulfate, rotating to remove the solvent, performing the column chromatography on crude products with petroleum ether/dichloromethane (the ratio of petroleum ether to dichloromethane is 1:500); naturally volatilizing final component points to obtain clear crystals.
Description
One, technical field
The present invention relates to a kind of new compound and preparation method thereof, particularly a kind of preparation method of chipal compounds, 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-A?European?Journal(2001),7(15),3321-3327.
3.[tBu2SnOH(Cl)]2?as?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-cyano group-6-methyl-2 hydroxy pyrimidine and chiral D-benzene glycinol synthesize in organic solvent under catalyzer nickel acetate tetrahydrate 59.4mol% existence condition, and chemical equation is as follows:
This chipal compounds (I) synthetic method comprises synthesis, abstraction and purification, it is characterized in that 3-cyano group-6-methyl-2 hydroxy pyrimidine 10.13mmol and chiral D-benzene glycinol 2.3063g, has Ni (OAc) in chlorobenzene
24H
2when O exists under anhydrous and oxygen-free condition back flow reaction 40 hours, Ni (OAc)
24H
2o consumption is the 98.0mol% (molar percentage) of material quantity 3-cyano group-6-methyl-2 hydroxy pyrimidine, 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 (1:500) column chromatography, volatilize last component point naturally, obtains clear crystal.
The reaction mechanism of this reaction can be presumed as follows:
3-cyano group-6-methyl-2 hydroxy pyrimidine and the effect of a large amount of Lewis acid nickel acetate tetrahydrate, discharge two molecule acetic acid, then with chirality (R)-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 Ni (OAc)
24H
2o 2.5231g (10.13mmol), 40ml chlorobenzene, 3-cyano group-6-methyl-2 hydroxy pyrimidine 1.3853g (10.3mmol), D-benzene glycinol 2.3063g, at high temperature reflux mixture 40h, stopped reaction, reduce 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 (1:500) column chromatography, volatilize last component point naturally, obtains clear crystal, productive rate: 53%; M.p.:115-117 DEG C; [a]
5 d=+66.8 ° of (c=0.052, 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:
Claims (1)
1. one kind has following structural formula
the synthetic method of chiral amide crystal compound (I), comprises synthesis and is separated, and it is characterized in that 3-cyano group-6-methyl-2 hydroxy pyrimidine 10.13mmol and chiral D-benzene glycinol 2.3063g, has Ni (OAc) in chlorobenzene
24H
2when O exists under anhydrous and oxygen-free condition back flow reaction 40 hours, Ni (OAc)
24H
2o consumption is the 98.0mol% molar percentage of material quantity 3-cyano group-6-methyl-2 hydroxy pyrimidine, stopped reaction, reduces pressure with except desolventizing, by residuum water dissolution, and uses CHCl
320mL × 2 extract, organic phase anhydrous sodium sulfate drying, rotate except desolventizing, and by thick product sherwood oil/methylene dichloride 1:500 column chromatography, volatilize last component point naturally, obtains clear crystal.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310570691.4A CN103570578B (en) | 2013-11-17 | 2013-11-17 | Synthetic method for chiral amide crystal compound |
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|---|---|---|---|
| CN201310570691.4A CN103570578B (en) | 2013-11-17 | 2013-11-17 | Synthetic method for chiral amide crystal compound |
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| Publication Number | Publication Date |
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| CN103570578A CN103570578A (en) | 2014-02-12 |
| CN103570578B true CN103570578B (en) | 2015-01-14 |
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|---|---|---|---|
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994024115A1 (en) * | 1993-04-16 | 1994-10-27 | Santen Pharmaceutical Co., Ltd. | Novel piperazine derivative |
| US20070123589A1 (en) * | 2003-12-19 | 2007-05-31 | Walther Jary | Method for producing chiral or enantiomer-enriched beta-amino acids, aldehydes, ketones and gama-amino alcohols |
-
2013
- 2013-11-17 CN CN201310570691.4A patent/CN103570578B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994024115A1 (en) * | 1993-04-16 | 1994-10-27 | Santen Pharmaceutical Co., Ltd. | Novel piperazine derivative |
| US20070123589A1 (en) * | 2003-12-19 | 2007-05-31 | Walther Jary | Method for producing chiral or enantiomer-enriched beta-amino acids, aldehydes, ketones and gama-amino alcohols |
Non-Patent Citations (1)
| Title |
|---|
| Trennung und Bestimmung der Konfigurationen der stereoisomeren N-Acetyl-2-(2"-cyclohexenyl)glycine;Sentot Santoso et al.;《Liebigs Ann. Chem.》;19811231;642-657 * |
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| CN103570578A (en) | 2014-02-12 |
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Effective date of registration: 20201207 Address after: 274100 north outer ring road, 500m east of connecting line, Dingtao District, Heze City, Shandong Province Patentee after: Shandong Meisen artificial lawn Co.,Ltd. Address before: 151 box 230009, South District, HeFei University of Technology, Anhui, Hefei, Tunxi Road, Hefei, 193 Patentee before: Luo Mei |
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