CN1262535C - Method ofr synthesizing S-(1)-2.2 dimethylcyclopropane formamide - Google Patents
Method ofr synthesizing S-(1)-2.2 dimethylcyclopropane formamide Download PDFInfo
- Publication number
- CN1262535C CN1262535C CN 200410017680 CN200410017680A CN1262535C CN 1262535 C CN1262535 C CN 1262535C CN 200410017680 CN200410017680 CN 200410017680 CN 200410017680 A CN200410017680 A CN 200410017680A CN 1262535 C CN1262535 C CN 1262535C
- Authority
- CN
- China
- Prior art keywords
- reaction
- solvent
- synthetic method
- acid
- gained
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title abstract description 10
- 230000002194 synthesizing effect Effects 0.000 title abstract 3
- RCNSYWXQFUUPBG-UHFFFAOYSA-N 1,1-dimethylcyclopropane;formamide Chemical compound NC=O.CC1(C)CC1 RCNSYWXQFUUPBG-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 230000035484 reaction time Effects 0.000 claims abstract description 14
- YYPNJNDODFVZLE-UHFFFAOYSA-N 3-methylbut-2-enoic acid Chemical compound CC(C)=CC(O)=O YYPNJNDODFVZLE-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 230000008025 crystallization Effects 0.000 claims abstract description 9
- 230000032050 esterification Effects 0.000 claims abstract description 9
- 238000005886 esterification reaction Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 3
- 238000005917 acylation reaction Methods 0.000 claims abstract 2
- 239000002904 solvent Substances 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- 238000010189 synthetic method Methods 0.000 claims description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- -1 methylene halide Chemical class 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 7
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical compound CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- SVVSJSVMXCEDDA-FYZOBXCZSA-N (3r)-3-hydroxy-4-(trimethylazaniumyl)butanoate;oxalic acid Chemical compound OC(=O)C(O)=O.C[N+](C)(C)C[C@H](O)CC([O-])=O SVVSJSVMXCEDDA-FYZOBXCZSA-N 0.000 claims description 5
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 238000010612 desalination reaction Methods 0.000 claims description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims 2
- 238000005516 engineering process Methods 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- 230000010933 acylation Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 3
- SBKPAATUNVVUJT-UHFFFAOYSA-N C(C(=O)[O-])(=O)[O-].C(CCC)(=O)O.[NH4+].[NH4+] Chemical compound C(C(=O)[O-])(=O)[O-].C(CCC)(=O)O.[NH4+].[NH4+] SBKPAATUNVVUJT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000000413 hydrolysate Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- JXXCENBLGFBQJM-UHFFFAOYSA-N (3-carboxy-2-hydroxypropyl)-trimethylazanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)CC(O)=O JXXCENBLGFBQJM-UHFFFAOYSA-N 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 229950010364 phenpromethamine Drugs 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YBZQRYWKYBZZNT-UHFFFAOYSA-N 2,2-dimethylcyclopropane-1-carboxamide Chemical compound CC1(C)CC1C(N)=O YBZQRYWKYBZZNT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 229940090955 Dipeptidase inhibitor Drugs 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- DHSUYTOATWAVLW-WFVMDLQDSA-N cilastatin Chemical compound CC1(C)C[C@@H]1C(=O)N\C(=C/CCCCSC[C@H](N)C(O)=O)C(O)=O DHSUYTOATWAVLW-WFVMDLQDSA-N 0.000 description 1
- 229960004912 cilastatin Drugs 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- PKAHQJNJPDVTDP-UHFFFAOYSA-N methyl cyclopropanecarboxylate Chemical class COC(=O)C1CC1 PKAHQJNJPDVTDP-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229940073569 n-methylephedrine Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Advantages are: short reaction time, mild reaction condition, simple process, total yield is more than 15%, ee is larger than 95.6%. The present invention relates to a method for synthesizing S-(+)-2, 2-dimethyl cyclopropane formyl amide from senecioic acid as an initial raw material orderly by esterification, cyclopropanization, hydrolyzation, acylation, salification, partial crystallization and ammonolysis. The synthesizing method of the present invention has the advantages of short reaction time, mild reaction condition and simple technology. Total yield is more than 15%, ee is more than 95.6%.
Description
Technical field:
The present invention relates to a kind of S-(+)-2, the synthetic method of 2-dimethyl-cyclopropane carboxamide.
Background technology:
The S-(+)-2 of molecular formula shown in S-1, the 2-dimethyl-cyclopropane carboxamide is the key intermediate of synthetic cilastatin (a kind of kidney dehydrogenation Dipeptidase inhibitor), generally takes following two kinds of methods to make in the prior art:
Graham etc. (J.Med Chem.1987,30,1074) have reported with the 2 to be raw material, through synthetic obtaining of six steps.This method is long reaction time not only, and the potassium cyanide that relates to severe toxicity is reactant and is resolution reagent with expensive quinine, so greatly to the danger of human body or environment, and the cost height.
With the S-(+)-2 of molecular formula shown in S-2, the chiral raw material of 2-dinethyl cyclopropane carboxylic acid is separated and is made S-1 through chloride, ammonia.But the building-up process of chiral raw material S-2 is difficulty.At first, (Tetrahedron, 1998,9,3971) such as Qinwei Wang are raw material with iso-butylene, and the chirality Tong Shiji is catalyzer asymmetric synthesis S-2, though this method yield is higher, chiral catalyst is very expensive, severe reaction conditions.Then, with 2,2-dinethyl cyclopropane carboxylic acid racemic modification with various biological fractionations or the chemical method that splits, obtains S-2, makes S-1 again.As patent CH682485, adopting the L-carnitine hydrochloride is chiral selectors, just obtains S-2 through acidylate, one-tenth hydrochloride, ion-exchange, one-tenth oxalate, hydrolysis five steps operation; EP93511 uses (+)-1, and the 2-phenpromethamine is a resolution reagent, though the yield of product and chiral purity are higher, and (+)-1, the 2-phenpromethamine costs an arm and a leg, the cost height; In addition, also has JP60056942 l-N-N-Methylephedrine, US4487956 l-menthol, EP474200 R-1-(3-p-methoxy-phenyl)-ethamine, EP461541 S-methyl mandelate, the biological enzyme of US5427934 after with gene recombination splits 2,2-dimethyl-cyclopropane carboxamide etc., and these methods exist defectives such as the expensive or preparation difficulty of resolution reagent, single resolution yield are low, complex operation, cost height at present.
Summary of the invention:
At problems of the prior art, the invention provides a kind of environmental friendliness, technology is simple, cost is low S-(+)-2, the synthetic method of 2-dimethyl-cyclopropane carboxamide.
The present invention is to realize by such technical scheme for reaching above purpose: a kind of S-(+)-2 is provided, and the synthetic method of 2-dimethyl-cyclopropane carboxamide is characterized in that: with senecioic acid is main starting raw material, makes S-1 through following step successively:
(1) esterification: senecioic acid carries out esterification with alcohol under the effect of catalyzer, temperature of reaction is 20 ℃～100 ℃, and the reaction times is 3h～10h, successively through operations such as neutralization, washing, rectifying, obtains the isopentene acid esters then;
(2) Cyclopropanated: the above-mentioned isopentene acid esters that obtains is under catalyst action, in solvent, carry out cyclopropanization reaction with methylene halide, temperature of reaction is 20 ℃～50 ℃, reaction times is 2h～8h, to react gained liquid again and carry out desalination, filtration, washing successively, concentrate, obtain cyclopropanated produce;
(3) hydrolysis: with the above-mentioned cyclopropanated produce that obtains, in 5%～15% alkali lye under 50 ℃～100 ℃ temperature hydrolysis 1h～4h, react, carry out acidifying, extraction, washing, drying more successively, concentrate, rectifying, obtain hydrolysate;
(4) acidylate: with the above-mentioned hydrolysate that obtains, with sulfur oxychloride at N, in solvent, react 1h～5h under the dinethylformamide catalysis, obtain acylate;
(5) salify: with the above-mentioned acylate that obtains, in solvent, react 2h～6h down, remove solvent then at 20 ℃～50 ℃ with chiral selectors;
(6) partial crystallization: with the product of gained after the described salt-forming reaction, partial crystallization obtains optically active oxalate in solvent;
(7) ammonia is separated: the product that described partial crystallization is reacted the back gained: oxalate, in solvent, react 10h～15h down with ammoniacal liquor with 20 ℃～60 ℃, and concentrate, extract, remove solvent more successively.
Synthetic method of the present invention, its synthetic route is as follows:
Synthetic method of the present invention, in the step (1): promptly used alcohol is that carbon number is 1～6 aliphatic alcohols in the esterification, and as methyl alcohol, ethanol, propyl alcohol, Virahol etc., catalyzer is mineral acid or organic acid, as sulfuric acid, tosic acid, phosphorus oxychloride etc.Senecioic acid is 1: 1～1: 4 with the mol ratio of alcohol, and optimum value is 1: 3; Catalyzer is 0.1: 3～1: 3 with the mol ratio of alcohol, and optimum value is 1: 1～1: 2; Temperature of reaction is controlled at 20 ℃～100 ℃, and is optimum with 60 ℃～80 ℃; Reaction times is 3h～10h, preferably 4h～6h.
In the step (2): promptly the used methylene halide of cyclopropanization reaction is methylene iodide or methylene bromide, and catalyzer is zinc/copper (I)-Acetyl Chloride 98Min. system.The mol ratio of isopentene acid esters and methylene halide is 1: 1～1: 5; The mol ratio of isopentene acid esters and zinc powder is 1: 1～1: 5, copper (I) consumption be zinc powder molar weight 1%～2%, the Acetyl Chloride 98Min. consumption is 1 ‰ of zinc powder consumption～5 ‰; Solvent is tetrahydrofuran (THF), ether, dioxane etc.; Temperature of reaction is 20 ℃～50 ℃, and the reaction times is 2h～8h.
In the step (3): hydrolysis basic solution, available hydrogen sodium oxide, potassium hydroxide etc.; Concentration of lye is 5%～15%; Hydrolysis temperature is 50 ℃～100 ℃; Hydrolysis time is 1h～4h.
In the step (4): the mol ratio of hydrolysate and sulfur oxychloride is 1: 1～1: 1.5; N, the consumption of dinethylformamide are 0.5%～1% of hydrolysates; Solvent is methylene dichloride, trichloromethane, hexanaphthene etc.; Temperature of reaction is a reflux temperature, and the reaction times is 1h～5h.
In the step (5): promptly used resolution reagent is a L-carnitine oxalate in the salt-forming reaction.The mol ratio of acylate and L-carnitine oxalate is 1: 1～1: 1.5; Solvent for use is methylene dichloride, trichloromethane etc.; Temperature of reaction is 20 ℃～50 ℃; Reaction times is 2h～6h.
In the step (6): i.e. used solvent is a ketone in the partial crystallization reaction, or ethers, or nitrile, as acetonitrile, ether, tetrahydrofuran (THF) etc.
In the step (7): promptly in the ammonolysis reaction, the mol ratio of oxalate and ammonia is 1: 10～1: 50, and solvent is methylene dichloride or trichloromethane.Temperature of reaction is 20 ℃～60 ℃, reaction times 10h～15h.
Using synthetic method of the present invention, is earlier with senecioic acid esterification under catalyst action, carries out Cyclopropanatedly with methylene bromide then, and hydrolysis obtains 2, the 2-dinethyl cyclopropane carboxylic acid, and the reaction times is short, reaction conditions gentleness, total recovery 44.1%.Then with 2, the 2-dinethyl cyclopropane carboxylic acid carries out chiral separation with L-carnitine oxalate as resolution reagent, and (being different from patent CH682485 employing L-carnitine hydrochloride is chiral selectors, the present invention has saved ion-exchange, has become two steps of oxalate), the direct ammonia of formed diastereoisomeric salt is separated and is made S-(+)-2, the 2-dimethyl-cyclopropane carboxamide, simplified splitting step, total recovery＞15%, ee＞95.6%.
Embodiment:
Embodiment 1: a kind of S-(+)-2, and the synthetic method of 2-dimethyl-cyclopropane carboxamide is characterized in that: with senecioic acid is main starting raw material, makes through following step successively:
(1) esterification, the i.e. preparation of senecioic acid methyl esters:
Senecioic acid (10.0g, 0.1mol) be dissolved in methyl alcohol (9.6g, 0.3mol) in, under 60 ℃～80 ℃ reflux temperature, drip phosphorus oxychloride (4.0mL), dripped off in 30 minutes.Keep reflux temperature till do not have hydrogen chloride gas and overflow, need 4～5 hours.Reaction finishes, and reaction solution adds saturated nacl aqueous solution saltouts, and tells the upper strata organic layer, with the saturated sodium carbonate solution neutralization, is washed till neutrality with saturated nacl aqueous solution again.Get crude product 10.5g, content about 85%.Rectification under vacuum, 230mmHg collects 99 ℃～100 ℃ cuts down, can get the senecioic acid methyl esters of pure product, and boiling point is 135 ℃～136 ℃ under the normal pressure.
(2) Cyclopropanated, promptly 2, the preparation of 2-dinethyl cyclopropane carboxylic acid methyl esters:
In reaction flask (band prolong), add successively zinc powder (26.2g, 0.4mol), cuprous chloride (3.96g, 0.04mol), methylene bromide (17.4g,, 0.1mol), ether 20ml, under agitation slowly dripping acetyl chloride (0.63g, 0.008mol).Dropwise, be warming up to 45 ℃～50 ℃, behind the reaction solution color burn, drip fast the senecioic acid methyl esters (11.4g, 0.1mol)-ether (15ml) solution, then drip methylene bromide (35.0g,, 0.2mol)-ether (15ml) solution, 30min drips off.Reaction 3h.Reaction solution cooling back adds saturated ammonium chloride solution and removes zinc salt, filters, and tells organic layer.Organic layer is washed till neutrality with 10% alkali lye and saturated nacl aqueous solution, and drying steams solvent, obtains crude product, need not purify, and is directly used in next step and synthesizes.
(3) hydrolysis, promptly 2, the preparation of 2-dinethyl cyclopropane carboxylic acid:
The crude product that cyclopropanization reaction is obtained adds 10% aqueous sodium hydroxide solution (50mL), at 80 ℃ of reaction 2h.Reaction solution is acidified to PH=1 with concentrated hydrochloric acid, and extracted with diethyl ether is told organic layer, and saturated common salt is washed to neutrality, and drying concentrates, and the cut of 81.5 ℃～82.5 ℃/5mmHg is collected in rectification under vacuum, obtains colourless liquid, and promptly 2,2-dinethyl cyclopropane carboxylic acid 6.1g.
(4), acidylate, promptly 2, the preparation of 2-dimethylcyclopropane formyl chloride:
With 2, and the 2-dinethyl cyclopropane carboxylic acid (11.4g 0.1mol) is dissolved in the 50ml methylene dichloride, splashes into the N of 0.08g, dinethylformamide, and reflux, slow dripping thionyl chloride (13.1g, O.11mol).Dropwise, continue back flow reaction 2h.Reaction solution is directly used in next step and synthesizes.
(5) salify:
(27.6g 0.11mol) is dissolved in the 50mL methylene dichloride, slowly splashes into previous step under 50 ℃, promptly in the reaction solution of step (4) gained with L-carnitine oxalate.Dropwise, continue reaction 3h, decompression removes solvent, obtains oily matter.
(6) partial crystallization, the i.e. preparation of (R)-3-((S)-2,2-dimethylcyclopropane carboxyl)-4-trimethylammonium ammonium butyric acid-oxalate:
Add the 30mL acetonitrile and dissolve in above-mentioned oily matter, the 7.7g clear crystal is separated out (fusing point: 130～133 ℃).With acetonitrile recrystallization (30mL * 2), 0 ℃ of following vacuum-drying of crystal 4.Obtain (R)-3-((S)-2,2-dimethylcyclopropane the carboxyl)-4-trimethylammonium ammonium butyric acid-oxalate of 5.9g clear crystal, fusing point: 134.5～136.5 ℃,
(c=1, H
2O).
(7) ammonia is separated, i.e. S-(+)-2, the preparation of 2-dimethyl-cyclopropane carboxamide
(R)-3-((S)-2,2-dimethylcyclopropane carboxyl)-4-trimethylammonium ammonium butyric acid-oxalate with above-mentioned 5.9g reacts 15h, 50 ℃ of temperature of reaction with 55g ammoniacal liquor (concentration is 25%) in the 30mL methylene dichloride.After reaction solution is told organic layer, water layer concentrating under reduced pressure, methylene dichloride (10mL * 3) extraction.Merge organic phase, remove solvent, obtain 1.6g white plates crystalline S-(+)-2, the 2-dimethyl-cyclopropane carboxamide.Measure 135～137 ℃ of fusing points,
(c=1, CHCl
3) structural formula is shown in S-1.
The above only is a specific embodiment of the present invention; should be pointed out that for the person of ordinary skill of the art, can also make many modification and improvement; for example change the mol ratio of oxalate and ammonia etc., all modification or improvement all should be considered as protection scope of the present invention.
Claims (9)
1, a kind of S-(+)-2, the synthetic method of 2-dimethyl-cyclopropane carboxamide is characterized in that, is main starting raw material with senecioic acid, makes through following step successively:
(1) esterification: senecioic acid carries out esterification with alcohol under the effect of catalyzer, temperature of reaction is 20 ℃～100 ℃, and the reaction times is 3h～10h, successively through neutralization, washing, rectifying, obtains the isopentene acid esters then;
(2) Cyclopropanated: with the product of methylene halide and step (1) gained: the isopentene acid esters, under catalyst action, in solvent, carry out cyclopropanization reaction, temperature of reaction is 20 ℃～50 ℃, reaction times is 2h～8h, will react gained liquid again and carry out desalination, filtration, washing successively, concentrates;
(3) hydrolysis: with the product of step (2) gained, in 5%～15% alkali lye under 50 ℃～100 ℃ temperature hydrolysis 1h～4h, carry out acidifying, extraction, washing, drying more successively, concentrate, rectifying;
(4) acidylate: the product that step (3) is obtained, with sulfur oxychloride at N, in solvent, react 1h～5h under the catalysis of dinethylformamide;
(5) salify: with the product of step (4) gained, in solvent, under 20 ℃～50 ℃, react 2h～6h, remove solvent then with chiral selectors;
(6) partial crystallization: with the product of step (5) gained, partial crystallization obtains optically active oxalate in solvent;
(7) ammonia is separated: with the product of step (6) gained: oxalate, with ammoniacal liquor in solvent in 20 ℃～60 ℃ reaction 10h～15h down, concentrate, extract, remove solvent more successively.
2, synthetic method according to claim 1 is characterized in that: described step (1) is that alcohol used in the esterification is that carbon number is 1～6 Fatty Alcohol(C12-C14 and C12-C18), and catalyzer is mineral acid or organic acid, and temperature of reaction is 60 ℃～80 ℃, and the reaction times is 4h～6h.
3, synthetic method according to claim 2 is characterized in that: described Fatty Alcohol(C12-C14 and C12-C18) is methyl alcohol or ethanol or propyl alcohol or Virahol, and described mineral acid is a sulfuric acid, and described organic acid is tosic acid or phosphorus oxychloride.
4, synthetic method according to claim 1 is characterized in that: described step (2) is that methylene halide used in the cyclopropanization reaction is methylene iodide or methylene bromide, and catalyzer is zinc/copper (I)-Acetyl Chloride 98Min. system.
5, synthetic method according to claim 1 is characterized in that: described step (4) is that solvent used in the acylation reaction is methylene dichloride or trichloromethane or hexanaphthene.
6, synthetic method according to claim 1 is characterized in that: described step (5) is that chiral selectors used in the salt-forming reaction is a L-carnitine oxalate, and solvent for use is methylene dichloride or trichloromethane.
7, synthetic method according to claim 1 is characterized in that: described step (6) is that used solvent is ketone or ethers or nitrile in the partial crystallization reaction.
8, synthetic method according to claim 7 is characterized in that: described nitrile is an acetonitrile, and described ethers is ether or tetrahydrofuran (THF).
9, synthetic method according to claim 1 is characterized in that: described step (7) is in the ammonolysis reaction, and the mol ratio of oxalate and ammoniacal liquor is 1: 10～1: 50, and described solvent is methylene dichloride or trichloromethane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410017680 CN1262535C (en) | 2004-04-12 | 2004-04-12 | Method ofr synthesizing S-(1)-2.2 dimethylcyclopropane formamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410017680 CN1262535C (en) | 2004-04-12 | 2004-04-12 | Method ofr synthesizing S-(1)-2.2 dimethylcyclopropane formamide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1562962A CN1562962A (en) | 2005-01-12 |
| CN1262535C true CN1262535C (en) | 2006-07-05 |
Family
ID=34479095
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410017680 Expired - Fee Related CN1262535C (en) | 2004-04-12 | 2004-04-12 | Method ofr synthesizing S-(1)-2.2 dimethylcyclopropane formamide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1262535C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090105498A1 (en) * | 2007-10-18 | 2009-04-23 | Porstmann Frank | Improved process for preparing 2-(substituted phenyol)-2-hydroxy-ethyl-carbamates |
| CN101735099B (en) * | 2009-12-18 | 2013-05-29 | 江苏宇翔化工有限公司 | Synthesizing method of S-(+)-2, 2-dimethylcyclopropane carboxamide |
| CN105037129A (en) * | 2015-05-14 | 2015-11-11 | 大丰跃龙化学有限公司 | Method for synthesizing cyclopropanecarboxylic acid |
| TWI758313B (en) * | 2016-10-12 | 2022-03-21 | 美商陶氏農業科學公司 | Process for the preparation of (1r,3r)- and (1s,3s)-2,2-dihalo-3-(substituted phenyl)cyclopropanecarboxylic acids |
| CN112920017B (en) * | 2021-01-27 | 2022-09-02 | 格林生物科技股份有限公司 | Preparation method of dicyclopropyl derivative compound |
-
2004
- 2004-04-12 CN CN 200410017680 patent/CN1262535C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1562962A (en) | 2005-01-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2008009897A1 (en) | Process for preparing pregabalin and its opposite enantiomer | |
| US3733352A (en) | Preparation of d-threo-1-p-methyl-sulfonylphenyl-2-dichloro-acet-amidopropane-1,3-diol | |
| US20120029230A1 (en) | Method for preparing chiral baclofen | |
| CN1262535C (en) | Method ofr synthesizing S-(1)-2.2 dimethylcyclopropane formamide | |
| JP5211876B2 (en) | Method for producing high purity 2'-trifluoromethylpropiophenone | |
| CN112645813B (en) | Preparation method of (R) -3-cyclohexene carboxylic acid | |
| EP1935866B1 (en) | Process for producing optically active fluorobenzyl alcohol | |
| JP5598330B2 (en) | Process for producing optically active organic carboxylic acid | |
| CN108358803B (en) | Deuterated glycine, hippuric acid-L-menthyl ester (2, 2-D)2) And a process for the synthesis of intermediates thereof | |
| CN103102280B (en) | The preparation method of optical voidness 1-(alpha-amido benzyl)-beta naphthal | |
| JPH0558970A (en) | Optically active substance of nitrogen-containing perfluorocarboxylic acid and its production | |
| US6639095B1 (en) | Process for preparing optically active α-hydroxy acids and derivatives thereof | |
| RU2309145C1 (en) | Separation of 3-aminoalkylnitryles | |
| CN111333529A (en) | Preparation method of pregabalin | |
| CN1160358C (en) | (8S,18S)-1,4,10,13,16-pentazatricyclo [16.3.0.0 4.8] heneicosane-9,17-diketone and its prepn process | |
| KR920000953B1 (en) | Method for preparing optically active 3.4-dihydroxy butyric acid derivatives | |
| CN107417531B (en) | Amplification synthesis process of 2-hydroxymethyl methyl acrylate and analogue | |
| KR100884558B1 (en) | Method of manufacturing optically active amide with high yield and high purity | |
| EP1489066B1 (en) | Process for production of optically active carboxylic acid | |
| JP2002332277A (en) | Method for manufacturing optically active 2- methylpiperazine | |
| US6689895B2 (en) | 4, 8-dodecadienedinitrile and process for its production | |
| WO1990008126A1 (en) | Resolution process | |
| JP3694923B2 (en) | Process for producing optically active 1- (2,4-dichlorophenyl) ethylamine | |
| JP4218310B2 (en) | Process for producing optically active 2-amino-2-phenylethanol and its intermediate | |
| JP4129765B2 (en) | Method for producing racemic aminopentanenitrile |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |