CN102532185B - Preparation methods of lovaamide hexamethyloxy disilane, simvastatin hexamethyloxy disilane and simvastatin - Google Patents
Preparation methods of lovaamide hexamethyloxy disilane, simvastatin hexamethyloxy disilane and simvastatin Download PDFInfo
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- simvastatin
- acid amides
- lip river
- silicon ether
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- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 title claims abstract description 30
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 title claims abstract description 30
- 229960002855 simvastatin Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- LMQGXNPPTQOGDG-UHFFFAOYSA-N trimethoxy(trimethoxysilyl)silane Chemical compound CO[Si](OC)(OC)[Si](OC)(OC)OC LMQGXNPPTQOGDG-UHFFFAOYSA-N 0.000 title abstract 6
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000011230 binding agent Substances 0.000 claims abstract description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims abstract description 6
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims abstract description 6
- 229960004844 lovastatin Drugs 0.000 claims abstract description 6
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 70
- 150000001408 amides Chemical class 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 37
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 35
- 229910052710 silicon Inorganic materials 0.000 claims description 35
- 239000010703 silicon Substances 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 150000002460 imidazoles Chemical class 0.000 claims description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical group CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 10
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- 150000003141 primary amines Chemical class 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical group CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 230000001035 methylating effect Effects 0.000 claims description 4
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 150000003852 triazoles Chemical class 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 150000007530 organic bases Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000002904 solvent Substances 0.000 abstract description 7
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000008092 positive effect Effects 0.000 abstract 1
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 abstract 1
- 238000002444 silanisation Methods 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000005406 washing Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- -1 tetracol phenixin Chemical compound 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229960004839 potassium iodide Drugs 0.000 description 3
- 235000007715 potassium iodide Nutrition 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 241000242583 Scyphozoa Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MXOSTENCGSDMRE-UHFFFAOYSA-N butyl-chloro-dimethylsilane Chemical group CCCC[Si](C)(C)Cl MXOSTENCGSDMRE-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- SYKWLIJQEHRDNH-CKRMAKSASA-N glutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)CCCC(O)=O)O[C@H]1N1C2=NC=NC(N)=C2N=C1 SYKWLIJQEHRDNH-CKRMAKSASA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UAXOELSVPTZZQG-UHFFFAOYSA-N tiglic acid Natural products CC(C)=C(C)C(O)=O UAXOELSVPTZZQG-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
Abstract
The invention provides preparation methods of lovaamide hexamethyloxy disilane, simvastatin hexamethyloxy disilane and simvastatin. The preparation method of lovaamide hexamethyloxy disilane comprises the following steps of: (1) reacting lovastatin with primary amine or secondary amine to generate lovaamide; and (2) adding an acid-binding agent into a water-insoluble reaction solvent, and reacting the lovaamide with a silanization reagent to generate lovaamide hexamethyloxy disilane. Compared with the prior art, the preparation methods have the positive effects of simplification of the production process, recyclability of the used solvent, environmental friendliness, reduction in production cost and suitability for industrial production.
Description
Technical field
The invention belongs to the field of chemical synthesis, in particular to a kind of Simvastatin intermediate---the preparation method of acid amides two silicon ether and Simvastatin two silicon ether and Simvastatin is cut down in Lip river.
Background technology
Simvastatin is a kind of hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor developed by Merck company of the U.S., and its structural formula is such as formula shown in I.Simvastatin has potent lipid-lowering effect, is to commonly use one of " statin " class blood lipid-lowering medicine in the world at present, is widely used in treating hyperlipidemia, simultaneously also for preventing cardiovascular and cerebrovascular diseases.
American documentation literature US4820850 discloses a kind of synthetic method of Simvastatin, and it is good that the method has reaction specificity, and the guaranteed advantage of quality product, therefore at present by Duo Jia manufacturing enterprise is used.
The synthetic method of current Simvastatin mostly is: first, and lovastatin (its structural formula is such as formula shown in II) is under primary amine or secondary amine effect, and open loop generates Lip river and cuts down acid amides (its structural formula is as shown in formula III).Secondly, Lip river is cut down acid amides and TERT-BUTYL DIMETHYL CHLORO SILANE (TBSCl) to react and generate Lip river and cut down acid amides two silicon ether (its structural formula is such as formula shown in IV).Then, alpha-carbon Lip river being cut down the side switch 2-Methyl Butyric Acid ester of acid amides two silicon ether methylates, and obtains pungently cutting down acid amides two silicon ether (its structural formula is such as formula shown in V).Its methylating reagent has: methyl iodide, monobromethane, methyl chloride, methyl-sulfate, methyl tosylate, methyl mesylate.Finally cut down acid amides two silicon ether deprotection by pungent, basic hydrolysis Cheng Xin cuts down acid (or becoming ammonium salt), and closed loop esterification obtains Simvastatin.
The method is cut down in the process of acid amides two silicon ether, with dimethyl formamide (DMF) for reaction solvent in preparation Lip river.The boiling point of dimethyl formamide (DMF) is high and water-soluble, and therefore dimethyl formamide, not only contaminate environment are recycled in production technique inconvenience at present, and improve production cost.
Summary of the invention
In order to solve the technical problem existed in above-mentioned prior art, the invention provides the preparation method that acid amides two silicon ether, Simvastatin two silicon ether and Simvastatin are cut down in a kind of Lip river, wherein cutting down in Lip river in the preparation method of acid amides two silicon ether and do not use DMF.
Specifically, the invention provides:
(1) preparation method for acid amides two silicon ether is cut down in Lip river, and it comprises:
1) make lovastatin and primary amine or secondary amine react, generate Lip river and cut down acid amides; And
2) in water-insoluble reaction solvent, add acid binding agent, make described Lip river cut down acid amides and silylating reagent reacts, generate Lip river and cut down acid amides two silicon ether.
(2) method Gen Ju (1), wherein, described reaction solvent is one or more in methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride, benzene, toluene, hexanaphthene, normal hexane.
(3) according to (1) or the method described in (2), wherein, described reaction solvent is methylene dichloride and/or hexanaphthene.
(4) method Gen Ju (1), wherein, the ratio that the weight of acid amides is cut down in volume and the described Lip river of described reaction solvent is 1-2: 1, and the unit of wherein said volume is mL, and the unit of described weight is g.
(5) method Gen Ju (1), wherein, described silylating reagent is TERT-BUTYL DIMETHYL CHLORO SILANE.
(6) method Gen Ju (1), wherein, step 2) described reaction carries out in the presence of a catalyst.
(7) method Gen Ju (6), wherein, described catalyzer is one or more in KI, Dimethylamino pyridine, N, N-xylidene(s).
(8) according to (6) or the method described in (7), wherein, described catalyzer is KI and/or Dimethylamino pyridine.
(9) method Gen Ju (1), wherein, step 2) temperature of reaction be 40-110 DEG C.
(10) method Gen Ju (8), wherein, described temperature of reaction is 60-90 DEG C.
(11) method Gen Ju (1), wherein, described acid binding agent is organic bases.
(12) method Gen Ju (11), wherein, described acid binding agent is one or more in imidazoles, triethylamine, pyridine, triazole, N-Methylimidazole.
(13) according to (11) or the method described in (12), wherein, described acid binding agent is imidazoles.
(14) method Gen Ju (1), wherein, described primary amine is n-Butyl Amine 99.
(15) preparation method for Simvastatin two silicon ether, the method comprises: acid amides two silicon ether is cut down in the Lip river that the method according to any one of (1)-(14) obtains and methylating reagent reacts, and generates Simvastatin two silicon ether.
(16) preparation method for Simvastatin, the method comprises: the Simvastatin two silicon ether (15) obtained, through deprotection, hydrolysis and closed loop esterification, obtains Simvastatin.
Preparation method of the present invention compared with prior art has the following advantages and positively effect:
1. simplify production technique.
The present invention's reaction terminates rear direct hydrolysis, extracts, recycled solvent without the need to another solubilizing agent.
2. environmental protection and reduce production cost.
Recycled solvent in the present invention, and the energy consumption and impact on quality product that avoid that high boiling solvent dimethyl formamide reclaims, or avoid another solubilizing agent extraction DMF and enter jellyfish liquid and negative impact that environment is caused.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
The invention provides the preparation method that acid amides two silicon ether is cut down in a kind of Lip river:
First, lovastatin is under primary amine or secondary amine effect, and open loop generates Lip river and cuts down acid amides.Wherein, R, R in formula III
1can be H or ethyl, n-propyl, cyclopropyl, primary, secondary, the tertiary butyl, tert-pentyl, cyclohexyl, benzyl, methoxyethyl, heptyl also can be diethyl, pyrryl, piperidyl.The preferred n-Butyl Amine 99 of primary amine in the present invention.
Secondly, Lip river is cut down acid amides and silylating reagent to react and generate Lip river and cut down acid amides two silicon ether.Silylating reagent includes but not limited to: TERT-BUTYL DIMETHYL CHLORO SILANE (TBSCl), the silica-based urea of six alkyl two, trimethylchlorosilane, Iodotrimethylsilane, hexamethyldisilane, and preferred tertiary butyldimethylchlorosilane, it can make product stability good.Reaction solvent preferably adopts lower boiling and water-fast polyhalohydrocarbon (methylene dichloride, chloroform, tetracol phenixin, ethylene dichloride) and varsol (benzene, toluene, hexanaphthene, normal hexane), one or more of preferred methylene dichloride, hexanaphthene, more preferably methylene dichloride.
The ratio that the weight (g) of acid amides is cut down in the volume (mL) of reaction solvent and Lip river can be 1-2: 1.In this article, the ratio that the weight of acid amides is cut down in volume and the Lip river of reaction solvent is for volume in units of milliliter, for weight situation in grams.Obviously, the unit of volume and weight can become large in proportion or reduce.Such as, volume and the Lip river of reaction solvent cut down the ratio of the weight of acid amides also can be for volume by be upgraded to unit, weight by kilogram in units of situation for.
The acid binding agent of reaction can be one or more in imidazoles, triethylamine, pyridine, triazole, N-Methylimidazole, preferred imidazoles.Preferably, reaction carries out under the condition of catalyzer.KI can be added and carry out activated silane reagent; Can add DMAP (Dimethylamino pyridine) and/or N, N-xylidene(s) to promote that reaction is carried out, preferably add DMAP or KI, it can Reaction time shorten.Temperature of reaction is preferably 40-110 DEG C, more preferably 60-90 DEG C.Till reaction times runs out of with TLC detecting reactant, general 2-5 hour.Reaction is finished, and directly can wash rear concentrating and obtain product, solvent recuperation is applied mechanically.What be applicable to is that cooling is finished in reaction, leaches throw out, reclaims acid binding agent (such as imidazoles).
It is the intermediate producing Simvastatin that acid amides two silicon ether is cut down in product Lip river of the present invention; the preparation method of Simvastatin can referenced patent document CN88104027; acid amides two silicon ether is cut down in Lip river can obtain Simvastatin two silicon ether after methylating; again through acid catalysis deprotection; be hydrolyzed in alkali and pungently cut down acid (or salify), closed loop lactonizes to obtain Simvastatin (formula I).
Further explain and describe content of the present invention below by way of example, but these examples are not to be construed as limiting the scope of the invention.
Embodiment 1
Lovastatin 50g, adds n-Butyl Amine 99 42ml, is warming up to 80 DEG C under stirring, and backflow 1-1.5h, is cooled to 50 DEG C, the excessive n-Butyl Amine 99 of reclaim under reduced pressure (be inserted in down batch use), obtains Lip river and cuts down acid amides and be directly used in the next step.
By above reaction in obtain Lip river cut down acid amides, add 50ml CH
2cl
2after dissolving, add 21g imidazoles and 43g TERT-BUTYL DIMETHYL CHLORO SILANE, potassiumiodide 2g, Dimethylamino pyridine 1g, reflux 4 hours, till TLC detecting reactant is exhausted.Mixture adds CH
2cl
2250ml, cold filtration.Filter cake 50ml CH
2cl
2after washing, reclaim imidazoles.The 1%NH of filtrate 500ml
3water washing twice, then with 500ml washing, divides and gets organic layer, use anhydrous Na
2sO
4dry 4h, filter, filtrate is concentrated into dry, obtains Lip river and cuts down acid amides two silicon ether 87g, be directly used in subsequent reactions.
Embodiment 2
Lip river prepared by the method by embodiment 1 is cut down after acid amides is dissolved in 50ml hexanaphthene, add imidazoles 21g and 43g TERT-BUTYL DIMETHYL CHLORO SILANE, potassiumiodide 2g, Dimethylamino pyridine 1g, reflux 3h, till TLC detecting reactant runs out of, mixture is cooled to 50 DEG C, adds cyclohexane 250ml and cools, filter, filter cake, with after the washing of 50ml cyclohexane, reclaims imidazoles, the 1%NH of filtrate 500ml
3water washing twice, then with 500ml washing, divides and gets organic layer, use anhydrous Na
2sO
4dry 4h, filter, filtrate is concentrated into dry, obtains Lip river and cuts down acid amides two silicon ether 88g, be directly used in subsequent reactions.
Embodiment 3
The Lip river of preparing by the method for embodiment 1 is cut down acid amides and is dissolved in 50ml toluene, add imidazoles 21g and TERT-BUTYL DIMETHYL CHLORO SILANE 43g, Dimethylamino pyridine 1g, be heated to 90 DEG C of reaction 3.5h, till TLC detecting reactant runs out of, mixture is cooled to 50 DEG C, adds 250ml toluene, cooling, filter, filter cake, with after 50ml toluene wash, reclaims imidazoles, the 1%NH of filtrate 500ml
3water washing twice, then with 500ml washing, divides and gets organic layer, use anhydrous Na
2sO
4dry 4h, filter, filtrate is concentrated into dry, obtains Lip river and cuts down acid amides two silicon ether 87.5g, be directly used in subsequent reactions.
Embodiment 4
The Lip river of preparing by the method for embodiment 1 is cut down acid amides and is dissolved in 80ml normal hexane, adds imidazoles 21g and TERT-BUTYL DIMETHYL CHLORO SILANE 43g, potassiumiodide 2g, backflow is warming up under stirring, till insulation reaction 4.5h, TLC detecting reactant runs out of, mixture is cooled to 50 DEG C, add normal hexane 250ml, cooling, filter, filter cake is with after 50ml n-hexane, reclaim imidazoles, the 1%NH of filtrate 500ml
3water washing twice, then with 500ml washing, divides and gets organic layer, use anhydrous Na
2sO
4dry 4h, filter, filtrate is concentrated into dry, obtains Lip river and cuts down acid amides two silicon ether 86.8g, be directly used in subsequent reactions.
Claims (11)
1. a preparation method for acid amides two silicon ether is cut down in Lip river, and the method comprises:
1) make lovastatin and primary amine or secondary amine instead give birth to react, generate Lip river and cut down acid amides; And
2) in water-insoluble reaction solvent, add acid binding agent, make described Lip river cut down acid amides and silylating reagent reacts, generate Lip river and cut down acid amides two silicon ether,
Wherein, described primary amine is n-Butyl Amine 99;
Wherein, described reaction solvent is one or more in methylene dichloride, hexanaphthene, normal hexane;
Wherein, described silylating reagent is TERT-BUTYL DIMETHYL CHLORO SILANE; And
Wherein, step 2) described reaction carries out in the presence of a catalyst, and described catalyzer is KI, Dimethylamino pyridine, N, one or more in N-xylidene(s).
2. method according to claim 1, wherein, described reaction solvent is methylene dichloride and/or hexanaphthene.
3. method according to claim 1, wherein, the ratio that the weight of acid amides is cut down in volume and the described Lip river of described reaction solvent is 1-2: 1, and the unit of wherein said volume is mL, and the unit of described weight is g.
4. method according to claim 1, wherein, described catalyzer is KI and/or Dimethylamino pyridine.
5. method according to claim 1, wherein, step 2) temperature of reaction be 40-110 DEG C.
6. method according to claim 5, wherein, described temperature of reaction is 60-90 DEG C.
7. method according to claim 1, wherein, described acid binding agent is organic bases.
8. method according to claim 7, wherein, described acid binding agent is one or more in imidazoles, triethylamine, pyridine, triazole, N-Methylimidazole.
9. method according to claim 8, wherein, described acid binding agent is imidazoles.
10. a preparation method for Simvastatin two silicon ether, the method comprises:
A) method according to any one of claim 1-9 prepares Lip river and cuts down acid amides two silicon ether;
B) acid amides two silicon ether is cut down in the Lip river that step a) obtains and methylating reagent reacts, generate Simvastatin two silicon ether.
The preparation method of 11. 1 kinds of Simvastatins, the method comprises:
A) method according to claim 10 prepares Simvastatin two silicon ether;
B) by steps A) the Simvastatin two silicon ether that obtains through deprotection, hydrolysis and closed loop esterification, obtain Simvastatin.
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| CN1754870A (en) * | 2004-09-30 | 2006-04-05 | 淮北市辉克药业有限公司 | Process for the preparation of simvastatin |
| US20070129437A1 (en) * | 2005-12-06 | 2007-06-07 | Ferenc Korodi | Process for preparing simvastatin and intermediates thereof |
| CN101190907A (en) * | 2006-11-24 | 2008-06-04 | 马群力 | Method for synthesizing statins compounds |
| CN101381356A (en) * | 2008-10-23 | 2009-03-11 | 河北科技大学 | Preparation method of simvastatin |
| CN101747357A (en) * | 2008-12-11 | 2010-06-23 | 北大方正集团有限公司 | Method for preparing simvastatin intermediate - simva-acylamide second silicon ether |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1754870A (en) * | 2004-09-30 | 2006-04-05 | 淮北市辉克药业有限公司 | Process for the preparation of simvastatin |
| US20070129437A1 (en) * | 2005-12-06 | 2007-06-07 | Ferenc Korodi | Process for preparing simvastatin and intermediates thereof |
| CN101190907A (en) * | 2006-11-24 | 2008-06-04 | 马群力 | Method for synthesizing statins compounds |
| CN101381356A (en) * | 2008-10-23 | 2009-03-11 | 河北科技大学 | Preparation method of simvastatin |
| CN101747357A (en) * | 2008-12-11 | 2010-06-23 | 北大方正集团有限公司 | Method for preparing simvastatin intermediate - simva-acylamide second silicon ether |
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