CN103497212B - A kind of preparation method of rosuvastain calcium intermediate - Google Patents
A kind of preparation method of rosuvastain calcium intermediate Download PDFInfo
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- CN103497212B CN103497212B CN201310439485.XA CN201310439485A CN103497212B CN 103497212 B CN103497212 B CN 103497212B CN 201310439485 A CN201310439485 A CN 201310439485A CN 103497212 B CN103497212 B CN 103497212B
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- methyl
- fluorophenyl
- pyrimidine
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Abstract
The invention discloses a kind of preparation method of rosuvastain calcium intermediate.4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol is joined in solvent; cool to-5 ~ 10 DEG C; add (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester; add NiNPs; 50-80 DEG C of reaction 15 ~ 24 hours; filter; filtrate reduced in volume; silicagel column on resistates; with trichloromethane wash-out, concentrating under reduced pressure obtains yellow oil dress liquid.Raw material of the present invention is simple, and reaction conditions is gentle, and environmental friendliness, may be used for industrialized production.
Description
Technical field
The present invention relates to the synthesis technique of compound, particularly relate to a kind of preparation method of rosuvastain calcium intermediate.
Background technology
7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester is the key intermediate (CurrentOrganicChemistry in synthesizing rosuvastatin spit of fland; 2010; 14,816-845).(Jiangsu pharmacy and the clinical study such as Cai Wei, 2005, 13(4) 8-10) report a kind of 6-[(1E)-2-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) is amino]-5-pyrimidine] vinyl]-2, 2-dimethyl-1, the synthetic method of 3-dioxane-4-methyl acetate, with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-formaldehyde for starting raw material, condensation reaction preparation is carried out with (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine methyl caproate.CN102617481 is by synthesis 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methanol-fueled CLC 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester.Japan Shionogi institute (US5260440) with 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-formaldehyde for raw material; Reactive Synthesis 6-[(1E)-2-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) is amino]-5-pyrimidine] vinyl]-2 is wished by ladder Wei; 2-dimethyl-1,3-dioxane-4-methyl acetate.NataliaAndrushko(Eur.J.Org.Chem.; 2008; 847-853) synthesize 6-[(1E)-2-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) is amino]-5-pyrimidine] vinyl]-2 with same route; 2-dimethyl-1; 3-dioxane-4-methyl acetate, has synthesized 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-formaldehyde unlike NataliaAndrushko by palladium chtalyst formylation.As from the foregoing, 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-formaldehyde synthesizes the most basic raw material in fact of 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl l-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester.Usually Swern(R.E.Ireland, D.W.Norbeck, J.Org.Chem.1985 is passed through by 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol, 50,2198 – 2200.), MnO
2(R.J.K.Taylor, M.Reid, J.Foot, S.A.406Raw, Acc.Chem.Res.2005, 38, 851 – 869), Dess-Martin(A.G.M.Barrett, D.Hamprecht, M.Ohkubo, J.Org.Chem.1997, 62, 9376 – 9378.), BaMnO4(S.Shuto, S.Niizuma, A.Matsuda, J.Org.Chem.1998, 63, 4114489 – 4493.), IBX(A.Maiti, J.S.Yadav, Synth.Commun.2001, 31, 1499 – 1506.), TPAP(R.N.MacCoss, E.P.Balskus, S.V.Ley, TetrahedronLett.2003, 44, 7779 – 7781.), PCC(A.R.Bressette, L.C.GloverIV, Synlett2004, 738 – 740), SO3.Py(F.R.PinachoCrisostomo, R.Carrillo, T.Martin, F.Garcia-Tellado, V.S.Martin, J.Org.Chem.2005, 70, 10099 – 10101) or TEMPO(J.M.Vatele, TetrahedronLett.2006, 47, 715 – 718.) oxidation obtain.These method choice are poor, and produce a large amount of waste water,waste gas and industrial residue, environment is unfriendly.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of preparation method of rosuvastain calcium intermediate is provided.
A kind of preparation method of rosuvastain calcium intermediate is: join in solvent by 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol, cool to-5 ~ 10 DEG C, add (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester, 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol is 1:1 ~ 1.05 with the mol ratio of (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester, add NiNPs, the mass ratio of 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol and NiNPs is 1:0.1 ~ 0.2, 50-80 DEG C of reaction 15 ~ 24 hours, filter, filtrate reduced in volume, silicagel column on resistates, with trichloromethane wash-out, concentrating under reduced pressure obtains 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester.Described solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran; Described NiNPs is the nano-nickel powder of 30-60nm or 60-100nm.
Raw material of the present invention is simple, and reaction conditions is gentle, and environmental friendliness, may be used for industrialized production.
Embodiment
Reaction equation of the present invention is as follows:
A kind of preparation method of rosuvastain calcium intermediate is: join in solvent by 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol, cool to-5 ~ 10 DEG C, add (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester, 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol is 1:1 ~ 1.05 with the mol ratio of (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester, add NiNPs, the mass ratio of 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol and NiNPs is 1:0.1 ~ 0.2, 50-80 DEG C of reaction 15 ~ 24 hours, filter, filtrate reduced in volume, silicagel column on resistates, with trichloromethane wash-out, concentrating under reduced pressure obtains 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester.Described solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran; Described NiNPs is the nano-nickel powder of 30-60nm or 60-100nm.
Embodiment 1
In the there-necked flask of 250ml, load onto thermometer, pH meter and constant pressure funnel and magnetic agitation.Under normal temperature, tetrahydrofuran (THF) 50ml is added in reaction flask, add 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol 35.3 grams again, cool to 10 DEG C, add (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester 50.8 grams, add the NiNPs of 7.06 grams of 60-100nm, 50 DEG C of reactions 24 hours, filter, filtrate reduced in volume, silicagel column on resistates, with trichloromethane wash-out, concentrating under reduced pressure obtains yellow oil dress liquid 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester 43.9 grams, yield 69.1%.
1H-NMR(CDCl
3)δ:0.05(3H,s,SiCH
3),0.061(3H,s,SiCH
3,0.80(9H,s,Si(CH
3)
3)),1.28(6H,d,J=7),2.48(2H,m),2.74(2H,m),3.36(1H,hept,J=7),3.51(3H,s),3.59(3H,s),3.69(9H,s),4.59(1H,m),6.51(1H,dd,J=6,16),7.11(2H,m),7.58(2H,m),7.60(1H,d,J=16).
Embodiment 2
In the there-necked flask of 250ml, load onto thermometer, pH meter and constant pressure funnel and magnetic agitation.Under normal temperature, 2-methyltetrahydrofuran 50ml is added in reaction flask, add 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol 35.3 grams again, cool to-5 DEG C, add (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester 48.4 grams, add the NiNPs of 3.53 grams of 30-60nm, 80 DEG C of reactions 15 hours, filter, filtrate reduced in volume, silicagel column on resistates, with trichloromethane wash-out, concentrating under reduced pressure obtains yellow oil dress liquid 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester 45.6 grams, yield 71.8%.
Embodiment 3
In the there-necked flask of 250ml, load onto thermometer, pH meter and constant pressure funnel and magnetic agitation.Under normal temperature, tetrahydrofuran (THF) 100ml is added in reaction flask, add 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol 35.3 grams again, cool to 0 DEG C, add (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester 50.0 grams, add the NiNPs of 5.29 grams of 30-60nm, 60 DEG C of reactions 20 hours, filter, filtrate reduced in volume, silicagel column on resistates, with trichloromethane wash-out, concentrating under reduced pressure obtains yellow oil dress liquid 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester 49.8 grams, yield 77.6%.
Claims (2)
1. the preparation method of a rosuvastain calcium intermediate, it is characterized in that comprising the steps: 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol to join in solvent, cool to-5 ~ 10 DEG C, add (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester, 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol is 1:1 ~ 1.05 with the mol ratio of (R)-3-[(t-butyldimethylsilyi) oxygen base]-5-oxo-6-triphenylphosphine hecanoic acid t-butyl ester, add NiNPs, the mass ratio of 4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-methyl alcohol and NiNPs is 1:0.1 ~ 0.2, 50-80 DEG C of reaction 15 ~ 24 hours, filter, filtrate reduced in volume, silicagel column on resistates, with trichloromethane wash-out, concentrating under reduced pressure obtains 7-[4-(4-fluorophenyl)-6-sec.-propyl-2-(N-methyl-N-methane sulfonylamino) pyrimidine-5-base]-(3R)-3-(t-butyldimethylsilyi)-5-oxo-6-heptanoic acid tert-butyl ester, described NiNPs is the nano-nickel powder of 30-60nm or 60-100nm.
2. the preparation method of a kind of rosuvastain calcium intermediate according to claim 1, is characterized in that described solvent is tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
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Citations (3)
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CN1415591A (en) * | 2001-10-30 | 2003-05-07 | 中国石油化工股份有限公司 | Technical method of dehydrogenating alcohols |
CN1958593A (en) * | 2005-11-03 | 2007-05-09 | 上海医药工业研究院 | Method for preparing intermediate of synthesizing rosuvastatin calcium |
EP2093230A1 (en) * | 2007-04-18 | 2009-08-26 | Teva Pharmaceutical Industries Ltd. | A process for preparing intermediates of HMG-CoA reductase inhibitors |
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CN1415591A (en) * | 2001-10-30 | 2003-05-07 | 中国石油化工股份有限公司 | Technical method of dehydrogenating alcohols |
CN1958593A (en) * | 2005-11-03 | 2007-05-09 | 上海医药工业研究院 | Method for preparing intermediate of synthesizing rosuvastatin calcium |
EP2093230A1 (en) * | 2007-04-18 | 2009-08-26 | Teva Pharmaceutical Industries Ltd. | A process for preparing intermediates of HMG-CoA reductase inhibitors |
Non-Patent Citations (2)
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