CN105503815A - Preparation method of synthetic intermediate of Lipitor - Google Patents
Preparation method of synthetic intermediate of Lipitor Download PDFInfo
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- CN105503815A CN105503815A CN201410491818.8A CN201410491818A CN105503815A CN 105503815 A CN105503815 A CN 105503815A CN 201410491818 A CN201410491818 A CN 201410491818A CN 105503815 A CN105503815 A CN 105503815A
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- 0 CC(C)(C)OC(CC1OC(C)(C)OC(CC*)C1)=O Chemical compound CC(C)(C)OC(CC1OC(C)(C)OC(CC*)C1)=O 0.000 description 1
- CEAXIISBBMFBSK-GHMZBOCLSA-N CC(C)(C)OC(C[C@@H]1OC(C)(C)O[C@H](CC=O)C1)=O Chemical compound CC(C)(C)OC(C[C@@H]1OC(C)(C)O[C@H](CC=O)C1)=O CEAXIISBBMFBSK-GHMZBOCLSA-N 0.000 description 1
Abstract
The invention discloses a novel preparation method for a side-chain fragment compound, ATS-9, of Lipitor and solves a problem that poisonous reagents, such as Raney nickel, are required in synthesis in the prior art. The preparation method includes the steps of: with epoxy chloropropane as an initial raw material, performing a ring opening reaction with Grignard reagent to obtain a first chiral hydroxyl group; performing cyano substitution, hydrolyzing the substituted cyano group into ester, performing homologation reaction to extend the carbon chain, and performing reduction with diethylmethoxylborane and sodium borohydride, and protecting the two hydroxyl groups and finally performing the Staudinger reaction to prepare the ATS-9.
Description
Technical field
The invention belongs to medicine, be specifically related to prepare Lipitor intermediate A TS-9 (6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate) brand-new synthetic method, in view of ATS-9 has two hydroxyl chiral structure, so synthesis focuses on the structure of two hydroxyl structure, the present invention is raw material by epoxy chloropropane cheap and easy to get, with grignard reagent attack epoxy chloropropane, open loop forms first chiral hydroxyl group, and under sodium borohydride and diethylmethoxyborane effect, selective reduction forms second chiral hydroxyl group afterwards.Protect using 2.2-Propanal dimethyl acetal as protecting group two hydroxyl, through the cut-out of double bond afterwards, the steps such as reduction amination finally form key intermediate.
Background technology
Atherosclerosis can cause coronary heart disease, stenocardia, numerous cardiovascular disorder such as myocardial infarction, his class D medicine is that novel 3-hydroxyl-3-methylglutaryl coenzyme A A (HMG-CoA) reductase inhibitor of class can effectively reduce serum total cholesterol, the solid enzyme of low-density lipoprotein courage, triglyceride.Thus slow down coronary artery pathological changes progress, significantly reduce cardiovascular event, or the mortality ratio of coronary heart disease.
In synthesis atorvastatincalcuim side chain ATS-9 method, condition Shortcomings used was mainly reflected in the following aspects (1) partial reaction overlong time in the past, and some reaction even needs more than 6 days.(2) adopt Intermediate Catalyst toxicity higher, all adopt the use of Raney's nickel in most reaction, its strong carinogenicity brings numerous inconvenience in synthesis.(3) in reduction process the use of hydrogen to bringing huge potential safety hazard in scale operation.(4) yield is on the low side, only has the yield of 30-50% in some reaction process.
Atorvastatincalcuim has following structural formula (1):
Atorvastatincalcuim structure is a polysubstituted pyrrole ring, synthesis adopts usually side chain segments ATS-9 and fragment M4 react through Paal_Knorr and carry out cyclisation, current M4 synthetic method is comparatively ripe, the present invention is with one green linear synthesis approach synthesis ATS-9, wherein do not use some poisonous reagents and inflammable gas, avoid the harm brought in testing and the potential potential safety hazard brought in the industrial production.The single step reaction time the longest in reaction has also only used ten hours, and each step reaction yield is considerable.
Summary of the invention
The present invention is for providing the efficient succinct synthetic method of atorvastatincalcuim intermediate A TS-9 mono-kind, wherein raw materials used cheap and easy to get, obtains ATS-9 (Scheme1) with high yield.
ATS-9 has following structural formula (2).
Above-mentioned atorvastatincalcuim intermediate A TS-9 synthetic method, has following steps
1. be starting raw material according to claims 2-1 with epoxy chloropropane, at catalyzer cuprous chloride, with under the acting in conjunction of vinyl magnesium bromide, formula (1) formed to epoxy chloropropane attack open loop, wherein first obtain first chiral hydroxyl group.
2. according to the chlorine atom in claims 2-2 compound (1) replace by cyano group, formed cyano group substitution compound (2).
3. be hydrolyzed under trimethylchlorosilane effect according to cyano group in claims 2-3 compound (2), and after methyl alcohol transesterify, form compound (3).
4. according to claims 2-4 compound (3) through tert-butyl acetate effect, carry out homologation obtain carbochain through extend compound (4).
5. according to claims 2-5 compound (4) at diethylmethoxyborane, sodium borohydride in tetrahydrofuran (THF) and methyl alcohol (5:1) mixed solvent-78 DEG C react and form compound (5)
6. according to claims 2-6 compound (5) 2.2-Propanal dimethyl acetal, the protection of two hydroxyl is obtained compound (6).
7. according to claims 2-7 compound (6) double bond through ozone oxidation, triphenyl phosphorus reduction formed compound (7).
8. under sodium borohydride effect, carry out reduction according to claims 2-8 compound (7) aldehyde radical and form compound (8).
9. obtain compound (9) according to the protection of claims 2-9 compound (8) hydroxyl Methanesulfonyl chloride.
10 replace formation compound (10) according to claims 2-10 compound (9) through sodiumazide.
11. react through Staudinger according to claims 2-11 compound (10), form ATS-9.
Concrete implementation step
1. formula (1): the preparation of (R)-1-chloropent-4-en-2-ol
Getting 500mL round-bottomed flask adds through the dry tetrahydrofuran (THF) 200mL of sodium sand backflow, add under-20 DEG C of conditions after vinyl magnesium bromide 153mL (0.15mol) stirs 20min with cuprous chloride 913mg (0.01mol) and add substrate by epoxy chloropropane 8mL (0.1mol), reaction is completed after TLC detects 2 hours, system is transferred to 100mL ammonium chloride solution, add ethyl acetate 300mL extraction, saturated common salt water washing, the anhydrous MgSO of organic phase
4drying, filters, and filtrate reduced in volume is separated (ethyl acetate/petroleum ether makes eluent) through silica gel column chromatography and obtains 11.6g yellow oily liquid, productive rate 91%.
Product nuclear magnetic data:
1HNMR(400MHz,CDCl
3):δ＝5.88～5.78(m,1H),5.21～5.16(m,2H),3.65(q,J＝4Hz,1H),3.53(d,J＝6.8Hz,1H),2.39～2.33(m，3H).
13CNMR(100MHZ,CDCl3):δ＝133.2,118.6,70.6,49.4,38.7.
2. formula (2): the preparation of (R)-3-hydroxyhex-5-enenitrile
Get in 200mL round-bottomed flask and add 100mL distilled water, formula (1) (R)-1-chloropent-4-en-2-ol11.6g (0.92mol) and sodium cyanide 6.8g (0.138mol) are stirred under 30 DEG C of conditions and spends the night, after TLC detection raw material thoroughly disappears, system is transferred in 100mL ethyl acetate and extracts, saturated common salt water washing, the anhydrous MgSO of organic phase
4dry filter, filtrate reduced in volume is separated (ethyl acetate/petroleum ether makes eluent) through silica gel column chromatography and obtains 8.4g yellow oily liquid, productive rate 93%.
Product nuclear magnetic data:
1HNMR(400MHz,CDCl
3):δ＝5.78～5.67(m,1H),5.15～5.10(m,2H),3.97～3.90(m,1H),3.30(d,J＝4.8Hz,1H),2.50～2.50(m，2H),2.31(d，J＝6.4Hz,2H).
13CNMR(100MHZ,CDCl3):δ＝132.5,118.9，117.6,66.4,40.5,24.8
3. the preparation of formula (3) (R)-methyl3-hydroxyhex-5-enoate
Get 200mL round-bottomed flask and add methyl alcohol 80mL and formula (2) (R)-3-hydroxyhex-5-enenit-rile8.4g (0.74mol), divide three times subsequently to add (interval 3h) trimethylchlorosilane and add 16mL (0.38mol) at every turn, after backflow 15 TLC detect raw materials thoroughly disappearance chromatography Rotary Evaporators is drained solvent through column chromatography (ethyl acetate/petroleum ether makes eluent) 8.2g yellow oily liquid, productive rate 76%.
Product nuclear magnetic data:
1HNMR(400MHz,CDCl
3):δ＝5.83～5.72(m,1H),5.10～5.06(m,2H),4.07～4.01(m,1H),3.66(s,3H),3.01(s,1H),2.50～2.36(m，2H),2.25～2.21(m,2H).
13CNMR(100MHZ,CDCl3):δ＝172.9,133.8,118.0，67.2，51.6，40.8，40.4.
The preparation of 4 formulas (4) (R)-tert-butyl5-hydroxy-3-oxooct-7-enoate
Getting 250mL round-bottomed flask adds through the dry tetrahydrofuran (THF) 80mL of sodium sand backflow, add Diisopropylamine 18.6mL (0.13mol), system is placed in-78 DEG C, add n-Butyl Lithium (specification 2.5mol) 56.6mL (0.13mol), after stirring 10min, rise to 0 DEG C of reaction 30min.Afterwards system is fallen and add formula (3) (R)-methyl-3-hydroxyhex-5-enoate8.2g (0.056mol) and tert-butyl acetate 17.7mL (0.13mol) with-78 DEG C, after reaction 30min, TLC detection raw material thoroughly disappears, system is transferred in the ammonium chloride solution of 100mL, add the water washing of 100mL extraction into ethyl acetate reaction saturated common salt, the anhydrous MgSO of organic phase
4drying, filters, and filtrate reduced in volume is separated (ethyl acetate/petroleum ether makes eluent) through silica gel column chromatography and obtains 8.4g yellow oily liquid, productive rate 65%.
Product nuclear magnetic data:
1HNMR(400MHZ,CDCl
3):δ＝5.86～5.75(m,1H),5.14～5.10(m,2H),4.17～4.11(m,1H),3.37(m,1H),2.80～2.60(m,3H),2.28～2.24(m，2H)1.48(d,J＝8Hz,9H).
13CNMR(100MHZ,CDCl3):δ＝173.0,133.9,118.1,67.3，51.7,40.9，40.5,27.9。
5. formula (5) (3R, 5R)-tert-butyl3, the preparation of 5-dihydroxyoct-7-enoate
Get 200mL round-bottomed flask and add dry tetrahydrofuran (THF) 90mL and dry methyl alcohol 16mL, diethylmethoxyborane 51mL (0.05mol) is added under system being placed in-78 DEG C of conditions, formula (4) (R)-tert-butyl5-hydroxy-3-oxooct-7-enoate8.4g (0.036mol), sodium borohydride 2.5g (0.066mol), stirring spend the night after TLC detect raw material thoroughly disappear, system is drained solvent on a rotary evaporator, add the thorough lysate of ethyl acetate 10mL, add hydrogen peroxide 15mL again borine is sloughed, after thoroughly sloughing according to TLC detection borine, ethyl acetate 50mL extracts, saturated common salt water washing, the anhydrous MgSO of organic phase
4drying, filters, and filtrate reduced in volume is separated (ethyl acetate/petroleum ether makes eluent) through silica gel column chromatography and obtains 7.45g yellow oily liquid, productive rate 88%.
Product nuclear magnetic data:
1HNMR(400MHZ,CDCl
3):δ＝5.86～5.76(m,1H),5.12～5.08(m,2H),4.25～4.18(m,1H),3.95～3.89(m,1H),2.80～2.60(m,3H),2.38(d,J＝6.8Hz,2H),2.25～2.22(m,2H),1.58～1.54(m,2H),1.45(s,9H)。
13CNMR(100MHZ,CDCl3):δ＝172.0,134.5,117.8，81.4，71.1，69.0，42.5,42.1,41.5,28.0.
6. the preparation of formula (6) tert-butyl-2-((4R, 6R)-6-allyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate.
By formula (5) (3R, 5R)-tert-butyl3,5-dihydroxyoct-7-enoate7.4g (0.032mol) tosic acid 270mg (0.0016mol) joins in 2.2-Propanal dimethyl acetal 10mL, react thorough according to TLC detection raw material after 1 hour, after system is drained solvent on a rotary evaporator, column chromatography obtains yellow oily liquid 7.82g, productive rate 90%.
Product nuclear magnetic data:
1HNMR(400MHZ,CDCl
3):δ＝5.78～5.70(m,1H),5.06～4.99(m,2H),4.23～4.16(m,1H),3.89～3.82(m,1H),2.40～2.35(m,1H),2.29～2.22(m,2H),2.14～2.07(m,1H),1.56～1.52(m,2H),1.40(s,12H),1.32(s,3H).
13CNMR(100MHZ,CDCl3):δ＝170.1,133.9,117.0,98.5,80.3,68.4,66.1,42.6,40.6,35.9,30.0,28.0,19.6.
7. the preparation of formula (7) tert-butyl-2-((4R, 6S)-2,2-dimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl) acetate.
By formula (6) ert-butyl2-((4R, 6R)-6-allyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate7.82g (0.029mol), join in dry methylene dichloride, system is placed in-78 DEG C to continue to pass into ozone, after thorough according to TLC detection raw material after 2 hours, add triphenyl phosphoric acid 11.73g (0.043mol) at room temperature stir drain solvent on a rotary evaporator after 1 hour after column chromatography obtain yellow oily liquid 7.1g, productive rate 90%.
Product nuclear magnetic data:
1HNMR(400MHZ,CDCl
3):δ＝9.73(s,1H),4.24～4.28(m,1H),4.27～4.23(m,1H),2.60～2.54(m,1H),2.47～2.41(m,3H),2.40(q,J＝6Hz,1H)1.64～1.61(m,2H)1.44(s,17H)1.35(s,4H),1.24～1.16(m,2H)
13CNMR(100MHZ,CDCl3):δ＝200.7,169.9,99.1,98.9,80.6,65.964.6,49.6,42.5,36.0,29.8,28.0,19.5.
8. the preparation of formula (8) tert-butyl2-(6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate.
Get 50mL round-bottomed flask and add methyl alcohol 50mL, formula (7) tert-butyl-2-((4R, 6S)-2,2-dimethyl-6-(2-oxoethyl)-1,3-dioxan-4-yl) acetate7.1g (0.26mol), sodium borohydride 1.2g (0.03mol), detect raw material according to TLC after stirring 10min thoroughly to disappear, ethyl acetate 50mL extracts, saturated common salt water washing, the anhydrous MgSO of organic phase
4drying, filters, and obtains 6.58g, productive rate 92% after column chromatography.
Product nuclear magnetic data:
1HNMR(400MHZ,CDCl
3):δ＝4.32～4.25(m,1H),4.17～4.11(m,1H),3.82～3.73(m,2H),2.47～2.28(m,3H),1.76～1.71(m,2H),1.59～1.54(m,1H),1.48(s,3H),1.45(s,9H),1.38(s,3H).
13CNMR(100MHZ,CDCl3):＝170.1,98.8,80.6,68.4,66.1,60.7,42.5,38.0,36.1,30.0,28.0.19.7.
9. the preparation of formula (9) tert-butyl2-(2,2-dimethyl-6-(2-((methylsulfonyl) oxy) ethyl)-1,3-dioxan-4-yl) acetate.
By formula (8) tert-butyl2-(6-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan-4--yl) acetate6.58g joins the 50mL round-bottomed flask of the methylene dichloride containing 30mL, add methane sulfonyl chloride 3.2mL (0.042mol) subsequently, triethylamine 5.7mL (0.042mol), detect raw material according to TLC after stirring 30min thoroughly to disappear, ethyl acetate 50mL extracts, saturated common salt water washing, the anhydrous MgSO of organic phase
4drying, filters, obtains yellow oily liquid 7.18g, yield 85% after filtrate reduced in volume through column chromatography.
Product nuclear magnetic data:
1HNMR(400MHZ,CDCl
3):δ＝4.39～4.22(m,3H),4.06～3.99(m,1H),2.99(s,3H),2.43(q,J＝7.2Hz,1H),2.31(q,J＝6.0Hz,1H),1.92～1.79(m,2H),1.61～1.55(m,1H),1.44(s,13H),1.35(s,3H),1.25～1.17(m,1H)
13CNMR(100MHZ,CDCl3):δ＝170.0,98.9,80.6,66.4,66.0,64.8,42.5,37.2,36.2,35.6,29.9,28.0,19.6.
10. the preparation of formula (10) tert-butyl2-(6-(2-azidoethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate.
By formula (9) tert-butyl2-(2,2-dimethyl-6-(2-((methylsulfonyl) oxy) ethyl)-1,3-dioxan-4-yl) acetate7.18g joins the N containing 10mL, in the 20mL round-bottomed flask of dinethylformamide, add sodium azide 2.66g (0.041mol), detect raw material according to TLC after return stirring spends the night thoroughly to disappear, ethyl acetate 30mL extracts, organic phase is washed 20mL*7 time, anhydrous MgSO
4drying, filters, obtains yellow oily liquid 4.94g, yield 81% after filtrate reduced in volume through column chromatography
Product nuclear magnetic data:
1HNMR(400MHZ,CDCl3):δ＝4.26～4.22(m,1H),4.00～3.95(m,1H),3.42～3.33(m,2H),2.43(d,J＝6.8Hz,1H),2.30(d,J＝6.4Hz,1H),1.68(d,J＝6.8Hz,2H),1.58～1.52(m.1H)1.43(s,12H)1.35(s,3H),1.24～1.18(m,1H)
13CNMR(100MHZ,CDCl3):δ＝170.1,98.8,80.6,66.0,65.7,47.4,42.6,36.3,35.5,29.9,28.0,19.6.
The preparation of 11. formulas (11) tert-butyl2-(6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetate.
By formula (10) 10.tert-butyl2-(6-(2-azidoethyl)-2,2-dimethyl-1,3-dioxan-4-yl) acetat4.94g joins the 20mL round-bottomed flask of the dry methyl alcohol containing 10mL, adds palladium carbon 290mg.Continue to pass into hydrogen, detect raw material according to TLC after 3 hours and thoroughly disappear, diatomite elimination palladium carbon, the finished product yellow oily liquid 3.83g after filtrate reduced in volume, yield 85%
Product nuclear magnetic data:
1HNMR(400MHZ,CDCl3):δ＝4.20～4.18(m,1H),4.08～4.03(m,1H),3.92(s,1H),2.76(s,2H),2.59(s,2H),2.37(q,J＝7.2,1H),2.24(q,J＝6.0Hz,1H),1.38(m,13H),1.30(s,3H)1.35(s,3H),1.21～1.15(m,4H)
13CNMR(100MHZ,CDCl3):δ＝170.1,98.5,80.4,67.3,66.1,60.2,42.5,39.1,38.1,36.4,29.9,29.5,27.9,16.6,14.0.
Claims (2)
1. a Lipitor intermediate A TS-9 is characterized in that, it has following structure.
。
2. according to claims ATS-9 synthetic method, it is characterized in that, this synthetic method comprises following synthesis step.
(1) take epoxy chloropropane as starting raw material, adopt Grignard reagent to be vinyl magnesium bromide, catalyzer is cuprous chloride, and solvent for use is tetrahydrofuran (THF), obtains compound (1) at-20 DEG C of epoxy additions.
(2) compound (1) forms compound (2) through the replacement of cyano group, and the cyanogen source adopted is sodium cyanide, potassium cyanide, and employing solvent is water, N.N-dimethyl formamide, dimethyl sulfoxide (DMSO).
(3) compound (2) hydrolysis obtains compound (3), and hydrolysising condition is, methanol hydrochloride solution 80 DEG C backflow, or is formed under 80 DEG C of backflow effects for trimethylchlorosilane and methyl alcohol.
(4) compound (3) carries out carbochain through homologation and extends to form compound (4), under n-Butyl Lithium effect, first lithium diisopropylamine is formed at diisopropyl ammonia, subsequently with tert-butyl acetate, lithium diisopropylamine is-78 DEG C of formation compound (4) in tetrahydrofuran (THF).
(5) compound (5) and diethylmethoxyborane, sodium borohydride in tetrahydrofuran (THF) and methyl alcohol (5:1) mixed solvent-78 DEG C react and form compound (5).
(6) protection that compound (5) carries out two hydroxyl obtains compound (6), and the protecting group adopted is 2.2-Propanal dimethyl acetal.
(7) compound (6) double bond is through ozone oxidation, and triphenyl phosphorus or dimethyl sulphide reduction form compound (7).
(8) compound (7) aldehyde radical carries out reduction and forms compound (8) under sodium borohydride effect, and employing solvent is methyl alcohol, room temperature reaction.
(9) hydroxyl carries out protection and obtains compound (9) in compound (8), adopt protecting group to be Methanesulfonyl chloride, formed in methylene dichloride, room temperature reaction.
(10) compound (9) forms compound (10) through azide substitution, and nitrine reagent is sodiumazide.React in N.N-dimethyl formamide 80 DEG C.
(11) compound (10) is through Staudinger reaction, forms ATS-9 (formula 9).Under triphenylphosphine and water effect, room temperature is reacted.
。
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|---|---|---|---|---|
| US20090216029A1 (en) * | 2005-09-16 | 2009-08-27 | Yatendra Kumar | Process for the production of atorvastatin calcium in amorphous form |
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| CN102391243A (en) * | 2011-10-17 | 2012-03-28 | 黄冈华阳药业有限公司 | Preparation method of atorvastatin intermediate (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate |
| CN103384659A (en) * | 2011-02-21 | 2013-11-06 | 公益财团法人微生物化学研究会 | Thioamide compound, method for producing thioamide compound, method for producing [(4r,6r)-6-aminoethyl-1,3-dioxane-4-yl]acetate derivative, and method for producing atorvastatin |
-
2014
- 2014-09-22 CN CN201410491818.8A patent/CN105503815A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20090216029A1 (en) * | 2005-09-16 | 2009-08-27 | Yatendra Kumar | Process for the production of atorvastatin calcium in amorphous form |
| CN101838221A (en) * | 2009-03-16 | 2010-09-22 | 罗田县华阳生化有限公司 | Manufacturing method of atorvastatin intermediate (R)-(-)-4-nitrile-3-hydroxybutyrate |
| CN103384659A (en) * | 2011-02-21 | 2013-11-06 | 公益财团法人微生物化学研究会 | Thioamide compound, method for producing thioamide compound, method for producing [(4r,6r)-6-aminoethyl-1,3-dioxane-4-yl]acetate derivative, and method for producing atorvastatin |
| CN102391243A (en) * | 2011-10-17 | 2012-03-28 | 黄冈华阳药业有限公司 | Preparation method of atorvastatin intermediate (3R, 5S)-7-amino-3,5-O-isopropylidene-3,5-dyhydroxyl heptylic acid tert-butyl acetate |
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| Title |
|---|
| FANG-JUN XIONG等: "An improved process for chiron synthesis of the atorvastatin side chain", 《TETRAHEDRON: ASYMMETRY》 * |
| YUJI KAWATO等: "A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; application to an enantioselective synthesis of atorvastatin", 《TETRAHEDRON》 * |
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