CN103739537B - New synthesis method of ezetimibe - Google Patents
New synthesis method of ezetimibe Download PDFInfo
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- CN103739537B CN103739537B CN201310722140.5A CN201310722140A CN103739537B CN 103739537 B CN103739537 B CN 103739537B CN 201310722140 A CN201310722140 A CN 201310722140A CN 103739537 B CN103739537 B CN 103739537B
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- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title abstract description 22
- 229960000815 ezetimibe Drugs 0.000 title abstract description 17
- 238000001308 synthesis method Methods 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical class C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 claims description 3
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims description 3
- 229940094989 trimethylsilane Drugs 0.000 claims description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical class COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 150000003869 acetamides Chemical class 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000013517 stratification Methods 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 7
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229910000077 silane Inorganic materials 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- XXSSRSVXDNUAQX-QGZVFWFLSA-N 1-(4-fluorophenyl)-5-[(4s)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]pentane-1,5-dione Chemical compound C1=CC(F)=CC=C1C(=O)CCCC(=O)N1C(=O)OC[C@@H]1C1=CC=CC=C1 XXSSRSVXDNUAQX-QGZVFWFLSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- 238000006683 Mannich reaction Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229940051223 zetia Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NGCHQYFXADRTDA-AATRIKPKSA-N C=C/C=C(\C=C)/F Chemical compound C=C/C=C(\C=C)/F NGCHQYFXADRTDA-AATRIKPKSA-N 0.000 description 1
- YSOQCCFIWNVPGL-VOTSOKGWSA-N CC/C(/F)=C(/C)\CC=[IH] Chemical compound CC/C(/F)=C(/C)\CC=[IH] YSOQCCFIWNVPGL-VOTSOKGWSA-N 0.000 description 1
- 239000005046 Chlorosilane Substances 0.000 description 1
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000030673 Homozygous familial hypercholesterolemia Diseases 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010063985 Phytosterolaemia Diseases 0.000 description 1
- 208000002227 Sitosterolemia Diseases 0.000 description 1
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 1
- 239000012675 alcoholic extract Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention relates to a new synthesis method of ezetimibe. Particularly, a new method for synthesizing ezetimibe (as shown in formula (I)) comprises the steps of addition, closed loop, deprotection and the like by using a compound shown in a formula (II) and having good stability as a starting raw material. The new synthesis method has the advantages of strong stability, simple operation, high yield and the like, and is suitable for large-scale industrial production. The formula (I) is described in the specification.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to the novel synthesis of Ezetimibe and 1-(4-fluorophenyl)-3 (R)-[3-(4-fluorophenyl)-3 (S)-hydroxypropyl]-4 (S)-(4-hydroxyphenyl)-2-azetidinone.
Background technology
Ezetimibe (Ezetimibe) as shown in the formula (I), another name ezetimibe, Zetia, for the first selectivity cholesterol absorption inhibitor that Schering Plough (Schering-Plough) company and Merck (Merck) company develop jointly, this product is first cholesterol absorption selective depressant class medicine be approved listing by U.S. FDA, trade(brand)name Zetia.This product obtains FDA approval on October 25th, 2002, and goes on the market on November 30th, 2002 in the U.S..At present, the indication that Ezetimibe obtains FDA approval has primary hypercholesterolemia (adult, paediatrics) homozygous familial hypercholesterolemia (adult, paediatrics), homozygous familial Sitosterolemia (adult, paediatrics), mixed type hyperlipidemia (adult).
European patent EP 720599 makes public for the first time the synthetic method of Ezetimibe:
This operational path is longer, employs active metal reagent and precious metal palladium, and gained midbody compound is unfavorable for purifying, and cost is higher, is not suitable for suitability for industrialized production.
Schering Plough company of the U.S. is optimized above-mentioned technique, discloses a kind of method of synthesis Ezetimibe newly in patent WO2000/34240:
This route has carried out larger improvement to technique in early stage: chiral reduction obtains chiral alcohol, protects in next step asymmetric Mannich reaction, and adopt TMSCl to protect one pot process intermediate, then Cheng Huan, deprotection prepare Ezetimibe finished product.But the asymmetric Mannich reaction in route due to intermediate character active, cause byproduct of reaction more, yield is lower, limits its application in suitability for industrialized production.
Summary of the invention
The object of this invention is to provide a kind of simple to operate, yield is high and the novel method of the synthesis Ezetimibe of applicable suitability for industrialized production.
Another object of the present invention is to the method providing a kind of preparation formula (I) compound, it comprises the following steps:
A) formula (III) compound and chlorosilane protect reagent to react under the existence of organic bases, the compound of obtained protected silane, then add formula (II) compound and Lewis acid, react, obtain formula (IV) compound under the existence of Lewis acid and organic bases,
B) formula (IV) compound cyclization under the existence of silane reagent and fluoride ion catalyst, obtains formula V compound,
Wherein, in formula (II), formula (IV) and formula V compound, R is selected from C
1-C
3alkyl, phenyl; Optional, described phenyl can be selected from alkyl further, the substituting group of alkoxyl group replaces;
C) formula V compound removes acyl group and silane protecting group, obtains Ezetimibe as shown in the formula (I),
Preferably, organic bases described in step a) is diisopropylethylamine.
Preferably, described in step b), silane reagent is selected from N, the two trimethylsilyl ethanamide of O-or trimethyl silane.
Preferably, fluoride ion catalyst described in step b) is three hydration tetrabutyl ammonium fluorides.
Preferably, acyl group and protected silane base group employing protonic acid solution is removed described in step c); Preferred, described protonic acid is selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Be particularly preferably sulfuric acid.
Another object of the present invention is also to provide a kind of such as formula the intermediate preparing Ezetimibe shown in (IV),
Wherein, R is methyl.
Another object of the present invention is also to provide a kind of intermediate preparing Ezetimibe as shown in formula V,
Wherein, R is methyl.
The present invention, by adopting acyl group protection to the alcoholic extract hydroxyl group of formula (II) compound, makes its difficult drop-off in reaction process, the corresponding activity that improve other reactive groups, contributes to the yield improving reaction.In addition, preparation technology of the present invention reacts less demanding, simple to operate, is easy to purifying, such that the preparation of Ezetimibe is more economical, more environmental protection, be more suitable for industrialization.
Embodiment
In order to understand content of the present invention better, below in conjunction with specific embodiment, the invention will be further described, but scope of the present invention is not limited to specific embodiment.
Embodiment 1: the preparation of Ezetimibe intermediate formula (IV) compound
At N
2under, add 150 milliliters of methylene dichloride and 21.5 grams of formula (III) compounds, stir and be cooled to-20 DEG C.Add 30.6 milliliters of diisopropylethylamine (DIPEA); Slow dropping 16.1 milliliters of trimethylchlorosilanes (TMSCl), keep temperature-15 DEG C to stir 1.5 hours.Reaction solution is cooled to-30 DEG C and adds 20.0 grams of formula (II) compounds, stir 10 minutes.Slow dropping 4.1 milliliters of TiCl
4, keep temperature-30 DEG C of stirring reactions 4 hours.Slowly water is added in reaction mixture, cancellation is reacted, add 60 milliliters of 1N aqueous hydrochloric acids, add 200 milliliters of methylene dichloride, stratification after stirring, organic layer is washed, anhydrous sodium sulfate drying, be concentrated into a small amount of solvent, add 15 milliliters of two trimethyl silane yl acetamides, reflux 30 minutes.Enriched mixture, removing methylene dichloride, makes product crystallization in ethyl acetate and normal heptane mixed solvent, and filter, 30 DEG C of vacuum-dryings, obtain product 27.1 grams, yield 79.1%.
Embodiment 2: the preparation of Ezetimibe intermediate formula V compound
Under nitrogen protection, add 300 milliliters of methyl tertiary butyl ethers and 20 grams of formula (II) compounds, add the two trimethylsilyl ethanamide (BSA) of 14.3 milliliters of N, O-, control temperature 10 DEG C.Add 0.48 gram of tetrabutyl ammonium fluoride (three water) (TBAF), stirring reaction 2 hours.Mixture is concentrated into dry, directly enters next step.
Embodiment 3: the preparation of Ezetimibe
In the product in embodiment 2, add 50 milliliters of Virahols and 15 milliliters of 2N sulphuric acid solns, stirred at ambient temperature 2 hours, separate out solid, filter, collect solid, in isopropyl alcohol and water, obtain white solid after recrystallization, target product formula (I) compound 14.54 grams is obtained, yield 93% after drying.
MS(ESI):432.14(M+Na
+).
1H-NMR(500MHz,DMSO)δ(ppm):1.761-1.804(m,3H),1.823-1.889(m,1H),3.079-3.101(m,1H),4.514-4.535(m,1H),4.804-4.808(d,1H),5.263-5.272(d,1H),6.772-6.789(d,2H),7.099-7.141(m,4H),7.218-7.249(m,4H),7.306-7.334(m,2H),9.504(s,1H).
Claims (1)
1. a method for preparation formula (I) compound, it comprises the following steps:
a)
At N
2under, add 150 milliliters of methylene dichloride and 21.5 grams of formula (III) compounds, stir and be cooled to-20 DEG C, add 30.6 milliliters of diisopropylethylamine; Slow dropping 16.1 milliliters of trimethylchlorosilanes, keep temperature-15 DEG C to stir 1.5 hours, reaction solution are cooled to-30 DEG C and add 20.0 grams of formula (II) compounds, stir 10 minutes, slowly drip 4.1 milliliters of TiCl
4keep temperature-30 DEG C of stirring reactions 4 hours, in reaction mixture, slowly add water, cancellation is reacted, and adds 60 milliliters of 1N aqueous hydrochloric acids, add 200 milliliters of methylene dichloride, stratification after stirring, organic layer is washed, anhydrous sodium sulfate drying, be concentrated into a small amount of solvent, add 15 milliliters of two trimethyl silane yl acetamides, reflux 30 minutes, enriched mixture, removing methylene dichloride, make product crystallization in ethyl acetate and normal heptane mixed solvent, filter, 30 DEG C of vacuum-dryings, obtain product 27.1 grams, yield 79.1%;
B) under nitrogen protection, add 300 milliliters of methyl tertiary butyl ethers and 20 grams of formula (IV) compounds, add 14.3 milliliters of N, the two trimethylsilyl ethanamide of O-, control temperature 10 DEG C, adds 0.48 gram of three water tetrabutyl ammonium fluoride, stirring reaction 2 hours, mixture is concentrated into dry, directly enters next step;
C) in the product of previous step, 50 milliliters of Virahols and 15 milliliters of 2N sulphuric acid solns are added, stirred at ambient temperature 2 hours, separate out solid, filter, collect solid, in isopropyl alcohol and water, obtain white solid after recrystallization, obtain target product formula (I) compound 14.54 grams after drying, yield 93%;
Wherein, in formula (II), formula (IV) and formula (V) compound, R is methyl.
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461649B (en) * | 2014-08-08 | 2019-10-22 | 浙江九洲药业股份有限公司 | A kind of Ezetimible intermediate and preparation method thereof |
| CN106892851A (en) * | 2017-03-09 | 2017-06-27 | 上海华源医药科技发展有限公司 | A kind of new method for preparing Ezetimibe crystal formation I |
| CN112441959A (en) * | 2020-12-07 | 2021-03-05 | 石家庄市华新药业有限责任公司 | Ezetimibe raw material medicine synthesis process |
| CN114621126B (en) * | 2020-12-12 | 2023-07-25 | 重庆圣华曦药业股份有限公司 | Improved ezetimibe preparation method |
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| 依折麦布中间体的合成工艺研究;蔡金刚,等;《精细化工中间体》;20110831;第41卷(第04期);第37-39页 * |
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| CN103739537A (en) | 2014-04-23 |
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