CN110483459A - A kind of synthetic method of Simvastatin - Google Patents
A kind of synthetic method of Simvastatin Download PDFInfo
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- CN110483459A CN110483459A CN201910854066.XA CN201910854066A CN110483459A CN 110483459 A CN110483459 A CN 110483459A CN 201910854066 A CN201910854066 A CN 201910854066A CN 110483459 A CN110483459 A CN 110483459A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen 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
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
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Abstract
The invention discloses a kind of synthetic methods of Simvastatin, the present invention reacts prepare compound III with tert-butylamine using compound ii, compound III is reacted with acetone is made compounds Ⅳ, is then methylated again, final product Simvastatin (I) is made in hydrolysis, lactonization reaction under sulfuric acid.Reaction raw materials used herein are easy to get, reaction process mild condition, easy to operate, and total yield of products and purity are higher, and product by-product is few, are suitble to industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, in particular to a kind of synthetic method of Simvastatin.
Background technique
Simvastatin be United States Merck company exploitation it is a kind of using Lovastatin be the semi-synthetic manufactured HMG-CoA of raw material also
Reductase inhibitor, the product were listed in 1988, obtain U.S. FDA approval in December, 1991, it is former to be clinically mainly used for treatment
High cholesterol blood lipid, Hypertriglyceridemia and other dyslipidemias occur.Activity is four times of Pravastatin in vivo, can be had
The development and heart disease recurrence for imitating prevention of arterial atherosis, reduce non-lethal myocardial infarction and myocardial vascular in the danger for forming art
Danger.
The method of prior art preparation Simvastatin mainly include the following types:
(1) route of patent US4444784 report is hydrolyzed so that excessive highly basic is added, and removes 2- methylacyl side
Chain, and make lactonic ring open loop simultaneously, then with the hydroxyl on TBDS selective silicon alkanisation protection lactonic ring, then hexahydro naphthalene nucleus C-8
The hydroxyl at place is acylated in the presence of dicyclohexyl carbodiimide or 2,2- dimethyl chloride with 2,2- acid dimethyl, then
It is deprotected with tetrabutyl ammonium fluoride and obtains finished product.
But this method needed high temperature in hydrolysis and acylation step and up to 56 hours reaction time, while lactonic ring
Hydroxyl is insufficient using silicon substrate selective protection, and there are competitive reaction, the yield and purity for eventually resulting in product are reduced, by-product
Content increases, and brings certain difficulty to post-processing；And using expensive silicon-based protecting group higher cost, the economy of process route
Property is relatively poor.
(2) U.S. Merk company applied the route technique patent (USP4820850, EP0299656B1 and
CN1019395B), synthetic route is that Lovastatin is carried out to amination open loop, and ring-opening product carries out double hydroxyl silicon substrate protections, then carries out
Then methylamine reaction carries out double hydroxyl deprotections, hydrolysis-ammonification, finished product Simvastatin is made at lactone.
But product yield and purity is not high in amination open loop step in the reaction, and by-product is more, is unfavorable for industrial metaplasia
It produces.
In order to solve a series of problems of the existing technology, the present invention, can by being improved the prior art
The presence of the above problem is solved or avoided, industrialized production is suitble to.
Summary of the invention
Present invention aims in view of the deficiencies of the prior art, provide a kind of synthetic method of Simvastatin, the synthesis side
Method reaction process mild condition, easy to operate, total yield of products and purity are higher, and product by-product is few, are suitble to industrialized production.
Synthetic route of the present invention is as follows:
A kind of Simvastatin synthetic method provided by the present invention, the synthetic method include the following steps:
A, compound III is made in compound ii and tert-butylamine under the conditions of trimethyl aluminium；
B, compound III is reacted under the conditions of the concentrated sulfuric acid with acetone is made compounds Ⅳ；
C, compounds Ⅳ carries out methylation reaction prepare compound V in lithium diisopropylamine and iodomethane condition；
D, first reflux carries out hydrolysis under the conditions of sulfuric acid for compound V, then carries out lactone reaction and prepare that finished product is pungent to be cut down
Statin (I).
Preferably, in step a, the molar ratio of compound ii, tert-butylamine and trimethyl aluminium is 1:1.6:2-2.3.
Preferably, in step b, the molar ratio of the compound III and the concentrated sulfuric acid is 1:1.3-1.5.
Preferably, in step c, the molar ratio of compounds Ⅳ, lithium diisopropylamine and iodomethane is 1:1-1.2:1；Institute
It is anhydrous tetrahydro furan with reaction dissolvent.
Preferably, in step d, the mass concentration of the sulfuric acid is 40%；The lactone reaction is in phosphorus pentoxide condition
It is reacted；Compound V and phosphorus pentoxide molar ratio are 1:1-1.4.
Specific embodiment
Summary of the invention of the invention is described in further detail below by specific embodiment, but is not therefore limited
Determine the contents of the present invention.
Embodiment 1
The preparation of compound III
Under the conditions of nitrogen protection and 0-5 DEG C of temperature, by trimethyl aluminium (0.196mol) hexane solution 140ml solution by
It is added dropwise in tert-butylamine solution (0.157mol), then anhydrous methylene chloride 100ml is added into reaction flask, and by above-mentioned mixing
Object is stirred at room temperature, and then adds compound ii 39.64g (0.098mol), is heated to reflux 4h, and reaction terminates to be cooled to 0
DEG C, 4N sodium hydrate aqueous solution quenching (3ml) is added dropwise.Mixture extracts (3 × 100ml) with methylene chloride, merges organic
Layer is washed with brine (3 × 100ml) and anhydrous MgSO4It is dry, compound III 42.13g, molar yield 90%, purity is made
99.1%, maximum single impurity 0.025%.
Embodiment 2
The preparation of compound III
Under the conditions of nitrogen protection and 0-5 DEG C of temperature, by trimethyl aluminium (0.198mol) hexane solution 140ml solution by
It is added dropwise in tert-butylamine solution (0.138mol), then anhydrous methylene chloride 100ml is added into reaction flask, and by above-mentioned mixing
Object is stirred at room temperature, and then adds compound ii 34.79g (0.086mol), is heated to reflux 4h, and reaction terminates to be cooled to 0
DEG C, 4N sodium hydrate aqueous solution quenching (3ml) is added dropwise.Mixture extracts (3 × 100ml) with methylene chloride, merges organic
Layer is washed with brine (3 × 100ml) and anhydrous MgSO4It is dry, compound III 38.20g, molar yield 93%, purity is made
99.5%, maximum single impurity 0.021%.
Embodiment 3
The preparation of compound III
Under the conditions of nitrogen protection and 0-5 DEG C of temperature, by trimethyl aluminium (0.180mol) hexane solution 129ml solution by
It is added dropwise in tert-butylamine solution (0.135mol), then anhydrous methylene chloride 100ml is added into reaction flask, and by above-mentioned mixing
Object is stirred at room temperature, and then adds compound ii 36.41g (0.090mol), is heated to reflux 4h, and reaction terminates to be cooled to 0
DEG C, 4N sodium hydrate aqueous solution quenching (3ml) is added dropwise.Mixture extracts (3 × 100ml) with methylene chloride, merges organic
Layer is washed with brine (3 × 100ml) and anhydrous MgSO4It is dry, compound III 36.11g, molar yield 84%, purity is made
98.6%, maximum single impurity 0.045%.
Embodiment 4
The preparation of compound III
Under the conditions of nitrogen protection and 0-5 DEG C of temperature, by trimethyl aluminium (0.086mol) hexane solution 61.4ml solution
It is added dropwise in tert-butylamine solution (0.086mol), then anhydrous methylene chloride 100ml is added into reaction flask, and will be above-mentioned mixed
It closes object to be stirred at room temperature, then adds compound ii 34.79g (0.086mol), be heated to reflux 4h, reaction terminates to be cooled to
0 DEG C, 4N sodium hydrate aqueous solution quenching (3ml) is added dropwise.Mixture extracts (3 × 100ml) with methylene chloride, merges organic
Layer is washed with brine (3 × 100ml) and anhydrous MgSO4It is dry, compound III 31.22g, molar yield 76%, purity is made
98.3%, maximum single impurity 0.086%.
Embodiment 5
The preparation of compounds Ⅳ
280ml acetone is added in reaction flask, ice water is cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise under nitrogen protection
(0.115mol), 30min is added, and compound III 42.13g is then added, and reaction 2.5h, end of reaction drop is stirred at room temperature in control
Temperature is to 10 DEG C hereinafter, there is solid precipitation, and with acetone washing, merging filtrate is concentrated under reduced pressure, and obtains compounds Ⅳ 40.18g, mole
Yield 88%, purity 99.4%, maximum single impurity 0.041%.
Embodiment 6
The preparation of compounds Ⅳ
280ml acetone is added in reaction flask, ice water is cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise under nitrogen protection
(0.120mol), 30min is added, and compound III 38.20g is then added, and reaction 2.5h, end of reaction drop is stirred at room temperature in control
Temperature is to 10 DEG C hereinafter, there is solid precipitation, and with acetone washing, merging filtrate is concentrated under reduced pressure, and obtains compounds Ⅳ 37.69g, mole
Yield 91%, purity 99.5%, maximum single impurity 0.035%.
Embodiment 7
The preparation of compounds Ⅳ
280ml acetone is added in reaction flask, ice water is cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise under nitrogen protection
(0.091mol), 30min is added, and compound III 36.11g is then added, and reaction 2.5h, end of reaction drop is stirred at room temperature in control
Temperature is to 10 DEG C hereinafter, there is solid precipitation, and with acetone washing, merging filtrate is concentrated under reduced pressure, and obtains compounds Ⅳ 32.49g, mole
Yield 83%, purity 99.2%, maximum single impurity 0.045%.
Embodiment 8
The preparation of compounds Ⅳ
280ml acetone is added in reaction flask, ice water is cooled to 0-5 DEG C.The concentrated sulfuric acid is added dropwise under nitrogen protection
(0.130mol), 30min is added, and compound III 31.22g is then added, and reaction 2.5h, end of reaction drop is stirred at room temperature in control
Temperature is to 10 DEG C hereinafter, there is solid precipitation, and with acetone washing, merging filtrate is concentrated under reduced pressure, and obtains compounds Ⅳ 30.29g, mole
Yield 90%, purity 98.9%, maximum single impurity 0.092%.
Embodiment 9
The preparation of compound V
Compounds Ⅳ 40.18g is dissolved in 260ml anhydrous tetrahydro furan, acquired solution is cooled to -40 DEG C.It is added two
Isopropylamino lithium (0.078mol) hexane solution, temperature are maintained at -40 DEG C, and iodomethane (0.078mol) is added and is stirred
It mixes.It is stirred to react until being reacted by tlc determination and completes.It adds water in reaction and dissipates to color, reaction is mixed
It closes object to be extracted with ethyl acetate, be washed with water, and be condensed into residue, obtain V 36.73g of compound, molar yield 89% is pure
Degree 99.0%.
Embodiment 10
The preparation of compound V
Compounds Ⅳ 37.69g is dissolved in 260ml anhydrous tetrahydro furan, acquired solution is cooled to -40 DEG C.It is added two
Isopropylamino lithium (0.087mol) hexane solution, temperature are maintained at -40 DEG C, and iodomethane (0.073mol) is added and is stirred
It mixes.It is stirred to react until being reacted by tlc determination and completes.It adds water in reaction and dissipates to color, reaction is mixed
It closes object to be extracted with ethyl acetate, be washed with water, and be condensed into residue, obtain V 35.62g of compound, molar yield 92% is pure
Degree 99.4%.
Embodiment 11
The preparation of compound V
Compounds Ⅳ 32.49g is dissolved in 260ml anhydrous tetrahydro furan, acquired solution is cooled to -40 DEG C.It is added two
Isopropylamino lithium (0.075mol) hexane solution, temperature are maintained at -40 DEG C, and iodomethane (0.125mol) is added and is stirred
It mixes.It is stirred to react until being reacted by tlc determination and completes.It adds water in reaction and dissipates to color, reaction is mixed
It closes object to be extracted with ethyl acetate, be washed with water, and be condensed into residue, obtain V 31.01g of compound, molar yield 93% is pure
Degree 98.2%.
Embodiment 12
The preparation of Simvastatin (I)
By V 36.73g of compound, 40% sulfuric acid (250ml) and water (250ml) has been reacted in about 130 DEG C of reflux about 2h
Reaction mixture is cooled to about 25 DEG C and is added in ice water by Quan Hou.Then ethyl acetate and hexane washing is added, and at 40 DEG C
Under be dried to obtain solid.
It is added in 280ml tetrahydrofuran, is added phosphorus pentoxide (0.069mol) into above-mentioned solid, control in room temperature item
It is stirred to react 3h under part, filters after the reaction was completed, removes filtrate, is dissolved with 180ml methylene chloride, and successively uses unsaturated carbonate hydrogen
Sodium solution, water, saturated common salt water washing (each 150ml), are removed under reduced pressure organic solvent, and vacuum drying prepares Simvastatin (I)
22.56g product yield 78%.Purity 98.8%, maximum single impurity 0.035%.
Embodiment 13
The preparation of Simvastatin (I)
By V 35.62g of compound, 40% sulfuric acid (250ml) and water (250ml) has been reacted in about 130 DEG C of reflux about 2h
Reaction mixture is cooled to about 25 DEG C and is added in ice water by Quan Hou.Then ethyl acetate and hexane washing is added, and at 40 DEG C
Under be dried to obtain solid.
It is added in 280ml tetrahydrofuran, is added phosphorus pentoxide (0.094mol) into above-mentioned solid, control in room temperature item
It is stirred to react 3h under part, filters after the reaction was completed, removes filtrate, is dissolved with 180ml methylene chloride, and successively uses unsaturated carbonate hydrogen
Sodium solution, water, saturated common salt water washing (each 150ml), are removed under reduced pressure organic solvent, and vacuum drying prepares Simvastatin (I)
22.99g product yield 82%.Purity 99.3%, maximum single impurity 0.042%.
Embodiment 14
The preparation of Simvastatin (I)
By V 31.01g of compound, 40% sulfuric acid (250ml) and water (250ml) has been reacted in about 130 DEG C of reflux about 2h
Reaction mixture is cooled to about 25 DEG C and is added in ice water by Quan Hou.Then ethyl acetate and hexane washing is added, and at 40 DEG C
Under be dried to obtain solid.
It is added in 280ml tetrahydrofuran, is added phosphorus pentoxide (0.117mol) into above-mentioned solid, control in room temperature item
It is stirred to react 3h under part, filters after the reaction was completed, removes filtrate, is dissolved with 180ml methylene chloride, and successively uses unsaturated carbonate hydrogen
Sodium solution, water, saturated common salt water washing (each 150ml), are removed under reduced pressure organic solvent, and vacuum drying prepares Simvastatin (I)
20.26g product yield 83%.Purity 99.1%, maximum single impurity 0.075%.
Claims (8)
1. a kind of synthetic method of Simvastatin, which is characterized in that the synthetic method includes the following steps:
A, compound III is made in compound ii and tert-butylamine under the conditions of trimethyl aluminium；
B, compound III is reacted under the conditions of the concentrated sulfuric acid with acetone is made compounds Ⅳ；
C, compounds Ⅳ carries out methylation reaction prepare compound V in lithium diisopropylamine and iodomethane condition；
D, first reflux carries out hydrolysis under the conditions of sulfuric acid for compound V, then carries out lactonization reaction and prepare that finished product is pungent to cut down him
Spit of fland (I)；
Its synthetic route is as follows:
2. synthetic method according to claim 1, which is characterized in that in step a, compound ii, tert-butylamine and trimethyl
The molar ratio of aluminium is 1:1.6:2-2.3.
3. synthetic method according to claim 1, which is characterized in that in step b, the compound III and the concentrated sulfuric acid
Molar ratio is 1:1.3-1.5.
4. synthetic method according to claim 1, which is characterized in that in step c, compounds Ⅳ, lithium diisopropylamine
And the molar ratio of iodomethane is 1:1-1.2:1.
5. synthetic method according to claim 1, which is characterized in that in step c, reaction dissolvent is anhydrous tetrahydro furan.
6. synthetic method according to claim 1, which is characterized in that in step d, the mass concentration of the sulfuric acid is
40%.
7. synthetic method according to claim 1, which is characterized in that in step d, the lactone reaction is to aoxidize two five
Phosphorus condition is reacted.
8. synthetic method according to claim 7, which is characterized in that in step d, compound V and phosphorus pentoxide mole
Than for 1:1-1.4.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1290261A (en) * | 1998-12-10 | 2001-04-04 | 钟渊化学工业株式会社 | process for producing simvastatin |
| US6294680B1 (en) * | 1997-01-28 | 2001-09-25 | Plus Chemicals, B.V. | Process for the production of semi synthetic statins via novel intermediates |
| 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 |
| CN102532184A (en) * | 2010-12-21 | 2012-07-04 | 北大方正集团有限公司 | Dihydroxyl protection method of lovaamide and preparation method of simvastatin |
-
2019
- 2019-09-10 CN CN201910854066.XA patent/CN110483459A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6294680B1 (en) * | 1997-01-28 | 2001-09-25 | Plus Chemicals, B.V. | Process for the production of semi synthetic statins via novel intermediates |
| CN1290261A (en) * | 1998-12-10 | 2001-04-04 | 钟渊化学工业株式会社 | process for producing 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 |
| CN102532184A (en) * | 2010-12-21 | 2012-07-04 | 北大方正集团有限公司 | Dihydroxyl protection method of lovaamide and preparation method of simvastatin |
Non-Patent Citations (1)
| Title |
|---|
| 包如生: ""辛伐他汀的合成研究"", 《中国优秀博硕士学位论文全文数据库(硕士) 工程科技Ⅰ辑》 * |
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Application publication date: 20191122 |