CN108101891A - A kind of preparation method of Atorvastatin intermediate - Google Patents
A kind of preparation method of Atorvastatin intermediate Download PDFInfo
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- CN108101891A CN108101891A CN201711276755.4A CN201711276755A CN108101891A CN 108101891 A CN108101891 A CN 108101891A CN 201711276755 A CN201711276755 A CN 201711276755A CN 108101891 A CN108101891 A CN 108101891A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a kind of preparation methods of Atorvastatin intermediate.Using 2 methyltetrahydrofurans as solvent,[(4R is added in autoclave,6R)‑2,2 dimethyl, 6 (2 aminoethyl) [1,3] dioxanes, the 4 guanidine-acetic acid tert-butyl ester (ATS 9) and [5 methyl, 4 isopropyl, 2 phenyl 1 (4 fluorophenyl), 3 (phenylcarbamoyl) 1,4 adipic ketones] (M4),Pivalic acid acid anhydride is slowly added under stirring,With the air 2~3 times in nitrogen displacement reaction kettle,It is warming up to 150~200 DEG C,When reaction 2~4 is small,After reaction,Be concentrated under reduced pressure recycling design,Obtain sticky oil object,Water is added in grease,Isopropanol,It is warming up to 40~60 DEG C,Progressively cool to 20~30 DEG C,Yellow solid is precipitated,It filters,It is dried to obtain Atorvastatin intermediate (4R,6R) 62 [5 isopropyl, 32 (4 fluorophenyl) 4 (phenylcarbamoyl) pyrroles of phenyl, 1 base ethyl } 2,2 dimethyl [1,3] dioxanes, the 4 guanidine-acetic acid tert-butyl ester.Operating cost of the present invention is low, and high selectivity, non-environmental-pollution are suitable for industrialized production.
Description
Technical field
Synthesis technology more particularly to a kind of preparation method of Atorvastatin intermediate the present invention relates to compound.
Background technology
(4R, 6R) -6- { 2- [5- isopropyl -3- phenyl -2- (4- fluorophenyls) -4- (phenylcarbamoyl)-pyrroles -1-
Base-ethyl }-dioxane-4-yls of -2,2- dimethyl-[1,3]-tert-butyl acetate be the key that synthesis Atorvastatin calcium centre
Body.EP1659110A1、IE20060197、US5280126、US5298627、US6476235、US6545153、WO2007/
The patents such as 096751A1 disclose the synthesis technology of Atorvastatin calcium and its intermediate.Disclosed in WO2007/096751A1
100 grams of M4 in patent, 261.9 grams of ATS-9 are added in 2L hexamethylenes, 100ml tetrahydrofurans, by the use of 11.0 Carter valeric acids as urging
Agent, postcooling adds in 500mL water to 25~35 DEG C when 70-85 DEG C of back flow reaction 18 is small, and liquid feeding ammonia tune pH is 8.5~9.5,
It is extracted with 1000mL dichloromethane, organic phase concentration, residue is dissolved with isopropanol plus elutriation goes out solid and obtains (4R, 6R) -6-
2- [5- isopropyl -3- phenyl -2- (4- fluorophenyls) -4- (phenylcarbamoyl)-pyrroles -1- bases-ethyl } -2,2- diformazans
- dioxane-4-yls of base-[1,3]-tert-butyl acetate.Reaction dissolvent consumption is big, and post processing is complicated.
CN101429195 disclose the acid catalyst of M4 and ATS-9 reaction for the carboxylic acid of 1-8 carbon atom, inorganic acid or
Acidic resins；Wherein, the carboxylic acid of 1-8 carbon atom is formic acid, acetic acid, n-butyric acie, positive valeric acid, n-caproic acid etc., and inorganic acid is salt
Acid, sulfuric acid, phosphoric acid etc.；Acidic resins are 732 strongly acidic styrene's cation exchange resins, 122 macropore phenolic aldehyde weak acid resins etc..
However, the structure of ketal occurs to hydrolyze and be deprotected under the conditions of strong acidity (inorganic acid, strong organic acid), also easily and amino
It is easily generated into salt, under mild acid conditions di-substituted (I), it is impossible to form pyrrole ring.
Therefore, pivalic acid is optimal catalyst.In order to which 2 mole of water that will react generation take reaction system out of, researcher adopts
With a variety of methods.Li Xingjuan (synthesising process research of Atorvastatin calcium, He'nan Normal University's master's degree opinion
Text) toluene, normal heptane, tetrahydrofuran, n-hexane and its mixing are studied as reaction dissolvent.React tetrahydrofuran：Just oneself
Alkane (1:4) it is best to be heated to reflux dehydrating effect.Yu Lili etc. is (using chemical industry, 2013,42 (11)：1972-1974) with orthogonal reality
The method of testing optimizes the synthesis technology of Atorvastatin calcium, employs normal heptane, tetrahydrofuran, toluene ternary solvent.
CN106938996A is then that employ normal heptane and tetrahydrofuran be solvent, and CN102766136A is then using tetrahydrofuran and just
Butyl ether is solvent.It is quickly to take reaction system out of by the water generated is reacted with water by azeotropic that solvent, which changes purpose, is accelerated anti-
Answer rate, the conversion ratio for improving raw material.102127060 A of CN are using the mixed solvent and perseverance with the immiscible suitable boiling point of water
The mode of warm reflux water-dividing, shortens dramatically the reaction time, and yield is higher.
Above method empirical tests reaction rate is slower, and the reaction time is all longer, at least need 24 it is small when can complete to react.
The content of the invention
It is long the purpose of the present invention is the water for reacting generation in the prior art is overcome to be not easy to take out of reaction system, reaction time
Deficiency, a kind of preparation method of Atorvastatin intermediate is provided.
Technical scheme is as follows：
Using 2- methyltetrahydrofurans as solvent, [(4R, 6R) -2,2- dimethyl -6- (2- ammonia second is added in autoclave
Base)-[1,3]-dioxane-4-yls-tert-butyl acetate and [5- methyl -4- isopropyl -2- phenyl -1- (4- fluorophenyls) -3- (benzene
Base carbamoyl)-Isosorbide-5-Nitrae-adipic ketone], [(4R, 6R) -2,2- dimethyl -6- (2- aminoethyls)-[1,3]-dioxane-4-yl -
Tert-butyl acetate and [5- methyl -4- isopropyl -2- phenyl -1- (4- fluorophenyls) -3- (phenylcarbamoyl) -1,4- two
Ketone] molar ratio be 1:1~1.1.Pivalic acid acid anhydride is slowly added under stirring, [(4R, 6R) -2,2- dimethyl -6- (2- ammonia second
Base) molar ratio of-[1,3]-dioxane-4-yls-tert-butyl acetate and pivalic acid acid anhydride is 1:2.5~3, with nitrogen displacement reaction kettle
Interior air 2~3 times is warming up to 150~200 DEG C, and when reaction 2~4 is small, after reaction, be concentrated under reduced pressure recycling design, obtains
Sticky oil object adds in water, isopropanol in grease, and the wherein volume ratio of water and isopropanol is 1:1~3, it is warming up to 40~
60 DEG C, 20~30 DEG C are progressively cooled to, yellow solid is precipitated, filters, be dried to obtain Atorvastatin intermediate (4R, 6R) -6-
2- [5- isopropyl -3- phenyl -2- (4- fluorophenyls) -4- (phenylcarbamoyl)-pyrroles -1- bases-ethyl } -2,2- diformazans
- dioxane-4-yls of base-[1,3]-tert-butyl acetate.
Present invention uses single solvent 2- methyltetrahydrofurans, facilitate and simplify the separated post processing work of mixed solvent
Sequence.The present invention still uses pivalic acid to ensure that the selectivity of reaction for catalyst, is generated using pivalic acid acid anhydride is synchronous with reaction
Water reaction generation pivalic acid, catalytic reaction, achieved the effect that quick, high selectivity, high income.Without cumbersome after reaction
Aftertreatment technology only need to remove solvent, recrystallize, and { [5- is different by 2- by i.e. available (4R, the 6R) -6- of the simple operations such as suction filtration, dry
Propyl -3- phenyl -2- (4- fluorophenyls) -4- (phenylcarbamoyl)-pyrroles -1- bases-ethyl } -2,2- dimethyl-[1,3] -
Dioxane-4-yl-tert-butyl acetate.
Specific embodiment
Reaction equation of the present invention is as follows：
Embodiment 1
Middle addition 500mL2- methyltetrahydrofurans, add in [(4R, 6R) -2,2- dimethyl -6- in 1000mL autoclaves
27.3 grams of (2- aminoethyls)-[1,3]-dioxane-4-yls-tert-butyl acetate, [5- methyl -4- isopropyl -2- phenyl -1- (4- fluorine
Phenyl) -3- (phenylcarbamoyl)-Isosorbide-5-Nitrae-adipic ketone] 41.7 grams, 46.5 grams of pivalic acid acid anhydride is slowly added under stirring, is closed
Kettle cover is reacted, with the air 2 times in nitrogen displacement reaction kettle, is warming up to 150 DEG C, when reaction 4 is small, after reaction, decompression is dense
50.1 grams of contracting recycling design 2- methyltetrahydrofurans 480mL and pivalic acid, obtain sticky oil object.It is added in grease
100ml water, 100mL isopropanols, are warming up to 40 DEG C, progressively cool to 20 DEG C, and yellow solid is precipitated, filters, be dried to obtain atropic
Cut down statin intermediate (4R, 6R) -6- { 2- [5- isopropyl -3- phenyl -2- (4- fluorophenyls) -4- (phenylcarbamoyl)-pyrroles
Cough up -1- bases-ethyl }-dioxane-4-yls of -2,2- dimethyl-[1,3] -65.0 grams of tert-butyl acetate.mp:145~148 DEG C, [α]
=4.6 ° of (c=1, CHCl3),1H NMR(400MHz,CDCl3):δ=1.18 (s, 3H), 1.30 (s, 3H), 1.35 (s, 6H),
1.40(s,9H),1.50-1.64(m,2H),2.30-2.33(m,1H),2.50(s,4H),3.20-3.25(m,1H),3.35(s,
1H),3.75-3.80(m,1H),3.90-3.95(m,1H),4.10-4.12(m,1H),6.96-7.02(m,2H),7.07-7.08
(m, 4H), 7.18-7.28 (m, 5H), 7.52 (d, J=8.0Hz, 2H), 9.80 (s, 1H).
Embodiment 2
Middle addition 500mL2- methyltetrahydrofurans, add in [(4R, 6R) -2,2- dimethyl -6- in 1000mL autoclaves
27.3 grams of (2- aminoethyls)-[1,3]-dioxane-4-yls-tert-butyl acetate, [5- methyl -4- isopropyl -2- phenyl -1- (4- fluorine
Phenyl) -3- (phenylcarbamoyl)-Isosorbide-5-Nitrae-adipic ketone] 45.9 grams, 55.8 grams of pivalic acid acid anhydride is slowly added under stirring, is closed
Kettle cover is reacted, with the air 3 times in nitrogen displacement reaction kettle, is warming up to 200 DEG C, when reaction 2 is small, after reaction, decompression is dense
56.7 grams of contracting recycling design 2- methyltetrahydrofurans 457mL and pivalic acid, obtain sticky oil object.It is added in grease
100ml water, 300mL isopropanols, are warming up to 60 DEG C, progressively cool to 30 DEG C, and yellow solid is precipitated, filters, be dried to obtain atropic
Cut down statin intermediate (4R, 6R) -6- { 2- [5- isopropyl -3- phenyl -2- (4- fluorophenyls) -4- (phenylcarbamoyl)-pyrroles
Cough up -1- bases-ethyl }-dioxane-4-yls of -2,2- dimethyl-[1,3] -58.7 grams of tert-butyl acetate.
Embodiment 3
Middle addition 500mL recycling 2- methyltetrahydrofurans, add in [(4R, 6R) -2,2- diformazans in 1000mL autoclaves
27.0 grams of base -6- (2- aminoethyls)-[1,3]-dioxane-4-yls-tert-butyl acetate, [5- methyl -4- isopropyl -2- phenyl -1-
(4- fluorophenyls) -3- (phenylcarbamoyl)-Isosorbide-5-Nitrae-adipic ketone] 45.0 grams, 55.0 grams of pivalic acid acid anhydride is slowly added under stirring,
Reaction kettle cover is closed, with the air 3 times in nitrogen displacement reaction kettle, 180 DEG C is warming up to, when reaction 2 is small, after reaction, subtracts
56.0 grams of concentration and recovery solvent 2- methyltetrahydrofurans 450mL and pivalic acid are pressed, obtains sticky oil object.In grease
100ml water, 300mL isopropanols are added in, is warming up to 50 DEG C, progressively cools to 25 DEG C, yellow solid is precipitated, filters, be dried to obtain
Atorvastatin intermediate (4R, 6R) -6- { 2- [5- isopropyl -3- phenyl -2- (4- fluorophenyls) -4- (phenylcarbamoyls
Base)-pyrroles -1- bases-ethyl }-dioxane-4-yls of -2,2- dimethyl-[1,3] -61.2 grams of tert-butyl acetate.
Claims (1)
1. a kind of preparation method of Atorvastatin intermediate, it is characterised in that include the following steps：
Using 2- methyltetrahydrofurans as solvent, added in autoclave [(4R, 6R) -2,2- dimethyl -6- (2- aminoethyls)-[1,
3]-dioxane-4-yls-tert-butyl acetate and [5- methyl -4- isopropyl -2- phenyl -1- (4- fluorophenyls) -3- (phenyl amino first
Acyl group)-Isosorbide-5-Nitrae-adipic ketone], [the tertiary fourth of (4R, 6R) -2,2- dimethyl -6- (2- aminoethyls)-[1,3]-dioxane-4-yls-acetic acid
Mole of ester and [5- methyl -4- isopropyl -2- phenyl -1- (4- fluorophenyls) -3- (phenylcarbamoyl) -1,4- adipic ketones]
Than for 1:1~1.1, pivalic acid acid anhydride is slowly added under stirring, [(4R, 6R) -2,2- dimethyl -6- (2- aminoethyls)-[1,3]-two
The molar ratio of oxane -4- bases-tert-butyl acetate and pivalic acid acid anhydride is 1:2.5~3, with the air 2~3 in nitrogen displacement reaction kettle
It is secondary, 150~200 DEG C are warming up to, when reaction 2~4 is small, after reaction, be concentrated under reduced pressure recycling design, obtains sticky oil object,
Water, isopropanol are added in grease, the wherein volume ratio of water and isopropanol is 1:1~3,40~60 DEG C are warming up to, it is slowly cold
But to 20~30 DEG C, yellow solid is precipitated, filters, be dried to obtain Atorvastatin intermediate (4R, 6R) -6- { 2- [5- isopropyls
Base -3- phenyl -2- (4- fluorophenyls) -4- (phenylcarbamoyl)-pyrroles -1- bases-ethyl } -2,2- dimethyl-[1,3]-two
Oxane -4- bases-tert-butyl acetate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004110998A1 (en) * | 2003-05-16 | 2004-12-23 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| CN102127060A (en) * | 2010-12-17 | 2011-07-20 | 蚌埠丰原医药科技发展有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN102344401A (en) * | 2011-09-15 | 2012-02-08 | 景德镇市富祥药业有限公司 | Method for preparing amorphous atorvastatin calcium |
-
2017
- 2017-12-06 CN CN201711276755.4A patent/CN108101891B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004110998A1 (en) * | 2003-05-16 | 2004-12-23 | Ambit Biosciences Corporation | Pyrrole compounds and uses thereof |
| CN102127060A (en) * | 2010-12-17 | 2011-07-20 | 蚌埠丰原医药科技发展有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN102344401A (en) * | 2011-09-15 | 2012-02-08 | 景德镇市富祥药业有限公司 | Method for preparing amorphous atorvastatin calcium |
Non-Patent Citations (2)
| Title |
|---|
| 周汨等，: "阿托伐他汀钙的合成工艺改进", 《精细化工中间体》 * |
| 精英化学编写组: "《精英化学：提高读本》", 31 March 2011 * |
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