CN1101805C - Key intermediates in manufacture of simvastatin - Google Patents
Key intermediates in manufacture of simvastatin Download PDFInfo
- Publication number
- CN1101805C CN1101805C CN97111497A CN97111497A CN1101805C CN 1101805 C CN1101805 C CN 1101805C CN 97111497 A CN97111497 A CN 97111497A CN 97111497 A CN97111497 A CN 97111497A CN 1101805 C CN1101805 C CN 1101805C
- Authority
- CN
- China
- Prior art keywords
- simvastatin
- lovastatin
- acid
- cyclopropyl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method for preparing simvastatin from the form of lovastatin or every markov noling acid salt, includes the step of processing the original substance by cyclopropyl or butyl amide, opening the pyrone ring when the lovastatin is the original substance, adding methyl to a 2- methyl butyrate side chain, then closing the pyrone ring to generate the simvastatin. Two hydroxy groups of the opened pyrone ring are no need to be protected or removed from protection when using the method. In a better technology scheme, the original substance is processed by cyclopropylamine and can generate simvastatin by a novel intermediate lovastatin cyclopropyl amide.
Description
The present invention relates to prepare intermediate crucial in the Simvastatin (simvastatin).
The structure I compound that shows below is active high anti-high cholesterol medicine, and it can limit cholesteric biosynthesizing by suppressing the HMG-CoA reductase enzyme.
The structure I compound comprises the every Fu Nuolin of natural fermented product (mevinolin) (structure I a, wherein R=CH
3, by United States Patent (USP) 4,231,938 disclose, be also referred to as lovastatin), Kang Paiting (compactin) (structure I b, R=H wherein is by United States Patent (USP) 3,983,140 disclose) and various semi-synthetic and complete synthesis analogue, all these has natural 2-Methyl Butyric Acid ester side chain.
What show below has 2, and the structure I I compound of 2-acid dimethyl ester side chain (as Simvastatin, structure I Ia, wherein R=CH
3) its activity of specific activity 2-Methyl Butyric Acid ester analogs that suppresses the HMG-CoA reductase enzyme is bigger, therefore in treatment atherosclerosis, hyperlipoidemia, familial hypercholesterolemia and similar disease more applications is arranged.
The Simvastatin (IIa) of introducing recently market is a kind ofly to suppress sharp than the more efficiently HMG-CoA reductase enzyme of lovastatin (Ia), need than prior art disclose more economical effectively and the high yield method that helps environment prepare.
Have 2, structure I I compound of 2-acid dimethyl ester side chain (as, Simvastatin) and their preparation method be at United States Patent (USP) 4,444,784 and EPO publication application 33538 in disclosed.Here the method for Jie Shiing relates to four chemical steps that separate:
(1) de-esterifying of 2-Methyl Butyric Acid ester side chain;
(2) the 4-hydroxyl of pyrone ring is protected;
(3) make the side chain resterification required 2,2-dimethyl butyrate acid esters to form; With
(4) make the 4-hydroxyl go protection.
This approach is very tediously long, and total yield is very low.
Simvastatin also can be by making as United States Patent (USP) 4,582, and 915 and 4,820,850 described ester moiety a-alkylations prepare.
United States Patent (USP) 4,582,915 (1986) have disclosed in single chemical step and make 2-(S)-methylbutyryl base oxygen base side chain of natural every Fu Nuolin directly methylate and can obtain Simvastatin with metal alkyl amide and methyl halide.This method has the bad shortcoming of C-methyl step transformation efficiency.In addition, owing to methylate in other site of this molecule, so many side reactions are arranged.Transformation efficiency can or add amide group and methyl halide obtains improvement to a certain degree but total recovery is still not high for the third time by second even C-methylates.The purity of the Simvastatin that obtains with this method approaches to be used for the minimum standard of HUMAN HEALTH care products.
United States Patent (USP) 4,820,850 (1989) have disclosed a kind of method, wherein by single adding amide group and alkylogen the C-of 2-(S)-methylbutyryl oxygen base side chain generation high conversion of every Fu Nuolin are methylated.The described method of this patent comprises six steps since it relate to expensive sillylation reagent, two hydroxyls that tetrabutyl dimetylsilyl chlorine makes the intermediate lovastatin are protected and go to protect, so be uneconomic.
The invention provides the method and the novel intermediate of the novelty of a kind of preparation Simvastatin (IIa).Novel method is shown by following reaction process:
Notable attribute bag of the present invention is estimated:
(a) salt rather than lovastatin that can every Fu Nuolin acid prepare Simvastatin as initial substance.
(b) Simvastatin prepares in four-step method, and described method does not comprise that two hydroxyls that make the pyrone ring of opening are protected and goes protection.Up to now, method described in the prior art is need be with hydroxyl protected and go protection as preparing the Simvastatin necessary procedure.
(c) in technical scheme preferably, the novel intermediate lovastatin cyclopropyl amide (IIIb) of preparation from initial substance (salt form of lovastatin or every Fu Nuolin acid).This novel intermediate is converted into the intermediate (IVb) of second novelty then.
Simvastatin with the inventive method preparation has certain advantage in the industry manufacturing.Purity and yield from the Simvastatin of the inventive method are high, the consumption of reagent, time, artificial and cost is all lower, and step is less.
The initial substance of the inventive method is lovastatin (Ia) or every Fu Nuolin acid (Ic), and latter's open loop has formed lovastatin.By making
Aspergillus terreusFermentation has produced every Fu Nuolin acid (referring to United States Patent (USP) 4,231,938).The salt form (Ic) of lovastatin (Ia) or every Fu Nuolin acid can typically be used as initial substance.Unless otherwise mentioned, term " every Fu Nuolin acid " comprises the salt form that it is suitable; Allow to use and do not disturb any salt that carries out other used reagent of the present invention or condition.Can use an alkali metal salt,, or be preferably ammonium salts as Na and K.
Lovastatin obtains from every Fu Nuolin acid by known the lactonizing of prior art, separates by the loss crystallization technique.In the transforming naturally of lovastatin, 20% material damage is arranged approximately in every Fu Nuolin acid.An object of the present invention is by eliminating this loss as initial substance with every Fu Nuolin acid rather than lovastatin.
The method of novelty according to the present invention by making lovastatin (Ia) or every Fu Nuolin acid (Ic), is preferably its ammonium salts, with formula be R
3-NH
2Positive alkylamine or Cycloalkyl amine react and prepare Simvastatin (IIa), wherein R
3Be C
3-C
6Be preferably amine R
3-NH
2Be cyclopropylamine, formed intermediate is lovastatin cyclopropyl amide (IIIb).Another kind method is amine R
3-NH
2Be n-butylamine, formed intermediate is a lovastatin normal-butyl acid amides (IIIa).
The cyclic midbody acid amide IIIa or the IIIb that make like this are dissolved in anhydrous tetrahydro furan, and are added to the solution of alkali metal amide under-35 ℃ to-40 ℃, as the solution of tetramethyleneimine lithium (lithium pyrrolidide) in THF.By making n-Butyl Lithium and tetramethyleneimine in THF, in same container, produce the tetramethyleneimine lithium.The solution of midbody acid amide IIIa or IIIb and the alkali that produces in same container wore out 1 hour down at about-35 ℃ to-40 ℃, once added anhydrous alkylogen, were preferably methyl-iodide (2-3.5 molar equivalent).Inclusion stirred 1 hour at about-30 ℃, was warming to-10 ℃, wore out 20 minutes under this temperature.Water is added in the reaction mixture, separates each layer.THF layer mineral acid is preferably the salt acid elution, concentrates then and obtains the buttery material, and it contains intermediate compound IV a or IVb.
Add 2.0N NaOH in the solution in methyl alcohol to not purified intermediate compound IV a or IVb,, be preferably and refluxed 2 hours at about 80-81 ℃ of following backflow 2-6 hour.Mixture is cooled to about 50 ℃, and methyl alcohol, dilute with water are then removed in decompression.This mixture makes pH remain 6 by adding 2.0N HCl carefully in the time of about 10 ℃.With ethyl acetate extraction, continue to be acidified to pH and reach 4.The separating ethyl acetate layer by add the methanol solution of ammonium hydroxide in the time that is no less than 30 minutes under about 22-25 ℃, is cooled to 5 ℃ then, and the product of hydrolysis becomes crystalline material with the form of ammonium salt (V) and is precipitated out.
By heating in such as the hydrocarbon solvent of toluene ammonium salt (V) is lactonized again.Mixture is suspended in the toluene, and heating and stirred 2-10 hour down at about 100-110 ℃ under nitrogen covers is preferably in about 105 ℃ of stirrings 5 hours down.Mixture is cooled to about 35 ℃ then, handles with carbon, filters, and concentrating under reduced pressure filtrate is to 1/10 of original volume under about 60 ℃ bath temperature.Use hydrocarbon solvent crystallization lactone to obtain highly purified Simvastatin (IIa) such as hexanaphthene.
In the best technique scheme of novel method of the present invention, the ammonium salts of every Fu Nuolin acid (Ic) is used as initial substance, and is converted into lovastatin cyclopropyl amide (IIIb).Every Fu Nuolin hydrochlorate is suspended in the toluene,, is preferably at about 105-107 ℃ of following backflow 5-6 hour at about 100-110 ℃.Under decompression and about 50-55 ℃, the solution concentration of gained is arrived 1/10 of its volume by toluene distillation.Add down cyclopropylamines at 30 ℃, under about 40-50 ℃ with mixture reheat 4-5 hour.Pressure reducing and steaming toluene and unreacted cyclopropylamine obtain the lovastatin cyclopropyl amide (IIIb) of quantitative yield.The not purified cyclic amide that makes like this is used for the methylated step of next C-and need not to protect the dihydroxyl system with above-mentioned similar methods, obtain Simvastatin (IIa).
The following example has further been set forth the present invention:
Example I
Prepare Simvastatin (IIa) with cyclopropylamine from every Fu Nuolin acid ammonium salt (Ib)
Step 1:N-cyclopropyl-7-[1,2,6,7,8,8a (R)-six hydrogen-2 (S), 6 (R)-dimethyl-8 (S)-[[2 (S)-methylbutyryl base] oxygen base]-1 (S)-naphthyl]-3 (R), 5 (R)-dihydroxyl enanthic acid acid amides (IIIb)
Every Fu Nuolin acid ammonium salt (Ic) (12.5g, 0.269 mole) is suspended in toluene (400 milliliters).Heated mixt also stirred 5 hours down at 105-107 ℃ under nitrogen covers.Allow temperature be reduced to 60 ℃, boil off about 350 milliliters of toluene.Add down cyclopropylamines (12 milliliters, 0.172 mole) at 30 ℃, 40-45 ℃ of following restir 4 hours.Decompression slowly boils off toluene under 55 ℃ bath temperature, obtains the title compound of colloidal.HPLC purity=99.63%;
1H NMR (CDCl
3, 300MHz); D 0.495 (m, 2H), d0.50 (m, 2H), d0.86 (m, 6H), d1.08 (m, 6H), d2.3 (d, 2H), d2.6 (m, 1H), and d3.7 (m, 1H), d4.1 8 (m, 1H), d5.4 (m, 1H), d5.5 (bt, J=3.0Hz, 1H), d5.7 (dd, J=6.1,9.5Hz, 1H), d5.9 (d, J=9.6Hz, 1H), d6.2 (bt, J=5.3Hz, 1H); IR (CHCl
3): l
Maximum3500-3300 (b), 3000,1740,1660,1530,1450,1210,860,760cm
-1
This colloid is directly used in next step and need not purifying.
Step 2:N-cyclopropyl-7-[1,2,6,7,8,8a (R)-six hydrogen-2 (S), 6 (R)-dimethyl-8 (S)-[[2,2-dimethyl-butyryl radicals] oxygen base]-1 (S)-naphthyl]-3 (R), 5 (R)-dihydroxyl enanthic acid acid amides (IVb)
The material of tetramethyleneimine (13.5ml, 0.163 mole) in THF (50 milliliters) is cooled to-45 ℃, under nitrogen, adds the material of n-Butyl Lithium in hexane (1.6M, 100ml, 0.163 mole) with the speed that temperature is remained on-20 ℃ to-15 ℃.Stirred 40 minutes down at-20 ℃ to-25 ℃ at the reinforced relief mixture that finishes.
Prepare the solution of compound III b in THF (300 milliliters) as mentioned above, slowly add by sleeve pipe so that add fashionable temperature under-35 ℃ then.Allow solution wear out 1 hour down at-35 ℃ to-40 ℃.The methyl-iodide of a collection of adding molecular sieve drying (4.82ml, 0.077 mole).The solution of the off-white color muddiness that obtains like this stirred 1 hour down at-35 ℃ to-33 ℃, was warming to-10 ℃ then, and aging 20 minutes.In reaction mixture, add distilled water (105 milliliters), with inclusion high degree of agitation 5 minutes.Separate each layer, the THF layer on top is handled with 1NHCl (105 milliliters).Concentrating under reduced pressure THF layer to volume is about 40 milliliters, obtains title compound IVb, wherein R
3It is cyclopropyl.
Step 3:6 (R)-[2-[8 (S)-(2,2-dimethyl butyrate acyloxy)-2 (S), 6 (R)-dimethyl-1,2,6,7,8,8a (R)-six hydrogen-1 (S)-naphthyl] ethyl]-4 (R)-hydroxyls-3,4,5,6-tetrahydrochysene-2H-pyran-2-one (IIa) (Simvastatin)
To from preceding step, contain and add the NaOH aqueous solution (2N, 25 milliliters) and MeOH (175 milliliters) solution in the concentrated solution of compound IV b.Allow mixture reflux 2 hours down at 80-81 ℃.Mixture is cooled to 50 ℃, under reduced pressure boils off a large amount of MeOH, water (90 milliliters) dilution.Make the solution acidifying by the careful 2NHCl (pH6) that adds down at 10 ℃.Add ethyl acetate (200 milliliters), the high degree of agitation mixture, being acidified to pH more simultaneously is 4.From water layer, isolate ethyl acetate layer.Under 22-25 ℃, slowly add NH being no less than 30 fens clock times
4OH and MeOH (1: 1,10ml) solution.Stir precipitation down at 25 ℃ and reach 1.5 hours, be cooled to 5 ℃, and under this temperature, stirred 30 minutes.Wash and after 35 ℃ of following vacuum-drying, obtain ammonium salt (V) with cold ethyl acetate (25 milliliters) behind the sedimentation and filtration.
Rough ammonium salt (V) (10 grams, 0.022 mole) from preceding step is suspended in the toluene (350 milliliters).Mixture heating under nitrogen covers, and under 105 ℃, stirred 5 hours.Solution is cooled to 35 ℃, adds activated carbon (0.5 gram), stirred 0.35 hour, filter by bed of diatomaceous earth then.Vacuum concentrated filtrate obtains 40 ml volumes under 60 ℃ of bath temperatures.Add hexanaphthene (125 milliliters), solution was refluxed 15 minutes, be cooled to 25 ℃ and continue 1 hour, be cooled to 10-12 ℃ again and reach 30 minutes.Throw out stirred 30 minutes down at 10-12 ℃, filtered and washed with cold hexanaphthene (50 milliliters), obtained white crystals product (IIa) 35 ℃ of following vacuum-dryings, obtained title product with the dehydrated alcohol crystallization again, purity＞99%.
Example II
From lovastatin (Ia), prepare Simvastatin (IIa) with cyclopropylamine
Step 1:N-cyclopropyl-7-[1,2,6,7,8,8a (R)-six hydrogen-2 (S), 6 (R)-dimethyl-8 (S)-[[2 (S)-methylbutyryl base] oxygen base]-1 (S)-naphthyl]-3 (R), 5 (R)-dihydroxyl enanthic acid acid amides (IIIb)
Under 25 ℃, lovastatin (Ia) (12.5g, 0.03 mole) is suspended in cyclopropylamine (13 milliliters, 0.174 mole).Mixture slowly heated be added to 40-45 ℃, under this temperature, stirred 5 hours.Under 40 ℃ of water-baths and decompression, boil off excessive amine, obtain the title compound of colloidal.This colloid can be directly used in next step and need not further purifying.
Step 2-3: by the compound (IIIb) of preceding step gained being converted into Simvastatin (IIa) with the described same procedure of example I.
EXAMPLE III and IV
Prepare Simvastatin (IIa) with n-Butyl Amine 99 from lovastatin (Ia) and every Fu Nuolin acid ammonium salt (Ic)
With the same steps as of example I and II but replace cyclopropylamine to prepare Simvastatin (IIa) as initial substance with lovastatin (Ia) and every Fu Nuolin acid ammonium salt (Ic) with the equivalent n-Butyl Amine 99.
Though the present invention is described with reference to specific technical scheme, this only uses as narration.The personnel of this technical field can make many alternate technology and change in the scope of these claims.
Claims (6)
1. structural formula II I ' compound:
Wherein R ' is a methyl, R
3Be cyclopropyl, n=1 or 2 wherein.
2. compound according to claim 1, wherein n=1.
3. compound according to claim 1, wherein n=2.
4. method for preparing structural formula II I compound:
R wherein
3Be cyclopropyl, this method comprises the compound with cyclopropyl amide Processing Structure formula I ':
Wherein R is
Or
R
2Be Na, K or NH
4
5. method according to claim 4, wherein R
2Be NH
4
6. method according to claim 4, it further comprises makes the methylbutyrate pendant methylization, produces the compound of structural formula IV:
R wherein
3Definition the same.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1683DE1996 IN184809B (en) | 1996-05-30 | 1996-05-30 | |
| IN1683/DEL/96 | 1996-07-30 | ||
| US08/816574 | 1997-03-13 | ||
| US08/816,574 US5763653A (en) | 1997-03-13 | 1997-03-13 | Key intermediates in the manufacture of simvastatin |
| US08/816,574 | 1997-03-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1173488A CN1173488A (en) | 1998-02-18 |
| CN1101805C true CN1101805C (en) | 2003-02-19 |
Family
ID=26324705
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97111497A Expired - Fee Related CN1101805C (en) | 1996-05-30 | 1997-05-30 | Key intermediates in manufacture of simvastatin |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR100503923B1 (en) |
| CN (1) | CN1101805C (en) |
| AU (1) | AU692409B2 (en) |
| HR (1) | HRP970436B1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010009846A (en) * | 1999-07-14 | 2001-02-05 | 구광시 | Intermediates useful for manufacturing simvastatin and processes for the preparation thereof |
| CN103254076A (en) * | 2008-05-09 | 2013-08-21 | 上海医药工业研究院 | Synthesis method for simvastatin ammonium salt, used intermediate and preparation methods for both |
| CN103864611B (en) * | 2013-12-24 | 2015-11-11 | 深圳华润九新药业有限公司 | The preparation method of a kind of preparation method of Simvastatin alcohol acid compound, composition, composition and application thereof |
-
1997
- 1997-05-12 KR KR1019970018306A patent/KR100503923B1/en not_active IP Right Cessation
- 1997-05-14 AU AU21409/97A patent/AU692409B2/en not_active Ceased
- 1997-05-30 CN CN97111497A patent/CN1101805C/en not_active Expired - Fee Related
- 1997-08-07 HR HR970436A patent/HRP970436B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| HRP970436B1 (en) | 2003-06-30 |
| AU692409B2 (en) | 1998-06-04 |
| KR100503923B1 (en) | 2005-10-13 |
| CN1173488A (en) | 1998-02-18 |
| AU2140997A (en) | 1998-01-29 |
| KR970074750A (en) | 1997-12-10 |
| HRP970436A2 (en) | 1999-06-30 |
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