CN1821242A - Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor - Google Patents
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Abstract
The present invention provides the preparation process of the compound as shown.
Description
Technical field:
The present invention relates to a kind of novel method for preparing dihydroxy acid HMG CoA reductase inhibitor.
Background technology:
Dihydroxy acid HMG CoA reductase inhibitor is also referred to as: 3-hydroxy-3-methyl glutaryl coenzyme reductase inhibitor A (3-hydroxy-3-methylglutaryl-coenzymeA, HMG-CoA), being the novel blood lipid-lowering medicine of a class, is clinical prevention atherosclerosis drug of first choice at present.
Since first statins mevastatin (mevastatin) in 1976 came out, statins had been developed to the third generation.Statins commonly used in the world at present has 5 kinds (by the appearance sequencing): lovastatin (lovastatin), Pravastatin (pravastatin), Simvastatin (simvastatin), fluvastatin (fluvastatin) and atorvastatin (atorvastatin).And the accent fat effect of not long ago also using in the international market is powerful, the taking dose Cerivastatin of Gamma Magnitude (cerivastatin) only, cause rhabdomyolysis to cause dead severely adverse event to take place again and again because of share with the fibrate lipid-lowering medicine, some countries and China stop using in succession in the world.(rosuvastatin's rosuvastatin of new statins---Astrazeneca company ZD4522) also goes on the market, and its effect for reducing fat is powerful, uses separately to surpass every other statins, is known as " super he spit of fland ".Japan development she he cuts down his spit of fland (itavastatin also is a kind of efficient lipid lowerers NK-104), mainly with the original shape metabolism, does not still go public.Statins is efficient, safety, is the choice drug in the fat-reducing medicament.
First statins lovastatin is separated from the mould culture, and Pravastatin and Simvastatin are the improvement of the chemical structure of lovastatin.The active structure that Hydroxymethylglutaryl is all arranged in the statins structure, just existence form difference.Lovastatin and Simvastatin are inactive lactone form medicines, and they must be metabolized to its corresponding open loop alcohol acid form could suppress the HMG-CoA reductase enzyme.Pravastatin exists to have active open hydrochlorate structure, water-soluble big, mainly act on liver, it is high 400～1200 times to suppress liver cholesterol synthetic energy force rate surrounding tissue, therefore do not have the effect that obviously suppresses peripheral tissues's synthetic cholesterol, thereby untoward reaction is few.The structure of lovastatin, Simvastatin, Pravastatin and relative molecular mass are very approaching, and curative effect, untoward reaction, tolerance etc. are variant slightly on the degree.Fluvastatin is first complete synthesis HMG-CoA reductase inhibitor, and it is obviously different that structure and above 3 kinds of his spit of fland medicines have, and it is the derivative with the mevalonolactone of fluorobenzene substituted indole ring, need not metabolic conversion and just has pharmacologically active.The same fluorobenzene ring and the nitrogen heterocyclic of all containing with fluvastatin of atorvastatin is the 2nd statins of total man worker's synthetic.The two is compared with lovastatin with Simvastatin, water-soluble increase, and fat-soluble reduction all shows dose-effect relationship.
Statins has many synthetic methods because complex structure is synthetic relatively more difficult in the prior art, but all exist yield low, step is long, the cost height, defectives such as operational difficulty the invention provides a kind of novel method for preparing dihydroxy acid HMG CoA reductase inhibitor, solve these problems.
Summary of the invention:
The invention provides a kind of novel method for preparing dihydroxy acid HMG CoA reductase inhibitor, this method is by the important intermediate of preparation, and compound in structural formula I realizes.
Therefore, the invention provides a kind of useful as intermediates, the formula I compound that structure is following
Wherein: R is:
Ra representative: hydrogen, the alkyl of C1～C6 such as methyl, ethyl, propyl group, butyl, sec.-propyl, bad propyl group, isobutyl-, the tertiary butyl etc., preferable methyl, ethyl, the tertiary butyl, the most preferably tertiary butyl.
Rb, Rc represent hydrogen respectively, the alkyl of C1～C4 or C3～C6 cyclic alkyl, preferable methyl, ethyl or cyclopropyl, cyclohexyl, most preferable.
Formula I compound obtains the end product dihydroxy acid HMG CoA reductase inhibitor through the reactions steps of step 3 of the present invention.
Dihydroxy acid HMG CoA reductase inhibitor of the present invention comprises their ester, salt, acid, free acid etc.
For this reason, the invention provides the preparation method of formula I compound, this method may further comprise the steps:
Step 1:
With precursor compound R-CH
2OH through oxidizing reaction obtain compound R-CH (=O),
Wherein the R representative is the same.
Described precursor compound R-CH
2OH is a known compound, can prepare by technology among the US5260440.
The reaction conditions of described oxidizing reaction is: the oxygenant of employing is pyridinium chloro-chromate (PCC), and reaction substrate and oxygenant mole proportioning are chosen between 1: 1 to 1: 1.5, between 0～50 ℃ of the temperature of reaction, and preferred 0～25 ℃.This is reflected in hydro carbons or the halogenated hydrocarbon solvent and carries out, as benzene, and toluene, methylene dichloride, trichloromethane etc., here our preferred methylene dichloride.
Step 2:
With gained compound R-CH (=O) with formula (II) compound prepared in reaction formula (I),
Wherein the R representative is the same,
Ra, Rb, the Rc representative is the same.
R
1, R
2The alkyl of C1-C7 or aryl such as the phenyl of C6～C12, tolyl, xylyl, the biphenylyl etc. represented independent of each other.Methyl preferably, ethyl, phenyl, tolyl, most preferred is methyl.
Reaction conditions is, adopted LiCl and organic bases such as triethylamine, temperature of reaction-10～30 ℃, and this is reflected in ether solvent or the halogenated hydrocarbon solvent and carries out, tetrahydrofuran (THF) for example, methylene dichloride, trichloromethane etc., our preferred methylene dichloride.Aldehyde and organophosphate mole proportioning are chosen between 1: 1 to 1: 2.
Its Chinese style (II) compound is through (R by formula (III) compound
1O) (R
2O) the P processing obtains
X wherein
1Represent halogen atom, as F, Cl, Br, I,
R
1, R
2, represent the same.
Here we obtain formula (II) with two kinds of raw materials at varsol such as reflux in toluene reaction.
Formula (III) compound is a known compound, can obtain by the method for setting forth in the U.S. Pat 5278313, as following method:
With the described compound of formula (IV) is that starting raw material is reduced to the described compound of formula V:
The described compound of formula V is obtained the described compound of formula (III) with (Va) or (Vb) or (Vc) reaction under acidic conditions:
X
1Be halogen atom, Ra is a hydrogen, alkyl or aryl, preferred alkyl, for example tertiary butyl.R
bR
cBe hydrogen, alkyl or cyclic alkyl, R
5, R
6Be alkyl.
Step 3:
Formula (I) compound obtains following useful dihydroxy acid HMG CoA reductase inhibitor by known method
A obtains following formula dihydroxy carboxylic acids ester with acid treatment:
B obtains acceptable salt on the following formula drug effect with alkaline purification, dihydroxy carboxylic acids salt:
C obtains the following formula dihydroxylated acid with acid treatment:
D obtains the saturated free acid of following formula with free acid hydrogenation:
Described known method can reference WO01/60804, WO01/49014, or realize according to the method in the embodiment of the invention.
The method of above step preparation formula (I) compound can be described in more detail by the reaction formula of following preparation rosuvastain calcium (ZD-4522).
Rosuvastain calcium (ZD-4522)
Method of the present invention, compared with prior art, advantage is, the yield height is easy to operate, mild condition, high chiral purity is synthetic to obtain target product, and environmental pollution is little, and reactions steps is few, and cost is low, can scale operation.
Embodiment
Further specify the present invention by the following examples, but not as limitation of the present invention.
With preparation rosuvastain calcium (ZD-4522) compound (H) is example.
Embodiment 1: the preparation of compound (B) 4-(4-fluorobenzene)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamido)-5-pyrimidine formaldehyde:
Add pyridinium chloro-chromate (PCC) 28.0g to exsiccant methylene dichloride 300ml, anhydrous sodium acetate 24.6g, stir, 20 ℃ of solution that drip the preparation of compound (A) [4-(4-fluorobenzene)-6-sec.-propyl-2-(N-methyl-N-methanesulfonamido) pyrimidine-5-yl] methyl alcohol 35.3g and 200ml methylene dichloride down, stir 1h, filter, filtrate 1N hydrochloric acid 500ml, 1N NaOH 500ml, saturated aqueous common salt 500ml washing, anhydrous magnesium sulfate drying, decompression removes methylene dichloride, the resistates column chromatography, the eluent methylene dichloride gets crystallization target product 29.1g (yield: 82.9%).
Embodiment 2: the preparation of compound (D):
Toluene 200ml adds trimethyl phosphite 13.0g, is warming up to backflow, drips compound (C) 2-[(4R, 6S)-and 6-brooethyl-2,2-dimethyl-1,3-dioxy-4-yl] solution of tert.-butyl acetate 32.3g and toluene 200ml preparation, back flow reaction 3h, decompression removes toluene, adds entry 500ml, chloroform 200ml * 3 extractions, anhydrous magnesium sulfate drying, decompression removes chloroform, resistates column chromatography, the eluent ethyl acetate gets target product 31.7g (yield: 90.1%).
Embodiment 3: the preparation of compound (E)
Add LiCl 15.3g to exsiccant methylene dichloride 300ml under the argon shield; compound (D) 42.2g; stir; 0 ℃ drips triethylamine 12.2g; drip and finish the solution that then drips compound (B) 35.1g and methylene dichloride 200ml preparation; 20 ℃ are stirred 1h; in reaction solution, add saturated ammonium chloride solution 300ml, layering, extract water methylene dichloride 200ml * 2; merge organic phase; anhydrous magnesium sulfate drying, decompression removes methylene dichloride, resistates column chromatography; eluent (normal hexane: ethyl acetate=5: 1), get target product 40.7g (yield: 70.5%).
Embodiment 4: the preparation of compound (F)
80% aqueous acetic acid 2500ml adding compound (E) 57.8g, stirring at room 20h gets settled solution, and decompression removes solvent to doing, and residual solvent is removed with toluene 250m1 * 3 azeotropic, gets white powder shape solid 53.7g (yield: 100.0%).
Embodiment 5: the preparation of rosuvastain calcium-compound (H)
Under the argon shield, acetonitrile 700m adds compound (F) 53.7g, adds 1N NaOH 1000ml, room temperature reaction lh, and decompression removes acetonitrile, and resistates adds entry 3000ml dilution, drips 1M CaCl under the room temperature
2Solution 900ml stirs 2h, suction filtration, and vacuum-drying gets white object product compound (H) 40.3g (yield: 80.7%).
Claims (10)
1, the formula that structure is following (I) compound
Wherein R is:
The Ra representative: hydrogen, the alkyl of C1～C6,
Rb, Rc represent hydrogen respectively, the alkyl of C1～C4 or C3～C6 cyclic alkyl.
2, the preparation method of the compound of claim 1 is characterized in that: the process following steps:
Step 1:
With precursor compound R-CH
2OH through oxidizing reaction obtain compound R-CH (=O),
Wherein the R representative is with claim 1.
Step 2:
With gained compound R-CH (=O) with formula (II) compound prepared in reaction formula (I),
Wherein R represents with claim 1,
Ra, Rb, Rc represents with claim 1.
R
1, R
2The alkyl of C1-C7 or the aryl of C6～C12 represented independent of each other.
3, the preparation method of claim 2 is characterized in that:
Its Chinese style (II) compound is through (R by formula (III) compound
1O) (R
2O) the P processing obtains
X wherein
1Represent halogen atom,
R
1, R
2, representative is with claim 2.
4, the preparation method of claim 2 is characterized in that:
The reaction conditions of step 1 is: the oxygenant of employing is a pyridinium chloro-chromate, and reaction substrate and oxygenant mole proportioning are between 1: 1 to 1: 1.5, and temperature of reaction is between 0～50 ℃, and this is reflected in hydro carbons or the halogenated hydrocarbon solvent and carries out;
The reaction conditions of step 2 is, adopts LiCl and organic bases such as triethylamine, temperature of reaction-10～30 ℃, and this is reflected in ether solvent or the halogenated hydrocarbon solvent and carries out, and aldehyde and organophosphate mole proportioning are between 1: 1 to 1: 2.
5, the preparation method of claim 3 is characterized in that:
Reaction conditions is the formula that obtains (II) that two kinds of raw materials are refluxed in varsol.
6, claim 2 or one of 3 preparation method is characterized in that:
The following group of R representative wherein:
Ra representative: hydrogen, methyl, ethyl, propyl group, butyl, sec.-propyl, cyclopropyl, the isobutyl-or the tertiary butyl;
Rb, Rc represent hydrogen, methyl, ethyl, cyclopropyl or cyclohexyl respectively separately;
R
1, R
2Represent methylidene independent of each other, ethyl, phenyl, tolyl.
7, the preparation method of claim 6 is characterized in that: wherein
Ra represents the tertiary butyl; Rb, the Rc difference is represent methylidene separately; R
1, R
2Represent methylidene independent of each other.
8, the preparation method of claim 7 is characterized in that:
The reaction conditions of step 1 is: the oxygenant of employing is a pyridinium chloro-chromate, reaction substrate and oxygenant mole proportioning between 1: 1 to 1: 1.5,0～25 ℃ of temperature of reaction, this is reflected in the dichloromethane solvent and carries out; The reaction conditions of step 2 is, adopts LiCl and triethylamine, temperature of reaction-10～30 ℃, and this is reflected in the dichloromethane solvent and carries out, and aldehyde and organophosphate mole proportioning are between 1: 1 to 1: 2.
9, the application of the compound of claim 1 in the following compound of preparation.
The following formula dihydroxy carboxylic acids ester that a obtains with acid treatment:
The dihydroxy carboxylic acids salt that b obtains with alkaline purification:
The dihydroxylated acid that c obtains with acid treatment:
The saturated free acid that d obtains free acid hydrogenation:
10, the application of claim 9 is characterized in that, the compound that obtains is
The following group of R representative wherein, M
+Represent calcium ion.
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Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007099561A1 (en) * | 2006-02-27 | 2007-09-07 | Cadila Healthcare Limited | Process for preparing rosuvastatin calcium |
| US20090275752A1 (en) * | 2006-05-03 | 2009-11-05 | Manne Satyanarayana Reddy | Novel Process for Statins and its Pharmaceutically Acceptable Salts Thereof |
| US7687660B2 (en) | 2007-04-18 | 2010-03-30 | Teva Pharmaceutical Industries Ltd. | Process for preparing intermediates of HMG-CoA reductase inhibitors |
| WO2010081861A1 (en) | 2009-01-14 | 2010-07-22 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of rosuvastatin |
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| US7884226B2 (en) | 2007-07-12 | 2011-02-08 | Teva Pharmaceutical Industries, Ltd. | Purification of rosuvatatin intermediate by thin film evaporation and chemical method |
| US7994178B2 (en) | 2006-09-18 | 2011-08-09 | Teva Pharmaceutical Industries, Ltd. | Crystalline rosuvastatin calcium and compositions thereof for treatment of hyperlipidaemia |
| CN102153463A (en) * | 2011-03-03 | 2011-08-17 | 上海应用技术学院 | 4-subsititued 3,5-dihydroxy carboxylic acid compound and preparation method thereof |
| CN102219780A (en) * | 2010-04-14 | 2011-10-19 | 上海京新生物医药有限公司 | Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid |
| CN102617481A (en) * | 2012-03-16 | 2012-08-01 | 湖南欧亚生物有限公司 | Preparation method of rosuvastatin calcium |
| CN102816152A (en) * | 2011-06-09 | 2012-12-12 | 上海京新生物医药有限公司 | Method for preparing rosuvastatin intermediate |
| US8404841B2 (en) | 2006-10-09 | 2013-03-26 | Msn Laboratories Limited | Process for the preparation of statins and their pharmaceutically acceptable salts thereof |
| US8487105B2 (en) | 2009-01-19 | 2013-07-16 | Msn Laboratories Limited | Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof |
| US8987444B2 (en) | 2010-01-18 | 2015-03-24 | Msn Laboratories Private Limited | Process for the preparation of amide intermediates and their use thereof |
| CN104788387A (en) * | 2015-04-17 | 2015-07-22 | 浙江海森药业有限公司 | Preparation method for high-purity rosuvastatin calcium |
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2006
- 2006-02-16 CN CN 200610007556 patent/CN1821242B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7851624B2 (en) | 2003-12-24 | 2010-12-14 | Teva Pharamaceutical Industries Ltd. | Triol form of rosuvastatin and synthesis of rosuvastatin |
| WO2007099561A1 (en) * | 2006-02-27 | 2007-09-07 | Cadila Healthcare Limited | Process for preparing rosuvastatin calcium |
| US20090275752A1 (en) * | 2006-05-03 | 2009-11-05 | Manne Satyanarayana Reddy | Novel Process for Statins and its Pharmaceutically Acceptable Salts Thereof |
| US8455640B2 (en) * | 2006-05-03 | 2013-06-04 | Msn Laboratories Limited | Process for statins and its pharmaceutically acceptable salts thereof |
| US7994178B2 (en) | 2006-09-18 | 2011-08-09 | Teva Pharmaceutical Industries, Ltd. | Crystalline rosuvastatin calcium and compositions thereof for treatment of hyperlipidaemia |
| US8404841B2 (en) | 2006-10-09 | 2013-03-26 | Msn Laboratories Limited | Process for the preparation of statins and their pharmaceutically acceptable salts thereof |
| US7687660B2 (en) | 2007-04-18 | 2010-03-30 | Teva Pharmaceutical Industries Ltd. | Process for preparing intermediates of HMG-CoA reductase inhibitors |
| US7964748B2 (en) | 2007-04-18 | 2011-06-21 | Teva Pharmaceutical Industries, Ltd. | Process for preparing intermediates of HMG-CoA reductase inhibitors |
| US7884226B2 (en) | 2007-07-12 | 2011-02-08 | Teva Pharmaceutical Industries, Ltd. | Purification of rosuvatatin intermediate by thin film evaporation and chemical method |
| EP2752407A1 (en) | 2009-01-14 | 2014-07-09 | Krka Tovarna Zdravil, D.D., Novo Mesto | Crystalline rosuvastatin calcium trihydrate |
| WO2010081861A1 (en) | 2009-01-14 | 2010-07-22 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of rosuvastatin |
| US8487105B2 (en) | 2009-01-19 | 2013-07-16 | Msn Laboratories Limited | Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof |
| US8987444B2 (en) | 2010-01-18 | 2015-03-24 | Msn Laboratories Private Limited | Process for the preparation of amide intermediates and their use thereof |
| CN102219780A (en) * | 2010-04-14 | 2011-10-19 | 上海京新生物医药有限公司 | Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid |
| CN102219780B (en) * | 2010-04-14 | 2014-08-06 | 上海京新生物医药有限公司 | Method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid |
| CN102153463A (en) * | 2011-03-03 | 2011-08-17 | 上海应用技术学院 | 4-subsititued 3,5-dihydroxy carboxylic acid compound and preparation method thereof |
| CN102816152A (en) * | 2011-06-09 | 2012-12-12 | 上海京新生物医药有限公司 | Method for preparing rosuvastatin intermediate |
| CN102816152B (en) * | 2011-06-09 | 2015-09-09 | 上海京新生物医药有限公司 | A kind of preparation method of Rosuvastatine intermediate |
| CN102617481A (en) * | 2012-03-16 | 2012-08-01 | 湖南欧亚生物有限公司 | Preparation method of rosuvastatin calcium |
| CN104788387A (en) * | 2015-04-17 | 2015-07-22 | 浙江海森药业有限公司 | Preparation method for high-purity rosuvastatin calcium |
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Application publication date: 20060823 Assignee: Jiangsu Yabang Shengyuan Medicine Co., Ltd. Assignor: Yabang Chemical Group Co. Ltd.|Changzhou kingyo Chemical Co. Ltd. Contract record no.: 2012320000932 Denomination of invention: Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor Granted publication date: 20120307 License type: Exclusive License Record date: 20120816 |
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