CN109824605B - Synthetic method of rosuvastatin calcium - Google Patents
Synthetic method of rosuvastatin calcium Download PDFInfo
- Publication number
- CN109824605B CN109824605B CN201910192741.7A CN201910192741A CN109824605B CN 109824605 B CN109824605 B CN 109824605B CN 201910192741 A CN201910192741 A CN 201910192741A CN 109824605 B CN109824605 B CN 109824605B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- synthesis method
- rosuvastatin calcium
- reaction
- 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.)
- Active
Links
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for synthesizing rosuvastatin calcium, which comprises the steps of preparing a bimolecular rosuvastatin calcium side chain intermediate by using a dienone as a raw material, reacting the dienone raw material of the bimolecular with cyclohexanedione to form the bimolecular side chain intermediate, and preventing the intermediate from forming cis-rosuvastatin calcium in a Wittig reaction due to steric hindrance, so that the optical purity of a product is effectively improved, and the cis-rosuvastatin calcium hardly exists in the product; and avoids harsh reaction conditions at low temperature, and is more favorable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a novel synthetic method of rosuvastatin calcium.
Background
Rosuvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and is useful in the treatment of hypercholesterolemia and mixed dyslipidemia and can reduce elevated concentrations of low density cholesterol, total cholesterol, triglycerides and apoprotein B while elevating concentrations of high density cholesterol. Can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia, and is called super statin. In therapy, rosuvastatin is administered as its calcium salt and is a single enantiomer having the following chemical structure.
The prior art reports a plurality of preparation methods of rosuvastatin: JP-B-2648897 discloses a process for the production of rosuvastatin calcium salt: (3R) -3- [ (tert-butyldimethylsilyl) oxy ] -5-oxo-6-triphenylphosphinenehexanoic acid methyl ester was condensed with 4- (4-fluorophenyl) -6-isopropyl-2- (N-methyl-N-methanesulfonylamino) -5-pyrimidinecarbaldehyde to introduce a side chain having one asymmetric center, followed by deprotection of 3-hydroxy group, asymmetric reduction of 5-oxo group, and hydrolysis. Since this method requires extremely low temperature conditions (-85 ℃ to-70 ℃) during the asymmetric reduction, it is not a industrially preferred production method at all. In the processes disclosed in international patents WO2010/047296a1, WO2005/042522a1, extremely low temperature conditions (-75 ℃) are also required during the Wittig reaction. In addition, since the Wittig reaction has a ratio of cis-trans isomers, even if recrystallization or the like is performed, the compound having the Z configuration remains in the compound having the E configuration, and thus, a cis-rosuvastatin calcium impurity is inevitably formed in the subsequent reaction, and the impurity affects the pharmaceutical efficacy of the drug or the like.
Recently, Bernhard Breit et al (org. Lett.2018,20,3286-3290) reported that a side chain of rosuvastatin calcium can be synthesized with high stereoselectivity by using allene as a raw material, however, in practice, it was found that rosuvastatin calcium synthesized from the prepared side chain, and a small amount of Z-configuration product remained. Chinese patent CN201410720698.4 discloses a bimolecular intermediate generated by introducing cyclohexanedione through one-step reaction, and the bimolecular intermediate is a novel rosuvastatin calcium synthesis intermediate.
In view of the clinical efficacy of rosuvastatin calcium, the rosuvastatin calcium has a wide market, and the synthesis method of the rosuvastatin calcium is always the key point of industrial research. The inventor researches the defects of the existing synthesis method and provides a new synthesis method of rosuvastatin calcium.
Disclosure of Invention
The invention provides a method for preparing a bimolecular rosuvastatin calcium side chain intermediate by using allene as a raw material, wherein the bimolecular rosuvastatin calcium side chain intermediate is formed by the reaction of the allene raw material of the bimolecular and cyclohexanedione, and the intermediate is not easy to form cis-rosuvastatin calcium in a Wittig reaction due to steric hindrance, so that the optical purity of a product is effectively improved, and the cis-rosuvastatin calcium (E: Z > >99.9:0.1) hardly exists in the product; and avoids harsh reaction conditions at low temperature, and is more favorable for industrial production.
In order to solve the technical problems, the invention provides a new synthesis method of rosuvastatin calcium, which comprises the following steps:
1) reacting the compound of the formula I with 1, 4-cyclohexanedione in the presence of a palladium catalyst, a phosphine ligand and an auxiliary agent to obtain a compound of a formula II;
2) oxidizing the compound of the formula II in a hydrogen peroxide-heteropoly acid system to obtain a compound of a formula III;
3) reacting the compound shown in the formula III with the compound shown in the formula IV to generate a compound shown in the formula V;
4) hydrolyzing the compound of the formula V to obtain a compound of a formula VI;
5) reacting the compound in the formula VI under an acidic condition to obtain a compound in a formula VII;
6) hydrolyzing the compound in the formula VII to form salt to obtain rosuvastatin calcium;
the reaction route is as follows:
wherein R is 1 Selected from alkyl; r 2 Is selected from P + (Ph) 3 X - Or PO (Ph) 2 ，X - Represents a halide ion.
In one inventive embodiment, R 1 Preferably C 1-6 An alkyl group;
in one inventive embodiment, R 1 Preferably methyl, ethyl, propyl, isopropyl or tert-butyl; most preferred are methyl and ethyl.
In one inventive embodiment, R 2 Is selected from P + (Ph) 3 Br - 。
As a preferred embodiment of the invention, in step 1), the palladium catalyst is selected from Pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(OAc) 2 Or Pd (acac) 2 。
As a preferred embodiment of the invention, the phosphine ligand is selected from (S) - (-) -SEGphos or DPEphos.
As a preferred embodiment of the invention, the auxiliary agent is selected from p-toluene sulfonic acidAcid, Ph 2 PO 4 H. Phosphoric acid, benzenesulfonic acid, methanesulfonic acid or acetic acid, preferably p-toluenesulfonic acid.
Preferably, the reaction solvent of step 1) is selected from benzene, toluene or xylene.
In an embodiment of the invention, the hydrogen peroxide used in step 2) is selected from hydrogen peroxide having a mass fraction of 30% to 60%.
In an embodiment of the invention, the heteropolyacid used in step 2) is selected from phosphomolybdic heteropolyacids, phosphotungstic heteropolyacids; preferably H 3 PW 12 O 40 、H 4 PMo 11 VO 40 、H 3 PMo 12 O 40 Or H 4 PW 11 VO 40 。
Preferably, the reaction solvent of step 2) is an alcohol, preferably methanol, ethanol, tert-butanol or isopropanol.
In one inventive embodiment, the reaction temperature of step 1) is in the range of 60 ℃ to 100 ℃, preferably 80 ℃ to 85 ℃.
In one embodiment of the invention, the reaction temperature in step 2) is between 10 ℃ and 40 ℃, preferably between 20 ℃ and 35 ℃.
In one embodiment of the invention, the reaction of step 3) is carried out in DMSO as a solvent in the presence of a base, preferably K 2 CO 3 、Na 2 CO 3 、KHCO 3 、NaHCO 3 、KOH、NaOH。
In one embodiment of the invention, step 4) the compound of formula V is hydrolyzed under basic conditions to provide the compound of formula VI. An aqueous solution of sodium hydroxide, potassium hydroxide or sodium carbonate is used to provide an alkaline environment. Preferably, an aqueous solution of 0.1-1.0M sodium hydroxide is used to provide the alkaline environment.
In an embodiment of the invention, the acidic conditions in step 5) are a hydrochloric acid concentration of 37% in a hydrochloric acid environment.
In the preparation method disclosed by the invention, the raw materials used are all known compounds in the field, and can be obtained commercially or synthesized by the preparation method known in the field.
Compared with the prior art, the invention adopts the allene as the raw material to form a bimolecular side chain intermediate with cyclohexanedione, and the generation of cis-rosuvastatin calcium is reduced in Wittig reaction due to steric hindrance, so that the optical purity of the product is improved, and the cis-rosuvastatin calcium (E: Z > >99.9:0.1) hardly exists in the product; and avoids harsh reaction conditions at low temperature, and is more favorable for industrial production.
Drawings
FIG. 1: rosuvastatin calcium synthesis roadmap of the present invention
Detailed Description
The present invention will be described in further detail with reference to examples in order to better illustrate embodiments of the present invention, but should not be construed as limiting the scope of the present invention.
Example 1
Compound II is prepared by reference to Bernhard Breit et al (org. Lett.2018,20, 3286-3290). Adding Pd (PPh) into the reaction bottle 3 ) 4 (3.56g, 3.07mmol, 2.0 mol%), (S) - (-) -SEGphos (4.69g, 7.69mmol, 5.0 mol%) and p-toluenesulfonic acid (2.65g, 15.39mmol,10 mol%), after 5min of nitrogen introduction, the compound of formula I (24.0g, 153.85mmol, 1.0 eq), 1, 4-cyclohexanedione (8.62g, 0.5 eq) and freshly distilled toluene (300mL) were added, warmed to 85 deg.C, stirred for 14 h, cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (silica gel column, n-hexane: EtOA) C 3:1) to give II (30.32g, 93%, d.r) as a colorless oil.>99:1)。MS(ESI)m/z:425.32(M+H) + ； 1 H-NMR(400MHz,CDC1 3 ):δ＝5.83-5.80(m,2H),5.27-5.25(m,2H),5.17-5.14(m,2H),4.64-4.55(m,1H),4.42-4.32(m,1H),4.14-3.93(m,2H),3.69(s,3H),3.66(s,3H),2.63-2.34(m,4H),2.11-1.65(m,12H)。
The effect of the choice of catalyst, ligand and adjuvant on the reaction was investigated according to the procedure of example 1 and the results are shown in table 1:
TABLE 1 Effect of different reaction conditions on yield and optical purity
Example 2
8.5g of the compound of the formula II are dissolved in 40ml of ethanol, 0.85g of heteropolyacid H are added 3 PW 12 O 40 Dropwise adding 30% H 2 O 2 30ml of aqueous solution, controlling the reaction temperature at 35 ℃, after 6 hours of reaction, evaporating the solvent, adding water, extracting by ethyl acetate, and obtaining an organic phase Na 2 SO 4 Drying and evaporation of the solvent under reduced pressure gave 8.42g of the compound of formula III in 98% yield. 1 H-NMR(400MHz,CDC1 3 ):δ＝9.8(d,1H),9.6(d,1H),4.56-4.52(m,1H),4.37-4.30(m,1H),4.18-3.92(m,2H),3.68(s,3H),3.66(s,3H),2.61-2.35(m,4H),2.07-1.63(m,12H)。
The influence of the selection of the oxidation system and the catalyst on the reaction was investigated according to the procedure of example 2, and the results are shown in Table 2:
TABLE 2
| Oxidation system | Catalyst and process for preparing same | Reaction temperature and time | Yield of |
| 30％H 2 O 2 + tert-butanol | H 4 PMo 11 VO 40 | 30℃、6h | 86％ |
| 60％H 2 O 2 + ethanol | H 3 PMo 12 O 40 | 25℃、5h | 95％ |
| 30％H 2 O 2 + isopropyl alcohol | H 4 PW 11 VO 40 | 35℃、7h | 92％ |
Example 3
13.56g (0.02mol) of the compound of the formula IV and 4.28g (0.01mol) of the compound of the formula III are dissolved in 40ml of DMSO and dissolved with stirring; heating to 85 ℃; adding 5.52g (0.04mol) of potassium carbonate, stirring, keeping the temperature at 85 ℃ for reaction for 15h, adding 120ml of water after the reaction is finished, separating out a white solid, washing with saturated saline, washing with 5% ethanol, and drying to obtain 9.81g of a white solid compound V, wherein the yield is 92%, and d.r.>99:1。MS(ESI)m/z:1068.12(M+H) + ； 1 H-NMR(400MHz,CDC1 3 ):δ＝7.70(m,4H),7.15(m,4H),6.54(m,2H),5.8(m,2H),4.64-4.55(m,1H),4.42-4.32(m,1H),4.14-3.93(m,2H),3.69(s,3H),3.66(s,3H),3.12-3.10(m,2H),2.84-2.78(s,6H),2.61-2.35(m,10H),2.10-1.64(m,12H),1.30-1.26(m,12H)。
Example 4
Dissolving 9g (8.43mmol) of the compound of formula V in 100ml ethanol, adding 0.1M aqueous sodium hydroxide solution 150ml, stirring at 80 deg.C for 12h, cooling to 0 deg.C, adjusting pH to 4 with hydrochloric acid, adding Dichloromethane (DCM)500ml, separating DCM layer, extracting aqueous layer with DCM for 3 times, 150ml each time, combining organic phase, washing with saturated common salt water, Na 2 SO 4 Drying and evaporation of the solvent under reduced pressure gave 8.33g of compound VI, HPLC: 99 percent; MS (ESI) M/z 1062.35(M + Na) + ； 1 H-NMR(400MHz,CDC1 3 ):δ＝7.71(m,4H),7.17(m,4H),6.53(m,2H),5.7(m,2H),4.65-4.56(m,1H),4.44-4.33(m,1H),4.15-3.92(m,2H),3.13-3.10(m,2H),2.86-2.79(s,6H),2.62-2.34(m,10H),2.12-1.65(m,12H),1.32-1.27(m,12H)。
Example 5
Dissolving 5g of the compound of formula VI in 40ml of toluene, adjusting the pH to 3 with 37% concentrated aqueous hydrochloric acid (hydrochloric acid may be added during the reaction to maintain the pH at 3), reacting at room temperature for 8h, adding 20ml of water and 50ml of DCM, cooling to 0 deg.C, stirring, adding NaHCO 3 Adjusting pH to 7 with aqueous solution, immediately separating organic phase, extracting aqueous phase with DCM 3 times (20 ml each time), combining organic phases, washing with saturated saline solution 3 times, and Na 2 SO 4 Drying and evaporation of the solvent under reduced pressure gave 3.88g of the compound of formula VII in 87% yield, HPLC: 99 percent. MS (ESI) M/z 464.19(M + H) + ； 1 H-NMR(400MHz,CDC1 3 ):δ＝7.63-7.58(m,2H),7.13-7.08(m,2H),6.73(dd,1H),5.48(dd,1H),5.25-5.21(m,1H),4.30(tt,1H),3.54(s,3H),3.52(s,3H),3.32(1H),2.72(dd,1H),2.65(m,1H),1.92(m,1H),1.85(s,1H),1.67(m,1H),1.28(d,3H),1.25(d,3H)。
Example 6
4g of a compound of the formula VII dissolved in 30ml of TAdding 20ml of 40% sodium hydroxide aqueous solution into HF (hydrogen fluoride) dropwise within 10min, stirring at room temperature for reacting for 3h after dropwise adding, adding 80ml of water and 20ml of n-hexane, demixing, extracting an organic phase with water for 3 times (10 ml each time), combining water phases, washing with methyl tert-butyl ether for 2 times, filtering to remove insoluble substances, cooling to 10 ℃, adding 10ml of 0.5g/ml calcium acetate solution dropwise, stirring for 30min after dropwise adding, precipitating a large amount of solid, filtering, washing a filter cake with water, and drying to obtain 3.82g of rosuvastatin calcium, E: Z>>99.9:0.1，HPLC:99.87％，MS(ESI)m/z:1001.32(M+H) + 。
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (13)
1. A method for synthesizing rosuvastatin calcium comprises the following steps:
1) reacting the compound shown in the formula I with 1, 4-cyclohexanedione in the presence of a palladium catalyst, a phosphine ligand and an auxiliary agent to obtain a compound shown in the formula II;
2) oxidizing the compound of the formula II in a hydrogen peroxide-heteropoly acid system to obtain a compound of a formula III;
3) reacting the compound shown in the formula III with the compound shown in the formula IV to generate a compound shown in the formula V;
4) hydrolyzing the compound of the formula V to obtain a compound of a formula VI;
5) reacting the compound in the formula VI under an acidic condition to obtain a compound in a formula VII;
6) hydrolyzing the compound shown in the formula VII to form salt to obtain rosuvastatin calcium;
the reaction route is as follows:
wherein R is 1 Selected from alkyl groups; r is 2 Is selected from P + (Ph) 3 X - Or PO (Ph) 2 ，X - Represents a halide ion;
step 1) the phosphine ligand is selected from (S) - (-) -SEGphos;
step 1) the auxiliary agent is selected from p-toluenesulfonic acid;
the heteropoly acid used in the step 2) is selected from phosphomolybdic heteropoly acid and phosphotungstic heteropoly acid.
2. A synthesis process according to claim 1, characterized in that: r is 1 Is C 1-6 An alkyl group.
3. A synthesis method according to claim 1, characterized in that: r 1 Is methyl, ethyl, propyl, isopropyl or tert-butyl.
4. A synthesis process according to claim 1, characterized in that: r is 1 Is methyl or ethyl.
5. The synthesis method according to any one of claims 1 to 4, characterized in that: r is 2 Is P + (Ph) 3 Br - 。
6. The synthesis method according to any one of claims 1 to 4, characterized in that: step 1) the palladium catalyst is selected from Pd (PPh) 3 ) 4 、Pd(PPh 3 ) 2 Cl 2 、Pd(OAc) 2 Or Pd (acac) 2 。
7. A synthesis method according to any one of claims 1 to 4, characterized in that: the reaction solvent of step 1) is selected from benzene, toluene or xylene.
8. The synthesis method according to any one of claims 1 to 4, characterized in that: the hydrogen peroxide used in the step 2) is 30-60% of hydrogen peroxide by mass fraction.
9. The synthesis method according to any one of claims 1 to 4, characterized in that: the heteropolyacid used in step 2) is selected from H 3 PW 12 O 40 、H 4 PMo 11 VO 40 、H 3 PMo 12 O 40 Or H 4 PW 11 VO 40 。
10. A synthesis method according to any one of claims 1 to 4, characterized in that: the reaction solvent in step 2) is alcohol.
11. The synthesis method according to any one of claims 1 to 4, characterized in that: the reaction solvent of the step 2) is methanol, ethanol, tert-butyl alcohol or isopropanol.
12. A synthesis method according to any one of claims 1 to 4, characterized in that: the reaction of the step 3) is carried out in the presence of a base and DMSO as a solvent.
13. The method of synthesis according to claim 12, characterized in that: the base is selected from K 2 CO 3 、Na 2 CO 3 、KHCO 3 、NaHCO 3 KOH or NaOH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910192741.7A CN109824605B (en) | 2019-03-14 | 2019-03-14 | Synthetic method of rosuvastatin calcium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910192741.7A CN109824605B (en) | 2019-03-14 | 2019-03-14 | Synthetic method of rosuvastatin calcium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109824605A CN109824605A (en) | 2019-05-31 |
| CN109824605B true CN109824605B (en) | 2022-07-26 |
Family
ID=66869033
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910192741.7A Active CN109824605B (en) | 2019-03-14 | 2019-03-14 | Synthetic method of rosuvastatin calcium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109824605B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315946A (en) * | 1999-06-29 | 2001-10-03 | 钟渊化学工业株式会社 | Process for selective lactonization |
| CN104447784A (en) * | 2014-12-02 | 2015-03-25 | 南京博优康远生物医药科技有限公司 | Statin medicine intermediate as well as preparation method and application thereof |
| CN107652170A (en) * | 2017-09-25 | 2018-02-02 | 青岛科技大学 | A kind of method that organic-inorganic heteropolyacid salt catalysis oxidation of cyclopentene prepares glutaraldehyde |
-
2019
- 2019-03-14 CN CN201910192741.7A patent/CN109824605B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1315946A (en) * | 1999-06-29 | 2001-10-03 | 钟渊化学工业株式会社 | Process for selective lactonization |
| CN104447784A (en) * | 2014-12-02 | 2015-03-25 | 南京博优康远生物医药科技有限公司 | Statin medicine intermediate as well as preparation method and application thereof |
| CN107652170A (en) * | 2017-09-25 | 2018-02-02 | 青岛科技大学 | A kind of method that organic-inorganic heteropolyacid salt catalysis oxidation of cyclopentene prepares glutaraldehyde |
Non-Patent Citations (2)
| Title |
|---|
| Palladium-Catalyzed Stereoselective Cyclization of in Situ Formed Allenyl Hemiacetals: Synthesis of Rosuvastatin and Pitavastatin;Pierre A. Spreider等;《Organic Letters》;20180517;第20卷(第11期);第3286页第5段倒数第1-3行和第3287页表1，第3287页第1段第4行，第3288页第1栏倒数第2段和scheme 6 * |
| 瑞舒伐他汀钙有关物质的合成;张雅然 等;《化学试剂》;20141215;第36卷(第12期);第1143-1146页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109824605A (en) | 2019-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2508514B1 (en) | Process for preparing amorphous rosuvastatin calcium free of impurities | |
| EP2049459B1 (en) | Novel process for the synthesis of (e)-stilbene derivatives which makes it possible to obtain resveratrol and piceatannol | |
| EP1863773A1 (en) | Process for preparation of rosuvastatin | |
| CN112661639A (en) | Synthesis method of 4-acetylbutyrate compound | |
| US8765947B2 (en) | Preparation method of Rosuvastatin calcium and its intermediates | |
| EA014530B1 (en) | Process for the preparation of pharmaceutical intermediate | |
| EP1756027B1 (en) | Process for producing indenol esters or ethers | |
| CN109824605B (en) | Synthetic method of rosuvastatin calcium | |
| KR20120016053A (en) | A method of preparing an alkylamine derivative | |
| CN109836386B (en) | Synthetic process of rosuvastatin calcium | |
| KR101063146B1 (en) | Method for preparing pitavastatin intermediate and method for preparing pitavastatin hemicalcium salt | |
| CN107428648B (en) | Process for the preparation of compounds such as 3-arylbutyraldehyde useful for the synthesis of medetomidine | |
| CN115108904A (en) | Synthesis method of betimeric acid bulk drug | |
| JP2641542B2 (en) | Method for producing asymmetric dihydropyridines | |
| CN109912515B (en) | Preparation method of rosuvastatin calcium | |
| EP0421472B1 (en) | Process for racemization of optically active 4-phenylbutanoic acid esters | |
| CN103193679B (en) | The preparation method of rivastigmine intermediate (R)-N-ethyl-N-methylamino formic acid-3-(1-hydroxyethyl) phenyl ester | |
| CN104447784A (en) | Statin medicine intermediate as well as preparation method and application thereof | |
| KR101710976B1 (en) | Method for preparing of chiral intermediate and method for the preparing of HMG-CoA reductase inhibitor using chiral intermadiate | |
| CN111423319B (en) | Preparation method of loxoprofen | |
| EP1319646B1 (en) | Process for preparation of 3,5-bisalkylphenols | |
| JP2003535855A (en) | Method for producing 2-coumarone and substituted 2-coumarones | |
| JP2007063165A (en) | Novel manufacturing method of aromatic compound | |
| CN114057790A (en) | Preparation method of vitamin A triphenylphosphine salt with high all-trans isomer content | |
| JP2680231B2 (en) | Process for producing optically active 24-hydroxycholesterols |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |