CN101624390B - Preparation method of key intermediate of rosuvastatin calcium side chain - Google Patents

Preparation method of key intermediate of rosuvastatin calcium side chain Download PDF

Info

Publication number
CN101624390B
CN101624390B CN200910127358.XA CN200910127358A CN101624390B CN 101624390 B CN101624390 B CN 101624390B CN 200910127358 A CN200910127358 A CN 200910127358A CN 101624390 B CN101624390 B CN 101624390B
Authority
CN
China
Prior art keywords
reaction
mixture
acetate
compound
temperature
Prior art date
Application number
CN200910127358.XA
Other languages
Chinese (zh)
Other versions
CN101624390A (en
Inventor
赵志全
邵杰
邓义
Original Assignee
鲁南制药集团股份有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 鲁南制药集团股份有限公司 filed Critical 鲁南制药集团股份有限公司
Priority to CN200910127358.XA priority Critical patent/CN101624390B/en
Publication of CN101624390A publication Critical patent/CN101624390A/en
Application granted granted Critical
Publication of CN101624390B publication Critical patent/CN101624390B/en

Links

Abstract

The invention provides a preparation method of a key intermediate of a rosuvastatin calcium side chain, comprising the following steps: using (S)-4-chlorine-3-hydroxybutanoate as an initial raw material; and preparing the key intermediate through four-step reactions of condensation, reduction, hydroxy group protection and condensation. The reaction process is simple to operate, the products in each step are easy to separate and purify, the purification and separation step is carried out without a silicagel column, and the yield is more than 80 percent, therefore, the intermediate with higher chemical purity and optical purity can be obtained. The GC determination shows that the chemical purity is more than or equal to 99.5 percent and the optical purity is more than or equal to 99.2 percent ee.

Description

A kind of preparation method of rosuvastatin calcium side chain key intermediate

Technical field

The present invention relates to a kind of preparation method of blood lipid-lowering medicine, relate in particular to a kind of preparation method of statins rosuvastatin calcium side chain key intermediate.

background technology

Rosuvastain calcium (rosuvastatin calcium) is the blood lipid-lowering medicine of clinical application; chemical name: two [(E)-7-[4-(4-fluorophenyl)-6-sec.-propyl-2-[methyl (methylsulfonyl) amino] pyrimidine-5-yl] (3R; 5S)-3; 5-dihydroxyl-6-heptenoic acid] calcium salt, chemical structural formula is as follows:

Be the statins of new generation of complete synthesis single enantiomer, belong to HMG-CoA reductase inhibitor, can reduce low density cholesterol, total cholesterol, triglyceride and the apoB concentration of rising, simultaneously the concentration of increasing high density cholesterol.Can be used for the complex therapy of primary hypercholesterolemia and mixed type lipodystrophy disease and the familial hypercholesterolemia that isozygotys, its ability to function is stronger than the statins of existing listing, and has liver cell selectivity, good market prospect.

The synthetic method of rosuvastain calcium is existing multiple both at home and abroad, its synthetic method mostly is synthetic parent nucleus and side chain respectively, after docking, obtain target product through a series of reaction again, its synthetic parent nucleus and side chain two portions of being divided into as disclosed in EP0521471, parent nucleus and side chain obtain rosuvastain calcium through Witting reaction, reduction, hydrolysis, salify.Synthetic route is as follows:

Route synthesizing rosuvastatin spit of fland calcium thus, in the reduction process of the intermediate obtaining through Witting, it is controlled that the content of chiral isomer is difficult to, and affects subsequent reactions, finally affects the optical purity of rosuvastain calcium.Therefore how obtaining high-optical-purity and stable side chain, is one of key issue in rosuvastain calcium building-up process.

US5278313, EP0319847, US5399722, US5481009, US5998633, US6140527, EP0104750, WO0307733 provide or relate to synthesizing of side chain intermediate, but mostly exist synthetic route long, nearly 7~9 steps, intermediate mostly is thick thing, need multistep high vacuum (0.1mmHg) distillation and silicagel column purifying, use violent in toxicity potassium cyanide or sodium cyanide, product purity is poor, unstable, be difficult to the problems such as industrialization production.

JP5-32680 and J.Org.Chem, 1994,59 (25) 7849-7854, side chain synthetic method, exist synthetic difficult route long, each step intermediate is mostly viscous liquid, separation and purification difficulty (must through multistep silicagel column purifying), product purity is poor, unstable, the problems such as when side chain and parent nucleus docking, yield is low, and product purity is poor.

In the preparation method of the disclosed rosuvastain calcium of WO2004052867, do not provide the synthetic method of side chain intermediate, when side chain and parent nucleus docking, yield is low, must be through multistep silicagel column purifying.

Summary of the invention

The object of the present invention is to provide a kind of rosuvastatin calcium side chain key intermediate (4R, 6S)-6-[acetyl-o-methyl]-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate] new synthetic method, structural formula is as follows:

The problems referred to above that exist for prior art, the invention provides the preparation technology that a kind of chemical formula is the compound of I, can obtain the intermediate of higher chemical purity and optical purity with this technique, this intermediate through reaction after in order to prepare the side chain of rosuvastain calcium, reaction process of the present invention is easy and simple to handle, each step product is easy to separation and purification, carries out purifies and separates without silicagel column, and reaction yield improves a lot.

Rosuvastatin calcium side chain key intermediate of the present invention is achieved through the following technical solutions:

(1) under alkaline condition, prepare (S)-6-chloro-5-hydroxyl-3-oxo hecanoic acid t-butyl ester (compound III) with tert.-butyl acetate generation condensation reaction by (S)-4-chloro-3-hydroxyl ethyl butyrate (Compound I I)

The solvent adopting in step (1) is ethers, halohydrocarbon or aromatic solvents or its mixture, be specially one or more the mixture in ether, ethylene-propylene ether, tetrahydrofuran (THF), chloroform, glycol dimethyl ether, benzene, toluene and dimethylbenzene, preferably the mixture of one or more in tetrahydrofuran (THF), glycol dimethyl ether and toluene.

The alkali that this reaction adopts is di-isopropyl nitrogen lithium; Can be made by Diisopropylamine and n-Butyl Lithium (n-BuLi), isobutyl-lithium (s-BuLi), tert-butyl lithium (t-BuLi) or two (TMS) Lithamide (LiHMDS).

Temperature of reaction is difference to some extent with the difference of reaction reagent, and general temperature of reaction is to carry out at the temperature of-80 ℃~-30 ℃, and preferable reaction temperature is-80 ℃~-60 ℃; Reaction times, the reaction times was generally: 1.5~4 hours, the preferred reaction time was: 2.5~3 hours with the difference of reaction reagent and temperature of reaction and different.

The feed ratio of reaction is: (S)-4-chloro-3-hydroxyl ethyl butyrate: alkali: tert.-butyl acetate=1mol: 2~5mol: 2~5mol, is preferably (S)-4-chloro-3-hydroxyl ethyl butyrate: alkali: tert.-butyl acetate=1mol: 3.8~4.2mol: 3.8~4.2mol.

After having reacted, mixture is with hydrochloric acid adjust pH to 1~4, then is extracted with ethyl acetate, and after organic phase washing, dry, concentrating under reduced pressure, obtains compound III.

(2) compound III generation reduction reaction preparation (R, S)-6-is chloro-3,5-dihydroxyl hecanoic acid t-butyl ester (compound IV)

The solvent adopting in step (2) reaction is ethers or alcohols or its mixture, the preferably mixture of one or more in tetrahydrofuran (THF), ether, methyl alcohol, ethanol, n-propyl alcohol, Virahol and ethylene glycol, the more preferably mixture of one or more in tetrahydrofuran (THF), methyl alcohol and ether.

Reductive agent is metal hydride, the boride with reductibility, the preferably mixture of one or more in sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, diethyl methoxyl group borine, triethyl-boron and tri butyl boron, the more preferably mixture of one or more in diethyl methoxyl group borine, sodium borohydride and triethyl-boron.

Temperature of reaction is difference to some extent with the difference of reaction reagent, and general temperature of reaction is to carry out at the temperature of-80 ℃~-30 ℃, and preferable reaction temperature is-80 ℃~-60 ℃; Reaction times, the reaction times was generally: 3~8 hours with the difference of reaction reagent and temperature of reaction and different.

The feed ratio of reaction is: compound III: borine: metal hydride=1mol: (1-2mol): (1-2mol).

The post-treating method of step (2), adds after acetone and hydrogen peroxide reaction, then mixture is poured into water, ethyl acetate extraction, and concentrating under reduced pressure solvent obtains crude product, and crude product obtains compound IV with normal hexane recrystallization.

(3), under catalyst action, compound IV is carried out to hydroxyl protection preparation (4R, 6S)-6-chloromethyl-2,2-dimethyl-1,3-dioxane-4-tert.-butyl acetate (compound V) with acetone

It is acetone that step (3) is reacted the reagent adopting, and in this reaction, acetone is that solvent participates in again reaction and carries out hydroxyl protection; Specific catalyzer is one or both mixture in p-methyl benzenesulfonic acid and Phenylsulfonic acid.

This reaction is carried out at the temperature of-10 ℃~50 ℃, and preferable reaction temperature is 30 ℃~50 ℃; Reaction times, the reaction times was generally: 3.5~5 hours with the difference of reaction reagent and temperature of reaction and different.The feed ratio of reaction is: compound IV: p-methyl benzenesulfonic acid: acetone=1mol: (0.01~0.03mol): (1000~1500) mL.

After having reacted, mixture is poured into water, ethyl acetate extraction, and organic phase obtains oily matter compound V after washing, be dried, concentrate.

(4) Compound I is prepared in compound V and acetate generation condensation reaction

The solvent that step (4) reaction adopts is the mixture of single non-protonic solvent or two kinds of solvents, preferably tetrahydrofuran (THF), acetonitrile, glycol dimethyl ether and N, one or more mixture, more preferably DMF in dinethylformamide.

The acetate that this reaction adopts is one or more mixture in Potassium ethanoate, sodium-acetate and Ammonium Acetate, preferably potassium acetate; Temperature of reaction is difference to some extent with the difference of reaction reagent, and this reaction is carried out at 50 ℃~120 ℃, and preferably temperature is 80 ℃~110 ℃; Reaction times, the reaction times was generally: 8~13 hours with the difference of reaction reagent and temperature of reaction and different.

The feed ratio of reaction is: compound V: acetate=1mol: (1.1~1.3) mol.

Post-reaction treatment process is: reaction mixture poured in frozen water, and ethyl acetate extraction, anhydrous sodium sulfate drying, decompression obtains faint yellow solid after evaporating solvent, and gained solid obtains white solid I with normal hexane recrystallization.

Technique effect of the present invention is: prepare rosuvastain calcium key intermediate I take II as raw material, raw material cheapness, be easy to get; Reaction process of the present invention is easy and simple to handle, and the part intermediate oily matter of gained is directly used in next step production without refining, and IV and product I are solid, the separation and purification of available ordinary method recrystallization; Product yield is high, obtains the intermediate of higher chemical purity and optical purity (measure through GC, chemical purity is 99.7%, optical purity is 99.2%ee), can be easily for the suitability for industrialized production of rosuvastain calcium.

Embodiment

Now further describe beneficial effect of the present invention by following examples, be interpreted as these embodiment only for the object of illustration, do not limit the scope of the invention, within the apparent change that those of ordinary skills make according to the present invention simultaneously and modification are also contained in the scope of the invention.

The preparation of the chloro-5-hydroxyl-3-of embodiment 1 (S)-6-oxo hecanoic acid t-butyl ester III:

N 2under protection; 225mL (1.61mol; 4.0eq) Diisopropylamine is dissolved in the tetrahydrofuran (THF) that 1400mL was dried; be cooled to-78 ℃, slowly drip the tetrahydrofuran solution 64mL (4.0eq, 2.5mol/L) of n-Butyl Lithium; at this temperature, react after 30min; slowly drip 217.5mL (1.61mol, 4.0eq) tert.-butyl acetate, then react 1h at-78 ℃ of temperature.Slowly add 66.76g (402.2mmol to reaction system, 1eq) the 300mL tetrahydrofuran solution of II, temperature is controlled at-78 ℃, at this temperature, react after 1h, mixture is poured into the hydrochloric acid of 500mL10%, ethyl acetate (150mL × 3) extraction, merge organic phase, organic phase washing (100mL × 2), anhydrous sodium sulfate drying, obtains oily matter 93.8g after pressure reducing and steaming solvent.

The preparation of the chloro-5-hydroxyl-3-of embodiment 2 (S)-6-oxo hecanoic acid t-butyl ester III:

N 2under protection; 168.8mL (1.21mol; 3.0eq) Diisopropylamine is dissolved in the tetrahydrofuran (THF) that 1200mL was dried; be cooled to-65 ℃, slowly drip the tetrahydrofuran solution 483mL (3.0eq, 2.5mol/L) of two (TMS) Lithamides; at this temperature, react after 30min; slowly drip 163.1mL (1.21mol, 3.0eq) tert.-butyl acetate, then react 1h at-55 ℃ of temperature.Slowly add 66.76g (402.2mmol to reaction system, 1eq) the 300mL tetrahydrofuran solution of II, temperature is controlled at-78 ℃, at this temperature, react after 1h, mixture is poured into the hydrochloric acid of 500mL10%, ethyl acetate (150mL × 3) extraction, merge organic phase, organic phase washing (100mL × 2), anhydrous sodium sulfate drying, obtains oily matter 83.5g after pressure reducing and steaming solvent.

Embodiment 3 (R, S)-6-is chloro-3, the preparation of 5-dihydroxyl hecanoic acid t-butyl ester IV:

Compound III 93.8g is dissolved in to tetrahydrofuran (THF) and the 400mL methyl alcohol that 1.5L is dry, under nitrogen protection, be cooled to-80 ℃, add 427mL diethyl methoxyl group borine (tetrahydrofuran solution of 1mol/L), after stirring reaction 20min, add sodium borohydride 16.5g, at this temperature, react after 3h, add 200mL acetone and 80mL30% hydrogen peroxide, after reacting 30min at-60 ℃, reaction system is poured in 800mL water, ethyl acetate extraction (400mL × 3), merge organic phase, organic phase washing (100mL × 3), anhydrous sodium sulfate drying, decompression obtains solid IV after evaporating solvent, normal hexane recrystallization obtains faint yellow solid 77.6g, yield 82.7%.

Embodiment 4 (R, S)-6-is chloro-3, the preparation of 5-dihydroxyl hecanoic acid t-butyl ester IV:

Compound III 93.8g is dissolved in to tetrahydrofuran (THF) and the 600mL methyl alcohol that 1.25L is dry, under nitrogen protection, be cooled to-78 ℃, add 595mL triethyl-boron (tetrahydrofuran solution of 1mol/L), after stirring reaction 20min, add sodium borohydride 22.6g, at this temperature, react after 3h, add 230mL acetone and 90mL30% hydrogen peroxide, after reacting 30min at-30 ℃, reaction system is poured in 800mL water, ethyl acetate extraction (400mL × 3), merge organic phase, organic phase washing (100mL × 3), anhydrous sodium sulfate drying, decompression obtains solid IV after evaporating solvent, normal hexane recrystallization obtains faint yellow solid 82.6g, yield 88%.

Embodiment 5 (4R, 6S)-6-chloromethyl-2,2-dimethyl-1, the preparation of 3-dioxane-4-tert.-butyl acetate V:

Compound IV 80.6g is dissolved in to 400mL acetone, add tosic acid 1.2g, after 20 ℃ of reaction 4h, mixture is poured in water (800mL), ethyl acetate extraction (300mL × 3), merge organic phase, washing (200mL × 3), anhydrous sodium sulfate drying, decompression obtains 78.6g oily matter V after evaporating solvent.

Embodiment 6 (4R, 6S)-6-chloromethyl-2,2-dimethyl-1, the preparation of 3-dioxane-4-tert.-butyl acetate V:

Gained compound IV 80.6g is dissolved in to 300mL acetone, add Phenylsulfonic acid 0.6g, after 50 ℃ of reaction 4h, mixture is poured in water (800mL), ethyl acetate extraction (300mL × 3), merge organic phase, washing (200mL × 3), anhydrous sodium sulfate drying, decompression obtains 73.0g oily matter V after evaporating solvent.

Embodiment 7 (4R, 6S)-6-[acetyl-o-methyl]-2,2-dimethyl-1, the preparation of 3-dioxane-4-tert.-butyl acetate I:

Gained compound V 78.6g is dissolved in to 200mL DMF, add potassium acetate 31.25g, in 100 ℃ of reaction 10h, mixture is poured in 400mL frozen water, ethyl acetate extraction (150mL × 3), anhydrous sodium sulfate drying, decompression obtains 72.4g faint yellow solid after evaporating solvent, and gained solid obtains 65.2g white solid with normal hexane recrystallization, yield 82.9%, measure through GC: chemical purity is 99.7%, optical purity is 99.2%ee.m.p.64~65.5℃。

Embodiment 8 (4R, 6S)-6-[acetyl-o-methyl]-2,2-dimethyl-1, the preparation of 3-dioxane-4-tert.-butyl acetate I:

Gained compound V 78.6g is dissolved in to 200mL tetrahydrofuran (THF), add potassium acetate 28.87g, in 66 ℃ of reaction 13h, mixture is poured in 400mL frozen water, ethyl acetate extraction (150mL × 3), anhydrous sodium sulfate drying, decompression obtains 71.4g faint yellow solid after evaporating solvent, and gained solid obtains 64.4g white solid with normal hexane recrystallization, yield 82%, measure through GC: chemical purity is 99.7%, optical purity is 99.2%ee.m.p.64.5~65℃。

Claims (5)

1. a rosuvastatin calcium side chain (4R, 6S)-6-[acetyl-o-methyl]-2,2-dimethyl-1, the preparation method of 3-dioxane-4-tert.-butyl acetate, comprises the following steps:
(1) by (S)-4-chloro-3-hydroxyl ethyl butyrate Compound I I di-isopropyl nitrogen lithium exist under with tert.-butyl acetate generation condensation reaction, after having reacted, mixture is adjusted PH to 1-4 with hydrochloric acid, be extracted with ethyl acetate again, organic phase washing, dry, the chloro-5-hydroxyl-3-of concentrating under reduced pressure preparation (S)-6-oxo hecanoic acid t-butyl ester compound III, solvent for use is tetrahydrofuran (THF), the mixture of one or more in glycol dimethyl ether and toluene, the feed ratio of material used is: Compound I I: di-isopropyl nitrogen lithium: tert.-butyl acetate=1mol:3.8~4.2mol:3.8~4.2mol, temperature of reaction is :-80 ℃~-60 ℃, the reaction times is: 2.5~3 hours
(2) after compound III generation reduction reaction, add after acetone and hydrogen peroxide reaction, again mixture is poured into water, ethyl acetate extraction, concentrating under reduced pressure solvent obtains crude product, crude product obtains (R with normal hexane recrystallization, S)-6-chloro-3, 5-dihydroxyl hecanoic acid t-butyl ester compound IV, wherein reductive agent is sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, diethyl methoxyl group borine, the mixture of one or more in triethyl-boron and tri butyl boron, reaction solvent is tetrahydrofuran (THF), the mixture of one or more in methyl alcohol and ether, temperature of reaction is-80 ℃~-60 ℃, reaction times is: 3~8 hours
(3) under the effect of catalyzer p-methyl benzenesulfonic acid; compound IV is carried out to hydroxyl protection preparation (4R with acetone; 6S)-6-chloromethyl-2; 2-dimethyl-1; 3-dioxane-4-tert.-butyl acetate compound V; the feed ratio of reaction mass is: intermediate compound IV: p-methyl benzenesulfonic acid: acetone=1mol:0.01-0.03mol:1000-1500mL, and temperature of reaction is 30 ℃~50 ℃, the reaction times is: 3.5~5 hours
(4) compound V and acetate generation condensation reaction, reaction mixture is poured in frozen water, ethyl acetate extraction, anhydrous sodium sulfate drying, decompression obtains faint yellow solid after evaporating solvent, gained solid obtains white solid I with normal hexane recrystallization, wherein the acetate of reaction is one or more mixture in Potassium ethanoate, sodium-acetate and Ammonium Acetate, the feed ratio of reaction is: intermediate V: acetate=1mol:1.1-1.3mol, temperature of reaction is 50 ℃~120 ℃, and the reaction times is: 8~13 hours
2. method according to claim 1, is characterized in that reductive agent in step (2) is one or more the mixture in diethyl methoxyl group borine, sodium borohydride and triethyl-boron.
3. method according to claim 1, is characterized in that reaction solvent in step (4) is one or more mixture in tetrahydrofuran (THF), acetonitrile, glycol dimethyl ether and DMF.
4. method according to claim 1, is characterized in that in step (4), reaction solvent is DMF.
5. method according to claim 1, is characterized in that the acetate of reaction in step (4) is Potassium ethanoate.
CN200910127358.XA 2009-03-09 2009-03-09 Preparation method of key intermediate of rosuvastatin calcium side chain CN101624390B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN200910127358.XA CN101624390B (en) 2009-03-09 2009-03-09 Preparation method of key intermediate of rosuvastatin calcium side chain

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN200910127358.XA CN101624390B (en) 2009-03-09 2009-03-09 Preparation method of key intermediate of rosuvastatin calcium side chain

Publications (2)

Publication Number Publication Date
CN101624390A CN101624390A (en) 2010-01-13
CN101624390B true CN101624390B (en) 2014-06-11

Family

ID=41520402

Family Applications (1)

Application Number Title Priority Date Filing Date
CN200910127358.XA CN101624390B (en) 2009-03-09 2009-03-09 Preparation method of key intermediate of rosuvastatin calcium side chain

Country Status (1)

Country Link
CN (1) CN101624390B (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102212082B (en) * 2010-04-05 2015-03-04 重庆博腾制药科技股份有限公司 Rosuvastatin calcium intermediate and preparation method thereof
CN102181493B (en) * 2011-01-12 2015-06-10 江苏阿尔法药业有限公司 Preparation method of intermediate of rosuvastatin calcium side chain
WO2013010488A1 (en) 2011-07-19 2013-01-24 Sunshine Lake Pharma Co., Ltd. An intermediate of statin drugs and preparation thereof
CN102766071A (en) * 2012-08-07 2012-11-07 浙江宏元药业有限公司 Chiral reduction method of statin intermediates
CN104016961B (en) * 2014-05-16 2016-05-25 南通常佑药业科技有限公司 A kind of preparation method of rosuvastain calcium intermediate
CN105622566B (en) * 2014-11-19 2018-07-27 上海弈柯莱生物医药科技有限公司 A kind of preparation method of bis- substituted hydroxy -6- substitution caproates of 3,5-

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457227A (en) * 1992-03-27 1995-10-10 E. R. Squibb & Sons, Inc. Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-CoA reductase inhibitors
CN1274356A (en) * 1998-08-05 2000-11-22 钟渊化学工业株式会社 Process for prepn. of optically active 2-(16-(hydroxymethyl)-1,3-dioxan-4-yl) acetic acid derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5457227A (en) * 1992-03-27 1995-10-10 E. R. Squibb & Sons, Inc. Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-CoA reductase inhibitors
US5594153A (en) * 1992-03-27 1997-01-14 E. R. Squibb & Sons, Inc. Process for the preparation of 1,3-dioxane derivatives useful in the preparation of HMG-COA reductase inhibitors
CN1274356A (en) * 1998-08-05 2000-11-22 钟渊化学工业株式会社 Process for prepn. of optically active 2-(16-(hydroxymethyl)-1,3-dioxan-4-yl) acetic acid derivatives

Also Published As

Publication number Publication date
CN101624390A (en) 2010-01-13

Similar Documents

Publication Publication Date Title
Bellina et al. Regioselective synthesis of natural and unnatural (Z)-3-(1-alkylidene) phthalides and 3-substituted isocoumarins starting from methyl 2-hydroxybenzoates
CN102633799B (en) Method for synthesizing sapropterin dihydrochloride from racemate intermediate separation route
CN101883763B (en) For the synthesis of intermediate and the method for halichondrin b analogs
CN1642897A (en) Methods of manufacturing derivatives of beta-hydroxycarboxylic acids
HU207841B (en) Process for producing biphenyl-carbonitrils
Overman et al. Chair topology of the palladium dichloride catalyzed Cope rearrangement of acyclic 1, 5-dienes
Whitesell et al. Auxiliary structure and asymmetric induction in the ene reactions of chiral glyoxylates
Grover et al. Chiral mandelic acid template provides a highly practical solution for (S)-oxybutynin synthesis
US20050014966A1 (en) Process for producing 5-(3-cyanophenyl)-3-formylbenzoic acid compound
WO2006076845A1 (en) Process for producing rosuvastatin calcium, intermediate for the preparation of the same and process for producing the intermediate
Calter et al. Catalytic, asymmetric synthesis of siphonarienal
de Sairre et al. Niobium (V) oxide: a new and efficient catalyst for the transesterification of β-keto esters
CN102952157B (en) For the synthesis of intermediate and its preparation of benzindene prostaglandin(PG)
Chan et al. Lewis acid-catalyzed one-pot crossed Prins cyclizations using allylchlorosilane as allylating agent
Zhang et al. Photochemically catalyzed Diels–Alder reaction of arylimines with N-vinylpyrrolidinone and N-vinylcarbazole by 2, 4, 6-triphenylpyrylium salt: synthesis of 4-heterocycle-substituted tetrahydroquinoline derivatives
Yadav et al. Selectfluor™: a novel and efficient reagent for the synthesis of β-hydroxy thiocyanates
RU2126412C1 (en) Optically active beta-aminoalkixyborane complex, method of its preparation, optically active beta-amino-alcohol derivative for preparation of aminoalkoxyborane complex, and methods of complex- mediated preparation of optically active alcohols
Wardrop et al. π-Face selective azaspirocyclization of ω-(methoxyphenyl)-N-methoxyalkylamides
Wang et al. Enantiopure N-ferrocenylmethylaziridin-2-ylmethanols from l-serine: synthesis, crystal structure and applications
Kojima et al. Characterization of Enantiomeric Pairs of Optically Active 10-P-5 Phosphoranes with Asymmetry Only at Phosphorus
Tiecco et al. Asymmetric selenomethoxylation of alkenes with camphorselenenyl sulfate
MX2010008627A (en) Process for preparing alkyl 2-alkoxymethylene-4,4-difluoro-3-oxob utyrates.
Lautens et al. The effect of remote oxygens on the ring-opening reactions of oxabicyclic compounds with organolithium reagents. Synthesis of the C21–C27 segment of rifamycin S
JP5628427B2 (en) Method for preparing rosuvastatin calcium intermediate
WO2014036823A1 (en) Novel preparation method of antithrombosis medicine

Legal Events

Date Code Title Description
PB01 Publication
C06 Publication
SE01 Entry into force of request for substantive examination
C10 Entry into substantive examination
C53 Correction of patent for invention or patent application
CB03 Change of inventor or designer information

Inventor after: Zhao Zhiquan

Inventor after: Shao Jie

Inventor after: Deng Yi

Inventor before: Zhao Zhiquan

Inventor before: Deng Yi

COR Change of bibliographic data

Free format text: CORRECT: INVENTOR; FROM: ZHAO ZHIQUAN DENG YI TO: ZHAO ZHIQUAN SHAO JIE DENG YI

C14 Grant of patent or utility model
GR01 Patent grant
COR Change of bibliographic data
CB03 Change of inventor or designer information

Inventor after: Zhang Guimin

Inventor after: Zhang Zicheng

Inventor after: Zhao Zhiquan

Inventor after: Shao Jie

Inventor after: Deng Yi

Inventor before: Zhao Zhiquan

Inventor before: Shao Jie

Inventor before: Deng Yi