CN116497082B - Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method - Google Patents

Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method Download PDF

Info

Publication number
CN116497082B
CN116497082B CN202310759919.8A CN202310759919A CN116497082B CN 116497082 B CN116497082 B CN 116497082B CN 202310759919 A CN202310759919 A CN 202310759919A CN 116497082 B CN116497082 B CN 116497082B
Authority
CN
China
Prior art keywords
alpha
reaction
iii
reaction time
weinreb
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
Application number
CN202310759919.8A
Other languages
Chinese (zh)
Other versions
CN116497082A (en
Inventor
张雷
操建春
孔鹏
李杉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
South China University of Technology SCUT
Original Assignee
South China University of Technology SCUT
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 South China University of Technology SCUT filed Critical South China University of Technology SCUT
Priority to CN202310759919.8A priority Critical patent/CN116497082B/en
Publication of CN116497082A publication Critical patent/CN116497082A/en
Application granted granted Critical
Publication of CN116497082B publication Critical patent/CN116497082B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P33/00—Preparation of steroids
    • C12P33/06—Hydroxylating
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a chemical-enzymatic synthesis method of 3 alpha, 7 alpha, 24R-a method of trihydroxy cholesterol. 3 alpha, 7 alpha, 24RThe invention adopts cheap and easily available 5 alpha-chenodeoxycholic acid as raw material, and under the action of alkali and condensing agent, the raw material and N, O-dimethylol hydroxylamine hydrochloride undergo Weinreb reaction to obtain Weinreb amide (III), the Weinreb amide (III) is reacted with organic metal nucleophilic reagent to obtain 24-carbonyl compound (II), the 24-carbonyl compound (II) undergoes chiral asymmetric carbonyl reduction reaction under the catalysis of ketoreductase, and the 24-carbonyl group is reduced to obtain 3 alpha, 7 alpha, 24R-trihydroxycholesterol (I). The synthesis method has the advantages of high efficiency, mild reaction condition, simple process, less byproducts and low cost, and is suitable for industrial mass production.

Description

Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method
Technical Field
The invention belongs to the technical field of medicine synthesis, and in particular relates to a method for efficiently synthesizing 3 alpha, 7 alpha, 24 by a chemical-enzymatic methodR-a method of trihydroxy cholesterol.
Background
Squalamine (squaramine) is a polyamine sterol conjugate in which cholesterol metabolites bind to spermidine, and has the structure shown in formula (1) below:
(1)
Squalamine has various biological activities, and has broad-spectrum antibacterial and antiviral effects, and also has certain activity on Parkinson disease, malaria, obesity and asthma, and can inhibit abnormal angiogenesis in senile macular degeneration, diabetic retinopathy and cancer production. However, the natural sources of squalamine are very limited, so chemical or biological synthesis of squalamine is an important source route of squalamine.
In the squalamine molecule, the configuration of 24-bit hydrogen sulfate has a great influence on activity, 24RThe hydrogen sulfate has strong antibacterial, antiviral and antitumor activities, so that a reasonable route for synthesizing the squalamine is designed firstlySynthesis of squalamine key intermediate and construction of 24 on steroid nucleus side chainR-OH. Existing construction side chain 24RThe method for synthesizing the key intermediates of the squalamine by using the OH mainly has the problems of expensive reagent, complex reaction conditions, unfriendly environment and the like: zhou Xiangdong A novel method for stereospecifically constructing squalamine side chain by 9 steps of reactions with methyl hyodeoxycholate as raw material to obtain total yield of 48% (Zhou Xiangdong, zhou Weishan. New method for stereospecifically constructing squalamine and neurosteroid side chain [ J)]) However, the Sharpless asymmetric dihydroxylation reaction introduced by the method requires an osmium-containing noble metal compound, and is not friendly to the environment; jiang Ning construction of 24 Using Grignard reagent Using 3 beta-acetoxy-7 alpha-methoxymethylene5 alpha-cholanic acid methyl ester as raw MaterialRSynthesis of important intermediates for squalamine-OH (Jiang Ning, chen Shuyan, song Qi, zhang Lili, shi Haijian) [ J ]]) The method has the advantages that part of operation conditions are complex and harsh, the raw materials can be obtained after multi-step synthesis, and the raw materials are not easy to obtain. Squai Zhou takes 3 beta-hydroxy-5-cholanic acid methyl ester as raw material, and is reacted in 7 steps to synthesize squalamine intermediate 3-oxo-7 alpha, 24R-dihydroxycholestanes of formula (2):
(2)
However, the synthesis method has a plurality of steps, the raw materials are expensive, and the obtained product is an isomer mixture, whereinRThe d.e. value of the configurational product is lower than 37%, and the subsequent isomer separation is still needed to obtain the product required for synthesizing the squalamineRConfigurational product (Shuai Zhou Study on synthesis of key squalamine intermediate alpha, 24R-dihydroxy-5 alpha-cholestan-3-one [ J ]].). The intermediate 3-oxo-7alpha, 24 of the formula (2) is also synthesized by using 3-oxo-5alpha-chenodeoxycholic acid methyl ester as raw material by Xiang-Dong ZhouR-a dihydroxycholestane compound,Rthe d.e. value of the configuration product can reach 99%, but the synthesis route is long, partial reaction conditions are complex, and the raw material itself can be obtained only by esterification and 3-site selective oxidation of 5 alpha-chenodeoxycholic acid (Xiang-Dong Zhou A new highly stereoselective construction of the sidechain ofsqualamine through impr)oved Sharpless catalyticasymmetricdihydroxylation[J].）。
Sterol core structure of 5 alpha-chenodeoxycholic acid and 3 alpha, 7 alpha, 24RThe sterol cores of the-trihydroxy cholesterol are identical in structure, 3 alpha, 7 alpha, 24RThe 3-oxo-7α,24 of formula (2) is obtained after specific oxidation of the trihydroxycholesterol by a 3α -HSD enzymeRDihydroxycholestanes. 5 alpha-chenodeoxycholic acid is mainly present in lower vertebrates including fish, birds. Up to now, no related studies have shown that 5α -chenodeoxycholic acid has a better biological activity, and as such, 5α -chenodeoxycholic acid is generally regarded as a by-product and is discarded during extraction of various other cholic acids from animal bile. Therefore, provides a method for efficiently synthesizing 3 alpha, 7 alpha, 24 by taking cheap and easily available 5 alpha-chenodeoxycholic acid as raw materialRThe method of the trihydroxy cholesterol has important significance for the large-scale production of the diagonal shark amine and the improvement of the value of the 5 alpha-chenodeoxycholic acid.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a method for synthesizing 3 alpha, 7 alpha, 24 with mild reaction conditions, simple process, few byproducts and low costR-a method of trihydroxy cholesterol.
The 3 alpha, 7 alpha, 24RThe structure of the trihydroxy cholesterol is shown as a formula (I):
（I）
the invention provides a method for efficiently synthesizing 3 alpha, 7 alpha, 24 by a chemical-enzymatic methodR-a method of trihydroxy cholesterol, comprising in particular the steps of:
,
,
(1) Condensation reaction is carried out on 5 alpha-chenodeoxycholic acid and N, O-dimethylol hydrochloride under the action of alkali and a condensing agent, so as to obtain Weinreb amide (III);
(2) Weinreb amide (III) is subjected to the action of an organometallic nucleophile to obtain Weinreb ketone (II);
(3) Under the NADPH regeneration reduction system, the ketoreductase catalyzes Weinreb ketone (II) to generate chiral asymmetric carbonyl reduction reaction to obtain 3 alpha, 7 alpha, 24R-trihydroxycholesterol (I).
Preferably, the base in step (1) is one or more of triethylamine, N-diisopropylethylamine, 1, 8-diazabicyclo undec-7-ene; the condensing agent is one or more of O-benzotriazole-N, N, N ', N ' -tetramethyl urea tetrafluoroboric acid, N, N ' -dicyclohexylcarbodiimide-1-hydroxybenzotriazole system and benzotriazole-N, N, N ', N ' -tetramethyl urea hexafluorophosphate.
Preferably, in the step (1), the molar ratio of the 5 alpha-chenodeoxycholic acid to the N, O-dimethylol hydrochloride is 1 (1-3); the step (1) is carried out in methylene dichloride serving as an organic solvent, and the reaction time is 8-24 hours.
Preferably, the molar ratio of 5 alpha-chenodeoxycholic acid to N, O-dimethylol hydrochloride in the step (1) is 1:1.5; the reaction time of the step (1) is 12h.
Preferably, in the step (2), the molar ratio of Weinreb amide (III) to the organic metal nucleophile is 1 (3-20).
Preferably, the molar ratio of Weinreb amide (III) to organometallic nucleophile in step (2) is 1:5.
Preferably, the organometallic nucleophile in step (2) is one or more of isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl lithium.
Preferably, the step (2) is performed in an organic solvent, wherein the organic solvent is one or more of tetrahydrofuran, diethyl ether, 1, 4-dioxane and methyltetrahydrofuran; the reaction temperature is-30-10 ℃, and the reaction time is 8-24 hours.
Preferably, the ketoreductase in step (3) is one or more of KRED-101, KRED-171 and mutants thereof; the reaction time is 3-24 hours.
Preferably, the reaction temperature in the step (2) is 0 ℃ and the reaction time is 12 hours; the reaction time in step (3) was 12h.
The invention has the beneficial effects that the invention provides a method for efficiently synthesizing 3 alpha, 7 alpha, 24 by a chemical-enzymatic methodR-a method of trihydroxy cholesterol. The method for synthesizing the squalamine intermediate adopts cheap and easily available 5 alpha-chenodeoxycholic acid as a raw material, and obtains 24-carbonyl compound (II) through Weinreb reaction, wherein (II) reduces 24-carbonyl under the catalysis of ketoreductase to obtain 3 alpha, 7 alpha, 24R-trihydroxycholesterol (i); 3 alpha, 7 alpha, 24RThe side chain of the trihydroxy cholesterol and the hydroxyl on the 24 th position are completely consistent with the squalamine, so that the squalamine can be efficiently and rapidly synthesized. The method has the advantages of simple steps, low cost, mild conditions, simple and convenient operation and environmental protection.
Drawings
FIG. 1 shows the compound of formula (I) obtained in example 1 1 H-NMR spectrum.
FIG. 2 shows the compound of formula (I) obtained in example 1 13 C-NMR spectrum.
Detailed Description
The present invention will be further described with reference to the following examples, but the process, conditions, reagents, experimental methods, etc. for carrying out the present invention are not limited to the examples, and unless specifically mentioned below, all the experimental materials used are readily available from commercial companies unless otherwise indicated.
The 5 a-chenodeoxycholic acid starting material used in the following examples was purchased from the mountain lark biotechnology company, ltd; ketoreductase KRED-101, KRED-171 were purchased from Shang Ke Bio-medicine (Shanghai) Inc.
Example 1
1. Synthesis of Compound of formula (III)
,
5 alpha-chenodeoxycholic acid (5.1 g,13 mmol), N, O-diMethanolamine hydrochloride (1.5 g,16 mmol) was added to dichloromethane (50 mL), triethylamine (4.5 mL,33 mmol) was added, and the mixture was stirred at room temperature for 30 min. 1-hydroxybenzotriazole (2.6 g,20 mmol) and N, N-dicyclohexylcarbodiimide (3.2 g,16 mmol) were then added in this order and reacted at room temperature 12h. After completion of TLC detection reaction, washing with water, drying over anhydrous sodium sulfate, spin-drying, and column chromatography purification gave the compound of formula (III) (5.0 g, 89%). 1 HNMR (400 MHz, CD 3 OD) δ 4.00-3.98 (m, 1H), 3.80-3.74 (m, 1H), 3.74 (s, 3H), 3.19 (s, 3H), 2.53-2.35 (m, 2H),2.05-1.94(m, 2H), 1.81-1.73 (m, 2H), 1.65 (dt,J= 4.7, 2.6 Hz, 1H), 1.48-1.41 (m, 6H), 1.38-1.28 (m, 9H), 1.21-1.09 (m, 4H), 0.99 (d,J= 6.5 Hz, 3H), 0.83 (s, 3H), 0.71 (s, 3H).
2. Synthesis of Compound of formula (II)
,
To a solution of the compound of formula (iii) (2.2 g,5.0 mmol) in anhydrous tetrahydrofuran (60 mL) was added dropwise a solution of 1.0. 1.0M isopropyl magnesium bromide (28 ml,28 mmol) in tetrahydrofuran at 0 ℃ under an argon atmosphere, and stirring was continued for 30 min at 0 ℃, followed by warming to room temperature and stirring was continued for 12h. After the reaction was completed, ice water was added to quench the reaction, and tetrahydrofuran was removed in vacuo. Then extracted with ethyl acetate (65 mL), washed with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, dried by spinning, and purified by column chromatography to give the compound of formula (II) (1.0 g, 48%). 1 H NMR (400 MHz, CD 3 OD) δ 4.00-3.98 (m, 1H), 3.80-3.78 (m, 1H), 2.71-2.68 (m, 1H), 2.60-2.41 (m, 2H), 2.14 (tt,J= 13.1, 3.5 Hz, 1H), 2.06-1.84 (m, 3H), 1.79-1.56 (m, 5H), 1.49-1.39 (m, 6H), 1.37-1.28 (m, 6H), 1.21-1.12 (m, 3H),1.09 (d,J= 6.9 Hz, 6H), 0.96 (d,J= 6.5 Hz, 3H), 0.83 (s, 3H), 0.70 (s, 3H).
3. Synthesis of Compound of formula (I)
,
Preparation of a Compound (0.084 g,0.20 mmol) containing formula (II), 1.0mg KRED-101, 100 mM glucose, 1.0 mM NADPH,1.0 mM NADP + 1mg/mL GDH reaction system 200 mL. The whole reaction system was reacted at 25℃and 220rpm for 12h, and the reaction was completed. The reaction was extracted with an equal volume of ethyl acetate, the extraction was repeated three times, and finally the organic phases were combined, dried by spin-drying and purified by column chromatography to give the compound of formula (i) (0.054 g,64%,99.2% d.e.). 1 H NMR (400 MHz, CD 3 OD) δ 4.00-3.98 (m, 1H), 3.80-3.78 (m, 1H), 3.26-3.22 (m, 1H), 2.20-1.87 (m, 3H), 1.83-1.60 (m,4H), 1.59-1.49 (m, 2H), 1.49-1.39 (m, 8H), 1.38-1.08 (m, 10H), 0.97 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.8 Hz, 6H), 0.83 (s, 3H), 0.71 (s, 3H); 13 C NMR (151 MHz, CD 3 OD) δ 76.39, 67.40, 65.82, 56.23, 50.38, 45.66, 42.28, 39.59, 39.53, 36.36, 35.81,35.69, 35.11, 33.48, 31.98, 31.90, 31.19, 30.12, 28.13, 27.91, 23.13, 20.32, 18.04, 17.80, 16.58, 10.89, 9.24; HRMS (ESI, m/z) Calcd for C 27 H 48 O 3 420.3603, found: 443.3500 [M+Na] + (Calcd 443.3496).
Example 2
Using the same procedure as in example 1 except changing the condensing agent N, N ' -dicyclohexylcarbodiimide-1-hydroxybenzotriazole system in step 1 of example 1 to benzotriazole-N, N, N ', N ' -tetramethylurea hexafluorophosphate, the yield of Compound III was 78%.
Example 3
Using the same procedure as in example 1 except changing the isopropyl magnesium bromide in step 2 of example 1 to isopropyl lithium, the yield of compound II was 36%.
Example 4
Using the same procedure as in example 1 except changing KRED-101 to KRED-171 in step 3 of example 1, the yield of Compound I was 58%, d.e. 99.3%.
The present invention is not limited to the above embodiments. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.

Claims (7)

1. Chemical-enzymatic synthesis of 3 alpha, 7 alpha, 24R-a method of trihydroxycholesterol, comprising the steps of:
,
,
(1) Condensation reaction is carried out on 5 alpha-chenodeoxycholic acid and N, O-dimethylol hydrochloride under the action of alkali and a condensing agent, so as to obtain Weinreb amide (III); the base is one or more of triethylamine, N, N-diisopropylethylamine and 1, 8-diazabicyclo undec-7-ene; the condensing agent is one or more of O-benzotriazole-N, N, N ', N ' -tetramethyl urea tetrafluoroboric acid, N, N ' -dicyclohexylcarbodiimide-1-hydroxybenzotriazole system, benzotriazole-N, N, N ', N ' -tetramethyl urea hexafluorophosphate;
(2) Weinreb amide (III) is subjected to the action of an organometallic nucleophile to obtain Weinreb ketone (II); the organic metal nucleophilic reagent is one or more of isopropyl magnesium chloride and isopropyl magnesium bromide;
(3) Under the NADPH regeneration reduction system, the ketoreductase catalyzes Weinreb ketone (II) to generate chiral asymmetric carbonyl reduction reaction to obtain 3 alpha, 7 alpha, 24R-trihydroxycholesterol (I); the ketoreductase is one or more of KRED-101 and KRED-171; the reaction time is 3-24 hours.
2. The method according to claim 1, wherein the molar ratio of 5 a-chenodeoxycholic acid to N, O-dimethylol hydrochloride in step (1) is 1 (1-3); the step (1) is carried out in methylene dichloride serving as an organic solvent, and the reaction time is 8-24 hours.
3. The method according to claim 2, wherein the molar ratio of 5 a-chenodeoxycholic acid to N, O-dimethylol hydrochloride in step (1) is 1:1.5; the reaction time of the step (1) is 12h.
4. The method of claim 1, wherein the molar ratio of Weinreb amide (III) to organometallic nucleophile in step (2) is 1 (3-20).
5. The method of claim 4, wherein the molar ratio of Weinreb amide (III) to organometallic nucleophile in step (2) is 1:5.
6. The method of claim 1, wherein step (2) is performed in an organic solvent, the organic solvent being one or more of tetrahydrofuran, diethyl ether, 1, 4-dioxane, methyl tetrahydrofuran; the reaction temperature is-30-10 ℃, and the reaction time is 8-24 hours.
7. The process according to any one of claims 1 to 6, wherein the reaction temperature in step (2) is 0 ℃ and the reaction time is 12 hours; the reaction time in step (3) was 12h.
CN202310759919.8A 2023-06-27 2023-06-27 Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method Active CN116497082B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310759919.8A CN116497082B (en) 2023-06-27 2023-06-27 Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310759919.8A CN116497082B (en) 2023-06-27 2023-06-27 Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method

Publications (2)

Publication Number Publication Date
CN116497082A CN116497082A (en) 2023-07-28
CN116497082B true CN116497082B (en) 2023-09-29

Family

ID=87323422

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310759919.8A Active CN116497082B (en) 2023-06-27 2023-06-27 Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method

Country Status (1)

Country Link
CN (1) CN116497082B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4360470A (en) * 1980-10-22 1982-11-23 Hoffmann-La Roche Inc. Process and intermediates for the synthesis of Vitamin D3 metabolites and chenodeoxycholic acid
EP2441771A1 (en) * 2010-10-13 2012-04-18 PharmaZell GmbH New 12alpha-hydroxysteroid dehydrogenase mutants, method for their manufacture and application thereof
CN107531743A (en) * 2015-04-29 2018-01-02 正大天晴药业集团股份有限公司 Chenodeoxycholic acid derivatives
CN109071593A (en) * 2016-01-28 2018-12-21 正大天晴药业集团股份有限公司 Steroid derivatives FXR agonist

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4360470A (en) * 1980-10-22 1982-11-23 Hoffmann-La Roche Inc. Process and intermediates for the synthesis of Vitamin D3 metabolites and chenodeoxycholic acid
EP2441771A1 (en) * 2010-10-13 2012-04-18 PharmaZell GmbH New 12alpha-hydroxysteroid dehydrogenase mutants, method for their manufacture and application thereof
CN107531743A (en) * 2015-04-29 2018-01-02 正大天晴药业集团股份有限公司 Chenodeoxycholic acid derivatives
CN109071593A (en) * 2016-01-28 2018-12-21 正大天晴药业集团股份有限公司 Steroid derivatives FXR agonist

Also Published As

Publication number Publication date
CN116497082A (en) 2023-07-28

Similar Documents

Publication Publication Date Title
US6333415B1 (en) Intermediates and processes for the preparation of optically active octanoic acid derivatives
CN105461777A (en) Purification method of abiraterone acetate
CN112028956A (en) Method for synthesizing 21-hydroxy-17- (1-oxopropoxy) pregn-4-ene-3,20-dione
CN116497082B (en) Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method
CN101575298B (en) Method for preparing chiral medicinal intermediate 2-amido-1-phenylethylalcohol
EP3235806A1 (en) Compound and method for producing same, as well as method for producing oseltamivir phosphate
CN112225647A (en) Method for synthesizing 5-bromo-2-methoxyphenol
CN114014903B (en) Synthesis method of ergosterol and derivatives thereof
CN107216335B (en) A kind of tert-butyl 1- (methylol) -3- oxa- -9- azaspiro [5.5] hendecane -9- formic acid base ester preparation method
CN101481334B (en) Rivastigmine preparation suitable for industrial production
CN102153611B (en) Method for synthesizing pregnenolol acetate and congener thereof
CN113004233B (en) Compound for preparing PRC2 inhibitor, preparation method and application thereof
CN109942397B (en) Preparation method of royal jelly acid
CN112321510A (en) Preparation method of 4-bromo-5-methyl-1H-indazole
CN115304477B (en) Preparation method of aromatic carboxylic ester
CN113004161B (en) Preparation method of (2R, 3R) -3-methyl-3-phenylalanine
CN114394933B (en) Synthesis method of 11, 12-dihydro-gamma-oxo-dibenzo [ F ] azo-5- (6H) -butyric acid
CN111138509B (en) Preparation method of obeticholic acid
CN112142629B (en) Preparation method of 3-aminosulfonylalanine
CN112778199B (en) Compound containing nitrate functional group and synthetic method thereof
KR20070082985A (en) Preparation method of oseltamivir
CN115611760A (en) Chemical synthesis method suitable for large-scale production of (S) -2-amino-5-alkynyl caproic acid
CN115894503A (en) Preparation method of azacyclopentane derivative
CN116574150A (en) Preparation method of dihydrotestosterone and intermediate thereof
CN112645805A (en) Method for preparing trimesic aldehyde from Wenlenbo amide

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