CN106279331B - Cholic acids hepatosis treating medicine - Google Patents
Cholic acids hepatosis treating medicine Download PDFInfo
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- CN106279331B CN106279331B CN201610596990.9A CN201610596990A CN106279331B CN 106279331 B CN106279331 B CN 106279331B CN 201610596990 A CN201610596990 A CN 201610596990A CN 106279331 B CN106279331 B CN 106279331B
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- 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
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Abstract
It is that raw material is synthesized by 3-5 β of Alpha-hydroxy-7- oxo-cholestane-24- acid methyl esters the present invention relates to a kind of cholestane compound, this preparation method is simple and easy to do, high income, and it is high-quality, it is convenient for industrialized production.Cholestane compound of the invention is used to prepare the composition for treating or preventing nonalcoholic fatty liver, primary biliary cirrhosis.
Description
Technical field:
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of Cholic acids hepatosis treating medicine and preparation method thereof.
Background technique:
Non-alcohol fatty liver refers to except fatty mistake in liver cell caused by alcohol and other specific damage liver factors
Degree is deposited as the clinical pathology syndrome of main feature, the closely related acquired metabolism with insulin resistance and genetic predisposition
Irritability hepatic injury includes simple fatty liver, nonalcoholic fatty liver disease and its related liver cirrhosis.Worldwide,
There is 15~32% population to suffer from non-alcoholic fatty liver disease, it has also become a kind of pandemic.
Shellfish cholic acid difficult to understand, also known as 6- ethyl chenodeoxycholic acid are that one kind of chenodeoxycholic acid in people's primary bile acid novel is spread out
Biology.In vitro study discovery, shellfish cholic acid difficult to understand increase mankind's islet cells insulin secretion, while increasing fatty in fat cell
Storage, and promote the secretion of adiponectin and leptin.In animal model, it was found that shellfish cholic acid difficult to understand can make specific fibrosis/
Hardening lesion takes a turn for the worse.
Compound patent WO 2013/192097 reports one kind 3 α, 7-6 α of alpha-dihydroxy-- 5 β of ethyl-cholanic acid conjunction
At method.One kind 3 α, 7-6 α of alpha-dihydroxy-- 5 β of the ethyl-cholanic acid conjunction of 02/072598 patent report of compound patent WO
At method.The route steps are longer, and yield is lower.Thus, it is found that treatment nonalcoholic fatty liver and primary biliary liver are hard
The cholane acid compounds of change are the hot spots studied at present.
Technical solution
The present invention relates to following compounds:
3 α, -6 β of 7 alpha-dihydroxy-(3,3,3- trifluoro propyl) -5 β-cholestane -24- acid
The present invention relates to the salt of 1 compound of formula: including sodium salt, sylvite and calcium salt.
The present invention relates to the preparations of 1 compound of formula: drug, health care product or functional food, excipient or carrier be pharmacy or
Common excipient or carrier, such as diluent, disintegrating agent, lubricant etc. in field of food.
The composition for treating or preventing nonalcoholic fatty liver is used to prepare the invention discloses 1 compound of formula.
The composition for treating or preventing nonalcoholic fatty liver, 1 chemical combination of formula are used to prepare the invention discloses 1 compound of formula
The dosage of object is 0.5-200mg/kg.
The composition for treating or preventing nonalcoholic fatty liver, 1 chemical combination of formula are used to prepare the invention discloses 1 compound of formula
The dosage of object is 5mg/kg.
The composition for treating or preventing nonalcoholic fatty liver, 1 chemical combination of formula are used to prepare the invention discloses 1 compound of formula
The dosage of object is 10mg/kg.
The composition for treating or preventing primary biliary cirrhosis is used to prepare the invention discloses 1 compound of formula.
The composition for treating or preventing primary biliary cirrhosis, formula 1 are used to prepare the invention discloses 1 compound of formula
The dosage of compound is 0.5-200mg/kg.
The composition for treating or preventing primary biliary cirrhosis, formula 1 are used to prepare the invention discloses 1 compound of formula
The dosage of compound is 5mg/kg.
The composition for treating or preventing primary biliary cirrhosis, formula 1 are used to prepare the invention discloses 1 compound of formula
The dosage of compound is 10mg/kg.
The invention discloses 1 compounds of formula to be used to prepare: drug, health care product or functional food, excipient or carrier are
Common excipient or carrier, such as diluent, disintegrating agent, lubricant etc. in pharmacy or field of food.
The invention discloses the synthesis technology of 1 compound of formula is as follows:
The synthesis of compound b (3 Alpha-hydroxy -7-, two -5 β of trimethylsiloxy group-cholestane -6- alkene -24- acid methyl esters):
Compound a 100g (0.25mol) is placed in dry reaction bottle, 600ml THF stirring and dissolving is added, and cooling
To -20~-25 DEG C, 120g trim,ethylchlorosilane (1.1mol) is added dropwise in temperature control -20~-25 DEG C under nitrogen atmosphere；Drop finishes, and temperature control adds
Enter to pre-cool to -20~-25 DEG C of lithium diisopropylamine (28%LDA solution), continues temperature control -20~-25 DEG C and react 3h；
It is added and is pre-cooled to the aqueous citric acid solution of 10 DEG C of 600ml 10% below in post-processing, stirring separates water phase, organic phase
50 DEG C of temperature control or less evaporated under reduced pressure solvents, obtaining pale tan oil is compound b, and the compound stability is slightly worse, is directly used
In the next step.
Compound a: trim,ethylchlorosilane material ratio: 1: 1.0~1.5, preferably 1: 1.1
Reaction dissolvent: THF, dioxane, preferably THF
Reaction temperature: -10~-40 DEG C, preferably -20~-25 DEG C.
Annihilation reaction: citric acid, citric acid, propionic acid, acetic acid etc., preferential citric acid
The synthesis of compound c (3 Alpha-hydroxy -6- (3,3,3- trifluoro allyl) -5 β of -7- oxo-cholestane -24- acid):
By compound b (being equivalent to 0.25mol) 300ml methylene chloride dissolution in the reaction of upper step, and it is cooled to -60~-
65 DEG C, and 56g trifluoro propionic aldehyde (0.5mol) is added in temperature control；Above-mentioned reaction solution is added to pre-cooling to -60 under nitrogen atmosphere
In the boron trifluoride acetonitrile complex solution of~-65 DEG C of 380g 16% (about 0.9mol), continue temperature control -60~-65 DEG C reaction
2h is again heated to 20-30 DEG C of reaction 3h；Reaction is finished, and is cooled to 0-10 DEG C, and the NaOH aqueous solution of 850ml 3%, stirring is added
10min separates water phase, and 50 DEG C of organic phase temperature control or less evaporated under reduced pressure solvents are dissolved with 150ml methanol in residue, is added
The NaOH solution of 50ml 25% is heated to 50-55 DEG C and is stirred to react 4h, 400ml water dilute reaction solution is added, and be cooled to 20
~30 DEG C of standing 30min separate water layer, and the aqueous citric acid solution of ethyl acetate 500ml and 200g 50% is added, is stirred at room temperature
10min, separate organic layer, then use 300ml ethyl acetate aqueous phase extracted, merge organic phase, anhydrous sodium sulfate dry, 50 DEG C of temperature control
Dry solvent is concentrated under reduced pressure below, residue 400ml recrystallizing methanol obtains 92g compound c, yield 76%, HPLC (CAD inspection
Survey device) purity: 98.7%.
Compound b: trifluoro propionic aldehyde material ratio: 1: 1.2~3, preferably 1: 2
Reaction dissolvent: aprotic solvent methylene chloride, chloroform, Bromofume, preferably THF
Reaction temperature: -40~-65 DEG C, preferably -60~-65 DEG C.
Hydrolysis temperature: 40~65 DEG C, preferably 50~55 DEG C.
ESI-MS (m/z): 485.6 (M+1)
1H-NMR(CDCl3, 500MHz), δ 6.315-6.333 (d, 1H, 25), δ 4.237~4.303 (m, 1H, H-3), δ
3.836~3.914 (m, 2H, H-26), δ 2.759~2.787 (t, 1H, H-8), δ 2.547~2.576 (m, 1H, H-5), δ
2.452~2.509 (m, 2H, H-23), δ 2.272~2.355 (m, 2H, H-22), δ 2.136~2.195 (m, 1H, H-14), δ
1.969~2.024 (m, 2H, H-4), δ 1.779~1.834 (m, 2H, H-2), δ 1.588~1.696 (m, 4H, H-16, H-6), δ
1.477~1.573 (m, 6H, H-12, H-11, H-14, H-9), δ 1.386~1.453 (m, 2H, H-15), δ 0.901~0.929
(t, 1H, H-17), δ 0.855~0.881 (t, 9H, H-18, H-19, H-21)
The synthesis of compound d (- 5 β of -6 α of 3 Alpha-hydroxy-(3,3,3- trifluoro propyl) -7- oxo-cholestane -24- acid):
Compound c 90g (0.185mol) is dissolved with 900mlTHF, and Pd/C (10%) 18g is added, after replacing H2 three times, room
10% sodium hydroxide solution of 150ml is added in temperature reaction 36h, filtering, 50 DEG C of filtrate temperature control or less evaporated under reduced pressure solvents, residue,
It is heated to return stirring for 24 hours, is cooled to room temperature and 600ml ethyl acetate is added, agitation and dropping 6N HCl tune PH to 2 or so, liquid separation,
Organic phase is washed, anhydrous sodium sulfate is dry, and 50 DEG C of temperature control or less are concentrated under reduced pressure dry solvent, residue 300ml ethyl acetate-second
Alcohol (8: 1) recrystallization, obtains 62g compound d, yield 68.5%, HPLC (CAD detector) chemical purity: 99.2%, 6 β isomeries
Body content 0.11%.
Compound c:Pd/C (10%) material ratio: 1: 0.1~0.3, preferably 1: 0.2 (w/w)
Reaction dissolvent: non-alcohols solvent THF, dioxane, methylene chloride, chloroform, Bromofume, preferably THF
Reaction temperature: 20~50 DEG C, preferably 20~30 DEG C, room temperature.
The hydrogenation time: 18~30h, preferably for 24 hours
Recrystallization ethyl acetate-ethanol ratio: 5~10: 1, preferably 8: 1.
ESI-MS (m/z): 487.3 (M+1)
1H-NMR(CDCl3, 500MHz), δ 3.667-3.733 (m, 1H, H-3), δ 2.196~2.224 (m, 2H, H-23), δ
1.934~2.041 (m, 3H, H-6, H-12), δ 1.259~1.832 (m, 21H, H-1, H-2, H-4, H-5, H-11, H-12, H-
14, H-15, H-16, H-20, H-22, H-26), δ 1.089~1.130 (m, 1H, H-17), δ 0.979~1.027 (m, 1H, H-
9), δ 0.893~0.907 (d, 3H, H-21), δ 0.860 (s, 6H, H-19, H-25).
The synthesis of compound K L-103 (3 α, -6 α of 7 alpha-dihydroxy-(3,3,3- trifluoro propyl) -5 β-cholestane -24- acid):
Compound d 60g (0.125mol) is added in 10% sodium hydroxide solution of 200ml, and stirring and dissolving is heated to flowing back
30min is stirred, the aqueous solution of the NaBH4 of 45ml 20% is added dropwise, 7~8h of Bi Jixu back flow reaction is dripped, is cooled to room temperature, is added
Organic phase is washed in the extraction of 200ml ethyl acetate, agitation and dropping 6N HCl tune PH to 2 or so, liquid separation, and anhydrous sodium sulfate is dry, control
Dry solvent is concentrated under reduced pressure in 50 DEG C of temperature or less, and residue 250ml recrystallize with dichloromethane obtains 40g compound K L-103 (formula 1
Compound), yield 66.6%, HPLC (CAD detector) chemical purity: 99.8%, isomers (6 β, 7 α), (6 α, 7 β), (6 β, 7
β) content is respectively less than 0.05%.
Compound d:NaBH4Material ratio: 1: 1.2~2, preferably 1: 1.5
Compound d:NaOH material ratio: 1: 4~6, preferably 1: 5
The reduction reaction time: 5~10h, preferably 7~8h
Recrystallization solvent: alkane solvents methylene chloride, chloroform, Bromofume, toluene；It is preferred that methylene chloride
ESI-MS (m/z): 489.3 (M+1)
1H-NMR(CDCl3, 500MHz), δ 3.667-3.733 (m, 1H, H-3), δ 3.321~3.359 (m, 1H, H-7), δ
2.196~2.224 (t, 2H, H-7, H-23), δ 1.915~1.975 (m, 2H, H-12), δ 1.634~1.831 (m, 8H, H-2,
H-4, H-15, H-26), δ 1.422~1.610 (m, 8H, H-1, H-11, H-16, H-22), δ 1.168~1.339 (m, 4H, H-6,
H-20, H-25), δ 1.1089~1.130 (m, 1H, H-17), δ 1.019~1.060 (m, 1H, H-5), δ 0.893~0.907 (d,
3H, H-21), δ 0.830~0.871 (m, 7H, H-8, H-18, H-19), δ 0.709~0.750 (m, 1H, H-14).
Experimental example 1, compound b (3 Alpha-hydroxy -7-, two -5 β of trimethylsiloxy group-cholestane -6- alkene -24- acid methyl esters)
Synthesis:
Compound a 100g (0.25mol) is placed in dry reaction bottle, 600ml THF stirring and dissolving is added, and cooling
To -20 DEG C, -20 DEG C of dropwise addition 120g trim,ethylchlorosilanes (1.1mol) of temperature control under nitrogen atmosphere；Drop finishes, and temperature control addition pre-cools
To -20 DEG C of lithium diisopropylamine (28%LDA solution), continue -20 DEG C of reaction 3h of temperature control；It is added and pre-cools in post-processing
To the aqueous citric acid solution of 10 DEG C of 600ml 10% below, stirring separates water phase, 50 DEG C of organic phase temperature control or less evaporated under reduced pressure
Solvent, obtaining pale tan oil is compound b, and the compound stability is slightly worse, is directly used in the next step.
Experimental example 2, compound c (3 Alpha-hydroxy -6- (3,3,3- trifluoro allyl) -5 β of -7- oxo-cholestane -24- acid)
Synthesis:
By compound b (being equivalent to 0.25mol) 300ml methylene chloride dissolution in the reaction of upper step, and it is cooled to -60~-
65 DEG C, and 56g trifluoro propionic aldehyde (0.5mol) is added in temperature control；Above-mentioned reaction solution is added to pre-cooling to -60 under nitrogen atmosphere
DEG C 380g16% boron trifluoride acetonitrile complex solution in (about 0.9mol), continue -60 DEG C of reaction 2h of temperature control, be again heated to 20
DEG C reaction 3h；Reaction is finished, and is cooled to 0 DEG C, and the NaOH aqueous solution of 850ml 3% is added, and stirs 10min, separates water phase, organic phase
50 DEG C of temperature control or less evaporated under reduced pressure solvents are dissolved with 150ml methanol in residue, and the NaOH solution of 50ml 25%, heating is added
It is stirred to react 4h to 50 DEG C, 400ml water dilute reaction solution is added, and be cooled to 20~30 DEG C of standing 30min, water layer is separated, adds
The aqueous citric acid solution for entering ethyl acetate 500ml and 200g 50%, is stirred at room temperature 10min, separates organic layer, then with 300ml second
Acetoacetic ester aqueous phase extracted merges organic phase, and anhydrous sodium sulfate is dry, and 50 DEG C of temperature control or less are concentrated under reduced pressure dry solvent, and residue is used
400ml recrystallizing methanol obtains 92g compound c, yield 76%, HPLC (CAD detector) purity: 98.7%.
Experimental example 3, compound d (- 5 β of -6 α of 3 Alpha-hydroxy-(3,3,3- trifluoro propyl) -7- oxo-cholestane -24- acid)
Synthesis:
Compound c 90g (0.185mol) is dissolved with 900mlTHF, and Pd/C (10%) 18g is added, after replacing H2 three times, room
10% sodium hydroxide solution of 150ml is added in temperature reaction 36h, filtering, 50 DEG C of filtrate temperature control or less evaporated under reduced pressure solvents, residue,
It is heated to return stirring for 24 hours, is cooled to room temperature and 600ml ethyl acetate is added, agitation and dropping 6N HCl tune PH to 2 or so, liquid separation,
Organic phase is washed, anhydrous sodium sulfate is dry, and 50 DEG C of temperature control or less are concentrated under reduced pressure dry solvent, residue 300ml ethyl acetate-second
Alcohol (8: 1) recrystallization, obtains 62g compound d, yield 68.5%, HPLC (CAD detector) chemical purity: 99.2%, 6 β isomeries
Body content 0.11%.
Experimental example 4, compound K L-103 (3 α, -6 α of 7 alpha-dihydroxy-(3,3,3- trifluoro propyl) -5 β-cholestane -24-
Acid) synthesis:
Compound d 60g (0.125mol) is added in 10% sodium hydroxide solution of 200ml, and stirring and dissolving is heated to flowing back
30min is stirred, the NaBH of 45ml 20% is added dropwise4Aqueous solution, drip 7~8h of Bi Jixu back flow reaction, be cooled to room temperature, be added
Organic phase is washed in the extraction of 200ml ethyl acetate, agitation and dropping 6N HCl tune PH to 2 or so, liquid separation, and anhydrous sodium sulfate is dry, control
Dry solvent is concentrated under reduced pressure in 50 DEG C of temperature or less, and residue 250ml recrystallize with dichloromethane obtains 40g compound K L-103 (formula 1
Compound), yield 66.6%, HPLC (CAD detector) chemical purity: 99.8%, isomers (6 β, 7 α), (6 α, 7 β), (6 β, 7
β) content is respectively less than 0.05%.
Embodiment 5: the condition of the HPLC of sample purity is:
High performance liquid chromatograph is equipped with evaporation photodetector
Chromatographic column: common C18 column
DC:80 DEG C
SC:70 DEG C
N2Pressure: 35Bar
Column temperature: 35 DEG C
Sample volume: 20 μ l
Mobile phase: using 0.05mol/L trifluoroacetic acid aqueous solution as mobile phase A, acetonitrile is Mobile phase B, and according to the form below is washed
It is de-.Flow velocity is 1.0ml per minute
The condition of gradient elution of compound C:
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 15 | 60 | 40 |
| 20 | 50 | 50 |
| 25 | 80 | 20 |
| 30 | 60 | 40 |
Compound C is dissolved with (mobile phase A 70%+ Mobile phase B 30%), and 20 μ l is taken to inject liquid chromatograph, records chromatography
Figure, compound C peak retention time are 19.2 minutes.
The condition of gradient elution of compound d:
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 70 | 30 |
| 15 | 60 | 40 |
| 20 | 15 | 85 |
| 25 | 50 | 50 |
| 30 | 70 | 30 |
Compound d is dissolved with (mobile phase A 70%+ Mobile phase B 30%), and 20 μ l is taken to inject liquid chromatograph, records chromatography
Figure, compound C peak retention time are 15.7 minutes.
The condition of gradient elution of compound K L-103:
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 75 | 25 |
| 15 | 20 | 80 |
| 20 | 15 | 85 |
| 25 | 50 | 50 |
| 30 | 70 | 30 |
Compound K L-103 is dissolved with (mobile phase A 75%+ Mobile phase B 25%), and 20 μ l is taken to inject liquid chromatograph, record
Chromatogram, compound C peak retention time are 16.2 minutes.
Embodiment 6
Compound K L-103 piece is formulated by following component, by 1000 dosages:
Preparation method includes the following steps:
1) compound K L-103 and pharmaceutic adjuvant are pulverized and sieved respectively, it is spare,
2) take raw material and the pharmaceutic adjuvant physical mixed of recipe quantity parts by weight uniform,
3) wet granulation,
4) dry, whole grain,
5) additional auxiliary material is converted, is uniformly mixed, it is tabletted
6) Opadry is dissolved using certain solvent, is coated as coating solution.
Test result
Medicament contg: qualified
Disintegration time limited: meet regulation
Embodiment 7
Compound K L-103 piece is formulated by following component, by 1000 dosages:
Preparation method includes the following steps:
1) compound K L-103 and pharmaceutic adjuvant are pulverized and sieved respectively, it is spare,
2) take raw material and the pharmaceutic adjuvant physical mixed of recipe quantity parts by weight uniform,
3) wet granulation,
4) dry, whole grain,
5) additional auxiliary material is converted, is uniformly mixed, it is tabletted
6) Opadry is dissolved using certain solvent, is coated as coating solution.
Test result
Medicament contg: qualified
Disintegration time limited: meet regulation
Embodiment 8
Embodiment 3
Therapeutic effect of 1 compound of formula to nonalcoholic fatty liver
Experimental animal and method:
C57BL mouse, SPF grades, male, weight (20 ± 2) g, 50, stochastic averagina is divided into five groups,
First group, it is normal group, gives chow diet,
Second group: high in fat group,
Third group: high in fat+Austria's shellfish cholic acid group (5mg/kg),
4th group: high in fat+1 compound low concentration group (2mg/kg) of formula,
5th group: high in fat+1 compound high concentration group (20mg/kg) of formula.
Second and third, four, five groups give respectively and give high lipid food (20% lard is added in basal feed, and 1.25% gallbladder is solid
Alcohol, 0.5% sodium taurocholate) it freely ingests, drink water.Administration 6 weeks
Observation index:
The ordinary circumstance of a animal
Experimental animal, illumination 12h night 12h, free diet drinking-water, animal state is normal during experiment.
B blood lipids: TC, TG, HDL, LDL
C Liver lipids accumulate index of correlation: TG in liver weight, liver, TC in liver
Mouse, blood lipid level are measured after administration.It is examined using t for statistical analysis.
2. interpretation of result
TC in the blood of mouse, TG, HDL-C, LDL-C are significantly increased after modeling, and have significant statistical difference,
Show modeling success, TC is administered, the reduction of the equal conspicuousness concentration dependent of TG, LDL-C has significant statistical difference, says
Mingzhi's therapeutic effect is significant.
Liver weight, unit: g
Total cholesterol level in liver, unit: mg cholesterol/g fresh liver tissue
Content of triglyceride in liver, unit: mg cholesterol/g fresh liver tissue
Claims (4)
1. a kind of pharmaceutical applications of cholestane compound, it is characterised in that:
3 α, -6 β of 7 alpha-dihydroxy-(3,3,3- trifluoro propyl) -5 β-cholestane -24- acid；
It is used to prepare Cholic acids hepatosis treating medicine；The dosage of 1 compound of formula is 0.5-200mg/kg.
2. a kind of pharmaceutical applications of cholestane compound according to claim 1, it is characterised in that: be used to prepare treatment
Or the composition of prevention nonalcoholic fatty liver.
3. a kind of pharmaceutical applications of cholestane compound according to claim 1, it is characterised in that: be used to prepare treatment
Or the composition of prevention primary biliary cirrhosis.
4. a kind of HPLC analytical method of cholestane compound according to claim 1, it is characterised in that:
High performance liquid chromatograph is equipped with evaporation photodetector
Chromatographic column: common C18 column
DC:80 DEG C
SC:70 DEG C
N2 pressure: 35Bar
Column temperature: 35 DEG C
Sample volume: 20 μ l
Mobile phase: using 0.05mol/L trifluoroacetic acid aqueous solution as mobile phase A, acetonitrile is Mobile phase B, according to washing for 1 compound of formula
De- condition is eluted, and flow velocity is 1.0ml per minute
Sampling condition is: the dissolution of 1 compound mobile phase A 75%+ Mobile phase B 25% of formula takes 20 μ l to inject liquid chromatograph；
The condition of gradient elution of 1 compound of formula is:
Chromatogram is recorded, compound C peak retention time is 16.2 minutes；
Compound C are as follows: 3 Alpha-hydroxy -6- (3,3,3- trifluoro allyl) -5 β of -7- oxo-cholestane -24- acid.
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|---|---|---|---|
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| CN109655571B (en) * | 2019-01-08 | 2021-07-13 | 丽珠集团新北江制药股份有限公司 | High performance liquid chromatography analysis method of obeticholic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
| CN105348534A (en) * | 2015-11-30 | 2016-02-24 | 苏州太湖电工新材料股份有限公司 | Nanometer silicon dioxide hybrid vinyl phenyl silicon intermediate material and preparing method and application thereof |
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| WO2016079518A1 (en) * | 2014-11-19 | 2016-05-26 | Dextra Laboratories Limited | 5.beta.-6-alkyl-7-hydroxy-3-one steroids as intermediates for the production of steroidal fxr modulators |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104781272A (en) * | 2012-06-19 | 2015-07-15 | 英特塞普特医药品公司 | Preparation, uses and solid forms of obeticholic acid |
| CN105348534A (en) * | 2015-11-30 | 2016-02-24 | 苏州太湖电工新材料股份有限公司 | Nanometer silicon dioxide hybrid vinyl phenyl silicon intermediate material and preparing method and application thereof |
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