CN114106076A - Preparation method of ursodeoxycholic acid EP impurity I - Google Patents
Preparation method of ursodeoxycholic acid EP impurity I Download PDFInfo
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- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 title claims abstract description 49
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 title claims abstract description 47
- 229960001661 ursodiol Drugs 0.000 title claims abstract description 40
- 239000012535 impurity Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000003756 stirring Methods 0.000 claims abstract description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000000047 product Substances 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 16
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 14
- -1 lithium aluminum hydride Chemical compound 0.000 claims abstract description 12
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- 238000001816 cooling Methods 0.000 claims abstract description 11
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- 238000001035 drying Methods 0.000 claims abstract description 9
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- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 8
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- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 9
- 229940126062 Compound A Drugs 0.000 claims description 6
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000003908 quality control method Methods 0.000 abstract description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 6
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- 238000002474 experimental method Methods 0.000 description 3
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- 231100000331 toxic Toxicity 0.000 description 3
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- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 2
- 239000004380 Cholic acid Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 2
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 2
- 229960002471 cholic acid Drugs 0.000 description 2
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- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
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- 238000012360 testing method Methods 0.000 description 2
- 150000004072 triols Chemical class 0.000 description 2
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- 208000005176 Hepatitis C Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
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- 102000003923 Protein Kinase C Human genes 0.000 description 1
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- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 238000007813 chromatographic assay Methods 0.000 description 1
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- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 238000012019 product validation Methods 0.000 description 1
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a preparation method of ursodeoxycholic acid EP impurity I, which takes ursodeoxycholic acid as a starting material to prepare the ursodeoxycholic acid EP impurity I by the following steps: dissolving ursodeoxycholic acid in small molecular alcohol, adding a catalyst for reaction, and crystallizing to obtain a compound B; adding the compound B into tetrahydrofuran, stirring for dissolving, slowly adding lithium aluminum hydride for reaction in several times, stirring, adding dilute hydrochloric acid for quenching reaction, filtering, washing with tetrahydrofuran, and concentrating the filtrate in vacuum to obtain a paste, namely a crude product of the compound C; adding the crude product of the compound C into acetone, stirring and pulverizing, cooling, filtering to obtain a wet product of the compound C, and drying until the weight is basically unchanged to obtain a dry ursodeoxycholic acid EP impurity I; wherein the small molecular alcohol is a straight chain alcohol or a branched chain alcohol containing 1-4 carbon atoms; the catalyst is sulfuric acid, hydrochloric acid or p-toluenesulfonic acid. The preparation method is mild and simple, and the prepared product has high purity and is more convenient for product quality control.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of ursodeoxycholic acid EP impurity I.
Background
Ursodeoxycholic acid (3 α,7 β -dihydroxy-5 β -cholanic acid), english name: ursoxycholic Acid (UDCA) is a nontoxic hydrophilic cholic Acid, is a 7-position isomer of chenodeoxycholic Acid, can competitively inhibit the absorption of toxic endogenous cholic Acid in ileum, and can increase the cholestasis effect by activating a signal network consisting of calcium ions and protein kinase C and activating cleavage active protein-based enzyme. Ursodeoxycholic acid can also competitively replace toxic bile acid molecules on cell break-in organelles, preventing hepatocytes and cholangiocytes from being damaged by more toxic bile acids. Clinically, ursodeoxycholic acid is mainly used for dissolving cholesterol gallstones, primary biliary cirrhosis PBC and chronic hepatitis C, and is also used for alcoholic liver diseases, non-alcoholic fatty liver, benign recurrent intrahepatic cholestasis and congenital intrabiliary cystic dilatation.
With the continuous and deep understanding of ursodeoxycholic acid by human beings, the usage amount of ursodeoxycholic acid is greatly increased, and the ursodeoxycholic acid synthesized by using chenodeoxycholic acid as a raw material contains a small amount of ursodeoxycholic acid EP impurity I (UA triol), and the ursodeoxycholic acid EP impurity I can be used as an impurity reference substance for researching the properties of the ursodeoxycholic acid by a pharmaceutical research institution. At present, patent and technical literature reports about the preparation of the ursodeoxycholic acid EP impurity I are not found, so that the preparation of the high-purity ursodeoxycholic acid EP impurity I and the research on the high-purity ursodeoxycholic acid EP impurity I have certain significance.
Disclosure of Invention
The invention aims to: provides a preparation method of ursodeoxycholic acid EP impurity I, which has simple reaction and high purity and is suitable for mass production.
The invention provides a preparation method of ursodeoxycholic acid EP impurity I, which comprises the following steps:
a. dissolving ursodeoxycholic acid (compound A) in small molecular alcohol, adding a catalyst for reaction, controlling the reaction temperature at 60-70 ℃, reacting for 3-5 h, and crystallizing to obtain a compound B;
b. adding the compound B into tetrahydrofuran, stirring for dissolving, slowly adding lithium aluminum hydride for reaction in several times, stirring for 5-7 hours, adding dilute hydrochloric acid for quenching reaction, filtering, washing with tetrahydrofuran, and vacuum-concentrating filtrate at 50-55 ℃ to obtain a paste, namely a crude product of the compound C;
c. adding the crude product of the compound C into acetone, stirring and pulverizing, cooling to 0-4 ℃, filtering to obtain a wet product of the compound C, and drying until the weight is basically unchanged to obtain a dry ursodeoxycholic acid EP impurity I;
wherein the small molecular alcohol is a straight chain alcohol or branched chain alcohol containing 1-4 carbon atoms, preferably methanol;
the R is a linear alkyl or branched alkyl of C1-C4;
the catalyst is sulfuric acid, hydrochloric acid or p-toluenesulfonic acid, preferably sulfuric acid.
In the invention, the volume-mass ratio of the small molecular alcohol to the compound A is 2.5-12.5 ml:1 g.
The concentration of the catalyst is 1.0-8.0%; the mass ratio of the catalyst to the compound A is 0.02-1: 1.
The volume-mass ratio of the tetrahydrofuran to the compound B is 20-60 ml:1 g.
The mass ratio of the lithium aluminum hydride to the compound B is 0.2-0.5: 1.
The concentration of the dilute hydrochloric acid is 1: 1-10 hydrochloric acid; the volume mass ratio of the dilute hydrochloric acid to the compound B is 0.85-4.25 ml:1 g.
The volume-mass ratio of the acetone to the compound B is 7.5-20 ml:1 g.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method is mild and simple, and the prepared product has high purity and is more convenient for product quality control.
Drawings
FIG. 1 is a chromatogram of a control;
FIG. 2 is a chromatogram of a sample.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Example 1
The preparation method of ursodeoxycholic acid EP impurity I (UA triol) in the embodiment comprises the following steps:
(1) weighing 25g of UDCA, pouring the UDCA into a 1000ml three-neck flask, adding 75ml of methanol and 0.6g of concentrated sulfuric acid, stirring and reacting for 2h, adding 60ml of methanol, cooling 90ml of water to about 0 ℃, stirring for 1h, filtering to obtain a wet product, and drying at 100 ℃ for more than 4h to obtain 23.4g of 3 alpha, 7 beta-dihydroxy-5 beta-methyl cholate;
(2) adding 23.4g of 3 alpha, 7 beta-dihydroxy-5 beta-methyl cholate and 530ml of tetrahydrofuran into a 1000ml three-necked bottle, stirring for dissolving, slowly adding 5.96g of lithium aluminum hydride in portions, and stirring for about 6 hours at the temperature of 0-25 ℃;
(3) adding 23ml of 1:1 hydrochloric acid to carry out quenching reaction, filtering, washing a filter cake with 20ml of tetrahydrofuran, concentrating the filter cake filtrate at 50-55 ℃ in vacuum to obtain paste, adding 180ml of acetone, stirring and pulverizing, cooling to 4 ℃, stirring for 1h, and filtering to obtain 21.3g of wet product; drying in a hot air circulating oven at 80 deg.C for 4h until the weight is substantially unchanged, and measuring that the weight of ursodeoxycholic acid EP impurity I is 17.0g, and the product purity is 98.122%.
Example 2
The preparation method of ursodeoxycholic acid EP impurity I (UA triol) in the embodiment comprises the following steps:
(1) weighing 25g of UDCA, pouring the UDCA into a 1000ml three-neck flask, adding 100ml of ethanol and 2.0g of concentrated hydrochloric acid, stirring and reacting for 2h, adding 150ml of ethanol, cooling 90ml of water to about 0 ℃, stirring for 1h, filtering to obtain a wet product, and drying at 100 ℃ for more than 4h to obtain 24.25g of 3 alpha, 7 beta-dihydroxy-5 beta-ethyl cholate;
(2) adding 3 alpha, 7 beta-dihydroxy-5 beta-ethyl cholate and 600ml tetrahydrofuran into a 1000ml three-neck flask, stirring to dissolve, cooling to 10 ℃, slowly adding 7.5g lithium aluminum hydride in portions, and stirring for about 6 hours.
(3) Adding 1:2 hydrochloric acid 30ml for quenching reaction, filtering, washing filter cake filtrate with 20ml tetrahydrofuran, concentrating the filter cake filtrate in vacuum at 50-55 ℃ to obtain paste, adding 220ml acetone, stirring and pulverizing, cooling to 10-15 ℃, stirring for 1h, and filtering to obtain a wet product 18.5 g;
(4) drying in a hot air circulating oven at 80 deg.C for 4h until the weight is basically unchanged, and measuring that the weight of ursodeoxycholic acid EP impurity I is 15.9g, and the product purity is 98.57%.
Example 3
The preparation method of ursodeoxycholic acid EP impurity I (UA triol) in the embodiment comprises the following steps:
(1) weighing 25g of UDCA, pouring into a 1000ml three-neck flask, adding 75ml of propanol and 1.0g of p-toluenesulfonic acid, stirring for reacting for 2h, adding 150ml of propanol, cooling 90ml of water to about 0 ℃, stirring for 1h, filtering to obtain a wet product, and drying at 100 ℃ for more than 4h to obtain 26.25g of 3 alpha, 7 beta-dihydroxy-5 beta-ethyl cholate;
(2) adding 3 alpha, 7 beta-dihydroxy-5 beta-ethyl cholate and 700ml tetrahydrofuran into a 1000ml three-necked bottle, stirring for dissolving, cooling to 10 ℃, slowly adding 7.5g of lithium aluminum hydride in portions, and stirring for about 6 hours;
(3) adding 1:10 hydrochloric acid 50ml for quenching reaction, filtering, washing filter cake filtrate with 20ml tetrahydrofuran, concentrating the filter cake filtrate in vacuum at 50-55 ℃ to obtain paste, adding 250ml acetone, stirring and pulverizing, cooling to 10-15 ℃, stirring for 1h, and filtering to obtain 19.5g of wet product;
(4) drying in a hot air circulating oven at 80 deg.C for 4h until the weight is substantially unchanged, and measuring that the weight of ursodeoxycholic acid EP impurity I is 17.8g, and the product purity is 98.57%.
Product validation experiment
In the experiment, the product synthesized in example 1 is used as a test sample, and the commercially available ursodeoxycholic acid EP impurity I (UA triol) is used as a reference sample to perform chromatographic analysis and comparison so as to determine whether the components of the product generated by the method are the same as those of the commercially available ursodeoxycholic acid EP impurity I or not, thereby verifying the accuracy and feasibility of the method. The specific operation steps of the product verification experiment are as follows:
1. preparing reference solution and test solution
The preparation method of the reference solution comprises the following steps: precisely weighing 25.0mg of a reference substance, adding the reference substance into a 25ml volumetric flask, adding about 15ml of diluent, ultrasonically dissolving, and fixing the volume to the scale by using the diluent (80% methanol);
the preparation method of the test solution comprises the following steps: precisely weighing 25.0mg of the sample, adding the sample into a 25ml volumetric flask, adding about 15ml of diluent, ultrasonically dissolving, and fixing the volume to the scale by using the diluent (80% methanol).
2. The following chromatographic conditions were selected
A chromatographic column: YMC-PACK 0DS-AQ 4.6 × 25mm, 5 um;
mobile phase: weighing 0.78g of sodium dihydrogen phosphate in a 5000ml beaker, adding 1000ml of water, stirring and dissolving, dropwise adding phosphoric acid to adjust the pH value of the aqueous solution to 3.0, adding 1094ml of acetonitrile and 1250ml of methanol, stirring and mixing uniformly, filtering by using a microporous filter, and carrying out ultrasonic treatment for about 20 min;
flow rate: 1.5 ml/min;
analysis time: 30 min;
column oven: 40 ℃;
a detector: a difference detector;
diluent agent: 80% methanol (80ml methanol added with 20ml water and mixed evenly);
3. performing chromatographic assay
20. mu.l of each of the control solution and the sample solution was taken and injected into a high performance liquid chromatograph, and chromatograms thereof are shown in FIG. 1 and FIG. 2, and peak values thereof are shown in Table 1 and Table 2.
TABLE 1 control peak table
| Peak number | Name of Compound | Retention time (min) | Area (%) |
| 1 | UA triols | 3.8730 | 98.943 |
| 2 | 6.000 | 1.057 | |
| Total of | 100.000 |
TABLE 2 Peak Table of test articles
| Peak number | Name of Compound | Retention time (min) | Area (%) |
| 1 | 3.420 | 0.456 | |
| 2 | UA triols | 3.892 | 98.570 |
| 3 | 4.113 | 0.233 | |
| 4 | 4.367 | 0.045 | |
| 5 | 5.971 | 0.626 | |
| 6 | 0.070 | ||
| Total of | 100.000 |
According to the chromatogram graphs of fig. 1 and fig. 2 and the data in table 1 and table 2, the chromatograms of the reference solution and the sample solution are basically consistent, thereby indicating that the main components of the reference solution and the sample are the same, i.e. confirming that the product synthesized by the invention is ursodeoxycholic acid EP impurity I (UA triol).
Claims (8)
1. A preparation method of ursodeoxycholic acid EP impurity I, which takes ursodeoxycholic acid as a starting material to prepare the ursodeoxycholic acid EP impurity I, is characterized by comprising the following steps:
wherein R is C1-C4 linear chain alkyl or branched chain alkyl;
a. dissolving ursodeoxycholic acid (compound A) in small molecular alcohol, adding a catalyst for reaction, controlling the reaction temperature at 60-70 ℃, reacting for 3-5 hours, and crystallizing to obtain a compound B;
b. adding the compound B into tetrahydrofuran, stirring for dissolving, slowly adding lithium aluminum hydride for reaction in several times, stirring for 5-7 hours, adding dilute hydrochloric acid for quenching reaction, filtering, washing with tetrahydrofuran, and vacuum-concentrating filtrate at 50-55 ℃ to obtain a paste, namely a crude product of the compound C;
c. adding the crude product of the compound C into acetone, stirring and pulverizing, cooling to 0-4 ℃, filtering to obtain a wet product of the compound C, and drying until the weight is basically unchanged to obtain a dry ursodeoxycholic acid EP impurity I;
the small molecular alcohol is straight chain alcohol or branched chain alcohol containing 1-4 carbon atoms;
the catalyst is sulfuric acid, hydrochloric acid or p-toluenesulfonic acid.
2. The method of claim 1, wherein: the small molecular alcohol is methanol, and the catalyst is concentrated sulfuric acid.
3. The process for the preparation of ursodeoxycholic acid EP impurity I according to claim 1 or 2, characterized in that: the volume-mass ratio of the small molecular alcohol to the compound A is 2.5-12.5 ml:1 g.
4. The process for the preparation of ursodeoxycholic acid EP impurity I according to claim 1 or 2, characterized in that: the concentration of the catalyst is 1.0-8.0%; the mass ratio of the catalyst to the compound A is 0.02-1: 1.
5. The method of claim 1, wherein: the volume-mass ratio of the tetrahydrofuran to the compound B is 20-60 ml:1 g.
6. The method of claim 1, wherein: the mass ratio of the lithium aluminum hydride to the compound B is 0.2-0.5: 1.
7. The method of claim 1, wherein: the concentration of the dilute hydrochloric acid is 1: 1-10 hydrochloric acid; the volume mass ratio of the dilute hydrochloric acid to the compound B is 0.85-4.25 ml:1 g.
8. The method of claim 1, wherein: the volume-mass ratio of the acetone to the compound B is 7.5-20 ml:1 g.
Priority Applications (1)
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106794188A (en) * | 2014-09-28 | 2017-05-31 | 华辉安健（北京）生物科技有限公司 | Polymerization bile acid derivative suppresses hepatitis type B virus and Hepatitis D virus and NTCP transports |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106794188A (en) * | 2014-09-28 | 2017-05-31 | 华辉安健（北京）生物科技有限公司 | Polymerization bile acid derivative suppresses hepatitis type B virus and Hepatitis D virus and NTCP transports |
Non-Patent Citations (3)
| Title |
|---|
| CAMERON ALEXANDER 等: "Imprinted Polymers as Protecting Groups for Regioselective Modification of Polyfunctional Substrates", 《J. AM. CHEM. SOC.》 * |
| JIE REN等: "Synthesis and antitumor activity of N-sulfonyl-3,7-dioxo-5β-cholan-24-amides，ursodeoxycholic acid derivatives", 《STEROIDS》 * |
| VALENTINA SEPE等: "Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1)", 《J.MED.CHEM.》 * |
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