CN111440223A - Preparation method of obeticholic acid impurity - Google Patents
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Abstract
The invention mainly researches (E) -3 β -hydroxy-6-ethylidene-7-ketone-5 β -cholestane-24-acid (D), 3 β 0,7 β 1-dihydroxy-6 β 4-ethyl-5 β -cholestane-24-acid (F), 3 β,7 α 0-dihydroxy-6 β -ethyl-5 β -cholestane-24-acid (G), 3 β - (3 β,7 β 6-dihydroxy-6 β 8-ethyl-5 β -cholestane-24-acyloxy) -7 β -hydroxy-6 α -ethyl-5 β -cholestane-24-acid (I), and 3-ketone-7 α -hydroxy-6-5-ethyl-5- β - α -cholanic acid (5731).
Description
Technical Field
The invention relates to a method for synthesizing five impurities of obeticholic acid, in particular to a method for preparing the impurities of obeticholic acid.
Background
Obeticholic acid (Obeticholic acid) belongs to a farnesoid X receptor agonist, and indirectly inhibits the gene expression of cytochrome 7a1(CYP7a1) by activating the farnesoid X receptor. CYP7A1 is the rate-limiting enzyme of cholic acid biosynthesis, and obeticholic acid can inhibit cholic acid synthesis and is used for treating primary biliary cirrhosis and non-alcoholic fatty liver disease.
Patent retrieval shows that patents WO2013192097 and US20130345188a1 report a synthetic method of obeticholic acid, and the process route is as follows:
the compound A is used as a raw material, and is reduced by palladium carbon and then reduced by sodium borohydride to prepare a compound H, namely obeticholic acid.
According to the structure, the compound contains a plurality of chiral centers, and the hydroxyl at the 3-position can be brought in by the raw materials and further reacted to the end. The chirality of 6-ethyl and 7-hydroxy is introduced in the synthesis process. Three diastereoisomeric impurities at the 6-position and 7-position are introduced during the process.
Patent WO2013192097 reports limits on obeticholic acid impurities, but does not provide a preparation method.
Patent CN105294801A reports a preparation method of 2 isomers of obeticholic acid, which is mainly a chromatographic separation method and has no chemical synthesis method with strong guidance.
Patent CN105646634A reports a process for the preparation of obeticholic acid isomer impurities, which is a mixture of 6-ethyl α and β configurations.
Disclosure of Invention
The invention aims to solve the problems and provides a preparation method of obeticholic acid impurities.
The technical scheme of the invention is that the preparation method of the obeticholic acid impurity comprises the preparation method of a compound (E) -3 β -hydroxy-6-ethylidene-7-ketone-5 β -cholestane-24-carboxylic acid (D):
the method comprises the following steps:
the method comprises the following steps: nucleophilic substitution of compound B to produce compound C;
step two: purifying the compound C by adopting column chromatography;
step three: deprotection of compound C yields compound D.
The process route is as follows:
further, in the first step, the reaction solvent is selected from tetrahydrofuran; the reaction temperature is 0-20 ℃; the molar ratio of the compound B to the benzoic acid, the triphenylphosphine and the DIAD is 1 (2-5) to (2-5).
Furthermore, column chromatography in step two adopts silica gel column packing, and eluent is selected from mixed solvent systems such as dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and the like, preferably the ratio of the petroleum ether/ethyl acetate is 150-10: 1.
6. Further, in the third step, the reaction solvent is selected from methanol, ethanol, acetone, sodium hydroxide aqueous solution and a mixture thereof; the reaction temperature is 40-60 ℃; the molar ratio of compound C to sodium hydroxide was 1: (1.5-3.5), adjusting the pH value to 6 by using citric acid aqueous solution after the reaction is completed, filtering, and pulping a filter cake by using EA.
Further, the test compound 3 α,7 α -dihydroxy-6 β -ethyl-5 β -cholest
Process for the preparation of alk-24-oic acid (F):
the method comprises the following steps:
step a: reducing the compound E to generate a compound F;
step b: compound F was purified by column chromatography.
The process route is as follows:
further, in the step a, a tetrahydrofuran solution of lithium borohydride is used as a reducing reagent, and the molar ratio of the compound E to the lithium borohydride is 1: 7; the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, and mixtures thereof, preferably methanol; in the step b, the column chromatography is carried out by silica gel packing, and the eluent is selected from dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and other mixed solvent systems, preferably dichloromethane/ethanol is 80-60: 1.
Further, the preparation method comprises the following steps of preparing the compound 3 α,7 β -dihydroxy-6 β -ethyl-5 β -cholestan-24-acid (G):
comprises the following steps;
step ① reduction of compound E to form compound G;
The process route is as follows:
in the step ①, a tetrahydrofuran solution of lithium borohydride is used as a reducing reagent, the molar ratio of the compound E to the lithium borohydride is 1:7, a reaction solvent is selected from methanol, ethanol, tetrahydrofuran and a mixture thereof, the reaction temperature is 0-20 ℃, in the step ②, silica gel is used for column chromatography, and an eluent is selected from mixed solvent systems of dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and the like, preferably, the dichloromethane/ethanol ratio is 80-60: 1.
Further, the preparation method comprises the following test compound 3 α - (3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholestane-24-acyloxy) -7 α -hydroxy-6 α -ethyl-5 β -cholestane-24-acid (I):
the method comprises the following steps:
step I: condensing the compound H to generate a compound I;
step II: the compound I is purified by column chromatography.
The process route is as follows:
wherein, in the step I, the reaction temperature is 120-130 ℃, and the reaction pressure is less than or equal to-0.09 Mpa; in the step II, the column chromatography adopts silica gel column packing, and the eluent is selected from mixed solvent systems of dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and the like, preferably dichloromethane/methanol/acetic acid is 100-50:1: 0.1.
Further, the preparation method comprises the following test compound 3-ketone-7 α -hydroxy-6 α -ethyl-5 β -cholestan-24-acid (L):
the method comprises the following steps:
step ⑴, oxidizing compound J to generate compound K;
step ⑵ hydrolysis of compound K to produce compound L:
and (3) purifying the compound L by adopting column chromatography.
The process route is as follows:
in the step ⑴, the reaction temperature is 100-130 ℃, the reaction solvent is toluene, o-xylene and a mixture thereof, preferably toluene, the molar ratio of the compound J to the AgCO3-celite is 1:6.37, water is brought by continuous reflux in the reaction process, in the step ⑵, the reaction solvent is selected from methanol, ethanol, acetone, an aqueous sodium hydroxide solution and a mixture thereof, preferably a mixed solution of methanol and an aqueous sodium hydroxide solution, the reaction temperature is 40-60 ℃, the molar ratio of the compound K to the sodium hydroxide is 1 (1.5-3.5), preferably 1:2.4, in the step (3), silica gel is adopted for column chromatography, and the eluent is selected from a mixed solvent system of dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and the like, preferably dichloromethane/methanol/acetic acid is 100-50:1: 0.1.
The method has the advantages that the method can quickly and efficiently synthesize the five impurities of obeticholic acid, and the obeticholic acid is semisynthetic chenodeoxycholic acid and is also a specific agonist of a farnesoid derivative X receptor (FXR), the FXR is a nuclear receptor expressed in liver and small intestine and is a key regulatory factor in bile acid, inflammation, fibrosis and metabolic pathways, so that the synthesis of the five impurities of obeticholic acid replaces the old standard therapeutic drug ursodeoxycholic acid, and the synthesis method of the five impurities of obeticholic acid also promotes the development of the pharmaceutical industry.
Drawings
FIG. 1 is a process scheme for the synthesis of Compound D;
FIG. 2 is a NMR spectrum of Compound D;
FIG. 3 is a process scheme for the synthesis of Compound F;
FIG. 4 is a NMR spectrum of Compound F;
FIG. 5 is a process scheme for the synthesis of Compound G;
FIG. 6 is a NMR spectrum of Compound G;
FIG. 7 is a process scheme for the synthesis of Compound I;
FIG. 8 is a NMR spectrum of Compound I;
FIG. 9 is a process scheme for the synthesis of compound L;
figure 10 is a nuclear magnetic resonance hydrogen spectrum of compound L.
Detailed Description
The present invention will be further described with reference to the drawings and the embodiments thereof, it should be understood that the following embodiments are merely illustrative of the present invention and the scope of the present invention should not be construed as being limited to the following embodiments.
EXAMPLE 1 preparation of (E) -3 β -hydroxy-6-ethylidene-7-one-5 β -cholestan-24-oic acid (D)
A1000 m L three-necked flask was charged with 20g of Compound A, 11g of EDCI, 1.2g of DMAP, 400m L of DCM, N2And (3) replacing, slowly adding methanol dropwise at 24 ℃, reacting for 2-3h at 24 ℃, monitoring the reaction completion by T L C (DCM: EtOH 20:1, UV), adding 200m of L diluted acid solution into the reaction liquid, stirring, standing for layering, washing an organic phase by 200m of L water and 200m of L saturated sodium chloride solution respectively, drying by anhydrous sodium sulfate, and carrying out column chromatography separation (eluent: DCM: EtOH 50:1) to obtain the off-white solid compound B14.856 g.
Adding 3.1g of compound B, 3.51g of benzoic acid, 7.55g of triphenylphosphine and 50m of L THF into a 100m L three-necked flask, cooling, adding 5.82g of DIAD at 0-10 ℃, reacting at 18 ℃ for 20h, monitoring by T L C the reaction is finished (PE: EA ═ 2:1, UV), concentrating under reduced pressure to dryness, adding 50m L EA and 20m L saturated KHCO into the residue3Stirring the solution, standing for layering, and saturating KHCO with 30m L for EA phase3Washing the solution once, and directly stirring and carrying out powder column chromatography (PE: EA: 150:1/100:1/80:1/40:1/20:1/15:1/10:1) to obtain a compound C.
Adding 1.8g of compound C and 20m L of methanol into a 100m L three-necked bottle, dropwise adding NaOH aqueous solution (0.4g/2m L) while stirring, heating to 40 ℃ after dropwise adding, reacting for 5 hours, monitoring the reaction completion by T L C (DCM: MeOH ═ 30:1, UV), concentrating under reduced pressure to dryness, adding 50m L of water, adjusting pH to 6 by using 30% of citric acid aqueous solution, precipitating white solid, filtering, pulping a filter cake by EA, filtering, drying to obtain a white solid compound D0.6 g, ensuring the purity of HP L C to be 90.0%, and keeping the time to be 11.99min, and confirming by HNMR (appended fig. 2).
A liquid chromatography analysis method:
a chromatographic column: chromatographic column using octyl silane bonded silica gel as filler
Mobile phase A: trifluoroacetic acid-water (0.1: 100) mobile phase B: methanol-acetonitrile (10: 90)
A detector: electrospray detector
Detector parameters: a Filter: 3.6s, acquisition frequency: 5.0Hz, atomization temperature: 50 deg.C
Gradient of mobile phase:
example 2 preparation of 3 α,7 α -dihydroxy-6 β -ethyl-5 β -cholestan-24-oic acid (F)
Adding 10g of compound E, 100M L THF, 7M L methanol and 20M L sodium hydroxide solution into a 500M L three-necked flask, cooling to 5 ℃, and dropwise adding (2M) L iBH4THF solution 60m L, keeping temperature for 7h, stirring overnight at 20 ℃, filtering, concentrating the filtrate to dryness, adding 200m L water for dissolving, adjusting pH to 5-6 with 30% citric acid solution, precipitating solid, filtering, adding 150m L EA into filter cake for dissolving, adding 50m L water for stirring, standing for layering, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness to obtain white solid 6.2g, performing column chromatography (DCM: EtOH 80:1/50:1/20:1/10:1) to obtain crude compound F, pulping with 20m L n-heptane and 1.1m L methyl tert-ether twice, drying to obtain compound F2 g, HP L C purity 94.5%, retention time 17.21min, and confirming by HNMR (shown in figure 4).
A liquid chromatography analysis method:
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as filler
Mobile phase A: trifluoroacetic acid-water (0.1: 100) mobile phase B: methanol-acetonitrile (5: 95)
A detector: electrospray detector
Detector parameters: a Filter: 3.6s, acquisition frequency: 5.0Hz, atomization temperature: 50 deg.C
Gradient of mobile phase:
example 3 preparation of 3 α,7 β -dihydroxy-6 β -ethyl-5 β -cholestan-24-oic acid (G)
Adding 6g of compound E, 60m of L THF and 4.2m of L methanol into a 250m L three-necked flask, stirring, cooling, and dropwise adding L iBH at 0 DEG C4THF solution, dripping to 4 ℃, keeping the temperature for reaction for 6h, stirring at 20 ℃ overnight, filtering, leaching a filter cake with 50m L THF, concentrating the filtrate to dryness, adding 50m L water, adjusting the pH to 6 with 30% citric acid solution, separating out a solid, filtering, extracting the filtrate with EA, taking an EA phase, dissolving the filter cake with EA, combining the EA solution, concentrating to dryness to obtain a white solid, performing column chromatography separation (DCM: EtOH 60: 1) to obtain a crude product I of the compound G, performing column chromatography separation (DCM: EtOH 80:1) to obtain a crude product II of the compound G, combining the crude product I and the crude product II, pulping with 20m L n-heptane, filtering to obtain a crude product III of the compound G, pulping the crude product III with 12m L n-heptane and 0.2m L methyl tert-ether, filtering, drying to obtain a compound G1.4g, the purity of HP L C93.0%, and the retention time of 13.74min, and confirming the purity by HNMR (shown in the attached figure 6).
A liquid chromatography analysis method:
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as filler
Mobile phase A: trifluoroacetic acid-water (0.1: 100) mobile phase B: methanol-acetonitrile (5: 95)
A detector: electrospray detector
Detector parameters: a Filter: 3.6s, acquisition frequency: 5.0Hz, atomization temperature: 50 deg.C
Gradient of mobile phase:
example 4 preparation of 3 α - (3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholestane-24-acyloxy) -7 α -hydroxy-6 α -ethyl-5 β -cholestane-24-oic acid (I)
10g of compound H is added into a 50m L single-neck bottle, the vacuum degree is vacuumized to be less than or equal to-0.09 MPa, the temperature is raised to 120 ℃ and 130 ℃, the temperature is kept for 31H, and column chromatography (DCM: MeOH: AcOH ═ 50:1:0.1) is carried out to obtain the compound H, 380mg of white solid, the purity of HP L C is 98.9 percent, the retention time is 37.36min, and the HNMR is confirmed to be attached to the attached figure 8.
A liquid chromatography analysis method:
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as filler
Mobile phase A: trifluoroacetic acid-water (0.1: 100) mobile phase B: methanol-acetonitrile (5: 95)
A detector: electrospray detector
Detector parameters: a Filter: 3.6s, acquisition frequency: 5.0Hz, atomization temperature: 50 deg.C
Gradient of mobile phase:
EXAMPLE 5 preparation of 3-keto-7 α -hydroxy-6 α -ethyl-5 β -cholestan-24-oic acid (L)
Adding 2g of compound H and 200m of L toluene into a 250m L reaction flask, stirring and dissolving, adding AgCO3-celite16.7g of N2Displacing, keeping out of the sun, heating to reflux reaction, refluxing and separating water in the reaction process, reacting for 5h, cooling to 50 ℃, filtering, rinsing with 30m L toluene, concentrating the filtrate under reduced pressure in a 50m L reaction bottle, adding 2.17g of yellow shaped substance and 20m L methanol, stirring for dissolving, adding NaOH aqueous solution (0.48g/12m L), heating to 40 ℃, reacting for 2h, cooling, adding 200m L EA and 24m L1N hydrochloric acid solution into the reaction solution, stirring, standing for layering, washing the EA phase with 200m L water, concentrating the EA phase under reduced pressure, performing column chromatography (DCM: MeOH: AcOH 60:1:0.1), obtaining an off-white solid compound L508 mg, HP L C98.1%, keeping for 17.62min, and confirming by HNMR (shown in figure 10).
A liquid chromatography analysis method:
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as filler
Mobile phase A: trifluoroacetic acid-water (0.1: 100) mobile phase B: acetonitrile
A detector: electrospray detector
Detector parameters: a Filter: 3.6s, acquisition frequency: 5.0Hz, atomization temperature: 50 deg.C
Gradient of mobile phase:
the technical solutions described above only represent the preferred technical solutions of the present invention, and some possible modifications to some parts of the technical solutions by those skilled in the art all represent the principles of the present invention, and fall within the protection scope of the present invention.
Claims (10)
1. The preparation method of the obeticholic acid impurity is characterized by comprising the preparation method of a compound (E) -3 β -hydroxy-6-ethylidene-7-ketone-5 β -cholestane-24-acid (D):
the method comprises the following steps:
the method comprises the following steps: nucleophilic substitution of compound B to produce compound C;
step two: purifying the compound C by adopting column chromatography;
step three: deprotection of compound C yields compound D.
The process route is as follows:
2. the method for preparing obeticholic acid impurities according to claim 1, wherein in the first step, the reaction solvent is selected from tetrahydrofuran; the reaction temperature is 0-20 ℃; the molar ratio of the compound B to the benzoic acid, the triphenylphosphine and the DIAD is 1 (2-5) to (2-5).
3. The method for preparing obeticholic acid impurity according to claim 1, wherein column chromatography in step two adopts silica gel column packing, and eluent is selected from mixed solvent systems of dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and the like, preferably petroleum ether/ethyl acetate is 150-10: 1.
4. The method for preparing obeticholic acid impurities according to claim 1, wherein in the third step, the reaction solvent is selected from methanol, ethanol, acetone, aqueous sodium hydroxide solution and a mixture thereof; the reaction temperature is 40-60 ℃; the molar ratio of compound C to sodium hydroxide was 1: (1.5-3.5), adjusting the pH value to 6 by using citric acid aqueous solution after the reaction is completed, filtering, and pulping a filter cake by using EA.
5. The method of preparing obeticholic acid impurity according to claim 1, comprising the preparation method of test compound 3 α,7 α -dihydroxy-6 β -ethyl-5 β -cholestan-24-oic acid (F):
the method comprises the following steps:
step a: reducing the compound E to generate a compound F;
step b: compound F was purified by column chromatography.
The process route is as follows:
6. the method for preparing obeticholic acid impurities according to claim 1, wherein in the step a, a tetrahydrofuran solution of lithium borohydride is used as a reducing reagent, and the molar ratio of the compound E to the lithium borohydride is 1: 7; the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, and mixtures thereof, preferably methanol; in the step b, the column chromatography is carried out by silica gel packing, and the eluent is selected from dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and other mixed solvent systems, preferably dichloromethane/ethanol is 80-60: 1.
7. The method of preparing obeticholic acid impurity according to claim 1, comprising the preparation method of test compound 3 α,7 β -dihydroxy-6 β -ethyl-5 β -cholestan-24-oic acid (G):
comprises the following steps;
step ① reduction of compound E to form compound G;
step ② Compound G was purified by column chromatography.
The process route is as follows:
in the step ①, a tetrahydrofuran solution of lithium borohydride is used as a reducing reagent, the molar ratio of the compound E to the lithium borohydride is 1:7, a reaction solvent is selected from methanol, ethanol, tetrahydrofuran and a mixture thereof, the reaction temperature is 0-20 ℃, in the step ②, silica gel is used for column chromatography, and an eluent is selected from mixed solvent systems of dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and the like, preferably, the dichloromethane/ethanol ratio is 80-60: 1.
8. The method of preparing obeticholic acid impurity according to claim 1, comprising the preparation method of test compound 3 α - (3 α,7 α -dihydroxy-6 α -ethyl-5 β -cholestane-24-acyloxy) -7 α -hydroxy-6 α -ethyl-5 β -cholestane-24-oic acid (I):
the method comprises the following steps:
step I: condensing the compound H to generate a compound I;
step II: the compound I is purified by column chromatography.
The process route is as follows:
wherein, in the step I, the reaction temperature is 120130 ℃, and the reaction pressure is less than or equal to-0.09 Mpa; in the step II, the column chromatography adopts silica gel column packing, and the eluent is selected from mixed solvent systems of dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and the like, preferably dichloromethane/methanol/acetic acid is 100-50:1: 0.1.
9. The method of preparing obeticholic acid impurity according to claim 1, comprising the preparation of the following compound 3-keto-7 α -hydroxy-6 α -ethyl-5 β -cholestan-24-oic acid (L):
the method comprises the following steps:
step ⑴, oxidizing compound J to generate compound K;
step ⑵ hydrolysis of compound K to produce compound L:
and (3) purifying the compound L by adopting column chromatography.
The process route is as follows:
10. the preparation method of obeticholic acid impurities according to claim 1, characterized in that in step ⑴, the reaction temperature is 100-130 ℃, the reaction solvent is toluene, o-xylene and a mixture thereof, preferably toluene, the molar ratio of the compound J to AgCO3-celite is 1:6.37, water is brought under continuous reflux in the reaction process, in step ⑵, the reaction solvent is selected from methanol, ethanol, acetone, an aqueous sodium hydroxide solution and a mixture thereof, preferably a mixed solution of methanol and an aqueous sodium hydroxide solution, the reaction temperature is 40-60 ℃, the molar ratio of the compound K to the sodium hydroxide is 1 (1.5-3.5), preferably 1:2.4, in step (3), a silica gel column is adopted, and the eluent is selected from a mixed solvent system of dichloromethane/methanol, dichloromethane/ethanol, petroleum ether/ethyl acetate and the like, preferably dichloromethane/methanol/acetic acid is 100-50:1: 0.1.
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| CN105294801A (en) * | 2015-07-02 | 2016-02-03 | 扬子江药业集团南京海陵药业有限公司 | Method for synthesizing, separating and determining obeticholic acid (OCA) isomer |
| CN106046094A (en) * | 2016-05-30 | 2016-10-26 | 福建广生堂药业股份有限公司 | Obeticholic acid dimer impurities and preparation method thereof |
| WO2016173397A1 (en) * | 2015-04-28 | 2016-11-03 | 上海翰森生物医药科技有限公司 | Cholic acid derivative, and preparation method and medical use thereof |
| CN108191939A (en) * | 2017-12-08 | 2018-06-22 | 丽珠集团新北江制药股份有限公司 | A kind of method for preparing shellfish cholic acid intermediate difficult to understand and shellfish cholic acid difficult to understand |
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2020
- 2020-04-09 CN CN202010272810.8A patent/CN111440223A/en active Pending
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| WO2016173397A1 (en) * | 2015-04-28 | 2016-11-03 | 上海翰森生物医药科技有限公司 | Cholic acid derivative, and preparation method and medical use thereof |
| CN105294801A (en) * | 2015-07-02 | 2016-02-03 | 扬子江药业集团南京海陵药业有限公司 | Method for synthesizing, separating and determining obeticholic acid (OCA) isomer |
| CN106046094A (en) * | 2016-05-30 | 2016-10-26 | 福建广生堂药业股份有限公司 | Obeticholic acid dimer impurities and preparation method thereof |
| CN108191939A (en) * | 2017-12-08 | 2018-06-22 | 丽珠集团新北江制药股份有限公司 | A kind of method for preparing shellfish cholic acid intermediate difficult to understand and shellfish cholic acid difficult to understand |
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