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WO2018054300A1 - Alcali exempt de dérivé d'acide cholique, forme cristalline, leurs procédés de préparation et leurs applications - Google Patents

Alcali exempt de dérivé d'acide cholique, forme cristalline, leurs procédés de préparation et leurs applications Download PDF

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Publication number
WO2018054300A1
WO2018054300A1 PCT/CN2017/102453 CN2017102453W WO2018054300A1 WO 2018054300 A1 WO2018054300 A1 WO 2018054300A1 CN 2017102453 W CN2017102453 W CN 2017102453W WO 2018054300 A1 WO2018054300 A1 WO 2018054300A1
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Prior art keywords
formula
compound
disease
solvent
acid
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English (en)
Chinese (zh)
Inventor
苏熠东
龚素娟
包如迪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Priority to CN201780049733.6A priority Critical patent/CN109641934B/zh
Publication of WO2018054300A1 publication Critical patent/WO2018054300A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • 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
    • C07J9/005—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 containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • 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

Definitions

  • the invention belongs to the technical field of medicines, in particular to a crystalline cholic acid derivative free base, a preparation method and application thereof, and a substantially pure bile acid derivative, a preparation method and application thereof, and a cholic acid Process for the preparation of derivatives and their use.
  • the farnesyl ester derivative X receptor is a member of the hormone nuclear receptor superfamily, which is mainly expressed in the liver, small intestine, kidney, and adrenal gland, and less expressed in adipose tissue and heart. Farnesol was originally thought to be its ligand and was named after it.
  • FXR ligand binds directly to the FXR carboxy terminal ligand binding region (LBD)
  • LBD FXR carboxy terminal ligand binding region
  • RXR retinoid receptor
  • the binding of FXR DNA response elements to regulate the transcription of target genes and participate in the regulation of sugar and lipid metabolism is an important energy regulator.
  • Primary bile acid chenodeoxycholic acid is the most potent ligand for FXR, and secondary bile acid bile acid and deoxycholic acid can also activate FXR.
  • FXR ligands such as 6-ECDCA, GW4064, etc.
  • the main target genes of FXR include bile salt export pump (BSEP), bile acid binding protein (IBABP) and small heterodimeric chaperone receptor (SHP), etc., FXR and FXR response elements on these gene promoters (FXRE) Binding to regulate the expression of these genes.
  • FXR agonists can both reduce bile acid-dependent bile flow by stimulating the bile salt output pump (BSEP) and also stimulate MRP2 to increase non-biliary acid-dependent bile flow to reduce cholestasis.
  • BSEP bile salt output pump
  • MRP2 biliary acid-dependent bile flow to reduce cholestasis.
  • FXR is expected to be a new drug target for screening and treating other metabolic diseases including cholestatic diseases and nonalcoholic steatohepatitis.
  • This compound has a significant agonistic effect on FXR activity and is expected to be developed as a novel FXR agonist, however, the compound of formula (I) disclosed in Example 14 of the patent PCT/CN2016/079167 is extracted with ethyl acetate and After purification by column chromatography, only a mixture containing another diastereomer can be obtained, which is difficult to prepare into a pharmaceutical preparation suitable for clinical application, and the final physicochemical properties of the product are further confirmed by experiments. Therefore, there is an urgent need to develop a stable, well-dissolved crystal to meet the needs of clinical development of drugs. There is also an urgent need in the art to develop a compound that is optically pure and stable in its ability to meet the needs of clinical development of drugs.
  • the patent uses 3 ⁇ -hydroxy-7-keto-5 ⁇ -cholane-24-acid and 3,4-dihydropyran as raw materials to first protect 3 ⁇ -hydroxyl; then react with ethyl bromide to replace at position 4 Ethyl, which is esterified at the same time, but the reaction needs to be carried out at -70 to -80 °C, and the dangerous n-butyllithium and the carcinogen hexamethylphosphoramide (HMPA) are used as catalysts. This route is not suitable for industrial applications.
  • HMPA carcinogen hexamethylphosphoramide
  • the patent also uses 3 ⁇ -hydroxy-7-keto-5 ⁇ -cholane-24-acid and 3,4-dihydropyran as raw materials, first esters, and then protects 3 ⁇ -hydroxyl by TMS, and then protects 6 positions.
  • the carbonyl group is then reacted with the aldehyde group compound, but the reaction is carried out at -60 to -90 ° C.
  • the solvent used in the reaction is a boron trifluoride diethyl ether solution; after hydrolysis with sodium hydroxide, it is reduced with palladium carbon, and then The configuration was switched at 95-105 ° C, and finally reduced with borohydride at 70-105 ° C to obtain oleic acid.
  • the preparation method requires expensive trimethylchlorosilane, palladium carbon, unstable aldehyde compound, unsafe boron trifluoride diethyl ether solution, and harsh reaction temperature, for example, configuration conversion and reduction at high temperature.
  • the reaction therefore, the synthetic route disclosed in this patent is also not suitable for industrial applications.
  • the patent uses oleic acid as raw material to prepare 5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13- When dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4-dione First esterification, then bromination, ring formation to obtain the final product, and no optimization method for the preparation of oleic acid, the same problem as WO2006122977A2, is not suitable for industrial production, so the development of a suitable pharmaceutical preparation process is also in the field The problem that technicians urgently need to solve.
  • One of the objects of the present invention is to provide a better pharmaceutical crystal.
  • the inventors have intensively studied the different aggregation states of the compound of the formula I, and finally obtained a crystalline form (5R)-5-((2R)-2- ((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-dimethylhexadehydro-1H-cyclopenta[a]phenanthrene- 17-yl)propyl)thiazolidine-2,4-dione of formula (I) greatly improves the physicochemical properties of the compound of formula (I) and is useful in the treatment of FXR-mediated diseases, including cardiovascular diseases, arteries Atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic liver disease, gastrointestinal disease, kidney disease, cardiovascular disease, metabolic disease, cancer (such as colorectal cancer) or nerve signs such as stroke, etc. Wide range of medical applications
  • the X-ray diffraction pattern includes peaks at diffraction angles (2 theta) at 16.5 ⁇ 0.2 °, 13.6 ⁇ 0.2 °, 12.1 ⁇ 0.2 °, 20.4 ⁇ 0.2 °; preferably also included at 11.5 ⁇ 0.2 °, 9.6 ⁇ 0.2 °, 19.6 ⁇ 0.2°, 15.0 ⁇ 0.2°, a peak at a diffraction angle (2 ⁇ ) of 20.0 ⁇ 0.2°; more preferably further included at 23.7 ⁇ 0.2°, 20.7 ⁇ 0.2°, 23.0
  • Another aspect of the present invention provides a crystalline form of (5R)-5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy- Process for the preparation of 10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4-dione free base, characterized by The following steps:
  • the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate, isopropyl acetate, toluene, n-butanol, cyclohexane, dichloromethane, and dimethyl.
  • Formamide dimethylacetamide, dimethyl sulfoxide, dioxane, diethyl ether, n-heptane, n-hexane, methyl ethyl ketone, isooctane, pentane, dipropanol, tetrahydrofuran, dimethyltetrahydrofuran, three Ethyl chloride, xylene or a mixture thereof.
  • the organic solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, n-hexane or a mixture thereof.
  • the powder X-ray diffraction pattern of the crystal obtained in the step 2) of the preparation method includes a diffraction angle (2 ⁇ ) at 16.5 ⁇ 0.2°, 13.6 ⁇ 0.2°, 12.1 ⁇ 0.2°, and 20.4 ⁇ 0.2°. The peak at the place.
  • a pharmaceutical composition comprising an effective amount of crystalline (5R)-5-((2R)-2-((3R,5S,6R,7R,10S,13R)) -6-ethyl-3,7-dihydroxy-10,13-dimethylhexadehydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4- Diketone free base, a pharmaceutically acceptable carrier or excipient thereof.
  • the FXR mediated disease or condition is selected from the group consisting of cardiovascular disease, hypercholesterolemia, hyperlipidemia chronic hepatitis disease, chronic liver disease, gastrointestinal disease, kidney disease, cerebrovascular disease, metabolic disease or cancer.
  • the chronic liver disease is selected from the group consisting of primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced cholestasis, and intrahepatic gestation Cholestasis, parenteral absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic fat Hepatitis (NASH), liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, sarcoidosis , Wilson's disease, Gaucher's disease, hemochromatosis or alpha 1 anti-membrane proteas
  • PBC primary
  • the gastrointestinal disease is selected from the group consisting of inflammatory bowel disease (I BD), irritable bowel syndrome (IBS), bacterial overgrowth, nutritional malabsorption, post-reflex colitis or microcolitis.
  • I BD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • the kidney disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, chronic glomerulitis, chronic allograft glomerulopathy, chronic interstitial Nephritis or polycystic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • hypertensive nephropathy chronic glomerulitis
  • chronic allograft glomerulopathy chronic interstitial Nephritis or polycystic kidney disease.
  • the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, atherosclerosis, dyslipidemia, hypercholesterolemia or hypertriglyceridemia.
  • the metabolic disease is selected from the group consisting of insulin resistance, type I diabetes, type II diabetes, or obesity; and cerebrovascular disease is selected from stroke.
  • the cancer is selected from the group consisting of colorectal cancer or liver cancer.
  • Another object of the present invention is to isolate a substantially pure compound of formula (I) which can greatly improve the physicochemical properties of the compound of formula (I) and meet the needs of clinical research; and can be used for the treatment of FXR-mediated diseases, including cardiovascular Disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic liver disease, gastrointestinal disease, kidney disease, cardiovascular disease, metabolic disease, cancer (such as colorectal cancer) or nerve signs such as stroke.
  • FXR-mediated diseases including cardiovascular Disease, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic liver disease, gastrointestinal disease, kidney disease, cardiovascular disease, metabolic disease, cancer (such as colorectal cancer) or nerve signs such as stroke.
  • a first aspect of the invention provides a substantially pure compound of formula (I) which means that the compound of formula (I) has an optical purity of greater than 90.0%.
  • the substantially pure compound of formula (I) means that the compound of formula (I) has an optical purity of 95.0% or more.
  • the substantially pure compound of formula (I) contains no more than 10.0% impurities
  • the substantially pure compound of formula (I) contains no more than 5.0% impurities.
  • the optical purity refers to the compound of the formula (II) relative to its non-isomer:
  • a second aspect of the invention provides a process for the preparation of a substantially pure compound of formula (I) comprising the steps of:
  • the positive solvent is selected from the group consisting of a lower ester solvent, a halogenated alkane solvent, a lower alcohol solvent, or a mixture thereof.
  • the positive solvent is selected from the group consisting of preferably ethyl acetate, isopropyl acetate, ethanol, isopropanol, dichloromethane or a mixture thereof.
  • the positive solvent is used in a volume of from 3-5 times the mass to volume ratio of the crude compound of the formula (I).
  • the anti-solvent is selected from the group consisting of a lower alkane solvent, a cycloalkane solvent, a lower ether solvent or a mixture thereof.
  • the anti-solvent is selected from the group consisting of n-heptane, n-hexane, petroleum ether, isopropyl ether or a mixture thereof.
  • the anti-solvent is used in a volume of from 1 to 3 times the volume ratio of the positive solvent.
  • step 5 is concentrated to dryness under reduced pressure, then distilled with a lower alcohol solvent or a mixture thereof, and then concentrated to dryness.
  • step 5 is concentrated under reduced pressure to dryness and then entrained with ethanol, isopropanol or a mixture thereof for distillation.
  • the substantially pure formula obtained in the step 5) (the optical purity of the obtained compound is 90.0% or more; preferably, the substantially pure formula obtained is obtained; the optical purity of the compound is 95.0% or more.
  • the third aspect of the present invention provides a substantially pure formula (the preparation method of the present compound, comprising the following steps:
  • the amount of the first solvent in the step 1) is 2 to 7 times the mass to volume ratio of the crude compound in the formula (1).
  • the amount of the second solvent in the step 2) is the first solvent volume ratio of 0.5-3. Times.
  • the first solvent is selected from the group consisting of a lower ester solvent, a halogenated alkane solvent, a lower alcohol solvent, or a mixture thereof.
  • the first solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, ethanol, isopropanol, dichloromethane or a mixture thereof.
  • the second solvent is selected from the group consisting of a lower alkane solvent, a cycloalkane solvent, a lower ether solvent or a mixture thereof.
  • the second solvent is selected from the group consisting of n-heptane, n-hexane, petroleum ether, isopropyl ether or a mixture thereof.
  • the substantially pure formula obtained in the step 4) (the optical purity of the compound obtained is 90.0% or more.
  • the substantially pure formula obtained in step 4) (the resulting compound has an optical purity of 95.0% or more.
  • the above preparation method formula (for the crude compound can be pretreated by the following steps:
  • the amount of the lower alcohol solvent used in the step 1) is 20 to 60 times the mass to volume ratio of sodium hydroxide or potassium hydroxide.
  • the lower alcohol solvent used in step 1) is selected from the group consisting of ethanol, isopropanol or a mixture thereof.
  • the ester solvent used in step 5 is selected from the group consisting of ethyl acetate, isopropyl acetate or a mixture thereof.
  • a fourth aspect of the invention provides a pharmaceutical composition comprising an effective amount of a substantially pure compound of formula (I), or a pharmaceutically acceptable carrier or excipient thereof.
  • a fifth aspect of the present invention provides the use of the aforementioned substantially pure formula (the compound of the invention, or the aforementioned pharmaceutical composition, for the preparation of a medicament for preventing or treating an FXR-mediated disease or condition.
  • the FXR-mediated disease or condition is selected from the group consisting of cardiovascular disease, hypercholesterolemia, hyperlipidemia, chronic hepatitis disease, chronic liver disease, gastrointestinal disease, kidney disease, cerebrovascular disease, metabolic disease or cancer. .
  • the chronic liver disease is selected from the group consisting of primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced cholestasis, and gestational liver Internal cholestasis, extraintestinal absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic Fatty hepatitis (NASH), liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, nodules Disease, Wilson's disease, Gaucher's disease, hemochromatosis or alpha 1 anti-membrane proteas
  • PBC primary s
  • the gastrointestinal disease is selected from the group consisting of inflammatory bowel disease (I BD), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption of malnutrition, post-reflex colitis or microcolitis.
  • I BD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • bacterial overgrowth malabsorption of malnutrition
  • malabsorption of malnutrition post-reflex colitis or microcolitis.
  • Inflammatory bowel disease is preferably Crohn's Disease or ulcerative bowel disease.
  • the kidney disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephropathy, chronic glomerulitis, chronic allograft glomerulopathy, chronic interstitial Nephritis or polycystic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • hypertensive nephropathy chronic glomerulitis
  • chronic allograft glomerulopathy chronic interstitial Nephritis or polycystic kidney disease.
  • the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, atherosclerosis, dyslipidemia, hypercholesterolemia or hypertriglyceridemia.
  • the metabolic disease is selected from the group consisting of insulin resistance, type I diabetes, type II diabetes, or obesity.
  • the cerebrovascular disease is selected from a stroke.
  • the cancer is selected from the group consisting of colorectal cancer or liver cancer.
  • the present invention has the following advantages:
  • the present invention solves the technical problem that the product obtained in the fourteenth embodiment of the patent PCT/CN2016/079167 is extracted by ethyl acetate and purified by column chromatography.
  • the compound of the formula (I) obtained by the invention has high optical purity and can reach up to 95%, and the optical purity raw material is beneficial to further pharmacological and toxicological research, and is more in line with the needs of clinical research.
  • the separation and purification process adopted by the invention is simple in operation, green and environmentally friendly, and the solvent used is simple and easy to obtain, the yield is stable, the quality is reliable, and it is beneficial to industrial applications.
  • Another object of the present invention is to provide a process for preparing a cholic acid derivative which has mild reaction conditions, mature process and stable quality, and is very suitable for industrial applications.
  • a first aspect of the invention provides a process for the preparation of a compound of formula (III), comprising the steps of:
  • R is selected from C 1-4 alkyl; Pg is a hydroxy protecting agent.
  • R is preferably selected from methyl or ethyl in the preparation process.
  • Pg in the preparation method is preferably a substituted or unsubstituted benzoyl group, a substituted or unsubstituted benzenesulfonyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted benzyl group or a trialkyl silicon group.
  • the Pg in the preparation method is preferably from the following structure:
  • the Pg in the preparation method is selected from the following structures:
  • the above compound of the formula (III) can be used as a preparation of oleic acid and 5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy- A key intermediate for 10,13-dimethylhexadehydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4-dione.
  • the esterification reaction of the step 1) in the production method is carried out in an acidic environment at a temperature of from 20 ° C to 35 ° C.
  • the esterification reaction of the step 1) in the production method is preferably carried out at a temperature of from 22 ° C to 27 ° C.
  • the esterification reaction of the step 1) in the preparation method is carried out under acidic conditions, and the acid may be selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, and hydroiodic acid. , methanesulfonic acid or a mixture thereof. Preferably, it is selected from hydrochloric acid or sulfuric acid.
  • the isomerization reaction of the step 3) in the production method is carried out by using sodium alkoxide in an alcohol solvent at a reaction temperature of 5 ° C to 35 ° C.
  • the reaction temperature is from 15 ° C to 25 ° C.
  • the sodium alkoxide used in the isomerization reaction of the step 3) in the preparation method is selected from the group consisting of sodium methoxide, sodium ethoxide or sodium t-butoxide.
  • the alcohol solvent used in the isomerization reaction of the step 3) in the preparation method is selected from the group consisting of methanol, ethanol, isopropanol or tert-butanol.
  • the step 5) reduction of the carbonyl group uses sodium borohydride to reduce the carbonyl group of the compound of the formula (VIII) in an alcohol solvent to obtain a compound of the formula (III), and the reaction temperature is -5 ° C to 10 °C.
  • the reaction temperature is from 0 ° C to 3 ° C.
  • the alcohol solvent used in the step 5) reduction of the carbonyl group in the preparation method is selected from the group consisting of methanol, ethanol, isopropanol or tert-butanol.
  • the reaction is quenched with acetone and citric acid.
  • Another aspect of the present invention provides a preparation method of the above preparation method for preparing oleic acid.
  • a compound of the formula (III) is prepared by the above preparation method, and then the reaction is carried out as follows. :
  • the acid is an organic acid or an inorganic acid.
  • the organic acid is preferably selected from the group consisting of trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid or a mixture thereof; Hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid or a mixture thereof.
  • Another aspect of the present invention provides a preparation method of the above preparation method for preparing oleic acid.
  • a compound of the formula (III) is prepared by the above preparation method, and then the reaction is carried out as follows. :
  • the compound of the formula (III) is preferably selectively acid-reacted under the action of lithium hydroxide to form a compound of the formula (IX).
  • Another aspect of the present invention provides a process for the preparation of 5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy).
  • -10,13-Dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4-dione in the preparation of 5-(( 2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopentadiene [a]phenanthroline-yl)propyl)thiazolidine-2,4-dione is prepared by the above preparation method to obtain a compound of the formula (III), and then the reaction is carried out as follows:
  • the compound of the formula (III) is preferably selectively acid-reacted under the action of lithium hydroxide to form a compound of the formula (IX).
  • the compound of the formula (XI) 5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3) obtained by purifying with dichloromethane is purified.
  • 7-dihydroxy-10,13-dimethylhexadehydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4-dione can be obtained by HPLC purity 98% or more.
  • the preparation method of the invention has the following advantages:
  • the present invention is (4R)-4-((3R,5R,10R,13R,14R,17R,Z)-6-ethylidene-3-hydroxy-10,13-dimethyl-7-carbonyl-10- Hexahydro-1H-cyclopenta[a]phenanthrene-17-yl)pentanoic acid is used as a raw material, and the esterification reaction is carried out in the first step until the preparation of oleic acid or 5-((2R)-2 -((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-dimethylhexadehydro-1H-cyclopenta[a]phenanthrene
  • the -17-yl)propyl)thiazolidine-2,4-dione has not undergone a hydrolysis reaction before, and the obtained ester-forming intermediates are easily soluble in a hydrophobic organic solvent, which is advantageous for post-treatment of each reaction.
  • the patent WO2002072598A1 is solved by using 3 ⁇ -hydroxy-7-keto-5 ⁇ -cholane-24-acid and 3,4-dihydropyran as raw materials, and is protected by 3 ⁇ -hydroxyl and reacted with ethyl bromide at 4 positions.
  • the simultaneous esterification reaction of the substituted ethyl group needs to be carried out at -70 to -80 ° C, and the defect of n-butyl lithium and the carcinogen hexamethylphosphoramide is required, and the esterification reaction temperature of the present invention can be carried out at around normal temperature.
  • the purity and yield of the obtained product are very high. Therefore, the esterification reaction of the present invention is suitable for industrial applications.
  • the present invention also provides a 5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl group) Purification method of hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4-dione, the purification method of the invention is simple in operation, and the obtained product has high purity and good quality. It is conducive to the development of follow-up drugs.
  • Figure 1 is an X-ray powder diffraction pattern of a crystalline form of a free base of the compound of Formula I; the abscissa is the diffraction peak angle 2? (?), and the ordinate is the intensity of the peak.
  • Figure 2 is a thermogravimetric analysis of the crystalline form of the free base of the compound of Formula I; the abscissa is temperature (°C) and the ordinate is percent weight loss (%).
  • Figure 3 is a differential scanning calorimetry diagram of the crystalline form of the free base of the compound of Formula I; the abscissa is temperature (°C) and the ordinate is heat flow (W/G).
  • the term "pharmaceutically acceptable” means that it is suitable for contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problematic complications, and reasonable benefits/risks. Compounds, materials, compositions and/or dosage forms that are more commensurate.
  • substantially pure means that in certain preferred embodiments of the invention the crystalline structure of the compound of formula I is in substantially pure form, and the HPLC purity or crystal form purity is substantially above 90% (inclusive), preferably above 95%. More preferably, it is 98% or more, and most preferably 99.5% or more.
  • polymorph or “polymorph” refers to a crystal form having the same chemical composition but constituting different spatial arrangements of molecules, atoms and/or ions of the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement and may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution. Rate and similar properties. Depending on their temperature-stability relationship, the two polymorphs may be mono- or trans-denatured. For a single denatured system, the relative stability between the two solid phases remains constant as the temperature changes.
  • the crystalline structure of the present invention can be prepared by a variety of methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state conversion from another phase, crystallization from a supercritical fluid, and jet spray.
  • Techniques for crystallizing or recrystallizing a crystalline structure from a solvent mixture including solvent evaporation, lowering the temperature of the solvent mixture, seeding of the supersaturated solvent mixture of the molecule and/or salt, lyophilizing the solvent mixture, adding an anti-solvent to the solvent mixture Wait.
  • Crystalline structures, including polymorphs can be prepared using high throughput crystallization techniques.
  • seed crystals are added to any of the crystallization mixtures to promote crystallization.
  • the present invention may also use seed crystals as a means of controlling the growth of a particular crystalline structure or as a means of controlling the particle size distribution of the crystalline product. Accordingly, the calculation of the amount of seed crystals required depends on the size of the available seed crystals, as described in "Programmed cooling of batch crystallizers," JW Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. The desired size of the average product particles. In general, small size seed crystals are required to effectively control the growth of crystals in the batch.
  • Small size seed crystals can be produced by sieving, grinding or micronizing of larger crystals or by microcrystallization of solution. It should be noted that grinding or micronization of crystals does not cause any change in the crystallinity of the desired crystal structure (ie, becomes no Shape or become another polymorph).
  • crystal structures of the crystal structures disclosed or claimed herein may exhibit similar but not identical analytical characteristics within reasonable margins based on test conditions, purity, equipment, and other constant variables known to those skilled in the art. Accordingly, it is apparent to those skilled in the art that various modifications and changes can be made in the present invention without departing from the scope and spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art in view of this disclosure. Applicants desire that the specification and examples be considered as illustrative and not limiting.
  • room temperature or "RT” as used herein refers to an ambient temperature of 20 to 25 ° C (68-77 ° F).
  • composition denotes a mixture containing one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, or other components such as physiology/pharmaceuticals. Acceptable carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the reagents used in the examples of the present invention are commercially available industrial grade or analytical grade reagents, and the starting materials of the selected compound of formula (I) are prepared according to Example 14 of Hausen Patent PCT/CN2016/079167.
  • the X-ray powder diffraction pattern can be obtained under measurement error that depends on the measurement conditions used.
  • the intensity in the X-ray powder diffraction pattern may fluctuate depending on the material conditions used.
  • the relative intensities may also vary with experimental conditions and, accordingly, the exact strength should not be taken into account.
  • the measurement error of the conventional X-ray powder diffraction angle is usually about 5% or less, and such measurement error degree should be regarded as belonging to the above diffraction angle.
  • the crystal structure of the present invention is not limited to a crystal structure that provides an X-ray diffraction pattern identical to the X-ray powder diffraction pattern depicted in the drawings disclosed herein. Any crystal structure that provides substantially the same X-ray powder diffraction pattern as those disclosed in the drawings is within the scope of the invention.
  • the ability to determine that the X-ray powder diffraction pattern is substantially the same is within the abilities of one of ordinary skill in the art. Other suitable standard calibrations known to those skilled in the art. However, the relative intensity may vary with crystal size and shape.
  • the polymorphic forms of the compounds of formula I are characterized by their X-ray powder diffraction pattern. Therefore, in Cu K ⁇ radiation
  • the X-ray powder diffraction pattern was acquired on a Rigaku Ultima IV X-ray powder diffractometer operating in a reflective manner.
  • the tube voltage and current quantities were set to 40kV and 40mA acquisition scans, respectively.
  • the sample was scanned for a period of 5 minutes in the range of 2 ⁇ from 5.0° to 45°. All analyses were performed at room temperature, typically between 20 ° C and 30 ° C.
  • the XRPD sample is prepared by placing the sample on a single crystal silicon wafer, and gently pressing the sample powder with a glass slide or equivalent to ensure that the sample surface is flat and has an appropriate height.
  • Measurement differences associated with such X-ray powder diffraction analysis results are produced by a variety of factors including: (a) errors in sample preparation (eg, sample height), (b) instrument error, (c) calibration differences, ( d) operator error (including those that occur when determining peak position), and (e) properties of the substance (eg, preferred orientation error). Calibration errors and sample height errors often result in displacement of all peaks in the same direction. In general, this calibration factor will align the measured peak position to the expected peak position and may be in the range of the expected 2 ⁇ value ⁇ 0.2°.
  • Thermogravimetric analysis (TGA) experiments were performed in a TA Instruments TM model Q500. A sample (approximately 2-10 mg) was placed in a pre-weighed platinum pan. The sample weight was accurately measured by the instrument and recorded to a thousand of a milligram. The furnace was purged with nitrogen at 100 ml/min. Data were collected at room temperature to 300 ° C at a heating rate of 10 ° C / min.
  • DSC Differential scanning calorimetry
  • the X-ray powder diffraction pattern is shown in Figure 1; the thermogravimetric analysis chart is shown in Figure 2 (loss of weight 0.29%), the differential scanning calorimetry diagram is shown in Figure 3 (melting point 132.9 ° C); dynamic water adsorption DVS isotherm
  • the DVS test conditions are as follows: without N 2 in the presence of temperature, 25.0 ° C, relative humidity (RH): from 0% to 95% to 0%; stability test is as follows:
  • Placement time (h) Relative purity 0 / 3 101.1% 6 102.1% twenty four 100.4%
  • Placement condition Placement time purity(%) Relative purity (%) 0 days / 98.9 / 25°C/RH75% 7 days 99.0 100.1 40°C/RH75% 7 days 98.2 99.3 50 ° C 7 days 98.8 99.9
  • the experimental results show that the crystal of the compound is placed at 25 ° C / RH 75%, 40 ° C / RH 75%, 50 ° C, 80 ° C and light conditions for 7 days, no significant degradation, and can remain stable.
  • the liquid phase analysis conditions are as follows:
  • C 1-4 alkyl means a straight-chain alkyl group having 1 to 4 carbon atoms and a branched alkyl group, and the alkyl group means a saturated aliphatic hydrocarbon group such as methyl group, ethyl group, n-propyl group or the like.
  • the "alcohol solvent” means an alkane compound having a hydroxyl group in the molecule, such as methanol, ethanol, or isopropanol.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • Step 1 methyl (4R)-4-((3R,5R,10R,13R,14R,17R,Z)-6-ethylidene-3-hydroxy-10,13-dimethyl-7-carbonyl-10- Preparation of hexahydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate
  • ⁇ Detection wavelength 205 nm; 214 nm; 254 nm.
  • Step 2 Methyl (4R)-4-((3R,5S,6S,10S,13R,14R,17R)-6-ethyl-3-hydroxy-10,13-dimethyl-7-carbonyl Preparation of hydrogen-1H-cyclopenta[a]phenanthrene-17-yl)valerate
  • Step 3 Methyl (4R)-4-((3R,5S,6R,10S,13R,14R,17R)-6-ethyl-3-hydroxy-10,13-dimethyl-7-carbonyl Preparation of hydrogen-1H-cyclopenta[a]phenanthrene-17-yl)valerate
  • Step 4 (3R,5S,6R,10S,13R,14R,17R)-6-ethyl-17-((R)-5-methoxy-5-carbonylpentan-2-yl)-10, Preparation of 13-dimethyl-7-carbonylhexadecahydro-1H-cyclopenta[a]phenanthr-3-yl-4-nitrobenzoate
  • ⁇ Detection wavelength 205 nm; 214 nm; 254 nm; 225 nm
  • the impurity structure is resolved as follows:
  • Step 5 (3R, 5S, 6R, 7R, 10S, 13R, 14R, 17R)-6-ethyl-7-hydroxy-17-((R)-5-methoxy-5-carbonylpentane-2 Of -10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthr-3-yl-4-nitrobenzoate
  • the impurity structure is resolved as follows:
  • Step 1 methyl (4R)-4-((3R,5S,6R,7R,10S,13R,14R,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-10- Preparation of hexahydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate
  • reaction liquid was added to 50 ml of a saturated aqueous solution of ammonium chloride precooled to 0 ° C, and the solvent was evaporated under reduced pressure. 50 ml of ethyl acetate was added to the residue, and the mixture was stirred and separated, and the organic phase was sequentially applied with 50 ml of 4% potassium phosphate. The aqueous solution and the saturated aqueous solution of 15 ml of brine were washed once, dried over anhydrous sodium sulfate, and evaporated to dryness to give 2.9 g (yield: 90.1%, HPLC: 100%).
  • Step 1 methyl (4R)-2-bromo-4-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-10- Preparation of hexahydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate
  • the reaction was further stirred at a temperature of -70 ° C to -65 ° C for 1 h.
  • 154.9 g (1.426 mol) of trimethylchlorosilane was added dropwise at a temperature of -70 ° C to -60 ° C, and the addition was completed in about 15 minutes, and the reaction was further stirred at a temperature of -60 ° C to -50 ° C for 3 hours.
  • the basic reaction of the TLC detection of the raw materials is completed.
  • 129.6g (728.2mmol) of N-bromosuccinimide was added in portions, and the natural temperature was raised to 22-27 °C.
  • the reaction was stirred for 22 h, and the basic reaction of the starting material was confirmed by TLC.
  • the reaction mixture was cooled to 0 ° C, 1000 ml of saturated sodium bicarbonate solution was added dropwise at a temperature control temperature of 10 ° C, stirred, and the organic phase was concentrated to about 500 ml, and the aqueous phase was extracted with 500 ml of methyl t-butyl ether, and the organic phase was combined.
  • the concentrate and the methyl tert-butyl ether extract are washed once with 1000 ml of water, 250 ml of 1 mol/L hydrochloric acid is added to the above organic phase, stirred at room temperature for 5 h, and the organic phase is washed once with 1500 ml of 20% sodium sulfite solution, and then 1000 ml.
  • Step 2 5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-dimethylhexadecahydro- Preparation of 1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4-dione
  • Optical purity is a measure of the amount of one enantiomer in an optically active sample over the other enantiomer.
  • the compound of formula (I) comprises a compound of formula (I) and (II) Proportion in the compound mixture.
  • the "lower alkane solvent” means a liquid alkane having 5 to 10 carbon atoms at normal temperature, such as n-hexane or n-heptane.
  • cycloalkane solvent means a saturated hydrocarbon having an alicyclic structure and being liquid at normal temperature, such as cyclopentane or cyclohexane.
  • halogenated alkane solvent means a halogen atom-containing alkane which is liquid at normal temperature, such as dichloromethane or chloroform.
  • the "lower alcohol solvent” means an alkane compound having a hydroxyl group in the molecule and having less than 12 carbon atoms, such as methanol, ethanol, or isopropanol.
  • the “lower ester solvent” means an ester compound having a small number of carbon atoms and a liquid state at a normal temperature, preferably an ester compound of an acid having less than 4 carbon atoms and an alcohol having less than 4 carbon atoms, such as acetic acid B. Ester, methyl acetate, isopropyl acetate.
  • “Lower ether solvent” means an ether compound formed by two hydrocarbon groups having a small number of carbon atoms, preferably an ether compound having two hydrocarbon groups of less than 4 carbon atoms, such as diethyl ether, diisopropyl ether, methyl isopropyl. ether.
  • Step 2 Methyl (4R)-2-bromo-4-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl Preparation of Hexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate
  • N-bromosuccinimide N-bromosuccinimide
  • the reaction temperature was raised from -60 °C to -40 °C.
  • the reaction was then naturally raised to room temperature (22 ° C) and the reaction was continued for 24 hours.
  • the basic reaction of the TLC detection raw material is completed, and the reaction liquid is cooled to 0 ° C, and the temperature control is less than 1000 ml of a saturated sodium hydrogencarbonate solution was added dropwise at 10 °C.
  • the liquid was separated, and the organic phase was concentrated to remove some solvent (about 500 ml).
  • the aqueous phase was extracted with 500 ml of methyl tert-butyl ether (MTBE), and the organic phase concentrate and methyl t-butyl ether extract were combined with 1000 ml of water. Wash the combined solution once.
  • MTBE methyl tert-butyl ether
  • the third step 5-((2R)-2-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-dimethylhexadecahydrol Of -1H-cyclopenta[a]phenanthrene-17-yl)propyl)thiazolidine-2,4-dione
  • Methyl (4R)-2-bromo-4-((3R,5S,6R,7R,10S,13R)-6-ethyl-3,7-dihydroxy-10,13-di prepared by the above procedure Methylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)valerate 134.8 g crude (calculated by theoretical calculation of 237.7 mmol) and thiourea 54.3 g (713.1 mmol, 3.0 eq. ) dissolved in 1000 ml of ethanol. The mixture was heated to 70 ° C and stirred for 5 hours. The basic reaction of the TLC detection of the raw materials is completed.

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Abstract

L'invention concerne une forme cristalline d'alcali exempt de dérivé d'acide cholique, son procédé de préparation et une application. Le nom chimique de l'alcali exempt de dérivé d'acide cholique est (5R)-5-((2R)-2-((3R,5S,6R,10S,10S,13R)-6-éthyl -3,7-dihydroxy -10,13-diméthylhexadécahydro -1 H-cyclopenta [a] phénanthrèn-17-yl) propyle) thiazolidine -2,4-dione, et le diagramme de diffraction des rayons X de l'énergie comprend des pics aux angles de diffraction (2θ) de 16,5 ± 0,2°, 13,6 ± 0,2°, 12,1 ± 0,2°, et 20,4 ± 0,2°. La présente invention concerne également un dérivé de l'acide cholique optiquement pur, son procédé de préparation et son application. La pureté de l'isomère optique obtenu atteint 90,0 % ou plus, et le problème dans l'état de la technique concernant la difficulté à obtenir une pureté optique par séparation est résolu. De plus, l'invention concerne également un procédé de préparation d'un dérivé d'acide cholique et une application de celui-ci. Le procédé de préparation permet de surmonter le défaut existant dans l'état de la technique; une réaction multi-étapes peut être mise en oeuvre à température ambiante; le produit obtenu présente une bonne pureté, un rendement élevé, et une opérabilité de processus élevée; la sécurité du processus est considérablement améliorée; le procédé de préparation est approprié pour une application industrielle.
PCT/CN2017/102453 2016-09-20 2017-09-20 Alcali exempt de dérivé d'acide cholique, forme cristalline, leurs procédés de préparation et leurs applications Ceased WO2018054300A1 (fr)

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