WO2016045480A1 - 一种奥贝胆酸的制备方法 - Google Patents
一种奥贝胆酸的制备方法 Download PDFInfo
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- WO2016045480A1 WO2016045480A1 PCT/CN2015/088238 CN2015088238W WO2016045480A1 WO 2016045480 A1 WO2016045480 A1 WO 2016045480A1 CN 2015088238 W CN2015088238 W CN 2015088238W WO 2016045480 A1 WO2016045480 A1 WO 2016045480A1
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- 238000000034 method Methods 0.000 title claims abstract description 22
- ZXERDUOLZKYMJM-ZWECCWDJSA-N obeticholic 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)CCC(O)=O)CC[C@H]21 ZXERDUOLZKYMJM-ZWECCWDJSA-N 0.000 title abstract 2
- 229960001601 obeticholic acid Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 31
- 125000006239 protecting group Chemical group 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 17
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 17
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 17
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 17
- 239000005642 Oleic acid Substances 0.000 claims description 17
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 17
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 claims description 7
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 6
- 230000009467 reduction Effects 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 8
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 0 C[C@](CCC(*)=O)[C@@](CC1)C(C)(CC[C@@]2[C@@](C)(CCC(C3)=*)[C@@]3C3=CC=CC(C)=C)[C@]1[C@]2C3=O Chemical compound C[C@](CCC(*)=O)[C@@](CC1)C(C)(CC[C@@]2[C@@](C)(CCC(C3)=*)[C@@]3C3=CC=CC(C)=C)[C@]1[C@]2C3=O 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003613 bile acid Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 3
- -1 enol compound Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 102100038495 Bile acid receptor Human genes 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- UIZPQBGXOSLNML-VSAVVYFVSA-N CCOC(CC[C@@H](C)[C@@H](CC1)[C@@](C)(CC[C@@H]2[C@@](C)(CC[C@H](C3)O)[C@@H]3/C3=C\C)[C@@H]1[C@@H]2C3=O)=O Chemical compound CCOC(CC[C@@H](C)[C@@H](CC1)[C@@](C)(CC[C@@H]2[C@@](C)(CC[C@H](C3)O)[C@@H]3/C3=C\C)[C@@H]1[C@@H]2C3=O)=O UIZPQBGXOSLNML-VSAVVYFVSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000002844 chenodeoxycholic acid derivative Substances 0.000 description 1
- 150000001801 chenodeoxycholic acids Chemical class 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 102000006255 nuclear receptors Human genes 0.000 description 1
- 108020004017 nuclear receptors Proteins 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 208000007232 portal hypertension Diseases 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention relates to a preparation method of oleic acid.
- Abecholic acid (as shown in Formula I) is a semi-synthetic chenodeoxycholic acid derivative for the treatment of portal hypertension and liver disease, including primary biliary cirrhosis, bile acid diarrhea, non-alcohol Sexual steatohepatitis.
- Obecholic acid acts by activating FXR receptors, a nuclear receptor that is expressed primarily in the liver, intestines, and kidneys. It regulates the expression of genes involved in bile acids, fats, and glucose metabolism, and regulates immune response. Activation of FXR inhibits bile acid synthesis and prevents toxic reactions caused by excessive accumulation of bile acids.
- WO2002072598 discloses for the first time the preparation method of oleic acid (as shown below), which is obtained by direct alkylation of compound VI with ethyl iodide under strong basic conditions to obtain compound VII, which is obtained by reduction and decarboxylation of compound VII.
- Abecholic acid due to the poor selectivity and low yield of direct alkylation with iodoethane, it is difficult to achieve amplification synthesis in this synthesis process.
- WO2006122977 has improved the above synthesis process (as shown below) by converting compound IX to a silicon-based protected enol compound X, which is condensed and dehydrated with acetaldehyde to give compound Vb, and compound Vb is subjected to basic conditions.
- the lower palladium carbon is hydrogenated and reduced to obtain compound XI, and compound XI is reduced by carbonyl to obtain oleic acid.
- choline acid provides a preparation method of oleic acid which is less suitable for large-scale production, has less by-products, is easy to operate, and has low synthesis cost.
- the invention provides a new method for synthesizing oleic acid
- R 1 is a hydroxy protecting group and R 2 is a carboxy protecting group.
- the synthesis method includes the following steps:
- Formula IV is obtained by catalytic hydrogenation of palladium on carbon under basic conditions to obtain a compound of formula III;
- Formula II is deprotected by hydroxy groups under acidic conditions to produce oleic acid as shown in Formula I.
- the compound V is synthesized according to the method described in WO2006122977.
- the hydroxy protecting group R 1 is MOM and the carboxy protecting group R 2 is ethyl.
- the hydroxy protecting group R 1 is MOM and the carboxy protecting group R 2 is methyl.
- the present invention provides a synthetic route for oleic acid as follows:
- the synthesis method includes the following steps:
- Formula IVa is obtained by catalytic hydrogenation of palladium on carbon under basic conditions to obtain a compound of formula IIIa;
- Formula IIa is hydrolyzed by hydrochloric acid to remove hydroxy group protection to obtain oleic acid as shown in Formula I.
- the compound Va is synthesized according to the method described in WO2006122977.
- the invention also provides a compound of formula IV,
- R 1 is a hydroxy protecting group and R 2 is a carboxy protecting group.
- the hydroxy protecting group R 1 is MOM and the carboxy protecting group R 2 is ethyl.
- the hydroxy protecting group R 1 is MOM and the carboxy protecting group R 2 is methyl.
- the invention further provides a process for the preparation of a compound of formula IV, which is prepared by hydroxy protecting a compound of formula V.
- R 1 is a hydroxy protecting group and R 2 is a carboxy protecting group.
- the invention also provides a compound of formula III,
- R 1 is a hydroxy protecting group
- the hydroxy protecting group R 1 is MOM.
- the invention further provides a process for the preparation of a compound of formula III, which is prepared by catalytic hydrogenation of palladium on carbon under basic conditions by a compound of formula VI.
- R 1 is a hydroxy protecting group
- the hydroxy protecting group R 1 is MOM.
- the invention also provides a compound of formula II,
- R 1 is a hydroxy protecting group
- the hydroxy protecting group R 1 is MOM.
- the present invention further provides a process for the preparation of a compound of the formula II, which is obtained by subjecting a compound of the formula III to a reduction reaction.
- R 1 is a hydroxy protecting group
- the hydroxy protecting group R 1 is MOM.
- the hydroxy protecting group of the present invention is a suitable group for hydroxy protection known in the art, see the hydroxy protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GM Wuts).
- the hydroxy protecting group may be a (C 1-10 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl, tert-butyldiphenylsilyl, etc.; may be a C 1-10 alkyl or substituted alkyl group, preferably an alkoxy or aryl substituted alkyl group, more preferably a C 1-6 alkoxy substituted C a 1-6 alkyl or phenyl substituted C 1-6 alkyl group, most preferably a C 1-4 alkoxy substituted C 1-4 alkyl group, for example: methyl, tert-butyl,
- Carboxylic acid protecting group is a suitable group for carboxylic acid protection known in the art, see the carboxylic acid protecting group in the literature ("Protective Groups in Organic Synthesis", 5 Th Ed. TW Greene & P. GMWuts), As an example, preferably, the carboxylic acid protecting group may be a substituted or unsubstituted C 1-10 linear or branched alkyl group, a substituted or unsubstituted C 2-10 linear or branched alkenyl group.
- alkynyl substituted or unsubstituted C 3-8 cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 alkyl or aryl) 3 silane
- a straight or branched alkyl group of C 1-6 is preferred, and a linear or branched alkyl group of C 1-4 is more preferred.
- the compound IIa (584 g) was dissolved in 6 liters of tetrahydrofuran, cooled to 0 ° C, 5 liters of 4N aqueous hydrochloric acid was added, the temperature was raised to 20 ° C, and the reaction was carried out for 8 hours, and 10 liters of ethyl acetate was added thereto, and the extract was concentrated and analyzed. Crystallization, filtration and drying gave 497 g of oleic acid in a yield of 94%.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Urology & Nephrology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
提供一种如式（III）所示的化合物及其制备方法，其中R 1为羟基保护基，优选MOM，以及通过该化合物制备奥贝胆酸的方法。所述制备方法反应条件温和，副产物少，操作简便，适于大规模生产。
Description
本发明涉及一种奥贝胆酸的制备方法。
奥贝胆酸(如式I所示)是一种半合成鹅去氧胆酸衍生物，用于治疗门静脉血压过高以及肝脏疾病，包括原发性胆汁性肝硬化、胆汁酸腹泻、非酒精性脂肪性肝炎。奥贝胆酸是通过激活FXR受体发挥作用，FXR是一种核受体，主要在肝脏、肠、肾脏中表达，它能够调节与胆汁酸、脂肪和糖代谢相关基因的表达，还能调节免疫反应。激活FXR能够抑制胆汁酸合成，预防胆汁酸过度积累导致的毒性反应。
WO2002072598首次公开了奥贝胆酸的制备方法(如下所示)，该方法通过化合物VI在强碱性条件下用碘乙烷直接烷基化得到化合物VII，化合物VII经过还原和羧基脱保护制得奥贝胆酸。但由于用碘乙烷直接烷基化的选择性差和收率过低，该合成过程很难实现放大合成。
奥贝胆酸合成方法(WO2002072598)
WO2006122977对以上合成工艺进行了改进(如下所示)，该方法通过把化合物IX转化为硅基保护的烯醇化合物X，化合物X与乙醛缩合脱水后得到化合物Vb，化合物Vb经过在碱性条件下钯碳加氢还原得到化合物XI，化合物XI经过羰基还原后制得奥贝胆酸。
奥贝胆酸合成方法(WO2006122977)
该合成工艺虽然可以实现放大合成，然而，在化合物Vb在强碱性条件下钯碳加氢还原和强碱性高温处理制备化合物XI过程中产生大量的副产物，从而导致该步反应的分离收率较低(约60％)，该步反应的低收率可能是由于化合物Vb和XI中的未保护羟基在强碱性(30％NaOH)和高温(95-105℃)条件下发生脱水等副反应造成的。
发明内容
针对现有奥贝胆酸的合成方法中存在的缺点，发明人经过潜心研究发现，通过对化合物V的羟基进行保护，可以避免强碱性和高温条件下发生脱水等副反应，大大提高了奥贝胆酸的合成效率，从而提供了一种副产物少，操作简便，合成成本低廉，适于大规模生产的奥贝胆酸制备方法。
本发明提供了一种合成奥贝胆酸的新方法，
其中，R1为羟基保护基，R2为羧基保护基。
具体来说，该合成方法包括以下步骤：
1)式V化合物通过羟基保护得到如式IV所示的化合物；
2)式IV在碱性条件下通过钯碳催化加氢反应制得如式III所示的化合物；
3)式III经过还原制得如式II所示的化合物；
4)式II在酸性条件下脱除羟基保护制得如式I所示的奥贝胆酸。
其中，化合物V根据WO2006122977中描述的方法合成得到。
本发明一个优选的实施方案中，羟基保护基R1为MOM，羧基保护基R2为乙基。
本发明另一个优选的实施方案中，羟基保护基R1为MOM，羧基保护基R2为甲基。
在一个特别优选的实施方案中，本发明提供奥贝胆酸的合成路线如下：
具体来说，该合成方法包括以下步骤：
1)式Va化合物与MOMCl反应得到如式IVa所示的化合物；
2)式IVa在碱性条件下通过钯碳催化加氢反应制得如式IIIa所示的化合物；
3)式IIIa经过硼氢化钠还原制得如式IIa所示的化合物；
4)式IIa经过盐酸水解脱除羟基保护制得如式I所示的奥贝胆酸。
其中，化合物Va根据WO2006122977中描述的方法合成得到。
本发明还提供一种如式IV所示的化合物，
其中，R1为羟基保护基，R2为羧基保护基。
本发明一个优选的实施方案中，羟基保护基R1为MOM，羧基保护基R2为乙基。
本发明另一个优选的实施方案中，羟基保护基R1为MOM，羧基保护基R2为甲基。
本发明进一步提供一种如式IV所示的化合物的制备方法，化合物IV通过如式V所示的化合物进行羟基保护后制得。
其中，R1为羟基保护基，R2为羧基保护基。
本发明还提供一种如式III所示的化合物，
其中，R1为羟基保护基。
本发明一个优选的实施方案中，羟基保护基R1为MOM。
本发明进一步提供一种如式III所示的化合物的制备方法，化合物III通过如式VI所示的化合物在碱性条件下通过钯碳催化加氢反应制得，
其中，R1为羟基保护基。
本发明一个优选的实施方案中，羟基保护基R1为MOM。
本发明还提供一种如式II所示的化合物，
其中，R1为羟基保护基。
本发明一个优选的实施方案中，羟基保护基R1为MOM。
本发明进一步提供一种如式II所示的化合物的制备方法，化合物II通过如式III所示的化合物经过还原反应后制得，
其中，R1为羟基保护基。
本发明一个优选的实施方案中，羟基保护基R1为MOM。
本发明所使用的术语，除有相反的表述外，具有如下的含义：
本发明的羟基保护基是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C1-10烷基或芳基)3硅烷基，例如：三乙基硅基，三异丙基硅基，叔丁基二甲基硅基，叔丁基二苯基硅基等；可以是C1-10烷基或取代烷基，优选烷氧基或芳基取代的烷基，更优选C1-6烷氧基取代的C1-6烷基或苯基取代的C1-6烷基，最优选C1-4烷氧基取代的C1-4烷基，例如：甲基，叔丁基，烯丙基，苄基，甲氧基甲基，乙氧基乙基，2-四氢吡喃基(THP)等；可以是(C1-10烷基或芳香基)酰基，例如：甲酰基，乙酰基，苯甲酰基等；可以是(C1-6烷基或C6-10芳基)磺酰基；也可以是(C1-6烷氧基或C6-10芳基氧基)羰基。
“羧酸保护基”是本领域已知的适当的用于羧酸保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5Th Ed.T.W.Greene&P.G.M.Wuts)
中的羧酸保护基团，作为示例，优选地，所述的羧酸保护基可以是取代或非取代的C1-10的直链或支链烷基、取代或非取代的C2-10的直链或支链烯基或炔基、取代或非取代的C3-8的环状烷基、取代或非取代的C5-10的芳基或杂芳基、或(C1-8烷基或芳基)3硅烷基；优选C1-6的直链或支链烷基，更优选C1-4的直链或支链烷基。
本发明中所采用英文缩写具有如下意义：
| 缩写 | 全称 |
| MOMCl | 氯甲基甲醚 |
| MOM | 甲氧基甲基 |
| TMS | 三甲基硅基 |
下表为实施例中所涉及的化合物的结构式
以下将结合具体实例详细地解释本发明，使得本专业技术人员更全面地理解本发明,具体实例仅用于说明本发明的技术方案，并不以任何方式限定本发明。
实施例1：制备化合物IVa
将化合物Va(646克，根据WO2006122977中的方法制得)溶于7升二氯甲烷中，加入762毫升二异丙乙基胺，冷却到0℃，加入166毫升MOMCl，反应体系升温至20℃，反应16小时，加水淬灭反应，加入10升乙酸乙酯萃取，分出有机相，有机相用无水硫酸钠干燥，过滤浓缩后得到696克化合物IVa，产率98％。
1H NMR(400MHz,CDCl3)δ6.16(q,1H),4.76–4.59(m,2H),4.28–4.01(m,2H),3.70–3.48(m,1H),3.42–3.29(m,3H),2.56(dd,1H),2.46–2.14(m,4H),2.07–1.87(m,4H),1.87–1.68(m,5H),1.55–1.04(m,16H),1.00(s,3H),0.92(t,3H),0.78–0.62(m,3H).
实施例2：制备化合物IIIa
将化合物IVa(696g)溶于乙醇(7升)中，加入钯碳(76g,10wt％)和500克30％氢氧化钠水溶液，在氢气(1.5大气压)和20℃下反应16h，然后升温到95℃，搅拌16小时，冷却到20℃后，过滤，浓缩后的母液用2N盐酸中和，加10升乙酸乙酯萃取，萃取液经浓缩后，析晶，过滤，干燥后得到606克化合物IIIa，产率92％。
1H NMR(400MHz,CDCl3)δ4.74–4.55(m,2H),3.52–3.39(m,1H),3.38–3.30(m,3H),2.68(dd,1H),2.49–2.13(m,4H),2.02–1.65(m,9H),1.58–1.02(m,15H),0.95(dd,4H),0.86–0.77(m,3H),0.67(d,3H).
实施例3：制备化合物IIa
将化合物IIIa(606克)溶于7升乙醇中，冷却到0℃，加入50克硼氢化钠，升温到20℃，反应8小时，缓慢滴加磷酸直至pH＝6，固体析出，过滤，固体用水洗涤，干燥后得到584克化合物IVa，产率96％。
1HNMR(400MHz,CDCl3)δ4.66(s,2H),3.72(m,2H),3.35(m,4H),2.25-1.07(m,28H),0.90(m,8H),0.65(s,3H).
实施例4：制备奥贝胆酸
将化合物IIa(584克)溶于6升四氢呋喃中，冷却到0℃，加入5升4N盐酸水溶液，升温到20℃，反应8小时，加10升乙酸乙酯萃取，萃取液经浓缩后，析晶，过滤，干燥得到497克奥贝胆酸，产率94％。
1HNMR(400MHz,CD3OD)δ3.65(m,1H),3.30(m,1H),2.32(m,1H),2.20(m,1H),2.03-1.65(m,8H),1.60-1.06(m,18H),0.90(m,9H),0.67(s,3H).
实施例5：制备化合物IVb
将化合物Vb(500克，根据WO2006122977中的方法制得)溶于5升二氯甲烷中，加入650毫升二异丙乙基胺，冷却到0℃，加入147毫升MOMCl，反应体系逐渐升到20℃，反应16小时，加水淬灭反应，加入10升乙酸乙酯萃取，分出有机相，有机相用无水硫酸钠干燥，过滤浓缩后得到524克化合物IVb，产率95％。
1HNMR(400MHz,CDCl3)δ6.16(m,1H),4.65(s,2H),3.66(s,3H),3.55(m,1H),3.34(s,3H),3.08(m,1H),2.55(m,2H),2.53(m,2H),2.22(m,2H),1.96(m,6H),1.80(m,2H),1.69(m,4H),1.56-1.01(m,14H),0.93(m，3H),0.62(s,3H).
实施例6：制备化合物IIIa
将化合物IVb(70g)溶于乙醇(750豪升)中，加入钯碳(8g,10wt％)和50克30％氢氧化钠水溶液，在氢气(1.5大气压)和20℃下反应10h，然后升温到100℃，搅拌10小时，冷却到20℃后，过滤，浓缩后的母液用2N盐酸中和，加1升乙酸乙酯萃取，萃取液经浓缩后，析晶，过滤，干燥后得到65克化合物IIIa，产率95％。
1H NMR(400MHz,CDCl3)δ4.62(m,2H),3.43(m,1H),3.34(m,3H),2.68(m,1H),2.25(m,4H),1.82(m,9H),1.58–1.02(m,15H),0.95(m,4H),0.80(m,3H),0.66(s,3H).
由于已根据其特殊的实施方案描述了本发明，某些修饰和等价变化对于精通此领域的技术人员是显而易见的且包括在本发明的范围内。
Claims (11)
- 一种如式III所示的化合物，
其中，R1为羟基保护基，优选为MOM。 - 一种如式III所示的化合物的制备方法，其特征在于通过如式V所示的化合物经过羟基的保护制得化合物IV，化合物IV通过加氢反应制得化合物III，优选为在碱性条件下通过钯碳催化加氢反应，
其中，R1为羟基保护基，优选为MOM；R2为羧基保护基，优选为C1-10的直链或支链烷基，更优选为乙基或甲基。 - 一种如式IIIa所示的化合物的制备方法，其特征在于包括如下步骤，
1)式Va化合物与MOMCl反应得到如式IVa所示的化合物；2)式IVa在碱性条件下通过钯碳催化加氢反应制得如式IIIa所示的化合物。 - 一种如式IV所示的化合物，
其中，R1和R2如权利要求2中定义。 - 一种如式IV所示的化合物的制备方法，其特征在于，通过如式V所示的化合物经过羟基保护后制得，
其中，R1和R2如权利要求2中定义。 - 一种如式II所示的化合物，
其中，R1如权利要求1中定义。 - 一种如式II所示的化合物的制备方法，其特征在于，通过如式III所示的化合物经过羰基还原后制得，优选使用硼氢化钠还原，
其中，R1如权利要求1中定义。 - 一种如式IIa所示的化合物的制备方法，其特征在于包括如下步骤，
1)式Va化合物与MOMCl反应得到如式IVa所示的化合物；2)式IVa在碱性条件下通过钯碳催化加氢反应制得如式IIIa所示的化合物；3)式IIIa经过硼氢化钠还原制得如式IIa所示的化合物。 - 一种奥贝胆酸的制备方法，其特征在于包括式II所示化合物经过羟基保护基脱除制备奥贝胆酸的步骤，
其中，R1如权利要求1中定义。 - 根据权利要求9所述的奥贝胆酸的制备方法，其特征在于还包括权利要求7所述的制备式II所示的化合物的步骤。
- 根据权利要求10所述的奥贝胆酸的制备方法，其特征在于还包括权利要求2所述的制备如式III所示的化合物的步骤。
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