CN106674069A - GFT505 and preparation method for intermediate thereof - Google Patents
GFT505 and preparation method for intermediate thereof Download PDFInfo
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- CN106674069A CN106674069A CN201611108807.2A CN201611108807A CN106674069A CN 106674069 A CN106674069 A CN 106674069A CN 201611108807 A CN201611108807 A CN 201611108807A CN 106674069 A CN106674069 A CN 106674069A
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- gft505
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- AFLFKFHDSCQHOL-IZZDOVSWSA-N gft505 Chemical compound C1=CC(SC)=CC=C1C(=O)\C=C\C1=CC(C)=C(OC(C)(C)C(O)=O)C(C)=C1 AFLFKFHDSCQHOL-IZZDOVSWSA-N 0.000 title claims abstract description 107
- 229950001279 elafibranor Drugs 0.000 title claims abstract description 105
- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000003960 organic solvent Substances 0.000 claims abstract description 25
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 19
- -1 tert-butanol alkali metal salt Chemical class 0.000 claims abstract description 14
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 11
- 238000006317 isomerization reaction Methods 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 95
- 239000000543 intermediate Substances 0.000 claims description 95
- 239000002904 solvent Substances 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 238000007697 cis-trans-isomerization reaction Methods 0.000 claims description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical group [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 238000012805 post-processing Methods 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 238000005119 centrifugation Methods 0.000 claims description 5
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 150000008280 chlorinated hydrocarbons Chemical group 0.000 claims description 4
- 150000008282 halocarbons Chemical group 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 150000003457 sulfones Chemical class 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N Butanol Natural products CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 239000012535 impurity Substances 0.000 abstract description 6
- 239000000047 product Substances 0.000 abstract description 5
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 abstract description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 abstract 3
- 239000006227 byproduct Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 239000007787 solid Substances 0.000 description 15
- 239000011780 sodium chloride Substances 0.000 description 12
- 229960002668 sodium chloride Drugs 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000000356 contaminant Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 5
- 229940011051 isopropyl acetate Drugs 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 208000004930 Fatty Liver Diseases 0.000 description 3
- 206010019708 Hepatic steatosis Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 208000010706 fatty liver disease Diseases 0.000 description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 description 3
- UYGBSRJODQHNLQ-UHFFFAOYSA-N 4-hydroxy-3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1O UYGBSRJODQHNLQ-UHFFFAOYSA-N 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VZGQWXFWLYEZQJ-UHFFFAOYSA-N C=CC(c(cc1)ccc1S)=O Chemical compound C=CC(c(cc1)ccc1S)=O VZGQWXFWLYEZQJ-UHFFFAOYSA-N 0.000 description 1
- XVNJAJFKDGNVED-MDWZMJQESA-N CC(C)(C)OC(C(C)(C)Oc1c(C)cc(/C=C/C(C2C=CC(S)=CC2)=O)cc1C)=O Chemical compound CC(C)(C)OC(C(C)(C)Oc1c(C)cc(/C=C/C(C2C=CC(S)=CC2)=O)cc1C)=O XVNJAJFKDGNVED-MDWZMJQESA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102100038831 Peroxisome proliferator-activated receptor alpha Human genes 0.000 description 1
- 102100038824 Peroxisome proliferator-activated receptor delta Human genes 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- YKYMGFHOJJOSEB-UHFFFAOYSA-N butan-1-ol;potassium Chemical compound [K].CCCCO YKYMGFHOJJOSEB-UHFFFAOYSA-N 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000010921 in-depth analysis Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 1
- 108091008765 peroxisome proliferator-activated receptors β/δ Proteins 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
Abstract
The invention discloses GFT505 and a preparation method for an intermediate thereof. The invention provides the preparation method for an intermediate I of GFT505, comprising the following steps: in an organic solvent, carrying out isomerization reaction on a compound II and tert-butanol alkali metal salt to obtain the intermediate I of GFT505. According to the preparation method disclosed by the invention, the operation is simple and safe, a special purifying device is not required, the reaction time is short, by-products are few, the yield is high, the tedious operation due to using column chromatography isolation in the aftertreatment process is avoided, and the purity of prepared products is greater than 99.0%; the content of the Z-type isomer falls to be below 0.1%, and the contents of other impurities are all less than 0.5%, so that the preparation method is suitable for industrial production. For GFT505III prepared from the intermediate I of the GFT505, which is obtained through adopting the preparation method of the invention, the purity is greater than 99.50%, and the content of all the impurities is less than 0.1%, thereby reaching the raw material medicine standard.
Description
Technical field
The present invention relates to GFT505 and its preparation method of intermediate.
Background technology
Liver is one of mostly important organ of human body, is also one of onset risk highest organ.Many factors all can
Cause the generation of liver diseases.For example drinking can excessively cause cirrhosis, and drug administration can excessively cause liver dysfunction, or even
Obesity also results in fatty liver.Therefore, the medicine for the treatment of fatty liver class disease also becomes the focus of biological medicine exploitation.
French Genfit biopharmaceutical companys represent that food and drug administration has agreed to its continual exploitation in the recent period
Peroxisome proliferator-activated receptor alpha/δ dual agonists GFT505, and beginning carries out the research of IIb phases in the U.S..GFT
505 are expected to control the early diagnosis of fatty liver, heart disease and its complication, prevention and treatment, diabetes-associated pionemia.France
The examination ＆ approval of Food and Drug Administration with the detailed in-depth analysis for being carried out to preclinical data and clinical data so far be base
Plinth.The expert of the management board represents that GFT505 is able to ensure that safe operation, and to research and can cause the liver of cirrhosis or liver cancer
Sick related all biological mark is favourable.GFT505 structures are as shown in formula III.
GFT505 intermediate compound Is are the key intermediates of GFT505III, (such as patent document under the conditions of prior art
US20060142611 or US20050176808) synthetic method be all by 4- methylthio phenyls ethyl ketone and 3,5- dimethyl -4- hydroxyls
Benzaldehyde is condensed to yield GFT505 intermediate compound IVs, then is obtained with the reaction of the 2- bromo acids tert-butyl ester.GFT505 intermediate compound Is
Double bond is configured as Z formulas, but in 4- methylthio phenyls ethyl ketone and 3,5- dimethyl -4- hydroxy benzaldehyde condensation courses, formation
During double bond, it is difficult to avoid produce GFT505 intermediate compound IVs Z formulas, E formula mixtures, then with the 2- bromo acid tert-butyl esters
Reaction obtains GFT505 intermediate IIs, is also Z formulas, E formula mixtures.E formula isomers polarity is with Z formulas closely, it is difficult to crystallize
Purifying, the very accurate column chromatography of product needed is unfavorable for industrialized production.
It is, thus, sought for a kind of effective synthetic method, reduces the content of Z formula isomer impurities, improves the pure of product
Degree and yield, and avoid being difficult to industrialized purification process using column chromatography etc..
The content of the invention
The technical problems to be solved by the invention easily go out in the preparation process of GFT505 in the prior art to be overcome
Existing Z formulas accessory substance, impurity content is high, be not easily purified, be not suitable for the defects such as industrialized production and provide a kind of GFT505 and
The preparation method of its intermediate.Preparation method of the invention is simple to operate, high income, with low cost, and obtained product purity is high
(purity can reach more than 98.5%, Z formula isomers and be down to less than 0.1%), is suitable for industrialized production.
The invention provides a kind of preparation method of GFT505 intermediate compound Is, it is comprised the following steps：In organic solvent, will
Compound II carries out isomerization reaction and obtains GFT505 intermediate compound Is with tert-butyl alcohol alkali metal salt；Described compound II is
The Z/E mixtures of double bond, described GFT505 intermediate compound Is are E formula compounds；The Z/E mixtures of described double bond refer to that Z formulas are produced
Thing accounts for the 0.1%~99.0% (including 0.1%, including 99.0%) of mixture gross mass；Described E formula compounds refer to E formulas
The content of compound reaches more than 99.0% (including 99.0%)；
In the described reaction for preparing GFT505 intermediate compound Is, the preferred protonic solvent of described organic solvent, polarity are non-
Proton-organic solvent or non-polar solven, further preferred non-polar solven.The preferred C of described protonic solvent1~C4Alcohols is molten
Agent；Described C1~C4The preferred tert-butyl alcohol of alcohols solvent.The preferred C of polar non-proton organic solvent1~C4Nitrile solvents, C1~
C6Ketones solvent, C1~C4Amide solvent and C1~C4One or more in sulfone class solvent.Described C1~C4Nitrile solvents
It is preferred that acetonitrile.Described C1~C6The preferred acetone of ketones solvent and/or methyl iso-butyl ketone (MIBK).Described C1~C4Amide solvent
It is preferred that N,N-dimethylformamide.Described C1~C4The preferred dimethyl sulfoxide (DMSO) of sulfone class solvent.The non-polar solven preferred fragrance
Varsol；The preferred toluene of described aromatic hydrocarbon solvent.
In the described reaction for preparing GFT505 intermediate compound Is, the matter of described organic solvent and described compound II
Amount ratio preferably 1~100, further preferred 2~10, such as 2,3.5,4.9,8 or 20.
In the described reaction for preparing GFT505 intermediate compound Is, the described preferred sodium tert-butoxide of tert-butyl alcohol alkali metal salt, uncle
One or more in butanol potassium and tert-butyl alcohol lithium.
In the described reaction for preparing GFT505 intermediate compound Is, described tert-butyl alcohol alkali metal salt and described compound
The molar ratio of II preferably 1~5, further preferred 1.3~5, such as 1.3,1.5,2.5,3 or 5.
In the described reaction for preparing GFT505 intermediate compound Is, preferably 30 DEG C of the temperature that described cis-trans isomerization reacts
~100 DEG C；Further preferred 40 DEG C~100 DEG C；Such as 40 DEG C~50 DEG C, 50 DEG C~60 DEG C, 60 DEG C~70 DEG C, 70 DEG C~80 DEG C
Or 90 DEG C~100 DEG C.
In the described reaction for preparing GFT505 intermediate compound Is, the process of described cis-trans isomerization reaction can be used
Routine monitoring method in this area is monitored, and is the terminal of reaction when typically being disappeared substantially with Z formula compounds II, described
Preferably 1 hour~10 hours time of cis-trans isomerization reaction, such as 1 hour~2 hours, 2 hours, 3 hours~4 hours, it is 4 small
When~5 hours or 9 hours~10 hours.
The described reaction for preparing GFT505 intermediate compound Is preferably uses following steps：At 10 DEG C~20 DEG C, to compound II
With organic solvent formed mixture in add tert-butyl alcohol alkali metal salt, be warming up to 30 DEG C~100 DEG C (such as 40 DEG C~50 DEG C,
50 DEG C~60 DEG C, 60 DEG C~70 DEG C or 70 DEG C~80 DEG C), carry out cis-trans isomerization reaction and obtain described GFT505 intermediate compound Is
.
The described reaction for preparing GFT505 intermediate compound Is preferably uses following post-processing step：After reaction terminates, add water,
Extraction, organic phase washing, solvent is removed, add alcohols solvent, be cooled to 0~10 DEG C, separated, dry, obtain described
GFT505 intermediate compound Is.Described extraction, washing, remove solvent, separate and drying can using in this area the generic operation it is normal
Rule method.The preferred methyl alcohol of described alcohols solvent.The solvent that described extraction is used can be esters solvent, and described esters are molten
Agent can be isopropyl acetate.Described washing is preferably washed with water and/or sodium-chloride water solution, described sodium chloride solution
Mass concentration preferably 1%~50%, further preferred 5%~30%, such as 10%, described mass concentration refers to sodium chloride
Quality accounts for the percentage of sodium-chloride water solution gross mass.Described separation preferably uses centrifugation or filtering.Described drying
It is preferred that being vacuum dried, preferably 40 DEG C~50 DEG C of described vacuum drying temperature；Described vacuum drying pressure preferably-
0.08MPa~-0.1MPa；Preferably 5 hours~24 hours, such as 12 hours described vacuum drying time.
Present invention also offers the preparation method of GFT505III, it is comprised the following steps：It is obtained according to the method described above
After GFT505 intermediate compound Is, then in organic solvent, under conditions of acid is present, be hydrolyzed reaction, obtains GFT505III i.e.
Can；
The preparation method of described GFT505III can be the conventional method of such hydrolysis in this area, the present invention
In particularly preferably following reaction condition：
In the described preparation method for preparing GFT505III, the preferred halogenated hydrocarbon solvent of described organic solvent；It is described
The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent；The preferred dichloromethane of described chlorinated hydrocarbon solvent.
In the described preparation method for preparing GFT505III, described organic solvent and described GFT505 intermediate compound Is
Mass values preferably 1~100, further preferred 2~10, such as 10.1 or 10.2.
In the described preparation method for preparing GFT505III, described acid preferably organic acid；Described organic acid is preferred
Trifluoroacetic acid.
In the described preparation method for preparing GFT505III, described sour and described GFT505 intermediate compound Is mole
Ratio preferably 5~20, further preferred 8~15, such as 10.4.
In the described preparation method for preparing GFT505III, preferably 0 DEG C~50 DEG C of the temperature of described hydrolysis,
Further preferred 20 DEG C~30 DEG C.
In the described preparation method for preparing GFT505III, the process of described hydrolysis can use this area
In routine monitoring method be monitored, be when typically being disappeared substantially with GFT505 intermediate compound Is reaction terminal, described hydrolysis
Preferably 1 hour~10 hours, further preferred 2 hours~8 hours, such as 5 hours~6 hours time of reaction.
The described preparation method for preparing GFT505III preferably uses following steps：At 20 DEG C~30 DEG C, in GFT505
Acid is added in the mixture that mesosome I is formed with organic solvent, the reaction that is hydrolyzed obtains described GFT505III.
The described preparation method for preparing GFT505III preferably uses following post-processing step：After reaction terminates, remove molten
Agent, extraction, washing, drying, filtering, crystallization, filter again, dry again, obtaining described GFT505III.Described removing
Solvent, extraction, washing, drying, filtering, crystallization can be using the conventional method of the generic operation in this area.Described extraction is adopted
The preferred esters solvent of solvent；Described esters solvent ethyl acetate.Described washing is preferably using washing.Described
Drying can use drier or vacuum drying.The preferred anhydrous sodium sulfate of described drier and/or anhydrous magnesium sulfate.Described
Preferably 40 DEG C~50 DEG C of vacuum drying temperature；Described vacuum drying pressure preferably -0.08MPa~-0.1MPa；Described
Preferably 5 hours~24 hours, such as 12 hours vacuum drying time.Preferably 10 DEG C~20 DEG C of the temperature of described crystallization, institute
Preferably 1 hour~5 hours, such as 2 hours time of the crystallization stated.
In the present invention, the GFT505III for obtaining after purification is obtained after GFT505III is preferably recrystallized.Described recrystallization
The preferred esters solvent of solvent of use；Described esters solvent ethyl acetate.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are commercially available.
In the present invention, described room temperature refers to environment temperature, is 10 DEG C~35 DEG C.
Positive effect of the invention is：Preparation method safety simple to operate of the invention, sets without special type purifying
The standby, reaction time is short, accessory substance is few, high income, avoid the troublesome operation used column chromatography in last handling process, obtained
Product purity is high, and (purity is more than 99.0%；Z formula isomers is down to less than 0.1%, and other impurities are respectively less than 0.5%.), it is suitable for
Industrialized production.GFT505III prepared by the GFT505 intermediate compound Is obtained using preparation method of the invention, purity is more than
99.50%, all impurity are respectively less than 0.1%, reach bulk drug standard.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, professional and technical personnel in the field can be made more fully
Understand the present invention, but therefore do not limit the present invention among described scope of embodiments.Unreceipted tool in the following example
The experimental technique of concrete conditions in the establishment of a specific crime, conventionally and condition, or selects according to catalogue.
Embodiment 1：The preparation method (referenced patent WO2011/144579) of GFT505 intermediate compound IVs
4- first sulfydryls acetophenone (50g, 0.301mol), the hydroxy benzaldehyde of 3,5- dimethyl -4 (45g, 0.301mol) are added
Enter in 200ml hydrogen chloride methanol solutions (4mol/L), 20~30 DEG C are stirred 3 hours, are cooled to 0~10 DEG C, are stirred 1 hour,
Filtering, drying obtains 83g GFT505 intermediates (IV) for yellow solid, yield 93%.
Embodiment 2：The preparation method (referenced patent WO2011/144579) of GFT505 intermediate compound IVs
4- first sulfydryls acetophenone (19Kg, 114mol), the hydroxy benzaldehyde of 3,5- dimethyl -4 (17.1Kg, 114mol) are added
Enter in 76L hydrogen chloride methanol solutions (4mol/L), 20~30 DEG C are stirred 3 hours, are cooled to 0~10 DEG C, are stirred 1 hour, from
The heart, 40 DEG C are vacuum dried 12 hours, obtain 31.6Kg GFT505 intermediates (IV) for yellow solid, yield 93%.LCMS：M/z=
299(M+H)+。
Embodiment 3：The preparation method (bibliography US2006/142611) of GFT505 intermediate IIs
GFT505 intermediate compound IVs (78.8g, 0.263mol) are added in reaction bulb, acetonitrile (480ml) is added, carbon is added
Sour potassium (54.5g, 0.395mol), the 2- bromo acids tert-butyl ester (39.3g, 0.176mol) are heated to 75~85 DEG C of reactions 10
Hour, potassium carbonate (54.5g, 0.395mol) is added, the 2- bromo acids tert-butyl ester (39.3g, 0.176mol) react 10 hours,
Add potassium carbonate (54.5g, 0.395mol) again, the 2- bromo acids tert-butyl ester (39.3g, 0.176mol) react 10 hours, directly
It is complete to compound reaction, it is concentrated under reduced pressure dry, add 800g water and 400g dichloromethane, layering, washing, organic phase anhydrous slufuric acid
Sodium is dried, filtering, and organic phase concentration is dry, is recrystallized with ethyl acetate and petroleum ether, obtains 81.1g solid chemical compound II, yield
70%.
Embodiment 4：The preparation method (bibliography US2006/142611) of GFT505 intermediate IIs
GFT505 intermediate compound IVs (30Kg, 100mol) are added in acetonitrile (183L), addition potassium carbonate (21Kg,
152mol), the 2- bromo acids tert-butyl ester (14.9Kg, 66.8mol), is heated to 75~85 DEG C and reacts 10 hours, adds carbonic acid
Potassium (21Kg, 152mol), the 2- bromo acids tert-butyl ester (14.9Kg, 66.8mol) react 10 hours, then add potassium carbonate
(21Kg, 152mol), the 2- bromo acids tert-butyl ester (14.9Kg, 66.8mol) react 10 hours, until compound has reacted
Entirely, 45~55 DEG C are concentrated under reduced pressure into and distillate slow, add 300Kg water and 160Kg dichloromethane, stratification to take organic layer,
100Kg water and 100Kg mass concentrations are that (described mass concentration refers to that the quality of sodium chloride is accounted for the washing of 10% sodium-chloride water solution
The percentage of sodium-chloride water solution gross mass), 15~25 DEG C be concentrated under reduced pressure into distillate it is slow.Add ethyl acetate 100Kg heating
It is molten clear to 75~85 DEG C, normal heptane 180Kg is added, it is cooled to 15~25 DEG C and stirs 2~3 hours.Centrifugation, normal heptane 40Kg are washed
Wash, 40~50 DEG C be vacuum dried 12 hours, obtain 31.6Kg GFT505 intermediate IIs, yield 71.6%.LC-MS：M/z=441 (M
+H)+。
Embodiment 5：The preparation method of GFT505 intermediate compound Is
Compound II (81.1g, 0.184mol) is added to 400g toluene, 10~20 DEG C are cooled to, sodium tert-butoxide is added
(26.8g, 0.279mol), is warming up to 50~60 DEG C and reacts 2 hours, adds 400g water, and layering, washing, organic phase is concentrated under reduced pressure
It is dry, methyl alcohol 200ml is added, 0-10 DEG C is cooled to, stir 1 hour, filtering, 40~50 DEG C of (- 0.08MPa~-0.1MPa) vacuum
Dry 12 hours, obtain 78.8g yellow solid GFT505 intermediate compound Is, yield 97.0%.HPLC：99.23% (in terms of E, Z structures
Type isomers accounts for 0.085%, other maximum single contaminants 0.41%).
Embodiment 6：The preparation method of GFT505 intermediate compound Is
Compound II (31Kg, 70.5mol) is added to 153Kg toluene, 10~20 DEG C are cooled to, sodium tert-butoxide is added
(10.3Kg, 107mol), is warming up to 50~60 DEG C and reacts 2 hours, adds 160Kg water, is layered, and 100Kg water and 100Kg mass are dense
Spend for 10% sodium-chloride water solution washing (described mass concentration refers to that the quality of sodium chloride accounts for sodium-chloride water solution gross mass
Percentage), 40~50 DEG C are concentrated under reduced pressure into and distillate slow, add methyl alcohol 60Kg, are cooled to 0~10 DEG C, stir 1 hour, centrifugation,
Methyl alcohol 20Kg washings, 40~50 DEG C (- 0.08MPa~-0.1MPa) are vacuum dried 12 hours, obtain 30.4Kg yellow solids GFT505
Intermediate compound I, yield 98.0%.LC-MS：M/z=441 (M+H)+；HPLC：99.50% (in terms of E, Z configurational isomers are accounted for
0.082%, other maximum single contaminants 0.32%.
Embodiment 7：The preparation method of GFT505 intermediate compound Is
Compound II (8.0g, 0.018mol) is added to the 64g tert-butyl alcohols, 10~20 DEG C are cooled to, potassium tert-butoxide is added
(6.05g, 0.054mol), is warming up to 70~80 DEG C and reacts 4~5 hours, adds 200g water, and two are extracted with isopropyl acetate 60g
Secondary, organic phase is concentrated under reduced pressure dry, adds methyl alcohol 20ml, is cooled to 0-10 DEG C, stirs 1 hour, filtering, 40~50 DEG C (-
0.08MPa~-0.1MPa) it is vacuum dried 12 hours, obtain 7.62g yellow solid GFT505 intermediate compound Is, yield 95.2%.HPLC：
99.36% (in terms of E, Z configurational isomers account for 0.079%, other maximum single contaminants 0.42%).
Embodiment 8：The preparation method of GFT505 intermediate compound Is
Compound II (8.0g, 0.018mol) is added to 16g DMFs, 10~20 DEG C are cooled to, plus
Enter sodium tert-butoxide (2.17g, 0.023mol), be warming up to 90~100 DEG C and react 1~2 hour, add 100g water, use isopropyl acetate
Ester 60g is extracted twice, and organic phase is concentrated under reduced pressure dry, adds methyl alcohol 20ml, is cooled to 0-10 DEG C, stirs 1 hour, filtering, 40~
50 DEG C (- 0.08MPa~-0.1MPa) is vacuum dried 12 hours, obtains 7.34g yellow solid GFT505 intermediate compound Is, yield
91.7%.HPLC：99.21% (in terms of E, Z configurational isomers account for 0.097%, other maximum single contaminants 0.48%).
Embodiment 9：The preparation method of GFT505 intermediate compound Is
Compound II (8.0g, 0.018mol) is added to 160g acetonitriles, 10~20 DEG C are cooled to, tert-butyl alcohol lithium is added
(7.21g, 0.090mol), is warming up to 40~50 DEG C and reacts 9~10 hours, adds 160g water, and two are extracted with isopropyl acetate 90g
Secondary, organic phase is concentrated under reduced pressure dry, adds methyl alcohol 20ml, is cooled to 0-10 DEG C, stirs 1 hour, filtering, 40~50 DEG C (-
0.08MPa~-0.1MPa) it is vacuum dried 12 hours, obtain 7.29g yellow solid GFT505 intermediate compound Is, yield 91.1%.HPLC：
99.16% (in terms of E, Z configurational isomers account for 0.089%, other maximum single contaminants 0.49%).
Embodiment 10：The preparation method of GFT505 intermediate compound Is
Compound II (8.0g, 0.018mol) is added to 28g dimethyl sulfoxides, 10~20 DEG C are cooled to, the tert-butyl alcohol is added
Potassium (5.04g, 0.045mol), is warming up to 60~70 DEG C and reacts 3~4 hours, adds 100g water, is extracted with isopropyl acetate 60g
Twice, organic phase is concentrated under reduced pressure dry, adds methyl alcohol 20ml, is cooled to 0-10 DEG C, stirs 1 hour, filtering, 40~50 DEG C (-
0.08MPa~-0.1MPa) it is vacuum dried 12 hours, obtain 7.33g yellow solid GFT505 intermediate compound Is, yield 91.6%.HPLC：
99.46% (in terms of E, Z configurational isomers account for 0.077%, other maximum single contaminants 0.27%).
Embodiment 11：The preparation method of GFT505III
GFT505 intermediate compound Is (77.9g, 0.177mol can be obtained for embodiment 10) are added in reaction bulb, are added
The dichloromethane of 790g, adds trifluoroacetic acid (209.7g, 1.84mol), and 20~30 DEG C are reacted 5-6 hours, and concentration is dry, are added
The ethyl acetate of 600ml and the water of 600ml, layering, washing, anhydrous sodium sulfate drying, filtering, organic phase concentration small size, 10-
20 DEG C of stirrings, 2 hours crystallizations, filtering, under -0.08MPa~-0.1MPa, 40 DEG C~50 DEG C vacuum drying obtain 60.1g Huangs for 12 hours
Color solid.Yellow solid 250mL re-crystallizing in ethyl acetate obtains 52.9g yellow solids GFT505 (III), yield 77.8%.
LC-MS：M/z=385 (M+H)+；HPLC：99.86%, maximum single contaminant 0.06%.
Embodiment 12：The preparation method of GFT505III
GFT505 intermediate compound Is (30Kg, 68.2mol can be obtained for embodiment 9) are added to the dichloromethane of 307Kg,
Add trifluoroacetic acid (80.8Kg, 709mol), 20-30 DEG C is reacted 5-6 hour, and concentration is dry, add the ethyl acetate of 197Kg with
The water of 231Kg, layering, 100Kg water and 100Kg mass concentrations are that (described mass concentration refers to chlorine to 10% sodium-chloride water solution
The quality for changing sodium accounts for the percentage of sodium-chloride water solution gross mass) washing, 40~50 DEG C are concentrated under reduced pressure into about 80Kg, are cooled to 10
2 hours crystallizations of~20 DEG C of stirrings, under centrifugation, ethyl acetate 20Kg washings, -0.08MPa~-0.1MPa, 40~50 DEG C of vacuum are done
Dry 12 hours, obtain 23.2Kg yellow solids.Yellow solid ethyl acetate 82Kg is recrystallized to give 20.9Kg yellow solids
GFT505III, yield 79.8%.LCMS：M/z=385 (M+H)+；HPLC：99.95%, maximum single contaminant 0.03%.
Claims (10)
1. a kind of preparation method of GFT505 intermediate compound Is, it is characterised in that it is comprised the following steps：In organic solvent, by chemical combination
Thing II carries out isomerization reaction and obtains GFT505 intermediate compound Is with tert-butyl alcohol alkali metal salt；Described compound II is double bond
Z/E mixtures, described GFT505 intermediate compound Is are E formula compounds；The Z/E mixtures of described double bond refer to that Z formula products are accounted for
The 0.1%~99.0% of mixture gross mass, including 0.1%, including 99.0%；Described E formula compounds refer to E formula compounds
Content reach more than 99.0%, including 99.0%；
2. the preparation method of GFT505 intermediate compound Is as claimed in claim 1, it is characterised in that：In described preparation GFT505
In the reaction of intermediate compound I, described organic solvent is protonic solvent, polar non-proton organic solvent or non-polar solven；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the mass ratio of described organic solvent and described compound II
Be worth is 1~100；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described tert-butyl alcohol alkali metal salt is sodium tert-butoxide, potassium tert-butoxide
With one or more in tert-butyl alcohol lithium；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described tert-butyl alcohol alkali metal salt is with described compound II's
Molar ratio is 1~5；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the temperature of described cis-trans isomerization reaction is 30 DEG C~100
℃；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the time of described cis-trans isomerization reaction is 1 hour~10 small
When.
3. the preparation method of GFT505 intermediate compound Is as claimed in claim 2, it is characterised in that：
In the described reaction for preparing GFT505 intermediate compound Is, described protonic solvent is C1~C4Alcohols solvent；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the polar non-proton organic solvent is C1~C4Nitrile solvents, C1
~C6Ketones solvent, C1~C4Amide solvent and C1~C4One or more in sulfone class solvent；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the non-polar solven is aromatic hydrocarbon solvent；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the mass ratio of described organic solvent and described compound II
Be worth is 2~10；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described tert-butyl alcohol alkali metal salt is with described compound II's
Molar ratio is 1.3~5；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the temperature of described cis-trans isomerization reaction is 40 DEG C~100
℃；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the time of described cis-trans isomerization reaction is 1 hour~2 small
When, 2 hours, 3 hours~4 hours, 4 hours~5 hours or 9 hours~10 hours.
4. the preparation method of GFT505 intermediate compound Is as claimed in claim 3, it is characterised in that：
In the described reaction for preparing GFT505 intermediate compound Is, described C1~C4Alcohols solvent is the tert-butyl alcohol；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described C1~C4Nitrile solvents are acetonitrile；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described C1~C6Ketones solvent is acetone and/or methyl-isobutyl
Ketone；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described C1~C4Amide solvent is N,N-dimethylformamide；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described C1~C4Sulfone class solvent is dimethyl sulfoxide (DMSO)；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described aromatic hydrocarbon solvent is toluene；
And/or,
It is described in the described reaction for preparing GFT505 intermediate compound Is in the described reaction for preparing GFT505 intermediate compound Is
Organic solvent is 2,3.5,4.9,8 or 20 with the mass values of described compound II；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, described tert-butyl alcohol alkali metal salt is with described compound II's
Molar ratio is 1.3,1.5,2.5,3 or 5；
And/or,
In the described reaction for preparing GFT505 intermediate compound Is, the temperature of described cis-trans isomerization reaction is 40 DEG C~50 DEG C,
50 DEG C~60 DEG C, 60 DEG C~70 DEG C, 70 DEG C~80 DEG C or 90 DEG C~100 DEG C.
5. the preparation method of GFT505 intermediate compound Is as claimed in claim 1, it is characterised in that：In described preparation GFT505
The reaction of mesosome I uses following steps：At 10 DEG C~20 DEG C, uncle is added in the mixture to compound II with organic solvent formation
Butanol alkali metal salt, is warming up to 30 DEG C~100 DEG C, carries out cis-trans isomerization reaction and obtains described GFT505 intermediate compound Is；
And/or,
The described reaction for preparing GFT505 intermediate compound Is uses following post-processing step：After reaction terminates, add water, extract, organic
Mutually washing, removing solvent, add alcohols solvent, are cooled to 0~10 DEG C, separate, dry, and obtain described GFT505 intermediates
I。
6. the preparation method of GFT505 intermediate compound Is as claimed in claim 5, it is characterised in that：
In the post-processing step that the described reaction for preparing GFT505 intermediate compound Is is used, described alcohols solvent is methyl alcohol；
And/or,
In the post-processing step that the described reaction for preparing GFT505 intermediate compound Is is used, the solvent that described extraction is used is ester
Class solvent；
And/or,
In the post-processing step that the described reaction for preparing GFT505 intermediate compound Is is used, described separation using centrifugation or
Filtering.
7. a kind of preparation method of GFT505III, it is characterised in that it is comprised the following steps：According to any one of claim 1~6
Described preparation method is obtained after GFT505 intermediate compound Is, then in organic solvent, under conditions of acid is present, is hydrolyzed anti-
Should, obtain GFT505III；
8. the preparation method of GFT505III as claimed in claim 7, it is characterised in that：
In the described preparation method for preparing GFT505III, described organic solvent is halogenated hydrocarbon solvent；
And/or,
In the described preparation method for preparing GFT505III, the matter of described organic solvent and described GFT505 intermediate compound Is
Amount ratio is 1~100；
And/or,
In the described preparation method for preparing GFT505III, described acid is organic acid；
And/or,
In the described preparation method for preparing GFT505III, the described sour molar ratio with described GFT505 intermediate compound Is
It is 5~20；
And/or,
In the described preparation method for preparing GFT505III, the temperature of described hydrolysis is 0 DEG C~50 DEG C；
And/or,
In the described preparation method for preparing GFT505III, the time of described hydrolysis is 1 hour~10 hours；
And/or,
The described preparation method for preparing GFT505III uses following steps：At 20 DEG C~30 DEG C, to GFT505 intermediate compound Is with
Acid is added in the mixture that organic solvent is formed, the reaction that is hydrolyzed obtains described GFT505III.
9. the preparation method of GFT505III as claimed in claim 8, it is characterised in that：
In the described preparation method for preparing GFT505III, described halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent；
And/or,
In the described preparation method for preparing GFT505III, the matter of described organic solvent and described GFT505 intermediate compound Is
Amount ratio is 2~10；
And/or,
In the described preparation method for preparing GFT505III, described organic acid is trifluoroacetic acid；
And/or,
In the described preparation method for preparing GFT505III, the described sour molar ratio with described GFT505 intermediate compound Is
It is 8~15；
And/or,
In the described preparation method for preparing GFT505III, the temperature of described hydrolysis is 20 DEG C~30 DEG C；
And/or,
In the described preparation method for preparing GFT505III, the time of described hydrolysis is 2 hours~8 hours；
And/or,
Prepared GFT505III obtains GFT505III after purification after recrystallization.
10. the preparation method of GFT505III as claimed in claim 9, it is characterised in that：
In the described preparation method for preparing GFT505III, described chlorinated hydrocarbon solvent is dichloromethane；
And/or,
In the described preparation method for preparing GFT505III, the matter of described organic solvent and described GFT505 intermediate compound Is
Amount ratio is 10.1 or 10.2；
And/or,
In the described preparation method for preparing GFT505III, the described sour molar ratio with described GFT505 intermediate compound Is
It is 10.4；
And/or,
In the described preparation method for preparing GFT505III, the time of described hydrolysis is 5 hours~6 hours；
And/or,
The solvent that described recrystallization is used is esters solvent.
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| WO2018133705A1 (en) * | 2017-01-22 | 2018-07-26 | 苏州科睿思制药有限公司 | Crystal form of gft-505 and preparation method and use thereof |
| CN109265380A (en) * | 2017-10-18 | 2019-01-25 | 深圳市塔吉瑞生物医药有限公司 | Substituted propyl- 2- alkene -1- ketone compound and its pharmaceutical composition |
| WO2019099761A1 (en) * | 2017-11-16 | 2019-05-23 | Teva Pharmaceuticals International Gmbh | Solid state forms of elafibranor |
| CN110156648A (en) * | 2019-05-30 | 2019-08-23 | 河北科技大学 | A kind of preparation method of Elafibranor intermediate |
| WO2019186410A1 (en) * | 2018-03-27 | 2019-10-03 | Lupin Limited | Solid forms of elafibranor and processes thereof |
| WO2020079541A1 (en) * | 2018-10-16 | 2020-04-23 | Glenmark Pharmaceuticals Limited; Glenmark Life Sciences Limited | Process for preparation of elafibranor |
| WO2020115628A1 (en) * | 2018-12-03 | 2020-06-11 | Mankind Pharma Ltd. | Solid forms of elafibranor and process of preparation thereof |
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