CN106674069B - The preparation method of GFT505 and its intermediate - Google Patents
The preparation method of GFT505 and its intermediate Download PDFInfo
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- CN106674069B CN106674069B CN201611108807.2A CN201611108807A CN106674069B CN 106674069 B CN106674069 B CN 106674069B CN 201611108807 A CN201611108807 A CN 201611108807A CN 106674069 B CN106674069 B CN 106674069B
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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 109
- 229950001279 elafibranor Drugs 0.000 title claims abstract description 107
- 238000002360 preparation method Methods 0.000 title claims abstract description 69
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tertiry butyl alcohol Natural products CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000003960 organic solvent Substances 0.000 claims abstract description 26
- 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 20
- -1 tert-butyl alcohol alkali metal salt Chemical class 0.000 claims abstract description 14
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 6
- 238000006317 isomerization reaction Methods 0.000 claims abstract description 3
- 239000000543 intermediate Substances 0.000 claims description 96
- 238000006243 chemical reaction Methods 0.000 claims description 65
- 239000002904 solvent Substances 0.000 claims description 54
- 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 15
- 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
- 238000001914 filtration 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- 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
- 238000000605 extraction Methods 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- 238000012805 post-processing Methods 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 5
- 239000012454 non-polar solvent Substances 0.000 claims description 5
- 238000000926 separation method Methods 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
- 238000001953 recrystallisation Methods 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
- 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
- 150000003457 sulfones Chemical class 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 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
- LRHPLDYGYMQRHN-UHFFFAOYSA-N Butanol Natural products CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract description 2
- 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
- 238000001291 vacuum drying Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 12
- 229960002668 sodium chloride Drugs 0.000 description 12
- 239000012074 organic phase Substances 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
- 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
- 238000005119 centrifugation Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 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
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000007796 conventional method Methods 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
- 0 CC1C=C(C=O)C=C(C)C1* Chemical compound CC1C=C(C=O)C=C(C)C1* 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 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
- 208000034189 Sclerosis Diseases 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
- 150000008062 acetophenones Chemical class 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002440 hepatic effect Effects 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
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- GEPOTYILZCVFHB-NTEUORMPSA-N CC(C)(C)OC(C(C)(C)Oc1c(C)cc(/C=C/C(C(CC2)=CC=C2SC)=O)cc1C)=O Chemical compound CC(C)(C)OC(C(C)(C)Oc1c(C)cc(/C=C/C(C(CC2)=CC=C2SC)=O)cc1C)=O GEPOTYILZCVFHB-NTEUORMPSA-N 0.000 description 1
- YYPZICPPNBONPZ-NTEUORMPSA-N CC(C)(C)OC(C(C)(C)Oc1c(C)cc(/C=C/C(c(cc2)ccc2SC)=O)cc1C)=O Chemical compound CC(C)(C)OC(C(C)(C)Oc1c(C)cc(/C=C/C(c(cc2)ccc2SC)=O)cc1C)=O YYPZICPPNBONPZ-NTEUORMPSA-N 0.000 description 1
- DMWCFYZBUIHPRR-RUDMXATFSA-N CC(C1)C(O)=C(C)C=C1/C=C/C(c(cc1)ccc1SC)=O Chemical compound CC(C1)C(O)=C(C)C=C1/C=C/C(c(cc1)ccc1SC)=O DMWCFYZBUIHPRR-RUDMXATFSA-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
- 239000000090 biomarker Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YKYMGFHOJJOSEB-UHFFFAOYSA-N butan-1-ol;potassium Chemical compound [K].CCCCO YKYMGFHOJJOSEB-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000005352 clarification Methods 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
- 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
- 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
- 239000000463 material Substances 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
- 238000011160 research Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the preparation method of GFT505 and its intermediate.The present invention provides a kind of preparation method of GFT505 intermediate compound Is, comprise the following steps：In organic solvent, compound II and tert-butyl alcohol alkali metal salt are subjected to isomerization reaction and obtain GFT505 intermediate compound Is.The preparation method safety easy to operate of the present invention, without extraordinary purifier apparatus, the reaction time is short, accessory substance is few, high income, avoids the troublesome operation used column chromatography in last handling process, and obtained product 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%, are suitable for industrialized production.GFT505III prepared by the GFT505 intermediate compound Is that preparation method using the present invention obtains, purity are more than 99.50%, and all impurity are respectively less than 0.1%, reach bulk pharmaceutical chemicals standard.
Description
Technical field
The present invention relates to the preparation method of GFT505 and its intermediate.
Background technology
Liver is one of mostly important organ of human body, and one of highest organ of onset risk.Many factors all can
Cause the generation of liver diseases.Such as drink and can excessively cause hepatic sclerosis, drug administration can excessively cause liver dysfunction, even
Obesity also results in fatty liver.Therefore, the medicine for treating fatty liver class disease also becomes the hot spot 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 start to carry 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 are using the detailed in-depth analysis carried out so far to preclinical data and clinical data as base
Plinth.The expert of the management board represents that GFT505 is able to ensure that safe operation, and to studying the liver with hepatic sclerosis or liver cancer can be caused
The relevant all biological marker of disease 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 the 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 reacts to obtain with the 2- bromo acid tert-butyl esters.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 producing the Z formulas of GFT505 intermediate compound IVs, 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 and Z formulas are very close, it is difficult to crystallize
Purifying, product need very accurate column chromatography, are 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 are to overcome in the preparation process of GFT505 in the prior art easily to go out
Existing Z formulas accessory substance, impurity content is high, be not easily purified, be not suitable for the defects of industrialized production and provide a kind of GFT505 and
The wherein preparation method of mesosome.Preparation method of the invention is easy to operate, high income, of low cost, obtained product purity height
(purity can reach more than 98.5%, Z formula isomers and be down to less than 0.1%), it is suitable for industrialized production.
The present invention provides a kind of preparation method of GFT505 intermediate compound Is, it comprises the following steps：, will in organic solvent
Compound II carries out isomerization reaction with tert-butyl alcohol alkali metal salt and obtains GFT505 intermediate compound Is；The compound II is
The Z/E mixtures of double bond, the GFT505 intermediate compound Is are E formula compounds；The Z/E mixtures of the 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；The E formula compounds refer to E formulas
The content of compound reaches more than 99.0% (including 99.0%)；
In the reaction for preparing GFT505 intermediate compound Is, the preferred protonic solvent of the organic solvent, polarity are non-
Proton-organic solvent or nonpolar solvent, further preferred nonpolar solvent.The preferred C of the protonic solvent1~C4Alcohols is molten
Agent；The 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.The C1~C4Nitrile solvents
It is preferred that acetonitrile.The C1~C6The preferred acetone of ketones solvent and/or methyl iso-butyl ketone (MIBK).The C1~C4Amide solvent
It is preferred that N,N-dimethylformamide.The C1~C4The preferred dimethyl sulfoxide (DMSO) of sulfone class solvent.The nonpolar solvent preferred fragrance
Varsol；The preferred toluene of the aromatic hydrocarbon solvent.
In the reaction for preparing GFT505 intermediate compound Is, the matter of the organic solvent and the compound II
Amount ratio preferably 1~100, further preferred 2~10, such as 2,3.5,4.9,8 or 20.
In the reaction for preparing GFT505 intermediate compound Is, the 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 reaction for preparing GFT505 intermediate compound Is, the tert-butyl alcohol alkali metal salt and the 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 reaction for preparing GFT505 intermediate compound Is, preferably 30 DEG C of the temperature of cis-trans isomerization reaction
~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 reaction for preparing GFT505 intermediate compound Is, the process of cis-trans isomerization reaction can use
Routine monitoring method in this area is monitored, described as the terminal of reaction when generally being disappeared substantially using Z formula compounds II
When the time preferably 1 of cis-trans isomerization reaction is small~10 it is small when, such as 1 it is small when~2 it is small when, 2 it is small when, 3 it is small when~4 it is small when, it is 4 small
When~5 it is small when or 9 it is small when~10 it is small when.
The 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 and react to obtain the GFT505 intermediate compound Is
.
The reaction for preparing GFT505 intermediate compound Is preferably uses following post-processing step：After reaction, add water,
Extraction, organic phase washing, remove solvent, adds alcohols solvent, is cooled to 0~10 DEG C, separation, dry, obtains described
GFT505 intermediate compound Is.The extraction, washing, remove solvent, separation and drying and can use the normal of the generic operation in this area
Rule method.The preferred methanol of the alcohols solvent.The solvent that the extraction uses can be esters solvent, and the esters are molten
Agent can be isopropyl acetate.The washing is preferably washed with water and/or sodium-chloride water solution, the sodium chloride solution
Mass concentration preferably 1%~50%, further preferred 5%~30%, such as 10%, the mass concentration refers to sodium chloride
Quality accounts for the percentage of sodium-chloride water solution gross mass.The separation is preferably using centrifugation or filtering.The drying
It is preferred that it is dried in vacuo, preferably 40 DEG C~50 DEG C of the vacuum drying temperature；The vacuum drying pressure preferably-
0.08MPa~-0.1MPa；When the vacuum drying time preferably 5 is small~24 it is small when, such as 12 it is small when.
Present invention also offers the preparation method of GFT505III, it comprises the following steps：It is made according to the method described above
GFT505 intermediate compound Is and then in organic solvent, under the conditions of acid is existing, is hydrolyzed reaction, obtains GFT505III i.e.
Can；
The preparation method of the GFT505III can be the conventional method of such hydrolysis in this area, of the invention
In particularly preferably following reaction condition：
The preparation method of GFT505III is prepared described, the preferred halogenated hydrocarbon solvent of the organic solvent；It is described
The preferred chlorinated hydrocarbon solvent of halogenated hydrocarbon solvent；The preferred dichloromethane of the chlorinated hydrocarbon solvent.
The preparation method of GFT505III is prepared described, the organic solvent and the GFT505 intermediate compound Is
Mass values preferably 1~100, further preferred 2~10, such as 10.1 or 10.2.
The preparation method of GFT505III is prepared described, the sour preferred organic acid；The organic acid is preferred
Trifluoroacetic acid.
The preparation method of GFT505III is prepared described, sour mole with the GFT505 intermediate compound Is
Ratio preferably 5~20, further preferred 8~15, such as 10.4.
The preparation method of GFT505III is prepared described, preferably 0 DEG C~50 DEG C of the temperature of the hydrolysis,
Further preferred 20 DEG C~30 DEG C.
The preparation method of GFT505III is prepared described, the process of the hydrolysis can use this area
In routine monitoring method be monitored, as the terminal of reaction when generally being disappeared substantially using GFT505 intermediate compound Is, the hydrolysis
When the time of reaction preferably 1 is small~10 it is small when, it is further preferred 2 it is small when~8 it is small when, such as 5 it is small when~6 it is small when.
The preparation method for preparing GFT505III preferably uses following steps：At 20 DEG C~30 DEG C, into GFT505
Acid is added in the mixture that mesosome I is formed with organic solvent, reaction is hydrolyzed and obtains the GFT505III.
The preparation method for preparing GFT505III preferably uses following post-processing step：After reaction, remove molten
Agent, extraction, washing, drying, filtering, crystallization, filter, dry again again, obtains the GFT505III.The removing
Solvent, extraction, washing, drying, filtering, crystallization can use this area in the generic operation conventional method.The extraction is adopted
The preferred esters solvent of solvent；The esters solvent ethyl acetate.The washing is preferably using washing.Described
Drying can use drier or vacuum drying.The preferred anhydrous sodium sulfate of the drier and/or anhydrous magnesium sulfate.Described
Preferably 40 DEG C~50 DEG C of vacuum drying temperature；The vacuum drying pressure preferably -0.08MPa~-0.1MPa；Described
When the vacuum drying time preferably 5 is small~24 it is small when, such as 12 it is small when.Preferably 10 DEG C~20 DEG C of the temperature of the crystallization, institute
When the time for the crystallization stated preferably 1 is small~5 it is small when, such as 2 it is small when.
In the present invention, GFT505III after purification is obtained after the preferred recrystallizations of GFT505III are made.The recrystallization
The preferred esters solvent of solvent of use；The esters solvent ethyl acetate.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, each preferably up to the present invention
Example.
The reagents and materials used in the present invention are commercially available.
In the present invention, the room temperature refers to environment temperature, is 10 DEG C~35 DEG C.
The positive effect of the present invention is：The preparation method safety easy to operate of the present invention, sets without special type purifying
It is standby, the reaction time is short, accessory substance is few, high income, avoids 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 that preparation method using the present invention obtains, purity are more than
99.50%, all impurity are respectively less than 0.1%, reach bulk pharmaceutical chemicals standard.
Embodiment
The present invention is further illustrated below by the mode of embodiment, can make professional and technical personnel in the field more fully
Understand the present invention, but therefore do not limit the present invention among the embodiment described scope.Tool is not specified in the following example
The experimental method of concrete conditions in the establishment of a specific crime, according to conventional methods and conditions, or selects according to product manual.
Embodiment 1：The preparation method (referenced patent WO2011/144579) of GFT505 intermediate compound IVs
4- first sulfydryl acetophenones (50g, 0.301mol), -4 hydroxy benzaldehyde of 3,5- dimethyl (45g, 0.301mol) are added
Enter into 200ml hydrogen chloride methanol solutions (4mol/L), when 20~30 DEG C of stirrings 3 are small, be cooled to 0~10 DEG C, when stirring 1 is small,
Filtering, drying, it is yellow solid to obtain 83g GFT505 intermediates (IV), yield 93%.
Embodiment 2：The preparation method (referenced patent WO2011/144579) of GFT505 intermediate compound IVs
4- first sulfydryl acetophenones (19Kg, 114mol), -4 hydroxy benzaldehyde of 3,5- dimethyl (17.1Kg, 114mol) are added
Enter into 76L hydrogen chloride methanol solutions (4mol/L), when 20~30 DEG C of stirrings 3 are small, be cooled to 0~10 DEG C, when stirring 1 is small, from
The heart, when 40 DEG C of vacuum drying 12 are small, it is yellow solid to obtain 31.6Kg GFT505 intermediates (IV), 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, add acetonitrile (480ml), add carbon
Sour potassium (54.5g, 0.395mol), the 2- bromo acids tert-butyl ester (39.3g, 0.176mol), is heated to 75~85 DEG C of reactions 10
Hour, potassium carbonate (54.5g, 0.395mol) is added, when the 2- bromo acids tert-butyl ester (39.3g, 0.176mol) reaction 10 is small,
Potassium carbonate (54.5g, 0.395mol) is added again, when the 2- bromo acids tert-butyl ester (39.3g, 0.176mol) reaction 10 is small, directly
To compound, the reaction was complete, is concentrated under reduced pressure dry, adds 800g water and 400g dichloromethane, is layered, washing, organic phase anhydrous slufuric acid
Sodium is dried, and filtering, organic phase is concentrated and is done, and is recrystallized with ethyl acetate and petroleum ether, is obtained 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), be heated to 75~85 DEG C reaction 10 it is small when, add carbonic acid
Potassium (21Kg, 152mol), when the 2- bromo acids tert-butyl ester (14.9Kg, 66.8mol) reaction 10 is small, then adds potassium carbonate
(21Kg, 152mol), when the 2- bromo acids tert-butyl ester (14.9Kg, 66.8mol) reaction 10 is small, until compound has been reacted
Entirely, it is concentrated under reduced pressure into and distillates slowly for 45~55 DEG C, adds 300Kg water and 160Kg dichloromethane, stratification and take organic layer,
(mass concentration refers to that the quality of sodium chloride accounts for for the washing of 10% sodium-chloride water solution for 100Kg water and 100Kg mass concentrations
The percentage of sodium-chloride water solution gross mass), 15~25 DEG C be concentrated under reduced pressure into distillate slowly.Add ethyl acetate 100Kg heating
To 75~85 DEG C of dissolved clarifications, add normal heptane 180Kg, be cooled to 15~25 DEG C of stirrings 2~3 it is small when.Centrifugation, normal heptane 40Kg are washed
Wash, 40~50 DEG C vacuum drying 12 it is small when, 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, is cooled to 10~20 DEG C, adds sodium tert-butoxide
(26.8g, 0.279mol), be warming up to 50~60 DEG C of reactions 2 it is small when, add 400g water, be layered, washing, organic phase is concentrated under reduced pressure
It is dry, methanol 200ml is added, 0-10 DEG C, when stirring 1 is small is cooled to, filters, 40~50 DEG C of (- 0.08MPa~-0.1MPa) vacuum
When drying 12 is small, 78.8g yellow solid GFT505 intermediate compound Is, yield 97.0% are obtained.HPLC：99.23% (in terms of E configuration, 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, is cooled to 10~20 DEG C, adds sodium tert-butoxide
(10.3Kg, 107mol), be warming up to 50~60 DEG C reaction 2 it is small when, add 160Kg water, layering, 100Kg water and 100Kg mass are dense
Spend for 10% sodium-chloride water solution washing (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 slowly, add methanol 60Kg, are cooled to 0~10 DEG C, when stirring 1 is small, centrifugation,
When methanol 20Kg washings, 40~50 DEG C (- 0.08MPa~-0.1MPa) vacuum drying 12 are small, 30.4Kg yellow solids GFT505 is obtained
Intermediate compound I, yield 98.0%.LC-MS：M/z=441 (M+H)+；HPLC：99.50% (in terms of E configuration, Z configurational isomers account 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, is cooled to 10~20 DEG C, adds potassium tert-butoxide
(6.05g, 0.054mol), be warming up to 70~80 DEG C reaction 4~5 it is small when, add 200g water, with isopropyl acetate 60g extract two
Secondary, organic phase is concentrated under reduced pressure dry, adds methanol 20ml, is cooled to 0-10 DEG C, when stirring 1 is small, filtering, 40~50 DEG C (-
0.08MPa~-0.1MPa) vacuum drying 12 it is small when, obtain 7.62g yellow solid GFT505 intermediate compound Is, yield 95.2%.HPLC：
99.36% (in terms of E configuration, 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 n,N-Dimethylformamide, 10~20 DEG C is cooled to, adds
Enter sodium tert-butoxide (2.17g, 0.023mol), be warming up to 90~100 DEG C reaction 1~2 it is small when, add 100g water, use isopropyl acetate
Ester 60g is extracted twice, and organic phase is concentrated under reduced pressure dry, adds methanol 20ml, is cooled to 0-10 DEG C, when stirring 1 is small, filtering, 40~
When 50 DEG C (- 0.08MPa~-0.1MPa) vacuum drying 12 is small, 7.34g yellow solid GFT505 intermediate compound Is, yield are obtained
91.7%.HPLC：99.21% (in terms of E configuration, 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, is cooled to 10~20 DEG C, adds tert-butyl alcohol lithium
(7.21g, 0.090mol), be warming up to 40~50 DEG C reaction 9~10 it is small when, add 160g water, with isopropyl acetate 90g extract two
Secondary, organic phase is concentrated under reduced pressure dry, adds methanol 20ml, is cooled to 0-10 DEG C, when stirring 1 is small, filtering, 40~50 DEG C (-
0.08MPa~-0.1MPa) vacuum drying 12 it is small when, obtain 7.29g yellow solid GFT505 intermediate compound Is, yield 91.1%.HPLC：
99.16% (in terms of E configuration, 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, is cooled to 10~20 DEG C, adds the tert-butyl alcohol
Potassium (5.04g, 0.045mol), be warming up to 60~70 DEG C reaction 3~4 it is small when, add 100g water, with isopropyl acetate 60g extract
Twice, organic phase is concentrated under reduced pressure dry, adds methanol 20ml, is cooled to 0-10 DEG C, when stirring 1 is small, filters, 40~50 DEG C (-
0.08MPa~-0.1MPa) vacuum drying 12 it is small when, obtain 7.33g yellow solid GFT505 intermediate compound Is, yield 91.6%.HPLC：
99.46% (in terms of E configuration, 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 that embodiment 10 is made) are added in reaction bulb, are added
The dichloromethane of 790g, adds trifluoroacetic acid (209.7g, 1.84mol), when 20~30 DEG C of reaction 5-6 are small, concentration is dry, adds
The ethyl acetate of 600ml and the water of 600ml, are layered, washing, anhydrous sodium sulfate drying, filtering, organic phase concentration small size, 10-
Crystallization when 20 DEG C of stirrings 2 are small, is filtered, and under -0.08MPa~-0.1MPa, 40 DEG C~50 DEG C vacuum drying 12 obtain 60.1g Huangs when small
Color solid.Yellow solid obtains 52.9g yellow solids GFT505 (III), yield 77.8% with 250mL re-crystallizing in ethyl acetate.
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 that embodiment 9 is made) are added to the dichloromethane of 307Kg,
Add trifluoroacetic acid (80.8Kg, 709mol), when 20-30 DEG C of reaction 5-6 is small, concentration is dry, add 197Kg ethyl acetate and
(mass concentration refers to chlorine for 10% sodium-chloride water solution for the water of 231Kg, layering, 100Kg water and 100Kg mass concentrations
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
Crystallization when~20 DEG C of stirrings 2 are small, centrifugation, ethyl acetate 20Kg are washed, under -0.08MPa~-0.1MPa, and 40~50 DEG C of vacuum are done
It is dry 12 it is small when, obtain 23.2Kg yellow solids.Yellow solid is recrystallized to give 20.9Kg yellow solids with ethyl acetate 82Kg
GFT505III, yield 79.8%.LCMS：M/z=385 (M+H)+；HPLC：99.95%, maximum single contaminant 0.03%.
Claims (12)
1. a kind of preparation method of GFT505 intermediate compound Is, it is characterised in that it comprises the following steps：In organic solvent, by chemical combination
Thing II carries out isomerization reaction with tert-butyl alcohol alkali metal salt and obtains GFT505 intermediate compound Is；The compound II is double bond
Z/E mixtures, the GFT505 intermediate compound Is are E formula compounds；The Z/E mixtures of the double bond refer to that Z formula products account for
The 0.1%~99.0% of mixture gross mass, including 0.1%, including 99.0%；The 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 the preparation GFT505
In the reaction of intermediate compound I, the organic solvent is protonic solvent, polar non-proton organic solvent or nonpolar solvent；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the mass ratio of the organic solvent and the compound II
It is worth for 1~100；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the tert-butyl alcohol alkali metal salt is sodium tert-butoxide, potassium tert-butoxide
With the one or more in tert-butyl alcohol lithium；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the tert-butyl alcohol alkali metal salt is with the compound II's
Molar ratio is 1~5；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the temperature of cis-trans isomerization reaction is 30 DEG C~100
℃；
And/or
In the reaction for preparing GFT505 intermediate compound Is, time of cis-trans isomerization reaction for 1 it is small when~it is 10 small
When.
3. the preparation method of GFT505 intermediate compound Is as claimed in claim 2, it is characterised in that：
In the reaction for preparing GFT505 intermediate compound Is, the protonic solvent is C1~C4Alcohols solvent；
And/or
In the 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 reaction for preparing GFT505 intermediate compound Is, the nonpolar solvent is aromatic hydrocarbon solvent；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the mass ratio of the organic solvent and the compound II
It is worth for 2~10；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the tert-butyl alcohol alkali metal salt is with the compound II's
Molar ratio is 1.3~5；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the temperature of cis-trans isomerization reaction is 40 DEG C~100
℃；
And/or
In the reaction for preparing GFT505 intermediate compound Is, time of cis-trans isomerization reaction for 1 it is small when~it is 2 small
When, 2 it is small when, 3 it is small when~4 it is small when, 4 it is small when~5 it is small when or 9 it is small when~10 it is small when.
4. the preparation method of GFT505 intermediate compound Is as claimed in claim 3, it is characterised in that：
In the reaction for preparing GFT505 intermediate compound Is, the C1~C4Alcohols solvent is the tert-butyl alcohol；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the C1~C4Nitrile solvents are acetonitrile；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the C1~C6Ketones solvent is acetone and/or methyl-isobutyl
Ketone；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the C1~C4Amide solvent is N,N-dimethylformamide；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the C1~C4Sulfone class solvent is dimethyl sulfoxide (DMSO)；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the aromatic hydrocarbon solvent is toluene；
And/or
It is described in the reaction for preparing GFT505 intermediate compound Is in the reaction for preparing GFT505 intermediate compound Is
The mass values of organic solvent and the compound II are 2,3.5,4.9 or 8；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the tert-butyl alcohol alkali metal salt is with the compound II's
Molar ratio is 1.3,1.5,2.5,3 or 5；
And/or
In the reaction for preparing GFT505 intermediate compound Is, the cis-trans isomerization reaction temperature for 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 2, it is characterised in that：In the preparation GFT505
In the reaction of intermediate compound I, the mass values of the organic solvent and the compound II are 20.
6. the preparation method of GFT505 intermediate compound Is as claimed in claim 1, it is characterised in that：In the preparation GFT505
The reaction of mesosome I uses following steps：At 10 DEG C~20 DEG C, uncle is added in the mixture formed to compound II and organic solvent
Butanol alkali metal salt, is warming up to 30 DEG C~100 DEG C, carries out cis-trans isomerization and reacts to obtain the GFT505 intermediate compound Is；
And/or
The reaction for preparing GFT505 intermediate compound Is uses following post-processing step：After reaction, water, extraction, organic is added
Mutually washing, removing solvent, add alcohols solvent, are cooled to 0~10 DEG C, separation, drying, obtain the GFT505 intermediates
I。
7. the preparation method of GFT505 intermediate compound Is as claimed in claim 6, it is characterised in that：
In the post-processing step that the reaction for preparing GFT505 intermediate compound Is uses, the alcohols solvent is methanol；
And/or
In the post-processing step that the reaction for preparing GFT505 intermediate compound Is uses, the solvent that the extraction uses is ester
Class solvent；
And/or
In the post-processing step that the described reaction for preparing GFT505 intermediate compound Is uses, the separation using centrifuging or
Filtering.
8. a kind of preparation method of GFT505III, it is characterised in that it comprises the following steps：According to any one of claim 1~7
GFT505 intermediate compound Is and then in organic solvent are made in the preparation method, under the conditions of acid is existing, are hydrolyzed anti-
Should, obtain GFT505III；
9. the preparation method of GFT505III as claimed in claim 8, it is characterised in that：
The preparation method of GFT505III is prepared described, the organic solvent is halogenated hydrocarbon solvent；
And/or
The preparation method of GFT505III is prepared described, the organic solvent and the matter of the GFT505 intermediate compound Is
It is 1~100 to measure ratio；
And/or
The preparation method of GFT505III is prepared described, the acid is organic acid；
And/or
The preparation method of GFT505III is prepared described, the sour molar ratio with the GFT505 intermediate compound Is
For 5~20；
And/or
The preparation method of GFT505III is prepared described, the temperature of the hydrolysis is 0 DEG C~50 DEG C；
And/or
Prepare the preparation method of GFT505III described, time of the hydrolysis for 1 it is small when~10 it is small when；
And/or
The 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, reaction is hydrolyzed and obtains the GFT505III.
10. the preparation method of GFT505III as claimed in claim 9, it is characterised in that：
The preparation method of GFT505III is prepared described, the halogenated hydrocarbon solvent is chlorinated hydrocarbon solvent；
And/or
The preparation method of GFT505III is prepared described, the organic solvent and the matter of the GFT505 intermediate compound Is
It is 2~10 to measure ratio；
And/or
The preparation method of GFT505III is prepared described, the organic acid is trifluoroacetic acid；
And/or
The preparation method of GFT505III is prepared described, the sour molar ratio with the GFT505 intermediate compound Is
For 8~15；
And/or
The preparation method of GFT505III is prepared described, the temperature of the hydrolysis is 20 DEG C~30 DEG C；
And/or
Prepare the preparation method of GFT505III described, time of the hydrolysis for 2 it is small when~8 it is small when；
And/or
Obtained GFT505III obtains GFT505III after purification after recrystallization.
11. the preparation method of GFT505III as claimed in claim 10, it is characterised in that：
The preparation method of GFT505III is prepared described, the chlorinated hydrocarbon solvent is dichloromethane；
And/or
The preparation method of GFT505III is prepared described, the sour molar ratio with the GFT505 intermediate compound Is
For 10.4；
And/or
Prepare the preparation method of GFT505III described, time of the hydrolysis for 5 it is small when~6 it is small when；
And/or
The solvent that the recrystallization uses is esters solvent.
12. the preparation method of GFT505III as claimed in claim 9, it is characterised in that：In the preparation GFT505III
Preparation method in, the mass values of the organic solvent and the GFT505 intermediate compound Is are 10.1 or 10.2.
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| 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 |
| 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 |
| CN110156648A (en) * | 2019-05-30 | 2019-08-23 | 河北科技大学 | A kind of preparation method of Elafibranor intermediate |
| WO2024175026A1 (en) * | 2023-02-24 | 2024-08-29 | 哈尔滨三联药业股份有限公司 | Nitrogen-containing heterocyclic compounds and medical use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1819986A (en) * | 2003-07-08 | 2006-08-16 | 基恩菲特公司 | Preparation of 1,3-diphenylprop-2-en-1-one derivatives |
| CN1878752A (en) * | 2003-11-14 | 2006-12-13 | 巴斯福股份公司 | Cis-trans isomerisation of semicarbazone compounds |
| CN103025703A (en) * | 2010-05-17 | 2013-04-03 | 金菲特公司 | Improved preparation of chalcone derivatives |
-
2016
- 2016-12-06 CN CN201611108807.2A patent/CN106674069B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1819986A (en) * | 2003-07-08 | 2006-08-16 | 基恩菲特公司 | Preparation of 1,3-diphenylprop-2-en-1-one derivatives |
| CN1878752A (en) * | 2003-11-14 | 2006-12-13 | 巴斯福股份公司 | Cis-trans isomerisation of semicarbazone compounds |
| CN103025703A (en) * | 2010-05-17 | 2013-04-03 | 金菲特公司 | Improved preparation of chalcone derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020039297A1 (en) * | 2018-08-24 | 2020-02-27 | Mankind Pharma Ltd. | Novel compounds and their use in preparation of elafibranor and pharmaceutical acceptable salts thereof |
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