CN110256343A - Chloro- 4- bromo-isoquinoline derivative of 3,5- bis- and its preparation method and application - Google Patents
Chloro- 4- bromo-isoquinoline derivative of 3,5- bis- and its preparation method and application Download PDFInfo
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- CN110256343A CN110256343A CN201910452634.3A CN201910452634A CN110256343A CN 110256343 A CN110256343 A CN 110256343A CN 201910452634 A CN201910452634 A CN 201910452634A CN 110256343 A CN110256343 A CN 110256343A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- HRWILRGBDZGABZ-UHFFFAOYSA-N 4-bromo-1-chloroisoquinoline Chemical class C1=CC=C2C(Cl)=NC=C(Br)C2=C1 HRWILRGBDZGABZ-UHFFFAOYSA-N 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 3
- JDMFXJULNGEPOI-UHFFFAOYSA-N 2,6-dichloroaniline Chemical compound NC1=C(Cl)C=CC=C1Cl JDMFXJULNGEPOI-UHFFFAOYSA-N 0.000 claims abstract 2
- -1 diphenyl t-butylsilane Chemical compound 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 238000006884 silylation reaction Methods 0.000 claims description 6
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 3
- KVYHYUJRKYXVRG-UHFFFAOYSA-N 4-bromo-3,5-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=C(Br)C(Cl)=C1 KVYHYUJRKYXVRG-UHFFFAOYSA-N 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 2
- 238000003747 Grignard reaction Methods 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000011698 potassium fluoride Substances 0.000 claims description 2
- 235000003270 potassium fluoride Nutrition 0.000 claims description 2
- 229910000077 silane Inorganic materials 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 239000011775 sodium fluoride Substances 0.000 claims description 2
- 235000013024 sodium fluoride Nutrition 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- GCSVCUMDOQKEMT-UHFFFAOYSA-N butan-1-amine;hydrofluoride Chemical compound [H+].[F-].CCCCN GCSVCUMDOQKEMT-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- VAPWFBQHRVYUDV-UHFFFAOYSA-N 1-chloroisoquinoline-4-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CN=C(Cl)C2=C1 VAPWFBQHRVYUDV-UHFFFAOYSA-N 0.000 abstract description 6
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 abstract description 6
- 229960005381 lifitegrast Drugs 0.000 abstract description 6
- 229940126214 compound 3 Drugs 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000007858 starting material Substances 0.000 abstract description 5
- NHDODQWIKUYWMW-UHFFFAOYSA-N 1-bromo-4-chlorobenzene Chemical compound ClC1=CC=C(Br)C=C1 NHDODQWIKUYWMW-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000005457 ice water Substances 0.000 description 5
- LPAJUVHHLMTJCX-UHFFFAOYSA-N CO.BrC=1C=CC(=CC1)Cl Chemical compound CO.BrC=1C=CC(=CC1)Cl LPAJUVHHLMTJCX-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- CASRSOJWLARCRX-UHFFFAOYSA-N 3,5-dichlorobenzaldehyde Chemical compound ClC1=CC(Cl)=CC(C=O)=C1 CASRSOJWLARCRX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- JAVZWSOFJKYSDY-UHFFFAOYSA-N 4-bromo-2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1Cl JAVZWSOFJKYSDY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000208445 Sarcodes Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010048222 Xerosis Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- MOFLDTNKLMFGSU-UHFFFAOYSA-N bromobenzene;methanol Chemical compound OC.BrC1=CC=CC=C1 MOFLDTNKLMFGSU-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 210000000795 conjunctiva Anatomy 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 208000013441 ocular lesion Diseases 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to technical field of medicine synthesis, and in particular to a kind of noval chemical compound 3, chloro- 4- bromo-isoquinoline derivative of 5- bis- and its preparation method and application.The chloro- 4- bromo-isoquinoline of the 3,5- bis- and derivative are obtained with the chloro- 4- bromobenzene halogen ethamine of 3,5- bis- through Friedel-Crafts reaction closed loop.The chloro- 4- bromo-isoquinoline of the 3,5- bis- and derivative can be used for synthesizing the chloro- 4- carboxyl isoquinoline of important intermediate 3,5- bis- of Lifitegrast.Technical solution provided by the invention is with cheap, well-off 2,6- dichloroaniline is starting material, through multistep mild condition, operation is mature, and yield is formed in 85% or more reaction, and pilot experiment is passed through in each step reaction, therefore the feasibility of industrialization conversion is very high, and whole production cost can substantially reduce.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of noval chemical compound 3, the chloro- 4- bromo-isoquinoline of 5- bis- spread out
Biology and its preparation method and application.
Background technique
Xerophthalmia (dry eye) also known as angle xerosis of conjunctiva (KCS), refer to lacrimal secretion caused by any reason it is insufficient or
Tear dynamics is abnormal, causes tear film stability to decline, and with ophthalmic uncomfortable and/or a variety of diseases of ocular lesion tissue feature
The general name of disease.Disease incidence is related with age and gender, and adult disease incidence is 5% within 30~40 years old, the disease incidence of over-65s old man
It is 10%~15%, women disease incidence is higher than male.The U.S.'s about 29,000,000 patients with dry eye.Lifitegrast is Shire
1.6 hundred million dollars were taken in 2013 to purchase from U.S. SARcode Bioscience, FDA granted priority evaluates qualification,
Market is 5 years (NCE) exclusive, and prediction sale peak value can be more than 1,000,000,000 dollars.
Lifitegrast entitled (the S) -2- of chemistry (2- (benzofuran-6-carbonyl) -5,7-dichloro-1,
2,3,4-tetrahedro Isoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)
The molecular formula of propanioc acid, Lifitegrast are C29H24Cl2N2O7S, and molecular weight is 615.5.Lifitegrast
Structural formula it is as follows:
The salt of the chloro- 4- carboxyl isoquinoline (Formulas I) of 3,5- bis- is an important intermediate of Lifitegrast synthesis:
United States Patent (USP) US7745460, US8084047, US7314938, US7928122 etc. disclose the chloro- 4- carboxylic of 3,5- bis-
The preparation method of base isoquinolin, reaction equation are as follows:
It is that starting material obtains formula (II) compound through four-step reaction, but the preparation method exists with 3,5- dichlorobenzaldehyde
Following disadvantage: firstly, starting material price is very high；Secondly, last severe reaction conditions, needs ultralow temperature in production process
Middle progress, and agents useful for same risk is high, therefore extremely difficult using route progress industrialized production, purification difficult, at
This is high, and total recovery is low.
Summary of the invention
The present invention provides a kind of noval chemical compound 3, chloro- 4- bromo-isoquinoline derivative of 5- bis- and its preparation method and application,
To solve the problems, such as that the chloro- 4- carboxyl isoquinoline industrialized production of 3,5- bis- is difficult.
In order to solve the above-mentioned technical problem, inventor's design has synthesized general formula II compound represented:
Wherein, R is selected from hydrogen or silylation protecting group.
Optionally, the silicon-based protecting group be selected from tert-butyldimethylsilane base (TBS), trimethylsilyl (TMS) or
Diphenyl t-butylsilane base.
The present invention also design synthesized it is a kind of for closing the compound of formula III of compound of formula II:
Wherein, X is selected from halogen.
Optionally, the halogen is selected from Cl (chlorine) or Br (bromine).
The present invention also provides the preparation methods of Compounds of formula II to react using general formula III as raw material through Friedel-Crafts
Closed loop obtains the compound that R in general formula II is hydrogen, and reaction equation is as follows:
Further by reacting with protected silane base, the chemical combination that R in general formula II is silylation protecting group is further obtained
Object.
Optionally, the compound of formula III is with formula IV compound (3,5- bis- chloro- 4- bromoacetophenone) for raw material, warp
Oxidation reaction obtains Formula V compound (3,5- bis- chloro- 4- bromobenzoic acid), then obtains Formula IV compound (3,5- bis- chloro- 4- through reduction reaction
Bromobenzene methanol), then halogenating reaction obtains Formula VII compound (3,5- bis- chloro- 4- bromine halogen benzyl), finally reacts acquisition with halogen ethamine
, specific reaction equation is as follows:
Optionally, the formula IV compound is with Formula VIII compound (2,6-DCA) for raw material, Jing Fuke acetyl
Change reaction and obtain Formula IX compound (3,5- bis- chloro- 4- bromoacetophenone), is then obtained again through diazo-reaction, reaction equation
It is as follows:
The present invention also provides the method that Compounds of formula II is used to prepare compound of formula I, specifically include when R is hydrogen
Then amido is protected first, is directly reacted as follows if R is silylation protecting group, grignard reaction obtains Formula X first
Compound, then deprotection and salt-forming reaction obtain the salt of compound of formula I, and reaction equation is as follows:
Optionally, in the deprotection reaction, deprotecting regent used is tetrabutyl ammonium fluoride, sodium fluoride and potassium fluoride
In one or more fluoride ions fluorine reagent.
Acidizing reagent used is selected from the inorganic acids or formic acid, acetic acid etc. such as hydrochloric acid, sulfuric acid or nitric acid in the salt-forming reaction
Organic acid is correspondingly formed hydrochloride, sulfate, nitrate, formates or acetate of compound of formula I etc..
The present invention also provides a kind of methods of salt for preparing the chloro- 4- carboxyl isoquinoline of 3,5- bis-, with 2,6- dichloro-benzenes
Amine is starting material, walks reaction through number and obtains, specifically reacts shown in following reaction equation:
Wherein, R is tert-butyldimethylsilane base, trimethylsilyl or diphenyl t-butylsilane base.
Technical solution provided by the invention is with cheap, and well-off 2,6-DCA is starting material, through more
Mild condition is walked, operation is mature, and yield is formed in 85% or more reaction, and pilot experiment, therefore work are passed through in each step reaction
The feasibility of industryization conversion is very high, and whole production cost can substantially reduce.
Specific embodiment
In order to make it easy to understand, illustrating the chloro- 4- bromo-isoquinoline derivative of 3, the 5- bis- and its preparation below with reference to embodiment
Methods and applications, it should be appreciated that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.Implement below
The used temperature of example and reagent can be used relevant temperature described above and reagent to substitute the purpose to realize the present invention.
Agents useful for same is commercial goods in following embodiments, and wherein nuclear magnetic resonance data is measured by Fourier 300,
Middle mass spectrum is measured by GCMS6800.
The synthesis of 1 4- acetyl group -2,6- dichloroaniline (IX) of embodiment
Compound VIII (50g) is added in 1L three-necked bottle, methylene chloride 600ml is stirred at room temperature dissolution, is added after dissolution
Alchlor (180g), ice bath are cooled to 0 DEG C, under stirring, are added dropwise aceticanhydride (50ml), finish, and restore to 2~4h of normal-temperature reaction.
After reaction, it is cooled to 0 DEG C, the HCl solution that concentration is 1N, layering is slowly added dropwise, water phase is extracted with 200ml methylene chloride,
Merge organic phase, it is dry, it is concentrated to give compound IX (51g), yield 98.9%, is in light yellow solid.
The synthesis of the chloro- 4- bromoacetophenone (IV) of 2 3,5- of embodiment bis-
Compound IX (40g) and 130ml hydrobromic acid solution and cuprous bromide (55g), ice bath are added in 500ml three-necked bottle
It is cooled to 0~5 DEG C, under stirring, the aqueous solution (32ml) of sodium nitrite is added dropwise, drop finishes within about 0.5 hour, stirs at 0~5 DEG C anti-
It answers 4 hours, reaction solution is poured into 500ml ice water, filter to obtain compound IV (43g), yield 90%.
The synthesis of the chloro- 4- bromobenzoic acid (V) of 3 3,5- of embodiment bis-
Compound IV (45g) and 230ml liquor natrii hypochloritis are added in 500ml three-necked bottle, is heated to reflux, is with concentration
The NaOH solution of 6N maintains pH value 10 or more, flows back 6 hours, and ice bath is cooled under 0~5 DEG C of stirring, and 6N hydrochloric acid solution is slow
It is slow to be added dropwise, to pH value to 2 or so, after stirring 1 hour, filter to obtain compound V (40g), yield 88%.
The synthesis of the chloro- 4- bromobenzene methanol (VI) of 4 3,5- of embodiment bis-
Compound V (35g) and 120ml dehydrated alcohol are added in 500ml three-necked bottle to be added portionwise under ice-water bath is cooling
Sodium borohydride (16g) warms naturally to room temperature reaction 4 hours.Ice bath is cooled under 0~5 DEG C of stirring, slowly by 6N hydrochloric acid solution
Dropwise addition is entered, and pH to 2 or so is arrived, and after stirring 1 hour, concentration removes ethyl alcohol, and ethyl acetate (200ml) is added and is extracted twice, does
It is dry, it is concentrated to give compound VI (33g), yield 92%.
The synthesis of the chloro- 4- bromine benzyl chloride (VII) of 5 3,5- of embodiment bis-
In 1000ml three-necked bottle, under ice-water bath is cooling, compound VI (60g) and 180ml concentrated hydrochloric acid is added, heats up naturally
To room temperature reaction 5 hours.Ethyl acetate (300mlX2) extraction is added, it is dry, it is concentrated to give compound VII (58g), yield 86%.
The synthesis of the chloro- 4- bromobenzene chlorethamin (III) of 6 3,5- of embodiment bis-
In 500ml three-necked bottle, 200ml acetone, compound VII (40g), chloroethylamine hydrochloride (25g) and carbonic acid is added
Potassium (86g) is heated to reflux 12 hours.After reaction, it is cooled to room temperature, filters, after filtrate concentration, addition 150ml water, then plus
Enter ethyl acetate (100ml) to be extracted twice, it is dry, it is concentrated to give compound III (38g), yield 90%.H1NMR (300MHz,
CD3OD)ppm:6.84(2H),3.81(2H),3.50(2H),2.83(2H)；MS:314.9(M+).
The synthesis of the chloro- 4- bromo-isoquinoline (II) of 7 3,5- of embodiment bis-
It in 250ml three-necked bottle, is added compound III (140g), it is complete to be heated to 140 DEG C of solids for alchlor (300g)
After portion's dissolution, the reaction was continued 4 hours.After reaction, it is cooled to room temperature, methylene chloride is added, NaOH solution slowly is added dropwise extremely
PH value about 7, liquid separation, water phase adds methylene chloride (100mlX2) extraction, dry, is concentrated to give compound 3, the chloro- 4- bromine of 5- bis- is different
Quinoline (128g), yield 91%.H1NMR (300MHz, CD3OD)ppm:6.79(1H),3.81(2H),2.88(2H),2.67
(2H)；MS:278.9(M+).
The synthesis of the chloro- 4- bromo-isoquinoline (II) of 8 N- of embodiment (dimethyl tertiary butyl silicon) -3,5- two
In 500ml three-necked bottle, addition compound 3, the chloro- 4- bromo-isoquinoline (30g) of 5- bis-, methylene chloride (150ml), three
Ethamine (45g), ice water are cooled to 0 degree, and dimethyl tertiary butyl chlorosilane (50g is dissolved in 100ml methylene chloride) slowly is added dropwise, after
Continuous reaction 2 hours.After reaction, 150ml water, liquid separation is added, water phase adds methylene chloride (150ml) and is extracted twice, and does
It is dry, it is concentrated to give the chloro- 4- bromo-isoquinoline (32g) of compound N-(dimethyl tertiary butyl silicon) -3,5- bis-, yield 94%.
The synthesis of the chloro- 4- carboxyl isoquinoline (X) of 9 N- of embodiment (dimethyl tertiary butyl silicon) -3,5- two
In 500ml three-necked bottle, be added Mg bits (24g), anhydrous THF (150ml), iodine (120mg), 45 DEG C or so 1 hour
Afterwards, the chloro- 4- bromo-isoquinoline (80g is dissolved in 100mlTHF) of N- (dimethyl tertiary butyl silicon) -3,5- bis- is slowly added dropwise, is added dropwise
After continue reflux 2 hours.Ice water is cooled to 0 DEG C, is slowly passed through CO2Terminate to reaction, 250ml water is added, adds dichloromethane
Alkane (500ml) is extracted twice, dry, is concentrated to give compound X (62g), yield 85%.
The synthesis of chloro- 4- carboxyl isoquinoline (I) hydrochloride of 10 3,5- of embodiment bis-
It in 250ml three-necked bottle, is added compound X (20g), THF (100ml), is slowly added into tetrabutyl fluorination at room temperature
Ammonium (18g), the reaction was continued 2 hours after adding.After reaction, 50ml water is added, adds methylene chloride (1200ml) extraction
Twice, the HCl (100ml) that methylene chloride is 2N with concentration is washed, and water phase is concentrated into solid precipitation, cooling, filters to obtain compound I
The hydrochloride of (16g), yield 88%.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations.Although
Present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that: it still may be used
To modify to technical solution documented by previous embodiment, or some or all of the technical features are equal
Replacement, and these modifications or substitutions, the model for technical solution of various embodiments of the present invention that it does not separate the essence of the corresponding technical solution
It encloses.
Claims (9)
1. a kind of compound, which is characterized in that general formula II compound represented:
Wherein, R is selected from hydrogen or silylation protecting group.
2. compound according to claim 1, which is characterized in that the silicon-based protecting group is selected from tert-butyldimethylsilane
Base, trimethylsilyl or diphenyl t-butylsilane base.
3. a kind of for closing the compound of compound of formula II, which is characterized in that be compound shown in general formula III:
Wherein, X is selected from halogen.
4. compound according to claim 3, which is characterized in that the halogen is selected from Cl or Br.
5. a kind of preparation method of Compounds of formula II obtains general formula through Friedel-Crafts reaction closed loop using general formula III as raw material
R is the compound of hydrogen in II, and reaction equation is as follows:
Further by reacting with protected silane base, the change that R in Compounds of formula II is silylation protecting group is further obtained
Close object.
6. preparation method according to claim 5, which is characterized in that the compound of formula III be with formula IV compound (3,
The chloro- 4- bromoacetophenone of 5- bis-) it is raw material, Formula V compound (3,5- bis- chloro- 4- bromobenzoic acid) is obtained through oxidation reaction, then through restoring
Formula IV compound (3,5- bis- chloro- 4- bromobenzene methanol) is reacted to obtain, then halogenating reaction obtains Formula VII compound (3,5- bis- chloro- 4- bromines
Halogen benzyl), acquisition is finally reacted with halogen ethamine, reaction equation is as follows:
7. preparation method according to claim 6, which is characterized in that the formula IV compound be with Formula VIII compound (2,
6- dichloroaniline) it is raw material, Jing Fuke acetylization reaction obtains Formula IX compound (3,5- bis- chloro- 4- bromoacetophenone), then again
It is obtained through diazo-reaction, reaction equation is as follows:
8. a kind of method that Compounds of formula II is used to prepare compound of formula I, which is characterized in that including when R is hydrogen then first
Amido is protected, is directly reacted as follows if R is silylation protecting group, grignard reaction obtains Formula X compound first,
Then deprotection and salt-forming reaction obtain the salt of compound of formula I, and reaction equation is as follows:
9. method according to claim 8, which is characterized in that in the deprotection reaction, deprotecting regent used is four
The fluorine reagent of one or more fluoride ions in butyl ammonium fluoride, sodium fluoride and potassium fluoride.
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| US20110092707A1 (en) * | 2009-10-21 | 2011-04-21 | Sarcode Corporation | Crystalline Pharmaceutical and Methods of Preparation and Use Thereof |
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| CN108084090A (en) * | 2017-12-20 | 2018-05-29 | 北京六合宁远科技有限公司 | Synthetic method of brominated compound containing nitrogen heterocycle as drug intermediate |
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| US20050267098A1 (en) * | 2003-11-05 | 2005-12-01 | Wang Shen | Modulators of cellular adhesion |
| US7745460B2 (en) * | 2003-11-05 | 2010-06-29 | Sarcode Corporation | Modulators of cellular adhesion |
| US20110092707A1 (en) * | 2009-10-21 | 2011-04-21 | Sarcode Corporation | Crystalline Pharmaceutical and Methods of Preparation and Use Thereof |
| CN104797574A (en) * | 2012-07-25 | 2015-07-22 | 原生质生物科学股份有限公司 | LFA-1 inhibitor and polymorph thereof |
| CN106831576A (en) * | 2017-03-10 | 2017-06-13 | 北京六合宁远科技有限公司 | Preparation method of 2-methyl-1-oxo-1, 2-dihydroisoquinoline-6-formic acid |
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