CN109776401A - A method of preparing the chloro- 5- trifluoromethyl -2-aminopyridine of 6- - Google Patents
A method of preparing the chloro- 5- trifluoromethyl -2-aminopyridine of 6- Download PDFInfo
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- CN109776401A CN109776401A CN201711125477.2A CN201711125477A CN109776401A CN 109776401 A CN109776401 A CN 109776401A CN 201711125477 A CN201711125477 A CN 201711125477A CN 109776401 A CN109776401 A CN 109776401A
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- 238000000034 method Methods 0.000 title claims abstract description 16
- WXNPZQIRDCDLJD-UHFFFAOYSA-N 3-chloro-5-(trifluoromethyl)pyridin-2-amine Chemical compound NC1=NC=C(C(F)(F)F)C=C1Cl WXNPZQIRDCDLJD-UHFFFAOYSA-N 0.000 title abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- 239000002994 raw material Substances 0.000 claims abstract description 11
- UUDNBWSHTUFGDQ-UHFFFAOYSA-N 3-iodopyridin-2-amine Chemical compound NC1=NC=CC=C1I UUDNBWSHTUFGDQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006692 trifluoromethylation reaction Methods 0.000 claims abstract description 5
- 125000003368 amide group Chemical group 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 235000003270 potassium fluoride Nutrition 0.000 claims description 6
- 239000011698 potassium fluoride Substances 0.000 claims description 6
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical group ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 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 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 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 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- RZJPBQGRCNJYBU-UHFFFAOYSA-N 3-chloropyridin-2-amine Chemical compound NC1=NC=CC=C1Cl RZJPBQGRCNJYBU-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 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 3
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 3
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 2
- 150000001721 carbon Chemical class 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000001119 stannous chloride Substances 0.000 description 2
- 235000011150 stannous chloride Nutrition 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- UPWAAFFFSGQECJ-UHFFFAOYSA-N 2,6-dichloro-3-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Cl)N=C1Cl UPWAAFFFSGQECJ-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- RGDQRXPEZUNWHX-UHFFFAOYSA-N 3-methylpyridin-2-amine Chemical compound CC1=CC=CN=C1N RGDQRXPEZUNWHX-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- NNYBQONXHNTVIJ-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=C1C(C=CC=C1CC)=C1N2 NNYBQONXHNTVIJ-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 229940063718 lodine Drugs 0.000 description 1
- BFXIKLCIZHOAAZ-UHFFFAOYSA-N methyltrimethoxysilane Chemical compound CO[Si](C)(OC)OC BFXIKLCIZHOAAZ-UHFFFAOYSA-N 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- BBDNZMUIQBRBJH-UHFFFAOYSA-N sulfurochloridic acid;toluene Chemical compound OS(Cl)(=O)=O.CC1=CC=CC=C1 BBDNZMUIQBRBJH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method of the chloro- 5- trifluoromethyl -2-aminopyridine of 6-, which is prepared, using the iodo- 2-aminopyridine of the chloro- 5- of 6- as raw material obtains product by reaction steps such as amido protecting, trifluoromethylation and deprotections.
Description
Technical field
Field of medicine and chemical technology.
Background technique
Existing method is with 3- trifluoromethyl -2,6- dichloropyridine for raw material, prepares the chloro- 5- trifluoro of 6- using ammonolysis reaction
Methyl-2-amino pyridine.The method has raw material to be not easy to obtain, and domain of the existence is selectively bad, and product is difficult to purify not
Foot.
Summary of the invention
In view of the drawbacks of the prior art, the invention discloses a kind of chloro- 5- fluoroforms of more economic, easily operated 6-
Base -2-aminopyridine preparation method.Using the iodo- 2-aminopyridine of the chloro- 5- of valence 6- as raw material, pass through amido protecting, trifluoromethyl
Change and the reaction steps such as deprotection obtain product.Entire reaction process is selectively good, is not difficult to isolated isomers, thus easily
In isolating and purifying.Reaction condition is mild, easy to operate, is suitable for producing in batches.
Preparing the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) starting material is the iodo- 2-aminopyridine of the chloro- 5- of 6-
(Formulas I) can occur iodide reaction with the chloro- 2-aminopyridine of 6- and N- N-iodosuccinimide etc. and be prepared, be referred to
Document European Journal of Medicinal Chemistry, 2014, p.404-416.
Prepare the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) the following steps are included:
A) it is reacted by amido protecting for raw material with the iodo- 2-aminopyridine of the chloro- 5- of 6- (Formulas I), obtains formula (II) compound,
Wherein, R1 H, R2 be acetyl group (Ac), tertbutyloxycarbonyl (Boc), mesyl (Ms), p-toluenesulfonyl (Ts),
Or R1 and R2 is simultaneously tertbutyloxycarbonyl (Boc)；
B) Formula II compound is reacted by trifluoromethylation, and compound formula III is prepared, wherein the definition of R1 and R2 is with before
It states identical；
C) formula III compound takes off amino protecting group, and the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) is prepared.
Wherein, in step a), upper amino protecting group agents useful for same be chloroacetic chloride, di-tert-butyl dicarbonate, methane sulfonyl chloride,
One of paratoluensulfonyl chloride.In step b), it is trifluoromethyl trimethylsilane and 1,10- that trifluoromethylation, which reacts agents useful for same,
Phenanthroline.In step c), being deprotected acid used is concentrated hydrochloric acid, trifluoroacetic acid, hydrobromic acid.
Specific embodiment
The preparation of the iodo- 2-aminopyridine of the chloro- 5- of 1 6- of embodiment (Formulas I)
Compound of formula I can refer to document European Journal of Medicinal Chemistry, and 2014, p.404-416
Preparation.The chloro- 2-aminopyridine of 100g 6- is dissolved in 400mL n,N-Dimethylformamide, 195g N- iodo fourth two is added
Acid imide.It stirs to fully reacting, reaction solution is poured into 400g water, is extracted with ethyl acetate, extract liquor anhydrous sodium sulfate
It is dry.Filtering, is concentrated to give fine work, and crude product ethyl alcohol obtains product 126.7g, yield 64%, HPLC testing product purity after must crystallizing
98.6%。
HRMS:m/e+H=254.9180, theoretical value: 254.9183.
The preparation of the iodo- 2-aminopyridine of the chloro- 5- of 2 6- of embodiment (Formulas I)
The chloro- 2-aminopyridine of 60g 6- is dissolved in 400mL glacial acetic acid, 75.5g lodine chloride is added.It stirs to fully reacting,
Reaction solution is poured into 200g water, is extracted with ethyl acetate, extract liquor is dry with anhydrous sodium sulfate.Filtering, is concentrated to give fine work,
Crude product ethyl alcohol obtains product 126.7g, yield 71%, HPLC testing product purity 99.5% after must crystallizing.
3 II a(R1 of embodiment=H, R2=Ac) preparation
By 2g chemical compounds I, triethylamine, methylene chloride is added in flask, cooling with ice salt bath under nitrogen protection.Second is added dropwise
The dichloromethane solution of acyl chlorides, after being added dropwise, temperature reaction to raw material disappears.Reaction solution 1M hydrochloric acid, saturated sodium bicarbonate,
Water successively washs, and crude product is obtained after concentration.With after ethyl alcohol recrystallization solid 0.85g, product purity 95.1%.
4 II b(R1 of embodiment=H, R2=Boc) preparation
By 2g compound I, THF is added in flask, under nitrogen protection, is bathed and is cooled down with dry ice-propanone, two silicon of hexamethyl is added dropwise
Base lithium amide (LHMDS) solution, is stirred to react 1h, di-tert-butyl dicarbonate is then added, and after being added dropwise, insulation reaction is extremely
Raw material disappears.Reaction solution is quenched with 10% citric acid, separates organic phase, and water phase is quenched with the tertiary ether of first to be taken, merges organic phase, anhydrous sulphur
Sour sodium dries, filters, and product, yield 75.3% are obtained after concentration.
1H-NMR (CDCl3, 400MHz): δ ppm 8.01(d, J=8.6Hz, 1H), 7.64(d, J=8.6Hz,
1H), 7.26(brs, 1H), 1.51(s, 9H).
13C-NMR (CDCl3, 100MHz): δ ppm 151.78, 151.69, 151.47, 150.14, 111.94,
84.46, 81.78, 28.10.
5 IIc(R1 of embodiment=H, R2=Ms) preparation
By 2g compound I, triethylamine, methylene chloride is added in flask, cooling with ice salt bath under nitrogen protection.First is added dropwise
The dichloromethane solution of alkanesulphonyl chlorides, after being added dropwise, temperature reaction to raw material disappears.Reaction solution 1M hydrochloric acid, saturated carbon
Sour hydrogen sodium, water successively wash, and crude product is obtained after concentration, obtains solid, yield 83.7%, product purity after crude product ethyl alcohol recrystallization
97.2%。
6 IId(R1 of embodiment=H, R2=Ts) preparation
By 2g compound I, triethylamine, methylene chloride is added in flask, cooling with ice salt bath under nitrogen protection.Dropwise addition pair
The dichloromethane solution of toluene sulfochloride, after being added dropwise, temperature reaction to raw material disappears.Reaction solution 1M hydrochloric acid, saturated carbon
Sour hydrogen sodium, water successively wash, and crude product is obtained after concentration.With after ethyl alcohol recrystallization solid 1.15g, product purity 95.1%.
7 IIe(R1 of embodiment=R2=Boc) preparation
By 2g compound I, THF is added in flask, cooling with ice salt bath under nitrogen protection, and 60% sodium hydride, stirring is added
2h is reacted, di-tert-butyl dicarbonate is then added, after being added dropwise, temperature reaction to raw material disappears.Reaction solution is slowly poured into
10% citric acid is quenched, and separates organic phase, and water phase is quenched with the tertiary ether of first to be taken, merges organic phase, and anhydrous sodium sulfate dries, filters, concentration
Product, yield 72.0% are obtained afterwards.
1H-NMR (CDCl3, 400MHz): δ ppm 8.12 (d, J=8.6Hz, 1H), 7.04(d, J=8.6Hz,
1H), 1.51(s, 18H).
13C-NMR (CDCl3, 100MHz): δ ppm 152.62, 151.43, 150.42, 149.95, 119.95,
90.84, 83.91, 27.80.
8 II a(R1 of I of embodiment=H, R2=Ac) preparation
Compound IIa, cuprous iodide, potassium fluoride, 1,10- phenanthroline, DMF, fluoroform are added into reaction flask for nitrogen protection
Base trimethylsilane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, organic phase anhydrous slufuric acid
Sodium dries, filters, and filtrate obtains solid after being concentrated to give.
9 II Ib(R1 of embodiment=H, R2=Boc) preparation
Compound IIb, stannous chloride, potassium fluoride, 1,10- phenanthroline, NMP, fluoroform are added into reaction flask for nitrogen protection
Base trimethylsilane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, organic phase anhydrous slufuric acid
Sodium dries, filters, and filtrate obtains solid after being concentrated to give.
1H-NMR (CDCl3, 400MHz): δ ppm7.93-8.02(m, 2H), 7.64(m 1H), 1.51(s,
9H).
10 IIIc(R1 of embodiment=H, R2=Ms) preparation
Compound IIc, stannous chloride, potassium fluoride, 1,10- phenanthroline, DMSO, trifluoro are added into reaction flask for nitrogen protection
Methyl trimethoxy silane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, the anhydrous sulphur of organic phase
Sour sodium dries, filters, and filtrate obtains solid after being concentrated to give.
11 IIId(R1 of embodiment=H, R2=Ts) preparation
Compound IId, cuprous iodide, potassium fluoride, 1,10- phenanthroline, DMF, fluoroform are added into reaction flask for nitrogen protection
Base trimethylsilane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, organic phase anhydrous slufuric acid
Sodium dries, filters, and filtrate obtains solid after being concentrated to give.
12 IIIe(R1 of embodiment=R2=Boc) preparation
Nitrogen protection, the addition compound ii e into reaction flask, cuprous iodide, tetrabutyl ammonium fluoride, 1,10- phenanthroline, DMF,
Trifluoromethyl trimethylsilane, stirring to fully reacting.Reaction solution is poured into 2M hydrochloric acid, ethyl acetate extraction, organic phase nothing
Aqueous sodium persulfate dries, filters, and filtrate obtains solid after being concentrated to give.
1H-NMR (CDCl3, 400MHz): δ ppm 8.12 (d, J=8.4Hz, 1H), 7.04(d, J=8.4Hz,
1H), 1.55(s, 18H).
13C-NMR (CDCl3, 100MHz): δ ppm 153.80, 150.34, 147.31, 138.37, 122.36,
121.92, 115.92. 27.89.
19F-NMR (CDCl3, 376Hz): 62.89.
The preparation of 13 formula IV compound of embodiment
Nitrogen protection, compound IIIa, ethyl alcohol are added into reaction flask, and concentrated hydrochloric acid is heated until fully reacting.By reaction solution
It is concentrated, methylene chloride and sodium bicarbonate solution is added in residue, after stirring, layering obtains crude product, ethyl alcohol weight after organic phase concentration
Crystallize to obtain product.
1H-NMR (CDCl3, 400MHz): δ ppm 7.65 (d, J=8.5Hz, 1H), 6.39(d, J=8.5Hz,
1H), 5.31( brs, 2H).
13C-NMR (CDCl3, 100MHz): δ ppm 159.87, 147.86, 137.87, 123.0, 113.8,
105.55.
The preparation of 13 formula IV compound of embodiment
Nitrogen protection, compound III b, ethyl alcohol are added into reaction flask, and concentrated hydrochloric acid is heated until fully reacting.Reaction solution is dense
It contracts, methylene chloride and sodium bicarbonate solution is added in residue, after stirring, layering obtains crude product after organic phase concentration, and ethyl alcohol is tied again
It is brilliant to obtain product.
The preparation of 14 formula IV compound of embodiment
Nitrogen protection, compound III e is added into reaction flask, and trifluoroacetic acid is heated until fully reacting.Reaction solution is concentrated,
Methylene chloride and sodium bicarbonate solution are added in residue, after stirring, layering obtains crude product, ethyl alcohol recrystallization after organic phase concentration
Obtain product.
The preparation of 15 formula IV compound of embodiment
Protection, compound III c is added into reaction flask, and hydrobromic acid solution is heated until fully reacting.Reaction solution is concentrated, it is residual
Methylene chloride and sodium bicarbonate solution are added in excess, after stirring, layering obtains crude product after organic phase concentration, and ethyl alcohol recrystallization obtains
Product.
Claims (10)
1. a kind of prepare the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) method, which comprises the following steps:
It a) is that raw material obtains formula (II) compound by the reaction of amido protecting with the iodo- 2-aminopyridine of the chloro- 5- of 6- (Formulas I),
Wherein, R1 H, R2 be acetyl group (Ac), tertbutyloxycarbonyl (Boc), mesyl (Ms), p-toluenesulfonyl (Ts),
Or R1 and R2 is simultaneously tertbutyloxycarbonyl (Boc)；
B) Formula II compound is reacted by trifluoromethylation, and compound formula III is prepared,
Wherein, the definition of R1 and R2 is same a)；
C) formula III compound takes off amino protecting group, and the chloro- 5- trifluoromethyl of 6- -2-aminopyridine (formula IV) is prepared.
2. according to the method described in claim 1, upper amino protecting group agents useful for same is chloroacetic chloride, two carbonic acid two in step a)
One of the tert-butyl ester, methane sulfonyl chloride, paratoluensulfonyl chloride.
3. according to the method described in claim 1, it is trifluoromethyl front three silicon that trifluoromethylation, which reacts agents useful for same, in step b)
Alkane and 1,10- phenanthroline.
4. according to the method described in claim 1, being deprotected acid used is concentrated hydrochloric acid, trifluoroacetic acid, hydrogen bromine in step c)
Acid.
5. according to the method described in claim 2, by compound I, triethylamine, methylene chloride is added to flask in step a)
In, it is cooling with ice salt bath under nitrogen protection, the dichloromethane solution of chloroacetic chloride is added dropwise, after reaction, prepares after post treatment
Obtain compound II(R1=H, R2=Ac).
6. according to the method described in claim 2, compound I, THF are added in flask in step a), under nitrogen protection,
It is bathed and is cooled down with dry ice-propanone, lithium hexamethyldisilazide (LHMDS) solution is added dropwise, is stirred to react, two carbonic acid two is then added
Compound II(R1=H, R2=Boc is prepared after reaction in the tert-butyl ester after post treatment).
7. according to the method described in claim 2, compound I, THF are added in flask in step a), under nitrogen protection,
It is cooling with ice salt bath, 60% sodium hydride is added, di-tert-butyl dicarbonate is then added, after reaction, is prepared into after post treatment
To compound II(R1=Boc, R2=Boc).
8. according to the method described in claim 3, compound II(R1=H, R2=Ac are added into reaction flask in step b)), iodine
Change cuprous, potassium fluoride, 1,10- phenanthroline, DMF, trifluoromethyl trimethylsilane, stirring to fully reacting, after post treatment, preparation
Obtain chemical combination III(R1=H, R2=Ac).
9. according to the method described in claim 3, compound II(R1=H, R2=Boc are added into reaction flask in step b)), chlorine
Change cuprous, potassium fluoride, 1,10- phenanthroline, N-Methyl pyrrolidone (NMP), trifluoromethyl trimethylsilane, stirring is to having reacted
Entirely, after post treatment, chemical combination III(R1=H, R2=Boc is prepared).
10. according to the method described in claim 3, in step b), it is added compound II(R1=Boc into reaction flask, R2=
Boc), cuprous iodide, tetrabutyl ammonium fluoride, 1,10- phenanthroline, DMF, trifluoromethyl trimethylsilane, stirring to fully reacting, warp
Later it handles, chemical combination III(R1=Boc, R2=Boc is prepared).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010222304A (en) * | 2009-03-24 | 2010-10-07 | Kyushu Univ | Process for producing trifluoromethylarenes |
| CN102137859A (en) * | 2008-06-13 | 2011-07-27 | Astex治疗学有限公司 | Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases |
| CN105228620A (en) * | 2013-03-15 | 2016-01-06 | 德西费拉制药有限责任公司 | Represent N-acyl group-N '-(pyridine-2-base) urea and the analog of anticancer and antiproliferative activity |
| WO2016168098A1 (en) * | 2015-04-16 | 2016-10-20 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
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2017
- 2017-11-14 CN CN201711125477.2A patent/CN109776401A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102137859A (en) * | 2008-06-13 | 2011-07-27 | Astex治疗学有限公司 | Imidazopyridine derivatives as inhibitors of receptor tyrosine kinases |
| JP2010222304A (en) * | 2009-03-24 | 2010-10-07 | Kyushu Univ | Process for producing trifluoromethylarenes |
| CN105228620A (en) * | 2013-03-15 | 2016-01-06 | 德西费拉制药有限责任公司 | Represent N-acyl group-N '-(pyridine-2-base) urea and the analog of anticancer and antiproliferative activity |
| WO2016168098A1 (en) * | 2015-04-16 | 2016-10-20 | Merck Sharp & Dohme Corp. | FACTOR XIa INHIBITORS |
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