CN111566075A - 一种制备克瑞沙硼的方法 - Google Patents
一种制备克瑞沙硼的方法 Download PDFInfo
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- CN111566075A CN111566075A CN201880081505.1A CN201880081505A CN111566075A CN 111566075 A CN111566075 A CN 111566075A CN 201880081505 A CN201880081505 A CN 201880081505A CN 111566075 A CN111566075 A CN 111566075A
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- 238000000034 method Methods 0.000 title claims abstract description 35
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims description 8
- 229910052796 boron Inorganic materials 0.000 title claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 12
- -1 alkyl lithium Chemical compound 0.000 claims description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000006722 reduction reaction Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- 239000012448 Lithium borohydride Substances 0.000 claims description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000012429 reaction media Substances 0.000 claims description 3
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical group COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 2
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims 3
- AYJRCSIUFZENHW-UHFFFAOYSA-L barium carbonate Chemical compound [Ba+2].[O-]C([O-])=O AYJRCSIUFZENHW-UHFFFAOYSA-L 0.000 claims 2
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
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- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 9
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- 239000000047 product Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- NVCRWSZZHGIOFU-UHFFFAOYSA-N BrC1=C(C=C(OC2=CC(=C(C#N)C(=C2)Cl)Cl)C=C1)CO Chemical compound BrC1=C(C=C(OC2=CC(=C(C#N)C(=C2)Cl)Cl)C=C1)CO NVCRWSZZHGIOFU-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- SCRQAWQJSSKCFN-UHFFFAOYSA-N 2-bromo-5-hydroxybenzaldehyde Chemical compound OC1=CC=C(Br)C(C=O)=C1 SCRQAWQJSSKCFN-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- UAOCIVQQKRQKRF-UHFFFAOYSA-N 2,6-dichloro-4-fluorobenzonitrile Chemical compound FC1=CC(Cl)=C(C#N)C(Cl)=C1 UAOCIVQQKRQKRF-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 4
- 239000003880 polar aprotic solvent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- AEMFITZCDVUFNN-UHFFFAOYSA-N 4-bromo-3-(hydroxymethyl)phenol Chemical compound OCC1=CC(O)=CC=C1Br AEMFITZCDVUFNN-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- KHHZNHGITCEDIL-UHFFFAOYSA-N BrC1=C(C=C(OC2=CC(=C(C#N)C(=C2)Cl)Cl)C=C1)C=O Chemical compound BrC1=C(C=C(OC2=CC(=C(C#N)C(=C2)Cl)Cl)C=C1)C=O KHHZNHGITCEDIL-UHFFFAOYSA-N 0.000 description 2
- 206010012438 Dermatitis atopic Diseases 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- QCTAZSAEMFXACJ-UHFFFAOYSA-N 2,6-dichloro-4-[(1-hydroxy-3H-2,1-benzoxaborol-5-yl)oxy]benzonitrile Chemical compound ClC1=C(C#N)C(=CC(=C1)OC1=CC2=C(B(OC2)O)C=C1)Cl QCTAZSAEMFXACJ-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
- AEKVBBNGWBBYLL-UHFFFAOYSA-N 4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C=C1 AEKVBBNGWBBYLL-UHFFFAOYSA-N 0.000 description 1
- ZVCVBAIYHXUBNV-UHFFFAOYSA-N 6-bromo-6-hydroxycyclohexa-2,4-diene-1-carbaldehyde Chemical compound OC1(Br)C=CC=CC1C=O ZVCVBAIYHXUBNV-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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 1
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- 238000005804 alkylation reaction Methods 0.000 description 1
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- 125000003118 aryl group Chemical group 0.000 description 1
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
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- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000007669 thermal treatment Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
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- C07F5/027—Organoboranes and organoborohydrides
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- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
- B01J23/42—Platinum
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals
- B01J23/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of noble metals of the platinum group metals
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/02—Sulfur, selenium or tellurium; Compounds thereof
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- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/20—Carbon compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B47/00—Formation or introduction of functional groups not provided for in groups C07B39/00 - C07B45/00
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/02—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis by substitution of halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
- C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
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- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
本发明涉及通过制备式(II)和(III)的中间体来制备式(I)的克瑞沙硼的方法：
Description
本发明涉及一种制备克瑞沙硼的方法，克瑞沙硼是一种用于治疗特应性皮炎的非甾体类药物。本发明还涉及新的合成中间体。
技术背景
克瑞沙硼是式(I)化合物5-(4-氰基苯氧基)-1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烯(benzoxaborole)的国际非专利名称:
克瑞沙硼是Eugrisa的活性成分，Eugrisa是美国FDA批准的用于治疗从两岁起患者特应性皮炎的局部非甾体药物。该分子目前正在进行治疗(尤其是)银屑病的临床试验(II期)。
克瑞沙硼及其合成路线在Anacor Pharmaceutical公司的专利申请WO2006/089067中首次描述和要求保护。迄今为止不存在与在该原研者的专利和出版物中描述的合成路线不同的合成路线。
WO2006/089067(方案)中使用的合成路线涉及许多步骤，并且总收率不是非常高，导致该方法是昂贵的。
方案
US2015/291629公开了作为抗炎剂的其它含硼的小分子。
令人惊奇地发现，通过使用如下所定义的式(V)的二氯芳基中间体(其在腈基的邻位被两个吸电子基团、特别是两个卤素活化)，2-溴-羟基苯甲醛保护步骤(步骤1)中所示的反应以及被保护的醛和氟化中间体之间的亲核取代反应以及所得产物(步骤2)的随后的还原反应可以由一锅法反应代替，从而消除了若干步骤。
本发明的方法以高纯度和优异的收率生产克瑞沙硼，并且可以在工业规模上进行。
发明详述
本发明的目的是制备式(I)的克瑞沙硼的方法：
其中所述方法包括以下步骤：
a)在硼酸三(C1-C4)烷基酯和(C4-C6)烷基锂或芳基锂的存在下将
式(II)化合物：
转化为式(III)的化合物:
随后酸化反应介质；和
b)通过催化氢化将所得式(III)化合物转化成式(I)的克瑞沙硼。
本发明的方法可以包括纯化克瑞沙硼的另外的步骤，优选通过使产物在水中的丙酮-水溶液沉淀来进行。
本文所用术语(C4-C6)烷基是指具有4-6个碳原子的直链或支链烷基链，例如正己基、正戊基、正丁基、异丁基、异戊基或叔丁基。
本文所用术语(C1-C4)烷基是指具有1-4个碳原子的直链或支链烷基链，例如甲基、乙基、正丙基、异丙基、正丁基或异丁基。
上述方法的步骤a)中使用的(C4-C6)烷基锂优选选自丁基锂和己基锂。
步骤a)中使用的硼酸三(C1-C4)烷基酯优选选自硼酸三甲酯和硼酸三异丙酯。
步骤a)在极性非质子溶剂如环状或链状醚或其混合物、优选四氢呋喃或甲基四氢呋喃中、在-30℃至-80℃的温度进行。
反应介质优选用酸如盐酸、硫酸、乙酸和甲酸，特别是盐酸或乙酸酸化。
步骤b)的催化氢化是用负载在碳、硫酸钡或碳酸钡上的钯或铂催化剂、如5％的钯碳，在溶剂如醚、醇或水或其混合物中，在0至50℃的温度进行的。
本发明的另一个目的是制备上述式(I)的克瑞沙硼的方法，其中式(II)的化合物通过以下步骤获得:
i)在无机碱存在下使式(IV)的化合物:
其中X是-COH或-CH2OH，与式(V)的化合物反应:
当X是-CH2OH时，得到式(II)的化合物，或当X是-COH时，得到式(VI)的化合物:
和
ii)还原式(VI)的化合物，得到式(II)的化合物。
步骤i)的亲核取代反应在极性非质子溶剂如甲苯、二甲基甲酰胺、二甲基乙酰胺和甲基异丁基酮或其混合物、优选二甲基甲酰胺或二甲基乙酰胺中、在无机碱如碱金属或碱土金属碳酸盐、特别是碳酸钾存在下进行。
反应在0-80℃的温度进行。
步骤ii)的还原反应用还原化合物如KBH4、NaBH4和LiBH4(硼氢化钾、硼氢化钠和硼氢化锂)、优选NaBH4、在极性非质子溶剂如THF、MeTHF、DMF和DMA(四氢呋喃、甲基四氢呋喃、二甲基甲酰胺、二甲基乙酰胺)或其混合物、优选四氢呋喃或甲基四氢呋喃中、在0-50℃的温度进行。
本发明的另一个目的是上述方法，其中X是-COH的式(IV)化合物与式(V)化合物反应，并且步骤i)和ii)在不分离式(VI)化合物的情况下进行(一锅法反应)。
在不分离中间体(VI)的情况下进行的亲核取代反应i)和还原反应ii)，可通过在溶剂如DMF、DMA和甲苯或其混合物中操作来进行，其中必要时加入相转移催化剂如溴化四丁基铵、苄基三乙基氯化铵、十六烷基三甲基溴化铵、四丁基硫氢酸铵和四甲基氯化铵(优选溴化四丁基铵)。
两个反应都在0至120℃的温度进行。
其中X是-CH2OH的式(IV)化合物可通过还原其中X是-COH的式(IV)化合物获得。其中X是-COH的式(IV)化合物是商业产品。
其中X是-COH的式(IV)化合物的还原可以在还原剂如硼氢化钾、硼氢化钠或硼氢化锂、优选硼氢化钠的存在下、在极性非质子溶剂中进行，所述极性非质子溶剂选自四氢呋喃、二噁烷、甲基四氢呋喃、二甲基甲酰胺、二甲基乙酰胺和甲苯或其混合物，优选四氢呋喃或甲基四氢呋喃。
反应在0至30℃的温度进行。
式V化合物是商业产品或可通过已知方法由商业产品获得。
本发明的另一个目的是式(II)和(III)的反应中间体。
本发明的另一个目的是提供一种纯化克瑞沙硼的方法，所述方法包括滴加丙酮:化合物与水的水混合物(5:1至8:1，优选7:1w/w)，然后在室温搅拌，并过滤所得沉淀。
这种方法是有利的，因为它使得可以从最终产物中优异地除去杂质，特别是源自本发明方法的氢化步骤的那些杂质。由所述纯化步骤得到的产物具有附图中所示的X射线衍射谱(在Cuα波长处)。
克瑞沙硼的制备方法公开于WO2006/089067和相同作者的Bioorg.Med.Chem.Lett:19(2009)2129-2132中，涉及五个化学步骤，总收率为32％(所述方法的平均值)，并且涉及在热处理(100℃)下的长时间反应。中间体的处理包括蒸馏干燥大量溶剂，这些溶剂昂贵且不是非常安全。需要不少于四个化学步骤(醛保护和烷基化，随后脱保护和还原)来获得关键中间体，并且尽管它们产生相当好的收率，但是它们是冗长和昂贵的。
在其优选的实施方案中，本发明方法从2-溴-5-羟基苯甲醛或相应的醇(2-溴-5-羟基苯基甲醇)开始，在室温下操作，能够在不分离中间体的情况下制备关键中间体(4-(4-溴-3-(羟基甲基)苯氧基)-2,6-二氯苄腈)。在向反应混合物中加入作为反溶剂的水后，通过简单过滤分离了产物。这是可能的，因为向4-氟苄腈中加入了两个氯原子，这激活了芳香亲核取代反应。然后除去两个氯原子，通过还原得到克瑞沙硼。尽管增加了该步骤，但本发明的方法仅由三个步骤组成，不同于五个步骤。总收率较高(74％相比于32％)，操作条件更温和，工艺更简单安全。
实施例
实施例1
合成4-溴-3-(羟基甲基)苯酚(式(IV)的化合物，其中X是-CH2OH)
将2-溴-5-羟基苯甲醛(式IV化合物，其中X是COH)(20.1g，100mmol)溶于THF(80mL)，将溶液冷却至0-5℃。在30分钟内加入NaBH4(1.9g，50mmol)在水(10mL，用NaOH稳定)中的溶液。将溶液再搅拌30分钟。在30分钟内向溶液中滴加丙酮(25mL)。然后加入水(50mL)，并蒸馏除去THF。用AcOEt(200mL)萃取残留的油。用盐水溶液(50mL)洗涤有机相，然后蒸馏除去AcOEt。在50℃用50mL甲苯处理所得固体，将混悬液冷却至20℃。过滤固体并在65℃干燥，得到标题化合物，为白色固体(18.6g，91％)。
1H-NMR；300MHz,DMSO-d6.δ9.64(brs,1H),7.27(d,1H),7.01(d,1H),6.60(dd,1H),5.37(brs,1H),4.41(s,2H)
13C-NMR；300MHz,DMSO-d6.δ157.1,142.4,132.9,115.9,115.6,109.4,63.0。
实施例2
合成式(II)的4-(4-溴-3-(羟基甲基)苯氧基)-2,6-二氯苄腈
将4-溴-3-(羟基甲基)苯酚(5.0g，25mmol)(式(IV)化合物，其中X是-CH2OH)溶于DMF(30mL)中。加入2,6-二氯-4-氟苯腈(4.9g，26mmol)(式(V)的化合物)和K2CO3(3.9g，28mmol)，搅拌混悬液5小时。加入水(100mL)，过滤收集白色固体状的式(II)化合物(7.3g，19.6mmol，80％)。
1H-NMR；300MHz,DMSO-d6.δ7.65(d,1H),7.30(d,1H),7.06(dd,1H),5.55(t,1H),4.49,(d,2H)。
13C-NMR；300MHz,DMSO-d6.δ161.8,153.6,144.4,139.1,134.4,120.9,102.1,118.0,117.4,114.0,107.5,62.8。
实施例3
合成式(III)的2,6-二氯-4-((1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊烯-5-基)氧基)苄腈
将式(II)的4-(4-溴-3-(羟基甲基)苯氧基)-2,6-二氯苄腈(50.0g，164mmol)、3,4-二氢吡喃(34.9g，415mmol)和对甲苯磺酸吡啶鎓(2.0g，8mmol)在THF中搅拌24小时。加入TiPrOB(49.2,262mmol)，并将该溶液冷却至-78℃，在40分钟内滴加2.3摩尔浓度的己基锂在己烷中的溶液。并在所述温度搅拌最终混合物90分钟。将溶液加热至室温并在所述温度下保持搅拌总共2小时。然后蒸馏出THF。缓慢加入100mL 6N HCl，并将混悬液搅拌16小时。加入EtOH(400mL)，过滤得到式(III)化合物(36.0g，112mmol，84％)。
1H-NMR；300MHz,DMSO-d6.δ9.25(s,1H),7.82(d,1H),7.33(s,2H),7.23(d,1H),7.15(dd,1H),4.98(s,2H)
13C-NMR；300MHz,DMSO-d6.δ161.8,157.2,156.4,139.1,133.2,119.6,118.4,114.1,113.7,107.5,70.1
实施例4
合成式(I)的克瑞沙硼
将2,6-二氯-4-((1-羟基-1,3-二氢苯并[c][1,2]氧杂硼杂环戊烯-5-基)氧基)-苄腈(10.0g，31mmol)和KOH(5.0g，84mmol)混悬于乙醇(100mL)和水(100mL)的混合物中。然后加入5％Pd/碳(1.0g)，将混合物置于1-5ATM的氢气氛中。1小时后反应完成，并滤出催化剂。向过滤后的溶液中加入37％盐酸，使pH小于2，真空浓缩溶液50mL，沉淀出白色固体。将混悬液冷却至室温并搅拌1小时。然后通过过滤分离克瑞沙硼(7.0g，28mmol，90％)。
实施例5
合成式(II)的4-(4-溴-3-(羟基甲基)苯氧基)-2,6-二氯苄腈(DMA中的一锅法反应)
将2-溴-5-羟基苯甲醛(30.0g，149mmol)和2,6-二氯-4-氟苯腈(30.0g，158mmol)溶于DMA(130mL)中，并向溶液中加入K2CO3(27.0g，195mmol)。将反应在20-30℃保持3-6小时，然后在20分钟内加入NaBH4(2.0g，53mmol)在水中的溶液(20mL，用5％NaOH稳定)。将溶液保持搅拌另外30分钟。然后加入水(500mL)。将溶液保持搅拌1小时，通过过滤分离白色固体形式的标题产物(54.6g，146mmol,98％)。
实施例6
合成式(VI)的4-(4-溴-3-(甲酰基苯氧基)-2,6-二氯苄腈
将2-溴-5-羟基苯甲醛(30.0g，149mmol)溶于DMF(120mL)中，并向溶液中加入2,6-二氯-4-氟苄腈(30.0g，158mmol)和K2CO3(27.0g，195mmol)，并将该混悬液搅拌1-4h，保持温度低于30℃。加入水(300mL)，通过过滤收集白色固体，并用水(100mL)洗涤。(54.2g，146mmol，97％)。
1H-NMR；300MHz,CDCl3.δ10.33(s,1H),7.76(d,1H),7.60(d,1H),7.22(dd,1H),6.98(s,2H)
13C-NMR；300MHz,CDCl3.δ190.5,160.6,153.7,139.9,136.1,135.2,127.3,123.2,117.3,113.2,109.1。
实施例7
合成式(II)的4-(4-溴-3-(羟基甲基)苯氧基)-2,6-二氯苄腈
将4-(4-溴-3-甲酰基苯氧基)-2,6-二氯苄腈(77.8g，210mmol)溶于THF(365mL)中，并将该溶液冷却至0-5℃。在1小时内加入NaBH4(2.7g，71mmol)在水中的溶液(25mL，用NaOH稳定)。将溶液保持搅拌另外30分钟。在30分钟内滴加丙酮(25mL)。然后加入水(150mL)。蒸出THF，得到固体沉淀。将混悬液冷却至室温，并通过过滤分离白色固体产物(77.6g，208mmol，98％)。将粗产物混悬于甲苯(320mL)中，并在回流下放置30分钟。将溶液缓慢冷却至室温，并通过过滤回收纯白色固体(75.3g，95％)。
实施例8
合成式(II)的4-(4-溴-3-(羟基甲基)苯氧基)-2,6-二氯苄腈(相转移条件)
将4-(4-溴-3-甲酰基苯氧基)-2,6-二氯苄腈(15.0g，40mmol)和TBAB(0.15g，0.5mmol)混悬于甲苯(140mL)中，并将该溶液加热至45-50℃。在10分钟内加入NaBH4(0.6g，16mmol)在水(6mL，用NaOH稳定)中的溶液。将该溶液保持搅拌另外60分钟。在30分钟内滴加乙酸(3.6g)，然后将混合物保持搅拌30分钟。将混悬液加热至80℃，并分离水相。蒸馏出70mL甲苯，将溶液冷却至室温。通过过滤分离出白色固体产物(13.0g，35mmol，88％)。
实施例9
合成式(II)的4-(4-溴-3-(羟基甲基)苯氧基)-2,6-二氯苄腈(相转移条件下的反应)
将2-溴-5-羟基-苯甲醛(10.0g，50mmol)、2,6-二氯-4-氟苄腈(9.9g，52mmol)、K2CO3(8.9g，64mmol)和TBAB(1g，0.3mmol)混悬于甲苯(100mL)中，将溶液加热至70℃达24小时。将溶液冷却至室温，用水(50ml)洗涤两次。滴加NaBH4(0.65g，170mmol)的水(15mL)溶液，并保持搅拌另外30分钟。将溶液用水(50mL)洗涤两次，并浓缩至40mL。然后将溶液冷却至室温，通过过滤分离白色固体产物(16.6g，44mmol，88％)。
实施例10
克瑞沙硼的纯化
在25℃，30’期间，将克瑞沙硼(100g)在350g丙酮和50g水的混合物中的溶液滴加到1升水中。将所得混合物搅拌约1-2小时。然后在室温过滤。在40℃真空干燥，得到96g产物，其色谱分析结果大于99.8％，其X射线衍射谱(CuαK)、DSC和HPLC分别如图1、2和3所示。
Claims (15)
1.制备式(I)的克瑞沙硼的方法:
其中所述方法包括以下步骤：
a)在硼酸三(C1-C4)烷基酯和(C4-C6)烷基锂或芳基锂的存在下将式(II)化合物:
转化为式(III)的化合物:
随后酸化反应介质；和
b)通过催化氢化将所得式(III)化合物转化成式(I)的克瑞沙硼。
2.根据权利要求1所述的方法，其中在方法步骤a)中使用的(C4-C6)烷基锂选自丁基锂和己基锂。
3.根据权利要求1或2的方法，其中步骤a)中使用的硼酸三(C1-C4)烷基酯选自硼酸三甲酯和硼酸三异丙酯。
4.根据前述权利要求中任一项所述的方法，其中步骤a)在选自环状或链状醚或其混合物的溶剂中进行。
5.根据前述权利要求中任一项所述的方法，其中步骤b)的催化氢化是用负载在碳、硫酸钡或碳酸钡上的钯或铂催化剂进行的。
6.根据前述权利要求中任一项所述的方法，其中通过以下步骤获得式(II)的化合物:
i)在无机碱存在下使式(IV)的化合物:
其中X是-COH或-CH2OH，与式(V)的化合物反应:
当X是-CH2OH时，得到式(II)的化合物，或当X是-COH时，得到式(VI)的化合物:
和
ii)还原式(VI)的化合物得到式(II)的化合物。
7.根据权利要求6的方法，其中步骤i)的反应在选自甲苯、二甲基甲酰胺、二甲基乙酰胺、甲基异丁基酮或其混合物的非质子极性溶剂中进行。
8.根据权利要求6或7的方法，其中所述无机碱是碱金属或碱土金属碳酸盐。
9.根据权利要求6至8中任一项所述的方法，其中步骤ii)的还原反应用选自硼氢化钾、硼氢化钠和硼氢化锂的还原化合物进行。
10.根据权利要求9的方法，其中所述还原在非质子极性溶剂或其混合物中进行。
11.根据权利要求6至10中任一项所述的方法，其中使其中X是-COH的式(IV)化合物与式(V)化合物反应，并且步骤i)和ii)在不分离式(VI)化合物的情况下进行。
12.根据权利要求11所述的方法，其中反应i)和ii)在选自DMF、DMA和甲苯或其混合物的非质子极性溶剂中、任选地在选自溴化四丁基铵、苄基三乙基氯化铵、十六烷基三甲基溴化铵、四丁基硫氢酸铵和四甲基氯化铵的相转移催化剂的存在下进行。
13.式(II)的化合物:
14.式(III)的化合物:
15.纯化克瑞沙硼的方法，所述方法包括滴加5:1-8:1、优选7:1w/w的丙酮:化合物与水的水混合物，然后在室温搅拌，并过滤所得产物。
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| CN101420854A (zh) * | 2006-02-16 | 2009-04-29 | 安纳考尔医药公司 | 作为抗炎药的含硼的小分子 |
| CN106928264A (zh) * | 2017-04-12 | 2017-07-07 | 湖南中智优库科技有限公司 | 一种crisaborole的合成方法 |
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| EP2564857B1 (en) | 2008-03-06 | 2017-05-03 | Anacor Pharmaceuticals, Inc. | Boron-containing small molecules as anti-inflammatory agents |
| WO2017093857A1 (en) | 2015-11-30 | 2017-06-08 | Anacor Pharmaceuticals, Inc. | Topical pharmaceutical formulations for treating inflammatory-related conditions |
| US11447506B2 (en) * | 2016-05-09 | 2022-09-20 | Anacor Pharmaceuticals, Inc. | Crystal forms of crisaborole in free form and preparation method and use thereof |
| KR102221472B1 (ko) * | 2016-05-09 | 2021-03-02 | 아나코르 파마슈티칼스 인코포레이티드 | 유리 형태의 크리사보롤의 결정 형태 및 그의 제조 방법 및 용도 |
| WO2017203514A1 (en) * | 2016-05-26 | 2017-11-30 | Perrigo Api Ltd | Polymorphs of crisaborole and production processes therefor |
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| CN101420854A (zh) * | 2006-02-16 | 2009-04-29 | 安纳考尔医药公司 | 作为抗炎药的含硼的小分子 |
| CN106928264A (zh) * | 2017-04-12 | 2017-07-07 | 湖南中智优库科技有限公司 | 一种crisaborole的合成方法 |
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| AU2018389809A1 (en) | 2020-06-18 |
| US10329311B1 (en) | 2019-06-25 |
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| US20210070781A1 (en) | 2021-03-11 |
| IL275381A (en) | 2020-07-30 |
| IL275381B1 (en) | 2024-03-01 |
| EP3728167A1 (en) | 2020-10-28 |
| EP3851429A1 (en) | 2021-07-21 |
| AU2018389809B2 (en) | 2023-08-03 |
| EP3728167B1 (en) | 2021-12-01 |
| ES2903436T3 (es) | 2022-04-01 |
| US20190194230A1 (en) | 2019-06-27 |
| US20200407377A1 (en) | 2020-12-31 |
| WO2019120637A1 (en) | 2019-06-27 |
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