CN115850233A - Synthetic method of apalutamide - Google Patents
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- CN115850233A CN115850233A CN202111121892.7A CN202111121892A CN115850233A CN 115850233 A CN115850233 A CN 115850233A CN 202111121892 A CN202111121892 A CN 202111121892A CN 115850233 A CN115850233 A CN 115850233A
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 7
- HJBWBFZLDZWPHF-UHFFFAOYSA-N apalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C2(CCC2)C(=O)N(C=2C=C(C(C#N)=NC=2)C(F)(F)F)C1=S HJBWBFZLDZWPHF-UHFFFAOYSA-N 0.000 title description 2
- 229950007511 apalutamide Drugs 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 10
- -1 1-amino-1-cyclobutylmethyl formate Chemical compound 0.000 claims abstract description 6
- OLCQSPCUCOQJTG-UHFFFAOYSA-N 6-amino-3-(trifluoromethyl)pyridine-2-carbonitrile Chemical compound Nc1ccc(c(n1)C#N)C(F)(F)F OLCQSPCUCOQJTG-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 5
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 150000003936 benzamides Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 7
- 238000001308 synthesis method Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- QCKBCJPTIBGUDA-UHFFFAOYSA-N N(C(=O)C(=O)N)C1=C(C=CC=C1C)C Chemical compound N(C(=O)C(=O)N)C1=C(C=CC=C1C)C QCKBCJPTIBGUDA-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical group [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- BWILYWWHXDGKQA-UHFFFAOYSA-M potassium propanoate Chemical group [K+].CCC([O-])=O BWILYWWHXDGKQA-UHFFFAOYSA-M 0.000 claims description 2
- 239000004331 potassium propionate Chemical group 0.000 claims description 2
- 235000010332 potassium propionate Nutrition 0.000 claims description 2
- 239000001632 sodium acetate Chemical group 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims description 2
- YMFBUTYXVRUNAR-UHFFFAOYSA-N n-(2-oxocyclohexyl)acetamide Chemical compound CC(=O)NC1CCCCC1=O YMFBUTYXVRUNAR-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000510 noble metal Inorganic materials 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 238000003756 stirring Methods 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 3
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000001307 androgen receptors Human genes 0.000 description 2
- 108010080146 androgen receptors Proteins 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000006713 insertion reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 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 description 1
- XNBLEAGPKPYTCT-UHFFFAOYSA-N 2,4-difluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=C(F)C=C1F XNBLEAGPKPYTCT-UHFFFAOYSA-N 0.000 description 1
- KUVVJHBHRIXJKI-UHFFFAOYSA-N 3-fluoro-4-iodoaniline Chemical compound NC1=CC=C(I)C(F)=C1 KUVVJHBHRIXJKI-UHFFFAOYSA-N 0.000 description 1
- BAJCFNRLEJHPTQ-UHFFFAOYSA-N 4-bromo-2-fluoro-n-methylbenzamide Chemical compound CNC(=O)C1=CC=C(Br)C=C1F BAJCFNRLEJHPTQ-UHFFFAOYSA-N 0.000 description 1
- WLMSCOVORZUSNW-UHFFFAOYSA-N 5-amino-3-(trifluoromethyl)pyridine-2-carbonitrile Chemical compound NC1=CN=C(C#N)C(C(F)(F)F)=C1 WLMSCOVORZUSNW-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 238000007059 Strecker synthesis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- MFNYBOWJWGPXFM-UHFFFAOYSA-N cyclobutanecarboxamide Chemical compound NC(=O)C1CCC1 MFNYBOWJWGPXFM-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003564 thiocarbonyl compounds Chemical class 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a synthetic method of apaluramine, which comprises the following steps of 1, reacting 6-amino-2-cyano-3-trifluoromethyl pyridine (I) and 1-amino-1-cyclobutylmethyl formate or a salt thereof (II) in a solvent A under the action of TCDI and an alkali A to obtain an intermediate (III); and 2, reacting the intermediate (III) with N-methyl-2-fluoro-4-halogenated benzamide (IV) in a solvent B under the action of a catalyst and alkali B to obtain the apaluramine. The method has the advantages of cheap and easily-obtained starting raw materials, no use of highly-toxic sodium cyanide and noble metal catalysts, reduced process cost, accordance with the requirements of green environmental protection, reduced generation of byproducts, improved product yield and purity, and suitability for large-scale production.
Description
Technical Field
The invention belongs to a preparation method in the field of medicinal chemistry, and particularly relates to a synthetic method of apaluramine and an intermediate thereof.
Background
Apaluamide (apaluamide) is an Androgen Receptor (AR) inhibitor developed by the university of california, usa, which was licensed to Aragon pharmaceutical, usa in 2009. In month 2 2018, apalutamine was approved by the U.S. FDA for marketing for the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC), and was marketed in china in 2019. Wherein the chemical name is 4- (7- (6-cyano-5- (trifluoromethyl) pyridine-3-yl) -8-oxo-6-sulfo-5, 7-diazaspiro [ 3.4 ] -octane-5-yl) -2-fluoro-N-methylbenzoyl, and the chemical structure is shown as the following structural formula:
the existing methods for synthesizing the apaluramine mainly comprise the following steps:
(1) Document WO2007126765A2 firstly reports that a compound 1 is used as a raw material, and is condensed with cyclobutanone and sodium cyanide to prepare a benzamide intermediate 2; reacting a compound 3 serving as a raw material with thiophosgene to obtain a thioisocyano pyridine intermediate 4; and finally preparing the apaluramine from the two intermediates under the microwave promotion. The route needs to use sodium cyanide and thiophosgene under acidic conditions, and the final cyclization reaction adopts microwaves, so that the industrial production is difficult.
(2) PCT patent WO2016100645 simplifies a new synthesis method of apaluramine, and utilizes a cyclobutanamide intermediate 2 obtained by a Strecker reaction of 3-fluoro-4-iodoaniline, cyclobutanone and cyanide and a 2-cyano-3-trifluoromethyl-5-aminopyridine compound 3 for condensation cyclization under the action of a thiocarbonyl compound, then completes a carbonyl insertion reaction under the catalysis of noble metal palladium to obtain a carboxylic ester intermediate or reacts with dry ice after Grignard exchange to obtain a carboxylic acid intermediate, and finally amidates to obtain the final product of apaluramine. Although the route has shorter steps, the cost of the route of the palladium-catalyzed carbonyl insertion reaction or Grignard exchange reaction is higher, the process production experimental conditions are harsher, and the method is not suitable for industrial production to synthesize the apaluramine.
(3) In patent CN104211683A, TMSCN is used for replacing NaCN, so that the use of a virulent reagent is avoided, but in the last step of condensation reaction, the one-pot method of the virulent reagent thiophosgene is adopted for synthesizing the apaluramine, and the process production experimental conditions are harsh, so that the method is not suitable for industrial production for synthesizing the apaluramine.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel synthetic method of apaluamide, which has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, simple and convenient operation and suitability for industrial production.
The invention provides a synthetic method of apaluramine, which comprises the following steps: step 1, reacting 6-amino-2-cyano-3-trifluoromethylpyridine (I) and 1-amino-1-cyclobutylmethyl formate or a salt thereof (II) in a solvent A under the action of TCDI and a base A to obtain an intermediate (III); step 2, reacting the intermediate (III) with N-methyl-2-fluoro-4-halogenated benzamide (IV) in a solvent B under the action of a catalyst and alkali B to obtain the apaluramine, wherein the reaction formula is as follows:
wherein X is fluorine, chlorine, bromine or iodine.
Preferably, the salt is a hydrochloride or sulfate salt.
The alkali A in the step 1 is triethylamine, pyridine, diisopropylethylamine or DBU; the solvent A is dichloromethane, THF, toluene or acetonitrile; the reaction temperature is 20-30 ℃.
The feeding molar ratio of compound I to compound II is 1, the feeding molar ratio of tcdi to compound 1 is 1.2-1.5.
The catalyst in the step 2 is cuprous chloride, cuprous bromide or cuprous iodide. The catalyst is matched with the catalyst for catalytic reaction of the auxiliary agent 2-acetamide cyclohexanone, N1, N2-bis (2, 6-dimethylphenyl) oxamide, N1-benzyl-N2- (2, 6-dimethylphenyl) oxamide or N1-benzyl-N2- (2-methylnaphthalene-1-yl) oxamide.
The structural formula of N1, N2-bis (2, 6-dimethylphenyl) oxamide is:
。
the structural formula of the N1-benzyl-N2- (2, 6-dimethylphenyl) oxamide is:
。
the structural formula of the N1-benzyl-N2- (2-methylnaphthalene-1-yl) oxamide is as follows:
。
and the base B in the step 2 is triethylamine, diisopropylethylamine, sodium acetate, potassium propionate, potassium carbonate, sodium carbonate, cesium carbonate or DBU. The solvent B is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide. The reaction temperature in step 2 is 80-90 ℃.
The feeding molar ratio of the compound III to the compound IV is 1.2, the feeding molar ratio of the catalyst to the auxiliary agent is 1.
The invention has the beneficial effects that: the method has the advantages of cheap and easily-obtained starting raw materials, no use of highly-toxic sodium cyanide and noble metal catalysts, reduced process cost, accordance with the requirements of green environmental protection, reduced generation of byproducts, improved product yield and purity, and suitability for large-scale production.
Drawings
FIG. 1 is a drawing of Compound III 1 H-NMR spectrum.
FIG. 2 shows the preparation of apaluamide 1 H-NMR spectrum.
Detailed Description
The present invention is further illustrated by the following examples, but the invention is not limited to the scope of the claims.
Example 1
Adding 1g (5.34 mmol) of 6-amino-2-cyano-3-trifluoromethylpyridine, 1.4g (8.01 mmol) of TCDI and 10mL of toluene into a three-neck flask, cooling to 0-10 ℃ under the protection of nitrogen, dropwise adding 1.1g (10.68 mmol) of triethylamine, heating to 20-30 ℃ for reaction for 3-4h after dropwise adding, adding 0.88g (5.34 mmol) of 1-amino-1-cyclobutylmethyl formate hydrochloride in batches, and continuing to react for 1-2h at 20-30 ℃ after dropwise adding. And after the reaction is finished, adding 10mL of water and 10mL of ethyl acetate, stirring and separating, washing the organic phase twice with water, separating, concentrating the organic phase under reduced pressure to obtain an oily substance, and purifying by column chromatography to obtain a compound III with the yield of 90%. The information of the hydrogen spectrum of the compound III is shown in FIG. 1.
Example 2
Adding 5g (26.7 mmol) of 6-amino-2-cyano-3-trifluoromethyl pyridine, 5.6g (32.04 mmol) of TCDI and 50mL of toluene into a three-neck flask, cooling to 0-10 ℃ under the protection of nitrogen, dropwise adding 10.5g (132.7 mmol) of pyridine, after dropwise adding, heating to 20-30 ℃ for reaction for 5 hours, adding 3.45g (26.7 mmol) of 1-amino-1-cyclobutylmethyl formate in batches, after completely adding, and continuing to react at 20-30 ℃ for 2 hours. And after the reaction is finished, adding 60mL of water and 50mL of ethyl acetate, stirring and separating, washing the organic phase twice with water, separating, concentrating the organic phase under reduced pressure to obtain an oily substance, and purifying by column chromatography to obtain a compound III with the yield of 92%.
Example 3
Into a three-necked flask were charged intermediate III10.4g (32 mmol), N-methyl-2-fluoro-4-bromobenzamide 8.8g (38 mmol) and dimethyl sulfoxide 50g, and under nitrogen protection, DBU9.8g (64 mmol), cuprous iodide 1.2g (6.4 mmol) and N1-benzyl-N2- (2-methylnaphthalen-1-yl) oxamide 2g (6.4 mmol) were added, and after stirring, the mixture was heated to 80 to 90 ℃ for reaction for 6 hours. After the reaction is finished, 50mL of water and 50g of ethyl acetate are added, the mixture is stirred and separated, the organic phase is washed twice by saturated saline solution and is layered, the organic phase is collected and concentrated to be dry, 50g of methanol and 150mL of water are added for crystallization, the crystallization is carried out, the filter cake is dried to obtain the apalumamide, the yield is 92%, the HPLC purity is 99.62%, and the hydrogen spectrogram is shown in figure 2.
Example 4
Into a three-necked flask were charged intermediate III10.4g (32 mmol), N-methyl-2, 4-difluorobenzamide 6.5g (38 mmol) and dimethyl sulfoxide 50g, and under nitrogen protection, DBU9.8g (64 mmol), cuprous iodide 1.2g (6.4 mmol) and N1-benzyl-N2- (2-methylnaphthalen-1-yl) oxamide 2g (6.4 mmol) were added, and after stirring, the mixture was heated to 80 to 90 ℃ for reaction for 6 hours. After the reaction is finished, 50mL of water and 50g of ethyl acetate are added, liquid separation is carried out by stirring, the organic phase is washed twice by saturated saline solution, layering is carried out, the organic phase is collected, concentrated and dried, 50g of methanol and 150mL of water are added for crystallization, filtration is carried out, and the filter cake is dried to obtain the apaluramine, wherein the yield is 85 percent, and the purity is 99.05 percent.
Claims (10)
1. A synthetic method of apaluramine is characterized by comprising the following steps: step 1, reacting 6-amino-2-cyano-3-trifluoromethylpyridine (I) and 1-amino-1-cyclobutylmethyl formate or a salt thereof (II) in a solvent A under the action of TCDI and a base A to obtain an intermediate (III); step 2, reacting the intermediate (III) with N-methyl-2-fluoro-4-halogenated benzamide (IV) in a solvent B under the action of a catalyst and alkali B to obtain the apaluramine, wherein the reaction formula is as follows:
wherein X is fluorine, chlorine, bromine or iodine.
2. The method of claim 1, wherein the salt is a hydrochloride or sulfate salt.
3. The synthesis method of claim 1, wherein the base A is triethylamine, pyridine, diisopropylethylamine or DBU.
4. The method of claim 1, wherein the solvent A is dichloromethane, THF, toluene or acetonitrile.
5. The synthesis method according to claim 1, wherein the reaction temperature of step 1 is 20-30 ℃.
6. The synthesis method according to claim 1, wherein the catalyst is cuprous chloride, cuprous bromide or cuprous iodide.
7. The synthesis method of claim 6, wherein the catalyst is prepared by catalytic reaction of 2-acetamidocyclohexanone, N1, N2-bis (2, 6-dimethylphenyl) oxamide, N1-benzyl-N2- (2, 6-dimethylphenyl) oxamide or N1-benzyl-N2- (2-methylnaphthalen-1-yl) oxamide.
8. The synthesis method of claim 1, wherein the base B is triethylamine, diisopropylethylamine, sodium acetate, potassium propionate, potassium carbonate, sodium carbonate, cesium carbonate or DBU.
9. The method according to claim 1, wherein the solvent B is N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide.
10. The synthesis method according to claim 1, wherein the reaction temperature of step 2 is 80-90 ℃.
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