CN107304204B - Method for preparing N-heterocyclic compound - Google Patents
Method for preparing N-heterocyclic compound Download PDFInfo
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- CN107304204B CN107304204B CN201610239390.7A CN201610239390A CN107304204B CN 107304204 B CN107304204 B CN 107304204B CN 201610239390 A CN201610239390 A CN 201610239390A CN 107304204 B CN107304204 B CN 107304204B
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- 238000000034 method Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
- 239000002253 acid Substances 0.000 claims abstract description 17
- 238000006482 condensation reaction Methods 0.000 claims abstract description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- 239000012074 organic phase Substances 0.000 claims description 22
- 239000003960 organic solvent Substances 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007810 chemical reaction solvent Substances 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- MAGOYBJJLVSJIC-UHFFFAOYSA-N 4-chlorobutan-2-one Chemical compound CC(=O)CCCl MAGOYBJJLVSJIC-UHFFFAOYSA-N 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 238000007112 amidation reaction Methods 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910002666 PdCl2 Inorganic materials 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- YBCQRRBECDWYIB-UHFFFAOYSA-N 5-chloro-2-ethoxy-1,3-benzoxazole Chemical compound ClC1=CC=C2OC(OCC)=NC2=C1 YBCQRRBECDWYIB-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000012805 post-processing Methods 0.000 description 4
- -1 t-butoxycarbonyl group Chemical group 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- JYTNQNCOQXFQPK-MRXNPFEDSA-N suvorexant Chemical compound C([C@H]1C)CN(C=2OC3=CC=C(Cl)C=C3N=2)CCN1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 JYTNQNCOQXFQPK-MRXNPFEDSA-N 0.000 description 3
- AOIBIXJDIRVIJB-UHFFFAOYSA-N tert-butyl N-[2-[(4-methoxyphenyl)methylamino]ethyl]carbamate Chemical compound COC1=CC=C(CNCCNC(=O)OC(C)(C)C)C=C1 AOIBIXJDIRVIJB-UHFFFAOYSA-N 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- VRGJQQHZKMGJKH-UHFFFAOYSA-N 5-methyl-2-(triazol-2-yl)benzoyl chloride Chemical compound ClC(=O)C1=CC(C)=CC=C1N1N=CC=N1 VRGJQQHZKMGJKH-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- HPOKESDSMZRZLC-UHFFFAOYSA-N propan-2-one;hydrochloride Chemical compound Cl.CC(C)=O HPOKESDSMZRZLC-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- SWFNPENEBHAHEB-UHFFFAOYSA-N 2-amino-4-chlorophenol Chemical compound NC1=CC(Cl)=CC=C1O SWFNPENEBHAHEB-UHFFFAOYSA-N 0.000 description 1
- SRBAGFIYKNQXDV-UHFFFAOYSA-N 5-methyl-2-(triazol-2-yl)benzoic acid Chemical compound OC(=O)C1=CC(C)=CC=C1N1N=CC=N1 SRBAGFIYKNQXDV-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000002512 Orexin Human genes 0.000 description 1
- 229940123730 Orexin receptor antagonist Drugs 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- FURCQDWTOXYTNN-CYBMUJFWSA-N [(7r)-7-methyl-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C[C@@H]1CCNCCN1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 FURCQDWTOXYTNN-CYBMUJFWSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 108060005714 orexin Proteins 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 229960001198 suvorexant Drugs 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- CWLNAJYDRSIKJS-UHFFFAOYSA-N triethoxymethoxyethane Chemical compound CCOC(OCC)(OCC)OCC CWLNAJYDRSIKJS-UHFFFAOYSA-N 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for preparing an N-heterocyclic compound, belonging to the technical field of pharmacy. The method for preparing the N-heterocyclic compound comprises the following steps: the N-heterocyclic intermediate compound and 2-ethoxy-5-chlorobenzoxazole are subjected to condensation reaction under the condition of adding acid, and then the compound (1) is prepared after post treatment. The method is simple and convenient, and can be used for industrial production.
Description
Technical Field
The invention relates to a method for preparing an N-heterocyclic compound, in particular to a method for preparing a compound containing a seven-membered nitrogen heterocycle and an intermediate thereof, which belongs to the technical field of pharmacy.
Background
Suvorexant (trade name belsmora), an Orexin receptor antagonist, can affect the signal conduction of an Orexin pathway, and is clinically used for treating diseases such as insomnia and the like; the structure is shown as the following formula (1):
the Suvorexant structure contains a seven-membered diazacyclo and chiral carbon, and in the preparation process, cyclization and construction of chiral carbon or resolution are required to obtain a target compound with a single configuration; the preparation method in the prior art is complex, and a simplified preparation method suitable for industrialization needs to be researched.
Disclosure of Invention
Summary of The Invention
The invention provides a method for preparing an N-heterocyclic compound, which simplifies the process and can be used for industrial production by using reagents such as 4-chloro-2-butanone and the like for reaction.
Detailed Description
The present invention provides a method for producing an N-heterocyclic compound such as the compound (1).
A process for preparing a compound (1) represented by the formula (1), comprising: a compound (01) represented by the formula (01) and a compound (02) represented by the formula (02) are subjected to a condensation reaction in an organic solvent in the presence of an acid, and are subjected to post-treatment to obtain a compound (1), wherein the reaction formula is as follows:
the acid is formic acid, acetic acid, phosphoric acid, trifluoroacetic acid, nitric acid, or a mixture thereof. The feeding molar ratio of the acid to the compound (01) is 0.1:1-2: 1. The feeding molar ratio of the compound (01) to the compound (02) is 1:0.9-1: 1.5.
The compound (01) and the compound (02) are subjected to condensation reaction in the presence of acid, and in the condensation reaction, the organic solvent is toluene, n-hexane, acetonitrile, acetone, dichloromethane, ethyl acetate, ethanol, dimethyl sulfoxide (DMSO), or a mixture thereof. In some embodiments, the organic solvent is toluene. The amount of the organic solvent used is 8mL to 32mL per gram of compound (01). In some embodiments, the organic solvent is used in an amount of 10mL to 30mL per gram of compound (01). The amount of the organic solvent used is 10mL-20mL per gram of compound (01).
The condensation reaction of the compound (01) and the compound (02) in the presence of an acid is carried out at a reaction temperature of 35 ℃ to 130 ℃. In some embodiments, the condensation reaction of compound (01) and compound (02) in the presence of an acid is carried out at a reaction temperature of 40 ℃ to 100 ℃. In some embodiments, the condensation reaction of compound (01) and compound (02) in the presence of an acid is carried out at a reaction temperature of 65 ℃ to 100 ℃. In some embodiments, the condensation reaction of compound (01) and compound (02) in the presence of an acid is carried out at a reaction temperature of 65 ℃ to 75 ℃. In some embodiments, the condensation reaction of compound (01) and compound (02) in the presence of an acid is carried out at a reaction temperature of 50 ℃ to 90 ℃.
In some embodiments, compound (01) is reacted with compound (02) in the presence of an acid for 2 hours to 24 hours, and the reaction is terminated and post-treated.
The post-processing comprises: adjusting the pH value of the reaction system to 10-14, separating to obtain an organic phase, and removing the solvent to obtain the compound (1) or a crude product thereof. The obtained compound (1) or the crude product thereof can be further purified, such as washing, pulping, crystallization, repeated crystallization and the like, so that the product quality is improved. In some embodiments, the post-processing comprises: decolorizing the compound (1) or the crude product thereof in ethyl acetate by using activated carbon, and removing the solvent to obtain the compound (1) product. In some embodiments, the post-processing comprises: dissolving the compound (1) by using ethyl acetate, then adding cyclohexane, cooling, crystallizing, separating solid, and removing solvent to obtain the compound (1) product. In some embodiments, the post-processing comprises: decolorizing the compound (1) or its crude product with active carbon in ethyl acetate, removing solvent to obtain solid, dissolving the solid with ethyl acetate, adding cyclohexane, cooling, crystallizing, separating solid, and removing solvent to obtain the compound (1).
The compound (01) can be prepared by carrying out deprotection reaction on a compound (03) shown as a formula (03):
in some embodiments, compound (03) is present in a catalyst such as Pd/C (palladium on carbon), Pd (OH)2(ii)/C (Palladium hydroxide/carbon), PdCl2(palladium chloride), or a combination thereof, in an organic solvent such as methanol, ethanol, ethyl acetate, acetone, acetonitrile, tetrahydrofuran, or a combination thereof, by subjecting to deprotection reaction with hydrogen or ammonium formate at 30 ℃ to 60 ℃ for 2 hours to 24 hours, followed by post-treatment, compound (01) is obtained. The dosage of the catalyst is 10-20% of the mass of the compound (03).
The compound (03) can be prepared by amidation reaction of a compound (04) represented by formula (04) or a salt thereof with a compound (05) represented by formula (05):
the compound (04) can be prepared as a hydrochloride and then reacted with the compound (05). Compound (04) or its hydrochloride is amidated with compound (05) in an organic solvent such as dichloromethane, ethyl acetate, acetone, acetonitrile, toluene, N-dimethylformamide or a combination thereof with the addition of a base at-5 ℃ to 35 ℃, followed by post-treatment to give compound (03). In the amidation reaction process, the alkali is sodium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine or a combination thereof, and the feeding molar ratio of the alkali to the compound (04) or a salt thereof is 1.5:1-2.5: 1. The amount of the organic solvent is 10mL to 30mL per gram of the compound (04) or a salt thereof. In some embodiments, the reaction temperature of the amidation reaction is from-5 ℃ to 15 ℃. In some embodiments, the reaction temperature of the amidation reaction is from 0 ℃ to 10 ℃. In some embodiments, the hydrochloride salt of compound (04) is liberated with sodium hydroxide or potassium hydroxide to give compound (04) or a solution thereof, which is then reacted with compound (05) in an organic solvent such as dichloromethane, ethyl acetate, dichloromethane, acetonitrile, toluene, N-dimethylformamide, or a combination thereof at-5 ℃ to 30 ℃ for 1 hour to 3 hours, followed by post-treatment to give compound (03).
The compound (04) can be prepared by carrying out reduction reaction on a compound (06) shown in a formula (06) and a hydrogen source under the action of a metal catalyst:
in some embodiments, compound (06) is reduced with a hydrogen source such as hydrogen, formic acid, ammonium formate or a combination thereof at-10 ℃ to 10 ℃ for 10 hours to 24 hours in an organic solvent such as dichloromethane, toluene, acetonitrile, tetrahydrofuran, isopropanol or a combination thereof under the action of a metal catalyst under the addition of an alkali agent such as potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium tert-butoxide, triethylamine, diisopropylethylamine or a combination thereof, followed by work-up to produce compound (04). The metal catalyst is a ruthenium metal catalyst, a rhodium metal catalyst or an iridium metal catalyst.
The metal catalyst accounts for 1-5% of the mass of the compound (06). The feeding molar ratio of the alkali reagent to the compound (06) is 1:1-3: 1. The feeding molar ratio of the hydrogen source to the compound (06) is 2:1-4: 1. The amount of the organic solvent used is 5mL to 20mL per gram of compound (06).
The compound (04) can react with gas or liquid containing hydrogen chloride in an organic solvent at the temperature of between 5 ℃ below zero and 40 ℃, and then the compound is post-treated to prepare hydrochloride of the compound (04); wherein the amount of the organic solvent is 4mL-12mL per gram of the compound (04). In some embodiments, the amount of organic solvent used is 5mL to 10mL per gram of compound (04). In some embodiments, compound (04) is reacted with hydrogen chloride gas, saturated concentrated hydrochloric acid, acetone hydrochloride solution, methanol hydrochloride solution, or a combination thereof in acetone, isopropanol, methanol, ethyl acetate, toluene, acetonitrile, N-dimethylformamide, dimethylacetamide, or a combination thereof at-5 ℃ to 30 ℃ for 0.1 hour to 1.5 hours, followed by crystallization and isolation to obtain the hydrochloride salt of compound (04). In some embodiments, compound (04) is reacted with hydrogen chloride gas, saturated concentrated hydrochloric acid, acetone hydrochloride solution, methanol hydrochloride solution, or a combination thereof in acetone, isopropanol, methanol, ethyl acetate, or a combination thereof at-5 ℃ to 30 ℃ for 0.3 hours to 1 hour, followed by crystallization and isolation to obtain the hydrochloride salt of compound (04).
The compound (06) can be prepared by performing cyclization reaction on a compound (07) shown in a formula (07) after removing a protecting group by acid:
after removing protecting group by acid, the compound (07) is added with alkali reagent to carry out cyclization reaction at-5-40 ℃ for 12-36 hours, and then post-treatment is carried out to prepare the compound (06). The acid may be hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid or a combination thereof, or the like, which can remove a protecting group of an amino group such as t-butoxycarbonyl group. The alkali reagent is sodium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine, pyridine or a combined reagent thereof. The reaction solvent for the cyclization reaction can be dichloromethane, ethyl acetate, toluene, acetonitrile, acetone, N, N-dimethylformamide and C1-C6Such as methanol, ethanol, isopropanol, n-butanol, or combinations thereof. The reaction solvent is used in an amount of 5mL to 15mL per gram of compound (07).
The compound (07) can be prepared by a substitution reaction of a compound (08) shown as a formula (08) and 4-chloro-2-butanone in a reaction solvent in the presence of a base:
in the substitution reaction, the reaction solvent is dichloromethane, N-dimethylformamide, tetrahydrofuran, toluene, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate or a combination thereof. The amount of the reaction solvent used is 5mL-20mL per gram of compound (08). The base is sodium hydroxide, potassium carbonate, pyridine, triethylamine, diisopropylethylamine or a combination thereof. The feeding molar ratio of the alkali to the compound (08) is 1.05:1-2.2: 1. The feeding molar ratio of the compound (08) to the 4-chloro-2-butanone is 1:1.05-1: 2.
The reaction temperature of the compound (08) and the 4-chloro-2-butanone is 0 ℃ to 90 ℃. The compound (08) is reacted with 4-chloro-2-butanone in a reaction solvent in the presence of a base for 3 hours to 24 hours to obtain a compound (07).
In some embodiments, compound (08) is reacted with 4-chloro-2-butanone in dichloromethane at 20 ℃ to 30 ℃ for 12 hours to 18 hours, then water is added and the organic phase is stripped of the solvent to give compound (07).
The compound (08) can be prepared by adding sodium borohydride into ethanol from p-methoxybenzaldehyde and N-tert-butoxycarbonylethylenediamine, and then carrying out post-treatment.
The method provided by the invention has the advantages of easily obtained reaction materials and mild reaction conditions. Simple operation and can be used for industrial production.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, Boc represents t-butyloxycarbonyl, Et represents ethyl, g represents g, mL represents mL, and mol/L represents mol/L.
EXAMPLE 1 preparation of N-tert-Butoxycarbonyl-N' - (4-methoxybenzyl) ethylenediamine
P-methoxybenzaldehyde (13.6g, 100mmol) and ethanol (272mL) are added to a reaction flask in sequence, N-boc ethylenediamine (16g, 100mmol) is stirred at room temperature for 24 hours, the system is cooled to 0 ℃, then sodium borohydride (5.67g, 150mmol) is added in 4 batches respectively, the addition is finished for 30 minutes, the mixture is stirred at the constant temperature for 30 minutes, and then the mixture is stirred at the room temperature for 2 hours. Adding 6mol/L hydrochloric acid into the system at room temperature to quench the system to be acidic (pH is 2-6), stirring for 30 minutes, adding sodium hydroxide to adjust the system to be alkaline, then concentrating under reduced pressure at 60 ℃ to remove ethanol, supplementing 200mL of water and dichloromethane, separating out an organic phase, extracting the aqueous phase once with dichloromethane, and concentrating the combined organic phase under reduced pressure at 40 ℃ to be dry to obtain N-tert-butoxycarbonyl-N' - (4-methoxybenzyl) ethylenediamine, namely the compound (08): 25.0g of a pale yellow oily liquid, MS: m/z (M + H) ═ 281.
EXAMPLE 2 preparation of Compound (07)
After N-t-butoxycarbonyl-N' - (4-methoxybenzyl) ethylenediamine (24g, 85.7mmol) and methylene chloride (240mL) were charged in this order, 10mol/L sodium hydroxide (21.3mL) was added thereto, and the mixture was stirred at room temperature. 4-chloro-2-butanone (11.8g, 111.4mmol) was then slowly added dropwise, stirring at room temperature, and the system changed from clear to orange-yellow. After 14 hours, 4-chloro-2-butanone (4.5g, 42.8mmol) was added to the reaction system, and the reaction was continued with stirring for 4 hours. Then 240mL of water was added to the reaction system, the organic phase was separated, the aqueous phase was extracted once with 180mL of dichloromethane, and the combined organic phases were concentrated under reduced pressure at 50 ℃ to give tert-butyl [2- ((4-methoxybenzyl) (3-oxobutyl) amino) ethyl ] carboxylate, compound (07): 30g of a reddish brown oil with an HPLC purity of 99%.
EXAMPLE 3 preparation of Compound (06)
Tert-butyl [2- ((4-methoxybenzyl) (3-oxobutyl) amino) ethyl ] carboxylate (29.7g, 85mmol) and dichloromethane (300mL) were added to the reaction flask in this order, stirred at room temperature, concentrated hydrochloric acid (28mL, 340mmol) was slowly added dropwise, and the system was stirred at room temperature for 24 hours at 28 ℃. 200mL of water was added to the system, and after stirring for 20 minutes, the aqueous phase was separated. Adding 200mL of dichloromethane into the water phase, adjusting the pH of the water phase to 12 by using 6mol/L sodium hydroxide, separating an organic phase, and extracting the water phase once by using 100mL of dichloromethane; the combined organic phases are concentrated under reduced pressure at 40 ℃ to give 1- (4-methoxybenzyl) -5-methyl-2, 3,6, 7-tetrahydro-1H-1, 4-diazepane, compound (06): 19.7g of a reddish brown oil, MS spectrum MS: m/z (M + H) ═ 233.
EXAMPLE 4 preparation of Compound (04)
1- (4-methoxybenzyl) -5-methyl-2, 3,6, 7-tetrahydro-1H-1, 4-diazepane (19.7g, 85mmol), (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium (II) chloride (1.35 g), and triethylamine (15.45g, 153mmol) were added to the reaction flask, the system was cooled to-5 ℃ and dichloromethane (200mL) was added. Formic acid (11.7g, 255mmol) was added dropwise to the reaction system, maintaining the internal temperature below 0 ℃. After the dropwise addition was completed, the system was controlled to 0 ℃ to react for 16 hours. Then maintaining the temperature of the system below 10 ℃, and adjusting the pH of the system to be more than 12 by using sodium hydroxide. Then the system is heated to room temperature, an organic phase is separated, and the organic phase is decompressed and concentrated at 30 ℃ to obtain 1- (4-methoxybenzyl) - (5R) -methyl-1, 4-diazepane, namely the compound (04): dark red oil 11.8g, MS spectrum MS: m/z (M + H) ═ 235.
1- (4-methoxybenzyl) - (5R) -methyl-1, 4-diazepane (11.0g, 47mmol) and dimethylacetamide (44mL) were added to a reaction flask, the system was stirred at 30 ℃, concentrated hydrochloric acid (4.3mL, 47.8mmol) was then added dropwise, and stirred for 30 minutes, followed by addition of acetone (88mL) to the system, and the system was cooled to-10 ℃ and stirred for 15 hours. Then, the mixture was filtered under reduced pressure, the filter cake was rinsed with acetone, and the resulting solid was dried to dryness at 40 ℃ to give 1- (4-methoxybenzyl) - (5R) -methyl-1, 4-diazepan hydrochloride: orange-red solid 6.0 g.
EXAMPLE 5 preparation of Compound (03)
5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoic acid (4.65g, 22.89mmol), N, N-dimethylformamide (3 drops), dichloromethane (52mL), thionyl chloride (2.79mL, 34.33mmol) were added to the flask in this order, and the system was stirred at room temperature for 2 hours. Then, the reaction system was concentrated under reduced pressure at 40 ℃ to obtain 5.06g of 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl chloride as a yellow oil.
To a reaction flask, 1- (4-methoxybenzyl) - (5R) -methyl-1, 4-diazepane hydrochloride (7.0g), dichloromethane (50mL), water (50mL) were added, the system was stirred at room temperature at 28 ℃ and pH was adjusted to 12 with 6mol/L sodium hydroxide, the organic phase was separated and concentrated under reduced pressure at 40 ℃ to give 5.7g of a brown oil. Dichloromethane (114mL) was added to the resulting oily substance, and the resulting solution was transferred to the yellow oily substance of 5-methyl-2- (2H-1,2, 3-triazol-2-yl) benzoyl chloride, stirred, and the temperature of the system was reduced to 10 ℃; triethylamine (7.39g, 73.2mmol) was then added dropwise to the system, and after the addition was complete, the system was warmed to room temperature (28 ℃ C.) and stirred for 2 hours. Adding water (114mL) into the system, adjusting the pH of the system to 12 by using 6mol/L sodium hydroxide, stirring the system for 10 minutes at room temperature, and separating an organic phase; water (114mL) was added to the organic phase, the pH of the system was adjusted to 2 using 4mol/L hydrochloric acid, the system was stirred at room temperature for 10 minutes, and the separated organic phase was concentrated under reduced pressure at 40 ℃ to give 1- [4- (4-methoxybenzyl) - (7R) -methyl-1, 4-diazepan-1-yl ] -1- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone, compound (03): pink solid 12.0g, MS spectrum MS: m/z (M + H) ═ 420.
EXAMPLE 6 preparation of Compound (01)
1- [4- (4-methoxybenzyl) - (7R) -methyl-1, 4-diazepan-1-yl ] -1- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone (6.0g, 14.3mmol), palladium on carbon (10%, 1.2g), methanol (120mL), ammonium formate (4.96g, 78.8mmol) was added to the reaction flask, the resulting reaction system was stirred at 50 deg.C, sampled at 5 hours and tested, the starting material was not reacted completely, and additional ammonium formate (1.5g) was added and the reaction was continued for 13 hours. Then cooling the system to room temperature, carrying out vacuum filtration, and concentrating the filtrate at 50 ℃ under reduced pressure to obtain a white solid. Water (120mL) and methylene chloride (120mL) were added to the resulting white solid, the mixture was stirred at room temperature (28 ℃ C.), the pH was adjusted to 12 with 6mol/L sodium hydroxide, the organic phase was separated, 120mL of water was added to the organic phase, the pH was adjusted to 2 with 4mol/L hydrochloric acid, and after stirring for 10 minutes, separating the aqueous phase, adding dichloromethane (120mL) to the aqueous phase, adjusting the pH to 12 with 6mol/L sodium hydroxide, separating the organic phase, extracting the aqueous phase once with dichloromethane (100mL), and concentrating the combined organic phases at 40 deg.C under reduced pressure to obtain 1- (7(R) -methyl-1, 4-diazepan-1-yl) -1- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone, compound (01): clear oil 3.4g, MS: m/z (M + H) 300.
Example 7
2-amino-4-chlorophenol (57.6g, 400mmol), tetraethyl orthocarbonate (84.4g, 438mmol) and phosphoric acid (0.48g, 4.9mmol) were added to the reaction flask, stirred, warmed to 70 ℃ and stirred for 2 hours. Then cooling to room temperature (30 ℃), and separating out orange solid; adding 600mL of water into the system, and stirring for 2 hours; filtering, washing the filter cake with tap water for three times; and drying the obtained filter cake at 40 ℃ in vacuum to dryness to obtain 2-ethoxy-5-chlorobenzoxazole: orange solid 75.4g, HPLC purity 99.43%.
To a reaction flask charged with 1- [4- (4-methoxybenzyl) - (7R) -methyl-1, 4-diazepan-1-yl ] -1- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone (3.4g, 11.4mmol) was added 2-ethoxy-5-chlorobenzoxazole (2.35g, 11.9mmol), formic acid (0.68g, 11.4mmol), toluene (68mL) and the reaction was stirred at 85 ℃ for 16H. Water (68mL) was added to the reaction system, the pH was adjusted to 12 with 6mol/L sodium hydroxide, the mixture was stirred for 10 minutes, the organic phase was separated, and after washing the organic phase once with water, the organic phase was concentrated at 70 ℃ under reduced pressure to give 4.7g of a brown oil, MS: m/z (M + H) ═ 451.
To the brown oil (4.7g, 10.4mmol) obtained above was added activated carbon (0.47g), ethyl acetate (47mL), the system was stirred under reflux at 70 ℃ for 2 hours, filtered while hot, the filter cake was rinsed with hot ethyl acetate, and the filtrate was concentrated at 50 ℃ under reduced pressure to remove the solvent to give a pale yellow solid; adding ethyl acetate (14mL) into the obtained light yellow solid, stirring and dissolving at 70 ℃, then slowly dropwise adding 169mL of cyclohexane, slowly cooling the system to 10 ℃ after the addition is finished, stirring for 2 hours, then carrying out suction filtration under reduced pressure, and drying the obtained filter cake at 70 ℃ in vacuum to dryness to obtain 1- [4- (5-chlorobenzoxazol-2-yl) -7(R) -methyl-1, 4-diazacycloheptan-1-yl ] -1- [ 5-methyl-2- (2H-1,2, 3-triazol-2-yl) phenyl ] methanone: 3g of off-white solid, HPLC purity 99.34%, single impurity less than 0.07%.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (4)
1. A process for preparing compound (1), comprising: the compound (06) is reduced with a hydrogen source at the temperature of minus 10 ℃ to 0 ℃ under the action of a metal catalyst and the condition of adding an alkali reagent for 10 hours to 24 hours, and then the compound (04) is prepared by post-treatment,
wherein the hydrogen source is hydrogen, formic acid, ammonium formate or a combination thereof; in the reduction reaction, an alkali reagent is potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium tert-butoxide, triethylamine, diisopropylethylamine or a combination thereof, and the metal catalyst is (S, S) -N- (p-toluenesulfonyl) -1, 2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (II);
carrying out amidation reaction on the compound (04) or hydrochloride thereof and the compound (05) in an organic solvent at the temperature of-5-35 ℃ under the condition of adding alkali, and then carrying out post-treatment to obtain a compound (03),
wherein, the organic solvent of the amidation reaction is dichloromethane, ethyl acetate, acetone, acetonitrile, toluene, N-dimethylformamide or the combination thereof; the base for amidation reaction is sodium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine or a combination thereof, and the feeding molar ratio of the base for amidation reaction to the compound (04) or a salt thereof is 1.5:1-2.5: 1;
the compound (03) is subjected to deprotection reaction for 2 to 24 hours at 30 to 60 ℃ by hydrogen or ammonium formate in an organic solvent in the presence of a catalyst, and then is subjected to post-treatment to prepare a compound (01),
wherein, the organic solvent of the deprotection reaction is methanol, ethanol, ethyl acetate, acetone, acetonitrile, tetrahydrofuran or a combined solvent thereof; the catalyst for the deprotection reaction is Pd/C, Pd (OH)2/C，PdCl2Or a combined reagent thereof, wherein the dosage of the catalyst is 10-20% of the mass of the compound (03);
carrying out condensation reaction on the compound (01) and the compound (02) in an organic solvent in the presence of acid, and carrying out post-treatment to obtain a compound (1),
the acid of the condensation reaction is formic acid, acetic acid, phosphoric acid, or a mixture thereof; the reaction temperature of the condensation reaction is 40-100 ℃; the organic solvent of the condensation reaction is toluene, n-hexane, acetonitrile, acetone, dichloromethane, ethyl acetate, ethanol, DMSO or a mixture thereof; the dosage of the organic solvent for the condensation reaction is 8mL-32mL per gram of the compound (01); the feeding molar ratio of the compound (01) to the compound (02) is 1:0.9-1: 1.5; the reaction time of the condensation reaction is 2-24 hours; the post-treatment of the condensation reaction comprises: adjusting the pH value of the reaction system to 10-14, separating to obtain an organic phase, and removing the solvent to obtain the compound (1).
2. The method of claim 1, the post-treatment of the condensation reaction comprising: dissolving the compound (1) with ethyl acetate, adding cyclohexane, cooling, crystallizing, separating solid, and removing solvent to obtain the compound (1).
3. The method of claim 1, comprising: after removing protecting group by acid, the compound (07) is added with alkali reagent to carry out cyclization reaction at-5-40 ℃ for 12-36 hours to prepare a compound (06),
wherein the alkali reagent is sodium hydroxide, potassium carbonate, triethylamine, diisopropylethylamine, pyridine or a combined reagent thereof; the reaction solvent of the cyclization reaction is dichloromethane, ethyl acetate, toluene, acetonitrile, acetone, N, N-dimethylformamide, methanol, ethanol, isopropanol, N-butanol or the combination thereof; the reaction solvent is used in an amount of 5mL to 15mL per gram of compound (07).
4. The method of claim 1, comprising: reacting the compound (08) with 4-chloro-2-butanone in a reaction solvent at 0-90 ℃ for 3-24 hours in the presence of alkali to obtain a compound (07),
wherein the reaction solvent is dichloromethane, N, N-dimethylformamide, tetrahydrofuran, toluene, dimethyl sulfoxide, acetonitrile, acetone, ethyl acetate or a combination thereof; the dosage of the reaction solvent is 5mL-20mL per gram of the compound (08); the feeding molar ratio of the alkali to the compound (08) is 1.05:1-2.2: 1.
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