JP2021098744A - 新規な4−ベンゾアゾニン誘導体の製造方法 - Google Patents
新規な4−ベンゾアゾニン誘導体の製造方法 Download PDFInfo
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- JP2021098744A JP2021098744A JP2021040939A JP2021040939A JP2021098744A JP 2021098744 A JP2021098744 A JP 2021098744A JP 2021040939 A JP2021040939 A JP 2021040939A JP 2021040939 A JP2021040939 A JP 2021040939A JP 2021098744 A JP2021098744 A JP 2021098744A
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- 238000004519 manufacturing process Methods 0.000 title description 36
- BDNJXCPWLLNGMV-UHFFFAOYSA-N 4h-4-benzazonine Chemical class C1=CNC=CC=C2C=CC=CC2=C1 BDNJXCPWLLNGMV-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 abstract description 135
- 150000003839 salts Chemical class 0.000 abstract description 55
- -1 tetrahydroazepine compound Chemical class 0.000 abstract description 49
- 238000000034 method Methods 0.000 abstract description 15
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 abstract description 11
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract description 8
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical group C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 abstract description 4
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 99
- 238000006243 chemical reaction Methods 0.000 description 81
- 239000002904 solvent Substances 0.000 description 74
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000002253 acid Substances 0.000 description 32
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- 239000002585 base Substances 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000001816 cooling Methods 0.000 description 14
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 150000007524 organic acids Chemical class 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 229910052783 alkali metal Inorganic materials 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 230000002411 adverse Effects 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- HBRVAASZQUATJY-UHFFFAOYSA-N 1,5-dimethyl-2,3,4,7-tetrahydroazepine Chemical compound CN1CCCC(C)=CC1 HBRVAASZQUATJY-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 8
- 238000010511 deprotection reaction Methods 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 7
- 150000001340 alkali metals Chemical class 0.000 description 7
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 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 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002168 alkylating agent Substances 0.000 description 6
- 229940100198 alkylating agent Drugs 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- 239000008096 xylene Substances 0.000 description 6
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 5
- 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 description 5
- GKHHTAKMPWHDHL-UHFFFAOYSA-N 4-methoxy-1,11-dimethyl-11-azatricyclo[7.4.1.02,7]tetradeca-2(7),3,5-triene Chemical compound C1C2(C)CCN(C)CC1CC1=CC=C(OC)C=C12 GKHHTAKMPWHDHL-UHFFFAOYSA-N 0.000 description 5
- 239000002841 Lewis acid Substances 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 229940125773 compound 10 Drugs 0.000 description 5
- 239000012024 dehydrating agents Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 5
- 150000007517 lewis acids Chemical class 0.000 description 5
- 239000012022 methylating agents Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 235000005985 organic acids Nutrition 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
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- 238000003756 stirring Methods 0.000 description 5
- CVWBIIGVZBJDDC-UHFFFAOYSA-N 1,4-dioxa-9-azaspiro[4.6]undecan-8-one Chemical compound C1CNC(=O)CCC21OCCO2 CVWBIIGVZBJDDC-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
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- 125000003118 aryl group Chemical group 0.000 description 3
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 3
- 239000002738 chelating agent Substances 0.000 description 3
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- IVIIAEVMQHEPAY-UHFFFAOYSA-N tridodecyl phosphite Chemical compound CCCCCCCCCCCCOP(OCCCCCCCCCCCC)OCCCCCCCCCCCC IVIIAEVMQHEPAY-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- FUCBQMFTYFQCOB-UHFFFAOYSA-N trityl perchlorate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCl(=O)(=O)=O)C1=CC=CC=C1 FUCBQMFTYFQCOB-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
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Abstract
Description
項1.
一般式(10):
R2は、置換基を有していてもよいアルキル基を示す。
X−Y結合及びY−Z結合のうち、どちらか一方は炭素−炭素二重結合を示し、残りは炭素−炭素単結合を示す。)
で表されるテトラヒドロアゼピン化合物又はその塩。
項2.
一般式(10)において、R1がメチル基であり、R2がメチル基である、項1に記載の化合物又はその塩。
項3.
一般式(10)で表されるテトラヒドロアゼピン化合物又はその塩の製造方法であって、(f):一般式(9)で表される化合物又はその塩と、
三フッ化ホウ素エーテル(BF3・Et2O)錯体、トリフルオロ酢酸(TFA)、トリフルオロ酢酸無水物(TFAA)、トリフルオロメタンスルホン酸トリメチルシリル(TMSOTf)、塩化アルミニウム(AlCl3)、塩化チタン(IV)(TiCl4)、塩化錫(IV)(SnCl4)、過塩素酸トリフェニルメチル(TrtClO4)、ビスマストリフラート(Bi(OTf)3)、イッテルビウムトリフラート(Yb(OTf)3)、スカンジウムトリフラート(Sc(OTf)3)、トリフルオロメタンスルホン酸(TfOH)、メタンスルホン酸(MsOH)、p-トルエンスルホン酸(p-TsOH)、ベンゼンスルホン酸、10-カンファースルホン酸(CSA)及び五酸化二リン(P2O5)からなる群より選ばれる少なくとも一種の脱水剤とを反応させる工程を含む、製造方法。
R2は、置換基を有していてもよいアルキル基を示す。
X−Y結合及びY−Z結合のうち、どちらか一方は炭素−炭素二重結合を示し、残りは炭素−炭素単結合を示す。)
項4.
項3に記載の一般式(10)で表されるテトラヒドロアゼピン化合物又はその塩の製造方法であって、
さらに、(e):一般式(8)で表される化合物又はその塩とメチル化剤とを反応させて、一般式(9)で表される化合物又はその塩を得る工程を含む、製造方法。
項5.
項4に記載の一般式(10)で表されるテトラヒドロアゼピン化合物又はその塩の製造方法であって、
さらに、(d):一般式(7)で表される化合物又はその塩と、酸とを反応させて、一般式(8)で表される化合物又はその塩を得る工程を含む、製造方法。
2つのR3は、同一又は異なって、置換基を有していてもよいアルキル基を示し、又は2つのR3は、互いに結合して、2つのR3がそれぞれ結合する酸素原子と共に環を形成していてもよい。)
項6.
項5に記載の一般式(10)で表されるテトラヒドロアゼピン化合物又はその塩の製造方法であって、
さらに、(c):一般式(6)で表される化合物又はその塩と還元剤とを反応させて、一般式(7)で表される化合物又はその塩を得る工程を含む、製造方法。
項7.
項6に記載の一般式(10)で表されるテトラヒドロアゼピン化合物又はその塩の製造方法であって、
さらに、(b):一般式(5)で表される化合物又はその塩と一般式(15)で表される化合物とを反応させて、一般式(6)で表される化合物又はその塩を得る工程を含む、製造方法。
項8.
項7に記載の一般式(10)で表されるテトラヒドロアゼピン化合物又はその塩の製造方法であって、
さらに、(a):一般式(4)で表される化合物又はその塩とアルキル化剤とを反応させて、一般式(5)で表される化合物又はその塩を得る工程を含む、製造方法。
項9.
一般式(11)で表される4-ベンゾアゾニン化合物又はその塩の製造方法であって、(g):一般式(10)で表されるテトラヒドロアゼピン化合物又はその塩と酸とを反応させる工程を含む、製造方法。
R2は、置換基を有していてもよいアルキル基を示す。
X−Y結合及びY−Z結合のうち、どちらか一方は炭素−炭素二重結合を示し、残りは炭素−炭素単結合を示す。)
項10.
項9に記載の一般式(11)で表される4-ベンゾアゾニン化合物又はその塩の製造方法であって、項3〜8の何れか一項に記載の工程を含む、製造方法。
項11.
一般式(13)で表される化合物又はその塩の製造方法であって、
項3〜10の何れか一項に記載の工程を含み、かつ、
(h):一般式(11)で表される4-ベンゾアゾニン化合物又はその塩と有機酸とを反応させて、一般式(12)で表される化合物又はその塩を得る工程及び
(i):一般式(12)で表される化合物又はその塩におけるOR1基を脱保護して、一般式(13)で表される化合物又はその塩を得る工程を含む、製造方法。
一般式(13)で表される化合物は、反応式−1で示される反応工程を経て製造される。
化合物(4)→(5):(a)工程
一般式(5)で表される化合物又はその塩(以下、「化合物(5)」という)は、一般式(4)で表される化合物又はその塩(以下、「化合物(4)」という)とアルキル化剤とを反応させること(N−アルキル化反応)により製造することができる。
一般式(6)で表される化合物又はその塩(以下、「化合物(6)」という)は、化合物(5)と一般式(15)で表される化合物(以下、「化合物(15)」という)とを反応させること(アルコキシベンジル化反応)により製造することができる。
一般式(7)で表される化合物又はその塩(以下、「化合物(7)」という)の製造方法は、化合物(6)と還元剤とを反応させる工程(還元反応)を含んでいる。
一般式(8)で表される化合物又はその塩(以下、「化合物(8)」という)は、化合物(7)と酸とを反応させること(脱アセタール化反応)により製造することができる。
一般式(9)で表される化合物又はその塩(以下、「化合物(9)」という)は、化合物(8)とメチル化剤とを反応させること(メチル化反応)により製造することができる。
一般式(10)で表されるテトラヒドロアゼピン化合物又はその塩(以下、「化合物(10)」という)は、化合物(9)と、BF3・Et2O錯体、TFA、TFAA、TMSOTf、AlCl3、TiCl4、SnCl4、TrtClO4、Bi(OTf)3、Yb(OTf)3、Sc(OTf)3、TfOH、MsOH、p-TsOH、ベンゼンスルホン酸、CSA及びP2O5からなる群より選ばれる少なくとも一種の脱水剤とを反応させること(脱水反応)により製造することができる。
一般式(11)で表される4-ベンゾアゾニン化合物又はその塩(以下、「化合物(11)」という)は、化合物(10)と酸とを反応させること(環化反応)により製造することができる。
一般式(12)で表される化合物又はその塩(以下、「化合物(12)」という)は、化合物(11)と有機酸とを反応させること(塩形成反応)により製造することができる。
一般式(13)で表される化合物又はその塩(以下、「化合物(13)」という)は、化合物(12)におけるOR1基を脱保護(R1を除去)することにより製造することができる。
化合物(4)は、例えば、下記反応式−2で示される各工程を経て製造することができる。具体的には、一般式(1)で表される化合物又はその塩(以下、「化合物(1)」という)と、ヒドロキシルアミン・塩酸塩とを反応させて、一般式(2)で表される化合物又はその塩(以下、「化合物(2)」という)を得る工程、得られた化合物(2)とメタンスルホニルクロリド(MsCl)とを反応させて、一般式(3)で表される化合物又はその塩(以下、「化合物(3)」という)を得る工程、及び該化合物(3)をDCM及び水混合溶媒中でベックマン転位させる工程を経て、化合物(4)を製造することができる。
下記の反応式−3に従い、化合物(4a)を製造した。
化合物(4a):
Mp. 93-95℃.
1H-NMR (CDCl3) δ: 1.78-1.88 (m, 4H), 2.48-2.55 (m, 2H), 3.24-3.32 (m, 2H), 3.94-4.02 (m, 4H), 6.06 (s, 1H).
下記の反応式−4に従い、化合物(13a)を製造した。
窒素雰囲気下、化合物4a(774 g、4.5 mol)とトルエン(6.7 kg)との混合物を室温で30分間かき混ぜ、カリウムt-ブトキシド(760 g、6.8 mol)を徐々に加えた。室温で1時間かき混ぜた後、ヨウ化メチル(950 g、6.7 mol)を徐々に滴下し、更に1時間かき混ぜた。水(800 g)を加えて反応を停止した後、トルエン層を分離し、水層をジクロロメタン(2.8 kg x 2)で抽出した。有機層を減圧下、35℃〜45℃で濃縮し、表題化合物5aを非晶質固体として814.5 g(97%)得た。
化合物(5a):
1H-NMR (CDCl3) δ: 1.75-1.86 (m, 4H), 2.52-2.60 (m, 2H), 3.00 (s, 3H), 3.36-3.46 (m, 2H), 3.92-4.01 (m, 4H).
窒素雰囲気下、ジイソプロピルアミン(540 g、5.3 mol)のトルエン(3.5 kg)溶液に、-20℃〜10℃で2.5 mol/L n-ブチルリチウムヘキサン溶液(2.1 L、5.3 mol)を徐々に滴下し、3時間かき混ぜた。次いで、-5℃〜0℃で化合物5a(800 g、4.3 mol)のトルエン(3.5 kg)溶液を徐々に滴下し、1時間かき混ぜた後、-5℃から0℃で4-メトキシベンジルクロリド(680 g、4.3 mol)を徐々に滴下した。-5℃から5℃で1時間かき混ぜた後、0℃から10℃で0.5 mol/L塩酸(14.0 kg、塩化水素として7 mol)を徐々に滴下し、30分間かき混ぜた。有機層を分離し、10 wt%炭酸水素ナトリウム水溶液(2.0 kg)で洗浄した後、減圧下、30℃から40℃で濃縮し、表題化合物を油状物として945 g(72%)得た。化合物(6):
1H-NMR (CDCl3) δ: 1.52 (dd, J = 11.1, 14.1 Hz, 1H), 1.72-1.77 (m, 3H), 2.53 (dd, J = 9.4, 14.4 Hz, 1H), 2.93-3.00 (m, 1H), 3.02 (s, 3H), 3.03-3.10 (m, 1H), 3.18 (dd, J = 5.5, 14.4 Hz, 1H), 3.45-3.49 (m, 1H), 3.76-3.88 (m, 7H), 6.81-6.86 (m, 2H), 7.16 (d, J = 8.7 Hz, 2H).
窒素雰囲気下、15℃〜25℃で70 wt%Red-Alトルエン溶液(3.4 kg、Red-Alとして11.8 mol)に化合物6a(900 g、2.9 mmol)のトルエン(4.5 kg)溶液を徐々に滴下し、15℃〜25℃で2時間かき混ぜた。氷冷下で、反応混合物に30 wt%酒石酸カリウムナトリウム水溶液(6.7 kg)を注意して加え、30分間かき混ぜた後、トルエン層を分離した。15℃〜25℃でトルエン層に4-ニトロ安息香酸(0.46 kg、2.8 mol)を加え、2時間かき混ぜた。析出した固体をろ取し、表題化合物7aを1.16 kg(86%)得た。
化合物(7a):
Mp. 97-100℃.
1H-NMR (DMSO-d6) δ: 1.66 (dd, J = 10.5, 14.3 Hz, 1H), 1.72-1.76 (m, 1H), 1.88-1.94 (m, 2H), 2.08-2.25 (m, 1H), 2.36-2.53 (m, 6H), 2.66-2.78 (m, 1H), 2.81-2.92 (m, 2H), 3.58-3.63 (m, 1H), 3.70-3.83 (m, 6H), 6.84 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 8.11 (d, J = 8.7 Hz, 2H), 8.25 (d, J = 8.7 Hz, 2H).
窒素雰囲気下、化合物7a(1.16 kg、2.5 mmol)と6 mol/L塩酸(4.4 kg、塩化水素として28.8 mol)との混合物を45℃で2時間かき混ぜた後、固体をろ去した。ろ液を50 wt%水酸化ナトリウム水溶液でpH 10〜12に調整し、トルエン(5.5 kg)で抽出した。有機層を減圧下、45℃〜55℃で濃縮し、表題化合物8aを油状物として575 g(92%)得た。化合物(8a):
1H-NMR (CDCl3) δ: 2.18-2.31 (m, 2H), 2.34 (s, 3H), 2.36-2.42 (m, 1H), 2.45-2.53 (m, 3H), 2.54-2.63 (m, 2H), 2.73-2.84 (m, 3H), 3.78 (s, 3H), 6.83 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H).
窒素雰囲気下、0℃〜5℃で3.0 mol/L塩化メチルマグネシウムTHF溶液(2 L、塩化メチルマグネシウムとして6.0 mol)に化合物8a(378 g、1.5 mol)のトルエン(1.1 kg)溶液を徐々に滴下し、30分間かき混ぜた。0℃〜20℃で氷水(3 kg)に反応混合物を注意して加えた後、トルエン層を分離し、水層をトルエン(3.8 kg)で抽出した。有機層を合わせて減圧下、45℃〜55℃で濃縮し、表題化合物9aを油状物として378 g(88%)得た。化合物(9a):
1H-NMR (CDCl3) δ: 1.13-1.22 (m, 3H), 1.60-2.02 (m, 4H), 2.13-2.88 (m, 10H), 3.79 (s, 3H), 6.79-6.84 (m, 2H), 7.02-7.08 (m, 2H).
化合物9a(0.5 g、1.9 mmol)のトルエン(5 mL)溶液にp-TsOH(1.0 g、5.7 mmol)を加え、20時間加熱還流した。放冷した後、反応混合物を10 wt%水酸化ナトリウム水溶液でpH 12〜13に調整し、酢酸エチル(10 mL)で抽出した。酢酸エチル層を無水硫酸ナトリウムで乾燥した後、溶媒を減圧下で留去して得られた残渣をシリカゲルカラムクロマトグラフィー(Wakogel C-300HG、クロロホルム:メタノール=99:1)で単離精製して、表題化合物10a(0.02 g、4%)及び10b(0.01 g、2%)をそれぞれ油状物として得た。 化合物(10a):
1H-NMR (CDCl3) δ: 1.70 (s, 3H), 2.10 (dd, J = 7.5, 15.8 Hz, 1H), 2.15 (dd, J = 1.9, 11.9 Hz, 1H), 2.22-2.28 (m, 1H), 2.33 (s, 3H), 2.44 (dd, J = 10.1, 15.7 Hz, 1H), 2.52-2.63 (m, 2H), 2.70-2.77 (m, 1H), 2.68 (d, J = 12.1 Hz, 1H), 2.80 (dd, J = 7.5, 11.7 Hz, 1H), 3.78 (s, 3H), 5.31-5.35 (m, 1H), 6.82 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H).
MS (EI) : m/z 245 [M]+.
化合物(10b):
1H-NMR (CDCl3) δ: 1.67 (s, 3H), 1.99 (d, J = 15.1 Hz, 1H), 2.00-2.09 (m, 1H), 2.18 (dd, J = 10.0, 15.0 Hz, 1H), 2.29 (s, 3H), 2.40 (d, J = 12.1 Hz, 1H), 2.43 (dd, J = 7.1, 13.8 Hz, 1H), 2.51 (dd, J = 7.1, 13.8 Hz, 1H), 2.71 (dd, J = 3.8, 12.1 Hz, 1H), 2.92-3.04 (m, 2H), 3.79 (s, 3H), 5.45-5.50 (m, 1H), 6.82 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H).
MS (EI) : m/z 245 [M]+.
p-TsOHをP2O5に代えた以外は、上記(1-6)と同様の方法で、化合物10(84.1%)を製造した。
p-TsOHをBF3・Et2O錯体に代えた以外は、上記(1-6)と同様の方法で、化合物10(93.8%)を製造した。
p-TsOHをTFA/TFAAに代えた以外は、上記(1-6)と同様の方法で、化合物10(80.4%)を製造した。
p-TsOHをMsOHに代えた以外は、上記(1-6)と同様の方法で、化合物10(71%)を製造した。
p-TsOHをTfOHに代えた以外は、上記(1-6)と同様の方法で、化合物10(87%)を製造した。
塩化アルミニウム(1.9 g、14.2 mmol)と無水DCM(5 mL)との混合物に、氷冷下で化合物10a及び化合物10bの混合物(1.18 g、4.8 mmol)の無水DCM(5 mL)溶液を3分間かけて滴下した。室温で5時間かき混ぜた後、10℃を超えない温度で水(50 mL)に反応混合物を加えた。15 wt%水酸化ナトリウム水溶液でpH 10〜11に調整した後、酢酸エチル(100 mL)を加え、固体をセライトで除去した。有機層を分離し、水層を酢酸エチル(50 mL)で抽出した。有機層を合せて無水硫酸ナトリウムで乾燥した後、溶媒を減圧下で留去して得られた残渣をシリカゲルカラムクロマトグラフィー(PSQ-100B、クロロホルム:メタノール=49:1)で精製して、表題化合物11a(1.15 g、97%)を油状物として得た。化合物(11a):
1H-NMR (CDCl3) δ: 1.26 (s, 3H), 1.65-1.78 (m, 4H), 1.81 (dd, J = 7.1, 13.4 Hz, 1H), 2.18-2.26 (m, 4H), 2.34-2.41 (m, 1H), 2.42-2.49 (m, 1H), 2.56-2.62 (m, 1H), 2.80 (dd, J = 4.5, 15.5 Hz, 1H), 2.98-3.06 (m, 1H), 3.79 (s, 3H), 6.69 (dd, J = 2.7, 8.4 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H). MS (EI) : m/z 245 [M]+.
(2-1)2,3,4,5,6,7-ヘキサヒドロ-1,4-ジメチル-10-メトキシ-1,6-メタノ-1H-4-ベンゾアゾニン(11a)の合成:ワンポット合成:(f)+(g)工程
窒素雰囲気下、25℃で化合物9a(100 g、0.38 mol)のトルエン(600 g)溶液にp-TsOH(196 g、1.1 mol)を加え、20時間加熱還流した。放冷した後、15℃〜25℃で水(800 g)を徐々に滴下し、30分間かき混ぜた。水層を分離し、15℃〜25℃で30 wt%水酸化ナトリウム水溶液でpH 12〜13に調整し、MTBE(1 L x 2)で抽出した。有機層を減圧下、25℃〜35℃で濃縮した後、残渣をジクロロメタン(500 mL)で希釈した。0℃〜5℃で、この希釈溶液を塩化アルミニウム(151 g、1.13 mol)とDCM(500 mL)との混合物に徐々に滴下し、30分間かき混ぜた。その後、15℃〜25℃に昇温して20時間かき混ぜた。0℃〜10℃で水(1 L)に反応混合物を滴下し、15℃〜25℃で30 wt%水酸化ナトリウム水溶液を用いてpH 12〜13に調整した。MTBE(1 L x 2)で抽出し、有機層を合わせて、減圧下、15℃〜25℃で濃縮し、表題化合物11aを油状物として68 g(73%)得た。
(3-1) (-)-(1S,6S)-2,3,4,5,6,7-ヘキサヒドロ-1,4-ジメチル-10-メトキシ-1,6-メタノ-1H-4-ベンゾアゾニン(12a)の合成:(h)工程
化合物11a(31.6 g、0.13 mol)のMTBE(310 mL)溶液に、15℃〜25℃でD-マンデル酸(9.5 g、0.06 mol)を加え、1時間かき混ぜた。析出した固体をろ取し、MTBE(31 mL)で洗浄した。15℃〜25℃で、得られた固体に1 mol/L水酸化ナトリウム水溶液(49 mL、水酸化ナトリウムとして49 mmol)を加え、1時間かき混ぜた。トルエン(150 mL x 2)で抽出し、減圧下、45℃〜55℃で濃縮し、表題化合物12aを油状物として12.0 g(38%)得た。化合物(12a):
1H-NMR (CDCl3) δ: 1.26 (s, 3H), 1.65-1.78 (m, 4H), 1.81 (dd, J = 7.1, 13.4 Hz, 1H), 2.18-2.26 (m, 4H), 2.34-2.41 (m, 1H), 2.42-2.49 (m, 1H), 2.56-2.62 (m, 1H), 2.80 (dd, J = 4.5, 15.5 Hz, 1H), 2.98-3.06 (m, 1H), 3.79 (s, 3H), 6.69 (dd, J = 2.7, 8.4 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H). MS (EI) : m/z 245 [M]+.
窒素雰囲気下、10℃〜20℃で化合物12a(10 g、0.04 mol)を48 wt%臭化水素−酢酸溶液(50 mL)に加え、15分間かき混ぜた。35℃〜40℃に加温し、12時間かき混ぜた。放冷した後、反応混合物を減圧下で濃縮し、更に、残渣にトルエン(100 mL)を加え、酢酸を共沸した結果、固体13bが得られた。得られた固体を水(200 mL)に溶かし、2.5 mol/L水酸化ナトリウム水溶液でpHを11〜12に調整した。窒素雰囲気下、20℃〜30℃で8時間かき混ぜた後、6 mol/L塩酸でpHを7〜8に調整し、懸濁液を1時間かき混ぜた。固体をろ取し、水(50 mL)で洗浄した後、エタノール(300 mL)に固体を加えスラリーとし、70℃〜75℃で1時間かき混ぜ、20℃〜30℃に放冷した。固体をろ取し、エタノール(50 mL)で洗浄し、減圧下、70℃〜80℃で乾燥し、表題化合物13aを8.2g(87%)得た。化合物(13a):
1H-NMR (DMSO-d6) δ:1.16 (s, 3H), 1.50-1.65 (m, 4H), 1.66-1.71 (m, 1H), 2.08-2.16 (m, 4H), 2.23-2.35 (m, 2H), 2.48-2.53 (m, 1H), 2.68 (dd, J = 4.5, 15.3 Hz, 1H), 2.87-2.93 (m, 1H), 6.50 (dd, J = 2.5, 8.1 Hz, 1H), 6.63 (d, J = 2.5 Hz, 1H)
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