CN112010797A - Benzazepine polycyclic compound and synthetic method thereof - Google Patents
Benzazepine polycyclic compound and synthetic method thereof Download PDFInfo
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- -1 Benzazepine polycyclic compound Chemical class 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title claims description 4
- 238000000034 method Methods 0.000 claims abstract description 23
- NGFRGAZJGZKPQC-UHFFFAOYSA-M [2-(bromomethyl)phenyl]methyl-triphenylphosphanium;bromide Chemical group [Br-].BrCC1=CC=CC=C1C[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 NGFRGAZJGZKPQC-UHFFFAOYSA-M 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 238000005580 one pot reaction Methods 0.000 claims abstract description 10
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical group [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 230000002194 synthesizing effect Effects 0.000 claims 3
- 239000002585 base Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 19
- 238000001308 synthesis method Methods 0.000 abstract description 7
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000575 pesticide Substances 0.000 abstract description 2
- 238000007239 Wittig reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000004809 thin layer chromatography Methods 0.000 description 17
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 4
- WCTXJAXKORIYNA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 3-oxopiperidine-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1=O WCTXJAXKORIYNA-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- JYFGIESQUYQLGM-UHFFFAOYSA-N ethyl 1-benzyl-3-oxopiperidine-4-carboxylate Chemical compound C1C(=O)C(C(=O)OCC)CCN1CC1=CC=CC=C1 JYFGIESQUYQLGM-UHFFFAOYSA-N 0.000 description 2
- QPXNWTGYAKMATA-UHFFFAOYSA-N ethyl 3-oxopiperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1=O QPXNWTGYAKMATA-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XCBHHKQAWFCCNI-UHFFFAOYSA-N tert-butyl 1h-isoquinoline-2-carboxylate Chemical compound C1=CC=C2C=CN(C(=O)OC(C)(C)C)CC2=C1 XCBHHKQAWFCCNI-UHFFFAOYSA-N 0.000 description 2
- GYYKEOVZMRCOIU-UHFFFAOYSA-N tert-butyl 3-oxo-4-pyridin-2-ylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C(=O)C1)C2=CC=CC=N2 GYYKEOVZMRCOIU-UHFFFAOYSA-N 0.000 description 2
- GYVKDTVLHDLKIT-UHFFFAOYSA-N 1,2-dihydroisoquinolin-2-ium-1-carboxylate Chemical compound C1=CC=C2C(C(=O)O)NC=CC2=C1 GYVKDTVLHDLKIT-UHFFFAOYSA-N 0.000 description 1
- LFGDBJLQEQWSDA-UHFFFAOYSA-N 1-o-tert-butyl 3-o-methyl 4-oxopyrrolidine-1,3-dicarboxylate Chemical compound COC(=O)C1CN(C(=O)OC(C)(C)C)CC1=O LFGDBJLQEQWSDA-UHFFFAOYSA-N 0.000 description 1
- FGOJCPKOOGIRPA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 5-oxoazepane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O FGOJCPKOOGIRPA-UHFFFAOYSA-N 0.000 description 1
- PPDWEOWNELSQEY-UHFFFAOYSA-N 1H-isoquinoline-1,2-dicarboxylic acid Chemical compound C1(N(C=CC2=CC=CC=C12)C(=O)O)C(=O)O PPDWEOWNELSQEY-UHFFFAOYSA-N 0.000 description 1
- IWAGGDFROAISJT-UHFFFAOYSA-N 1h-isoquinoline-2-carboxylic acid Chemical compound C1=CC=C2C=CN(C(=O)O)CC2=C1 IWAGGDFROAISJT-UHFFFAOYSA-N 0.000 description 1
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 1
- ZTPXSFLESKDOLP-UHFFFAOYSA-N 3H-isoindole-2,3a-dicarboxylic acid Chemical compound C1C2(C=CC=CC2=CN1C(=O)O)C(=O)O ZTPXSFLESKDOLP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- DBUCVJIIHOMERH-UHFFFAOYSA-N ethyl 1,2-dihydroisoquinoline-1-carboxylate Chemical compound CCOC(=O)C1NC=CC2=CC=CC=C12 DBUCVJIIHOMERH-UHFFFAOYSA-N 0.000 description 1
- FHQDNCAJELNFTI-UHFFFAOYSA-N ethyl 4-benzylpiperidine-3-carboxylate Chemical compound C(C1=CC=CC=C1)C1C(CNCC1)C(=O)OCC FHQDNCAJELNFTI-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- XAAKCCMYRKZRAK-UHFFFAOYSA-N isoquinoline-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=NC=CC2=C1 XAAKCCMYRKZRAK-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/08—Aza-anthracenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a benzazepine polycyclic compound and a synthesis method thereof, wherein the compound takes beta-keto ester as an initial raw material, is subjected to substitution with (2- (bromomethyl) benzyl) triphenyl phosphonium bromide and Wittig reaction under an alkaline condition through a one-pot method to obtain a benzazepine polycyclic containing double bonds, and is prepared by catalytic hydrogenation reduction. The invention realizes the synthesis of various benzoazepine polycycles by a one-pot method, has simple and convenient operation, can realize the rapid preparation in a laboratory, and can be used as an important intermediate in the pharmaceutical and pesticide industries.
Description
Technical Field
The invention relates to a benzazepine polycyclic compound and a synthesis method thereof, in particular to a method for preparing various benzazepine polycyclic compounds by using beta-keto acid ester as a starting material through substitution, Wittig one-pot reaction and catalytic hydrogenation reduction reaction.
Background
Various benzazepine polycycles and related derivatives have wide application values in pharmaceutical chemistry and organic synthesis. At present, few reports on synthesis of benzazepine polycyclic rings exist, reaction routes similar to the literature are relatively long, and operating conditions are relatively harsh.
Reimann (Scientia pharmaceutical, 1996, vol.64, #3-4, p.637-646) et al reported that a benzazepine polycyclic containing a carbonyl group was prepared by a cyclization reaction using ethyl 4-benzylpiperidine-3-carboxylate as a starting material at 140 ℃ in a polyphosphoric acid system. Then reducing carbonyl in a perchloric acid/hydrogen/palladium carbon/acetic acid system to prepare the benzazepine polycyclic. The raw materials adopted in the method are not only difficult to directly purchase, but also the synthesis method is rarely reported, and the polyphosphoric acid is used in the operation process, so that the operation is inconvenient, the reaction temperature is high, the laboratory rapid preparation is difficult to realize, and the method is difficult to apply to industrial production.
Disclosure of Invention
The invention relates to a benzazepine polycyclic compound and a synthesis method thereof, and the benzazepine polycyclic compound has the advantages of easily obtained raw materials, convenient operation, easily controlled reaction and proper total yield.
In order to realize the purpose, the method adopted by the invention is as follows: a benzazepine polycyclic compound having the structure of formula i:
wherein R is COOEt or COOMe or pyridine; g is Boc or Bn; m is 1 or 2; n is 1 or 2.
Preferred R ═ COOMe, G ═ Boc, m ═ 1, n ═ 1;
preferred R ═ COOEt, G ═ Boc, m ═ 2, n ═ 1;
preferred R ═ COOEt, G ═ Boc, m ═ 2, n ═ 2;
preferred R ═ COOEt, G ═ Bn, m ═ 1, n ═ 1;
preferred R ═ COOEt, G ═ Bn, m ═ 2, n ═ 1;
preferred R ═ COOEt, G ═ Bn, m ═ 2, n ═ 2;
preferred R ═ 2-pyridyl, G ═ Boc, m ═ 2, and n ═ 1.
A synthesis method of a benzazepine polycyclic compound comprises the steps of substituting a raw material formula II with (2- (bromomethyl) benzyl) triphenyl phosphonium bromide under an alkaline condition, carrying out a Wittig one-pot reaction to generate a compound shown as a formula III, and then carrying out catalytic hydrogenation reduction on double bonds through palladium carbon to obtain a compound shown as a formula I, wherein the reaction formula is as follows:
the specific process of the substitution and the Wittig one-pot reaction is as follows: dissolving beta-keto ester shown as a formula II in an aprotic solvent, adding alkali under a cooling condition, stirring for 30min, then adding (2- (bromomethyl) benzyl) triphenyl phosphonium bromide, reacting overnight, quenching, and purifying to obtain the benzoazepine polycyclic containing the double bond shown as a formula III, wherein the molar ratio of the beta-keto ester to the (2- (bromomethyl) benzyl) triphenyl phosphonium bromide is 1: 1.1.
The specific process of catalytic hydrogenation reduction of double bonds comprises the steps of dissolving the benzoazepine polycyclic containing double bonds as shown in the formula III in methanol, adding palladium carbon, reacting in a hydrogen atmosphere, filtering, concentrating and purifying to obtain the compound shown in the formula I.
The alkali is sodium hydrogen, potassium tert-butoxide, lithium bistrimethylsilyl amide or lithium diisopropylamide, and preferably sodium hydrogen.
The aprotic solvent is tetrahydrofuran, diethyl ether, dioxane, N-dimethylformamide or N, N-dimethylacetamide, and is preferably tetrahydrofuran.
The reaction temperature is-10 to 25 ℃, and preferably 0 to 10 ℃.
The beneficial effects are as follows: the invention discloses a benzoazepine polycyclic compound which can be used as an important chemical intermediate and has very wide application in the industries of medicine, pesticide and the like. The synthesis method of the benzo-aza-polycyclic compound adopts a one-pot reaction to obtain the benzo-aza-polycyclic containing double bonds through two-step reactions of substitution and Wittig, and then prepares the benzo-aza-polycyclic through catalytic hydrogenation reduction.
Detailed Description
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations where mutually exclusive features and/or steps are present.
Any feature disclosed in this specification (including any accompanying claims, abstract) may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.
A benzazepine polycyclic compound having the structure of formula i:
wherein R is COOEt or COOMe or pyridine; g is Boc or Bn; m is 1 or 2; n is 1 or 2.
Preferred R ═ COOMe, G ═ Boc, m ═ 1, n ═ 1;
preferred R ═ COOEt, G ═ Boc, m ═ 2, n ═ 1;
preferred R ═ COOEt, G ═ Boc, m ═ 2, n ═ 2;
preferred R ═ COOEt, G ═ Bn, m ═ 1, n ═ 1;
preferred R ═ COOEt, G ═ Bn, m ═ 2, n ═ 1;
preferred R ═ COOEt, G ═ Bn, m ═ 2, n ═ 2;
preferred R ═ 2-pyridyl, G ═ Boc, m ═ 2, and n ═ 1.
A synthesis method of a benzazepine polycyclic compound comprises the steps of substituting a raw material formula II with (2- (bromomethyl) benzyl) triphenyl phosphonium bromide under an alkaline condition, carrying out a Wittig one-pot reaction to generate a compound shown as a formula III, and then carrying out catalytic hydrogenation reduction on double bonds through palladium carbon to obtain a compound shown as a formula I, wherein the reaction formula is as follows:
the specific process of the substitution and the Wittig one-pot reaction is as follows: dissolving beta-keto ester shown as a formula II in an aprotic solvent, adding alkali under a cooling condition, stirring for 30min, then adding (2- (bromomethyl) benzyl) triphenyl phosphonium bromide, reacting overnight, quenching, and purifying to obtain the benzoazepine polycyclic containing the double bond shown as a formula III, wherein the molar ratio of the beta-keto ester to the (2- (bromomethyl) benzyl) triphenyl phosphonium bromide is 1: 1.1.
The specific process of catalytic hydrogenation reduction of double bonds comprises the steps of dissolving the benzoazepine polycyclic containing double bonds as shown in the formula III in methanol, adding palladium carbon, reacting in a hydrogen atmosphere, filtering, concentrating and purifying to obtain the compound shown in the formula I.
The alkali is sodium hydrogen, potassium tert-butoxide, lithium bistrimethylsilyl amide or lithium diisopropylamide, and preferably sodium hydrogen.
The aprotic solvent is tetrahydrofuran, diethyl ether, dioxane, N-dimethylformamide or N, N-dimethylacetamide, and is preferably tetrahydrofuran.
The reaction temperature is-10 to 25 ℃, and preferably 0 to 10 ℃.
Example 12 preparation of tert-butyl-3-methyl-3 a, 4, 9, 9 a-tetrahydro-1H-benzo [ f ] isoindole-2, 3 a-dicarboxylic acid dimethyl ester, i.e. its R ═ COOMe, G ═ Boc, m ═ 1, n ═ 1.
Preparation of methyl 12-tert-butyl-3 a, 4-dihydro-1H-benzo [ f ] isoindole-2, 3a (3H) -dicarboxylate
N24-Oxopyrrolidine-1, 3-dicarboxylic acid 1-tert-butyl 3-methyl ester (125mg, 0.51mmol) was dissolved in 3mL of anhydrous THF under an atmosphere and cooled to 0 ℃ with stirring. 60% NaH (51.4mg, 1.29mmol) was added and stirred for 30 min. Bromine (2- (bromine) is addedMethyl) benzyl) triphenyl-l 5-phosphine (298mg, 0.57mmol), reacted for 1h, followed by TLC, and the reaction was complete. Adding 2mL of water into the system, extracting with ethyl acetate (2mL x 2), combining organic phases, washing the organic phases with water, drying, concentrating, and purifying by column chromatography to obtain 95mg of white solid, namely the 2-tert-butyl-3 a, 4-dihydro-1H-benzo [ f ] f]Isoindole-2, 3a (3H) -dicarboxylic acid methyl ester (yield: 56.1%). LC-MS (ESI +): M/z 352.2(M + Na);1H NMR(300MHz,CDCl3):7.20-7.15(m,3H),7.06(d,J＝6.9Hz,1H),6.49(s, 0.5H),6.45(s,0.5H),4.40-4.36(m,1H),4.21-4.07(m,2H),3.59(s,3H),3.51-3.34 (m,2H),2.86(d,J＝15.3Hz,1H),1.49(s,9H)。
preparation of dimethyl 22-tert-butyl-3-methyl-3 a, 4, 9, 9 a-tetrahydro-1H-benzo [ f ] isoindole-2, 3 a-dicarboxylate
2-tert-butyl-3 a, 4-dihydro-1H-benzo [ f)]Isoindole-2, 3a (3H) -dicarboxylic acid methyl ester (90 mg,0.27mmol) was dissolved in 2mL methanol, Pd/C (18mg, 20% wt) was added and stirred at room temperature, H2Stir overnight under ambient. The reaction was followed by TLC and was complete. Filtering, concentrating, and purifying by column chromatography to obtain 72mg of colorless oily substance, i.e. the 2-tert-butyl-3-methyl-3 a, 4, 9, 9 a-tetrahydro-1H-benzo [ f]Isoindole-2, 3 a-dicarboxylic acid dimethyl ester (yield: 79.5%). LC-MS (ESI +): M/z 354.0 (M + Na);1H NMR(300MHz,CDCl3):7.17-7.12(m,4H),3.77(d,J＝15.3Hz, 1H),3.69(s,3H),3.58(d,J＝6.3Hz,1H),3.40-3.14(m,2H),3.02-3.2.62(m,5H), 1.42(s,9H)。
example 22-tert-butyl-3, 4, 5, 10, 10-hexahydrobenzo [ G ] isoquinoline-2, 9-dicarboxylic acid ethyl ester, i.e. its R ═ COOEt, G ═ Boc, m ═ 2, n ═ 1.
Preparation of ethyl 12-tert-butyl-3, 4, 5-tetrahydrobenzo [ g ] isoquinoline-2, 1-dicarboxylate
N2Under an atmosphere, 1-tert-butyl 4-ethyl 3-oxopiperidine-1, 4-dicarboxylate (100mg,0.37mmol) was dissolved in 3mL anhydrous THF and cooled to 0 ℃ with stirring. 60% NaH (37mg,0.93mmol) was added and stirred for 30 min. Bromine (2- (bromomethyl) benzyl) triphenyl-l 5-phosphine (214mg, 0.41mmol) was added and the reaction was followed by TLC for 1h, ending the reaction. Adding 2mL of water into the system, extracting with ethyl acetate (2mL x 2), combining organic phases, washing the organic phases with water, concentrating, and purifying by column chromatography to obtain 130mg of colorless oily substance, namely the 2-tert-butyl-3, 4, 5-tetrahydrobenzo [ g ]]Isoquinoline-2, 1-dicarboxylic acid ethyl ester (yield: 98.7%). LC-MS (ESI +): M/z 380.0(M + Na);1H NMR(300MHz,CDCl3): 7.15-7.03(m,4H),6.45(s,1H),4.59(s,1H),4.07-3.95(m,4H),3.25(d,J＝15.3 Hz,1H),3.08-3.01(m,1H),2.81(d,J＝15.3Hz,1H),2.33(d,J＝10.8Hz,1H), 1.73(m,1H),1.48(s,9H),1.09(t,J＝6.9Hz,3H)。
preparation of 22-tert-butyl-3, 4, 5, 10, 10-hexahydrobenzo [ g ] isoquinoline-2, 9-dicarboxylic acid ethyl ester
2-tert-butyl-3, 4, 5-tetrahydrobenzo [ g)]Isoquinoline-2, 1-dicarboxylic acid ethyl ester (120mg,0.34 mmol) is dissolved in 2.5mL of methanol, Pd/C (24mg, 20% wt) is added, stirring at room temperature, H2Under the atmosphere, stirring is carried out overnight, TLC is used for tracking the reaction, and the reaction is finished. Filtering, concentrating, and purifying by column chromatography to obtain 112 mg of colorless oily substance, i.e. the 2-tert-butyl-3, 4, 5, 10, 10-hexahydrobenzo [ g ]]Isoquinoline-2, 9-dicarboxylic acid ethyl ester (yield: 92.8%). LC-MS (ESI +): M/z 382.2(M + Na);1H NMR (300MHz,CDCl3):7.11-7.04(m,4H),4.19-4.14(m,1H),4.01(q,J＝7.2Hz, 2H)，3.41-3.08(m,3H),2.96-2.59(m,4H),2.19-1.88(m,2H),1.61(s,1H),1.47 (s,9H),1.08(t,J＝7.2Hz,3H)。
example 33 a preparation of tert-butyl-4, 5, 6, 11, 11 a-hexahydro-1H-naphtho [2, 3-d ] aza-3, 11a (2H) -dicarboxylic acid ethyl ester, i.e. R ═ COOEt, G ═ Boc, m ═ 2, n ═ 2.
Preparation of 3.13-tert-butyl-4, 5, 6-tetrahydro-1H-naphtho [2, 3-d ] aza-3, 6-dicarboxylic acid ethyl ester
N2Under the atmosphere, 5-oxo-azacycloheptane-1, 4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (100mg, 0.35mmol is dissolved in 3mL of anhydrous THF, stirring and cooling are carried out to 0 ℃, 60% NaH (35mg,0.88 mmol) is added, stirring is carried out for 30min, bromine (2- (bromomethyl) benzyl) triphenyl-l 5-phosphine (203mg,0.39 mmol) is added, reaction is carried out for 1H, TLC tracking reaction is carried out, reaction is finished, 2mL of water is added into the system, ethyl acetate is used for extraction (2mL of x 2), organic phases are combined, washed, concentrated and purified by column chromatography to obtain 130mg of colorless oily substance, namely the 3-tert-butyl-4, 5, 6-tetrahydro-1H-naphtho [2, 3-d ]]Aza-3, 6-dicarboxylic acid ethyl ester (yield: 99.9%). LC-MS (ESI +): M/z 394.2(M + Na);1H NMR(300 MHz,CDCl3):7.11-7.08(m,3H),6.97(s,1H),6.34(s,0.5H),6.30(s,0.5H),4.20 (q,J＝6.9Hz,2H),3.76-3.57(m,2H),3.32-3.14(m,3H),2.85-2.72(m,3H), 1.88-1.72(m,2H),1.45-1.32(m,9H),1.25(t,J＝7.2Hz,3H)。
preparation of ethyl 23-tert-butyl-4, 5, 6, 11, 11 a-hexahydro-1H-naphtho [2, 3-d ] aza-3, 11a (2H) -dicarboxylate
3-tert-butyl-4, 5, 6-tetrahydro-1H-naphtho [2, 3-d]Aza-3, 6-dicarboxylic acid ethyl ester (120mg, 0.32mmol) was dissolved in 2.5mL of methanol and Pd/C (24mg, 20% w/C) was addedt), stirring at room temperature, H2Under the atmosphere, stirring is carried out overnight, TLC is used for tracking the reaction, and the reaction is finished. Filtering, concentrating, and purifying by column chromatography to obtain colorless oily substance 102mg, i.e. the 3-tert-butyl-4, 5, 6, 11, 11 a-hexahydro-1H-naphtho [2, 3-d ]]Aza-3, 11a (2H) -dicarboxylic acid ethyl ester (yield: 84.5%). LC-MS (ESI +): M/z 396.2(M + Na);1H NMR(300MHz,CDCl3):7.12-7.04(m,4H),4.18-3.98(m,2H),3.91-3.68(m, 1H),3.51-3.25(m,2H),3.21-2.61(m,5H),2.40-1.88(m,2H),1.87-1.66(m,3H), 1.45(s,9H),1.25-1.06(m,3H)。
example 42 preparation of benzyl-1, 3, 4, 5, 10, 10-hexahydrobenzo [ G ] isoquinoline-1 (2H) -carboxylic acid ethyl ester, i.e. its R ═ COOEt, G ═ Bn, m ═ 2, n ═ 1.
Preparation of trifluoroacetic acid salt of ethyl 4.13-oxopiperidine-4-carboxylate
3-Oxopiperidine-1, 4-dicarboxylic acid 1- (tert-butyl) 4-ethyl ester (5.6g, 20.6mmol) was dissolved in 32mL DCM, 8mL TFA was added, and the reaction was stirred overnight. The reaction was followed by TLC, and after completion of the reaction, the reaction was directly concentrated under reduced pressure to give 5.5g of a yellow viscous product, namely, the trifluoroacetic acid salt of ethyl 3-oxopiperidine-4-carboxylate (yield: 93%). LC-MS (ESI +): M/z 172.2(M + 1).
Preparation of ethyl 4.21-benzyl-3-oxopiperidine-4-carboxylate
The trifluoroacetic acid salt of ethyl 3-oxopiperidine-4-carboxylate (2g, 7.02mmol) and benzaldehyde (0.82 g, 7.72mmol) are dissolved in 30mL DCM and reacted with stirring at ambient temperature for 1h, then NaBH (OAc) is added3(2.98g, 14.0mmol) and stirred at room temperatureThe reaction was followed by TLC overnight, and after completion of the reaction, 15mL of water was added to the system, and extracted with ethyl acetate (15 mL. times.3), the organic phases were combined, washed with saturated brine, concentrated, and purified by column chromatography to give 1.38g of a yellow oily liquid which was the ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (yield: 78%). LC-MS (ESI +): M/z 262.2(M + 1);1H NMR (300MHz,CDCl3):7.53-7.36(m,5H),4.37(s,2H),4.25(q,J＝7.2Hz,2H), 3.91-3.78(m,1H),3.62-3.35(m,2H),2.53-2.30(m,2H),1.73-1.50(m,2H),1.01(t, J＝7.2Hz,3H)。
preparation of ethyl 32-benzyl-1, 3, 4, 5-tetrahydrobenzo [ g ] isoquinolinecarboxylate
N2Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (230mg, 0.88mmol) was dissolved in 15mL THF under stirring, cooled to 0 deg.C, 60% NaH (70mg, 1.76mmol) was added, stirring was carried out for 30min, bromo (2- (bromomethyl) benzyl) triphenyl-5-phosphine (510mg, 0.97mmol) was added, and the reaction was carried out overnight. TLC tracking reaction, after the reaction is finished, adding 20mL of water into the system, extracting with ethyl acetate (10mL x 3), combining organic phases, washing the organic phases with saturated salt water, concentrating, and purifying by column chromatography to obtain 180mg of yellow oily liquid, namely the 2-benzyl-1, 3, 4, 5-tetrahydrobenzo [ g ]]Isoquinolinecarboxylic acid ethyl ester (yield: 59%). LC-MS (ESI +): M/z 348.2(M + 1);1H NMR(300MHz, CDCl3):7.42-7.27(m,5H),7.12-6.98(m,4H),6.40(s,1H),4.73(s,2H),4.04(q, J＝6.9Hz,2H),3.71-3.53(m,2H),3.25(d,J＝15.6Hz,1H),3.14(d,J＝15.6Hz, 1H),2.96-2.80(m,2H),2.25-2.09(m,1H),1.97-1.82(m,1H),1.08(t,J＝7.2Hz, 3H)。
preparation of ethyl 42-benzyl-1, 3, 4, 5, 10, 10-hexahydrobenzo [ g ] isoquinoline-1 (2H) -carboxylate
2-benzyl-1, 3, 4, 5-tetrahydroBenzo [ g ]]Ethylisoquinoline carboxylate (60mg, 0.17mmol) was dissolved in 10mL of methanol, Pd/C (6mg) was added, and the mixture was stirred at room temperature under hydrogen peroxide (H)2Stirring overnight under atmosphere, tracking reaction by TLC, filtering, concentrating, and purifying by thin layer chromatography to obtain 48mg of oily liquid, i.e. 2-benzyl-1, 3, 4, 5, 10, 10-hexahydrobenzo [ g ]]Isoquinoline-1 (2H) -carboxylic acid ethyl ester (yield: 80%). LC-MS (ESI +): M/z 350.2(M + 1);1H NMR(300MHz,MeOD): 7.42-7.27(m,5H),7.12-6.98(m,4H),4.07(q,J＝6.9Hz,2H),3.78-3.60(s,2H), 3.25-3.13(m,2H),2.98-2.88(m,2H),2.72-2.64(m,2H),2.33-2.21(m,2H), 2.01-1.92(m,1H),1.89-1.76(m,1H),1.70-1.53(m,1H),1.02(t,J＝7.2Hz, 3H)。
example 54 a- (pyridin-2-yl) -3, 4, 4a, 5, 10, 10 a-hexahydrobenzo [ G ] isoquinoline-2 (1H) -carboxylic acid tert-butyl ester is prepared by the process wherein R is 2-pyridyl, G is Boc, m is 2 and n is 1.
Preparation of 1- (tert-butyl) 4-ethyl 13-oxo-4- (pyridin-2-yl) piperidine-1, 4-dicarboxylate
N23-Oxopiperidine-1, 4-dicarboxylic acid 1- (tert-butyl) 4-ethyl ester (5g, 18.4mmol) was dissolved in 100mL THF under ambient conditions, the system was cooled to-78 deg.C and LHMDS (37mL, 37mmol,1M in THF) was added and stirred for 30 min. Then 2-fluoropyridine (3.58g, 36.8mmol) was added and the reaction stirred overnight. The reaction was followed by TLC, after completion of the reaction, water was added to the system, and extraction was performed with ethyl acetate (30 mL. times.3), and the organic phases were combined, concentrated, and purified by column chromatography to obtain 2.5g of a yellow viscous product, i.e., the 1- (tert-butyl) 4-ethyl 3-oxo-4- (pyridin-2-yl) piperidine-1, 4-dicarboxylate (yield: 39%). LC-MS (ESI +): M/z 349.2(M + 1).
Preparation of tert-butyl 23-oxo-4- (pyridin-2-yl) piperidine-1-carboxylate
N2Under an atmosphere, 1- (tert-butyl) 4-ethyl 3-oxo-4- (pyridin-2-yl) piperidine-1, 4-dicarboxylate (2g, 5.7mmol) and LiCl (1.95g, 46mmol) were dissolved in 70mL of DMF, and the mixture was reacted with heating to 110 ℃ with stirring. TLC tracing reaction, after the reaction, adding 150mL water into the system, extracting with ethyl acetate (30mL x 3), combining organic phases, washing the organic phases with saturated salt water, concentrating, and purifying by column chromatography to obtain 900mg yellow solid, namely the 3-oxo-4- (pyridine-2-yl) piperidine-1-carboxylic acid tert-butyl ester (yield: 56%). LC-MS (ESI +): M/z 277.2(M + 1).
Preparation of 34 a- (pyridin-2-yl) -3, 4, 4a, 5-tetrahydrobenzo [ g ] isoquinoline-2 (1H) -carboxylic acid tert-butyl ester
N23-oxo-4- (pyridin-2-yl) piperidine-1-carboxylic acid tert-butyl ester (900mg, 3.3mmol) was dissolved in 20mL THF under ambient conditions, cooled to 0 deg.C with stirring, 60% NaH (300mg, 7.5mmol) was added, stirring was continued for 30min, and bromine (2- (bromomethyl) benzyl) triphenyl-l 5-phosphine (1.89g, 3.6mmol) dissolved in 5mL THF was added and reacted overnight. TLC (thin layer chromatography) tracking reaction, after the reaction is finished, adding 20mL of water into the system, extracting with ethyl acetate (10mL x 3), combining organic phases, washing the organic phases with saturated salt water, concentrating, and purifying by column chromatography to obtain 600mg of solid, namely the 4a- (pyridine-2-yl) -3, 4, 4a, 5-tetrahydrobenzo [ g ]]Isoquinoline-2 (1H) -carboxylic acid tert-butyl ester (yield: 51%). LC-MS (ESI +): M/z 363.2(M + 1);1H NMR(300MHz,MeOD):8.40(d,J＝4.2Hz,1H), 7.50-7.47(m,1H),7.45-7.44(m,2H),7.27-7.11(m,3H),6.96-6.93(m,1H), 6.17-6.16(m,1H),4.14-4.00(m,2H),3.52-3.46(m,1H),3.31-3.30(m,1H), 2.92-2.90(m,1H),2.37-2.28(m,2H),1.82-1.78(m,1H),1.12(s,9H)。
preparation of t-butyl 44 a- (pyridin-2-yl) -3, 4, 4a, 5, 10, 10 a-hexahydrobenzo [ g ] isoquinoline-2 (1H) -carboxylate
Reacting 4a- (pyridin-2-yl) -3, 4, 4a, 5-tetrahydrobenzo [ g]Isoquinoline-2 (1H) -carboxylic acid tert-butyl ester (600mg, 1.7mmol) is dissolved in 15mL of methanol, Pd/C (200mg) is added, stirring at room temperature, H2Stir overnight under ambient. TLC tracing reaction, after the reaction is finished, filtering, concentrating, and purifying by column chromatography to obtain 480mg of white solid, namely the 4a- (pyridine-2-yl) -3, 4, 4a, 5, 10, 10 a-hexahydrobenzo [ g)]Isoquinoline-2 (1H) -carboxylic acid tert-butyl ester (yield: 80%). LC-MS (ESI +): M/z 363.2(M + 1);1H NMR(300MHz,MeOD):8.42(d,J＝4.2Hz,1H),7.61-7.55(m,1H), 7.26-7.14(m,4H),7.10-7.05(m,1H),6.93(d,J＝7.5Hz,1H),3.99-3.93(m,2H), 3.58-3.53(m,1H),3.30-3.24(m,1H),2.48-2.39(m,2H),2.14-2.13(m,1H), 1.94-1.89(m,2H),1.68-1.50(m,2H),1.10(s,9H)。
in the above examples, DCM was dichloromethane, TFA was trifluoroacetic acid, DMF was N, N-dimethylformamide, LHMDS was lithium bistrimethylsilyl amide, TLC was thin layer chromatography, and LC-MS was liquid chromatography-mass spectrometry.
The invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification and any novel method or process steps or any novel combination of features disclosed.
Claims (9)
1. A benzazepine polycyclic compound having the structure of formula i:
2. the benzazepine polycyclic compound according to claim 1, wherein R is COOEt or COOMe or pyridine; g is Boc or Bn; m is 1 or 2; n is 1 or 2.
3. Benzapolycyclic compound according to claim 2,
preferred R ═ COOMe, G ═ Boc, m ═ 1, n ═ 1;
preferred R ═ COOEt, G ═ Boc, m ═ 2, n ═ 1;
preferred R ═ COOEt, G ═ Boc, m ═ 2, n ═ 2;
preferred R ═ COOEt, G ═ Bn, m ═ 1, n ═ 1;
preferred R ═ COOEt, G ═ Bn, m ═ 2, n ═ 1;
preferred R ═ COOEt, G ═ Bn, m ═ 2, n ═ 2;
preferred R ═ 2-pyridyl, G ═ Boc, m ═ 2, and n ═ 1.
4. A synthetic method for preparing the benzazepine polycyclic compound of claim 1, wherein the synthetic method comprises the steps of substituting a raw material formula II with (2- (bromomethyl) benzyl) triphenyl phosphonium bromide under an alkaline condition, carrying out a Wittig one-pot reaction to generate a compound shown as a formula III, and then carrying out catalytic hydrogenation reduction on double bonds through palladium carbon to obtain a compound shown as a formula I, wherein the reaction formula is as follows:
5. the method for synthesizing benzazepine polycyclic compounds according to claim 4, wherein the specific process of the substitution and Wittig one-pot reaction is as follows: dissolving beta-keto ester shown as a formula II in an aprotic solvent, adding alkali under a cooling condition, stirring for 30min, then adding (2- (bromomethyl) benzyl) triphenyl phosphonium bromide, reacting overnight, quenching, and purifying to obtain the benzoazepine polycyclic containing double bonds shown as a formula III, wherein the molar ratio of the beta-keto ester to the (2- (bromomethyl) benzyl) triphenyl phosphonium bromide is 1: 1.1.
6. The method for synthesizing benzazepine polycyclic compounds according to claim 4, wherein the specific process of catalytic hydrogenation reduction of double bonds comprises dissolving benzazepine polycyclic compounds containing double bonds as shown in formula III in methanol, adding palladium carbon, reacting in hydrogen atmosphere, filtering, concentrating, and purifying to obtain formula I.
7. A process for the synthesis of benzazepine polycyclic compounds according to claim 5 wherein the base is sodium hydrogen, potassium tert-butoxide, lithium bistrimethylsilylamide or lithium diisopropylamide, preferably sodium hydrogen.
8. A process for the synthesis of benzazepine polycyclic compounds according to claim 5 wherein the aprotic solvent is tetrahydrofuran, diethyl ether, dioxane, N-dimethylformamide or N, N-dimethylacetamide, preferably tetrahydrofuran.
9. The method for synthesizing benzazepine polycyclic compounds according to claim 5, wherein the reaction temperature is-10 to 25 ℃, preferably 0 to 10 ℃.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3890347A (en) * | 1971-12-08 | 1975-06-17 | Allen & Hanburys Ltd | Isoindoline derivatives |
| US6586446B1 (en) * | 1999-10-15 | 2003-07-01 | Bristol-Myers Squibb Company | Bicyclic and tricyclic amines as modulators of chemokine receptor activity |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3890347A (en) * | 1971-12-08 | 1975-06-17 | Allen & Hanburys Ltd | Isoindoline derivatives |
| US6586446B1 (en) * | 1999-10-15 | 2003-07-01 | Bristol-Myers Squibb Company | Bicyclic and tricyclic amines as modulators of chemokine receptor activity |
Non-Patent Citations (1)
| Title |
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| WOLFGANG OPPOLZER 等: "Stereoselective Syntheses of Benz[f]isoindoline-Derivatives by Intramolecular Cycloadditions of Styrenes to Olefins", 《HELVETICA CHIMICA ACTA》 * |
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