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【结 构 式】 
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【分子编号】11934 【品名】m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether 【CA登记号】151-10-0 |
【 分 子 式 】C8H10O2 【 分 子 量 】138.1662 【元素组成】C 69.55% H 7.3% O 23.16% |
合成路线1
该中间体在本合成路线中的序号：(V)1) The Friedel-Crafts condensation of 4,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester (I) with benzoyl chloride (II) by means of AlCl3 in dichloroethane, followed by hydrolysis with ethanolic NaOH gives 5-benzoyl-4,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (III), which by reaction with hydroxylamine in refluxing pyridine is converted into the corresponding oxime (IV). Finally, this compound is cyclized with NaH in DMF or with KOH in ethanol. 2) The Friedel-Crafts condensation of (V) with (II) as before gives 2-hydroxy-4-methoxybenzophenone (XVI), which by cyclocondensation with hydroxylamine as before is converted into 6-methoxy-3-phenyl-1,2-benzisoxazole (XVII). Demethylation of (XVII) as already indicated yields 6-hydroxy-3-phenyl-1,2-benzisoxazole (XVIII), which is converted into the allyloxy derivative (XIX). The rearrangement of (XIX) with N,N-dimethylamine as before affords the 7-allyl derivative (XX), which is cyclized with m-chloroperbenzoic acid (m-CPBA) to 3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol (XXI). Finally, this compound is chlorinated with SO2Cl2 in CH2Cl2 yielding compound (XV), which is oxidized with CrO3 / H2SO4 or KMnO4 in dichloromethane.
| 【1】 Sato, H.; Koga, H.; Dan, T.; Onuma, E. (Chugai Pharmaceutical Co. Ltd.); Furobenzisoxazole derivs. EP 0205872; US 4791209 . |
| 【2】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the preparation of furobenzisoxazole derivs. JP 1989131180 . |
| 【3】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the synthesis of furobenzisoxazole derivs. JP 1989143876 . |
| 【4】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Industrial process for the preparation of furobenzisoxazole derivs. JP 1989143875 . |
| 【5】 Prous, J.; Castaner, J.; AA-193. Drugs Fut 1991, 16, 11, 985. |
| 【6】 Onuma, E.; Dan, T.; Koga, H.; Sato, H.; Aoki, B.; Tanaka, H.; Studies on uricosuric diuretics. II. Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids. Chem Pharm Bull 1991, 39, 7, 1760-72. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11930 | ethyl 4,7-dichloro-2,3-dihydro-1-benzofuran-2-carboxylate | C11H10Cl2O3 | 详情 | 详情 | |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 11932 | 5-Benzoyl-4,7-dichloro-2,3-dihydro-1-benzofuran-2-carboxylic acid | C16H10Cl2O4 | 详情 | 详情 | |
| (IV) | 11933 | 4,7-Dichloro-5-[(hydroxyimino)(phenyl)methyl]-2,3-dihydro-1-benzofuran-2-carboxylic acid | C16H11Cl2NO4 | 详情 | 详情 | |
| (V) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (XV) | 11941 | (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H12ClNO3 | 详情 | 详情 | |
| (XVI) | 11935 | 2-Hydroxy-4-methoxybenzophenone; (2-Hydroxy-4-methoxyphenyl)(phenyl)methanone | 131-57-7 | C14H12O3 | 详情 | 详情 |
| (XVII) | 11936 | Methyl 3-phenyl-1,2-benzisoxazol-6-yl ether; 6-Methoxy-3-phenyl-1,2-benzisoxazole | C14H11NO2 | 详情 | 详情 | |
| (XVIII) | 11937 | 3-Phenyl-1,2-benzisoxazol-6-ol | C13H9NO2 | 详情 | 详情 | |
| (XIX) | 11938 | 6-(Allyloxy)-3-phenyl-1,2-benzisoxazole; Allyl 3-phenyl-1,2-benzisoxazol-6-yl ether | C16H13NO2 | 详情 | 详情 | |
| (XX) | 11939 | 7-Allyl-3-phenyl-1,2-benzisoxazol-6-ol | C16H13NO2 | 详情 | 详情 | |
| (XXI) | 11940 | (3-Phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H13NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)3) The chlorination of 1,3-dimethoxybenzene (V) with SO2Cl2 in CHCl3 gives 1-chloro-2,4-dimethoxybenzene (VI), which is condensed with (II) by means of AlCl3 in dichloroethane yielding 5-chloro-2-hydroxy-4-methoxybenzophenone (VII). The cyclocondensation of (VII) with hydroxylamine - HCl and then with acetic anhydride - sodium acetate in refluxing DMF affords 5-chloro-6-methoxy-3-phenyl-1,2-benzoisoxazole (VIII), which is demethylated with pyridine hydrochloride at 180 C, giving 5-chloro-6-hydroxy-3-phenyl-1,2-benzoisoxazole (IX). The condensation of (IX) with dimethylamine and formaldehyde in water gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenyl-1,2-benzoisoxazole (X), which is cyclized with (ethoxycarbonylmethyl)dimethylsulfonium bromide (XI) by means of K2CO3 in DMF, yielding 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzoisoxazole-7-carboxyli c acid ethyl ester (XII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol. 4) The condensation of isoxazole (IX) with allyl bromide by means of K2CO3 in DMF gives 6-allyloxy-5-chloro-3-phenyl-1,2-benzoisoxazole (XIII), which is rearranged with refluxing N,N-dimethylaniline yielding 7-allyl-5-chloro-6-hydroxy-3-phenyl-1,2-benzisoxazole (XIV). The cyclization of (XIV) with m-chloroperbenzoic acid (MCPBA) in refluxing CHCl3 or N-bromosuccinimide in DMSO affords 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol (XV), which is finally oxidized with CrO3-H2SO4 in acetone or KMnO4 in dichloroethane. 5) The alkylation of phenol (IX) with ortho-acrylic acid trietyl ester (XXI) by means of pivalic acid in refluxing toluene gives the substituted chromane (XXIII), which is then treated with Br2 in pyridine-CHCl3 to afford ethyl ester (XII), already obtained.
| 【1】 Sato, H.; Koga, H.; Dan, T.; Onuma, E. (Chugai Pharmaceutical Co. Ltd.); Furobenzisoxazole derivs. EP 0205872; US 4791209 . |
| 【2】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Industrial process for the preparation of furobenzisoxazole derivs. JP 1989143875 . |
| 【3】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the synthesis of furobenzisoxazole derivs. JP 1989143876 . |
| 【4】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the preparation of furobenzisoxazole derivs. JP 1989131180 . |
| 【5】 Prous, J.; Castaner, J.; AA-193. Drugs Fut 1991, 16, 11, 985. |
| 【6】 Onuma, E.; Dan, T.; Koga, H.; Sato, H.; Aoki, B.; Tanaka, H.; Studies on uricosuric diuretics. II. Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids. Chem Pharm Bull 1991, 39, 7, 1760-72. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (V) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (VI) | 11942 | 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether | 7051-13-0 | C8H9ClO2 | 详情 | 详情 |
| (VII) | 11943 | (5-Chloro-2-hydroxy-4-methoxyphenyl)(phenyl)methanone | C14H11ClO3 | 详情 | 详情 | |
| (VIII) | 11944 | 5-Chloro-3-phenyl-1,2-benzisoxazol-6-yl methyl ether; 5-Chloro-6-methoxy-3-phenyl-1,2-benzisoxazole | C14H10ClNO2 | 详情 | 详情 | |
| (IX) | 11945 | 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol | C13H8ClNO2 | 详情 | 详情 | |
| (X) | 11946 | 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol | C16H15ClN2O2 | 详情 | 详情 | |
| (XI) | 11947 | (2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide | 5187-82-6 | C6H13BrO2S | 详情 | 详情 |
| (XII) | 11948 | ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate | C18H14ClNO4 | 详情 | 详情 | |
| (XIII) | 11949 | Allyl 5-chloro-3-phenyl-1,2-benzisoxazol-6-yl ether; 6-(Allyloxy)-5-chloro-3-phenyl-1,2-benzisoxazole | C16H12ClNO2 | 详情 | 详情 | |
| (XIV) | 11950 | 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol | C16H12ClNO2 | 详情 | 详情 | |
| (XV) | 11941 | (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H12ClNO3 | 详情 | 详情 | |
| (XXII) | 11951 | 3,3,3-Triethoxy-1-propene; 1,1-Diethoxy-2-propenyl ethyl ether | C9H18O3 | 详情 | 详情 | |
| (XXIII) | 11952 | 5-Chloro-7-ethoxy-3-phenyl-8,9-dihydro-7H-chromeno[6,5-d]isoxazol-7-yl ethyl ether; 5-Chloro-7,7-diethoxy-3-phenyl-8,9-dihydro-7H-chromeno[6,5-d]isoxazole | C20H20ClNO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Several related syntheses for AA-193 have been reported: 1) The Friedel-Crafts' condensation of 2,5-dichlorophenol (I) with benzoyl chloride (II) by means of AlCl3 gives 2,5-dichloro-4-hydroxybenzophenone (III), which by reaction with hydroxylamine and KOH is converted to 5-chloro-6-hydroxy-3-phenylbenzisoxazole (IV). The condensation of (IV) with allyl bromide (V) by means of K2CO3 affords the 7-allyl derivative (VI), which is cyclized by means of N-bromosuccinimide and NaOH to 5-chloro-7-(hydroxymethyl)-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisox azole (VII). Finally, this compound is oxidized to the final product with KMnO4 in refluxing dichloromethane. 2) The chlorination of 1,3-dimethoxybenzene (VIII) with SO2Cl2 gives 1-chloro-2,4-dimethoxybenzene (IX), which is condensed with benzoyl chloride (II) as before, yielding 5-chloro-2,4-dihydroxybenzophenone (X). Tosylation of (X) with tosyl chloride gives the corresponding ditosyl derivative (XI), which by reaction with hydroxylamine is converted to the oxime (XII). Finally, this compound is treated with KOH in order to cyclize to the benzisoxazole (IV). 3) The reaction of the benzisoxazole (IV) with formaldehyde and dimethylamine gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenylbenzisoxazole (XIII), which is condensed and cyclized with the ylide (XIV) to yield the ethyl ester of the desired product (XV). Finally, this compound is hydrolyzed with NaOH.
| 【1】 Koga, H.; Kuromaru, K.; Ishizawa, T.; Aoki, B.; Sato, H.; Studies on uricosuric diuretics. V. Convenient and efficient synthesis of 2,3-dihydrobenzofuran derivatives. Chem Pharm Bull 1992, 40, 10, 2597. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11953 | 2,5-Dichlorophenol | 583-78-8 | C6H4Cl2O | 详情 | 详情 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 11955 | (2,5-Dichloro-4-hydroxyphenyl)(phenyl)methanone | C13H8Cl2O2 | 详情 | 详情 | |
| (IV) | 11945 | 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol | C13H8ClNO2 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 11950 | 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol | C16H12ClNO2 | 详情 | 详情 | |
| (VII) | 11941 | (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H12ClNO3 | 详情 | 详情 | |
| (VIII) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (IX) | 11942 | 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether | 7051-13-0 | C8H9ClO2 | 详情 | 详情 |
| (X) | 11962 | (5-Chloro-2,4-dihydroxyphenyl)(phenyl)methanone | C13H9ClO3 | 详情 | 详情 | |
| (XI) | 11963 | 2-benzoyl-4-chloro-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate | C27H21ClO7S2 | 详情 | 详情 | |
| (XII) | 11964 | 4-chloro-2-[(hydroxyimino)(phenyl)methyl]-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate | C27H22ClNO7S2 | 详情 | 详情 | |
| (XIII) | 11946 | 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol | C16H15ClN2O2 | 详情 | 详情 | |
| (XIV) | 11966 | 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt | C6H12O2S | 详情 | 详情 | |
| (XV) | 11948 | ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate | C18H14ClNO4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The key diaryl ethyl fragment of LY293111 begins with the deprotonation and alkylation of 1,3-dimethoxybenzene (VII) to provide compound (VIII). Two routes may be used to construct the diaryl ether phenol (X). The first route, utilizing an Ullmann ether synthesis, begins with the demethylation of (VIII) with molten pyridinium hydrochloride to give diol (IX). Subsequent coupling of (IX) with methyl 2-iodobenzoate in the presence of copper and potassium carbonate in refluxing pyridine provides the target phenol (X). In the alternative route, compound (VIII) is mono-demethylated with sodium ethanethiolate in hot N,N-dimethylformamide to provide phenol (XI). The addition of 2-fluorobenzonitrile to (XI), mediated by potassium fluoride-alumina and 18-crown-6 in refluxing acetonitrile, provides nitrile (XII). Boron tribromide-assisted demethylation of (XII), followed by hydrolysis and esterification, completes the alternate synthesis of intermediate (X).
| 【1】 Schmittling, E.A.; Sawyer, J.S.; Synthesis of diaryl ethers, diaryl thioethers, and diaryl amines mediated by potassium fluoride-alumina and 18-crown-6. J Org Chem 1993, 58, 3229-30. |
| 【2】 Sawyer, J.S.; Bach, N.J.; Baker, S.R.; et al.; Synthetic and structure/activity studies on acid-substituted 2-arylphenols: The discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist. J Med Chem 1995, 38, 22, 4411-32. |
| 【3】 Sawyer, J.S.; Baldwin, R.F.; Sofia, M.J.; et al.; Biphenylyl-substituted xanthones: Highly potent leukotriene B4 receptor antagonists. J Med Chem 1993, 36, 24, 3982-4. |
| 【4】 Sawyer, J.S.; LY-293111 Sodium. Drugs Fut 1996, 21, 6, 610. |
| 【5】 Sawyer, J.S.; Baldwin, R.F.; Saussy, D.L. Jr.; Froelich, L.L.; Jackson, W.T.; Diaryl ether/carboxylic acid derivatives of LY255283: Receptor antagonists of leukotriene B4. Bioorg Med Chem Lett 1993, 3, 10, 1985-90. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 41199 | 2-fluorobenzonitrile | 394-47-8 | C7H4FN | 详情 | 详情 | |
| 64701 | methyl 2-iodobenzoate | C8H7IO2 | 详情 | 详情 | ||
| (VII) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (VIII) | 16215 | 3-methoxy-2-propylphenyl methyl ether; 1,3-dimethoxy-2-propylbenzene | C11H16O2 | 详情 | 详情 | |
| (IX) | 16216 | 2-propyl-1,3-benzenediol | C9H12O2 | 详情 | 详情 | |
| (X) | 16217 | methyl 2-(3-hydroxy-2-propylphenoxy)benzoate | C17H18O4 | 详情 | 详情 | |
| (XI) | 16218 | 3-methoxy-2-propylphenol | C10H14O2 | 详情 | 详情 | |
| (XII) | 16219 | 2-(3-methoxy-2-propylphenoxy)benzonitrile | C17H17NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Treatment of N-Boc-4-bromo-L-phenylalanine (I) with ethanolic or methanolic HCl gave aminoester (II). Subsequent condensation of (II) with 2,6-dichlorobenzoyl chloride (III) produced amide (IV). Lithiation of 1,3-dimethoxybenzene (V) with n-butyllithium, followed by reaction with trimethyl borate and aqueous hydrolysis yielded boronic acid (VI). Suzuki coupling of bromide (IV) with boronic acid (VI) in the presence of palladium catalyst furnished biphenyl derivative (VII). Finally, hydrolysis of the ethyl ester of (VII) with LiOH provided the title carboxylic acid.
| 【1】 Sircar, I.; et al.; Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035, a dual alpha4beta7/alpha4beta1 integrin antagonist. Bioorg Med Chem 2002, 10, 6, 2051. |
| 【2】 Gudmundsson, K.S.; Sircar, I.; Martin, R. (Tanabe Seiyaku Co., Ltd.); Inhibitors of alpha4 mediated cell adhesion. WO 9936393 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 32546 | (2S)-3-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H18BrNO4 | 详情 | 详情 | |
| (II) | 32547 | ethyl (2S)-2-amino-3-(4-bromophenyl)propanoate | C11H14BrNO2 | 详情 | 详情 | |
| (III) | 25087 | 2,6-dichlorobenzoyl chloride | 4659-45-4 | C7H3Cl3O | 详情 | 详情 |
| (IV) | 32548 | ethyl (2S)-3-(4-bromophenyl)-2-[(2,6-dichlorobenzoyl)amino]propanoate | C18H16BrCl2NO3 | 详情 | 详情 | |
| (V) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (VI) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (VII) | 32550 | ethyl (2S)-2-[(2,6-dichlorobenzoyl)amino]-3-(2',6'-dimethoxy[1,1'-biphenyl]-4-yl)propanoate | C26H25Cl2NO5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Resorcinol dimethyl ether (I) was metallated with n-butyllithium and the resultant organolithium compound (II) was treated with triisopropyl borate to provide, after acidic hydrolysis, boronic acid (III). Suzuki coupling of boronic acid (III) with methyl 5-nitro-2-bromobenzoate (IV) furnished biphenyl (V). Cleavage of the methyl ether groups of (V) with concomitant lactonization in the presence of BBr3 produced the benzocoumarin (VI), which was further O-methylated with iodomethane to afford the methyl ether (VII). The reduction of the nitro group of (VII) by catalytic hydrogenation over Pd/C gave amine (VIII). This was converted to the quinoline derivative (IX) via a modified Skraup ring annulation with acetone and a catalytic amount of iodine. Addition of the organolithium reagent (X) (prepared from 3-(methoxymethoxy)phenyl bromide) to the lactone (IX) provided the cyclic hemiketal (XI). The methoxymethyl protecting group was then cleaved under acidic conditions to afford diol (XII).
| 【1】 Coghlan, M.J.; et al.; Synthesis and characterization of non-steroidal ligands for the glucocorticoid receptor: Selective derivatives with prednisolone-equivalent functional activity. J Med Chem 2001, 44, 18, 2879. |
| 【2】 Wang, A.X.; Kym, P.R.; Jones, T.K.; Kort, M.E.; Edwards, J.P.; Moore, J.L.; Elmore, S.W.; Coughlan, M.J.; Pratt, J.K. (Abbott Laboratories Inc.; Ligand Pharmaceuticals, Inc.); Glucocorticoid-selective anti-inflammatory agents. EP 1053239; WO 9941256 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (II) | 49860 | (2,6-dimethoxyphenyl)lithium | C8H9LiO2 | 详情 | 详情 | |
| (III) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (IV) | 26874 | methyl 2-bromo-5-nitrobenzoate | 6942-36-5 | C8H6BrNO4 | 详情 | 详情 |
| (V) | 49861 | methyl 2',6'-dimethoxy-4-nitro[1,1'-biphenyl]-2-carboxylate | C16H15NO6 | 详情 | 详情 | |
| (VI) | 49862 | 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one | C13H7NO5 | 详情 | 详情 | |
| (VII) | 49863 | 1-methoxy-8-nitro-6H-benzo[c]chromen-6-one | C14H9NO5 | 详情 | 详情 | |
| (VIII) | 49864 | 8-amino-1-methoxy-6H-benzo[c]chromen-6-one | C14H11NO3 | 详情 | 详情 | |
| (IX) | 49865 | 10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one | C20H19NO3 | 详情 | 详情 | |
| (X) | 49866 | [3-(methoxymethoxy)phenyl]lithium | C8H9LiO2 | 详情 | 详情 | |
| (XI) | 49867 | 10-methoxy-5-[3-(methoxymethoxy)phenyl]-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C28H29NO5 | 详情 | 详情 | |
| (XII) | 49868 | 5-(3-hydroxyphenyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C26H25NO4 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Lithiation of 1,3-dimethoxybenzene (I), followed by addition of triisopropyl borate to the resultant lithio derivative (II) provided boronic acid (III). This was subjected to palladium-catalyzed Suzuki coupling with methyl 5-nitro-2-bromobenzoate (IV) to afford the biphenyl compound (V). Cleavage of the methyl ethers of (V) using boron tribromide gave rise to the tricyclic lactone (VI). After methylation of the hydroxyl group of (VI) with iodomethane and cesium carbonate, the resultant nitro derivative (VII) was reduced to amine (VIII) by catalytic hydrogenation. Iodine-catalyzed condensation of amine (VIII) with acetone at 105 ºC in a sealed vessel furnished the benzopyranoquinoline system (IX). The lactone function of (IX) was then reduced to the corresponding lactol (X) by means of DIBAL in cold dichloromethane. Subsequent treatment of (X) with methanol and p-toluenesulfonic acid produced acetal (XI). The acetal methoxy group of (XI) was finally displaced with allyl trimethylsilane (XII) in the presence of boron trifluoride etherate to furnish the title allyl derivative
| 【1】 Halbeisen, S.; Schmitt, R.; Birnbock, H.; Hopfgartner, G.; Van Marle, S.P.; Weber, C.; Single dose pharmacokinetics of bosentan in healthy man. 4th Int Conf Endothelin (April 23 1995, London) 1995, Abst P131. |
| 【2】 Wang, A.X.; Kym, P.R.; Jones, T.K.; Kort, M.E.; Edwards, J.P.; Moore, J.L.; Elmore, S.W.; Coughlan, M.J.; Pratt, J.K. (Abbott Laboratories Inc.; Ligand Pharmaceuticals, Inc.); Glucocorticoid-selective anti-inflammatory agents. EP 1053239; WO 9941256 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (I) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (II) | 49860 | (2,6-dimethoxyphenyl)lithium | C8H9LiO2 | 详情 | 详情 | |
| (III) | 32549 | 2,6-dimethoxyphenylboronic acid | 23112-96-1 | C8H11BO4 | 详情 | 详情 |
| (IV) | 26874 | methyl 2-bromo-5-nitrobenzoate | 6942-36-5 | C8H6BrNO4 | 详情 | 详情 |
| (V) | 49861 | methyl 2',6'-dimethoxy-4-nitro[1,1'-biphenyl]-2-carboxylate | C16H15NO6 | 详情 | 详情 | |
| (VI) | 49862 | 1-hydroxy-8-nitro-6H-benzo[c]chromen-6-one | C13H7NO5 | 详情 | 详情 | |
| (VII) | 49863 | 1-methoxy-8-nitro-6H-benzo[c]chromen-6-one | C14H9NO5 | 详情 | 详情 | |
| (VIII) | 49864 | 8-amino-1-methoxy-6H-benzo[c]chromen-6-one | C14H11NO3 | 详情 | 详情 | |
| (IX) | 49865 | 10-methoxy-2,2,4-trimethyl-1,2-dihydro-5H-chromeno[3,4-f]quinolin-5-one | C20H19NO3 | 详情 | 详情 | |
| (X) | 62365 | 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-ol | C20H21NO3 | 详情 | 详情 | |
| (XI) | 62366 | 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinolin-5-yl methyl ether; 5,10-dimethoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline | C21H23NO3 | 详情 | 详情 | |
| (XII) | 61128 | C4H8 | 详情 | 详情 |