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【结 构 式】 
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【分子编号】16194 【品名】2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine 【CA登记号】100-35-6 |
【 分 子 式 】C6H14ClN 【 分 子 量 】135.6366 【元素组成】C 53.13% H 10.4% Cl 26.14% N 10.33% |
合成路线1
该中间体在本合成路线中的序号：(VI)The benzoylation of tyrosine (I) with benzoyl chloride (II) in aqueous NaOH gives O,N-(di-benzoyl)-D,L-tyrosine (III), which by reaction with di-n-propylamine (A) by means of ethyl chlorocarbonate and triethylamine in acetone is converted into O,N-(di-benzoyl)-D,L-tyrosyl-di-n-propylamide (IV). Selective hydrolysis of (IV) with NaOH in methanol - water affords N-benzoyl-D,L-tyrosyl-di-n-propylamide (V), which is finally condensed with 2-(diethylamino)ethyl chloride (VI) by means of sodium methoxide in refluxing toluene.
| 【1】 Senin; et al.; Activity of derivatives of tyrosine on gastrointestinal motility. Gastrointestinal Motility in Health and Disease. Duthie, H.L. (Ed.); MTP Press Limited, Lancaster 1978, 417-427. |
| 【2】 Makovec, F.; Rovati, L.; Senini, P. (Rotta Research Laboratorium SpA); O-Tertiary amino-alkyl-N-benzoyl tyrosil amides. DE 2503992; FR 2259592; GB 1467927; JP 50116442; NL 167683C; US 4004008 . |
| 【3】 Serradell, M.N.; de Angelis, L.; Blancafort, P.; Castaner, J.; Tiropramide. Drugs Fut 1982, 7, 6, 413. |
| 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) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (I) | 31970 | 4-Hydroxy-17O-phenylalanine; Hydroxy Phenyl Alanine; DL-tyrosine; 2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)alanine; beta-(p-Hydroxyphenyl)alanine; tyrosine | 556-03-6 | C9H11NO3 | 详情 | 详情 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 31971 | N-benzoyl-4-(benzoyloxy)phenylalanine | C23H19NO5 | 详情 | 详情 | |
| (IV) | 31972 | 4-[2-(benzoylamino)-3-(dipropylamino)-3-oxopropyl]phenyl benzoate | C29H32N2O4 | 详情 | 详情 | |
| (V) | 31973 | N-[2-(dipropylamino)-1-(4-hydroxybenzyl)-2-oxoethyl]benzamide | C22H28N2O3 | 详情 | 详情 | |
| (VI) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The target product can be prepared by reacting para-benzylphenol (I) with 2-diethylaminoethylchloride hydrochloride (II) either by means of NaOH in H2O or with K2CO3 in DMF/acetone (at 60 C in both cases), followed by treatment with HCl to obtain the corresponding hydrochloride salt.
| 【1】 Delarue, F.; Poirot, M.; Klaebe, A.; De Medina, P.; Faye, J.-C.; Perie, J.-J.; Synthesis, binding and structure-affinity studies of new ligands for the microsomal anti-estrogen binding site (AEBS). Bioorg Med Chem 2000, 8, 8, 2007. |
| 【2】 Hermonat, M.W.; Brandes, L.J. (University of Manitoba); Novel cytotoxic aminoalkyl phenol ethers. EP 0153160; JP 1985190742; US 4803227 . |
合成路线3
该中间体在本合成路线中的序号：(IV)Treatment of 8-bromomethyl-2-phenylflavone (I) with KCN in EtOH-H2O for 3 h gives the nitrile intermediate (II) (m.p. 165-7 C) in 67% yield, which in diluted acetic-sulfuric acid is hydrolyzed to flavoneacetic acid (III) in 88% yield. On refluxing the potassium salt of the acid with 2-diethylaminoethyl chloride in acetone for 4 h, followed by converting the resulting ester to the hydrochloride salt, the diethylaminoethyl ester of flavoneacetic acid (m.p. 186 C) is produced in 70% yield.
| 【1】 Briet, P.; Berthelon, J.J.; Collonges, F.; Atassi, G.; Synthesis and antitumor activity of some 8-substit. Eur J Med Chem 1985, 20, 393. |
| 【2】 Berthelon, J.-J.; Collonges, F.; Briet, P. (Lipha Santé); 8-Haloalkyl-4H-(1)-benzopyran-4-ones and preparati. EP 0080419 . |
| 【3】 Berthelon, J.-J.; Collonges, F.; Briet, P. (Lipha Santé); (Oxo-4-4H-(1)-benzopyran-8-yl) alkanoic acids, sal. EP 0080934; US 4602034 . |
| 【4】 Berthelon, J.-J.; Collonges, F.; Briet, P. (Lipha Santé); 8-Haloalkyl-4H-1-benzopyran-4-ones and methods of . FR 2536396 . |
| 【5】 Cheng, C.C.; Zee-Cheng, R.K.-Y.; Flavoneacetic acid. Drugs Fut 1987, 12, 2, 123. |
| 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) | 22859 | 8-(bromomethyl)-2-phenyl-4H-chromen-4-one | C16H11BrO2 | 详情 | 详情 | |
| (II) | 22860 | 2-(4-oxo-2-phenyl-4H-chromen-8-yl)acetonitrile | C17H11NO2 | 详情 | 详情 | |
| (III) | 22861 | 2-(4-oxo-2-phenyl-4H-chromen-8-yl)acetic acid | C17H12O4 | 详情 | 详情 | |
| (IV) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XVII)2) The condensation of aldehyde (IV) with bromoform by means of LiOH in hot dioxane/water gives (±)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XI), which is submitted to optical resolution by fractional crystallization of its 2(R)-aminobutanol salt in isopropanol and acidification with HCl to yield (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XII). The cyclization of (XII) with acetone and concentrated H2SO4 affords (R)-(-)-5-(benzo[b]thiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one (XIII), which, by treatment with methanol and H2SO4, is converted into (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid methyl ester (XIV). The protection of the OH group of (XIV) with dihydropyran (DHP) and pyridinium p-toluenesulfonate (Pyr·TsOH) affords the corresponding tetrahydropyranyl ether (XV), which is reduced with NaBH4 in ethanol, giving (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)ethanol (XVI). Finally, this compound is condensed with 2-(diethylamino)ethyl chloride (XVII) by means of NaOH and tetrabutylammonium hydrogensulfate in toluene/water, followed by acidification with HCl. 3) The (R)-dioxolane (XIII) can also be obtained as follows: The racemic hydroxyacetic acid (XI) is cyclized with acetone and H2SO4 as before, giving the racemic dioxolane (XVIII). This compound is dissolved in hot (50 C) tert-amyl alcohol along with 1,8-diazabicyclo[5.4.0]-7-undecene (DCU); this solution is then seeded with a suspension of the (R)-(-)-isomer (XIII) in the same solvent and is slowly cooled at 25 C; a 81% yield of pure crystals of (R)-(-)-isomer (XIII) is obtained. This procedure allows for improving the yields by recovering the unused (S)-(+)-isomer.
| 【1】 Martel, A.M.; Prous, J.; Castaner, J.; T-588. Drugs Fut 1997, 22, 4, 386. |
| 【2】 Nakano, J.; Taya, N.; Chaki, H.; Yamafuji, T.; Momonoi, K. (Toyama Chemical Co., Ltd.); Benzo b thiophen-5-yl deriv. and process for producing the same. EP 0565965 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 48572 | (S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol | 5856-62-2 | C4H11NO | 详情 | 详情 | |
| (IV) | 16181 | 1-benzothiophene-5-carbaldehyde | C9H6OS | 详情 | 详情 | |
| (XI) | 16188 | 2-(1-benzothiophen-5-yl)-2-hydroxyacetic acid | C10H8O3S | 详情 | 详情 | |
| (XII) | 16189 | (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid | C10H8O3S | 详情 | 详情 | |
| (XIII) | 16190 | (5R)-5-(1-benzothiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one | C13H12O3S | 详情 | 详情 | |
| (XIV) | 16191 | methyl (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoate | C11H10O3S | 详情 | 详情 | |
| (XV) | 16192 | methyl (2S)-2-(1-benzothiophen-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)propanoate | C17H20O4S | 详情 | 详情 | |
| (XVI) | 16193 | (2R)-2-(1-benzothiophen-5-yl)-3-(tetrahydro-2H-pyran-2-yloxy)-1-propanol | C16H20O3S | 详情 | 详情 | |
| (XVII) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (XVIII) | 16195 | 5-(1-benzothiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one | C13H12O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The reaction of 4-aminobenzophenone (I) with benzylmagnesium bromide (II) in ether gives the carbinol (III), which by reaction with acetic anhydride in hot pyridine yields the olefinic acetamide (IV). The chlorination of (IV) with Cl2 in CCl4 followed by refluxing in the same solvent affords the chlorovinyl acetamide (V), which is alkylated at the amidic nitrogen with 2-chloroethyl(diethyl)amine (VI) by means of KOH in refluxing acetone giving the disubstituted acetamide (VII). Finally, the deacetylation of (VII) with hot 10% HCl and salification with citric acid affords the target compound.
| 【1】 Bitonti, A.J.; Baumann, R.J. (Merrell Pharmaceuticals, Inc.); Non-metabolizable clomiphene analogs for treatment of tamoxifen-resistant tumors. EP 0660821; JP 1997500863; WO 9406762 . |
| 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) | 28307 | (4-aminophenyl)(phenyl)methanone | 1137-41-3 | C13H11NO | 详情 | 详情 |
| (II) | 28308 | benzyl(bromo)magnesium; benzylmagnesium bromide | 1589-82-8 | C7H7BrMg | 详情 | 详情 |
| (III) | 28309 | 1-(4-aminophenyl)-1,2-diphenyl-1-ethanol | C20H19NO | 详情 | 详情 | |
| (IV) | 28310 | N-[4-[(Z)-1,2-diphenylethenyl]phenyl]acetamide | C22H19NO | 详情 | 详情 | |
| (V) | 28311 | N-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenyl]acetamide | C22H18ClNO | 详情 | 详情 | |
| (VI) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (VII) | 28312 | N-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenyl]-N-[2-(diethylamino)ethyl]acetamide | C28H31ClN2O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The acetylation of 4-aminobenzophenone (I) with acetic anhydride and TEA in dichloromethane gives the acetamide (II), which is N-alkylated with 2-chlorethyl(diethyl)amine (III) by means of KOH in refluxing acetone yielding the disubstituted acetamide (IV). The reaction of the ketonic group of (IV) with benzylphosphonic acid diethyl ester (V) by means of butyllithium and benzenesulfonyl chloride in THF affords the chlorovinyl acetamide (VI), which is finally hydrolyzed with HCl and salified with citric acid to provide the target compound.
| 【1】 Bitonti, A.J. (Aventis Pharmaceuticals, Inc.); Method of using triaryl-ethylene derivs. in the treatment and prevention of osteoporosis. US 5691384; WO 9616646 . |
| 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) | 28307 | (4-aminophenyl)(phenyl)methanone | 1137-41-3 | C13H11NO | 详情 | 详情 |
| (II) | 28313 | N-(4-benzoylphenyl)acetamide | C15H13NO2 | 详情 | 详情 | |
| (III) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (IV) | 28314 | N-(4-benzoylphenyl)-N-[2-(diethylamino)ethyl]acetamide | C21H26N2O2 | 详情 | 详情 | |
| (V) | 28315 | diethyl benzylphosphonate | 1080-32-6 | C11H17O3P | 详情 | 详情 |
| (VI) | 28312 | N-[4-[(E)-2-chloro-1,2-diphenylethenyl]phenyl]-N-[2-(diethylamino)ethyl]acetamide | C28H31ClN2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)Treatment of rebeccamycin (I) with 2-(diethylamino)ethyl chloride (II) and NaH in DMF at r.t. gave 8-N-(2-diethylaminoethyl)- rebeccamycin (III) (1). The target phosphate salt was then prepared by addition of H3PO4 to a suspension of (III) in water until a pH of 3-4.
| 【1】 Kaneko, T.; Wong, H.S.; Utzig, J.J. (Bristol-Myers Squibb Co.); Rebeccamycin analogs. AU 8781148; EP 0269025; JP 1988198695; US 4808613 . |
| 【2】 Venkataram, U.V. ; Franchini, M.K.; Bogardus, J.B. (Bristol-Myers Squibb Co.); Stable solutions of rebeccamycin analog and preparation thereof . EP 0397147 . |
| 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) | 19164 | 1,11-dichloro-12-[(2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-2-yl]-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione | C27H21Cl2N3O7 | 详情 | 详情 | |
| (II) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (III) | 19166 | 1,11-dichloro-6-[2-(diethylamino)ethyl]-12-[(2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-methoxytetrahydro-2H-pyran-2-yl]-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione | C33H34Cl2N4O7 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XII)Condensation of anisole (I) with gamma,gamma-dimethylbutyrolactone (II) in the presence of AlCl3 in 1-nitropropane gave 4-(4-methoxyphenyl)-4-methylpentanoic acid (III), which was cyclized to the tetralone (V) using polyphosphoric acid. Subsequent treatment of (V) with refluxing N,N-dimethylformamide dimethyl acetal provided the dimethylamino-methylene compound (VI). This was cyclized with guanidinium carbonate in boiling isopropanol to furnish the benzoquinazoline (VII). Then, diazotization of (VII) in aqueous sulfuric acid generated the quinazolinone (VIII), which was subsequently converted to chloroquinazoline (IX) with phosphoryl chloride in the presence of DMF. Condensation of (IX) with aniline (X) in refluxing ethoxyethanol gave (XI). Finally, the hydroxyl group of (XI) was alkylated with (diethylamino)ethyl chloride (XII) in the presence of Cs2CO3 in DMF at 110 C to yield the title compound.
| 【1】 Davis, J.M.; Hutchings, M.C.; Moffat, D.; Batchelor, M.; Parry, D.M.; Johnson, J.; Berg, D.A.; Davis, P.D.; Benzo[h]-5,6-dihydroquinazoline-2-amines as potent. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.234. |
| 【2】 Moffat, D.F.C.; Davis, J.M.; Batchelor, M.J.; Davis, P.D. (Celltech Chiroscience plc); Fused polycyclic 2-aminopyrimidine derivs., their . EP 0946523; US 6057329; WO 9828281 . |
| 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) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (II) | 23768 | 5,5-dimethyldihydro-2(3H)-furanone | C6H10O2 | 详情 | 详情 | |
| (III) | 23769 | 4-(4-methoxyphenyl)-4-methylpentanoic acid | 23203-48-7 | C13H18O3 | 详情 | 详情 |
| (V) | 23770 | 7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C13H16O2 | 详情 | 详情 | |
| (VI) | 23771 | 2-[(E)-(dimethylamino)methylidene]-7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C16H21NO2 | 详情 | 详情 | |
| (VII) | 23772 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-ylamine; 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-amine | C15H17N3O | 详情 | 详情 | |
| (VIII) | 23773 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one | C15H16N2O2 | 详情 | 详情 | |
| (IX) | 23774 | 2-chloro-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-9-yl methyl ether; 2-chloro-9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazoline | C15H15ClN2O | 详情 | 详情 | |
| (X) | 23775 | 5-amino-2,3-dimethoxyphenol | C8H11NO3 | 详情 | 详情 | |
| (XI) | 23776 | 2,3-dimethoxy-5-[(9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-yl)amino]phenol | C23H25N3O4 | 详情 | 详情 | |
| (XII) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XI)Condensation of anisole (I) with gamma,gamma-dimethylbutyrolactone (II) in the presence of AlCl3 in 1-nitropropane gave 4-(4-methoxyphenyl)-4-methylpentanoic acid (III), which was cyclized to the tetralone (V) using polyphosphoric acid. Subsequent treatment of (V) with refluxing N,N-dimethylformamide dimethyl acetal provided the dimethylamino-methylene compound (VI). This was cyclized with guanidinium carbonate in boiling isopropanol to furnish the benzoquinazoline (VII). Then, diazotization of (VII) in aqueous sulfuric acid generated the quinazolinone (VIII), which was subsequently converted to the chloroquinazoline (IX) using phosphoryl chloride and DMF. Aniline (XIII) was obtained by alkylation of 2,6-dimethoxy-4-nitrophenol (X) with (diethylamino)ethyl chloride (XI) in the presence of Cs2CO3 to give (XII), followed by catalytic transfer hydrogenation of the nitro group of (XII) with ammonium formate and Pd/C. Finally, condensation of chloroquinazoline (IX) with aniline (XIII) in refluxing ethoxyethanol yielded the title compound.
| 【1】 Davis, J.M.; Hutchings, M.C.; Moffat, D.; Batchelor, M.; Parry, D.M.; Johnson, J.; Berg, D.A.; Davis, P.D.; Benzo[h]-5,6-dihydroquinazoline-2-amines as potent. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.234. |
| 【2】 Moffat, D.F.C.; Davis, J.M.; Batchelor, M.J.; Davis, P.D. (Celltech Chiroscience plc); Fused polycyclic 2-aminopyrimidine derivs., their . EP 0946523; US 6057329; WO 9828281 . |
| 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) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
| (II) | 23768 | 5,5-dimethyldihydro-2(3H)-furanone | C6H10O2 | 详情 | 详情 | |
| (III) | 23769 | 4-(4-methoxyphenyl)-4-methylpentanoic acid | 23203-48-7 | C13H18O3 | 详情 | 详情 |
| (V) | 23770 | 7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C13H16O2 | 详情 | 详情 | |
| (VI) | 23771 | 2-[(E)-(dimethylamino)methylidene]-7-methoxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone | C16H21NO2 | 详情 | 详情 | |
| (VII) | 23772 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-ylamine; 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2-amine | C15H17N3O | 详情 | 详情 | |
| (VIII) | 23773 | 9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-2(1H)-one | C15H16N2O2 | 详情 | 详情 | |
| (IX) | 23774 | 2-chloro-6,6-dimethyl-5,6-dihydrobenzo[h]quinazolin-9-yl methyl ether; 2-chloro-9-methoxy-6,6-dimethyl-5,6-dihydrobenzo[h]quinazoline | C15H15ClN2O | 详情 | 详情 | |
| (X) | 23778 | 2,6-dimethoxy-4-nitrophenol | C8H9NO5 | 详情 | 详情 | |
| (XI) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (XII) | 23779 | N-[2-(2,6-dimethoxy-4-nitrophenoxy)ethyl]-N,N-diethylamine; 2-(2,6-dimethoxy-4-nitrophenoxy)-N,N-diethyl-1-ethanamine | C14H22N2O5 | 详情 | 详情 | |
| (XIII) | 23780 | 4-[2-(diethylamino)ethoxy]-3,5-dimethoxyaniline; N-[2-(4-amino-2,6-dimethoxyphenoxy)ethyl]-N,N-diethylamine | C14H24N2O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XV)Treatment of salicylaldehyde (I) with methyl chloroacetate (II) in DMF in the presence of potassium carbonate provides methyl o-formylphenoxyacetate (III), which is converted into methyl 2-benzofuranecarboxylate (IV) by reaction with DBU in toluene. Reduction of (IV) by means of LiAlH4 in ether yields hydroxy derivative (V), which then reacts with SOCl2 in ether/DMF to furnish chloro derivative (VI). Treatment of (VI) with NaCN in DMSO affords cyano derivative (VII), which is converted into 2-benzofuraneacetic acid (VIII) by treatment with NaOH in boiling water. Esterification of (VIII) by treatment with HCl in refluxing MeOH affords methyl acetate derivative (IX), which is condensed with p-anisoyl chloride (X) by means of SnCl4 in 1,2-dichloroethane to yield compound (XI). Treatment of (XI) with aluminum powder and iodine crystals (to generate AlI3) in refluxing benzene gives acetic acid derivative (XII), which is iodinated with iodine and K2CO3 in H2O to give derivative (XIII). Esterification of (XIII) by means of iPrOH and H2SO4 provides isopropyl acetate derivative (XIV), which is finally converted into the desired product by reaction with diethylaminoethyl chloride (XV) in NaOH and CH2Cl2 in the presence of benzyltriethylammonium chloride.
| 【1】 Druzgala, P. (ARYx Therapeutics, Inc.); Benzoylbenzofurane derivs. for treatment of cardiac arrhythmia. EP 0703910; JP 1996511546; US 5364880; WO 9429289 . |
| 【2】 Druzgala, P. (ARYx Therapeutics, Inc.); Cpd. for treatment of cardiac arrhythmia, synthesis, and methods of use. US 5849788 . |
| 【3】 Druzgala, P. (ARYx Therapeutics, Inc.); Cpd. for treatment of cardiac arrhythmia, synthesis, and methods of use. US 6130240 . |
| 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) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
| (II) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (III) | 49708 | methyl 2-(2-formylphenoxy)acetate | C10H10O4 | 详情 | 详情 | |
| (IV) | 49709 | methyl 1-benzofuran-2-carboxylate | C10H8O3 | 详情 | 详情 | |
| (V) | 38335 | 1-benzofuran-2-ylmethanol | C9H8O2 | 详情 | 详情 | |
| (VI) | 49710 | 2-(chloromethyl)-1-benzofuran | C9H7ClO | 详情 | 详情 | |
| (VII) | 38336 | 2-(1-benzofuran-2-yl)acetonitrile | C10H7NO | 详情 | 详情 | |
| (VIII) | 49711 | 2-(1-benzofuran-2-yl)acetic acid | C10H8O3 | 详情 | 详情 | |
| (IX) | 49712 | methyl 2-(1-benzofuran-2-yl)acetate | C11H10O3 | 详情 | 详情 | |
| (X) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (XI) | 49713 | methyl 2-[3-(4-methoxybenzoyl)-1-benzofuran-2-yl]acetate | C19H16O5 | 详情 | 详情 | |
| (XII) | 49714 | 2-[3-(4-hydroxybenzoyl)-1-benzofuran-2-yl]acetic acid | C17H12O5 | 详情 | 详情 | |
| (XIII) | 49715 | 2-[3-(4-hydroxy-3,5-diiodobenzoyl)-1-benzofuran-2-yl]acetic acid | C17H10I2O5 | 详情 | 详情 | |
| (XIV) | 49716 | isopropyl 2-[3-(4-hydroxy-3,5-diiodobenzoyl)-1-benzofuran-2-yl]acetate | C20H16I2O5 | 详情 | 详情 | |
| (XV) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(B)Iodination of 3-(trifluoromethyl)nitrobenzene (I) was accomplished by using N-iodosuccinimide in concentrated sulfuric acid to provide (II), which was then reduced to aniline (III) with SnCl2 in refluxing EtOH. Treatment of aniline (III) with sulfuryl chloride, followed by addition of ethyl (methylthio)acetate and Et3N gave rise to a mixture of regioisomeric 3-(methylthio)oxindoles (IV) and (V). Oxidation of this mixture with CuCl2/CuO generated the respective isatins (VI) and (VII) (1). After N-alkylation with 2-(diethylamino)ethyl chloride and NaH, the desired regioisomer (VIII) could be separated by column chromatography. Addition to (VIII) of the Grignard reagent (IX) provided the racemic 3-aryl-3-hydroxy oxindole (X). The enantiomers of (X) were separated using chiral, preparative HPLC, and the desired (S)-enantiomer (XI) was then converted to nitrile (XII) by iodide displacement with zinc cyanide in the presence of palladium catalyst. Finally, partial hydrolysis of nitrile (XII) with KOH in tert-butanol furnished the title amide
| 【1】 Tokunaga, T.; Hume, W.E.; Umezome, T.; Okazaki, K.; Yasuyuki, U.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R.; Oxindole derivatives as orally active potent growth hormone secretagogues. J Med Chem 2001, 44, 26, 4641. |
| 【2】 Okazaki, K.; Kumagai, K.; Tokunaga, T.; Ueki, Y.; Nagata, R.; Umezome, T.; Hume, W.E. (Sumitomo Pharmaceuticals Co., Ltd.); Oxindole derivs. as growth hormone releasers. EP 1105376; JP 2002523400; WO 0010975 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (A) | 48543 | Ethyl methylthioacetate; (Methylthio)acetic acid ethyl ester; ethyl 2-(methylsulfanyl)acetate | 4455-13-4 | C5H10O2S | 详情 | 详情 |
| (I) | 26346 | 1-nitro-3-(trifluoromethyl)benzene | 98-46-4 | C7H4F3NO2 | 详情 | 详情 |
| (II) | 60054 | 1-iodo-3-nitro-5-(trifluoromethyl)benzene | C7H3F3INO2 | 详情 | 详情 | |
| (III) | 60055 | 3-iodo-5-(trifluoromethyl)phenylamine; 3-iodo-5-(trifluoromethyl)aniline | C7H5F3IN | 详情 | 详情 | |
| (IV) | 60057 | 4-iodo-3-(methylsulfanyl)-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C10H7F3INOS | 详情 | 详情 | |
| (V) | 60056 | 6-iodo-3-(methylsulfanyl)-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C10H7F3INOS | 详情 | 详情 | |
| (VI) | 60059 | 4-iodo-6-(trifluoromethyl)-1H-indole-2,3-dione | C9H3F3INO2 | 详情 | 详情 | |
| (VII) | 60058 | 6-iodo-4-(trifluoromethyl)-1H-indole-2,3-dione | C9H3F3INO2 | 详情 | 详情 | |
| (VIII) | 60060 | 1-[2-(diethylamino)ethyl]-6-iodo-4-(trifluoromethyl)-1H-indole-2,3-dione | C15H16F3IN2O2 | 详情 | 详情 | |
| (IX) | 60061 | (2-chlorophenyl)(iodo)magnesium | C6H4ClIMg | 详情 | 详情 | |
| (X) | 60062 | 3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-6-iodo-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C21H21ClF3IN2O2 | 详情 | 详情 | |
| (XI) | 60063 | (3S)-3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-6-iodo-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C21H21ClF3IN2O2 | 详情 | 详情 | |
| (XII) | 60064 | (3S)-3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-indole-6-carbonitrile | C22H21ClF3N3O2 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(V)The reaction of 4-acetyldiphenylsulfide (I) with carbon disulfide by means of sodium tert-amyloxide in benzene gives 4-phenylthiobenzoyldithioacetic acid (II), which is cyclized with o-phenylenediamine (III) in refluxing toluene yielding 4-(p-phenylthiophenyl)-1,3-dihydro-2H-1,5-benzodiazepine-2-thione (IV). The condensation of (IV) with diethylaminoethyl chloride (V) by means of NaH in refluxing benzene affords 2-[beta-(N-diethylamino)ethylthio]-4-(p-phenylthio)phenyl-3H-1,5-benzodiazepine (VI), which is finally quaternized with methyl iodide in isopropanol. (1,2)
| 【1】 Castaner, J.; de Angelis, L.; Tibezonium Iodide. Drugs Fut 1978, 3, 2, 152. |
| 【2】 Nardi, D.; et al.; New 2-methyldialkylammoniumalkylthio-4-p-substituted phenyl-3-H-1,5-benzodiazepine iodides with antibacterial activity. II Farmaco (ed. sc.) 1975, 30, Suppl. 3, 248. |
| 【3】 Degen, L. (Recordati S.A. Chem Pharm. Co.); AT 321922; CH 555347; GB 1412008; GB 1412009; US 3993793 . |
| 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) | 60710 | 1-[4-(phenylsulfanyl)phenyl]-1-ethanone | C14H12OS | 详情 | 详情 | |
| (II) | 60711 | 3-oxo-3-[4-(phenylsulfanyl)phenyl]propanedithioic acid | C15H12OS3 | 详情 | 详情 | |
| (III) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (IV) | 60712 | 4-[4-(phenylsulfanyl)phenyl]-1,3-dihydro-2H-1,5-benzodiazepine-2-thione | C21H16N2S2 | 详情 | 详情 | |
| (V) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (VI) | 60713 | N,N-diethyl-2-({4-[4-(phenylsulfanyl)phenyl]-3H-1,5-benzodiazepin-2-yl}sulfanyl)-1-ethanamine; N,N-diethyl-N-[2-({4-[4-(phenylsulfanyl)phenyl]-3H-1,5-benzodiazepin-2-yl}sulfanyl)ethyl]amine | C27H29N3S2 | 详情 | 详情 |