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【结 构 式】 
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【分子编号】12079 【品名】Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide 【CA登记号】776-74-9 |
【 分 子 式 】C13H11Br 【 分 子 量 】247.13434 【元素组成】C 63.18% H 4.49% Br 32.33% |
合成路线1
该中间体在本合成路线中的序号：(I)This compound can be prepared in several different ways: 1) The reaction of benzhydryl bromide (I) with thiourea (II) in refluxing water gives diphenyl - methanethiol (III), which is condensed with chloroacetic acid (A) by means of NaOH in hot water yielding (benzhydrylthio)acetic acid (IV). The esterification of (IV) with ethanol and H2SO4 affords the corresponding ethyl ester (V), which is treated with hydroxylamine hydrochloride and KOH in methanol to give benzhydrylthioacetohydroxamic acid (VI). Finally, this compound is oxidized with H2O2 in acetic acid. 2) Compound (III) can also be obtained by reaction of benzhydrol (VII) with thiourea and aqueous 48% HBr at 100 C. 3) Compound (IV) can be oxidized with H2O2 in water to give benzhydrylsulfinylacetic acid (VIII), which is methylated with dimethyl sulfate and NaHCO3 in water to the corresponding methyl ester (IX). Finally, this compound is treated with hydroxylamine and NaOH in water
| 【1】 Lafon, L. (Laboratoires L. Lafon); New benzhydrysulphinyl derivatives. DE 2642511; FR 2326181; GB 1520812; JP 52046058; US 4066686 . |
| 【2】 Mignonac, S.; Guy, A.; De Lamer, V. (Sanofi-Synthelabo); Preparation of polyamine(s), substd. on terminal nitrogen atoms. FR 2714052 . |
| 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) | 11847 | 2-Chloroacetic acid; Chloroacetic Acid | 79-11-8 | C2H3ClO2 | 详情 | 详情 |
| (I) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (II) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (III) | 32695 | diphenylmethanethiol; benzhydrylhydrosulfide | C13H12S | 详情 | 详情 | |
| (IV) | 11848 | 2-(Benzhydrylsulfanyl)acetic acid | C15H14O2S | 详情 | 详情 | |
| (V) | 32696 | ethyl 2-(benzhydrylsulfanyl)acetate | C17H18O2S | 详情 | 详情 | |
| (VI) | 32697 | 2-(benzhydrylsulfanyl)-N-hydroxyacetamide | 63547-44-4 | C15H15NO2S | 详情 | 详情 |
| (VII) | 11845 | Diphenylmethanol; Benzhydrol | 91-01-0 | C13H12O | 详情 | 详情 |
| (VIII) | 11851 | 2-(Benzhydrylsulfinyl)acetic acid | C15H14O3S | 详情 | 详情 | |
| (IX) | 11852 | methyl 2-(benzhydrylsulfinyl)acetate | C16H16O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IIb)Synthesis of intermediate (X): 4-Hydroxypiperidine (V) is protected with ethyl chloroformate to give (VI), which is then condensed with bromodiphenylmethane in the presence of sodium carbonate yielding (VII). AIkali hydrolysis of (VII) gives (VIII), which is then treated with N-(2-bromoethyl)phthalimide to yield (IX). (IX) is then deprotected by a treatment of 80% hydrazine hydrate, producing (X).
| 【1】 Tasaka, K.; TMK-688. Drugs Fut 1988, 13, 12, 1056. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 37025 | 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione | 574-98-1 | C10H8BrNO2 | 详情 | 详情 | |
| (IIb) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (V) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (VI) | 22709 | ethyl 4-hydroxy-1-piperidinecarboxylate | C8H15NO3 | 详情 | 详情 | |
| (VII) | 12080 | ethyl 4-(benzhydryloxy)tetrahydro-1(2H)-pyridinecarboxylate | C21H25NO3 | 详情 | 详情 | |
| (VIII) | 12081 | 4-(Benzhydryloxy)piperidine; Benzhydryl 4-piperidinyl ether | C18H21NO | 详情 | 详情 | |
| (IX) | 22713 | 2-[2-[4-(benzhydryloxy)-1-piperidinyl]ethyl]-1H-isoindole-1,3(2H)-dione | C28H28N2O3 | 详情 | 详情 | |
| (X) | 22707 | 2-[4-(benzhydryloxy)-1-piperidinyl]ethylamine; 2-[4-(benzhydryloxy)-1-piperidinyl]-1-ethanamine | C20H26N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)This compound can be obtained by two related routes: 1) Condensation of 4-hydroxypiperidine (I) with p-tert-butyl-omega-chlorobutyrophenone (II) in hot methyl isobutyl ketone in presence of sodium bicarbonate gives 1-[3-(4-tert-butylbenzoyl)propyl]-4-hydroxypiperidine (III), which reacts with diphenylmethyl bromide (IV) in methyl isobutyl ketone to give ebastine. 2) 4-Diphenylmethoxypiperidine (VI), obtained by alkaline hydrolysis of 1-ethoxycarbonyl-4-diphenyl-methoxypiperidine (V) was reacted with p-tert-butyl-omega-chlorobutyrophenone (II) to give ebastine.
| 【1】 Spickett, R.G.W.; Moragues, J.; Prieto, J.; Vega, A. (Fordonal S.A.); Piperidine derivs. EP 0134124B; US 4550116 . |
| 【2】 Moragues, J.; Roberts, D.J.; EBASTINE. Drugs Fut 1990, 15, 7, 674. |
| 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) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (II) | 12077 | 4-Chloro-1-[4-(1,1-dimethylethyl)phenyl]-1-butanone; 1-[4-(tert-Butyl)phenyl]-4-chloro-1-butanone; 4'-tert-Butyl-4-chlorobutyrophenone | 43076-61-5 | C14H19ClO | 详情 | 详情 |
| (III) | 12078 | 1-[4-(tert-Butyl)phenyl]-4-(4-hydroxypiperidino)-1-butanone | C19H29NO2 | 详情 | 详情 | |
| (IV) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (V) | 12080 | ethyl 4-(benzhydryloxy)tetrahydro-1(2H)-pyridinecarboxylate | C21H25NO3 | 详情 | 详情 | |
| (VI) | 12081 | 4-(Benzhydryloxy)piperidine; Benzhydryl 4-piperidinyl ether | C18H21NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)1) The reaction of 2-(4-piperazinyl)ethanol (I) with diphenylmethyl bromide (II) by means of K2CO3 in DMF gives 2-[4-(diphenylmethyl)-1-piperazinyl] ethanol (III), which is condensed with diketene (IV) at 80 C to yield 2-[4-(diphenylmethyl)-1-piperazinyl] ethyl acetoacetate (V). The condensation of (V) with 3-nitrobenzaldehyde (VI) gives the intermediate benzylidene derivative (VII), which is finally cyclized with methyl 3-aminocrotonate (VIII) in refluxing isopropanol.
| 【1】 Meguro, K.; Kawamatsu, Y.; Aizawa, M.; Nagaoka, A.; Sohda, T.; New 1,4-dihydropyridine derivatives with potent an. Chem Pharm Bull 1985, 33, 9, 3787. |
| 【2】 Meguro, K.; Nagaoka, A. (Takeda Chemical Industries, Ltd.); Dihydropyridine derivs., their production and use. EP 0138505; JP 1985084269; US 4603135 . |
| 【3】 Prous, J.; Castaner, J.; CV-4093. Drugs Fut 1988, 13, 3, 207. |
| 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) | 21893 | 2-(1-piperazinyl)-1-ethanol; 1-piperazineethanol; 1-(2-Hydroxyethyl)piperazine | 103-76-4 | C6H14N2O | 详情 | 详情 |
| (II) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (III) | 12674 | 2-(4-Benzhydryl-1-piperazinyl)-1-ethanol | C19H24N2O | 详情 | 详情 | |
| (IV) | 21896 | 4-methyl-2H-oxet-2-one | C4H4O2 | 详情 | 详情 | |
| (V) | 21897 | 2-(4-benzhydryl-1-piperazinyl)ethyl 3-oxobutanoate | C23H28N2O3 | 详情 | 详情 | |
| (VI) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (VII) | 21899 | 2-(4-benzhydryl-1-piperazinyl)ethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C30H31N3O5 | 详情 | 详情 | |
| (VIII) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)2) The reaction of 2-(4-piperazinyl)ethanol (I) with diphenylmethyl bromide (II) by means of K2CO3 in DMF gives 2-[4-(diphenylmethyl)-1-piperazinyl] ethanol (III), which is condensed with diketene (IV) at 80 C to yield 2-[4-(diphenylmethyl)-1-piperazinyl] ethyl acetoacetate (V). The reaction of acetoacetate (V) with NH3 in ethanol gives the corresponding aminocrotonate (IX), which is then cyclized with methyl (3-nitrobenzylidene)acetoacetate (VI) [prepared from methyl acetoacetate (X) and 3-nitrobenzaldehyde (VI)] in refluxing isopropanol.
| 【1】 Meguro, K.; Kawamatsu, Y.; Aizawa, M.; Nagaoka, A.; Sohda, T.; New 1,4-dihydropyridine derivatives with potent an. Chem Pharm Bull 1985, 33, 9, 3787. |
| 【2】 Meguro, K.; Nagaoka, A. (Takeda Chemical Industries, Ltd.); Dihydropyridine derivs., their production and use. EP 0138505; JP 1985084269; US 4603135 . |
| 【3】 Prous, J.; Castaner, J.; CV-4093. Drugs Fut 1988, 13, 3, 207. |
| 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) | 21893 | 2-(1-piperazinyl)-1-ethanol; 1-piperazineethanol; 1-(2-Hydroxyethyl)piperazine | 103-76-4 | C6H14N2O | 详情 | 详情 |
| (II) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (III) | 12674 | 2-(4-Benzhydryl-1-piperazinyl)-1-ethanol | C19H24N2O | 详情 | 详情 | |
| (IV) | 21896 | 4-methyl-2H-oxet-2-one | C4H4O2 | 详情 | 详情 | |
| (V) | 21897 | 2-(4-benzhydryl-1-piperazinyl)ethyl 3-oxobutanoate | C23H28N2O3 | 详情 | 详情 | |
| (VI) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 21900 | 2-(4-benzhydryl-1-piperazinyl)ethyl (E)-3-amino-2-butenoate | C23H29N3O2 | 详情 | 详情 | |
| (X) | 11791 | methyl 3-oxobutanoate; Methyl acetoacetate | 105-45-3 | C5H8O3 | 详情 | 详情 |
| (XI) | 12276 | methyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C12H11NO5 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Reaction of theophylline (I) with 1,3-dibromopropane (II) in DMF in the presence of triethylamine afforded the bromo intermediate (III)) in 77% yield. Reaction of (III) with 4-hydroxypiperidine (IV) in DMF in the presence of sodium bicarbonate afforded the unsubstituted hydroxypiperidinyl intermediate (V) in 31% yield which was subsequently alkylated with diphenylmethylbromide (VI) to afford Wy-49,051 in 29% yield.
| 【1】 Abou-Gharbia, M.A.; Nielsen, S.T.; Webb, M.B. (American Home Products Corp.); Histamine H1-antagonists. EP 0271192; GB 2196963; JP 1988152381; US 4716166 . |
| 【2】 Abou-Gharbia, M.; Wy-49,051. Drugs Fut 1990, 15, 2, 137. |
| 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) | 63786 | 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione | C7H8N4O2 | 详情 | 详情 | |
| (II) | 12581 | 1,3-Dibromopropane | 109-64-8 | C3H6Br2 | 详情 | 详情 |
| (III) | 13592 | 7-(3-Bromopropyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione | C10H13BrN4O2 | 详情 | 详情 | |
| (IV) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (V) | 13593 | 7-[3-(4-Hydroxy-1-piperidinyl)propyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione | C15H23N5O3 | 详情 | 详情 | |
| (VI) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (VII) | 63787 | 7-{3-[4-(benzhydryloxy)-1-piperidinyl]propyl}-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione | C28H33N5O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Reaction of 2-(4-aminophenyl)ethanol (I) with bis(2-chloroethyl)amine hydrochloride (II) in butanol gives 2-[4-(1-piperazinyl)phenyl]ethanol (III), which is alkylated with diphenylbromomethane (IV) and potassium carbonate in dimethyl formamide to afford 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethanol (V). Treatment of (V) with diketene (VI) in the presence of 4-dimethylaminopyridine in tetrahydrofuran yields 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl acetoacetate (VII), which is finally condensed with 3-nitrobenzaldehyde (VIII) and methyl 3-aminocrotonate (IX) in isopropanol (1-5). This last condensation can be performed in two steps by reaction of compound (VII) with compound (VIII) in the presence of piperidine and acetic acid in benzene to give 2-[4-[4-(diphenylmethyl)-1-piperazinyl]phenyl]ethyl 2-(3-nitrobenzylidene)acetoacetate (X), which is finally treated with (IX) in isopropanol. An alternative procedure involves condensation of 3-nitrobenzaldehyde (VIII), diketene (VI), methyl 3-aminocrotonate (IX) and 3-hydroxypropionitrile (XI) in isopropanol to give 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 2-cyanoethyl ethyl diester (XII), which is hydrolyzed with sodium hydroxide to 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid monomethyl ester (XIII). Compound (XIII) is finally esterified with compound (V) in a mixture of dimethylformamide and chloroform.
| 【1】 Ashimori, A.; Ono, T.; Inoue, Y.; Fukaya, C. (Welfide Corporation); Dihydropyridine derivs. and pharmaceutical compsns. Thereof. EP 0257616; JP 1988099042; JP 1988225356; US 4886819 . |
| 【2】 (Welfide Corporation); Use of dihydropyridines in cardiotonic pharmaceutical compsns. EP 0109039; US 4543354 . |
| 【3】 Kido, H.; Uchida, T.; Fukaya, C.; Yokoyama, K.; Uchida, Y. (Welfide Corporation); Dihydropyridine derivs. for the treatment of angiospasm. EP 0379737; JP 1990180826 . |
| 【4】 Ono, T.; Ashimori, A.; Inoue, Y.; Novel 1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive activity of 3-[4-(substituted amino)phenylalkyl]ester derivatives. Chem Pharm Bull 1991, 39, 1, 91-9. |
| 【5】 Ohe, K.; Tanaka, M.; Yokoyama, K.; Uchida, T.; Fukaya, C.; Watanabe, M.; Ohtaki, Y.; Ashimori, A.; Kagitani, M.; Synthesis and pharmacological effects of optically active 2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicrboxylate hydrochloride. Chem Pharm Bull 1991, 39, 1, 108-11. |
| 【6】 Castaner, J.; Mealy, N.; Prous, J.; AE0047. Drugs Fut 1994, 19, 7, 627. |
| 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) | 14019 | p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol | 104-10-9 | C8H11NO | 详情 | 详情 |
| (II) | 14020 | N,N-Bis(2-chloroethyl)amine hydrochloride; 2-Chloro-N-(2-chloroethyl)-1-ethanamine hydrochloride | C4H10Cl3N | 详情 | 详情 | |
| (III) | 14021 | 2-(4-Piperazinophenyl)-1-ethanol | C12H18N2O | 详情 | 详情 | |
| (IV) | 12079 | Bromodiphenylmethane; 1-[Bromo(phenyl)methyl]benzene; Benzhydrylbromide | 776-74-9 | C13H11Br | 详情 | 详情 |
| (V) | 14023 | 2-[4-(4-Benzhydrylpiperazino)phenyl]-1-ethanol | C25H28N2O | 详情 | 详情 | |
| (VI) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (VII) | 14025 | 4-(4-benzhydrylpiperazino)phenethyl 3-oxobutanoate | C29H32N2O3 | 详情 | 详情 | |
| (VIII) | 12646 | 3-Nitrobenzaldehyde | 99-61-6 | C7H5NO3 | 详情 | 详情 |
| (IX) | 11372 | Methyl (E)-3-amino-2-butenoate; Methyl 3-aminocrotonate | C5H9NO2 | 详情 | 详情 | |
| (X) | 14028 | 4-(4-benzhydryl-1-piperazinyl)phenethyl (Z)-2-acetyl-3-(3-nitrophenyl)-2-propenoate | C36H35N3O5 | 详情 | 详情 | |
| (XI) | 14029 | Ethylene cyanohydrin; ECN; 3-Hydroxypropanenitrile | 109-78-4 | C3H5NO | 详情 | 详情 |
| (XII) | 14030 | 3-(2-cyanoethyl) 5-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylate | C19H19N3O6 | 详情 | 详情 | |
| (XIII) | 13950 | 5-(Methoxycarbonyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C16H16N2O6 | 详情 | 详情 |