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【结 构 式】 
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【分子编号】32658 【品名】2-bromopropane 【CA登记号】75-26-3 |
【 分 子 式 】C3H7Br 【 分 子 量 】122.99258 【元素组成】C 29.3% H 5.74% Br 64.97% |
合成路线1
该中间体在本合成路线中的序号：(B)The reaction of p-chloroaniline (I) with ethyl 4-oxopiperidine-1-carboxylate (II) by means of tosyl chloride in refluxing toluene gives ethyl 4-(p-chlorophenylimino)piperidine-1-carboxylate (III), which is reduced with NaBH4 in refluxing methanol to afford ethyl 4-(p-chloroanilino)piperidine-1-carboxylate (IV). The acylation of (IV) with phenylacetyl chloride (A) in refluxing benzene yields ethyl 4-[N-(p-chlorophenyl)-N-(phenylacetyl)amino]piperidine-1-carboxylate (V), which is decarboxylated with hot aqueous HBr giving N-(p-chlorophenyl)-N-(piperidin-4-yl)phenylacetamide hydrochloride (VI). Finally, this compound is alkylated with 2-bromopropane (B) and Na2CO3 in refluxing butanol.
| 【1】 Hermans, H.K.; Sanczuk, S.; N-aryl-N-(1-L-4-piperidinyl)-arylacetamides. BE 0846473; US 4151286; US 4157393; ZA 7605684 . |
| 【2】 Castaner, J.; Weetman, D.F.; Lorcainide hydrochloride. Drugs Fut 1978, 3, 7, 518. |
| 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) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (B) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (I) | 12034 | 4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline | 106-47-8 | C6H6ClN | 详情 | 详情 |
| (II) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (III) | 33565 | ethyl 4-[(4-chlorophenyl)imino]-1-piperidinecarboxylate | C14H17ClN2O2 | 详情 | 详情 | |
| (IV) | 33566 | ethyl 4-(4-chloroanilino)-1-piperidinecarboxylate | C14H19ClN2O2 | 详情 | 详情 | |
| (V) | 33567 | ethyl 4-[4-chloro(2-phenylacetyl)anilino]-1-piperidinecarboxylate | C22H25ClN2O3 | 详情 | 详情 | |
| (VI) | 33568 | N-(4-chlorophenyl)-2-phenyl-N-(4-piperidinyl)acetamide | C19H21ClN2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(D)Compound can be prepared in several different ways: 1) The reaction of 2-acetyl-7-hydroxybenzofuran (I) with epichlorohydrin by means of piperidine hydrochloride (A) at 105 C gives 2-acetyl-7-(2,3-epoxypropoxy)benzofuran (II), which is then condensed with isopropylamine (B) in refluxing ethanol. 2) By reaction of (I) with 1-chloro-3-isopropylamino-2-propanol (C) by means of NaOH at 80 C in a sealed tube. 3) By reductocondensation of 2-[1,1-(ethylenedioxy)ethyl]-7-[2-oxo-3-(hydroxyimino)propoxy]benzofuran (III) with acetone by means of H2 and PtO2 in ethanol, followed by hydrolysis of the reduced product with HCl in ethanol. 4) The reaction of 2-[1,1-(ethylenedioxy)ethyl]-7-glyoxylmethoxybenz-furan (IV) with isopropylamine (B) in ethanol gives the corresponding Schiff base (V), which is then reduced with NaBH4 and hydrolyzed with HCl in ethanol. 5) By hydrolysis of 3-isopropyl-5-(2-acetyl-7-benzofuryloxymethyl)oxazolidinone (VI) with aqueous refluxing NaOH. 6) By reaction of 2-acetyl-7-(2-hydroxy-3-aminopropoxy)benzofuran (VII) with isopropyl bromide (D) in ethanol at 100 C.
| 【1】 Ito, K.; Ikemoto, M.; Kimura, K.; Uchida, K.; Nakanishi, T.; JP 7436664 . |
| 【2】 Ito, K.; Ikemoto, M.; Kimura, K.; Uchida, K.; Nakanishi, T.; JP 7442664 . |
| 【3】 Ito, K.; Ikemoto, M.; Kimura, K.; Uchida, K.; Nakanishi, T.; JP 7441358 . |
| 【4】 Ito, K.; Ikemoto, M.; Kimura, K.; Nakanishi, T.; JP 7443960 . |
| 【5】 Ito, K.; Ikemoto, M.; Kimura, K.; Uchida, K.; Nakanishi, T.; JP 7443961 . |
| 【6】 Ito, K.; Ikemoto, M.; Kimura, K.; Nakanishi, T. (Kaken Pharmaceutical Co., Ltd.); 2-Substittuted-(2-hydroxy-3-lower alkalinopropoxy)benzofurans. DE 2223184; FR 2137901; JP 7242747; US 3853923 . |
| 【7】 Castaner, J.; Blancafort, P.; Weetman, D.F.; Serradell, M.N.; Befunolol. Drugs Fut 1981, 6, 10, 601. |
| 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) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (B) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (D) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (I) | 32291 | 1-(7-hydroxy-1-benzofuran-2-yl)-1-ethanone | 40020-87-9 | C10H8O3 | 详情 | 详情 |
| (II) | 32292 | 1-[7-(2-oxiranylmethoxy)-1-benzofuran-2-yl]-1-ethanone | C13H12O4 | 详情 | 详情 | |
| (III) | 32293 | 3-[[2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-yl]oxy]-2-oxopropanal oxime | C15H15NO6 | 详情 | 详情 | |
| (IV) | 32294 | 3-[[2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-yl]oxy]-2-oxopropanal | C15H14O6 | 详情 | 详情 | |
| (V) | 32295 | 1-(isopropylimino)-3-[[2-(2-methyl-1,3-dioxolan-2-yl)-1-benzofuran-7-yl]oxy]acetone | C18H21NO5 | 详情 | 详情 | |
| (VI) | 32296 | 5-[[(2-acetyl-1-benzofuran-7-yl)oxy]methyl]-3-isopropyl-1,3-oxazolidin-2-one | C17H19NO5 | 详情 | 详情 | |
| (VII) | 32297 | 1-[7-(3-amino-2-hydroxypropoxy)-1-benzofuran-2-yl]-1-ethanone | C13H15NO4 | 详情 | 详情 | |
| (C) | 32298 | 1-chloro-3-(isopropylamino)-2-propanol | C6H14ClNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The synthesis of heptadeuterated flutamide has been reported: The reaction of deuterated isopropyl bromide (I) with Mg in THF gives the corresponding Grignard reagent (II), which is treated with CO2 yielding the deuterated isobutyric acid (III). The reaction of (III) with oxalyl chloride affords the expected acyl chloride (IV), which is finally condensed with 4-nitro-3-(trifluoromethyl)aniline (V).
| 【1】 Passarella, D.; et al.; Synthesis of flutamide-d7 and its main metabolite-d6. J Label Compd Radiopharm 1999, 42, 3, 275. |
| 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) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (II) | 33398 | bromo(isopropyl)magnesium | 920-39-8 | C3H7BrMg | 详情 | 详情 |
| (III) | 33399 | 2-methylpropionic acid | 79-31-2 | C4H8O2 | 详情 | 详情 |
| (IV) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (V) | 33400 | 4-nitro-3-(trifluoromethyl)phenylamine; 4-nitro-3-(trifluoromethyl)aniline; 3-Trifluoromethyl-4-nitroaniline | 393-11-3 | C7H5F3N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)The alkylation of 3-hydroxy-5-methoxy-1-phenylindole-2-carboxylic acid methyl ester (I) with isopropyl bromide (II) and KOH gives the corresponding 2-isopropoxy compound (III), which is hydrolyzed with KOH and HOAc, yielding the carboxylic acid (IV). The condensation of (IV) with 1H-tetrazol-5-amine (V) by means of CDI affords the expected amide (VI), which is finally treated with L-arginine to furnish the target arginine salt.
| 【1】 Unangst, P.C.; Carethers, M.E.; Indole esters as heterocyclic synthons. III. Preparation and reactions of furo[3,2-b]indoles. J Heterocycl Chem 1984, 21, 709-714. |
| 【2】 Kunz, K.; Friendlander, P.; Concerning N,N'-diphenyl-indigo. Chem Ber 1922, 55, 1597-1607. |
| 【3】 Unangst, P.C.; Conroy, M.C.; CI-949 AND RELATED INDOLECARBOXAMIDOTETRAZOLES: A NEW CLASS OF POTENTIAL ANTIALLERGY AGENTS. Drugs Fut 1990, 15, 10, 1005. |
| 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) | 42913 | methyl 3-hydroxy-5-methoxy-1-phenyl-1H-indole-2-carboxylate | C17H15NO4 | 详情 | 详情 | |
| (II) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (III) | 42914 | methyl 3-isopropoxy-5-methoxy-1-phenyl-1H-indole-2-carboxylate | C20H21NO4 | 详情 | 详情 | |
| (IV) | 42915 | 3-isopropoxy-5-methoxy-1-phenyl-1H-indole-2-carboxylic acid | C19H19NO4 | 详情 | 详情 | |
| (V) | 14092 | 1H-1,2,3,4-Tetraazol-5-ylamine; 1H-Tetrazol-5-amine; 1H-1,2,3,4-Tetraazol-5-amine; 5-Amino-1H-1,2,3,4-tetrazole | 4418-61-5 | CH3N5 | 详情 | 详情 |
| (VI) | 42916 | 3-isopropoxy-5-methoxy-1-phenyl-N-(1H-1,2,3,4-tetraazol-5-yl)-1H-indole-2-carboxamide | C20H20N6O3 | 详情 | 详情 | |
| (VII) | 42917 | L-2-Amino-5-guanidinopentanoic acid; (S)-(+)-Arginine; L-Arginine | 74-79-3 | C6H14N4O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：2-Bromo-5-isopropoxybenzoic acid (I) was treated with oxalyl chloride to give the corresponding acid chloride (II) and subsequently condensed with the enantiomerically pure tetrahydroisoquinoline (III), yielding ester (IV). Intramolecular biaryl coupling by means of palladium acetate and tri(o-tolylphosphine) produced lactone (V), existing as an interconvertible mixture of its two atropo-diastereomeric forms. Reductive ring cleavage of this lactone using several hydride transfer reagents gave a separable mixture of two atropisomeric diols, from which the S-biar atropisomer (VI) was isolated by chromatography. After protection of the phenolic hydroxyl group of (VI) as the isopropyl ether (VII), oxidation of the primary alcohol with pyridinium chlorochromate (PCC) gave aldehyde (VIII). Stobbe condensation of (VIII) with diethyl succinate (IX) and NaOEt afforded the benzylidene succinic derivative (X).
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 | |
| (I) | 35400 | 2-bromo-4-isopropoxybenzoic acid | C10H11BrO3 | 详情 | 详情 | |
| (II) | 35401 | 2-bromo-4-isopropoxybenzoyl chloride | C10H10BrClO2 | 详情 | 详情 | |
| (III) | 35402 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C21H27NO2 | 详情 | 详情 | |
| (IV) | 35403 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinyl 2-bromo-4-isopropoxybenzoate | C31H36BrNO4 | 详情 | 详情 | |
| (V) | 35404 | (2R,4R)-3-benzyl-5,10-diisopropoxy-2,4-dimethyl-1,2,3,4-tetrahydro-8H-isochromeno[4,3-f]isoquinolin-8-one | C31H35NO4 | 详情 | 详情 | |
| (VI) | 35405 | (1R,3R)-2-benzyl-5-[2-(hydroxymethyl)-4-isopropoxyphenyl]-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C31H39NO4 | 详情 | 详情 | |
| (VII) | 35406 | [2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]methanol | C34H45NO4 | 详情 | 详情 | |
| (VIII) | 35407 | 2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxybenzaldehyde | C34H43NO4 | 详情 | 详情 | |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：2-Bromo-5-isopropoxybenzoic acid (I) was treated with oxalyl chloride to give the corresponding acid chloride (II) and subsequently condensed with the enantiomerically pure tetrahydroisoquinoline (III), yielding ester (IV). Intramolecular biaryl coupling by means of palladium acetate and tri(o-tolylphosphine) produced lactone (V), existing as an interconvertible mixture of its two atropo-diastereomeric forms. Reductive ring cleavage of this lactone using several hydride transfer reagents gave a separable mixture of two atropisomeric diols, from which the R-biar atropisomer (VI) was isolated by chromatography. After protection of the phenolic hydroxyl group of (VI) as the isopropyl ether (VII), oxidation of the primary alcohol with pyridinium chlorochromate (PCC) gave aldehyde (VIII). Stobbe condensation of (VIII) with diethyl succinate (IX) and NaOEt afforded the benzylidene succinic derivative (X).
| 【1】 Bringmann, G.; et al.; First atropo-divergent total synthesis of the antimalarial korupensamines A and B by the "lactone method". J Org Chem 2000, 65, 7, 2069. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 | |
| (I) | 35400 | 2-bromo-4-isopropoxybenzoic acid | C10H11BrO3 | 详情 | 详情 | |
| (II) | 35401 | 2-bromo-4-isopropoxybenzoyl chloride | C10H10BrClO2 | 详情 | 详情 | |
| (III) | 35402 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C21H27NO2 | 详情 | 详情 | |
| (IV) | 35403 | (1R,3R)-2-benzyl-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinyl 2-bromo-4-isopropoxybenzoate | C31H36BrNO4 | 详情 | 详情 | |
| (V) | 35404 | (2R,4R)-3-benzyl-5,10-diisopropoxy-2,4-dimethyl-1,2,3,4-tetrahydro-8H-isochromeno[4,3-f]isoquinolin-8-one | C31H35NO4 | 详情 | 详情 | |
| (VI) | 35405 | (1R,3R)-2-benzyl-5-[2-(hydroxymethyl)-4-isopropoxyphenyl]-8-isopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-6-isoquinolinol | C31H39NO4 | 详情 | 详情 | |
| (VII) | 35406 | [2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]methanol | C34H45NO4 | 详情 | 详情 | |
| (VIII) | 35407 | 2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxybenzaldehyde | C34H43NO4 | 详情 | 详情 | |
| (IX) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (X) | 35408 | (E)-4-[2-[(1R,3R)-2-benzyl-6,8-diisopropoxy-1,3-dimethyl-1,2,3,4-tetrahydro-5-isoquinolinyl]-5-isopropoxyphenyl]-3-(ethoxycarbonyl)-3-butenoic acid | C40H51NO7 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)Condensation of 2,6-dichloropurine (I) with benzylamine (II) in boiling butanol afforded 6-(benzylamino)-2-chloropurine (III), which was subsequently alkylated at the 9-N with isopropyl bromide (IV), yielding purine (V). The 2-chloro group was finally displaced with (R)-2-amino-1-butanol (VI) in a sealed tube at 160 C to provide the title compound.
| 【1】 Wang, S.; et al.; Synthesis and configuration of the cyclin-dependent kinase inhibitor roscovitine and its enantiomer. Tetrahedron Asymmetry 2001, 12, 20, 2891. |
| 【2】 Havlicek, L.; et al.; Cytokinin-derived cyclin-dependent kinase inhibitors: Synthesis and cdc2 inhibitory activity of olomoucine and related compounds. J Med Chem 1997, 40, 4, 408. |
| 【3】 Meijer, L.; Bisagni, E.; Legraverend, M. (CNRS (Centre National de la Recherche Scientifique)); Novel purine derivs. having, in particular, antiproliferative properties, and biological uses thereof. EP 0874847; FR 2741881; JP 2000501408; US 2002049218; US 6316456; WO 9720842 . |
| 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) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 36315 | N-benzyl-2-chloro-9H-purin-6-amine; N-benzyl-N-(2-chloro-9H-purin-6-yl)amine | C12H10ClN5 | 详情 | 详情 | |
| (IV) | 32658 | 2-bromopropane | 75-26-3 | C3H7Br | 详情 | 详情 |
| (V) | 36316 | N-benzyl-2-chloro-9-isopropyl-9H-purin-6-amine; N-benzyl-N-(2-chloro-9-isopropyl-9H-purin-6-yl)amine | C15H16ClN5 | 详情 | 详情 | |
| (VI) | 48572 | (S)-(+)-2-Amino-1-butanol; L-(+)-2-Amino-1-butanol; (S)-2-Amino-1-butanol | 5856-62-2 | C4H11NO | 详情 | 详情 |