|
【结 构 式】 
|
【分子编号】14575 【品名】Dihydroxyacetone; 1,3-dihydroxyacetone 【CA登记号】96-26-4 |
【 分 子 式 】C3H6O3 【 分 子 量 】90.07884 【元素组成】C 40% H 6.71% O 53.28% |
合成路线1
该中间体在本合成路线中的序号：(VII)The acylation of valienamine (I) with benzyloxycarbonyl chloride (II) by means of NaHCO3 in ethyl acetate gives the corresponding N-benzyloxycarbonyl derivative (III), which by reaction with Br2 in water is converted to the cyclic carbamate (IV). Elimination of bromine from (IV) with NaBH4 in water affords the new cyclic carbamate (V), which by hydrolysis with Ba(OH)2 in refluxing water is converted to valiolamine (VI). Finally, this compound is reductocondensed with 1,3-dihydroxyacetone (VII) and sodium cyanoborohydride in DMF 2N HCl.
| 【1】 Horii, S.; et al.; Synthesis and alpha-D-glucosidase inhibitory activity of N-substituted valiolamine derivatives as potential oral antidiabetic agents. J Med Chem 1986, 29, 6, 1038. |
| 【2】 Horii, S.; Kameda, Y.; Fukase, H. (Takeda Chemical Industries, Ltd.); N-substituted pseudo-aminosugars, their production and use. EP 0056194; US 4701559; US 4777294; US 4803303 . |
| 【3】 Prous, J.; Castaner, J.; AO-128. Drugs Fut 1986, 11, 9, 729. |
| 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) | 24260 | (1S,2S,3R,6S)-4-(hydroxymethyl)-6-(methylamino)-4-cyclohexene-1,2,3-triol | C8H15NO4 | 详情 | 详情 | |
| (II) | 24261 | 1-[2-(chlorooxy)-2-oxoethyl]benzene | C8H7ClO2 | 详情 | 详情 | |
| (III) | 24262 | (1S,2S,3R,6S)-4-(hydroxymethyl)-6-[methyl[(2-phenylacetyl)oxy]amino]-4-cyclohexene-1,2,3-triol | C16H21NO6 | 详情 | 详情 | |
| (IV) | 24263 | (1S,5R,6S,7R,8S,9S)-9-bromo-6,7,8-trihydroxy-1-(hydroxymethyl)-4-methyl-2-oxa-4-azabicyclo[3.3.1]nonan-3-one | C9H14BrNO6 | 详情 | 详情 | |
| (V) | 24264 | (1S,5S,6S,7R,8S)-6,7,8-trihydroxy-1-(hydroxymethyl)-4-methyl-2-oxa-4-azabicyclo[3.3.1]nonan-3-one | C9H15NO6 | 详情 | 详情 | |
| (VI) | 24265 | (1S,2S,3R,4S,5S)-1-(hydroxymethyl)-5-(methylamino)-1,2,3,4-cyclohexanetetrol | C8H17NO5 | 详情 | 详情 | |
| (VII) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)3) The cyclization of 1,3-dihydroxyacetone (XV) with pentanamidine (XVI) in liquid ammonia gives 2-butyl-5-(hydroxymethyl)imidazole (XVII), which is acetylated with acetic anhydride yielding 5 (acetoxymethyl)-1-acetyl-2-butylimidazole (XVIII). The condensation of (XVIII) with methyl 4-(hydroxymethyl)benzoate (XIX) by means of trifluoroacetic anhydride and diisopropylethylamine in dichloromethane affords 4-[5-(acetoxymethyl)-2-butylimidazol-1-ylmethyl)benzoic acid methyl ester (XX), which is hydrolyzed with NaOH in methanol/water giving 4-[2-butyl-5-(hydroxymethyl)imidazol-1-ylmethyl)benzoic acid (XXI). The controlled oxidation of (XXI) with activated MnO2 in toluene/dichloromethane yields the corresponding aldehyde (XXII), which is condensed with methyl 3-(2-thienyl)propionate (XI) with LDA in THF affording (XXIII). The acetylation of (XXIII) with acetic anhydride and DMAP gives the corresponding acetate (XXIV), which is treated with DBU as before yielding the propenoate (XXV). Finally, this compound is hydrolyzed with NaOH as already described.
| 【1】 Wittenberger, S.J.; Tasker, A.; Sorensen, B.K.; Donner, B.G.; 2-Butyl-4-iodoimidazole-5-carboxaldehyde: A versatile intermediate for the synthesis of highly functionalized imidazoles. Synth Commun 1993, 23, 22, 3231-48. |
| 【2】 Merlos, M.; Casas, A.; Graul, A.; Castaner, J.; Eprosartan. Drugs Fut 1997, 22, 10, 1079. |
| 【3】 Weinstock, J.; Keenan, R.M.; Samanen, J.; et al.; 1-(Carboxybenzyl)imidazole-5-acrylic acids: Potent and selective angiotensin II receptor antagonists. J Med Chem 1991, 34, 4, 1514-7. |
| 【4】 Keenan, R.M.; Weinstock, J.; Finkelstein, J.A.; et al.; Potent nonpeptide angiotensin II receptor antagonists. 2. 1-(Carboxybenzyl)imidazole-5-acrylic acids. J Med Chem 1993, 36, 13, 1880-92. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 14568 | methyl 3-(2-thienyl)propanoate | 16862-05-8 | C8H10O2S | 详情 | 详情 |
| (XV) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (XVI) | 14576 | pentanimidamide | 109-51-3 | C5H12N2 | 详情 | 详情 |
| (XVII) | 13923 | 2-Butyl-5-hydroxymethylimidazole; (2-Butyl-1H-imidazol-5-yl)methanol | 68283-19-2 | C8H14N2O | 详情 | 详情 |
| (XVIII) | 14578 | (1-acetyl-2-butyl-1H-imidazol-5-yl)methyl acetate | 136701-34-3 | C12H18N2O3 | 详情 | 详情 |
| (XIX) | 14579 | methyl 4-(hydroxymethyl)benzoate; Methyl 4-hydroxymethylbenzoate | 6908-41-4 | C9H10O3 | 详情 | 详情 |
| (XX) | 14580 | methyl 4-([5-[(acetoxy)methyl]-2-butyl-1H-imidazol-1-yl]methyl)benzoate | C19H24N2O4 | 详情 | 详情 | |
| (XXI) | 14581 | 4-[[2-butyl-5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzoic acid | C16H20N2O3 | 详情 | 详情 | |
| (XXII) | 14582 | 4-[(2-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid | C16H18N2O3 | 详情 | 详情 | |
| (XXIII) | 14583 | 4-([2-butyl-5-[1-hydroxy-3-methoxy-3-oxo-2-(2-thienylmethyl)propyl]-1H-imidazol-1-yl]methyl)benzoic acid | C24H28N2O5S | 详情 | 详情 | |
| (XXIV) | 14584 | 4-([5-[1-(acetoxy)-3-methoxy-3-oxo-2-(2-thienylmethyl)propyl]-2-butyl-1H-imidazol-1-yl]methyl)benzoic acid | C26H30N2O6S | 详情 | 详情 | |
| (XXV) | 14585 | 4-([2-butyl-5-[(E)-3-methoxy-3-oxo-2-(2-thienylmethyl)-1-propenyl]-1H-imidazol-1-yl]methyl)benzoic acid | C24H26N2O4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXI)The intermediate (XIX) can be obtained by two related ways: 1. The condensation of 1,3-dichloroacetone (XIII) with 2,4-difluorobromobenzene (XII) by means of n-BuLi gives 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol (XIV), which is converted into the epoxide (XV) by reaction with KOH in toluene. The reaction of (XV) with isobutyric anhydride (XXII) yields the diester (XX), which is stereoselectively hydrolyzed with Lipase D in an acetate buffer to afford the (R)-monoester (XXIV). The reaction of (XXIV) with Ms-Cl and pyridine provides the monomesylate (XXV), which is treated with KOH in toluene to give the hydroxymethyl epoxide (XVII). Finally, this compound is treated with 1,2,4-triazole (XVIII) and K2CO3 in refluxing THF to afford the target intermediate. Alternatively, the mesylate (XXV) can be treated with 1,2,4-triazole (XVIII) and Na2CO3 in refluxing methanol to yield directly the target intermediate (XIX). 2. The acylation of 1,3-dihydroxypropanone (XXI) with butyric anhydride (XXII), pyridine and DMAP gives the diester (XXIII), which is submitted to a Grignard condensation with 2,4-difluorobromobenzene (XIII) by means of Mg to afford the already described intermediate, the diester (XIX).
| 【1】 Yasohara, Y.; et al.; A practical chemoenzymatic synthesis of a key intermediate of antifungal agents. Tetrahedron Lett 2001, 42, 19, 3331. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
| (XIII) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (XIV) | 15489 | 1,3-dichloro-2-(2,4-difluorophenyl)-2-propanol | C9H8Cl2F2O | 详情 | 详情 | |
| (XV) | 15490 | 2-(chloromethyl)-2-(2,4-difluorophenyl)oxirane | C9H7ClF2O | 详情 | 详情 | |
| (XVII) | 17058 | [(2S)-2-(2,4-difluorophenyl)oxiranyl]methanol | C9H8F2O2 | 详情 | 详情 | |
| (XVIII) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XIX) | 15494 | (2S)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol | C11H11F2N3O2 | 详情 | 详情 | |
| (XX) | 50741 | 2-(2,4-difluorophenyl)-2-hydroxy-3-(isobutyryloxy)propyl 2-methylpropanoate | C17H22F2O5 | 详情 | 详情 | |
| (XXI) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (XXII) | 22334 | 1-methylpropionic anhydride | 97-72-3 | C8H14O3 | 详情 | 详情 |
| (XXIII) | 50742 | 3-(isobutyryloxy)-2-oxopropyl 2-methylpropanoate | C11H18O5 | 详情 | 详情 | |
| (XXIV) | 50743 | (2R)-2-(2,4-difluorophenyl)-2,3-dihydroxypropyl 2-methylpropanoate | C13H16F2O4 | 详情 | 详情 | |
| (XXV) | 50744 | (2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-[(methylsulfonyl)oxy]propyl 2-methylpropanoate | C14H18F2O6S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXI)In a further procedure, bromide (XV) was reacted with hexamethylenetetramine in refluxing EtOH followed by acid hydrolysis to produce the benzyl amine (XX). Mercapto imidazole (XXII) was then obtained by condensation of amine (XX) with dihydroxyacetone (XXI) and KSCN. Subsequent oxidative desulfuration gave the hydroxymethyl imidazole (XVIII). This was converted to the corresponding chloride (XXIII) by treatment with either SOCl2 in DMF or the Vilsmeier reagent. Finally, chloride (XXIII) was condensed with piperazinone (VIII) in the presence of diisopropylethylamine.
| 【1】 Cowen, J.A.; Askin, D.; McWilliams, J.C.; Maligres, P.E.; McCauley, J.A. (Merck & Co., Inc.); Process for making farnesyl-protein transferase inhibitors. WO 0001691 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 47289 | 1-(3-chlorophenyl)-2-piperazinone | C10H11ClN2O | 详情 | 详情 | |
| (XV) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (XVIII) | 38389 | 4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile | C12H11N3O | 详情 | 详情 | |
| (XX) | 47293 | 4-(aminomethyl)benzonitrile | C8H8N2 | 详情 | 详情 | |
| (XXI) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (XXII) | 47294 | 4-[[5-(hydroxymethyl)-2-sulfanyl-1H-imidazol-1-yl]methyl]benzonitrile | C12H11N3OS | 详情 | 详情 | |
| (XXIII) | 47295 | 4-[[5-(chloromethyl)-1H-imidazol-1-yl]methyl]benzonitrile | C12H10ClN3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IX)Reaction of L-aspartic acid (I) with trifluoroacetic acid and trifluoroacetic anhydride afforded N-trifluoroacetyl-L-aspartic anhydride (II). Then, Friedel-Crafts acylation of 1,3-difluorobenzene (III) with this anhydride in the presence of AlCl3 gave ketone (IV). The reduction of the carbonyl group of (IV) was effected by catalytic hydrogenation in the presence of Pearlman's catalyst, and the resulting phenylbutyric acid (V) was converted to acid chloride on treatment with PCl5 in cold dichloromethane, and subsequently cyclized by addition of AlCl3 to yield tetralone (VI). Hydrogenolysis of (VI) in the presence of Pearlman's catalyst gave tetrahydronaphthalene (VII), and further hydrolysis of trifluoroacetamide with LiOH yielded (S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl amine (VIII). Imidazole ring was then constructed by treatment of this amine with 1,3-dihydroxyacetone (IX) and potassium thiocyanate in acidic medium, and the hydroxyl group of the resulting X was substituted by a formamido group by either heating in formamide at 175 C or with ammonium formate. Finally, formamide (XI) was hydrolyzed in refluxing isopropanolic HCl.
| 【1】 Martinez, G.R.; Repke, D.B.; Teitelbaum, P.J.; Walker, K.A.M.; Gooding, O.W.; Whiting, R.L.; Bansal, R.P.; Muehldorf, A.V. (Syntex (USA), Inc.); Benzocycloalkylazolethione derivs.. JP 1997512269; US 5438150; WO 9529165 . |
| 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) | 13070 | L-Aspartic acid; (2S)-2-Aminobutanedioic acid | 56-84-8 | C4H7NO4 | 详情 | 详情 |
| (II) | 18410 | N-[(3S)-2,5-dioxotetrahydro-3-furanyl]-2,2,2-trifluoroacetamide | 777-33-3 | C6H4F3NO4 | 详情 | 详情 |
| (III) | 13095 | m-Difluorobenzene; 1,3-Difluorobenzene | 372-18-9 | C6H4F2 | 详情 | 详情 |
| (IV) | 18412 | (2S)-4-(2,4-difluorophenyl)-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C12H8F5NO4 | 详情 | 详情 | |
| (V) | 18413 | (2S)-4-(2,4-difluorophenyl)-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C12H10F5NO3 | 详情 | 详情 | |
| (VI) | 18414 | N-[(2S)-5,7-difluoro-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl]-2,2,2-trifluoroacetamide | C12H8F5NO2 | 详情 | 详情 | |
| (VII) | 18415 | N-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2,2,2-trifluoroacetamide | C12H10F5NO | 详情 | 详情 | |
| (VIII) | 18416 | (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenamine | C10H11F2N | 详情 | 详情 | |
| (IX) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (X) | 18418 | 1-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-5-(hydroxymethyl)-1,3-dihydro-2H-imidazole-2-thione | C14H14F2N2OS | 详情 | 详情 | |
| (XI) | 18419 | [3-[(2S)-5,7-difluoro-1,2,3,4-tetrahydro-2-naphthalenyl]-2-thioxo-2,3-dihydro-1H-imidazol-4-yl]methylformamide | C15H15F2N3OS | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)The mercaptoimidazole (IX) was prepared by condensation between 4-bromobenzylamine (VII), 1,3-dihydroxyacetone (VIII) and potassium thiocyanate. Oxidative desulfuration of (IX) with hydrogen peroxide in acidic medium yielded imidazole (X). The biphenyl derivative (XII) was obtained by Suzuki coupling of aryl bromide (X) with 4-(trifluoromethyl)benzeneboronic acid (XI). Subsequent oxidation of the alcohol group of (XII) under Swern conditions gave aldehyde (XIII). Finally, reductive coupling of aldehyde (XIII) with piperazinone (VI) in the presence of sodium triacetoxyborohydride furnished the title compound.
| 【2】 Williams, T.M. (Merck & Co., Inc.); Biaryl inhibitors of prenyl-protein transferase. WO 0075135 . |
| 【1】 Kohl, N.E.; Nguyen, D.N.; Lobell, R.B.; Williams, T.M.; Heimbrook, D.C.; Buser, C.A.; Huber, H.E.; Stump, C.A.; Graham, S.L.; Potent inhibitors of farnesyltransferase and geranylgeranyltransferase. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 56. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 47289 | 1-(3-chlorophenyl)-2-piperazinone | C10H11ClN2O | 详情 | 详情 | |
| (VII) | 15869 | 4-bromobenzylamine; (4-bromophenyl)methanamine | 26177-44-6 | C7H8BrN | 详情 | 详情 |
| (VIII) | 14575 | Dihydroxyacetone; 1,3-dihydroxyacetone | 96-26-4 | C3H6O3 | 详情 | 详情 |
| (IX) | 48637 | [1-(4-bromobenzyl)-2-sulfanyl-1H-imidazol-5-yl]methanol | C11H11BrN2OS | 详情 | 详情 | |
| (X) | 48638 | [1-(4-bromobenzyl)-1H-imidazol-5-yl]methanol | C11H11BrN2O | 详情 | 详情 | |
| (XI) | 48639 | 4-(Trifluoromethyl)phenylboronic acid | C7H6BF3O2 | 详情 | 详情 | |
| (XII) | 48640 | (1-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-yl)methanol | C18H15F3N2O | 详情 | 详情 | |
| (XIII) | 48641 | 1-[[4'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazole-5-carbaldehyde | C18H13F3N2O | 详情 | 详情 |