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【结 构 式】 
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【分子编号】28617 【品名】5-(chloromethyl)-1,3-benzodioxole 【CA登记号】 |
【 分 子 式 】C8H7ClO2 【 分 子 量 】170.59508 【元素组成】C 56.33% H 4.14% Cl 20.78% O 18.76% |
合成路线1
该中间体在本合成路线中的序号：(I)Condensation of piperonyl chloride (I) with diethyl malonate (II) by means of Na in anhydrous refluxing EtOH (NaOEt) provides 2-[3,4-(methylenedioxy)benzyl]malonic acid diethyl ester (III), which is converted into the monoethyl ester (IV) by saponification with KOH in EtOH. Treatment of (IV) with diethylamine in paraformaldehyde/H2O affords acrylic ester (V), which is then subjected to saponification with NaOH in acetone/H2O to provide [3,4-(methylenedioxy)benzyl]-2-propenoic acid (VI). Alternatively, derivative (VI) can also be obtained by following this route: treatment of piperonal (VII) with diethyl malonate (II) in refluxing toluene in the presence of piperidine and acetic acid provides diethyl piperonylidene malonate (VIII), which is then hydrogenated over Pd/C to furnish diethyl piperonylmalonate (IX). Saponification of the ethyl ester moiety of (IX) by refluxing with NaOH in H2O affords piperonylmalonic acid (X), which is finally converted into intermediate (VI) by decarboxylation by treatment with diethylamine in refluxing paraformaldehyde. Reaction of (VI) with thioacetic acid at 70 C affords a racemic mixture of propionic acid derivatives (XI), which is resolved by first formation of a chiral salt (either by reaction with (R)-alpha-methylbenzylamine or by reaction with (+)-ephedrine in ether), recrystallization of the corresponding diastereomer and finally liberation of the 2-(S)-(acetylthiomethyl)-3-[3,4-(methylenedioxy)benzyl]propionic acid [(S)-(XII)] by hydrolysis with HCl in H2O/CH2Cl2. Finally, fasidotril is obtained by condensation of (S)-(XII) with benzyl alaninate (XIII) by means of HOBt and DCC in THF/CHCl3 in the presence of Et3N.
| 【1】 Plaquevent, J.-C.; Danvy, D.; Monteil, T.; Greciet, H.; Duhamel, L.; Duhamel, P.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs., method for their preparation and their therapeutic application. EP 0419327; FR 2652087; WO 9104246 . |
| 【2】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III),(IX) | 49496 | diethyl 2-(1,3-benzodioxol-5-ylmethyl)malonate | C15H18O6 | 详情 | 详情 | |
| (S)-(XII) | 49501 | (2S)-3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid | C13H14O5S | 详情 | 详情 | |
| (I) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (IV) | 49497 | 2-(1,3-benzodioxol-5-ylmethyl)-3-ethoxy-3-oxopropionic acid | C13H14O6 | 详情 | 详情 | |
| (V) | 38469 | ethyl (E)-3-(1,3-benzodioxol-5-yl)-2-propenoate | C12H12O4 | 详情 | 详情 | |
| (VI) | 11634 | (E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid | 2373-80-0 | C10H8O4 | 详情 | 详情 |
| (VII) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (VIII) | 49499 | diethyl 2-(1,3-benzodioxol-5-ylmethylene)malonate | C15H16O6 | 详情 | 详情 | |
| (X) | 49500 | 2-(1,3-benzodioxol-5-ylmethyl)malonic acid | C11H10O6 | 详情 | 详情 | |
| (XI) | 49498 | 3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid | C13H14O5S | 详情 | 详情 | |
| (XIII) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The esterification of 3,4-dimethoxy-2-nitrobenzoic acid (I) with methyl iodide and cesium carbonate gives the corresponding methyl ester (II), which is reduced with H2 over Pd/C yielding the expected 2-amino compound (III). The reaction of (III) with NaNO2 and SO2 affords the disulfide (IV), which is cyclized with methyl glycinate (V) by means of KNO3 and SO2Cl2 giving the benzoisothiazolone derivative (VI). The rearrangement of (VI) by means of sodium methoxide yields the 1,2-benzothiazine derivative (VII), which is condensed with 3,4-methylenedioxybenzyl chloride (VIII) by means of NaH in DMF affording the N-substituted benzothiazine (IX). The reaction of (IX) with triflic anhydride gives the triflate ester (X), which is condensed with 3,4-methylenedioxythiophenol (XI) by means of NaH in DMF and hydrolyzed with LiOH in THF to provide the target compound.
| 【1】 Berryman, K.A.; Edmunds, J.J.; Bunker, A.M.; Haleen, S.; Bryant, J.; Welch, K.M.; Doherty, A.M.; Endothelin receptor antagonists: Synthesis and structure-activity relationships of substituted benzothiazine-1,1-dioxides. Bioorg Med Chem 1998, 6, 9, 1447. |
| 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) | 28611 | 3,4-dimethoxy-2-nitrobenzoic acid | C9H9NO6 | 详情 | 详情 | |
| (II) | 28612 | methyl 3,4-dimethoxy-2-nitrobenzoate | C10H11NO6 | 详情 | 详情 | |
| (III) | 28613 | methyl 2-amino-3,4-dimethoxybenzoate | C10H13NO4 | 详情 | 详情 | |
| (IV) | 28614 | methyl 2-[[2,3-dimethoxy-6-(methoxycarbonyl)phenyl]disulfanyl]-3,4-dimethoxybenzoate | C20H22O8S2 | 详情 | 详情 | |
| (V) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (VI) | 28615 | methyl 2-(6,7-dimethoxy-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C12H13NO7S | 详情 | 详情 | |
| (VII) | 28616 | methyl 4-hydroxy-7,8-dimethoxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C12H13NO7S | 详情 | 详情 | |
| (VIII) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (IX) | 28618 | methyl 2-(1,3-benzodioxol-5-ylmethyl)-4-hydroxy-7,8-dimethoxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C20H19NO9S | 详情 | 详情 | |
| (X) | 28619 | methyl 2-(1,3-benzodioxol-5-ylmethyl)-7,8-dimethoxy-1,1-dioxo-4-[[(trifluoromethyl)sulfonyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C21H18F3NO11S2 | 详情 | 详情 | |
| (XI) | 28620 | 1,3-benzodioxole-5-thiol | C7H6O2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)Intermediate (III) was prepared by condensation of epoxide (I) with piperazine (II). After removal of the carbobenzoxy protecting group of (III) by catalytic hydrogenation, the resulting amine (IV) was coupled to the valine derivative (V) using EDC to afford amide (VI). Subsequent cleavage of the Boc protecting group of (VI) under acidic conditions gave (VII), which was finally alkylated with the benzodioxolylmethyl halide (VIII) to provide the target compound.
| 【1】 Chen, X.; Kempf, D.J.; Sham, H.L.; Green, B.E.; Molla, A.; Korneyeva, M.; Vasavanonda, S.; Wideburg, N.E.; Saldivar, A.; Marsh, K.C.; McDonald, E.; Norbeck, D.W.; Potent piperazine hydroxyethylamine HIV protease inhibitors containing novel P3 ligands. Bioorg Med Chem Lett 1998, 8, 24, 3531. |
| 【2】 Chen, X.; Mohammadi, F.; Norbeck, D.W.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. WO 9959994 . |
| 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) | 14522 | benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate | C18H19NO3 | 详情 | 详情 | |
| (II) | 16422 | methyl (1R,4S)-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate | C8H11NO2 | 详情 | 详情 | |
| (III) | 30251 | tert-butyl (3S)-4-((2R,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C32H46N4O6 | 详情 | 详情 | |
| (IV) | 30252 | tert-butyl (3S)-4-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C24H40N4O4 | 详情 | 详情 | |
| (V) | 30255 | (2S)-2-([[(2-isopropyl-1,3-thiazol-4-yl)methoxy]carbonyl]amino)-3-methylbutyric acid | C13H20N2O4S | 详情 | 详情 | |
| (VI) | 30253 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]-4-((2R,3S)-2-hydroxy-3-[[(2S)-2-([[(2-isopropyl-1,3-thiazol-4-yl)methoxy]carbonyl]amino)-3-methylbutanoyl]amino]-4-phenylbutyl)-1-piperazinecarboxylate | C37H58N6O7S | 详情 | 详情 | |
| (VII) | 30254 | (2-isopropyl-1,3-thiazol-4-yl)methyl (1S)-1-[[((1S,2R)-1-benzyl-3-[(2S)-2-[(tert-butylamino)carbonyl]piperazinyl]-2-hydroxypropyl)amino]carbonyl]-2-methylpropylcarbamate | C32H50N6O5S | 详情 | 详情 | |
| (VIII) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 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 title compound has been prepared by two related ways. The alkylation of 2-fluoro-4-hydroxybenzonitrile (I) with 3,4-(methylenedioxy)benzyl chloride (II) afforded ether (III). This was coupled with (R,S)-2-hydroxy-2-(2-methylphenyl)acetic acid (IV) in the presence of NaH in DMSO to produce the racemic adduct (V). Resolution was then achieved by fractional crystallization of the diastereoisomeric salts with (-)-ephedrine to furnish the desired (S)-enantiomer, which was finally isolated as the corresponding sodium salt.
| 【1】 Astles, P.C.; Brown, T.J.; Halley, F.; et al.; Selective ETA antagonists. 5. Discovery and structure-activity relationships of phenoxyphenylacetic acid derivatives. J Med Chem 2000, 43, 5, 900. |
| 【2】 Porter, B.; Astles, P.C.; Bridge, A.W.; McLay, I.M.; Van Sickle, A.P.; Walsh, R.J.A.; McCarthy, C.; Morley, A.D.; Halley, F.; Harris, N.V.; Majid, T.N.; Smith, C. (Rhône-Poulenc Rorer Ltd.); Substd. phenyl cpds. as endothelin antagonists. US 6048893; US 6124343; WO 9622978 . |
| 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) | 20094 | 2,4-dihydroxybenzaldehyde | 95-01-2 | C7H6O3 | 详情 | 详情 |
| (II) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (III) | 38975 | (3S,5R)-1-[(2S,4R)-5-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-4-benzyl-2-hydroxy-5-oxopentyl]-3,5-dibenzyl-2-pyrrolidinone | C42H46N2O4 | 详情 | 详情 | |
| (IV) | 38977 | 2-hydroxy-2-(2-methylphenyl)acetic acid | C9H10O3 | 详情 | 详情 | |
| (V) | 38978 | 2-[5-(1,3-benzodioxol-5-ylmethoxy)-2-cyanophenoxy]-2-(2-methylphenyl)acetic acid | C24H19NO6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)In a related procedure, alkylation of 2,4-dihydroxybenzaldehyde (VI) with chloride (II) gave ether (VII). Subsequent conversion of the aldehyde group of (VII) into the desired nitrile (X) was effected by the following sequence, including formation of the corresponding oxime (VIII), dehydration with concomitant acetylation using Ac2O, and then hydrolysis of acetate (IX) using K2CO3. Alternatively, aldehyde (VII) was directly converted to nitrile (X) by reaction with hydroxylamine-O-sulfonic acid, followed by basic treatment. Racemic alpha-bromo-(2-methylphenyl)acetic acid (XI) was resolved via formation of the corresponding salt with (-)-ephedrine (XII). Hydroxy nitrile (X) was then alkylated with the chiral bromide (XII), and the resulting compound was finally converted to the corresponding sodium salt.
| 【1】 Porter, B.; Astles, P.C.; Bridge, A.W.; McLay, I.M.; Van Sickle, A.P.; Walsh, R.J.A.; McCarthy, C.; Morley, A.D.; Halley, F.; Harris, N.V.; Majid, T.N.; Smith, C. (Rhône-Poulenc Rorer Ltd.); Substd. phenyl cpds. as endothelin antagonists. US 6048893; US 6124343; WO 9622978 . |
| 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) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (VI) | 20094 | 2,4-dihydroxybenzaldehyde | 95-01-2 | C7H6O3 | 详情 | 详情 |
| (VII) | 38979 | 4-(1,3-benzodioxol-5-ylmethoxy)-2-hydroxybenzaldehyde | C15H12O5 | 详情 | 详情 | |
| (VIII) | 38980 | 4-(1,3-benzodioxol-5-ylmethoxy)-2-hydroxybenzaldehyde oxime | C15H13NO5 | 详情 | 详情 | |
| (IX) | 38981 | 5-(1,3-benzodioxol-5-ylmethoxy)-2-cyanophenyl acetate | C17H13NO5 | 详情 | 详情 | |
| (X) | 38982 | 4-(1,3-benzodioxol-5-ylmethoxy)-2-hydroxybenzonitrile | C15H11NO4 | 详情 | 详情 | |
| (XI) | 38983 | 2-bromo-2-(2-methylphenyl)acetic acid | C9H9BrO2 | 详情 | 详情 | |
| (XII) | 38984 | (2R)-2-bromo-2-(2-methylphenyl)ethanoic acid | C9H9BrO2 | 详情 | 详情 |