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【结 构 式】 
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【分子编号】13714 【品名】Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate 【CA登记号】4068-78-4 |
【 分 子 式 】C8H7ClO3 【 分 子 量 】186.59448 【元素组成】C 51.5% H 3.78% Cl 19% O 25.72% |
合成路线1
该中间体在本合成路线中的序号：(I)The nitration of 5-chloro-2-hydroxybenzoic acid methyl ester (I) with nitric acid in sulfuric acid gives 5-chloro-2-hydroxy-3-nitrobenzoic acid methyl ester (II), which is reduced with Fe and NH4Cl in water yielding 3-amino-5-chloro-2-hydroxybenzoic acid methyl ester (III). The cyclization of (III) with chloroacetyl chloride (IV) by means of NaHCO3 in CHCl3 - water affords 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid methyl ester (V), which is methylated with methyl iodide and K2CO3 in DMF affording the corresponding 4-methyl derivative (VI). Hydrolysis of (VI) with ethanolic NaOH gives the corresponding acid (VII), which by treatment with refluxing SOCl2 is converted into its acyl chloride (VIII). Finally, this compound is condensed with 3-aminoquinuclidine (IX) by means of N-methylmorpholine (NMM) in CHCl3.
| 【1】 Tahara, T.; Kawakita, T.; Yasumoto, M.; Fukuda, T. (Welfide Corporation); Benzoxazine cpds. and pharmaceutical use thereof. EP 0313393; JP 1989207290; JP 1990005415; US 4892872 . |
| 【2】 Prous, J.; Castaner, J.; Azasetron Hydrochloride. Drugs Fut 1993, 18, 3, 206. |
| 【3】 Kawakita, T.; Tahara, T.; Kuroita, T.; Yasumoto, M.; Sano, M.; Fukuda, T.; Inaba, K.; Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists. Chem Pharm Bull 1992, 40, 3, 624-30. |
| 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) | 13714 | Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate | 4068-78-4 | C8H7ClO3 | 详情 | 详情 |
| (II) | 13715 | Methyl 5-chloro-2-hydroxy-3-nitrobenzoate | C8H6ClNO5 | 详情 | 详情 | |
| (III) | 13716 | Methyl 3-amino-5-chloro-2-hydroxybenzoate | C8H8ClNO3 | 详情 | 详情 | |
| (IV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (V) | 13718 | Methyl 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate | C10H8ClNO4 | 详情 | 详情 | |
| (VI) | 13719 | Methyl 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate | C11H10ClNO4 | 详情 | 详情 | |
| (VII) | 13720 | 6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid | C10H8ClNO4 | 详情 | 详情 | |
| (VIII) | 13721 | 6-Chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carbonyl chloride | C10H7Cl2NO3 | 详情 | 详情 | |
| (IX) | 13722 | 1-Azabicyclo[2.2.2]oct-3-ylamine; 3-Quinuclidinamine; 3-Aminoquinuclidin | 6238-14-8 | C7H14N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)5) The unsaturated pentanoic acid methyl ester derivative (XLV) obtained in scheme 16133803a can also be obtained as follows: The reaction of lactol (II) with methyltriphenylphosphonium bromide and t-BuOK in THF, followed by oxidation with PCC in dichloromethane gives the allyl ketone (XLVIII), which is methylenated with Zn/CH2Br2/TiCl4 to yield compound (XLIX). The reaction of (XLIX) with disiamylborane (DSB) and H2O2 hydroxylates the two double bonds, affording compound (L) with two primary hydroxy groups, which are oxidized with oxalyl chloride to the corresponding (LI) with two aldehyde groups. This compound cyclizes to the bicyclic hydroxyaldehyde (LII), which is dehydrated with dibenzylammonium trifluoroacetate to the unsaturated bicyclic aldehyde (LIII). The condensation of (LIII) with 3-carboxypropyltriphenylphosphonium bromide (LIV) by means of t-BuOK in THF followed by methylation with diazomethane gives the bicyclic dienoic ester (LV), which is then selectively reduced to the previously described intermediate (XLV).
| 【1】 Sodeoka, M.; Shibasaki, M.; The highly potent carbon analog of prostacyclin. Chem Lett 1984, 4, 4, 579-82. |
| 【2】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【3】 Shibasaki, M.; Mase, T.; Sodeoka, M.; Ogawa, Y. (Sagami Chemical Research Center); Bicyclo[3.3.0]octane deriv. and preparation thereof. EP 0134153 . |
| 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) | 13714 | Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate | 4068-78-4 | C8H7ClO3 | 详情 | 详情 |
| (II) | 13725 | (3aR,4S,5R,6aS)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C20H38O5Si | 详情 | 详情 | |
| (XLV) | 13768 | methyl 5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C27H48O5Si | 详情 | 详情 | |
| (XLVIII) | 13771 | (2R,3S,4R)-2-Allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentanone | C21H38O4Si | 详情 | 详情 | |
| (XLIX) | 13772 | [(1R,2R,3R)-3-Allyl-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenecyclopentyl]methyl tetrahydro-2H-pyran-2-yl ether; ([(1R,2R,5R)-2-Allyl-3-methylene-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methoxy)(tert-butyl)dimethylsilane | C22H40O3Si | 详情 | 详情 | |
| (L) | 13773 | 3-[(1S,2R,3R,5S)-2-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-1-propanol | C22H44O5Si | 详情 | 详情 | |
| (LI) | 13774 | (1S,2R,3R,4R)-3-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2-(3-oxopropyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentanecarbaldehyde | C22H40O5Si | 详情 | 详情 | |
| (LII) | 13775 | (1R,3aR,4R,5R,6aS)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-1-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-2-pentalenecarbaldehyde | C22H40O5Si | 详情 | 详情 | |
| (LIII) | 13776 | (3aS,5R,6R,6aS)-6-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenecarbaldehyde | C22H38O4Si | 详情 | 详情 | |
| (LIV) | 13777 | (3-Carboxypropyl)phosphonium bromide | C4H10BrO2P | 详情 | 详情 | |
| (LV) | 13778 | methyl (Z)-5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-4-pentenoate | C27H46O5Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)1) The esterification of 5-chloro-2-hydroxybenzoic acid (I) with methanol - HCl gives the corresponding methyl ester (II), which is alkylated with 3-chloro-2-methylpropene (III) to afford methyl 5-chloro-2-(2-methyl-2-propenyloxy)benzoate (IV). The rearrangement of (IV) by heating with N-methylpyrrolidine yields methyl 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoate (V). The cyclization of (V) in formic acid followed by hydrolysis with NaOH gives 5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylic acid (VI), which is finally treated with SOCl2, condensed with 3alpha-aminotropane (VII) and treated with maleic acid.
| 【1】 Cohen, M.L.; Lacefield, W.B. (Eli Lilly and Company); Improvements in or relating to specific 5-HT3 antagonists. AU 8821916; EP 0307172; JP 1989110684 . |
| 【2】 Robertson, D.W.; Bloomquist, W.; Pfiefer, W.; Cohen, M.L.; Simon, R.L.; Lacefield, W.B.; Zatosetron, a potent, selective, and long-acting 5-HT3 receptor antagonist: Synthesis and structure-activity relationships. J Med Chem 1992, 35, 2, 310-9. |
| 【3】 Graul, A.; Castaner, J.; Prous, J.; Zatosetron Maleate. Drugs Fut 1994, 19, 9, 850. |
| 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) | 13895 | 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid | 321-14-2 | C7H5ClO3 | 详情 | 详情 |
| (II) | 13714 | Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate | 4068-78-4 | C8H7ClO3 | 详情 | 详情 |
| (III) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
| (IV) | 13898 | methyl 5-chloro-2-[(2-methyl-2-propenyl)oxy]benzoate | C12H13ClO3 | 详情 | 详情 | |
| (V) | 13899 | methyl 5-chloro-2-hydroxy-3-(2-methyl-2-propenyl)benzoate | C12H13ClO3 | 详情 | 详情 | |
| (VI) | 13900 | 5-Chloro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid | C11H11ClO3 | 详情 | 详情 | |
| (VII) | 12412 | (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-amine; (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]oct-3-ylamine | C8H16N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)5-Chlorosalicylic acid (I) was esterified to ester (II) by refluxing in MeOH in the presence of H2SO4. Iodination of methyl ester (II) was performed by treatment with chloramine-T (III) and NaI in DMF to afford methyl 5-chloro-3-iodosalicylate (IV). Subsequent methylation of (IV) with dimethyl sulfate and K2CO3 in refluxing acetone gave methyl ether (V), which was then saponified with NaOH in aqueous EtOH. The resulting carboxylic acid (VI), after conversion to the corresponding acid chloride (VII) by treatment with SOCl2, was coupled with (S)-3-aminoquinuclidine (VIII) in acetonitrile to furnish unlabeled compound (IX). Treatment with bis(tri-n-butyltin) in the presence of Pd(PPh3)4 in refluxing Et3N afforded the tributylstannyl derivative (X), which was then iodinated with chloramine-T (III) in the presence of 125INa to yield the labeled product.
| 【1】 Mason, N.S.; et al.; Labeling of (S)-des-4-amino-3-[125I]iodozacopride (DAIZAC), a high-affinity radioligand for the 5-HT-3 receptor. J Label Compd Radiopharm 1996, 38, 11, 955. |
| 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) | 13895 | 5-Chloro-2-hydroxybenzoic acid; 5-Chlorosalicylic acid | 321-14-2 | C7H5ClO3 | 详情 | 详情 |
| (II) | 13714 | Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate | 4068-78-4 | C8H7ClO3 | 详情 | 详情 |
| (III) | 19670 | Chloramine T | 127-65-1 | C7H7ClNNaO2S | 详情 | 详情 |
| (IV) | 19671 | methyl 5-chloro-2-hydroxy-3-iodobenzoate | C8H6ClIO3 | 详情 | 详情 | |
| (V) | 19672 | methyl 5-chloro-3-iodo-2-methoxybenzoate | C9H8ClIO3 | 详情 | 详情 | |
| (VI) | 19673 | 5-chloro-3-iodo-2-methoxybenzoic acid | C8H6ClIO3 | 详情 | 详情 | |
| (VII) | 19674 | 5-chloro-3-iodo-2-methoxybenzoyl chloride | C8H5Cl2IO2 | 详情 | 详情 | |
| (VIII) | 16984 | (3S)-1-azabicyclo[2.2.2]octan-3-amine; 1-aza-Bicyclo[2.2.2]oct-3-ylamine; (3S)-1-azabicyclo[2.2.2]oct-3-ylamine | 120570-05-0 | C7H14N2 | 详情 | 详情 |
| (IX) | 19676 | N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-3-iodo-2-methoxybenzamide | C15H18ClIN2O2 | 详情 | 详情 | |
| (X) | 19677 | N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-chloro-2-methoxy-3-(tributylstannyl)benzamide | C27H45ClN2O2Sn | 详情 | 详情 |