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【结 构 式】 
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【分子编号】12563 【品名】(2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid 【CA登记号】17199-29-0 |
【 分 子 式 】C8H8O3 【 分 子 量 】152.14972 【元素组成】C 63.15% H 5.3% O 31.55% |
合成路线1
该中间体在本合成路线中的序号：(VI)Semotiadil fumarate has been obtained by several related ways: 1) The reaction of 2-(2-hydroxy-5-methoxyphenyl)-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (I) with 3-chloropropyl bromide (II) by means of NaH in DMF gives 2-[2-(3-bromopropoxy)-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (III) , which is condensed with N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-methylamine (IV) by means of NaI in NaHCO3 in DMF yielding 2-[2-[3-[N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-methylamino]propoxy]-5-methoxyphenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (V). Finally, this compound is submitted to optical resolution by salification with L-(+)-2-hydroxy-2-phenylacetic acid (VI), fractional crystallization of the resulting salts, elimination of the chiral acid with NaHCO3 and salification with fumaric acid in ethanol. 2) Compound (V) can also be obtained by condensation of benzothiazinone (I) with N-[2-(1,3-benzodioxol-5-yloxy)ethyl]-N-(3-bromopropyl)-N-methylamine (VII) by means of NaH in DMF. 3) Compound (V) can also be obtained by condensation of 2-[5-methoxy-2-[3-(methylamino)propoxy]phenyl]-4-methyl-3,4-dihydro-2H-1,4-benzothiazin-3-one (VIII) with 2-(1,3-benzodioxol-5-yloxy)ethyl methanesulfonate (IX) by means of triethylamine in ethanol. 4) The optical resolution of the racemic compound (V) can also be performed by chromatography over a column packed with crystalline cellulose triacetate eluted with 95% ethanol.
| 【1】 Robinson, K.A.; Robinson, C.P.; Castaner, J.; Sesamodil Fumarate. Drugs Fut 1997, 22, 3, 229. |
| 【2】 Iwao, J.; Iso, T.; Oya, M. (Santen Pharmaceutical Co., Ltd.); Novel benzothiazine derivs.. EP 0237573; JP 1987123181; US 4786635; WO 8700838 . |
| 【3】 Yamauchi, H.; Kawashima, Y.; Yamamoto, K.; Ito, S.; Iwao, J.-I.; Fujita, M.; Ota, A.; Kato, N.; Synthesis and Ca2+ antagonistic activity of 2-[2-[(aminoalkyl)oxy]-5-methoxyphenyl]-3,4-dihydro-4-methyl-3-oxo-2H -1,4-benzothiazines. J Med Chem 1990, 33, 7, 1898-905. |
| 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) | 12558 | 2-(2-Hydroxy-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C16H15NO3S | 详情 | 详情 | |
| (II) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (III) | 12560 | 2-[2-(3-Bromopropoxy)-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C19H20BrNO3S | 详情 | 详情 | |
| (IV) | 12561 | 2-(1,3-Benzodioxol-5-yloxy)-N-methyl-1-ethanamine; N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-N-methylamine | C10H13NO3 | 详情 | 详情 | |
| (V) | 12562 | 2-(2-[3-[[2-(1,3-Benzodioxol-5-yloxy)ethyl](methyl)amino]propoxy]-5-methoxyphenyl)-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C29H32N2O6S | 详情 | 详情 | |
| (VI) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (VII) | 12564 | N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-3-bromo-N-methyl-1-propanamine; N-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-N-(3-bromopropyl)-N-methylamine | C13H18BrNO3 | 详情 | 详情 | |
| (VIII) | 12565 | 2-[5-Methoxy-2-[3-(methylamino)propoxy]phenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one | C20H24N2O3S | 详情 | 详情 | |
| (IX) | 12566 | 2-(1,3-benzodioxol-5-yloxy)ethyl methanesulfonate | C10H12O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(S)(+)-(IV)The synthesis of the intermediates, the chiral amines (R)(-)-1,2-dimethylpropylamine (R)(-)-(I) and (S)(+)-1,2-dimethylpropylamine (S)(+)-(I) has been performed as follows: (R)(-)-1,2-Dimethylpropylamine (R)(-)-(I): The reaction of racemic 1,2-dimethylpropylamine (rac)(I) with 2(S)-(6-methoxynaphthalen-2-yl)propionic acid (S)(+)-(II) (S-naproxen) in ethanol gives the ammonium salt (III) as a diastereomeric mixture from which the (R,S)-diastereomer is obtained by successive crystallizations. Finally, this diastereomer is treated with NaOH in water to obtain the target (R)(-)-amine (R)(-)-(I). (S)(+)-1,2-Dimethylpropylamine (S)(+)-(I): The reaction of racemic 1,2-dimethylpropylamine (rac)-(I) with 2(S)-hydroxy-2-phenylacetic acid (S)(+)-(IV) (S-mandelic acid) in ethanol gives the ammonium salt (V) as a diastereomeric mixture from which the (S,S)-diastereomer is obtained by successive crystallizations. Finally, this diastereomer is treated with NaOH in water to obtain the target (S)(+)-amine (S)(+)-(I).
| 【1】 de Tullio, P.; Khelili, S.; Lebrun, P.; et al.; Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2'-butylamino)-4H- and 3-(3'-methyl-2'-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers. Bioorg Med Chem 1999, 7, 8, 1513. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (S)(+)-(IV) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (S)(+)-(II) | 30839 | (2S)-2-(6-methoxy-2-naphthyl)propionic acid;(S)-naproxen;(S)-6-Methoxy-alpha-methyl-2-naphthaleneacetic acid | 22204-53-1 | C14H14O3 | 详情 | 详情 |
| rac-(I) | 38919 | 1,2-dimethylpropylamine; 3-methyl-2-butanamine | C5H13N | 详情 | 详情 | |
| (R)(-)-(I) | 38922 | (1R)-1,2-dimethylpropylamine; (2R)-3-methyl-2-butanamine | C5H13N | 详情 | 详情 | |
| (S)(+)-(I) | 38923 | (1S)-1,2-dimethylpropylamine; (2S)-3-methyl-2-butanamine | C5H13N | 详情 | 详情 | |
| (III) | 38920 | 3-methyl-2-butanaminium (2S)-2-(6-methoxy-2-naphthyl)propanoate | C19H27NO3 | 详情 | 详情 | |
| (V) | 38921 | 3-methyl-2-butanaminium (2S)-2-hydroxy-2-phenylethanoate | C13H21NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)Racemic cyclohexylphenyl glycolic acid (CHPGA) (I) is dissolved with (L)-tyrosine methyl ester (II) in refluxing acetonitrile/water to yield a mixture of diastereomeric salts, which is resolved by crystallization to afford the desired diastereomeric salt [(S)-CHPGA-(L)-TME] (III). Finally, the hydrolysis of salt (III) with HCl or H2SO4 at 40-50ºC in toluene yields the enantiomer (IV). Alternatively intermediate (IV) can be obtained as follows: acetalization of (S)-mandelic acid (V) with pivaldehyde (VI) in pentane and catalytic TfOH provides derivative (VII), which is then treated with LHMDS and then condensed with cyclohexanone (VIII) in THF to furnish aldol adduct (IX). Elimination of tertiary alcohol in (IX) with SOCl2 and pyridine in THF gives derivative (X), which is then converted into intermediate (IV) either by first hydrolysis of lactone (X) with KOH in MeOH and subsequent hydrogenation of the obtained derivative (XI) over Pd/C in MeOH, or by first hydrogenation of (X) over Pd/C in MeOH to give (XII), followed by hydrolysis with KOH in MeOH. On turn, derivative (XII) can alternatively be synthesized by treatment of derivative (VII) with LHMDS, followed by reaction with 3-bromocyclohexene (XIII) in THF to provide derivative (XIV), which is then hydrogenated over Pd/C.
| 【1】 Grover, P.T.; et al.; Chiral mandelic acid template provides a highly practical solution for (S)-oxybutynin synthesis. J Org Chem 2000, 65, 19, 6283. |
| 【2】 Senanayake, C.H.; Bakale, R.P.; Vandenbossche, C.P.; McConville, F.X.; Lopez, J.L. (Sepracor Inc.); Synthesis of optically active cyclohexylphenylglycolic acid and its esters. US 5973182; US 6140529; WO 0023414 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (Ia) | 51214 | (2R)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid | C14H18O3 | 详情 | 详情 | |
| (Ib),(IV) | 51215 | (2S)-2-cyclohexyl-2-hydroxy-2-phenylethanoic acid | C14H18O3 | 详情 | 详情 | |
| (II) | 21431 | methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 1080-06-4 | C10H13NO3 | 详情 | 详情 |
| (III) | 51216 | n/a | C24H31NO6 | 详情 | 详情 | |
| (V) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (VI) | 19797 | Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal | 630-19-3 | C5H10O | 详情 | 详情 |
| (VII) | 31681 | (2R,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one | C13H16O3 | 详情 | 详情 | |
| (VIII) | 11059 | Cyclohexanone | 108-94-1 | C6H10O | 详情 | 详情 |
| (IX) | 51217 | (2S,5R)-2-(tert-butyl)-5-(1-hydroxycyclohexyl)-5-phenyl-1,3-dioxolan-4-one | C19H26O4 | 详情 | 详情 | |
| (X) | 51218 | (2S,5S)-2-(tert-butyl)-5-(1-cyclohexen-1-yl)-5-phenyl-1,3-dioxolan-4-one | C19H24O3 | 详情 | 详情 | |
| (XI) | 51219 | (2S)-2-(1-cyclohexen-1-yl)-2-hydroxy-2-phenylethanoic acid | C14H16O3 | 详情 | 详情 | |
| (XII) | 51220 | (2S,5S)-2-(tert-butyl)-5-cyclohexyl-5-phenyl-1,3-dioxolan-4-one | C19H26O3 | 详情 | 详情 | |
| (XIII) | 30800 | 3-bromo-1-cyclohexene | 1521-51-3 | C6H9Br | 详情 | 详情 |
| (XIV) | 51221 | (2S,5S)-2-(tert-butyl)-5-[(1R)-2-cyclohexen-1-yl]-5-phenyl-1,3-dioxolan-4-one | C19H24O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)OP C-33509 has been obtained by coupling imidazolecarboxamide (VI) with amine (IX) in refluxing CHCl3. The intermediates (VI) and (IX) have been obtained as follows: 1) Alkylation of 6-hydroxycarbostyril (I) with N-(3-bromopropyl)- phthalimide (II) in the presence of K2CO3 in DMF furnished the phthalimidopropyl ether (III). Subsequent hydrazinolysis of the phthalimide in refluxing EtOH provided the primary amine (IV). Then, the imidazolecarboxamide (VI) was obtained by treating amine (IV) with 1,1'-carbonyldiimidazole (V) and two equivalents of imidazole in DMSO. 2) Ring opening of 1,2 epoxycyclohexane (VII) with cyclopropylamine (VIII) gave the racemic trans aminoalcohol. Resolution of enantiomers (IX) and (X) was accomplished by esterification with (S)-mandelic acid (XI), followed by chromatographic separation of the diastereomeric esters. Hydrolysis of the desired ester (XII) then provided optically pure aminoalcohol (IX). Finally, the target urea derivative was obtained by coupling imidazolyl urea (VI) with amine (IX) in refluxing chloroform.
| 【1】 Koga, Y.; Kihara, Y.; Okada, M.; Inoue, Y.; Tochizawa, S.; Toga, K.; Tachibana, K.; Kimura, Y.; Nishi, T.; Hidaka, H.; 2(1H)- Quinoline derivatives as novel anti-arteriostenotic agents showing anti-thrombotic and anti-hyperplastic activities. Bioorg Med Chem Lett 1998, 8, 12, 1471. |
| 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) | 13913 | 6-Hydroxy-2(1H)-quinolinone | C9H7NO2 | 详情 | 详情 | |
| (II) | 15216 | N-(3-Bromopropyl)phthalimide; 2-(3-bromopropyl)-1H-isoindole-1,3(2H)-dione | 5460-29-7 | C11H10BrNO2 | 详情 | 详情 |
| (III) | 18912 | 2-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione | C20H16N2O4 | 详情 | 详情 | |
| (IV) | 18913 | 6-(3-aminopropoxy)-2(1H)-quinolinone | C12H14N2O2 | 详情 | 详情 | |
| (V) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (VI) | 18915 | N-[3-[(2-oxo-1,2-dihydro-6-quinolinyl)oxy]propyl]-1H-imidazole-1-carboxamide | C16H16N4O3 | 详情 | 详情 | |
| (VII) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (VIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (IX) | 18918 | (1R,2R)-2-(cyclopropylamino)cyclohexanol | C9H17NO | 详情 | 详情 | |
| (X) | 18919 | (1S,2S)-2-(cyclopropylamino)cyclohexanol | C9H17NO | 详情 | 详情 | |
| (XI) | 12563 | (2S)-2-Hydroxy-2-phenylethanoic acid; S-(+)-Mandelic acid | 17199-29-0 | C8H8O3 | 详情 | 详情 |
| (XII) | 18921 | (1R,2R)-2-(cyclopropylamino)cyclohexyl (2S)-2-hydroxy-2-phenylethanoate | C17H23NO3 | 详情 | 详情 |