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【结 构 式】 
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【分子编号】18430 【品名】2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid 【CA登记号】156-38-7 |
【 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：(I)The esterification of 4-hydroxyphenylacetic acid (I) with isopropanol and H2SO4 gives the corresponding isopropyl ester (II), which is then cyclocondensed with 1-isobutoxy-2-chloroethyl isothiocyanate (III) by means of K2CO3 in acetone yielding isopropyl 2-[4-(4-isobutoxy-2-thiazolin-2-yloxy) phenyl]acetate (IV). Elimination of isobutanol from (IV) by means of p-toluenesulfonic acid in hot DMF affords isopropyl 2-[4-(2-thiazolyloxy)phenyl] acetate (V), which is methylated with methyl bromide and KOH in DMF giving isopropyl 2-[4-(2-thiazo)yloxy)phenyl]propionate (VI). Finally, this compound is hydrolyzed with NaOH in aqueous methanol.
| 【1】 Hamada, Y.; Ando, S. (Shionogi & Co. Ltd.); Improved process for the production of 2-(4-(2-thiazolyloxy)phenyl)propionic acid. CA 1188699; EP 0088008; JP 58148870 . |
| 【2】 Castaner, J.; Serradell, M.N.; Arrigoni-Martelli, E.; 480156-S. Drugs Fut 1985, 10, 1, 37. |
| 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) | 19250 | 2-propanol | 67-63-0 | C3H8O | 详情 | 详情 |
| (I) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (II) | 28901 | isopropyl 2-(4-hydroxyphenyl)acetate | C11H14O3 | 详情 | 详情 | |
| (III) | 28902 | 1-(2-chloro-1-isothiocyanatoethoxy)butane | C7H12ClNOS | 详情 | 详情 | |
| (IV) | 28903 | isopropyl 2-[4-[(4-butoxy-1,3-thiazol-2-yl)oxy]phenyl]acetate | C18H23NO4S | 详情 | 详情 | |
| (V) | 28904 | isopropyl 2-[4-(1,3-thiazol-2-yloxy)phenyl]acetate | C14H15NO3S | 详情 | 详情 | |
| (VI) | 28905 | isopropyl 2-[4-(1,3-thiazol-2-yloxy)phenyl]propanoate | C15H17NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of p-hydrophenylacetic acid (I) with N,N-dimethylbromoacetamide (II) by means of triethylamine in reftuxing acetonitrile gives N,N-dimethylcarbamoylmethyl-p-hydroxyphenylacetate (III), which is then condensed with p-guanidinobenzoyl chloride (IV) [obtained from the corresponding acid p-guanidinobenzoic acid (V) and thionyl chloride] in pyridine.
| 【1】 Fujii, S.; Uegai, Y.; Watanabe, T.; Kayama, N. (Ono Pharmaceutical Co., Ltd.); Guanidinobenzoic acid derivatives. DE 2548886; FR 2289181; GB 1472700; JP 76054530; US 4021472 . |
| 【2】 Fujii, S.; et al. (Ono Pharmaceutical Co., Ltd.); Guanidinobenzoic acid derivatives and antiplasmin agents and remedies for pancreas diseases containing the said guanidinobensolc acid derivatives. JP 52089640 . |
| 【3】 Castaner, J.; Serradell, M.N.; Hashimoto, K.; Camostat Mesylate. Drugs Fut 1985, 10, 11, 897. |
| 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) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (II) | 29753 | 2-bromo-N,N-dimethylacetamide | C4H8BrNO | 详情 | 详情 | |
| (III) | 29754 | 2-(dimethylamino)-2-oxoethyl 2-(4-hydroxyphenyl)acetate | C12H15NO4 | 详情 | 详情 | |
| (IV) | 29755 | 4-[[amino(imino)methyl]amino]benzoic acid | C8H9N3O2 | 详情 | 详情 | |
| (V) | 22548 | 4-[[amino(imino)methyl]amino]benzoyl chloride | C8H8ClN3O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Reaction of 4-hydroxyphenylacetic acid (I) with refluxing SOCl2, followed by treatment of the resulting polymeric phenol ester with 3,5-dimethylaniline (II) in refluxing xylene provided amide (III). Condensation of this compound with acetone and chloroform in the presence of powdered NaOH yielded the corresponding isobutyric acid derivative.
| 【1】 McIntyre, J.; Castaner, J.; Efaproxiral Sodium. Drugs Fut 2003, 28, 12, 1159. |
| 【2】 Abraham, D.J.; Mehanna, A.; Randad, R.; Mahran, M.; Allosteric hemoglobin modifiers. US 5049695; WO 9112235 . |
| 【3】 Randad, R.S.; et al.; Allosteric modifiers of hemoglobin. 1. Design, synthesis, testing, and structure-allosteric activity relationship of novel hemoglobin oxygen affinity decreasing agents. J Med Chem 1991, 34, 2, 752. |
合成路线4
该中间体在本合成路线中的序号：(I)Friedel-Crafts reaction between 4-hydroxyphenylacetic acid (I) and resorcinol (II) by means of BF3.Et2O provides trihydroxydeoxy benzoin (III), which is then protected with dihydropyran (IV) in the presence of TsOH to give the bis-THP ether (V). Knoevenagel reaction of (V) with 4-hydroxybenzaldehyde (VI) in the presence of piperidine in refluxing benzene, followed by alkylation with 1-(2-chloroethyl)piperidine (VII) in the presence of Cs2CO3 in refluxing acetone:H2O to yield chromanone (VIII). Alternatively, (VIII) can be synthesized by reaction of (V) with compound (IX) (obtained in turn from reaction between aldehyde (VI) and chloro derivative (VII) with K2CO3 in DMF) by means of piperidine in refluxing toluene, followed by treatment with NaOAc in refluxing MeOH. Chromanone (VIII) is then alkylated either with MeLi or with methylmagnesium bromide in THF and then dehydrated and deprotected in HOAc furnishing chromene (X). Racemic compound (X) is then resolved to afford enantiomer (XI) either by preparative chiral HPLC or by chemical resolution of the corresponding diastereomeric salt obtained by reaction with (+)-CSA in DMF/CH2Cl2, and treatment of the resulting salt with saturated K2CO3 . Finally, the target product is obtained by acylation of (XI) by reaction with pivaloyl chloride (XII) and Et3N in CH2Cl2.
| 【1】 Caron, B.; Cloutier, J.; Gauthier, S.; (S)-(+)-4-[7-(2, 2-Dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl 2, 2-dimethylpropanoate (EM-800): A highly potent, specific, and orally active nonsteroidal antiestrogen. J Med Chem 1997, 40, 14, 2117. |
| 【2】 Labrie, F.; Merand, Y.; Gauthier, S. (Endorecherche Inc.); Benzopyran-containing cpds. and method for their use. EP 0811006; EP 1167364; JP 1999500133; WO 9626201 . |
| 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) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (II) | 10361 | 1,3-Dihydroxybenzene; m-Dihydroxybenzene; Resorcinol; Resorcin; 1,3-Benzenediol | 108-46-3 | C6H6O2 | 详情 | 详情 |
| (III) | 51229 | 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C14H12O4 | 详情 | 详情 | |
| (IV) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (V) | 51230 | 1-[2-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-1-ethanone | C24H28O6 | 详情 | 详情 | |
| (VI) | 13433 | 4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde | 123-08-0 | C7H6O2 | 详情 | 详情 |
| (VII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (VIII) | 51231 | 2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-7-(tetrahydro-2H-pyran-2-yloxy)-3-[4-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,3-dihydro-4H-chromen-4-one | C38H45NO7 | 详情 | 详情 | |
| (IX) | 35795 | 4-[2-(1-piperidinyl)ethoxy]benzaldehyde | 26815-04-3 | C14H19NO2 | 详情 | 详情 |
| (X) | 51232 | 3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-chromen-7-ol | C29H31NO4 | 详情 | 详情 | |
| (XI) | 51233 | (2S)-3-(4-hydroxyphenyl)-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-chromen-7-ol | C29H31NO4 | 详情 | 详情 | |
| (XII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Esterification of p-hydroxyphenylacetic acid (I) with NaHSO4 in refluxing butanol provides butyl acetate derivative (II), which is then subjected to reaction with epichlorohydrin (III) in pyridine to furnish a mixture of epoxypropane (IV) and chloro derivative (V). Treatment of the mixture (IV)/(V) with HCl affords derivative (VI), which is then selectively acylated by means of Lipase Amano PS (LAPS) and vinyl acetate or acetic anhydride/diisopropyl ether to yield compound (S)-(VII). Treatment of the mixture (IV)/(V) with acetyl chloride gives derivative (VIII), which is selectively deacylated using LAPS in butanol/diisopropyl ether to afford derivative (S)-(IX). Coupling of derivative (S)-(VII) with isopropylamine (X) in H2O, followed by removal of the acetyl group with NaOH furnishes derivative (XI) (alternatively, (XI) can also be synthesized by coupling of (S)-(IX) with amine (X)). Finally, conversion of (XI) into the desired product is achieved by treatment with ammonium hydroxide in MeOH.
| 【1】 Banerji, A.A.; Bevinakatti, H.S.; Lipase catalysis in organic solvents. Application to the synthesis of (R)- and (S)-atenolol. J Org Chem 1992, 57, 22, 6003. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V),(VI) | 51078 | butyl 2-[4-(3-chloro-2-hydroxypropoxy)phenyl]acetate | C15H21ClO4 | 详情 | 详情 | |
| (S)-(VII) | 51079 | butyl 2-(4-[[(2R)-2-(acetoxy)-3-chloropropyl]oxy]phenyl)acetate | C17H23ClO5 | 详情 | 详情 | |
| (S)-(IX) | 51080 | butyl 2-(4-[[(2R)-3-chloro-2-hydroxypropyl]oxy]phenyl)acetate | C15H21ClO4 | 详情 | 详情 | |
| (I) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (II) | 51075 | butyl 2-(4-hydroxyphenyl)acetate | C12H16O3 | 详情 | 详情 | |
| (III) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (IV) | 51077 | butyl 2-[4-(2-oxiranylmethoxy)phenyl]acetate | C15H20O4 | 详情 | 详情 | |
| (VIII) | 51082 | butyl 2-[4-[2-(acetoxy)-3-chloropropoxy]phenyl]acetate | C17H23ClO5 | 详情 | 详情 | |
| (X) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (XI) | 51081 | butyl 2-(4-[[(2S)-2-hydroxy-3-(isopropylamino)propyl]oxy]phenyl)acetate | C18H29NO4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Friedel-Crafts acylation of 3-methoxyphenol (I) with 4-hydroxyphenylacetic acid (II) in the presence of ZnCl2 and POCl3 furnished ketone (III), which was subsequently protected with triisopropylsilyl chloride and Et3N to yield the mono-silyl ether (IV). Coumarin (VI) was then synthesized by condensation of hydroxy ketone (IV) with phenylacetyl chloride (V) in the presence of K2CO3. Alkylation of the phenolic hydroxyl group of (VI) with N-(2-chloroethyl)piperidine (VII) gave the piperidinylethyl ether (VIII). Finally, selective methyl ether hydrolysis using HBr in refluxing HOAc led to the title compound.
| 【1】 Bhagwat, S.S.; McKie, J.A.; Khammungkhune, S. (Signal Pharmaceuticals, Inc.); Cpds. and methods for modulation of estrogen receptors. WO 0149673 . |
| 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) | 22389 | 3-Methoxyphenol | 150-19-6 | C7H8O2 | 详情 | 详情 |
| (II) | 18430 | 2-(4-Hydroxyphenyl)acetic acid; 4-Hydroxyphenylacetic acid | 156-38-7 | C8H8O3 | 详情 | 详情 |
| (III) | 56078 | 1-(2-hydroxy-4-methoxyphenyl)-2-(4-hydroxyphenyl)-1-ethanone | C15H14O4 | 详情 | 详情 | |
| (IV) | 56079 | 1-(2-hydroxy-4-methoxyphenyl)-2-{4-[(triisopropyl-lambda~4~-sulfanyl)oxy]phenyl}-1-ethanone | C24H34O4S | 详情 | 详情 | |
| (V) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (VI) | 56080 | 4-(4-hydroxybenzyl)-7-methoxy-3-phenyl-2H-chromen-2-one | C23H18O4 | 详情 | 详情 | |
| (VII) | 10117 | 1-(2-Chloroethyl)piperidine; N-(2-Chloroethyl)piperidine | 1932-03-2 | C7H14ClN | 详情 | 详情 |
| (VIII) | 56081 | 7-methoxy-3-phenyl-4-{4-[2-(1-piperidinyl)ethoxy]benzyl}-2H-chromen-2-one | C30H31NO4 | 详情 | 详情 |