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【结 构 式】 
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【药物名称】Esatenolol, (S)-Atenolol, TN-891 【化学名称】(S)-2-[4-[2-Hydroxy-3-(isopropylamino)propoxy]phenyl]acetamide 【CA登记号】93379-54-5 【 分 子 式 】C14H22N2O3 【 分 子 量 】266.34304 |
【开发单位】Taiyo (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, beta-Adrenoceptor Antagonists |
合成路线1
Condensation of acetamide (I) with (R)-epichlorohydrin (II) by means of either NaOH, LiOH or NaOH/benzyltrimethylammonium chloride (BTA-Cl) in H2O yields a mixture of epoxypropane (III) and chloropropanol derivative (IV) that can be converted into the desired product either by direct coupling with isopropylamine (V) in MeOH, or by first reaction of the mixture (III)/(IV) with NaOH to give (S)-(III) and next coupling with (V) as described above (1-3). Alternatively, derivative (S)-(III) can also be obtained by coupling of glycidyl nosylate (VI) with acetamide (I) by means of CsF in DMF.
| 【1】 Kitaori, K.; et al.; A practical synthesis of optically active atenolol from chiral epichlorohydrin. Chem Pharm Bull 1997, 45, 2, 412. |
| 【2】 Kitaori, K.; et al.; CsF in organic synthesis. Regioselective nucleophilic reactions of phenols with oxiranes leading to enantiopure beta-blockers. Tetrahedron 1999, 55, 50, 14381. |
| 【3】 Kitaori, K.; et al.; Convenient preparation of enantiopure atenolol by means of preferential crystallization. Chem Pharm Bull 1998, 46, 3, 505. |
| 【4】 Saragai, N.; Takehira, Y.; Kitaori, K. (Daiso Co., Ltd.); Process for producing optically active atenolol and intermediate thereof. EP 0435068 . |
| 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)-(III) | 51074 | 2-[4-[(2S)oxiranylmethoxy]phenyl]acetamide | C11H13NO3 | 详情 | 详情 | |
| (I) | 32754 | p-Hydroxyphenylacetamide; 2-(4-hydroxyphenyl)acetamide; 4-Hydroxybenzeneacetamide; 4-Hydroxyphenylacetamide | 17194-82-0 | C8H9NO2 | 详情 | 详情 |
| (II) | 38067 | (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin | 51594-55-9 | C3H5ClO | 详情 | 详情 |
| (III) | 51072 | 2-[4-[oxiranylmethoxy]phenyl]acetamide | C11H13NO3 | 详情 | 详情 | |
| (IV) | 51073 | 2-(4-[[(2R)-3-chloro-2-hydroxypropyl]oxy]phenyl)acetamide | C11H14ClNO3 | 详情 | 详情 | |
| (V) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (VI) | 45631 | (2S)oxiranylmethyl 4-nitrobenzenesulfonate | C9H9NO6S | 详情 | 详情 |
合成路线2
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3
Treatment of sodium phenoxide derivative (I) with Amberlite IRA-400 (containing quaternary ammonium groups) provides resin (II), which is then coupled with epichlorohydrin (III) in refluxing MeOH to afford arylepoxyether (IV). Finally, (S)-atenolol is obtained by reaction of (IV) with isopropylamine (V) in refluxing MeOH.
| 【1】 Damle, S.V.; et al.; One pot synthesis of (±)/(S)-atenolol and (±)/(S)-propranolol by employing polymer supported reagent. Synth Commun 1999, 29, 10, 1639. |
| 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) | 51083 | sodium 4-(2-amino-2-oxoethyl)benzenolate | C8H8NNaO2 | 详情 | 详情 | |
| (II) | 51084 | N,N,N-trimethylmethanaminium 4-(2-amino-2-oxoethyl)benzenolate | C12H20N2O2 | 详情 | 详情 | |
| (III) | 38067 | (2R)-2-(Chloromethyl)oxirane; (R)-Epichlorohydrin | 51594-55-9 | C3H5ClO | 详情 | 详情 |
| (IV) | 51072 | 2-[4-[oxiranylmethoxy]phenyl]acetamide | C11H13NO3 | 详情 | 详情 | |
| (V) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线4
The preparation of (S)-atenolol can be performed by resolution of racemic atenolol (I) in different ways: 1. Incubation of (I) with R. arrhizus or G. candidum followed by chromatographic separation, 2. Acetylation of (I), followed by resolution of the enantiomers by incubation with R. arrhizus or G. candidum and subsequent chromatographic separation to afford acetylated derivative (S)-(III). Finally, (S)-atenolol can be recovered by hydrolysis with K2CO3 in MeOH. 3. Treatment of (I) with Lipase PS-D and vinyl acetate or succinic anhydride (which selectively acetylates the nondesired enantiomer), followed by chromatographic separation.
| 【1】 Damle, S.V.; et al.; Biotransformations with Rhizopus arrhizus and Geotrichum candidum for the preparation of (S)-atenolol and (S)-propranolol. Bioorg Med Chem 2000, 8, 8, 2067. |
| 【2】 Damle, S.V.; et al.; Chemoenzymatic synthesis of (R)- and (S)-atenolol and propranolol employing lipase catalyzed enantioselective esterification and hydrolysis. Synth Commun 1999, 29, 22, 3855. |
| 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)-(III) | 51087 | (1S)-2-[4-(2-amino-2-oxoethyl)phenoxy]-1-[(isopropylamino)methyl]ethyl acetate | C16H24N2O4 | 详情 | 详情 | |
| (I) | 51085 | 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetamide | C14H22N2O3 | 详情 | 详情 | |
| (II) | 51086 | 2-[4-(2-amino-2-oxoethyl)phenoxy]-1-[(isopropylamino)methyl]ethyl acetate | C16H24N2O4 | 详情 | 详情 |
合成路线5
In this scheme various methods are shown for the synthesis of (S)-atenolol: 1. Treatment of (R)-glycidyl 4-nitrobenzenesulfonate (I) with HCl (either concentrated or with dichloromethane) provides 3-chloropropyl derivative (II), which is then coupled with isopropylamine (III) in dichloromethane to afford 3-chloropropylisopropylamine (IV). Finally, condensation of (IV) with 2-(4-hydroxyphenyl)acetamide (V) by means of KOH in MeOH gives the desired product. Alternatively, derivative (IV) can be converted into (S)-atenolol by its condensation with 2-(4-hydroxy-phenyl)acetonitrile (VI) by means of KOH to yield compound (VII), followed by hydrolysis with HCl at 40 C. 2. Condensation of (R)-glycidyl 3-nitrobenzenesulfonate (VIII) with isopropylamine (III) followed by coupling with acetamide (V) by means of potassium tert-butylate in DMSO provides the desired product. 3. Treatment of (VIII) with HCl affords 2(S)-hydroxy-3-chloropropyl-3-nitrobenzenesulfonate (IX), which is first coupled with isopropylamine (III) to give (IV) and finally condensed with amide (V). 4. Coupling of chloro derivative (IX) with benzyl-protected isopropylamine (X) provides protected derivative (XI), which is then condensed with acetamide (V) by means of KOH in MeOH to give (XII). Finally, compound (XII) is hydrogenated over Pd/C in MeOH for removal of the benzyl group.
| 【1】 Westfelt, A.; Andersson, L.; Birgersson, B.; Westfelt, L.; Process for preparing homochiral amines and process for preparing intermediates for the preparation thereof, and the intermediates prepared in accordance with this process. WO 9110642 . |
| 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) | 45631 | (2S)oxiranylmethyl 4-nitrobenzenesulfonate | C9H9NO6S | 详情 | 详情 | |
| (II) | 51089 | (2S)-3-chloro-2-hydroxypropyl 4-nitrobenzenesulfonate | C9H10ClNO6S | 详情 | 详情 | |
| (III) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (IV) | 51090 | (2S)-1-chloro-3-(isopropylamino)-2-propanol | C6H14ClNO | 详情 | 详情 | |
| (V) | 32754 | p-Hydroxyphenylacetamide; 2-(4-hydroxyphenyl)acetamide; 4-Hydroxybenzeneacetamide; 4-Hydroxyphenylacetamide | 17194-82-0 | C8H9NO2 | 详情 | 详情 |
| (VI) | 32753 | 2-(4-hydroxyphenyl)acetonitrile; 4-Hydroxybenzyl cyanide | 14191-95-8 | C8H7NO | 详情 | 详情 |
| (VII) | 51088 | 2-(4-[[(2S)-2-hydroxy-3-(isopropylamino)propyl]oxy]phenyl)acetonitrile | C14H20N2O2 | 详情 | 详情 | |
| (VIII) | 16259 | (2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate | 115314-14-2 | C9H9NO6S | 详情 | 详情 |
| (IX) | 51091 | (2S)-3-chloro-2-hydroxypropyl 3-nitrobenzenesulfonate | C9H10ClNO6S | 详情 | 详情 | |
| (X) | 39750 | N-benzyl-N-isopropylamine; N-benzyl-2-propanamine | 102-97-6 | C10H15N | 详情 | 详情 |
| (XI) | 51092 | (2S)-1-[benzyl(isopropyl)amino]-3-chloro-2-propanol | C13H20ClNO | 详情 | 详情 | |
| (XII) | 51093 | 2-[4-([(2S)-3-[benzyl(isopropyl)amino]-2-hydroxypropyl]oxy)phenyl]acetamide | C21H28N2O3 | 详情 | 详情 |