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【结 构 式】 
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【分子编号】32754 【品名】p-Hydroxyphenylacetamide; 2-(4-hydroxyphenyl)acetamide; 4-Hydroxybenzeneacetamide; 4-Hydroxyphenylacetamide 【CA登记号】17194-82-0 |
【 分 子 式 】C8H9NO2 【 分 子 量 】151.165 【元素组成】C 63.56% H 6% N 9.27% O 21.17% |
合成路线1
该中间体在本合成路线中的序号：(IV)This compound has been obtained by two related ways: 1) The reaction of phenol (I) with formaldehyde gives 4-(hydroxymethyl)phenol (II), which is treated with NaCN in hot DMF to yield 2-(4-hydroxyphenyl)acetonitrile (III). The hydrolysis of (III) in refluxing ethanol/water, catalyzed by a Pt catalyst affords the corresponding acetamide (IV), which is condensed with an excess of hot epichlorohydrin (V) by means of piperidine gives 2-[4-(2-oxiranylmethoxy)phenyl]acetamide (VI). Finally, the oxirane ring of (VI) is opened with isopropylamine in methanol. 2)The condensation of acetonitrile (III) with epichlorohydrin (V) as before gives the 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile (VIII), which is treated with isopropylamine (VII) in methanol yielding 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile (IX). Finally, this compound is hydrolyzed with refluxing ethanol/water catalyzed by a Pt catalyst as before to afford the target acetamide.
| 【1】 Akisanya, J.; et al.; A synthesis of atenolol using a nitrile hydration catalyst. Org Process Res Dev 1998, 2, 4, 274. |
| 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) | 23540 | Phenol | 108-95-2 | C6H6O | 详情 | 详情 |
| (II) | 29474 | 4-(hydroxymethyl)phenol; 4-hydroxyphenylmethanol 4-hydroxybenzenemethanol; 4-Hydroxybenzyl alcohol | 623-05-2 | C7H8O2 | 详情 | 详情 |
| (III) | 32753 | 2-(4-hydroxyphenyl)acetonitrile; 4-Hydroxybenzyl cyanide | 14191-95-8 | C8H7NO | 详情 | 详情 |
| (IV) | 32754 | p-Hydroxyphenylacetamide; 2-(4-hydroxyphenyl)acetamide; 4-Hydroxybenzeneacetamide; 4-Hydroxyphenylacetamide | 17194-82-0 | C8H9NO2 | 详情 | 详情 |
| (V) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (VI) | 32755 | 2-[4-(2-oxiranylmethoxy)phenyl]acetamide | C11H13NO3 | 详情 | 详情 | |
| (VII) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
| (VIII) | 32756 | 2-[4-(2-oxiranylmethoxy)phenyl]acetonitrile | C11H11NO2 | 详情 | 详情 | |
| (IX) | 32757 | 2-[4-[2-hydroxy-3-(isopropylamino)propoxy]phenyl]acetonitrile | C14H20N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Prepared in two steps by condensation of p-hydroxyphenylacetamide (I) and epichlorhydrine (II) with piperidine as catalyst, giving 1-(p-carbamoylmethylphenoxy)-2,3-epoxypropane (III), m.p. 158-60 C, followed by reaction of the epoxy ring with isopropylamine (IV).
| 【1】 Barret, A.; et al.; Alkanolaminderivate. CH 547257; CH 553747; DE 2007751; ES 376788; FR 2034561 . |
| 【2】 Castaner, J.; Atenolol. Drugs Fut 1976, 1, 1, 7. |
| 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) | 32754 | p-Hydroxyphenylacetamide; 2-(4-hydroxyphenyl)acetamide; 4-Hydroxybenzeneacetamide; 4-Hydroxyphenylacetamide | 17194-82-0 | C8H9NO2 | 详情 | 详情 |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 32755 | 2-[4-(2-oxiranylmethoxy)phenyl]acetamide | C11H13NO3 | 详情 | 详情 | |
| (IV) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(V)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 |