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【结 构 式】 
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【分子编号】18327 【品名】benzyl(chloro)magnesium 【CA登记号】6921-34-2 |
【 分 子 式 】C7H7ClMg 【 分 子 量 】150.89028 【元素组成】C 55.72% H 4.68% Cl 23.5% Mg 16.11% |
合成路线1
该中间体在本合成路线中的序号：(IV)The syntheses of remacemide [13C]-, [14C]-, [2H]-,and [3H]-labeled in several different positions have been described: The Friedel Crafts condensation of benzene with acetyl chloride (II) by means of AlCl3 in CS2 gives acetophenone (III), which by a Grignard condensation with benzylmagnesium chloride (IV) in THF yields 1,2-diphenyl-3-propanol (V). Reaction of (V) with NaCN and sulfuric acid in acetic acid affords the formamide (VI), which is hydrolyzed with refluxing aqueous HCl to give the amine (VII). The condensation of (VII) with N-Boc-glycine (VIII) and DCC or with the N-Boc-glycine mixed anhydride (IX) and TEA in dichloromethane yields the protected glycinamide (X), which is finally deprotected with HCl in refluxing methanol. Alternatively, condensation of amine (VII) with chloroacetyl chloride (XI) by means of pyridine in dichloromethane provides the chloroacetamide (XII), which is finally treated with ammonia in ethanol/dichloromethane. In this reaction sequence, the use of [carbonyl-14C]-acetophenone (III), [13C6]-benzene (I), [13C2]-acetyl chloride (II), the [1-13C]-glycines (VIII) and (IX) or the [2-3H]-glycine (VIII) as starting materials affords remacemide labeled in the corresponding positions. [2H or 3H]-remacemide labeled in 2,6-positions of the 1-phenyl ring is obtained by submitting the amine (VII) to isotopic exchange with 2H2O/RhCl3, 2H2/Iridium complex, or 3H2/Iridium complex.
| 【1】 Dawson, G.E.; Coombs, M.E.; Fedorchuk, M.; et al.; Preparation of remacemide hydrochloride labelled with carbon-14, carbon-13, deuterium and tritium. J Label Compd Radiopharm 2000, 43, 6, 533. |
| 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) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (II) | 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 |
| (III) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (IV) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (V) | 41763 | 1,2-diphenyl-2-propanol | 5342-87-0 | C15H16O | 详情 | 详情 |
| (VI) | 41764 | 1-methyl-1,2-diphenylethylformamide | C16H17NO | 详情 | 详情 | |
| (VII) | 41765 | 1-methyl-1,2-diphenylethylamine; 1,2-diphenyl-2-propanamine | C15H17N | 详情 | 详情 | |
| (VIII) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (IX) | 41766 | [(tert-butoxycarbonyl)amino]acetic 1,1-dimethylpropionic anhydride | C12H21NO5 | 详情 | 详情 | |
| (X) | 41767 | tert-butyl 2-[(1-methyl-1,2-diphenylethyl)amino]-2-oxoethylcarbamate | C22H28N2O3 | 详情 | 详情 | |
| (XI) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (XII) | 41768 | 2-chloro-N-(1-methyl-1,2-diphenylethyl)acetamide | C17H18ClNO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The cyclization of 4-chloro-3,3-dimethylbutyronitrile (I) with benzylmagnesium chloride (II) in ethyl ether containing some iodine gives 2-benzyl-4,4-dimethyl-1-pyrroline (III), which is cyclized with 4'-chlorophenacyl bromide (IV) by means of NaHCO3 in methanol, yielding 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro.1H-pyrrolizine (V). The condensation of (V) with oxalyl chloride (VI) in THF affords 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetyl chloride (VII), which is finally reduced and hydrolyzed with hydrazine in hot diethyleneglycol to provide the target licofelone.
| 【1】 Laufer, S.; Striegel, H.-G.; Kammermeier, T.; Merckle, P. (Merckle GmbH); Method for producing 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl acetic acid. US 6417371; WO 0155149 . |
| 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) | 60052 | 4-chloro-3,3-dimethylbutanenitrile | C6H10ClN | 详情 | 详情 | |
| (II) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (III) | 16719 | 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole | 116673-95-1 | C13H17N | 详情 | 详情 |
| (IV) | 16720 | 2-bromo-1-(4-chlorophenyl)-1-ethanone; 2-Bromo-4'-chloroacetophenone | 536-38-9 | C8H6BrClO | 详情 | 详情 |
| (V) | 16721 | 6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine | C21H20ClN | 详情 | 详情 | |
| (VI) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
| (VII) | 60053 | 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetyl chloride | C23H19Cl2NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot ethanol/water gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII). The protection of the amino group of (VII) with Boc2O and K2CO3 in methyl tert-butyl ether yields the carbamate (VIII), which is debenzylated with ammonium formate over Pd/C in methanol affording the amino compound (IX). The condensation of (IX) with 2-(2,6-dimethylphenoxy)acetic acid (X) by means of EDAC in DMF provides the corresponding amide (XI), which is deprotected at the carbamate group with TFA in dichloromethane to give (XII) with a free amino group. Finally, this compound is condensed with 3-methyl 2(S)-(2-oxoperhydropyrimidin-1-yl)butyric acid (XIII) by means of EDAC in DMF or SOCl2 and imidazole to furnish the target compound. The intermediate 2-(2,6-dimethylphenoxy)acetic acid (X) has been obtained by condensation of 2,6-dimethylphenol (XIV) with ethyl 2-bromoacetate (XV) by means of Cs2CO3 in refluxing dioxane to give the acetate ester (XVI), which is hydrolyzed with LiOH ethanol/water to afford the target intermediate (X).
| 【1】 Stoner, E.J.; et al.; Synthesis of ABT-378, an HIV protease inhibitor candidate: Avoiding the use of carbodiimides in a difficult peptide coupling. Org Process Res Dev 1999, 3, 2, 145. |
| 【2】 Sham, H.L.; Stewart, K.D.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. EP 0876353; JP 2000502997; WO 9721683 . |
| 【3】 Retroviral protease inhibiting cpds.. EP 0882024; JP 2000502085; US 5914332; WO 9721685 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 | |
| (I) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (III) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IV) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (V) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (VI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (VII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (VIII) | 38542 | tert-butyl (1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentylcarbamate | C37H44N2O3 | 详情 | 详情 | |
| (IX) | 38543 | tert-butyl (1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentylcarbamate | C23H32N2O3 | 详情 | 详情 | |
| (X) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 | |
| (XI) | 38545 | tert-butyl (1S,3S,4S)-1-benzyl-4-[[2-(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenylpentylcarbamate | C33H42N2O5 | 详情 | 详情 | |
| (XII) | 38546 | N-[(1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl]-2-(2,6-dimethylphenoxy)acetamide | C28H34N2O3 | 详情 | 详情 | |
| (XIII) | 38264 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid | C9H16N2O3 | 详情 | 详情 | |
| (XIV) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (XV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XVI) | 38544 | ethyl 2-(2,6-dimethylphenoxy)acetate | C12H16O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The reaction of L-phenylalanine (I) with benzyl bromide and K2CO3 in hot EtOH/H2O gives N,N,O-tribenzyl derivative (II), which is condensed with acetonitrile (III) by means of NaNH2 in THF yielding the pentanenitrile (IV). The reaction of nitrile (IV) with benzylmagnesium chloride (V) in THF affords the diphenylhexenone (VI), which is reduced with NaBH4 in THF to give the diphenylhexanol (VII) (slightly impurified (~10%) with other diastereomers that are not eliminated at this stage). The condensation of (VII) with acid chloride (VIII) (obtained by reaction of acid (IX) with SOCl2) in the presence of imidazole yields the amide (X), which is debenzylated with ammonium formate over Pd/C in methanol affording the amine (XI). At this stage the purification (elimination of the diastereomers) has been performed by crystallization of its salt with L-pyroglutamic acid (XII) in EtOH/DMF, pure salt (XIII) being obtained. Finally, this compound is condensed with the acid chloride (XIV) (obtained by reaction of acid (XV) with SOCl2) by means of NaHCO3 in ethyl acetate/water. The intermediates, the acids (IX) and (XV), have been obtained as indicated in schemes 24659001a and 24659001b (intermediates (XIII) and (X) of these schemes, respectively).
| 【1】 Stoner, E.J.; et al.; Synthesis of HIV protease inhibitor ABT-378 (lopinavir). Org Process Res Dev 2000, 4, 4, 264. |
| 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) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (II) | 37670 | benzyl (2S)-2-(dibenzylamino)-3-phenylpropanoate | C30H29NO2 | 详情 | 详情 | |
| (III) | 37210 | acetonitrile | 75-05-8 | C2H3N | 详情 | 详情 |
| (IV) | 38263 | (4S)-4-(dibenzylamino)-3-oxo-5-phenylpentanenitrile | C25H24N2O | 详情 | 详情 | |
| (V) | 18327 | benzyl(chloro)magnesium | 6921-34-2 | C7H7ClMg | 详情 | 详情 |
| (VI) | 37671 | (2S,4E)-5-amino-2-(dibenzylamino)-1,6-diphenyl-4-hexen-3-one | C32H32N2O | 详情 | 详情 | |
| (VII) | 37672 | (2S,3S,5S)-5-amino-2-(dibenzylamino)-1,6-diphenyl-3-hexanol | C32H36N2O | 详情 | 详情 | |
| (VIII) | 38265 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl chloride | C9H15ClN2O2 | 详情 | 详情 | |
| (IX) | 38264 | (2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butyric acid | C9H16N2O3 | 详情 | 详情 | |
| (X) | 38266 | (2S)-N-[(1S,3S,4S)-1-benzyl-4-(dibenzylamino)-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanamide | C41H50N4O3 | 详情 | 详情 | |
| (XI) | 38267 | (2S)-N-[(1S,3S,4S)-4-amino-1-benzyl-3-hydroxy-5-phenylpentyl]-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanamide | C27H38N4O3 | 详情 | 详情 | |
| (XII) | 32406 | (2S)-5-oxo-2-pyrrolidinecarboxylic acid | 98-79-3 | C5H7NO3 | 详情 | 详情 |
| (XIII) | 38268 | (2S,3S,5S)-3-hydroxy-5-([(2S)-3-methyl-2-[2-oxotetrahydro-1(2H)-pyrimidinyl]butanoyl]amino)-1,6-diphenyl-2-hexanaminium (2S)-5-oxo-2-pyrrolidinecarboxylate | C32H45N5O6 | 详情 | 详情 | |
| (XIV) | 38269 | 2-(2,6-dimethylphenoxy)acetyl chloride | C10H11ClO2 | 详情 | 详情 | |
| (XV) | 38270 | 2-(2,6-dimethylphenoxy)acetic acid | C10H12O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Conjugate addition of benzylmagnesium chloride (II) to unsaturated ketone (I) in the presence of cuprous iodide-dimethyl sulfide complex afforded the 2-benzyl derivative (III). Then, the ester function was saponified with NaOH in MeOH to give the title acid. Resolution of the enantiomers was effected by fractional crystallization of the ephedrine salts.
| 【1】 Giordani, A.; Pevarello, P.; Cini, M.; Bormetti, R.; Greco, F.; Toma, S.; Speciale, C.; Varasi, M.; 4-Phenyl-4-oxo-butanoic acid derivatives inhibitors of kynurenine 3-hydroxylase. Bioorg Med Chem Lett 1998, 8, 20, 2907. |