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【结 构 式】 
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【分子编号】16240 【品名】3-phenylpropanoyl chloride; Hydrocinnamoylchloride 【CA登记号】645-45-4 |
【 分 子 式 】C9H9ClO 【 分 子 量 】168.62256 【元素组成】C 64.11% H 5.38% Cl 21.02% O 9.49% |
合成路线1
该中间体在本合成路线中的序号：(III)1) The reaction of cis-(1S,2R)-indanediol (I) with acetonitrile and concentrated H2SO4 gives cis-(1S,2R)-1-aminoindan-2-ol (II), which is cyclocondensed with 3-phenylpropionyl chloride (III), isopropenyl methyl ether and triethylamine to yield the acetonide amide (IV). The condensation of amide (IV) with (S)-(+)-glycidyl p-toluenesulfonate (V) in the presence of lithium hexamethyldisylazide (LHS) affords the chiral epoxide (VI), which is condensed with 4-(tert-butoxycarbonyl)-N-tert-butylpiperazine-2(S)-carboxamide (VII) in refluxing isopropyl acetate and deprotected with aqueous HCl to give the dihydroxy-diamide (VIII). Finally, this compound is condensed with 3-(chloromethyl)pyridine (IX) by means of triethylamine in DMF. 2) The amide (IV) can also be alkylated with allyl bromide and butyllithium to the pentenyl amide (X), which is diastereoselectively converted to the chiral iodohydrine (XI) by means of N-iodosuccinimide (NIS). Finally, this compound is cyclized in basic medium, yielding the epoxide (VI), already obtained.
| 【1】 Maligres, P.E.; Upadhyay, V.; Rossen, K.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate. Tetrahedron Lett 1995, 36, 13, 2195-8. |
| 【2】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600. |
| 【3】 Askin, D.; Volante, R.P.; Eng, K.K. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502584 . |
| 【4】 Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 . |
| 【5】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6. |
| 【6】 Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 | |
| 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 | |
| (I) | 16238 | (1S,2R)-2,3-dihydro-1H-indene-1,2-diol | 67528-22-7 | C9H10O2 | 详情 | 详情 |
| (II) | 16239 | (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol | 126456-43-7 | C9H11NO | 详情 | 详情 |
| (III) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (IV) | 16241 | 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone | C21H23NO2 | 详情 | 详情 | |
| (V) | 16242 | (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate | 113826-06-5 | C10H12O4S | 详情 | 详情 |
| (VI) | 16243 | (2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone | C24H27NO3 | 详情 | 详情 | |
| (VII) | 16244 | tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate | 150323-35-6 | C14H27N3O3 | 详情 | 详情 |
| (VIII) | 16245 | (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide | C30H42N4O4 | 详情 | 详情 | |
| (IX) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (X) | 16247 | (2S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-penten-1-one | C24H27NO2 | 详情 | 详情 | |
| (XI) | 16248 | (2R,4S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone | C24H28INO3 | 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 reaction of 4(R)-benzyloxazolidin-2-one (I) with 3-phenylpropionyl chloride (II) by means of BuLi in THF gives 4(R)-benzyl-3-(3-phenylpropionyl)oxazolidin-2-one (III), which is condensed with 4-bromo-2-fluorobenzaldehyde (IV) by means of dibutylboron triflate or TiCl4 yielding the chiral intermediate (V). The reductive elimination of the oxazolidinone group affords (1R,2S)-2-benzyl-1-(4-bromo-2-fluorophenyl)propane-1,3-diol (VI), which is cyclized by means of sodium bis(trimethylsilyl)amide in hot DMSO to give the chiral dihydro-1-benzopyran (VII).The reaction of (VII) with the borane-THF complex and methyllithium in THF affords the boronic acid (VIII), which is condensed with 2-iodo-4-(trifluoromethyl)benzoic acid ethyl ester (IX) by means of KF and Pd/C in refluxing ethanol to provide the ethyl ester (X) of the target comopound. Finally, this compound is hydrolyzed with NaOH in refluxing isopropanol.
| 【1】 Piscopio, A.D.; Hawkins, J.M.; Caron, S.; Kelly, S.E.; Raggon, J.W.; Ruggeri, S.G.; Castaldi, M.J.; Dugger, R.W. (Pfizer Inc.); Processes and intermediates for preparing substd. chromanol derivs.. WO 9811085 . |
| 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) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (II) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (III) | 27829 | (4R)-4-benzyl-3-(3-phenylpropanoyl)-1,3-oxazolidin-2-one | C19H19NO3 | 详情 | 详情 | |
| (IV) | 27830 | 4-bromo-2-fluorobenzaldehyde | 57848-46-1 | C7H4BrFO | 详情 | 详情 |
| (V) | 27831 | (4R)-4-benzyl-3-[(2R,3R)-2-benzyl-3-(4-bromo-2-fluorophenyl)-3-hydroxypropanoyl]-1,3-oxazolidin-2-one | C26H23BrFNO4 | 详情 | 详情 | |
| (VI) | 27832 | (1R,2S)-2-benzyl-1-(4-bromo-2-fluorophenyl)-1,3-propanediol | C16H16BrFO2 | 详情 | 详情 | |
| (VII) | 27833 | (3S,4R)-3-benzyl-7-bromo-5-fluoro-3,4-dihydro-2H-chromen-4-ol | C16H14BrFO2 | 详情 | 详情 | |
| (VIII) | 27834 | (3S,4R)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-ylboronic acid | C16H17BO4 | 详情 | 详情 | |
| (IX) | 27835 | ethyl 2-iodo-4-(trifluoromethyl)benzoate | C10H8F3IO2 | 详情 | 详情 | |
| (X) | 27836 | ethyl 2-[(3S,4R)-3-benzyl-4-hydroxy-3,4-dihydro-2H-chromen-7-yl]-4-(trifluoromethyl)benzoate | C26H23F3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The cyclization of 2-amino-5-bromobenzoic acid (I) with 3-phenylpropionyl chloride (II) by means of DMAP and Et3N in DMF gives the benzoxazinone (III), which by heating with glycine methyl ester (IV) yields the quinazolinone (V). The hydrolysis if (V) with NaOH in THF/water affords 2-[6-bromo-4-oxo-2-(2-phenylethyl)-3,4-dihydroquinazolin-3-yl]acetic acid (VI), which is condensed with the monoprotected hexane-1,6-diamine (VII), by means of HOBt, EDC and NMM to provide the amide (VIII). The condensation of (VIII) with phenylboronic acid (IX) by means of palladium tetrakis(triphenylphosphoine) gives the 6-phenyl substituted quinazolinone (X), which is finally deprotected with HCl.
| 【1】 Ye, Z.; Bakshi, R.K.; Gao, Y.; et al.; Modeling directed design and biological evaluation of quinazolinones as non-peptidic growth hormone secretagogues. Bioorg Med Chem Lett 2000, 10, 1, 5. |
| 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) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (I) | 31634 | 2-amino-5-bromobenzoic acid | 5794-88-7 | C7H6BrNO2 | 详情 | 详情 |
| (II) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (III) | 31635 | 6-bromo-2-phenethyl-4H-3,1-benzoxazin-4-one | C16H12BrNO2 | 详情 | 详情 | |
| (IV) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (V) | 31636 | methyl 2-[6-bromo-4-oxo-2-phenethyl-3(4H)-quinazolinyl]acetate | C19H17BrN2O3 | 详情 | 详情 | |
| (VI) | 31637 | 2-[6-bromo-4-oxo-2-phenethyl-3(4H)-quinazolinyl]acetic acid | C18H15BrN2O3 | 详情 | 详情 | |
| (VII) | 31638 | tert-butyl 6-aminohexylcarbamate | 51857-17-1 | C11H24N2O2 | 详情 | 详情 |
| (VIII) | 31639 | tert-butyl 6-([2-[6-bromo-4-oxo-2-phenethyl-3(4H)-quinazolinyl]acetyl]amino)hexylcarbamate | C29H37BrN4O4 | 详情 | 详情 | |
| (IX) | 31640 | tert-butyl 6-([2-[4-oxo-2-phenethyl-6-phenyl-3(4H)-quinazolinyl]acetyl]amino)hexylcarbamate | C35H42N4O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VIII)Alkylation of diphenylamine (I) with THP-protected 3-bromopropanol (II) using NaH in 15-crown-5 yields tertiary amine (III), which is then deprotected with HOAc/H2O to provide (IV). Alcohol (IV) is treated with PPh3 and CBr4 to afford alkyl bromide (V), which is then converted into amine (VII) by reaction with 2,6-dimethylpiperazine (VI) in DMF/H2O in the presence of K2CO3. Finally, (VII) is acylated with 3-phenylpropionyl chloride (VIII) and reduced with LAH.
| 【1】 Vilner, B.J.; Husbands, S.M.; Bowen, W.D.; Newman, A.H.; Kopajtic, T.; Izenwasser, S.; Katz, J.L.; Structure-activity relationships at the monoamine transporters and sigma receptors for a novel series of 9-[3-(cis-3,5-dimethyl-1-piperazinyl)-propyl]carbazole (rimcazole) analogues. J Med Chem 1999, 42, 21, 4446. |
| 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) | 42251 | Diphenylamine; N-phenylaniline; N,N-diphenylamine | 122-39-4 | C12H11N | 详情 | 详情 |
| (II) | 42252 | 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran | C8H15BrO2 | 详情 | 详情 | |
| (III) | 42253 | N-phenyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]aniline; N,N-diphenyl-N-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]amine | C20H25NO2 | 详情 | 详情 | |
| (IV) | 42254 | 3-(diphenylamino)-1-propanol | C15H17NO | 详情 | 详情 | |
| (V) | 42255 | N-(3-bromopropyl)-N-phenylaniline; N-(3-bromopropyl)-N,N-diphenylamine | C15H16BrN | 详情 | 详情 | |
| (VI) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (VII) | 42256 | N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-N,N-diphenylamine; N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-N-phenylaniline | C21H29N3 | 详情 | 详情 | |
| (VIII) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XI)The CuI-assisted coupling between methyl N-(4-fluorophenyl)carbamate (I) and 1-bromo-4-fluorobenzene (II) produced the N,N-bis(4-fluorophenyl)carbamate (III), which was subsequently hydrolyzed to bis(4-fluorophenyl)amine (IV) using ethanolic KOH. Acylation of diarylamine (IV) with 3-bromopropionyl chloride (V) gave bromopropionamide (VI). This was then condensed with cis-2,6-dimethylpiperazine (VII) to yield the 3-piperazinylpropionamide (VIII). Amide reduction with LiAlH4 provided the triamino compound (IX). Acid chloride (XI), prepared from hydrocinnamic acid (X), was then coupled with piperazine (IX) to furnish amide (XII). The amide function was finally reduced to the corresponding amine by using LiAlH4.
| 【1】 Cao, J.; Husbands, S.M.; Kopajtic, T.; Newman, A.H.; Katz, J.L.; [3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amine analogues as novel for the dopamine transporter. Bioorg Med Chem Lett 2001, 11, 24, 3169. |
| 【2】 Ca, J.; Newman, A.H.; Kopajtic, T.; Katz, J.L.; Husbands, S.M.; [3-cis-3,5-Dimethyl-1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amines analogs as novel probes for the dopamine transporter. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 96. |
| 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) | 49174 | methyl 4-fluorophenylcarbamate | C8H8FNO2 | 详情 | 详情 | |
| (II) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |
| (III) | 49175 | methyl bis(4-fluorophenyl)carbamate | C14H11F2NO2 | 详情 | 详情 | |
| (IV) | 49176 | 4-fluoro-N-(4-fluorophenyl)aniline; N,N-bis(4-fluorophenyl)amine | C12H9F2N | 详情 | 详情 | |
| (V) | 49177 | 3-Bromopropionyl chloride; beta-Bromopropionyl chloride | 15486-96-1 | C3H4BrClO | 详情 | 详情 |
| (VI) | 49178 | 3-bromo-N,N-bis(4-fluorophenyl)propanamide | C15H12BrF2NO | 详情 | 详情 | |
| (VII) | 20848 | (2R,6S)-2,6-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (VIII) | 49179 | 3-[(3R,5S)-3,5-dimethylpiperazinyl]-N,N-bis(4-fluorophenyl)propanamide | C21H25F2N3O | 详情 | 详情 | |
| (IX) | 49180 | N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-N,N-bis(4-fluorophenyl)amine; N-[3-[(3R,5S)-3,5-dimethylpiperazinyl]propyl]-4-fluoro-N-(4-fluorophenyl)aniline | C21H27F2N3 | 详情 | 详情 | |
| (X) | 49181 | Hydrocinnamic acid; 3-Phenylpropionic acid; Benzylacetic acid | 501-52-0 | C9H10O2 | 详情 | 详情 |
| (XI) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (XII) | 49182 | 1-((2R,6S)-4-[3-[bis(4-fluorophenyl)amino]propyl]-2,6-dimethylpiperazinyl)-3-phenyl-1-propanone | C30H35F2N3O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)Condensation of 4-bromoaniline (I) with 3-phenylpropionyl chloride (II) by means of triethylamine in dichloromethane gives the propionamide (III), which is cyclized with dimethylformamide by means of POCl3 in hot DMF to yield 3-benzyl-6-bromo-2-chloroquinoline (IV). Reaction of compound (IV) with NaOMe in refluxing methanol affords the 2-methoxyquinoline derivative (V), which is condensed with 3-(dimethylamino)-1-(1-naphthyl)propanone (VI) by means of BuLi in THF to provide a mixture of two diastereomeric racemates (R*,R*/R*,S*) (VII) that are separated by column chromatography. Finally, the desired (R*,S*)-racemic mixture is submitted to chiral chromatography (1). Scheme 1.
In an improved process, 3-benzyl-6-bromo-2-methoxyquinoline (V) is condensed with 3-(dimethylamino)-1-(1-naphthyl)propanone (VI) by means of LDA in THF and then treated with AcOH to afford the tertiary alcohol (VII). Finally, alcohol (VII) is submitted to optical resolution by crystallization with chiral 4-hydroxydinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepin 4-oxide (2). Scheme 1.
| 【1】 Van Gestel, J.F.E., Venet, M.G., Vernier, D.F.J., Decrane, L.F.B., Poignet, H.J.J. (Janssen Pharmaceutica NV). Quinoline derivatives and their use as mycobacterial inhibitors. CA 2493225, EP 1527050, JP 2006504658, WO 2004011436. |
| 【2】 Porstmann, F.R., Horns, S., Bader, T. (Janssen Pharmaceutica NV). Process for preparing (alphaS,betaR)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol. CA 2606675, EP 1888604, US 2008200683, WO 2006125769. |
| 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) | 22531 | 4-Bromoaniline; 4-Bromophenylamine | 106-40-1 | C6H6BrN | 详情 | 详情 |
| (II) | 16240 | 3-phenylpropanoyl chloride; Hydrocinnamoylchloride | 645-45-4 | C9H9ClO | 详情 | 详情 |
| (III) | 65794 | N-(4-Bromophenyl)-3-Phenylpropanamide | 316146-27-7 | C15H14BrNO | 详情 | 详情 |
| (IV) | 65795 | 6-Bromo-2-chloro-3-(phenylmethyl)quinoline | 654655-68-2 | C16H11BrClN | 详情 | 详情 |
| (V) | 65796 | 3-Benzyl-6-bromo-2-methoxyquinoline | 654655-69-3 | C17H14BrNO | 详情 | 详情 |
| (VI) | 65797 | 3-(Dimethylamino)-1-(naphthalen-1-yl)propan-1-one; (2-alpha-Naphthoylethyl)dimethylamine; 2-(Dimethylamino)ethyl 1-naphthyl ketone | 10320-49-7 | C15H17NO | 详情 | 详情 |
| (VII) | 65798 | 6-Bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol | 654655-80-8 | C32H31BrN2O2 | 详情 | 详情 |