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【结 构 式】 
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【分子编号】14461 【品名】2,3-Dihydro-4H-chromen-4-one; 4-Chromanone 【CA登记号】491-37-2 |
【 分 子 式 】C9H8O2 【 分 子 量 】148.16132 【元素组成】C 72.96% H 5.44% O 21.6% |
合成路线1
该中间体在本合成路线中的序号：(I)The racemic compound RP 58866 was synthesized as follows: The ethyl ester of (2,3-dihydro-4H-1-benzopyran-4-ylidene)acetic acid (II) is prepared by carrying out the Wittig-Horner reaction on commercially available chromanone (I), followed by catalytic hydrogenation over 10% Pd on carbon to yield the ethyl ester of 3,4-dihydro-2H-1-benzopyran-4-acetic acid (III). Reduction of this ester with lithium aluminum hydride gives the alcohol (IV), which is converted into the corresponding bromide (V) (1, 3) by reaction with N,N'-carbonyldiimidazole and an excess of allyl bromide. Subsequent condensation of (V) with 4-(3,4-dimethoxyphenyl)piperidine (VI) by refluxing in 2-butanone, followed by the addition of (E)-2-butenedioic acid (fumaric acid), yields the salt (RS)-1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)piperidine (E)-2-butenedioate (1:1) (VII).
| 【1】 Hardy, J.-C.; Renault, C. (Aventis SA); Novel benzopyran derivs., their preparation and medicines containing them. (Rhône-Poulenc Santé). AU 8819713; EP 0300908; FR 2618437; JP 1989040476; US 4977166 . |
| 【2】 Barreau, M.; Hardy, J.-C.; Martin, J.-P.; Renault, C. (Aventis SA); Benzopyran derivs., their preparation and pharmaceutical compsns. Containing them. (Rhône-Poulenc Santé). AU 9048584; EP 0379441; FR 2642069; JP 1990233675; US 5025013 . |
| 【3】 Barreau, M.; Hardy, J.-C.; Renault, C. (Aventis SA); Novel benzopyran derivs., their preparation and pharmaceutical compsns. containing them. (Rhône-Poulenc Santé). AU 9048583; EP 0379440; FR 2642068; JP 1990229188; US 4994470 . |
| 【4】 Mestre, M.; Cavero, I.; Hardy, J.-C.; Barreau, M.; Terikalant Fumarate. Drugs Fut 1992, 17, 12, 1097. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 | |
| 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 | |
| (I) | 14461 | 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone | 491-37-2 | C9H8O2 | 详情 | 详情 |
| (II) | 14462 | ethyl 2-(2,3-dihydro-4H-chromen-4-ylidene)acetate | C13H14O3 | 详情 | 详情 | |
| (III) | 14463 | ethyl 2-(3,4-dihydro-2H-chromen-4-yl)acetate | C13H16O3 | 详情 | 详情 | |
| (IV) | 14464 | 2-(3,4-dihydro-2H-chromen-4-yl)-1-ethanol | C11H14O2 | 详情 | 详情 | |
| (V) | 14465 | 4-(2-bromoethyl)chromane | C11H13BrO | 详情 | 详情 | |
| (VI) | 14466 | 4-(3,4-dimethoxyphenyl)piperidine; 2-methoxy-4-(4-piperidinyl)phenyl methyl ether | C13H19NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Nitration of chromanone (I) with fuming HNO3 at -35 C afforded 6-nitro-4-chromanone (II). Subsequent aldol condensation of (II) with glyoxylic acid (III) in the presence of H2SO4 produced the alpha-beta-unsaturated acid (IV). Further hydrogenation of the nitro, keto, and olefin groups of (IV) with concomitant esterification produced the benzopyranylacetate (V). After protection of (V) as the N-Boc derivative (VI), optical resolution was achieved by preparative HPLC on a Chiralcel-OD column. The desired (S)-enantiomer (VI) was deprotected using ethanolic HCl to afford amine (VII), which was condensed with 4-cyanobenzoyl chloride (VIII) to give amide (IX). Treatment of (IX) with HCl-EtOH produced imidate (X), and subsequent treatment with morpholine (XI) furnished the target amidine, which was isolated as the hydrochloride salt.
| 【1】 Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.; Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H.; New platelet fibrinogen receptor glycoprotein IIb-. J Med Chem 1998, 41, 21, 4036. |
| 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) | 14461 | 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone | 491-37-2 | C9H8O2 | 详情 | 详情 |
| (II) | 23176 | 6-nitro-2,3-dihydro-4H-chromen-4-one | C9H7NO4 | 详情 | 详情 | |
| (III) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (IV) | 23178 | 2-[6-nitro-4-oxo-2H-chromen-3(4H)-ylidene]acetic acid | C11H7NO6 | 详情 | 详情 | |
| (V) | 23179 | methyl 2-(6-amino-3,4-dihydro-2H-chromen-3-yl)acetate | C12H15NO3 | 详情 | 详情 | |
| (VI) | 23180 | methyl 2-[(3S)-6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate | C17H23NO5 | 详情 | 详情 | |
| (VII) | 23181 | ethyl 2-[(3S)-6-amino-3,4-dihydro-2H-chromen-3-yl]acetate | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (IX) | 23183 | ethyl 2-[(3S)-6-[(4-cyanobenzoyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate | C21H20N2O4 | 详情 | 详情 | |
| (X) | 23184 | ethyl 2-[(3S)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate | C23H26N2O5 | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Nitration of chromanone (I) with fuming HNO3 at -35 C afforded 6-nitro-4-chromanone (II). Subsequent aldol condensation of (II) with glyoxylic acid (III) in the presence of H2SO4 produced the alpha-beta-unsaturated acid (IV). Further hydrogenation of the nitro, keto, and olefin groups of (IV) with concomitant esterification produced the benzopyranylacetate (V). After protection of (V) as the N-Boc derivative (VI), optical resolution was achieved by preparative HPLC on a Chiralcel-OD column. The desired (S)-enantiomer (VI) was deprotected using ethanolic HCl to afford amine (VII), which was condensed with 4-cyanobenzoyl chloride (VIII) to give amide (IX). Treatment of (IX) with HCl-EtOH produced imidate (X), and subsequent treatment with morpholine (XI) furnished amidine (XII). Finally, basic hydrolysis of the ester function provided the target amidinoacid, which was isolated as the hydrochloride salt.
| 【1】 Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.; Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H.; New platelet fibrinogen receptor glycoprotein IIb-. J Med Chem 1998, 41, 21, 4036. |
| 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) | 14461 | 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone | 491-37-2 | C9H8O2 | 详情 | 详情 |
| (II) | 23176 | 6-nitro-2,3-dihydro-4H-chromen-4-one | C9H7NO4 | 详情 | 详情 | |
| (III) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (IV) | 23178 | 2-[6-nitro-4-oxo-2H-chromen-3(4H)-ylidene]acetic acid | C11H7NO6 | 详情 | 详情 | |
| (V) | 23179 | methyl 2-(6-amino-3,4-dihydro-2H-chromen-3-yl)acetate | C12H15NO3 | 详情 | 详情 | |
| (VI) | 23180 | methyl 2-[(3S)-6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate | C17H23NO5 | 详情 | 详情 | |
| (VII) | 23181 | ethyl 2-[(3S)-6-amino-3,4-dihydro-2H-chromen-3-yl]acetate | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (IX) | 23183 | ethyl 2-[(3S)-6-[(4-cyanobenzoyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate | C21H20N2O4 | 详情 | 详情 | |
| (X) | 23184 | ethyl 2-[(3S)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate | C23H26N2O5 | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XII) | 23186 | ethyl 2-[(3S)-6-([4-[imino(4-morpholinyl)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate | C25H29N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Condensation of 2-(1-benzyl-4-piperidinyl)ethyl amine (I) with phenyl isocyanate (II) provided the corresponding urea (III), which was debenzylated by hydrogenolysis over Pd/C to afford the secondary amine (IV). Subsequent Mannich reaction of (IV) with 4-chromanone (V) and paraformaldehyde produced the (chromanylmethyl)piperidine (VI). After ketone reduction of (IV) by means of NaBH4, the resulting alcohol (VII) was dehydrated in refluxing 6 N HCl to furnish the target chromene.
| 【1】 Mayer, P.; et al.; Modulation of the benzodioxane heterocycle in a novel series of potent alpha2 adrenoceptor antagonists. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 112. |
| 【2】 Vidaluc, J.-L.; Imberg, T.; Marien, M.; Briley, M. (Pierre Fabre Medicament); Novel benzodioxanes and 1-(2H)-benzopyranes, their preparation and their use as medicine. WO 9802435 . |
| 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) | 17606 | 2-(1-benzyl-4-piperidinyl)-1-ethanamine; 2-(1-benzyl-4-piperidinyl)ethylamine | C14H22N2 | 详情 | 详情 | |
| (II) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (III) | 25201 | N-[2-(1-benzyl-4-piperidinyl)ethyl]-N'-phenylurea | C21H27N3O | 详情 | 详情 | |
| (IV) | 25202 | N-phenyl-N'-[2-(4-piperidinyl)ethyl]urea | C14H21N3O | 详情 | 详情 | |
| (V) | 14461 | 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone | 491-37-2 | C9H8O2 | 详情 | 详情 |
| (VI) | 25203 | N-(2-[1-[(4-oxo-3,4-dihydro-2H-chromen-3-yl)methyl]-4-piperidinyl]ethyl)-N'-phenylurea | C24H29N3O3 | 详情 | 详情 | |
| (VII) | 25204 | N-(2-[1-[(4-hydroxy-3,4-dihydro-2H-chromen-3-yl)methyl]-4-piperidinyl]ethyl)-N'-phenylurea | C24H31N3O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XV)Bromochromanone (XVI) was prepared by bromination of 4-chromanone (XV). Subsequent reduction of (XVI) with NaBH4 provided bromohydrin (XVII). Ritter reaction of (XVII) with acetonitrile and sulfuric acid, followed by acidic hydrolysis, led to racemic cis-3-bromo-4-chromanol, which was then resolved by means of (S)-(+)-mandelic acid. The desired (S,S)-isomer (XVIII) was coupled with hydrocinnamic acid (XIX) giving amide (XX). After protection of hydroxy amide (XX) as the acetonide (XXI), the lithium enolate of amide (XXI) was alkylated with allyl bromide (XXII) to furnish the (S)-2-benzyl-4-pentenamide (XXIII) as the main diastereoisomer. Halogenation of (XXIII) with N-iodosuccinimide in H2O-EtOAc afforded iodohydrin (XXIV), which was cyclized to epoxide (XXV) in the presence of NaOMe.
| 【1】 gamma-Hydroxy-2-(fluoroalkylaminocarbonyl)-1-piperazinepentanamides as HIV protease inhibitors. EP 1242426; WO 0138332 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 14461 | 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone | 491-37-2 | C9H8O2 | 详情 | 详情 |
| (XVI) | 56263 | 3-bromo-2,3-dihydro-4H-chromen-4-one | C9H7BrO2 | 详情 | 详情 | |
| (XVII) | 56264 | 3-bromo-4-chromanol | C9H9BrO2 | 详情 | 详情 | |
| (XVIII) | 56265 | (3S,4S)-4-amino-3,4-dihydro-2H-chromen-3-ol | C9H11NO2 | 详情 | 详情 | |
| (XIX) | 49181 | Hydrocinnamic acid; 3-Phenylpropionic acid; Benzylacetic acid | 501-52-0 | C9H10O2 | 详情 | 详情 |
| (XX) | 56266 | N-[(3S,4S)-3-hydroxy-3,4-dihydro-2H-chromen-4-yl]-3-phenylpropanamide | C18H19NO3 | 详情 | 详情 | |
| (XXI) | 56267 | 1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-3-phenyl-1-propanone | C21H23NO3 | 详情 | 详情 | |
| (XXII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXIII) | 56268 | (2S)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-4-penten-1-one | C24H27NO3 | 详情 | 详情 | |
| (XXIV) | 56269 | (2R,4S)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone | C24H28INO4 | 详情 | 详情 | |
| (XXV) | 56270 | (2R)-1-[(3aS,9bS)-2,2-dimethyl-3a,9b-dihydro-2H-chromeno[4,3-d][1,3]oxazol-1(4H)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone | C24H27NO4 | 详情 | 详情 |