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【结 构 式】 
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【分子编号】17568 【品名】methyl 2-aminoacetate 【CA登记号】 |
【 分 子 式 】C3H7NO2 【 分 子 量 】89.09412 【元素组成】C 40.44% H 7.92% N 15.72% O 35.92% |
合成路线1
该中间体在本合成路线中的序号：(I)Several novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), a key intermediate in the synthesis of losartan, have been described: 1) Treatment of glycine methyl ester hydrochloride (I) with NaOH in methanol, followed by reaction with methyl pentanimidate (II), gives 2-butyl-4,5-dihydro-1H-imidazol-5-one (III), which is treated with POCl3 to give the 2-butyl-5-chloro-1H-imidazole (IV). Reaction of (IV) with POCl3 and DMF yields the enamine (V), which is finally hydrolyzed with water to 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (XI), the desired intemediate in the synthesis of losartan. 2) Imidazolinone (III) can also be obtained by cyclization of chloroacetic acid methyl ester (VI), chloroacetyl chloride (VII) or bromoacetyl bromide (VIII) with pentanamidine (IX) by means of NaOH in methanol. 3) Alternatively, imidazolinone (III) can be treated with dimethylformamide dimethylacetal in dichloromethane yielding the enamine (X), which is finally treated with POCl3 and hydrolyzed with water. 4) The reaction of glycine (XI) with methyl pentanimidate (II) in NaOH/MeOH gives amidine (XII), which, without isolation, is treated with POCl3 and DMF at 100 C for 2 h, and then hydrolyzed with water to give the desired 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde. Methyl pentanimidate (II) is obtained treating a solution of valeronitrile in MeOH with HCl gas followed by neutralization with aqueous KOH and extraction with Et2O.
| 【1】 Kohr, J.; Griffiths, G.J.; Imwinkelried, R.; Hauck, M.B.; Roten, C.A.; Stucky, G.C.; Novel syntheses of 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde: A key intermediate for the synthesis of the angiotensin II antagonist losartan. J Org Chem 1999, 64, 22, 8084. |
| 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) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (II) | 34050 | methyl pentanimidoate | C6H13NO | 详情 | 详情 | |
| (III) | 34051 | 2-butyl-3,5-dihydro-4H-imidazol-4-one | C7H12N2O | 详情 | 详情 | |
| (IV) | 34052 | 2-butyl-5-chloro-1H-imidazole | C7H11ClN2 | 详情 | 详情 | |
| (V) | 34053 | N-[(2-butyl-5-chloro-4H-imidazol-4-ylidene)methyl]-N,N-dimethylamine; (2-butyl-5-chloro-4H-imidazol-4-ylidene)-N,N-dimethylmethanamine | C10H16ClN3 | 详情 | 详情 | |
| (VI) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (IX) | 14576 | pentanimidamide | 109-51-3 | C5H12N2 | 详情 | 详情 |
| (X) | 34054 | 2-butyl-5-[(E)-(dimethylamino)methylidene]-3,5-dihydro-4H-imidazol-4-one | C10H17N3O | 详情 | 详情 | |
| (XI) | 13925 | 2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde | 83857-96-9 | C8H11ClN2O | 详情 | 详情 |
| (XII) | 20436 | glycine | 56-40-6 | C2H5NO2 | 详情 | 详情 |
| (XIII) | 34055 | 2-(pentanimidoylamino)acetic acid | C7H14N2O2 | 详情 | 详情 | |
| (XIV) | 13921 | Pentanenitrile; n-Valeronitrile | 110-59-8 | C5H9N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of L-tyrosine methyl ester (I) with ethyl chloroformate and K2CO3 in water gives the carbamate (II), which is protected with Bn-Br and K2CO3 in DMF, yielding the benzyl ether (III). The reduction of (III) by means of LiAlH4 in refluxing THF affords the chiral 2-methylaminopropanol (IV), which is protected as its Boc derivative (V) by means of Boc2O. The oxidation of (V) by means of DMP provides the carbaldehyde (VI), which is reductocondensed with glycine methyl ester (VII) by means of NaBH3CN in methanol to give the adduct (VIII). Elimination of the Boc protecting group of (VIII) by means of TFA yields the diamine (IX), which is cyclized by means of NH4OH in ethanol to afford the piperazinone (X). Elimination of the benzyl protecting group of (X) by hydrogenation with H2 over Pd/C provides the phenol (XIa)-(XIb), which is cyclized by means of bis(acetoxy)iodobenzene in hexafluoroisopropanol to give the spiranic cyclohexadienone (XII). The hydrogenation of (XII) by means of Tes-H and CuI in dichloromethane yields the spiranic cyclohexanone (XIII), which is finally ketalized by means of ethyleneglycol (XIV) and PPTS in refluxing benzene to provide the target ethyleneketal intermediate (XV) (See scheme no. 18599903a, intermediate (XV)).
| 【1】 Mizutani, H.; et al.; Facile synthesis of enantiopure (-)-TAN1251A. Tetrahedron Lett 2002, 43, 13, 2411. |
| 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) | 21431 | methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 1080-06-4 | C10H13NO3 | 详情 | 详情 |
| (II) | 57099 | methyl (2S)-2-[(ethoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | C13H17NO5 | 详情 | 详情 | |
| (III) | 57100 | methyl (2S)-3-[4-(benzyloxy)phenyl]-2-[(ethoxycarbonyl)amino]propanoate | C20H23NO5 | 详情 | 详情 | |
| (IV) | 57101 | (2S)-3-[4-(benzyloxy)phenyl]-2-(methylamino)-1-propanol | C17H21NO2 | 详情 | 详情 | |
| (V) | 57102 | tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-hydroxyethyl(methyl)carbamate | C22H29NO4 | 详情 | 详情 | |
| (VI) | 57103 | tert-butyl (1S)-1-[4-(benzyloxy)benzyl]-2-oxoethyl(methyl)carbamate | C22H27NO4 | 详情 | 详情 | |
| (VII) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (VIII) | 57104 | methyl 2-({(2S)-3-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)(methyl)amino]propyl}amino)acetate | C25H34N2O5 | 详情 | 详情 | |
| (IX) | 57105 | methyl 2-{[(2S)-3-[4-(benzyloxy)phenyl]-2-(methylamino)propyl]amino}acetate | C20H26N2O3 | 详情 | 详情 | |
| (X) | 57106 | (6S)-6-[4-(benzyloxy)benzyl]-1-methyl-2-piperazinone | C19H22N2O2 | 详情 | 详情 | |
| (XI) | 57107 | (6S)-6-(4-hydroxybenzyl)-1-methyl-2-piperazinone | C12H16N2O2 | 详情 | 详情 | |
| (XII) | 57108 | C12H14N2O2 | 详情 | 详情 | ||
| (XIII) | 57109 | C12H18N2O2 | 详情 | 详情 | ||
| (XIV) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XV) | 48806 | C14H22N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)A new synthesis of ML-3000 has been published: The reaction of 3-phenyl-2-propynyl chloride (I) with isobutyraldehyde (II) by means of tetrabutylammonium iodide/NaI/NaOH in toluene/water gives 2,2-dimethyl-5-phenyl-4-pentynal (III), which is condensed with glycine methyl ester by means of NaBH(OAc)3 and triethylamine in dichloromethane yielding the N-alkyl-glycine (V). The cyclization of (V) by means of pivalic acid at 150 C affords the bicyclic ketone (VI), which is condensed with diethyl oxalate (VII) by means of sodium ethoxide in ethanol giving the ethoxalyl derivative (VIII). The esterification of (VIII) with the triflic amide (IX) yields the triflate (X), which is condensed with 4-chlorophenylboronic acid (XI) by means of palladium tetrakis(triphenylphosphine) as catalyst in refluxing THF affording the compound (XII). The reduction of the oxoacetic group with tosyl hydrazide (XIII) in refluxing ethanol gives the expected acetate derivative (XIV), which is finally hydrolyzed with NaOH in hot ethanol/water.
| 【1】 Cossy, J.; Belotti, D.; Synthesis of ML-3000, an inhibitor of cyclooxygenase and 5-lipoxygenase. J Org Chem 1997, 62, 23, 7900. |
| 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) | 17565 | 1-(3-chloro-1-propynyl)benzene | C9H7Cl | 详情 | 详情 | |
| (II) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (III) | 17567 | 2,2-dimethyl-5-phenyl-4-pentynal | C13H14O | 详情 | 详情 | |
| (IV) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (V) | 17569 | methyl 2-[(2,2-dimethyl-5-phenyl-4-pentynyl)amino]acetate | C16H21NO2 | 详情 | 详情 | |
| (VI) | 17570 | 2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-6(5H)-one | C15H17NO | 详情 | 详情 | |
| (VII) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (VIII) | 17572 | ethyl 2-(6-hydroxy-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate | C19H21NO4 | 详情 | 详情 | |
| (IX) | 17573 | N-Phenyltrifluoromethanesulfonimide; Trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide | 37595-74-7 | C8H5F6NO4S2 | 详情 | 详情 |
| (X) | 17574 | ethyl 2-(2,2-dimethyl-7-phenyl-6-[[(trifluoromethyl)sulfonyl]oxy]-2,3-dihydro-1H-pyrrolizin-5-yl)-2-oxoacetate | C20H20F3NO6S | 详情 | 详情 | |
| (XI) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (XII) | 17576 | ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]-2-oxoacetate | C25H24ClNO3 | 详情 | 详情 | |
| (XIII) | 17577 | p-Toluenesulfonyl Hydrazide; 4-methylbenzenesulfonohydrazide | 1576-35-8 | C7H10N2O2S | 详情 | 详情 |
| (XIV) | 16723 | ethyl 2-[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl]acetate | C25H26ClNO2 | 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 racemic 4-methoxytryptophan amide (I) is resolved using immobilized Penicillin G acylase, to afford the desired L-aminoacid (III), while leaving unaltered the enantiomeric D-amide (II). After protection of aminoacid (III) as the N-benzyloxycarbonyl derivative (IV), coupling with glycine methyl ester (V) gives dipeptide (VI). Hydrogenolysis of the benzyloxycarbonyl protecting group of (VI) yields amine (VII), which is then coupled with N-Cbz-L-tryptophan (VIII) to produce the protected tripeptide (IX). Hydrogenolysis of (IX) in the presence of Pd/C provides the tripeptide building block (X).
| 【1】 Ley, S.V.; et al.; Total synthesis of the cyclic heptapeptide argyrin B: A new potent inhibitor of T-cell independent antibody formation. Org Lett 2002, 4, 5, 711. |
| 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) | 58827 | 4-methoxy-N-(2-phenylacetyl)tryptophan | C20H20N2O4 | 详情 | 详情 | |
| (II) | 58828 | (2R)-3-(4-methoxy-1H-indol-3-yl)-2-[(2-phenylacetyl)amino]propanoic acid | C20H20N2O4 | 详情 | 详情 | |
| (III) | 58829 | (2S)-2-amino-3-(4-methoxy-1H-indol-3-yl)propanoic acid | C12H14N2O3 | 详情 | 详情 | |
| (IV) | 58830 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoic acid | C20H20N2O5 | 详情 | 详情 | |
| (V) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (VI) | 58831 | methyl 2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C23H25N3O6 | 详情 | 详情 | |
| (VII) | 58832 | methyl 2-{[(2S)-2-amino-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C15H19N3O4 | 详情 | 详情 | |
| (VIII) | 18652 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid | 7432-21-5 | C19H18N2O4 | 详情 | 详情 |
| (IX) | 58833 | methyl (5S,8S)-5-(1H-indol-3-ylmethyl)-8-[(4-methoxy-1H-indol-3-yl)methyl]-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oate | C34H35N5O7 | 详情 | 详情 | |
| (X) | 58834 | methyl 2-{[(2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C26H29N5O5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The reductive condensation of N-Boc-L-isoleucinal (I) with glycine methyl ester (II) using sodium triacetoxyborohydride afforded secondary amine (III), which was further reductively condensed with 1-naphthaldehyde (IV), yielding tertiary amine (V). After basic hydrolysis of the methyl ester group of (V), the resulting carboxylic acid (VI) was coupled with L-methionine methyl ester (VII) by means of EDC and HOBt to give peptide (VIII). Subsequent deprotection of the Boc group of (VII) with HCl in cold EtOAc furnished the required intermediate (IX).
| 【1】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 . |
| 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) | 34733 | tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (II) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (III) | 34734 | methyl 2-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]amino)acetate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 34735 | methyl 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetate | C25H36N2O4 | 详情 | 详情 | |
| (VI) | 34736 | 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetic acid | C24H34N2O4 | 详情 | 详情 | |
| (VII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VIII) | 34737 | methyl (6S,12S)-2,2-dimethyl-6-[(1S)-1-methylpropyl]-12-[2-(methylsulfanyl)ethyl]-8-(1-naphthylmethyl)-4,10-dioxo-3-oxa-5,8,11-triazatridecan-13-oate | C30H45N3O5S | 详情 | 详情 | |
| (IX) | 34738 | methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate | C25H37N3O3S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The reductive condensation of N-Boc-L-isoleucinal (I) with glycine methyl ester (II) using sodium triacetoxyborohydride afforded secondary amine (III), which was further reductively condensed with 1-naphthaldehyde (IV), yielding tertiary amine (V). After basic hydrolysis of the methyl ester group of (V), the resulting carboxylic acid (VI) was coupled with L-methionine methyl ester (VII) by means of EDC and HOBt to give peptide (VIII). Subsequent deprotection of the Boc group of (VIII) with HCl in cold EtOAc furnished the required intermediate (IX).
| 【1】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 . |
| 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) | 34733 | tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (II) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (III) | 34734 | methyl 2-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]amino)acetate | C14H28N2O4 | 详情 | 详情 | |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 34735 | methyl 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetate | C25H36N2O4 | 详情 | 详情 | |
| (VI) | 34736 | 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetic acid | C24H34N2O4 | 详情 | 详情 | |
| (VII) | 17950 | D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride | 21691-49-6 | C6H13NO2S | 详情 | 详情 |
| (VIII) | 34737 | methyl (6S,12S)-2,2-dimethyl-6-[(1S)-1-methylpropyl]-12-[2-(methylsulfanyl)ethyl]-8-(1-naphthylmethyl)-4,10-dioxo-3-oxa-5,8,11-triazatridecan-13-oate | C30H45N3O5S | 详情 | 详情 | |
| (IX) | 34738 | methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate | C25H37N3O3S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IV)The condensation of 5-methylindoline (I) with benzonitrile (II) by means of BCl3 and AlCl3 in dichloroethane gives the 7-benzoyl-5-methylindoline (III), which is cyclized with glycine methyl ester (IV) in pyridine yielding the tricyclic pyrrolobenzodiazepinone (V). The reaction of (V) with isoamyl nitrite and potassium tert-butoxide in THF affords the oxime (VI), which is reduced with H2 over Ru/C in methanol providing the racemic amine (VII). The optical resolution of (VII) with N-acetyl-L-phenylalanine gives the desired isomer (VIII), which is finally condensed with pyridine-4-carboxylic acid (IX) by means of O-[1-(ethoxycarbonyl)-1-cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and DIEA in dichloromethane.
| 【1】 Andrianjara, C.R.; Auclair, E.; Pascal, Y.; et al.; Synthesis and structure-activity relationships of 4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indoles: Novel PDE4 inhibitors. Bioorg Med Chem Lett 2000, 10, 1, 35. |
| 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) | 31641 | 5-methylindoline | C9H11N | 详情 | 详情 | |
| (II) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (III) | 31642 | (5-methyl-2,3-dihydro-1H-indol-7-yl)(phenyl)methanone | C16H15NO | 详情 | 详情 | |
| (IV) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (V) | 31643 | 9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H16N2O | 详情 | 详情 | |
| (VI) | 31644 | 9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime | C18H15N3O2 | 详情 | 详情 | |
| (VII) | 31645 | 3-amino-9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H17N3O | 详情 | 详情 | |
| (VIII) | 31646 | (3R)-3-amino-9-methyl-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H17N3O | 详情 | 详情 | |
| (IX) | 25028 | isonicotinic acid | 55-22-1 | C6H5NO2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(IV)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9
该中间体在本合成路线中的序号：(V)The esterification of 3,4-dimethoxy-2-nitrobenzoic acid (I) with methyl iodide and cesium carbonate gives the corresponding methyl ester (II), which is reduced with H2 over Pd/C yielding the expected 2-amino compound (III). The reaction of (III) with NaNO2 and SO2 affords the disulfide (IV), which is cyclized with methyl glycinate (V) by means of KNO3 and SO2Cl2 giving the benzoisothiazolone derivative (VI). The rearrangement of (VI) by means of sodium methoxide yields the 1,2-benzothiazine derivative (VII), which is condensed with 3,4-methylenedioxybenzyl chloride (VIII) by means of NaH in DMF affording the N-substituted benzothiazine (IX). The reaction of (IX) with triflic anhydride gives the triflate ester (X), which is condensed with 3,4-methylenedioxythiophenol (XI) by means of NaH in DMF and hydrolyzed with LiOH in THF to provide the target compound.
| 【1】 Berryman, K.A.; Edmunds, J.J.; Bunker, A.M.; Haleen, S.; Bryant, J.; Welch, K.M.; Doherty, A.M.; Endothelin receptor antagonists: Synthesis and structure-activity relationships of substituted benzothiazine-1,1-dioxides. Bioorg Med Chem 1998, 6, 9, 1447. |
| 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) | 28611 | 3,4-dimethoxy-2-nitrobenzoic acid | C9H9NO6 | 详情 | 详情 | |
| (II) | 28612 | methyl 3,4-dimethoxy-2-nitrobenzoate | C10H11NO6 | 详情 | 详情 | |
| (III) | 28613 | methyl 2-amino-3,4-dimethoxybenzoate | C10H13NO4 | 详情 | 详情 | |
| (IV) | 28614 | methyl 2-[[2,3-dimethoxy-6-(methoxycarbonyl)phenyl]disulfanyl]-3,4-dimethoxybenzoate | C20H22O8S2 | 详情 | 详情 | |
| (V) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (VI) | 28615 | methyl 2-(6,7-dimethoxy-1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C12H13NO7S | 详情 | 详情 | |
| (VII) | 28616 | methyl 4-hydroxy-7,8-dimethoxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C12H13NO7S | 详情 | 详情 | |
| (VIII) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (IX) | 28618 | methyl 2-(1,3-benzodioxol-5-ylmethyl)-4-hydroxy-7,8-dimethoxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C20H19NO9S | 详情 | 详情 | |
| (X) | 28619 | methyl 2-(1,3-benzodioxol-5-ylmethyl)-7,8-dimethoxy-1,1-dioxo-4-[[(trifluoromethyl)sulfonyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C21H18F3NO11S2 | 详情 | 详情 | |
| (XI) | 28620 | 1,3-benzodioxole-5-thiol | C7H6O2S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(VIII)Reaction of 2-nitroanisole (I) with methyl dichloroacetate (II) in the presence of potassium tert-butoxide at -5 C produced the arylacetic acid derivative (III). Hydrogenation of (III) over Pd/C produced both reduction of the nitro group and hydrogenolysis of the halogen atom to afford amine (IV), which was then condensed with o-tolyl isocyanate (V) giving urea (VI). Basic hydrolysis of the methyl ester of (VI) provided the corresponding acid (VII). This was coupled with glycine methyl ester (VIII) using EDC and HOBt to yield amide (IX). Then, ester (IX) hydrolysis with LiOH gave rise to carboxylic acid.
| 【1】 Morley, A.D.; Harris, N.V.; Astles, P.C. (Rhone-Poulenc Rorer Ltd.); Substd. beta-alanines. WO 9933789 . |
| 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) | 39714 | methyl 2-nitrophenyl ether; 1-methoxy-2-nitrobenzene | 91-23-6 | C7H7NO3 | 详情 | 详情 |
| (II) | 36413 | methyl 2,2-dichloroacetate | 116-54-1 | C3H4Cl2O2 | 详情 | 详情 |
| (III) | 39715 | methyl 2-chloro-2-(3-methoxy-4-nitrophenyl)acetate | C10H10ClNO5 | 详情 | 详情 | |
| (IV) | 39716 | methyl 2-(4-amino-3-methoxyphenyl)acetate | C10H13NO3 | 详情 | 详情 | |
| (V) | 27106 | 1-isocyanato-2-methylbenzene | 614-68-6 | C8H7NO | 详情 | 详情 |
| (VI) | 39717 | methyl 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetate | C18H20N2O4 | 详情 | 详情 | |
| (VII) | 39718 | 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid | C17H18N2O4 | 详情 | 详情 | |
| (VIII) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (IX) | 39719 | methyl 2-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]acetate | C20H23N3O5 | 详情 | 详情 | |
| (X) | 39720 | 2-[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]acetic acid | C19H21N3O5 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(II)Coupling of N-Boc-D-pyridylalanine (I) to glycine methyl ester (II) produced the protected dipeptide (III). Subsequent catalytic hydrogenation of the pyridine ring of (III) over PtO2 gave piperidine (IV), which was then treated with the guanylating reagent (V) to afford the guanidine derivative (VI). Acid cleavage of the Boc protecting group of (VI) provided amine (VII). This was condensed with benzylsulfonyl chloride to give sulfonamide (VIII). After basic hydrolysis of the methyl ester of (VIII), the resultant carboxylic acid (IX) was coupled to nitroargininal ethyl aminal (X), yielding amide (XI).
| 【1】 Levy, O.E.; Uong, T.H.; Tamura, S.Y.; et al.; Guanylpiperidine peptidomimetics: Potent and selective bis-cation inhibitors of factor Xa. Bioorg Med Chem Lett 2000, 10, 8, 745. |
| 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) | 51044 | Boc-D-4-Pyridylalanine; Boc-D-4-Pyridylala | 37535-58-3 | C13H18N2O4 | 详情 | 详情 |
| (II) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (III) | 51045 | methyl 2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-pyridinyl)propanoyl]amino]acetate | C16H23N3O5 | 详情 | 详情 | |
| (IV) | 51046 | methyl 2-[[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-piperidinyl)propanoyl]amino]acetate | C16H29N3O5 | 详情 | 详情 | |
| (V) | 32861 | benzyl (E)-[[(benzyloxy)carbonyl]amino](methylsulfanyl)methylidenecarbamate | C18H18N2O4S | 详情 | 详情 | |
| (VI) | 51047 | methyl 2-([(2R)-3-[1-([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)-4-piperidinyl]-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)acetate | C33H43N5O9 | 详情 | 详情 | |
| (VII) | 51048 | methyl 2-([(2R)-2-amino-3-[1-([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)-4-piperidinyl]propanoyl]amino)acetate | C28H35N5O7 | 详情 | 详情 | |
| (VIII) | 51049 | methyl 2-([(2R)-3-[1-([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)-4-piperidinyl]-2-[(benzylsulfonyl)amino]propanoyl]amino)acetate | C35H41N5O9S | 详情 | 详情 | |
| (IX) | 51050 | 2-([(2R)-3-[1-([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)-4-piperidinyl]-2-[(benzylsulfonyl)amino]propanoyl]amino)acetic acid | C34H39N5O9S | 详情 | 详情 | |
| (X) | 29388 | 3(S)-Amino-2-ethoxy-N2-nitropiperidine-1-carboxamidine | C8H17N5O3 | 详情 | 详情 | |
| (XI) | 51051 | C42H54N10O11S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(II)The reductive condensation between 2-indanone (I) and glycine methyl ester (II) in the presence of sodium cyanoborohydride furnished methyl (2-indanylamino)acetate (III). Subsequent ammonolysis of the methyl ester group of (III) in methanolic ammonia gave the glycinamide derivative (IV), which was finally converted to the title hydrochloride salt.
| 【1】 Chiesi, P.; Ventura, P.; Delcanale, M.; De Fanti, R.; Armani, E.; Villetti, G.; Pietra, C. (Chiesi Farmaceutici SpA); alpha-Amino acid amides, preparation thereof and the therapeutical use thereof. EP 0951465; JP 2001506577; US 6114391; WO 9803472 . |
合成路线13
该中间体在本合成路线中的序号：(VII)Condensation of 4-vinylpyridine (I) with diethyl malonate (II) affords the bis(pyridylethyl)malonate (III) which, upon acidic hydrolysis and decarboxylation leads to mono-acid (IV). Catalytic hydrogenation of the pyridine rings of (IV) in the presence of Pd/C furnishes the corresponding piperidinyl compound (V), which is further protected as the N-Boc derivative (VI) employing di-t-butyl dicarbonate. Acid (VI) is coupled to glycine methyl ester (VII) via activation with cyanuric fluoride to yield amide (VIII). Then, alkaline hydrolysis of the methyl ester group provides carboxylic acid (IX).
| 【1】 Lesur, B.; Henry, M.; Yue, C.; Giboulot, T. (Laboratoires L. Lafon); Bispiperidines as antithrombotic agents. EP 1098878; FR 2781223; JP 2002520393; US 6333338; WO 0003986 . |
| 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) | 45857 | 4-vinylpyridine | C7H7N | 详情 | 详情 | |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (III) | 63020 | diethyl 2,2-bis[2-(4-pyridinyl)ethyl]malonate | C21H26N2O4 | 详情 | 详情 | |
| (IV) | 63022 | 4-(4-pyridinyl)-2-[2-(4-pyridinyl)ethyl]butanoic acid | C16H18N2O2 | 详情 | 详情 | |
| (V) | 63023 | 4-(4-piperidinyl)-2-[2-(4-piperidinyl)ethyl]butanoic acid | C16H30N2O2 | 详情 | 详情 | |
| (VI) | 63024 | 4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoic acid | C26H46N2O6 | 详情 | 详情 | |
| (VII) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (VIII) | 63025 | tert-butyl 4-(5-[1-(tert-butoxycarbonyl)-4-piperidinyl]-3-{[(2-methoxy-2-oxoethyl)amino]carbonyl}pentyl)-1-piperidinecarboxylate | C29H51N3O7 | 详情 | 详情 | |
| (IX) | 63026 | 2-[(4-[1-(tert-butoxycarbonyl)-4-piperidinyl]-2-{2-[1-(tert-butoxycarbonyl)-4-piperidinyl]ethyl}butanoyl)amino]acetic acid | C28H49N3O7 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(II)The bromo pyrazinone intermediate (VII) has been obtained as follows. The condensation of ethyl glycinate (I) with ethoxalyl chloride (II) by means of TEA in dichloroethane gives the corresponding amide (III), which is condensed with aminoacetaldehyde dimethyl acetal (IV) in isopropanol to yield the diamide (V). The cyclization of (V) by means of HCl in refluxing AcOH affords the hydroxypyrazinone (VI), which is finally treated with POBr3 in refluxing 1,2-dichloroethane to provide the target bromopyrazinone intermediate (VII) (1).
| 【1】 Selnick, H.G.; Newton, R.C.; Newton, C.L.; Barrow, J.C.; Nantermet, P.G. (Merck & Co., Inc.); Thrombin inhibitors. WO 0311222 . |
| 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) | 11043 | Ethyl 2-chloro-2-oxoacetate; Ethyl oxalyl chloride | 4755-77-5 | C4H5ClO3 | 详情 | 详情 |
| (II) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (III) | 63817 | ethyl 2-oxo-2-[(2-oxo-2-propoxyethyl)amino]acetate | C9H15NO5 | 详情 | 详情 | |
| (IV) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (V) | 63818 | propyl 2-({2-[(2,2-dimethoxyethyl)amino]-2-oxoacetyl}amino)acetate | C11H20N2O6 | 详情 | 详情 | |
| (VI) | 63819 | propyl 2-[3-hydroxy-2-oxo-1(2H)-pyrazinyl]acetate | C9H12N2O4 | 详情 | 详情 | |
| (VII) | 63820 | propyl 2-[3-bromo-2-oxo-1(2H)-pyrazinyl]acetate | C9H11BrN2O3 | 详情 | 详情 |