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【结 构 式】 
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【分子编号】19280 【品名】4-cyanobenzoyl chloride 【CA登记号】6068-72-0 |
【 分 子 式 】C8H4ClNO 【 分 子 量 】165.5786 【元素组成】C 58.03% H 2.43% Cl 21.41% N 8.46% O 9.66% |
合成路线1
该中间体在本合成路线中的序号：(I)Coupling between 4-cyanobenzoyl chloride (I) and 4-aminobenzonitrile (II) in the presence of Et3N afforded the corresponding amide (III). The dicyano compound (III) was then treated with sodium azide and ammonium chloride in hot DMF to produce the title bis-tetrazolyl derivative.
| 【1】 Makovec, F.; Peris, W.; Rovati, A.L. (Rotta Research Laboratorium SpA); Derivs. of N-phenylbenzamide with anti-ulcer and anti-allergy activity and a method for their preparation. EP 0460083; JP 1992503514; US 5232937; WO 9009989 . |
合成路线2
该中间体在本合成路线中的序号：(III)2) An improved procedure consisted of condensation of 5-nitroisatoic anhydride (I) with beta-alanine ethyl ester (V) to give amide (XIV). The amino group of (XIV) was protected with benzhydryl bromide (VII) yielding (XV), and then the nitro group of (XV) was reduced to aniline (XVI) by catalytic transfer hydrogenation. Protection of the amine of (XVI) as the tert-butyl carbamate (XVIII) was effected using 2-(tert-butoxycarbonyloxymino)-2-phenylacetonitrile (XVII). The sequence of condensation of (XVIII) with bromoacetyl bromide (IX), followed by cyclization of the intermediate bromoacetamide with DBU provided the benzodiazepinedione (XIX). Hydrogenolysis of the N-benzhydryl group of (XIX) in the presence of Pearlman's catalyst, followed by treatment with trimethylsilyl azide furnished the tetrazole (XX). The Boc group of (XX) was deprotected with trifluoroacetic acid, and subsequent coupling with 4-cyanobenzoyl chloride (III) gave amide (XXI). The cyano group was of (XXI) then converted to hydroxyamidine (XXII) with hydroxylamine. Catalytic hydrogenation of (XXII) in the presence of Ac2O and AcOH produced the corresponding amidine. Finally, the ester group was hydrolyzed with LiOH.
| 【1】 Robarge, K.D.; Dina, M.S.; Somers, T.C.; Lee, A.; Rawson, T.E.; Olivero, A.G.; Tischler, M.H.; Webb, R.R. II; Weese, K.J.; Aliagas, I.; Blackburn, B.K.; Preparation and biological activity of novel tricyclic GPIIb/IIIa antagonists. Bioorg Med Chem 1998, 6, 12, 2345. |
| 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) | 22347 | 5-Nitroisatoic anhydride; 6-nitro-2H-3,1-benzoxazine-2,4(1H)-dione | 4693-02-1 | C8H4N2O5 | 详情 | 详情 |
| (III) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (VII) | 17639 | beta-Alanine, ethyl ester; ethyl 3-aminopropanoate | 924-73-2 | C5H11NO2 | 详情 | 详情 |
| (IX) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIV) | 22360 | ethyl 3-[(2-amino-5-nitrobenzoyl)amino]propanoate | C12H15N3O5 | 详情 | 详情 | |
| (XV) | 22361 | ethyl 3-[[2-(benzhydrylamino)-5-nitrobenzoyl]amino]propanoate | C25H25N3O5 | 详情 | 详情 | |
| (XVI) | 22362 | ethyl 3-[[5-amino-2-(benzhydrylamino)benzoyl]amino]propanoate | C25H27N3O3 | 详情 | 详情 | |
| (XVII) | 22363 | 2-[[(tert-butoxycarbonyl)oxy]imino]-2-phenylacetonitrile | 58632-95-4 | C13H14N2O3 | 详情 | 详情 |
| (XVIII) | 22364 | ethyl 3-([2-(benzhydrylamino)-5-[(tert-butoxycarbonyl)amino]benzoyl]amino)propanoate | C30H35N3O5 | 详情 | 详情 | |
| (XIX) | 22365 | ethyl 3-[1-benzhydryl-7-[(tert-butoxycarbonyl)amino]-2,5-dioxo-1,2,3,5-tetrahydro-4H-1,4-benzodiazepin-4-yl]propanoate | C32H35N3O6 | 详情 | 详情 | |
| (XX) | 22366 | ethyl 3-[8-[(tert-butoxycarbonyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate | C19H24N6O5 | 详情 | 详情 | |
| (XXI) | 22357 | ethyl 3-[8-[(4-cyanobenzoyl)amino]-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate | C22H19N7O4 | 详情 | 详情 | |
| (XXII) | 22368 | ethyl 3-[8-([4-[amino(hydroxyimino)methyl]benzoyl]amino)-6-oxo-4H-[1,2,3,4]tetraazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl]propanoate | C22H22N8O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)1) The condensation of benzyloxycarbonyl-L-alanine (I) with 2-(4-piperidyloxy)acetic acid ethyl ester (II) by means of pivaloyl chloride and triethylamine in ethyl acetate gives the protected alanyl-piperidine (III), which is deprotected by hydrogenation over Pd/C in ethanol to yield compound (IV). The condensation of (IV) with 4-cyanobenzoyl chloride (V) by means of triethylamine in toluene affords the corresponding benzoyl derivative (VI), which is finally treated with hydroxylamine in the same solvent.
|
【1】
Castañer, J.; Graul, A.; Merlos, M.; Sibrafiban |
| 【2】 Trussardi, R.; Karpf, M. (F. Hoffmann-La Roche AG); Process for the preparation of mixed anhydrides. EP 0847994 . |
| 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) | 61209 | CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine | C11H13NO4 | 详情 | 详情 | |
| (II) | 19277 | ethyl 2-(4-piperidinyloxy)acetate | C9H17NO3 | 详情 | 详情 | |
| (III) | 19278 | ethyl 2-[[1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-4-piperidinyl]oxy]acetate | C20H28N2O6 | 详情 | 详情 | |
| (IV) | 19279 | ethyl 2-([1-[(2S)-2-aminopropanoyl]-4-piperidinyl]oxy)acetate | C12H22N2O4 | 详情 | 详情 | |
| (V) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (VI) | 19281 | ethyl 2-[(1-[(2S)-2-[(4-cyanobenzoyl)amino]propanoyl]-4-piperidinyl)oxy]acetate | C20H25N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)2) The reaction of 4-hydroxypiperidine (VII) with benzyl chloroformate (VIII) by means of triethylamine in dichloromethane gives the expected benzyloxycarbonyl derivative (IX), which is condensed with tert-butyl 2-bromoacetate (X) by means of tetrabutylammonium bisulfate and NaOH, yielding 2-[1-(benzyloxycarbonyl)piperidin-4-yloxy]acetic acid tert-butyl ester (XI). The deprotection of (XI) as ususal affords 2-(4-piperidinyloxy)acetic acid tert-butyl ester (XII), which is condensed with N-(benzyloxycarbonyl)-L-alanine (XIII) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and N-methyl-morpholine (NMM) in dichloromethane to yield the acylated piperidine (XIV). The deprotection of (XIV) as usual affords compound (XV), which is acylated at the free amino group with 4-cyanobenzoyl chloride (V) and tetrabutylammonium bisulfate to give 2-[1-[N-(4-cyanobenzoyl)-L-alanyl]piperidin-4-yloxy]acetic acid tert-butyl ester (XVI). The reaction of the cyano group of (XVI) with hydroxylamine affords compound (XVII) with a hydroxyamidino substituent. Finally, the tert-butyl ester group of (XVII) is converted in ethyl ester by hydrolysis with hot fomic acid to the corresponding acetic acid (XVIII) and subsequent esterification with ethanol/H2SO4.
| 【1】 Alig, L.; Beresini, M.; Weller, T.; et al.; Orally active fibrinogen receptor antagonists. 2. Amidoximes as prodrugs of amidines. J Med Chem 1996, 39, 16, 3139. |
| 【2】 Weller, T.; Hadvary, P.; Trzeciak, A.; Knopp, D.; Steiner, B.; Edenhofer, A.; Muller, M.; Hurzeler, M.; Alig, L.; Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 1992, 35, 23, 4393. |
|
【3】
Castañer, J.; Graul, A.; Merlos, M.; Sibrafiban |
| 【4】 Alig, L.; Hadvary, P.; Hurzeler Muller, M.; Muller, M.; Steiner, B.; Weller, T. (F. Hoffmann-La Roche AG); Acetic acid derivs. as medicaments. EP 0656348; JP 1995196592; US 5726185 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (VII) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (VIII) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (IX) | 19284 | benzyl 4-hydroxy-1-piperidinecarboxylate | C13H17NO3 | 详情 | 详情 | |
| (X) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (XI) | 19286 | benzyl 4-[2-(tert-butoxy)-2-oxoethoxy]-1-piperidinecarboxylate | C19H27NO5 | 详情 | 详情 | |
| (XII) | 19287 | tert-butyl 2-(4-piperidinyloxy)acetate | C11H21NO3 | 详情 | 详情 | |
| (XIII) | 61209 | CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine | C11H13NO4 | 详情 | 详情 | |
| (XIV) | 19289 | tert-butyl 2-[[1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-4-piperidinyl]oxy]acetate | C22H32N2O6 | 详情 | 详情 | |
| (XV) | 19290 | tert-butyl 2-([1-[(2S)-2-aminopropanoyl]-4-piperidinyl]oxy)acetate | C14H26N2O4 | 详情 | 详情 | |
| (XVI) | 19291 | tert-butyl 2-[(1-[(2S)-2-[(4-cyanobenzoyl)amino]propanoyl]-4-piperidinyl)oxy]acetate | C22H29N3O5 | 详情 | 详情 | |
| (XVII) | 19292 | tert-butyl 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetate | C22H32N4O6 | 详情 | 详情 | |
| (XVIII) | 19293 | 2-([1-[(2S)-2-([4-[amino(hydroxyimino)methyl]benzoyl]amino)propanoyl]-4-piperidinyl]oxy)acetic acid | C18H24N4O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)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6
该中间体在本合成路线中的序号：(VIII)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7
该中间体在本合成路线中的序号：(X)Alkylation of an equimolecular mixture of trans-2,5-dimethylpiperazine dihydrochloride (I) and the free base (II) with benzyl chloride produced the racemic monobenzyl piperazine, which was resolved using (-)-tartaric acid to yield the required (2R,5S)-isomer (III). (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (IV) was protected as the silyl derivative (V) using bis(trimethylsilyl)urea, and subsequently converted to acid chloride (VI) by means of oxalyl chloride. Coupling of acid chloride (VI) with the chiral piperazine (III) afforded amide (VII), which was desilylated in methanolic HCl yielding (VIII). Hydrogenolysis of the N-benzyl group of (VIII) over Pd/C gave piperazine (IX). Finally, coupling of (IX) with 4-cyanobenzoyl chloride (X) furnished the corresponding bisamide.
| 【1】 Anderson, R.C.; Aicher, T.D.; Bebernitz, G.R.; et al.; (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamides are orally active inhibitors of pyruvate dehydrogenase kinase. J Med Chem 1999, 42, 15, 2741. |
| 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),(II) | 20687 | (2R,5S)-2,5-dimethylpiperazine | C6H14N2 | 详情 | 详情 | |
| (III) | 34550 | (2R,5S)-1-benzyl-2,5-dimethylpiperazine | C13H20N2 | 详情 | 详情 | |
| (IV) | 34551 | (2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid | 114715-77-4 | C4H5F3O3 | 详情 | 详情 |
| (V) | 34552 | trimethylsilyl (2R)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoate | C10H21F3O3Si2 | 详情 | 详情 | |
| (VI) | 34553 | (2S)-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]propanoyl chloride | C7H12ClF3O2Si | 详情 | 详情 | |
| (VII) | 34554 | (2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-methyl-2-[(trimethylsilyl)oxy]-1-propanone | C20H31F3N2O2Si | 详情 | 详情 | |
| (VIII) | 34555 | (2R)-1-[(2S,5R)-4-benzyl-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-1-propanone | C17H23F3N2O2 | 详情 | 详情 | |
| (IX) | 34556 | (2R)-1-[(2S,5R)-2,5-dimethylpiperazinyl]-3,3,3-trifluoro-2-hydroxy-2-methyl-1-propanone | C10H17F3N2O2 | 详情 | 详情 | |
| (X) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XIV)The reaction of 5(S)-methyl-3-phenyl-4,5-dihydro-3H-1,2,3-oxathiazol (VIII) with benzhydrylamine (IX) gives the sulfamic acid (X), which is deprotected by hydrogenation with H2 over Pd/C to yield N-(2(R)-aminopropyl-N-(2-pyridyl)sulfamic acid (XI). The hydrolysis of (XI) with 3N HCl affords N1-(2-pyridyl)propane-1,2(R)-diamine (XII). The cyclization of the intermediate dimesylate (VI) with sulfamic acid (XI) or diamine (XII) by means of K2CO3 and NaI in hot DMF or refluxing acetonitrile provides the disubstituted piperazine (XIII) (1), which is finally condensed with 4-cyanobenzoyl chloride (XIV) by means of K2CO3 in ethyl acetate to give the target benzamide (1,2).
| 【1】 Kelly, M.G.; Childers, W.E.; Rosenzweig-Lipson, S.J. (Wyeth); Serotonergic agents. US 2002107254; US 6469007; WO 0244142 . |
| 【2】 Jirkovsky, I.; Zeldis, J.; Chan, A.W.-Y.; Fiegelson, G.B. (Wyeth); Preparation of N1-(2'-pyridyl)-1,2-propanediamine sulfamic acid and its use in the synthesis of biologically active piperazines. WO 0378396 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 64786 | 2-(2,3-dihydro-1,4-benzodioxin-5-yl{2-[(methylsulfonyl)oxy]ethyl}amino)ethyl methanesulfonate | C14H21NO8S2 | 详情 | 详情 | |
| (VIII) | 64787 | (5S)-5-methyl-3-(2-pyridinyl)-1,2lambda~6~,3-oxathiazolidine-2,2-dione | C8H10N2O3S | 详情 | 详情 | |
| (IX) | 15149 | alpha-Aminodiphenylmethane; diphenylmethanamine; benzhydrylamine | 91-00-9 | C13H13N | 详情 | 详情 |
| (X) | 64788 | (2R)-2-(benzhydrylamino)propyl(2-pyridinyl)sulfamic acid | C21H23N3O3S | 详情 | 详情 | |
| (XI) | 64789 | (2R)-2-aminopropyl(2-pyridinyl)sulfamic acid | C8H13N3O3S | 详情 | 详情 | |
| (XII) | 64790 | N-[(2R)-2-aminopropyl]-N-(2-pyridinyl)amine; (2R)-N~1~-(2-pyridinyl)-1,2-propanediamine | C8H13N3 | 详情 | 详情 | |
| (XIII) | 64791 | N-{(2R)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl}-2-pyridinamine; N-{(2R)-2-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl}-N-(2-pyridinyl)amine | C20H26N4O2 | 详情 | 详情 | |
| (XIV) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(V)Coupling of 5-methoxy-2-nitrobenzoic acid (I) with 2-amino-5-chloropyridine (II) by means of POCl3 and pyridine , optionally in acetonitrile solution , yields the corresponding amide (III) , which is then subjected to nitro group reduction to give amine (IV) by either treatment with SnCl2·H2O in refluxing EtOAc or catalytic hydrogenation over sulfided Pt/C in EtOAc or CH2Cl2 . Acylation of aniline (IV) with 4-cyanobenzoyl chloride (V) in the presence of pyridine in CH2Cl2 or THF affords diamide (VI). Finally, nitrile (VI) is converted to amidine by either Pinner reaction with MeOH and HCl in EtOAc and subsequent treatment of the intermediate imino ether with Me2NH in refluxing MeOH , or direct addition of lithium dimethylamide (generated from Me2NH and HexLi) to the cyano group in cold THF .
In an altenative procedure, betrixaban is obtained by coupling of aniline (IV) with the 4-amidinobenzoic acid (VII) in the presence of EDC and a catalytic amount of HCl in DMF or DMA .
| 【1】 Zhu, B.-Y., Wang, L., Goldman, E. et al. (Millennium Pharmaceuticals, Inc.). Benzamides and related inhibitors of factor Xa. EP 1259485, US 6376515, WO 200106442, WO 2001064643. |
| 【2】 Zhang, P., Huang, W., Wang, L. et al. Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl) benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett 2009, 19(8):2179-85. |
| 【3】 Kanter, J.P., Sujino, K., Zuberi, S.S. (Millennium Pharmaceuticals, Inc.).WO 2008057972. |
| 【4】 Pandey, A., Leitao, E.P.T., Rato, J., Song, Z.J. (Millennium Pharmaceuticals, Inc.; Merck & Co., Inc.). Methods of synthesizing factor Xa inhibitors. EP 2513058, US 201131927, WO 201108419. |
| 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) | 68321 | 5-methoxy-2-nitrobenzoic acid;2-Nitro-5-methoxybenzoic acid | C8H7NO5 | 详情 | 详情 | |
| (II) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (III) | 68322 | N-(5-chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide | C13H10ClN3O4 | 详情 | 详情 | |
| (IV) | 68323 | 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide | C13H12ClN3O2 | 详情 | 详情 | |
| (V) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (VI) | 68324 | N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide | C21H15ClN4O3 | 详情 | 详情 | |
| (VII) | 68325 | 4-(N,N-dimethylcarbamimidoyl)benzoic acid hydrochloride | C10H12N2O2.HCl | 详情 | 详情 |