合成路线1
该中间体在本合成路线中的序号:
(IV) The reductocondensation of ethyl glycinate (I) with 2-indanone (II) by means of sodium cyanoborohydride in methanol gives ethyl N-(2-indanyl)glycinate (III), which is condensed with N-benzyloxycarbonyl-L-alanine (IV) by means of isobutyl chlorocarbonate and triethylamine in THF yielding N-(N-benzyloxycarbonyl-L-alanyl)-N-(2-indanyl)glycine ethyl ester (V). The partial hydrolysis of (V) with NaOH in methanol affords N-(N-benzyloxycarbonyl-L-alanyl)-N-(2-indanyl)glycine (VI), which is deprotected by hydrogenolysis with H2 over Pd/C in ethanol giving N-(L-alanyl)-N-(2-indanyl)glycine (VII). Finally, this compound is reductocondensed with ethyl 2-oxo-4-phenylbutanoate (VIII) by means of sodium cyanoborohydride in ethanol.
【1】
Oka, Y.; Nishikawa, K.; Miyake, A. (Takeda Chemical Industries, Ltd.); Bicyclic compounds, their production and use. EP 0051391; GB 2086393; JP 82179141; JP 8277651; US 4385051 .
|
【2】
Serradell, M.N.; Castaner, J.; CV-3317. Drugs Fut 1984, 9, 5, 324.
|
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) |
10309 |
ethyl 2-aminoacetate; Glycine ethyl ester
|
459-73-4 |
C4H9NO2 |
详情 | 详情
|
(II) |
30550 |
1,3-dihydro-2H-inden-2-one
|
615-13-4 |
C9H8O |
详情 | 详情
|
(III) |
30551 |
ethyl 2-(2,3-dihydro-1H-inden-2-ylamino)acetate
|
|
C13H17NO2 |
详情 |
详情
|
(IV) |
61209 |
CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine
|
|
C11H13NO4 |
详情 |
详情
|
(V) |
30552 |
ethyl 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetate
|
|
C24H28N2O5 |
详情 |
详情
|
(VI) |
30553 |
2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetic acid
|
|
C22H24N2O5 |
详情 |
详情
|
(VII) |
30554 |
2-[[(2S)-2-aminopropanoyl](2,3-dihydro-1H-inden-2-yl)amino]acetic acid
|
|
C14H18N2O3 |
详情 |
详情
|
(VIII) |
20896 |
Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester
|
64920-29-2 |
C12H14O3 |
详情 | 详情
|
合成路线2
该中间体在本合成路线中的序号:
(IV) The reductocondensation of (II) with tert-butyl glycinate (IX) by means of sodium cyanoborohydride in ethanol gives tert-butyl-N-(2-indanyl)glycinate (X), which is condensed with (IV) by means of isobutyl chlorocarbonate as before yielding tert-butyl-N-[N-(tert-butoxycarbonyl)-L-alanyl]-N-(2-indanyl)glycinate (XI). Deprotection of (XI) by hydrogenolysis with H2 over Pd/C in methanol affords tert-butyl N-(L-alanyl)-N-(2-indanyl)glycinate (XII), which is reductocondensed with (VIII) using H2 and Raney-Ni in ethanol to afford tert-butyl N-[N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N-(2-indanyl)glycinate (XIII). Finally, this compound is saponified with HBr in acetic acid.
【1】
Oka, Y.; Nishikawa, K.; Miyake, A. (Takeda Chemical Industries, Ltd.); Bicyclic compounds, their production and use. EP 0051391; GB 2086393; JP 82179141; JP 8277651; US 4385051 .
|
【2】
Serradell, M.N.; Castaner, J.; CV-3317. Drugs Fut 1984, 9, 5, 324.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(II) |
30550 |
1,3-dihydro-2H-inden-2-one
|
615-13-4 |
C9H8O |
详情 | 详情
|
(IV) |
61209 |
CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine
|
|
C11H13NO4 |
详情 |
详情
|
(VIII) |
20896 |
Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester
|
64920-29-2 |
C12H14O3 |
详情 | 详情
|
(IX) |
27841 |
tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester |
6456-74-2 |
C6H13NO2 |
详情 | 详情
|
(X) |
30555 |
tert-butyl 2-(2,3-dihydro-1H-inden-2-ylamino)acetate
|
|
C15H21NO2 |
详情 |
详情
|
(XI) |
30556 |
tert-butyl 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetate
|
|
C26H32N2O5 |
详情 |
详情
|
(XII) |
30557 |
tert-butyl 2-[[(2S)-2-aminopropanoyl](2,3-dihydro-1H-inden-2-yl)amino]acetate
|
|
C18H26N2O3 |
详情 |
详情
|
(XIII) |
30558 |
ethyl (2S)-2-([(1S)-2-[[2-(tert-butoxy)-2-oxoethyl](2,3-dihydro-1H-inden-2-yl)amino]-1-methyl-2-oxoethyl]amino)-4-phenylbutanoate
|
|
C30H40N2O5 |
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 condensation of ethyl indoline-2-carboxylate (I) with N-benzyloxycarbonylalanine (II) by means of CH2Cl2 gives ethyl N-(benzyloxycarbonylalanyl)indoline-2-carboxylate (III), which is hydrolyzed partially with LiOH in DMF water yielding N-(benzyloxycarbonylalanyl)indoline-2-carboxylic acid (IV). Debenzylation of (IV) by hydrogenation with H2 over Pd/C in aqueous ethanol affords N-alanylindoline-2-carboxylic acid, which is finally reductocondensed with ethyl 2-oxo-3-phenylbutyrate (VI) by means of NaOH and sodium cyanoborohydride or H2 and RaNi in ethanol.
【1】
Renfroe, H.B.; Stanton, J.L.; Sele, A. (Novartis AG); 1-Carboxy-azaalkyl-indolin-2-carboxylic acids, process for preparing them, pharmaceutical compositions containing them and their therapeutical use. DD 201888; EP 0051301; GB 2086390 .
|
【2】
Serradell, M.N.; Castaner, J.; CGS-13928C. Drugs Fut 1985, 10, 3, 190.
|
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) |
29042 |
ethyl (2S)-1-methyl-2,3-dihydro-1H-indole-2-carboxylate
|
|
C12H15NO2 |
详情 |
详情
|
(II) |
61209 |
CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine
|
|
C11H13NO4 |
详情 |
详情
|
(III) |
29043 |
ethyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-2,3-dihydro-1H-indole-2-carboxylate
|
|
C22H24N2O5 |
详情 |
详情
|
(IV) |
29044 |
(2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-2,3-dihydro-1H-indole-2-carboxylic acid
|
|
C20H20N2O5 |
详情 |
详情
|
(V) |
29045 |
(2S)-1-[(2S)-2-aminopropanoyl]-2,3-dihydro-1H-indole-2-carboxylic acid
|
|
C12H14N2O3 |
详情 |
详情
|
(VI) |
20896 |
Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester
|
64920-29-2 |
C12H14O3 |
详情 | 详情
|
合成路线4
该中间体在本合成路线中的序号:
(I) 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 . Drugs Fut 1998, 23, 12, 1297.
|
【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5
该中间体在本合成路线中的序号:
(XIII) 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 . Drugs Fut 1998, 23, 12, 1297.
|
【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6
该中间体在本合成路线中的序号:
(VIII) N-Cbz-D-Alanine (VIII) is activated as the mixed anhydride (IX) and subsequently coupled to the dipeptide amide (VII), producing (X). Deprotection of the N-Cbz group of tripeptide (X) by hydrogenolysis over Pd/C yields (XI). The mixed anhydride (XIII) (prepared from N-Cbz-L-tyrosine (XII) and isobutyl chloroformate) is then coupled to tripeptide (XI), producing (XIV). Finally, removal of the N-Cbz group of (XIV) by catalytic hydrogenolysis furnishes the title compound.
【1】
Franzen, H. (AstraZeneca plc); Process for the preparation of a tetrapeptide. WO 9947548 .
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VII) |
61044 |
(2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide
|
|
C18H20FN3O2 |
详情 |
详情
|
(VIII) |
61209 |
CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine
|
|
C11H13NO4 |
详情 |
详情
|
(IX) |
61210 |
|
|
C16H21NO6 |
详情 |
详情
|
(X) |
61211 |
benzyl (1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethylcarbamate
|
|
C29H31FN4O5 |
详情 |
详情
|
(XI) |
61045 |
(2S)-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-2-{[(2R)-2-aminopropanoyl]amino}-3-(4-fluorophenyl)propanamide
|
|
C21H25FN4O3 |
详情 |
详情
|
(XII) |
39328 |
(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid
|
|
C17H17NO5 |
详情 |
详情
|
(XIII) |
61212 |
|
|
C22H25NO7 |
详情 |
详情
|
(XIV) |
61213 |
(1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoate
|
|
C38H39FN4O8 |
详情 |
详情
|
合成路线7
该中间体在本合成路线中的序号:
(IX) The selective monobenzylation of the hydroxysuccinic acid (I) with trifluoroacetic anhydride and benzyl alcohol gives the monoester (II), which is esterified again with 4-methoxybenzyl chloride (PMB-Cl) and K2CO3 in hot DMF yielding the asymetric diester (III). The reaction of (III) with trifluoromethanesulfonic anhydride, CH3SNa and 15-crown-5 affords the methylsulfanyl derivative (IV), which is selectively debenzylated to give the hemiester (V). The condensation of (V) with the intermediate aminomethyl amide (VI) by means of EDAC and HOBT yields the expected amide (VII), which is oxidized with MCPBA or Oxone to afford the methylsulfanyl derivative (VIIIa-b). Unfortunately, during the preceding oxidation, during a variety of conditions, inevitably lead to epimerization of the stereocenter bearing the methylsulfonyl group. Finally (VIIIa-b) is deprotected by hydrogenolysis with Pd/C and formic acid in methanol.
The intermediate aminomethyl amide (VI) has been obtained by condensation of N-benzyloxycarbonyl-L-alanine (X) with glycinamide (IX) by means of CDI and TEA in THF to give the dipeptide (XI), which is submitted to an acidic Hofmann rearrangement using I,I-bis(trifluoroacetoxy)iodobenzene (PIFA) yielding the desired aminomethyl amide (VI).
【1】
Sutton, A.E.; Clardy, J.; The total synthesis of pantocin B. Org Lett 2000, 2, 3, 319.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(VIIIa) |
41533 |
benzyl (5S,12S)-5-methyl-12-(methylsulfonyl)-3,6,10-trioxo-1-phenyl-2-oxa-4,7,9-triazatridecan-13-oate
|
|
C24H29N3O8S |
详情 |
详情
|
(VIIIb) |
41534 |
benzyl (5S,12R)-5-methyl-12-(methylsulfonyl)-3,6,10-trioxo-1-phenyl-2-oxa-4,7,9-triazatridecan-13-oate
|
|
C24H29N3O8S |
详情 |
详情
|
(I) |
11058 |
(S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid
|
97-67-6 |
C4H6O5 |
详情 | 详情
|
(II) |
41527 |
(3S)-4-(benzyloxy)-3-hydroxy-4-oxobutyric acid
|
|
C11H12O5 |
详情 |
详情
|
(III) |
41528 |
1-benzyl 4-(4-methoxybenzyl) (2S)-2-hydroxybutanedioate
|
|
C19H20O6 |
详情 |
详情
|
(IV) |
41529 |
1-benzyl 4-(4-methoxybenzyl) (2R)-2-(methylsulfanyl)butanedioate
|
|
C20H22O5S |
详情 |
详情
|
(V) |
41530 |
(3R)-4-(benzyloxy)-3-(methylsulfanyl)-4-oxobutyric acid
|
|
C12H14O4S |
详情 |
详情
|
(VI) |
41531 |
benzyl (1S)-2-[(aminomethyl)amino]-1-methyl-2-oxoethylcarbamate
|
|
C12H17N3O3 |
详情 |
详情
|
(VII) |
41532 |
benzyl (5S,12R)-5-methyl-12-(methylsulfanyl)-3,6,10-trioxo-1-phenyl-2-oxa-4,7,9-triazatridecan-13-oate
|
|
C24H29N3O6S |
详情 |
详情
|
(IX) |
61209 |
CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine
|
|
C11H13NO4 |
详情 |
详情
|
(X) |
41435 |
N'-[3-(tert-butyl)-5-methoxy-2-(methoxymethoxy)phenyl]-N-(3-pyridinyl)-N-(4-pyridinylmethyl)urea
|
|
C25H30N4O4 |
详情 |
详情
|
(XI) |
41356 |
tert-butyl (4R)-4-[[(benzyloxy)carbonyl]amino]-4-cyanobutanoate
|
|
C17H22N2O4 |
详情 |
详情
|