合成路线1
该中间体在本合成路线中的序号:
(I) This compound can be prepared by two related ways:
1) The diazotation of L-serine methyl ester (I) with NaNO2 - HCl gives methyl (S)-glycerate (II), which by reaction with 2,2-dimethoxypropane and p-toluenesulfonic acid (or acetone and ZnCl2) is converted to methyl (S)-O-isopropylideneglycerate (III). The reduction of (III) with LiAlH4 in refluxing ether affords (S)-2,3-O-isopropylideneglycerol (IV), which by reaction with tosyl chloride in pyridine is converted to the corresponding tosylate (V). The partial hydrolysis of (V) with HCl in acetone affords (S)-glycerol-1-tosylate (VI), which is finally condensed with 1-phenylpiperazine (VII) in refluxing benzene.
2) The partial hydrolysis of (S)-2,3-epoxypropyl tosylate (VIII) with HCl as before gives the glycerol tosylate (VI), already obtained.
【1】
Borsa, M.; Tonon, G.; Malandrino, S. (Dompé Farm. SpA); Optically active compounds with antitussive and central sedative activity, a process for the preparation thereof and compositions containing the same. EP 0147847; US 4699911; US 4764515 . |
【2】
Giani, R.; Marione, E.; Melillo, G.; Borsa, M.; Tonon, G.C.; Synthesis and pharmacological screening of new phenylpiperazinepropane derivatives and their enantiomers. Arzneim-Forsch Drug Res 1988, 38, 8, 1139-41.
|
【3】
Prous, J.; Castaner, J.; LEVDROPROPIZINE < Rec INN >. Drugs Fut 1989, 14, 6, 522.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
10272 |
[[Amino(imino)methyl]sulfanyl]methane
|
2986-19-8 |
C2H6N2S |
详情 | 详情
|
(I) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
(II) |
20916 |
methyl (2R)-2,3-dihydroxypropanoate
|
|
C4H8O4 |
详情 |
详情
|
(III) |
20917 |
methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate
|
52373-72-5 |
C7H12O4 |
详情 | 详情
|
(IV) |
12709 |
[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methanol
|
22323-82-6 |
C6H12O3 |
详情 | 详情
|
(V) |
20919 |
[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate
|
23788-74-1 |
C13H18O5S |
详情 | 详情
|
(VI) |
20920 |
(2R)-2,3-dihydroxypropyl 4-methylbenzenesulfonate
|
|
C10H14O5S |
详情 |
详情
|
(VII) |
10756 |
N-Phenylpiperazine; 1-Phenylpiperazine; Phenyl piperazine
|
92-54-6 |
C10H14N2 |
详情 | 详情
|
(VIII) |
16242 |
(2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate
|
113826-06-5 |
C10H12O4S |
详情 | 详情
|
合成路线2
该中间体在本合成路线中的序号:
(XVI) The synthesis of L-serine pentylamide (intermediate in the synthesis of 174639) (see Scheme no. 17463901a) has been described by two similar ways:
1) The condensation of N-(benzyloxycarbonyl)-L-serine (XIII) with pentylamine (XIV) by means of WSC and HOBT gives the protected amide (XV), which is deprotected with H2 over Pd/C (59% overall yield).
2) By aminolysis of L-serine methyl ester (XVI) with pentylamine at 15-25 C (81% yield).
【1】
Reid, J.G.; et al.; Synthesis of a seranamide by aminolysis of an N-unsubstituted alpha-amino ester. Org Process Res Dev 1997, 1, 2, 174.
|
【2】
Misra, R.N.; Brown, B.R.; Sher, P.M.; et al.; Thromboxane receptor antagonist BMS-180291: A new pre-clinical lead. Bioorg Med Chem Lett 1992, 2, 1, 73.
|
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) |
14871 |
(2S)-2-amino-3-hydroxy-N-pentylpropanamide
|
|
C8H18N2O2 |
详情 |
详情
|
(XIII) |
32794 |
(2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropionic acid
|
|
C11H13NO5 |
详情 |
详情
|
(XIV) |
15764 |
amylamine; 1-pentanamine; pentylamine
|
110-58-7 |
C5H13N |
详情 | 详情
|
(XV) |
32795 |
benzyl (1S)-1-(hydroxymethyl)-2-oxo-2-(pentylamino)ethylcarbamate
|
|
C16H24N2O4 |
详情 |
详情
|
(XVI) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
合成路线3
该中间体在本合成路线中的序号:
(X) In a different synthetic strategy, L-serine methyl ester (X) was protected as the N-benzyl derivative (XI) by reductive alkylation with benzaldehyde and NaBH4. Ammonolysis of ester (XI) then produced N-benzyl serinamide (XII). Subsequent reduction of the amide function of (XII) employing borane-dimethyl sulfide complex gave diamine (XIII). This was condensed with the chloropyrimidine (XIV) to afford adduct (XV). After protection of the exocyclic amine with di-tert-butyl dicarbonate, alcohol (XVI) oxidation with Dess-Martin periodinane reagent yielded aldehyde (XVII). Reductive coupling of (XVII) with p-aminobenzoyl glutamic acid (XVIII), followed by acidic Boc group deprotection, led to the triaminopropane derivative (XIX). Catalytic hydrogenation of the nitro group of (XIX) and N-debenzylation over Pd/C yielded the pteridine ring precursor (XX).
【1】
Bailey, S.W.; et al.; Synthesis of tetrahydropteridine C6-stereoisomers, including N5-formyl-(6S)-tetrahydrofolic acid. J Org Chem 1992, 57, 16, 4470.
|
中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
(X) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
(XI) |
56820 |
methyl (2S)-2-(benzylamino)-3-hydroxypropanoate
|
|
C11H15NO3 |
详情 |
详情
|
(XII) |
56821 |
(2S)-2-(benzylamino)-3-hydroxypropanamide
|
|
C10H14N2O2 |
详情 |
详情
|
(XIII) |
56822 |
(2R)-3-amino-2-(benzylamino)-1-propanol
|
|
C10H16N2O |
详情 |
详情
|
(XIV) |
56823 |
2-amino-6-chloro-5-nitro-4(1H)-pyrimidinone
|
|
C4H3ClN4O3 |
详情 |
详情
|
(XV) |
56824 |
2-amino-6-{[(2R)-2-(benzylamino)-3-hydroxypropyl]amino}-5-nitro-4(1H)-pyrimidinone
|
|
C14H18N6O4 |
详情 |
详情
|
(XVI) |
56825 |
tert-butyl (1R)-2-[(2-amino-5-nitro-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]-1-(hydroxymethyl)ethyl(benzyl)carbamate
|
|
C19H26N6O6 |
详情 |
详情
|
(XVII) |
56826 |
tert-butyl (1R)-2-[(2-amino-5-nitro-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]-1-formylethyl(benzyl)carbamate
|
|
C19H24N6O6 |
详情 |
详情
|
(XVIII) |
56827 |
(2S)-2-[(4-aminobenzoyl)amino]pentanedioic acid
|
|
C12H14N2O5 |
详情 |
详情
|
(XIX) |
56828 |
(2S)-2-[(4-{[(2S)-3-[(2-amino-5-nitro-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]-2-(benzylamino)propyl]amino}benzoyl)amino]pentanedioic acid
|
|
C26H30N8O8 |
详情 |
详情
|
(XX) |
56829 |
(2S)-2-{[4-({(2S)-2-amino-3-[(2,5-diamino-6-oxo-3,6-dihydro-4-pyrimidinyl)amino]propyl}amino)benzoyl]amino}pentanedioic acid
|
|
C19H26N8O6 |
详情 |
详情
|
合成路线4
该中间体在本合成路线中的序号:
(I) The amidation of L-serine methyl ester (I) with ethylenediamine (II) gives the amide (III), which is reduced with borane/THF to 2(R)-(hydroxymethyl)diethylenetriamine (IV). The reaction of (IV) with bromoacetic acid tert-butyl ester (V) by means of DIEA in DMF affords the penta tert-butyl acetate (VI), which is condensed with the chlorophosphoramidite (VII) by means of DIEA in dichloromethane giving the phosphoramidite intermediate (VIII). The condensation of (VIII) with 4,4-diphenylcyclohexanol (IX) (see scheme 23537901b) by means of tetrazole in acetonitile, with simultaneous oxidation with tert-butyl hydroperoxide yields the phosphate (X), which is selectively hydrolyzed at the 2-cyanoethyl ester group with ammonia in methanol affording the ammonium phosphate (XI). Finally, the hydrolysis of (XI) with HCl in ether/water eliminates the tert-butyl groups affording the desired chelating ligand (XII)
【1】
Scott, D.M.; Sajiki, H.; McMurray, T.J.; Lauffer, R.B. (Epix Medical, Inc.); Diagnostic imaging contrast agents with extended blood retention. WO 9623526 .
|
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) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
(II) |
14754 |
ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine;1,2-Ethanediamine |
107-15-3 |
C2H8N2 |
详情 | 详情
|
(III) |
30315 |
(2S)-2-amino-N-(2-aminoethyl)-3-hydroxypropanamide
|
|
C5H13N3O2 |
详情 |
详情
|
(IV) |
30316 |
(2R)-2-amino-3-[(2-aminoethyl)amino]-1-propanol
|
|
C5H15N3O |
详情 |
详情
|
(V) |
17430 |
2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate
|
5292-43-3 |
C6H11BrO2 |
详情 | 详情
|
(VI) |
30317 |
3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-(hydroxymethyl)-3,6,9-triazaundecanedioic acid di-tert-butyl ester
|
|
C35H65N3O11 |
详情 |
详情
|
(VII) |
22791 |
2-Cyanoethyl N,N-diisopropylphosphoramidochloridite
|
89992-70-1 |
C9H18ClN2OP |
详情 | 详情
|
(VIII) |
30318 |
3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(diisopropylamino)phosphinyloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester
|
|
C44H82N5O12P |
详情 |
详情
|
(IX) |
30319 |
4,4-diphenylcyclohexanol
|
|
C18H20O |
详情 |
详情
|
(X) |
30320 |
3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[2-cyanoethoxy(4,4-diphenylcyclohexyloxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester
|
|
C56H87N4O14P |
详情 |
详情
|
(XI) |
30321 |
3,6,9-Tris(tert-butoxycarbonylmethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid di-tert-butyl ester ammonium salt
|
|
C53H87N4O14P |
详情 |
详情
|
(XII) |
30322 |
3,6,9-Tris(carboxymethyl)-4(R)-[4,4-diphenylcyclohexyloxy(hydroxy)phosphoryloxymethyl]-3,6,9-triazaundecanedioic acid
|
|
C33H44N3O14P |
详情 |
详情
|
合成路线5
该中间体在本合成路线中的序号:
(I) The protection of the NH2 group of L-serine (I) gives N-(benzyloxycarbonyl)-L-serine (II), which is converted into the N-methylamide (III). The reduction of the amide group of (III) affords the diaminopropanol (IV), which is N-protected to provide the Boc-protected compound (V). The mesylation of the OH group of (V) gives the mesylate (VI), which is treated with ethylamine to yield the triaminopropane (VII). Boc deprotection in (VII) with HCl affords intermediate (VIII), which is submitted to a reductive cyclization with glyoxal and BH3/TEA to provide the perhydro-1,4-diazepine (IX). Cbz deprotection in (IX) by hydrogenation with H2 over Pd/C gives the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (X), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (XI) by means of ethyl chloroformate and TEA to yield the target amide (XII). Finally, this compound is treated with fumaric acid (XIII) in ethanol to afford the desired fumarate salt.
【1】
Hirokawa, Y.; et al.; Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine. Org Process Res Dev 2002, 6, 1, 28.
|
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) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
(II) |
51660 |
methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate
|
|
C12H15NO5 |
详情 |
详情
|
(III) |
53991 |
benzyl (1S)-1-(hydroxymethyl)-2-(methylamino)-2-oxoethylcarbamate
|
n/a |
C12H16N2O4 |
详情 | 详情
|
(IV) |
53992 |
benzyl (1R)-2-hydroxy-1-[(methylamino)methyl]ethylcarbamate
|
n/a |
C12H18N2O3 |
详情 | 详情
|
(V) |
53993 |
benzyl (1R)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-(hydroxymethyl)ethylcarbamate
|
n/a |
C17H26N2O5 |
详情 | 详情
|
(VI) |
53994 |
(2R)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate
|
n/a |
C18H28N2O7S |
详情 | 详情
|
(VII) |
53995 |
benzyl (1S)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-[(ethylamino)methyl]ethylcarbamate
|
n/a |
C19H31N3O4 |
详情 | 详情
|
(VIII) |
53996 |
benzyl (1R)-2-(ethylamino)-1-[(methylamino)methyl]ethylcarbamate
|
n/a |
C14H23N3O2 |
详情 | 详情
|
(IX) |
53997 |
benzyl (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylcarbamate
|
n/a |
C16H25N3O2 |
详情 | 详情
|
(X) |
17802 |
(6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine
|
|
C8H19N3 |
详情 |
详情
|
(XI) |
17801 |
5-bromo-2-methoxy-6-(methylamino)nicotinic acid
|
|
C8H9BrN2O3 |
详情 |
详情
|
(XII) |
53998 |
5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide
|
n/a |
C16H26BrN5O2 |
详情 | 详情
|
(XIII) |
23808 |
Fumaric acid; (E)-2-butenedioic acid
|
110-17-8 |
C4H4O4 |
详情 | 详情
|
合成路线6
该中间体在本合成路线中的序号:
(I) The protection of the NH2 group of L-serine (I) gives N-(benzyloxycarbonyl)-L-serine (II), which is converted into the N-methylamide (III). The reduction of the amide group of (III) affords the diaminopropanol (IV), which is N-protected to provide the Boc-protected compound (V). The mesylation of the OH group of (V) gives the mesylate (VI), which is treated with ethylamine to yield the triaminopropane (VII). The condensation of (VII) with ethyl bromoacetate (VIII) affords the aminoacetate (IX), which is selectively deprotected with HCl to provide the intermediate (X). The cyclization of (X) by means of NaOEt gives the perhydro-1,4-diazepin-2-one (XI), which is reduced with BH3/THF to yield the perhydro-1,4-diazepine (XII). Cbz deprotection in (XII) by hydrogenation with H2 over Pd/C gives the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (XIII), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (XIV) by means of ethyl chloroformate and TEA to yield the target amide (XV). Finally, this compound is treated with fumaric acid (XVI) in ethanol to afford the desired fumarate salt.
【1】
Hirokawa, Y.; et al.; Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine. Org Process Res Dev 2002, 6, 1, 28.
|
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) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
(II) |
51660 |
methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropanoate
|
|
C12H15NO5 |
详情 |
详情
|
(III) |
53991 |
benzyl (1S)-1-(hydroxymethyl)-2-(methylamino)-2-oxoethylcarbamate
|
n/a |
C12H16N2O4 |
详情 | 详情
|
(IV) |
53992 |
benzyl (1R)-2-hydroxy-1-[(methylamino)methyl]ethylcarbamate
|
n/a |
C12H18N2O3 |
详情 | 详情
|
(V) |
53993 |
benzyl (1R)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-(hydroxymethyl)ethylcarbamate
|
n/a |
C17H26N2O5 |
详情 | 详情
|
(VI) |
53994 |
(2R)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)(methyl)amino]propyl methanesulfonate
|
n/a |
C18H28N2O7S |
详情 | 详情
|
(VII) |
53995 |
benzyl (1S)-2-[(tert-butoxycarbonyl)(methyl)amino]-1-[(ethylamino)methyl]ethylcarbamate
|
n/a |
C19H31N3O4 |
详情 | 详情
|
(VIII) |
16640 |
Ethyl 2-bromoacetate; Ethyl bromoacetate
|
105-36-2 |
C4H7BrO2 |
详情 | 详情
|
(IX) |
53999 |
ethyl 2-[{(2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butoxycarbonyl)(methyl)amino]propyl}(ethyl)amino]acetate
|
n/a |
C23H37N3O6 |
详情 | 详情
|
(X) |
54000 |
ethyl 2-[[(2R)-2-{[(benzyloxy)carbonyl]amino}-3-(methylamino)propyl](ethyl)amino]acetate
|
n/a |
C18H29N3O4 |
详情 | 详情
|
(XI) |
54001 |
benzyl (6S)-4-ethyl-1-methyl-2-oxo-1,4-diazepan-6-ylcarbamate
|
n/a |
C16H23N3O3 |
详情 | 详情
|
(XII) |
53997 |
benzyl (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylcarbamate
|
n/a |
C16H25N3O2 |
详情 | 详情
|
(XIII) |
17802 |
(6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine
|
|
C8H19N3 |
详情 |
详情
|
(XIV) |
17801 |
5-bromo-2-methoxy-6-(methylamino)nicotinic acid
|
|
C8H9BrN2O3 |
详情 |
详情
|
(XV) |
53998 |
5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide
|
n/a |
C16H26BrN5O2 |
详情 | 详情
|
(XVI) |
23808 |
Fumaric acid; (E)-2-butenedioic acid
|
110-17-8 |
C4H4O4 |
详情 | 详情
|
合成路线7
该中间体在本合成路线中的序号:
(I) The protection of the NH2 group of L-serine (I) with Ts-Cl and TEA gives N-tosyl-L-serine (II), which is converted into the N-methylamide (III). The cyclization of (III) by means of diisopropylazodicarboxylate (DIAD) yields the N-tosylaziridine (IV), which is treated with ethylamine (V) to afford the diaminopropionamide (VI). The reduction of the amide group of (VI) with LiAlH4 provides the triaminopropane (VII), which is submitted to a reductive cyclization with glyoxal and BH3/TEA to give the perhydro-1,4-diazepine (VIII). Ts deprotection in (VIII) by means of HBr affords the 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (IX), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (X) by means of ethyl chloroformate and TEA to yield the target amide (XI). Finally, this compound is treated with fumaric acid (XII) in ethanol to afford the desired fumarate salt.
【1】
Hirokawa, Y.; et al.; Process development of the synthetic route to (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine. Org Process Res Dev 2002, 6, 1, 28.
|
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) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
(II) |
54002 |
methyl (2S)-3-hydroxy-2-{[(4-methylphenyl)sulfonyl]amino}propanoate
|
n/a |
C11H15NO5S |
详情 | 详情
|
(III) |
54003 |
(2S)-3-hydroxy-N-methyl-2-{[(4-methylphenyl)sulfonyl]amino}propanamide
|
n/a |
C11H16N2O4S |
详情 | 详情
|
(IV) |
54004 |
(2S)-N-methyl-1-[(4-methylphenyl)sulfonyl]-2-aziridinecarboxamide
|
n/a |
C11H14N2O3S |
详情 | 详情
|
(V) |
10928 |
Ethanamine
|
75-04-7 |
C2H7N |
详情 | 详情
|
(VI) |
54005 |
(2S)-3-(ethylamino)-N-methyl-2-{[(4-methylphenyl)sulfonyl]amino}propanamide
|
n/a |
C13H21N3O3S |
详情 | 详情
|
(VII) |
54006 |
N-{(1R)-2-(ethylamino)-1-[(methylamino)methyl]ethyl}-4-methylbenzenesulfonamide
|
n/a |
C13H23N3O2S |
详情 | 详情
|
(VIII) |
54007 |
N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-4-methylbenzenesulfonamide
|
n/a |
C15H25N3O2S |
详情 | 详情
|
(IX) |
17802 |
(6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine
|
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C8H19N3 |
详情 |
详情
|
(X) |
17801 |
5-bromo-2-methoxy-6-(methylamino)nicotinic acid
|
|
C8H9BrN2O3 |
详情 |
详情
|
(XI) |
53998 |
5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide
|
n/a |
C16H26BrN5O2 |
详情 | 详情
|
(XII) |
23808 |
Fumaric acid; (E)-2-butenedioic acid
|
110-17-8 |
C4H4O4 |
详情 | 详情
|
合成路线8
该中间体在本合成路线中的序号:
(I) The cyclization of L-serine (I) with pivalaldehyde (II) by means of LDA in THF gives the oxazolidine (III), which is acylated with formic and acetic anhydride yielding the N-formyloxazolidine (IV). The reaction of (IV) with LDA affords the chiral enol (V), which is treated with allyl bromide in THF to give the chiral 4-allyloxazolidine (VI). Cleavage of the oxazolidine ring with acetyl chloride and treatment with benzyl chloroformate yields the protected chiral 2-allylserine (VII), which is oxidized with oxalyl chloride to the corresponding aldehyde (VIII). The Wittig condensation of (VIII) with triphenylphosphoranylideneacetic acid methyl ester (IX) affords the intermediate (X), which is submitted to UV irradiation with an Hanovia medium pressure mercury lamp through a Pyrex filter in benzene containing benzophenone. A mixture of isomeric bicyclic compounds from which the desired compound (XI) is isolated by column chromatography. The hydrogenation of (IX) with H2 over Pd/C in methanol provides the bicyclic aminoester (XII), which is finally hydrolyzed with 6N HCl.
【1】
von Diester, S.; et al.; Stereoselektive Alkylierung an C(alpha) von Serin, Glycerinsaure, Threonin und Weinsaure uber heterocyclische Enolate mit exocyclischer Doppelbindung. Helv Chim Acta 1987, 70, 1194-1216.
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【2】
Kozikowski, A.P.; et al.; Synthesis and biology of the conformationally restricted ACPD analogue, 2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylic acid-I, a potent mGluR agonist. J Med Chem 1998, 41, 10, 1641.
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中间体序号 |
中间体编号 |
品名 |
CAS号 |
分子式 |
供应商 |
用于合成 |
|
10101 |
Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene
|
501-53-1 |
C8H7ClO2 |
详情 | 详情
|
|
11463 |
3-Bromo-1-propene; 3-Bromopropene;allyl bromide |
106-95-6 |
C3H5Br |
详情 | 详情
|
(I) |
20915 |
methyl (2S)-2-amino-3-hydroxypropanoate
|
5680-80-8 |
C4H9NO3 |
详情 | 详情
|
(II) |
19797 |
Trimethylacetaldehyde; pivalaldehyde; 2,2-Dimethylpropionaldehyde; 2,2-Dimethylpropanal
|
630-19-3 |
C5H10O |
详情 | 详情
|
(III) |
36839 |
methyl (4S)-2-(tert-butyl)-1,3-oxazolidine-4-carboxylate
|
|
C9H17NO3 |
详情 |
详情
|
(IV) |
36840 |
methyl (4S)-2-(tert-butyl)-3-formyl-1,3-oxazolidine-4-carboxylate
|
|
C10H17NO4 |
详情 |
详情
|
(V) |
36841 |
lithium [(2R)-2-(tert-butyl)-3-formyl-1,3-oxazolidin-4-ylidene](methoxy)methanolate
|
|
C10H16LiNO4 |
详情 |
详情
|
(VI) |
36842 |
methyl (2R,4S)-4-allyl-2-(tert-butyl)-3-formyl-1,3-oxazolidine-4-carboxylate
|
|
C13H21NO4 |
详情 |
详情
|
(VII) |
36843 |
methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-2-(hydroxymethyl)-4-pentenoate
|
|
C15H19NO5 |
详情 |
详情
|
(VIII) |
36844 |
methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-2-(2-oxoethyl)-4-pentenoate
|
|
C16H19NO5 |
详情 |
详情
|
(IX) |
14689 |
Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane;Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate |
2605-67-6 |
C21H19O2P |
详情 | 详情
|
(X) |
36845 |
dimethyl (E,4S)-4-allyl-4-[[(benzyloxy)carbonyl]amino]-2-pentenedioate
|
|
C18H21NO6 |
详情 |
详情
|
(XI) |
36846 |
dimethyl (1R,2S,4R,5S)-2-[[(benzyloxy)carbonyl]amino]bicyclo[2.1.1]hexane-2,5-dicarboxylate
|
|
C18H21NO6 |
详情 |
详情
|
(XII) |
36847 |
dimethyl (1R,2S,4R,5S)-2-aminobicyclo[2.1.1]hexane-2,5-dicarboxylate
|
|
C10H15NO4 |
详情 |
详情
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