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【结 构 式】 
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【分子编号】20694 【品名】methyl (2S)-2-aminopropanoate 【CA登记号】 |
【 分 子 式 】C4H9NO2 【 分 子 量 】103.121 【元素组成】C 46.59% H 8.8% N 13.58% O 31.03% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Alternatively, a chiral synthesis of intermediate (V) was developed from enantiopure amino acids. N-Boc-D-alanine (VI) was N-alkylated with allyl bromide in the presence of two equivalents of NaH, and the resulting N-allyl amino acid (VII) was coupled with L-alanine methyl ester (VIII) using 1-dimethylaminopropyl-3-ethylcarbodiimide (DEC) to provide dipeptide (IX). Subsequent acid treatment of (IX) produced both Boc deprotection and cyclization to the diketopiperazine (X), which was finally reduced to piperazine (V) with LiAlH4.
| 【1】 Chang, K.-J.; Bishop, M.J.; Bubacz, D.G.; McNutt, R.W. Jr. (Glaxo Wellcome plc); Piperazine cpds. used in therapy. EP 0711289; JP 1997501156; WO 9504051 . |
| 【2】 Chang, K.; Boswell, G.E.; Bubacz, D.G.; Collins, M.A.; Davis, A.O.; McNutt, R.W. (Delta Pharmaceuticals, Inc.); Opioid diarylmethylpiperazines and piperidines. JP 1995503247; US 5658908; US 5681830; WO 9315062 . |
| 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) | 20690 | (2R,5S)-1-allyl-2,5-dimethylpiperazine | C9H18N2 | 详情 | 详情 | |
| (VI) | 15859 | Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid | 7764-95-6 | C8H15NO4 | 详情 | 详情 |
| (VII) | 20693 | (2R)-2-[allyl(tert-butoxycarbonyl)amino]propionic acid | C11H19NO4 | 详情 | 详情 | |
| (VIII) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (IX) | 20695 | (2S)-2-([(2R)-2-[allyl(tert-butoxycarbonyl)amino]propanoyl]amino)propionic acid | C14H24N2O5 | 详情 | 详情 | |
| (X) | 20696 | (3S,6R)-1-allyl-3,6-dimethyl-2,5-piperazinedione | C9H14N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)In an alternative procedure, N-Cbz-L-tyrosine (I) is condensed with D-alanine methyl ester (II), either employing TBTU as the coupling reagent or via previous activation as the mixed anhydride with isobutyl chloroformate, to produce dipeptide (III). After alkaline hydrolysis of the methyl ester function of (III), the resultant carboxylic acid (IV) is coupled to dipeptide amide (V) yielding the protected tetrapeptide (VI). Finally, deprotection of (VI) is carried out by catalytic hydrogenolysis over Pd/C.
| 【1】 Franzen, H.M.; Bessidskaia, G.; Abedi, V.; Nilsson, A.; Nilsson, M.; Olsson, L.; Frakefamide, an analgesic tetrapeptide: Development of a pilot-plant-scale process. Org Process Res Dev 2002, 6, 6, 788. |
| 【2】 Nilsson, M.; Ellburg, M.; Franzen, H. (AstraZeneca AB); A process for the preparation of H-Tyr-D-Ala-Phe(F)-Phe-NH2. EP 1212350; JP 2003509437; WO 0119849 . |
| 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) | 39328 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid | C17H17NO5 | 详情 | 详情 | |
| (II) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (III) | 61214 | methyl (2R)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoyl]amino}propanoate | C21H24N2O6 | 详情 | 详情 | |
| (IV) | 61215 | (2R)-2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-hydroxyphenyl)propanoyl]amino}propanoic acid | C20H22N2O6 | 详情 | 详情 | |
| (V) | 61044 | (2S)-2-amino-N-[(1S)-2-amino-1-benzyl-2-oxoethyl]-3-(4-fluorophenyl)propanamide | C18H20FN3O2 | 详情 | 详情 | |
| (VI) | 61216 | benzyl (1S)-2-[((1R)-2-{[(1S)-2-{[(1S)-2-amino-1-benzyl-2-oxoethyl]amino}-1-(4-fluorobenzyl)-2-oxoethyl]amino}-1-methyl-2-oxoethyl)amino]-1-(4-hydroxybenzyl)-2-oxoethylcarbamate | C38H40FN5O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)Treatment of triethyl phosphoacetate (I) with NaH and 4-bromobenzyl bromide (II) in DMF provides the 2-substituted triethyl phosphoacetate (III), which then undergoes reaction with formaldehyde and K2CO3 to afford acrylate derivative (IV). Michael condensation of (IV) with phosphinic acid (V) in N,O-bistrimethylsilylacetamide (BSA) yields intermediate (VI), which then undergoes Suzuki condensation in toluene with phenylboronic acid (VII) and NaHCO3 in MeOH catalyzed by Pd(PPh3)4 to give (VIII). Hydrolysis of ethyl ester (VIII) by means of NaOH in EtOH furnishes carboxylic acid (IX), which is then coupled to L-alanine (X) by means of BOP and DIEA or Et3N in DMF to yield methyl ester (XI). Compound (XI) is then hydrolyzed by treatment with NaOH or LiOH in EtOH and, finally, the Z-protecting group is removed with BBr3 in dichloromethane.
| 【1】 Chen, H.; Noble, F.; Coric, P.; Fournie-Zaluski, M.-C.; Roques, B.P.; Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics. Proceedings of the National Academy of Sciences of the United States of America 1998, 95, 20, 12028. |
| 【2】 Noble, F.; Morthé, A.; Chen, H.; et al.; Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors: Synthesis, biological properties, and antinociceptive activities. J Med Chem 2000, 43, 7, 1398. |
| 【3】 Fournie-Zaluski, M.-C.; Chen, H.; Roques, B.P. (INSERM (Institut National de la Sante et de la Recherche Medicale)); Novel (alpha-aminophosphino) peptide derivs., method for making same and therapeutic applications thereof. EP 1009750; WO 9818803 . |
| 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) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (II) | 16109 | 1-bromo-4-(bromomethyl)benzene; 4-Bromobenzyl bromide | 589-15-1 | C7H6Br2 | 详情 | 详情 |
| (III) | 42984 | ethyl 3-(4-bromophenyl)-2-(diethoxyphosphoryl)propanoate | C15H22BrO5P | 详情 | 详情 | |
| (IV) | 42985 | ethyl 2-(4-bromobenzyl)acrylate | C12H13BrO2 | 详情 | 详情 | |
| (V) | 42986 | 1-[[(benzyloxy)carbonyl]amino]ethylphosphinic acid | C10H14NO4P | 详情 | 详情 | |
| (VI) | 42987 | 1-[[(benzyloxy)carbonyl]amino]ethyl[2-(4-bromobenzyl)-3-ethoxy-3-oxopropyl]phosphinic acid | C22H27BrNO6P | 详情 | 详情 | |
| (VII) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (VIII) | 42988 | 1-[[(benzyloxy)carbonyl]amino]ethyl[2-([1,1'-biphenyl]-4-ylmethyl)-3-ethoxy-3-oxopropyl]phosphinic acid; 4-(2-[[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]methyl]-3-ethoxy-3-oxopropyl)-1,1'-biphenyl | C28H32NO6P | 详情 | 详情 | |
| (IX) | 42989 | 3-[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]-2-([1,1'-biphenyl]-4-ylmethyl)propionic acid | C26H28NO6P | 详情 | 详情 | |
| (X) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (XI) | 42990 | 1-[[(benzyloxy)carbonyl]amino]ethyl(2-([1,1'-biphenyl]-4-ylmethyl)-3-[[(1S)-2-methoxy-1-methyl-2-oxoethyl]amino]-3-oxopropyl)phosphinic acid; 4-(2-[[(1-[[(benzyloxy)carbonyl]amino]ethyl)(hydroxy)phosphoryl]methyl]-3-[[(1S)-2-methoxy-1-methyl-2-oxoethyl]amino]-3-oxopropyl)-1,1'-biphenyl | C30H35N2O7P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The intermediate phosphorochloridate (III) has been obtained as follows: The reaction of 4-bromophenol (IV) with POCl3 and triethylamine in ethyl ether gives the corresponding phosphorodichloridate (V), which is finally condensed with L-alanine methyl ester (VI) by means of triethylamine in dichloromethane.
| 【1】 Uckun, F.M. (Parker Hughes Institute); Aryl phosphate derivatives of d4T having anti-HIV activity. WO 0000501 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 32793 | methyl (2S)-2-[[(4-bromophenoxy)(chloro)phosphoryl]amino]propanoate | C10H12BrClNO4P | 详情 | 详情 | |
| (IV) | 25313 | 4-bromophenol | 106-41-2 | C6H5BrO | 详情 | 详情 |
| (V) | 25314 | Dichlorophoephoric acid 4-bromophenyl ester | C6H4BrCl2O2P | 详情 | 详情 | |
| (VI) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Title compound was obtained by condensation of betulinic acid (I) with L-alanine methyl ester (II) in the presence of DCC and DMAP, followed by ester hydrolysis of the resulting intermediate (III) with LiOH.
| 【1】 Chai, H.-B.; Jeong, H.-J.; Park, S.-Y.; Kim, D.S.H.L.; Preparation of amino acid conjugates of betulinic acid with activity against human melanoma. Bioorg Med Chem Lett 1999, 9, 8, 1201. |
| 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) | 25809 | (1R,5aR,5bS,7aR,9S,11aR,11bS,13aS,13bS)-9-hydroxy-1-isopropenyl-5b,8,8,11a-tetramethylicosahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid | C29H46O3 | 详情 | 详情 | |
| (II) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (III) | 25810 | methyl (2S)-2-([[(1R,5aR,5bS,7aR,9S,11aR,11bS,13aS,13bS)-9-hydroxy-1-isopropenyl-5b,8,8,11a-tetramethylicosahydro-3aH-cyclopenta[a]chrysen-3-yl]carbonyl]amino)propanoate | C33H53NO4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)The reaction of 6-chloro-9-[2-(hydroxymethyl)cyclopropylidenemethyl]purine-2-amine (I) with methanol and K2CO3 gives of 9-[2-(hydroxymethyl)cyclopropylidenemethyl]-6-methoxypurine-2-amine (II) which is then condensed with the phosphorylated L-alanine ester (III) by means of N-methylimidazole (NMI) in pyridine/THF. The intermediate the phosphorylated L-alanine ester (III) has been obtained by condensation of L-alanine methyl ester (IV) with phenyl dichlorophosphate (V) by means of TEA in dichloromethane.
| 【1】 Kern, E.R.; Qiu, Y.-L.; Ptak, R.G.; Breitenbach, J.M.; Zemlicka, J.; Drach, J.C.; Cheng, Y.-C.; Lin, J.-S.; Synthesis and antiviral activity of phosphoralaninate derivatives of methylenecyclopropane analogues of nucleosides. Antivir Res 1999, 43, 1, 37. |
| 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) | 41415 | [2-[(Z)-(2-amino-6-chloro-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C10H10ClN5O | 详情 | 详情 | |
| (II) | 41416 | [2-[(Z)-(2-amino-6-methoxy-9H-purin-9-yl)methylidene]cyclopropyl]methanol | C11H13N5O2 | 详情 | 详情 | |
| (III) | 41417 | methyl (2S)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate | C10H13ClNO4P | 详情 | 详情 | |
| (IV) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (V) | 39640 | Phenyl dichlorophosphate;phenyl phosphorodichloridate | 770-12-7 | C6H5Cl2O2P | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Alanine methyl ester (I) was protected by N-alkylation with benzyl bromide to afford (II), which was further reduced to amino alcohol (III) using LiAlH4. Swern oxidation of (III) provided aldehyde (IV). Addition of the Grignard reagent obtained from 1-bromopentadecane (A) to aldehyde (IV) produced the anti-aminoalcohol (V). The N-benzyl groups were finally removed by catalytic hydrogenolysis.
| 【1】 Cuadros, R.; et al.; The marine compound spisulosine, an inhibitor of cell proliferation, promotes the disassembly of actin stress fibers. Cancer Letters 2000, 152, 1, 23. |
| 【2】 Garcia Gravalos, D.; Warwick, R.A.; Avila, J.; Rinehart, K.L.; Fregeau, N.L.; Faircloth, G.T. (University of Illinois); Spisulosine cpds. having antitumour activity. WO 9952521 . |
| 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) | 47265 | bromo(tetradecyl)magnesium | C14H29BrMg | 详情 | 详情 | |
| (I) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (II) | 47262 | methyl (2S)-2-(dibenzylamino)propanoate | C18H21NO2 | 详情 | 详情 | |
| (III) | 47263 | (2S)-2-(dibenzylamino)-1-propanol | C17H21NO | 详情 | 详情 | |
| (IV) | 47264 | (2S)-2-(dibenzylamino)propanal | C17H19NO | 详情 | 详情 | |
| (V) | 47266 | (2S,3R)-2-(dibenzylamino)-3-octadecanol | C32H51NO | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(V)Esterification of (R)-3-chloromandelic acid (I) with MeOH and H2SO4 to yield ether (II), followed by hydroxyl group silylation using t-butyldimethylsilyl chloride and imidazole furnished (III). Reduction of the ester function of (III) by means of DIBAL produced aldehyde (IV), which was subjected to reductive amination with D-alanine methyl ester (V) to produce amino ester (VI). After protection of the amino group of (VI) as the N-Boc derivative (VII), further DIBAL reduction of the ester group afforded aldehyde (VIII).
| 【1】 Uehling, D.E.; Donaldson, K.H.; Deaton, D.N.; Hyman, C.E.; Sugg, E.E.; Barret, D.G.; Hughes, R.G.; Reitter, B.; Adkison, K.K.; Lancaster, M.E.; Lee, F.; Hart, R.; Paulik, M.A.; Sherman, B.W.; True, T.; Cowan, C.; Synthesis and evaluation of potent and selective beta3 adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres. J Med Chem 2002, 45, 3, 567. |
| 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) | 59930 | (2R)-2-(3-chlorophenyl)-2-hydroxyethanoic acid | C8H7ClO3 | 详情 | 详情 | |
| (II) | 59931 | methyl (2R)-2-(3-chlorophenyl)-2-hydroxyethanoate | C9H9ClO3 | 详情 | 详情 | |
| (III) | 59932 | methyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethanoate | C15H23ClO3Si | 详情 | 详情 | |
| (IV) | 59933 | (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethanal | C14H21ClO2Si | 详情 | 详情 | |
| (V) | 20694 | methyl (2S)-2-aminopropanoate | C4H9NO2 | 详情 | 详情 | |
| (VI) | 59934 | methyl (2R)-2-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]amino}propanoate | C18H30ClNO3Si | 详情 | 详情 | |
| (VII) | 59935 | methyl (2R)-2-{(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]amino}propanoate | C23H38ClNO5Si | 详情 | 详情 | |
| (VIII) | 59936 | tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl[(1R)-1-methyl-2-oxoethyl]carbamate | C22H36ClNO4Si | 详情 | 详情 |