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【结 构 式】 
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【分子编号】16730 【品名】1-(Isocyanatomethyl)benzene; Benzyl Isocyanate 【CA登记号】3173-56-6 |
【 分 子 式 】C8H7NO 【 分 子 量 】133.14972 【元素组成】C 72.17% H 5.3% N 10.52% O 12.02% |
合成路线1
该中间体在本合成路线中的序号：(VII)1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with trimethylsulfonium iodide (II) and potassium tert-butoxide gives the epoxide (III), which is treated with benzyl alcohol and NaH to perform epoxide ring opening and simultaneous cyclization to yield the oxazolidinone (IV). The hydrolysis of (IV) with KOH affords compound (V), which is condensed with N-(benzylaminocarbonyl)-L-proline (VI) (prepared in situ with benzyl isocyanate (VII) and L-proline (VIII) in the presence of triethylamine) by means of diphenyl phosphoryl azide (DPPA) giving the dipeptide analogue (IX). The oxidation of (IX) with P2O5 in DMSO yields the benzylated JTP-4819 product (X), which is finally deprotected by hydrogenolysis with H2 over Pd/C.
| 【1】 Wroblewski, T.; Silvestre, J.S.; Castañer, J.; JTP-4819. Drugs Fut 1998, 23, 4, 384. |
| 【2】 Fujiwara, T.; Iwamoto, Y.; Uchida, I.; Shinoda, M.; Abe, H.; Toide, K.; A novel prolyl endopeptidase inhibitor, JTP-4819, for the treatment of Alzheimer's disease: Review of preclinical pharmacology. CNS Drug Rev 1996, 2, 3, 343-62. |
| 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) | 16724 | tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal | 69610-41-9 | C10H17NO3 | 详情 | 详情 |
| (II) | 16725 | trimethylsulfonium iodide | 2181-42-2 | C3H9IS | 详情 | 详情 |
| (III) | 16726 | tert-butyl (2S)-2-[(2R)oxiranyl]tetrahydro-1H-pyrrole-1-carboxylate | C11H19NO3 | 详情 | 详情 | |
| (IV) | 16727 | (1R,7aS)-1-[(benzyloxy)methyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one | C14H17NO3 | 详情 | 详情 | |
| (V) | 16728 | (1R)-2-(benzyloxy)-1-[(2S)tetrahydro-1H-pyrrol-2-yl]-1-ethanol | C13H19NO2 | 详情 | 详情 | |
| (VI) | 16729 | (2S)-1-[(benzylamino)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid | C13H16N2O3 | 详情 | 详情 | |
| (VII) | 16730 | 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate | 3173-56-6 | C8H7NO | 详情 | 详情 |
| (VIII) | 16731 | L-proline | 147-85-3 | C5H9NO2 | 详情 | 详情 |
| (IX) | 16732 | (2S)-N-benzyl-2-([(2S)-2-[(1R)-2-(benzyloxy)-1-hydroxyethyl]tetrahydro-1H-pyrrol-1-yl]carbonyl)tetrahydro-1H-pyrrole-1-carboxamide | C26H33N3O4 | 详情 | 详情 | |
| (X) | 16733 | (2S)-N-benzyl-2-([(2S)-2-[2-(benzyloxy)acetyl]tetrahydro-1H-pyrrol-1-yl]carbonyl)tetrahydro-1H-pyrrole-1-carboxamide | C26H31N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)Condensation between aminomalononitrile (I) and benzyl isocyanate (II) produces imidazole (III). This is then cyclized with benzoyl isothiocyanate (IV) in the presence of NaOH to furnish the mercaptopurine derivative (V). Finally, alkylation of thiol (V) with 2-bromoethanol (VI) gives rise to the target hydroxyethyl sulfide.
| 【1】 Kawakami, H.; Ogino, T.; Kurimoto, A. (Japan Energy Corp.; Sumitomo Pharmaceuticals Co., Ltd.); Novel heterocyclic cpds.. EP 1035123; US 6329381; WO 9928321 . |
| 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) | 63650 | 2-aminomalononitrile | C3H3N3 | 详情 | 详情 | |
| (II) | 16730 | 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate | 3173-56-6 | C8H7NO | 详情 | 详情 |
| (III) | 63651 | 5-amino-1-benzyl-2-hydroxy-1H-imidazole-4-carbonitrile | C11H10N4O | 详情 | 详情 | |
| (IV) | 23530 | benzoyl isothiocyanate | 532-55-8 | C8H5NOS | 详情 | 详情 |
| (V) | 63652 | 6-amino-9-benzyl-2-sulfanyl-9H-purin-8-ol | C12H11N5OS | 详情 | 详情 | |
| (VI) | 10059 | Ethylene bromohydrin; 2-Bromo-1-ethanol | 540-51-2 | C2H5BrO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Condensation of Boc-D-Orn(COOCH2Ph)-OH (I) with the lithium salt of ethyl acetate (A) in the presence of CDI in THF affords derivative (II), which is then hydrogenated over Pd/C to yield the mixture of isomers (IIIa-b). Condensation of (IIIa-b) with benzyl isocyanate in THF, followed by simultaneous reduction and cyclization by means of NaH in THF, provides 1,3-dioxoperhydropyrido[1,2-c]pyrimidine (Va-b), whose N-Boc group is removed by treatment with TFA in CH2Cl2 to furnish amine (VI). Coupling of (VIa-b) to Boc-L-Trp-OH (VII) by means of BOP and Et3N in CH2Cl2, followed by chromatographic separation, gives derivative (VIII), which is subjected to Boc removal by treatment with TFA in CH2Cl2 to provide amine (IX). Finally, amine (IX) is condensed with t-butyl isocyanate in the presence of Et3N in THF to yield the target compound.
| 【1】 Martin-Martinez, M.; et al.; Synthesis and stereochemical structure-activity relationships of 1,3-dioxoperhydropyrido[1, 2-c]pyrimidine derivatives: Potent and selective cholecystokinin-A receptor antagonists. J Med Chem 1997, 40, 21, 3402. |
| 【2】 Bartolomé-Nebreda, J.M.; Gómez-Monterrey, I.; García-López, M.T.; González-Muñiz, R.; Martín-Martinez, M.; Ballaz, S.; Cenarruzabeitia, E.; LaTorre, M.; Del Rio, J.; Herranz, R.; 5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK1 receptor antagonists: Structural modifications at the tryptophan domain. J Med Chem 1999, 42, 22, 4659. |
| 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) | 44205 | (2-ethoxy-2-oxoethyl)lithium | C4H7LiO2 | 详情 | 详情 | |
| (IIIa) | 44207 | ethyl 2-[(2R,3R)-3-[(tert-butoxycarbonyl)amino]piperidinyl]acetate | C14H26N2O4 | 详情 | 详情 | |
| (IIIb) | 44208 | ethyl 2-[(2S,3R)-3-[(tert-butoxycarbonyl)amino]piperidinyl]acetate | C14H26N2O4 | 详情 | 详情 | |
| (Va) | 44209 | tert-butyl (4aR,5R)-2-benzyl-1,3-dioxooctahydro-1H-pyrido[1,2-c]pyrimidin-5-ylcarbamate | C20H27N3O4 | 详情 | 详情 | |
| (Vb) | 44210 | tert-butyl (4aS,5R)-2-benzyl-1,3-dioxooctahydro-1H-pyrido[1,2-c]pyrimidin-5-ylcarbamate | C20H27N3O4 | 详情 | 详情 | |
| (VIa) | 44211 | (4aR,5R)-5-amino-2-benzylhexahydro-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione | C15H19N3O2 | 详情 | 详情 | |
| (VIb) | 44212 | (4aS,5R)-5-amino-2-benzylhexahydro-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione | C15H19N3O2 | 详情 | 详情 | |
| (I) | 44215 | (2R)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid | C18H26N2O6 | 详情 | 详情 | |
| (II) | 44206 | ethyl (4R)-7-[[(benzyloxy)carbonyl]amino]-4-[(tert-butoxycarbonyl)amino]-3-oxoheptanoate | C22H32N2O7 | 详情 | 详情 | |
| (IV) | 16730 | 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate | 3173-56-6 | C8H7NO | 详情 | 详情 |
| (VII) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (VIII) | 44213 | tert-butyl (1S)-2-[[(4aS,5R)-2-benzyl-1,3-dioxooctahydro-1H-pyrido[1,2-c]pyrimidin-5-yl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethylcarbamate | C31H37N5O5 | 详情 | 详情 | |
| (IX) | 44214 | (2S)-N-[(4aS,5R)-2-benzyl-1,3-dioxooctahydro-1H-pyrido[1,2-c]pyrimidin-5-yl]-2-amino-3-(1H-indol-3-yl)propanamide | C26H29N5O3 | 详情 | 详情 | |
| (X) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Acetylation of 2-thiazolylhydrazine (I) with Ac2O in pyridine gave hydrazide (II). This was then converted to the title semicarbazide by carbamoylation with benzyl isocyanate (III) in the presence of DMAP.
| 【1】 Andurkar, S.V.; et al.; Synthesis and structural studies of aza analogues of functionalized amino acids: New anticonvulsant agents. J Med Chem 2001, 44, 9, 1475. |
合成路线5
该中间体在本合成路线中的序号：(XI)Selective deprotection of the N-Boc group of (IX) is accomplished by means of trifluoroacetic acid in CH2Cl2 at 0 C. The resultant primary amine (X) is then coupled to benzyl isocyanate (XI) to furnish urea (XII). Then, acidic cleavage of the tert-butyl ester group of (XII) leads to the title carboxylic acid (1,2).
| 【1】 Rej, R.; Lamothe, S.; Zacharie, B.; Labrecque, D.; Courchesne, M.; Falardeau, G.; Abbot, S.; Wang, W.; Chan, L.; Meerovitch, K.; Bergeron, F.; Attardo, G.; Synthesis and in vitro potency of quinolizinone-based alphavbeta3 receptor antagonists. Proc Am Assoc Cancer Res 2002, 43. |
| 【2】 Attardo, G.; Lamothe, S.; Rej, R.; Zacharie, B.; Falardeau, G.; Labrecque, D.; Courchesne, M.; Abbott, S. (Shire BioChem Inc.); Quinolizinones as integrin inhibitors. EP 1115724; US 6630488; WO 0017197 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 63679 | tert-butyl (2S)-3-{[(7-{[(tert-butoxycarbonyl)amino]methyl}-4-oxo-4H-quinolizin-2-yl)carbonyl]amino}-2-[(phenylsulfonyl)amino]propanoate | C29H36N4O8S | 详情 | 详情 | |
| (X) | 63680 | tert-butyl (2S)-3-({[7-(aminomethyl)-4-oxo-4H-quinolizin-2-yl]carbonyl}amino)-2-[(phenylsulfonyl)amino]propanoate | C24H28N4O6S | 详情 | 详情 | |
| (XI) | 16730 | 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate | 3173-56-6 | C8H7NO | 详情 | 详情 |
| (XII) | 63681 | tert-butyl (2S)-3-({[7-({[(benzylamino)carbonyl]amino}methyl)-4-oxo-4H-quinolizin-2-yl]carbonyl}amino)-2-[(phenylsulfonyl)amino]propanoate | C32H35N5O7S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The cyclization of (3R)-N-Boc-3-cyclohexyl-D-serine (I) with 1-benzylpiperidin-4-one (II), benzyl isonitrile (III) and butylamine (IV) in refluxing methanol gives the piperidine derivative (V), whose Boc group is removed by treatment with TFA in dichloromethane, yielding compound (VI). The cyclization of (VI) by means of AcOH in hot toluene affords the spiro[piperazine-2,4'-piperidine] derivative (VII), which is hydrogenated in methanol over palladium hydroxide on carbon to cleave the benzyl protecting group and provide the unprotected spiro derivative (VIII). Finally, this compound is reductocondensed with 4-(4-formylphenoxy)benzoic acid (IX) by means of sodium triacetoxyborohydride in DMF/AcOH to give the target spiro[piperazine-2,4'-piperidine] derivative.
| 【1】 Shibayama, S.; Hamano, S.; Takaoka, Y.; Habashita, H. (Ono Pharmaceutical Co., Ltd.); Triazaspiro[5.5]undecane derivs. and drugs containing the same as the active ingredient. EP 1378510; WO 0274770 . |
| 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) | 64663 | (2R,3R)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexyl-3-hydroxypropanoic acid | C14H25NO5 | 详情 | 详情 | |
| (II) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (III) | 16730 | 1-(Isocyanatomethyl)benzene; Benzyl Isocyanate | 3173-56-6 | C8H7NO | 详情 | 详情 |
| (IV) | 39041 | butylamine; 1-butanamine | 109-73-9 | C4H11N | 详情 | 详情 |
| (V) | 64664 | tert-butyl (1R)-2-[{1-benzyl-4-[(benzylamino)carbonyl]-4-piperidinyl}(butyl)amino]-1-[(R)-cyclohexyl(hydroxy)methyl]-2-oxoethylcarbamate | C38H56N4O5 | 详情 | 详情 | |
| (VI) | 64665 | 4-[[(2R,3R)-2-amino-3-cyclohexyl-3-hydroxypropanoyl](butyl)amino]-N,1-dibenzyl-4-piperidinecarboxamide | C33H48N4O3 | 详情 | 详情 | |
| (VII) | 64666 | (3R)-9-benzyl-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione | C26H39N3O3 | 详情 | 详情 | |
| (VIII) | 64667 | (3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione | C19H33N3O3 | 详情 | 详情 | |
| (IX) | 64668 | 4-(4-formylphenoxy)benzoic acid | C14H10O4 | 详情 | 详情 |