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【结 构 式】 
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【分子编号】16976 【品名】tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane 【CA登记号】1609-86-5 |
【 分 子 式 】C5H9NO 【 分 子 量 】99.1326 【元素组成】C 60.58% H 9.15% N 14.13% O 16.14% |
合成路线1
该中间体在本合成路线中的序号：(VII)Reduction of N-Cbz-L-phenylalaninyl chloromethyl ketone (I) with NaBH4 provided a 1:3 mixture of diastereoisomeric chlorohydrins (II) and (III), from which the required isomer (III) was isolated by recrystallization from ethyl acetate-hexane. Treatment of (III) with KOH afforded epoxide (IV), which was opened with isobutyl amine (V) in refluxing isopropanol to give amino alcohol (VI). Subsequent coupling of the amino group of (VI) with tert-butyl carbamate (VII) produced urea (VIII). Removal of the carbamate protecting group of (VIII) by hydrogenation over Pd/C and coupling of the free amine (IX) with N-Cbz-L-asparagine (X) yielded amide (XI). Further removal of the Cbz group of (XI) gave rise to amine (XII), which was finally coupled with 2-quinolinecarboxylic acid N-hydroxysuccinimidyl ester (XIII) to furnish the title quinolinecarboxamide.
| 【1】 Talley, J.J.; Getman, D.P.; DeCrescenzo, G.A.; Lin, K.-O.; Vazquez, M.L.; Mueller, R.A.; Reed, K.L.; Heintz, R.M.; Clare, M.; Freskos, J.N.; Sun, E.T. (Pharmacia Corp.); Urea-containing hydroxyethylamine cpds. as retroviral protease inhibitors. JP 1995508041; WO 9323368 . |
| 【2】 Clare, M.; DeCrescenzo, G.A.; Freskos, J.N.; Getman, D.P.; Heintz, R.M.; Lin, K.-C.; Mueller, R.A.; Reed, K.L.; Talley, J.J.; Vazquez, M.L.; Sun, E.T.O. (Pharmacia Corp.); Retroviral protease inhibitors. EP 0558630; WO 9208701 . |
| 【3】 Getman, D.P.; et al.; Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. J Med Chem 1993, 36, 2, 288. |
| 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) | 37926 | benzyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate | 26049-94-5 | C18H18ClNO3 | 详情 | 详情 |
| (II) | 37927 | benzyl (1S,2R)-1-benzyl-3-chloro-2-hydroxypropylcarbamate | C18H20ClNO3 | 详情 | 详情 | |
| (III) | 37928 | benzyl (1S,2S)-1-benzyl-3-chloro-2-hydroxypropylcarbamate | C18H20ClNO3 | 详情 | 详情 | |
| (IV) | 14522 | benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate | C18H19NO3 | 详情 | 详情 | |
| (V) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (VI) | 37929 | benzyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | C22H30N2O3 | 详情 | 详情 | |
| (VII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (VIII) | 37930 | benzyl (1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropylcarbamate | C27H39N3O4 | 详情 | 详情 | |
| (IX) | 37931 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N'-(tert-butyl)-N-isobutylurea | C19H33N3O2 | 详情 | 详情 | |
| (X) | 14529 | (2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid | 2304-96-3 | C12H14N2O5 | 详情 | 详情 |
| (XI) | 37932 | benzyl (1S)-3-amino-1-[([(1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropyl]amino)carbonyl]-3-oxopropylcarbamate | C31H45N5O6 | 详情 | 详情 | |
| (XII) | 37933 | (2S)-2-amino-N(1)-[(1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropyl]butanediamide | C23H39N5O4 | 详情 | 详情 | |
| (XIII) | 37934 | 1-[(2-quinolinylcarbonyl)oxy]-2,5-pyrrolidinedione | C14H10N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)An alternative procedure for the preparation of the intermediate urea (IX) has been reported. Alkylation of L-phenylalanine (XIV) with benzyl bromide provided the N,N-dibenzyl amine (XV), which was reduced to amino alcohol (XVI) using DIBAL in cold toluene. In an improved large-scale process, amino alcohol (XVI) was prepared by benzylation of L-phenylalaninol (XVII). Swern oxidation of the alcohol function of (XVI) afforded aldehyde (XVIII). Subsequent reaction of (XVIII) with chloromethyllithium at low temperature furnished the desired epoxide (XX) along with minor amounts of its diastereoisomer (XIX). Opening of this mixture with isobutyl amine (V) gave diamino alcohol (XXIa-b). After coupling of (XXIa-b) with tert-butyl isocyanate (VII) to produce the corresponding ureas (XXIIa-b) [the required isomer (XXIIb) was isolated by recrystallization]. Removal of the benzyl protecting groups of (XXIIb) then yielded the target intermediate (IX).
| 【1】 Talley, J.J.; Getman, D.P.; DeCrescenzo, G.A.; Lin, K.-O.; Vazquez, M.L.; Mueller, R.A.; Reed, K.L.; Heintz, R.M.; Clare, M.; Freskos, J.N.; Sun, E.T. (Pharmacia Corp.); Urea-containing hydroxyethylamine cpds. as retroviral protease inhibitors. JP 1995508041; WO 9323368 . |
| 【2】 Liu, C.; et al.; Development of large-scale process for an HIV protease inhibitor. Org Process Res Dev 1997, 1, 1, 45. |
| 【3】 Getman, D.P.; et al.; Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. J Med Chem 1993, 36, 2, 288. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 | |
| (XXIa) | 37939 | (2S,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol | C28H36N2O | 详情 | 详情 | |
| (XXIb) | 37940 | (2R,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol | C28H36N2O | 详情 | 详情 | |
| (XXIIa) | 37941 | N'-(tert-butyl)-N-[(2S,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutylurea | C33H45N3O2 | 详情 | 详情 | |
| (XXIIb) | 37942 | N'-(tert-butyl)-N-[(2R,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutylurea | C33H45N3O2 | 详情 | 详情 | |
| (V) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (VII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (IX) | 37931 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N'-(tert-butyl)-N-isobutylurea | C19H33N3O2 | 详情 | 详情 | |
| (XIV) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XV) | 37935 | (2S)-2-(dibenzylamino)-3-phenylpropionic acid | C23H23NO2 | 详情 | 详情 | |
| (XVI) | 30457 | (2S)-2-(dibenzylamino)-3-phenyl-1-propanol | 111060-52-7 | C23H25NO | 详情 | 详情 |
| (XVII) | 28523 | (2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol | 5267-64-1 | C9H13NO | 详情 | 详情 |
| (XVIII) | 37936 | (2S)-2-(dibenzylamino)-3-phenylpropanal | C23H23NO | 详情 | 详情 | |
| (XIX) | 37937 | N,N-dibenzyl-N-[(1S)-1-[(2R)oxiranyl]-2-phenylethyl]amine; (1S)-N,N-dibenzyl-1-[(2R)oxiranyl]-2-phenyl-1-ethanamine | C24H25NO | 详情 | 详情 | |
| (XX) | 37938 | N,N-dibenzyl-N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]amine; (1S)-N,N-dibenzyl-1-[(2S)oxiranyl]-2-phenyl-1-ethanamine | C24H25NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)ABT-431 can be obtained by two related ways: 1) The reduction of 6,7-dimethoxy-1-tetralone (I) with NaBH4 in ethanol followed by dehydration with p-toluenesulfonic acid in refluxing toluene gives 6,7-dimethoxy-1,2-dihydronaphthalene (II), which is nitrated with tetranitromethane and pyridine in acetone yielding 6,7-dimethoxy-3-nitro-1,2-dihydronaphthalene (III). The condensation of (III) with N-tert-butyl-5-propylthiophene-2-carboxamide (IV) by means of butyllithium in THF affords the trans racemic (V), which is reduced with Zn/HCl to the corresponding amine (VI). The reaction of (VI) with 10% H2SO4 in refluxing methanol gives a mixture of the decarboxylated compound (VII) and the cyclization compound (VIII). The enantiomeric separation of (VIII) by chiral chromatography in a Chiracel(TM) OD column affords the (5aR,11bS)-enantiomer, which is demethylated with BBr3 in dichloromethane to the chiral diol (IX), and finally acetylated with acetyl chloride in trifluoroacetic acid and treated with ethereal HCl. 2) The condensation of (III) with 5-allyl-N-tert-butylthiophene-2-carboxamide (X) by means of butyllithium in THF affords the trans racemic (XI), which by successive treatments with Zn/HCl, hydrogenation with H2 over Pd/C, p-toluenesulfonic acid in refluxing toluene and finally with BH3 in THF, is converted into the previously reported tetracyclic racemic compound (VIII). N-tert-Butyl-5-propylthiophene-2-carboxamide (IV) has been obtained by condensation of 2-propylthiophene (XII) with tert-butyl isocyanate (XIII) by means of butyllithium in THF.
| 【1】 Merlos, M.; Graul, A.; Castañer, J.; ABT-431. Drugs Fut 1997, 22, 8, 821. |
| 【2】 Michaelides, M.R.; Hong, Y.; DiDomenico, S. Jr.; Bayburt, E.K.; Asin, K.E.; Britton, D.R.; Lin, C.W.; Shiosaki; Substituted hexahydrobenzo[f]thieno[c]quinolines as dopamine D1-selective agonists: Synthesis and biological evaluation in vitro and in vivo. J Med Chem 1997, 40, 11, 1585-99. |
| 【3】 Michaelides, M.R.; Hong, Y.; DiDomenico, S. Jr.; Asin, K.E.; Britton, D.R.; Lin, C.W.; Williams, M.; Shiosaki, K.; (5aR,11bS)-4,5,5a,6,7,11b-Hexahydro-2-propyl-3-thia-5-azacyclopent-1-ena[c]phenanthrene-9,10-diol(A-86929): A potent and selective dopamine D1 agonist. J Med Chem 1995, 38, 18, 3445-7. |
| 【4】 Michaelides, M.R.; Hong, Y. (Abbott Laboratories Inc.); Tetracyclic cpds. as dopamine agonists. EP 0690863; JP 1996508487; US 5597832; WO 9422858 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(VIII) | 16971 | (rac)-(5aR*,11bS*)-10-methoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinolin-9-yl methyl ether; (rac)-(5aR*,11bS*)-9,10-dimethoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline | C20H25NO2S | 详情 | 详情 | |
| (I) | 16964 | 6,7-dimethoxy-1-tetralone; 6,7-dimethoxy-3,4-dihydro-1(2H)-naphthalenone | 13575-75-2 | C12H14O3 | 详情 | 详情 |
| (II) | 16965 | 3-methoxy-5,6-dihydro-2-naphthalenyl methyl ether; 6,7-dimethoxy-1,2-dihydronaphthalene | C12H14O2 | 详情 | 详情 | |
| (III) | 16966 | 3-methoxy-6-nitro-7,8-dihydro-2-naphthalenyl methyl ether; 6,7-dimethoxy-3-nitro-1,2-dihydronaphthalene | C12H13NO4 | 详情 | 详情 | |
| (IV) | 16967 | N-(tert-butyl)-5-propyl-2-thiophenecarboxamide | C12H19NOS | 详情 | 详情 | |
| (V) | 16968 | N-(tert-butyl)-3-[(1S,2R)-6,7-dimethoxy-2-nitro-1,2,3,4-tetrahydro-1-naphthalenyl]-5-propyl-2-thiophenecarboxamide | C24H32N2O5S | 详情 | 详情 | |
| (VI) | 16969 | 3-[(1S,2R)-2-amino-6,7-dimethoxy-1,2,3,4-tetrahydro-1-naphthalenyl]-N-(tert-butyl)-5-propyl-2-thiophenecarboxamide | C24H34N2O3S | 详情 | 详情 | |
| (VII) | 16970 | (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenylamine; (1S,2R)-6,7-dimethoxy-1-(5-propyl-3-thienyl)-1,2,3,4-tetrahydro-2-naphthalenamine | C19H25NO2S | 详情 | 详情 | |
| (VIII) | 65064 | (5aR,11bS)-9,10-dimethoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline; (5aR,11bS)-10-methoxy-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinolin-9-yl methyl ether | C20H25NO2S | 详情 | 详情 | |
| (IX) | 16972 | (5aR,11bS)-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno[2,3-c]quinoline-9,10-diol | C18H21NO2S | 详情 | 详情 | |
| (X) | 16973 | 5-allyl-N-(tert-butyl)-2-thiophenecarboxamide | C12H17NOS | 详情 | 详情 | |
| (XI) | 16974 | 5-allyl-N-(tert-butyl)-3-[(1S,2R)-6,7-dimethoxy-2-nitro-1,2,3,4-tetrahydro-1-naphthalenyl]-2-thiophenecarboxamide | C24H30N2O5S | 详情 | 详情 | |
| (XII) | 16975 | 2-propylthiophene; Thiophene, 2-propyl- | 1551-27-5 | C7H10S | 详情 | 详情 |
| (XIII) | 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：Condensation of pyrimidine carboxaldehyde (I) with 3,5-dimethoxy-phenylacetonitrile (II) using NaH in 2-ethoxyethanol provided the pyridopyrimidine (III). Then, regioselective condensation of (III) with tert-butyl isocyanate at the 7-amino group in the presence of NaH in DMF furnished the corresponding urea.
| 【1】 Connolly, C.J.C.; Schroeder, M.C.; Hamby, J.M.; et al.; Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. J Med Chem 1997, 40, 15, 2296. |
| 【2】 Hamby, J.M.; Connolly, C.J.C.; Schroeder, M.C.; et al.; Discovery and structure-activity studies of a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. Bioorg Med Chem Lett 1997, 7, 18, 2415. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 | |
| (I) | 26525 | 2,4-diamino-5-pyrimidinecarbaldehyde | C5H6N4O | 详情 | 详情 | |
| (II) | 26526 | 2-(3,5-dimethoxyphenyl)acetonitrile | 13388-75-5 | C10H11NO2 | 详情 | 详情 |
| (III) | 26527 | 2-amino-6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-ylamine | C15H15N5O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X)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6
该中间体在本合成路线中的序号：(XII)The condensation of N-(tert-butyldimethylsilyl)-4-oxoazetidine-2(S)-carboxylic acid (I) with 1-chloro-3-iodopropane (II) by means of BuLi and triisopropylamine (TIA) in THF, followed by treatment with HCl, gives the 3(R)-(3-chloropropyl) derivative (III), which is treated with tetrabutylammonium azide and tetrabutylammonium iodide in DMF to yield the 3-azidopropyl derivative (IV). The reduction of (IV) with H2 over Pd/C in DMF affords the 3-aminopropyl compound (V), which is treated with 1-[N,N'-bis(benzyloxycarbonyl)-1H-pyrazole] (VI) in the same solvent to provide the protected 3-guanidinopropyl compound (VII). The esterification of (VII) with NaHCO3, tetrabutylammonium iodide and Bn-Br in DMF gives the benzyl ester (VIII), which is condensed with N-tert-butylpiperazine-1-carboxamide (IX) and phosgene by means of TEA in toluene to yield the protected precursor (X). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in dioxane to give the target azetidine-carboxylic acid.
| 【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 . |
| 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) | 49426 | (2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (II) | 49416 | 1-Chloro-3-iodopropane | 6940-76-7 | C3H6ClI | 详情 | 详情 |
| (III) | 49417 | (2S,3R)-3-(3-chloropropyl)-4-oxo-2-azetidinecarboxylic acid | C7H10ClNO3 | 详情 | 详情 | |
| (IV) | 49418 | (2S,3R)-3-(3-azidopropyl)-4-oxo-2-azetidinecarboxylic acid | C7H10N4O3 | 详情 | 详情 | |
| (V) | 49419 | (2S,3R)-3-(3-aminopropyl)-4-oxo-2-azetidinecarboxylic acid | C7H12N2O3 | 详情 | 详情 | |
| (VI) | 49420 | benzyl (E)-[[(benzyloxy)carbonyl]amino](1H-pyrazol-1-yl)methylidenecarbamate | C20H18N4O4 | 详情 | 详情 | |
| (VII) | 49421 | (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-4-oxo-2-azetidinecarboxylic acid | C24H26N4O7 | 详情 | 详情 | |
| (VIII) | 49422 | benzyl (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-4-oxo-2-azetidinecarboxylate | C31H32N4O7 | 详情 | 详情 | |
| (IX) | 49423 | N-(tert-butyl)-1-piperazinecarboxamide | C9H19N3O | 详情 | 详情 | |
| (X) | 49424 | benzyl (2S,3R)-3-[3-[([[(benzyloxy)carbonyl]amino][[(benzyloxy)carbonyl]imino]methyl)amino]propyl]-1-([4-[(tert-butylamino)carbonyl]-1-piperazinyl]carbonyl)-4-oxo-2-azetidinecarboxylate | C41H49N7O9 | 详情 | 详情 | |
| (XI) | 13225 | N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate | 143238-38-4 | C9H18N2O2 | 详情 | 详情 |
| (XII) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (XIII) | 49425 | tert-butyl 4-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate | C14H27N3O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)After protection of L-tert-leucine (VIIa) as the corresponding silyl ester (VIII) with TMSCl by means of HMDS or Et3N in refluxing CH2Cl2, condensation with tert-butyl isocyanate (IX), followed by acidic work up leads to urea derivative (X) . Subsequent coupling of carboxylic acid (X) with methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt (XI) in the presence of EDC, HOBt and 2,6-lutidine in acetonitrile yields the dipeptide ester (XII) , which is finally hydrolyzed with LiOH in THF/H2O and optionally purified via its α-methylbenzylamine salt .
Alternatively, coupling of N-Boc-L-tert-leucine (VIIb) with the bicyclic amino ester (XI) in the presence of BOP reagent and NMM in CH2Cl2/DMF affords the N-Boc dipeptide (XIII), which is then deprotected by means of HCl in dioxane to give compound (XIV) . Finally, intermediate (XIV) is condensed with tert-butyl isocyanate (IX) in CH2Cl2 to give the urea compound (XII).
| 【2】 Saksena, A., Nair, L.G., Lovey, R.G. et al. (Schering Corp.; Dendreon Corp.). Novel peptides as NS3-serine protease inhibitors of hepatitis C virus. CA 2473032, EP 1481000, JP 2005524628, US 2007032433, US 7244721, WO 2003062265. |
| 【3】 Lovey, R.G., Tamura, S.Y., Bennett, F. (Dendreon Corp.; Schering Corp.).Novel peptides as NS3-serine protease inhibitors of hepatitis C virus. CA 2410662, EP 1385870, JP 2004504404, JP 2009051860, US 2003216325, US 2004254117, US 7012066, WO 2002008244. |
| 【4】 Venkatraman, S., Bogen, S.L., Arasappan, A. et al. Discovery of (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[2(S)-[[[(1,1-dimethylethyl)amino]carbonyl] amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S) carboxamide (SCH 503034), a selective, potent, orally bioavailable hepatitis C virus NS3 protease inhibitor: A potential therapeutic agent for the treatment of hepatitis C infection. J Med Chem 2006, 49(20): 6074-86. |
| 【5】 Wu, G.G., Xie, J., Rashatasakhon, P. (Schering Corp.). An oxidation process for the preparation of N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[N-[(tert-butylamino)carbonyl]-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide and related compounds. CA 2628738, EP 1966233, JP 2009515894, US 2007149459, US 7528263, WO 2008010831. |
| 【6】 Wong, G.S.K., Lee, H.-C., Vance, J.A., Tong, W., Iwama, T. (Schering Corp.). Process for preparing (1R,2S,5S)-N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]-carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. CA 2672620, WO 2008079216. |
| 【7】 Sudhakar, A., Dahanukar, V., Zavialov, I.A. et al. (Schering Corp.). Process and intermediates for the preparation of (1R,2S,5S)-3-azabicyclo-[3,1,0]hexane-2-carboxamide, N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[1,1-dimethylethyl]amino]carbonylamino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl. CA 2526629, EP 1641754, JP 2006528133, US 2005059800, US 7326795, WO 2004113294. |
| 【8】 Dener, J.M. (Virobay, Inc.). Process for the preparation of (S)-2-(3-tertbutylureido)-3,3-dimethylbutanoic acid. WO 2009039361. |
| 【1】 Njoroge, F.G., Venkatraman, S. (Schering Corp.). An inhibitor of heptatitis C. US 2005249702, WO 2005107745. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 69075 | (S)-2-amino-3,3-dimethylbutanoic acid;L-tert-leucine;L-2-Amino-3,3-dimethylbutanoic acid | 20859-02-3 | C6H13NO2 | 详情 | 详情 |
| (VIIb) | 22251 | (2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine | 62965-35-9 | C11H21NO4 | 详情 | 详情 |
| (I) | 69331 | (1R,2S,5S)-3-(2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid | C19H33N3O4 | 详情 | 详情 | |
| (VIII) | 69337 | (S)-trimethylsilyl 2-amino-3,3-dimethylbutanoate | C9H21NO2Si | 详情 | 详情 | |
| (IX) | 16976 | tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane | 1609-86-5 | C5H9NO | 详情 | 详情 |
| (X) | 69338 | (S)-2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoic acid | C11H22N2O3 | 详情 | 详情 | |
| (XI) | 69339 | methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl salt | 565456-77-1 | C9H15NO2.HCl | 详情 | 详情 |
| (XII) | 69340 | methyl (1R,2S,5S)-3-(2-(3-(tert-butyl)ureido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate | C20H35N3O4 | 详情 | 详情 | |
| (XIII) | 69341 | methyl (1R,2S,5S)-3-(2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate | C20H34N2O5 | 详情 | 详情 | |
| (XIV) | 69342 | methyl (1R,2S,5S)-3-(2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride | C15H26N2O3.HCl | 详情 | 详情 |