【结 构 式】 |
【分子编号】41485 【品名】4-chloro-1-methyl-2-nitrobenzene;4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene 【CA登记号】89-59-8 |
【 分 子 式 】C7H6ClNO2 【 分 子 量 】171.58288 【元素组成】C 49% H 3.52% Cl 20.66% N 8.16% O 18.65% |
合成路线1
该中间体在本合成路线中的序号:(IX)The cyclization of N-Boc-L-glutamic acid (I) with paraformaldehyde in refluxing DCE gives the oxazolidinone (II), which is benzylated with benzyl bromide and LiHMDS in THF yielding the benzyl derivative (III). The reaction of (II) with CDI in THF affords the activated acid (IV), which is condensed with the protected glutamic acid (V) by means of LiHMDS in THF to provide the adduct (VI). The decarboxylation of the allyloxycarbonyl group of (VI) by means of a Pd catalyst furnishes the compound (VII), which is deprotected and cyclized by hydrogenation with H2 over Pd/C and PtO2 to give the substituted proline (VIII). The lactam cyclization of (VIII) by means of NaOH in methanol, followed by crystallization yields the bicyclic carboxylic acid (IX), which is condensed with the arginine derivative (X) by means of EDC, HOBT and DIEA in THF affording the adduct (XI). The oxidation of the OH group of (XI) with DMP in dichloromethane gives the precursor (XII), which is finally deprotected by a treatment with TFA and PhS-Me. The intermediate arginine derivative (X) has been obtained as follows: The condensation of the fully protected arginine aldehyde derivative (XIII) with benzothiazole (XIV) by means of n-BuLi in ethyl ether gives the adduct (XV), which is then treated with TFA in order to eliminate the Boc protecting groups and furnish the desired arginine derivative intermediate (X).
【1】 Lee, M.S.; Eguchi, M.; Gardner, B.S.; Boatman, P.D.; Kahn, M.; Kim, H.-O.; Nakanishi, H.; Synthesis of dipeptide secondary structure mimetics. Proc. 15th Am. Pep. Symposium, Kluwer Acad. Publ. 1998, 212. |
【2】 Nakanishi, H.; Ogbu, C.O.; Shea, J.P.; Cao, B.; Kahn, M.; Boatman, P.D.; Kim, H.-O.; Eguchi, M.; Secondary structure peptide mimetics: Design, synthesis, and evaluation of beta-strand mimetic thrombin inhibitors. J Med Chem 1999, 42, 8, 1367. |
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) | 12895 | (2S)-2-[(tert-Butoxycarbonyl)amino]pentanedioic acid | 2419-94-5 | C10H17NO6 | 详情 | 详情 |
(II) | 41838 | 3-[(4S)-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propionic acid | C11H17NO6 | 详情 | 详情 | |
(III) | 41839 | 3-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propionic acid | C18H23NO6 | 详情 | 详情 | |
(IV) | 41840 | tert-butyl (4R)-4-benzyl-4-[3-(1H-imidazol-1-yl)-3-oxopropyl]-5-oxo-1,3-oxazolidine-3-carboxylate | C21H25N3O5 | 详情 | 详情 | |
(V) | 41841 | 5-allyl 1-benzyl (2S)-2-[[(benzyloxy)carbonyl]amino]pentanedioate | C23H25NO6 | 详情 | 详情 | |
(VI) | 41842 | 1-allyl 5-benzyl (4S)-2-[3-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]propanoyl]-4-[[(benzyloxy)carbonyl]amino]pentanedioate | C41H46N2O11 | 详情 | 详情 | |
(VII) | 41843 | tert-butyl (4R)-4-benzyl-4-((6S)-7-(benzyloxy)-6-[[(benzyloxy)carbonyl]amino]-3,7-dioxoheptyl)-5-oxo-1,3-oxazolidine-3-carboxylate | C37H42N2O9 | 详情 | 详情 | |
(VIII) | 41844 | (2S,5R)-5-[2-[(4R)-4-benzyl-3-(tert-butoxycarbonyl)-5-oxo-1,3-oxazolidin-4-yl]ethyl]-2-pyrrolidinecarboxylic acid | C22H30N2O6 | 详情 | 详情 | |
(IX) | 41485 | 4-chloro-1-methyl-2-nitrobenzene;4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene | 89-59-8 | C7H6ClNO2 | 详情 | 详情 |
(X) | 40421 | N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C33H35N5O2S | 详情 | 详情 | |
(XI) | 41846 | tert-butyl (3S,6R,8aR)-3-[([(1S)-1-[1,3-benzothiazol-2-yl(hydroxy)methyl]-4-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxooctahydro-6-indolizinylcarbamate | C54H61N7O6S | 详情 | 详情 | |
(XII) | 41847 | tert-butyl (3S,6R,8aR)-3-[([(1S)-1-(1,3-benzothiazol-2-ylcarbonyl)-4-[(imino[[(4-methoxyphenyl)(diphenyl)methyl]amino]methyl)amino]butyl]amino)carbonyl]-6-benzyl-5-oxooctahydro-6-indolizinylcarbamate | C54H59N7O6S | 详情 | 详情 | |
(XIII) | 41848 | tert-butyl (Z)-([(4S)-4-[(tert-butoxycarbonyl)amino]-5-oxopentyl]amino)[[(4-methoxyphenyl)(diphenyl)methyl]amino]methylidenecarbamate | C36H46N4O6 | 详情 | 详情 | |
(XIV) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
(XV) | 41849 | tert-butyl (Z)-([(4S)-5-(1,3-benzothiazol-2-yl)-4-[(tert-butoxycarbonyl)amino]-5-hydroxypentyl]amino)[[(4-methoxyphenyl)(diphenyl)methyl]amino]methylidenecarbamate | C43H51N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)Synthesis of intermediate (3S)-(XI): Iodination of 4-chloro-2-nitrotoluene (I) with NaI, I2 and H2SO4 yields (II), which is then treated with dimethyl oxalate (A) in toluene in presence of KOMe or alternatively NaOMe, in MeOH to afford (III). Cyclization of (III) is performed by a first treatment with SnCl2 in dimethoxyethane followed by TiCl3/H2O to provide indole (IV), which is converted into (VI) by reaction with alcohol (V) in presence of NaHCO3, benzyltriethyl ammonium chloride and Pd(OAc)2, followed by a treatment with sodium thiosulfate. The reaction of aldehyde (VI) with KOtBu and triethyl phosphonoacetate (B) in THF yields ethyl ester (VIIa-b), which is then converted into iodo derivative (VIIIa-b) by means of NaI and NCS in DMF. Cyclization of (VIIIa-b) by treatment with Pd(PPh3)4 in DMF and Ag3PO4/H2O affords tetrahydrobenzindole (IX), which is reduced by means of Sm, and I2 in MeOH/THF to give (X). Alternatively (X) is obtained by simultaneous cyclization and reduction of (VIIIa-b) by treatment with SnBu3H and AIBN in chlorobenzene. Finally ethyl ester (X) is selectively hydrolyzed with HCl in HOAc to provide (XI) in its racemic form. Enantiomer (3S)-(XI) can be isolated by separation of the corresponding diasteromers obtained by reaction of (XI) with L-(-) norphedrine in isopropanol followed by hydrolysis with HCl in EtOAc and THF.
【1】 Katayama, S.; Kishimoto, H.; Ae, N.; Nagata, R. (Sumitomo Pharmaceuticals Co., Ltd.); Tricyclic indole-2-carboxylic acid cpd. used as NMDA receptor antagonist. WO 0056711 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(B) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
(A) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
(VIIa) | 41490 | methyl 6-chloro-4-[(E)-5-ethoxy-5-oxo-3-pentenyl]-1H-indole-2-carboxylate | C17H18ClNO4 | 详情 | 详情 | |
(VIIb) | 41491 | methyl 6-chloro-4-[(Z)-5-ethoxy-5-oxo-3-pentenyl]-1H-indole-2-carboxylate | n/a | C17H18ClNO4 | 详情 | 详情 |
(VIIIa) | 41492 | methyl 6-chloro-4-[(E)-5-ethoxy-5-oxo-3-pentenyl]-3-iodo-1H-indole-2-carboxylate | n/a | C17H17ClINO4 | 详情 | 详情 |
(VIIIb) | 41493 | methyl 6-chloro-4-[(Z)-5-ethoxy-5-oxo-3-pentenyl]-3-iodo-1H-indole-2-carboxylate | n/a | C17H17ClINO4 | 详情 | 详情 |
(3S)-(XI) | 41497 | 2-[(3S)-7-chloro-2-(methoxycarbonyl)-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl]acetic acid | C15H14ClNO4 | 详情 | 详情 | |
(I) | 41485 | 4-chloro-1-methyl-2-nitrobenzene;4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene | 89-59-8 | C7H6ClNO2 | 详情 | 详情 |
(II) | 41486 | 5-chloro-1-iodo-2-methyl-3-nitrobenzene | n/a | C7H5ClINO2 | 详情 | 详情 |
(III) | 41487 | methyl 3-(4-chloro-2-iodo-6-nitrophenyl)-2-oxopropanoate | C10H7ClINO5 | 详情 | 详情 | |
(IV) | 41488 | methyl 6-chloro-4-iodo-1H-indole-2-carboxylate | C10H7ClINO2 | 详情 | 详情 | |
(V) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
(VI) | 41489 | methyl 6-chloro-4-(3-oxopropyl)-1H-indole-2-carboxylate | C13H12ClNO3 | 详情 | 详情 | |
(IX) | 41494 | methyl 7-chloro-3-[(Z)-2-ethoxy-2-oxoethylidene]-4,5-dihydrobenzo[cd]indole-2(1H)-carboxylate | C17H16ClNO4 | 详情 | 详情 | |
(X) | 41495 | methyl 7-chloro-3-(2-ethoxy-2-oxoethyl)-1,3,4,5-tetrahydrobenzo[cd]indole-2-carboxylate | C17H18ClNO4 | 详情 | 详情 | |
(XI) | 41496 | 2-[7-chloro-2-(methoxycarbonyl)-1,3,4,5-tetrahydrobenzo[cd]indol-3-yl]acetic acid | C15H14ClNO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XXIV)In one method, oxidation of 4-chloro-2-nitrotoluene (XXIV) with NaIO4 in the presence of DMFA in DMF at 135 °C yields 4-chloro-2-nitrobenzaldehyde (XXV). Reduction of the nitro group in compound (XXV) with Fe and HCl in EtOH/H2O, followed by Friedländer condensation of the resulting aminoaldehyde with acetophenone (XIV) using KOH at reflux gives 7-chloro-2-phenylquinoline (XXVI). Miyaura borylation of chloroquinoline (XXVI) with bis(pinacolato)diboron (XXVII) in the presence of 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride [IPr·HCl], Pd(OAc)2 and KOAc in refluxing THF furnishes boronate ester (XI).
In another method, arylation of 7-quinolinol (XXVIII) using phenyl lithium in THF, optionally after protection of the hydroxyl group with TBDMSCl in the presence of DMAP and Et3N in CH2Cl2, leads to 2-phenyl-7-quinolinol (XXIX). Quinolinol (XXIX) is then activated by Tf2O in pyr/CH2Cl2 to produce the aryl triflate (XXX), which condenses with bis(pinacolato)diboron (XXVII) in the presence of PdCl2(dppf) CH2Cl2, dppf and KOAc in 1,4-dioxane to afford the dioxaborolane derivative (XI) .
【1】 Arnold, L.D., Cesario, C., Coate, H. et al. (OSI Pharmaceuticals, Inc.). 6,6-Bicyclic ring substituted heterobicyclic protein kinase inhibitors. EP 1740591, EP 2168968, EP 2305682, EP 2308879, JP 2007531754, JP 2009197013, US 200635031, WO 005097800. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 68928 | 2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline | C21H22BNO2 | 详情 | 详情 | |
(XIV) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
(XXIV) | 41485 | 4-chloro-1-methyl-2-nitrobenzene;4-chloro-2-nitrotoluene;4-chloro-1-methyl-2-nitro-benzene | 89-59-8 | C7H6ClNO2 | 详情 | 详情 |
(XXV) | 68938 | 4-chloro-2-nitrobenzaldehyde;2-Nitro-4-chlorobenzaldehyde | 5551-11-1 | C7H4ClNO3 | 详情 | 详情 |
(XXVI) | 68939 | 7-chloro-2-phenylquinoline | C15H10ClN | 详情 | 详情 | |
(XXVII) | 53342 | 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester | 73183-34-3 | C12H24B2O4 | 详情 | 详情 |
(XXVIII) | 68940 | quinolin-7-ol | C9H7NO | 详情 | 详情 | |
(XXIX) | 68941 | 2-phenyl-7-quinolinol;2-phenylquinolin-7-ol | C15H11NO | 详情 | 详情 | |
(XXX) | 68942 | 2-phenylquinolin-7-yl trifluoromethanesulfonate | C16H10F3NO3S | 详情 | 详情 |