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【结 构 式】 
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【分子编号】36784 【品名】1,3-benzothiazole 【CA登记号】95-16-9 |
【 分 子 式 】C7H5NS 【 分 子 量 】135.18944 【元素组成】C 62.19% H 3.73% N 10.36% S 23.72% |
合成路线1
该中间体在本合成路线中的序号：(II)The precursor aminoalcohol (IV) was prepared as follows: Addition of the organolithium derivative of benzothiazole (II) to the protected argininal (I) gave alcohol (IIIa-b) as a diastereomeric mixture. Then, selective removal of the Boc groups of (IIIa-b) using TFA provided compound (IVa-b).
| 【1】 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 |
|---|---|---|---|---|---|---|
| (IIIa) | 36785 | tert-butyl (E)-([(4S,5S)-5-(1,3-benzothiazol-2-yl)-4-[(tert-butoxycarbonyl)amino]-5-hydroxypentyl]amino)[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methylidenecarbamate | C33H47N5O8S2 | 详情 | 详情 | |
| (IIIb) | 36786 | tert-butyl (E)-([(4S,5R)-5-(1,3-benzothiazol-2-yl)-4-[(tert-butoxycarbonyl)amino]-5-hydroxypentyl]amino)[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methylidenecarbamate | C33H47N5O8S2 | 详情 | 详情 | |
| (IVa) | 36787 | 2-[(1S,2S)-2-amino-1-hydroxy-5-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]pentyl]-1,3-benzothiazole | C23H31N5O4S2 | 详情 | 详情 | |
| (IVb) | 36788 | 2-[(1R,2S)-2-amino-1-hydroxy-5-[(imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl)amino]pentyl]-1,3-benzothiazole | C23H31N5O4S2 | 详情 | 详情 | |
| (I) | 36783 | tert-butyl (E)-([(4S)-4-[(tert-butoxycarbonyl)amino]-5-oxopentyl]amino)[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methylidenecarbamate | C26H42N4O8S | 详情 | 详情 | |
| (II) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)The intermediate argininol derivative (XIV) has been obtained by condensation of N-omega(4-methoxytrityl)-L-argininal (XVI) with benzothiazole (XVII) by means of n-BuLi in ethyl ether.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (XIV) | 40421 | N-[(4S)-4-amino-5-(1,3-benzothiazol-2-yl)-5-hydroxypentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C33H35N5O2S | 详情 | 详情 | |
| (XVI) | 40423 | N-[(4S)-4-amino-5-oxopentyl]-N'-[(4-methoxyphenyl)(diphenyl)methyl]guanidine | C26H30N4O2 | 详情 | 详情 | |
| (XVII) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIV)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4
该中间体在本合成路线中的序号：(VI)Serine derivative (I) is converted into butyric acid derivative (II) by first treatment with isobutyl chloroformate and Et3N in THF, followed by reaction with ethereal diazomethane, Wolf rearrangement with Et3N in THF/H2O catalyzed by AgOBz and benzylation with benzyl bromide and DBU in acetonitrile. Conversion of (II) into azetidinone derivative (III) is achieved by Boc group removal by means of HCl in dioxane followed by cyclization by treatment with TMSCl, Et3N in Et2O and then t-BuMgCl. Protection of (III) using TIPSOTf and 2,5-lutidine in CH2Cl2 followed by removal of benzyl ether by hydrogenolysis over Pd(OH)2 in THF gives beta-lactam alcohol (IV), which is then oxidized by means of Dess-Martin periodinane in CH2Cl2 to yield aldehyde (V). Reaction of (V) with benzothiazole (VI) and n-BuLi in THF yields alcohol (VII), which is then deoxygenated by treatment with 1,1-(thiocarbonyl)diimidazole and DMAP in CH2Cl2 followed by reduction with Ph3SnH and AIBN in benzene to afford (VIII). Removal of the TIPS group from (VIII) by means of CsF in MeOH followed by condensation with chloride (IX) by means of KHMDS in THF finally furnishes the target product.
| 【1】 Ogilvie, W.W.; Naud, J.; Hache, B.; Yoakim, C.; O'Meara, J.A.; Do, F.; Deziel, R.; Lagace, L.; Synthesis and antiviral activity of monobactams inhibiting the human cytomegalovirus protease. Bioorg Med Chem 1999, 7, 8, 1521. |
| 【2】 Ogilvie, W.W.; O'Meara, J.; Deziel, R.; Yoakim, C. (Boehringer Ingelheim (Canada) Ltd.); Azetidinone derivs. for the treatment of HCMV infections. EP 1021405; WO 9918072 . |
| 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) | 43532 | (4R)-4-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]-1-(triisopropylsilyl)-2-azetidinone | C20H30N2O2SSi | 详情 | 详情 | |
| (VIIb) | 43533 | (4R)-4-[(S)-1,3-benzothiazol-2-yl(hydroxy)methyl]-1-(triisopropylsilyl)-2-azetidinone | C20H30N2O2SSi | 详情 | 详情 | |
| (I) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (II) | 43528 | benzyl (3R)-4-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]butanoate | C23H29NO5 | 详情 | 详情 | |
| (III) | 43529 | (4R)-4-[(benzyloxy)methyl]-2-azetidinone | C11H13NO2 | 详情 | 详情 | |
| (IV) | 43530 | (4R)-4-(hydroxymethyl)-1-(triisopropylsilyl)-2-azetidinone | C13H27NO2Si | 详情 | 详情 | |
| (V) | 43531 | (2R)-4-oxo-1-(triisopropylsilyl)-2-azetidinecarbaldehyde | C13H25NO2Si | 详情 | 详情 | |
| (VI) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
| (VIII) | 43534 | (4R)-4-(1,3-benzothiazol-2-ylmethyl)-1-(triisopropylsilyl)-2-azetidinone | C20H30N2OSSi | 详情 | 详情 | |
| (IX) | 28425 | 1-[[(chlorocarbonyl)(methyl)amino]methyl]-4-(trifluoromethyl)benzene | C10H9ClF3NO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Condensation of the Weinreb amide of N-Boc-proline (I) with the lithium anion of benzothiazole (II) in THF at -78 C gave benzothiazolyl ketone (III), which was reduced with NaBH4 to afford the diastereomeric mixture of alcohols (IV). Deprotection of the Boc group of (IV) by means of HCl in EtOAc provided pyrrolidine (V). This was then coupled with Z-leucyl-glycine (VI) in the presence of PyBOP to give the peptidyl alcohol (VII). Finally, Swern oxidation of (VII) furnished the corresponding ketone.
| 【1】 Santana, J.; Gullet, C.; Schrével, J.; Frappier, F.; Maoulida, C.; Grellier, P.; Joyeau, R.; Teixeira, A.R.L.; Synthesis and activity of pyrrolidinyl- and thiazolidinyl-dipeptide derivatives as inhibitors of the Tc80 prolyl oligopeptidase from Trypanosoma cruzi. Eur J Med Chem 2000, 35, 2, 257. |
| 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) | 46320 | tert-butyl (2S)-2-[[methoxy(methyl)amino]carbonyl]-1-pyrrolidinecarboxylate | C12H22N2O4 | 详情 | 详情 | |
| (II) | 36784 | 1,3-benzothiazole | 95-16-9 | C7H5NS | 详情 | 详情 |
| (III) | 46321 | tert-butyl (2S)-2-(1,3-benzothiazol-2-ylcarbonyl)-1-pyrrolidinecarboxylate | C17H20N2O3S | 详情 | 详情 | |
| (IV) | 46322 | tert-butyl (2S)-2-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]-1-pyrrolidinecarboxylate | C17H22N2O3S | 详情 | 详情 | |
| (V) | 46323 | (R)-1,3-benzothiazol-2-yl[(2S)pyrrolidinyl]methanol | C12H14N2OS | 详情 | 详情 | |
| (VI) | 46318 | 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoyl)amino]acetic acid | C16H22N2O5 | 详情 | 详情 | |
| (VII) | 46324 | benzyl (1S)-1-[[(2-[(2S)-2-[(R)-1,3-benzothiazol-2-yl(hydroxy)methyl]pyrrolidinyl]-2-oxoethyl)amino]carbonyl]-3-methylbutylcarbamate | C28H34N4O5S | 详情 | 详情 |