|
【结 构 式】 
|
【药物名称】Cenicriviroc mesylate, Cenicriviroc mesilate, TAK-652, TBR-652 【化学名称】1-Benzazocine-5-carboxamide, 8-[4-(2-butoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-(2-methylpropyl)-N-[4-[(S)-[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-, methanesulfonate (1:1) 【CA登记号】497223-28-6;497223-21-9 (free base, no stereochemistry); 497223-25-3 (free base);497223-27-5 (oxalate salt) 【 分 子 式 】C41H52N4O4S.CH4O3S 【 分 子 量 】793.047 |
【开发单位】Originated by Takeda Pharmaceutical Co., Ltd. (JP); licensed exclusively worldwide to Tobira Therapeutics, Inc. (US). 【药理作用】Chemokine CCR2/CCR5 Receptor Antagonist，Anti-HIV Agent |
合成路线1
Cenicriviroc mesilate can be prepared by two related strategies:
In one strategy, chlorination of benzazocine-5-carboxylic acid derivative (I) with (COCl)2 (1, 2) or SOCl2 in THF (3) yields the corresponding acyl chloride (II) (1-3), which then couples with S-Cbz-4-thioaniline (III) in the presence of Et3N in THF to afford, after hydrolysis of the Cbz group with NaOH in MeOH, the corresponding N-(4-sulfanylphenyl)amide (IV). Subsequent S-alkylation of thiol (IV) with 5-(chloromethyl)-1-propylimidazole (V) in the presence of NaOH in MeOH yields thioether (VI). After oxidation of (VI) with mCPBA in CH2Cl2, the resulting racemic sulfoxide is resolved employing chiral HPLC to furnish the target (S)-enantiomer, which is then treated with MsOH in EtOAc to afford cenicriviroc mesilate (2). In another strategy, acyl chloride (II) couples with the substituted aniline (VII) in the presence of DIEA in THF (1) or Et3N in THF (3) to yield cenicriviroc, which is then reacted with MsOH in methyl isobutyl ketone, producing the target cenicriviroc mesilate (1, 3). Scheme 1.
| 【1】 Nishiguchi, A., Adachi, M., Ito, T., Ikemoto, T., Tawada, H. (Takeda Pharmaeutical Co., Ltd.). Process for producing optically active sulfoxide derivative. CA 2479071, EP 1484322, JP 2004123694, WO 2003076411. |
| 【2】 Shiraishi, M., Baba, M., Iizawa, Y., Kanzaki, N., Seto, M., Aikawa, K. (Takeda Pharmaceutical Co., Ltd.). Bicyclic compounds, production and use thereof. CA 2459172, CA 2607992, EP 1423376, EP 1889839, EP 2206702, JP 2003335776, JP 2007084578, JP 2009209154, US 2004259876, US 7371772, US 2008161287, US 2009030032, WO 2003014105. |
| 【3】 Seto, M., Aikawa, K., Miyamoto, N. et al. Highly potent and orally active CCR5 antagonists as Anti-HIV-1 agents: Synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety. J Med Chem 2006, 49(6): 2037-48. |
合成路线2
Synthesis of intermediate (VII):
Reaction of 4-sulfanylaniline (XX) with TFAA in the presence of Et3N in THF gives trifluoroacetamide (XXI), which then condenses with 5-(chloromethyl)-1-propylimidazole (V) using TEA in MeOH/H2O to yield thioether (XXII). Oxidation of sulfanyl derivative (XXII) by means of H2O2 in AcOH, followed by hydrolysis with NaOH affords the racemic sulfinyl derivative (XXIII), which is then submitted to optical resolution with di-p-toluoyl-D-tartaric acid to provide the desired (S)-enantiomer (VII) (1). Scheme 3.
| 【1】 Nishiguchi, A., Adachi, M., Ito, T., Ikemoto, T., Tawada, H. (Takeda Pharmaeutical Co., Ltd.). Process for producing optically active sulfoxide derivative. CA 2479071, EP 1484322, JP 2004123694, WO 2003076411. |
| 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) | 66041 | 5-(chloromethyl)-1-propylimidazole | C7H11ClN2 | 详情 | 详情 | |
| (VII) | 66043 | C13H17N3OS | 详情 | 详情 | ||
| (XX) | 16490 | 4-aminophenylhydrosulfide; 4-aminothiophenol; 4-aminobenzenethiol | 1193-02-8 | C6H7NS | 详情 | 详情 |
| (XXI) | 66054 | 2,2,2-Trifluoro-N-(4-Mercaptophenyl)Acetamide; 2,2,2-Trifluoro-N-(4-Sulfanylphenyl)Ethanamide | 94006-35-6 | C8H6F3NOS | 详情 | 详情 |
| (XXII) | 66055 | C15H16F3N3OS | 详情 | 详情 | ||
| (XXIII) | 66056 | C13H17N3OS | 详情 | 详情 |
合成路线3
Synthesis of intermediate (I):
N-Protection of 2-piperidone (VIII) with PMB-Cl using KOH and TBAB in toluene gives N-PMB-2-piperidone (IX), which is then hydrolyzed with NaOH to afford 5-(4-methoxybenzylamino)pentanoic acid (X). Condensation of amine (X) with 5-bromo-2-fluorobenzaldehyde (XI) by means of Na2CO3 in DMSO/H2O then provides the tertiary amine (XII). Methylation of carboxylic acid (XII) with MeI in the presence of K2CO3 leads to the corresponding methyl ester (XIII), which then undergoes intramolecular cyclization by means of NaOMe and CO(OMe)2 to yield the N-PMB-1-benzazocine derivative (XIV). Debenzylation of compound (XIV) by means of TFA in toluene affords N-unsubstituted benzazocine (XV), which is then reductocondensed with isobutyraldehyde (XVI) by means of NaBH(OAc)3 in CH2Cl2, affording the 1-isobutyl derivative (XVII). Suzuki coupling of the 8-bromo-1-benzazocine derivative (XVII) with 4-(2-butoxyethoxy)phenylboronic acid (XVIII) by means of Pd(PPh3)4 provides adduct (XIX). Finally, hydrolysis of methyl ester (XIX) with NaOH in THF/MeOH gives the target carboxylic acid (I) (3). Scheme 2.
| 【3】 Seto, M., Aikawa, K., Miyamoto, N. et al. Highly potent and orally active CCR5 antagonists as Anti-HIV-1 agents: Synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety. J Med Chem 2006, 49(6): 2037-48. |
| 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) | 66037 | C28H37NO4 | 详情 | 详情 | ||
| (VIII) | 43366 | 2-piperidinone | 675-20-7 | C5H9NO | 详情 | 详情 |
| (IX) | 66044 | 1-(p-Methoxybenzyl)-2-piperidinone | 128773-73-9 | C13H17NO2 | 详情 | 详情 |
| (X) | 66045 | 5-[N-(4-methoxybenzyl)amino]pentanoic acid | C13H19NO3 | 详情 | 详情 | |
| (XI) | 66046 | 5-bromo-2-fluorobenzaldehyde | 93777-26-5 | C7H4BrFO | 详情 | 详情 |
| (XII) | 66047 | C20H22BrNO4 | 详情 | 详情 | ||
| (XIII) | 66048 | C21H24BrNO4 | 详情 | 详情 | ||
| (XIV) | 66049 | C21H22BrNO3 | 详情 | 详情 | ||
| (XV) | 66050 | C13H14BrNO2 | 详情 | 详情 | ||
| (XVI) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (XVII) | 66051 | C17H22BrNO2 | 详情 | 详情 | ||
| (XVIII) | 66052 | C12H19BO4 | 详情 | 详情 | ||
| (XIX) | 66053 | C29H39NO4 | 详情 | 详情 |