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【结 构 式】 
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【药物名称】Tirofiban hydrochloride, MK-383, L-700462, Aggrastat 【化学名称】N-(Butylsulfonyl)-4-O-[4-(4-piperidyl)butyl]-L-tyrosine monohydrochloride 【CA登记号】142373-60-2, 144494-65-5 (free base), 150915-40-5 (monoH2O) 【 分 子 式 】C22H37ClN2O5S 【 分 子 量 】477.06759 |
【开发单位】Merck & Co. (Originator), Banyu (Licensee), Guilford Pharmaceuticals (Licensee) 【药理作用】Acute Myocardial Infarction, Treatment of, Angina pectoris, Treatment of, Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, NEUROLOGIC DRUGS, Stroke, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
4-Pyridineacetic acid (I) was hydrogenated to the corresponding piperidine (II) in the presence of PtO2. After protection of (II) as the N-Boc derivative (III), reduction of its carboxylate group with borane in THF provided alcohol (IV). Subsequent Swern oxidation of alcohol (IV) furnished aldehyde (V). This was then subjected to a Wittig condensation with carbomethoxytriphenylphosphorane to yield the unsaturated ester (VI), which was further hydrogenated to (VII) in the presence of Pd/C. After saponification of the methyl ester function of (VII), the resultant carboxylic acid was reduced to alcohol (VIII) by means of borane in THF. Conversion of alcohol (VIII) into the alkyl bromide (IX) was accomplished by treatment with carbon tetrabromide and triphenylphosphine. Then, alkylation of the phenolic hydroxyl of N-Cbz-L-tyrosine (X) with bromide (IX) in the presence of NaH in DMF afforded adduct (XI).
| 【1】 Egbertson, M.S.; Laswell, W.L.; Hartman, G.D.; Duggan, M.E.; Halczenko, W. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. EP 0478363; EP 0743302; JP 1992288051; US 5292756 . |
| 【2】 Egbertson, M.S.; Hartman, G.D.; Halczenko, W.; Laswell, W.L.; Duggan, M.E. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. WO 9319046 . |
| 【3】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537. |
| 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) | 17883 | 2-(4-pyridinyl)acetic acid | 28356-58-3 | C7H7NO2 | 详情 | 详情 |
| (II) | 45854 | 2-(4-piperidinyl)acetic acid; 4-piperidinylacetic acid | 51052-78-9 | C7H13NO2 | 详情 | 详情 |
| (III) | 19346 | 1-Boc-piperidin-4-ylacetic acid; 2-[1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid | 157688-46-5 | C12H21NO4 | 详情 | 详情 |
| (IV) | 43453 | tert-butyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate | C12H23NO3 | 详情 | 详情 | |
| (V) | 59541 | tert-butyl 4-(2-oxoethyl)-1-piperidinecarboxylate | C12H21NO3 | 详情 | 详情 | |
| (VI) | 45855 | tert-butyl 4-[(E)-4-methoxy-4-oxo-2-butenyl]-1-piperidinecarboxylate | C15H25NO4 | 详情 | 详情 | |
| (VII) | 45856 | tert-butyl 4-(4-methoxy-4-oxobutyl)-1-piperidinecarboxylate | C15H27NO4 | 详情 | 详情 | |
| (VIII) | 59542 | tert-butyl 4-(4-hydroxybutyl)-1-piperidinecarboxylate | C14H27NO3 | 详情 | 详情 | |
| (IX) | 59543 | tert-butyl 4-(4-bromobutyl)-1-piperidinecarboxylate | C14H26BrNO2 | 详情 | 详情 | |
| (X) | 39328 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid | C17H17NO5 | 详情 | 详情 | |
| (XI) | 59544 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid | C31H42N2O7 | 详情 | 详情 |
合成路线2
Acid (XI) was converted to the methyl ester (XII) by alkylation with iodomethane in the presence of Cs2CO3. After removal of the N-Cbz group of (XII) by catalytic hydrogenolysis, the resultant amine (XIII) was acylated by butanesulfonyl chloride (XIV) producing sulfonamide (XV). Saponification of the ester group of (XV) with LiOH gave acid (XVI). The N-Boc group of (XVI) was finally cleaved by treatment with HCl in EtOAc.
| 【1】 Egbertson, M.S.; Hartman, G.D.; Halczenko, W.; Laswell, W.L.; Duggan, M.E. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. WO 9319046 . |
| 【2】 Egbertson, M.S.; Laswell, W.L.; Hartman, G.D.; Duggan, M.E.; Halczenko, W. (Merck & Co., Inc.); Novel sulfonamide fibrinogen receptor antagonists. EP 0478363; EP 0743302; JP 1992288051; US 5292756 . |
| 【3】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537. |
| 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) | 59544 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid | C31H42N2O7 | 详情 | 详情 | |
| (XII) | 59545 | tert-butyl 4-{4-[4-((2S)-2-{[(benzyloxy)carbonyl]amino}-3-methoxy-3-oxopropyl)phenoxy]butyl}-1-piperidinecarboxylate | C32H44N2O7 | 详情 | 详情 | |
| (XIII) | 59546 | tert-butyl 4-(4-{4-[(2S)-2-amino-3-methoxy-3-oxopropyl]phenoxy}butyl)-1-piperidinecarboxylate | C24H38N2O5 | 详情 | 详情 | |
| (XIV) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XV) | 59547 | tert-butyl 4-[4-(4-{(2S)-2-[(butylsulfonyl)amino]-3-methoxy-3-oxopropyl}phenoxy)butyl]-1-piperidinecarboxylate | C28H46N2O7S | 详情 | 详情 | |
| (XVI) | 59548 | (2S)-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)-2-[(butylsulfonyl)amino]propanoic acid | C27H44N2O7S | 详情 | 详情 |
合成路线3
Intermediate (XI) was converted to the title compound by an alternative method, reported to provide a higher enantiomeric excess. Hydrogenolysis of the N-Cbz group of (XI) in the presence of Pd/C gave the aminoacid (XV). Subsequent acylation of (XV) with butanesulfonyl chloride (XIV) under Schotten-Baumann conditions furnished sulfonamide (XVI), which was then treated with HCl in EtOAc to remove the N-Boc protecting group.
| 【1】 Egbertson, M.S.; Chang, C.T.C.; Duggan, M.E.; et al.; Non-peptide fibrinogen receptor antagonists. 2. Optimization of a tyrosine template as a mimic for Arg-Gly-Asp. J Med Chem 1994, 37, 16, 2537. |
| 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) | 59544 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)propanoic acid | C31H42N2O7 | 详情 | 详情 | |
| (XIV) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XV) | 59547 | tert-butyl 4-[4-(4-{(2S)-2-[(butylsulfonyl)amino]-3-methoxy-3-oxopropyl}phenoxy)butyl]-1-piperidinecarboxylate | C28H46N2O7S | 详情 | 详情 | |
| (XVI) | 59548 | (2S)-3-(4-{4-[1-(tert-butoxycarbonyl)-4-piperidinyl]butoxy}phenyl)-2-[(butylsulfonyl)amino]propanoic acid | C27H44N2O7S | 详情 | 详情 |
合成路线4
In a different strategy, the lithium derivative of 4-picoline (XVII) was alkylated with 2-(3-bromopropoxy)tetrahydropyran (XVIII) to afford (XIX). Acidic hydrolysis of the tetrahydropyranyl protecting group furnished 4-(4-pyridinyl)butanol (XX). Alternatively, lithiation of 4-picoline (XVII), followed by alkylation with 1-bromo-3-chloropropane (XXI) gave rise to 4-(4-pyridinyl)butyl chloride (XXII).
| 【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. US 5312923; WO 9316994 . |
| 【2】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. WO 9316995 . |
| 【3】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L.; Grabowski, E.E.; A practical synthesis of fibrinogen receptor antagonist MK-383 - Selective functionalization of (S)-tyrosine. Tetrahedron 1993, 49, 26, 5767. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (XVIII) | 42252 | 3-bromopropyl tetrahydro-2H-pyran-2-yl ether; 2-(3-bromopropoxy)tetrahydro-2H-pyran | C8H15BrO2 | 详情 | 详情 | |
| (XIX) | 59549 | 4-(4-pyridinyl)butyl tetrahydro-2H-pyran-2-yl ether; 4-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]pyridine | C14H21NO2 | 详情 | 详情 | |
| (XX) | 59550 | 4-(4-pyridinyl)-1-butanol | C9H13NO | 详情 | 详情 | |
| (XXI) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (XXII) | 59551 | 4-(4-chlorobutyl)pyridine | C9H12ClN | 详情 | 详情 |
合成路线5
Tyrosine methyl ester (XXIII) was acylated with butanesulfonyl chloride (XIV) in the presence of pyridine to produce sulfonamide (XXIV). Mitsunobu coupling of pyridinyl butanol (XX) with the phenolic compound (XXIV) furnished ether (XXV). Subsequent hydrolysis of the methyl ester group of (XXV) employing LiOH afforded acid (XXVI). The title piperidine compound was then obtained by catalytic hydrogenation of the pyridine ring of (XXVI) in the presence of Pd/C.
| 【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. US 5312923; WO 9316994 . |
| 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) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XX) | 59550 | 4-(4-pyridinyl)-1-butanol | C9H13NO | 详情 | 详情 | |
| (XXIII) | 21431 | methyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate | 1080-06-4 | C10H13NO3 | 详情 | 详情 |
| (XXIV) | 59552 | methyl (2S)-2-[(butylsulfonyl)amino]-3-(4-hydroxyphenyl)propanoate | C14H21NO5S | 详情 | 详情 | |
| (XXV) | 59553 | methyl (2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoate | C23H32N2O5S | 详情 | 详情 | |
| (XXVI) | 59554 | (2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoic acid | C22H30N2O5S | 详情 | 详情 |
合成路线6
In a variation of this process, L-tyrosine (XXVII) was initially protected as the bis-O-silylated derivative (XXVIII) employing N,O-bis(trimethylsilyl) trifluoroacetamide. Acylation of (XXVIII) with butanesulfonyl chloride (XIV), followed by hydrolysis of the silyl groups, gave rise to N-butanesulfonyl tyrosine (XXIX). The phenolic hydroxyl of (XXIX) was then alkylated by 4-(4-pyridinyl)butyl chloride (XXII) to produce ether (XXVI). Finally, hydrogenation of the pyridine ring furnished the target piperidine derivative, which was isolated as the corresponding hydrochloride salt.
| 【1】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L. (Merck & Co., Inc.); Process for preparing fibrinogen receptor antagonists. WO 9316995 . |
| 【2】 Chung, J.Y.L.; Zhao, D.; Hughes, D.L.; Grabowski, E.E.; A practical synthesis of fibrinogen receptor antagonist MK-383 - Selective functionalization of (S)-tyrosine. Tetrahedron 1993, 49, 26, 5767. |
| 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) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XXII) | 59551 | 4-(4-chlorobutyl)pyridine | C9H12ClN | 详情 | 详情 | |
| (XXVI) | 59554 | (2S)-2-[(butylsulfonyl)amino]-3-{4-[4-(4-pyridinyl)butoxy]phenyl}propanoic acid | C22H30N2O5S | 详情 | 详情 | |
| (XXVII) | 48794 | (S)-(-)-Tyrosine; (S)-2-Amino-3-(4-hydroxyphenyl)propionic acid; 3-(4-Hydroxyphenyl)-L-alanine; L-(-)-Tyrosine; L-3-(4-Hydroxyphenyl)alanine; L-4-Hydroxy-17O-phenylalanine; L-beta-(p-Hydroxyphenyl)alanine; L-Hydroxy Phenyl Alanine; L-tyrosine | 60-18-4 | C9H11NO3 | 详情 | 详情 |
| (XXVIII) | 59555 | trimethylsilyl (2S)-2-amino-3-{4-[(trimethylsilyl)oxy]phenyl}propanoate | C15H27NO3Si2 | 详情 | 详情 | |
| (XXIX) | 59556 | (2S)-2-[(butylsulfonyl)amino]-3-(4-hydroxyphenyl)propanoic acid | C13H19NO5S | 详情 | 详情 |