药物详细合成路线
Chemical Name: |
1-[(2S)-2-[(1S)-1-Carbethoxybutylamino]-1-oxopropyl]-(2S,3aS,7aS)-perhydroindol-2-carboxylic acid |
Generic Name: |
培哚普利;Perindopril |
Other Names: |
Perindopril;DW-7950(as erbumine);SED-9490(as erbumine);McN-A-2833;S-9490;Coverene Cor;Coverex;Aceon;Coversum;Coversyl |
CAS: |
82834-16-0 |
Formula: |
C19H32N2O5 |
Mole Weight: |
368.47729 |
structure: |
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Company: |
Servier (Originator), Daiichi Pharmaceutical (Licensee), Egis (Licensee), Solvay (Licensee) |
Usage: |
CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Heart Failure Therapy, Hypertension, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors |
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Route 1
S-9490 is synthesized by coupling (2S,3aS,7aS)-2-tert-butoxycarbonylperhydroindole (II) with N-[(S)-1-carbethoxybutyl-(S)-alanine (I). |
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Intermediates: |
Serial No. |
Benzaldehyde-2,4-disulfonic acid disodium; disodium 4-formyl-1,3-benzenedisulfonate |
(I) |
4-[[5-(4-cyanophenoxy)pentyl]oxy]benzonitrile |
(II) |
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Reference 1:
Vincent, M.; et al.; Stereoselective synthesis of a new perhydroindole derivative of dural iminodiacid, a potent inhibitor of angiotensin converting enzyme. Tetrahedron Lett 1982, 23, 2, 1677.
Reference 2:
Mich, T.F.; Goel, O.P.; Mulhern, T.A.; Burk, M.J.; Hoekstra, M.S.; Ramsden, J.A. (Pfizer Inc.); Asymmetric synthesis of pregabalin. WO 0155090 . |
Route 2
[U-14C]-Aniline (I) is converted to [U-14C]phenyldiazonium chloride (II), which is condensed in situ with ethyl 2-(ethoxyalyl)propionate (III) to give [U-14C]phenylhydrazone of ethyl pyruvate (IV). Cyclization of (IV) by polyphosphoric acid in xylene affords ethyl [U-14C-phenyl]indole-2-carboxylic acid (V). Catalytic hydrogenation of compound (V) in the presence of platinum gives ethyl [U-14C-cyclohexyl]-(RS)-perhydroindole-2-carboxylic acid (VI), which is saponified to the corresponding acid (VIII). Compound (VI) can also be prepared by reduction of compound (V) with tin and hydrochloric acid to give compound (VII), and hydrogenation of the latter in the presence of palladium. Compound (VIII) is reesterified to the benzyl ester (IX), which is condensed with N-[(S)-1-carbethoxybutyl]-(S)-alanine (X) in the presence of DCC and 1-hydroxy-1-benzotriazole. The resulting compound (X) is separated fom the mixture of isomers by silica gel column chromatography. Hydrogenolysis of the latter compound gives [U-14C-cyclohexyl]perindopril, which is isolated as the tert-bytylamine salt. |
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Intermediates: |
Serial No. |
1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid |
(I) |
3-(4-aminothieno[3,2-c]pyridin-2-yl)-N-(tert-butoxycarbonyl)alanine |
(II) |
([(2S,3S,4S,6R)-4-azido-6-[((2S,3S,4S,6S)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy]-2-methyltetrahydro-2H-pyran-3-yl]oxy)(trimethyl)silane; (2S,3S,4S,6R)-4-azido-6-[((2S,3S,4S,6S)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy]-2-methyltetrahydro-2H-pyran-3-yl trimethylsilyl ether |
(III) |
(2S,4S,5S,6S)-4-azido-5-([(2R,4S,5S,6S)-4-azido-6-methyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl]oxy)-6-methyltetrahydro-2H-pyran-2-yl phenyl sulfoxide; [((2S,3S,4S,6R)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfinyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy](trimethyl)silane |
(IV) |
(2S,3S,4S,6S)-4-azido-6-[((2S,3S,4S,6S)-4-azido-6-[[(2S,3S,4S,6S)-4-azido-2-methyl-6-(phenylsulfanyl)tetrahydro-2H-pyran-3-yl]oxy]-2-methyltetrahydro-2H-pyran-3-yl)oxy]-2-methyltetrahydro-2H-pyran-3-ol |
(V) |
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(VI) |
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(VII) |
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(X) |
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(XI) |
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(VIII) |
ethyl (2E,4E)-2,4-hexadienoate |
(IX) |
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Reference 1:
Pichat, L.; et al.; Syntheses du S-9490-3. J Label Compd Radiopharm 1988, 25, 5, 553. |
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