• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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  • 优先权
    • 专利摘要:
    Derivatives of pyrrolidinecarboxaldehyde and piperidinecarboxaldehyde, and intermediates therefor, which have the general formula <IMAGE> wherein R is hydrogen, lower alkanoyl or <IMAGE> R1 is hydrogen or lower alkyl; R2 is hydrogen or hydroxy; R3 is hydroxymethyl, di(lower alkoxy)methyl or formyl; n is 1 or 2; and their bisulfite addition products, are useful as hypotensive agents.
    公开号:SU791227A3
    申请号:SU792753363
    申请日:1979-04-13
    公开日:1980-12-23
    发明作者:Айер Натараджан Сеша；Анджел Ондетти Мигуел
    申请人:Е.Р.Сквибб Энд Санз,Инк (Фирма)；
    IPC主号:
    专利说明:

    or methyl to heptyl branched hydrocarbon radicals, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and similar C-J-C4 substituents are preferred, especially C, and C 2 representatives. Lower alkanoyl groups are those having lower acyl radicals (Co-Su) fatty acids, for example, acetyl, propionyl and butyryl. Similarly, lower alkanoyl groups having up to 4 carbon atoms, especially acetyl, are preferred. The preferred method for the synthesis of compounds of formula 1 is the oxidation of an intermediate alcohol having the formula AND R-S-CHj-CM-CO- "The method consists in the interaction of an acid of the formula U. RS-CH3 -CH-COOM C. an amino alcohol of the formula (X nsn-one and the target product is isolated or when R is hydrogen oxidized by iodine to obtain compounds of the formula where R is the group | (sleep) y, 1.L -cH OH -sc ".- cv -coaldehydes of the formula, i.e. where is formyl, form bisulfite adducts with bisulic phyts of metals, especially alkali metal bisulfites, such as sodium and potassium sulfite. Compounds of formula I, where R is di (lower yoshkoxy) methyl, can be hydrolyzed to produce a product in which R is Formi Prod ykts of formula I have asymmetric carbon aTONfiJ, which are marked with asterisks.The shadow inventive compounds respectively exist in stereoisomeric forms or in the form of racemic mixtures. The described synthesis methods can use the racemate or one of the enantiomers in the starting material. When a racemic starting material is used in the synthesis procedure, the stereoisomers obtained in the product can be isolated. using conventional chromatography or fractional crystallization techniques. In general, the Z-isomer with respect to the carbon atom of the heterocycle is the preferred isomeric form. Example 1. 3- (Acetylthio) propanoic acid in the form of p-nitrophenyl ester. To a stirred ice-cooled solution of ethyl acetate (75 ml) containing 3- (acetylthio) propanoic acid (7.4 g, 50 mol) and p-nitrophenol 8, 4 g, 60 mol, is added in portions of dicyclohexylcarbodiimyl (10.3 g , 50 mol). After 30 minutes, the ice bath is removed and the solution is stirred overnight at room temperature. The precipitated dicyclohexyl urea is filtered off, the ethyl acetate is evaporated, and the residue is dissolved in ethanol. P-nitrophenyl 3- (acetylthio) propanoic acid is obtained in the form of crystals, yield 8.6 g (63.7%), m.p. 71-73 C. Example 2. 1- (3-Acetylthiopropanoyl) -2-2- (hydroxymethyl) pyrodiline. A solution of Z-prolinol (2.25 g, 22.5 mol) and 3- (acetylthio) propanoic acid p-nitrophenyl ester (6.4 g, 25 mol) in dimethylformamide: (45 ml) is stored at room temperature for 6 h. Dimethylformamide is evaporated and the residual 1- (3-acetylthiopropanoyl) -2-1- (hydroxymethyl) pyrrolidine is chromatographed on silica gel (400 g. Mallinkrodt, Silikar CC-7) using a mixture of benzene:: acetone (1: 9) for aluminization. The output of 4.6 g (88%), R 0,17 silica gel, benzene: acetone (4: 1). Example 3. 1- (3-Acetylthiopropanoyl) -2-2-pyrrodidinecarbox ChCH. To a solution of 1- (3-acetylthiopropanoyl) -2-Z-oxymethylpyrrolidine (1.84 g) in dimethyl sulfoxide (10.6 ml) was added a benzene solution (10 ml) containing pyridine (0.64 ml) and trifluoroacetic acid ( 0.32 mp). Dicyclohexylcarbodiimide (4.96 g) is added to this mixture in portions. After keeping the solution at room temperature for 16 hours, it is diluted with ether (200 ml), followed by the addition of a solution of oxalic acid (2.2 g) in methanol (5 ml). After 30 minutes, the solution is filtered to remove the precipitated dicyclohexyl urea. The ether solution is concentrated and redissolved in toluene (10 ml) when a small amount of oil is released. The toluene soluble substances are chromatographed on silica gel (150 g, Mallinkrodt, Silikar CC-7) using 7% acetone in toluene for elution. The yield of 1- (3 acetylthyropropanoyl) -2-Z-pyrrolidinecarboxaldehyde is 1.2 g, silica gel, Rf 0.33 (benzene: acetone, 4: 1), oJ, .25 103 "C (1.5 CHS1 ). Example 4. 3- (acetylthio) -2-methylpropanoic acid p-nitrophenyl ester. By the 3-way 3-sterile thiopropic acid, in the procedure of Example 1, 3- (acetylthio) -2-methylpropanoic acid, 3- (acetylthio) -2-methylpropanoic acid p-nitrophenyl ester was obtained, Rf 0.66 (silica gel: chloroform). Example 5. 1- (3-Acetylthio-2-methylpropanoyl) -2-Z-hydroxymethylpyrrolidine. When replacing, in the procedure of Example 2 3-acetylthio propionic acid p-nitrophenyl ester with 3- (acetylthio) -2-methylpropanoic acid p-nitrophenyl ester, 1- (3-acetylthio-2-methylpropanoyl) -2-Z-hydroxymethylpyrrolidine is obtained, R 0.17 (silica gel, toluene: acetone 4: l) c) (, l (c 0.83 MeOH). Example 6. 1- (3-Acetylthio-2-methyl propropenoyl) -2-Z-pyroprolidine ok with al In the procedure of Example 3, 1- (3-acetylthiopropanoyl -2-Z-hydroxymethylpyrrolidine 1- (3-acetylthio-2-methylpropanoyl) -2-Z-hydroxymethylpyrrolidine gives 1- (3-acetylthio - 2-Methylpyo-panoyl) -2-Z-pyro-polycarboxylic dehydrate, Rp b, 4 0 Dsilykagel, toluene: acetone 4: l) olS. (With 1, СНС1). PRI me R 7. 1- (3-Acetylthiopropanoyl) -2-D2-hydroxymethylpiperidine. When replacing 2-DZ-oxymethylpiperidine Z- prolinol, in the procedure of Example 2, 1- (Z-acetylthiopropanoyl) -2-DZ-oxymethylpiperidine is obtained. Example 8. 1- (3-Acetylthiopropanoyl) -2-DZ-piperidinkorbocaldegi When replacing 1- (3-acetylthiopropanoyl) - 2-DZ-oxymethylpiperidine 1- (3-acetylthiopropanoyl) -2-Z-hydroxymethylpyrrolidine, in the procedure of Example 3, is obtained from 1- (3-ac etylthiopropanoyl) -2-DZ-piperidincarbocaldehyde. Example 9. 1- (3-Butanoylthio propanoyl) -2-DZ-pyrolidine carboxydehyde. By replacing 3- (butanoylthio) propanoic acid with 3- (acetylthio) propanoic acid, in the procedure of Example 1, 3- (b-tanoylthio) propanoic acid p-nitrophenyl ester is obtained. When using this product in the procedure of example 2 and replacing Z-prolinol with DZ-prolinol, and then following the techniques; described in Example 3, 1- (3 butanoylthiopropanoyl) -2-DZ-pyrrolidinecarboxylamine is obtained, Example 10. 1- (3-Acetylthiopropanoyl) -2-Z-pyrrolidinecarboxylic aldehyde is the product of sodium bisulfite adduct. A solution of sodium bisulfite (172 mg) in water (15 ml) was added to 1- (3-acetylthiopropanoyl) -2-Z-pyrrolidinecarboxaldehyde (400 mg) and the suspension was stirred for 16 hours at room temperature. It becomes an almost clear clean solution. The solution is filtered and a white powder is obtained after diophilization (510 mg). The NMR of this substance shows the absence of an aldehyde proton, but the presence of a new doublet at 4.9 (G o (. | -38.6 o (1.4, HjO). T p and mep 11. 1- (3-Mercaptopropanoyl) -2-Z-oxymethyl pyroprolidine. 1 (3-Acetyl thiopropanoyl) -2-Z-o-methyl pyrrolidine (1 g) is dissolved in 5.5 M ammonium hydroxide (6 ml) and the solution is kept at room temperature in an argon atmosphere for 30 minutes, the Mixture is concentrated in vacuo, then passed through a column of Dowex 50 ion exchange resin (in hydrogen form) and washing water is removed. The water is removed by drying, freezing, 770 mg output, R p g (sleep I, MeOH, 9: 1, silica gel) ol -53.30 (0.1, CHCI)., Example 12. 1 , 1- Dithiobis (3-propanoyl) 3-bis-2-2-hydroxymethylpyrrolidine. 1- (3-Macro-apopropanoyl) -2-Z-oxymethylpyrolidine (0.95 g) is dissolved in water (20 ml) and the pH is adjusted to 6.5 with normal sodium hydroxide. An ethanol solution of iodine is added dropwise until a constant yellow color appears. The color disappears when a drop of sodium triosulfate is added and the solution is passed through a column of Dowex 50 ion exchange resin. The aqueous solution is concentrated to dryness to obtain 1,1-dithiobis (3-propanoyl) Zbc-2-Z-oxymethylpyrrolidine. , Example 13: 1,1-Dithiobis (3-pr6panoyl) 5bis-2-Z-pyrrolidinecarboxaldehyde. . When replacing 1,1-Dithiobis (3-propanoyl) Zbic-2-Z-oxymethylpiritsinim 1- (3-acetylthiopropanoyl) -2-Z-hydroxymethylpyrrolidine, in the procedure of example 3, get 1,1-dithiobis- (3-propanoyl) bis-2-Z-pyprolidine hydroxaldehyde. Example 14. 1- (3-Mercaptopropanoyl) -2-Z-pyrrolidinecarboxalde D1- (3-Acetylthiopropanoyl) -2-2-pyrrolidinecarboxaldehyde {1 g) is dissolved in a mixture of methanol (5 ml) and 2 HJ sodium hydroxide (5 ml) in an argon atmosphere. After 30 minutes, the reaction mixture was diluted with two-normal hydrochloric acid (20 ml) and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness in vacuo to give 1- (3-mercaptopropanoyl) -2-2-pyrrolidinecarboxaldehyde. This substance should be used as soon as possible after it is obtained because it is unstable. Example 15. 1,1-dithiobis- (2-methyl-3-propanoyl)} bis-2-g-pyrrolidinecarboxaldehyde. When replacing 1- {3-acetylthio-2-methyl propanoyl) -2-2-hydroxymethylpyrrolidine 1- (3-acetylthiopropanoyl) -2-hydroxymethyl pyrrolidine, in the procedure of example 11 and then subjecting the product to treatment in accordance with the procedure of examples 12 and 13 , get 1,1-Ldithiobis- (2-methyl-3-propanoyl) Zbis-2-1-pyrrolidinecarboxaldehyde, P p. and measure 16. 1- (3-Mercapto-2-methylpropanoyl) -2-2-pyrrolidinecarboxaldehyde. When replacing 1- (3-acetylthio-2-methylpropanoyl) -2-g-pyrrolidinecarboxaldehydodam, 1- (3-acetylthiopropanoyl -2-Z-pyrrolidinecarboxaldehyde .1- (3-acetylthiopropanoyl) -2-g-pyrrolidinecarboxaldehydedehydedehydedehydedehydedehydemine-2-g-pyrrolidinecarboxaldehyde. 14, 1- (3-mercapto-2-methylpropanoyl) -2-g-pyrrolidinecarboxydehyde is obtained. Example 17. 1-Benzyloxycarbonyl-4-benzyl-2-2-α-pyrrolidinecarboxaldehyde dimethyl acetal, a) 1-benzyloxycarbonyl-4-benyleloxy -2-proline (4.55 g) and 3,5-dimethylpyrazole (1.15 g) were dissolved in chloroform (200 ml). Dicyclohexylcarbodiimide (2.06 g) is added and the mixture is stirred in an ice bath for one hour and at room temperature for 16 hours. The precipitate is filtered and the filtrate is concentrated to dryness. The residue is dissolved in ethyl acetate, hydrochloric acid hydrochloric acid and water. The organic layer is dried and concentrated to dryness in vacuo to give 1-benzyloxy.-Carbonyl-4-benoyloxy-2-proline-3, 5-dimethylpyrazolide. b) Dimethylpyrazolid (5.3 g) dissolved in tetrahydrofuran (200 ml) is added to a suspension of dithium aluminum hydride (20 mol) in tetrahydrofuran (200 ml) for one hour, keeping the temperature between -15s and. After stirring for another hour with this tagger, 2N hydrochloric acid (12 ml) was added slowly while slowly passing an argon stream. The aluminum hydroxide precipitate is centrifuged and the solvent is removed in vacuo. The precipitate is dissolved in ether, washed with water and evaporated. The residue was dissolved in absolute methanol and 0.02 ml of concentrated hydrochloric acid was added. The mixture is stored at room temperature for 3 days, concentrated to dryness, the residue is dissolved in ethyl acetate and washed with saturated sodium bicarbonate and water. The organic phase is dried and concentrated to dryness in vacuo to give 1-benzyloxycarbonyl-4-benzyl-2-Z-pyrrolidinecarboxaldehyde dimethyl acetal. Example 18. 1- (3-Acetylthiopropanoyl) -4-oxy-2-Z-pyrrolidinacarbondedet. a) 1-Benzyl6-hydroxycarbonyl-4-benzyl-2-Z-pyrrolidinecarboxaldehyde dimethyl acetal (4.8 g) was dissolved in methanol (150 ml), 10% palladium on charcoal (500 mg) was added and the mixture was stirred in a stream of hydrogen until more carbon dioxide is released. The catalyst was filtered off and the filtrate was concentrated to dryness in vacuo. The residue and 3- (acetylthio) propanoic acid p-nitrophenyl ether (2.8 g) are dissolved in dimethylformamide (20 ml) and the mixture is kept at room temperature for 16 hours. The solvent is removed in vacuo and the residue is chromatographed on a column of silica gel using a benzene gradient:: acetone to isolate 1- (3-acetylthiopropanoyl) -4-hydroxy-2-Z-pyrrolidinecarboxaldehyde dimethyl acetal. b) The dimethyl acetal obtained under a) is suspended in 0.1 N hydrochloric acid and the mixture is stirred at room temperature until the acetal is fully hydrolyzed. The aqueous mixture is extracted with ethyl acetate, the organic phase is washed with water, dried with magnesium sulfate and; It is concentrated to dryness in vacuo to give 1- (3-acetylthiopropanoyl) -4-hydroxy-2-2-pyrrole. Idinecarboxaldehyde, Example 19. 1- (3-Acetylthio-2-methylpropanoyl) -4-hydroxy-2-Z-pyrrolidinecarboxaldehyde. By replacing the 3-acetylthio-2-methylpropanoic acid p-nitrophenyl ester of the 3-acetylthipropanoic acid p-nitrophenyl ester, in the procedure of Example 18, 1- (3-acetylthio-2-methylpropanoyl) -4-hydroxy-2-Z-pyrrolidinecarboxaldehyde is obtained . Example 20. 1- (3-Acetylthiopropanoyl -2-2-pyrrolidinecarboxaldehyde dimethyl acetal. A solution of 1- (3-acetylthiopropanoyl) -2-1-pyrrolidinecarboxaldehyde (1 g) in absolute methanol (10 ml) and 0.02 MP of concentrated hydrochloric acid kept at room temperature
    temperature for three days. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate and washed with sodium bicarbonate and water. The organic layer was dried and concentrated to dryness to give 1- (3-acetylthiopropanoyl) -2-Z-pyrrolidinecarboxaldehydecymethyl acetal.
    Example 21. 1- / 3-Acetylthio-2-methylpropanoyl) -Z-pyrphenol dinocarboxylate dehydroxymethyl.
    Using -replacement of 1- (3-acetylthio - 2-methylpropanoyl) -2-2 pyrrolidineroxaldehyde 1- (3-acetylthiopropanoyl) -2-Z-pyrrolidinecarboxaldehyde, in the procedure of Example 20, 1- (3-acetylthio-2- methylpropanoyl) -2-Z-pyrrolidinecarboxaldehyde dimethyl acetal.
    Example 22. 1- (3-Replica-2-methylpropanoyl) -2-Z-pyrrolidinacarboxydehyde dimethyl.
    1- {3-Acetylthio-2 methylpropanoyl) -2-Z-pyru-idincarboxylamine dimethyl acetal (1 g) is dissolved in a mixture of methanol (5 ml) and 2 N sodium hydroxide (5 ml). After 60 minutes, the mixture was diluted with water (30 ml), the pH was adjusted to 5, and the mixture was extracted with ethyl acetate. The organic layer is washed, dried and concentrated to dryness to give 1- (3-mercapto-2-methylpropanoyl) -2-Z-pyrrolidinecarboxaldehyde dimethyl acetal.
    The following additional products are obtained using the procedure of the example given in brackets using the corresponding pipecolic acid and 2- (oxymethyl) piperidine derivatives as starting materials.
    Example 23. 1- (3-Mercaptopropanoyl) -2-Z-hydroxymethylpiperidine example 11.
    Example 24. 1,1-Dithiobis (3-propanoyl} bis-2-Z-hydroxymethylpiperidine (Example 12).
    Example 25. 1,1-Dithiobis- (3-propanoyl) 4bis-2-2-piperidinecarboxaldehyde (Example 13).
    Example 26. 1- (3-Mercaptopropanoyl) -2-Z-piperidincarboxaldehyde (Example 14).
    Example 27. 1,1-Datiobis- (2-methyl-3-propanoyl) 11 bic-2-Z-pi-pidyridinecarboxaldehyde (Example 15).
    Example 28. 1- (3-Mercapto-2-methylpropanoyl) -2-Z-piperidine capboxaldehyde (Example 16).
    Example 29. 1- (3-Acetylthiopropanoyl) -5-oxy-2-Z-piperidinecarboxaldehyde (examples 17-18).
    Example 30. 1- (3-Acetylthio-: g2-methylpropanoyl) -5-hydroxy-2-Z-piperidinecarboxaldehyde (Example 19).
    Example 31. 1- (3-Acetylthiopropanoyl) -2-2-piperidinecarboxaldehydecymethyl acetal (Example 20).
    Example 32. 1- (3-Acetylthio-2-methylpropanoyl) -2-Z-piperidi n carb oxaldehydecymethyl acetal (Example 21).
    Example 33. 1- (3-Mercapto-2-metalpropzyl -2-Z-piperidine carobaldehyde dimethyl acetal (Example 22.
    Example 34. -1- (3-Butanoylthiopropanoyl) -2-DZ-piperidinecarboxaldehyde (Example 9).
    Example 35 Addition of sodium bisulfite to 1- (3-acetylthiopropanoyl) -2-And-piperidinecarboxal cegid (Example ID).
    Example 36. 1- (3-Mercapto-2-methylpropanoyl) -2-Z-pyrrolidine parabox aldehyde as a product of sodium bisulfite addition (Example 10).
    five
    Example 37. The addition product of sodium bisulfite to 1,1-dithiobis- (3-propanoyl) l-cis-2-Z-pyrolidinecarboxaldehyde.
    Replacing 1,1-dithiobis- (3-pro0 panoyl) | bic 2-Z-T and propyl-lincarboxyldehyde 1- (3-acetylthiopropanoyl) -2-Z-pyrrolidinecarboxaldehyde, in the procedure of Example 10, the product of sodium bisulfate is obtained
    5 to 1,1- {; 1itiobis- (3-propanoyl) bis-2-Z-pyrrolidinecarboxaldehyde.
    Example 38 Addition of sodium bisulfite to 1,1-dithiobis- (2-methyl-3-propanoyl) bis-2-pyr-rollidinecarboxaldehyde.
    By replacing 1,1-cytobis- (2-methyl-3-propanoyl) with bis-2-Z-pyrrolidinecarboxaldehyde 1- (3-acetylthiopropanoyl) -2-2-pyrrolidinecarboxaldehyde, in the procedure of Example 10,
    5, a product of addition of sodium bisulfite to 1,1-ichio-bis- (2-methyl-3-propanoyl) bis-2-pyrrolidinecarboxaldehyde is obtained.
    Example 39. The product of the addition of sodium bisulfite to 1,1-dithiobis- (2-methyl-3-propanoyl) bis-2-Z-piperidinecarboxaldehyde.
    Using sg1meny 1,1-dithiobis- (2-methyl-3-propanoyl) bis-2-7-piperidylcarboxaldehyde 1- (3-acetylt. Iopropanoyl) -2-Z-pyrrolidinecarboxydehyde, in the procedure of example 10, get the addition product sodium bisulfite to 1,1-cytobis- (20-methyl-3-propanoyl) J bic-2-Z-piperidinecarboxaldehyde.
    权利要求:
    Claims (1)
    [1]
    1. Buhler K., Pearson D. Organic syntheses. 1973, Part 2, p. 384.
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    法律状态:
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