• 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:

    公开号:SU895291A3
    申请号:SU802877159
    申请日:1980-01-30
    公开日:1981-12-30
    发明作者:Фрейзер Кэмпбелл Саймон；Кристофер Данилевич Джон；Вильямс Гринграсс Колин
    申请人:Пфайзер Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    38 where the values of X and R are given above, and the resulting desired product is isolated in free form or as a salt with a pharmaceutically acceptable acid or, if necessary, with an R-benzyl, the benzyl group is removed by hydrogenation, and the resulting compound of general formula I wherein R is a hydrogen atom, is reacted with an alkyl halide of the formula R-Hal, where Hal is chlorine, bromine or iodine and RC is j-alkyl or (C, -Ci RC. -alkyl or .X 4 "e - "loalkyl methyl, and the obtained target product is isolated. The target products can be allocated in the form of hydrochloride yes, hydrobromide, sulfate or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, saharit or p-tolu olsulfonat. Compounds of formula I containing one or more asymmetric centers exist as one or more pairs of enantiomers and such pairs or individual enantiomers can be separated using physical methods, for example, by fractional crystallization of suitable salts. The invention includes individual pairs, as well as their mixtures, racemic mixtures or separated d- and 1-optically active isomeric forms. The reaction of compounds of the general formulas II and III is carried out in an organic solvent at 70-130 ° C, preferably at the boiling point of the solvent. The compounds of general formula I can be administered to humans for the treatment of high blood pressure either orally or parenterally and can be administered orally in doses of from about 1 to 50 mg / day for an average adult patient (70 kg) administered as a single dose or up to 3 separate doses. Intravenous dosages are about 1 / 5-1 / 10 of the daily oral dose. Thus, for an average adult patient, individual oral dosages in the form of tablets or capsules typically comprise 1-50 mg of active compound depending on the weight of the patient — and on the particular mode of administration, which is selected by a known method by those skilled in the art. Compounds of general formula I can also be used in the treatment of animals. Example 1 4-Amino 6, 7-dimethoxy-2-4.2-ethoxy-1-phenylethoxy-piperidino-quinazoline hydrochloride. 4-amino-2-chloro-6,7-dimethoxyquinazoline (2.6 g) and 4- (2-ethoxy-1-phenylethoxy) piperidine (3.0 g in C-butanol (100 ml) is heated under reflux in 22 hours. The solution is cooled, filtered and the filtrate evaporated in vacuo. The residue is triturated with diethyl ether and recrystallized twice from isopropanol. piperidino quinazoline 2.0 g, mp 229-230 ° C, Found,%: C 61.0; H 6.9; N, 11.5 HCl; Calculated,%: C, 61.4; H 6.8; N 11.5 Example 2. 4-Amino-6,7-dimethoxy-2- 4- (2-phenoxy-1-phenylethoxy) -piperidine hydrochloride hydrate o quinazoline. 4-Amino-2-chloro-6,7-dimethoxyquinazoline (1.44 g) and 4- (2-phenoxy-1-phenylethoxy) piperidine (2.0 g) in N butanol (100 ml) are heated with reflux for 20 hours. The solvent is distilled off in vacuo, the residue is triturated with ether and crystallized from isopropanol. To a solid, an aqueous solution of sodium carbonate and chloroform, the chloroform extract is dried (MgSO4 and the solvent is distilled off in vacuo. The residue is chromatographed on silica gel (100 g), eluted with chloroform, followed by elution with a mixture of chloroform and methanol (20: 1). The fractions containing the product are combined, the solvent is chased under vacuum, and the residue is taken up in hydrochloride by treating the chloroform solution with an ethereal hydrogen chloride solution. The hydrochloride is collected and recrystallized from isopropanol, the yield of 4-amino-6,7-dimethoxy-2 4- (2-phenoxy-1-phenylethoxy) piperidino quinazoline hydrochloride hydrate is 0.85 g, so pl. 202-204 s. Found,%: C 62.8; H 6.1; N 10.0 C1 2 ° Calculated, C 62.8; H 6.4; N 10.1 Examples 3-6. The following compounds were prepared analogously to those described in the preceding examples, starting from 4-amino-2-chloro-6,7-dimethoxyquinazole 58952916
    and the corresponding piperidine (see the products of examples 4-6 are analogous to the table, namely: the product of example 2, but the product of example 5 is not pe3 prepared analogously to example 1, but transferred to hydrochloride.
    OCHj-C
    N /
    Example 7, 4-Amino-6-cyclopropylmethoxy-2- 4- (2-ethoxy-1-phenylethoxy) piperidine-7-methoxyquinazoline, D (+) - tartrate, 4-amino-2- {4- (2- ethoxy-1-phenylethoxy-piperidino 3-6-hydroxy-7-methoxyquinazoline (0.75 g) in dimethylformamide (50 ml) and the sodium hydroxide solution (1 ml, 5n) is stirred at room temperature under nitrogen atmosphere for 40 minutes in the dark, cyclopropylmethyl bromide (0.27 g) is added and the solution is stirred under nitrogen for an additional 20 hours. Potassium iodide (5 mg) and cyclopropyl methyl bromide (0.27 g) are then added and stirring is continued in t chenie 2 hours at room temperature. The solvent is distilled off in vacuo and the residue is weighed in water (50 ml), basified to pH 12 with. 2N sodium hydroxide solution and extracted with chloroform (3x100 ml). The combined chloroform layers are dried over sodium sulfate and the solvent is distilled off in vacuo to give a semi-solid. The product is cloned on silica gel (7 g) with elution with chloroform. The fractions containing the product are combined and the solvent is distilled off in vacuo. The residue is converted to a tartrate salt by treating the chloroform solution of the resulting product with a solution of D (+) - tartaric acid in ether. The solid is filtered off, washed with ether and dried under reduced pressure, the yield of D (+) - tartrate 4-amino-6-cyclopropylmethoxy-2- 4- (2-ethoxy--1-phenylethoxy) piperidino-7methoxyquinazoline 115 mg, t, pl . 142-145 C. Found,%: C 59.8; H 6.5; , N 8.9 C2gH 6N404C Calculated,%: C 59.8; H 6.6; N 8.7 Example 8. 4-Amino-6-ethoxy-2- 4- (2-ETOXI-1-phenylethoxy) piperidino 2-7-methoxyquinazoline. The title compound was prepared in a manner similar to that described in Example 7, starting from 4-amino-2- | 4- (2-ethoxy-1-phenylethoxy) piperidino-6-hydroxy-7-methoxyquinazoline and iodide ester in the presence of sodium hydroxide, t, mp, 227228 ° C. Found,%: C 52.1; H 5.8; N 9.4 789 Calculated,%: C 52.5; .H 5.9; N 9.4 Example 9. 4-amino-6-benzyloxy-2- 4- (2-ethoxy-1-phenyl ethoxy) hydrochloride piperidino-7-methoxyquinoline. 4-amino-6-benzyloxy-2-chloro-7-methoxyquinazoline (0.72 g) and A- (2-ethoxy-1-phenylethoxy) piperidine (0.57 g) in H-butanol (50 ml) is heated at refluxing for 30 hours. The solvent is distilled off under vacuum and the residue is triturated with ether, a solid is obtained which is recrystallized from a mixture of isopropanol and diisopropyl ether, the yield is 4-amino-6-benzyloxy-2- | 4- (2-is xi-1-phenylethoxy) piperidino-7-methoxy-iiiiazoline 740 mg. A sample recrystallized from ethanol is m.p. 238-240C. Calculated,%: C 65.5; H 6.5; N4O, O C31CHL04- Calculated,%: C 65.9; H 6; 6; N9.9. The following examples illustrate the preparation of some starting materials. A. Preparation of 4- (2-hydroxyphenethyloxy) piperidine, L-Lethyl-4-hydroxypiperidine (5.0 g) in tetrahydrofuran (THF, 50 ml) is added to a stirred suspension of sodium hydride (1.84 g, 50% - for dispersion in mineral oil) in tetrahydrofuran (THF, 25 ml) under nitrogen atmosphere. After the violent gas evolution ceases, styrene oxide (4.6 g) in THF (25 ml) is added, then the reaction mixture is diluted with dimethyl forms. (DMF, 25 mm) and stirred at 60 ° C for 18 hours. After the isopropanol solution was added to the cooled solution, the solvent was distilled off in vacuo, the residue Dissolve with water, adjust to pH 4 with 2 N hydrochloric acid, and: Extract with chloroform. The chloroform extract was dried with sodium sulfate and the solvent was distilled off in vacuo to give N-a4eTHn-4- (2-hydroxyphenethyloxypiperidine. The resulting product was dissolved in ethanol (50 ml) and 5N sodium hydroxide solution (100 ml), heated at reflux for 3 hours. The solvent is distilled off in vacuo, the residue is taken up in water, extracted with chloroform, dried and the solvent is distilled off in vacuo. The product in chloroform is taken up in hydrochloride by treatment with an ethereal solution of hydrogen chloride and the solvent is distilled off. t in me anol, treated with ether and the precipitated precipitate is filtered and recrystallized from isopropanol to obtain 4- (2-hydroxyphenethyloxy) piperidine hydrochloride (o, 6 g), mp 174-175 pp. Found: C: 60.1; H 7 , 8; N 5.2 CH 9 i-HCl Calculated,%: C 60.6; H 7.8; N 5.4 B. Preparation of 4- (2-ethoxyphenethyloxy) piperidine. N-Acetyl-4- (2 α-oxifenethyloxy) piperidine (8.0 g), prepared as described in A, and 1,2-dimethoxyethane (0.3 g) in dry DMF (50 ml) are added dropwise to a stirred suspension of sodium hydride (2, 96 g, 50% dispersion in mineral oil) in, dry DMF (50 ml). The suspension is stirred at room temperature for 3.5 hours, cooled to, then a solution of ethyl iodide (8.6 g) in DMF (25 ml) is added dropwise. The mixture is warmed to room temperature (20 ° C), then stirred at this temperature for 2 hours. Isopropanol (75 ml) is added, the solvent is removed in vacuo, the residue is distributed between chloroform and water. The chloroform layer is dried and the solvent is evaporated in vacuo to give S-acetyl-4- (2-ethoxy-1-phenethyloxy) piperidine (5.2 g. This product in ethanol (50 ml) and sodium hydroxide solution (50 ml, 5n,} is heated under reflux for 3.5 hours. The organic solvent is removed in vacuo and the aqueous residue is extracted with chloroform. The organic extract is dried with sodium sulfate, evaporated in vacuo, then the residue is partitioned between 2N hydrochloric acid and ether. the phase is alkalinized with sodium carbonate solution and extracted with chloro The chloroform extract is dried with sodium sulfate, the solvent is evaporated in vacuo, then the residue is taken up in ether and converted to the oxalate salt. Recrystallization from isopropanol gives 4- (2-ethoxyphenyloxy) piperidine oxalate (1.6 g), mp 136137 ° C Found,%: C 60.3; H 7.4; N 4.1 se.EngSi-s HgOd Calculated,%: C 60.2; H 7.4; N 4.1 C. Preparation 4- (2-ethoxy-1-phenylethoxy) piperidine, 1) Ethyl ester - (M-acetyl-4 - piperidinoxy) phenylacetic acid.
    9895
    N-Adethyl-4-oxyciperidine (27.5 g in dry DMF (100 ml) is added slowly to a mixed suspension of sodium hydrate (25 g, 50% dispersion in mineral oil) in DMF (150 ml and 1, 2-dimethoxyethane ( 10 ml), bromophenylacetic acid (45 g) and DMF (250 ml) are added slowly while cooling with a mixture of ice and water. The mixture is stirred at room temperature for 20 hours. Isopropanol is then added and the solvent is evaporated in vacuo. The residue is taken up in water and acidified to pH 1 with 2N hydrochloric acid. acids and extracted four times with chloroform (300 ml). The combined chloroform extracts are washed with water and brine, dried with magnesium sulfate and the solvent evaporated in vacuo. The residue in anhydrous ethanol (450 ml) with concentrated sulfuric acid (9 ml) is heated at reflux temperature. within 8 hours. The cooled solution is carefully neutralized with an aqueous solution of sodium carbonate, and the organic solvent is evaporated in vacuo. The aqueous residue is brought to rI 10 with sodium carbonate solution and the organic solvent is evaporated in vacuo. The aqueous residue is adjusted to pH 10 with sodium carbonate solution and extracted twice with chloroform. The combined chloroform extracts are dried with magnesium sulfate and evaporated in vacuo. Distillation of the residue yields 1- (N-acetyl-4-piperidinoxy) phenylacetic acid ethyl ester (37.2 g), m.p. 190-194C / 0.18 mm.
    Found,%: C 66.4; H 7.8; N 4,5
    Calculated,%: C, 66.9; H 7.6; N 4,6
    2). M-Acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine.
    Lithium borohydride (3.24 g) is added in portions to a solution of oL- (H-acetyl-4-piperidinoxy) phenylacetic acid ethyl ester (11.2 g) in dry THF (200 ml). When hydrogen removal ceases, the reaction mixture is heated at reflux for 4 hours, water is added to the cooled solution, the solvent is evaporated in vacuo, then the residue is taken up in chloroform (200 ml and washed with dilute hydrochloric acid).
    ten
    acid, water and saline. The chloroform extract is dried with a sulfate of magic and the solvent evaporated in vacuo. Analysis of the thin layer chromatography of the product showed that the reduction was incomplete, therefore the product in THF (100 ml) was treated with additional lithium borohydride (3.24 g) and heated at reflux temperature for 4 hours. The reaction mixture was treated as described above, yielding Y acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine (9.5 g) as an oil, which solidifies on standing. A sample crystallized from ether has m.p. 92-94 S.
    Bulk%: C 68.1; H 8.1; N 5.7
    C.
    Calculated,%: C 68.4; H 8.1; N 5.3
    3). 4- (2-Ethoxy-1-phenylethoxy) piperidine.
    This compound is prepared as described in preparation B, starting from α-acetyl-4- (2-OXY-1-phenylethoxy) piperidine (prepared as described in part 2) and ethyl iodide with subsequent basic hydrolysis of the N-acetyl group. The sample is characterized as an oxalate salt, m.p. 137-139 ° C.
    Found,%: C 59.9; H 7.4; N 4,0
    C, CrIg04
    Calculated,%: C 60.2; H 7.4; N 4.1
    D. 4- (2-phenoxy-1-phenylethoxy) piperidine,
    M-Acetyl-4- (2-hydroxy-1-phenylethoxy) piperidine (5.25 g) (obtained as in C 2), diethyl azodicarboxylate (4.2 g) triphenylphosphineSb, 3 g) and phenol (2.25 g in dry tetrahydrofuran (100 ml) was stirred at 0 ° C for 2 hours, then left at room temperature for 48 hours. The solvent was evaporated in vacuo the residue was dissolved by heating in diethyl ether (50 ml) and left in a refrigerator overnight The precipitated by-products are removed by filtration and the filtrate is evaporated to dryness. The residue is redissolved in ether, cooled and the precipitated solid. The ether filtrate is evaporated to dryness and the residue is taken up in methanol (50 mm) and the sodium hydroxide solution (30 ml, 5 N) is heated at reflux for 5 hours. The organic solvent is removed in vacuo, the aqueous residue is acidified to pH 3 2 n With 1189 hydrochloric acid and extracted twice with ether, the organic extracts are removed. The aqueous phase is adjusted to pH 12 with sodium hydroxide solution, extracted with ether (3 x 100 ml), the ether extracts are dried with magnesium sulfate and the solvent is evaporated in vacuo, Dawa 4- 2-phenoxy-1-f enilethoxy) piperidine g) in the form of oil. The sample is converted to the oxalate salt, which is recrystallized from isopropanol, m.p. 170-172p. Found,%: C 64.9; H 6.6; N 3.8 C IL NO -qHjO Calculated,%: C 65.1; H 6.5; N 3.6 E. Preparation of 4- (2-hydroxy-2-phenyl-n-propoxy) piperidine. one . M-Acetyl-4- (2-phenylallyloxy) -piperidine. M-Acetyl-4-hydroxypiperidine (13.6 g) in DMF (50 ml) is added dropwise to a stirred suspension of sodium hydride (10 g, 50% dispersion in mineral oil) in DMF (50 ml) in an atmosphere nitrogen. The mixture was stirred at room temperature for 3 hours, then cL-bromomethylstyrene (20 g) in DMF (50 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours, then diluted with water and extracted with chloroform (3 x X 200 ml). The combined chloroform extracts were dried with sodium sulfate, evaporated in vacuo and distilled to give N-acetyl-4- (2-phenylallyloxy) -piperidine (25 g), b.p. 170-180 ° C (0.3 mm NMR spectrum corresponds to this structure). 2). 4- (2-Oxy-2-phenyl-y-propoxy) -piperidine. L-Acetyl-4- (2-phenylallyloxy) -piperidine (4.0 g) in dry THF (60 ml) is added dropwise to a stirred solution of mercury acetate (6.35 g) in water 60 ml) and the solution is stirred at room temperature for 1 h. A solution of sodium hydroxide (40 ml, 3N) and sodium borohydride (0.75 g) in a solution of sodium hydroxide (40 ml, 3N) are added dropwise to the stirred solution to the stirred solution. The sulfur slurry is stirred at 0 ° C for 1 hour, added to pH 6 with ice and acetic acid, then the suspension is filtered and the filtrate is extracted with chloroform (3 x 150 mm). The combined chloroform extracts were dried with sodium sulfate 112 and evaporated in vacuo to give N-acethyl-4- (2-hydroxy-2-phenyl-n-propoxy) -piperidine (2.1 g) This product in methanol (30 ml) and the sodium hydroxide solution (20 ml, 5N) is heated under reflux for 4 hours. The organic solvent is evaporated and the aqueous solution is extracted with chloroform (3 X 20 ml), dried with sodium sulfate and the solvent is evaporated in vacuo to give 4 (-2- hydroxy-2-phenyl-n-propoxy) -piperidine (1.8 g) as an oil. The sample is characterized as the oxapate salt, which is recrystallized from ethyl acetate, m.p. 132-134p. Found,%: C 68.8; H 7.1; N 4.8, Calculated,%: C 59.1; H 7.1; N4.3 F. Preparation of 4- (2-ethoxy-2-phenyl-n-propoxy) -piperidine. L-Acetyl-4- (2-phenylallyloxy) -p-. Peridine (7.0 g) (prepared as described in F) in ethanol (10 ml) is added to a stirred suspension of mercury acetate (9.2 g) in ethanol (50 ml) at room temperature. The mixture is stirred at room temperature for 1 h, then cooled to. A solution of sodium hydroxide (200 ml, 5 N) is added to the stirred suspension, followed by addition of sodium borohydride, 1.03 g in a solution of hydroxide, sodium (20 ml, 5N), and after 10 minutes ice glacial acetic acid is added. acid to pH 6. The suspension is filtered, the filtrate is concentrated and the residue is partitioned between chloroform and water. The organic layer is dried with sodium sulfate and the solvent is evaporated in vacuo. Analysis of the gas-liquid chromatography (GLC) of the product showed: 1l incomplete conversion to the target product, therefore, the process of oxymerculation is repeated as described above, giving H-acetyl-4- (2-ethoxy-2-phenyl-n-propoxy) piperidine (7, 7 g) 84% purity by GLC. The product in ethanol (100 ml) and sodium hydroxide solution (30 ml) are heated at reflux for 11 hours. The organic solvent is evaporated and the aqueous solution is extracted with chloroform (3 x 30 ml). The combined chloroform extracts were dried with sodium sulfate and the solvent was evaporated in vacuo to give 4- (2-ethoxy-2-phenyl-n-propoxy) piperidine as an oil (G3.8 g). The sample is converted to the oxalate salt,
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining derivatives of 4 · **
    no-2-piperidinoquinaeolin general form mules If 2 80 '
    (where R is C ^ _ ^ -alkyl, benzyl or (C ^ _ £ -cycloalkyl) -me- 4 $ tyl;
    О -X- 0R • 2 where the values of X and R are given above, and the obtained target product is either alkali free, or as a salt with a pharmaceutically acceptable acid, or, if necessary, with Rbenzyl, the benzyl group is removed by hydrogenation, and the obtained compound . general formula I, in which R is a hydrogen atom, is reacted with a halide alkyl of the formula R-Hal, where Hal are chlorine, bromine or iodine atoms and RC 4 _ ^ anKHH or (C ^ _ ^ - cycloalkyl) methyl, and the resulting the target product is isolated.
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    同族专利:
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    PL121890B1|1982-06-30|
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    CS231970B2|1985-01-16|
    JPS5728711B2|1982-06-18|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA1088068A|1977-11-16|1980-10-21|Simon F. Campbell|Piperidino-quinazolines|
    GB2021108B|1978-05-18|1982-07-21|Pfizer Ltd|6,7 - di - 4 - amino - 2 - quinazolines|FR2483920B1|1980-06-09|1983-07-22|Synthelabo|
    ES8405389A1|1981-09-09|1983-11-01|Orion Yhtymae Oy|Substituted piperidinyl quinazolines.|
    US5280032A|1989-02-14|1994-01-18|Toyama Chemical Co., Ltd.|1,2-ethanediol derivative and salt thereof, process for producing the same, and cerebral function-improving agent comprising the same|
    US9458131B2|2011-11-08|2016-10-04|Emory University|Compounds and compositions used to epigenetically transform cells and methods related thereto|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7903398|1979-01-31|
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