• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Certain 2-(4-aroylpiperazin-1-yl)-4-amino-6,7-dimethoxyquinazolines are prepared by a novel process wherein certain 2-(4-substituted-piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline intermediates wherein said substituent is cyano, certain carbon-oxygen double bond containing groups or certain carbon-nitrogen double bond containing groups, are reacted with certain metalloaryl compounds followed by hydrolysis. The products are known hypotensive agents. Certain of the process intermediates are novel compounds.
    公开号:SU847919A3
    申请号:SU772522448
    申请日:1977-09-19
    公开日:1981-07-15
    发明作者:Дитрих Хаммен Филип
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    where R, is a cyano group, C / O / U group, or C / "NH / y, where YORj, sSR is silt, where R, j -, is alkyl or fe and R and RJ are the same or different C | -C - alkyl or phenyl is reacted with 1-3 moles of the dinene of the general formula, III where (it has the indicated values and M is lithium, sodium or MdH and where X is chlorine, bromine or iodine, an absolute organic solvent at a temperature from -80 to followed by hydrolysis of the reaction mixture. The process is preferably carried out at a temperature of from -60 to -20 ° C. According to the proposed method, it is preferable to use x imolar amounts of reagents, The solvent used is such a solvent that provides the required dissolution or dispersion of chemical reagents and does not chemically react with reagents or reaction products. Examples of such solvents are ethers, such as diethyl ether, diisopropyl ether, di-di - butyl ether, methyl isobutyl ether, tetra hydrofuran, tetrahydropyran, dioxane, ethylene glycryldimethyl ether, diethylene glycol dimethyl ether and anisole; hydrocarbons such as hexane, heptane, cyclohexane, 1-decene, benzene and xylene, as well as tertiary amines, such as triethylamine, and mixtures of these solvents. The solvents used should not contain water and the method should be protected from moisture. The time required for a chemical reaction to complete its completion depends on both the temperature and the nature of the chemical reagents of formula I and formula III. Typically, the reaction takes from a few minutes to several hours. The reaction that takes place between the reagents of formula II and formula III leads to the formation of an intermediate that readily hydrolyzes to form the desired product of formula 1. The process is generally illustrated for the case where the cyano group w / VN is T-eN + KjM MNa H, 0 1 If-C-RI-T vOf-dHjO .No Hydrolysis also serves to decompose the excess reagent of the formula. The hydrolysis can be carried out using only one water, resulting in the formation of an alkaline mixture, either by adding dilute aqueous solutions of acids, such as sulfuric, hydrochloric, forsforny and acetic acid, or with the addition of aqueous solutions of acidic salts, such as chloride, ammonium, ammonium bromide, ammonium phosphate, ammonium phosphate, ammonium phosphate, sodium phosphate and triethylamine hydrochloride. The hydrolysis can occur in a wide range of temperatures, for example, within temperatures of about -20 to + 100 ° C, but preferably at or near room temperature. In such a case, it is desirable to cool the reaction mixture during the addition of water, an aqueous solution of an acid or an aqueous solution of a salt, since in some cases hydrolysis is an exothermic process. After complete hydrolysis, the reaction mixture is processed by standard methods. For example, when using acid hydrolysis, the aqueous layer is extracted with a water-immiscible solvent that can be used during a chemical reaction, or with another solvent, such as chloroform, methylene chloride, ethyl acetate, methyl isobutyl ketone, etc. During this extraction, neutral side substances are removed, since the desired product is soluble in diluted Wx aqueous acid solutions. The iodine phase is then alkalinized by adding, for example, sodium hydroxide, potassium hydroxide or sodium carbonate and extracted again, the extracts are evaporated to a small volume and the product is precipitated by adding a solubilizing solvent product such as hexane, heptane or petroleum ether. The precipitated product is then separated by filtration and then it can be purified by standard methods such as recrystallization or silica gel chromatography using a chromatographic column. When carrying out hydrolysis using the extra & water alone is alkaline, and the aqueous layer can be extracted with one of these solvents, and the extracts containing the desired product are treated in the same manner as for the case of acid hydrolysis. Example 1. (2-Furayl) piperaenoyl-1-4-amino-6,7-dimethoxane quinazoline. In a 100 ml flask equipped with a thermometer and a tube with a desiccant, 10 ml of dry tetrahydrofuran and 0.5 ml (6.2 mol) of furan are introduced. The solution is cooled to and 2.8 ml (6.2 mmol) of p-butyl lithium in hexane are added to it. To the obtained light amber mixture, 400 mg (1.25 mmol) of 2- (4-cyanopiperazinyl-1) -4-amino-6,7-dimethoxyquinazoline in 30 ml of dry tetrahydrofuran are added. After termination, the added-and the reaction mixture is brought to room temperature and stirred overnight. Next, the reaction mixture is rapidly cooled, poured 88 ml of 2 n. hydrochloric acid, washed with 100 ml of chloroform, adjusted to pH 10 with an aqueous solution of sodium hydroxide solution and extracted twice with chloroform in 100 ml portions. The aqueous phase is evaporated in vacuo to a volume of 2 ml and filtered, resulting in 15 mg of the title compound having a mp. 263-264 ° C. Infrared and thin layer chromatography data show that the product obtained is identical to the product obtained in a known manner. Using equimolar amounts of the reagents (5.2 mmol) of 2 - (4-cyano-piperazinyl-1) -4-aminoJ-6, 7-dimethoxyquinazoline), the yield of the target compound is 37%. Example 2. A solution of 6.8 g (0.10 mol) of furan in 100 ml of dry ether is cooled to -60 ° C under an atmosphere of dry nitrogen. To this solution, 0.01 mol of 15% strength (wt.% ) anhydrous solution of butyl lithium in hexane and the resulting mixture is stirred for 10-15 minutes. Then, 3.60 g (0.01 mol) of 2-C4- (M, M-dimethylcarbamyl) piperazinyl-1 -4-amino-6,7-dimethoxyquinazoline in 25 ml of ethyl ether are added to this mixture. The resulting mixture was stirred at -60 ° C for 2 hours, then stirred overnight at room temperature. This mixture is poured into 100 ml 2 n. hydrochloric acid containing an equal volume of ice is extracted with two portions of chloroform, 50 ml each, and the extracts are separated. The pH of the water of the aqueous layer was adjusted to 10 with aqueous sodium hydroxide solution, then extracted with three portions of chlorofom in 50 ml each. The extracts are dried with sodium sulfate, then evaporated to a small volume. When hexane is added, precipitation occurs. (2-Furoyl) piperazinyl-1-4-amino-b, 7-dimethoxyquinazoline, which is filtered off. By performing the procedure described, identical results are obtained instead. Example 3. 2.3 g (0.10 gtoma) of coarse metallic sodium and 10.7 g of amyl chloride in 200 MP of ethyl ether are vigorously stirred at (-5) (0) C until all sodium is dissolved. Then 10 g of chemically pure toluene is added and the mixture is heated to boiling point and boiled for 3 hours. The resulting benzyl sodium is treated with 13.6 g (0.2 mol) of furan and stirred at room temperature for 1 hour, to give 2-furyl sodium. 32.9 g (0.10 mol) of 2- (4-carbethoxypiperazinyl-1) -4-amino-6,7-dimethoxyquinazoline in 300 ml of ethyl ether are slowly added to this mixture in -20 ° C. The reaction mixture was stirred at -20 ° C for 2 hours, then heated to room temperature. The resulting mixture is hydrolyzed by the addition of 100 ml of water and the ether layer. separate yut. The aqueous layer was extracted with 300 MP of ether and the combined extracts were dried with anhydrous magnesium sulphate. After evaporation of the solvent, 2-f4- (2-furoyl) piperazinyl-lj-4-amino-6, 7-dimethoxyquinzoline is obtained, which can be purified by silica gel column chromatography. Example 4. 2- (4-Benzoylpiperazinyl-1) -4-amino-6, 7-dimethoxyquinaeolin. A solution of 5.43 g (0.03 mol) of phenylmagnesium bromide in 100 ml of tetrahydrofuran is saturated with dry nitrogen and a solution of 3.15 g (0.01 mol) of 2- (4-cyano-dipropyzanyl -) - 4 is added dropwise to it. -amino-6,7-dimethoxyquinadoline in 75 ml of the same solvent at room temperature for 30 minutes. After the addition is complete, the reaction mixture is heated for 6 hours, then maintained at room temperature overnight. Next, 25 ml of 2 N was added to the reaction mixture. hydrochloric acid and stirred for an additional 30 minutes. Next, the reaction mixture is alkalized with a solution of sodium hydroxide, the organic layer is separated, the aqueous layer is extracted with two portions of tetrahydrofuran and 100 ml each, and the combined organic layers are dried with anhydrous magnesium sulfate and evaporated to dryness to give a crude target product, which can be further purified by cryslization from ethanol or by chromatographic separation on a column of silica gel.
    Example 5. (2-Tenoyl) Piperazinyl-1-4-amino-b, 7-dimethoxyquinazoline.
    O., 73 g (0.03 g-atom) of magnesium powder and 75 ml of ethyl ether are introduced into a flask equipped with a stirrer, reflux condenser, addition funnel, feed and nitrogen. While stirring, 6.3 g (0.03 mol) of 2-iodothiophene in 25 MP ethyl ether are added dropwise. During the addition, the reaction mixture is heated to boiling. After the addition is complete, boiling is continued until
    those: until most of the magnesium is consumed. Then a solution of 3.60 g (0.01 mol) of (N, N dimethylcarbamyl) piperazinyl-1 -4-amino-6,7-dimethoxyquinazoline in 50 ml of ether is added dropwise in 30 minutes, the mixture is boiled t for 8 h. Then the reaction mixture is treated as in example 1.
    Example 6. Using 2-chlorofurin, 2-bromofuran or 2-iodofuran instead of 2-iodothiophene, get, analogously to example 5,2-G4- (2-furoyl) - piperazini I - 1 -4-amino-6,7-dimethoxyquinazoline.
    Similarly, the compounds listed in the table are prepared.
    Z-Furillium COSCHj,
    Phenyllithium — CH OZSNc CH (CK 2-Tynillithium —COOCH,. (CHi), jCH ,, Z-Tyenillithium —COOCH,
    2-Furillium -: ONCH2 CCH, j), .CH, THF
    VH
    2-Furillium, j (CHji; CHj Isopropyl -25
    l
    -CON (C (, H5i
    Phenyllithium, j phenyllithium
    2-Furillium-SOSN,
    v
     NH
    2-Thienyl lithium-COCH, CH (CH) H
    NH-C5C, N
    Phenyllithium

    NH
    5 2-Furillium-CSCH2CH (GHj) 2 Ethyl ether
    NH
    Phenyllithium-SSCHSN)
    NH
    2-Thienyl lithium-CN (CH-j) C H
    NH 2-Thienyl Sodium-SMSSn (CH, 2) SND Ethyl ether
    11 NH
    12 2-Furyl sodium -CN (CH) CH4 (- THF

    12 2 Furyl sodium -CSCH,
    NH
    -80
    Ethyl ester -60 THF -20
    Monoglyme -30 THF -20
    ether
    Ethyl Ether-30
    Diglyme-20 CH,
    THF-20
    Anisol-20
    Ethyl Ether-20
    g-80 -20.
    Ethyl ester -60 Ethyl ester -20 25
    Ethyl ether
    2-Furyl sodium -COM (C, H5) "ethyl ester 35
    2-Furyl sodium-COSC, Hg THF-60
    2-Furyl sodium-COSCHj CH (CH,}, j Ethyl ether-20
    2-Furyl sodium-SOOCH, ethyl ester10
    2-Furyl sodium-COOCHijL (CH5), j CH Ethyl ester 25
    2-Furyl sodium -N-ethyl ester-10
    2-furilmagniy-.
    chloride - СООС, N Ethyl ester 35
    Phenylmagnesium chloride —COOCH, (Ctij ijCH THF 65
    Phenyl magnesium chloride - OS with HO, Ethyl ester 35
    2-Furylmagnesium bromide-COSCH (CH,) Ethyl ester 25
    2-Furylmagnesium iodide, (CH), SC THF 65
    2-Thienyl magnesium iodide —CON {Cj H5) ethyl ester 35
    3-Thienyl magnesium bromide -CON (CH) -C Kg Ethyl ester 25
    Phenylmagnesium iodide - SOSNL-ethyl ester 35
    2-Furylmagnesium bromide-COCHjCH (CH) - ethyl ester25
    2-Furilmagnesium bromide-COCHjTGF40
    2-Furilmagnesium bromide - 65
    2-Furylmagnesium bromide-C5CH (CH), CH "Ethyl ester 35
    84791910
    .Table continuation
    CHj
    )
    II
    NH ..
    And
    NH;
    权利要求:
    Claims (3)
    [1]
    Claim
    1. The method of obtaining derivatives
    [2]
    2- (4-aroylpiperazinyl-1) -4-amino-6,7-dimethoxyquinazoline of the general formula D
    L i j > - Η * ’ 0 Rhi where is furyl, phenyl or thienyl, different I am that. '
    in order to simplify the process, a mole of the compound of the general formula II • chng where Rj is a cyano group, a C / O / Y group C / = NH / Y, where Y is —OR ,,, s SR a or NR A R 5 , where RJ, - C <-C A -alkyl or phenyl, and H ^ and R5 are the same
    35 1 J or various C 1 -C l- alkyl or phenyl are reacted with 1-3 moles of the compound of general formula III
    40 R 1 M 'where R., has the indicated meanings, and M is lithium, sodium or MDX and where X is chlorine, bromine or iodine in absolute. organic solvent at a temperature from -80 to + 65 ° С followed by 45 hydrolysis of the reaction mixture.
    2. The method of pop. 1, characterized in that the process is carried out at a temperature of from -60 to -20 C.
    [3]
    3. The method according to PP. 1 and 2, about t l and -
    50, the process being carried out using equimolar amounts of reagents.
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    同族专利:
    公开号 | 公开日
    MY8100266A|1981-12-31|
    DE2740331C3|1981-03-12|
    NL7709736A|1978-03-22|
    GR69792B|1982-07-07|
    SE435381B|1984-09-24|
    IE45966B1|1983-01-12|
    PT67006A|1977-10-01|
    PL200710A1|1978-05-22|
    RO73051A|1981-09-24|
    AU500908B2|1979-06-07|
    ES462146A1|1978-06-16|
    GB1543668A|1979-04-04|
    AR213659A1|1979-02-28|
    ATA636877A|1979-12-15|
    AT357542B|1980-07-10|
    NL189132C|1993-01-18|
    CA1068699A|1979-12-25|
    BG28054A3|1980-02-25|
    HK31181A|1981-07-10|
    AU2822177A|1979-03-01|
    FI772629A|1978-03-21|
    DK143340B|1981-08-10|
    PL105830B1|1979-11-30|
    NO147423C|1983-04-06|
    DE2740331B2|1980-06-19|
    YU39155B|1984-06-30|
    FR2364918B1|1981-11-20|
    DE2740331A1|1978-03-23|
    PT67006B|1979-02-12|
    JPS5337676A|1978-04-06|
    HU180041B|1983-01-28|
    NO773073L|1978-03-21|
    LU78149A1|1979-05-25|
    US4062844A|1977-12-13|
    IE45966L|1978-03-20|
    CS203172B2|1981-02-27|
    BE858844A|1978-03-20|
    CH632507A5|1982-10-15|
    SE7708942L|1978-03-21|
    NO147423B|1982-12-27|
    YU209677A|1982-06-30|
    DD132661A5|1978-10-18|
    NL189132B|1992-08-17|
    FI66610C|1984-11-12|
    DK143340C|1981-12-14|
    FI66610B|1984-07-31|
    FR2364918A1|1978-04-14|
    DK395877A|1978-03-21|
    ZA775098B|1978-07-26|
    引用文献:
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    US3511836A|1967-12-13|1970-05-12|Pfizer & Co C|2,4,6,7-tetra substituted quinazolines|
    US3935213A|1973-12-05|1976-01-27|Pfizer Inc.|Process for hypotensive 4-amino-2- quinazoline derivatives|EP0022481A1|1979-06-21|1981-01-21|Mitsubishi Yuka Pharmaceutical Co., Ltd.|5,6-Alkylenepyrimidine derivatives, processes for preparing the same and pharmaceutical compositions|
    US4607034A|1979-10-29|1986-08-19|Mitsubishi Yuka Pharmaceutical Co., Ltd.|Quinazoline derivatives and pharmaceutical composition thereof|
    JPS6330910B2|1980-11-26|1988-06-21|Sankyo Co|
    FI70411C|1980-12-29|1986-09-19|Pfizer|FORM OF ANTHYPERTENSIVE 4-AMINO-6,7-DIMETOXY-2-PIPERAZINOQUINAZOLE DERIVATIVES|
    US4625012A|1985-08-26|1986-11-25|Essex Specialty Products, Inc.|Moisture curable polyurethane polymers|
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    GB9708917D0|1997-05-01|1997-06-25|Pfizer Ltd|Compounds useful in therapy|
    US6313294B1|1998-02-04|2001-11-06|Development Center For Biotechnology|Process for preparing amides|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/724,707|US4062844A|1976-09-20|1976-09-20|Process for preparing hypotensive 2--amino-6,7-dimethoxyquinazolines|
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