• 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:
    6-Amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine of the formula …<IMAGE>… is prepared by a process in which 2-iminopyrimidine derivatives containing [an] acyl and/or acyloxy group(s), of the formula …<IMAGE>… in which… R1 represents a hydrogen atom or a radical of the formula …<IMAGE>… in which formula… R denotes an alkyl radical or an aryl radical optionally substituted by a halogen atom,… R2 represents a hydroxyl group or a radical of the general formula …<IMAGE>… in which formula… R has the above meanings,… and… X represents a chlorine or bromine atom or an optionally substituted arylsulphonyloxy radical,… with the further proviso that,… in the case in which… R1 represents a hydrogen atom,… R2 is different from a hydroxyl group,… are reacted with piperidine and the 2-imino-4-piperidinopyrimidine derivatives containing [an] acyl and/or acyloxy group(s) obtained of the formula …<IMAGE>… in which… R1 and R2 have the above meanings… are hydrolysed. …<??>6-Amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine has a hypotensive action.
    公开号:SU1498390A3
    申请号:SU874202922
    申请日:1987-07-10
    公开日:1989-07-30
    发明作者:Ведреш Андраш；Сантаи Чаба；Штефко Бела；Крайдль Янош；Немеш Андраш；Блашко Габор；Богш Эрик；Мате Денеш；Хегедюш Иштван；Суховски Андриенн；Мештер Тамаш
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    IR spectrum, cm-: 34SO; 3420; CSA 3370; 3260; 12 SO; 1210; 1165; 1020.
     m NMR (ZlllCO-d): 1.52;
    3, to; 5.36; 6.8D.
     C-NMR (IC CO-d 4 +)): 156.6; 153.7; 152.1; 74.1; 45.7; 25.7; 24.7.
    Example 2. Preparation of 6-amides of o- 1, 2-dihydro-1-hydroxy-2-imino-4-g1 nperidinopyrimidine.
    Under stirring, 2.02 g (Schmmol 6-lmino-1,2-DIHYDRO-1-apethoxy-2-imi-iio-4-chloropyrimidium) is added at room temperature to 8 ml of nineridine. The mixture is stirred for 2 hours at At room temperature, the piperidine is distilled off in vacuo. OcTaioK is dissolved in a mixture of 20 ml of ethanol and 10 ml of 1N aqueous sodium hydroxide solution and boiled for 1 min for 30 minutes, then concentrated in vacuo. The residue is dissolved in 20 NUI water , the crystals are filtered, washed with water and dried to give 1.74 g (86%) of the title compound, which when mixed with the product obtained m in Example 1, shows s depression TE fflepatypy mp.
    Example 3. Preparation of 6-amio 1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine.
    To a mixture of 10 ml of chloroform and 2 ml of piperidine, 0.3 g (0.88 mmol) of 6-amino-1.2-dihydro-1-acetoxy-2-imino-4-p-toluenesulfonyloxy-pyrimidine was added with peremoshivat. The mixture was boiled under stirring for 30 minutes and concentrated in vacuo. Add 5 MP of ethanol and 1 ml of 1 and. water of sodium hydroxide solution. The mixture is then left for 1 hour at room temperature, after which the k) H-center in vacuo. The residue is mixed with 10 ml of water, kristaples are clarified, washed with water and dried. 0.14 g (75%) of the title compound is obtained, which, when mixed with the product obtained in Example 1, does not show a melting point depression.
    Example 4: By; 6-awino 1,2-dihydro-1-hydroxy-2-imino-4-piperidine-pyrimidine metabolism.
    To a mixture of 10 MJ1 of chloroform and 2 km of piperidine was added n1T under a transfer of 0.49 g (2 mm.hr) b-a.c; amido-1, dihydro-1-a1 etoxy-2- and 11 Io-4-x. G1C) 1; 11rimidine. The mixture is then boiled for 30 minutes and concentrated in vacuo Residue) (tn1. | Rd in a mixture of 10 UI ethanol, i p 3 ml 1 and heated aqueous hydroxide solution, then left for 1 h at room temperature and again concentrated in vacuo. The stack is dissolved in 10 ml of water, the crystals (filtered, washed with (. yes and dried). 0.34 g (80%) of the title compound is obtained, q.1 (mix with product , by .. in example 1, does not show depression of i-eMriepaTypbi plan.
    Example 5. Preparation of 6-amino-I, 2-dihydro-1 -11Ks: and-2-imino-4-11-pyridicypyrimidine.
    To 760 ml of anhydrous piperidine, add 1% to 5 ° C and, with stirring, 76 g (0.2 mol) of b-acetamido-1,2-dihydro-1 -am I o to Si-2-no-4-cc Toluene sulfonyloxypyrimidine. Stirring is continued at this temperature, after 2 hours, let the temperature rise: - to room temperature and stirring is continued for another 24 hours. Piperidine is distilled off in vacuum and residue (500 ml of water is added. The mixture is left to cool). until the next day, filter through the filter thoroughly, rinse it with water, and carefully extinguish it.The substance left on the filter is suspended three times in 50 NUT chafir, washed and then dried. 23.0 g (55%) of the compound indicated in lariDJioBKe is obtained.
    75 ml of a 10% sodium hydroxide solution are added to the mother liquor, then it is concentrated. 200 ml of water are added to the residue and the pH of the solution is adjusted to 7. The solution is left in the fridge until the next day, then the resulting crystalline gel is filtered off, dried with M1.1 and water and dried. An additional 8.9 g (21%) of the title compound and the title compound are obtained. Only 31.9 g (76%) of the title compound are obtained, which, when mixed with the product obtained in Example 1, does not show a depression in the melting point.
    Example 6. Preparation of 6-apet-amido-1,2-dihydro-1-hydroxy-2-imino-4-piperine-schinepyrimidine.
     mixtures of 20 mi of chloroform and 5 mi of lipididium add 1.01 g (5 mmol)
    6-s Yu-2-acetamido-h-chloro 1 primidii- 1-g) Ksida. The mixture is boiled with stirring for 30 NUUI. The resulting solution is cooled and ekstcht prht-t three times 10 m; 1 n. r-o; 1 psy acid, then triple mr | MUP ayut 10 mch oxen. The chloroform phase is dried with sodium sulfate and concentrated in vacuo. The residue was mixed with T in 50 ml of ether, the crystals were filtered off, washed with ether and dried. Obtain 0.86 g (69%) of cum;, —nogo in the title compound) 1i, T. square 204-205 S.
    IR spectrum (KBG), cm-: 1670; 1600 1570; 1500
    UV spectrum (Eton), im-, 245; 325.
    NMR spectrum (CBC1E + CD, OD): 1.63 (w, 6H); 2.30 (s, 311); 3.57 (t, 61); 7.04 (s, 111).
    Example 7. Preparation of 6-apet-amido-1,2-dig1-p-1-apethoxy-2-imino 4-11 hyperidino-11 irimidine.
    A mixture of 20 ml of acetonitrile, 0.5% of piperidine and 0.5 g- (0.0013 mol) of 6-acetamido-1,2-dihydro-1-acetoxy-2-imino-4- (n-toluenesulfonic) pyrimidine and stirred at room temperature for 3 hours. The mixture is then concentrated under reduced
    pressure and 30 ml of ether are added to the residue. The resulting crystalline white matter is filtered off, washed first with ether, then with water and dried. 0.24 g (64%) of the title compound is obtained. M.p. 217-218 ° C.
    IR spectrum (KVg), cm-: 1710; 1680 1630; 1530,
    UV spectrum (Eton), im: 241; 293;
    323.
    NMR spectrum (CDClI + TFA-d): 1.76 (n, 6K); 2.43 (S, 3N); 2.57 (S, 3N); 3.80 (gp, 4H); 7.55 {s, 111).
    Example 8. Preparation of 6-amino 1,2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine.
    In a mixture of 10 ml of ethanol and 4 ml of 1N. a solution of sodium hydroxide dissolved 0.5 g obtained in Example 6 with 6-acetamido-1,2-d1p-idro-1-hydroxy-2-but-4-piperidinopirpmidine. The solution is boiled for 30 minutes, then concentrated in vacuo and the residue is diluted with 10 MJT of water. The crystals are filtered off, washed with water, then dried. This gives 0.35 g (85%) of the title compound, which, when mixed with: P1n aukg, semi590
    The sample in Example I does not show a melting point depression.
    Example 9. Preparation of 6-Nanoeno 1, 2-dihydro-1-hydroxy-2-imino-4-g1Iperi-: iloirimidine.
    In a mixture of 20 NUI ethanol and 5 ml of 1N. a solution of sodium hydroxide is dissolved 1.0 g (3.4 mmol) of 6-acetamido-1,2 dihydro-1-acetoxy-2-imino-4-piperidinopyrimidine, G7 obtained according to example 7. The solution is boiled for 30 min, then concentrated in vacuo. The residue is dissolved in 10 ml of water, the crystals are filtered off, washed with a node and dried. 0.54 g (76%) of the title compound is obtained, which, when mixed with the product obtained according to Example 1, does not show a melting point depression.
    Example 10. Preparation of 6-amino-1, 2-dihydro-1-hydroxy-2 -imino-4-pyperidino lire and a dyne.
    2.0 g (0.0093 mol) of 6-amino-1,2-dihydro-1-procionyloxy-2-imino-4-chloropyrimidine and 6 mp of piperidine are boiled for 30 minutes and then 10 ml of 1 : aqueous solution of sodium hydroxide and 5 ml. After boiling for more than 30 minutes, the solution is clarified with animal charcoal and concentrated in vacuo to half the volume. The crystals are left to stand for 1 hour, ptfm and 1 are watered and washed with water. 1.36 g (83%) of the title compound are obtained.
    Example 11. Preparation of 6-amine-HO-2-IMINO-1-hydroxy-4-piperidino-1,2-dihydropyrimidine.
    In a round-bottomed flask equipped with a stirrer and a thermometer, while stirring and cooling with an ice-water mixture, 40.8 g (0.1 mol) of the unreadable b-acetamido-1-acetoxy-2-imino-4-mesitylenesulfonyloxy-1, 2-dihydropyrimidine, 380 ul (327 g, 3.84 mol) piperidine. After heating the reaction mixture to room temperature1 (the temperature of stirring is continued until the starting product is detected (duration 24 hours). Then hp: peridine is removed under vacuum at 60 ° C. 250 ml of water is added to the residue. The separated iiocjie cooling is filtered and washed The water is then dried on a filter. From the os-Gllegos on the solid filter is washed with a small amount of toluene, the amide of a cel. p foxyl., the formed clump of the by-product. By overproduction of a toluene solution, 3.9 g (14 g) are obtained. , 5%) mesityleasulfonylpip - r-. Uina. The substance remaining on the filter (13 g) represents the target product.
    The mother liquor is further processed. 38 ml of a 10% aqueous solution of sodium hydroxide are added to it and evaporated in vacuo to an oily state (the residual piperidine is removed. Then add 100 ml of water and adjust the pH of the solution to 7 by adding 10%). hydrochloric acid. After long-term cooling, the separated material is filtered and washed with water. An additional 5.3 g of substance is obtained. A total of 17.9 g (85.5%) of 6-amylo-2-imino-1-hydroxy-4 is obtained. piperidino-1, 2-dihydropyrimidine, mp 240-260 C, (decomp.).
    The chromatographic and spectroscopic properties of the product coincide with the properties given in the examples.
    As a result of the implementation of the proposed method, the yield rises to 70-80% (from 55-65% by a known method), while REACH1 simplifies the process by performing it under mild conditions using easy-to-use starting materials.
    权利要求:
    Claims (3)
    [1]
    1. A method for preparing a 6-amino-1,2-dihydro-1-hydroxy-2-imino-4-piperidino-pyrimidine of the formula
    40
    HE
    H2N
    t T
    about
    45
    Editor M.Petrova
    where R, and K.2 have the indicated meanings, if necessary, isolate and hydrolyze.
    [2]
    2. Method POP1, characterized in that an excess of piperidine is used as a solvent.
    [3]
    3. A process according to claim 1, characterized in that a solvent selected from ethanol, acetonitrile or chloroform is used as the solvent of the solvent.
    Compiled by V. Volkov
    TehredM.LidykKorrektor M.Pojo
    N
    50
    by reacting the pro- duction (; 4th of 6-amino-1,2-dihydro-1-hydroxy-2-imino-pyrimidine and piperidine in an organic solvent when heated, about that and with The aim is to simplify the process and increase the yield of the target product. As the pyrimidine derivative, irimidine of general formula
    D.
    Ri-UHv N, II t
    one
    NH
    where k
    Where
    R, R
    X
    - hydrogen or a group of the general formula
    —CO — R, where R is —C, —C — alkyl;
    a hydroxyl or group of the general formula -0-CO-R has the indicated meanings; chlorine, bromine, p-toluene or mesitylenesulfonyloxy, provided that if R is hydrogen, then RJ has values other than hydroxyl, the resulting derivative of the general formula
    Rz
    R cH
     4463/58
    Circulation 352
    VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113035, Moscow, Zh-35, Raushsk nab. 4/5
    Subscription
    类似技术:
    公开号 | 公开日 | 专利标题
    US4940793A|1990-07-10|Pharmacologically active piperazino derivatives
    US4599408A|1986-07-08|Perylene-3,4,9,10-tetracarboxylic acid monoanhydride monoimides
    US4716243A|1987-12-29|α-|-aminomethylene-β-formylaminopropionitrile
    SU1498390A3|1989-07-30|Method of producing 6-amino-1,2-dihydro-1-oxy-2-imino-4-piperidinpyrimedine
    US5162584A|1992-11-10|Fluorobenzene derivatives
    US4062854A|1977-12-13|Process for preparing N-substituted-8,13-dioxodinaphtho-(2,1-b; 2&#39;,3&#39;-di-fluran-6-carboxamides
    CS202069B2|1980-12-31|Method of preparing 2-/4-substituted piperazine-1-yl/-4-amino-6,7-dimethoxyquinazolines
    US4182880A|1980-01-08|1,8-Naphthyridine compounds and process for preparing the same
    US4985563A|1991-01-15|Process for the preparation of 6-piperidino-2,4-diamino pyrimidine-3-oxide
    JP2678758B2|1997-11-17|Novel propane derivative
    US4304918A|1981-12-08|Process for preparing benzoxazolyl propionic acid derivatives
    JP2578797B2|1997-02-05|Method for producing N- | formamides
    EP0047674B1|1984-02-29|Novel process for preparing isoindolin derivatives
    US4847366A|1989-07-11|5-fluorouridine derivative and preparation of the same
    JP3042123B2|2000-05-15|Method for producing N-cyanoacetamidine derivative
    RU2425047C1|2011-07-27|Method of producing substituted 4-hydroxy-3-oxo-3,4-dihydro-2h-1,4-benzoxazine-6,7-dicarbonitriles based on 4-bromo-5-nitrophthalonitrile
    US6084134A|2000-07-04|Process for preparing 9-anthracenecarbaldehyes
    US5399682A|1995-03-21|Process for preparing 2,3&#39;-O-cyclocytidine
    SU1313856A1|1987-05-30|Method for producing derivatives of cis- or trans-diaminodibenzoyl-dibenzo-18-crown-6
    US2748120A|1956-05-29|2-amino-6-aryl-5, 6-dihydro-4-hydroxy-pyrimidines
    SU598900A1|1978-03-25|Method of obtaining derivatives of 8-azaxanthine
    SU902664A3|1982-01-30|Method of preparing derivatives of 2-amino- or 4-amino-5-alkthiopyrimidines
    RU2065440C1|1996-08-20|Method for production of derivatives of 3-phenylthioanthra[1,9-cd]-isoxazol-6-on
    KR890002425B1|1989-07-03|Process for synthesis of 1-|-3-methyl-4-difluoromethyl-2-1,2,4-triazoline)-5-one derivative
    SU550829A1|1992-05-23|Derivatives of dipyrimido [|]-| thiazines and method of obtaining the same
    同族专利:
    公开号 | 公开日
    PL266755A1|1988-06-23|
    CN1020724C|1993-05-19|
    DD263989A5|1989-01-18|
    JPS6323872A|1988-02-01|
    KR920002127B1|1992-03-12|
    FI873050A0|1987-07-10|
    FI873050A|1988-01-11|
    PL151850B1|1990-10-31|
    IL83155A|1991-09-16|
    CA1297479C|1992-03-17|
    HUT44531A|1988-03-28|
    US4960888A|1990-10-02|
    ZA875050B|1988-03-30|
    CS271474B2|1990-10-12|
    DK361387A|1988-01-11|
    KR880001632A|1988-04-25|
    CN87104694A|1988-02-03|
    HU196067B|1988-09-28|
    IL83155D0|1987-12-31|
    CS527587A2|1990-02-12|
    EP0252515A1|1988-01-13|
    DK361387D0|1987-07-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3461461A|1965-11-01|1969-08-12|Upjohn Co|6-amino-4--1,2-dihydro-1-hydroxy-2-iminopyrimidines|
    US3644364A|1970-03-31|1972-02-22|Upjohn Co|Compounds and process|
    US3998827A|1971-04-07|1976-12-21|The Upjohn Company|6-amino-4--1,2-dihydro-1-hydroxy-2-iminopyrimidines|
    HU177601B|1978-10-27|1981-11-28|Egyt Gyogyszervegyeszeti Gyar|New process for preparing 6-piperidino-2,4-diamino-pyrimidine-3-oxide|
    CA1179344A|1981-07-15|1984-12-11|Jean-Claude Muller|Process for the preparation of 6-¬3,6-dihydro-1- pyridyl| pyrimidine-3-oxides|HU196061B|1986-07-10|1988-09-28|Richter Gedeon Vegyeszet|Process for production of pirimidine-derivatives|
    US4959475A|1989-01-04|1990-09-25|Lonza Ltd.|Process for the production of 2,4-diamino-6-piperidinyl-pyrimidine-3-N-oxide|
    CN107235919B|2017-06-22|2020-05-12|安徽拜善晟制药有限公司|Process for synthesizing minoxidil|
    CN107987027A|2018-01-18|2018-05-04|天津药物研究院药业有限责任公司|A kind of minoxidil crystal, preparation method and the pharmaceutical composition containing this crystal|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU862855A|HU196067B|1986-07-10|1986-07-10|Process for production of 6-amin-1,2-dihydro-1-hydroxi-2-imino-4-piperidin-piramidin|LV930052A| LV5251A3|1986-07-10|1993-01-18|Extraction of 6-amino-1,2-dihydro-1-oxo-2-imino-4-piperidinopyrimidine|
    LTRP855A| LT2200B|1986-07-10|1993-08-13|6-AMINO-1,2-DIHIDRO-1-OKSI-2-IMIN-4-PIPERIDIN OPIRIMIDINE RECEIVING BUDGET|
    [返回顶部]