CN1115338C - 4－[(2′,5′－二氨基－6′－卤代嘧啶－4′－基)氨基]－环戊－2－烯基甲醇的制备方法 - Google Patents

4－[(2′,5′－二氨基－6′－卤代嘧啶－4′－基)氨基]－环戊－2－烯基甲醇的制备方法 Download PDF

Info

Publication number
CN1115338C
CN1115338C CN99812845A CN99812845A CN1115338C CN 1115338 C CN1115338 C CN 1115338C CN 99812845 A CN99812845 A CN 99812845A CN 99812845 A CN99812845 A CN 99812845A CN 1115338 C CN1115338 C CN 1115338C
Authority
CN
China
Prior art keywords
diamino
amino
methyl alcohol
general formula
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN99812845A
Other languages
English (en)
Other versions
CN1325386A (zh
Inventor
W·布里登
E·塞卡利
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lonza AG
Original Assignee
Lonza AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lonza AG filed Critical Lonza AG
Publication of CN1325386A publication Critical patent/CN1325386A/zh
Application granted granted Critical
Publication of CN1115338C publication Critical patent/CN1115338C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

本发明涉及通式(I)表示的4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的新颖制备方法，式中X表示卤原子。按照本发明方法，在碱的存在下和在极性质子溶剂中使通式(II)的2，5-二氨基-4，6-卤代嘧啶(式中X的定义同上)与式(III)的4-氨基环戊-2-烯基甲醇或其盐反应。

Description

4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]- 环戊-2-烯基甲醇的制备方法
说明
本发明涉及通式I的4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的新制备方法
4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇是制备抗病毒核苷酸衍生物的重要中间体(WO91/01310)。
以4-乙酰氨基环戊-2-烯基甲醇为原料，将二异丙基乙基胺用作碱，通过在丁醇中与2-氨基-4，6-二氯嘧啶反应合成4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的三步法是已知的。在该方法中，先形成[(2’-氨基-6’-氯嘧啶-4’-基)氨基]-环戊-2-烯基甲醇，然后在一个后续步骤中通过重氮化转化成相应的胺，再水解成最终产物(J.Chem.Soc.Perkin.Trans.，1，1992)。该方法的缺点是成本太高，而所需最终产物的收率仅为一般。
本发明的任务是提供一种4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的一步制备方法。该方法的成本较低，且能高收率地得到所需的最终产物。
这个任务由权利要求1所述的方法加以解决。
令人惊奇地发现，当用通式II的2，5-二氨基-4，6-二卤代嘧啶代替2-氨基-4，6-二氯嘧啶用作原料，且在碱的存在下和在极性质子溶剂中使其与式III的4-氨基环戊-2-烯基甲醇或其盐反应时，可以低几倍的成本和高收率地得到所需的通式I最终产物。取代基X是指卤原子，如F、Cl、Br或I。
2，5-二氨基-4，6-二卤代嘧啶，如2，5-二氨基-4，6-二氯嘧啶可根据EP-A-0684326所述的方法进行制备。
外消旋的和光学活性的化合物如(1R，4S)-、(1S，4R)-、(1R，4R)-或(1S，4S)-4-氨基环戊-2-烯基甲醇可用作4-氨基环戊-2-烯基甲醇。其合适的盐是酸加成盐，特别是氢卤酸盐，如盐酸盐或氢溴酸盐。4-氨基环戊-2-烯基甲醇，特别是(1R，4S)-或(1S，4R)-对映体可按WO97/45529所述的方法制备。
该反应宜在碱金属或碱土金属碳酸盐、碱金属或碱土金属碳酸氢盐或氮碱(如叔胺)(均用作碱)的存在下进行。碳酸钠、碳酸钾、碳酸氢钠或碳酸氢钾可用作碱金属碳酸盐或碱金属碳酸氢盐。碳酸钙、碳酸镁、碳酸氢钙可用作碱金属碳酸盐或碱金属碳酸氢盐。三乙胺和二异丙基乙基胺可适用作叔胺。该反应较好地在碱金属碳酸氢盐(如碳酸氢钠)或叔胺(二异丙基乙基胺)的存在下进行。
相对于2，5-二氨基-4，6-二卤代嘧啶，上述的碱宜过量使用，较好每摩尔2，5-二氨基-4，6-二卤代嘧啶使用1-4摩尔的碱。
适用作极性质子溶剂的特别是C1-4烷醇，如甲醇、乙醇、丙醇及其异构体和丁醇及其异构体。
该反应宜在20℃至相应溶剂的回流温度之间的一个温度进行，较好在50℃至回流温度之间的一个温度进行。宜等摩尔地使用4-氨基环戊-2-烯基甲醇和2，5-二氨基-4，6-二卤代嘧啶。
在2-20小时的常规反应时间后，可以用常规的后处理方法得到式I的最终产物，较好是(1S，4R)-4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇。
实施例
实施例1
在碳酸氢钠的存在下制备4-[(2’，5’-二氨基-6’-氯嘧啶-4’-基)氨基]-环戊-2-烯基甲醇
在一个干燥的反应器中加入(1S，4R)-4-氨基环戊-2-烯基甲醇盐酸盐(0.14摩尔，23.25克)、乙醇(3摩尔，138.12克、176毫升)、2，5-二氨基-4，6-二氯嘧啶(0.14摩尔，25克)和碳酸氢钠(0.34摩尔，28.68克)。在回流温度(约80℃)将该混合物加热16小时。然后用薄层色谱法(TLC)检测转化率。13/1二氯甲烷：甲醇用作展开剂。将该反应混合物冷却至室温，搅拌45分钟。过滤除去盐，用乙醇(0.86摩尔，39.5克，50毫升)将滤饼洗涤两次。
通过真空蒸馏除去2/3有机相后，滴加己烷(150毫升)。将该悬浮液冷却至10℃以下。过滤后在50℃真空干燥。
得到21.5克(0.08摩尔)产物，相当于60％的收率。
实施例2
在二异丙基乙基胺的存在下制备4-[(2’，5’-二氨基-6’-氯嘧啶-4’-基)氨基]-环戊-2-烯基甲醇
在一个干燥的反应器中加入(1S，4R)-4-氨基环戊-2-烯基甲醇盐酸盐(0.14摩尔，23.18克)、丁醇(1.26摩尔，93.39克、115.3毫升)、2，5-二氨基-4，6-二氯嘧啶(0.14摩尔，25.67克)和二异丙基乙基胺(0.29摩尔，37.09克，49.99毫升)。在回流温度(约115℃)将该混合物加热过夜。然后用薄层色谱法(TLC)检测转化率。13/1二氯甲烷：甲醇用作展开剂。将该反应混合物冷却至室温。然后加入水，最后用乙酸乙酯萃取两次。
有机相用水洗涤两次，然后用C盐(Celite)过滤有机相。通过真空蒸馏除去2/3有机相后，滴加己烷。将该悬浮液冷却至10℃以下。过滤后在50℃真空干燥。
得到21.47克(0.08摩尔)产物，相当于60％的收率。

Claims (3)

1.通式I表示的4-[(2’，5’-二氨基-6’-卤代嘧啶-4’-基)氨基]-环戊-2-烯基甲醇的制备方法，式中X表示卤原子，其特征在于在碱金属或碱土金属碳酸盐的存在下或在碱金属或碱土金属碳酸氢盐的存在下和在极性质子溶剂中使通式II的2，5-二氨基-4，6-卤代嘧啶
Figure C9981284500022
式中X的定义同上，与式III的4-氨基环戊-2-烯基甲醇
Figure C9981284500023
或其盐反应，产生通式I的最终产物。
2.如权利要求1所述的方法，其特征在于C1-4链烷醇用作极性质子溶剂。
3.如权利要求1或2所述的方法，其特征在于反应在20℃至相应溶剂的回流温度之间的一个温度下进行。
CN99812845A 1998-10-30 1999-10-29 4－[(2′,5′－二氨基－6′－卤代嘧啶－4′－基)氨基]－环戊－2－烯基甲醇的制备方法 Expired - Fee Related CN1115338C (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP98120529 1998-10-30
EP98120529.7 1998-10-30
US14610599P 1999-07-29 1999-07-29
US60/146,105 1999-07-29

Publications (2)

Publication Number Publication Date
CN1325386A CN1325386A (zh) 2001-12-05
CN1115338C true CN1115338C (zh) 2003-07-23

Family

ID=56289961

Family Applications (1)

Application Number Title Priority Date Filing Date
CN99812845A Expired - Fee Related CN1115338C (zh) 1998-10-30 1999-10-29 4－[(2′,5′－二氨基－6′－卤代嘧啶－4′－基)氨基]－环戊－2－烯基甲醇的制备方法

Country Status (14)

Country Link
EP (1) EP1124805B1 (zh)
JP (1) JP4457496B2 (zh)
CN (1) CN1115338C (zh)
AT (1) ATE240945T1 (zh)
AU (1) AU1158000A (zh)
CA (1) CA2348374C (zh)
CZ (1) CZ300155B6 (zh)
DK (1) DK1124805T3 (zh)
ES (1) ES2200594T3 (zh)
HU (1) HU227559B1 (zh)
IL (1) IL142760A (zh)
PL (1) PL198180B1 (zh)
SK (1) SK285271B6 (zh)
WO (1) WO2000026193A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626745A (zh) * 2013-12-04 2014-03-12 青岛黄海制药有限责任公司 一种替卡格雷中间体的制备方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100606625B1 (ko) 1998-10-30 2006-07-28 론자 아게 4-[(2',5'-디아미노-6'-할로피리미딘-4'-일)아미노]-시클로펜트-2-에닐메탄올의 제조 방법
MX2009007200A (es) 2007-01-10 2009-07-15 Angeletti P Ist Richerche Bio Indazoles sustituidos con amida como inhibidores de poli(adp-ribosa)polimerasa (parp).
US8436185B2 (en) 2008-01-08 2013-05-07 Merck Sharp & Dohme Corp. Pharmaceutically acceptable salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
YU47791B (sr) * 1988-01-20 1996-01-09 Regents Of The University Of Minnesota Postupak za dobijanje dideoksihidrokar-bocikličnih nukleozida
GB8916698D0 (en) * 1989-07-21 1989-09-06 Beecham Group Plc Novel process
MY104575A (en) * 1989-12-22 1994-04-30 The Wellcome Foundation Ltd Therapeutic nucleosides.
CA2145928C (en) * 1994-04-27 2007-10-09 Gerhard Stucky N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide, and a process for its preparation
IL127235A (en) * 1996-05-30 2003-04-10 Lonza Ag Process for the preparation of amino alcohols and derivatives thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626745A (zh) * 2013-12-04 2014-03-12 青岛黄海制药有限责任公司 一种替卡格雷中间体的制备方法
CN103626745B (zh) * 2013-12-04 2016-02-24 青岛黄海制药有限责任公司 一种替卡格雷中间体的制备方法

Also Published As

Publication number Publication date
WO2000026193A1 (de) 2000-05-11
JP4457496B2 (ja) 2010-04-28
SK5692001A3 (en) 2001-12-03
HUP0104045A3 (en) 2002-07-29
AU1158000A (en) 2000-05-22
HU227559B1 (en) 2011-08-29
PL198180B1 (pl) 2008-06-30
IL142760A (en) 2005-12-18
ATE240945T1 (de) 2003-06-15
CZ300155B6 (cs) 2009-02-25
IL142760A0 (en) 2002-03-10
CA2348374A1 (en) 2000-05-11
ES2200594T3 (es) 2004-03-01
CA2348374C (en) 2009-04-07
HUP0104045A2 (hu) 2002-05-29
EP1124805A1 (de) 2001-08-22
CZ20011486A3 (cs) 2001-10-17
CN1325386A (zh) 2001-12-05
SK285271B6 (sk) 2006-10-05
EP1124805B1 (de) 2003-05-21
PL347503A1 (en) 2002-04-08
JP2003500333A (ja) 2003-01-07
DK1124805T3 (da) 2003-09-15

Similar Documents

Publication Publication Date Title
AU2004245291B2 (en) Improved production of rosuvastatin calcium salt
EP1883639B1 (en) Preparation of famciclovir and other purine derivatives
CA2658953A1 (en) Chemical process for preparation of aromatic cyclopropane esters and amides
CN101861298B (zh) 甜菜碱的制备方法
WO2007000121A1 (en) A method for the production of the hemi-calcium salt of (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid
CA2188181C (en) Preparation of purines
KR101787159B1 (ko) 루비프로스톤의 제조 방법
DE602004010820D1 (de) Verfahren zur herstellung von 4-aryl-nicotinamidderivaten
CN1115338C (zh) 4－[(2′,5′－二氨基－6′－卤代嘧啶－4′－基)氨基]－环戊－2－烯基甲醇的制备方法
TWI294426B (en) Process for the preparation of ccr-2 antagonist
CN116218942A (zh) 一种非奈利酮关键中间体及成品的制备方法
CN1321975C (zh) 4－[(4－氧代－3－溴)丁基]苯甲酰－l－谷氨酸二乙酯及制备和应用
CN102796036A (zh) 一种阿托伐他汀钙的制备方法
JPH05286889A (ja) アリール酢酸及びそれらのアルカリ金属塩の製造方法
CN111909148A (zh) 一种吲哚嗪衍生物及其制备方法
AU4459000A (en) Process for preparing mkc-442
CN115677639B (zh) 一种四氢-3-氧代-2h-吡喃-4-羧酸甲酯中间体的制备方法
GB2229721A (en) Optically active compounds useful as chiral dopants or intermediates
KR100878035B1 (ko) 생체 촉매 효소를 이용한 선택적 가수분해방법
JP2003509517A (ja) メチレンビスホスホン酸および塩の調製方法
IE64393B1 (en) Process for the production of vinyl-gaba
CA2367971A1 (en) Synthesis of 3-amino-3-aryl propanoates
KR100606625B1 (ko) 4-[(2',5'-디아미노-6'-할로피리미딘-4'-일)아미노]-시클로펜트-2-에닐메탄올의 제조 방법
TW202309009A (zh) 製備黃嘌呤氧化酶抑制劑的方法
CS277196B6 (cs) Způsob přípravy disodné a didraselné soli kyseliny 1,1-cyklobutandikarboxylové

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20030723

Termination date: 20131029