CN106458898B - 哌啶-4-硫代酰胺的制备 - Google Patents

哌啶-4-硫代酰胺的制备 Download PDF

Info

Publication number
CN106458898B
CN106458898B CN201580030993.XA CN201580030993A CN106458898B CN 106458898 B CN106458898 B CN 106458898B CN 201580030993 A CN201580030993 A CN 201580030993A CN 106458898 B CN106458898 B CN 106458898B
Authority
CN
China
Prior art keywords
alcohol
solvent
reaction
piperidines
thioamides
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.)
Active
Application number
CN201580030993.XA
Other languages
English (en)
Other versions
CN106458898A (zh
Inventor
M·布鲁杰斯
M·J·福特
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.)
Bayer CropScience KK
Original Assignee
Bayer CropScience KK
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 Bayer CropScience KK filed Critical Bayer CropScience KK
Publication of CN106458898A publication Critical patent/CN106458898A/zh
Application granted granted Critical
Publication of CN106458898B publication Critical patent/CN106458898B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Environmental Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Medicinal Chemistry (AREA)
  • Dentistry (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明记载了一种制备哌啶‑4‑硫代酰胺的新方法。

Description

哌啶-4-硫代酰胺的制备
本发明涉及一种制备哌啶-4-硫代酰胺的新方法。
哌啶-4-硫代酰胺衍生物是活性药物和农业化学成分的重要前体(参见WO 2008/013622、WO 2011/072207和WO 2011/076699)。
WO 2008/013622和WO 2011/072207以及特别是WO 2011/146182、WO 2009/094407和US 2010/0240619中涉及的用于制备哌啶-4-硫代酰胺衍生物的方法均采用N-取代的4-氰基哌啶作为原料。然而，这些方法的缺点在于它们要么需要化学计量的碱(例如，二乙醇胺)、作为溶剂的DMF、干冰冷凝器要么需要含水后处理(大量废弃物)。还认为所述方法需要大大过量的硫化氢。
在特别是WO 2011/072207和 zhurnal1983,36,610-614中，列举二乙胺、吡啶和三乙胺作为替代的碱，同样地，硫化氢也可以其盐(硫化钠、硫氢化钠等)之一的形式来使用。第一篇文献在实验部分所记载的实施例反应中涉及长的反应时间(72小时)。
可利用的另一个硫化氢来源——如例如WO 2013/127808在取代的哌啶-4-硫代酰胺的合成中所记载——为硫化铵(仅作为水溶液是稳定的)。该文献再次记载了相对长的反应时间(24小时)，此外，在此还需要DMF反应溶液的含水后处理，以及需要通过后续色谱纯化来萃取产物。
文献US2010/197703记载了甲醇和四氢呋喃的混合物替代广泛使用的二甲基甲酰胺。在此，同样使用了含水硫化铵。然而，此处也遇到了上述缺点，另一问题为仅25％的非常低的收率。
合成哌啶-4-硫代酰胺(I)的唯一文献记载——关于这一点，参见J.Org.Chem.1957,22,984-986——包括首先进料30％的氨甲醇溶液和4-氰基哌啶，以及随后引入硫化氢直至完全饱和。然而，该方法也具有缺点，例如额外地使用碱(氨)以及48小时的长的反应时间。
鉴于上文所描述的现有技术，本发明解决的问题是提供一种没有上述缺点并因此提供高收率制备哌啶-4-硫代酰胺(I)的路线的方法。
现已发现，上述问题通过一种制备式(I)的哌啶-4-硫代酰胺的方法而解决，
特征在于使式(II)的4-氰基哌啶
与硫化氢(III)在溶剂的存在下反应，得到式(I)的化合物。
令人惊讶的是，在不加入另外的碱的情况下，在多种溶剂中得到了高收率和高纯度的式(I)的哌啶-4-硫代酰胺，本发明的方法因此克服了现有技术制备方法的上述缺点。该反应优选在密封的反应容器中进行。
方法说明
方案1：
哌啶-4-硫代酰胺(I)通过使4-氰基哌啶(II)与硫化氢(III)在合适的溶剂中，在≥0℃的温度下，在密封的反应容器中反应而制备。
合适的溶剂为选自如下的溶剂：醚(例如四氢呋喃、乙醚、甲基叔丁基醚)、脂肪族和芳香族化合物(例如庚烷、环己烷、苯、甲苯或二甲苯)、醇(例如甲醇、乙醇、异丙醇、正丁醇、异丁醇、叔丁醇、环戊醇、环己醇)、酰胺(例如二甲基甲酰胺、二甲基乙酰胺)、水及其混合物。其中，优选醇，包括伯醇和仲醇以及叔醇。特别优选包含1至10个碳原子的醇。非常特别优选为甲醇、乙醇、异丙醇、正丁醇、异丁醇、环己醇、环戊醇。特别优选正丁醇。进一步特别优选甲醇。进一步特别优选乙醇。进一步特别优选异丙醇。进一步特别优选异丁醇。进一步特别优选环己醇。进一步特别优选环戊醇。
将硫化氢(III)以气体形式引入至反应容器中，监控反应容器内压并调节至0-10巴(相对压力)的压力范围。通常，根据在所使用的具体溶剂中的溶解度，硫化氢(III)需要使用至少等摩尔量或过量(1.00-10当量，优选1.1-5当量，更优选1.5-3当量)，基于式(II)的化合物计。
本发明的方法通常在0-200℃，优选20-100℃，更优选40-80℃的范围内进行。
反应时间通常为30分钟至24小时，优选2至12小时。
式(I)的化合物的后处理和分离通常包括将反应混合物冷却至-20℃至25℃的温度范围，从而使式(I)的化合物沉降为沉淀物。释放残余超压，将沉淀物滤出，用所使用的具体溶剂洗涤并干燥。
用酸处理由此得到的式(I)的化合物，提供相应的盐。
制备哌啶-4-硫代酰胺的实施例
在250ml的压力反应器中，将100ml的正丁醇和25g的氰基哌啶(220mmol)加热至60℃，然后将硫化氢引入至反应器中以保持4巴的恒定超压(反应期间将总共17.5g(513mmol)硫化氢引入到反应器中)。6小时后，不再引入硫化氢，并将反应混合物在60℃下再搅拌6小时，然后历经2小时冷却至10℃。通过氯漂白洗涤器释放过量的硫化氢，然后将反应器的气体空间用氮气吹扫15分钟，并通过玻璃吸滤器抽滤出沉降的固体。将制得的固体用正丁醇洗涤一次并抽干，然后在40℃的真空下充分干燥。
得到了29.9g(207mmol，理论的90％)的所需产物哌啶-4-硫代酰胺(I)，纯度97％(1H NMR)。
1H NMR(DMSO-d6,600MHz)δ＝9.31(1H,bs),9.04(1H,bs),2.94(2H,m),2.50(1H,m),2.43(m,2H),2.30(bs,1H),1.58ppm(m,4H)；
13C NMR(DMSO-d6,125MHz)δ＝212.1,50.2,45.5,32.2ppm。
使用替代溶剂进行相同的反应得到下面记录的收率和纯度：
溶剂 温度/超压/eq.H<sub>2</sub>S 收率 纯度(<sup>1</sup>H NMR)
甲醇 60℃/4巴/3.2 85％ 98％
乙醇 60℃/4巴/2.0 94％ 96％
2-丙醇 60℃/4巴/2.0 87％ 98％
正丁醇 60℃/4巴/2.3 90％ 97％
2-丁醇 60℃/4巴/1.9 85％ 98％
1-戊醇 60℃/4巴/2.0 80％ 96％
环戊醇 60℃/4巴/2.3 94％ 97％

Claims (8)

1.制备式(I)的哌啶-4-硫代酰胺的方法，
特征在于使式(II)的4-氰基哌啶
与硫化氢(III)在溶剂的存在下且在不加入另外的碱的情况下反应，得到式(I)的化合物。
2.权利要求1的方法，其特征在于所述反应在密封的反应容器中进行。
3.权利要求1或2的方法，其特征在于所述反应在≥0℃的反应温度下进行。
4.权利要求3的方法，其特征在于所述反应在20-100℃的反应温度下进行。
5.权利要求4的方法，其特征在于所述反应在40-80℃的反应温度下进行。
6.权利要求1或2的方法，其特征在于所述溶剂为伯醇、仲醇或叔醇或其混合物，或者将这些醇中的任一种与另外的溶剂混合。
7.权利要求1或2的方法，其特征在于所述溶剂为包含1至10个碳原子的醇。
8.权利要求7的方法，其特征在于所述溶剂为甲醇、乙醇、异丙醇、叔丁醇、异丁醇、正丁醇、环戊醇或环己醇。
CN201580030993.XA 2014-06-11 2015-06-08 哌啶-4-硫代酰胺的制备 Active CN106458898B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP14172038 2014-06-11
EP14172038.3 2014-06-11
PCT/EP2015/062650 WO2015189115A1 (en) 2014-06-11 2015-06-08 Preparation of piperidine-4-carbothioamide

Publications (2)

Publication Number Publication Date
CN106458898A CN106458898A (zh) 2017-02-22
CN106458898B true CN106458898B (zh) 2019-11-12

Family

ID=50896206

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201580030993.XA Active CN106458898B (zh) 2014-06-11 2015-06-08 哌啶-4-硫代酰胺的制备

Country Status (12)

Country Link
US (1) US9790182B2 (zh)
EP (1) EP3154942B1 (zh)
JP (1) JP6603242B2 (zh)
KR (1) KR102430612B1 (zh)
CN (1) CN106458898B (zh)
BR (1) BR112016028698B1 (zh)
DK (1) DK3154942T3 (zh)
ES (1) ES2753582T3 (zh)
IL (1) IL249130B (zh)
MX (1) MX2016016398A (zh)
TW (1) TWI666199B (zh)
WO (1) WO2015189115A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR112017018991B1 (pt) * 2015-03-05 2022-02-15 Bayer Cropscience Aktiengesellschaft Processo para preparação de hidrocloreto de piperidina-4-carbotioamida
DE102018212696B3 (de) 2018-07-30 2019-11-07 Thyssenkrupp Ag Verstellantrieb für eine Lenksäule und Lenksäule für ein Kraftfahrzeug

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1807409A (zh) * 2006-02-09 2006-07-26 朱凯琴 硫代酰胺类化合物的合成方法
CN101010308A (zh) * 2004-08-04 2007-08-01 同和药品工业株式会社 新型苯甲脒衍生物、其制备方法以及包含它们的药物组合物
WO2009026319A1 (en) * 2007-08-20 2009-02-26 Wyeth Naphthylpyrimidine, naphthylpyrazine and naphthylpyridazine analogs and their use as agonists of the wnt-beta-catenin cellular messaging system
CN102816148A (zh) * 2006-07-27 2012-12-12 杜邦公司 杀真菌的氮环酰胺

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0749966A4 (en) * 1994-03-11 1997-07-02 Yamanouchi Pharma Co Ltd 5-HT 3 RECEPTOR AGONIST, NEW THIAZOLE DERIVATIVE AND INTERMEDIATE FOR OBTAINING IT
DE10252102A1 (de) * 2002-11-08 2004-05-27 Merck Patent Gmbh Indolderivate
WO2009019295A2 (en) 2007-08-06 2009-02-12 Nv Remynd Phenyl- and benzylthiazolylpiperazine derivatives for the treatment of neurodegenerative diseases
TWI428091B (zh) 2007-10-23 2014-03-01 Du Pont 殺真菌劑混合物
CN101925598B (zh) 2008-01-25 2014-03-05 杜邦公司 杀真菌酰胺
US20130045948A1 (en) 2009-12-11 2013-02-21 E I Du Pont De Nemours And Company Azocyclic inhibitors of fatty acid amide hydrolase
EP2516426B1 (de) 2009-12-21 2015-09-16 Bayer CropScience AG Bis(difluormethyl)pyrazole als fungizide
US8722678B2 (en) 2010-05-20 2014-05-13 E I Du Pont De Nemours And Company Fungicidal oximes and hydrazones
CN109674753A (zh) * 2010-06-23 2019-04-26 希玛贝治疗股份有限公司 固态分散体
US20150031541A1 (en) 2012-03-02 2015-01-29 Syngenta Participations Ag Microbiocidal pyrazole derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101010308A (zh) * 2004-08-04 2007-08-01 同和药品工业株式会社 新型苯甲脒衍生物、其制备方法以及包含它们的药物组合物
CN1807409A (zh) * 2006-02-09 2006-07-26 朱凯琴 硫代酰胺类化合物的合成方法
CN102816148A (zh) * 2006-07-27 2012-12-12 杜邦公司 杀真菌的氮环酰胺
WO2009026319A1 (en) * 2007-08-20 2009-02-26 Wyeth Naphthylpyrimidine, naphthylpyrazine and naphthylpyridazine analogs and their use as agonists of the wnt-beta-catenin cellular messaging system

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
2-(4-N-硝基，N-甲基氨基苯基)-(4-硝基苯基)-5-(2，4，6 -三硝基苯基) 噻唑的合成及其性能研究;赵雷，等;《有机化学》;20001231;第20卷(第5期);第750-753页 *
3,3-Dinitrobutyl-1,2,4-oxadiazoles (1);Mark D. Bjorklund等;《Journal of Heterocyclic chemistry》;19800630;第17卷;第819页右栏倒数第1-2段 *
Synthesis of Compounds for Chemotherapy of Tuberculosis. VII. Pyridine V-Oxides with Sulfur-Containing Groups;Thomas S. Gardner等;《Journal of Organic Chemistry》;19570831;第22卷;第986页左栏第1段 *
硫代酰胺的绿色化学合成方法;吴瑜亮，等;《浙江化工》;20081231;第39卷(第10期);第3-5页 *

Also Published As

Publication number Publication date
TWI666199B (zh) 2019-07-21
WO2015189115A1 (en) 2015-12-17
JP6603242B2 (ja) 2019-11-06
BR112016028698B1 (pt) 2021-05-04
BR112016028698A2 (pt) 2017-08-22
DK3154942T3 (da) 2019-11-18
IL249130B (en) 2018-12-31
MX2016016398A (es) 2017-04-06
IL249130A0 (en) 2017-01-31
EP3154942A1 (en) 2017-04-19
KR102430612B1 (ko) 2022-08-08
CN106458898A (zh) 2017-02-22
JP2017517531A (ja) 2017-06-29
US9790182B2 (en) 2017-10-17
US20170137381A1 (en) 2017-05-18
TW201625530A (zh) 2016-07-16
ES2753582T3 (es) 2020-04-13
EP3154942B1 (en) 2019-08-28
KR20170016387A (ko) 2017-02-13

Similar Documents

Publication Publication Date Title
JP5652628B2 (ja) ２−アミノ−ｎ−（２，２，２−トリフルオロエチル）アセトアミド化合物又はその塩の製造方法
WO2009135860A1 (de) Verfahren zur herstellung von arylcarboxamiden
CN106458898B (zh) 哌啶-4-硫代酰胺的制备
CN110878084A (zh) 一种烟嘧磺隆原药的制备方法
US9469593B2 (en) Process for preparing cinacalcet hydrochloride
CN111170965A (zh) 一种新的卡利拉嗪制备方法
CN111465594B (zh) 已知作为制备尼达尼布中间体的2-吲哚满酮的合成
RU2307828C1 (ru) Способ получения этилендиамин-n,n`-дипропионовой кислоты дигидрохлорида
KR101276667B1 (ko) 3,4-디클로로이소티아졸카복실산의 제조방법
KR100881890B1 (ko) 사포그렐레이트 염산염의 제조방법
EP3154933A1 (en) Process for the preparation of 2-(trihalomethyl) benzamide
JP6700292B2 (ja) ピペリジン−４−カルボチオアミド塩酸塩を調製する方法
CN104926682A (zh) 一种对氯苯肼盐酸盐的制备方法
JP4356111B2 (ja) Ｎ−（２−アミノ−１，２−ジシアノビニル）ホルムアミジンの製造方法
JP4191008B2 (ja) アミノカルボン酸エステルの製造法
JP5142241B2 (ja) ニコチン酸エステル化合物の製造方法
JP5988253B2 (ja) ［４，６−ビス−ジメチルアミノ−２−［４−（４−トリフルオロメチルベンゾイル−アミノ）ベンジル］ピリミジン−５−イル］酢酸の調製方法
WO2015087291A1 (en) 3-carboxy-4-(r)-phenylpyrrolydine-2-one salt and its use
WO2011019680A1 (en) Process for preparing 4-methyl-3-thienylamine hydrochloride

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant