[go: up one dir, main page]

TWI666199B - 哌啶－４－硫代甲醯胺之製備 - Google Patents

哌啶－４－硫代甲醯胺之製備 Download PDF

Info

Publication number
TWI666199B
TWI666199B TW104118564A TW104118564A TWI666199B TW I666199 B TWI666199 B TW I666199B TW 104118564 A TW104118564 A TW 104118564A TW 104118564 A TW104118564 A TW 104118564A TW I666199 B TWI666199 B TW I666199B
Authority
TW
Taiwan
Prior art keywords
piperidine
reaction
formula
solvent
butanol
Prior art date
Application number
TW104118564A
Other languages
English (en)
Other versions
TW201625530A (zh
Inventor
馬可 布林耶斯
馬克 福特
Original Assignee
德商拜耳作物科學股份有限公司
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 德商拜耳作物科學股份有限公司 filed Critical 德商拜耳作物科學股份有限公司
Publication of TW201625530A publication Critical patent/TW201625530A/zh
Application granted granted Critical
Publication of TWI666199B publication Critical patent/TWI666199B/zh

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)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Plant Pathology (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

本發明說明一種製備哌啶-4-硫代甲醯胺之新穎方法。

Description

哌啶-4-硫代甲醯胺之製備
本發明說明一種製備哌啶-4-硫代甲醯胺之新穎方法。
哌啶-4-硫代甲醯胺衍生物為活性醫藥與農化成份之重要前驅物(參見WO 2008/013622、WO 2011/072207及WO 2011/076699)。
在WO 2008/013622與WO 2011/072207中，及特別在WO 2011/146182、WO 2009/094407與US 2010/0240619所提及製備哌啶-4-硫代甲醯胺衍生物之方法均使用N-經取代之4-氰基哌啶作為起始物。然而，此等方法之缺點在於其需要化學計量之鹼(例如：二乙醇胺)，需要DMF作為溶劑，及需要乾冰冷凝劑或水性操作法(大量廢棄物)。且該等方法亦需要大量過量之硫化氫。
特別在WO 2011/072207及 zhurnal 1983,36,610-614中提到改用二乙胺、吡啶及三乙胺作為鹼，但同樣仍以一種鹽之型式使用硫化氫(硫化鈉、氫硫化鈉，等等)。前述第一份文件在實驗部分所說明之反應實例中提及長的反應時間(72小時)。
如，例如：WO 2013/127808於經取代之哌啶-4-硫代甲醯胺之合成法中所說明，另一種可使用之硫化氫來源係硫化銨(僅在水溶液中時安定)。此文件再度說明需要相當長之反應時間(24小 時)，此外仍然需要在水性條件下操作DMF反應溶液，隨後亦需要利用層析純化法萃取產物。
文件US2010/197703說明改用甲醇與四氫呋喃之混合物替代最常用之二甲基甲醯胺。此例中同樣使用硫化銨水溶液。然而，仍然在此時遭遇上述缺點，另一個問題為產率極低，僅25%。
哌啶-4-硫代甲醯胺(I)之唯一文獻合成法(此方面參見J.Org.Chem. 1957,22,984-986)包括先添加30%氨之甲醇溶液及4-氰基哌啶，隨後再引進硫化氫，直到完全飽和為止。然而，此製程亦有缺點，例如：需額外添加鹼(氨)及反應時間長達48小時。
基於上文所述先前技藝，本發明提出一種沒有上述缺點之方法來解決問題，因此提供產生哌啶-4-硫代甲醯胺(I)之高產率途徑。
現已發現可藉由製備式(I)哌啶-4-硫代甲醯胺之方法解決上述問題， 其特徵在於由式(II)4-氰基哌啶， 與硫化氫(III)於溶劑之存在下反應，產生式(I)化合物。
驚人地發現，在不額外添加鹼之各種不同溶劑中所 製得式(I)哌啶-4-硫代甲醯胺之產量佳，且純度高，因此根據本發明方法可克服上述先前技藝製備方法之缺點。此反應較佳係在密封反應容器中進行。
方法說明
哌啶-4-硫代甲醯胺(I)方法係由4-氰基哌啶(II)與硫化氫(III)於合適溶劑中，於0℃之溫度下，於密封容器中反應。
合適溶劑為選自下列各物所組成群中之溶劑：醚類(例如：四氫呋喃、乙醚、甲基第三丁基醚)、脂系與芳香系(例如：庚烷、環己烷、苯、甲苯或二甲苯)、醇類(例如：甲醇、乙醇、異丙醇、正丁醇、異丁醇、第三丁醇、環戊醇、環己醇)、醯胺類(例如：二甲基甲醯胺、二甲基乙醯胺)、水及其混合物。其中較佳者係醇類，包括一級醇與二級醇，但亦包括三級醇類。特別佳者係包含1至10個碳原子之醇類。極特別佳者係甲醇、乙醇、異丙醇、正丁醇、異丁醇、環己醇、環戊醇。明確較佳者係正丁醇。亦明確較佳者係甲醇。亦明確較佳者係乙醇。亦明確較佳者係異丙醇。亦明確較佳者係異丁醇。亦明確較佳者係環己醇。亦明確較佳者係環戊醇。
硫化氫(III)係呈氣態加至反應容器中，監測反應容器內部壓力，並調整壓力至0至10巴之範圍內(相對壓力)。通常依硫 化氫(III)在所使用特定溶劑中之溶解度而定，其需要之用量係以式(II)化合物為基準計之至少等莫耳量或過量(1.00至10當量，較佳係1.1至5當量，更佳係1.5至3當量)。
根據本發明方法通常在0℃至200℃之間進行，較佳範圍係20℃至100℃之間，更佳係40℃至80℃之間。
反應時間通常在30分鐘至24小時之間，較佳係2至12小時之間。
式(I)化合物之操作與單離法通常包括冷卻反應混合物至-20℃至25℃之溫度範圍，使式(I)化合物沉澱析出。解除任何殘餘超壓，濾出沉澱，利用所使用之特定溶劑洗滌，及乾燥。
所得式(I)化合物經過酸處理，產生相應鹽類。
哌啶-4-硫代甲醯胺之製備實例
在250ml加壓反應器中，由100ml正丁醇與25g氰基哌啶(220mmol)加熱至60℃，然後添加硫化氫至反應器中，以維持在4巴之恆定超壓(反應期間共添加17.5g(513mmol)硫化氫至反應器中)。6小時後，不再添加硫化氫，於60℃下再攪拌反應混合物6小時，然後以2小時時間冷卻至10℃。利用氯漂白劑洗滌器解除過量硫化氫，然後使用氮氣吹掃反應器之氣體空間15分鐘，利用玻璃抽吸濾器抽吸濾出吹掃下來之固體。所得固體使用正丁醇洗滌一次，抽吸乾燥後，於40℃真空下完全乾燥。
結果產生29.9g(207mmol，理論值之90%)所需產物：哌啶-4-硫代甲醯胺(I)，純度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
使用其他替代溶劑進行相同反應，其產率與純度出示如下：

Claims (6)

  1. 一種製備式(I)哌啶-4-硫代甲醯胺之方法，
    Figure TWI666199B_C0001
    其特徵在於式(II)4-氰基哌啶，
    Figure TWI666199B_C0002
    與硫化氫(III)於溶劑之存在下反應，產生式(I)化合物。
  2. 根據申請專利範圍第1項之方法，其中該反應係在密封反應容器中進行。
  3. 根據申請專利範圍第1或2項之方法，其中該反應係在
    Figure TWI666199B_C0003
    0℃之反應溫度下進行。
  4. 根據申請專利範圍第1或2項之方法，其中該溶劑為一級醇、二級醇或三級醇或其混合物，或此等醇類之任一者與其他溶劑之混合物。
  5. 根據申請專利範圍第1或2項之方法，其中該溶劑為包含1至10個碳原子之醇類。
  6. 根據申請專利範圍第1或2項之方法，其中該溶劑為甲醇、乙醇、異丙醇、第三丁醇、異丁醇、正丁醇、環戊醇或環己醇。
TW104118564A 2014-06-11 2015-06-09 哌啶－４－硫代甲醯胺之製備 TWI666199B (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
??14172038.3 2014-06-11
EP14172038 2014-06-11

Publications (2)

Publication Number Publication Date
TW201625530A TW201625530A (zh) 2016-07-16
TWI666199B true TWI666199B (zh) 2019-07-21

Family

ID=50896206

Family Applications (1)

Application Number Title Priority Date Filing Date
TW104118564A TWI666199B (zh) 2014-06-11 2015-06-09 哌啶－４－硫代甲醯胺之製備

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) MX380240B (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
US10093626B2 (en) * 2015-03-05 2018-10-09 Bayer Cropscience Aktiengesellschaft Process for preparing piperidine-4-carbothioamide hydrochloride
DE102018212696B3 (de) 2018-07-30 2019-11-07 Thyssenkrupp Ag Verstellantrieb für eine Lenksäule und Lenksäule für ein Kraftfahrzeug

Family Cites Families (14)

* 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
KR20060017929A (ko) * 2004-08-04 2006-02-28 동화약품공업주식회사 티아졸 유도체가 치환된 신규한 벤즈아미딘 유도체, 그의제조방법 및 이를 유효성분으로 하는 약학 조성물
CN1807409A (zh) * 2006-02-09 2006-07-26 朱凯琴 硫代酰胺类化合物的合成方法
WO2008013622A2 (en) * 2006-07-27 2008-01-31 E. I. Du Pont De Nemours And Company Fungicidal azocyclic amides
WO2009019295A2 (en) 2007-08-06 2009-02-12 Nv Remynd Phenyl- and benzylthiazolylpiperazine derivatives for the treatment of neurodegenerative diseases
US20090054392A1 (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
TWI428091B (zh) 2007-10-23 2014-03-01 Du Pont 殺真菌劑混合物
KR20100105890A (ko) 2008-01-25 2010-09-30 이 아이 듀폰 디 네모아 앤드 캄파니 살균제 아미드
BR112012013801A2 (pt) 2009-12-11 2019-09-24 Du Pont composto,método para inibir a atividade de hidrolase de amida de ácido graxo em um indivíduo,composição farmacêutica e método para tratar um individuo com dor
EP2516426B1 (de) 2009-12-21 2015-09-16 Bayer CropScience AG Bis(difluormethyl)pyrazole als fungizide
AU2011256730B2 (en) 2010-05-20 2015-07-09 E. I. Du Pont De Nemours And Company Fungicidal oximes and hydrazones
WO2011163090A1 (en) * 2010-06-23 2011-12-29 Metabolex, Inc. Compositions of 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine
IN2012DE00621A (zh) 2012-03-02 2015-07-17 Syngenta Participations Ag

Also Published As

Publication number Publication date
JP6603242B2 (ja) 2019-11-06
IL249130B (en) 2018-12-31
WO2015189115A1 (en) 2015-12-17
US20170137381A1 (en) 2017-05-18
DK3154942T3 (da) 2019-11-18
MX380240B (es) 2025-03-12
BR112016028698A2 (pt) 2017-08-22
IL249130A0 (en) 2017-01-31
JP2017517531A (ja) 2017-06-29
KR20170016387A (ko) 2017-02-13
TW201625530A (zh) 2016-07-16
US9790182B2 (en) 2017-10-17
BR112016028698B1 (pt) 2021-05-04
EP3154942A1 (en) 2017-04-19
CN106458898A (zh) 2017-02-22
KR102430612B1 (ko) 2022-08-08
ES2753582T3 (es) 2020-04-13
MX2016016398A (es) 2017-04-06
EP3154942B1 (en) 2019-08-28
CN106458898B (zh) 2019-11-12

Similar Documents

Publication Publication Date Title
US11952341B2 (en) Method of preparing high chiral purity lactam intermediate and brivaracetam
JP2014097981A (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
BR112016010568B1 (pt) Processo para preparação de um derivado de 2-etilaminopiridina substituída
TWI666199B (zh) 哌啶－４－硫代甲醯胺之製備
BR112017023411B1 (pt) Processos para preparar derivados de 2- metilaminopiridina substituída e para preparar piridilmetilbenzamidas substituídas
BR112020010049A2 (pt) processo para a preparação de fluopicolida
WO2022206742A1 (zh) 一种一步法合成乙内酰硫脲衍生物的方法
CN101370795A (zh) 制备噻唑化合物的方法
EP3133063A1 (de) Verfahren zur herstellung von 2-amino-1,3,4-oxadiazolen
CN111170965A (zh) 一种新的卡利拉嗪制备方法
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
ES2927010T3 (es) Método de producción optimizado para agente de control de plagas
CN101863836B (zh) 制备5,5-二苯基-2-硫代海因的方法
CN102791692B (zh) 叔丁氧基羰基胺化合物的制造方法
JP6660393B2 (ja) ４−シアノピペリジン塩酸塩を調製する方法
JP2016108332A (ja) アミノ化合物の製造方法
CN111892556A (zh) 新的卡利拉嗪制备方法
JP2016020320A (ja) モンテルカストナトリウムの製造方法