TWI455911B - 用以合成（１ｓ，２ｒ）－米那普侖（ｍｉｌｎａｃｉｐｒａｎ）的方法 - Google Patents

用以合成（１ｓ，２ｒ）－米那普侖（ｍｉｌｎａｃｉｐｒａｎ）的方法 Download PDF

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TWI455911B
TWI455911B TW099101933A TW99101933A TWI455911B TW I455911 B TWI455911 B TW I455911B TW 099101933 A TW099101933 A TW 099101933A TW 99101933 A TW99101933 A TW 99101933A TW I455911 B TWI455911 B TW I455911B
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toluene
formula
carried out
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TW099101933A
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TW201031623A (en
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Marc Nicolas
Paul Hellier
Catherine Diard
Laurent Subra
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Pf Medicament
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/58—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Steroid Compounds (AREA)

Claims (12)

  1. 一種用以合成具有下列化學式(I)的(1S,2R)-米那普侖之一藥學上可接受的酸加成鹽的方法： 其包含有下列依序步驟：(a)在一含有一鹼金屬的鹼之存在下，令苯基乙腈以及(R)-表氯醇相反應，繼而以一鹼處理，並且接而為一酸處理，俾以獲得具有下列化學式(II)的內酯： (b)在一路易士酸-胺複合物(其中胺是選自於二乙基胺、三乙基胺、二異丙基乙基胺、N,N-二乙苯胺、N,N-二甲基苄胺、N-甲基哌啶、N-甲基嗎福啉、N,N’-二甲基哌以及六亞甲基四胺)的存在下，令在先前步驟(a)中所獲得的該內酯(II)與MNEt2 (其中M代表一鹼金屬)或者與NHEt2 相反應，俾以獲得具有下列化學式(III)的醯胺-醇： (c)令在先前步驟(b)中所獲得之具有化學式(III)的醯胺-醇與亞硫醯氯相反應，俾以獲得具有下列化學式(IV)的氯化醯胺： (d)令在先前步驟(c)中所獲得之具有化學式(IV)的氯化醯胺與一酞醯亞胺鹽相反應，俾以獲得具有下列化學式(V)的酞醯亞胺衍生物： (e)水解在先前步驟(d)中所獲得之具有化學式(V)的酞醯亞胺衍生物的酞醯亞胺基團，俾以獲得(1S,2R)-米那普侖；以及(f)在一藥學上可接受的酸之存在下，於一合適的溶劑系統中鹽化在先前步驟(e)中所獲得的(1S,2R)-米那普侖； 其中步驟(a)至(e)是在一種包含有一相同並且單一的溶劑的反應介質中被進行，該溶劑是甲苯。
  2. 如申請專利範圍第1項的方法，其中在步驟(d)中之酞醯亞胺鹽是酞醯亞胺的鉀鹽。
  3. 如申請專利範圍第1項的方法，其中在步驟(a)至(d)中所獲得的中間產物中沒有任一者呈乾燥或者半-乾燥的形式而被分離。
  4. 如申請專利範圍第1項的方法，其中在步驟(a)至(e)中所獲得的中間產物中沒有任一者呈乾燥或者半-乾燥的形式而被分離。
  5. 如申請專利範圍第1項的方法，其中步驟(b)是在NHEt2 以及AlCl3 (作為一路易士酸)的存在下被進行。
  6. 如申請專利範圍第1項的方法，其中該水解步驟(e)是藉由與肼、一烷基胺、或者一羥基烷基胺相反應而被進行。
  7. 如申請專利範圍第6項的方法，其中該烷基胺是甲基胺，且該羥基烷基胺是乙醇胺。
  8. 如申請專利範圍第1項的方法，其中該鹽化步驟(f)是在氫氯酸的存在下被進行，俾以獲得(1S,2R)-米那普侖氯化氫。
  9. 如申請專利範圍第1項的方法，其中該鹽化步驟(f)是在一包含有甲苯之溶劑系統中被進行。
  10. 如申請專利範圍第9項的方法，其中該溶劑系統是一含有甲苯、乙酸異丙基酯以及異丙醇的混合物。
  11. 如申請專利範圍第10項的方法，其中相對於該等溶劑的 總體積，該溶劑系統具有下列組成物：- 30至50%，以體積計的甲苯；- 40至90%，以體積計的乙酸異丙基酯；以及- 5至25%，以體積計的異丙醇。
  12. 如申請專利範圍第11項的方法，其中相對於該等溶劑的總體積，該溶劑系統具有下列組成物：- 30至40%，以體積計的甲苯；- 50至80%，以體積計的乙酸異丙基酯；以及- 10至20%，以體積計的異丙醇。
TW099101933A 2009-01-29 2010-01-25 用以合成（１ｓ，２ｒ）－米那普侖（ｍｉｌｎａｃｉｐｒａｎ）的方法 TWI455911B (zh)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR0950552A FR2941454B1 (fr) 2009-01-29 2009-01-29 Proced de synthese du (1s,2r)-milnacipran

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TW201031623A TW201031623A (en) 2010-09-01
TWI455911B true TWI455911B (zh) 2014-10-11

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US (1) US8604241B2 (zh)
EP (1) EP2391599B1 (zh)
JP (1) JP5646509B2 (zh)
KR (1) KR101719011B1 (zh)
CN (2) CN110204455A (zh)
AR (2) AR077526A1 (zh)
AU (1) AU2010209686B2 (zh)
BR (1) BRPI1007404B8 (zh)
CA (1) CA2750488C (zh)
ES (1) ES2472695T3 (zh)
FR (1) FR2941454B1 (zh)
GE (1) GEP20135903B (zh)
IL (1) IL214241A (zh)
MA (1) MA33025B1 (zh)
MX (1) MX2011007846A (zh)
NZ (1) NZ594291A (zh)
PL (1) PL2391599T3 (zh)
RU (1) RU2521342C2 (zh)
TN (1) TN2011000363A1 (zh)
TW (1) TWI455911B (zh)
UA (1) UA104884C2 (zh)
WO (1) WO2010086394A1 (zh)
ZA (1) ZA201105414B (zh)

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RU2617696C2 (ru) 2012-02-17 2017-04-26 ЭЙСАЙ Ар ЭНД Ди МЕНЕДЖМЕНТ КО., ЛТД Способы и соединения, которые можно использовать для синтеза антагонистов рецепторов орексина-2
WO2014009767A1 (en) 2012-07-07 2014-01-16 Micro Labs Limited An improved process for the preparation of 1-aryl 2-aminomethyl cyclopropane carboxyamide (z) derivatives, their isomers and salts
EP2805936A1 (en) 2013-05-20 2014-11-26 Cosma S.p.A. Process for preparing levomilnacipran HCL
WO2014203277A2 (en) * 2013-06-19 2014-12-24 Msn Laboratories Private Limited Process for the preparation of (1s,2r)-2-(aminomethyl)-n,n-diethyl-1-phenylcyclopropanearboxamide hydrochloride
CN103694162B (zh) * 2014-01-03 2015-09-02 上海现代制药股份有限公司 (1s,2r)-1-苯基2-(酞酰亚胺)甲基-n,n-二乙基-环丙甲酰胺的制备方法
CN104058992A (zh) * 2014-06-13 2014-09-24 上海现代制药股份有限公司 左旋米那普仑盐酸盐的晶型
US10144702B2 (en) 2014-10-03 2018-12-04 Purac Biochem B.V. Method for the manufacture of N,N-dialkyllactamide
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RU2011135326A (ru) 2013-03-10
RU2521342C2 (ru) 2014-06-27
MA33025B1 (fr) 2012-02-01
KR20110108409A (ko) 2011-10-05
BRPI1007404B1 (pt) 2020-10-13
MX2011007846A (es) 2011-12-14
EP2391599A1 (en) 2011-12-07
FR2941454A1 (fr) 2010-07-30
KR101719011B1 (ko) 2017-03-22
FR2941454B1 (fr) 2011-04-01
BRPI1007404B8 (pt) 2021-05-25
ZA201105414B (en) 2012-03-28
PL2391599T3 (pl) 2014-09-30
AR077526A1 (es) 2011-09-07
GEP20135903B (en) 2013-08-12
TN2011000363A1 (en) 2013-03-27
NZ594291A (en) 2012-11-30
AR115475A2 (es) 2021-01-20
WO2010086394A1 (en) 2010-08-05
JP5646509B2 (ja) 2014-12-24
IL214241A (en) 2015-03-31
CA2750488A1 (en) 2010-08-05
EP2391599B1 (en) 2014-04-09
CN110204455A (zh) 2019-09-06
UA104884C2 (uk) 2014-03-25
IL214241A0 (en) 2011-09-27
US20110295036A1 (en) 2011-12-01
US8604241B2 (en) 2013-12-10
CA2750488C (en) 2016-12-13
ES2472695T3 (es) 2014-07-02
AU2010209686B2 (en) 2014-06-05
AU2010209686A1 (en) 2011-08-18
BRPI1007404A2 (pt) 2016-02-16
TW201031623A (en) 2010-09-01
JP2012516307A (ja) 2012-07-19
CN102300840A (zh) 2011-12-28

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