WO2007144409A1 - Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine - Google Patents
Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine Download PDFInfo
- Publication number
- WO2007144409A1 WO2007144409A1 PCT/EP2007/055914 EP2007055914W WO2007144409A1 WO 2007144409 A1 WO2007144409 A1 WO 2007144409A1 EP 2007055914 W EP2007055914 W EP 2007055914W WO 2007144409 A1 WO2007144409 A1 WO 2007144409A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- phenylpiperazine
- protease
- enzyme
- hydrolysis
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
- C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
Definitions
- This invention provides for a compound according to formula 1
- R 1 is methyl, ethyl, n-propyl, isopropyl, benzyl or 2-haloethyl (such as 2- chloro-ethyl and 2,2,2-trifluorethyl), which compound is unique for use in a novel method to prepare separate (S)- and (R)-1-methyl-3-phenylpiperazine by enzymatic hydrolysis of such a compound.
- this invention provides for a method to prepare (S)- and (R)-1-methyl-3-phenylpiperazine by enzymatic hydrolysis of the compound defined above, followed by separation of the hydrolysis product and cleavage of the oxalamic groups, whereby the protease of Streptomyces griseus is used as enzyme for the enzymatic hydrolysis.
- the starting compound can be used as a (C1-C3)alkyl-, benzyl- or 2-haloethyl- oxalamate, of racemic 1-methyl-3-phenylpiperazine or any degree optically active mixture in order to obtain (S)- or (R)-1-methyl-3-phenylpiperazine of high optically active purity.
- (C1-C3)alkyl means methyl, ethyl, n-propyl and isopropyl.
- (S)-1-methyl-3-phenylpiperazine can now be obtained in 36 % overall yield at 99.8 % ee and about 98 % purity.
- the protease of Streptomyces griseus is an enzyme of the very large family of hydrolases. Hydrolases are able to perform reactions with water, but also in near anhydrous organic solvents. Some examples of hydrolases are lipases (hydrolysis of fats), proteases (hydrolysis of proteins) and esterases (hydrolysis of esters).
- the use of the protease of Streptomyces griseus as hydrolase has a number of advantages. It is a relatively stable enzyme that can be stored as concentrated aqueous solutions or freeze dried powders. The enzyme does not require any cofactor, which, if needed would not only be economically unattractive, but many cofactors can be more fragile than the enzyme itself. The enzyme has a large active site and can handle the substrate needed for this reaction very well, despite the fact that small variations can give dramatic differences in reaction rate. Lastly, the enzyme has high stability in water/co-solvent mixtures or even neat organic solvents.
- the enantiomeric ratio can be calculated at any point in the reaction if two out the following three parameters are known: conversion, product ee and substrate ee.
- the E is constant throughout the reaction. There are a number of assumptions in the formulas that are not always valid. Furthermore, at very high or very low conversion the E varies strongly with small variations of the conversion or ee. This means that the value becomes more sensitive to the accuracy of the measurement. Since selectivity is never really absolute, at 100% conversion you end up with a racemate again.
- E 1 No selectivity, equal rates for both enantiomers
- E 1-5 Low selectivity. High ee can only be reached if the undesired enantiomer is consumed in the reaction and then only at conversions >90%.
- E 5-25 Good possibilities for a process by consuming the wrong enantiomer.
- the invention provides the method as defined above, whereby the hydrolysis is performed in a buffer free medium.
- the absence of a need to add a buffer to the reaction medium not only simplifies the method, but even improves the method by obtaining higher enantiomeric ratios.
- the nitrogen at the 1 position in the piperazine ring contributes to this.
- a more specific embodiment of the invention is to use in the method as defined above the methyloxalate of 1-methyl-3-phenylpiperazine in combination with a medium comprising toluene or methyl-t-butylether.
- Another specific embodiment of the invention is to use in the method as defined above the ethyloxalate of 1-methyl-3-phenylpiperazine in combination with a medium comprising cyclohexane.
- the racemic substrates were prepared by acylation of 1-methyl-3-phenylpiperazine using commercially available methyl chlorooxalate, yielding a crystalline oxalamate that could be purified by recrystallisation.
- a range of commercially available proteases were tested (table 1 ). Only esperase showed any activity, as observed by enrichment of one of the enantiomers.
- the absolute configuration was determined by comparison with a confirmed sample of the (S)-enantiomer.
- a short screen for reaction conditions was conducted (table 2).
- the E values were calculated on the basis of the conversion and the ee of the starting material and the product. The conversion was estimated using a small impurity in the starting material (already present in the starting piperazine) as an internal standard.
- the enzyme was further tested in a range of conditions using (now pure) methyloxalamate and ethyloxalamate (table 6). Using co-solvent free conditions the methyloxalamate solidified, resulting in a thick suspension with obvious diffusion limitations that hampered complete optical purity at relatively high conversion. Only a small amount of the enzyme was needed. The 2 esters showed differences in optimal conditions for resolution.
- ao ie o ⁇ -ur xner cone mions screen o ⁇ t>.
- j griseus [ xoiease ana (m ieinyic ester mg enz ⁇ /me Solvent pH enc i ee (all S) E estim.
- protease B polymyxa MTBE 7.2 0
- 18 vials are filled with 28 mg oily ethyl oxalamate or 1 ml of a 0.1 M solution of the methyl oxalamate in MTBE/5%isopropanol (otherwise no solubility). Water is added to 2 ml reaction volume (taking into account the volume of the enzyme). Indicated amount of enzyme. * Exp 1 and 10 contain 1 ml 0.1 M pH 8 tris buffer.
- the main aim was to lower the loading of the enzyme and increase the substrate concentration without compromising on the final enantiopurity of the product.
- the pH dropped considerable to well outside the optimum pH of the enzyme.
- the first test was a pH screen, using a pH stat while comparing it to the unbuffered reaction (table 9).
- a reaction without pH control showed a higher ee in an earlier stage of the reaction.
- the ee of the isolated oxalamic acid product (R-enantiomer) was also higher, indicating a much more selective reaction (higher E).
- the same effects were seen with the ethyloxalamate, but solidification of the substrate complicated the comparison of the results a bit (table 10).
- a scale-up of much smaller magnitude using the recrystallised methyloxalamate provided a more pure sample, as the 0.5 % impurity in the starting material is not concentrated in the final product.
- TLC was performed using silica plates, CH 2 CI 2 /Me0H mixtures (typically 90:10) as eluent and both UV fluoresence and I 2 detection.
- Triethylamine (5 ml; ca 0.03 mol) was added.
- a solution of methyl chlorooxalate (10 ml; 0.10 mol) in dichloromethane was slowly added under cooling. After the total addition a white suspension was formed. TLC showed complete conversion. The mixture was quenched with 10% sodium carbonate. The organic layer was washed again with carbonate, dried and evaporated to an oil (25.5 g; 97 %).
- Acetyl 1 -methyl-3-phenylpiperazine 1 -Methyl-3-phenylpiperazine (17.6 g; 0.1 mol) was dissolved in 100 dichloromethane. Acetic anhydride and triethylamine were added. Aqueous work-up yielded >100 % of smelly oil (excess Ac2O). Kugelrohr distillation at 160 "C/0.05 mbar yielded 20.6 g oil (94 %). Chiral GC: 10.3/10.6 min
- Butyryl 1 -methyl-3-phenylpiperazine 1 -Methyl-3-phenylpiperazine (17.6 g; 0.1 mol) was dissolved in 100 dichloromethane. Triethylamine (5 ml; 0.05 mol) was added. A solution of butyroyl chloride (11.6 g; 0.1 1 mol) in dichloromethane was slowly added under cooling. After the total addition a white suspension was formed. The mixture was quenched with 10% sodium carbonate. The organic layer was washed again with carbonate, dried and evaporated to an oil (24g). Kugelrohr distillation of 22.5 g at >200 °C/0.05 mbar yielded 22.0 g oil (95 %). Chiral GC: 12.87/12.98 min, severe overlap.
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2007800224091A CN101472901B (en) | 2006-06-16 | 2007-06-14 | Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine |
US12/304,557 US20100036126A1 (en) | 2006-06-16 | 2007-06-14 | Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine |
EP07730171A EP2038260B1 (en) | 2006-06-16 | 2007-06-14 | Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine |
DE602007008898T DE602007008898D1 (en) | 2006-06-16 | 2007-06-14 | STEREOSELECTIVE SYNTHESIS OF (S) -1-METHYL-3-PHENYLPIPERAZINE |
PL07730171T PL2038260T3 (en) | 2006-06-16 | 2007-06-14 | Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine |
MX2008016121A MX2008016121A (en) | 2006-06-16 | 2007-06-14 | Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine. |
AT07730171T ATE479663T1 (en) | 2006-06-16 | 2007-06-14 | STEREOSELECTIVE SYNTHESIS OF (S)-1-METHYL-3-PHENYLPIPERAZINE |
JP2009514804A JP5216762B2 (en) | 2006-06-16 | 2007-06-14 | Stereoselective synthesis of (S) -1-methyl-phenylpiperazine |
SI200730428T SI2038260T1 (en) | 2006-06-16 | 2007-06-14 | Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06115607.1 | 2006-06-16 | ||
EP06115607 | 2006-06-16 |
Publications (1)
Publication Number | Publication Date |
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WO2007144409A1 true WO2007144409A1 (en) | 2007-12-21 |
Family
ID=36781960
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2007/055914 WO2007144409A1 (en) | 2006-06-16 | 2007-06-14 | Stereoselective synthesis of (s)-1-methyl-3-phenylpiperazine |
Country Status (13)
Country | Link |
---|---|
US (1) | US20100036126A1 (en) |
EP (1) | EP2038260B1 (en) |
JP (1) | JP5216762B2 (en) |
CN (1) | CN101472901B (en) |
AR (1) | AR061378A1 (en) |
AT (1) | ATE479663T1 (en) |
DE (1) | DE602007008898D1 (en) |
ES (1) | ES2349484T3 (en) |
MX (1) | MX2008016121A (en) |
PL (1) | PL2038260T3 (en) |
SI (1) | SI2038260T1 (en) |
TW (1) | TW200815370A (en) |
WO (1) | WO2007144409A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1930325A1 (en) * | 2005-09-26 | 2008-06-11 | Sumitomo Chemical Company, Limited | Process for producing optically active piperazine compound |
WO2008125578A2 (en) | 2007-04-11 | 2008-10-23 | N.V. Organon | A method for the preparation of mirtazapine |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP1426356A1 (en) * | 2001-09-14 | 2004-06-09 | Medichem S.A. | Intermediate compounds for the preparation of mirtazapine and the production methods thereof |
US20040242879A1 (en) * | 2003-06-02 | 2004-12-02 | Handa Vijay Kumar | Process for preparing 1-methyl-3-phenylpiperazine using a novel intermediate |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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NL189199C (en) * | 1975-04-05 | 1993-02-01 | Akzo Nv | PROCESS FOR THE PREPARATION OF PHARMACEUTICAL PREPARATIONS WITH ACTION ON THE CENTRAL NERVOUS SYSTEM BASED ON BENZ (ARYL) AZEPINE DERIVATIVES, THE PHARMACEUTICAL PREPARATIONS OBTAINED, AND METHOD FOR PREPARING THE PRODUCT TO BE USED. |
CA2400977C (en) * | 2000-02-21 | 2011-03-22 | Kuraray Co., Ltd. | Processes for preparing quinoline derivatives and intermediates thereof |
UA83666C2 (en) * | 2003-07-10 | 2008-08-11 | Н.В. Органон | Method for the preparation of enantiomerically pure mirtazapine |
-
2007
- 2007-06-11 TW TW096121040A patent/TW200815370A/en unknown
- 2007-06-14 EP EP07730171A patent/EP2038260B1/en active Active
- 2007-06-14 MX MX2008016121A patent/MX2008016121A/en active IP Right Grant
- 2007-06-14 DE DE602007008898T patent/DE602007008898D1/en active Active
- 2007-06-14 JP JP2009514804A patent/JP5216762B2/en active Active
- 2007-06-14 WO PCT/EP2007/055914 patent/WO2007144409A1/en active Application Filing
- 2007-06-14 AT AT07730171T patent/ATE479663T1/en active
- 2007-06-14 SI SI200730428T patent/SI2038260T1/en unknown
- 2007-06-14 ES ES07730171T patent/ES2349484T3/en active Active
- 2007-06-14 CN CN2007800224091A patent/CN101472901B/en active Active
- 2007-06-14 US US12/304,557 patent/US20100036126A1/en not_active Abandoned
- 2007-06-14 PL PL07730171T patent/PL2038260T3/en unknown
- 2007-06-15 AR ARP070102627A patent/AR061378A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1426356A1 (en) * | 2001-09-14 | 2004-06-09 | Medichem S.A. | Intermediate compounds for the preparation of mirtazapine and the production methods thereof |
US20040242879A1 (en) * | 2003-06-02 | 2004-12-02 | Handa Vijay Kumar | Process for preparing 1-methyl-3-phenylpiperazine using a novel intermediate |
Non-Patent Citations (4)
Title |
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BREEN G F: "Enzymatic resolution of a secondary amine using novel acylating reagents", TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 15, no. 9, 10 May 2004 (2004-05-10), pages 1427 - 1430, XP004505346, ISSN: 0957-4166 * |
HU S ET AL: "An Efficient and Practical Chemoenzymatic Preparation of Optically Active Secondary Amines", ORGANIC LETTERS, ACS, WASHINGTON, DC, US, vol. 7, no. 20, 27 August 2005 (2005-08-27), pages 4329 - 4331, XP002395193, ISSN: 1523-7060 * |
MORGAN B ET AL: "Enzymatic Kinetic Resolution of Piperidine Atropisomers: Synthesis of a Key Intermediate of the Farnesyl Protein Transferase Inhibitor SCH66336", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 65, no. 18, 8 September 2000 (2000-09-08), pages 5451 - 5459, XP002395194, ISSN: 0022-3263 * |
ORSAT B ET AL: "Homocarbonates as Substrates for the Enantioselective Enzymatic Protection of Amines", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 118, no. 3, 1996, pages 712 - 713, XP002395195, ISSN: 0002-7863 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1930325A1 (en) * | 2005-09-26 | 2008-06-11 | Sumitomo Chemical Company, Limited | Process for producing optically active piperazine compound |
EP1930325A4 (en) * | 2005-09-26 | 2010-02-24 | Sumitomo Chemical Co | Process for producing optically active piperazine compound |
WO2008125578A2 (en) | 2007-04-11 | 2008-10-23 | N.V. Organon | A method for the preparation of mirtazapine |
WO2008125578A3 (en) * | 2007-04-11 | 2008-12-24 | Organon Nv | A method for the preparation of mirtazapine |
Also Published As
Publication number | Publication date |
---|---|
DE602007008898D1 (en) | 2010-10-14 |
JP5216762B2 (en) | 2013-06-19 |
SI2038260T1 (en) | 2011-01-31 |
TW200815370A (en) | 2008-04-01 |
JP2009539939A (en) | 2009-11-19 |
AR061378A1 (en) | 2008-08-20 |
EP2038260B1 (en) | 2010-09-01 |
MX2008016121A (en) | 2009-01-15 |
ATE479663T1 (en) | 2010-09-15 |
CN101472901A (en) | 2009-07-01 |
PL2038260T3 (en) | 2011-02-28 |
US20100036126A1 (en) | 2010-02-11 |
CN101472901B (en) | 2011-08-03 |
EP2038260A1 (en) | 2009-03-25 |
ES2349484T3 (en) | 2011-01-04 |
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