WO2009010231A1 - Process for the production of tertiary alcohols - Google Patents
Process for the production of tertiary alcohols Download PDFInfo
- Publication number
- WO2009010231A1 WO2009010231A1 PCT/EP2008/005638 EP2008005638W WO2009010231A1 WO 2009010231 A1 WO2009010231 A1 WO 2009010231A1 EP 2008005638 W EP2008005638 W EP 2008005638W WO 2009010231 A1 WO2009010231 A1 WO 2009010231A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- carboxylic ester
- solution
- aryl
- formula
- Prior art date
Links
- 0 *OC(c1c(CCC(C(C=CC2)=C[C@]2C=Cc(cc2)nc3c2ccc(Cl)c3)O)cccc1)=O Chemical compound *OC(c1c(CCC(C(C=CC2)=C[C@]2C=Cc(cc2)nc3c2ccc(Cl)c3)O)cccc1)=O 0.000 description 1
- ZSHIDKYITZZTLA-XNTDXEJSSA-N CC(C)(c1c(CCC(c2cc(/C=C/c(cc3)nc4c3ccc(Cl)c4)ccc2)O)cccc1)O Chemical compound CC(C)(c1c(CCC(c2cc(/C=C/c(cc3)nc4c3ccc(Cl)c4)ccc2)O)cccc1)O ZSHIDKYITZZTLA-XNTDXEJSSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B49/00—Grignard reactions
Definitions
- the invention relates to a process for the production of tertiary alcohol of formula
- R 1 is Ci_ 4 alkyl and Q is Ci_ 10 alkyl, C 2 -I 0 alkenyl, C 3 _ 8 cycloalkyl, aryl or heteroaryl or an organic moiety composed of any two or more of the beforementioned, each Ci_ 10 alkyl, C 2 _ 10 alkenyl, C 3 _ 8 cycloalkyl, aryl and heteroaryl optionally being substituted with one or more sub- stituents independently selected from the group consisting of hydroxy, fluorine, chlorine, amino, Ci ⁇ t alky lamino and di(C ! - 4 alkyl)amino.
- montelukast 1 - [[ [( 1 R)- 1 - [3 - [( 1 £)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3 - [2-( 1 -hydroxy- 1 -methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid).
- EP-A-I 759 765 discloses solutions of anhydrous lanthanide salts of formula MX 3 ⁇ z LiA, such as LaCl 3 »2 LiCl, and their use in Grignard-type reactions, in particular with ketones and imines.
- said lanthanide salts are employed in equimolar amounts and examples are given where carboxylic ester moieties are unaffected.
- the addition of a trace of water to the reaction mixture is said to initiate a precipitation of the lanthanide salt.
- the method should not involve tedious activation steps, heterogeneous reaction mixtures and cumbersome work-up procedures.
- R 1 is C 1 ⁇ alkyl and Q is C 1 - I0 alkyl, C 2 _ 10 alkenyl, C 3 _ 8 cycloalkyl, aryl or heteroaryl or an organic moiety composed of any two or more of the beforementioned, each C 1 - I0 alkyl, C 2 _ 10 alkenyl, C 3 _ 8 cycloalkyl, aryl and heterocyclyl, optionally being substituted with one or more substituents independently selected from the group consisting of hydroxy, fluorine, chlorine, amino, C 1 - 4 alkylamino and di(Ci_ 4 alkyl)amino can be prepared by reacting a carbo- xylic ester of formula
- R is Ci_ 10 alkyl, aryl or arylalkyl, with a Grignard reagent of formula
- Ci-,, alkyl is to be understood to comprise any linear or branched alkyl group having from 1 to n carbon atoms.
- C 1 - 4 alkyl comprises methyl, ethyl, propyl, isopropyl, butyl, isobutyl, .sec-butyl and tert-butyl.
- Ci_io alkyl comprises groups such as pentyl, isopentyl, neo- pentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl and the like.
- C 2 - 10 alkenyl comprises any linear or branched hydrocarbyl group having from 2 to 10 carbon atoms and at least one carbon-carbon double bond.
- C 3 - S cycloalkyl is to be understood to comprise any mono- or bicyclic cycloali- phatic group having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norcaryl and the like.
- aryl is to be understood to comprise any mono-, bi- or polycarbocyclic group comprising at least one aromatic ring, such as phenyl, naphthyl, anthracenyl, phenanthryl, biphenyl- yl, fluorenyl, tetrahydronaphthalenyl and the like.
- aromatic ring such as phenyl, naphthyl, anthracenyl, phenanthryl, biphenyl- yl, fluorenyl, tetrahydronaphthalenyl and the like.
- a preferred meaning of "aryl” is phenyl.
- heterocyclyl comprises any aromatic and non-aromatic heterocyclic groups, such as tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyranyl, furanyl, thiophenyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, thiazolyl, indolyl, quinolinyl, carbazolyl and the like.
- Preferred meanings of "heterocyclyl” are pyridyl and quinolinyl.
- organic moiety composed of any two or more of the beforementioned is to be understood to mean any organic moiety having one free (open) valency that comprises two or more of the beforementioned groups, for example arylalkyl or alkylaryl, (arylalkyl)aryl, (aryl- alkenyl)aryl, [(alkenylaryl)alkyl]aryl, [[(heterocyclylalkenyl)aryl]alkyl]aryl and the like.
- Each C 1 - K ) alkyl, C 2 _ 10 alkenyl, C 3 _ 8 cycloalkyl, aryl and heteroaryl occurring alone or as a com- ponent of an organic moiety composed of two or more of these groups, as described above, may independently be substituted with one or more substituents selected from the group consisting of hydroxy, fluorine and chlorine.
- ethereal solvent is to be understood to include any solvent or solvent mixture com- prising a substantial amount of an acyclic or cyclic ether that is liquid at the reaction temperature, such as diethyl ether, dibutyl ether, methyl tert-butyl ether, dimethoxyethane, tetrahydro- furan (THF), 2-methyltetrahydrofuran, 1 ,4-dioxane and the like. It also includes cyclic acetals such as 1,3-dioxolane or 1,3-dioxane.
- the lithium chloride solubilizes the lanthanum trichloride, resulting in a true solution of the two salts in the ethereal solvent and thus in a homogeneous reaction mixture.
- lanthanum trichloride and lithium chloride are present in a molar ratio of 1 :2 or less.
- a THF solution Of LaCl 3 and LiCl in a molar ratio of 1 :2 is commercially available from Che- metall GmbH, Frankfurt (Main), Germany.
- the alkyl group R 1 of the Grignard reagent III is preferably methyl.
- the halogen component X of the Grignard reagent III is preferably chlorine.
- the organic moiety Q of the tertiary alcohol I and the carboxylic ester II comprises at least one aryl group. More preferably, the carboxylate group of the carboxylic ester II is directly bound to an aryl group.
- Q is the group of formula
- the secondary alcohol groups of the above structures have 5-configuration to make them suitable as intermediates in the synthesis of (i?)-montelukast.
- the preferred carboxylic ester depicted above is used in the mono- hydrate form, thus rendering a separate drying step superfluous.
- the water of crystallization simply reacts with one equivalent of the Grignard reagent to yield the corresponding alkane and magnesium hydroxyhalide. This is surprising in view of EP-A-I 759 765 which stated that even traces of water initiate precipitation of the lanthanide salt.
- the lanthanum trichloride is advantageously used in a molar ratio of lanthanum trichloride to carboxylic ester (II) of from 1.5:1 to 1 :2.
- the preferred carboxylic ester depicted above is used in the anhydrous form which may be obtained by azeotropic dehydration of the monohydrate using a suitable entraining agent such as toluene. It has been found that it is possible to directly use the solution obtained by azeotropic removal of the water of crystallization and to add said solution to a solution comprising the Grignard reagent, the lanthanum trichloride and the lithium chloride.
- the amount of lanthanum trichloride can be reduced to a preferred molar ratio of lanthanum trichloride to carboxylic ester (II) of from 1 :1 to 1 :10, more preferably from 1:2 to 1 :10 or from 1:3 to 1 :10.
- the starting carboxylic ester II is preferably a methyl ester.
- the ethereal solvent used in the process of the invention is preferably tetrahydrofuran alone or a mixture of tetrahydrofuran and an inert solvent such as an aliphatic or aromatic hydrocarbon. Also preferred are 2-methyltetrahydrofuran and 1,3-dioxolane.
- the reaction temperature can be in the range that is commonly employed in Grignard reactions, it is preferably between -20 °C and room temperature, more preferably from -10 0 C to +10 °C.
- the work-up of the reaction mixture can be accomplished according to the methods commonly used in the art, e.g. by quenching with water or weak aqueous acids and extracting the product with a suitable solvent.
- Methyl 2-[(3S)-3-[3-[(lE)-2-(7-chloro-2-quinolinyl)ethenyl> phenyl]-3-hydroxypropyl]benzoate monohydrate (0.916 g, 2.00 mmol; prepared according to EP 0 480 717 Al, Example 146, Step 2) was added, and after 1 h stirring at room temperature under nitrogen the mixture was cooled to -5 °C.
- Methylmagnesium chloride (3 M solution in THF, 3.4 mL, 10 mmol) was added dropwise while the temperature was not allowed to exceed -5 °C.
- the residue was triturated at 50 °C with heptane (3 mL) and then cooled to 20 °C during 3 h.
- the precipitated product was isolated by filtration at 20 °C, washed first with heptane/toluene (1 : 1 v/v, 4 mL), then with heptane (4 mL), and finally dried at 40 °C to yield 0.63 g of the desired product.
- Example 2 The procedure of Example 1 was repeated using different amounts of lanthanum trichloride (0.5, 1.0 and 1.5 molar equivalents) and 10 molar equivalents of methylmagnesium chloride (instead of 5 molar equivalents).
- the yield of the desired product was determined by HPLC. The observed yields were as follows: 0.5 equivalents LaCl 3 : 88.3% 1.0 equivalents LaCl 3 : 94.9% 1.5 equivalents LaCl 3 : 98.5%
- the solution was cooled to 20 °C and transferred into the first reaction mixture while keeping the internal temperature of the first reaction vessel in the range of -9 0 C to -5 °C.
- the reaction mixture was allowed to stand for an additional 1.5 h while the reaction progression was monitored by HPLC.
- the solution was cooled to -15 °C and was quenched by addition of 4 M aqueous acetic acid (128 mL) while keeping the internal temperature below 10 0 C.
- the resulting biphasic system was kept to 10 °C. Toluene (50 mL) was added and the system was stirred for 15 min at 10 °C, settled for 5 min at 10 0 C to give a clear two phase separation.
- the organic layer was then separated and washed with a 10 wt.% solution OfNa 2 CO 3 (104 mL) at 10 °C and with a 10 wt.% solution of NaCl (104 mL) at 10 °C.
- the organic phase was concentrated (to 60 mL) in vacuo (40 °C, 150 mbar).
- the distillation residue was heated to 60 °C and heptane (15 g) was added over 10 min followed by seeding with crystals of the desired product in order to initiate crystallisation at 60 °C.
- the suspension was stirred for an additional 2 h at 60 °C.
- Heptane (60 g) was added over 10 h at 60 °C.
- a 13.9 wt.% solution of LaCl 3 /LiCl in THF (14.84 g, 8.4 mmol, 0.2 equiv) was diluted with THF (50 mL).
- a 3.0 M solution of methylmagnesium chloride (42.86 g, 126 mmol, 3 equiv) was added to the solution at room temperature.
- the solution was then cooled to -9 °C and a mixture of ethyl benzoate (6.30 g, 42.9 mmol, 1 equiv) in toluene (7 mL) was added to the first solution over 60 min within a temperature range of -9 °C to —5 °C.
- reaction mixture was cooled to -20 °C and was quenched by addition of 4 M aqueous acetic acid (128 mL) while the temperature was kept below 10 °C.
- the resulting biphasic system was allowed to warm to 20 °C.
- Toluene 50 mL was added and the system was agitated for 15 min at 20 °C and settled for 5 min at 20 °C to give a clear phase separation.
- the organic layer was washed at 20 0 C with a 10 wt.% aqueous Na 2 CO 3 solution (104 mL), followed by a 10 wt.% aqueous NaCl solution.
- Example 6 The procedure of Example 6 was repeated using 5 equivalents of MeMgCl. The isolated yield was 93.9% with 99.6% purity.
- Example 6 The procedure of Example 6 was repeated using methyl decanoate instead of ethyl benzoate. The isolated yield was 76.6 % with 97.6% purity.
- Methylmagnesium chloride (59.04 g, 175.24 mmol) was charged under nitrogen to a second 250 mL reactor and cooled to —10 °C. Then, 14.10 g of a 16.06 wt.% solution of LaCl 3 » 2 LiCl in tetrahydrofuran was added within 0.5 h. The resulting suspension was cooled to -15 °C. The solution in the first reactor was syringed into the second reactor at such a rate as to maintain the temperature below -10 °C. The reaction was monitored by HPLC. After the reaction was completed, 4 M acetic acid (90 mL) was added slowly, while maintaining the temperature below 0 °C (pH of water phase: 5—6).
- the mixture was heated to 20 °C.
- the organic phase was separated and washed twice with 10 wt.% aqueous Na 2 CO 3 (90 mL) and twice with 10 wt.% aqueous NaCl (60 mL each).
- 15.0 g of solvent was distilled from above solution.
- 2-methyltetrahydrofuran (32.0 g) was added, followed by distillation of another 24.0 g of solvent.
- the residue was cooled to 30 °C and then «-heptane (22.4 g) was added to form a saturated solution.
- 0.4 g of the diol product was added as seed crystals and the resulting suspension was stirred overnight.
- Methyl 2- [(35)-3 - [3 - [( 1 E)-2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3 -hydroxypropyljbenzoate monohydrate (10.0 g, 21.62 mmol) followed by 1,3-dioxolane (50 mL) were charged to a 100 mL reactor.To remove water, 30 mL of solvent was distilled from the solution at 79 °C and normal pressure. Karl Fischer analysis showed that water content was 0.07% (1 mL of solution was drawn). The solution was stored at 20-30 °C. Methylmagnesium chloride (30.10 g, 89.34 mmol) was charged under nitrogen to a 250 mL reactor and cooled to -10 °C. Then
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Quinoline Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2010516406A JP2010533208A (en) | 2007-07-13 | 2008-07-10 | Method for producing tertiary alcohol |
EA201000144A EA201000144A1 (en) | 2007-07-13 | 2008-07-10 | METHOD OF OBTAINING TERTIARY ALCOHOLS |
CA 2692919 CA2692919A1 (en) | 2007-07-13 | 2008-07-10 | Process for the production of tertiary alcohols |
US12/668,100 US20100217004A1 (en) | 2007-07-13 | 2008-07-10 | Process for the production of tertiary alcohols |
AU2008277939A AU2008277939A1 (en) | 2007-07-13 | 2008-07-10 | Process for the production of tertiary alcohols |
CN200880024435A CN101808960A (en) | 2007-07-13 | 2008-07-10 | Process for the production of tertiary alcohols |
EP08773960A EP2178812A1 (en) | 2007-07-13 | 2008-07-10 | Process for the production of tertiary alcohols |
BRPI0814525-3A2A BRPI0814525A2 (en) | 2007-07-13 | 2008-07-10 | PROCESS FOR THE PRODUCTION OF TERTIARY ALCOHOLS |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07013809.4 | 2007-07-13 | ||
EP07013809A EP2014633A1 (en) | 2007-07-13 | 2007-07-13 | Process for the production of tertiary alcohols |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009010231A1 true WO2009010231A1 (en) | 2009-01-22 |
Family
ID=38950822
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2008/005638 WO2009010231A1 (en) | 2007-07-13 | 2008-07-10 | Process for the production of tertiary alcohols |
Country Status (12)
Country | Link |
---|---|
US (1) | US20100217004A1 (en) |
EP (2) | EP2014633A1 (en) |
JP (1) | JP2010533208A (en) |
KR (1) | KR20100046007A (en) |
CN (1) | CN101808960A (en) |
AU (1) | AU2008277939A1 (en) |
BR (1) | BRPI0814525A2 (en) |
CA (1) | CA2692919A1 (en) |
EA (1) | EA201000144A1 (en) |
TW (1) | TW200918492A (en) |
WO (1) | WO2009010231A1 (en) |
ZA (1) | ZA201000237B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012077133A1 (en) * | 2010-12-07 | 2012-06-14 | Ind-Swift Laboratories Limited | Processes for preparation of montelukast sodium and purification of diol intermediate |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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ES2891352T3 (en) * | 2017-06-14 | 2022-01-27 | Basf Agro Bv | Process for the preparation of substituted phenoxyphenyl alcohols |
CN109879755A (en) * | 2019-02-22 | 2019-06-14 | 江苏南大光电材料股份有限公司 | The preparation method of 1- ethylcyclohexyl (methyl) acrylate |
CN116332220B (en) * | 2023-05-29 | 2023-08-11 | 研峰科技(北京)有限公司 | Synthesis method of lanthanum (III) chloride bis (lithium chloride) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1759765A1 (en) * | 2005-09-01 | 2007-03-07 | Ludwig-Maximilians-Universität München | Solutions of anhydrous lanthanide salts and its preparation |
Family Cites Families (1)
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TW448160B (en) | 1993-12-28 | 2001-08-01 | Merck & Co Inc | Novel dicyclohexylamine salt and process for the preparation of leukotriene antagonists |
-
2007
- 2007-07-13 EP EP07013809A patent/EP2014633A1/en not_active Withdrawn
-
2008
- 2008-07-10 JP JP2010516406A patent/JP2010533208A/en not_active Withdrawn
- 2008-07-10 BR BRPI0814525-3A2A patent/BRPI0814525A2/en not_active IP Right Cessation
- 2008-07-10 EP EP08773960A patent/EP2178812A1/en not_active Withdrawn
- 2008-07-10 KR KR1020107003156A patent/KR20100046007A/en not_active Application Discontinuation
- 2008-07-10 AU AU2008277939A patent/AU2008277939A1/en not_active Abandoned
- 2008-07-10 WO PCT/EP2008/005638 patent/WO2009010231A1/en active Application Filing
- 2008-07-10 CN CN200880024435A patent/CN101808960A/en active Pending
- 2008-07-10 EA EA201000144A patent/EA201000144A1/en unknown
- 2008-07-10 US US12/668,100 patent/US20100217004A1/en not_active Abandoned
- 2008-07-10 CA CA 2692919 patent/CA2692919A1/en not_active Abandoned
- 2008-07-11 TW TW097126207A patent/TW200918492A/en unknown
-
2010
- 2010-01-12 ZA ZA201000237A patent/ZA201000237B/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1759765A1 (en) * | 2005-09-01 | 2007-03-07 | Ludwig-Maximilians-Universität München | Solutions of anhydrous lanthanide salts and its preparation |
Non-Patent Citations (4)
Title |
---|
CONLON D A ET AL: "INSIGHTS INTO THE CERIUM CHLORIDE-CATALYZED GRIGNARD ADDITION TO ESTERS", ADVANCED SYNTHESIS AND CATALYSIS, WILEY, WEINHEIM, DE, vol. 346, no. 11, 2004, pages 1307 - 1315, XP009058825, ISSN: 1615-4169 * |
FUMIE SATO ET AL.: "Cp2TiCL2-CATALYSED GRIGNARD REACTIONS. 3. REACTIONS WITH ESTERS:EFFICIENT METHODOLOGY FOR THE SYNTHESIS OF SECONDARY ALCOHOLS AND FOR THE REDUCTION OF ESTERS TO PRIMARY ALCOHOLS", TETRAHEDRON LETTERS, vol. 21, 1980, pages 2175 - 2178, XP002465947 * |
HEINZ BECKER ET AL.: "ORGANIKUM, ORGANISCH-CHEMISCHES GRUNDPRAKTIKUM", 1976, VEB DEUTSCHER VERLAG DER WISSENSCHAFTEN BERLIN, XP002465981 * |
See also references of EP2178812A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012077133A1 (en) * | 2010-12-07 | 2012-06-14 | Ind-Swift Laboratories Limited | Processes for preparation of montelukast sodium and purification of diol intermediate |
Also Published As
Publication number | Publication date |
---|---|
EP2014633A1 (en) | 2009-01-14 |
EP2178812A1 (en) | 2010-04-28 |
AU2008277939A1 (en) | 2009-01-22 |
JP2010533208A (en) | 2010-10-21 |
EA201000144A1 (en) | 2010-06-30 |
CA2692919A1 (en) | 2009-01-22 |
US20100217004A1 (en) | 2010-08-26 |
ZA201000237B (en) | 2010-09-29 |
KR20100046007A (en) | 2010-05-04 |
TW200918492A (en) | 2009-05-01 |
CN101808960A (en) | 2010-08-18 |
BRPI0814525A2 (en) | 2015-02-03 |
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