EP2102218A2 - Verfahren zur herstellung von 1,3,2-oxazaborolidin-verbindungen - Google Patents

Verfahren zur herstellung von 1,3,2-oxazaborolidin-verbindungen

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Publication number
EP2102218A2
EP2102218A2 EP07871918A EP07871918A EP2102218A2 EP 2102218 A2 EP2102218 A2 EP 2102218A2 EP 07871918 A EP07871918 A EP 07871918A EP 07871918 A EP07871918 A EP 07871918A EP 2102218 A2 EP2102218 A2 EP 2102218A2
Authority
EP
European Patent Office
Prior art keywords
formula
compound
alkyl
iii
acid
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.)
Withdrawn
Application number
EP07871918A
Other languages
English (en)
French (fr)
Inventor
Alain Burgos
Stéphane FREIN
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.)
Zach System SA
Original Assignee
Zach System SA
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 Zach System SA filed Critical Zach System SA
Publication of EP2102218A2 publication Critical patent/EP2102218A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/022—Boron compounds without C-boron linkages

Definitions

  • the present invention relates to a new process for the preparation of compounds of formula (I) called CBS compounds. More particularly, the invention relates to a process for preparing an alkyl-CBS, in particular Me-CBS, optically active compound of formula (IA).
  • the compounds of formula (I) and (IA) are precursors for the synthesis of catalysts widely used in enantioselective prochiral ketone reduction processes.
  • the BASF process which utilizes the second boronate reagent of formula II results in a much higher final catalyst slump than in the context of the present invention.
  • the BASF document is an interposable interposable document only as novelty against the invention.
  • the main object of the present invention is to provide a process for the preparation of the compounds of formula (I) called CBS compounds, and particularly a process for the preparation of an optically active alkyl-CBS compound, in particular methyl or ethyl-CBS, of the formula (IA) above which does not require or eliminate the step of removing water by azeotropic distillation.
  • the main purpose of the present invention is also to provide a new process for the preparation of the compounds of formula (I) or (IA) above, which completely avoids the formation of water or without substantial formation of water, or without any contamination or contamination. sensitive by boronic acid.
  • the main object of the present invention is also to provide a process for the preparation of compounds of formula (I) or (IA) which is very economically advantageous because it uses either less starting material, as a boroxin is an inexpensive raw material such as a boronic acid.
  • the main object of the present invention is also to solve these technical problems in a process which makes it possible to obtain a high purity of the products of formula (I) or (IA) mentioned above to allow their use as pre-catalysts in enantioselective reduction reactions. of prochiral ketone.
  • the present invention solves for the first time the technical problems stated above by the development of a process for the preparation of the compounds of formula (I) or (IA) which completely or essentially avoids the formation of water or contamination with boronic acid (R1B (OH) 2 ).
  • the present invention makes it possible to obtain compounds of formula (I) and more specifically compounds of formula (IA) that are chemically pure and at a very attractive financial cost for industrial use.
  • the Applicant has developed a process for the preparation of the compounds of formula (I) or (IA), (i) (I) Alkyl-CBS
  • R1 represents alkyl or aryl
  • R2, R3, R4 and R5 independently represent a hydrogen atom, an alkyl, an aryl, the alkyl or aryl groups may have one or more hydrogen atoms replaced by a substituent (s);
  • R4 and R5 together form a heterocycle with the nitrogen atom, itself comprising one or more substituent (s);
  • R4 and R3 together form a carbocycle, itself comprising one or more substituents; characterized in that a precursor boric compound is reacted, preferably in situ, in two steps: a) a compound of formula (III) to obtain a boronate compound of formula (IV), according to the chemical reaction below
  • G represents an alkoxy group (OR '2) or an amino group
  • R ', R1 are the same or different and represent an alkyl group or an acyl
  • R 'and R may together form a carbocyclic ring C 2 3 optionally substituted by alkyl;
  • R represents a hydrogen atom, an alkyl group or an aryl group.
  • R1, R2, R3, R4, and R5 have the same definitions as above; to obtain the compound of formula (I), in particular of formula (IA) above.
  • the process according to the invention is characterized in that the boronate compound of formula (IV) is obtained by reaction of the borous precursor compound consisting of a boroxine of formula (II) with an acetal of formula (III) according to the chemical reaction below:
  • G represents an alkoxy group (OR '2) or an amino group
  • R ', R'1 and R'2 are identical or different and represent an alkyl group or an acyl;
  • R 'and R1 together form a C2-3 carbocycle optionally substituted with alkyl;
  • the process is characterized in that the boronate compound of formula (IV) is prepared from the boronic precursor compound consisting of a boronic acid of formula (VI) with an acetal of formula (III), according to the chemical reaction below:
  • the process is characterized in that the compound of formula (II) used is a trialkyl or a triaryl boroxine.
  • the process is characterized in that the compound of formula (II) used is trimethylboroxine.
  • the process is characterized in that the compound of formula (III) used is chosen from the group consisting of a trialkyl or triaryl orthoformate, an acetal of a formamide, a trimethoxymethyl d aryl and / or alkyl.
  • the process is characterized in that the compound of formula (III) is trimethylorthoformate or tri methoxy methane, dimethylformamide dimethylacetal, tri methoxymethyl benzene, 1,1,1-tri-methoxyethane, 1,1,1-tri-methoxy-propane, 1,1,1-trimethoxy-2-methyl-propane.
  • the process is characterized in that the reaction takes place in the presence of an acid, preferably selected from an organic acid, a Lewis acid, a mineral acid.
  • the reaction takes place in the presence of an organic acid, preferably comprising essentially consisting of or consisting of methanesulfonic acid (MeSO3H).
  • organic acid preferably comprising essentially consisting of or consisting of methanesulfonic acid (MeSO3H).
  • the process is characterized in that the reaction takes place in at least one organic solvent, used alone or as a mixture, in particular chosen from an alcohol, a halogenated compound and an aromatic compound. , a nitrile compound, an ether compound and an ester compound.
  • the process is characterized in that the reaction takes place in a aforementioned organic solvent and the amount of compound of formula (III) is adjusted to the amount of water present in the solvent.
  • the compound of formula (III) is present in a molar amount in excess relative to the precursor boric compound to absorb the amount of water present in the solvent used and the formation of water that is formed in the medium.
  • the organic solvent used is toluene.
  • the process is characterized in that the compound of formula (VI) is an alkyl or aryl boronic acid, in particular commercially available.
  • the compound of formula (VI) is methyl boronic acid, in particular commercially available.
  • the process is characterized in that the aminoalcohol of formula (V) is an optically active compound, supported or not.
  • the aminoalcohol of formula (V) is (R) or (S) 2- (diphenylhydroxymethyl) pyrrolidine; (R) or (S) 2- (2-dinaphthylhydroxymethyl) -pyrrolidine; (1R, 2S) -1-amino-2-indanol; (R) or (S) 2-amino-3-methyl-1,1-diphenyl-1-butanol; (R) or (S) 2-amino-3,3-dimethyl-1,1-diphenyl-1-butanol; (R) or (S) 2-hydroxymethylindoline; (R) or (S) ⁇ , ⁇ -diphenyl- (indolin-2-yl) methanol; (R) or (S) (5,5-dimethyl-thiazolidin-4-y
  • the number of equivalent moles of compound of formula (II) relative to the number of moles of aminoalcohol of formula (V) is between 0.33 (II) / 1 ( V) and 0.37 (II) / 1 (V).
  • the process is characterized in that the number of equivalent moles of compound of formula (VI) relative to the number of moles of aminoalcohol of formula (V) is between 1 and 1, 2 equivalents of (VI).
  • the present invention still covers the use of the compound of formula (I), in particular of formula (IA) in a process according to an asymmetric reduction method of a prochiral ketone.
  • the Applicant has developed a process for the preparation of the compounds of formula (I), characterized in that compounds of formula (II) and compounds of formula (III) then the compounds of formula (V) according to the scheme SI below:
  • G represents an alkoxy group (OR '2) or an amino group (NR'R' 1);
  • R ', R'1 and R'2 are identical or different and represent an alkyl group or a carbonyl group
  • R 'and R may together form a carbocycle or C 2-3 optionally substituted by alkyl;
  • R2, R3, R4 and R5 independently represent a hydrogen atom, an alkyl, an aryl, the alkyl or aryl groups may have one or more hydrogen atoms replaced by a substituent (s); R4 and R5 together form a heterocycle with the nitrogen atom, itself comprising one or more substituent (s);
  • R4 and R3 together form a carbocyclic C 3 to 7, itself comprising one or more substituent (s).
  • the Applicant has developed a process for the preparation of the compounds of formula (I), characterized in that the compounds of formula (VI) and the compounds of formula (III) are reacted then the compounds of formula (V) according to Scheme S-2 below:
  • R 1, R ', R 1, R ", R 2, R 3, R 4, R 5 and G have the same definitions as above.
  • the process of the invention according to the first embodiment described by the scheme S1 is defined in that a boroxin of formula (II) is reacted in an organic solvent with an acetal of formula (III ) in the presence of an acid and that an aminoalcohol of formula (V) is added.
  • R 1, R ', R 1, R ", R 2, R 3, R 4, R 5 and G have the same definitions as above.
  • the compound of formula (II) used is a trialkyl or triaryl boroxine.
  • the compound of formula (II) used is the tri methyl boroxine commercially available.
  • the compound of formula (III) used is a trialkyl or a triaryl orthoformate, an acetal of a formamide, a methoxy methyl group of an aryl or of an alkyl.
  • the compound of formula (III) is a commercially available compound.
  • the acid used is an organic acid, a Lewis acid, a mineral acid.
  • the acid used is methanesulfonic acid (MeSOsH).
  • MeSOsH methanesulfonic acid
  • this solvent may be an alcohol, a halogenated compound, an aromatic compound, a nitrile, an ether or an ester.
  • the amount of compound of formula (III) used is adjusted the amount of water present in the solvent.
  • the solvent used is toluene.
  • the aminoalcohol of formula (V) used is an optically active compound, supported or not.
  • the latter is characterized in that the reaction is carried out at a temperature of between 5 ° C. and 30 ° C., preferably at a temperature of 20 ° C. vs.
  • the number of equivalent moles of compound of formula (II) relative to the number of moles of amino alcohol of Formula (V) is between 0.33 (II) / 1 (V) and 0.37 (II) / 1 (V), preferably the number of equivalents is 0.35 (II) / 1 (V).
  • the number of equivalent moles of compound of formula (II) relative to the number of moles of the compound of formula (III) is between 0 , 33 and 0.37 equivalents of (II), preferentially it is 0.35 equivalents of (III).
  • the process of the invention according to the Scheme SI is characterized in that the trimethylboroxine of formula (HA) is reacted in toluene with the trimethylorthoformate of formula (IIIA) in the presence of methanesulfonic acid. and that (R) - or (S) -2- (diphenylhydroxymethyl) -pyrrolidine of formula (V) is added according to scheme S-IA.
  • the reaction is carried out at a temperature of 20 ° C.
  • the process of the invention described by Scheme S-2 is characterized in that a boronic acid of formula (VI) is reacted in an organic solvent with an acetal of formula ( III) in the presence of an acid and that an aminoalcohol of formula (V) is added.
  • the compound of formula (VI) used is an alkyl or aryl boronic acid.
  • alkyl or aryl boronic acid By way of example but not limiting, mention may be made as commercially available products, methylboronic acid, phenylboronic acid, p-tolylboronic acid.
  • the amount of compound of formula (III) used is adjusted to the amount of water present in the solvent.
  • the solvent used is toluene.
  • the reaction is carried out at a temperature of between 5 ° C. and 30 ° C., preferably at a temperature of 50.degree. 20 0 C.
  • the number of equivalent moles of compound of formula (VI) relative to the number of moles of aminoalcohol of formula (V) is between 1 and 1.5 equivalents of (VI), preferably it is 1.2 equivalents of (VI).
  • the number of mole equivalents of compound of formula (III) relative to the number of moles of the compound of formula (VI) is included between 2 and 2.5 equivalents of (VI), preferentially it is 2.1 equivalent of (III).
  • the process of the invention according to Scheme S-2 is characterized in that methylboronic acid of formula (VIA) is reacted in toluene with trimethylorthoformate of formula (IIIA) in the presence of methanesulfonic acid and that the (R) - or (S) -2- (diphenylhydroxymethyl) -pyrrolidine of formula (V) is added according to scheme S-2A.
  • alkyl means a linear or branched C1-C6 hydrocarbon chain. By way of example, mention is made of methyl, ethyl and tert-butyl.
  • aryl means a substituted or unsubstituted C6-C12 aromatic ring.
  • substituent means a halogen atom X ', an alkyl
  • the organic acid may be by way of example but not limited to a sulphonic acid (methanesulphonic acid, paratoluene sulphonic acid).
  • the Lewis acid may be by way of example but not limited to a boron trihalide, an aluminum trihalide, an iron trihalide.
  • the mineral acid may be, by way of example but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid.
  • the organic solvent may be by way of example but not limited to a sulfoxide such as dimethylsulfoxide (DMSO), a nitrile such as acetonitrile, an alcohol such as ethanol, tert-butanol, isopropanol (IPA), a solvent halogen such as dichloromethane (CH 2 Cl 2 ), an amide such as dimethylformamide (DMF), an ether such as ethyl ether, a hydrocarbon such as hexane, an aromatic such as toluene, an ester such as ethyl acetate etc.
  • DMSO dimethylsulfoxide
  • IPA isopropanol
  • a solvent halogen such as dichloromethane (CH 2 Cl 2 )
  • an amide such as dimethylformamide (DMF)
  • an ether such as ethyl ether
  • a hydrocarbon such as hexane
  • an aromatic such as toluene
  • the percentages are given by weight, the temperature is the ambient temperature (22 0 C +/- 3 0 C) or is given in degrees Celsius, the pressure is the atmospheric pressure unless otherwise indicated.
  • the medium is stirred at room temperature for 1 hour.
  • the medium is stirred for 30 minutes at room temperature. 5 g of ketone dissolved in 10 ml of THF are added over a period of 1 hour and at a temperature of 18-20 ° C. 3 ml of acetone are then added and the medium is stirred for 15 minutes.
  • the aqueous phase is again extracted with 20 ml of toluene.
  • the reaction is analyzed by chiral HPLC.
  • the diastereomeric excess is 98.1%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
EP07871918A 2006-12-12 2007-12-12 Verfahren zur herstellung von 1,3,2-oxazaborolidin-verbindungen Withdrawn EP2102218A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0655449A FR2909671B1 (fr) 2006-12-12 2006-12-12 Procede de preparation de composes 1,3,2-oxazaborolidines
PCT/FR2007/052488 WO2008078041A2 (fr) 2006-12-12 2007-12-12 Procede de preparation de composes 1,3,2-oxazaborolidines

Publications (1)

Publication Number Publication Date
EP2102218A2 true EP2102218A2 (de) 2009-09-23

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EP07871918A Withdrawn EP2102218A2 (de) 2006-12-12 2007-12-12 Verfahren zur herstellung von 1,3,2-oxazaborolidin-verbindungen

Country Status (6)

Country Link
US (1) US7586015B2 (de)
EP (1) EP2102218A2 (de)
CN (1) CN101657457A (de)
CA (1) CA2672619A1 (de)
FR (1) FR2909671B1 (de)
WO (1) WO2008078041A2 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2496553A4 (de) * 2009-11-05 2013-03-06 Biocon Ltd Neues verfahren zur herstellung von prostaglandinen und zwischenprodukten davon
CN102942525B (zh) * 2012-11-01 2014-08-06 万华化学集团股份有限公司 一种制备含脲二酮基团的多异氰酸酯的方法
CN103664976B (zh) * 2013-12-12 2015-11-04 惠州市莱佛士制药技术有限公司 一种顺式六氢呋喃并[2,3-b]呋喃-3-醇的制备方法
EP3705472B1 (de) 2017-10-31 2023-06-21 AGC Inc. Verfahren zur herstellung eines prostaglandinderivats
CN113943317B (zh) * 2021-10-31 2024-02-27 大连双硼医药化工有限公司 一种MeCBS固体的制备方法

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Publication number Priority date Publication date Assignee Title
US4943635A (en) * 1987-08-27 1990-07-24 President & Fellows Of Harvard College Enantioselective reduction of ketones
US5801280A (en) * 1995-04-07 1998-09-01 Sumitomo Chemical Company, Limited Processes for preparing optically active alcohols and optically active amines
US6509472B2 (en) * 2000-09-11 2003-01-21 Schering Corporation 4-Cyclohexyl-1,3,2-oxazaborolidine chiral accessories
AU2006259086B2 (en) * 2005-06-13 2011-05-26 Basf Se Process for synthesis of dialkoxyorganoboranes

Non-Patent Citations (1)

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Title
See references of WO2008078041A2 *

Also Published As

Publication number Publication date
WO2008078041A2 (fr) 2008-07-03
WO2008078041A3 (fr) 2008-11-13
FR2909671A1 (fr) 2008-06-13
US20080139851A1 (en) 2008-06-12
CN101657457A (zh) 2010-02-24
FR2909671B1 (fr) 2009-03-06
CA2672619A1 (fr) 2008-07-03
US7586015B2 (en) 2009-09-08

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