WO2001025215A2 - Verfahren zur selektiven spaltung cyclischer carbonsäureanhydride - Google Patents
Verfahren zur selektiven spaltung cyclischer carbonsäureanhydride Download PDFInfo
- Publication number
- WO2001025215A2 WO2001025215A2 PCT/EP2000/009636 EP0009636W WO0125215A2 WO 2001025215 A2 WO2001025215 A2 WO 2001025215A2 EP 0009636 W EP0009636 W EP 0009636W WO 0125215 A2 WO0125215 A2 WO 0125215A2
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- Prior art keywords
- alkyl
- atoms
- aryl
- radicals
- alkenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
Definitions
- the present invention relates to a new selective method
- a very important intermediate step in the biotin synthesis is the opening of the 'anhydride' (4S, 5R) -1, 3-dibenzyl-1 H-furo [3,4-d] imidazole-2,4,6-trione with alcohol for racemic mixing Halbester.
- the desired half-ester [4S, 5RJ-1, 3-dibenzyl-5-ethoxycarbonyl-2-oxo-imidazoline-4-carboxylic acid] is isolated from the mixture of the enantiomers by resolution with ephedrine.
- the ester function is then reduced to the hydroxymethyl group with borohydride and the ring acidifies to the 'lactone' (3aS, 6aR) -1, 3-dibenzyl-dihydro-1 H-furo [3,4-d] imidazole-2,4- dion closed.
- this optically active lactone is a known and valuable intermediate in the synthesis of (+) - biotin and of derivatives and related compounds thereof.
- the unwanted enantiomer is reintroduced into the synthesis cycle by saponification of the ester group and conversion of the dicarboxylic acid to the 'anhydride'.
- the throughput of this synthetic sequence can be significantly improved if the reaction of the 'anhydride' with the reagent is selective, i.e. one of the two possible products is preferably formed. With a correspondingly high selectivity, it is no longer necessary to recycle the undesired ring opening product, so that the processing time for the implementation is significantly shorter.
- EP 0 161 580 describes the reaction of the 'anhydride' with chiral secondary alcohols of the CH 3 CH (OH) R type in tetrahydrofuran in EP 0 161 580.
- the ( ⁇ S ⁇ RJ half ester is preferably formed, which - as described above - can be further converted to the 'lactone'.
- the free carboxylic acid group of the intermediate compound must first be esterified with an alcohol before the 'lactone' can be obtained by reduction with borohydrides and subsequent acidic cyclization.
- the invention therefore relates to a process for the selective cleavage of cycloanhydrides of the formula I.
- R denotes benzyl, alkyl having 1 to 6 carbon atoms or aryl
- X 1 and X 2 each represent R or OH, with the proviso that X 1 is not equal to X 2 and one of the two radicals is OH,
- R 2 in each case H, alkyl with 1-12 C atoms, unsubstituted or substituted cycloalkyi with 3-8 C atoms, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and condensed
- R and R 1 or R and R 2 together also mean unsubstituted or substituted cycloalkyi with 5-8 C atoms, which may also contain one or two O, N and / or S atoms and which may also be partially or may be completely unsaturated, and where the substituents may be alkyl, alkenyl, alkoxy, aryl, aryloxy, dialkylamine or generally aprotic radicals, with the proviso that at least one of the radicals R, R 1 and R 2 is an unsubstituted or substituted cycloalkyl, alkenyl , Heteroaryl, heteroarylalkyl or a condensed system, or R and R 1 or R and R 2 together also mean unsubstituted or substituted cycloalkyi having 5-8 C atoms, as described above,
- R 3 and R 4 are each alkyl with 1-12 C atoms, unsubstituted or substituted cycloalkyl with 3-8 C atoms, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and condensed systems, with the possible substituents described in R,
- X 1 and X 2 each represent R 'or OH, with the proviso that X 1 is not equal to X 2 and one of the two radicals is OH,
- R 6 in each case H, alkyl having 1-12 C atoms or aryl, which can be substituted by alkyl or alkoxy, and
- R 7 and R 8 are each alkyl with 1-12 C atoms or aryl, which can be substituted by alkyl or alkoxy,
- X 1 or X 2 have the meaning of R or R '
- the 25 two radicals X 1 and R or X 2 and R or X 1 and R ' or X 2 and R ' can have different meanings.
- alkyl means straight e r chain or branched alkyl having 1 to 12 carbon atoms, preferably having 1 to 8 carbon atoms, and is accordingly preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl , tert-butyl, pentyl, hexyl, heptyl or also octyl.
- alkyl in the formulas above and below particularly preferably denotes straight-chain or branched alkyl having 1 to 4 carbon atoms.
- Cycloalkyi means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or also cyclooctyl, which can also be substituted.
- Alkyl, alkoxy, alkenyl, aryl or aryloxy, dialkylamino and other aprotic radicals are preferred as substituents in the groups above and below. Are particularly preferred
- Substituents such as methyl, ethyl, methoxy, ethoxy, ethenyl, propenyl, phenyl, phenoxy, dimethylamino or diethylamino.
- Alkenyl preferably means ethenyl, propenyl, butenyl or pentenyl
- aryl preferably means phenyl and arylalkyl preferably means benzyl or phenethyl.
- Heteroaryl preferably means pyridinyl, pyrimidinyl and similar rings with heteroatoms, heteroarylalkyl consequently then means pyridinylmethyl, pyrimidinylmethyl and the like.
- the condensed systems are preferably the radicals naphthyl, biphenyl, quinolinyl or also cinnolinyl and similar systems.
- R in formula II preferably denotes aryl, heteroaryl and condensed aromatics, optionally with substituents such as alkyl, alkenyl, alkoxy, aryl, aryloxy or dialkylamino.
- R 1 and R 2 are preferably H or straight-chain alkyl having 1 to 4 carbon atoms.
- R 3 and R 4 likewise preferably denote the groups mentioned for R, R 1 and R 2 , but not H.
- those chiral auxiliaries are also suitable for the process according to the invention in which R and R 1 or R and R 2 together also contain unsubstituted or substituted cycloalkyl with 5-8
- C atoms preferably having 6-8 C atoms, and in particular 0 are cyclohexyl.
- cycloalkyl groups it is also possible for one or two, preferably non-adjacent, CH 2 groups to be replaced by O, S and / or N - ( . Atoms, and mean, for example, piperidinyl or dioxanyl. Furthermore, these cycloalkyl groups can also partially or are completely unsaturated, that is to say, for example, cyclohexenyl.
- chiral auxiliaries in which two or more, preferably 2 or 3, of the radicals R 1 to R 4 are linked to one another are also suitable for the process according to the invention.
- examples of such chiral auxiliaries are compounds in which the rest
- R 1 and R 2 have the meaning given above.
- R 3 here preferably denotes alkyl or alkenyl, in particular with up to 4 carbon atoms.
- substituents are also possible at other points in the ring systems.
- Alkyl, alkoxy, alkenyl, aryl, aryloxy, dialkylamino and other aprotic radicals are preferred as substitutes in the ring systems.
- Substituents such as methyl, ethyl, methoxy, ethoxy, ethenyl, propenyl, phenyl, phenoxy, dimethylamino or diethylamino are particularly preferred.
- Groups can also be substituted by alkyl, alkenyl, alkoxy, aryloxy, dialkylamino and generally aprotic radicals,
- R 1 and R 2 are each H, alkyl with 1-4 C atoms,
- R 3 and R 4 are each alkyl with 1-4 C atoms, and R and R 1 or
- R and R 2 together also unsubstituted or substituted
- Cycloalkyi with 5-8 C atoms including one or two
- N and / or S atoms can be contained and which can also be partially or completely unsaturated, and where the substituents alkyl, alkenyl, alkoxy, aryl,
- Aryloxy, dialkylamine or generally aprotic radicals are preferred.
- R ', R 5 and R 6 each preferably denote H, alkyl having 1-4 C atoms or aryl, which may be substituted by alkyl or alkoxy, and R 7 and R 8 each preferably alkyl having 1-4 C -Atoms or aryl, which can be substituted by alkyl or alkoxy.
- R ', R 5 and R 6 are particularly preferably methyl, ethyl, propyl, isopropyl or butyl, phenyl, benzyl, tolyl or methoxyphenyl.
- the process according to the invention is preferably carried out with the chiral auxiliary reagents of the formula II in an inert solvent at temperatures between 0 ° C. and the boiling point of the one used
- Solvent particularly preferably between 20 ° and 50 ° C.
- solvents are suitable as solvents.
- Solvents such as benzene, toluene, xylene, ethylbenzene, tetrahydrofuran, dioxane or other ethers, methylene chloride, chloroform or else ethyl acetate are preferably used.
- the solvents toluene, benzene or tetrahydrofuran are particularly preferred.
- auxiliary reagents of the formula III it has surprisingly been found that a higher selectivity of a diastereomer can be achieved with these compounds if the process is carried out here in toluene, benzene or xylene at temperatures between 15 ° and 35 ° C.
- Japanese patent application JP 58055464 describes the use of the chiral amino alcohols of the formula III for the preparation of optically active 2-oxoimidazolidine derivatives (by ring opening a
- Carboxylic anhydride is known.
- the method described in variant b) of this invention represents a selection invention with regard to this document.
- the reaction is carried out in tetrahydrofuran, preferably at temperatures as low as possible (around freezing point and below). Both educts are placed in the apparatus and THF is added as a solvent at 4 ° C, as a chiral auxiliary reagent (1 R, 2S) -2-
- the corresponding anhydride is suspended or dissolved in the solvent, then the chiral auxiliary reagent, dissolved in the same solvent, is slowly added.
- the reaction times are between 2 hours and 3 days, preferably between 2 and 20 hours.
- Suitable ratios of chiral auxiliary reagent to starting material are between 0.9 and 1.5 equivalents of auxiliary reagent. Preferred ratios are between 1.0 and 1.2 equivalents.
- Particularly preferred chiral auxiliaries for the inventive method n are selected from the following compounds:
- the chiral auxiliary reagents of the formula II or III can also be prepared, for example, from natural or unnatural amino acids.
- the free amino acid can be converted into the N, N-dimethyl compound using formaldehyde / H 2 / Pt (King, JA; McMillan, FHJ Am. Chem. Soc. 1951, 73, 4451-4453) and in alcohols are esterified under acidic catalysis (Davtyan, SM; Papayan, GL; Chachoyan, AM; Samvelyan, KG Pharm. Chem. J. 1982, 16, 517).
- the esterification Cohen, A .; Bergmann, ED Tetrahedron 1966, 22, 3545 - 3547 and Klyne, W .; Scopes, PM; Thomas, RN; Dahn, H.
- the scheme does not list the possibility of amino acids with NaBH (Abiko, A .; Masamune, S. Tetrahedron Lett. 1992, 33, 5517-5518) or LiAIH 4 (Dieter, RK; Deo, N .; Lagu, B .; Dieter, JWJ Org. Chem. 1992, 57, 1663 - 1671) to 2-aminoethanoien and then reductively alkylate these compounds (Dieter, RK; Deo, N .; Lagu, B .; Dieter, JWJ Org. Chem. 1992, 57, 1663-1671).
- the N, N-dialkylamino acid ester can be reduced by partial reduction with DiBAIH (Dondoni, A .; Perrone, D .; Merino, PJ Org. Chem. 1995, 60, 8074-8080) or complete reduction with LiAIH 4 and Swem Oxidation (Genisson, Y .; Mehmandoust, M .; Marazano, C; Das, BC Heterocycles 1994, 39, 811 - 818) of the resulting alcohol can be converted into N, N-dialkylamino aldehydes.
- DiBAIH Dondoni, A .; Perrone, D .; Merino, PJ Org. Chem. 1995, 60, 8074-8080
- LiAIH 4 and Swem Oxidation Genisson, Y .; Mehmandoust, M .; Marazano, C; Das, BC Heterocycles 1994, 39, 811 - 818
- the N, N-dialkylaminoaldehydes can be dialkylzinc (Andres, J. M .;
- the mixture of the diastereomeric half esters obtained can be checked for selectivity by HPLC.
- the half esters do not need to be isolated first, but can optionally be further processed in situ by reducing the ester function and cyclizing to the 'lactone'.
- the purity can then be checked by HPLC on a chiral column using known methods. This also proves that the chiral information in the reactions to the 'lactone' is passed on as expected.
- the above-mentioned disadvantages of the competitive process can be avoided.
- the combination of preferably a primary or secondary alcohol function and a tertiary amino group present in the structures mentioned allows only the formation of an ester bond in the reaction with the 'anhydride'.
- the amino group can, however, be protonated so that it can be assumed that the half ester is present as an inner salt.
- the reduction with borohydride formally cleaves the ester bond and the chiral auxiliary reagent is released unchanged. Under the conditions of the acidic cyclization to the 'lactone', the chiral auxiliary reagent is protonated and transferred to the water phase during processing. This makes it easy to separate and recover the auxiliary level.
- the solvents suitable for the process according to the invention are dependent on the reagent chosen, as are also in the different ones
- Variants a) and b) of the method is described.
- the (1 R, 2S) -N, N-dialkyl-ephedrines give significantly better results in toluene than in THF.
- the reactions with (-) - quinine take place both in THF and in
- the invention also relates to the use of the process according to the invention for the selective cleavage of (4S, 5R) -1, 3-dibenzyl-1 H-furo [3,4-d] imidazole-2,4,6-trione described above.
- Methyl ephedrine in 19 g of toluene was added dropwise at 24 ° -29 ° C. After another 4 h
- Methyl ephedrine was added dropwise in 14 g of THF. After stirring for 20 h at 64 ° C., a solution of 1.9 g (10.4 mmol; 70 mol%) of (+) - N-methyl-ephedrine is added
- reaction solution is cooled and turned on a rotary evaporator
- reaction is warmed to 62-64 ° C in 20 minutes, 70 minutes at this temperature and a further 14 h while cooling to room temperature
- Methyl ephedrine in 16 g of benzene was added dropwise at 24 ° -27 ° C. After stirring for a further 16 h at RT, the reaction solution is spun in.
- the solution of the crude product in 30 g THF and 2.47 g methanol is added dropwise within 125 minutes at 63 ° -64 ° C. to a suspension of 1.52 g (38.6 mmol; 261 mol%) sodium borohydride in 20 g THF and the reaction solution was stirred for a total of 3 h.
- the reaction solution is concentrated on a rotary evaporator, added dropwise to 36 g of demineralized water at about 57 ° C., and 9.54 ml of 37% HCl are added.
- the two-phase mixture is stirred at approx. 62 ° C. for 75 minutes and then with cooling to RT for 16 h.
- Rotary evaporator evaporated and the residue between 50 g of demineralized water, 8 ml of 32% NaOH solution and 100 g of toluene (pH 6.5 - 7).
- the aqueous phase is extracted with 20 ml of toluene and the organic extracts are spun in.
- the residue is washed with toluene / ethyl acetate
- reaction solution is concentrated for 95 minutes, the residue is taken up in 240 g of water, and 66 ml of 37% aqueous HCl solution are added.
- the emulsion is stirred for 2 hours at a reaction temperature of 70 ° C.
- the remaining THF is then distilled off, the water phase is adjusted to pH 5-5.5 with 38 ml of 32% sodium hydroxide solution and 200 g of toluene are added. After phase separation, the organic fraction is concentrated to the residue.
- the crude product thus obtained (30 g) is recrystallized from 75 g of toluene. Yield: 25.2 g (79%) Content: 99.9% (HPLC)
- N-methyl-ephedrine in 24 g of xylene was added dropwise at 24 ° -27 ° C. After stirring for a further 65 h at RT, the reaction solution is spun in.
- reaction solution is concentrated on a rotary evaporator, added dropwise to 36 g of demineralized water at about 55 ° C., and 9.54 ml of 37% HCl are added.
- the two-phase mixture is stirred for 75 minutes at approx. 62 ° C. and then with cooling to RT 5 for 16 h.
- the remaining THF is drawn off on a rotary evaporator,
- reaction solution is rotated in on a rotary evaporator and the residue is distributed between 100 g of demineralized water and 50 g of toluene.
- the organic extracts are spun in and the residue is added
- the solution of the crude product in 30 g THF and 2.48 g methanol is added dropwise within 2 h at 63 ° -64 ° C. to a suspension of 1.52 g (38.6 mmol; 261 mol%) sodium borohydride in 20 g THF and the reaction solution was stirred for a total of 3 h.
- the reaction solution is concentrated on a rotary evaporator, added dropwise at 36 ° C. to 36 g of demineralized water, and 9.52 ml of 37% HCl are added.
- the two-phase mixture is 75 minutes at about 62 ° C and then with cooling to RT
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU10208/01A AU1020801A (en) | 1999-10-06 | 2000-10-02 | Method for selectively dissociating cyclic carboxylic acid anhydrides |
EP00971309A EP1218349A2 (de) | 1999-10-06 | 2000-10-02 | Verfahren zur selektiven spaltung cyclischer carbonsäureanhydride |
US10/110,068 US6884893B1 (en) | 1999-10-06 | 2000-10-02 | Method for selectively dissociating cyclic carboxylic acid anhydrides |
JP2001528161A JP2003511374A (ja) | 1999-10-06 | 2000-10-02 | 環式カルボン酸無水物の選択的開裂方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19947953.4 | 1999-10-06 | ||
DE19947953A DE19947953A1 (de) | 1999-10-06 | 1999-10-06 | Verfahren zur selektiven Spaltung cyclischer Carbonsäureanhydride |
Publications (2)
Publication Number | Publication Date |
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WO2001025215A2 true WO2001025215A2 (de) | 2001-04-12 |
WO2001025215A3 WO2001025215A3 (de) | 2001-10-25 |
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ID=7924571
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2000/009636 WO2001025215A2 (de) | 1999-10-06 | 2000-10-02 | Verfahren zur selektiven spaltung cyclischer carbonsäureanhydride |
Country Status (6)
Country | Link |
---|---|
US (1) | US6884893B1 (de) |
EP (1) | EP1218349A2 (de) |
JP (1) | JP2003511374A (de) |
AU (1) | AU1020801A (de) |
DE (1) | DE19947953A1 (de) |
WO (1) | WO2001025215A2 (de) |
Cited By (1)
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US10986165B2 (en) | 2004-01-13 | 2021-04-20 | May Patents Ltd. | Information device |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US20060074248A1 (en) * | 2003-04-22 | 2006-04-06 | Christof Wehrli | Process for the stereoselective synthesis of lactones |
CN109748924A (zh) * | 2019-01-31 | 2019-05-14 | 浙江圣达生物药业股份有限公司 | 一种生物素手性内酯的不对称合成新方法 |
CN110804062B (zh) * | 2019-11-06 | 2021-03-30 | 浙江工业大学 | 一种(3s,6r)-1,3-二苄基四氢呋喃并咪唑-2,4-二酮的合成方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0044158A1 (de) * | 1980-07-10 | 1982-01-20 | Sumitomo Chemical Company, Limited | Optisch aktive 2-Imidazolidon-Derivate und ihre Herstellung |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5855464A (ja) * | 1981-09-29 | 1983-04-01 | Sumitomo Chem Co Ltd | 新規光学活性2−オキソイミダゾリジン誘導体およびその製法 |
-
1999
- 1999-10-06 DE DE19947953A patent/DE19947953A1/de not_active Withdrawn
-
2000
- 2000-10-02 US US10/110,068 patent/US6884893B1/en not_active Expired - Fee Related
- 2000-10-02 WO PCT/EP2000/009636 patent/WO2001025215A2/de not_active Application Discontinuation
- 2000-10-02 EP EP00971309A patent/EP1218349A2/de not_active Withdrawn
- 2000-10-02 JP JP2001528161A patent/JP2003511374A/ja active Pending
- 2000-10-02 AU AU10208/01A patent/AU1020801A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0044158A1 (de) * | 1980-07-10 | 1982-01-20 | Sumitomo Chemical Company, Limited | Optisch aktive 2-Imidazolidon-Derivate und ihre Herstellung |
Non-Patent Citations (1)
Title |
---|
PATENT ABSTRACTS OF JAPAN vol. 7, no. 143 (C-172), 22. Juni 1983 (1983-06-22) & JP 58 055464 A (SUMITOMO CHEM. CO. LTD.), 1. April 1983 (1983-04-01) in der Anmeldung erwähnt * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10986165B2 (en) | 2004-01-13 | 2021-04-20 | May Patents Ltd. | Information device |
Also Published As
Publication number | Publication date |
---|---|
US6884893B1 (en) | 2005-04-26 |
WO2001025215A3 (de) | 2001-10-25 |
DE19947953A1 (de) | 2001-04-12 |
EP1218349A2 (de) | 2002-07-03 |
AU1020801A (en) | 2001-05-10 |
JP2003511374A (ja) | 2003-03-25 |
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