GB2283971A - Preparation of 2-alkoxycycloalkanone - Google Patents
Preparation of 2-alkoxycycloalkanone Download PDFInfo
- Publication number
- GB2283971A GB2283971A GB9423015A GB9423015A GB2283971A GB 2283971 A GB2283971 A GB 2283971A GB 9423015 A GB9423015 A GB 9423015A GB 9423015 A GB9423015 A GB 9423015A GB 2283971 A GB2283971 A GB 2283971A
- Authority
- GB
- United Kingdom
- Prior art keywords
- enantiomer
- process according
- oxidation
- alkoxycycloalkanone
- oxidising agent
- 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.)
- Granted
Links
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 9
- 230000003647 oxidation Effects 0.000 claims abstract description 9
- 230000001737 promoting effect Effects 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 11
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical group Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 6
- 150000002576 ketones Chemical group 0.000 claims description 5
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- JYJURPHZXCLFDX-UHFFFAOYSA-N 2-methoxycyclohexan-1-one Chemical compound COC1CCCCC1=O JYJURPHZXCLFDX-UHFFFAOYSA-N 0.000 claims 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 5
- 235000011007 phosphoric acid Nutrition 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 235000011149 sulphuric acid Nutrition 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 3
- ZKQDCIXGCQPQNV-UHFFFAOYSA-N Calcium hypochlorite Chemical compound [Ca+2].Cl[O-].Cl[O-] ZKQDCIXGCQPQNV-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229910019093 NaOCl Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000005708 Sodium hypochlorite Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- 239000004296 sodium metabisulphite Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JYJURPHZXCLFDX-ZETCQYMHSA-N (2s)-2-methoxycyclohexan-1-one Chemical compound CO[C@H]1CCCCC1=O JYJURPHZXCLFDX-ZETCQYMHSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- RFAZFSACZIVZDV-UHFFFAOYSA-N butan-2-one Chemical group CCC(C)=O.CCC(C)=O RFAZFSACZIVZDV-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- -1 cycloalkane epoxide Chemical class 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- JQOAZIZLIIOXEW-UHFFFAOYSA-N zinc;chromium(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Cr+3].[Cr+3].[Zn+2] JQOAZIZLIIOXEW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/517—Saturated compounds containing a keto group being part of a ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A process for preparing an enantiomer of a 2-alkoxycycloalkanone comprises contacting a corresponding 2-alkoxycyclohexanol enantiomer with an oxidising agent, under conditions promoting the oxidation, wherein the oxidising agent is a hypohalite or a source thereof.
Description
OXIDATION PROCESS
2-Alkoxycycloalkanones in single-enantiomer form are important as pharmaceutical intermediates. For instance, EP-A-0416952 and EP-A-0416953 disclose that (S)-2-methoxycyclohexanone is a precursor of tricyclic B-lactam antibiotics.
Czech Patent Publication No. 265359/1990 discloses that the singleenantiomer 2-alkoxycycloalkanones can be obtained by oxidation of the hydroxyl group in the corresponding 2-alkoxycycloalkanols that are prepared, in turn, by a technique such as resolution of the racemate, e.g. by biocatalysis of an ester.
However, difficulty exists in the finding of an oxidation procedure that is scaleable and does not promote racemisation of the configurationally-labile product. For instance, the reported oxidation procedure of 2-alkoxycyclohexanols to the ketones using zinc chromite catalyst at over 3000C would certainly promote racemisation and, additionally, use of basic reaction conditions would result in racemised ketone product. Chromic acid is effective at the oxidation without promoting racemisation but the stoichiometric use of chromium is unacceptable on environmental grounds and similar difficulties emerge with other metal-based oxidation procedures.
According to the present invention, it has been found that using hypohalorite as oxidant gives a surprisingly high yielding oxidation, with minimal racemisation, in a conversion as represented in Scheme 1. The procedure is scaleable and economic.
In Scheme 1, n indicates that the ring is of 5-8 C atoms, Rl is C,10 alkyl and R2 represents H or optional substituent(s) in the ring which do not directly affect the oxidation reaction. A particularly valuable case is where R2 is a substituent vicinal to the hydroxyl function, prepared for example by opening of the 2,3-epoxy-1 -alkoxycycloalkanone with an alkyl (R2) nucleophile. Configuration at the hydroxyl group could be cis or trans to the adjacent alkoxy substituent, depending on the mode of preparation; for instance, if prepared by reaction of a cycloalkane epoxide with an alcohol (R'OH), the hydroxyl group would be trans to the alkoxy.The configuration at the alkoxy function could be as indicated in
Scheme 1 or, equally, as the opposite enanriomer The reaction is preferably conducted using simply an oxidising mixture of a hypohalite, e.g. hypochlorite, or a source thereof which generates the hypohalite in situ. For example, the oxidising agent may be an aqueous solution of sodium hypochlorite or, for example, calcium hypochlorite, an organic solvent, and an acid.
The hypochlorite source may be bleaching powder. The acid is any that can provide a pH < 2; examples are sulphuric acid, hydrochloric acid, phosphoric acid and potassium hydrogen sulphate. Preferred solvents possess a ketone function, such as acetone, methyl ethyl ketone or methyl isobutyl ketone.
The following Example illustrates the invention.
ExamDle
A solution of lS,S]-2-methoxycyclohexanol (194 g, 1.5 mol) in acetone (1164 ml) was added to a stirred mixture of orthophosphoric acid (85%; 291 g, 2.45 mol) in water (11 64 ml). With the mixture maintained at less than 250C and pH < 1.7, sodium hypochlorite solution (8% min. available chlorine, 1261 ml) was added over 1-2 h. The mixture was then stirred for a further 0.5 h and excess oxidant destroyed by the addition of sodium metabisulphite until the mixture no longer darkened start-iodide paper. A further amount of sodium metabisulphite was added (5 g) and the product extracted with methyl tert-butyl ether (4 x 450 ml).The combined extracts were washed with 30% sodium chloride solution (660 ml), dried over magnesium sulphate and concentrated under vacuum to give the product (as 180 ml being a 90% solution of product).
The following Table shows the results from a series of experiments, using a variety of related reaction conditions.
TABLE SHOWING RESULTS FROM MCH EXPERIMENTATION
No Oxidant Solvent* Acid Complete? EE+ 2 equiv 1 5% NaOCl MEK H2SO4 100% 97 1 equiv 2 " xI n N HOAc 0% NA 3 " " " " KHSO4 0% NA 0.4 equiv 4 " " NONE " " 0% NA 5 * n MEK KHSO4 95% 96% 4 equiv 6 " " " " NaHSO4 75% NA 7 " " MEK KHSO4 50% NA 2,2 equiv 8 " " DCM " " 50% NA 9 " " Heptane H2SO4 10% NA 1 equiv 10 " " NONE " " 40% NA 11 " " MEK H2SO4 98% 97% 12 " " MIBK " " 97% 91% 13 " " MEK " " 100% 97% 14 " " Acetone " " 100% 97% 15 8% NaOCl " " " " 97% 93% 16 " " " " H3PO4 100% 97% 17 " " " " HCl 100% 97% 18 " " " " H3PO4 100% 97% 19 " " " " HCl 95% 96% 20 Ca(OCl)2 " " H3PO4 82% NA * MEK = methyl ethyl ketone (2-butanone)
DCM = dichloromethane
MIBK = methyl isobutyl ketone + Enantiomeric excess of recovered ketone product
Scheme 1
Claims (6)
- CLAIMS 1. A process for preparing an enantiomer of a 2-alkoxycycloalkanone by contacting a corresponding 2-alkoxycyclohexanol enantiomer with an oxidising agent, under conditions promoting the oxidation, wherein the oxidising agent is a hypohalite or a source thereof.
- 2. A process according to claim 1, which is conducted in the presence of an acid, providing acidity at least equivalent to 2.2 eq. KHSO4.
- 3. A process according to claim 2, which is conducted in the presence of a solvent.
- 4. A process according to claim 3, wherein the solvent is a ketone.
- 5. A process according to any preceding claim, wherein the product is an enantiomer of 2-methoxycyclohexanone.
- 6. A process according to any preceding claim, wherein the oxidising agent is a hypochlorite.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB939323632A GB9323632D0 (en) | 1993-11-16 | 1993-11-16 | Oxidation process |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9423015D0 GB9423015D0 (en) | 1995-01-04 |
| GB2283971A true GB2283971A (en) | 1995-05-24 |
| GB2283971B GB2283971B (en) | 1997-11-26 |
Family
ID=10745262
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB939323632A Pending GB9323632D0 (en) | 1993-11-16 | 1993-11-16 | Oxidation process |
| GB9423015A Expired - Fee Related GB2283971B (en) | 1993-11-16 | 1994-11-15 | Oxidation process |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB939323632A Pending GB9323632D0 (en) | 1993-11-16 | 1993-11-16 | Oxidation process |
Country Status (1)
| Country | Link |
|---|---|
| GB (2) | GB9323632D0 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998000382A1 (en) * | 1996-07-02 | 1998-01-08 | Toray Industries, Inc. | Processes for the preparation of optically active ketones |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4005932A1 (en) * | 1990-02-25 | 1991-08-29 | Bayer Ag | Cycloalkanone(s) prepn., useful as plant protectant intermediates |
-
1993
- 1993-11-16 GB GB939323632A patent/GB9323632D0/en active Pending
-
1994
- 1994-11-15 GB GB9423015A patent/GB2283971B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4005932A1 (en) * | 1990-02-25 | 1991-08-29 | Bayer Ag | Cycloalkanone(s) prepn., useful as plant protectant intermediates |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998000382A1 (en) * | 1996-07-02 | 1998-01-08 | Toray Industries, Inc. | Processes for the preparation of optically active ketones |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9323632D0 (en) | 1994-01-05 |
| GB2283971B (en) | 1997-11-26 |
| GB9423015D0 (en) | 1995-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tanaka et al. | A novel “Ti (O)” induced allylation of imines in a TiCl4 (cat.)/A1 bimetal system. Chirality transfer of l-valine to homoallylamine | |
| US20040077901A1 (en) | Process for the synthesis of trifluorophenylacetic acids | |
| AU626488B2 (en) | Peroxide process for producing n-phosphonomethylglycine | |
| CN113549659A (en) | A kind of method for preparing β-haloether and β-halohydrin catalyzed by peroxidase | |
| JPH02199002A (en) | Method for recovering hydrobromic acid and methanol | |
| DE2834547A1 (en) | PRODUCTION OF (1R, CIS) CARONALDEHYDIC ACID | |
| GB2283971A (en) | Preparation of 2-alkoxycycloalkanone | |
| Takai et al. | Stereoselective addition of α-chloro allylic chromium reagents to aldehydes | |
| JPH07505405A (en) | Manufacturing method of sclareolide | |
| US4347386A (en) | Process for preparing cyclopentenolones | |
| JPWO2001066495A1 (en) | Method for producing higher-order oxides of alcohols | |
| JPH05310671A (en) | Production of 4-chloro-3-hydroxybutyronitrile | |
| US5998634A (en) | One-step synthesis of vitamin-C (L-ascorbic acid) | |
| CA1313879C (en) | Process for the production of high-purity tetrachloro -1,4-benzoquinone | |
| EP0897910B1 (en) | Process for the preparation of 2-carboxy-5-nitrobenzene sulphonic acid and its salts by oxidation | |
| EP1463706B1 (en) | Process for production of 3,3-dimethyl-2-formylcyclopropanecarboxylic acid derivatives | |
| JPH10212281A (en) | Method for producing 3-carane epoxide | |
| US4339607A (en) | Process for preparing anisaldehyde | |
| CN107879925B (en) | Synthesis method of high-purity high-yield L-2-chloropropionic acid | |
| US4906416A (en) | Preparation of perfluoroalkanecarboxylic acids and novel perfluoroalkanedichloroethylenes obtained | |
| Young et al. | Stereoselective synthesis of some acetylenic analogues of leukotrienes A and D | |
| EP0180325B1 (en) | Process for the manufacture of (ir,cis)-4-acetyl-6,6-dimethyl-3-oxa-bicyclo(3.1.0)hex-2-one | |
| KR100245772B1 (en) | Monobromination process of 6-aminopenicillanic acid | |
| Kim et al. | UNEXPECTED IODINE CATALYZED CYCLIZATION FOR | |
| HU205081B (en) | Process for produicng 3-methylquinoline-8-carboxylic acid and its derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20001115 |