CA2085748A1 - Process for 2-deoxyglucosides - Google Patents
Process for 2-deoxyglucosidesInfo
- Publication number
- CA2085748A1 CA2085748A1 CA 2085748 CA2085748A CA2085748A1 CA 2085748 A1 CA2085748 A1 CA 2085748A1 CA 2085748 CA2085748 CA 2085748 CA 2085748 A CA2085748 A CA 2085748A CA 2085748 A1 CA2085748 A1 CA 2085748A1
- Authority
- CA
- Canada
- Prior art keywords
- formula
- deoxyglucoside
- process according
- acetyl
- preparation
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biotechnology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a process for the preparation of methyl tri-O-acetyl-2-deoxyglucoside by the reaction of tri-O-acetyl-D-glucal with methanol in the presence of hydrogen bromide or a source thereof. .alpha.-Methyl tri-O-acetyl-2-deoxyglucoside is especially useful as an intermediate in the preparation of pharmaceutically useful mevalonic acid derivatives.
Description
VO 91/19724 2C8579~8 PCr/GB91/00995 DESCRIPIION
THIS INVENTION relates to a new process for the preparation of intermediates useful in the preparation of pharmaceuticals, to their use in the preparation of said pharmaceu~.icals, and to pharmaceuticals prepared from said intermediates.
The new process of the present invention, which has not ~ee~ described specifically hitherto, is for -the preparation o~ methyl tri-O-acetyl-2-deoxyglucoside hereinafter depicted in formula I from tri-O-acetyl-D-glucal hereinafter depicted in formula II.
The pxocess is carried out by reaction with methanol in a suitable solvent selected from, for example, chloroform, dichloromethane, toluene, ethyl acetate, dimethylformamide, dimethyl sulphoxide, N-methylpyrrolidinonë 7 acetone, and ethers, e.g.
tetrahydrofuran and t-butyl methyl ether, and, more especially, acetonitrile and 1,2-dimethoxyethane, and in the presence of a catalyst comprising hydrogen bromide or a source thereof, for ex~mple h~drobromic acid or triphenylphosphine hydrobromide. Preferably the molar proportion of catalyst to starting material of formula II is at least 10~, preferably from 20% to 50%
or more. The reaction is conveniently carried out ~Osl/l9724 2C85748 pcT/GBsl/oo995 under an inert atmosphere, e~g. nitrogen, and at or near room temperature.
The compound of formula Ia is a key intermediate in a reaction sequence which permits the stereospecific preparation of analoguès of mevalonic acid without the necessity to use potentially hazardous mercury compounds employed in previously known processes described, for example, by Rosen et al, J. org. Chem., ~. _ 1984, 49, 3g94-4003 and Corey et al, J. Am. Chem. Soc., --1980, 102, 1439.
The use of compounds prepared by the pxocess of the present invention in a reaction seguence which permits the preparation of analogues of mevalo~ic acid, and analogues of mevalonic acid prepared thereby, are further features of the present ~nvention.
The said analogues of mevalonic acid are valuable pharmaceutically active compounds, more especially competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, and are consequently inhibitors of cholesterol biosynthesis and as a result are of use in the prevention or treatment of hypercholesterolaemic and hyperlipoproteinaemic states, atherosclerosis and as~sociated conditions.
Examples of such mevalonic acid analogues are described, for example, in the specifications of ... ; ' , . ' .
THIS INVENTION relates to a new process for the preparation of intermediates useful in the preparation of pharmaceuticals, to their use in the preparation of said pharmaceu~.icals, and to pharmaceuticals prepared from said intermediates.
The new process of the present invention, which has not ~ee~ described specifically hitherto, is for -the preparation o~ methyl tri-O-acetyl-2-deoxyglucoside hereinafter depicted in formula I from tri-O-acetyl-D-glucal hereinafter depicted in formula II.
The pxocess is carried out by reaction with methanol in a suitable solvent selected from, for example, chloroform, dichloromethane, toluene, ethyl acetate, dimethylformamide, dimethyl sulphoxide, N-methylpyrrolidinonë 7 acetone, and ethers, e.g.
tetrahydrofuran and t-butyl methyl ether, and, more especially, acetonitrile and 1,2-dimethoxyethane, and in the presence of a catalyst comprising hydrogen bromide or a source thereof, for ex~mple h~drobromic acid or triphenylphosphine hydrobromide. Preferably the molar proportion of catalyst to starting material of formula II is at least 10~, preferably from 20% to 50%
or more. The reaction is conveniently carried out ~Osl/l9724 2C85748 pcT/GBsl/oo995 under an inert atmosphere, e~g. nitrogen, and at or near room temperature.
The compound of formula Ia is a key intermediate in a reaction sequence which permits the stereospecific preparation of analoguès of mevalonic acid without the necessity to use potentially hazardous mercury compounds employed in previously known processes described, for example, by Rosen et al, J. org. Chem., ~. _ 1984, 49, 3g94-4003 and Corey et al, J. Am. Chem. Soc., --1980, 102, 1439.
The use of compounds prepared by the pxocess of the present invention in a reaction seguence which permits the preparation of analogues of mevalo~ic acid, and analogues of mevalonic acid prepared thereby, are further features of the present ~nvention.
The said analogues of mevalonic acid are valuable pharmaceutically active compounds, more especially competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, and are consequently inhibitors of cholesterol biosynthesis and as a result are of use in the prevention or treatment of hypercholesterolaemic and hyperlipoproteinaemic states, atherosclerosis and as~sociated conditions.
Examples of such mevalonic acid analogues are described, for example, in the specifications of ... ; ' , . ' .
2~57~
"'091/197~ PC~/GB91/00995 granted South African Patents Nos. 88/5~52 and 89/0645 and of their equivalents in other countries, for example United states Patent Applications Nos. 07~230038 and 07~302389.
The process of the present invention has good stereospecificity, i.e. the product contains a high ratio.
of ~-methyl tri-O-acetyl-2-deoxyglucoside, hereinafter depicted in formula Ia, to ~-methyl tri-O-acetyl-2-deoxyglucoside, he~einafter depicted in formula Ib~
typically a ratio of up to lO:l or more. The compound of .._ formul~ Ia may be sPparated by the application or adaptation of known methods, for example by chromatography, or, especially when the product contains at least 90% of Ia, it may be used as such.
The ~-methyl tri-0-acetyl-2-deoxyglucoside anomer is the preferred product because currently it is of greater utility in the preparation of pharmaceuticals than is the ~-methyl tri-O-acetyl-2-deoxyglucoside anomer.
The compound of formula Ia may be hydrolysed by the application or adaptation of known methods to give ~-methyl 2-deoxyglucoside, hereinafter depicted in formula III, which may thereafter be elaborated to prepare the said mevalonic acid analogues, by the application or adaptation of known methods.
Compounds of formula II may be prepared by the application or adaptation of known methods.
- By the ~erm "known methods" as used in this specifica~ion is meant methods used heretofore or known in the literature.
2~8574~3 ~0 91/19724 P~/CB91 /00995 ~ 4 --- C~3COOC~2 C~3COO '~\ ~ OC 3 C~3COO
C~ CGOC~
. CII3COO ~),.. ,OC~I3 Ia .
C~3COOC~2 CH3CCC ""~~ CC~3 Ib C~3C
C~3~~2 C~13COO "' ' S~ II
IIOCE[2~_o HO ~
~0 2~ 74~
`VO9l/l9724 PCT/GB91/00995 The following Examples illustrate the present invention.
In the Examples, "% cat" denol:es the molar proportion of catalyst to compound ol formula II in the initial reactio~ mixture, "TPHB" denotes triphenyl-phosphine hydrobromide, "aq.~3r" denotes 48%w/w hydrobromic acid, "DCM" denotes dichloromethane, "MeCN"
denotes acetonitrile, "DME" denotes 1,2-dimethoxy-. .~. _ -ethane,'"% yield" denotes the percentage yield of compound of formula I based upon the starting material of formula II, and ":~" denotes the ratio of the anomers in the product ~determined by examination of the nuclear magnetic resonance spectrum of the crude product in deuterochloroform).
` EX~MPLES 1 to 10 No.~ catcatal~st solvent % yield :~
1 5 TPHB DCM 75 2:1 2 5 TPHB MeCN 86 4:1 3 10 TP B MeCN 81 8:1 4 20 TP B MeCN 81 9:1 TP B MeCN 82 lO:1 6 20 TPHB DME 81 10:1 7 20 aq. B r DME 53 5:1 8 5 aq.~Br DME 38 2:1 9 5 ' aqOHBr MeCN 64 4:1 lQ 20 ~3r DME ~ 3:1 ~C85~48 --~091/19724 PCT/GB91/00995 In Examples 1 to lO the catalyst was added to a 10%w/w solution of tri-O-acetyl-D-glucal (4~moles) and methanol ~6mmoles) in the solvent at room temperature under nitrogen and stirred overnight at room temperature. The solution was then concentrated and the product was subjected to chromatography on silica gel, eluting with a mixture of ethyl acetate ancl cyclohexane (l:3v/v) to give a mixture of a-methyl tri-O-ace~yl-2-deoxyglucoside and ~-methyl tri-O-- -- acetyl-2-deoxyglucoside in the ratio stated in the table.
*In Example lO the product was a complex mixture.
% cat cataly~t solvent % ~ield a:~
20 HBr MeCN 93 5:l A 25%w/w solution of hydrogen bromide in 6 mmoles of methanol was added to a lO~w/w solution of tri-O-acetyl-D-glucal (4mmoles) in acetonitrile a~ room temperature under nitrogen and stirred overnight at room temperature. The solution was then concentrated and the residue was partitioned between water and dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with water, dried over magnesium sulphate, and concentrated in vacuo to give a mixture of a-methyl - ' : ' ' ' :, 2~857~8 ~91/19724 PCT/GB91/00995 tri-O-acetyl-2-deoxyglucoside and ~-methyl tri-O-acetyl-2-deoxyglucoside in the ratio 5:1.
"'091/197~ PC~/GB91/00995 granted South African Patents Nos. 88/5~52 and 89/0645 and of their equivalents in other countries, for example United states Patent Applications Nos. 07~230038 and 07~302389.
The process of the present invention has good stereospecificity, i.e. the product contains a high ratio.
of ~-methyl tri-O-acetyl-2-deoxyglucoside, hereinafter depicted in formula Ia, to ~-methyl tri-O-acetyl-2-deoxyglucoside, he~einafter depicted in formula Ib~
typically a ratio of up to lO:l or more. The compound of .._ formul~ Ia may be sPparated by the application or adaptation of known methods, for example by chromatography, or, especially when the product contains at least 90% of Ia, it may be used as such.
The ~-methyl tri-0-acetyl-2-deoxyglucoside anomer is the preferred product because currently it is of greater utility in the preparation of pharmaceuticals than is the ~-methyl tri-O-acetyl-2-deoxyglucoside anomer.
The compound of formula Ia may be hydrolysed by the application or adaptation of known methods to give ~-methyl 2-deoxyglucoside, hereinafter depicted in formula III, which may thereafter be elaborated to prepare the said mevalonic acid analogues, by the application or adaptation of known methods.
Compounds of formula II may be prepared by the application or adaptation of known methods.
- By the ~erm "known methods" as used in this specifica~ion is meant methods used heretofore or known in the literature.
2~8574~3 ~0 91/19724 P~/CB91 /00995 ~ 4 --- C~3COOC~2 C~3COO '~\ ~ OC 3 C~3COO
C~ CGOC~
. CII3COO ~),.. ,OC~I3 Ia .
C~3COOC~2 CH3CCC ""~~ CC~3 Ib C~3C
C~3~~2 C~13COO "' ' S~ II
IIOCE[2~_o HO ~
~0 2~ 74~
`VO9l/l9724 PCT/GB91/00995 The following Examples illustrate the present invention.
In the Examples, "% cat" denol:es the molar proportion of catalyst to compound ol formula II in the initial reactio~ mixture, "TPHB" denotes triphenyl-phosphine hydrobromide, "aq.~3r" denotes 48%w/w hydrobromic acid, "DCM" denotes dichloromethane, "MeCN"
denotes acetonitrile, "DME" denotes 1,2-dimethoxy-. .~. _ -ethane,'"% yield" denotes the percentage yield of compound of formula I based upon the starting material of formula II, and ":~" denotes the ratio of the anomers in the product ~determined by examination of the nuclear magnetic resonance spectrum of the crude product in deuterochloroform).
` EX~MPLES 1 to 10 No.~ catcatal~st solvent % yield :~
1 5 TPHB DCM 75 2:1 2 5 TPHB MeCN 86 4:1 3 10 TP B MeCN 81 8:1 4 20 TP B MeCN 81 9:1 TP B MeCN 82 lO:1 6 20 TPHB DME 81 10:1 7 20 aq. B r DME 53 5:1 8 5 aq.~Br DME 38 2:1 9 5 ' aqOHBr MeCN 64 4:1 lQ 20 ~3r DME ~ 3:1 ~C85~48 --~091/19724 PCT/GB91/00995 In Examples 1 to lO the catalyst was added to a 10%w/w solution of tri-O-acetyl-D-glucal (4~moles) and methanol ~6mmoles) in the solvent at room temperature under nitrogen and stirred overnight at room temperature. The solution was then concentrated and the product was subjected to chromatography on silica gel, eluting with a mixture of ethyl acetate ancl cyclohexane (l:3v/v) to give a mixture of a-methyl tri-O-ace~yl-2-deoxyglucoside and ~-methyl tri-O-- -- acetyl-2-deoxyglucoside in the ratio stated in the table.
*In Example lO the product was a complex mixture.
% cat cataly~t solvent % ~ield a:~
20 HBr MeCN 93 5:l A 25%w/w solution of hydrogen bromide in 6 mmoles of methanol was added to a lO~w/w solution of tri-O-acetyl-D-glucal (4mmoles) in acetonitrile a~ room temperature under nitrogen and stirred overnight at room temperature. The solution was then concentrated and the residue was partitioned between water and dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with water, dried over magnesium sulphate, and concentrated in vacuo to give a mixture of a-methyl - ' : ' ' ' :, 2~857~8 ~91/19724 PCT/GB91/00995 tri-O-acetyl-2-deoxyglucoside and ~-methyl tri-O-acetyl-2-deoxyglucoside in the ratio 5:1.
Claims (11)
1. A process for the preparation of methyl tri-O-acetyl-2-deoxyglucoside of the formula:
I
which comprises the reaction with methanol of a compound of the formula:
II
in the presence of a catalyst comprising hydrogen bromide or a source thereof.
I
which comprises the reaction with methanol of a compound of the formula:
II
in the presence of a catalyst comprising hydrogen bromide or a source thereof.
2. A process according to claim 1 in which the methyl tri-O-acetyl-2-deoxyglucoside product comprises at least 90% of .alpha.-methyl tri-O-acetyl-2-deoxyglucoside of the formula:
Ia
Ia
3. A process according to claim 1 or 2 in which the reaction is carried out in, as solvent, chloroform, dichloromethane, toluene, ethyl acetate, dimethylformamide, dimethyl sulphoxide, N-methylpyrrolidinone, acetone, tetrahydrofuran or t-butyl methyl ether.
4. A process according to claim 1 or 2 in which the process is carried out in, as solvent, acetonitrile or 1,2-dimethoxyethane.
5. A process according to any one of the preceding claims in which the reaction is carried out in the presence of, as catalyst, hydrobromic acid or triphenylphosphine hydrobromide.
6. A process according to any one of the preceding claims in which the molar proportion of catalyst to starting material of formula II is at least 10%.
7. A process according to claim 6 in which the molar proportion is from 20% to 50%.
8. A process according to any one of the preceding claims in which the reaction is carried out under an inert atmosphere and at or near room temperature.
9. A process for the preparation of .alpha.-methyl 2-deoxyglucoside of the formula III
which comprises the hydrolysis of a compound of the formula:
Ia
which comprises the hydrolysis of a compound of the formula:
Ia
10. Use of a compound of the formula Ia depicted in claim 9 in the preparation of mevalonic acid analogues.
11. Use of a compound of the formula III
depicted in claim 9 in the preparation of mevalonic acid analogues.
depicted in claim 9 in the preparation of mevalonic acid analogues.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909013699A GB9013699D0 (en) | 1990-06-20 | 1990-06-20 | New process |
| GB9013699.5 | 1990-06-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2085748A1 true CA2085748A1 (en) | 1991-12-21 |
Family
ID=10677881
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2085748 Abandoned CA2085748A1 (en) | 1990-06-20 | 1991-06-20 | Process for 2-deoxyglucosides |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0535083A1 (en) |
| JP (1) | JPH05507711A (en) |
| CA (1) | CA2085748A1 (en) |
| GB (1) | GB9013699D0 (en) |
| WO (1) | WO1991019724A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335182B (en) * | 2010-07-21 | 2013-04-17 | 苏州天人合生物技术有限公司 | Application of triacetylglucal in medicine preparation |
| CN103694279B (en) * | 2013-12-23 | 2015-12-02 | 江西苏克尔新材料有限公司 | A kind of method preparing 2-deoxidation-L-ribose |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4677211A (en) * | 1984-06-29 | 1987-06-30 | Sandoz Pharmaceuticals Corp. | Preparation of lactones |
| DE3722809A1 (en) * | 1987-07-10 | 1989-01-19 | Hoechst Ag | 3-DESMETHYL-4-FLUOR-MEVALONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS, THEIR USE AND INTERMEDIATE PRODUCTS |
-
1990
- 1990-06-20 GB GB909013699A patent/GB9013699D0/en active Pending
-
1991
- 1991-06-20 JP JP91511387A patent/JPH05507711A/en active Pending
- 1991-06-20 CA CA 2085748 patent/CA2085748A1/en not_active Abandoned
- 1991-06-20 WO PCT/GB1991/000995 patent/WO1991019724A2/en not_active Application Discontinuation
- 1991-06-20 EP EP19910911674 patent/EP0535083A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1991019724A3 (en) | 1992-02-20 |
| WO1991019724A2 (en) | 1991-12-26 |
| JPH05507711A (en) | 1993-11-04 |
| GB9013699D0 (en) | 1990-08-08 |
| EP0535083A1 (en) | 1993-04-07 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |