WO2021224295A1 - A process for producing d-biotin intermediates - Google Patents
A process for producing d-biotin intermediates Download PDFInfo
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- WO2021224295A1 WO2021224295A1 PCT/EP2021/061781 EP2021061781W WO2021224295A1 WO 2021224295 A1 WO2021224295 A1 WO 2021224295A1 EP 2021061781 W EP2021061781 W EP 2021061781W WO 2021224295 A1 WO2021224295 A1 WO 2021224295A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention is related to a process for the preparation of D-biotin intermediates.
- the D-Biotin also known as Vitamin H, is mainly applied to the fields of medicine and sanitation, nutrition enhancer, feed additive, cosmetics and drinks, etc.
- the molecular structural formula of the D-Biotin is shown as follows:
- the compound (b) is hydrogenated into compound (c) in the presence of a catalyst.
- high pressure i.e., about 30-40 bar of hydrogen pressure, is essential for this step, and the hydrogenation does not progress under lower pressure (see US 3740416).
- the process needs high investment on safety and regulatory requirements in industry.
- the present invention provides a process for producing a biotin intermediate compound of formula (I), or a geometrical isomer thereof or a geometrical isomeric mixture thereof in the presence of palladium hydroxide as a catalyst, wherein Ri and Ri' are independently H, lower alkyl, aryl or acyl group, optionally substituted by one or more substituents; and R is lower alkyl optionally substituted by lower alkoxyl or carboxyl group.
- the process surprisingly reduces the reaction pressure while maintaining high yield and selectivity in industrial scale, and thus saves investment on facility and increases safety in industry.
- the term "lower alkyl” as used refers to C -C alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms.
- the "lower alkyl” is Ci-C 6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert- butyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclonononyl, ter
- aryl refers to aromatic hydrocarbon such as substituted and unsubstitued phenyl, benzyl, xylyl and naphthalenyl.
- lower alkoxyl refers to the structure represented by (lower alkyl)-0-, wherein the “lower alkyl” is defined as above.
- substituted refers to lower alkyl, lower alkoxyl, hydroxyl (OH), phenyl, halo, NH 2 , and N0 2 .
- halo or halogen as used refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably refers to Cl or Br.
- the present invention provides a process for producing a compound of formula (I), or a geometrical isomer thereof or a geometrical isomeric mixture thereof, comprising hydrogenating a compound of formula (II), or a geometrical isomer thereof or a geometrical isomeric mixture thereof, in the presence of palladium hydroxide as a catalyst,
- Ri and Ri' are independently H, lower alkyl, aryl or acyl group, optionally substituted by one or more substituents; and R 2 is lower alkyl optionally substituted by lower alkoxyl or carboxyl group.
- Ri and Ri' are independently H, Ci-C 6 alkyl, aryl or Ci-C 6 acyl group, optionally substituted by one or more substituents. More preferably, Ri and Ri' are independently H, methyl, ethyl, propyl, butyl, phenyl, benzyl, formyl, acetyl, optionally substituted by one or more substituents. The most preferably, Ri and Ri' are independently H, benzyl or acetyl, optionally substituted by one or more substituents.
- R 2 is Ci-C 6 alkyl optionally substituted by Ci-C 6 alkoxyl or carboxyl group. More preferably R 2 is methyl, ethyl, propyl or butyl, optionally substituted by methoxyl or ethoxyl, or carboxyl group. The most preferably, R 2 is ethyl or propyl substituted by methoxyl or carboxyl group.
- Ri and Ri' are independently H, benzyl or acetyl; and R 2 is ethyl or propyl substituted by methoxyl.
- Ri and Ri' are independently H, benzyl or acetyl; and R 2 is ethyl or propyl substituted by carboxyl group.
- the geometrical isomer of the compound of formula (I) may be an isomer of formula (la) or (lb), and the geometrical isomer of the compound of formula (II) may be an isomer of formula (lla) or (lib): wherein Ri, Ri' and R 2 are dependently defined as above.
- the compound of formula (I) is one of the following compounds:
- the compound of formula (II) is preferably one of the following compounds:
- the catalyst may be added in an amount of from 0.05 mol to 0.15 mol, preferably from 0.06 mol to 0.12 mol, more preferably from 0.07 mol to 0.11 mol such as 0.08, 0.09, 0.1 and 0.11 mol, per 1 mole of the compound of formula (II).
- the catalyst may be loaded on a carrier known in the art.
- the carrier include but are not limited to activated carbon, silicon dioxide (Si0 2 ), titanium dioxide (Ti0 2 ), basic aluminum oxide (basic Al 2 0 3 ), cerium dioxide (Ce0 2 ), barium carbonate (BaC0 3 ), and barium sulphate (BaS0 ).
- the catalyst is loaded on a carrier.
- the catalyst may be loaded in an amount of from lwt% to 50wt%, preferably from 1.5wt% to 40wt%, more preferable from 2wt% to 30wt% such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30wt% of the carrier.
- the compound of the formula (II) is hydrogenated by hydrogen gas.
- the hydrogenation is carried out under a hydrogen pressure of less than 30 bar, preferably from 2 bar to 20 bar, more preferably from 2.5 bar to 15 bar such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 bar.
- a base may be added to increase the selectivity and reaction rate.
- a suitable base includes but are not limited to inorganic bases such as sodium hydroxide, sodium acetate and sodium carbonate, and organic bases such as triethylamine.
- the amount of the base may be from 0.1 eq to 10 eq, preferably from 0.2 eq to 8 eq, more preferably 0.3 eq to 5 eq such as 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4 and 5 eq, relative to the catalyst.
- the hydrogenation of the process according to the present invention may be carried out in a solvent known in the art.
- the solvent include but are not limited to alcoholic solvents such as methanol, ethanol and isopropanol; and aromatic solvents such as benzene, toluene and xylene; and ethyl acetate, acetone and water.
- the amount of the solvent used in the hydrogenation may be from 5 L to 50 L, preferably from 8 L to 40 L, more preferably from 2 L to 25 L such as 2, 4, 6, 8,10, 12, 14, 18, 20, 22, 24 and 25 L, per 1 mole of the compound of formula (II).
- the hydrogeneration of the process may be carried out at the temperature of 20°C to 100°C, preferably 25°C to 70°C such as 30, 40, 50, 60 and 70°C.
- the obtained compound of formula (I) may be used for further synthesis of biotin with or without isolation or purification by known process in the art such as concentration and extraction.
- the process of the present invention surprisingly reduces the reaction pressure while remaining comparable yield and selectivity in industrial scale, so it reduces investment on facility and increases safety.
- the compound 2 (9.5 g, 94.92% purity, 0.024 mol) in methanol (0.095 L) was added at room temperature. After purged with nitrogen gas twice, 20% Pd(OH) 2 on activated carbon (1.187 g, 0.00169 mol) was added in five lots for every four hours intervals and the reaction mixture was maintained at 4-5 bar hydrogen pressure at room temperature for 65 hours. After the reaction completed, the reaction mixture was cooled down to room temperature and filtered through celite followed by micron filters and the bed was washed by methanol (47.5 mL). Filtrate was concentrated to give the compound 1 as brown color liquid (HPLC purity: 92.18%, yield: 80.7%).
- the compound 2 (12.5 g, 0.0317 mol) in methanol (0.125 L) was added at room temperature and sodium acetate (0.125 g, 0.048 mol) was added to the reaction mass.
- 20% Pd(OH) 2 on activated carbon (2.5 g, 0.00356 mol) was added in four lots for every eight hours interval under nitrogen atmosphere.
- the reaction mixture was maintained at 4-5 bar hydrogen pressure at 50°C for 32 hours.
- the reaction mixture was filtered through celite bed followed by micron filters and the bed was washed by methanol (25 mL). Solvent was removed by distillation at below 45°C under vacuum to obtain the compound 1 (HPLC purity: 93.85%, Yield: 85%).
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Abstract
The present invention provides a process for producing a biotin intermediate compound of formula (I), or a geometrical isomer thereof or a geometrical isomeric mixture thereof in the presence of a catalyst, wherein R1 and R1' are independently H, lower alkyl, aryl or acyl group, optionally substituted by one or more substituents; and R2 is lower alkyl optionally substituted by lower alkoxyl or carboxyl group. According to the present invention, the process surprisingly reduces the reaction pressure while maintaining high yield and selectivity in industrial scale, and thus saves investment on facility and increases safety in industry.
Description
A process for producing D-biotin intermediates
Technical Field
The present invention is related to a process for the preparation of D-biotin intermediates.
Background of the Invention
The D-Biotin, also known as Vitamin H, is mainly applied to the fields of medicine and sanitation, nutrition enhancer, feed additive, cosmetics and drinks, etc. The molecular structural formula of the D-Biotin is shown as follows:
Since the debut of industrially synthetized D-biotin of a Swiss company Roche in 1949, the synthesis methods have been still undergone many researches in the world. To date, many about total synthesis routes have been reported. Yet, the most industrial process for D-biotin uses thiolactone compounds (a) to produce the intermediate compound (b) which is then converted by catalytic hydrogenation to the compound (c) and finally to the D-biotin (see US 3,740,416).
In the above process, the compound (b) is hydrogenated into compound (c) in the presence of a catalyst. However, high pressure, i.e., about 30-40 bar of hydrogen pressure, is essential for this step, and the hydrogenation does not progress under lower pressure (see US 3740416). As a result, the process needs high investment on safety and regulatory requirements in industry.
Therefore, there is still demand in a process with low pressure for producing intermediate compounds of biotin in industrial scale.
Summary of the Invention
The present invention provides a process for producing a biotin intermediate compound of formula (I), or a geometrical isomer thereof or a geometrical isomeric mixture thereof in the presence of palladium hydroxide as a catalyst,
wherein Ri and Ri' are independently H, lower alkyl, aryl or acyl group, optionally substituted by one or more substituents; and R is lower alkyl optionally substituted by lower alkoxyl or carboxyl group.
According to the present invention, the process surprisingly reduces the reaction pressure while maintaining high yield and selectivity in industrial scale, and thus saves investment on facility and increases safety in industry.
Description of the Invention
In the present invention, the term "lower alkyl" as used refers to C -C alkyl, i.e., branched or unbranched, cyclic or non-cyclic, saturated hydrocarbon comprising 1-10 carbon atoms. Preferably, the "lower alkyl" is Ci-C6 alkyl, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert- butyl, cyclobutyl, pentyl, iso-pentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl, cyclohexyl, octyl, isooctyl, tert-octyl, cyclooctyl, nonyl, isononyl, tert-nonyl, cyclononyl, decyl, isodecyl, tert-decyl, cyclodecyl. More preferably, the "lower alkyl" is methyl or ethyl.
In the present invention, the term "aryl" as used refers to aromatic hydrocarbon such as substituted and unsubstitued phenyl, benzyl, xylyl and naphthalenyl.
In the present invention, the term "acyl group" as used refers to the structure R'-C(=0)-, wherein R' is H or lower alkyl.
In the present invention, the term "lower alkoxyl" as used refers to the structure represented by (lower alkyl)-0-, wherein the "lower alkyl" is defined as above.
In the present invention, the term "carboxyl group" as used refers to the structure -C(=0)0H.
In the present invention, the term "substituents" as used refers to lower alkyl, lower alkoxyl, hydroxyl (OH), phenyl, halo, NH2, and N02.
In the present invention, the term "halo" or "halogen" as used refers to a group of elements including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I), preferably refers to Cl or Br.
The present invention provides a process for producing a compound of formula (I), or a geometrical isomer thereof or a geometrical isomeric mixture thereof, comprising hydrogenating a compound of formula (II), or a geometrical isomer thereof or a geometrical isomeric mixture thereof, in the presence of palladium hydroxide as a catalyst,
(II) (I) wherein Ri and Ri' are independently H, lower alkyl, aryl or acyl group, optionally substituted by one or more substituents; and R2 is lower alkyl optionally substituted by lower alkoxyl or carboxyl group.
Preferably, Ri and Ri' are independently H, Ci-C6 alkyl, aryl or Ci-C6 acyl group, optionally substituted by one or more substituents. More preferably, Ri and Ri' are independently H, methyl, ethyl, propyl, butyl, phenyl, benzyl, formyl, acetyl, optionally substituted by one or more substituents. The most preferably, Ri and Ri' are independently H, benzyl or acetyl, optionally substituted by one or more substituents.
Preferably, R2 is Ci-C6 alkyl optionally substituted by Ci-C6 alkoxyl or carboxyl group. More preferably R2 is methyl, ethyl, propyl or butyl, optionally substituted by methoxyl or ethoxyl, or carboxyl group. The most preferably, R2 is ethyl or propyl substituted by methoxyl or carboxyl group.
In one embodiment, Ri and Ri' are independently H, benzyl or acetyl; and R2 is ethyl or propyl substituted by methoxyl.
In another embodiment, Ri and Ri' are independently H, benzyl or acetyl; and R2 is ethyl or propyl substituted by carboxyl group.
In the present invention, the geometrical isomer of the compound of formula (I) may be an isomer of formula (la) or (lb),
and the geometrical isomer of the compound of formula (II) may be an isomer of formula (lla) or (lib):
wherein Ri, Ri' and R2 are dependently defined as above.
Preferably, the compound of formula (I) is one of the following compounds:
Correspondingly, the compound of formula (II) is preferably one of the following compounds:
In the process of the present invention, the catalyst may be added in an amount of from 0.05 mol to 0.15 mol, preferably from 0.06 mol to 0.12 mol, more preferably from 0.07 mol to 0.11 mol such as 0.08, 0.09, 0.1 and 0.11 mol, per 1 mole of the compound of formula (II).
In the process of the present invention, the catalyst may be loaded on a carrier known in the art. Examples of the carrier include but are not limited to activated carbon, silicon dioxide (Si02), titanium dioxide (Ti02), basic aluminum oxide (basic Al203), cerium dioxide (Ce02), barium carbonate (BaC03), and barium sulphate (BaS0 ).
Preferably, the catalyst is loaded on a carrier. In such cases, the catalyst may be loaded in an amount of from lwt% to 50wt%, preferably from 1.5wt% to 40wt%, more preferable from 2wt% to 30wt% such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30wt% of the carrier.
In the process of the present invention, the compound of the formula (II) is hydrogenated by hydrogen gas. Preferably, the hydrogenation is carried out under a hydrogen pressure of less than 30 bar, preferably from 2 bar to 20 bar, more preferably from 2.5 bar to 15 bar such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 bar.
In the process of the present invention, a base may be added to increase the selectivity and reaction rate. Examples of a suitable base includes but are not limited to inorganic bases such as sodium hydroxide, sodium acetate and sodium carbonate, and organic bases such as triethylamine. The amount of the base may be from 0.1 eq to 10 eq, preferably from 0.2 eq to 8 eq, more preferably 0.3 eq to 5 eq such as 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4 and 5 eq, relative to the catalyst.
The hydrogenation of the process according to the present invention may be carried out in a solvent known in the art. Examples of the solvent include but are not limited to alcoholic solvents such as methanol, ethanol and isopropanol; and aromatic solvents such as benzene, toluene and xylene; and ethyl acetate, acetone and water. The amount of the solvent used in the hydrogenation may be from 5 L to 50 L, preferably from 8 L to 40 L, more preferably from 2 L to 25 L such as 2, 4, 6, 8,10, 12, 14, 18, 20, 22, 24 and 25 L, per 1 mole of the compound of formula (II).
The hydrogeneration of the process may be carried out at the temperature of 20°C to 100°C, preferably 25°C to 70°C such as 30, 40, 50, 60 and 70°C. The obtained compound of formula (I) may be used for further synthesis of biotin with or without isolation or purification by known process in the art such as concentration and extraction.
Compared to the prior arts, the process of the present invention surprisingly reduces the reaction pressure while remaining comparable yield and selectivity in industrial scale, so it reduces investment on facility and increases safety.
The following Examples are intended to further illustrate the invention and are not to be construed as being limitations thereon.
Into an autoclave, the compound 2 (9.5 g, 94.92% purity, 0.024 mol) in methanol (0.095 L) was added at room temperature. After purged with nitrogen gas twice, 20% Pd(OH)2 on activated carbon (1.187 g, 0.00169 mol) was added in five lots for every four hours intervals and the reaction mixture was maintained at 4-5 bar hydrogen pressure at room temperature for 65 hours. After the reaction completed, the reaction mixture was cooled down to room temperature and filtered through celite followed by micron filters and the bed was washed by methanol (47.5 mL). Filtrate was concentrated to give the compound 1 as brown color liquid (HPLC purity: 92.18%, yield: 80.7%).
Into an autoclave, the compound 2 (12.5 g, 0.0317 mol) in methanol (0.125 L) was added at room temperature and sodium acetate (0.125 g, 0.048 mol) was added to the reaction mass. 20% Pd(OH)2 on activated carbon (2.5 g, 0.00356 mol) was added in four lots for every eight hours interval under nitrogen atmosphere. The reaction mixture was maintained at 4-5 bar hydrogen pressure at 50°C for 32 hours. After the reaction completed, the reaction mixture was filtered through celite bed followed by micron filters and the bed was washed by methanol (25 mL). Solvent was removed by distillation at below 45°C under vacuum to obtain the compound 1 (HPLC purity: 93.85%, Yield: 85%).
Example 3
A stirred solution of the compound 2 (25g, 0.064 mole) in methanol (125 ml) was treated with Norit CA1 activated carbon (2.5 g) twice at room temperature for 1 -2 hours. The reaction mass was filtered through celite bed and the celite bed was washed with methanol (75 ml). The filtrate and the washing were combined and taken into an autoclave for hydrogenation as follows. The reaction mass was purged with nitrogen gas for 20-30 min and added sodium acetate (0.25 g, 0.003 mole) followed by 10% Pd(OH (50% wet catalyst) (3.75 g). The reaction was maintained under 4-5 kg hydrogen pressure at room temperature for 10-12 hours and the progress of the reaction was monitored by HPLC. A second lot of 10% Pd(OH)2 (50% wet catalyst) (0.5 g) was added and the hydrogenation was continued with 4-5 kg hydrogen pressure at room temperature for 4-6 hours. After complete reaction, the hydrogen gas was released with nitrogen gas and the reaction mass was purged with nitrogen. The reaction mass was filtered through celite bed and the celite bed was washed with methanol (75 ml). The filtrate and the washing were combined and concentrated at below 50°C under vacuum to give the compound 1 (23.5g, 93.6% yield) with >95% purity by HPLC.
Claims
1. A process for producing a compound of formula (I), or a geometrical isomer thereof or a geometrical isomeric mixture thereof, comprising hydrogenating a compound of formula (II), or a geometrical isomer thereof or a geometrical isomeric mixture thereof, in the presence of palladium hydroxide as a catalyst,
(II) (I) wherein Ri and Ri' are independently H, lower alkyl, aryl or acyl group, optionally substituted by one or more substituents; and R is lower alkyl optionally substituted by lower alkoxyl or carboxyl group.
2. The process of claim 1, wherein Ri and Ri' are independently H, methyl, ethyl, propyl, butyl, phenyl, benzyl, formyl, acetyl, optionally substituted by one or more substituents.
3. The process of claim 1, wherein R2 is methyl, ethyl, propyl or butyl, optionally substituted by methoxyl or ethoxyl, or carboxyl group.
4. The process of claim 1, wherein Ri and Ri' are independently H, benzyl or acetyl; and R2 is ethyl or propyl substituted by methoxyl.
5. The process of claim 1, wherein Ri and Ri' are independently H, benzyl or acetyl; and R2 is ethyl or propyl substituted by carboxyl group.
7. The process of claim 1, wherein the compound of formula (II) is one of the following compounds:
8. The process of any one of claims 1-7, wherein the catalyst is added in an amount of from 0.05 mol to 0.15 mol, preferably from 0.06 mol to 0.12 mol, more preferably from 0.07 mol to 0.11 mol such as 0.08, 0.09, 0.1 and 0.11 mol, per 1 mole of the compound of formula (II).
9. The process of any one of claims 1-7, wherein the catalyst is loaded on a carrier.
10. The process of claim 9, wherein the carrier is selected from the group consisting of activated carbon, silicon dioxide (Si02), titanium dioxide (Ti02), basic aluminium oxide (basic Al203), cerium dioxide (Ce02), barium carbonate (BaC03), and barium sulphate (BaS0 ).
11. The process of claim 9 or 10, wherein the catalyst is loaded on the carrier in an amount of from lwt% to 50wt%, preferably from 1.5wt% to 40wt%, more preferable from 2wt% to 30wt% such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30wt% of the carrier.
12. The process of any one of claims 1-7, wherein the compound of the formula (II) is hydrogenated under a hydrogen pressure of less than 30 bar, preferably from 2 bar to 20 bar, more preferably from 2.5 bar to 15 bar such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15 bar..
13. The process of any one of claims 1-7, wherein the process is carried out in a solvent selected from the group consisting of alcoholic solvents such as methanol, ethanol and isopropanol; and aromatic solvents such as benzene, toluene and xylene; and ethyl acetate, acetone and water.
14. The process of any one of claims 1-7, wherein a base may be added into the reaction.
15. The process of claim 14, wherein the base is selected from the group consisting of inorganic bases such as sodium hydroxide, sodium acetate and sodium carbonate, and organic bases such as triethylamine.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3740416A (en) | 1969-11-29 | 1973-06-19 | Hoffmann La Roche | (+)-cis - 1,3-dibenzyl-hexahydro-1h-thieno-(3,4-d)imidazoles - 2,4-dione, and process for tis preparation |
EP0780392A1 (en) * | 1995-12-20 | 1997-06-25 | Sumitomo Chemical Company Limited | Process for preparing imidazole derivatives |
EP1462444B1 (en) * | 2001-12-04 | 2009-09-16 | Mitsubishi Tanabe Pharma Corporation | Intermediate for biotin and process for producing the same |
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- 2021-05-05 WO PCT/EP2021/061781 patent/WO2021224295A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3740416A (en) | 1969-11-29 | 1973-06-19 | Hoffmann La Roche | (+)-cis - 1,3-dibenzyl-hexahydro-1h-thieno-(3,4-d)imidazoles - 2,4-dione, and process for tis preparation |
EP0780392A1 (en) * | 1995-12-20 | 1997-06-25 | Sumitomo Chemical Company Limited | Process for preparing imidazole derivatives |
EP1462444B1 (en) * | 2001-12-04 | 2009-09-16 | Mitsubishi Tanabe Pharma Corporation | Intermediate for biotin and process for producing the same |
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