Improved method for producing D-biotin intermediate

Abstract

The present invention provides a process for the production of a compound of general formula (I) comprising hydrogenating a compound of general formula (II) in the presence of a catalyst comprising nickel and a nickel oxide to obtain a compound of general formula (I) # imgabs0 # wherein R1 and R1'are each independently H, lower alkyl, aryl or acyl, optionally substituted by one or more substituents; and R2 is lower alkyl, optionally substituted by lower alkoxy or carboxyl.

Description

Technical Field

[0001] The present invention relates to a method for preparing a D-biotin intermediate. Background Art

[0002] D-biotin, also known as vitamin H, is mainly used in the fields of medicine and health, nutrition, feed additives, cosmetics and beverages. The molecular structure of D-biotin is shown below:

[0003]

[0004] Since the first industrial synthesis of D-biotin by Roche in 1949, the synthesis method has been explored by researchers around the world. To date, many total synthesis routes have been reported. However, the most commonly used industrial production method of D-biotin uses a thiolactone compound (a) to produce an intermediate compound (b), which is then converted to a compound (c) by catalytic hydrogenation and finally converted to D-biotin. In the catalytic hydrogenation step, a hydrogen pressure of 40 atmospheres and a 10 wt% Raney-nickel catalyst are used (see US 3,740,416 A).

[0005]

[0006] An improved catalytic hydrogenation process for compound (b) uses 5 wt% palladium on carbon and 50 bar hydrogen pressure and provides a yield of about 70% for compound (c) (see US Pat. No. 4,876,350 A).

[0007] However, all of the above methods generate a large amount of by-products, which limits the selectivity and efficiency of the methods.

[0008] Therefore, there is still a need in industry for improved methods for producing biotin intermediates. Summary of the invention

[0009] The present invention provides an improved process for producing an intermediate compound (I), comprising hydrogenating a compound (II) in the presence of a catalyst comprising nickel metal and nickel oxide to obtain a compound (I).

[0010]

[0011] wherein R1 and R1' are each independently H, lower alkyl, aryl or acyl, optionally substituted by one or more substituents; and R2 is lower alkyl, optionally substituted by lower alkoxy or carboxyl.

[0012] According to the method of the present invention, compound (II) can be hydrogenated to compound (I) in high yield while the amount of by-products produced is significantly reduced. Therefore, the method of the present invention has higher selectivity and efficiency compared with the prior art. DETAILED DESCRIPTION

[0013] In the present invention, the term "lower alkyl" refers to a C1-C 10 The term "lower alkyl" refers to an alkyl group, i.e., a branched or straight chain, cyclic or acyclic saturated hydrocarbon containing 1 to 10 carbon atoms. More preferably, the "lower alkyl" is an alkyl group of C1-C6, including but not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, isopentyl, tert-pentyl, cyclopentyl, hexyl, isohexyl, tert-hexyl and cyclohexyl. More preferably, the "lower alkyl" is methyl or ethyl.

[0014] In the present invention, the term "aryl" refers to aromatic hydrocarbons such as substituted and unsubstituted phenyl, tolyl, xylyl and naphthyl.

[0015] In the present invention, the term "acyl" refers to the structure R'-C(=O)-, wherein R' is H or lower alkyl or aryl.

[0016] In the present invention, the term "lower alkoxy" refers to a structure represented by (lower alkyl)-O-, wherein "lower alkyl" is as defined above.

[0017] In the present invention, the term "carboxyl group" refers to the structure -C(=O)OH.

[0018] In the present invention, the term "halogen" or "halo" refers to an element group including fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0019] In the present invention, the term "substituent" or "substituent group" refers to a C1-C6 alkyl group, a C1-C6 alkoxy group, a C1-C6 alkylthio group, an aryl group, a hydroxyl group, a halogen group, a halide group, -NH2, -NO2, a cyano group and / or an isocyano group.

[0020] In the present invention, the term "nickel metal" refers to nickel in an oxidation state of zero.

[0021] In the present invention, the term "nickel oxide" refers to oxide forms of nickel such as NiO, Ni2O3 and NiO2.

[0022] The present invention particularly provides a method for producing a compound of general formula (I), comprising hydrogenating a compound of general formula (II) in the presence of a catalyst comprising nickel metal and nickel oxide to obtain a compound of general formula (I).

[0023]

[0024] wherein R1, R1' and R2 are each independently as defined above.

[0025] Preferably, R1 and R1' are each independently H, C1-C6 alkyl, aryl or C1-C6 acyl, optionally substituted by one or more substituents. More preferably, R1 and R1' are each independently H, methyl, ethyl, propyl, butyl, phenyl, benzyl, formyl, acetyl, benzoyl, optionally substituted by one or more substituents. Most preferably, R1 and R1' are each independently H, benzyl, acetyl or benzoyl, optionally substituted by one or more substituents.

[0026] Preferably, R2 is C1-C6 alkyl, optionally substituted by C1-C6 alkoxy or carboxyl. More preferably, R2 is methyl, ethyl, propyl or butyl, optionally substituted by methoxy or ethoxy, or carboxyl. Most preferably, R2 is ethyl or propyl substituted by methoxy or carboxyl.

[0027] In one embodiment, R1 and R1' are each independently H, benzyl, acetyl or benzoyl; R2 is ethyl or propyl substituted with methoxy, such as -CH2CH2OCH3.

[0028] In another embodiment, R1 and R1' are each independently H, benzyl, acetyl or benzoyl; and R2 is ethyl or propyl substituted with carboxyl, for example -CH2CH2CH2COOH.

[0029] In the process of the present invention, the catalyst contains 30wt%-80wt%, preferably 40wt%-70wt% of nickel metal, and 5wt%-40wt%, preferably 10wt%-30wt% of nickel oxide based on the total weight of the catalyst.

[0030] In the process of the present invention, the catalyst may also contain a carrier known in the prior art. Examples of carriers include, but are not limited to, activated carbon, silicon dioxide (SiO2), titanium dioxide (TiO2), basic aluminum oxide (basic Al2O3), cerium dioxide (CeO2), barium carbonate (BaCO3) and barium sulfate (BaSO4).

[0031] The catalyst can be prepared by prior art processes or purchased commercially. Preferably, the catalyst is one of the "NiSat" catalyst series, such as NiSat 760, NiSat 730 and NiSat 720 (Clariant Product GmbH, Germany).

[0032] In the method of the present invention, the amount of catalyst used is based on the weight of the compound of general formula (II), ranging from 0.01wt% to 10wt%, preferably from 0.02wt% to 1wt%, more preferably from 0.05wt% to 0.5wt%, for example 0.05wt%, 0.1wt%, 0.12wt%, 0.15wt%, 0.2wt%, 0.25wt%, 0.3wt%, 0.35wt%, 0.4wt%, 0.45wt% and 0.5wt% (calculated based on the total amount of nickel contained in the catalyst).

[0033] In the process of the present invention, the catalyst obtained from the catalyst manufacturer can be used directly, or the catalyst can be subjected to a pretreatment and / or activation step before being used in the process of the present invention. The pretreatment and / or activation step may include treatment with hydrogen at room temperature or at an elevated temperature.

[0034] In the process of the present invention, compound (II) is hydrogenated by hydrogen. Preferably, the hydrogenation is carried out at a hydrogen pressure of less than 50 bar, more preferably from 5 bar to 40 bar, particularly preferably from 10 bar to 35 bar, for example 30 bar.

[0035] The hydrogenation process of the present invention can be carried out in a solvent known in the prior art. Examples of solvents include, but are not limited to, alcohol solvents such as methanol, ethanol and isopropanol; aromatic solvents such as benzene, toluene and xylene; ethers such as tetrahydrofuran and 2-methyltetrahydrofuran; esters such as ethyl acetate and isopropyl acetate; and acetone and water. The amount of solvent used in the hydrogenation can be from 0.5 liters to 50 liters, preferably from 2 liters to 40 liters, more preferably from 2 liters to 25 liters, for example 2, 4, 6, 8, 10, 12, 14, 18, 20, 22, 24 and 25 liters per 1 mole of compound (II).

[0036] The hydrogenation process may be carried out at a temperature of 20°C to 100°C, preferably 25°C to 70°C, such as 30, 40, 50, 60 and 70°C.

[0037] According to the process of the present invention, compound (II) can be hydrogenated to compound (I) in high yield while significantly reducing the amount of by-products.

[0038] The present invention also provides a method for producing (+)-biotin, which comprises the method for producing compound (I) as described above.

[0039] The method of the present invention is further illustrated by the following examples.

[0040] Example

[0041]

[0042] In an autoclave, THE (2.5 g) was dissolved in methanol (20 ml). The catalyst was added to the reaction mixture. After flushing with nitrogen, the reaction mixture was stirred at 30 bar of hydrogen pressure and 50° C. After reacting for 16 hours, the reaction mixture was cooled to room temperature, hydrogen was released, and the reactor was flushed with nitrogen. After evaporating all volatile substances, the yield was determined by gas chromatography (GC). The results are shown in Table 1.

[0043] Table 1

[0044]

[0045] 1. NiSat 720RS Pow, NiSat 730RS Pow and NiSat 760RS Pow are catalysts containing 50-70% nickel, of which at least 40% is nickel metal, provided by ClariantProduct GmbH of Germany.

[0046] 2. Nickel alloy MC113 is an active nickel alloy catalyst provided by Evonik of Germany, containing nickel metal and aluminum.

[0047] 3. Nickel catalyst A-7063 is an active nickel alloy catalyst provided by Johnson Matthey Company of the United States, containing nickel metal, aluminum, and molybdenum as an additive.

[0048] 4. Cobalt catalyst A-8B46 is an active cobalt catalyst produced by Johnson Matthey Company in the United States. It contains nickel metal, aluminum, and iron and chromium as additives.

[0049] 5. Nickel on silica gel Ni-5249P is a reduced nickel catalyst supported on silica gel provided by Strem Chemicals Inc. of the United States, containing nickel metal.

Claims

1. A method for producing a compound of general formula (I), comprising hydrogenating a compound of general formula (II) in the presence of a catalyst comprising nickel metal and nickel oxide to obtain a compound of general formula (I), wherein R1 and R1' are each independently H, lower alkyl, aryl or acyl, optionally substituted by one or more substituents; and R2 is lower alkyl, optionally substituted by lower alkoxy or carboxyl.

2. The method according to claim 1, wherein R1 and R1' are each independently H, benzyl, acetyl or benzoyl; R2 is ethyl or propyl, which is substituted by methoxy, preferably -CH2CH2OCH3.

3. The method according to claim 1, wherein R1 and R1' are each independently H, benzyl, acetyl or benzoyl; and R2 is ethyl or propyl, which is substituted by a carboxyl group, preferably -CH2CH2CH2COOH.

4. The process according to any one of claims 1 to 3, wherein the catalyst contains 30 wt% to 80 wt%, preferably 40 wt% to 70 wt% of nickel metal, and 10 wt% to 40 wt%, preferably 15 wt% to 30 wt% of nickel oxide, based on the total weight of the catalyst.

5. The method according to claim 4, wherein the catalyst is one of the "NiSat" catalyst series, including but not limited to NiSat 760, NiSat 730 and NiSat 720.

6. A method according to any one of claims 1 to 3, wherein the amount of catalyst used is 0.01wt% to 10wt%, preferably 0.02wt% to 1wt%, more preferably 0.05wt% to 0.5wt% (calculated based on the total amount of nickel contained in the catalyst) based on the weight of the compound of general formula (II).

7. The process according to any one of claims 1 to 3, wherein the hydrogenation is carried out in a solvent selected from the group consisting of: alcohol solvents such as methanol, ethanol and isopropanol; aromatic solvents such as benzene, toluene and xylene; ethers such as tetrahydrofuran and 2-methyltetrahydrofuran; esters such as ethyl acetate and isopropyl acetate; and acetone and water.

8. The process according to any one of claims 1 to 3, wherein the hydrogenation is carried out at a hydrogen pressure of less than 50 bar, preferably from 5 bar to 40 bar, more preferably from 10 bar to 35 bar, such as 30 bar.

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