Process for production of biotin intermediates

Abstract

The present application relates to a novel process for the production of imidazolidine compounds of formula (I) or salts thereof or stereoisomers thereof or stereoisomeric mixtures thereof. According to the process of the invention, additional reducing agents such as zinc are avoided and imidazolidine compounds of formula (I), or salts thereof, or stereoisomers thereof, or stereoisomers thereof, are produced in high yield and selectivity, # imgabs0 wherein: R1 and R2 are each independently of one another lower alkyl, optionally substituted with one or more substituents, or R1 and R2 together with the carbon atom to which they are attached form a lower cycloalkyl group optionally substituted by one or more substituents; r3 is H or a protecting group suitable for a nitrogen atom; and X and Y are each independently of one another O or S.

Description

Technical Field

[0001] The present invention relates to a process for producing an important biotin intermediate. Background Art

[0002] D-biotin, also known as vitamin H, is mainly used in medicine and health, nutritional supplements, feed additives, cosmetics and beverages. The molecular structure of D-biotin is as follows:

[0003]

[0004] Since the Swiss company Roche first introduced industrially synthesized D-biotin in 1949, its synthesis method has been extensively studied worldwide. To date, many general synthetic routes have been reported. However, most industrial methods for D-biotin use lactone compounds (a) to produce intermediate compounds (b), which are then converted into compounds (c) by catalytic hydrogenation and finally converted into D-biotin (see US 3,740,416).

[0005]

[0006] A known method for producing the above-mentioned lactone compound (a) comprises converting an intermediate compound of formula (d) derived from L-cysteine ​​or L-serine into a compound of formula (e) in two steps, followed by reduction with zinc in an acidic medium to obtain an imidazolidine compound (f), which is cyclized to obtain a lactone compound (a) (see US 5,095,118 A). This method requires a reducing agent such as zinc, which has safety issues in industry and generates a large amount of waste.

[0007]

[0008] Therefore, there remains a need for new methods for producing lactone compounds or intermediates thereof. Summary of the invention

[0009] The present invention provides a novel method for producing an imidazolidine compound of formula (I) or a salt thereof or a stereoisomer thereof or a mixture of stereoisomers thereof from a compound of formula (II) or a salt thereof or a stereoisomer thereof or a mixture of stereoisomers thereof:

[0010]

[0011] in:

[0012] R1 and R2 are each independently lower alkyl, optionally substituted by one or more substituents, or

[0013] R1 and R2 together with the carbon atoms to which they are attached form a lower cycloalkyl group, optionally substituted with one or more substituents; and

[0014] R3 is H or a suitable protecting group for the nitrogen atom; and

[0015] X and Y are each independently O or S.

[0016] According to the process of the present invention, an additional reducing agent such as zinc is avoided, and the imidazolidine compound of formula (I), or a salt thereof, or a stereoisomer thereof, or a stereoisomeric mixture thereof is produced with high yield and selectivity. DETAILED DESCRIPTION

[0017] In the present invention, the term "lower alkyl" as used herein refers to a C1-C 10 Alkyl, that is, a branched or unbranched, cyclic or non-cyclic saturated hydrocarbon containing 1 to 10 carbon atoms. Preferably, "low alkyl" is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, isopentyl, 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, "low alkyl" is methyl or ethyl.

[0018] In the present invention, the term "lower cycloalkyl" as used herein refers to a C3-C 10 Cycloalkyl, i.e., monocyclic, bicyclic or spirocyclic aliphatic hydrocarbon groups having 3 to 10 carbon atoms, may optionally contain one or more alkenylene groups as part of the ring structure. Preferably, low cycloalkyl is C3-C7 cycloalkyl or C5-C6 cycloalkyl. Examples of low cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, etc. Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0019] In the present invention, the term "lower alkoxy" as used refers to a structure represented by (lower alkyl)-O-, wherein lower alkyl is as defined herein.

[0020] In the present invention, the term "halo" as used refers to iodide, bromide, chloride and fluoride, preferably bromide or iodide, more preferably bromide.

[0021] In the present invention, the term "substituent" as used herein means lower alkyl, lower alkoxy, hydroxy, halo, -NH2, -NO2, cyano and / or isocyano.

[0022] In the present invention, the structure of the compound formula of the present invention This means that the group R is oriented away from the viewer compared to the chiral carbon to which it is attached.

[0023] In the present invention, the structure of the compound formula of the present invention This means that the group R' is oriented closer to the viewer than the chiral carbon to which it is attached.

[0024] In the present invention, the symbols used in the compound formula of the present invention are It means that the attached group is attached to the chiral carbon in the S- and / or R-configuration according to the Cahn-Ingold-Prelog priority rules.

[0025] In particular, the present invention provides a method for producing a compound of formula (I) or a salt thereof or a stereoisomer thereof or a stereoisomeric mixture thereof, which method comprises treating a compound of formula (II) or a salt thereof or a stereoisomer thereof or a stereoisomeric mixture thereof with an acid to obtain a compound of formula (I) or a salt thereof or a stereoisomer thereof or a stereoisomeric mixture thereof,

[0026]

[0027] wherein R1, R2, R3, X and Y are each independently as defined above.

[0028] In the present invention, R1 and R2 are each independently preferably a C1-C6 alkyl group, optionally substituted by one or more substituents, and more preferably, R1 is a methyl group and R2 is also a methyl group.

[0029] In the present invention, the protecting group may be one of tert-butyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-methylbenzyl, allyl, methallyl, crotyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0030] In the present invention, R3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents, more preferably, R3 is benzyl.

[0031] In one embodiment of the present invention, R1 is methyl, R2 is methyl, R3 is benzyl, X is S, and Y is O.

[0032] In another embodiment of the present invention, R1 and R2 together with the carbon atoms to which they are attached form a C3-C7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, R3 is benzyl, X is S, and Y is O.

[0033] The salt of the compound of formula (I) and the compound of formula (II) can be any metal salt, such as alkali metal salt (i.e., lithium salt, sodium salt, potassium salt, rubidium salt and cesium salt) and basic metal salt (such as calcium salt and magnesium salt). Preferably, the salt is potassium salt and / or sodium salt.

[0034] The stereoisomers of the present invention include enantiomers and diastereomers. For example, the compound of formula (I) has the following stereoisomers:

[0035]

[0036] And the compound of formula (II) has the following stereoisomers:

[0037]

[0038] wherein R1, R2, R3, X and Y are each independently as defined above.

[0039] More particularly, the stereoisomers of the compounds of formula (I) are compounds of formula (Ia') or (Ib') below:

[0040]

[0041] More particularly, the stereoisomer of the compound of formula (II) is a compound of formula (IIa') or (IIb') below:

[0042]

[0043] In the present invention, the acid can be any strong Bronsted acid. Examples of acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid (MSA), p-toluenesulfonic acid, trifluoroacetic acid, solid acids (such as Aquivion PW79S (Solvay Specialty Polymers, USA), Amberlyst 15 (Merck, USA) and Dowex DR-2030 (The Dow Chemical Company, USA)), and mixtures thereof. Preferably, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid and solid acids (such as Dowex DR-2030).

[0044] The acid can be used in an amount sufficient to adjust the reaction mixture to pH 3 or lower, preferably to pH 1 or lower, for example, in an amount of 1 to 40 mol, preferably 3 to 40 mol, more preferably 5 to 40 mol, per 1 mol of the compound of formula (II) or a salt thereof, or a stereoisomer thereof, or a stereoisomeric mixture thereof.

[0045] In the method of the present invention, the reaction may be carried out at a temperature of 20°C to 100°C, preferably 25°C to 80°C, more preferably 30°C to 70°C (such as 55°C).

[0046] In the process of the present invention, preferably, no reducing agent such as zinc powder is used.

[0047] The obtained compound of formula (I) can be separated and / or purified by methods well known in the art and used in the next step of preparing (+)-biotin. Therefore, the present invention also provides a method for producing (+)-biotin, which comprises a method for producing a compound of formula (I) as described herein, or a salt thereof, or a stereoisomer thereof, or a stereoisomeric mixture thereof.

[0048] The method of the present application avoids the use of additional reducing agents such as zinc powder for producing the compound of formula (I), or its salt, or its stereoisomer, or its stereoisomeric mixture, and thus reduces waste, so the method is safer, more cost-effective and more environmentally friendly.

[0049] The present invention further provides intermediate compounds of formula (I) and compounds of formula (II), or salts thereof, or stereoisomers thereof, or stereoisomeric mixtures thereof, which are surprisingly novel:

[0050]

[0051] wherein R1, R2, R3, X and Y are each independently as defined above.

[0052] The present invention will be further illustrated by the following examples.

[0053] Example

[0054] In the following examples of the present application, "Bn" is benzyl and "CN" is cyano.

[0055] Example 1

[0056]

[0057] L-cysteine ​​hydrochloride (50.0 g, 98.0% purity, 311 mmol) was added to acetone (518 mL) under nitrogen. The reaction mixture was kept under reflux for 18 hours. After cooling to room temperature, the mixture was filtered to obtain 48.7 g of compound 1 as a solid (81.4% yield, >99.0% purity).

[0058]

[0059] Compound 1 (10.0 g, >99.0% purity, 50.6 mmol) and sodium cyanate (3.29 g, 50.6 mmol) were added to acetic acid (84 mL). The reaction mixture was stirred at room temperature for 18 hours. After removing the solvent, water (10 mL) was added. The mixture was stirred for 1 hour and then filtered. The resulting filter cake was washed with water (15 mL) and dried to produce 6.39 g of compound 2 as a white solid (62.0% yield, 90.7% purity).

[0060]

[0061] Benzyl bromide (16.6 g, 97.0 mmol) was added to a mixture of compound 2 (17.9 g, 91.7% purity, 88.2 mmol), K2CO3 (13.4 g, 97.0 mmol) and DMF (294 mL). The mixture was stirred at room temperature for 3 hours. After all compound 2 was consumed by checking by LCMS, the reaction mixture was filtered. The resulting mixture was then extracted with ethyl acetate (300 mL) and water (300 mL). The aqueous phase was further extracted with ethyl acetate (150 mL × 3), and the organic phase was washed with saturated NH4Cl (150 mL × 2) and saturated NaCl (150 mL × 2). The organic phases were combined and dried with Na2SO4. The solvent was removed to obtain 30.0 g of crude compound 3 (97.8% yield, 79.4% purity).

[0062]

[0063] Compound 3 (30.0 g, 99.2% purity, 108 mmol) and methanol (360 mL) were added to a 1 L reactor. The resulting suspension was cooled to 0 ° C. NaBH4 (8.48 g, 96.0% purity, 215 mmol) was added at a temperature below 5 ° C. After stirring for 3 hours, the mixture was warmed to room temperature. When the reaction was completed by LCMS, water (540 mL) was added to quench the reaction at 0 ° C. The filter cake was washed with water (20 mL) and dried by crystallization and filtration to obtain 25.3 g of compound 4 as a white solid (82.5% yield, 97.7% purity).

[0064]

[0065] Under nitrogen protection, compound 4 (7.68g, 97.7% purity, 26.9mmol), TMSCN (13.8g, 96.0% purity, 134mmol) and DCM (90mL) are placed in a 250mL three-necked flask. Under stirring, TMSOTf (595mg, 2.68mmol) is added. The reaction mixture is kept at room temperature overnight. The solvent is removed by a rotary evaporator to obtain 9.70g of crude compound 5, which is a solid (74.2% yield, 74.3% purity).

[0066]

[0067] Crude compound 5 (9.70 g, 74.3% purity, 25.1 mmol) was hydrolyzed with 10% aqueous KOH (94 mL) and ethanol (94 mL) at 80° C. for 2-4 hours. Removal of ethanol gave an aqueous solution containing the potassium salt of compound 6 (8.4% purity, 98.0% yield by HPLC).

[0068] Example 2

[0069]

[0070] The aqueous solution containing the potassium salt of compound 6 obtained according to Example 1 was acidified with 37% aqueous HCl to a pH of about 1. The resulting mixture was heated to 55-60° C. and maintained for 3 hours. After filtration, the resulting filter cake was washed with water (10 mL) and dried to obtain 6.77 g of compound 7 (90.0% yield, based on compound 5, 88.7% purity).

[0071] Example 3

[0072]

[0073] At room temperature, under nitrogen, compound 7 (8.0g, 99.0% purity, 30mmol) and sodium acetate (2.5g, 30mmol) were added to a 250mL three-necked flask equipped with a magnetic stirrer. DMF (75mL) and acetic anhydride (15.0g, 150mmol) were added. The mixture was heated to 150°C for 4 hours. After cooling to room temperature, ethyl acetate (75mL) and water (75mL) were added for extraction. The aqueous phase was further extracted with ethyl acetate (75mL×3), and the organic phase was washed with saturated NH4Cl (50mL×2) and saturated NaCl (50mL×2). The organic phases were combined and dried with Na2SO4. After removing the solvent, the crude product was purified by column chromatography. 2.4g crude compound 8 (23.0% yield, 72.0% purity) was obtained.

[0074]

[0075] At room temperature, compound 8 (77.0 mg, 72.0% purity, 223 μmol) and K2CO3 (33.9 mg, 246 μmol) were added to a 10 mL flask equipped with a magnetic stirrer. DMF (2.5 ml) and benzyl bromide (106 μL, 200 μmol) were added. The mixture was kept at 150° C. for 5 hours to obtain thiolactone. The yield was about 7.0% by HPLC.

Claims

1. A method for producing a compound of formula (I) or a salt thereof or a stereoisomer thereof or a stereoisomer thereof, the method comprising treating a compound of formula (II) or a salt thereof or a stereoisomer thereof or a stereoisomer thereof with an acid to obtain the compound of formula (I) or a salt thereof or a stereoisomer thereof or a stereoisomer thereof, in: R1 and R2 are each independently lower alkyl, optionally substituted by one or more substituents, or R1 and R2 together with the carbon atoms to which they are attached form a lower cycloalkyl group, optionally substituted with one or more substituents; R3 is H or a suitable protecting group for the nitrogen atom; and X and Y are each independently O or S.

2. The method according to claim 1, wherein R1 and R2 are each independently C1-C6 alkyl, optionally substituted by one or more substituents.

3. The method according to claim 1, wherein the protecting group is selected from the group consisting of tert-butyl, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 4-methylbenzyl, allyl, methallyl, crotyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl.

4. The method according to claim 1, wherein R3 is preferably tert-butyl or benzyl, optionally substituted by one or more substituents.

5. The method of claim 1, wherein R1 is methyl, R2 is methyl, R3 is benzyl, X is S, and Y is O.

6. The method according to claim 1, wherein the stereoisomer of the compound of formula (I) is a compound of the following formula (Ia') or (Ib'):

7. The method according to claim 1, wherein the stereoisomer of the compound of formula (II) is a compound of the following formula (IIa') or (IIb'):

8. The method according to any one of claims 1 to 7, wherein the acid is selected from strong Bronsted acids, including but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid (MSA), p-toluenesulfonic acid, trifluoroacetic acid, solid acids such as Aquivion PW79S, Amberlyst 15 and Dowex DR-2030, and mixtures thereof.

9. The process according to any one of claims 1 to 7, wherein the acid is used in an amount sufficient to adjust the reaction mixture to pH 3 or less.

10. The process according to any one of claims 1 to 7, wherein no reducing agent is used.

11. A method for producing (+)-biotin, the method comprising the method for producing a compound of formula (I) or a salt thereof or a stereoisomer thereof or a stereoisomeric mixture thereof according to any one of claims 1 to 10.

12. A compound of formula (I) and a compound of formula (II), or a salt thereof, or a stereoisomer thereof, or a stereoisomeric mixture thereof, wherein R1, R2, R3, X and Y are each independently defined as in any one of claims 1 to 5.

Images