Process for production of biotin intermediates

Abstract

The present invention provides a novel process for the production of imidazo thiazolone compounds of formula (I). According to the invention, the process can be operated at lower temperatures and provides higher yields compared to the prior art: # imgabs0 # wherein R1 and R2 are each independently of one another lower alkyl, optionally substituted by one or more substituents, or R1 and R2 together with the carbon atom to which they are attached form a lower cycloalkyl, optionally substituted by one or more substituents; 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 imidazothiazolone compounds. Background Art

[0002] Biotin (vitamin H) is one of the B-complex vitamins and is of great commercial importance in animal health and nutrition.

[0003] To date, several synthetic routes for biotin have been reported. Among the various methods described for biotin, cysteine ​​has received a lot of attention in recent years. As shown below, the method includes converting L-cysteine ​​into a thiazolidine derivative (a) and further converting it into an imidazothiazolone compound (b), which is a very important intermediate and can ultimately be converted into biotin via a thiolactone (THL) (see: US5095118A).

[0004]

[0005] One method for preparing imidazothiazolone compound (b) comprises reacting thiazolidine derivative (a) with benzyl isocyanate at reflux temperature in one step to obtain compound (b). However, benzyl isocyanate is an expensive reagent (see: CN102010434A and CN109503619A).

[0006] An alternative method uses sodium cyanate instead of benzyl isocyanate to convert thiazolidine derivative (a) into imidazothiazolone compound (c), which is then treated with benzyl bromide to obtain imidazothiazolone compound (b). However, this method requires elevated temperature and the yield of compound (b) is only about 69% (CN101735242A).

[0007]

[0008] Therefore, there remains a need for new methods for producing imidazothiazolone compounds. Summary of the invention

[0009] The present invention provides a novel process for producing an imidazothiazolone compound of formula (I) or a stereoisomer thereof or a stereoisomeric mixture 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] X and Y are each independently O or S.

[0015] According to the method of the present invention, the compound of formula (I) or its stereoisomer or its stereoisomeric mixture is produced in higher yield at lower temperature (such as room temperature) compared with the prior art. DETAILED DESCRIPTION

[0016] 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.

[0017] 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.

[0018] 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.

[0019] In the present invention, the term "halo" as used refers to iodide, bromide, chloride and fluoride, preferably bromide or iodide, more preferably bromide.

[0020] In the present invention, the term "substituent" as used herein means lower alkyl, lower alkoxy, hydroxy, halo, -NH2, -NO2, cyano and / or isocyano.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] In particular, the present invention provides a method for producing a compound of formula (I) or a stereoisomer thereof or a stereoisomeric mixture thereof, which comprises reacting a compound of formula (II) or a salt thereof or a stereoisomer thereof or a stereoisomeric mixture thereof with a cyanate in a solvent to obtain a compound of formula (I) or a stereoisomer thereof or a stereoisomeric mixture thereof,

[0025]

[0026] wherein R1, R2, X and Y are each independently as defined above.

[0027] Preferably, R1 and R2 are each independently methyl. Preferably, X is S and Y is O.

[0028] The salt of the compound of formula (II) can be represented by the following formula (II'):

[0029]

[0030] wherein R1, R2 and X are each independently as defined above, and R3 is an anion such as Cl - Br - ,I - 、SO4 2- 、HSO4 - 、ClO4 - CF3COO - 、CH3SO3 - CF3SO3 - 、CH3C6H4SO3 - and PO4 3- Preferably, the salt of the compound of formula (II) is a hydrochloride salt.

[0031] In the method of the present invention, the cyanate may be selected from the group consisting of sodium cyanate, potassium cyanate, silver cyanate, calcium cyanate, cesium cyanate, lithium cyanate and ammonium cyanate. Preferably, the cyanate is sodium cyanate, potassium cyanate, calcium cyanate or ammonium cyanate. More preferably, the cyanate is sodium cyanate or potassium cyanate.

[0032] The cyanate in the method of the present invention can be used in an amount of 0.1 to 10.0 mol, preferably 0.5 to 8.0 mol, more preferably 1.0 to 5.0 mol (such as 1.0, 1.5, 2.0, 3.0, 4.0 and 5.0 mol) per 1 mol of the compound of formula (II) or a salt thereof.

[0033] The solvent used in the method of the present invention is a non-aqueous solvent. The solvent may be selected from the group consisting of an acid and an aprotic dipolar solvent. The acid may be any Bronsted acid, preferably a Bronsted acid with a pKa <5. Examples of acids include, but are not limited to, aliphatic organic acids such as formic acid, acetic acid, trifluoroacetic acid (TFA), propionic acid and butyric acid, or mixtures thereof. Examples of aprotic dipolar solvents include, but are not limited to, acetonitrile (ACN), benzonitrile, valeronitrile, N,N-dimethylformamide (DMF), N,N-diethylformamide, N,N-dibutylformamide, N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone, N,N'-dimethylpropylene urea (DMPU), dimethyl sulfoxide, sulfolane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, anisole and cyclopentyl methyl ether.

[0034] In the method of the present invention, the solvent may be used in an amount of 0.1 L to 10 L, preferably 0.5 L to 3 L, per 1 mol of the compound of formula (II) or a salt thereof or a stereoisomer thereof or a stereoisomeric mixture thereof.

[0035] In the method of the present invention, other cyclization reagents can be used. The cyclization reagent can be any reagent suitable for cyclization in the art. Preferably, the cyclization reagent is selected from acid. Examples of acid include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, methanesulfonic acid (MSA), p-toluenesulfonic acid (PTSA), trifluoroacetic acid, solid acid (such as Aquivion PW79S (Solvay Specialty Polymers, the United States), Amberlyst 15 (Merck, the United States) and Dowex DR-2030 (TheDow Chemical Company, the United States)), and mixtures thereof. Preferably, the acid is selected from the group consisting of acetic acid, oxalic acid and trifluoroacetic acid (TFA).

[0036] In the present invention, the cyclizing agent can be used in an amount of 0.01 to 10 moles, preferably 0.1 to 5 moles (such as 0.1, 0.5, 1.0, 2.0, 3.0, 4.0 and 5.0 moles) per 1 mole of the compound of formula (II) or its salt or its stereoisomer or its stereoisomeric mixture.

[0037] Preferably, in the method of the present application, the solvent is selected from the group consisting of ACN, DMF, THF, NMP and DMPU, more preferably ACN, and the cyclization reagent is TFA and / or oxalic acid, more preferably TFA.

[0038] As expected by any skilled person in the art, when the solvent in the present invention is selected from an acid as defined above, it can also serve as a cyclization reagent, and therefore no additional cyclization reagent is required. In one embodiment of the invention, the solvent is selected from an acid such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, and no additional cyclization reagent is used.

[0039] The reaction of the method of the present invention is carried out at 0°C to 150°C, preferably 10°C to 120°C, more preferably 50°C or below, even more preferably 40°C or below (such as 10°C to 30°C), and especially preferably at room temperature.

[0040] The obtained compound of formula (I) can be isolated and / or purified by methods well known in the art and used in the next step of preparing (+)-biotin.

[0041] Thus, the present invention provides a process for producing compounds of formula (I) in high yield at relatively low temperatures, such as at room temperature.

[0042] More surprisingly, the inventors of the present invention have found that the compound of formula (I) or its stereoisomer or its stereoisomeric mixture can be used to produce the compound of formula (III) or its stereoisomer or its stereoisomeric mixture with improved yield. Therefore, the present invention also provides a method for producing the compound of formula (III) or its stereoisomer or its stereoisomeric mixture, which method comprises the steps of reacting the compound of formula (I) or its stereoisomer or its stereoisomeric mixture with benzyl bromide to obtain the compound of formula (III) or its stereoisomer or its stereoisomeric mixture,

[0043]

[0044] wherein R1, R2, X and Y are each independently as defined above.

[0045] The reaction conditions of the method are known in the art, for example, as disclosed in CN101735242A. According to the method of the present invention, the compound of formula (III) or its stereoisomer or its stereoisomeric mixture can be produced in a yield of more than 90%.

[0046] The compound of formula (III) or its stereoisomer or its stereoisomeric mixture can be used to produce thiolactone (THL), which can be ultimately converted into (+)-biotin. Therefore, the present invention also provides a method for producing (+)-biotin, which comprises a method for producing a compound of formula (I) or (III) as described herein or its stereoisomer or its stereoisomeric mixture.

[0047] The present invention further provides an intermediate compound of formula (IV) or a stereoisomer thereof or a stereoisomeric mixture thereof, which is novel:

[0048]

[0049] wherein R1, R2, X and Y are each independently as defined above; and R4 is H or benzyl, optionally substituted with one or more substituents.

[0050] The present invention is further illustrated by the following examples.

[0051] Example

[0052] In the following examples of the present application, "Bn" is benzyl and "CN" is cyano.

[0053] Example 1

[0054]

[0055] 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 48.71 g of compound 1 as a solid (81.4% yield, >99.0% purity).

[0056] Example 2

[0057]

[0058] 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).

[0059] Example 3

[0060]

[0061] The cyclization reagent (as shown in Table 1, 4.12 mmol) was added to a mixture of compound 1 (500 mg, 2.06 mmol) and sodium cyanate (268 mg, 4.12 mmol) in a solvent (3.43 mL) (Table 2). The reaction mixture was stirred at 25°C for 18 hours. The yield was detected by HPLC, and the results are shown in Table 2.

[0062] Table 1

[0063]

[0064] Example 4

[0065]

[0066] 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).

[0067]

[0068] 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).

[0069]

[0070] 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).

[0071]

[0072] The 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. The ethanol was then removed and a 37% aqueous HCl solution was added to adjust the pH of the mixture to about 1. The resulting mixture was heated to 55-60°C. After 3 hours, the mixture was filtered, and the filter cake was washed with water (10 mL) and dried to give 6.77 g of compound 7 (90.0% yield, 88.7% purity).

[0073]

[0074] At room temperature, under nitrogen, compound 7 (8.0g, 99.0% purity, 30mmol) and sodium acetate (2.5g, 30mmol) are added to a 250mL three-necked flask equipped with a magnetic stirrer. DMF (75mL) and acetic anhydride (15.0g, 150mmol) are added. The mixture is heated to 150°C for 4 hours. After cooling to room temperature, ethyl acetate (75mL) and water (75mL) are added for extraction. The aqueous phase is further extracted with ethyl acetate (75mL×3), and the organic phase is washed with saturated NH4Cl (50mL×2) and saturated NaCl (50mL×2). The organic phases are combined and dried with Na2SO4. After removing the solvent, 2.4g crude compound 8 (23.0% yield, 72.0% purity) is obtained.

[0075]

[0076] 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 stereoisomer thereof or a stereoisomer mixture thereof, the method comprising reacting a compound of formula (II) or a salt thereof or a stereoisomer thereof or a stereoisomer mixture thereof with a cyanate in a solvent to obtain the compound of formula (I) or a stereoisomer thereof or a stereoisomer mixture thereof, wherein 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; and X and Y are each independently O or S.

2. The method according to claim 1, wherein the salt of the compound of formula (II) is represented by the following formula (II'): wherein R1, R2 and X are each independently as defined in claim 2, and R3 is an anion such as Cl - Br - ,I - 、SO4 2- 、HSO4 - 、ClO4 - CF3COO - 、CH3SO3 - CF3SO3 - 、CH3C6H4SO3 - and PO4 3- .

3. The method according to claim 1, wherein the salt of the compound of formula (II) is a hydrochloride salt.

4. The method according to any one of claims 1 to 3, wherein the cyanate is selected from the group consisting of sodium cyanate, potassium cyanate, silver cyanate, calcium cyanate, cesium cyanate, lithium cyanate and ammonium cyanate; preferably sodium cyanate, potassium cyanate, calcium cyanate or ammonium cyanate; more preferably sodium cyanate or potassium cyanate.

5. The method according to any one of claims 1 to 3, wherein the solvent is a non-aqueous solvent.

6. The method according to any one of claims 1 to 3, wherein the solvent is selected from the group consisting of: an acid such as formic acid, acetic acid, trifluoroacetic acid (TFA), propionic acid and butyric acid; and an aprotic dipolar solvent such as acetonitrile (ACN), benzonitrile, valeronitrile, N,N-dimethylformamide (DMF), N,N-diethylformamide, N,N-dibutylformamide, N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP), N-ethyl-2-pyrrolidone, N,N'-dimethylpropylene urea (DMPU), dimethyl sulfoxide, sulfolane, tetrahydrofuran (THF), 2-methyltetrahydrofuran, anisole and cyclopentyl methyl ether.

7. The method according to any one of claims 1 to 3, wherein a cyclizing agent is used and the cyclizing agent is selected from acids, including but not limited to hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, methanesulfonic acid (MSA), p-toluenesulfonic acid (PTSA), trifluoroacetic acid, solid acids such as Aquivion PW79S, Amberlyst 15 and Dowex DR-2030, and mixtures thereof.

8. The method according to claim 7, wherein the solvent is selected from the group consisting of ACN, DMF, THF, NMP and DMPU, more preferably ACN, and the cyclization reagent is TFA and / or oxalic acid, more preferably TFA.

9. The method according to any one of claims 1 to 3, wherein the reaction is carried out at 0°C to 150°C, preferably 10°C to 120°C, more preferably 50°C or below, even more preferably 40°C or below, such as 10°C to 30°C, especially preferably at room temperature.

10. A method for producing a compound of formula (III), comprising the step of reacting a compound of formula (I) or a stereoisomer thereof or a stereoisomeric mixture thereof with benzyl bromide to obtain a compound of formula (III) or a stereoisomer thereof or a stereoisomeric mixture thereof, 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; and X and Y are each independently O or S.

11. A method for producing (+)-biotin, the method comprising the method for producing a compound of formula (I) or a stereoisomer thereof or a stereoisomeric mixture thereof according to any one of claims 1 to 9, or the method for producing a compound of formula (III) or a stereoisomer thereof or a stereoisomeric mixture thereof according to claim 10.

12. A compound of formula (IV), or a stereoisomer thereof, or a stereoisomeric mixture 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; R4 is H or benzyl, optionally substituted with one or more substituents; and X and Y are each independently O or S.

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