Production of panthenol

Abstract

The present invention provides a novel process for the production of panthenol from pantothenic acid or salts and / or esters thereof. This process makes it possible for a "hybrid process" to produce panthenol, which is generally more environmentally friendly, more sustainable, and reduced in carbon footprint compared to pure chemical processes.

Description

[0001] The present invention relates to a new method for producing panthenol from pantothenic acid or its salts and / or esters.

[0002] Panthenol is an alcohol derivative of pantothenic acid or vitamin B5 and is widely commercially used in various cosmetics. Conventional production of panthenol is achieved by chemical synthesis through the condensation of 3-aminopropanol with pantolactone, and pantolactone usually requires multiple chemical steps in industrial production and additional resolution treatment to obtain the desired (R)-pantolactone.

[0003] Over the years, a variety of microbial fermentation methods have been developed with the aim of replacing existing chemical methods. Currently, the fermentation of pantothenic acid and its salts using genetically engineered Bacillus subtilis is the most effective method (see WO0121772 and WO02057474). However, there has been no report on the direct production of panthenol by fermentation methods so far.

[0004] Therefore, there is still an urgent need in the industry for an effective method to convert fermentatively produced pantothenic acid into panthenol.

[0005] Accordingly, the present invention provides a new method for producing panthenol from pantothenic acid or its salts and / or esters, which method comprises converting pantothenic acid or its salts and / or esters (especially fermentatively produced pantothenic acid or its salts) into panthenol. Since this method can use compounds produced by biotechnology, including but not limited to pantothenic acid or its salts and / or esters, this method can also meet the requirements for producing environmentally friendly, sustainable and carbon-neutral products.

[0006] In particular, the present invention provides a method for producing a compound of formula (I), which method comprises reacting a compound of formula (II) with an amino alcohol of formula (III) to obtain a compound of formula (I),

[0007]

[0008] wherein R is selected from the group consisting of M, hydrogen or a substituted or unsubstituted alkyl group, wherein M is an alkali metal or an alkaline earth metal, especially sodium, potassium, calcium or magnesium, and m and n are each independently an integer between 0 and 5.

[0009] Preferably, the substituted or unsubstituted alkyl group is selected from substituted or unsubstituted C1-C 10 alkyl groups, such as C1, C2, C3, C4, C5, C6, C7, C8, C9 or C 10 alkyl groups, more preferably selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.

[0010] Preferably, m and n are each independently 1, 2 or 3, and more preferably, m and n are each independently 1.

[0011] In the present invention, the compound of formula (II) is preferably selected from pantothenic acid (R = H), pantothenates (M is an alkali metal or alkaline earth metal), such as calcium pantothenate, sodium pantothenate, magnesium pantothenate and potassium pantothenate, or pantothenic acid esters (R = substituted or unsubstituted alkyl), including but not limited to methyl pantothenate or ethyl pantothenate. These compounds can be produced by chemical methods, such as those described by Martin et al. (J. Am. Chem. Soc., Vol. 116, No. 11, 1994) or WO2017099822, or by biocatalytic methods or preferably by fermentation methods, such as those described in WO0121772 or WO02057474, including the esterification of fermentatively produced pantothenic acid.

[0012] It should be understood that in the case where M is an alkaline earth metal, the corresponding ion is divalent, and thus, formally, the proportion of these metals in formula (II) is 1 / 2, for example, 1 / 2Ca, 1 / 2Mg.

[0013] In the present invention, the compound of formula (II) is preferably pantothenic acid or its salt, and more preferably pantothenic acid or its calcium salt.

[0014] In the present invention, the compound of formula (II) is preferably produced by a fermentation method.

[0015] In the present invention, the amino alcohol of formula (III) is preferably 3-aminopropanol.

[0016] In the present invention, the compound of formula (I) is preferably panthenol.

[0017] In the present invention, the compound of formula (I) or the compound of formula (II) can exist in any configuration, such as the (R) or (S) configuration, or in the form of a racemate of the (R / S) configuration, or in the form of an enantiomerically enriched mixture with an excess of one isomer, wherein the (R) or (R / S) configuration is preferred. Generally, if the compound of formula (II) is produced by a fermentation method, then based on the total weight of the compound of formula (II), at least about 95% (e.g., about 97%, 98%, 99% or even 100%) is in the (R) configuration.

[0018] In the method of the present invention, the amount of the amino alcohol of formula (III) used can be from 1 mole to 20 moles per 1 mole of the compound of formula (II), preferably from 3 moles to 15 moles, and more preferably from 5 moles to 10 moles.

[0019] In the method of the present invention, the reaction is preferably carried out in the presence of a catalyst, which can be a protonic acid and / or a Lewis acid.

[0020] The protonic acid suitable for the method of the present invention can be any organic acid, such as carboxylic acids (e.g., formic acid, acetic acid, benzoic acid, and proline), and / or any inorganic acid, such as sulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, hydroxylamine hydrochloride, boric acid (B(OH)3), and phenylboronic acid (PhB(OH)2).

[0021] The Lewis acid suitable for the method of the present invention can be any metal salt, such as trifluoromethanesulfonates, sulfonates, acetates, and halides of aluminum (Al), bismuth (Bi), and transition metals (e.g., zinc (Zn), copper (Cu), scandium (Sc), and lanthanides such as lanthanum (La), europium (Eu), neodymium (Nd), and ytterbium (Yb)); and any metal amide. Examples of Lewis acids include, but are not limited to, Sc(OTf)3, La(OTf)3, Eu(OTf)3, Nd(OTf)3, Yb(OTf)3, Eu(OTf)3, Cu(OAc)2, Ti(NMe2)4, and Al(NMe2)3.

[0022] Preferably, the catalyst used in the method of the present invention is an inorganic acid, such as B(OH)3 and / or a metal trifluoromethanesulfonate, such as a transition metal trifluoromethanesulfonate. More preferably, the catalyst is B(OH)3 and / or Sc(OTf)3.

[0023] In the method of the present invention, the amount of the catalyst can be from 0.0001 mole to 1 mole per 1 mole of the compound of formula (II), preferably from 0.001 mole to 0.1 mole, and more preferably from 0.005 mole to 0.05 mole.

[0024] In the method of the present invention, an additional solvent can be used, but it is not preferred. The solvent can be a non-aqueous, organic, polar, or non-polar solvent. Suitable solvents can be selected from alcohols and polyols, esters, ethers, amides, nitriles, hydrocarbons, or chlorinated hydrocarbons (with or without substituents). Preferably, no additional solvent is used in the method of the present invention.

[0025] In the method of the present invention, the reaction can be carried out at an elevated temperature. The "elevated temperature" referred to herein includes, but is not limited to, a temperature range of about 40 °C to about 150 °C, preferably about 60 °C to about 120 °C, such as 80 °C, at which panthenol is produced.

[0026] Preferably, the present invention provides a method for producing panthenol, comprising step i) fermentatively producing pantothenic acid / pantothenate, optionally followed by esterification thereof to a pantothenate of formula (II), and step ii) reacting the pantothenic acid or its salt and / or ester obtained in step i) with 3-aminopropanol to obtain panthenol, wherein step ii) is carried out according to the above-described method of the present invention.

[0027] Fermentative production of pantothenic acid is a known technique in the art, see for example WO0121772 or WO02057474. Esterification can be carried out according to standard procedures in the art, including but not limited to biocatalytic or fermentation methods. However, chemical esterification (e.g., reacting pantothenic acid with the corresponding alcohol in the presence of an acid) is more preferred. Herein, this process combining chemical production steps and biotechnological steps is referred to as a "hybrid method".

[0028] More preferably, in all embodiments of the present invention, pantothenic acid produced by microbial metabolism of plant-derived sugars or alcohols is preferably used, and the carbon of these sugars or alcohols is derived from the atmosphere rather than fossil fuel carbon. The anthropogenic CO2 emission curve of this pantothenic acid is zero during biodegradation, which is particularly desirable.

[0029] The product containing the compound of formula (I) can be purified according to known methods as needed, for example, by distillation as described in US Patent US20120149903.

[0030] The method of the present invention enables the "hybrid method" for producing compounds of formula (I) such as panthenol, which is generally more environmentally friendly, more sustainable, and reduces the carbon footprint compared to pure chemical methods using fuel-based raw materials. In addition, the compound of formula (I) (such as panthenol) provided by the method of the present invention is preferably in the (R) configuration, wherein at least about 95% (e.g., about 97%, 98%, 99% or even 100%) of the compound of formula (I) is present in the (R) configuration based on the total weight of the compound of formula (I).

[0031] The present invention is illustrated by the following examples. All percentages in the examples are related to weight.

[0032] Example 1

[0033] (R)-Pantothenic acid (1.63 g, purity 69%, 5.11 mmol) was added to a dry 50 mL Schlenk flask. 3-Aminopropan-1-ol (3.88 g, 3.95 mL, 51.1 mmol) and Sc(OTf)3 (127 mg, 0.255 mmol) were added, and the mixture was heated to 80 °C and reacted for 4 hours. After cooling, the resulting crude oil was purified twice by flash chromatography on silica gel (eluent: dichloromethane / methanol / water 75:22.5:2.5), and finally (R)-panthenol (0.75 g, purity 92.6%, yield 66%) was obtained as a colorless oil.

[0034] Example 2

[0035] (R)-Pantothenic acid (3.2 g, purity 81.7%, 12 mmol), boric acid (37 mg, 0.60 mmol) and 3-aminopropan-1-ol (9.0 g, 9.2 mL, purity 99%, 0.12 mol) were weighed into a 20 mL vial flushed with argon. After sealing the vial, the mixture was stirred at 80 °C for 16 hours. The resulting reaction mixture was dissolved in 10 mL of dichloromethane / methanol (3:1 by volume) and filtered through 100 g of silica gel, eluting with dichloromethane / methanol (3:1 by volume). After concentrating the fractions, 1.48 g of fraction 1 containing 61.2% (qNMR) of (R)-panthenol and 3.0 g of fraction 2 containing 36.5% (qNMR) of (R)-panthenol were obtained. Total yield: 2.0 g (81%) of (R)-panthenol.

Claims

1. A method for producing a compound of formula (I), comprising the step of reacting a compound of formula (II) with an amino alcohol of formula (III) to obtain a compound of formula (I), wherein, R is selected from the group consisting of M, hydrogen or a substituted or unsubstituted alkyl group, where M is an alkali metal or an alkaline earth metal, in particular sodium, potassium, calcium or magnesium, and m and n are each independently an integer between 0 and 5.

2. The method according to claim 1, wherein the compound of formula (II) is selected from pantothenic acid, pantothenate or pantothenate ester, preferably pantothenic acid, wherein the pantothenate is, for example, calcium pantothenate, sodium pantothenate, magnesium pantothenate and potassium pantothenate, and the pantothenate ester is, for example, methyl pantothenate or ethyl pantothenate.

3. The method according to claim 1, wherein the amino alcohol of formula (III) is 3-aminopropanol.

4. The method according to any one of claims 1 to 3, wherein the compound of formula (II) is produced by fermentation.

5. The method according to any one of claims 1 to 3, wherein the amount of the amino alcohol of formula (III) used is 1 mole to 20 moles per 1 mole of the compound of formula (II), preferably 3 moles to 15 moles, more preferably 5 moles to 10 moles.

6. The method according to any one of claims 1 to 3, wherein the reaction is carried out in the presence of a catalyst.

7. The method according to claim 6, wherein the catalyst is a protonic acid and / or a Lewis acid.

8. The method according to claim 7, wherein the protonic acid is any organic acid, such as carboxylic acid (e.g., formic acid, acetic acid, benzoic acid and proline), and / or any inorganic acid, such as sulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, hydroxylamine hydrochloride, boric acid (B(OH)3) and phenylboronic acid (PhB(OH)2).

9. The method according to claim 7, wherein the Lewis acid is any metal salt, such as trifluoromethanesulfonates, sulfonates, acetates and halides of aluminum (Al), bismuth (Bi) and transition metals (e.g., zinc (Zn), copper (Cu), scandium (Sc) and lanthanide elements such as lanthanum (La), europium (Eu), neodymium (Nd) and ytterbium (Yb)), and any metal amide, including but not limited to Sc(OTf)3, La(OTf)3, Eu(OTf)3, Nd(OTf)3, Yb(OTf)3, Eu(OTf)3, Cu(OAc)2, Ti(NMe2)4 and Al(NMe2)3.

10. The method according to claim 6, wherein the catalyst is an inorganic acid, such as B(OH)3 and / or metal trifluoromethanesulfonate (such as transition metal trifluoromethanesulfonate), and preferably the catalyst is B(OH)3 and / or Sc(OTf)3.

11. The method according to any one of claims 1 to 10, wherein no solvent is used in the reaction.

12. The method according to any one of claims 1 to 10, wherein the reaction is carried out in a temperature range of about 40 °C to about 150 °C, preferably about 60 °C to about 120 °C, such as 80 °C.

13. The method according to any one of claims 1 to 12, wherein at least about 95% (such as about 97%, 98%, 99% or even 100%) of the compound of formula (I) is present in the (R) configuration, relative to the total weight of the resulting compound of formula (I).

14. A method for producing panthenol, comprising step i) fermenting to produce pantothenic acid / pantothenate, optionally followed by esterifying it to a pantothenate ester of formula (II), and step ii) reacting the pantothenic acid or its salt and / or ester obtained in step i) with 3-aminopropanol to obtain panthenol.

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