Panthenol production

Abstract

The present invention provides a novel method for producing panthenol from pantothenic acid or its salts and / or esters, which allows for the production of panthenol by a "hybrid method," which is generally more environmentally friendly and sustainable than purely chemical methods and reduces the carbon footprint.

Description

Detailed Description of the Invention

[0001] The present invention relates to a novel 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 commercially used in various cosmetic products. Traditionally, panthenol is produced by chemical synthesis by condensing 3-aminopropanol with pantolactone, which is produced in industry through multiple chemical steps and usually requires an additional resolution process to obtain the desired (R)-pantolactone.

[0003] Over the years, several microbial fermentation methods have been developed with the aim of replacing existing chemical methods. Currently, the use of genetically engineered Bacillus subtilis strains is the most efficient method for producing pantothenic acid and its salts by fermentation (see WO 0121772 and WO 02057474). However, there are still no reports of fermentation methods for the direct production of panthenol.

[0004] Therefore, there is a continuing need in the industry to effectively convert pantothenic acid produced by fermentation into panthenol.

[0005] Thus, the present invention provides a novel 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, particularly pantothenic acid or its salts produced by fermentation, to panthenol. Because the method can use biotechnologically produced compounds, including but not limited to pantothenic acid or its salts and / or esters, the route can further fulfill the need for producing environmentally friendly, sustainable, and carbon-neutral products.

[0006] In particular, the present invention relates to a method for preparing 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). [ka] wherein R is selected from the group consisting of M, hydrogen, or substituted or unsubstituted alkyl; M is an alkali metal or alkaline earth metal, particularly sodium, potassium, calcium, or magnesium; and each of m and n is independently an integer from 0 to 5. The present invention provides a method comprising:

[0007] Preferably, the substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C 10 Alkyl, for example C1, C2, C3, C4, C5, C6, C7, C8, C9 or C 10 -alkyl, and more preferably selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl or benzyl.

[0008] Preferably, each of m and n is independently 1, 2 or 3; more preferably, m and n is independently 1.

[0009] In the present invention, the compound of formula (II) is preferably selected from pantothenic acid (R=H), salts of pantothenic acid (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, which may be produced by chemical or biocatalytic methods, e.g., as described in Martin et al. (J. Am. Chem. Soc., Vol. 116, No. 11, 1994) or WO 2017099822, or preferably by fermentation methods comprising esterification of fermentatively produced pantothenic acid, e.g., as described in WO 0121772 or WO 02057474.

[0010] Of course, when M is an alkaline earth metal, each ion is divalent, so formally, such metal in formula (II) would be 1 / 2, e.g., 1 / 2Ca, 1 / 2Mg.

[0011] In the present invention, the compound of formula (II) is preferably pantothenic acid or a salt thereof, more preferably pantothenic acid or a calcium salt thereof.

[0012] In the present invention, the compound of formula (II) is preferably produced by fermentation.

[0013] In the present invention, the amino alcohol of formula (III) is preferably 3-aminopropanol.

[0014] According to the present invention, the compound of formula (I) is preferably panthenol.

[0015] In the present invention, the compound of formula (I) or the compound of formula (II) may be present in any configuration, for example, the (R) or (S) configuration, or may be present in the (R / S) configuration as a racemate or as an enantiomerically enriched mixture in which one isomer is in excess, whereby the (R) or (R / S) configuration is preferred. Typically, when the compound of formula (II) is produced by a fermentation process, a percentage of the (R) configuration is obtained, for example, about 95%, for example, about 97%, 98%, 99% or even 100%, based on the total weight of the compound of formula (II).

[0016] In the method of the present invention, the amino alcohol of formula (III) may be used in an amount of 1 mol to 20 mol, preferably 3 mol to 15 mol, more preferably 5 mol to 10 mol per 1 mol of the compound of formula (II).

[0017] In the process of the invention, the reaction is advantageously carried out in the presence of a catalyst which may be a protic acid and / or a Lewis acid.

[0018] The protic acid suitable for the process of the present invention can be 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).

[0019] Lewis acids suitable for the method of the present invention can be any metal salt, such as aluminum (Al), bismuth (Bi), and transition metal (e.g., zinc (Zn), copper (Cu), scandium (Sc), and lanthanides such as lanthanum (La), europium (Eu), neodymium (Nd), and ytterbium (Yb)) salts, triflates, sulfonates, acetates, and halide salts, as well as any metal amide. Examples of Lewis acids include, but are not limited to, Sc(OTf), La(OTf), Eu(OTf), Nd(OTf), Yb(OTf), Eu(OTf), Cu(OAc), Ti(NMe), and Al(NMe).

[0020] Preferably, the catalyst used in the process of the present invention is an inorganic acid such as B(OH) and / or a metal triflate, such as a transition metal triflate. More preferably, the catalyst is B(OH) and / or Sc(OTf).

[0021] In the method of the present invention, the catalyst may be used in an amount of 0.0001 mol to 1 mol, preferably 0.001 mol to 0.1 mol, more preferably 0.005 mol to 0.05 mol per 1 mol of the compound of formula (II).

[0022] In the method of the present invention, an additional solvent may be used, but it is not preferred. The solvent may be a non-aqueous, organic, polar or non-polar solvent. Suitable solvents may be selected from alcohols and polyols, esters, ethers, amides, nitriles, substituted or unsubstituted hydrocarbons or chlorinated hydrocarbons. Preferably, in the method of the present invention, no additional solvent is used.

[0023] In the process of the present invention, the reaction may be carried out at an elevated temperature, the term "elevated temperature" as used herein including, but not limited to, temperatures ranging from about 40°C to about 150°C, preferably from about 60°C to about 120°C, such as 80°C, at which panthenol is produced.

[0024] Preferably, the present invention provides a method for producing panthenol, comprising step i) of producing pantothenic acid / pantothenate by fermentation and optionally subsequently esterifying it to a pantothenic acid ester of formula (II), and step ii) of reacting the pantothenic acid or its salts and / or esters obtained in step i) with 3-aminopropanol to obtain panthenol, wherein step ii) is performed as described above according to the present invention.

[0025] The production of pantothenic acid by fermentation is known in the art, see for example WO 0121772 or WO 02057474. Esterification can be carried out according to standard procedures in the art, such as, but not limited to, biocatalytic or fermentative methods. However, chemical esterification is preferred, for example, by reacting pantothenic acid with the respective alcohol in the presence of an acid. As used herein, such methods that combine chemical production steps with biotechnological steps are referred to as "hybrid methods."

[0026] Even more preferably, in all embodiments of the present invention, pantothenic acid derived from microbial metabolism of plant-derived sugars or alcohols composed of carbon from atmospheric sources and not fossil fuels is used, as pantothenic acid has a zero anthropogenic CO2 emission profile upon biodegradation and is particularly desirable.

[0027] The product, including the compound of formula (I), may be purified (if desired) using commonly known methods, such as distillation, for example, as described in U.S. Patent Application Publication No. 20120149903.

[0028] The method of the present invention allows for the production of compounds of formula (I), such as panthenol, by a "hybrid method," which is generally more environmentally friendly and sustainable than purely chemical methods using fuel-based feedstocks, and reduces the carbon footprint. In addition, the method of the present invention provides compounds of formula (I), such as panthenol, preferably in the (R) configuration, wherein at least about 95%, for example about 97%, 98%, 99%, or even 100%, of the compounds of formula (I), based on the total weight of the compounds of formula (I), are present in the (R) configuration.

[0029] The invention is illustrated by the following examples in which all percentages are by weight.

[0030] [Example 1] (R)-Pantothenic acid (1.63 g, 69% purity, 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) (127 mg, 0.255 mmol) were added and heated to 80 °C for 4 h. After cooling, the resulting crude oil was purified twice by flash chromatography on silica gel (eluent dichloromethane / MeOH / water 75:22.5:2.5) to give (R)-panthenol (0.75 g, 92.6% purity, 66% yield) as a colorless oil.

[0031] [Example 2] (R)-Pantothenic acid (3.2 g, 81.7% purity, 12 mmol), boric acid (37 mg, 0.60 mmol), and 3-aminopropan-1-ol (9.0 g, 9.2 mL, 99% purity, 0.12 mol) were weighed into an argon-flushed 20 mL vial. The vial was sealed, and the mixture was stirred at 80 °C for 16 h. The resulting reaction mixture was dissolved in 10 mL of 3:1 dichloromethane / methanol (v / v) and filtered through 100 g of silica gel, eluting with 3:1 dichloromethane / methanol. The fractions were concentrated to give 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. Overall yield of (R)-panthenol: 2.0 g (81%).

Claims

1. A method for preparing a compound of formula (I), comprising reacting a compound of formula (II) with an amino alcohol of formula (III) to obtain said compound of formula (I). 【Chemistry 1】 wherein R is selected from the group consisting of M or hydrogen or substituted or unsubstituted alkyl; M is an alkali metal or alkaline earth metal, particularly sodium, potassium, calcium or magnesium; and each of m and n is independently an integer from 0 to 5. A method comprising:

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

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

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 of claim 6 , wherein the catalyst is a protonic acid and / or a Lewis acid.

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

9. The Lewis acid may be any metal salt, such as aluminum (Al), bismuth (Bi), and transition metal (e.g., zinc (Zn), copper (Cu), scandium (Sc), and lanthanides such as lanthanum (La), europium (Eu), neodymium (Nd), and ytterbium (Yb)), triflate salts, sulfonate salts, acetate salts, and halide salts, as well as any metal amide, such as Sc(OTf). ３ , La(OTf) ３ , Eu(OTf) ３ , Nd(OTf) ３ , Yb(OTf) ３ , Eu(OTf) ３ , Cu(OAc) ２ , Ti(NMe ２ ) ４ and Al(NMe ２ ) ３ 8. The method of claim 7, including, but not limited to:

10. The catalyst may be an inorganic acid, such as B(OH). ３ and / or a metal triflate, such as a transition metal triflate, preferably the catalyst is B(OH) ３ and / or Sc(OTf) ３ The method of claim 6, wherein

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

12. 11. The process according to any one of claims 1 to 10, wherein the reaction is carried out at a temperature ranging from about 40°C to about 150°C, preferably from about 60°C to about 120°C, for example 80°C.

13. 13. The method of any one of claims 1 to 12, wherein the compound of formula (I) is prepared such that at least about 95%, such as about 97%, 98%, 99% or even 100% of the compounds of formula (I), based on the total weight of the compounds of formula (I), are present as the (R) configuration.

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

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