WO2022219173A1

WO2022219173A1 - Production of panthenol

Info

Publication number: WO2022219173A1
Application number: PCT/EP2022/060156
Authority: WO
Inventors: Jonathan Alan Medlock; Peter Louis HOUSTON
Original assignee: Dsm Ip Assets B.V.
Priority date: 2021-04-15
Filing date: 2022-04-15
Publication date: 2022-10-20
Also published as: EP4323331A1

Abstract

The present invention relates to a novel and inventive process for the production of panthenol from pantothenic acid or derivatives such as salts and/or esters thereof.

Description

Production of panthenol

Panthenol is an alcohol derivative of pantothenic acid or vitamin B5 which is commercially used in cosmetics. Conventional production of panthenol is through chemical synthesis by condensing 3-aminopropanol with pantolactone. Aminopropanol however is a highly unwanted chemical reagent which should be avoided, also because it remains as an impurity in the final product.

Thus, there is an ongoing need for an efficient and sustainable process for the preparation of panthenol on an industrial scale which does not involve the use of aminopropanol as a reagent. Furthermore, there is a strong demand for more biological production processes, whereby the use or generation of hazardous substances is reduced or eliminated, such as e.g. for establishing a carbon- neutral route wherein fermentatively produced pantothenic acid is converted preferably into highly pure panthenol.

Surprisingly, we now found a way for the production of panthenol wherein the use of aminopropanol can be avoided, said process comprisingthe conversion of pantothenic acid, pantothenate or pantothenic acid esters, particularly fermentatively produced pantothenic acid, into panthenol. As said process can use biotechnologically produced compounds including but not limited to pantothenic acid or derivatives such as e.g. esters, said route furthermore can satisfy the need for production of more eco-friendly and carbon neutral products.

Particularly, the present invention is related to a process for the production of a compound accordingto formula (ll): said process comprising the step of reduction of a compound according to formula (l) into a compound of formula (ll)

wherein R is selected from the group consisting of M or hydrogen or substituted or unsubstituted alkyl, wherein M is an alkali metal or earth alkali metal, particularly sodium, potassium, calcium, or magnesium.

Preferably, the substituted or unsubstituted alkyl is selected from substituted or unsubstituted C1-C10 alkyl, such as e.g. Cl, C2, C3, C4, C5, C6, C7, C8, C9 or C10- alkyl, more preferably selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, or benzyl.

It is well understood that in case of M being earth alkali metal, the respective ions are divalent and, hence, formally such metals in the formula (l) would be ½, e.g. V2 Ca, V2 Mg.

As used herein, the "compound of formula (ll)" is also referred to as panthenol.

Suitable compounds according to formula (l) can be selected from pantothenic acid, respectively a salt thereof, such as e.g. calcium-pantothenate, sodium- pantothenate, magnesium-pantothenate, potassium-pantothenate or pantothenic acid esters, including but not limited to pantothenic acid methyl ester or pantothenic acid ethyl ester, wherein those compounds can either be produced by a chemical process as e.g. described in Martin et al. (J. Am. Chem. Soc., Vol. 116, No. 11, 1994) or in WO2017099822, or biocatalytic process or preferably via a fermentative process as e.g. described in WO0121772 or WO02057474, including esterification of fermentatively produced pantothenic acid. As used herein, the term "reduction" includes a process, wherein a reducing agent is contacted with a compound of formula (l) as defined herein as well as a process commonly known as "hydrogenation", i.e. conversion of a compound according to formula (l), particularly pantothenic acid esters, in the presence of a hydrogen source, preferably in the presence of hydrogen (H₂) gas, and in the presence of a catalyst as defined herein into a compound according to formula (ll). Thus, a process including said reduction or hydrogenation step as further defined herein is also referred to as "conversion" of a compound of formula (l) into a compound of formula (ll).

Thus, in one embodiment, the present invention is preferably directed to a process as described herein comprising hydrogenation of a compound according to formula (l), said process furthermore comprising the step of (a) fermentative production of pantothenic acid/pantothenate followed by (b) esterification thereof into pantothenic acid esters according to formula (l). Fermentative production of pantothenic acid is known in the art, see e.g. WO0121772 or WO02057474. The esterification can be done according to standard procedures in the art. Particularly, a process according to the present invention comprises hydrogenation of a bio-based compound according to formula (l), wherein said bio-based compound of formula (l) is generated via conversion of fermentative pantothenic acid into said pantothenic acid ester as described herein which is furthermore hydrogenated into panthenol.

Preferably, the hydrogenation of the compound according to formula (l) to produce panthenol is carried out in the presence of a transition metal complex, such as either a heterogenous or homogeneous transition metal complex, more preferably in the presence of a homogenous transition metal complex.

For the purpose of the present invention, a suitable transition metal-complex to be used in the hydrogenation as defined herein includes catalytic complexes comprising a transition metal catalyst, in particular wherein the transition metal is selected from the group consisting of V, Mn, Fe, Co, Ni, Cu, Ru, Rh, Pd, Os, Ir, Pt, Au, preferably from Ru, Mn, Co or Os.

In one aspect of the invention, the above-described complex to be used in the hydrogenation as defined herein furthermore includes one or more organic ligand(s), particularly including bi-, tri- or tetradentate ligands, more particularly organic ligand(s) containing at least one nitrogen, phosphorus, oxygen and/or sulphur donor(s). According to one particular embodiment, a specifically useful transition metal complex comprises Ru as transition metal in combination with an organic ligand, wherein said ligand particularly contains at least one nitrogen as donor.

Usually, the hydrogenation according to the present invention is furthermore carried out under pressure, in particular in the presence of H₂ gas.

In one embodiment, the present invention comprisingthe hydrogenation of a compound of formula (l) into panthenol as described herein is carried out in the presence of H₂ gas or a gaseous mixture comprising H₂ gas, wherein in said gaseous mixture the percentage of H₂ gas is at least in the range of about 10 to about 90 volume% of the total mixture and at a pressure of about 1 to about 100 bar, preferably at about 10 to 60 bar.

In a further aspect of the present invention, the hydrogenation of a compound according to formula (l) is carried out at elevated temperatures. The term "elevated temperature" as used herein includes but is not limited to temperatures in the range of about 40 to about 150° C, preferably of about 60 to about 120°C, wherein panthenol is produced.

The compounds accordingto formula (l) or (ll) might be present in any configuration, such as e.g. in the (R) or (S)-configu ration or occurring as racemate in (R/S)-configuration, whereby the (R) or (R/S)-configuration is preferred. Typically, if the compounds accordingto formula (l) are produced by a fermentation process, a percentage of at least about 95%, such as e.g. about 97, 98, 99 or even 100% of (R)-configu ration based on total pantothenic compounds can be expected.

As used herein, such process combining chemical production steps and biotechnological steps is referred to as a "hybrid process".

As used herein, the term "pantothenic compounds" includes but is not limited to pantothenic acid, pantothenate, pantothenic acid ester and panthenol.

The reduction of a compound accordingto formula (l) to produce the compound accordingto formula (ll) as described herein includes the use of reducing agents, particularly wherein the reducing agents are selected from the group consisting of lithium aluminium hydride (LiAlH₄), sodium borohydride (NaBH₄), potassium borohydride (KBH₄), and lithium borohydride (LiBH₄).

In one embodiment, said reduction as described herein leadingto panthenol, with particularly at least about 95% panthenol based on total pantothenic compounds, is performed in the presence of an additive or activating agent, particularly wherein said agents and/or additives are selected from silanes such as chlorotrimethyl silane, iodine, Lewis acids such as zinc chloride or calcium chloride, or crown ethers.

Usually, such reduction processes as described herein, including the hydrogenation as defined herein, are performed in the presence of a suitable solvent or a mixture of solvents.

In one embodiment, said reduction step, including hydrogenation, as described herein is performed in the presence of a solvent, particularly wherein the solvent is a non-aqueous, organic, polar or non-polar solvent. Suitable solvents might be selected from alcohols and polyols, esters, ethers, amides, nitriles or hydrocarbons with or without substitutions, with a preference for substituted hydrocarbons. Particularly suitable solvents for the performance of the reduction step according to the present invention are selected from alcohols, ethers, amides and (substituted or unsubstituted) hydrocarbons. Preferably, ethers, alcohols and hydrocarbons are used as solvents in the hydrogenation of a compound accordingto formula (l) as described herein.

The term "solvent" as used herein is understood as meaning a solvent which does not take part in a chemical reaction in the reaction medium and under the operating conditions, and which is inert to both the reactants and the reaction products. It is however not excluded by theory, that the solvent may form an intermediate solvate or additive with the reducing agent or that the solvent can aggregate with the catalyst.

The reduction step leading to panthenol as of the present invention might be carried out at a suitable temperature, particularly at about 0 to about 100°C, preferably at a temperature of about 0 to about 40°C.

In one aspect, the present invention is directed to production of panthenol, preferably in (R)-configu ration, wherein at least about 95%, such as e.g. about 97, 98, 99 or even 100% panthenol based on total pantothenic compounds is generated, preferably with at least about 95% present as (R)-panthenol based on total pantothenic compounds, wherein the formation of by-products, especially formation of aminopropanol, could be reduced or eliminated.

In another embodiment, the present invention is related to a product comprising panthenol in a purity of at least about 95%, preferably of at least about 97, 98, 99 or 100% as measurable via known methods including but not limited to HPLC or qNMR analysis, wherein the product is substantially free of impurities, such as e.g. aminopropanol, pantolactone and/or pantoic acid.

As used herein, the term "substantially free of" in the context of impurities means concentration (total amount) of aminopropanol of less than 0.1%, most preferably below any limit of detection as measured by any known method including but not limited to HPLC or qNMR. It furthermore refers to a product wherein aminopropanol is not used (neither as intermediate nor as reagent) in the production process and thus, in contrast to the commonly used chemical process, no traceable amounts thereof are present, as it can be measured via known methods including but not limited to HPLC or qNMR.

In one embodiment, the process accordingto the present invention comprises the use of a hydrogenation step, such as particularly wherein pantothenic acid, preferably bio-based pantothenic acid, is first converted into pantothenic acid ester and in a further step said pantothenic acid ester is then converted via a hydrogenation step into a compound accordingto formula (l l), such as panthenol, particularly said second step being carried out in the presence of a transition metal complex and a gaseous mixture comprising at least about 10 to about 90% H₂ and wherein said process is not carried out in the presence of aminopropanol and as defined herein.

It is well understood, that the term bio-based as used herein refers to a product which is prepared by fermentation.

The esterification of pantothenic acid can be performed by standard means in the art, including but not limited to biocatalytic or fermentative processes. Chemical esterification, e.g. by reacting pantothenic acid with the respective alcohol in the presence of an acid is however preferred.

As used herein, the term "by-product" or "side-product" is used interchangeably herein and includes but is not limited to pantoic acid, pantolactone, aminopropanol or solvents present in the final product.

The product comprisingthe compound of formula (ll) can be purified (when needed) using commonly known methods, such as e.g. distillation as described in e.g. US20120149903.

Particularly, the present invention is directed to the following embodiments:

(l) A process for the production of a compound of formula (ll): said process comprising the step of reduction of a compound accordingto formula (l) to the compound of formula (ll)

wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, and M, preferably wherein the substituted or unsubstituted alkyl is C1-C10 alkyl, such as e.g. Cl, Cl, C3, C4, C5, C6, C7, C8, C9 or ClO-alkyl, more preferably selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso butyl, tert-butyl, or benzyl; and wherein M is an alkali metal or earth alkali metal, particularly sodium, potassium, calcium, or magnesium, preferably wherein M is selected from ½ calcium, ½ magnesium, sodium or potassium.

(2) The process of embodiment (1), wherein the compound accordingto formula (l) is selected from pantothenic acid, sodium-pantothenate, calcium- pantothenate, magnesium-pantothenate, or potassium-pantothenate, preferably wherein said compounds are fermentatively produced.

(3) The process of embodiment (2), further comprising the step of preparing said compounds of formula (l) by esterifying pantothenic acid or pantothenate with the respective alcohol.

(4) The process of embodiments (1) and/or (2) and/or (3), wherein the percentage of panthenol is at least about 95% based on total pantothenic compounds.

(5) The process of embodiments (1) and/or (2) and/or (3) and/or (4), wherein the reduction step is carried out in the presence of a reducing agents, preferably selected from the group consisting of lithium aluminium hydride (LIAIH ), sodium borohydride (NaBH₄), potassium borohydride (KBH₄), and lithium borohydride (LiBH₄).

(6) The process of embodiments (1) and/or (2) and/or (3) and/or (4) and/or (5), wherein the reduction step is carried out in the presence of an additive or activating agent, preferably selected from silanes such as chlorotrimethyl silane, iodine, Lewis acids such as zinc chloride or calcium chloride, or crown ethers.

(7) The process of embodiments (1) and/or (2) and/or (3) and/or (4) and/or (5) and/or (6), wherein the reduction step is carried out in the presence of a solvent selected from non-aqueous, organic, polar or non-polar solvents, particularly solvents selected from alcohols and polyols, esters, ethers, hydrocarbons with or without substitutions, amides or nitriles.

(8) The process of embodiments (1) and/or (2) and/or (3) and/or (4) and/or (5) and/or (6) and/or (7), wherein the reduction step is carried out at a temperature of about 0 to about 100°C, preferably of about 0 to about 40°C. (9) A process for the production of a compound of formula (ll):

said process comprising the step of hydrogenation of a compound according to formula (l) to the compound of formula (ll)

wherein R is selected from substituted or unsubstituted alkyl, preferably substituted or unsubstituted C1-C10 alkyl, such as e.g. Cl, C2, C3, C4, C5, C6, C7, C8, C9 or ClO-alkyl, more preferably wherein R is selected from methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, or benzyl, preferably wherein the compound according to formula (l) is selected from pantothenic acid methyl ester or pantothenic acid ethyl ester. (10) The process of embodiment (9), wherein the compound of formula (l) is obtained by esterification of pantothenic acid or pantothenate, preferably wherein the pantothenic acid or pantothenate is fermentatively produced.

(11) The process of embodiment (9) and/or (10), wherein the hydrogenation step is carried out in the presence of a transition metal complex, preferably a homogenous transition metal complex, more preferably transition metal complex comprising a metal catalyst selected from the group consisting of V, Mn, Fe, Co, Ni, Cu, Ru, Rh, Pd, Os, Ir, Pt, and Au, most preferably selected from Ru, Mn, Co or Os; preferably, wherein the transition metal complex comprises one or more organic ligand(s), preferably ligands containing at least one nitrogen, phosphorus, oxygen and/or sulphur.

(12) The process of embodiment (9) and/or (10) and/or (11), wherein the hydrogenation step is carried out in the presence of a solvent selected from non-aqueous, organic, polar or non-polar solvents, particularly solvents selected from alcohols, esters, ethers, hydrocarbons with or without substitutions, amides or nitriles.

(13) The process of embodiment (9), and/or (10) and/or (11) and/or (12), wherein the hydrogenation step is carried out in the presence of a hydrogen source, preferably in the presence of hydrogen (H₂) gas, more preferably in the presence of about 10 to 90 vol% hydrogen gas, based on the total mixture of gas.

(14) The process of embodiment (9) and/or (10) and/or (11) and/or (12) and/or (13), wherein the hydrogenation step is carried out at a pressure of about 1 to about 100 bar, preferably of about 10 to about 60 bar.

(15) The process of embodiment (9) and/or (10) and/or (11) and/or (12) and/or (13) and/or (14), wherein the hydrogenation step is carried out at a temperature of about 40 to about 150°C, preferably of about 60 to 120°C.

(16) A process for the production of a product comprising a compound of formula (l l), said process comprising a reduction step of embodiments (1) and/or (2) and/or (3) and/or (4) and/or (5) and/or (6) and/or (7) and/or (8) or a hydrogenation step of embodiments (9) and/or (10) and/or (11) and/or (12) and/or (13) and/or (14) and/or (15), wherein the product is substantially free of aminopropanol. (17) A product produced via the process of embodiment (16) comprising a percentage of aminopropanol in the range of less than 0.1% as measured by HPLC or qNMR.

The invention is illustrated by the following Examples. All percentages are related to the weight.

Example 1: Reduction of methyl pantothenate with lithium aluminium hydride

A solution of lithium aluminium hydride (2.4M in THF, 0.44 ml) was diluted with THF (1 ml) and cooled to approximately 5°C. A solution of methyl pantothenate (0.2 g, 95% purity) in THF (0.7 ml) was added dropwise over 15 minutes and the reaction mixture was stirred for a further 1 hour at 5-10°C. The mixture was quenched with saturated sodium sulfate solution and the organic layer was separated, dried and evaporated to give 0.128 g of panthenol (94.8% purity by qNMR).

Example 2: Hydrogenation of methyl pantothenate with metal catalysts

Ru-MACHO

A solution of methyl pantothenate (250 mg) in anhydrous THF (10 ml) was added to an autoclave, followed by Ru-MACHO (Carbonylchlorohydrido[bis(2- (diphenylphosphinoethyl)amino]ruthenium(ll), CAS [1295649-40-9], 13 mg) and solid sodium methoxide (5.8 mg). The autoclave was sealed and purged 3 times with nitrogen (pressurize to 5 bar and release) and then 3 times with hydrogen. The autoclave was pressurized to 25 bar and was heated under stirring at 125°C for 16 hours. The autoclave was cooled, the pressure was released and a sample was taken for GC-MS analysis. The sample showed 41% panthenol and 36% starting methyl pantothenate.

Claims

1. A process for the production of a compound of formula (ll):

said process comprising the step of reduction of a compound according to formula (l) to the compound of formula (ll)

wherein R is selected from the group consisting of M or hydrogen or substituted or unsubstituted alkyl, wherein M is an alkali metal or earth alkali metal, particularly sodium, potassium, calcium, or magnesium; and wherein the substituted or unsubstituted alkyl preferably is C1-C10 alkyl, such as e.g. Cl, C2, C3, C4, C5, C6, C7, C8, C9 or C10-alkyl, more preferably selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, or benzyl.

2. The process according to claim 1, wherein M is selected from ½ calcium, ½ magnesium, sodium or potassium.

3. The process according to claim 1 or 2, wherein the compound accordingto formula (l) is selected from pantothenic acid, sodium-pantothenate, calcium- pantothenate, magnesium-pantothenate, potassium-pantothenate, pantothenic acid methyl ester or pantothenic acid ethyl ester.

4. The process accordingto claim 3, wherein said compounds are fermentatively produced.

5. The process accordingto claim 3 or 4, further comprising the step of preparing said compounds of formula (l) by esterifying pantothenic acid or pantothenate with the respective alcohol.

6. The process according to any one of claims 1 to 5, wherein the reduction step is carried out in the presence of a reducing agents, preferably selected from the group consisting of lithium aluminium hydride (LiAlH₄), sodium borohydride (NaBH₄), potassium borohydride (KBH₄), and lithium borohydride (Li BH₄).

7. The process according to any one of claims 1 to 6, wherein the reduction step is carried out in the presence of an additive or activating agent, preferably selected from silanes such as chlorotrimethyl silane, iodine, Lewis acids such as zinc chloride or calcium chloride, or crown ethers.

8. The process according to any one of claims 1 to 7, wherein the conversion of a compound accordingto formula (l) into a compound of formula (ll) process is carried out in the presence of a solvent selected from non-aqueous, organic, polar or non-polar solvents, particularly solvents selected from alcohols and polyols, esters, ethers, hydrocarbons with or without substitutions, amides or nitriles.

9. The process accordingto any one of claims 1 to 8, wherein the reduction step is carried out at a temperature of about 0 to about 100°C, preferably of about 0 to about 40°C.

10. The process accordingto claim 8, wherein the conversion is selected from reduction accordingto any one of claims 1 to 7 or a hydrogenation of a compound of formula (l) into a compound of formula (ll), preferably hydrogenation of pantothenic acid methyl ester or pantothenic acid ethyl ester.

11. The process according to claim 10 comprising a hydrogenation step carried out in the presence of a transition metal complex, preferably a homogenous transition metal complex, more preferably transition metal complex comprising a metal catalyst selected from the group consisting of V, Mn, Fe, Co, Ni, Cu, Ru, Rh, Pd, Os, Ir, Pt, and Au, most preferably selected from Ru, Mn, Co or Os.

12. The process according to claim 11, wherein the transition metal complex comprises one or more organic ligand(s), preferably ligands containing at least one nitrogen, phosphorus, oxygen and/or sulphur donor(s).

13. The process for the production of a product comprising a compound of formula (ll), said process comprising a reduction step accordingto any one of claims 1 to 9 or a hydrogenation step accordingto any one of claims 10 to 12, wherein the product is substantially free of aminopropanol.

14. A product produced via the process according to claim 13 comprising a percentage of aminopropanol in the range of less than 0.1% as measured by HPLC or qNMR.