EP4323331A1 - Herstellung von panthenol - Google Patents
Herstellung von panthenolInfo
- Publication number
- EP4323331A1 EP4323331A1 EP22723125.5A EP22723125A EP4323331A1 EP 4323331 A1 EP4323331 A1 EP 4323331A1 EP 22723125 A EP22723125 A EP 22723125A EP 4323331 A1 EP4323331 A1 EP 4323331A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- accordingto
- pantothenic acid
- pantothenate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 16
- SNPLKNRPJHDVJA-ZETCQYMHSA-N D-panthenol Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCCO SNPLKNRPJHDVJA-ZETCQYMHSA-N 0.000 title abstract description 27
- 229940101267 panthenol Drugs 0.000 title abstract description 26
- 235000020957 pantothenol Nutrition 0.000 title abstract description 26
- 239000011619 pantothenol Substances 0.000 title abstract description 26
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 61
- 235000019161 pantothenic acid Nutrition 0.000 claims abstract description 42
- 239000011713 pantothenic acid Substances 0.000 claims abstract description 42
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229940055726 pantothenic acid Drugs 0.000 claims abstract description 35
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 54
- 238000005984 hydrogenation reaction Methods 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 18
- 229910052723 transition metal Inorganic materials 0.000 claims description 16
- 150000003624 transition metals Chemical class 0.000 claims description 16
- MXZROAOUCUVNHX-UHFFFAOYSA-N 2-Aminopropanol Chemical compound CCC(N)O MXZROAOUCUVNHX-UHFFFAOYSA-N 0.000 claims description 13
- -1 pantothenic acid methyl ester Chemical class 0.000 claims description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 239000011591 potassium Substances 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000001340 alkali metals Chemical class 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 150000002430 hydrocarbons Chemical class 0.000 claims description 7
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 7
- 229940014662 pantothenate Drugs 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000011575 calcium Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 229910052762 osmium Inorganic materials 0.000 claims description 6
- 238000010966 qNMR Methods 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 239000012448 Lithium borohydride Substances 0.000 claims description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 229910052791 calcium Inorganic materials 0.000 claims description 5
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000013110 organic ligand Substances 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 claims description 4
- 229960002079 calcium pantothenate Drugs 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000012454 non-polar solvent Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 229910052707 ruthenium Inorganic materials 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000005864 Sulphur Chemical group 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 150000003983 crown ethers Chemical class 0.000 claims description 3
- 229910052737 gold Inorganic materials 0.000 claims description 3
- 229910052741 iridium Inorganic materials 0.000 claims description 3
- 229910052742 iron Inorganic materials 0.000 claims description 3
- ONSCBWDZUUNMMK-UBKPKTQASA-L magnesium;3-[[(2r)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]propanoate Chemical compound [Mg+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O ONSCBWDZUUNMMK-UBKPKTQASA-L 0.000 claims description 3
- 229910052748 manganese Inorganic materials 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Chemical group 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Chemical group 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 229920005862 polyol Polymers 0.000 claims description 3
- 150000003077 polyols Chemical class 0.000 claims description 3
- VUOLWBPDWWANLX-FJXQXJEOSA-M potassium 3-[[(2R)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]propanoate Chemical compound [K+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O VUOLWBPDWWANLX-FJXQXJEOSA-M 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- 150000004756 silanes Chemical class 0.000 claims description 3
- GQTHJBOWLPZUOI-FJXQXJEOSA-M sodium D-pantothenate Chemical compound [Na+].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O GQTHJBOWLPZUOI-FJXQXJEOSA-M 0.000 claims description 3
- 229940068459 sodium pantothenate Drugs 0.000 claims description 3
- 229910052720 vanadium Inorganic materials 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 9
- 239000007789 gas Substances 0.000 description 7
- 230000032050 esterification Effects 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 6
- XUOLPZAHXIRZLN-QMMMGPOBSA-N methyl 3-[[(2r)-2,4-dihydroxy-3,3-dimethylbutanoyl]amino]propanoate Chemical compound COC(=O)CCNC(=O)[C@H](O)C(C)(C)CO XUOLPZAHXIRZLN-QMMMGPOBSA-N 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 150000002948 pantothenic acids Chemical class 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000008246 gaseous mixture Substances 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- SERHXTVXHNVDKA-UHFFFAOYSA-N pantolactone Chemical compound CC1(C)COC(=O)C1O SERHXTVXHNVDKA-UHFFFAOYSA-N 0.000 description 3
- 229940115458 pantolactone Drugs 0.000 description 3
- SIEVQTNTRMBCHO-UHFFFAOYSA-N pantolactone Natural products CC1(C)OC(=O)CC1O SIEVQTNTRMBCHO-UHFFFAOYSA-N 0.000 description 3
- OTOIIPJYVQJATP-BYPYZUCNSA-N (R)-pantoic acid Chemical compound OCC(C)(C)[C@@H](O)C(O)=O OTOIIPJYVQJATP-BYPYZUCNSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000002210 biocatalytic effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000012262 fermentative production Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930003571 Vitamin B5 Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- WMFHTIJCSNSMDO-UHFFFAOYSA-N diphenylphosphinoethyl-pss Chemical group C=1C=CC=CC=1P(C=1C=CC=CC=1)CC[Si](O1)(O2)O[Si](O3)(C4CCCC4)O[Si](O4)(C5CCCC5)O[Si]1(C1CCCC1)O[Si](O1)(C5CCCC5)O[Si]2(C2CCCC2)O[Si]3(C2CCCC2)O[Si]41C1CCCC1 WMFHTIJCSNSMDO-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 235000009492 vitamin B5 Nutrition 0.000 description 1
- 239000011675 vitamin B5 Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Definitions
- 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.
- 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.
- panthenol on an industrial scale which does not involve the use of aminopropanol as a reagent.
- reagents for 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 e
- reaction 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 (H 2 ) gas, and in the presence of a catalyst as defined herein into a compound according to formula (ll).
- hydrogenation i.e. conversion of a compound according to formula (l), particularly pantothenic acid esters
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- the hydrogenation according to the present invention is furthermore carried out under pressure, in particular in the presence of H 2 gas.
- the present invention comprisingthe hydrogenation of a compound of formula (l) into panthenol as described herein is carried out in the presence of H 2 gas or a gaseous mixture comprising H 2 gas, wherein in said gaseous mixture the percentage of H 2 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.
- the hydrogenation of a compound according to formula (l) is carried out at elevated temperatures.
- elevated temperature 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.
- 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.
- hybrid process As used herein, such process combining chemical production steps and biotechnological steps is referred to as a "hybrid process”.
- 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 (LiAlH 4 ), sodium borohydride (NaBH 4 ), potassium borohydride (KBH 4 ), and lithium borohydride (LiBH 4 ).
- the reducing agents are selected from the group consisting of lithium aluminium hydride (LiAlH 4 ), sodium borohydride (NaBH 4 ), potassium borohydride (KBH 4 ), and lithium borohydride (LiBH 4 ).
- 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.
- 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.
- 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.
- ethers, alcohols and hydrocarbons are used as solvents in the hydrogenation of a compound accordingto formula (l) as described herein.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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% H 2 and wherein said process is not carried out in the presence of aminopropanol and as defined herein.
- 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 gas
- bio-based 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.
- 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.
- a process for the production of a compound of formula (ll) 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 1 ⁇ 2 calcium, 1 ⁇ 2 magnesium, sodium or potassium.
- a process for the production of a compound of formula (ll) 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.
- 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.
- 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 sulph
- 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.
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|---|---|---|---|
| US202163175198P | 2021-04-15 | 2021-04-15 | |
| US202163175183P | 2021-04-15 | 2021-04-15 | |
| EP21181256.5A EP4108654A1 (de) | 2021-06-23 | 2021-06-23 | Herstellung von panthenol |
| PCT/EP2022/060156 WO2022219173A1 (en) | 2021-04-15 | 2022-04-15 | Production of panthenol |
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| EP22723125.5A Pending EP4323331A1 (de) | 2021-04-15 | 2022-04-15 | Herstellung von panthenol |
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| WO (1) | WO2022219173A1 (de) |
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| CN1420931A (zh) | 1999-09-21 | 2003-05-28 | Basf公司 | 制备泛化合物的方法和微生物 |
| JP4217070B2 (ja) | 2001-01-19 | 2009-01-28 | ビーエーエスエフ ソシエタス・ヨーロピア | パントテネートの産生増強法 |
| RU2295949C1 (ru) * | 2005-08-15 | 2007-03-27 | ООО "Лаборатории "Новые Горизонты Химии" | Стимулятор роста волос на основе производных пантотеновой кислоты |
| CN101851171B (zh) * | 2010-05-06 | 2012-09-19 | 北京京卫信康医药科技发展有限公司 | 一种d-泛醇的制备方法 |
| EP2468712A1 (de) | 2010-12-14 | 2012-06-27 | Basf Se | Verfahren zur Herstellung und Aufreinigung von 3-Aminopropanol |
| WO2012158811A2 (en) * | 2011-05-19 | 2012-11-22 | Rfs Pharma, Llc | Purine monophosphate prodrugs for treatment of viral infections |
| CA3007063A1 (en) | 2015-12-08 | 2017-06-15 | Retrophin, Inc. | Cyclic phosphates and cyclic phosphoramidates for the treatment of neurologic disorders |
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