Use of Pyridoxal Acetal Salts as Water-Triggered Profragrances

Abstract

A pro-fragrance delivery system based on a vitamin scaffold and a fragrant alcohol. The vitamin scaffold may be a vitamer of vitamin B6 or derivatives thereof. The pro-fragrance releases the fragrant alcohol by action of water at neutral pH.

Claims

1. A compound of formula I: ##STR00009## wherein: R.sub.1 is a C1-C20 hydrocarbyl group, and R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently hydrogen or a C1-C10 hydrocarbyl group; and X is a counterion, or the corresponding free base.

2. The compound of claim 1, wherein R.sub.6 is C1-C6 straight, branched, or cyclic alkyl.

3. The compound of claim 2, wherein R.sub.6 is methyl.

4. The compound of claim 3, wherein the compound is of formula II: ##STR00010## wherein: R.sub.1 is a C5-C20 hydrocarbyl group.

5. The compound of claim 1, wherein X is HSO.sub.4, H.sub.2PO.sub.4, F, Cl, Br, I, or OH, or X is an organic counterion such as a sulfosuccinate, preferably docusate, or a carboxylate, preferably cinnamate.

6. The compound of claim 1, wherein R.sub.1 is C1-C10 alkyl that is unsubstituted or substituted with one or more aryl groups, wherein each aryl group is unsubstituted or substituted with one or more C1-C6 straight, branched, or cyclic alkyl groups.

7. The compound of claim 6, wherein R.sub.1 is substituted with one or more substituted or unsubstituted phenyl groups.

8. The compound of claim 7, wherein each phenyl is independently unsubstituted or substituted at any position with a C1-C6 straight, branched, or cyclic alkyl group or with a phenyl group.

9. The compound of claim 8, wherein the compound is: ##STR00011## or the corresponding free base.

10. The compound of claim 1, wherein R.sub.1 comprises one or more ethenyl groups.

11. The compound of claim 10, wherein the compound is: ##STR00012## or the corresponding free base.

12. The compound of claim 1, wherein R.sub.1 is a C8-C15 hydrocarbyl group.

13. The compound of claim 1, wherein R.sub.1 is a C8-C13 hydrocarbyl group.

14. The compound of claim 1, wherein when R.sub.6 is methyl and R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each hydrogen, then R.sub.1 is not C1-C4 alkyl.

15. A compound as shown below as free base or salt, preferably wherein X is HSO.sub.4, H.sub.2PO.sub.4, F, Cl, Br, I, or OH, or X is an organic counterion such as a sulfosuccinate, preferably docusate, or a carboxylate, preferably cinnamate: ##STR00013## ##STR00014## ##STR00015## ##STR00016## ##STR00017##

16. A composition comprising the compound of claim 1 and a carrier, adjuvant, or active agent suitable for skin care, hair care, or cosmetics.

17. The composition of claim 16 in the form of an emulsion.

18. A method of providing a scent to a subject, comprising administering an effective amount of a composition according to claim 16 to a subject.

19. The method of claim 18, wherein the scent is released in a timed-release manner.

20. A chewing gum comprising (a) a gum base, (b) a compound according to claim 1, and (c) optionally flavors such as wintergreen, spearmint, peppermint, birch, anise, fruit flavors, or mixtures thereof.

21. The chewing gum of claim 20, wherein the gum base is a chewable, substantially water insoluble base, such as chicle and substitutes thereof, sorva, guttakay, jelutong, synthetic polymers such as polyvinyl acetate, synthetic resins, rubbers, or mixtures thereof.

22. A method to confer, improve, enhance or modify a taste or flavor property of a composition or article, comprising adding to the composition or article a flavor effective amount of a compound or mixture of compounds according to claim 1.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0021] FIG. 1 shows how an embodiment of the pro-fragrance releases the target fragrance by action of water, e.g., by hydrolysis.

[0022] FIG. 2 is a stack plot of H NMR spectra per hour (y-axis) demonstrating the release of ethanol in the presence of deuterium oxide at a concentration of 0.2 M in DMSO-d.sub.6/D.sub.2O (50:50; v/v).

[0023] FIG. 3 is a graph showing a kinetic reaction profile for the release of ethanol from 3a at varying concentrations in DMSO-d.sub.6/D.sub.2O. The D.sub.2O concentrations are 25% (green), 35% (blue), 50% (red), and 100% (violet) (colors from bottom to top).

[0024] FIG. 4 is a graph showing time-dependent release of ethanol (blue), 2-phenylethanol (green), isopropanol (red) (colors at left of graph from bottom to top) from the pyridoxal acetal salts in 0.2 M DMSO-d.sub.6/D.sub.2O (70:30; v/v).

[0025] FIG. 5 is a stack plot for 2-phenylethoxy acetal showing release of 2-phenylethanol in 30% deuterium oxide in DMSO-d.sub.6.

[0026] FIG. 6 is a stack plot for isopropoxy acetal showing release of isopropanol in 30% deuterium oxide in DMSO-d.sub.6.

[0027] FIG. 7 is a stack plot for geranyl acetal showing the release of geraniol in 30% deuterium oxide in DMSO-d.sub.6.

[0028] FIGS. 8-11 are stack plots showing release of ethanol in 20% D.sub.2O, 35% D.sub.2O, 50% D.sub.2O, and 100% D.sub.2O, respectively.

[0029] FIG. 12 contains .sup.1H and .sup.13C spectra of compound 3a.

[0030] FIG. 13 contains .sup.1H and .sup.13C spectra of compound 3b.

[0031] FIG. 14 contains .sup.1H and .sup.13C spectra of compound 3c.

[0032] FIG. 15 contains .sup.1H and .sup.13C spectra of compound 3d.

DETAILED DESCRIPTION

[0033] Those skilled in the art will understand that this invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth in this application. Rather, these embodiments are provided so that this disclosure will fully convey the invention to those skilled in the art. Many modifications and other embodiments of the invention will come to mind in one skilled in the art to which this invention pertains having the benefit of the teachings presented herein.

[0034] Hydrocarbyl means any univalent radical, derived from a hydrocarbon. This includes a branched, unbranched, or cyclic hydrocarbon of 1-20 carbon atoms. Representative examples include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 2-phenylethyl, and n-decyl and the like.

[0035] Aryl means monocyclic or polycyclic aromatic ring systems, including fused aromatic ring systems. Representative examples include, but are not limited to, phenyl, naphthyl, anthryl, and the like. The term aryl is intended to include both substituted and unsubstituted aryl rings.

[0036] A carrier or adjuvant includes any additive used for personal care products, e.g., an oil, treated water, emollient, soap, detergent, surfactant, emulsifier, thickening agent, mineral powder, dye or other colorant, pigment, fragrance, wax, or stabilizer. Examples of specific ingredients include, but are not limited to, petroleum jelly, lanoline, polyethylene glycol, alcohols, or transdermal enhancers. Additional active agents may be included, e.g., any medicinal or therapeutic agents, anti-aging or anti-wrinkle agents, deodorants, antiperspirants, astringents, or hair treatments. The composition is preferably suitable for topical application to the skin, e.g., as an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Veterinary use is also contemplated.

[0037] A fragrance or Perfume Raw Material (PRM) relates to a compound that is used to provide a pleasant odor and fragrance profile to a material. These include known natural oils that can be found in journals commonly used in the field, such as Perfume and Flavorist or Journal of Essential Oil Research or reference texts such as S. Arctander, Perfume and Flavor Chemicals, 1969, Montclair, N.J., USA, republished by Allured Publishing Corporation Illinois (1994).

[0038] This disclosure relates to the utilization of pyridoxal acetal salts as bio-based pro-fragrances that are released in the presence of water at neutral pH. This delivery system conforms to the pro-fragrance desired traits of precursor stability, biodegradability, and cost efficiency as described by Hermann. The present invention is preferably a vitamin-based pro-fragrance. For example, vitamin B6 is an essential nutrient consisting of several vitamers as illustrated in Scheme 1 including pyridoxal, pyridoxine, pyridoxamine, and their phosphorylated derivatives.

##STR00003##

[0039] While pyridoxine HCl is the most common form of the vitamin Be complex found in dietary supplements and in treatments for various skin conditions, pyridoxal 5-phosphate is the active form of the vitamin. S. Mooney et al., Molecules, 2009, 14, 329; H. Hellmann et al., Molecules, 2010, 15, 442. The vitamers of vitamin B can interconvert in biological systems to generate pyridoxal 5-phosphate, which is a cofactor in over 100 enzyme-catalyzed reactions involved in metabolism and regulatory functions.

[0040] Pyridoxal HCl and pyridoxine have been known to undergo ortho-pyridinone methide chemistry for decades (D. Heyl et al., J. Am. Chem. Soc., 1951, 73, 3430; A. Pocker, J. Org. Chem., 1973, 38, 4295); however, this reactivity has received little attention. L. K. Kibardina et al., Synthesis, 2015, 47, 721; (b) L. K. Kibardina et al., Russ. J. Gen. Chem., 2015, 85, 514; L. K. Kibardina et al., Heteroat. Chem., 2016, 27, 221. Recently, we reported a study on the catalyst-free, regioselective etherification of pyridoxine (J. A. Yazarians et al., Tetrahedron Lett., 2017, 58, 2258), although the reaction suffers from long reaction times and high temperatures. While commonly drawn as the aldehyde tautomer, pyridoxal HCl exists as the furopyridine 1 as illustrated in Scheme 2.

##STR00004##

[0041] This tautomer enables pyridoxal HCl to undergo ortho-pyridinone methide formation through 2 under mild conditions due to the stability imparted by the dihydrofuran moiety as compared to the primary alcohol of pyridoxine. Once the ortho-pyridinone methide 2 is generated, oxa-Michael addition of the alcohol occurs to provide the pyridoxal acetal salt 3.

[0042] A series of conditions were screened to determine the optimal parameters for the purpose of avoiding the need for purification. Exposing pyridoxal HCl to the desired alcohol at 60 C. in the absence of catalyst provided clean conversion to the acetal in quantitative yields as illustrated in Scheme 3. For volatile alcohols, the solvent was evaporated to provide analytically pure product, 3a and 3c. Geraniol and 2-phenylethanol were used as substrates due to their use as fragrances in industry. Any other fragrant alcohols could be used. With respect to 2-phenylethyl acetal 3b and the geranyl acetal 3d, diethyl ether was added to the reaction mixture to precipitate the acetal that was then isolated by filtration.

##STR00005##

[0043] The hydrolysis of the target alcohol from the pyridoxal acetal salt in the presence of D.sub.2O was monitored by .sup.1H NMR spectroscopy. This was accomplished by comparing the formation of hemiacetal CH peak to the loss of the acetal CH peak. For substrate 3a, the integration of the acetal CH peak at 6.58 ppm was compared to the integration of the pyridoxal hemiacetal CH peak at 6.41 ppm hourly to determine conversion. A stack plot of the NMR spectra for 50% D.sub.2O solution in DMSO-d.sub.6 over 20 hours is illustrated in FIG. 2.

[0044] To determine the kinetics of the hydrolysis with respect to the concentration of water, acetal 3a was exposed to varying concentrations of D.sub.2O The release of ethanol from 3a was measured at concentrations of 25%, 35%, 50%, and 100% D.sub.2O in DMSO-d.sub.6 and is plotted in FIG. 3. The plot demonstrates the controlled release of ethanol where the rate increases with higher concentrations of D.sub.2O. The 100% D.sub.2O trial provides full cleavage after 10 hours whereas a lowest concentration of D.sub.2O (25%) provides the slowest release at only 28% cleaved after 25 hours. The 50% D.sub.2O trial provided 74% release after 25 hours and the 35% D.sub.2O trial provided 42% release.

[0045] The rate of release for ethanol (blue), isopropanol (red), 2-phenylethanol (green), and geraniol (purple) were monitored at a 0.2 M concentration of 30% D.sub.2O in DMSO-d.sub.6 from the respective pyridoxal acetal. As shown in FIG. 4 each acetal demonstrated linear controlled-release with ethanol providing the slowest release at 35% after 22 hours and isopropanol providing the highest release of 37% after 22 hours. In all cases, the acetals hydrolyze to release the target molecule and pyridoxal HCl quantitatively. Since other fragrance delivery systems can lose material in side reactions (H. Q. N. Gunaratne et al., Chem. Commun., 2015, 51, 4455), the high fidelity in the release for these alcohols is significant.

[0046] The following examples serve to illustrate certain aspects of the disclosure and should not be construed as limiting the claims. The contents of all references, pending patent applications and published patents, cited throughout this application are hereby expressly incorporated by reference.

EXAMPLES

General Information

[0047] Proton and carbon nuclear magnetic resonance spectra (.sup.1H and .sup.13C NMR) were recorded at 400 and 100 MHz, respectively, with solvent resonance as the internal standard (.sup.1H NMR: DMSO-d.sub.6 at 2.500 ppm; .sup.13C NMR: DMSO-d.sub.6 at 39.52 ppm). .sup.1H NMR data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, dd=doublet of doublets, t=triplet, q=quartet, m=multiplet), coupling constants (Hz), and integration. Mass spectra were recorded on a high-resolution electrospray ionization quadrupole mass spectrometer. All reactions were carried out under air with magnetic stirring. Yield refers to isolated yield of analytically pure material. Yields are reported for a specific experiment and as a result may differ slightly from those found in the tables, which are averages of at least two experiments.

General Procedure for the Synthesis of the Pyridoxal Acetal Salts (3a-3c).

[0048] Pyridoxal HCl was added to the appropriate alcohol (0.5 M) and the solution was heated to 60 C. for 2 hours. The solution was then cooled to room temperature and either concentrated in vacuo (3a, 3c) or diluted with ether and allowed to crystallize in the freezer before being filtered to provide pure material (3b, 3d).

Analytical Data for Pyridoxal Acetal Salts (3a-3d)

##STR00006##

Example 1

[0049] 1-ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-5-ium chloride (3a): The title compound was prepared according to the general procedure using pyridoxal HCl 1 (100 mg, 0.491 mmol, 1 equiv) in ethanol (1.0 mL, 0.5 M) affording 115 mg (99%) of the product as a white solid. Analytical Data for 3a: m.p.: 97-103 C. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .sub.H 12.05 (br. s, 1H), 8.28 (s, 1H), 6.58 (s, 1H), 5.14-5.03 (m, 2H), 3.75-3.70 (m, 2H) 2.61 (s, 3H), 1.11 (t, J=7.0 Hz, 3H) .sup.13C NMR (100 MHz, CDCl.sub.3): .sub.C 149.5, 143.7, 139.0, 138.8, 125.4, 104.2, 70.0, 64.1, 15.7, 14.9.

Example 2

[0050] 7-hydroxy-6-methyl-1-phenethoxy-1,3-dihydrofuro[3,4-c]pyridin-5-ium chloride (3b): The title compound was prepared according to the general procedure using pyridoxal HCl 1 (100 mg, 0.491 mmol, 1 equiv) in 2-phenylethanol (1.0 mL, 0.5 M) affording 133.4 mg (89%) of the product as a white solid. Analytical Data for 3b: m.p. 168-172 C. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .sub.H 12.09 (br. s, 1H), 8.28 (s, 1H), 7.27-7.15 (m, 5H), 6.67 (s, 1H), 5.11-5.06 (m, 2H), 3.96-3.89 (m, 2H), 2.88-2.83 (m, 2H), 2.62 (s, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): .sub.C 149.0, 143.3, 138.6, 138.5, 138.1, 128.8, 128.3, 126.1, 124.97, 103.8, 69.6, 68.7, 35.6, 14.4.

Example 3

[0051] 7-hydroxy-1-isopropoxy-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-5-ium chloride (3c): The title compound was prepared according to the general procedure using pyridoxal HCl 1 (100 mg, 0.491 mmol, 1 equiv) in isopropanol (1.0 mL, 0.5 M) affording 120 mg (99%) of the product as a white solid. Analytical Data for 3c: m.p. 116-121 C. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .sub.H 1.92 (br. s, 1H), 8.29 (s, 1H), 6.71 (s, 1H), 5.08, (s, 2H), 4.14-4.08 (m, 1H), 2.62 (s, 3H), 1.16 (d, J=4.0 Hz, 6H) .sup.13C NMR (100 MHz, CDCl.sub.3): .sub.C 149.3, 143.8, 139.9, 139.0, 125.6, 72.1, 69.6, 24.1, 23.2.

Example 4

[0052] (E)-1-((3,7-dimethylocta-2,6-dien-1-yl)oxy)-7-hydroxy-6-methyl-1,3-dihydrofuro[3,4-c]pyridin-5-ium chloride (3d): The title compound was prepared according to the general procedure using pyridoxal HCl 1 (100 mg, 0.491 mmol, 1 equiv) in geraniol (1.0 mL 0.5 M) and in DMSO (0.02 mL, 25 M) to aid with solubility affording 123 mg (73%) of the product as a white solid. Analytical data for 3d: m.p. 140-142 C. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .sub.H 12.04 (br. s, 1H), 8.28 (s, 1H), 6.63 (s, 1H), 5.30-5.27 (s, 1H), 5.12-5.04 (m, 3H), 4.29-4.19 (m, 2H), 2.62 (s, 3H), 2.03-1.95 (m, 4H), 1.62 (s, 3H), 1.61 (s, 3H), 1.53 (s, 3H) .sup.13C NMR (100 MHz, CDCl.sub.3): .sub.C 149.0, 143.2, 139.6, 138.5, 138.3, 131.0, 125.0, 123.9, 120.4, 103.3, 69.6, 64.5, 39.0, 25.9, 25.5, 17.6, 16.3, 14.4.

Time-Dependent Stack Plots of Acetal Cleavage

[0053] ##STR00007##

[0054] The acetal cleavage was measured by comparing the integration of H.sub.a to H.sub.b whereas H.sub.b/(H.sub.a+H.sub.b) provides the percent completion for the acetal cleavage for 3a and 3b. The stack plots in FIGS. 7-11 provide a visual counterpart to the graphs. 3c had some overlap between H.sub.a and H.sub.b so the fully separated methyl groups of the isopropyl were integrated instead.

##STR00008##

Conditions for the Kinetic Reaction Profile for the Release of Ethanol

[0055] 3a (0.1636 mmol) was dissolved in 0.4 mL of DMSO-d.sub.6 (except for 100% D.sub.2O) and varying amounts of D.sub.2O were added, as shown in the table below (see corresponding stack plots in FIGS. 7-11).

TABLE-US-00001 % D.sub.2O 100% 50% 35% 20% D.sub.2O Added 0.8 mL 0.4 mL 0.23 mL 0.1 mL Final Molarity 0.2M 0.2M 0.25M 0.3M