FLAVOR MOLECULES

This application claims the benefit of the filing date, under 35 U.S.C. §119(e), of U.S. Provisional Application for Patent Ser. No. 61/031,146, filed Feb. 25, 2008, incorporated herein by reference.

This disclosure relates to flavours, compounds for providing flavours and methods for providing flavours.

Flavoring is added to many orally-receivable or ingestible products, such as foodstuffs, confectionery, beverages, mouthwashes, dentrifices and the like. It is preferred that these be identical to natural materials known to be safe, or to be close derivatives of such materials.

Flavonoids are usually regarded as bitter or neutral-tasting plant constituents. However, there are flavonoids in two structural classes, which are known as sweet representative: the dihydrochalcones (DHCs) and the dihydroflavonols. Only a few dihydrochalcones have been identified from natural sources. Glycyphylin, Phloridzin and trilobtain are the examples isolated from Smilax glycyphylla Sm. (Liliaceae), Symplocos lancifolia Sieb. Et Zucc., and Symplocus microcaly, respectively. Normally, DHCs, molecules with a basic structure according to the following formula

are derived from bitter flavanone glycosides in citrus fruits by catalytic reduction of the chalcones. The best-known semi-synthetic DHC is neohesperidine dihydrochalcone (NDHC), which can be obtained as a by-product of citrus industry and is used in a wide variety of foodstuffs as a sweetener and flavor ingredient.

In the past 20 years there have been many attempts to produce dihydrochalcone analogs with taste qualities as good as that of sucrose. It was concluded from these studies that highly sweet compounds in this series required a 3-hydroxy-4-alkoxy substitution in ring B (Whitelaw and Daniel, Journal of Agricultural and Food Chemistry (1991), 39(4), pp. 663-7; and Journal of Agricultural and Food Chemistry (1991), 39(1), pp. 44-51).

It has now been found that a range of DHC-based compounds are capable of conferring a wide variety of flavors and flavor modifications. There is therefore provided a method of providing flavor to a composition adapted to be received orally, comprising adding thereto at least one compound, including salts thereof of the formula:

wherein R₁comprises H, OH, O(CH₂)₂OH, OCH₂OCH₃or

wherein R₂comprises a heterocyclic moiety selected from

and wherein R₃comprises H or OH.

Suitable non-limiting examples of salts of the above identified compounds include K⁺, NH₄⁺, Na⁺, Ca²⁺, Mg²⁺, Al³⁺, Zn²⁺.

Certain illustrative embodiments comprise compounds comprising moieties (iii), (iv), (vii), (viii), (xiii), (xvii), or (xviii).

The compounds confer a wide variety of desirable flavors, such as sweet, sour and umami, to orally receivable or digestable products. Specific examples of these flavor characteristics are described in further detail in the examples hereinunder provided.

A number of the molecules hereinabove provided are novel materials. Some of the compounds hereinabove described are novel. There is therefore additionally provided a compound (including salts thereof) the formula:

wherein R₁comprises H, OH, O(CH₂)₂OH, OCH₂OCH₃or

wherein R₃comprises H or OH,

with the proviso that

(a) when R¹comprises H, R²comprises a moiety selected from (iii), (iv), (vi), (viii), (x), (xii), (xiii), (xiv), (xvi), (xvii), (xviii), (xix), or (xx);

(b) when R¹comprises OH, R²comprises moiety (iii) or (iv);

(c) when R¹comprises —OCH₂OCH₃, R²comprises moiety (iii) or (iv):

(d) when R¹comprises

R²comprises moiety (iii) or (iv); and

(e) when R¹comprises —OCH₂CH₂OH, R²comprises moiety (iii).

The compounds may be used in all variety of orally-receivable and ingestible products. Non-limiting examples of such products include:

Consumable products, including, but not limited to all food products, food additives, nutraceuticals, pharmaceuticals and any product placed in the mouth including chewing gum, oral care products, and oral hygiene products including but not limited to, cereal products, rice products, tapioca products, sago products, baker's products, biscuit products, pastry products, bread products, confectionery products, dessert products, gums, chewing gums, flavored or flavor-coated straws, flavor or flavor-coated food/beverage containers, chocolates, ices, honey products, treacle products, yeast products, baking-powder, salt and spice products, savoury products, mustard products, vinegar products, sauces (condiments), tobacco products, cigars, cigarettes, processed foods, cooked fruits and vegetable products, meat and meat products, jellies, jams, fruit sauces, egg products, milk and dairy products, yoghurts, cheese products, butter and butter substitute products, milk substitute products, soy products, edible oils and fat products, medicaments, beverages, carbonated beverages, alcoholic drinks such as beers, wines and spirits, non-alcoholic drinks such as soft drinks, mineral and aerated waters, fruit drinks, fruit juices, coffee, artificial coffee, tea, cocoa, including forms requiring reconstitution including, without limitation, beverage powder, milk based beverage powder, sugar-free beverage powder, beverage syrup, beverage concentrate, instant coffee, instant tea, instant cocoa, and coffee whitener, food extracts, plant extracts, meat extracts, condiments, gelatins, pharmaceutical and non-pharmaceutical gums, tablets, lozenges, drops, emulsions, elixirs, syrups and other preparations for making beverages, and combinations thereof.

Oral care products, including, but not limited to, any composition applied to the oral cavity for the purposes of cleaning, freshening, healing, deodorising the cavity or any part thereof, may include, but are not limited to, toothpastes, tooth gels, tooth powders, tooth whitening products, mouthwashes, lozenges, dental floss, toothpicks, anti-plaque and anti-gingivitis compositions, throat lozenges, throat drops, inflammatory compositions, compositions for treatment of nasal symptoms, cold symptoms and upper gastrointestinal tract distress, compositions for cold relief, for alleviating discomfort of hot flash, and gargle compositions.

The proportion of compound used will vary in every case, depending upon the end use and the nature and extent of taste required. This may be readily determined in every case by one having ordinary skill in the art by routine experimentation. Without limitation, and by way of illustration only, proportions of compound may be in the range of about 0.01 to about 600 ppm depending on the application. Typical, non-limiting examples in a beverage are from about 1 to about 50 ppm, in ice cream from about 10 to about 100 ppm, and in cereal from about 10 top about 150 ppm.

According to certain illustrative embodiments, the compounds may be used in such products with known flavor compounds, and also with all the known ancillary compounds used in flavoured products.

According to one illustrative aspect of the disclosure, it has been found that one of these compounds enhances the sweetness of a sugar-containing product in a synergistic fashion, that is, the overall sweetness is higher than the simple sum of the sweetness of two sweet substances. This compound has little sweet taste of its own, but it causes a considerable increase in the perceived sweetness of a sugar-containing product. This is of great interest, given the current interest in improved diet and the desire to decrease the sugar content of consumable products sweetness for dietary or health reasons.

According to other embodiments, also provided is a method of decreasing the sugar content of a sugar-containing consumable product, comprising adding to said sugar-containing consumable product an effective amount of 1-(2-hydroxyphenyl)-3-(pyridin-4-yl)propan-1-one (hereinafter referred to as “Compound 13”, the number of the Example below in which it is described).

The sweet enhancement effect of Compound 13 is illustrated in the following tables: the isointensity of Compound 13 at 20 ppm equals 0.5% sucrose. The isointensity of 7% sucrose with 20 ppm 1-(2-hydroxyphenyl)-3-(pyridin-4-yl)propan-1-one is 8% sucrose. Therefore, the perceived enhancement of sucrose is about 0.5% sucrose (8%-7.5%). This sweet enhancement effect is also observed with other natural and artificial sweeteners, for example, carbohydrates; sucrose, lactose, D-glucose, D-tagatose, D-fructose whether naturally- or synthetically-produced, erythritol, threitol, arabitol, ribitol, xylitol, sorbitol, mannitol, maltitol, isomaltitol, dulcitol, and lactitol, thaumatin, glycin, D-phenylalanine, D-tryptophan, sodium cyclamate, acesulfam K, neohesperidine dihydrochalcone, sodium salt of saccharin, aspartame, superaspartame, neotam, alitam, sucralose, and stevioside.

Isointensity of 20 ppm Compound 13 in water.

sample
R-index
Critical value

solutions compared
sweetness
[%]
[%]
p-value

0.5% sucrose vs.
isosweet
61%
64.61
P > 0.05

20 ppm Compound 13

1% sucrose vs.
less sweet
14%
35.39
P < 0.05

20 ppm Compound 13

Isointensity of 7% sucrose +20 ppm Compound 13 in water.

sample
R-
Critical
p-

solutions compared
sweetnes
index
value
value

7% sucrose vs.
sweeter
66%
64.61
P < 0.05

7% sucrose + 20 ppm Cmpd 13

8% sucrose vs.
isosweet
43%
35.39
P > 0.05

7% sucrose + 20 ppm Cmpd 13

9% sucrose vs.
less
8%
35.39
P < 0.05

7% sucrose + 20 ppm Cmpd 13
sweet

10% sucrose vs.
less
4%
35.39
P < 0.05

7% sucrose + 20 ppm Cmpd 13
sweet

By “effective amount” is meant the amount needed to produce the desired level of sweetness, while reducing the level of sugar to the desired extent. This will naturally depend on the nature of the product and how much sweetness is desired, so no rigid limits can or should be set, but in every case a suitable level my be determined by one having ordinary skill in the art by routine experimentation. Without limitation, and by way of illustration only, proportions may be in the range of about 0.1 to about 500 ppm.

Compound 13 may be used in conjunction with any knoll flavour molecule, sweetener, and sweetness enhancer such as naringen dihydro chalcone.

The disclosure is now further illustrated by the following examples, which are purely exemplary and which are not intended to be in any manner limiting on the scope of the disclosure.

EXAMPLE 1
1-(2-hydroxyphenyl)-3-(6-methoxypyridin-3-yl)propan-1-one

To a stirring solution of 2-hydroxyacetophenone (2.19 g, 16.1 mmol) in EtOH (30 ml) at room temperature was added 6-methoxy-3-pyridine-carboxaldehyde (1.98 g, 14.4 mmol) and 10 ml solution of KOH in water (1.8 g, 32.1 mmol). The solution was continuously stirred at room temperature for 5 hours, and then water was added to the reaction flask. The aqueous layer was acidified to pH=7 using 1N HCl and extracted three times with EtAOc. The organic layers combined and dried (Na₂SO₄). The solvent was removed in vacuo and the residue chromatographed on silica gel (5% EtOAc/Hex) to give the yellow solid which was recystallized with hot EtOAc/hex to yield 1.2 g of product (32%). ¹H NMR (300 MHz, CDCl₃): δ 12.83 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.96-7.89 (m, 2H), 7.91 (d, J=15.3 Hz, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.52 (d, d, J=6.9, 7.2 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.97 (d, d, J=6.9, 7.5 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 4.01 (s, 3H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.28, 165.72, 163.64, 149.47, 141.94, 136.61, 136.39, 129.50, 124.04, 119.94, 118.88, 118.84, 118.69, 111.74, 53.92.

HPLCMS (APCl⁺): m/z=256.2.

In a 100 ml round-bottom flask, 0.53 g of chalcone (2.08 mmol) and 90 mg of 10% Pd/C (0.86 mmol) was mixed together in 20: 10 ml THF: MeOH solution. Hydrogenation at atmospheric pressure then filtered off the catalyst. The crude was purified by chromatography on silica gel (10% EtOAc/hexane) to provide 0.35 g (58%) of final compound. ¹H NMR (300 MHz, CDCl₃): δ 12.15 (s, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.65 (d, d, J=1.5, 8.1 Hz, 1H), 7.41-7.36 (m, 2H), 6.91 (d, d, J=0.9, 8.4 Hz, 1H), 6.80 (d, d, d, J=1.2, 7.5, 8.4 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 3.84 (s, 3H), 3.21 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H).

¹³C NMR (75.5 Hz, CDCl₃) δ 204.86, 163.00, 162.50, 146.22, 138.95, 136.43, 129.69, 128.63, 119.24, 118.95, 118.63, 110.67, 53.33, 39.74, 26.18.

HPLCMS (APCl⁺): m/z=−258.1.

EXAMPLE 2
1-(2-hydroxyphenyl)-3-(6-methoxypyridin-2-yl) propan-1-one

2.35 g (17.3 mmol) of 2-hydroxyacetophenone, 2.13 g of 6-methoxy-2-pyridinecarboxaldehyde (15.5 mmol), and 8 ml of 25% NaOCH₃were reacted in 70 ml dry THF to give 1.2 g (30%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.15 (s, 1H), 8.24 (d, J=14.7 Hz, 1H), 8.01 (d, d, J=1.2, 7.8 Hz, 1H), 7.79 (d, J==15.0 Hz, 1H), 7.65 (d, d, J=7.2, 7.2 Hz, 1H), 7.53 (d, d, J=7.2, 7.2 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.06 (d, d, J=0.9, 8.1 Hz, 1H), 6.99 (d, d, J=7.2, 8.1 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.08 (s, 3H).

¹³C NMR (75.5 Hz, CDCl₃) δ 194.32, 163.81, 163.66, 150.24, 143.26, 139.15, 136.52, 130.03, 123.57, 120.18, 119.71, 118.88, 118.58, 113.32, 53.33.

HPLCMS (APCl⁺): m/z=256.0.

Hydrogenation of 1.52 g of chalcone with catalytic amount of 10% Pd/C obtained 1.25 g (82%) of dihydrochalcone after purification on silica gel chromatography (5% EtOAc/hexane). ¹H NMR (300 MHz, CDCl₃): δ 12.39 (s, 1H), 7.83 (d, d, J=1.5, 7.8 Hz, 1H), 7.46-7.41 (m, 2H), 6.96 (d, d, J=0.9, 8.4 Hz, 1H), 6.86 (d, d, J=6.9, 7.5 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 6.54 (d, J=8.1 Hz, 1H), 3.77 (s, 3H), 3.46 (1, J=7.2 Hz, 2H), 3.17 (t, J=7.2 Hz, 2H).

¹³C NMR (75.5 Hz, CDCl₃) δ 205.86, 163.71, 162.43, 157.65, 138.79, 136.11, 129.99, 119.54, 118.83, 118.37, 115.34, 107.96, 52.95, 36.57, 31.39.

HPLCMS (APCl⁺): m/z=258.1.

EXAMPLE 3
1-(2-hydroxyphenyl)-3-(2-methoxypyridin-3-yl)propan-1-one

2.39 g (17.6 mmol) of 2-hydroxyacetophenone, 2.10 g of 2-methoxy-3-pyridinecarboxaldehyde (15.3 mmol), and 10 ml of 25% NaOCH₃were reacted in 50 ml of dry THF to give 2.35 g (60%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.85 (s, 1H), 8.24 (d, d, J=1.8, 4.8 Hz, 1H), 8.02 (d, J=15.6 Hz, 1H), 7.94-7.86 (m, 2H), 7.90 (d, J=15.9 Hz, 1H), 7.52 (d, d, J=8.4, 8.7 Hz, 1H), 7.06-6.98 (m, 3H), 4.12 (s, 3H).

¹³C NMR (75.5 Hz, CDCl₃) δ 194.06, 163.65, 162.40, 148.70, 139.84, 138.91, 136.36, 129.72, 122.69, 120.08, 118.83, 118.62, 118.23, 117.17, 53.88. HPLCMS (APCl+): m/z=256.0.

Hydrogenation of 0.45 g of chalcone with catalytic amount of 10% Pd/C obtained 0.39 g (87%) of dihydrochalcone after purification on silica gel chromatography (5% EtOAc/hexane). ¹H NMR (300 MHz, CDCl₃): δ 12.31 (s, 1H), 8.07 (d, d, J=12.1, 5.1 Hz, 1H), 7.78 (d, d, J=1.8, 8.1 Hz, 1H), 7.50-7.45 (m, 2H), 6.99 (d, d, J=0.9, 8.1 Hz, 1H), 6.89 (d, d, J=7.2, 8.1 Hz, 1H), 6.85 (d, d, J=5.1, 5.6 Hz, 1H), 3.98 (s, 3H), 3.32 (t, J=7.8 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H).

¹³C NMR (75.5 Hz, CDCl₃) δ 205.66, 162.47, 162.11, 144.87, 138.32, 136.28, 129.89, 123.11, 119.34, 118.87, 118.52, 116.82, 53.32, 37.57, 25.23.

HPLCMS (APCl⁺): m/z=258.1.

EXAMPLE 4
1-(2-hydroxyphenyl)-3-(4-methylthiazol-5-yl)propan-1-one

2.21 g (16.3 mmol) of 2-hydroxyacetophenone, 1.96 g of 4-methylthiazole-5-carboxaldehyde (7.86 mmol), and 10 ml of 25% NaOCH₃were reacted in 50 ml of dry THF to give 1.59 g (52%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.73 (s, 1H), 8.76 (s, 1H), 8.05 (d, d, J=0.9, 15.0 Hz, 1H), 7.82 (d, d, J=1.5, 8.1 Hz, 1H), 7.49 (d, d, d, J=1.5, 7.2, 8.4 Hz, 1H), 7.31 (d, J=15.0 Hz, 1H), 7.00 (d, d, J=0.9, 8.4 Hz, 1H), 6.95-6.93 (m, 1H), 2.62 (s, 3H).

¹³C NMR (75.5 Hz, CDCl₃) δ 192.60, 163.62, 157.68, 153.29, 136.66, 134.28, 132.96, 129.46, 129.03, 121.63, 119.71, 119.26, 118.93, 118.66, 15.82.

HPLCMS (APCl⁺): m/z=246.1

Hydrogenation of 0.48 g (1.96 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.15 g (27%) of dihydrochalcone after purification on silica gel chromatography (25% EtOAc/hexane). ¹H NMR (300 MHz, CD₃OD): δ 8.73 (s, 1H), 7.87 (d, d, J=1.8, 8.4 Hz, 1H), 7.49 (d, d, d, J=1.5, 7.2, 8.1 Hz, 1H), 6.97-6.91 (m, 2H), 3.42 (t, J=6.9 Hz, 2H), 3.25 (t, J=6.9 Hz, 2H), 2.41 (s, 3H).

¹³C NMR (75.5 Hz, CD₃OD) δ 206.17, 163.24, 151.88, 149.84, 137.49, 132.31, 131.43, 120.82, 120.27, 119.05, 40.66, 21.40, 1457. HPLCMS (APCl⁺): m/z=248.0

EXAMPLE 5
1-(2-hydroxyphenyl)-3-(6-(pyrrolidin-1-yl)pyridin-3-yl)propan-1-one

1.85 g (13.6 mmol) of 2-hydroxyacetophenone, 2.0 g of 6-(pyrrolidin-1-yl)nicotinaldehyde (1.34 mmol), and 10 ml of 25% NaOCH₃were reacted in 50 ml of dry THF to give 2.2 g (65%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 13.13 (bs, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.85 (d, J=15.3 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.74 (d, d, J=2.4, 9.0 Hz, 1H), 7.43 (d, d, d, J=1.5, 7.2, 8.4 Hz, 1H), 7.37 (d, J=15.3 Hz, 1H), 6.98 (d, d, J=0.9, 8.4 Hz, 1H), 6.89 (d, d, d, J=0.9, 7.2, 8.1 Hz, 1H), 6.37 (d, J=9.0 Hz, 1H), 3.49 (bs, 4H), 2.05-1.96 (m, 4H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.18, 163.52, 157.88, 152.24, 143.78, 135.76, 135.03, 129.32, 120.21, 118.62, 118.46, 118.37, 114.49, 107.04, 46.97, 25.38.

HPLCMS (API-ES): m/z=295.1.

Hydrogenation of 0.65 g (2.21 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.46 g (70%) of dihydrochalcone after purification on silica gel chromatography (5% EtOAc/hexane). ¹H NMR (300 MHz, CD₃OD): δ 7.89-7.85 (m, 2H), 7.50-7.43 (m, 2H), 6.94-6.89 (m, 2H), 6.43 (d, J=8.7 Hz, 1H), 3.39-3.29 (m, 6H), 2.90 (t, J=7.2 Hz, 2H), 2.02-1.98 (m, 4H).

¹³C NMR (75.5 Hz, CD₃OD) δ 205.95, 161.92, 155.96, 146.25, 137.93, 135.92, 130.13, 123.17, 119.41, 118.77, 117.62, 106.91, 46.45, 39.55, 26.03, 25.02.

HPLCMS (API-ES): m/z=297.2.

EXAMPLE 6
1-(2-hydroxyphenyl)-3-(5-methylisoxazol-3-yl)propan-1-one

2.24 g (16.5 mmol) of 2-hydroxyacetophenone, 1.65 g of 5-methylisoxazole-3-carbaldehyde (14.9 mmol), and 10 ml of 25% NaOCH₃were reacted in 50 ml of dry THF to give 1.59 g (29%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.53 (s, 1H), 7.87 (d, d, J=0.6, 7.5 Hz, 1H), 7.80 (d, J=15.6 Hz, 1H), 7.69 (d, J=15.6 Hz, 1H), 7.56-7.51 (m, 1H), 7.05 (d, d, J=0.6, 8.4 Hz, 1H), 6.99-6.93 (m, 11H), 6.31 (d, J=0.3 Hz, 1H), 2.50 (s, 3H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.08, 170.59, 163.68, 159.84, 136.96, 132.03, 129.81, 126.62, 119.62, 119.02, 118.73, 99.99, 12.32. HPLCMS (APCl+): m/z=230.1.

Hydrogenation of 0.61 g (2.66 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.69 g (68%) of dihydrochalcone after purification on silica gel chromatography (10% EtOAc/hexane). ¹H NMR (300 MHz, CD₃OD): δ 7.92 (d, d, J=1.5, 8.4 Hz, 1H), 7.51 (d, d, d, J=1.5, 7.2, 8.4 Hz, 1H) 6.98-6.93 (m, 2H), 6.95 (bs, 1H), 3.49 (t, J=7.2 Hz, 2H), 3.05 (t, J=7.2 Hz, 2H), 2.39 (bs, 3H).

¹³C NMR (75.5 Hz, CD₃OD) δ 206.08, 171.14, 164.76, 163.23, 137.42, 131.41, 120.75, 120.26, 119.04, 102.77, 37.30, 21.21, 11.92.

HPLCMS (API-ES): m/z=232.1.

EXAMPLE 7
1-(2-hydroxyphenyl)-3-(pyridin-3-yl)propan-1-one

2.36 g (17.3 mmol) of 2-hydroxyacetophenone, 1.7 g of 3-pyridine-carboxaldehyde (15.9 mmol), and 9 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 2.05 g (57%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.66 (s, 1H), 8.93 (d, J=1.8 Hz, 1H), 8.67 (d, d, J=1.5, 4.8 Hz, 1H), 8.03-8.00 (m, 1H), 7.92 (d, J=15.7 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H), 7.76 (d,=15.6 Hz, 1H), 7.58-7.52 (m, 1H), 7.43 (d, d, J=5.1, 8.1 Hz, 1H), 7.07 (d, d, J=0.9, 8.1 Hz, 1H, 6.99 (d, d, d, J=1.2, 7.2, 8.1 Hz, 1H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.11, 163.70, 151.26, 149.97, 141.47, 136.75, 134.87, 130.49, 129.64, 123.86, 122.22, 119.81, 119.00, 118.77.

HPLCMS (APCl+): m/z=226.1.

Hydrogenation of 0.62 g (2.76 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.31 g (50%) of dihydrochalcone after purification on silica gel chromatography (10% EtOAc/hexane). ¹H NMR (300 MHz. CD₃OD): δ 8.51 (d, J=1.8 Hz, 1H), 8.37 (d, d, J=1.5, 4.8 Hz, 1H), 7.91 (d, d, J=1.8, 8.4 Hz, 1H), 7.81 (d, d, J=1.8, 7.8 Hz, 1H), 7.49 (m, 1H), 7.37 (d, d, J=5.1, 8.1 Hz, 1H), 6.97-6.91 (m, 2H), 3.49 (t, J=7.2 Hz, 2H), 3.11 (t, J=7.2 Hz, 2H).

¹³C NMR (75.5 Hz, CD₃OD) δ 206.61, 163.27, 150.33, 147.81, 138.92, 138.43, 137.41, 131.49, 125.14, 120.80, 120.24, 119.04, 40.28, 27.94.

HPLCMS (API-ES): m/z=228.1.

EXAMPLE 8
3-(furan-2-yl)-1-(2-hydron phenyl)propan-1-one

2.27 g (16.7 mmol) of 2-hydroxyacetophenone, 1.52 g of furan-2-carbaldehyde (15.8 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 2.4 g (71%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.90 (s, 1H), 7.94 (d, d, J=1.5, 8.1 Hz, 1H), 7.71 (d, J=15.0 Hz, 1H), 7.58 (d, J=15.0 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.51 (d, d, d, J=1.5, 7.2, 8.4 Hz, 1H), 7.04 (d, d, J=0.9, 8.4 Hz, 1H), 6.96 (d, d, J=8.1, 8.1 Hz, 1H), 6.79 (d, J=3.3 Hz, 1H), 6.56 (d, d, J=1.5, 3.3 Hz, 1H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.31, 163.57, 151.56, 145.41, 136.27, 131.11, 129.63, 120.08, 118.83, 118.54, 117.67, 117.06, 112.88.

HPLCMS (APCl+): m/z=215.1.

Hydrogenation of 0.48 g (2.24 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.26 g (54%) of dihydrochalcone after purification on silica gel chromatography (5% EtOAc/hexane). ¹H NMR (300 MHz, CDCl₃): 12.25 (s, 1H), 7.79 (d, d, J=1.5, 8.1 Hz, 1H), 7.48 (d, d, d, J=1.5, 7.2, 8.4 Hz, 1H), 7.34-7.28 (m, 1H), 7.01 (d, d, J=0.9, 8.4 Hz, 1H), 6.92 (d, d, d, J=1.2, 7.5, 8.4 Hz, 1H), 6.32-6.30 (m, 1H), 6.09-6.08 (m, 1H), 3.39 (t, J=7.2 Hz, 2H), 3.12 (t, J=7.5 Hz, 2H).

¹³C NMR (75.5 Hz, CDCl₃) δ 204.75, 162.44, 154.27, 141.26, 136.37, 129.83, 119.28, 118.96, 118.53, 110.36, 105.58, 36.56, 22.55.

HPLCMS (API-ES): m/z=216.9.

EXAMPLE 9
1-(2-hydroxyphenyl)-3-(6-morpholinopyridin-3-yl)propan-1-one

2.15 g (15.8 mmol) of 2-hydroxyacetophenone, 2.8 g of 4-morpholinobenzaldehyde (14.5 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 2.52 g (56%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.99 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.93-7.84 (m, 3H), 7.52-7.48 (m, 2H), 7.03 (d, d, J=0.9, 8.4 Hz, 1H), 6.97-6.92 (m, 1H), 6.68 (d, J=9.0 Hz, 1H), 3.86-3.83 (m, 4H), 3.69-3.66 (m, 4H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.27, 163.58, 159.87, 151.09, 142.84, 136.03, 135.90, 129.38, 120.18, 120.13, 118.70, 118.59, 116.27, 106.44, 66.58, 45.09.

HPLCMS (APCl+): m/z 311.2.

Hydrogenation of 0.341 g (1.10 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.44 g of dihydrochalcone after purification on silica gel chromatography (10% EtOAc/hexane). ¹H NMR (300 MHz, CD₃OD): δ 8.04 (d, J=1.8 Hz, 1H), 7.90 (d, d, J=1.5, 8.1 Hz, 1H), 7.55 (d, d, J=2.7, 8.7 Hz, 1H), 7.52-7.46 (m, 1H), 6.96-6.88 (m, 2H), 6.79 (d, J=7.2 Hz, 1H) 3.81-3.78 (m, 4H), 3.43-3.35 (m, 6H), 2.97 (t, J=7.2 Hz, 2H).

¹³C NMR (75.5 Hz, CD₃OD) δ 205.19, 160.51, 157.95, 146.96, 137.79, 135.95, 130.68, 125.65, 120.35, 119.17, 117.60, 106.86, 65.93, 45.42, 25.68, 0.07.

HPLCMS (API-ES): m/z=3313.0.

EXAMPLE 10
3-(4,5-dimethylfuran-2-yl)-1-(2-hydroxyphenyl)propan-1-one

2.0 g (14.7 mmol) of 2-hydroxyacetophenone, 1.75 g of 4,5-dimethylfuran-2-carbaldehyde (14.1 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 1.71 g (50%) of chalcone after purification. ¹H NMR (300 MHz. CDCl₃): δ 13.07 (s, 1H). 7.95 (d, J=7.8 Hz, 1H), 7.61 (d, J=15.0 Hz, 1H), 7.51-7.42 (m, 2H), 7.02 (d, d, J=0.9, 8.4 Hz, 1H), 6.94 (d, d, d, J=1.2, 8.4, 9.0 Hz, 1H), 6.60 (s, 1H), 2.34 (s, 3H), 2.00 (s, 3H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.29, 163.52, 152.60, 148.96, 135.91, 131.22, 129.56, 121.57, 120.22, 118.67, 118.46, 118.43, 115.20, 11.88, 9.68.

HPLCMS (APCl+): m/z=243.1.

Hydrogenation of 1.06 g (4.38 mmol) of chalcone with catalytic amount of 10% Pd/C gives the dihydrochalcone after purification on silica gel chromatography. ¹H NMR (300 MHz, CD₃OD): δ 7.91 (d, d, J=1.8, 8.4 Hz, 1H), 7.50 (d, d, d, J=1.8, 7.2, 9.0 Hz, 1H), 6.97-6.92 (m, 2H), 5.83 (s, 1H), 3.34 (t, J=7.8 Hz, 2H), 2.96 (t, J=7.2 Hz, 2H), 2.13 (s, 3H), 1.87 (s, 3H).

¹³C NMR (75.5 Hz, CD₃OD) δ 207.01, 163.31, 152.56, 146.67, 137.33, 131.50, 120.80, 120.18, 119.02, 115.46, 109.61, 37.88, 23.56, 11.10, 9.84.

HPLCMS (APCl+): m/z=245.1.

EXAMPLE 11
1-(2-hydroxyphenyl)-3-(4-methylthiazol-2-yl)propan-1-one

2.27 g (16.7 mmol) of 2-hydroxyacetophenone, 2.0 g of 4-methylthiazole-2-carbaldehyde (15.7 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 0.67 g (17%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.67 (s, 1H), 7.98-7.95 (m, 1H), 7.80 (d, J=15.3 Hz, 1H), 7.89 (d, J=15.0 Hz, 1H), 7.53 (d, d, J=8.4, 8.4 Hz, 1H), 7.11 9s, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.97 (d, d, J=7.5, 7.8 Hz, 1H), 2.56 (s, 3H).

¹³C NMR (75.5 Hz, CDCl₃) δ193.04, 163.65, 162.50, 155.71, 136.77, 135.40, 129.95, 123.40, 119.90, 118.99, 118.60, 117.52, 17.14.

HPLCMS (APCl+): m/z=246.1.

Hydrogenation of 1.2 g (4.90 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.99 g (81%) of dihydrochalcone after purification on silica gel chromatography (10% EtOAc/hexane). ¹H NMR (300 MHz, CD₃OD): δ 7.93 (d, d, J=1.5, 8.4 Hz, 1H), 7.51 (d, d, d, J=1.5, 7.5, 8.4 Hz, 1H), 6.97-6.96 (m, 1H), 6.93 (s, 1H), 3.61 (t, J=7.2 Hz, 2H), 3.40 (1, J=6.9 Hz, 2H).

¹³C NMR (75.5 Hz. CD₃OD) δ 205.69, 171.34, 163.20, 153.11, 137.47, 131.42, 120.77, 120.29, 119.06, 114.50, 103.55, 38.87, 227.90, 16.65.

HPLCMS (API-ES): m/z 248.0.

EXAMPLE 12
1-(2-hydroxyphenyl)-3-(pyridin-2-yl)propan-1-one

2.08 g (15.3 mmol) of 2-hydroxyacetophenone, 1.55 g of 2-pyridine-carboxaldehyde (14.5 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 1.4 g (43%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.76 (s, 1H), 8.73 (d, J=4.5 Hz, 1H), 8.29 (d, J=15.3 Hz, 1H), 8.06 (d, d, J=1.5, 8.1 Hz, 1H), 7.78 (d, J=15.0 Hz, 1H), 7.77 (d, d, d, J=1.8, 7.5, 9.3, 1H), 7.56-7.50 (m, 2H), 7.37-7.32 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 7.01-6.94 (m, 1H).

¹³C NMR (75.5 Hz, CDCl₃) δ 194.12, 163.66, 152.80, 150.21, 143.14, 137.00, 136.66, 130.28, 125.83, 124.67, 124.29, 120.10.118.94, 118.51.

HPLCMS (APCl+): m/z=226.1.

Hydrogenation of 1.22 g (4.44 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.57 g (46%) of dihydrochalcone after purification on silica gel chromatography (30% EtOAc/hexane). ¹H NMR (300 MHz, CDCl₃): δ 12.29 (s, 1H), 8.52 (d, J=4.8 Hz, 1H), 7.84 (d, d, J=1.5, 8.1 Hz, 1H), 7.61 (d, d, d, J=1.8, 7.5, 9.3 Hz, 1H), 7.45 (d, d, d, J=1.8, 8.7, 9.9 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.13 (d, d, J=5.7, 7.2 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.92-6.86 (m, 1H), 3.56 (t, J=7.2 Hz, 2H), 3.25 (t, J=7.2 Hz, 2H).

HPLCMS (API-ES): m/z=228.0.

EXAMPLE 13
1-(2-hydroxyphenyl)-3-(pyridin-4-yl)propan-1-one

2.26 g (16.6 mmol) of 2-hydroxyacetophenone, 1.68 g of 4-pyridine-carboxaldehyde (15.7 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 1.02 g (29%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.56 (s, 1H), 8.72-8.70 (m, 2H), 7.90 (d, d, J=1.5, 7.8 Hz, 1H), 7.80 (s, 2H), 7.56-7.48 (m, 3H), 7.05 (d, d, J=0.9, 8.4 Hz, 1H), 6.97 (d, d, J=7.2, 7.5 Hz, 1H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.08, 163.64, 150.62, 142.04, 141.70, 136.91, 129.74, 124.45, 122.06, 120.08, 119.05, 118.70.

HPLCMS (APCl+): m/z=226.1.

Hydrogenation of 1.4 g (6.22 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.195 g (14%) of dihydrochalcone after purification on silica gel chromatography (30% EtOAc/hexane). ¹H NMR (300 MHz, CDCl₃): δ 12.16 (s, 1H), 8.53-8.51 (m, 2H), 7.73 (d, d, J=1.5, 7.8 Hz, 1H), 7.48 (, d, d, d, J=1.8, 7.5, 8.7 Hz, 1H), 7.19-7.17 (m, 2H), 6.99 (d, d, J=0.9, 8.1 Hz, 1H), 6.89 (d, d, d, J=1.2, 7.2, 8.1 Hz, 1H), 3.36 (t, J=7.2 Hz, 2H), 3.07 (t, J=7.5 Hz, 2H).

¹³C NMR (75.5 Hz, CDCl₃) δ 204.18, 162.45, 149.93, 149.67, 136.55, 129.57, 123.77, 119.12, 119.00, 118.66, 38.40, 28.95.

HPLCMS (API-ES): m/z=228.0.

EXAMPLE 14
1-(2-hydroxyphenyl)-3-(6-(piperidin-1-yl)pyridin-3-yl)propan-1-one

1.72 g (12.6 mmol) of 2-hydroxyacetophenone, 2.0 g of 6-(piperidin-1-yl)nicotinaldehyde (10.5 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 1.41 g (43.5%) of chalcone after purification. ¹H NMR (300 Hz, CDCl₃): δ 13.10 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.93-7.89 (m, 2H), 7.80 (d, d, J=2.4, 9.0 Hz), 7.51-7.42 (m, 2H), 7.03 (d, d, J=0.9, 8.4 Hz, 1H), 6.94 (d, d, d, J=1.2, 7.2, 8.1 Hz, 1H), 6.68 (d, J=9.0 Hz, 1H), 3.71-3.67 (m, 4H), 1.75-1.67 (m, 6H).

¹³C NMR (75.5 Hz, CDCl₃) δ 193.28, 163.55, 159.69, 151.69, 143.34, 135.84, 135.60, 129.35, 120.23, 118.79, 118.64, 118.53, 115.07, 106.47, 45.99, 25.61, 24.64.

HPLCMS (APCl+): m/z=309.2.

Hydrogenation of 0.5 g (1.62 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.33 g (66%) of dihydrochalcone after purification on silica gel chromatography (5% EtOAc/hexane). ¹H NMR (300 MHz, CD₃OD): δ 7.97 (d, J=0.3 Hz, 1H), 7.88 (d, d, J=1.8, 8.4 Hz, 1H), 7.51-7.45 (m, 2H), 6.95-6.89 (m, 2H), 6.75 (d, J=8.1 Hz, 1H), 3.47-3.45 (m, 4H), 3.34 (t, J=7.2 Hz, 2H), 2.92 (t, J=7.2 Hz, 2H).

¹³C NMR (75.5 Hz, CD₃OD) δ 207.28, 163.33, 160.16, 147.92, 139.59, 137.34, 131.55, 126.46, 120.83, 120.20, 119.04, 109.25, 27.34, 26.57, 25.74.

HPLCMS (API-ES): m/z=311.1.

EXAMPLE 15
1-(2-hydroxyphenyl)-3-(thiazol-2-yl)propan-1-one

2.29 g (16.8 mmol) of 2-hydroxyacetophenone, 1.8 g of thiazole-2-carbaldehyde (15.9 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 0.254 g (27%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 12.62 (s, 1H), 8.08-7.94 (m, 4H), 7.57-7.51 (m, 2H), 7.06 (d, d, J=1.2, 8.4 Hz, 1H), 6.98 (d, d, d, J=1.2, 7.2, 8.1 Hz, 1H).

¹³C NMR (75.5 Hz, CDCl₃) δ 192.97, 163.67, 163.45, 145.16, 136.89, 135.4, 129.91, 124.11, 122.33, 119.87, 119.06, 118.66.

HPLCMS (APCl⁺): m/z=232.1.

Hydrogenation of 0.27 g (1.16 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 0.26 g (27%) of dihydrochalcone after purification on silica gel chromatography (20% EtOAc/hexane). ¹H NMR (300 MHz, CD₃OD): δ 7.83 (d, d, J=1.8, 8.7 Hz, 1H), 7.63 (d, J=−3.3 Hz, 1H), 7.46-7.38 (m, 2H), 6.90-6.85 (m, 2H), 3.55 (t, J=6.3 Hz, 2H), 3.39 (t, J=6.6 Hz, 2H).

¹³C NMR (75.5 Hz, CD₃OD) δ 205.56, 171.57, 163.11, 142.96, 137.58, 131.43, 120.68, 120.39, 120.37, 119.20, 38.37, 27.77.

HPLCMS (API-ES): m/z=234.0.

EXAMPLE 16
3-(6-chloropyridin-3-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one

2.08 g (15.3 mmol) of 2-hydroxyacetophenone, 2.05 g of 6-chloronicotinaldehyde (14.5 mmol), and 10 ml of 25% wt NaOCH₃were reacted in 50 ml of dry THF to give 0.55 g (15%) of chalcone after puirification. ¹H NMR (300 MHz, CDCl₃): δ 12.61 (s, 1H), 8.66 (d, J=2.4 Hz, 1H), 7.97-7.92 (m, 2H), 7.90 (D, J=15.9 Hz, 1H), 7.71 (d, J=15.6 Hz, 1H), 7.55 (d, d, d, J=1.5, 7.2, 8.7 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.06 (d, d, J=0.9, 8.4 Hz, 1H), 6.98 (d, d, d, J=1.2, 7.5, 8.1 Hz, 1H).

¹³C NMR (75.5 Hz, CDCl₃) δ 192.84, 163.72, 153.18, 149.97, 139.93, 137.06, 136.87, 129.61, 129.42, 124.69, 122.63, 119.71, 119.05, 118.80.

HPLCMS (APCl+): m/z—260.1.

EXAMPLE 17
1-(2-hydroxy-4-(methoxy)phenyl)-3-(6-methoxpyridin-3-yl)propan 1-one

4.18 g (21.3 mmol) of 1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethanone, 2.8 g of 6-methoxy-3-pyridine-carboxaldehyde (20.4 mmol), and 1.8 g (32.1 mmol) of KOH were reacted in 60 ml of EtOH and 20 ml of H₂O ml to give 2.18 g (34%) of chalcone after purification. ¹H NMR (300 MHz, CDCl₃): δ 13.27 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.95-7.82 (m, 3H), 7.50 (d, J=15.6 Hz, 1H), 6.83 (d, J=8.7 Hz, 1H), 6.67 (d, J=2.7 Hz, 1H), 6.61 (d, d, J=2.4, 9.0 Hz, 1H), 5.25 (s, 2H), 4.02 (s, 3H), 3.51 (s, 3H).

¹³C NMR (75.5 Hz, CDCl₃) δ 191.62, 166.27, 165.56, 163.72, 149.14, 141.03, 136.65, 131.18, 124.21, 119.15, 114.88, 111.67, 108.26, 104.05, 94.08, 56.39, 53.92.

HPLCMS (API-ES): m/z=316.0.

Hydrogenation of 1.78 g (5.65 mmol) of chalcone with catalytic amount of 10% Pd/C obtained 1.2 g (67%) of dihydrochalcone and 2-(1-hydroxy-3-(6-methoxypyridin-3-yl)propyl)-5-(methoxymethoxy)phenol after purification on silica gel chromatography (15% EtOAc/hexane).

Dihydrochalcone: ¹H NMR (300 MHz, CDCl₃): δ 12.60 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.64 (d, J=9.0 Hz, 1H), 7.48 (d, d, J=2.4, 8.7 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 6.51 (d, d, J=2.4, 8.7 Hz, 1H), 5.21 (s, 2H), 3.92 (s, 3H), 3.48 (s, 3H), 3.22 (t, J=7.5 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H).

¹³C NMR (75.5 Hz, CDCl₃) δ 203.12, 165.00, 163.59, 162.91, 146.06, 139.06, 131.40, 128.79, 114.23, 110.66, 108.27, 103.79, 94.01, 91.26, 60.35, 56.35, 39.37, 26.39.

HPLCMS (API-ES): m/z=318.0.

2-(1-hydroxy-3-(6-methoxypyridin-3-yl)propyl)-5-(methoxymethoxy)phenol: ¹H NMR (300 MHz, CDCl₃): δ 7.99 (d, d, J=0.6, 2.4 Hz, 1H), 7.44 (d, d, J=2.4, 8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.70 (d, d, J=0.6, 9.0 Hz, 1H), 6.61 (d, J=3.0 Hz, 1H), 6.52 (d, d, J=2.7, 8.4 Hz, 1H), 5.15 (s, 2H), 4.77 (d, d, J=5.4, 8.1 Hz, 1H), 3.92 (s, 3H), 3.48 (s, 3H), 2.71-2.64 (m, 2H), 2.26-2.16 (m, 1H), 2.09-2.02 (m, 1H).

¹³C NMR (75.5 Hz, CDCl₃) δ 162.72, 157.96, 156.68, 145.82, 139.21, 129.37, 127.70, 121.17, 110.62, 107.62, 105.30, 94.42, 74.17, 56.00, 53.53, 38.31, 28.05.

HPLCMS (API-ES): m/z=320.1.

EXAMPLE 18
1-(2,4-dihydroxyphenyl-3-(6-methoxypyridin-3-yl)propan-1-one

To a solution of 1-(2-hydroxy-4-(methoxymethoxy)phenyl)-3-(6-methoxypyridin-3-yl)propan-1-one (1.62 g, 5.11 mmol) in CH₃CN (30 ml) at room temperature was added TFA (2 ml) dropwise, two drops of water. The reaction was stirred at same temperature for 8 h. Aqueous 1N NaOH was added to the reaction mixture until pH=7. The aqueous was extracted with 100 ml EtOAc, and the organic layers were combined. The organic layer was washed with brine, dried (Na₂SO₄) and concentrated. The residue was purified by silica gel chromatography (15% EtOAc/Hexane) to provide 0.5 g (35%) of white solid.

¹H NMR (300 MHz, CD₃OD): δ 8.00 (s, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.61 (d, d, J=2.4, 8.4 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.33 (d, d, J=2.4, 9.0 Hz), 6.23 (d, J=2.4 Hz, 1H), 3.86 (s, 3H), 3.24 (t, J=7.2 Hz, 2H), 2.93 (t, J=7.2 Hz, 2H).

¹³C NMR (75.5 Hz, CD₃OD) δ 204.8, 166.4, 164.3, 147.1, 141.0, 133.6, 130.9, 114.1, 111.2, 109.1, 103.6, 54.1, 40.0, 27.6.

HPLCMS (APCl+): m/z—274.3.

EXAMPLE 19
1-(2-hydroxy-4-((3R,4S,5S,6R)-3,4,5,-trhydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)phenyl)-3-(6-methoxypyridin-3-yl)propan-1-one

To a solution of 1-(2,4-dihydroxyphenyl-3-6-methoxypyridin-3-yl)propan-1-one (0.234 g, 0.86 mmol) in 1:1 1N KCl: 1N NaHCO₃(10 ml) at room temperature was added D-glucopyranosyl bromide (0.7 g, 1.7 mmol, 10 ml in dry CH₂Cl₂) dropwise. The mixture was refluxed for 24 h under N₂. After the addition of water, the mixture was extracted 3× with CH₂Cl₂. The organic layers were combined and washed with 1N HCl, water, brine, dried (Na₂SO₄) and concentrated. Silica gel chromatography purification (35% EtOAc/Hexane) provided 0.25 g (48%) sugar dihydrochalcone, which was de-protected by NaOMe in MeOFH at room temperature provided 88 mg (49%) final glycosylated dihydrochalcone product.

Intermediate A: ¹H NMR (300 MHz, CDCl₃): δ 12.63 (s, 1H), 8.08 (d, J=2.1 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.51 (d, d, J=2.7, 8.7 Hz, 1H), 6.85-66.80 (d, J=8.7 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 6.53 (d, d, J=3.9, 6.3 Hz, 1H), 5.36-5.29 (m, 2H), 5.24-5.13 (m, 2H), 4.35-4.25 (m, 1H), 4.21-4.13 (m, 1H), 3.95 (s, 3H), 3.25 (t, J=7.2 Hz, 2H), 3.03 (t, J=7.2 Hz, 2H).

HPLCMS (APCl+): m/z=604.0.

Final product: ¹H NMR (300 MHz, CD₃OD): δ 8.02 (d, J==1.8 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.63 (d, d, J=2.4, 8.4 Hz, 1H), 6.74 (d, d, J=0.6, 8.4 Hz, 1H), 6.65 (d, d, J=2.4, 8.7 Hz, 1H), 6.61 (d, J=2.4, 1H), 4.96 (d. J=7.5 Hz, 1H), 3.92 (d, J=3.0 Hz, 1H), 3.84-3.71 (m, 4H), 3.60 (d, d, J=3.3, 9.6, Hz, 1H), 3.37-3.29 (m, 2H), 2.99 (t, J=7.2 Hz, 2H).

¹³C NMR (75.5 Hz, CD₃OD) δ 205.4, 165.7, 165.2, 164.4, 147.1, 140.9, 133.2, 130.8, 115.9, 111.2, 109.5, 105.1, 101.9, 77.1, 74.7, 72.1, 70.1, 62.3, 54.0, 40.3, 27.4.

HPLCMS (ES⁺): m/z=436.1.

EXAMPLE 20
1-(2-hydroxy-4-(2-hydroxyethoxy)phenyl)-3-(6-methoxypyridin-3-yl)propan-1-one

To a solution of 2,4 dihydroxyacetophenone (1.58 g, 10.4 mmol) in dry acetone (30 ml) at room temperature was added potassium carbonate (1.56 g, 27.8 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane. The solution was reflux for 7 hrs, then pour into water. Aqueous layer was extracted with 3× EtOAc and the organic layers were combined. The organic layer was washed with 1N HCl, water, brine, dried (Na₂SO₄) and concentrated. Chromatography purification obtained 0.36 g of intermediate A and 0.58 g of intermediate B.

In a 100 ml round-bottom flask, 0.36 g of intermediate A (1.80 mmol), 0.25 g of 6-methoxynicotinaldehyde (1.80 mmol) in 10 ml EtOH was treated 0.154 g of KOH (2.75 mmol) in 5 ml water at room temperature. The reaction was stirred at room temperature for 7 hrs and poured into water. Adjusted pH=7 by 1NHCl and extracted with EtOAc. The organic layer was washed three times with water, brine, dried (Na₂SO₄), and concentrated. The chalcone (0.18 g, 0.57 mmol) was then hydrogenated in 2:1 TBF:MeOH with catalytic amount of 10% Pd/C obtained 0.15 g (83%) of final product.

Intermediate A: ¹H NMR (300 MHz, CDCl₃): δ 12.6 (s, 1H), 7.54 (d, J=9.0 Hz, 1H), 6.37 (d, d, J=2.4, 9.0 Hz, 1H), 6.34 (d, d, J=2.4, 8.7 Hz, 1H), 4.02 (t, J=4.8 Hz, 2H), 3.88 (t, J=4.2 Hz, 2H), 2.46 (s, 3H).

HPLCMS (ES⁺): m/z=196.9.

Intermediate B: ¹H NMR (300 MHz, CDCl₃): δ 12.6 (s, 1H), 7.53 (d, J=8.7 Hz, 1H), 6.37-6.36 (m, 2H), 3.97 (t, J=4.5 Hz, 2H), 3.87 (t, J=4.5 Hz, 2H), 2.45 (s, 3H), 0.81 (s, 9H), 0.00 (s, 6H).

Final product: ¹H NMR (300 MHz, CD₃OD): δ 8.00 (d, J=0.3 Hz, 1H), 7.79 (d, J=9.0 Hz, 1H), 7.61 (d, d, J=2.4, 8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 1H), 6.51 (d, d, J=2.4, 9.0 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H) 4.08 (t, J=4.2 Hz, 2H), 3.93-3.85 (m, 5H), 3.31-3.21 (t, J=7.5 Hz, 2H), 2.97 (t, J=7.2 Hz, 2H).

¹³C NMR (75.5 Hz, CD₃OD) δ 205.1, 166.9, 166.2, 164.4, 147.1, 140.9, 133.2, 130.9, 114.8, 111.2, 108.7, 102.5, 70.9, 61.3, 54.0, 40.1, 27.5.

HPLCMS (ES⁺): m/z=318.0.

EXAMPLE 21

Taste test data of some compounds are shown below. The taste testing was made by a panel of experienced tasters.

Example
Structure
Taste results in water

1

5 ppm, very weak sweet, 20 ppm weakly sweet, 100 ppm very strong sweet, weak bitter taste

3

Very weak sweet at 1 ppm, 10 ppm , 50 ppm bitter, weakly sweet and burning

2

Slightly sweet/bitter at 10 ppm, sweet, bitter, slight fruity at 100 ppm

6

0.1 ppm, slightly bitter, 1 ppm, slightly bitter, weakly sweet, 10 ppm, brothy, umami, soapy, irritating, garlic, 100 ppm, umami, bitter, soapy, garlic

4

0.1 to 1 ppm, petroleum, sulfur, 10 ppm very weak sweet, brothy, 100 ppm sweet, brothy, gassy, bitter, linger

7

0.1 ppm, nothing, 1 ppm, very weak sweet, astringent, 10 ppm, waxy, delayed sweet, astringent, 100 ppm, weak sweet, chemical, bitter

8

0.01 ppm, nothing, 0.1 ppm, soap, delayed sweet, 1 ppm, soap, umami, bitter, 10 ppm, licorice aroma, soapy, weak sweet, bitter, vegetable, terpen, 100 ppm, bitter, licorice aroma, weak sweet, celery, umami, brothy

10

0.01 ppm, nothing. 0.1 ppm, floral, soapy, 1 ppm, floral, soap, astringent, piney, 10 ppm, weak bitter, vegetable, piney, astringent, 100 ppm, slightly sweet, bitter, piney, vegetable, sour

15

0.01 ppm, 0.1 ppm, delayed umami aftertaste, 1 ppm, weak plastic, soap, umami, astringent, 10 ppm, astringent, strong umami, weak soap, slight bitter, 100 ppm, bitter, umami

11

0.01 ppm, nothing, 0.1 ppm, very weak bitter, 1 ppm, astringent, bitter, 10 ppm, bitter, astringent, 100 ppm, bitter, terpen, weak sweet

13

0.01 ppm to 0.1 ppm, nothing, 1 ppm, weak sweet, 10 ppm, sweet, 100 ppm, very sweet, licorice linger

12

1 ppm, umami, 10 ppm, high umami like taste, 100 ppm, strong umami, slightly bitter.

18

100 ppm, sweet

EXAMPLE 22

Evaluation data on the compound of Example 13, showing how it modifies a flavor in water and in application.

Strawberry A=candy strawberry, Strawberry B=green strawberry, Strawberry C=floral strawberry, Strawberry D=fruity strawberry, Vanillic Flavor A=vanillic, milky, creamy flavor:

Application
Flavor
Flavorist Evaluation

water
Strawberry A @ 0.2%
Green, candy-like, moderate lactone

character, overripe rotten

water
Strawberry A @ 0.2% +
Green character remains but softer, sweeter

20 ppm compound 13
character removing the candy-like edge

associated with the flavor. Character is juicier,

and more of a strawberry & cream with some

plastic off-notes.

water
Strawberry B @ 0.2%
Slightly green strawberry

water
StrawberryB @0.2% +
Sweeter, less green, jammier, maltol-like note,

20 ppm compound 13
some plastic off-notes

water
Strawberry C @ 0.2%
Slightly green, floral, kool-aid type strawberry

water
Strawberry C @ 0.2% +
Less green, less floral, burnt sugar caramel

20 ppm compound 13
note, strawberry character and coumarin-type

character is intensified.

water
Sweetness Improver
Sweet grape character, some of the acidic

Flavor A in 25% sugar
middle profile was suppressed, lingering sweet

reduction Grape Type
character not seen in target

Drink

water
Sweetness Improver
Sweet grape character with the acidic middle

Flavor A + 5 ppm
regained, enhanced sweet character without

compound 13 in 25%
the lingering, more of an abrupt sugar-like

sugar reduction Grape
finish to the flavor profile

Type Drink

Vanilla ice cream
Vanilla flavour A @ 0.5%
vanillic, milky, creamy

8% vegetable fat

ice cream

Vanilla ice cream
Vanilla flavour A @ 0.5% +
creamy, vanillic, sweet, slightly cooked

8% vegetable fat
10 ppm of compound

ice cream
13

Vanilla ice cream
Vanilla flavour A @ 0.5% +
creamy, sweet, vanillic, lingering sweet vanilla

8% vegetable fat
15 ppm of compound
aftertaste

ice cream
13

Vanilla ice cream
Vanilla flavour A @ 0.5% +
sweet, vanillic, lingering sweet vanilla

8% vegetable fat
30 ppm of compound
aftertaste

ice cream
13

Strawberry
Strawberry flavour D @
Fruity, green, fresh, jammy, floral

yoghurt
0.1%

3% fat, 7% sugar

Strawberry
Strawberry flavour D @
Fruity, slightly fermented, caramellic, green

yoghurt
0.1% + 10 ppm of

3% fat, 7% sugar
compound 13

Strawberry
Strawberry flavour D @
Fruity, sweet, fermented, caramellic, apple like

yoghurt
0.1% + 25 ppm of

3% fat, 7% sugar
compound 13

Strawberry
Strawberry flavour D @
Fermented, sweet, brown, caramellic, overripe

yoghurt
0.1% + 50 ppm of
banana

3% fat, 7% sugar
compound 13

water
7% sugar + 20 ppm of
Sweeter than 7% sugar, little floral, fuller, slight

compound 13
longer sweet character, backend slightly

delayed, sweeter than 7% with a delayed onset

water
7% sugar + 50 ppm of
Sweeter than above, very close to 9% sugar-

compound 13
just a very small difference, slight plastic

water
7% sugar with 0.105%
Sweeter than control, not effecting acidity,

Citric acid +
nice backend. sweeter brown notes, cotton

20 ppm of compound
candy

13

water
7% sugar with 0.105%
Sweeter than sample at 20 ppm, musty, clean,

Citric acid +
not that lingering

50 ppm of compound

13

2% milk
20 ppm compound 13
Slight change in profile, Sweeter than control

(2% milk)

cereal
50% reduced sugar + 20 ppm
Not lingering, more brown notes. roasted,

of compound 13
sweeter than control

cereal
50% reduced sugar + 50 ppm
Sweeter than 50% reduced control, better

of compound 13
performance, sweeter than 20 ppm, maybe

slight offnote, close to target

cereal
50% reduced sugar + 20 ppm
Nice, works well, more close to sugar taste,

of compound 13 +
clearly sweeter than 50% red., Sweeter, close

100 ppm of Sweet Flavor B
to target, higher late sweetness and longer

sweetness than above

While the compounds, methods of providing flavors and orally receivable and ingestable products have been described above in connection with illustrative embodiments, it is to be understood that other similar embodiments may be used or modifications and additions may be made to the described embodiments for performing the same function without deviating therefrom. Further, all embodiments disclosed are not necessarily in the alternative, as various embodiments of the invention may be combined to provide the desired characteristics. Variations can be made by one having ordinary skill in the art without departing from the spirit and scope of the invention. Therefore, the compounds, methods and products should not be limited to any single embodiment, but rather construed in breadth and scope in accordance with the recitation of the attached claims.

FLAVOR MOLECULES

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Provisional Applications (1)