DESC:FIELD OF THE INVENTION
The present invention relates to aromatic compounds.
More particularly, the present invention relates to a class of hydroxy compounds with distinct aroma, and a method for preparation of the compounds thereof.

BACKGROUND
An aromatic compound, also known as an odorant, aroma, fragrance or flavour, is a chemical compound that has a smell or odor. A wide variety of chemicals, both natural and synthetic, are known to possess organoleptic effects in humans. Of these, a small proportion possess pleasing aromatic notes and are used commercially as fragrant or aroma materials.

The fragrance industry is constantly working to develop new chemicals possessing aromatic properties. Such new aromatic compounds can be used to create new fragrance compositions having a unique fragrance or can modify or enhance the organoleptic properties of existing fragrance compositions. The fragrance compositions are commonly used in a wide variety of consumer products, including fine fragrances, eau de parfum, eau de toilette, cologne, personal care products, home care products, air care products, and the like.

While developing new fragrances and aroma compounds the researchers are required to conform with several factors such as toxicological restrictions, environmental regulations, biodegradability, performance and cost effectiveness. Furthermore, there is a need to synthesize new fragrances from relatively inexpensive and easily available raw materials. Also, consideration must be given to the rigid regulatory policies in many countries governing use of ingredients in consumable products. Although all of the afore-noted factors are crucial, most importance is given to the performance properties including odor activity, notes, solubility, etc., and cost effectiveness including manufacturing costs and effectiveness of the compound at imparting fragrance to the product or composition.

Several efforts have been made in the past to meet at least some of the above-mentioned criteria.

One US Application having Pub. No. 20190153354 teaches a fragrance compound having structure “ ” and derivatives thereof, wherein R is selected from C(O)ORa, C(O)Rb, a C3-C5 branched or straight-chained alkenyl group, or CH2(3-cyclohexenyl); Ra is any C1-C4 straight chain or branched alkyl or alkenyl group; and Rb is selected from CH(OH)CH3, CH2(CO)CH3, and CH2OH. The fragrance compound provides multi-faceted odors with a combination of different odor notes.

Another US Patent 7169748 teaches a compound having the structure “ ” characterized by a fruity cassis odor, wherein R is methyl, ethyl or propyl, R1 is methyl or H, R2 is methyl, ethyl or propyl, R3 is methyl or H, R4 is methyl or ethyl, R5 is H or methyl. The fragrance compound are specific N, N-disubstituted amides.

Another US Patent 9109186 teaches a fragrance compound having the structure “ ”, wherein R is methyl or ethyl. These fragrance compounds are substituted 4-cyclopentylidenebutanals that can be used as fragrance and perfumed products.

Differences in the chemical structures have a significant impact on the odor, notes, and other organoleptic, chemical, and physical characteristics of the compound. Thus, there is a continuous need for new chemical structures that have favorable organoleptic properties.

More importantly, there continuous to be an on-going need for new fragrance materials that can be readily synthesized from relatively inexpensive raw natural materials and can meet most of the criteria set-forth above, including possessing improved performance properties and cost-effectiveness while meeting the toxicological restrictions, environmental regulations and regulatory policies.

OBJECTS OF THE INVENTION
Surprisingly, the inventors of the present disclosure have found that the hydroxy compounds of formula 1 as described herein constitute a fresh and floral odor and can be advantageously employed in the fragrance industry. A group of dihydronepetalactone compounds, defined according to the structure shown in formula 1 below, provide a fragrance compound having improved performance properties for use in a fragrance composition or as a perfume by itself. The dihydronepetalactones may be delivered in a variety of forms for application to the skin or in a consumable product.

Another object of the present invention is to provide an effective synthesis route for the hydroxy compounds of formula 1 as described herein. A further object of the present invention is to provide a synthesis route for hydroxy compounds of formula 1 that allows easy upscaling of the route.

Yet another object of the present invention is to provide the hydroxy compounds of formula 1 in pure enantiomer or diastereoisomer form.

SUMMARY OF THE INVENTION
An embodiment of the invention pertains to the hydroxy compounds of formula I,

Formula 1

wherein, R is C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl, or C2-C12 alkenyl.

According to a particular aspect of the above embodiment of the invention, C1-C12 alkyl denotes unsubstituted or substituted, straight-chain and branched hydrocarbon groups, for non- limiting examples methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, isoheptyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, nonyl, decyl, or undecyl group.

According to a particular aspect of the above embodiment of the invention, C6-C15 aryl denotes unsubstituted or substituted aryl hydrocarbon groups. Each Aryl can be substituted by at least one C1-C12 alkyl. For non-limiting examples cyclohexyl, phenyl, benzyl, phenyl ethyl or phenyl propyl group.

According to a particular aspect of the above embodiment of the invention, C3-C12 cycloalkyl denotes unsubstituted or substituted by one or more than one C1-C4 alkyl cycloalkyl hydrocarbon group, for non-limiting examples cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, cyclo-nonyl, cyclodecyl, cycloundecyl, cyclododecyl, or 1-isopropyl-4-methyl-cyclohexyl.

According to a particular aspect of the above embodiment of the invention, C2-C20 alkenyl denotes unsubstituted or substituted alkenyl groups, for non-limiting examples are allyl, isopropenyl, 2-butenyl, 3-butenyl, isobutenyl, n-penta-2,4-dienyl, 3-methyl-but-2-enyl, n-oct-2-enyl, n-dodec-2-enyl, iso-dodecenyl, n-dodec-2-enyl or n-octadec-4-enyl.

According to a particular aspect of the above embodiment of the invention, R is selected from the group consisting of methyl, ethyl, propyl, butyl, n-pentyl, hexyl cyclohexyl, phenyl, benzyl, phenyl ethyl and phenyl propyl.

According to a particular aspect of the above embodiment of the invention, the compounds corresponding to formula (1) is in the form of any one of its stereoisomers and mixtures thereof, protonated or deprotonated form.

Another embodiment of the invention provides a process for manufacturing the hydroxy compounds of formula I,

Formula 1

wherein, R is C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl, or C2-C12 alkenyl.

The process comprises -

a) providing a compound of formula 2,

Formula 2

b) providing a Grignard reagent of formula 3,

Formula 3

wherein, R is C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl, or C2-C12 alkenyl,
wherein, X is chloride, bromide or iodide,

and,

c) reacting the Grignard reagent of formula 3 with the compound of formula 2.

DETAILED DESCRIPTION

Surprisingly, the inventors of the present invention found that the hydroxy compounds of formula 1 as described herein,

Formula 1

wherein, R is C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl, or C2-C12 alkenyl,

have distinct aroma and can be used as perfume ingredients, for instance to impart odor notes of the floral type.
According to a particular aspect of the above embodiment of the invention, the compounds corresponding to formula (1) can be in their stereoisomer form or mixtures thereof, and/or can be in their protonated or deprotonated form.

In the context of the present invention, the expression “stereoisomer form” means that the compound can be pure enantiomer (if chiral) or diastereoisomer.

In the context of the present invention, the expression “protonated” means that in acidic medium, proton is added to the oxygen atom of the hydroxyl group.

In the context of the present invention, the expression “deprotonated form”, means that in the presence of strong bases, proton from the hydroxyl group is removed to form alkoxide.

In the context of the present invention, the expression “substituted” means that an atom or group of atoms have replaced one or more hydrogen atoms on the parent chain of a hydrocarbon, becoming a moiety of the resultant new molecule. The terms substituent and functional group, as well as other ones (e.g. side chain, pendant group) are used almost interchangeably to describe branches from a parent structure.

C1-C12 alkyl denotes unsubstituted or substituted, straight-chain and branched hydrocarbon groups, for non- limiting examples methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, iso-heptyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, nonyl, decyl, or undecyl group.
C6 to C15 aryl denotes unsubstituted or substituted aryl hydrocarbon groups. Each Aryl can be substituted by at least one C1-C15 alkyl. For non-limiting examples cyclohexyl, phenyl, benzyl, Phenyl ethyl or phenyl propyl group.

C3-C12 cycloalkyl denotes unsubstituted or by one or more than one C1-C4 alkyl substituted cycloalkyl hydrocarbon group, for non-limiting examples cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl, cyclo-nonyl, cyclodecyl, cycloundecyl, cyclododecyl, or 1-isopropyl-4-methyl-cyclohexyl.

Non-limiting examples of C2-C20 alkenyl are allyl, isopropenyl, 2-butenyl, 3-butenyl, isobutenyl, n-penta-2,4-dienyl, 3-methyl-but-2-enyl, n-oct-2-enyl, n-dodec-2-enyl, iso-dodecenyl, n-dodec-2-enyl or n-octadec-4-enyl.

According to a particular aspect of the above embodiment of the invention, R is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl cyclohexyl, phenyl, benzyl, phenyl ethyl and phenyl propyl.

Another embodiment of the invention provides a process for manufacturing the hydroxy compounds of formula I, by Grignard reaction,

Formula 1

wherein, R is C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl, or C2-C12 alkenyl, wherein, the compounds corresponding to formula (1) can be in their stereoisomer form or mixtures thereof, and/or can be in their protonated or deprotonated form.
The process comprises:
a) providing an aldehyde compound of formula 2 -

Formula 2

b) providing a Grignard reagent of formula 3 -

Formula 3

wherein, R is C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl, or C2-C12 alkenyl,
wherein, X is chloride, bromide or iodide,
and,
c) reacting the Grignard reagent with the compound of formula 2.

The compounds of formula (I) are prepared by Grignard reaction as depicted in Scheme 1, Grignard reagent of formula 3 is added to the aldehyde compound of formula 2 to obtain the compound of formula 1.

The process of the desired products depends on the respective starting materials as well as solvent and temperature.

SCHEME 1

The compound of formula 2, for non-limiting example 2-methylene valeraldehyde, is obtained via known aldol condensation process e.g. by cross-aldol condensation of valeraldehyde and formaldehyde under alkaline conditions, as depicted in scheme 2.

SCHEME 2

The compound of formula 3, R-MgX, is obtained via known process for preparing Grignard reagent as depicted in scheme 3. A halo-hydrocarbon compound is added to magnesium turnings activated with catalytic amount of iodine and the reaction is carried out in suitable solvents such as ether or tetrahydrofuran.

SCHEME 3

R represents C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl, or C2-C12 alkenyl.
X represents chloride, bromide or iodide.
According to the process provided by the invention, the compounds of formula I are obtained in the form of an isomer mixture in which the transform predominates to a large extent.

The compounds of formula 1 have desirable organoleptic properties and can be suited as odorant and/or flavouring substances.

Odour of the compounds of formula 1 can be described as having green, grass, sweet, floral and lavender notes.

The compounds of formula (I) may be used alone, as mixtures thereof, or in combination with a base material. As used herein, the "base material" includes all known odorants or flavours selected from the extensive range of natural products and synthetic molecules currently available, such as essential oils, alcohols, aldehydes and ketones, ethers and acetals, esters and lactones, macrocycles and heterocycles, and nitriles, and/or in admixture with one or more ingredients or excipients conventionally used in conjunction with odorants or flavours in fragrance/flavour compositions, for example, carrier materials, and other auxiliary agents commonly used in the art.

The compounds according to formula (I) may be used in a broad range of fragranced articles, e.g. in any field of fine and functional perfumery, such as perfumes, air care products, household products, laundry products, body care products and cosmetics.

The compounds can be employed in widely varying amounts, depending upon the specific article and on the nature and quantity of other odorant ingredients.

The compounds as described hereinabove may be employed in a consumer product base simply by directly mixing at least one compound of formula (I), or a fragrance composition comprising said compound, with the consumer product base, or they may, in an earlier step, be entrapped with an entrapment material, for example, polymers, capsules, microcapsules and Nano capsules, liposomes, film formers, absorbents such as carbon or zeolites, cyclic oligosaccharides and mixtures thereof, or they may be chemically bonded to substrates, which are adapted to release the fragrance molecule upon application of an external stimulus such as light, enzyme, or the like, and then mixed with the consumer product base.

The invention is now further described with reference to the following non-limiting examples. These examples are for the purpose of illustration only and it is understood that variations and modifications can be made by one skilled in the art.

Example 1

Synthesis of 4-methylene-5-decenol

Step 1: Preparation of Grignard Reagent
To a mixture of magnesium turnings (2.42 gm, 0.1 mole), Iodine (0.1 gm) and tetrahydrofuran (100 ml) maintained under inert atmosphere at room temperature was added a solution of 1-bromo pentane (15.1 g, 0.1 mole) in THF (25ml). During addition, exothermicity was observed and the temperature of the mixture increased to refluxing temperature of tetrahydrofuran. The addition of the solution was carried out dropwise maintaining the refluxing temperature of tetrahydrofuran. After the addition of the solution, the mixture was stirred at refluxing temperature of tetrahydrofuran for 30 minutes and subsequently cooled to room temperature to yield pentyl magnesium bromide solution.

Step 2: Preparation of 2-Methylene valeraldehyde
2-methylene valeraldehyde is prepared by the aldol condensation of Valeraldehyde and Formaldehyde in presence of catalyst. Fractional distillation is carried out of the Crude mass obtained from the reaction which yield pure 2-Methylene valeraldehyde.

Step 3: Preparation of 4-methylene-5-decenol
The pentyl magnesium bromide solution of step 1 was cooled to 10 0C and a solution of 2-Methylene valeraldehyde (10 g, 0.1 mol) in THF (25 ml) was added dropwise. During addition, the temperature of the reaction mixture increased to 25 0C. The reaction was continued at 25 0C to 35 0C for a period of 1 hour and the complex so formed was decomposed with a mixture of crushed ice and saturated ammonium chloride solution. The aqueous layer was separated, and the organic layer washed with saturated sodium chloride solution and concentrated to remove tetrahydrofuran. The crude product (20 g) so obtained was distilled to yield 10 g of product (boiling point about 1000C @ 3 mmHg).

Table 1: 1H NMR Shifts (CDCl3)
Atom Number (Position) Chemical shifts (d ppm) No. of protons
H (1,10) 0.858 - 0.942(m) 6
H (2,3,6,7,8,9) (e) 1.273 - 1.284 (m) 6
H (2,7,8,9) (a) 1.386 - 1.526 (m) 4
H (3,6) (a) 1.916 - 2.056 (m) 2
H (5) 4.034 (t) 1
H (11) (cis) 4.811 (s) 1
H (11) (Trans) 4.989 (s) 1
- OH data not available 1

Table 2: C NMR Shifts (CDCl3)
Atom Number (Position) Chemical shifts (d ppm) No. of protons
C (1,10) 14.03 2
C (2) 22.63 1
C (3) 33.45 1
C (4) 152.09 1
C (5) 75.52 1
C (6) 35.45 1
C (7) 31.81 1
C (8) 25.40 1
C (9) 21.15 1
C (11) 109.14 1

Table 3: DEPT Spectra
Atom Number (Position) Chemical shifts (d ppm) Nature of carbons
C (1,10) 14.03 -CH3
C (2) 22.63 -CH2
C (3) 33.45 -CH2
C (4) 152.09 Quaternary
C (5) 75.52 -CH
C (6) 35.45 -CH2
C (7) 31.81 -CH2
C (8) 25.40 -CH2
C (9) 21.15 -CH2
C (11) 109.14 -CH2

Table 4: Fourier-transform infrared spectroscopy (FTIR)

Wavenumber (cm-1) Function Group - Stretch
3353, 3080 OH
2956, 2930, 2871, 2860 CH3-C
1646 C-O
1458 CH3-C, CH2-OH
1378, 1340, 1297, 1258 OH
1118 CH2-OH
1054, 1022 C - O, C-H
960, 899 C – C
878, 634 C - H

Remarks: 1H, 13C and DEPT NMR spectra matches with the structure of 4-methylene-5-decenol.

Structure of 4-methylene-5-decenol.

Olfactive Profile:
Very powerful fresh, vegetable herbal odor.

Example 2

12.2 grams of magnesium activated with 0.1 gm iodine was mixed with 50 ml of anhydrous tetrahydrofuran in an apparatus and in an inert atmosphere which is customary for Grignard reactions. To this mixture, a solution of 63.3 grams (0.5 moles) of Benzyl chloride in 150 ml of tetrahydrofuran was added drop-wise with stirring and the exothermicity was maintained at the boiling temperature of tetrahydrofuran. The reacted mixture was subsequently chilled in an ice bath and to this mixture was added 50 grams (0.50 moles) of 2-Methylene valeraldehyde, diluted with equal volume of tetrahydrofuran, slowly, maintaining the temperature in the range of 20 to 25°C. The reaction was continued for 2 hours at a temperature of 25 to 35°C and the complex so formed was decomposed with ice-concentrated ammonium chloride solution. 100 Grams of a crude product was obtained. After fractional distillation 50 grams of a product was obtained, the product was identified as a-(1-Methylenebutyl) benzene ethanol.

Olfactive Profile:
Floral, green and reminiscent violet character

Example 3

A 3 M solution of methyl magnesium chloride (160 mL, 480 mmol) in THF was added dropwise to a solution of 2-Methylene valeraldehyde (47.1 g, 480 mmol) in THF (960 mL) at room temperature under inert atmosphere. The reaction mixture was then refluxed for 2 h, subsequently cooled and quenched at a temperature range of 0-10 °C. with saturated aq. NH4Cl (250 ml), followed by water (250 ml). The product so formed was extracted with Et2O (500 mL), and the extracts were washed with brine (200 ml) and concentrated on a rotatory evaporator at 60 °C/500 mbar. The resulting residue was purified by distillation to yield 35 gm of 3-methylene hexan-2-ol as a colourless liquid.

Olfactive Profile:
Strong fruity, green, waxy mix vegetable like odor
Example 4

To an ice cooled solution of freshly distilled 2-methylene valeraldehyde (17.5 g, 178 mmole) in THF (270 ml) was added dropwise of 1M butyl magnesium bromide (180 ml,180mmole) in THF. After stirring the mixture for 30 minutes at room temperature, the reaction mixture was poured into 200 ml of ice cooled saturated ammonium chloride solution and the pH was adjusted to 1 with concentrated HCl. After usual treatment and evaporation of the solvent (Rotavapor), the crude alcohol was distilled using a packed column to yield 20 gm of 4-Methylene-5-nonanol.

Olfactive Profile:
Fresh floral oily herbaceous green character.

Technical Advancements:
The technical advancements of the present disclosure include, but are not limited to, the following:
a) The hydroxy compounds of formula 1 as described herein above constituting a fragrance compound having a fresh and floral odor, for use in fragrances, perfumes and other consumable product;
b) The hydroxy compounds can be produced in large scale by simple reactions; and
c) A synthesis process for the hydroxy compounds of formula 1 that allows easy upscaling and effective synthesis.

Embodiment of the present invention is applicable over a wide number of uses and other embodiments may be developed beyond the embodiment discussed heretofore. Only the most preferred embodiments and their uses have been described herein for purpose of example, illustrating the advantages over the prior art obtained through the present invention; the invention is not limited to these specific embodiments or their specified uses. Thus, the forms of the invention described herein are to be taken as illustrative only and other embodiments may be selected without departing from the scope of the present invention. It should also be understood that additional changes and modifications, within the scope of the invention, will be apparent to one skilled in the art and that various modifications to the composition described herein may fall within the scope of the invention.
,CLAIMS:We Claim:

1. A hydroxy compound of formula 1 -

(1)

wherein, R is selected from the group consisting of C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl and C2-C12 alkenyl.

2. The hydroxy compound as claimed in claim 1, wherein R is C1-C12 alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, iso-heptyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, nonyl, decyl and undecyl.

3. The hydroxy compound as claimed in any one of the preceding claims, wherein, R is selected from the group consisting of methyl, butyl and n-pentyl.

4. The hydroxy compound as claimed in claim 1, wherein C6-C15 aryl is selected from the group consisting of phenyl, benzyl, phenyl ethyl and phenyl propyl.

5. The hydroxy compound as claimed in any one of the preceding claims, wherein R is n-pentyl.

6. The hydroxy compound as claimed in claim 1, wherein the compound corresponding to formula (1) is in the form of any one of its stereoisomers and mixtures thereof, protonated and deprotonated form.

7. A method for preparation of hydroxy compound of formula 1,
(1)
wherein, R is selected from the group consisting of C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl and C2-C12 alkenyl,
said method comprising the steps of,
a) providing an aldehyde compound of formula 2;

(2)

b) providing a Grignard reagent of formula 3;

(3)

wherein, R is selected from the group consisting of C1-C12 alkyl, C3-C12 cycloalkyl, C6-C15 aryl, and C2-C12 alkenyl,

wherein, X is selected from the halogen group consisting of chloride, bromide and iodide; and

c) reacting the Grignard reagent of formula 3 with the aldehyde compound of formula 2.

8. The hydroxy compound as claimed in claim 7, wherein R is C1-C12 alkyl selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2-ethylbutyl, n-pentyl, isopentyl, 1-methylpentyl, 1,3-dimethylbutyl, n-hexyl, 1-methylhexyl, n-heptyl, iso-heptyl, 1-methylheptyl, 3-methylheptyl, n-octyl, 2-ethylhexyl, nonyl, decyl and undecyl.

9. The hydroxy compound as claimed in claim 7, wherein R is C6-C15 aryl selected from the group consisting of phenyl, benzyl, phenyl ethyl and phenyl propyl.

10. The hydroxy compound as claimed in any one of the preceding claims, wherein R is selected from the group consisting of methyl, butyl and n-pentyl.

11. The hydroxy compound as claimed in any one of the preceding claims, wherein R is n-pentyl.