DESC:
FIELD OF INVENTION:
The present disclosure is in relation to synthetic organic chemistry. The disclosure provides process for preparation of compounds of Formula I and its cis isomers. Particularly, the present invention provides a process for the preparation of a type of Vitamin K2, Menaquinone 7 (MK-7). More particularly the disclosure involves process of preparing Menaquinone 7 (MK-7) and its intermediates from Prenyl Ketones.
BACKGROUND AND PRIOR ART
The role of various Vitamins in the maintenance of our body is ubiquitously known. Key ingredient of vitamin K2, Menaquinone 7 is known for enhancing skin collagen and to increase testosterone level. They are useful in treatment of bone conditions like osteoporosis and arteriosclerosis; as tranquillizers, for the prevention and counteraction of diet induced thrombosis risk and for improving cardiovascular health. Food sources of MK-7 are Japanese natto, fermented soy, goose liver, cheese and butter. Conventionally, MK-7 is produced by prokaryotic fermentation in organisms like B. subtilis, E. coli and Lactic acid bacteria. This method involves many purification steps, as chances of - harmful growth of microorganisms is high, product has a sticky texture, stringiness and specific fermentation odour. Synthetic routes of preparation are also known in the literature. However, the known synthetic routes suffer from usage of unstable intermediates, toxic, hazardous and pyrophoric chemicals. Further, the known process would lead to formation of several isomers of MK-7 along with desired all trans isomer.
The US patent application US2015/0126763 A1 describes the preparation of MK-7 by using concept of Umpolung to extend the prenol chain length. The process involves thiols which are known to have very bad odour and hazardous reaction conditions to de-protect the thiol group like refluxing the hydrazine containing reaction mass at 125 °C.
Baj et al. (Org. Process Res. Dev., 2016, 20 (6), pp 1026–1033) reported convergent synthesis of menaquinone-7. The process involves usage of highly pyrophoric chemical such as Lithium triethylborohydride (LiTEBH) and expensive palladium catalysts. LiTEBH is highly flammable and very expensive. Lithium borohydride commonly referred to as Superhydride, is a powerful reducing agent and reacts exothermically, potentially violently, with water, alcohols, and acids, releasing hydrogen and the pyrophoric triethylborane.
Considering the importance of MK-7, it is necessary to develop a method that can overcome the lacuna with respect to the method of its preparation. The present invention aims to provide facile, economical, high yielding, environmentally benign method that can cater to the demand.
OBJECTS OF INVENTION
It is an object of the present invention to provide a novel, safe, scalable and efficient process for the preparation of compounds of Formula I including Vitamin K2.
It is another object of the present invention to provide an improved and industrially advantageous process for the preparation of 2-[(2~{E},6~{E},10~{E},14~{E},18~{E},22~{E})-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaenyl]-3-methylnaphthalene-1,4-dione and its intermediates from commercially available reagents.
It is yet another object of the present invention to provide novel intermediates, which serve as industrially useful starting compound for the efficient synthesis of compounds that are pharmaceutically significant.

SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided a novel and efficient process for preparation of compounds of formula I including Vitamin K2 by condensing the compounds formula II with compounds of formula III in the presence of a suitable base and optionally lewis acid.

According to another aspect of the present invention there is provided novel intermediates for synthesis of compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The following description is provided to assist in a comprehensive understanding of exemplary embodiments of the invention. It includes various specific details to assist in that understanding but these are to be regarded as merely exemplary.
Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of the invention. In addition, descriptions of well-known functions and constructions are omitted for clarity and conciseness.
The terms and words used in the following description and claims are not limited to the bibliographical meanings, but, are merely used by the inventor to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustration purpose only and not for the purpose of limiting the scope of the invention as defined by the appended claims and their equivalents.
It is to be understood that the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
Features that are described and/or illustrated with respect to one embodiment may be used in the same way or in a similar way in one or more other embodiments and/or in combination with or instead of the features of the other embodiments.
It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, steps or components but does not preclude the presence or addition of one or more other features, steps, components or groups thereof.
The present disclosure provides a method for preparation of formula I including Vitamin K2 using compounds of formula II and compounds of formula III.

More specifically the invention is pertaining to coupling of compounds of formula II with compounds of formula III in the presence of a suitable base and optionally a Lewis acid.
The base for the preparation is selected from group comprising but not limiting to Lithium bis(trimethylsilyl)amide, Sodium bis(trimethylsilyl)amide, Potassium bis(trimethylsilyl)amide, n-Butyllithium, Lithium diisopropylamide, Potassium diisopropylamide, Sodium hydride, Potassium hydride and Cesium carbonate.
The lewis acid for the preparation is selected from group comprising but not limiting to Cerium(III) chloride, Magnesium chloride, Boron trifluoride etherate, and Titanium isopropoxide.
General formula of compound II adopted in the preparation is:

wherein,
n ranges from 0 to 3;
R1 is selected from group of compounds having general formula -OR4 and compounds comprising in Table 1.
wherein,
Table 1

wherein,
R4 is selected from protecting group comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl, and Benzoyl group.
P1 and P2 are individually selected from groups comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl, and Benzoyl group.
R7 and R8 is selected from ketone protecting groups comprising but not limited to ethylene glycol, propylene glycol, alcohols and thioalcohols including ethanedithiol and propanedithiol.
R2 is selected from group of compounds comprising compounds described in Table 2.
Table 2

wherein,
R6 is selected from group comprising H, alkyl, aryl, aralkyl and hetero aryl group.
Examples of compounds of formula II are mentioned in Table 3.
Table 3
S. No Structure

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

wherein,
R4 is selected from protecting group comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, pivalyl and benzoyl group.
R6 is selected from group comprising hydrogen, alkyl, aryl, aralkyl and hetero aryl group.
P1 and P2 are individually selected from groups consisting of hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl and Benzoyl group.
General formula of compound III adopted in the preparation is:

Wherein,
n ranges from 0 to 3;
R3 is selected from group of compounds comprising compounds described in Table 4.
Table 4

Wherein,
R5 is selected from hydrogen, alkyl, alkoxy, aryl, hetero aryl, Cycloalkane and X, where in X is selected from group comprising F, Cl, Br, I, NO2, CF3, and CN.
R6 is selected from group comprising hydrogen, alkyl, aryl, aralkyl and hetero aryl group.
Examples of compounds of formula III are mentioned in Table 5.
Table 5
S. No Structure

1

2

3

4

5

6

7

8

9

10

11

General formula of compound I obtained through the present invention is:

Examples of compounds of formula I are mentioned in Table 6.
Table 6
S. No Structure

1


(MK-7)
2

3

4

5

6

7

8

9

wherein,
R4 is selected from protecting groups comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, Acyl, Pivalyl and Benzoyl group.
R7 and R8 is selected from ketone protecting groups comprising ethylene glycol, propylene glycol, alcohols, thioalcohols, ethanedithiol andpropanedithiol.
P1 and P2 are individually selected from groups comprising hydrogen, Alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl and benzoyl group.
EXAMPLES:
The following examples illustrate the present invention in more detail, however it should not be interpreted as limiting the scope of the invention
EXAMPLE 1:
Preparation of MK-7 according to present invention:

(MK-7)
The general scheme of preparation procedure is depicted in Scheme A below:

Scheme A
The compound MK-7 was prepared by condensing the intermediate compounds of formula 7 and 8 above in presence of a base (Step 7) to form the mixture of dimethoxy protected cis and trans isomers of MK-7 according to present invention which was further deprotected and purified (Step 8) to obtain the substantially pure trans isomer of MK-7. Intermediate compound of formula 7 was prepared by the steps 1-6. The detailed process steps are given below:

Step 1:Preparation of 3-[(3E,7E)-9-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-3,7-dimethylnona-3,7-dien-1-yl]-2,2-dimethyloxirane (2)

To a solution of 1,4-dimethoxy-2-methyl-3-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]naphthalene 1 (100 g, 0.25 mol, 1.0 eq.) in tetrahydrofuran (8 V), water (1.6 V), N-bromosuccinamide (49 g, 0.27 mol, 1.1 eq.) is added portion wise at ice cold temperature (0-5 °C). The reaction mixture is allowed to stir at 25-30 °C over a period of 1-3 h.
To the above reaction mixture methanol (10 V), potassium carbonate (69 g, 0.5 mol, 2.0 eq.) is added at ice cold temperature (0-5 °C). The reaction mixture is allowed to stir at room temperature over a period of 1-3 h. The resulting reaction mixture is diluted with methyl tertiary butyl ether (1600 mL), washed with water (800 mL) and brine solution (800 mL).The organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 2 as a pale-yellow liquid.
Step 2: (4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimethyldeca-4,8-dienal (3)

To a solution of 3-[(3E,7E)-9-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-3,7-dimethylnona-3,7-dien-1-yl]-2,2-dimethyloxirane (2) (100 g, 0.24 mol, 1.0 eq) in tetrahydrofuran (5 V) is added sodium metaperiodate (103 g, 0.48 mol, 2.0 eq.) in water (10 V) at ice cold temperature (0-5 °C). Then periodic acid (27.4 g, 0.12 mol, 0.5 eq) in tetrahydrofuran (10 V) is added dropwise at ice cold temperature (0-5 °C). The reaction mixture was allowed to stir at about 25-30 °C for over a period of 1 h. The resulting reaction mixture is diluted with ethyl acetate (1000 mL), washed with 5% NaHCO3 solution (400 mL) and water (400 mL), the organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 3 as a pale-yellow liquid.
Step 3:Preparation of (4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimethyldeca-4,8-dien-1-ol (4)

To a solution of (4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimethyldeca-4,8-dienal (3) (50 g, 0.13 mol, 1.0 eq) in methanol, sodium borohydride (4.81 g, 0.13 mol, 1.0 eq) (5 V) is added portion wise at 0-5 °C. The mixture is stirred at same temperature over a period of 30 min. The resulting reaction mixture is quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (700 mL).The organic layer is washed with water (2 X 500 mL), dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column (5% ethyl acetate in hexanes) to give product 4 as a pale-yellow liquid.
Step 4: Preparation of 2-[(2E,6E)-10-bromo-3,7-dimethyldeca-2,6-dien-1-yl]-1,4-dimethoxy-3-methylnaphthalene (5)

To a solution of (4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimethyldeca-4,8-dien-1-ol (4) (50 g, 0.13 mol, 1.0 eq) in tetrahydrofuran, triethylamine (36 mL, 0.26 mol, 2 eq.) (10 V) is added at 25-30 °C. The reaction mixture is cooled to -45 °C and then methanesulphonyl chloride (20 mL, 0.26 mol, 2.0 eq.) is added drop wise over a period of 10 min. The reaction mixture is stirred at same temperature for another 30 min and then allowed to warm to about 25-30 °C. Lithium bromide (113 g, 1.3 mol, 10 eq.) is added slowly to the reaction mixture portion wise at 25-30 °C and stirred over a period of 12 h. The resulting reaction mixture is quenched with water (500 mL) and extracted with hexane (1000 mL).The organic layer is washed with water (1 X 500 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 5 as a pale-yellow liquid.
Step 5:Preparation of 5-{[(4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimethyldeca-4,8-dien-1-yl]sulfanyl}-1-phenyl-1H-1,2,3,4-tetrazole (6)

To a solution of 2-[(2E,6E)-10-bromo-3,7-dimethyldeca-2,6-dien-1-yl]-1,4-dimethoxy-3-methylnaphthalene (5) (75 g, 0.16 mmol, 1.0 eq) in DMF, 10 volumes of K2CO3 (55.2 g, 0.4 mol, 2.5 eq) and 1-Phenyl-1H-tetrazole-5-thiol (43 g, 0.24 mol, 1.5 eq) is added at 25-30 ° C. The above reaction mixture is heated to 50 °C over a period of 2 h. The resulting reaction mixture is diluted with ethyl acetate (1000 mL).The organic layer is washed with water (2 X 500 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column to give product 6 as a as a pale-yellow liquid.
Step 6:Preparation of 5-[(4E,8E)-4,8-Dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienylsulfanyl]-1-phenyl-1H-tetrazole (7)

To a stirring solution of 5-{[(4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimethyldeca-4,8-dien-1-yl]sulfanyl}-1-phenyl-1H-1,2,3,4-tetrazole (6) (50 g, 0.092 mol) in methanol, sodium tungstate dihydrate (7.3 g, 0.022 mol, 0.24 eq.) is added at 0-5 °C. The mixture is stirred at same temperature over a period of 10 min. Hydrogen peroxide (94 mL, 1.38 mol, 15 eq.) is then added dropwise at the same temperature. The reaction mixture is allowed to warm to about 25-30 °C and stirred over a period of 12 h. The reaction mixture is quenched with 5% aqueous sodium bicarbonate solution (10 V) and extracted with ethyl acetate (1000 mL).The organic layer is washed with water (2 X 500 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 7 (Formula II) as a pale yellow liquid.
Step 7:Preparation of 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene and 2-[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene (9)

To a cold solution of 5-[(4E,8E)-4,8-Dimethyl-10-(tetrahydro-pyran-2-yloxy)-deca-4,8-dienylsulfanyl]-1-phenyl-1H-tetrazole (7) (226 g, 0.4 mol, 1.3 eq) in tetrahydrofuran, 1.0 M Lithium bis(trimethylsilyl)amide (LiHMDS) (900 mL, 0.9 mol, 3.0 eq) is added drop wise at -70° C and stirred for 10 min. To the above reaction mixture (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one 8 (Formula III) (100 g, 0.30 mol, 1.0 eq)) in THF is added over a period of 30 min. The reaction mixture is allowed to stir at same temperate over a period of 1-2 h. The resulting reaction mixture is quenched with aqueous ammonium chloride solution (750 mL) and extracted with ethyl acetate (1500 mL). The organic layer is washed with water (2 X 750 mL). The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column (alone hexanes) to give product 9 (Formula I) as a pale yellow liquid. Compound 9 contains mixture of 2-[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene (Cis isomer) and 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene (Trans isomer). Cis isomer ranging from 0.1% to 60% and Trans isomer ranging from 40% to 99.9%.
Step8:Preparation of 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-3-methyl-1,2,3,4-tetrahydronaphthalene-1,4-dione (10)
To a stirring solution of 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene and 2-[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene (9) (135 g, 0.2 mol, 1.0 eq.) in acetonitrile (6 V), DCM (6V) and H2O (3 V), is added a solution of ceric ammonium nitrate (240 g, 0.44 mol, 2.2 eq.) in acetonitrile (4 V) and H2O (4V) over a period of 30 min below 5°C. The reaction mixture is allowed to stir at ambient temperate over a period of 4 - 5 h. The reaction was monitored by TLC. The reaction mixture was poured into ice-water (4V) and was extracted with DCM (3X5V). The combined organic layers were washed with ice-water (5V), brine (3V). The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles (35 °C) is purified through silica gel (230-400) column (2.5-5 % ethyl acetate in hexanes) to give product 10 (Formula I) as a yellow solid. MK-7 was crystallized from acetone, methanol combination or ethyl acetate, methanol combination. Formula I contains Trans isomer ranging from 90-99.95% and Cis isomer ranging from 0.05% to 10%.
IUPAC of Cis Isomer: 2-[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-3-methyl-1,4-dihydronaphthalene-1,4-dione

EXAMPLE 2:
Preparation of MK-7 according to present invention:

(MK-7)
The general scheme of preparation procedure is depicted in Scheme B.

Scheme B
The compound MK-7 was prepared by condensing the intermediate compounds of formula 3 and 8 above in presence of a base (Step 7) to form the mixture of dimethoxy protected cis and trans isomers of MK-7 according to present invention which was further deprotected and purified (Step 8) to obtain the substantially pure trans isomer of MK-7. Intermediate compounds of formula 3 and 8 above are prepared by the steps 1-6. The detailed process steps are given below:

Step 1:Preparation of 3-[(3E,7E)-9-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-3,7-dimethylnona-3,7-dien-1-yl]-2,2-dimethyloxirane (2)

To a solution of 1,4-dimethoxy-2-methyl-3-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]naphthalene 1 (100 g, 0.25 mol, 1.0 eq.) in tetrahydrofuran (8 V), water (1.6 V), N-bromosuccinamide (49 g, 0.27 mol, 1.1 eq.) is added portion wise at ice cold temperature (0-5 °C). The reaction mixture is allowed to stir at 25-30 °C over a period of 1-3 h.
To the above reaction mixture methanol (10 V), potassium carbonate (69 g, 0.5 mol, 2.0 eq.) is added at ice cold temperature (0-5 °C). The reaction mixture is allowed to stir at room temperature over a period of 1-3 h. The resulting reaction mixture is diluted with methyl tertiary butyl ether (1600 mL), washed with water (800 mL) and brine solution (800 mL).The organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 2 as a pale-yellow liquid.
Step 2: (4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimethyldeca-4,8-dienal (3)

To a solution of 3-[(3E,7E)-9-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-3,7-dimethylnona-3,7-dien-1-yl]-2,2-dimethyloxirane (2) (100 g, 0.24 mol, 1.0 eq) in tetrahydrofuran (5 V) is added sodium metaperiodate (103 g, 0.48 mol, 2.0 eq.) in water (10 V) at ice cold temperature (0-5 °C). Then periodic acid (27.4 g, 0.12 mol, 0.5 eq) in tetrahydrofuran (10 V) is added dropwise at ice cold temperature (0-5 °C). The reaction mixture was allowed to stir at about 25-30 °C for over a period of 1 h. The resulting reaction mixture is diluted with ethyl acetate (1000 mL), washed with 5% NaHCO3 solution (400 mL) and water (400 mL), the organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 3 (Formula II) as a pale-yellow liquid.
Step 3:Preparation of ((5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-ol; (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one (5)

To a solution of (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-ol; (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one (4) (50 g, 0.15 mol, 1.0 eq) in methanol, sodium borohydride (8.3 g, 0.225 mol, 1.5 eq) (5 V) is added portion wise at 0-5 °C. The mixture is stirred at same temperature over a period of 30 min. The resulting reaction mixture is quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (750 mL).The organic layer is washed with water (2 X 500 mL), dried over sodium sulphate and concentrated under reduced pressure to give product 5 as a colourless liquid.
Step 4:Preparation of (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one; (6E,10E,14E)-18-bromo-2,6,10,14-tetramethylnonadeca-2,6,10,14-tetraene (6)

To a solution of ((5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-ol; (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one (5) (50 g, 0.15 mol, 1.0 eq) in 2-methyl tetrahydrofuran (10 V), PBr3 (7.1 mL, 0.075 mol, 0.5 eq.) (10 V) is added at 0-5 °C. The reaction mixture is stirred at same temperature for another 30 min. The resulting reaction mixture is quenched with cold water (500 mL) and extracted with 2-methyl tetrahydrofuran (250 mL).The organic layer is washed with water (1 X 500 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 6 as a pale-brown liquid.
Step 5:Preparation of 1-phenyl-5-{[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-yl]sulfanyl}-1H-1,2,3,4-tetrazole (7)

To a solution of (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one; (6E,10E,14E)-18-bromo-2,6,10,14-tetramethylnonadeca-2,6,10,14-tetraene (6) (75 g, 0.19 mmol, 1.0 eq) in DMF, K2CO3 (65.5 g, 0.47 mol, 2.5 eq) and 1-Phenyl-1H-tetrazole-5-thiol (50.7 g, 0.29 mol, 1.5 eq) is added at 25-30 ° C. The above reaction mixture is heated to 50 °C over a period of 2 h. The resulting reaction mixture is diluted with ethyl acetate (1000 mL).The organic layer is washed with water (2 X 500 mL) and brine (1X500 mL). The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column (5% ethyl acetate in hexanes) to give product 7 as a colourless liquid.
Step 6:Preparation of 1-phenyl-5-[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraene-2-sulfonyl]-1H-1,2,3,4-tetrazole (8)

To a stirring solution of 1-phenyl-5-{[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-yl]sulfanyl}-1H-1,2,3,4-tetrazole (7) (50 g, 0.1 mol) in methanol, sodium tungstate dihydrate (8.0 g, 0.024 mol, 0.24 eq.) is added at 0-5 °C. The mixture is stirred at same temperature over a period of 10 min. Hydrogen peroxide (102 mL, 1.5 mol, 15 eq.) is then added dropwise at the same temperature. The reaction mixture is allowed to warm to about 25-30 °C and stirred over a period of 12 h. The reaction mixture is quenched with 5% aqueous sodium bicarbonate solution (10 V) and extracted with ethyl acetate (1000 mL).The organic layer is washed with water (2 X 500 mL). The crude product obtained upon evaporation of volatiles is purified through neutral alumina column to give product 8 (Formula III) as a colourless liquid.
Step 7:Preparation of 1-phenyl-5-[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraene-2-sulfonyl]-1H-1,2,3,4-tetrazole; 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene and 2-[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene (9)

To a cold solution of 1-phenyl-5-[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraene-2-sulfonyl]-1H-1,2,3,4-tetrazole (8) (Formula III) (177.1 g, 0.34 mol, 1.3 eq) in tetrahydrofuran, 1.0 M Lithium bis(trimethylsilyl)amide (LiHMDS) (900 mL, 0.9 mol, 3.0 eq) is added drop wise at -70° C and stirred for 10 min. To the above reaction mixture (4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimethyldeca-4,8-dienal (3) (Formula II) (100 g, 0.26 mol, 1.0 eq)) in THF is added over a period of 30 min. The reaction mixture is allowed to stir at same temperate over a period of 1-2 h. The resulting reaction mixture is quenched with aqueous ammonium chloride solution (750 mL) and extracted with ethyl acetate (1500 mL).The organic layer is washed with water (2 X 750 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column (alone hexanes) to give product 9 (Formula I) as a yellow liquid. Compound 9 contains mixture of 2-[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene (Cis isomer) and 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene (Trans isomer). Cis isomer ranging from 0.1% to 60% and Trans isomer ranging from 40% to 99.9%.
Step 8:Preparation of 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-3-methyl-1,2,3,4-tetrahydronaphthalene-1,4-dione (10)
To a stirring solution of 1-phenyl-5-[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraene-2-sulfonyl]-1H-1,2,3,4-tetrazole; 2-[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-1,4-dimethoxy-3-methylnaphthalene (9) (135 g, 0.2 mol, 1.0 eq.) in acetonitrile (6 V), DCM (6V) and H2O (3 V), is added a solution of ceric ammonium nitrate (240 g, 0.44 mol, 2.2 eq.) in acetonitrile (4 V) and H2O (4V) over a period of 30 min below 5°C. The reaction mixture is allowed to stir at ambient temperate over a period of 4 - 5 h. The reaction was monitored by TLC. The reaction mixture was poured into ice-water (4V) and was extracted with DCM (3X5V). The combined organic layers were washed with ice-water (5V), brine (3V). The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles (35 °C) is purified through silica gel (230-400) column (2.5-5 % ethyl acetate in hexanes) to give product 10 (Formula I) as a yellow solid. MK-7 was crystallized from acetone, methanol or ethyl acetate, methanol combination. Formula I contains Trans isomer ranging from 90-99.95% and Cis isomer ranging from 0.05% to 10%.
IUPAC of Cis Isomer: 2-[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]-3-methyl-1,4-dihydronaphthalene-1,4-dione
EXAMPLE 3:
Preparation of heptaprenol (Formula I):

(Heptaprenol)
The general scheme of preparation procedure is depicted in Scheme C.

Scheme C
The compound of Formula I was prepared by condensing the intermediate compounds of formula 8 and 9 above in presence of a base (Step 7) to form the mixture of THP protected cis and trans isomers of heptaprenol according to present invention which was further deprotected and purified (Step 8) to obtain the substantially pure trans isomer of heptaprenol. Intermediate compounds of formula 8 above was prepared by the steps 1-6. The detailed process steps are given below:
Step 1: Preparation of 2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]oxy}oxane (2)

To a solution of (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol (1) (100 g, 0.449 mol, 1.0 eq.) in dichloromethane (5 V), p-Toluenesulfonic acid (11.3 g, 0.044 mol, 0.1 eq.) is added at 25-30 °C. The reaction mixture is cooled to 0-5 °C and then 3,4-Dihydro-2H-pyran (51.4 mL, 0.562 mol, 1.25 eq.) is added drop wise over a period of 10 min. The reaction mixture is allowed to stir at 25-30 °C over a period of 4 h. The resulting mixture was quenched with water (500 mL). The organic layer is washed with water (500 mL) and brine solution (500 mL), dried over sodium sulphate and concentrated under reduced pressure to give product 2 as a pale-yellow liquid.
Step 2: Preparation of 2-{[(2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1 -yl]oxy}oxane (3)

To a solution of 2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]oxy}oxane (2) (137.8 g, 0.447 mol, 1.0 eq.) in tetrahydrofuran (4 V), water (0.8 V), N-bromosuccinamide (120 g, 0.670 mol, 1.5 eq.) is added portion wise at ice cold temperature (0-5 °C). The reaction mixture is allowed to stir at 25-30 °C over a period of 1-3 h. The resulting reaction mixture is diluted with hexane (689 mL), washed with water (1102 mL) and brine solution (689 mL). The separated organic layer was dried over sodium sulphate and concentrated under reduced pressure resulted a pale-yellow liquid.
To the above reaction mixture methanol (5 V), potassium carbonate (92.67 g, 0.671 mol, 1.5 eq.) is added at ice cold temperature (0-5 °C). The reaction mixture is allowed to stir at room temperature over a period of 3-4 h. The resulting reaction mixture is diluted with hexane (689 mL), washed with water (1102 mL) and brine solution (689 mL).The separated organic layer dried over sodium sulphate and concentrated under reduced pressure to give product 3 as a pale-yellow liquid.
Step 3: Preparation of (4E,8E)-4,8-dimethyl-10-(oxan-2-yloxy)deca-4,8-dien-1-al (4)

To a solution of 2-{[(2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl] oxy}oxane (3) (16.66 g, 0.051 mol, 1.0 eq) in tetrahydrofuran (4 V) is added sodium metaperiodate (22.12 g, 0.102 mol, 2.0 eq.) in water (8 V) at ice cold temperature (0-5 °C). Then periodic acid (5.85 g, 0.025 mol, 0.5 eq) in tetrahydrofuran (4 V) is added dropwise at ice cold temperature (0-5 °C). The reaction mixture was allowed to stir at about 25-30 °C for over a period of 3 h. The resulting reaction mixture is quenched with aqueous sodiumbicarbonate solution and filtered. The filtrate was extracted with ethyl acetate (83.3 mL).The organic layer is washed with water (83.3 mL) and brine solution (83.3 mL), dried over sodium sulphate and concentrated under reduced pressure to give product 4 as a pale-yellow liquid.

Step 4: Preparation of (4E,8E)-4,8-dimethyl-10-(oxan-2-yloxy)deca-4,8-dien-1-ol (5)

To a solution of (4E,8E)-4,8-dimethyl-10-(oxan-2-yloxy)deca-4,8-dien-1-al (4) in methanol (5V) was added sodium borohydride (2.0 g, 0.053 mol, 1.5 eq) is added portion wise at 0-5 °C. The mixture is stirred at same temperature over a period of 30 min. The resulting reaction mixture is quenched with aqueous ammonium chloride solution and filtered. The filtrate was extracted with ethyl acetate (83.3 mL).The organic layer is washed with water (83.3 mL) and brine solution (83.3 mL), dried over sodium sulphate and concentrated under reduced pressure to give product 5 as a pale-yellow liquid.
Step 5: Preparation of 2-{[(2E,6E)-10-iodo-3,7-dimethyldeca-2,6-dien-1-yl]oxy}oxane (6)

To a solution of (4E,8E)-4,8-dimethyl-10-(oxan-2-yloxy)deca-4,8-dien-1-ol (5) (64.8 g, 0.229 mol, 1.0 eq) in tetrahydrofuran (5.0 V), triethylamine (64 mL, 0.458 mol, 2.0 eq.) is added at 25-30 °C. The reaction mixture is cooled to 0-5 °C and then methanesulphonyl chloride (121.3 mL, 0.275 mol, 1.5 eq.) is added drop wise over a period of 10 min. The reaction mixture is stirred at same temperature for another 1h. Lithium iodide (61.4 g, 0.458 mol, 2.0 eq.) is added slowly to the reaction mixture portion wise at 0-20 °C and stirred over a period of 12 h at 25-30 °C. The resulting reaction mixture was quenched with water (648 mL) and extracted with ethyl acetate (648 mL).The organic layer is washed with water (2 X 648 mL) and brine solution (324 mL) .The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 6 as a pale-yellow liquid.
Step 6: Preparation of 5-{[(4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-dimeth yldeca-4,8-dien-1-yl]sulfanyl}-1-phenyl-1H-1,2,3,4-tetrazole (7)

To a solution of 2-{[(2E,6E)-10-iodo-3,7-dimethyldeca-2,6-dien-1-yl]oxy}oxane (6) (75 g, 0.191 mol, 1.0 eq) in DMF (10 V), were added K2CO3 (66.0 g, 0.478 mol, 2.5 eq) and 1-Phenyl-1H-tetrazole-5-thiol (37.5 g, 0.210 mol, 1.1 eq) is added at 25-30 ° C. The above reaction mixture was stirred at 25-30 °C over a period of 5 h. The resulting reaction mixture is diluted with ethyl acetate (750 mL).The organic layer is washed with water (2 X 375 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column to give product 7 as a as a pale-yellow liquid.
Step 7: Preparation of 5-[(4E,8E)-4,8-dimethyl-10-(oxan-2-yloxy)deca-4,8-diene-1-sulfonyl]-1-phenyl-1H-1,2,3,4-tetrazole (8)

To a stirring solution of 5-{[(4E,8E)-10-(1,4-dimethoxy-3-methylnaphthalen-2-yl)-4,8-di methyldeca-4,8-dien-1-yl]sulfanyl}-1-phenyl-1H-1,2,3,4-tetrazole (7) (6.0 g, 0.013 mol, 1eq.) in ethanol (10 V), Ammonium heptamolybdate (73 g, 2.71 mmol, 0.2 eq.) and Hexamethylphosph oric acid triamide (12 mL, 2V) were added at 0-5 °C. The mixture is stirred at same temperature over a period of 10 min. Hydrogen peroxide (15.3 mL, 0.13 mol, 10 eq.) is then added dropwise at the same temperature. The reaction mixture is allowed to warm to about 25-30 °C and stirred over a period of 12 h. The reaction mixture is quenched with 5% aqueous sodium bicarbonate solution (60 V) and extracted with ethyl acetate (90 mL).The organic layer is washed with water (2 X 60 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure The crude product obtained upon evaporation of volatiles is purified through neutral alumina column to give product 8 as a pale yellow liquid.
Step 8: Preparation of 2-{[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacos a-2,6,10,14,18,22,26-heptaen-1-yl]oxy}oxane (10)

To a solution of 5-[(4E,8E)-4,8-dimethyl-10-(oxan-2-yloxy)deca-4,8-diene-1-sulfonyl]-1-phenyl-1H-1,2,3,4-tetrazole (8) (8.6 g, 0.018 mol, 1.2 eq) in THF (10 V), cerium chloride (4.0 g, 0.015 mol, 1.0 eq.) is added at room temperature. To the above reaction mixture 1.0 M Lithium bis(trimethylsilyl)amide (LiHMDS) (52.9 mL, 0.052 mol, 3.5 eq) and (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one (9) (5.0 g, 0.013 mol, 1.0 eq)) in THF (3 V) are added at -78° C over a period of 30-45 min. The reaction mixture, slowly warmed to room temperature and stir over a period of 2h. The resulting reaction mixture is quenched with aqueous ammonium chloride solution (150 mL). The organic layer is washed with water (500 mL) and brine solution (250 mL). The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column (2.5% EA/hexanes) to give product 10 as a pale brown liquid. Compound 10 contains mixture of 2-{[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]oxy}oxane (Cis isomer) and 2-{[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl] oxy}oxane (Trans isomer). Cis isomer ranging from 0.1% to 60% and Trans isomer ranging from 40% to 99.9%.
Step 9: Preparation of (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2, 6,10,14,18,22,26-heptaen-1-ol (11)

To a stirring solution of 2-{[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloct acosa-2,6,10,14,18,22,26-heptaen-1-yl]oxy}oxane (10) (15.7 g, 0.027 mol, 1.0 eq.) in Methanol (5 V), was added p-Toluenesulfonic acid (681 mg, 2.716 mmol, 0.1 eq.) and heated to 60±5°C and stir the reaction mass for about 6 hours at 60±5°C. The reaction was monitored by TLC. The resulting reaction mixture is diluted with ethyl acetate (157 mL), washed with water (2 X 157 mL) and brine solution (78.5 mL). The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles (35 °C) was purified through silica gel (60-120) column (10-20 % ethyl acetate in hexanes) to give product 11 (Formula I) as a Pale yellow syrup. Heptaprenol was crystallized from acetone, heptane, methanol or ethyl acetate, methanol combination. Formula I contains Trans isomer ranging from 95-99.95% and Cis isomer ranging from 0.05% to 5%.
EXAMPLE 4:
Preparation of heptaprenol (Formula I):

(Heptaprenol)
The general scheme of preparation procedure is depicted in Scheme D.

Scheme D
The compound of Formula I was prepared by condensing the intermediate compounds of formula 4 and 9 above in presence of a base (Step 8) to form the mixture of THP protected cis and trans isomers of heptaprenol according to present invention which was further deprotected and purified (Step 9) to obtain the substantially pure trans isomer of heptaprenol. Intermediate compounds of formula 4 and 9 above was prepared by the steps 1-7. The detailed process steps are given below:
Step 1: Preparation of 2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]oxy}oxane (2)

To a solution of (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-ol (1) (100 g, 0.449 mol, 1.0 eq.) in dichloromethane (5 V), p-Toluenesulfonic acid (11.3 g, 0.044 mol, 0.1 eq.) is added at 25-30 °C. The reaction mixture is cooled to 0-5 °C and then 3,4-Dihydro-2H-pyran (51.4 mL, 0.562 mol, 1.25 eq.) is added drop wise over a period of 10 min. The reaction mixture is allowed to stir at 25-30 °C over a period of 4 h. The resulting mixture was quenched with water (500 mL). The organic layer is washed with water (500 mL) and brine solution (500 mL), dried over sodium sulphate and concentrated under reduced pressure to give product 2 as a pale-yellow liquid.
Step 2: Preparation of 2-{[(2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1 -yl]oxy}oxane (3)

To a solution of 2-{[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]oxy}oxane (2) (137.8 g, 0.447 mol, 1.0 eq.) in tetrahydrofuran (4 V), water (0.8 V), N-bromosuccinamide (120 g, 0.670 mol, 1.5 eq.) is added portion wise at ice cold temperature (0-5 °C). The reaction mixture is allowed to stir at 25-30 °C over a period of 1-3 h. The resulting reaction mixture is diluted with hexane (689 mL), washed with water (1102 mL) and brine solution (689 mL). The separated organic layer was dried over sodium sulphate and concentrated under reduced pressure resulted a pale-yellow liquid.
To the above reaction mixture methanol (5 V), potassium carbonate (92.67 g, 0.671 mol, 1.5 eq.) is added at ice cold temperature (0-5 °C). The reaction mixture is allowed to stir at room temperature over a period of 3-4 h. The resulting reaction mixture is diluted with hexane (689 mL), washed with water (1102 mL) and brine solution (689 mL).The separated organic layer dried over sodium sulphate and concentrated under reduced pressure to give product 3 as a pale-yellow liquid.

Step 3: Preparation of (4E,8E)-4,8-dimethyl-10-(oxan-2-yloxy)deca-4,8-dien-1-al (4)

To a solution of 2-{[(2E,6E)-9-(3,3-dimethyloxiran-2-yl)-3,7-dimethylnona-2,6-dien-1-yl] oxy}oxane (3) (16.66 g, 0.051 mol, 1.0 eq) in tetrahydrofuran (4 V) is added sodium metaperiodate (22.12 g, 0.102 mol, 2.0 eq.) in water (8 V) at ice cold temperature (0-5 °C). Then periodic acid (5.88 g, 0.025 mol, 0.5 eq) in tetrahydrofuran (4 V) is added dropwise at ice cold temperature (0-5 °C). The reaction mixture was allowed to stir at about 25-30 °C for over a period of 3 h. The resulting reaction mixture is quenched with aqueous sodiumbicarbonate solution and filtered. The filtrate was extracted with ethyl acetate (83.3 mL).The organic layer is washed with water (83.3 mL) and brine solution (83.3 mL), dried over sodium sulphate and concentrated under reduced pressure to give product 4 as a pale-yellow liquid.Step 4: Preparation of (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-ol (6)

To a solution of (5E, 9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-one (5) (50 g, 0.15 mol, 1.0 eq) in methanol, sodium borohydride (8.3 g, 0.225 mol, 1.5 eq) (5 V) is added portion wise at 0-5 °C. The mixture is stirred at same temperature over a period of 30 min. The resulting reaction mixture is quenched with aqueous ammonium chloride solution and extracted with ethyl acetate (750 mL).The organic layer is washed with water (2 X 500 mL), dried over sodium sulphate and concentrated under reduced pressure to give product 6 as a colourless liquid.
Step 5: Preparation of (6E,10E,14E)-18-bromo-2,6,10,14-tetramethylnonadeca-2,6,10,14-tetraene (7)

To a solution of (5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-ol (6) (50 g, 0.15 mol, 1.0 eq) in 2-methyl tetrahydrofuran (10 V), PBr3 (7.1 mL, 0.075 mol, 0.5 eq.) (10 V) is added at 0-5 °C. The reaction mixture is stirred at same temperature for another 30 min. The resulting reaction mixture is quenched with cold water (500 mL) and extracted with 2-methyl tetrahydrofuran (250 mL).The organic layer is washed with water (1 X 500 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure to give product 7 as a pale-brown liquid.
Step 6: Preparation of 1-phenyl-5-{[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraen-2-yl]sulfanyl}-1H-1,2,3,4-tetrazole (8)

To a solution of (6E,10E,14E)-18-bromo-2,6,10,14-tetramethylnonadeca-2,6,10,14-tetraene (7) (75 g, 0.19 mmol, 1.0 eq) in DMF, K2CO3 (65.5 g, 0.47 mol, 2.5 eq) and 1-Phenyl-1H-tetrazole-5-thiol (50.7 g, 0.29 mol, 1.5 eq) is added at 25-30 ° C. The above reaction mixture is heated to 50 °C over a period of 2 h. The resulting reaction mixture is diluted with ethyl acetate (1000 mL).The organic layer is washed with water (2 X 500 mL) and brine (1X500 mL). The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column (5% ethyl acetate in hexanes) to give product 8 as a colourless liquid.
Step 7: Preparation of 1-phenyl-5-[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraene-2-sulfonyl]-1H-1,2,3,4-tetrazole (9)

To a stirring solution of 1-phenyl-5-{[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9, 13,17-tetraen-2-yl]sulfanyl}-1H-1,2,3,4-tetrazole (8) (50 g, 0.1 mol) in methanol, sodium tungstate dihydrate (8.0 g, 0.024 mol, 0.24 eq.) is added at 0-5 °C. The mixture is stirred at same temperature over a period of 10 min. Hydrogen peroxide (102 mL, 1.5 mol, 15 eq.) is then added dropwise at the same temperature. The reaction mixture is allowed to warm to about 25-30 °C and stirred over a period of 12 h. The reaction mixture is quenched with 5% aqueous sodium bicarbonate solution (10 V) and extracted with ethyl acetate (1000 mL).The organic layer is washed with water (2 X 500 mL). The crude product obtained upon evaporation of volatiles is purified through neutral alumina column to give product 9 as a colourless liquid.
Step 8: Preparation of 2-{[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacos a-2,6,10,14,18,22,26-heptaen-1-yl]oxy}oxane (10)

To a cold solution of 1-phenyl-5-[(5E,9E,13E)-6,10,14,18-tetramethylnonadeca-5,9,13,17-tetraene-2-sulfonyl]-1H-1,2,3,4-tetrazole (9) (316.6 g, 0.603 mol, 1.3 eq) in tetrahydrofuran, 1.0 M Lithium bis(trimethylsilyl)amide (LiHMDS) (1071 mL, 1.071 mol, 3.0 eq) is added drop wise at -78° C and stirred for 10 min. To the above reaction mixture (4E,8E)-4,8-dimethyl-10-(oxan-2-yloxy)deca-4,8-dienal (4) (100 g, 0.357 mol, 1.0 eq)) in THF is added over a period of 30 min. The reaction mixture is allowed to stir at same temperate over a period of 1-2 h. The resulting reaction mixture is quenched with aqueous ammonium chloride solution (750 mL) and extracted with ethyl acetate (1500 mL).The organic layer is washed with water (2 X 750 mL).The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles is purified through neutral alumina column (alone hexanes) to give product 10 as a yellow liquid. Compound 10 contains mixture of 2-{[(2E,6E,10Z,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]oxy}oxane (Cis isomer) and 2-{[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-yl]oxy}oxane (Trans isomer). Cis isomer ranging from 0.1% to 60% and Trans isomer ranging from 40% to 99.9%.
Step 9: Preparation of (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2, 6,10,14,18,22,26-heptaen-1-ol (11)
To a stirring solution of 2-{[(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloct acosa-2,6,10,14,18,22,26-heptaen-1-yl]oxy}oxane (10) (15.7 g, 0.027 mol, 1.0 eq.) in methanol (5 V), was added p-Toluenesulfonic acid (681 mg, 2.716 mmol, 0.1 eq.) and heated to 60±5°C and stir the reaction mass for about 6 hours at 60±5°C. The reaction was monitored by TLC. The resulting reaction mixture is diluted with ethyl acetate (157 mL), washed with water (2 X 157 mL) and brine solution (78.5 mL). The separated organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product obtained upon evaporation of volatiles (35 °C) was purified through silica gel (60-120) column (10-20 % ethyl acetate in hexanes) to give product 11 (Formula I) as a Pale yellow syrup. Heptaprenol was crystallized from acetone, heptane, methanol or ethyl acetate, methanol combination. Formula I contains Trans isomer ranging from 95-99.95% and Cis isomer ranging from 0.05% to 5%.
In a similar way of Examples 1, 2, 3 and 4, the compounds of Formula I set out at Table 6 are synthesized.
Thus the novel preparation method of compounds of formula I including Vitamin K2 involving novel intermediates is facile and environmentally benign adding value to the compound. The preparation method helps to serve the needy patients who require the vitamin K2 in an economical way.
It is to be understood that the present invention is susceptible to modifications, changes and adaptations by those skilled in the art. Such modifications, changes, adaptations are intended to be within the scope of the present invention.
,CLAIMS:
1. A process for preparing a compound of Formula I :

Or an isomer or mixture of isomers thereof;
Wherein the said process comprises the step of:
Reacting a compound of Formula II:

With a compound of Formula III:

in the presence of a base and optionally Lewis acid to obtain the Compound of Formula I;
Wherein:
n ranges from 0 to 3;
R1 is selected from the group of compounds having formula -OR4 or compounds selected from:

Wherein,
R4 is selected from protecting group comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl, and Benzoyl group;
P1 and P2 are individually selected from groups comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl, and Benzoyl group;
R7 and R8 is a ketone protecting groups selected from ethylene glycol, propylene glycol, alcohols and thioalcohols including ethanedithiol and propanedithiol;
Wherein,
R2 is selected from the group comprising:

Wherein,
R6 is selected from group comprising H, alkyl, aryl, aralkyl and hetero aryl group;
Wherein,
R3 is selected from group comprising:

Wherein,
R5 is selected from hydrogen, alkyl, alkoxy, aryl, hetero aryl, Cycloalkane and X, where in X is selected from group comprising F, Cl, Br, I, NO2, CF3, and CN;
R6 is selected from group comprising hydrogen, alkyl, aryl, aralkyl and hetero aryl group.

2. The process as claimed in claim 1, wherein the base is selected from Lithium bis(trimethylsilyl)amide, Sodium bis(trimethylsilyl)amide, Potassium bis(trimethylsilyl)amide, n-Butyllithium, Lithium diisopropylamide, Potassium diisopropylamide, Sodium hydride, Potassium hydride and Cesium carbonate.

3. The process as claimed in claim 1, wherein the lewis acid is selected from Cerium(III) chloride, Magnesium chloride, Boron trifluoride etherate, and Titanium isopropoxide.

4. The process as claimed in claim 1, wherein the compound of Formula II is any one of the compound selected from:

Wherein R4, R6, P1 and P2 are defined as above.

5. The process as claimed claim 1, wherein the compound of Formula III is any one of the compound selected from:

6. The process as claimed in claim 1, wherein the compound of Formula I is any one of the compound selected from:

(MK-7)

Wherein R4, R7, R8, P1 and P2 are as defined above.

7. The process as claimed in claim 6, wherein the compound of Formula I is
Or an isomer or a mixture of isomers thereof.

8. A compound of Formula II:

Wherein:
n ranges from 0 to 3;
R1 is selected from the group of compounds having formula -OR4 or compounds selected from:

Wherein,
R4 is selected from protecting group comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl, and Benzoyl group;
P1 and P2 are individually selected from groups comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl, and Benzoyl group;
R7 and R8 is a ketone protecting groups selected from ethylene glycol, propylene glycol, alcohols and thioalcohols including ethanedithiol and propanedithiol;
Wherein,
R2 is selected from the group comprising:

Wherein,
R5 is selected from hydrogen, alkyl, alkoxy, aryl, hetero aryl, Cycloalkane and X, where in X is selected from group comprising F, Cl, Br, I, NO2, CF3, and CN;
R6 is selected from group comprising H, alkyl, aryl, aralkyl and hetero aryl group.

9. The compound as claimed in claim 8, wherein the compound of Formula II is any one of the compound selected from:

wherein,
R4 is selected from protecting group comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, pivalyl and benzoyl group;
R6 is selected from group comprising hydrogen, alkyl, aryl, aralkyl and hetero aryl group;
P1 and P2 are individually selected from groups consisting of hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl and Benzoyl group.

10. A compound of Formula III:

Wherein:
n ranges from 0 to 3;
R3 is selected from group comprising:

Wherein,
R5 is selected from hydrogen, alkyl, alkoxy, aryl, hetero aryl, Cycloalkane and X, where in X is selected from group comprising F, Cl, Br, I, NO2, CF3, and CN;
R6 is selected from group comprising hydrogen, alkyl, aryl, aralkyl and hetero aryl group.

11. The compound as claimed in claim 10, wherein the compound of Formula III is any one of the compound selected from:

12. Compounds of Formula I:

Or an isomer or mixture of isomers thereof;
Wherein:
R1 is selected from the group of compounds having formula -OR4 or compounds selected from :

Wherein,
R4 is selected from protecting group comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl, and Benzoyl group;
P1 and P2 are individually selected from groups comprising hydrogen, alkyl, Tetrahydropyranyl, Methoxymethyl, ethoxyethyl, Benzyloxy methyl, t-Butyl, Allyl, Benzyl, 4-Methoxy benzyl, t-Butyldimethylsilyl, t-Butyldiphenylsilyl, acyl, Pivalyl, and Benzoyl group;
R7 and R8 is a ketone protecting groups selected from ethylene glycol, propylene glycol, alcohols and thioalcohols including ethanedithiol and propanedithiol.

13. The compound as claimed in claim 12, wherein the compound of Formula I is any one of the compound selected from:

14. A pharmaceutical or nutraceutical composition comprising the compounds of Formula I as claimed in claim 13.