Description:RELATED APPLICATION
This application is filed as a Provisional Application with the Indian Patent Office.

FIELD OF INVENTION
The present disclosure relates to an improved process for the regio- and stereospecific synthesis of polyprenyl compounds. More particularly it discloses regio- and stereospecific synthesis of (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14, 18, 22,26 heptane-1-ol which finds use in the synthesis of Vitamin K2-7.

BACKGROUND OF THE INVENTION
Polyprenols denote a family of unsaturated, acyclic, aliphatic alcohols bearing at least four isoprene units linked head-to-tail wherein the hydroxyl group is attached to the head of the chain. The members differ from each other in their chain length and the stereochemistry of their internal isoprene units. Polyprenols are integral components of biological membranes of living cells, and are present either as free alcohols and /or their carboxylic esters. Three types of natural polyprenols are (a) all-trams-polyprenols, (b) ditrans polycis- or tritrans , polycis-prenols, and (c) ditrans, polycis a - saturated prenols. Polyprenols are widely are found in bacteria, plants, yeast and fungi. Umbreit et. al. (J. Bacteriology (1972), 1302-1305) isolated and characterized C5-isoprenyl alcohol and its derivatives from Streptococcus faecalis. Basyuni et. al. (Sys Rev Pharm (2020) 11(7):89-97) analysed the distribution of polyprenyl alcohols in the seed tissues of oil palms using two-dimensional thin layer chromatography.
Polyprenols are reportedly non-toxic, non-mutagenic, non-teratogenic and non-carcinogenic in humans. They exhibit anti-tumour, anti-hepatitis C virus and anti-HIV effects and are used as adjuvants for chemotherapy for leukaemia and radiotherapy. They are also remedy for hypertension, high cholesterol, diabetes, gout, lupus and other immune function disorders and have therefore been widely researched. Substitution of the hydroxyl group has been explored for applications in the development of anti-tumour and anti-anaemia effects, and as anti-psychotic drugs. Prenylacetic esters exhibit anti-ulcer and antithrombotic activities. EP 0 239 729 B1 discloses polyprenyl alcohol-containing injections for enhancing utilization of polyprenyl alcohol in vivo. Larodan in Sweden and Indofine in the US, supply polyprenols. The medicinal product Ropren which exhibits cerebroprotective and hepatoprotective effects, contains a 95% purity concentrate of polyprenols. (Zhang et. al. Fitoterapia 106 (2015) 184- 193).
Solanesol was the first polyprenol to be isolated from tobacco leaves with methanol and ether. It has also been isolated from tobacco, mulberry and from unsaponifiable matter of silkworm faeces. Polyprenols were isolated from a contaminant of cellulose pulp in a paper plant. The isolation, purification, synthesis, structure and function biological activity correlation, and pharmacology of polyprenols and derivatives has been extensively studied and reviewed. Yan et.al. (Phytochem. Rev. (2015)14 (3) 403-417) reviewed resources, derivatives, bioactivities, medicinal applications, and biosynthesis of Solanesol.
While polyprenols are widely distributed in nature, their low content in plants and low yields during isolation and purification leads to high recovery costs.
Muramatsu et. al. (J.Biosci. and Bioengg.106 (3) 263–267 (2008), J. Biosci. and Bioengg.
(108) (1) 52–55, (2009)) described microbial production farnesol and related prenyl alcohols
In view of their diverse applications and importance in the synthesis of isoprenoid quinones of biological importance and limited occurrence in nature, efforts have been made for the synthesis of polyprenols especially all trans polyprenols.
Cheng and Loh (Pure Appl. Chem., 77, (7)1199–1206, 2005.) disclosed asymmetric a-prenylation of various aldehydes to yield corresponding a-prenyl alcohols.
Sato et al (J Chem Soc Perkin I (1981) 761) reported stereo selective synthesis of solanesol and all-trans- decaprenol. Altman et al (J . Am.Chem. Soc., 1972, 94, 3257; Synthesis, 1974, 129) reported the synthesis of all trams-geranyl geraniol.
Masaki et. al. (Tetrahedron Lett. (1978), 4539, J. Chern. Soc., Chern. Comm.,(1979), 855; Tetrahedron Lett., 1978, 5123) discussed the preparation of terminal trans-allylic alcohols from linear isoprenoids.
Turi and Crans (Molecules (2020), 25, 4477-4514) in a review of synthesis of naphthoquinone derivatives disclosed the Diels-Alder reactions between the naphthoquinone and polyprenyl halides for the synthesis of vitamin K.
Synthesis of polyprenyl acetate was reported by Zhou et al. (Chem. Ind. For. Prod. 33 (2013) 53–56).
The synthesis of long chain poly isoprenyl alcohols entails coupling two all-trans polyprenyl
side chains. Although explored by researchers (WO 2011/117324 A2 and WO 2010/034999 A1), Biellmann chemistry doesn’t always ensure the retention of all-trans character. Synthesis of polyprenyl alcohols starting from farnesol adding one prenyl unit at a time, retaining the stereoselectively was described by Coates et. al (Org. Synth. 2007, 84, 43-57). However, it has been recognized that as the number of prenyl units increases, it may not be practical to add one unit at a time since overall yield of the process decreases at each step.
US 9,012,693 disclosed that Biellmann chemistry could be exploited to make polyprenyl compounds. It disclosed a method to synthesize heptaprenol from farnesol.
US patent 9,464,021 B2 (2016) pointed out the loss of stereoselectivity when Biellmann chemistry was used to synthesize higher polyprenols and disclosed polyprenyl side chain bearing 1,3-dithiane terminal group for the synthesis of Vitamin K2.
The patent application 20232100851, “Synthesis of polyprenyl alcohols” disclosed that starting from commercially available building blocks such as isoprene, farnesol, farnesol acetone, geraniol, polyprenyl (phenyl sulfonyl) alcohols bearing 5 to 10 prenyl units can be obtained which can then be desulphonated in the presence of a catalyst, a reducing agent and a mixture of solvent and a co-solvent to yield polyprenyl alcohols.
The synthesis 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 according to the method of the patent application 20232100851 involved incorporation of phenyl sulphonyl group and its removal by reduction in the presence of super hydride followed by incorporation of a second phenyl sulphonyl group, reaction with chloro isoprenyl acetate followed by hydrolysis and removal of the second phenyl sulphonyl group by a second reduction in the presence of the super hydride.

SUMMARY OF THE INVENTION
It has now been surprisingly found that (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-hepta methyloctacosa-2,6, 10,14,18,22,26 heptaen-1-ol can be synthesized by incorporating the second phenyl sulphonyl group into 1-((2E,6E,10E,14E,18E)-1-chloro-3,7,11,15,19,23-hexamethyl tetracosa-2,6,10,14,18,22-hexaen-9-ylsulfonyl)benzene by reacting with sodium benzene sulphinate, in DMF , reacting 1-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl
-1-(phenylsulfonyl) tetracosa-2,6,10,14,18,22-hexaen-9-ylsulfonyl) benzene obtained with 4-chloro prenyl acetate followed by hydrolysis and removal of both phenyl sulphonyl groups by reduction in a single step in the presence of super hydride.

The improved synthesis method has the advantage that it eliminates one reaction step of reduction in the presence of super hydride before the introduction of the second phenyl sulphonyl group, and the need for the purification of the compound of the intermediate step.
The improved process has the advantage of 1) reducing the number of reaction steps, 2) eliminating the need for the purification of the reaction intermediate 3) higher product yield and improved process economy.
In an embodiment of the disclosure 1-((2E,6E,10E,14E,18E)-1-chloro-3,7,11,15,19,23-hexamethyltetracosa -2,6,10,14,18,22-hexaen-9-ylsulfonyl)benzene is reacted with Sodium benzene sulphinate in dimethyl formamide solvent to yield 1-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl-1-(phenylsulfonyl)tetracosa-2,6,10,14,18,22-hexaen-9ylsulfonyl) benzene .

In an embodiment of the disclosure 1-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl-1-(phenylsulfonyl)tetracosa-2,6,10,14,18,22-hexaen-9ylsulfonyl) benzene is reacted with 4- chloro prenyl acetate in the presence of Potassium t-Butoxide TBAB and 18-Crown-6 to obtain (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl-5,13-bis(phenylsulfonyl) octacosa - 2,6,10,14,18,22,26-heptaenyl acetate.

In an embodiment of the disclosure (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl-5,13-bis(phenylsulfonyl) octacosa - 2,6,10,14,18,22,26-heptaenyl acetate is hydrolysed in the presence of potassium hydroxide and methanol to (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl-5,13-bis(phenylsulfonyl) octacosa - 2,6,10,14,18,22,26-heptaen-1-ol.

In an embodiment of the disclosure both phenyl sulphonyl groups in 2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl-5,13-bis(phenylsulfonyl)octacosa-2,6,10,14,18,22,26-heptaen-1-ol are reduced in the presence of super hydride and tetrahydrofuran to yield (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyloctacosa-2,6,10,14,18,22,26-heptaen-1-ol.

In an embodiment of the disclosure is disclosed a novel compound of the formula

1-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl-1-(phenyl sulfonyl) tetracosa
-2,6,10,14,18,22-hexaen-9-ylsulfonyl)benzene
In an embodiment of the disclosure is disclosed a novel compound of the formula

(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl -5,13-bis(phenyl
sulfonyl )octacosa-2,6,10,14,18,22,26-heptaen-1-ol
DETAILED DESCRIPTION OF THE INVENTION
The invention is now described by examples which are representative and do not limit the scope of the invention.
2,6,10,14,18,22-Tetracosahexaen-1-ol, 3,7,11,15,19,23-hexamethyl-9-(phenylsulfonyl)-, (2E, 6E,10E,14E,18E)- C30-SO2Ph-OH was synthesized as disclosed in the patent application 20232100851 “Synthesis of polyprenyl alcohols” filed with the Indian Patent Office.
Example-1
Preparation of 1-((2E,6E,10E,14E,18E)-1-chloro-3,7,11,15,19,23-hexamethyl tetracosa-2,6,10,14,18,22-hexaen-9-ylsulfonyl) benzene (C30-SO2Ph-Cl).
460 ml N, N-dimethyl formamide was cooled to -5°C. 36.33 g (0.265 mol) phosphorus trichloride was slowly added over 10-15 min at -5°C. The reaction mass was stirred for additional 30 mins maintaining the temperature constant. 200 g (0.353 mol) C30-SO2Ph-OH dissolved in 240 ml N, N-dimethyl formamide was added to the above solution at 5-10°C over 20 mins. Reaction mass was stirred for additional 2 hrs at the same temperature and then quenched with sodium bicarbonate to adjust pH to 8 and extracted with Ethyl acetate. Organic layer was washed with water followed by brine and dried over anhydrous sodium sulphate. Ethyl acetate was distilled under vacuum to yield 215 g C30-SO2Ph-Cl as dark red coloured oil with 95% yield.
Example-2
Preparation of 1-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl -1- (phenyl sulfonyl) tetracosa-2,6,10,14,18,22-hexaen-9-ylsulfonyl) benzene : C30-(SO2Ph)2
79.6 g (0.485 mol) sodium benzene sulphinate in 473 ml N, N-dimethyl formamide was cooled to 10-15°C. 215 g (0.367 mol) C30-SO2Ph-Cl dissolved in 258 ml of N, N-dimethyl formamide, was added to the above solution over 10 mins at 10-15°C. Reaction mass was brought to room temperature and stirred for 15 hrs. It was then quenched with distilled water and extracted in Ethyl acetate. Organic layer was washed with water followed by brine and dried over anhydrous sodium sulphate. Ethyl acetate was distilled under vacuum to yield 232 g crude C30-(SO2Ph)2 as dark red colour oil with 84% yield. Crude product was purified by column chromatography in mixture of hexane and ethyl acetate to get pure product and characterized.
1H NMR and 13C NMR characterization of C30-(SO2Ph)2
1H NMR (400 MHz, CDCl3) d 7.80 (M 4H), 7.62 (M 2H), 7.54 (M 4H), 5.10 (M 5H), 4.90 (D 1H), 3.90 (M 1H), 3.80 (D 1H), 2.89 (D 1H), 2.26 (T 1H), 1.95-2.05 (M 16H), 1.66 (S 3H), 1.58 (S 9H), 1.50 (S 3H), 1.28 (S 3H), 1.14 (S 3H).
13C NMR (400 MHz, CDCI3) d 146.02, 145.13, 138.65, 137.88, 135.61, 133.59, 133.40, 131.22, 130.64, 129.22, 128.99, 128.71, 128.45, 127.29, 124.35, 124.05, 123.43, 117.20, 110.42, 63.41, 60.37, 55.99, 39.73, 39.28, 29.68, 26.73, 26.40, 25.88, 17.69, 16.35, 16.15, 16.02, 15.99 and 14.20.
Example-3
Preparation of (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl-5,13-bis(phenyl sulfonyl)octacosa-2,6,10,14,18,22,26-heptaenyl acetate (C35-(SO2Ph)2-OAc).
340 g (0.492 mol) C30-(SO2Ph)2 was dissolved in 952 ml tetrahydrofuran under inert atmosphere. 124 g (0.762 mol) 4-chloroprenyl acetate was added to it. The reaction mass was cooled to 0 to -5°C. 13.07 g. tetra butyl ammonium bromide and 2.13 g 18-Crown-6 were added. The reaction mass was stirred for 5 minutes maintaining the temperature constant. 82.65 g (0.736 mol) potassium tert-butoxide in 680 ml tetrahydrofuran were added to the above solution over 10 minutes and the reaction mass was stirred for 2 hrs maintaining the temperature constant and the reaction was continued overnight. The reaction mass was quenched into 20% ammonium chloride soln and pH was adjusted to 5-6 using 1 M HCl. Tetrahydrofuran was distilled off under vacuum and the residue was extracted in ethyl acetate. Ethyl acetate layer was washed with water followed by brine and dried over anhydrous sodium sulphate. Ethyl acetate was distilled under vacuum to yield 383 g crude C35-(SO2Ph)2-OAc as oil with 75% yield.
Example-4
Preparation of (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl-5,13-bis(phenyl sulfonyl)octacosa-2,6,10,14,18,22,26-heptaen-1-ol : C35-(SO2Ph)2-OH.
18.9 g (0.028 mol) C35-(SO2Ph)2-OAc was dissolved in 57 ml methanol. The contents were cooled to 0 to 5°C. 0.47 g (0.0084 mol) potassium hydroxide dissolved in 2.35 ml water was slowly added over 5 mins. and the reaction mass was stirred overnight. Methanol was distilled off and the residue was extracted in ethyl acetate. The reaction mass was quenched into water and acidified with 1 M HCl. Ethyl acetate layer was washed with water followed by brine and dried over anhydrous sodium sulphate. Ethyl acetate was distilled off under vacuum to yield 17.6 g crude C35-(SO2Ph)2-OH as oil. Crude product was purified by column chromatography to yield 10.4 g pure C35-(SO2Ph)2-OH as yellow oil with 90% yield.
1H NMR and 13C NMR characterization of C35-(SO2Ph)2-OH
1H NMR (400 MHz, CDCl3) d 7.80 (T 4H), 7.57 (T 2H), 7.48 (T 4H), 5.35 (T 1H), 5.05 (M 4H), 4.85 (D 2H), 4.03 (M 3H), 3.88 (M 2H), 2.85 (D 2H), 2.24 (M 4H), 1.84-2.06 (M 18H), 1.63 (S 3H), 1.57 (S 12H), 1.48 (S 3H), 1.20 (S 3H).
13C NMR (400 MHz, CDCI3) d 145.19, 137.76, 137.69, 135.56, 134.97, 133.51, 133.43, 133.29, 131.16, 129.15, 128.74, 128.70, 127.57, 127.55, 127.42, 127.35, 124.33, 124.04, 123.42, 117.17, 117.13, 117.09, 63.45, 63.41, 63.09, 60.36, 58.92, 39.71, 39.67, 39.65, 39.21, 37.25, 37.18, 26.70, 26.55, 26.38, 26.09, 25.69, 20.99, 17.67, 16.31, 16.23, 16.14, 15.99, 15.89, 15.83 and 14.16.
Example-5
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 (C35-OH).
100 g (0.129 mol) of C35-(SO2Ph)2-OH was dissolved in 1000 ml of Tetrahydrofuran under nitrogen atmosphere and 400 mg of (1,3-Bis (diphenyl phosphino) propane) palladium II chloride was added. The reaction mass was cooled to -5°C. 95.72 g (0.903 mol) super hydride solution was added in 60 minutes. Reaction mass was stirred at room temperature for 10-12 hrs. After completion of reaction, it was quenched by dropwise addition of methanol followed by acetic acid and stirred for 1 hr, THF was distilled off under vacuum and the residue was extracted twice with ethyl acetate. Ethyl acetate was washed off with water followed by brine and the residue was dried over anhydrous sodium sulphate. Ethyl acetate was distilled under vacuum to give 78 gm of crude C35-OH as oil with 84.47% yield.
Crude product was purified by column chromatography in a mixture of hexane and ethyl acetate to recover pure product . Purity 90%
1H NMR and 13C NMR characterisation of Heptaprenol (C35-OH).
1H NMR (400 MHz, CDCl3) d 5.45 (T 1H), 5.11 (M 6H), 4.17 (D 2H), 1.98-2.14 (M 24H), 1.70 (S 6H), 1.62 (S 18H), 1.30 (Br 1H).
13C NMR (400 MHz, CDCI3) d 139.57, 135.32, 134.93, 134.85, 134.83, 131.15, 124.38, 124.23, 124.14, 123.74, 123.36, 59.28, 39.70, 39.54, 26.73, 26.64, 26.63, 26.30, 25.66, 17.64, 16.24, 15.98.
, Claims:We Claim:
1. A process for the synthesis of (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-hepta
methyl octacosa-2,6,10,14,18,22,26-heptaen-1-ol comprising
a) reacting2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl-9-(phenylsulfonyl)
tetracosa -2,6,10,14,18,22-hexaen-1-ol with PCl3 I dimethyl formamide and hexane to
obtain1-((2E,6E,10E,14E,18E)-1-chloro-3,7,11,15,19,23-hexamethyltetracosa-2,6,10,
14,18,22- hexaen-9-ylsulfonyl)benzene

b) reacting 1- (2E,6E,10E,14E,18E)-1-chloro-3,7,11,15,19,23-hexamethyltetracosa-
2,6,10,14,18,22- hexaen-9-ylsulfonyl)benzene with sodium benzene sulphinate in
DMF to yield1-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl-1-
(phenylsulfonyl) tetracosa -2,6,10,14,18,22-hexaen-9-ylsulfonyl)benzene

c) reacting 1-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl-1-(phenylsulfonyl)
tetracosa -2,6,10,14,18,22-hexaen-9-ylsulfonyl)benzene with 4- chloro prenyl acetate
in the presence of Potassium t-Butoxide TBAB /and 18-Crown-6 in THF to yield
(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl -5,13-bis(phenyl sulfonyl)
octacosa -2,6,10,14,18,22,26-heptaenyl acetate

d) hydrolysing(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl-5,13-
bis(phenyl sulfony octacosa -2,6,10,14,18,22,26-heptaenyl acetate tin the presence of
KOH and methanol to (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl
-5,13 -bis(phenylsulfonyl)octacosa-2,6,10,14,18,22,26-heptaen-1-ol

e) reducing (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl -5,13 -bis
(phenylsulfonyl)octacosa-2,6,10,14,18,22,26-heptaen-1-ol in the presence of super
hydride in THF to (2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27- heptamethyl
octacosa-2,6,10,14,18,22,26-heptaen-1-ol.

2. A compound of the formula

1-((2E,6E,10E,14E,18E)-3,7,11,15,19,23-hexamethyl-1-(phenyl sulfonyl) tetracosa
-2,6,10,14,18,22-hexaen-9-yl sulfonyl) benzene
3. A compound of the formula

(2E,6E,10E,14E,18E,22E)-3,7,11,15,19,23,27-heptamethyl -5,13-bis(phenyl
sulfonyl) octacosa-2,6,10,14,18,22,26-heptaen-1-ol.