Method for synthesizing vitamin K2

Abstract

The present disclosure relates to the synthesis of vitamin K2 bearing different isoprenyl side chains. The synthesis comprises reacting a phenylsulfone of a tert-butyldimethylsilyl (TBDMS) protected monoisoprenyl menadione with an isoprenyl halide bearing a different isoprenyl unit in the presence of a phase transfer catalyst followed by reductive desulfonation to produce a TBDMS ether of vitamin K2. The TBDMS ether is then oxidized in the presence of chromium trioxide and periodic acid to produce the corresponding vitamin K2.

Description

[0001] Related Applications

[0002] This application is related to and claims priority from Indian Provisional Application No. 202221039642, and the Indian Provisional Application is incorporated herein in its entirety. Technical Field

[0003] The present disclosure relates to the synthesis of vitamin K2 with different prenyl side chains. Background Art

[0004] Vitamin K2 is a 2-methyl-1,4-naphthoquinone derivative and represents a series of molecules containing a naphthoquinone structure and an isoprenyl chain of varying length attached to the 3-position. Their occurrence, structure, physicochemical, pharmacological properties and actions are well documented in the literature. Despite the presence of vitamin K2 in nature, significant efforts to isolate these compounds from natural sources continue, and these compounds have also been synthesized by synthetic chemical routes as well as biotechnological routes. Chemical synthesis allows the preparation of specific members of the vitamin K2 series of interest with high selectivity, rather than producing a mixture of different vitamin K2s produced by biotechnological routes and isolating the specific member of interest from the mixture. Among the various members of the vitamin K2 series, vitamin K2-7 has significant commercial interest, although other members of the series and their derivatives have also attracted significant interest following the publication by Suhara et al. (Biorganic Med. Chem Lett. [Journal of Bioorganic Medicinal Chemistry] 17 (2007) 1622-1625), which indicates the development of new drugs based on alkyl-based side chain modifications. It also reports various syntheses of menaquinone analogs in which the terminal methyl group was converted to a hydroxyl, aldehyde, or acid group.

[0005] There is also interest in exploring vitamin K2-type compounds for the inhibition of osteoporosis, as potential anticancer agents, and for the control of cardiovascular activity.

[0006] Isler et al. Helv. Chim. Acta [Swiss Chemical Journal] 1958, 41, 786-807 reported the first chemical synthesis of vitamin K2-7.

[0007] In the case of compounds of the vitamin K2 group, the "lack of biological activity" of the cis form was determined in the journal J. Nutrition 105: 1519-1524, 1975. According to O. Isler et al. Angew. Chem. 71. (1959) No. 1, pp. 13-15, in the case of vitamins K1 and K2, the mono-cis compounds (the cis double bond is adjacent to the naphthoquinone ring system) show significantly lower activity than the all-trans forms.

[0008] US 4089873 (1978) describes the preparation of vitamin K2 using a copper-mediated coupling reaction. US 4199531 (1980) describes the preparation of quinones using arylsulfonyl / halogen coupling chemistry. The synthesis of side chains of menadione derivatives having 1 to n terminal activated prenyl units at the C-3 position is accomplished by stereo- and regio-selective alkylation thereof with activated side chain precursors consisting of prenyl units.

[0009] Naruta, J Org. Chem [Journal of Organic Chemistry] 1980, 45, 4097-4104 describes the synthesis of vitamin K2 analogs using trialkylallyl stannanes to attach preformed side chains to naphthoquinone groups. U.S. Pat. No. 4,229,356 (1980) discloses the reaction of 2-methyl 1,4-hydronaphthoquinone with a compound selected from phytyl halide, isophytyl halide, geranyl halide, farnesyl halide, geranyl, geranyl halide (preferably bromide) in a heterogeneous medium containing quaternary ammonium ions or tetraalkylphosphonium ions, followed by oxidation of the resulting hydrogen precursor to produce the corresponding vitamin K2. According to the inventors of U.S. Pat. No. 4,603,223 (1986), the then known methods for making vitamin K2 and related compounds starting from hydroquinone or monoacylated hydroquinone were unsatisfactory because of the relatively large number of reaction steps involved. Methods starting from menadione itself or its readily available derivatives were unknown. The patent describes the synthesis of substituted 2-methylquinone / 2-methylmenaquinone cyclopentadiene adducts which are then prenylated at the 3-position and then the desired vitamin K derivative is recovered by subjecting the prenylated derivative of the menaquinone cyclopentadiene adduct to a Retro Diels Alder reaction wherein the stereospecificity of the prenyl side chain is maintained.

[0010] Min et al. (J. Org. Chem. 2003, 68, 7925-7927) describe the Friedel-Crafts allylation of isoprenyl groups stabilized by sulfone moieties. The reference further relates to the synthesis of ubiquinone and menaquinone from the resulting protected p-hydroquinone containing a C5 trans-allyl sulfone moiety.

[0011] Vitamin K2 with different numbers of isoprenoid units is prepared, and it is a challenging task to maintain the stereospecificity of the side chain. A method for maintaining selectivity by expanding one isoprenoid unit at a time has been developed (Coates et al. Org. Synth. [Organic Synthesis] 2007, 84, 43-57). However, each time an isoprenoid unit is added, both the yield and the stereospecificity are reduced. Kumada and Suzuki chemistry have been used to connect the isoprenyl side chain composed of the desired number of isoprenyl units to the naphthoquinone ring. The isoprenyl side chain composed of the desired number of isoprenyl units can be obtained using Biellmann chemistry. Using this method, vitamin K2-7 can be synthesized by any of the following methods. 1) The heptenyl chain is attached directly to the menadione molecule, a "0+7" strategy; 2) shorter chain fragments are attached to monoprenyl derivatives of menadione, a "1+n+m" strategy; and 3) the hexaprenyl chain is attached to monoprenyl derivatives of menadione, a "1+6" strategy. Other members of the vitamin K2 family can be synthesized similarly.

[0012] WO 2010 / 035000 A1 (2010) discloses the synthesis of vitamin K2 according to the "0+7 strategy" based on the attachment of a polyprenyl ring to a protected activated menadione derivative under Grignard / Kumada or Suzuki conditions.

[0013] WO 2011117324 A2 (2011) reports a new procedure for the synthesis of polyphenols, wherein vitamin K2 is produced when reacted with appropriate menaquinone derivatives by Kumada synthesis or Suzuki coupling. Pentaprenols are synthesized from diprenoyl-alcohol bromides, which have protected acetyl and phenylsulfonyl triprenyl groups. After each step of the process: alkylation, desulfonylation and removal of hydroxyl protecting groups, purification of the product by silica gel flash chromatography are required. The polyprenoyl halides obtained according to this procedure are used to synthesize vitamin K2-7 under Grignard / Kumada or Suzuki conditions according to the "0+7" or "2+5" strategy.

[0014] Chinese patent CN 102351677 A (2014) describes the catalytic hydrogenation of 2-methyl-1,4-naphthoquinone to 2-methyl-1,4-hydronaphthoquinone, followed by Friedel-Crafts alkylation with geraniol and oxidation of the alkylated product to produce vitamin K2.

[0015] U.S. Patent 9,012,693 (2015) describes a strategy for the synthesis of vitamin K2-7 and other menadiones using Kumada or Suzuki chemistry to attach side chains to the naphthoquinone ring, which can be further manipulated using Biermann chemistry to produce the desired vitamin K2. In both cases, alkyl-protected menadiones can be used. The reaction is illustrated using methyl-protected menadiones. This route to the synthesis of vitamin K2 requires polyisoprenyl compounds containing the necessary isoprenyl units, which need to be synthesized if they are not commercially available.

[0016] Biermann chemistry provides the synthesis of phenylthio or phenylsulfonyl substituted compounds and the reaction with electrophilic reagents (such as halides) in the presence of bases. Two or more isoprenoid chains can be coupled to produce new isoprenoid chains containing the desired number of isoprenyl units using double Biermann chemistry. However, chain extension reactions require the use of very low temperatures. In the presence of ceric ammonium nitrate (CAN), protected naphthoquinones are oxidized to naphthoquinones. Vitamin K2-7 can also be obtained by using Kumada coupling twice.

[0017] EP 2346806 B1 (2016) describes the synthesis of novel intermediate compounds and compounds that form part of vitamin K2. The patent describes the use of Biermann chemistry to synthesize precursors of -E polyisoprene side chains. This involves the formation of phenylthio or phenylsulfonyl substituted compounds and the reaction of these sulfur compounds with electrophilic reagents (such as halides) in the presence of a base. The polyisoprene units are reacted with protected menadione derivatives prepared using Kumada or Suzuki coupling reactions. Phenylthio or phenylsulfonyl derivatives are reduced using lithium metal or metal hydrides. The product is then deprotected and oxidized using ammonium cerium nitrate to obtain the desired vitamin K2. The strategy used in this article to synthesize vitamin K2-7 is a 2+5 strategy, which the patentee claims produces better stereochemistry and produces solid crystalline vitamin K2-7. Kumada or Suzuki coupling reactions produce vitamin K2 containing only short isoprenyl chains. Vitamin K2 with increased chain length can be prepared by using double Biermann coupling or triple Biermann coupling. Another benefit according to the patentee is that the selenium dioxide reduction step used to form the naphthoquinone reactant occurs more readily on naphthoquinones carrying 2 isoprenoid units than on longer chain molecules. The synthesis of these compounds involves multiple synthesis steps and the use of very low temperatures.

[0018] U.S. Patent 9,464,021 (2016) describes a method for the regio- and stereospecific synthesis of polyprenylated quinone derivatives (e.g., vitamin K1, K2, and ubiquinone) using dithioacetals, particularly 1,3-dithianes.

[0019] U.S. Patent 9,828,323 (2017) describes a method for preparing vitamin K2-7, which involves a) reacting an α-sulfonyl carbon anion generated in situ from the phenyl sulfone of a monoisoprenyl derivative of an alkyl-protected menadione with a hexaisoprenyl halide in the presence of a strong organometallic base to produce a phenylsulfonyl derivative of menadione, b) removing the phenylsulfonyl group from the menadione derivative by reductive elimination to produce an alkyl-protected menadione containing a heptaisoprenyl unit, and c) subjecting the alkyl menadione containing a heptaisoprenyl unit to oxidative deetherification to produce vitamin K 2-7.

[0020] More specifically, the phenylsulfone of the monoisoprenyl derivative of ethyl-protected menadione is obtained by reacting diethoxymenadione with chloroisoprenyl phenylsulfone at 0°C in the presence of SnCl4. It is reacted with 12-phenylsulfonylhexaprenyl bromide in the presence of sodium bis(trimethylsilyl)amide (NaHMDS) at -20°C to obtain phenylsulfonylheptanoprenyldimethoxymenadione, and then reacted with [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II) and lithium triethylborohydride at 0°C to produce heptanoprenyldiethoxymenadione. Treatment with ammonium cerium nitrate produces vitamin K2-7. 12-phenylsulfonylhexaprenyl bromide is obtained by brominating the corresponding alcohol using PBr3 at 0°C. The alcohol is in turn obtained by a multistep synthesis starting from farnesyl acetate, which involves reactions at very low temperatures.

[0021] EP 2917171 (2018) describes the synthesis of vitamin K2-7 using a 1+6 strategy. The patent describes the synthesis of synthon A as an ethoxy-protected monoprenyl menadione with a terminal phenylsulfonyl functional group on the allyl moiety attached to the C-3 position. Synthon B is a hexaprenyl halide containing a phenylsulfonyl group -SO2Ph. The coupling of synthons A and B in an alkylation reaction produces a vitamin K2 derivative with a phenylsulfonyl group in the heptenyl chain and a hydroxyl group protected in ether form. Vitamin K2-7 is obtained after removal of the phenylsulfonyl group, deetherification and oxidation.

[0022] U.S. Patent No. 10,472,314 (2019) claims a method for preparing vitamin K2-7, the method comprising:

[0023]

[0024] wherein R is an alkyl group; conversion to vitamin K2-7: wherein the conversion is achieved using ceric ammonium nitrate.

[0025] EP 3 018 116 (2020) claims the following compounds:

[0026]

[0027] Wherein R is ethyl, i.e., menadione is protected by an ethyl group. This compound is then oxidized using cerium ammonium nitrate to produce vitamin K2-7.

[0028] In view of the stability issues associated with vitamin K2-7, efforts have been made to synthesize prodrugs of vitamin K2-7. US 9,512,153 B2 (2016) and US 10,159,687 B2 (2018) describe the conversion of diketones of vitamin K2 into mono- or di-substituted esters, which are converted into vitamin K2-7 in vivo. Summary of the invention

[0029] A detailed study of the prior art reveals that more emphasis is being placed on new chemical routes for the synthesis of vitamin K2, especially vitamin K2-7, which will be in the all-trans form, which involve a minimum number of steps, use readily available starting materials, avoid extreme reaction conditions, maximize yields and minimize impurities. The inventors of the present disclosure have discovered that vitamin K2 can be obtained by reacting the phenyl sulfone of a monoisoprenyl derivative of TBDMS-protected menadione with an isoprenyl halide containing a different isoprenyl unit in the presence of a phase transfer catalyst and potassium tert-butoxide at -5°C to 0°C, followed by reductive desulfonation to produce TBDMS-protected vitamin K2, and subsequent oxidation in the presence of chromium trioxide and periodic acid to produce vitamin K2. Individual members of the family can be obtained by selecting the corresponding isoprenyl halide.

[0030] According to an embodiment of the present invention, the phenylsulfone of the mono-isoprenyl derivative of menadione protected by TBDMS is reacted with an isoprenyl halide containing different isoprenyl units in the presence of a phase transfer catalyst and a base (such as potassium tert-butoxide). According to an embodiment of the present invention, the number of isoprenyl units in the isoprenyl halide varies from 1 to 8.

[0031] According to an embodiment of the present invention, the molar ratio of phenyl sulfone to prenyl halide of the TBDMS-protected monoprenyl derivative of menadione is in the range of 1:1.25 to 1:1.33.

[0032] According to an embodiment of the present invention, the prenyl halide is a chloride.

[0033] According to an embodiment of the present invention, the prenyl halide is a bromide.

[0034] According to an embodiment of the present invention, the reaction between the phenyl sulfone of the mono-isoprenyl derivative of menadione protected by TBDMS and the isoprenyl halide is carried out in a temperature range of -5°C to 0°C.

[0035] According to an embodiment of the present invention, the phase transfer catalyst comprises quaternary alkylammonium halide and crown ether.

[0036] According to an embodiment of the present invention, the phase transfer catalyst comprises tetrabutylammonium bromide (TBAB) and 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown 6). According to an embodiment of the present invention, the molar ratio of TBAB to 18-crown 6 varies in the range of 0.5 to 20.

[0037] According to an embodiment of the present invention, the reaction time varies between 0.25 hours and 6 hours.

[0038] According to an embodiment of the present invention, the sulfophenyl isoprenyl derivative of TBDMS-protected menadione is reduced in the presence of (1,3-bis(diphenylphosphino)propane)palladium II chloride and lithium triethylborohydride to produce TBDMS-protected vitamin K2. According to an embodiment of the present invention, TBDMS-protected vitamin K2 is oxidized in the presence of chromium trioxide and periodic acid to produce vitamin K2.

[0039] According to an embodiment of the present invention, the molar ratio of periodic acid to TBDMS vitamin K2-SO2Ph is in the range of 2:1 to 4:1.

[0040] According to an embodiment of the present invention, the ratio of chromium trioxide to TBDMS vitamin K2-SO2Ph is in the range of 0.5 wt.% to 2 wt.%.

[0041] According to an embodiment of the present invention, the TBDMS ether of vitamin K2SO2Ph is oxidized to the corresponding isoprene sulfone of menadione.

[0042] According to an embodiment of the present invention, the oxidation is performed at a temperature ranging from -5°C to 0°C. DETAILED DESCRIPTION

[0043] Among the various methods for synthesizing vitamin K2, the Kumada and Suzuki coupling of alkyl-protected menadiones with isoprenyl derivatives containing the desired number of isoprenyl units as described in EP 2346806 B1 (2016) and EP 3018116 B1 (2020) are the most recent methods. The latter disclosure states that "Kumada or Suzuki coupling reactions can thus only produce relatively short side chains, which can then be built up to form compounds containing longer side chains. To complete the synthesis of longer-chain menadiones, Kumada, Suzuki or any other chemical method can further be used." And it seems that the choice of protecting group significantly affects these reactions.

[0044] US Patent 9828323 (2017) describes a process for preparing vitamin K 2-7, which involves reacting an α-sulfonyl carbanion generated in situ from the phenyl sulfone of a monoisoprenyl derivative of an alkyl-protected menadione hydroquinone with a hexaprenyl halide in the presence of a strong organometallic base to produce a phenylsulfonyl derivative of menadione hydroquinone. The phenyl sulfone of the monoisoprenyl derivative of an ethyl-protected menadione hydroquinone is obtained by reacting diethoxymenadione hydroquinone with chloroisoprenyl phenyl sulfone at 0°C in the presence of SnCl4. It is reacted with 12-phenylsulfonylhexaprenyl bromide in the presence of sodium bis(trimethylsilyl)amide (NaHMDS) at -20°C to obtain phenylsulfonylheptanoprenyldiethoxymenadione, and then reacted with [1,2-bis(diphenylphosphino)ethane]dichloropalladium(II) and lithium triethylborohydride at 0°C to produce heptanoprenyldiethoxymenadione. Treatment with cerium ammonium nitrate produces vitamin K2-7.

[0045] The present inventors surprisingly discovered that the reaction between the phenylsulfone of the mono-isoprenyl derivative of TBDMS-protected menadione and the hexa-isoprenyl halide can be carried out more efficiently in the presence of a two-phase transfer catalyst, namely tetrabutylammonium bromide (TBAB) and 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown 6), to produce the phenylsulfonyl derivative of menadione. Removal of the phenylsulfonyl group from the menadione derivative by reductive elimination produces a TBDMS-protected menadione containing a heptenyl unit, which is oxidatively deetherified in the presence of chromium trioxide and periodic acid to produce vitamin K2-7. Other members of the vitamin K2 family can be obtained by appropriately selecting the isoprenyl halide.

[0046] The present invention is illustrated by the following examples, which are purely illustrative in nature and do not limit the scope of the invention in any way.

[0047] Example 1: tert-butyldimethylsilyl (TBDMS) ether of menadione: TBDMS-menadione: (C23 H 38 Synthesis of O2Si2)(402.72)

[0048]

[0049] 50g (0.29mol) of menadione is dissolved in 666ml of methylene dichloride, and 151.46g (0.869mol) of sodium dithionite dissolved in 500ml of water is added. Content was stirred at room temperature for 90 minutes. Reaction mass is filtered, separate each layer and resistates is dissolved in ethyl acetate and mixed with methylene dichloride layer. The organic layer merged is washed with water, subsequently carried out brine washing and dried over sodium sulfate. Stripping solvent is to reclaim menadione (50g).

[0050] 50g (0.287mol) menadione is dissolved in 500ml tetrahydrofuran (THF), and 173.24g (1.14mol) tert-butyldimethylsilyl chloride (TBDMS-C1), 145.20g (1.43mol) triethylamine, 4g TBAB catalyst and 4g 4-dimethylaminopyridine are added at room temperature. The reaction mass is kept overnight under agitation at room temperature. The reaction is monitored by thin layer chromatography (TLC). After the reaction is completed, the reaction mass is quenched in 500ml ice-cold water, and the pH is adjusted to 7 with 1M HCl. Tetrahydrofuran is distilled out and the residue is extracted with ethyl acetate. Separate the layers. The organic layer is washed with water, then washed with brine and dried over sodium sulfate. Solvent and isolated product are distilled out. Reclaim the menadione (123g) protected by TBDMS.

[0051] TBDMS-menadione was purified by flash chromatography. The yield of the purified product was 70%.

[0052] 1 HNMR(DMSO): 8.12(dd)1H; 8.05(dd)1H; 7.45(m)2H; 6.71(s)1H; 1.15(D)18H; 0.93(s)3H, 0.31(s)6H, 0.21(s)6H. 13 CMR (CDCl3): 145.62, 142.55, 129.06, 127.39, 125.15, 124.31, 122.74, 122.63, 122.51, 115.98, 77.39, 77.07, 76.75, 26.25, 26.03, 25.81, 25.76, 18.78, 18.50, 17.80, -2.83, -3.12, -4.15. Mass: 403.0 (m+1).

[0053] Example 2

[0054] TBDMS-Vitamin-K2-3: (C 38 H 62 Synthesis of O2Si2

[0055] 0.5g magnesium was activated by adding a little iodine and 4ml bromoethane in ether (6ml). At 0°C-5°C, in 20-25min, a bromo derivative of the TBDMS ether of 10g (0.0207mol) menadione dissolved in 30ml tetrahydrofuran was added to this activated magnesium. Stirring was continued at room temperature for 1 hour. The reaction mass was cooled to 0°C-5°C, and then 10ml tetrahydrofuran was added, followed by addition of 3.27g (0.0227mol) cuprous bromide in batches in 10-15min. The reaction mass was kept at room temperature for 1 hour. It was cooled to 0°C-5°C, and then 4.98g (0.0207mol) farnesyl chloride dissolved in 30ml tetrahydrofuran was added. The reaction mass was kept at room temperature overnight. The reaction was monitored by TLC. However, the reaction did not proceed.

[0056] Example 3

[0057] TBDMS-Vitamin-K2-1-SO2Ph: (C 34 H 50 Synthesis of O4Si2)(611.01)

[0058]

[0059] 40.27g (0.1mol) TBDMS-menadione is dissolved in 200ml dichloromethane and 21.36g (0.12mol) N-bromosuccinimide (NBS) is added. The reaction mass is stirred for 1-2 hours. After the reaction is completed, the unreacted NBS is washed with sodium thiosulfate solution, then the dichloromethane aqueous layer is extracted and then dried over sodium sulfate. The solvent is stripped to produce the bromo derivative of TBDMS menadione, with a productive rate of 80%.

[0060] 2.88g (0.12mol) of activated magnesium chips are placed in 20ml of tetrahydrofuran and cooled to 5°C-10°C, then 48.27g (0.1mol) of the bromo derivative of TBDMS menadione dissolved in tetrahydrofuran (124ml) are added at the same temperature. The reaction mass is stirred for 1 hour, followed by addition of 51ml of tetrahydrofuran and 15.8g (0.11mol) of cuprous bromide in batches, and kept for 1 hour. 24.4g (0.1mol) of chloroisoprene sulfonate dissolved in 90ml of tetrahydrofuran is added dropwise within 1 hour. After the reaction is complete, the reaction mass is filtered and quenched with 25% ammonium chloride solution. Tetrahydrofuran is recovered and the residue is extracted with dichloromethane. The organic layer is washed twice with water, then washed with brine, and dried over anhydrous sodium sulfate. Dichloromethane is distilled under vacuum to produce 60g of crude TBDMS-vitamin K2-1-SO2Ph. The product was purified by column chromatography in a mixture of hexane and ethyl acetate to yield 42.7 g of TBDMS-vitamin-K2-1-SO2Ph as an oil.

[0061] 1 HNMR(CDCl3):7.99(m)2H;7.77(m)2H;7.37(m)2H,7.26(m)3H;4.95(m)1H;4.15(m)2H ;3.43(m)2H;2.10(s)3H;1.94(s)3H;1.14(s)9H;1.09(s)9H;0.14(s)6H,0.11(s)6H. 13 CMR (CDCl3): 171.09, 143.19, 142.57, 137.97, 134.91, 133.26, 128.76, 128.18, 127.40, 127.00, 125.57, 124.44, 124.10, 123.62, 123.10, 122.94, 122.64, 77.15, 65.98, 60.38, 31.96, 29.73, 27.36, 26.20, 26.05, 25.72, 21.06, 18.71, 18.70, 17.08, 14.49, 14.23, 14.19. Mass: 608.17 (m-3).

[0062] Example 4

[0063] TBDMS-Vitamin-K2-2(C 33 H 54 Synthesis of O2Si2)(538.96)

[0064]

[0065] Under an inert atmosphere, 6.11 g (about 0.01 mol) of TBDMS-vitamin-K2-1-SO2Ph(II) was dissolved in 21 ml of tetrahydrofuran and 1.85 ml of dimethylformamide. 1.3 g (about 0.0125 mol) of isoprenyl chloride was added. The reaction mixture was cooled to 0°C to -5°C. 0.266 g (about 0.000825 mol) of tetrabutylammonium bromide (TBAB) and 0.044 g (about 0.000165 mol) of 1,4,7,10,13,16-hexaoxacyclooctadecane (18 crown 6) were added. The reaction mass was stirred at the same temperature for 5 minutes. 1.68 g (0.015 mol) of potassium tert-butoxide in 16 ml of tetrahydrofuran was added to the above solution over 30 minutes and stirred at the same temperature for 2 hours. After the reaction is complete, the reaction is quenched by dropping 20% ​​ammonium chloride solution, and the pH is adjusted to 5-6 using 1M HCl. Tetrahydrofuran is distilled under vacuum and the residue is extracted in ethyl acetate. The ethyl acetate layer is washed with water, then washed with brine, and dried over anhydrous sodium sulfate. Ethyl acetate is distilled under vacuum to produce 7.3g of crude TBDMS-vitamin-K2-2-SO2Ph in the form of an oil. The crude product is purified by column chromatography using a mixture of hexane and ethyl acetate to produce 4.75g of TBDMS-vitamin-K2-2-SO2Ph in the form of an oil.

[0066] Under an inert atmosphere, 6.79 g (about 0.01 mol) of TBDMS-vitamin-K2-2-SO2Ph was dissolved in 68 ml of tetrahydrofuran, and 0.01 g (about 0.000017 mol) (1,3-bis(diphenylphosphino)propane) palladium chloride II was added. The reaction mass was cooled to -5 °C. Within 30 minutes, 3.18 g (0.03 mol) of superhydride (lithium triethylborohydride) solution was added. The reaction mass was stirred at room temperature for 10-12 hours. After the reaction was completed, it was quenched by adding methanol followed by acetic acid and water. The reaction mass was stirred for 3 hours and extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to produce 6 g of crude TBDMS-vitamin-K2-2 in the form of an oil. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate to yield 3.7 g of TBDMS-vitamin-K2-2 as an oil.

[0067] 1HNMR(CDCl3):8.10(m),2H,7.43(m),2H,5.15(m),2H,3.61(D),2H,2.38(s),3H,2.0 7-2.14(m),4H,1.84(s),3H,1.73(s),3H,1.65(s),3H,1.18(s),18H,0.25(D),12H. 13 CMR(CDCl3):143.15,142.91,135.05,131.31,127.65,127.16,127.11,124.39,124.29,123.97,123.91,123.12,39.64,27.14,26.98, 26.69,26.31,26.25,25.78,25.62,18.83,18.77,17.78,16.45,16.29,15.49,14.48,-2.81,-2.87,-3.08,-3.15,-3.36,-3.46,-4.16. Mass: 537.7 (m-1) and 556.8 (m+18).

[0068] Example 5

[0069] TBDMS-Vitamin-K2-3: (C 38 H 62 Synthesis of O2Si2)(607.08)

[0070]

[0071] Under an inert atmosphere, 6.11 g (about 0.01 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 21 ml of tetrahydrofuran and 1.85 ml of dimethylformamide. 2.158 g (about 0.0125 mol) of geranyl chloride was added thereto. The reaction mass was cooled to 0°C to -5°C. 0.266 g (about 0.000825 mol) of tetrabutylammonium bromide and 0.044 g (about 0.000165 mol) of 18 crown 6 were added. The reaction mass was stirred at the same temperature for 5 minutes. 1.68 g (0.015 mol) of potassium tert-butoxide in 16 ml of tetrahydrofuran was added to the above solution within 30 minutes, and the reaction mass was stirred at the same temperature for 2 hours. After the reaction was completed, it was quenched by dropping a 20% ammonium chloride solution, and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then washed with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to produce 8 g of crude TBDMS-vitamin-K2-3-SO2Ph in the form of an oil. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 5.2 g of TBDMS-vitamin-K2-3-SO2Ph in the form of an oil.

[0072] Under an inert atmosphere, 7.47 g (about 0.01 mol) of TBDMS-vitamin-K2-3-SO2Ph was dissolved in 75 ml of tetrahydrofuran, and 0.01 g (about 0.000017 mol) (1,3-bis(diphenylphosphino)propane) palladium chloride II was added. The reaction mass was cooled to -5 °C. 3.18 g (0.03 mol) of superhydride solution was added within 30 minutes. The reaction mass was stirred at room temperature for 10-12 hours. After the reaction was completed, it was quenched by dropping methanol followed by acetic acid and water. The reaction mass was stirred for 3 hours and extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to produce 6.9 g of crude TBDMS-vitamin-K2-3 in the form of an oil. It was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 4.2 g of TBDMS-vitamin-K2-3 in the form of an oil.

[0073] 1 HNMR(DMSO):8.01(m),2H,7.36(m),2H,5.08(m),3H,3.55(dd),2H,1.94-2.29 (m),3H,1.76(s),6H,1.68(s),6H,1.57(m),8H,1.13(m),18H,0.16(dd),12H. 13CMR (CDCl3): 143.10, 142.49, 135.14, 135.0, 131.22, 127.60, 127.22, 127.06, 124.43, 124.18, 124.09, 123.90, 123.52, 122.99, 122.65, 77.36, 77.04, 76.72, 39.77, 39.61, 27.09, 26.77, 26.66, 26.26, 26.19, 25.72, 18.78, 18.73, 17.70, 16.46, 15.99, 14.46, -3.13, -3.20. Mass: 607 (m-1).

[0074] Comparative example:

[0075] Preparation of TBDMS-K2-3-SO2Ph from TBDMS-K2-1-SO2Ph (without phase transfer catalyst)

[0076] Under an inert atmosphere, 2g (about 0.003mol) TBDMS-vitamin-K2-1-SO2Ph was dissolved in 20ml tetrahydrofuran. 0.71g (about 0.004mol) geranyl chloride was added. The reaction mass was cooled to 0°C to -5°C and kept at the same temperature for 5 minutes. 0.697g (0.006mol) potassium tert-butoxide in 6ml tetrahydrofuran was added to the above solution within 10 minutes, and stirred for 24 hours while keeping the same temperature. The conversion rate of the reaction was monitored at specific time intervals, and the reaction was quenched by dropping 20% ​​ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then washed with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to produce a crude TBDMS-vitamin-K2-3-SO2Ph in an oily state. The conversion rate values ​​obtained at different time intervals are summarized in Table 1 below.

[0077] Preparation of TBDMS-K2-3-SO2Ph from TBDMS-K2-1-SO2Ph (using only TBAB as phase transfer catalyst)

[0078] Under an inert atmosphere, 2g (about 0.003mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 20ml of tetrahydrofuran. 0.71g (about 0.004mol) of geranyl chloride was added. 0.088g (0.27mmol) of TBAB was subsequently added. The reaction mass was cooled to 0°C to -5°C and stirred for 5min at the same temperature. 0.697g (0.006mol) of potassium tert-butoxide in 6ml of tetrahydrofuran was added to the above solution within 10 minutes, and stirred for 24 hours at the same temperature. The conversion rate of the reaction was monitored at specific time intervals, and the reaction was quenched by dropping 20% ​​ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to yield crude TBDMS-vitamin-K2-3-SO2Ph as an oil. The conversion values ​​obtained at different time intervals are summarized in Table 1 below.

[0079] Preparation of TBDMS-K2-3-SO2Ph from TBDMS-K2-1-SO2Ph (using only 18-crown 6 as phase transfer catalyst)

[0080] Under an inert atmosphere, 2 g (about 0.003 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 20 ml of tetrahydrofuran. 0.71 g (about 0.004 mol) of geranyl chloride was added, followed by 0.014 g (0.054 mmol) of 18 crown 6 catalyst. The reaction mass was cooled to 0°C to -5°C and stirred at the same temperature for 5 minutes. 0.697 g (0.006 mol) of potassium tert-butoxide in 6 ml of tetrahydrofuran was added to the above solution within 10 minutes and stirred at the same temperature for 24 hours. The conversion of the reaction was monitored at specific time intervals, and the reaction was quenched by dropping 20% ​​ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to yield crude TBDMS-vitamin-K2-3-SO2Ph as an oil. The conversion values ​​obtained at different time intervals are summarized in Table 1 below.

[0081] Preparation of TBDMS-K2-3-SO2Ph from TBDMS-K2-1-SO2Ph (using both TBAB and 18-crown 6 as phase transfer catalysts)

[0082] Under an inert atmosphere, 2 g (about 0.003 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 20 ml of tetrahydrofuran. 0.71 g (about 0.004 mol) of geranyl chloride was added, followed by 0.088 g (0.27 mmol) of TBAB and 0.014 g (0.054 mmol) of 18 crown 6 catalyst. The reaction mass was cooled to 0°C to -5°C and stirred at the same temperature for 5 minutes. 0.697 g (0.006 mol) of potassium tert-butoxide in 6 ml of tetrahydrofuran was added to the above solution within 10 minutes and stirred at the same temperature for 24 hours. The conversion of the reaction was monitored at specific time intervals, and the reaction was quenched by dropping 20% ​​ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to yield crude TBDMS-vitamin-K2-3-SO2Ph as an oil. The conversion values ​​obtained at different time intervals are summarized in Table 1 below.

[0083] TBDMS-K2-3-SO2Ph was prepared from TBDMS-K2-1-SO2Ph (using both TBAB and 18 crown 6 catalysts at different catalyst ratios).

[0084] Under an inert atmosphere, 2 g (about 0.003 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 20 ml of tetrahydrofuran. 0.71 g (about 0.004 mol) of geranyl chloride was added, followed by 0.176 g (0.54 mmol) of TBAB and 0.007 g (0.027 mmol) of 18 crown 6 catalyst. The reaction mass was cooled to 0°C to -5°C and stirred at the same temperature for 5 minutes. 0.697 g (0.006 mol) of potassium tert-butoxide in 6 ml of tetrahydrofuran was added to the above solution within 10 minutes and stirred at the same temperature for 24 hours. The conversion of the reaction was monitored at specific time intervals, and the reaction was quenched by dropping 20% ​​ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to yield crude TBDMS-vitamin-K2-3-SO2Ph as an oil. The conversion values ​​obtained at different time intervals are summarized in Table 1 below.

[0085] Preparation of TBDMS-K2-3-SO2Ph from TBDMS-K2-1-SO2Ph (using both TBAB and 18 Crown 6 catalysts with different catalyst ratios)

[0086] Under an inert atmosphere, 2 g (about 0.003 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 20 ml of tetrahydrofuran. 0.71 g (about 0.004 mol) of geranyl chloride was added, followed by 0.044 g (0.136 mmol) of TBAB and 0.0285 g (0.108 mmol) of 18 crown 6 catalyst. The reaction mass was cooled to 0°C to -5°C and stirred at the same temperature for 5 minutes. 0.697 g (0.006 mol) of potassium tert-butoxide in 6 ml of tetrahydrofuran was added to the above solution within 10 minutes and stirred at the same temperature for 24 hours. The conversion of the reaction was monitored at specific time intervals, and the reaction was quenched by dropping 20% ​​ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to yield crude TBDMS-vitamin-K2-3-SO2Ph as an oil. The conversion values ​​obtained at different time intervals are summarized in Table 1 below.

[0087] Table 1

[0088]

[0089] Example 6

[0090] TBDMS-Vitamin-K2-4(C 43 H 70 Synthesis of O2Si2)(675.20)

[0091]

[0092] Under an inert atmosphere, 6.11 g (about 0.01 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 21 ml of tetrahydrofuran and 1.85 ml of dimethylformamide. 3 g (about 0.0125 mol) of farnesyl chloride was added thereto. The reaction mass was cooled to 0°C to -5°C. 0.266 g (about 0.000825 mol) of tetrabutylammonium bromide and 0.044 g (about 0.000165 mol) of 18 crown 6 were added. The reaction mass was stirred at the same temperature for 5 minutes. 1.68 g (0.015 mol) of potassium tert-butoxide in 16 ml of tetrahydrofuran was added to the above solution within 30 minutes and stirred at the same temperature for 2 hours. After the reaction was completed, it was quenched by dropping a 20% ammonium chloride solution, and the pH was adjusted to 5-6 using 1 M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled under vacuum to produce 8.5 g of crude TBDMS-vitamin-K2-4-SO2Ph as an oil. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 5.7 g of TBDMS-vitamin-K2-4-SO2Ph as an oil.

[0093] Under an inert atmosphere, 8.15 g (about 0.01 mole) of TBDMS-vitamin-K2-4-SO2Ph was dissolved in 81 ml of tetrahydrofuran, and 0.01 g (about 0.000017 mole) (1,3-bis(diphenylphosphino)propane) palladium chloride II was added. The reaction mass was cooled to -5 ° C. 3.18 g (0.03 mole) of superhydride solution was added within 30 minutes. The reaction mass was stirred at room temperature for 10-12 hours. After the reaction was completed, it was quenched by adding methanol and then acetic acid and water. The reaction mass was stirred for 3 hours and extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under vacuum to produce 7.5 g of crude TBDMS-vitamin-K2-4 in the form of an oil. It was purified by column chromatography using a mixture of hexane and ethyl acetate to give 4.7 g of TBDMS-vitamin-K2-4 in the form of an oil.

[0094] 1 HNMR(CDCl3):8.04(m),2H,7.39(m),2H,5.11(m),4H,3.55(dd),2H,2.33(s),3H,1.9 3-2.11(m),12H,1.77(s),3H,1.66(s),6H,1.11(m),18H,0.95(m),9H,0.21(dd),12H. 13CMR(CDCl3):143.11,142.50,137.18,136.89,136.02,135.78,135.21,135.17,127.60,127.23,127.07,126.87,124 .10,124.01,123.95,123.91,123.63,123.57,123.52,123.47,123.00,122.66,119.82,48.97,40.64,40.38,39.90,3 9.69,39.63,35.00,34.71,33.19,32.58,31.68,31.65,29.87,29.77,29.11,28.67,28.47,27.95,27.58,27.48,27.10,26.73,26.71,26.27,26.21,25.75,25.33,23.51,23.09,22.71,19.86,19.61,19.25,18.79,18.74,16.53,16.29,

[0095] 16.07,16.04,16.02,15.90,14.48,14.18,11.49,-2.89,-2.97,-3.00,-3.12,-3.19. Mass: 693(m+18).

[0096] Example 7

[0097] TBDMS-Vitamin-K2-5(C 48 H 78 Synthesis of O2Si2)(743.3)

[0098]

[0099] Under an inert atmosphere, 6.11 g (about 0.01 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 21 ml of tetrahydrofuran and 1.85 ml of dimethylformamide. 3.86 g (about 0.0125 mol) of geranylgeranyl chloride was added. The reaction mass was cooled to 0°C to -5°C. 0.266 g (about 0.000825 mol) of tetrabutylammonium bromide and 0.044 g (about 0.000165 mol) of 18 crown 6 were added. The reaction mass was stirred at the same temperature for 5 minutes. 1.68 g (0.015 mol) of potassium tert-butoxide in 16 ml of tetrahydrofuran was added to the above solution within 30 minutes and stirred at the same temperature for 2 hours. After the reaction was completed, it was quenched by dropping a 20% ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled under vacuum to produce 9 g of crude TBDMS-vitamin-K2-5-SO2Ph as an oil. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 6.1 g of TBDMS-vitamin-K2-5-SO2Ph as an oil.

[0100] Under an inert atmosphere, 8.83 g (about 0.01 mol) of TBDMS-vitamin-K2-5-SO2Ph was dissolved in 88 ml of tetrahydrofuran, and 0.01 g (about 0.000017 mol) (1,3-bis(diphenylphosphino)propane) palladium chloride II was added. The reaction mass was cooled to -5 °C. 3.18 g (0.03 mol) of superhydride solution was added within 30 minutes. The reaction mass was stirred at room temperature for 10-12 hours. After the reaction was completed, it was quenched by dropping methanol followed by acetic acid and water. The reaction mass was stirred for 3 hours and extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to produce 8.1 g of crude TBDMS-vitamin-K2-5 in the form of an oil. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 5.2 g of TBDMS-vitamin-K2-5 in the form of an oil.

[0101] Example 8

[0102] TBDMS-Vitamin-K2-6(C 53 H 86 Synthesis of O2Si2)(811.44)

[0103]

[0104] Under an inert atmosphere, 6.11 g (about 0.01 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 21 ml of tetrahydrofuran and 1.85 ml of dimethylformamide. 4.71 g (about 0.0125 mol) of pentaisoprene chloride was added. The reaction mass was cooled to 0°C to -5°C. 0.266 g (about 0.000825 mol) of tetrabutylammonium bromide and 0.044 g (about 0.000165 mol) of 18 crown 6 were added. The reaction mass was stirred at the same temperature for 5 minutes. 1.68 g (0.015 mol) of potassium tert-butoxide in 16 ml of tetrahydrofuran was added to the above solution within 30 minutes and stirred at the same temperature for 2 hours. After the reaction was completed, it was quenched by dropping a 20% ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled under vacuum to produce 9.7 g of crude TBDMS-vitamin-K2-6-SO2Ph as an oil. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 6.6 g of TBDMS-vitamin-K2-6-SO2Ph as an oil.

[0105] Under an inert atmosphere, 9.51 g (about 0.01 mol) of TBDMS-vitamin-K2-6-SO2Ph was dissolved in 95 ml of tetrahydrofuran, and 0.01 g (about 0.000017 mol) (1,3-bis(diphenylphosphino)propane) palladium chloride II was added. The reaction mass was cooled to -5 °C. 3.18 g (0.03 mol) of superhydride solution was added within 30 minutes. The reaction mass was stirred at room temperature for 10-12 hours. After the reaction was completed, it was quenched by adding methanol followed by acetic acid and water. The reaction mass was stirred for 3 hours and extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to produce 8.9 g of crude TBDMS-vitamin-K2-6 as an oil. It was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 5.6 g of TBDMS-vitamin-K2-6 as an oil.

[0106] 1 HNMR(CDCl3):8.01(m),2H,7.36(m),2H,5.13(m),3H,3.52(dd),2H,2.29(m),3H,1.99-2.07 (m),20H,1.77(s),3H,1.73(s),3H,1.61(m),6H,1.13(m),18H,0.92(s),3H,0.16(dd),12H,13 CMR(CDCl3):143.07,142.47,135.16,135.03,134.91,134.90,131.27,127.60,127.20,127.04, 124.43,124.31,124.29,124.25,124.16,124.09,123.90,123.45,122.98,122.68,39.76,39.62 ,31.97,29.75,29.71,29.41,27.07,26.78,26.73,26.69,26.25,26.18,25.75,25.73,25.68,22.74,18.77,18.72,18.16,17.72,16.48,16.04,14.45,14.18,-2.90,-2.98,-3.01,-3.14,-3.21. Mass: 808(m-3).

[0107] Example 9

[0108] TBDMS-Vitamin-K2-7(C 58 H 94 Synthesis of O2Si2)(879.55)

[0109]

[0110] Under an inert atmosphere, 6.11 g (about 0.01 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 21 ml of tetrahydrofuran and 1.85 ml of dimethylformamide. 5.56 g (about 0.0125 mol) of hexaisoprene chloride was added. The reaction mass was cooled to 0°C to -5°C. 0.266 g (about 0.000825 mol) of tetrabutylammonium bromide and 0.044 g (about 0.000165 mol) of 18 crown 6 were added. The reaction mass was stirred at the same temperature for 5 minutes. 1.68 g (0.015 mol) of potassium tert-butoxide in 16 ml of tetrahydrofuran was added to the above solution within 30 minutes and stirred at the same temperature for 2 hours. After the reaction was completed, it was quenched by dropping a 20% ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled under vacuum to produce 10.5 g of crude TBDMS-vitamin-K2-7-SO2Ph as an oil. It was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 7.1 g of TBDMS-vitamin-K2-7-SO2Ph as an oil.

[0111] Under an inert atmosphere, 10.19 g (about 0.01 mol) of TBDMS-vitamin-K2-7-SO2Ph was dissolved in 101 ml of tetrahydrofuran, and 0.01 g (about 0.000017 mol) (1,3-bis(diphenylphosphino)propane) palladium chloride II was added. The reaction mass was cooled to -5 °C. 3.18 g (0.03 mol) of superhydride solution was added within 30 minutes. The reaction mass was stirred at room temperature for 10-12 hours. After the reaction was completed, it was quenched by adding methanol followed by acetic acid and water. The reaction mass was stirred for 3 hours and extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to produce 9.7 g of crude TBDMS-vitamin-K2-7 in the form of an oil. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 6.1 g of TBDMS-vitamin-K2-7 in the form of an oil.

[0112] 1 HNMR(CDCl3):8.01(m),2H,7.36(m),2H,5.0(m),1H,5.12(m),6H,3.51(m),2 H,2.28(s),3H,1.98-2.06(m),12H,1.60(m),24H,1.0(s),18H,0.08(d),12H. 13 CMR(CDCl3):143.09,142.48,135.16,135.03,134.91,131.24,127.59,127.20,127.04, 124.43,124.30,124.25,124.16,124.07,123.88,123.46,122.98,122.63,43.53,39.76, 39.62,36.30,34.23,31.96,29.74,29.69,29.40,27.08,26.79,26.77,26.71,26.24,26.18,25.73,22.73,18.77,18.72,17.71,16.46,16.03,16.01,14.44,14.15,-3.15,-3.22. Mass: 880(m+1).

[0113] Example 10

[0114] TBDMS-Vitamin-K2-9: (C 68 H 110 Synthesis of O2Si2)(1015.79)

[0115]

[0116] Under an inert atmosphere, 6.11 g (about 0.01 mol) of TBDMS-vitamin-K2-1-SO2Ph was dissolved in 21 ml of tetrahydrofuran and 1.85 ml of dimethylformamide. 7.26 g (about 0.0125 mol) of octaisoprene chloride was added. The reaction mass was cooled to 0°C to -5°C. 0.266 g (about 0.000825 mol) of tetrabutylammonium bromide and 0.044 g (about 0.000165 mol) of 18 crown 6 were added. The reaction mass was stirred at the same temperature for 5 minutes. 1.68 g (0.015 mol) of potassium tert-butoxide in 16 ml of tetrahydrofuran was added to the above solution within 30 minutes and stirred at the same temperature for 2 hours. After the reaction was completed, it was quenched by dropping a 20% ammonium chloride solution and the pH was adjusted to 5-6 using 1M HCl. Tetrahydrofuran was distilled under vacuum and the residue was extracted in ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. The ethyl acetate was distilled under vacuum to produce 13 g of crude TBDMS-vitamin-K2-9-SO2Ph as an oil. The crude product was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 8 g of TBDMS-vitamin-K2-9-SO2Ph as an oil.

[0117] Under an inert atmosphere, 11.55 g (about 0.01 mol) of TBDMS-vitamin-K2-9-SO2Ph was dissolved in 115 ml of tetrahydrofuran, and 0.01 g (about 0.000017 mol) (1,3-bis(diphenylphosphino)propane) palladium chloride II was added. The reaction mass was cooled to -5 ° C. 3.18 g (0.03 mol) of superhydride solution was added within 30 minutes. The reaction mass was stirred at room temperature for 10-12 hours. After the reaction was completed, it was quenched by dropping methanol followed by acetic acid and water. The reaction mass was stirred for 3 hours and extracted twice with ethyl acetate. The ethyl acetate layer was washed with water, then with brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled under vacuum to produce 10.4 g of crude TBDMS-vitamin-K2-9 in the form of an oil. It was purified by column chromatography using a mixture of hexane and ethyl acetate to produce 7.1 g of TBDMS-vitamin-K2-9 in the form of an oil.

[0118] Example 11

[0119] Oxidation of the TBDMS ether of vitamin K2-1-SO2Ph to carbonyl compounds

[0120] By vigorous stirring at room temperature for 20 minutes, CrO3 20mg (0.2mmol) and H5IO6 1.09g (4.781mmol) are dissolved in acetonitrile (4ml). At -5°C to 0°C, in 10-15 minutes, the solution is slowly added to a pre-cooled solution of 1g (1.636mmol) TBDMS-vitamin-K2-1-SO2Ph in 5ml dichloromethane. After the addition is complete, the reaction mixture is stirred at -5°C to 0°C for an additional hour, quenched with saturated Na2S2O3 aqueous solution (10ml) and then filtered. The filtrate is concentrated under vacuum, and the residue is diluted with ethyl acetate (20ml), washed with water (10ml), saturated Na2S2O3 aqueous solution (10ml), brine (10ml), and then dried over Na2SO4 (1g). The solvent was removed under reduced pressure and the residue was purified by flash chromatography (hexane-ethyl acetate 2:8) to give K2-1-SO2Ph.

[0121] 1 HNMR(CDCl3): 7.96-8.03(m)2H; 7.67(m)4H; 7.23(m)3H; 4.82(m)1H; 3.72(s)2H; 3.22(D)2H; 1.98(s)3H; 1.92(s)3H. 13 CMR (CDCl3): 184.93, 183.82, 144.05, 143.58, 137.79, 133.56, 133.32, 131.91, 131.81, 130.63, 128.75, 128.29, 126.22, 126.20, 125.86, 65.80, 26.27, 16.96, 12.71. Mass: 381.4 (m+1).

[0122] Example 12

[0123] Oxidation of compound (TBDMS-K2-6) to vitamin K2-6

[0124] By vigorous stirring at room temperature for 20 minutes, CrO3 10mg (0.1mmol) and H5IO6 0.421g (1.84mmol) are dissolved in acetonitrile (5ml). At -5°C to 0°C, in 10-15 minutes, the solution is slowly added to a pre-cooled solution of 0.5g (0.616mmol) TBDMS-vitamin-K2-6 in 5ml dichloromethane. After the addition is complete, the reaction mixture is stirred for an additional hour at -5°C to 0°C, quenched with saturated Na2S2O3 aqueous solution (10ml) and filtered. The filtrate is washed with water (10ml), brine (10ml) and then dried over Na2SO4 (1g). The solvent is removed under reduced pressure, and the residue is purified by flash chromatography (hexane-ethyl acetate 2:8v / v) to produce vitamin K2-6.

[0125] 1 HNMR(CDCl3):8.10(m),2H,7.71(m),2H,5.12(m),6H,3.39(D),2H,2.20( s),3H,1.93-2.07(m),20H,1.81(s),3H,1.69(s),3H,1.52-1.61(d),15H. 13 CMR(CDCl3):185.26,184.34,146.06,143.27,137.45,135.14,134.84, 134.80,133.25,133.19,132.13,132.10,131.13,126.26,126.14,124. 43,124.28,124.16,123.86,119.12,39.73,39.68,26.76,26.68,26.65 ,26.63,26.48,25.99,25.70,17.67,16.40,16.03,16.00,15.98,12.64. Mass: 581.19(m+1).

[0126] Oxidation of compound (TBDMS-K2-7) to vitamin K2-7

[0127] By vigorous stirring at room temperature for 20 minutes, CrO3 20mg (0.2mmol) and H5IO6 0.777g (3.41mmol) are dissolved in acetonitrile (5ml). At 0°C to -5°C, in 10-15 minutes, the solution is slowly added to the pre-cooled solution of 1g (1.13mmol) TBDMS-vitamin-K2-7 in 5ml dichloromethane. After the addition is completed, the reaction mixture is stirred for an additional hour at 0°C to -5°C, quenched with saturated Na2S2O3 aqueous solution (10ml) and then filtered. The filtrate is washed with water (10ml), brine (10ml) and then dried over Na2SO4 (1g). The solvent is removed under reduced pressure, and the residue is purified by flash chromatography (hexane-ethyl acetate 2: 8v / v) to produce vitamin K2-7.

[0128] 1 HNMR(CDCl3):8.11(m),2H,7.71(m),2H,5.12(m),7H,3.40(D),2H,2.21( s),3H,1.93-2.07(m),24H,1.81(s),3H,1.70(s),3H,1.52-1.61(d),18H. 13 CMR (CDCl3): 185.34, 184.41, 146.10, 143.30, 137.49, 135.17, 134.86, 133.28, 133.23, 132.15, 132.12, 131.18, 126.28, 126.17, 124.42, 124.27, 124.15, 123.85, 119.10, 39.73, 39.69, 26.77, 26.69, 26.66, 26.48, 26.00, 25.71, 17.68, 16.42, 16.02, 12.66. Mass: 649.81 (m+1).

[0129] Comparative Examples

[0130] 6.07g (0.01mol) TBDMS K2-3 is dissolved in 25ml tetrahydrofuran, and at room temperature 7.83g (0.03mol) tetrabutylammonium fluoride (TBAF) is added. The reaction is monitored by thin layer chromatography. As indicated by thin layer chromatography, TBDMS K2-3 reacted completely in 2 hours, but did not form desired product, but TBDMS K2-3 was hydrolyzed.

[0131] 6.07 g (0.01 mol) of TBDMS K2-3 were dissolved in 25 ml of 50% aqueous methanol, and 9.22 g (0.03 mol) of potassium persulfate (potassium peroxymonosulfate) were added in portions at room temperature over 30 minutes. The reaction was monitored by thin layer chromatography. Even at the end of 24 hours, only TBDMS K2-3 was found to be present, indicating that oxidation did not proceed.

[0132] 6.07g (0.01mol) TBDMS K2-3 is dissolved in 25ml methanol, and at room temperature add 2.4g (0.005mol) tetrabutylammonium tribromide (TBATB). The reaction continues at room temperature for 24 hours and is monitored by thin layer chromatography. At the end of 24 hours, only starting compound TBDMS K2-3 is present. The temperature of reaction mass is raised to 50 ℃ and further monitored by thin layer chromatography for 4-5 hours. At the end of 5 hours, only starting compound TBDMS K2-3 is present, indicating that oxidation reaction does not occur.

[0133] 6.07g (0.01mol) TBDMS K2-3 is dissolved in 25ml acetonitrile, and at room temperature add 2.4g (0.005mol) tetrabutylammonium tribromide (TBATB).Reaction was continued at room temperature for 24 hours and monitored by thin layer chromatography.Even after 24 hours, it was found that only starting compound TBDMS K2-3 existed, indicating that oxidation reaction did not occur.

[0134] 6.07g (0.01mol) TBDMS K2-3 is dissolved in 25ml tetrahydrofuran, and 2.4g (0.005mol) tetrabutylammonium tribromide (TBATB) is added at room temperature. The reaction continues at room temperature for 24 hours and is monitored by thin layer chromatography. Even after 24 hours, it is found that only starting compound TBDMS K2-2 exists. Add 25ml methanol and the reaction continues at 50 ℃ and is monitored by thin layer chromatography for 4-5 hours. Even after 5 hours, it is found that only starting compound TBDMS K2-3 exists, indicating that oxidation reaction does not occur.

[0135] 6.07g (0.01mol) TBDMS K2-3 is dissolved in 25ml methanol and cooled to 0 ℃-5 ℃. 2.35g (0.03mol) acetyl chloride is added dropwise in 10-15 minutes. The reaction is continued at 0 ℃-5 ℃ for 1-2 hours and monitored by thin layer chromatography. Even after 24 hours, only the starting compound is present, indicating that oxidation reaction does not occur. 6.07g (0.01mol) TBDMSK2-3 is dissolved in 25ml methanol, and 0.55g (0.0015mol) tetrabutylammonium iodide (TBAI) is added at room temperature. The reaction is monitored by thin layer chromatography. Even after 24 hours, only the starting compound TBDMS K2-3 is present, indicating that oxidation reaction does not occur.

[0136] Oxidation of compound (dimethyl K2-7) to vitamin K2-7

[0137] CrO3 20mg (0.2mmol) and H5IO6 1g (4.4mmol) were dissolved in acetonitrile (20ml) by vigorous stirring at room temperature for 20 minutes. The solution was slowly added to a pre-cooled solution of 1g (1.47mmol) of dimethyl K2-7 in 20ml of dichloromethane at -5°C to 0°C over 10-15 minutes. After the addition was complete, the reaction mixture was stirred at -5°C to 0°C for an additional hour. The reaction was monitored by TLC. The reaction did not proceed.

[0138] Oxidation of the compound (dibenzyl K2-3) to vitamin K2-3

[0139] CrO3 20 mg (0.2 mmol) and H5IO6 1.22 g (5.37 mmol) were dissolved in acetonitrile (20 ml) by vigorous stirring at room temperature for 20 minutes. The solution was slowly added to a pre-cooled solution of 1 g (1.79 mmol) of dibenzyl K2-3 in 20 ml of dichloromethane at -5°C to 0°C over 10-15 minutes. After the addition was complete, the reaction mixture was stirred at -5°C to 0°C for an additional hour. The reaction was monitored by TLC. The reaction did not proceed.

[0140] Oxidation of compound (dimethyl K2-3) to vitamin K2-3

[0141] CrO3 30mg (0.3mmol) and H5IO6 2.48g (10.8mmol) were dissolved in acetonitrile (20ml) by vigorous stirring at room temperature for 20 minutes. The solution was slowly added to a pre-cooled solution of 1g (2.4mmol) of dimethyl K2-3 in 20ml of dichloromethane at -5°C to 0°C over 10-15 minutes. After the addition was complete, the reaction mixture was stirred at -5°C to 0°C for an additional hour. The reaction was monitored by TLC. The reaction did not proceed.

[0142] Example 13

[0143] 2g (0.0033mol) TBDMS-K2-1-SO2Ph was dissolved in 20ml dichloromethane. The reaction mass was cooled to 0°C to -5°C. 2.2g (0.0098mol) periodic acid and 40mg chromium trioxide were dissolved in 20ml acetonitrile and added to the reaction mass within 5 minutes. The reaction mass was stirred at 0°C to -5°C, and the reaction was monitored using thin layer chromatography and high pressure liquid chromatography at specific time intervals and finally at room temperature overnight. The reaction was quenched with 10% sodium thiosulfate solution, and the reaction mass was filtered through a diatomaceous earth bed. The water layer was further extracted with dichloromethane. The organic layer was washed twice with water, then washed with a saline solution and dried over anhydrous sodium sulfate. The solvent was stripped to recover the product. The reaction was carried out at different CrO3 wt.% based on TBDMS-K2-1-SO2Ph and different molar ratios of TBDMS-K2-1-SO2Ph to periodic acid. The following summarizes the % conversion values ​​versus time at various time intervals.

[0144]

Claims

1. A process for condensing a phenylsulfone of a protected monoisoprenyl menadione of formula (I) with an isoprenyl halide of formula (II) in the presence of a strong organometallic base and a phase transfer catalyst to produce a phenylsulfonyl derivative of menadione of formula (III), wherein R1 is a protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) ether, and m is selected from 0 to 7, wherein X represents a halogen atom selected from chlorine and bromine, These phase transfer catalysts include Quaternary alkylammonium halides and crown ethers.

2. A process for condensing a phenylsulfone of a protected monoisoprenyl menadione of formula (I) with an isoprenyl halide of formula (II) as claimed in claim 1, wherein: The molar ratio of phenyl sulfone to prenyl halide of the protected monoprenyl menadione is in the range of 1:1.25 to 1:1.

33.

3. A process for condensing a phenylsulfone of a protected monoisoprenyl menadione of formula (I) with an isoprenyl halide of formula (II) as claimed in claim 1, wherein: The reaction is carried out at a temperature ranging from -5°C to 0°C.

4. A process for condensing a phenylsulfone of a protected monoisoprenyl menadione of formula (I) with an isoprenyl halide of formula (II) as claimed in claim 1, wherein: The quaternary alkylammonium halide is tetrabutylammonium bromide (TBAB).

5. The method for condensing a phenylsulfone of a protected monoisoprenyl menadione of formula (I) with an isoprenyl halide of formula (II) as claimed in claim 1, wherein: The crown ether is 1,4,7,10,13,16-hexaoxacyclooctadecane.

6. A process for condensing a phenylsulfone of a protected monoisoprenyl menadione of formula (I) with an isoprenyl halide of formula (II) as claimed in claim 1, wherein: The molar ratio of tetrabutylammonium bromide to 1,4,7,10,13,16-hexaoxacyclooctadecane is in the range of 0.5 to 20.

7. A process for condensing a phenylsulfone of a protected monoisoprenyl menadione of formula (I) with an isoprenyl halide of formula (II) as claimed in claim 1, wherein: The reaction time is in the range of 0.25 to 6 hours.

8. A method for oxidizing silyl-protected vitamin K2 in the presence of chromium trioxide and periodic acid to produce vitamin K2, wherein: The vitamin K2 is selected from vitamin K2-2 to K2-9, and the silyl protecting group is selected from trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS).

9. The method for oxidizing a silyl-protected vitamin K2 compound according to claim 8, wherein The molar ratio of periodic acid to the silyl-protected vitamin K2 is in the range of 2:1 to 4:

1.

10. The method for oxidizing silyl-protected vitamin K2 according to claim 8, wherein The ratio of chromium trioxide to the silyl-protected vitamin K2 is in the range of 0.5 wt. % to 2 wt. %.

11. The method for oxidizing silyl-protected vitamin K2 according to claim 8, wherein: The oxidation is carried out in a temperature range of -5°C to 0°C.

12. A method for synthesizing vitamin K2 represented by the following formula, Wherein m is selected from 0 to 7, the method comprises the following steps: (a) a phenylsulfone derivative of a monoisoprenyl menadione having the formula wherein R1 represents a protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) ether, reacted with an isoprenyl halide having the formula To produce a phenylsulfonyl derivative of menadione having the formula b) removing the phenylsulfonyl group from the compound of formula (III) by reductive elimination in the presence of [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride and lithium triethylborohydride to produce a menadione derivative having the formula wherein m is selected from 0 to 7, c) subjecting a menadione derivative of formula (V) to oxidative deetherification in the presence of chromium trioxide and periodic acid to produce vitamin K2 having the formula And optionally purify the crude product to obtain pure vitamin K2.

13. The method for synthesizing vitamin K2 according to claim 12, wherein The phenylsulfone of the protected monoisoprenyl menadione of formula (I) is obtained from a bromo derivative of the protected monoisoprenyl menadione by reacting the derivative with chloroisoprenyl sulfonate in the presence of activated magnesium in a polar solvent under the catalysis of cuprous bromide.

14. A compound having the formula, wherein R1 represents a protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) ether.

15. A compound having the formula, wherein R1 is a protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) ether, and m is in the range of 0 to 7.

16. A compound having the formula, wherein R1 is a protecting group selected from the group consisting of trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), and triisopropylsilyl (TIPS) ether, and m is in the range of 0 to 7.

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