Application of fluoboric acid or aqueous solution thereof as catalyst in preparation of vitamin K2 intermediate

Abstract

The invention discloses application of fluoboric acid or an aqueous solution thereof as a catalyst in preparation of a compound as shown in a formula II. Wherein the compound as shown in the formula II is generated by reacting a compound as shown in a formula I with geranyl linalool; in the formula, R0 is C1-C4 alkyl; preferably, R0 is a methyl group. The fluoboric acid or the aqueous solution thereof is used as the catalyst, so that the reaction selectivity of the compound shown in the formula I and the geranyl linalool can be improved, the purity of a compound product shown in the formula II in reaction products is effectively improved, generation of Z-type isomer impurities is reduced, and the fluoboric acid or the aqueous solution thereof can be further used for preparing vitamin K2. And a vitamin K2 product with high yield and high purity can be obtained. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to the application of fluoroboric acid or its aqueous solution as a catalyst in the preparation of a vitamin K2 intermediate. Background Art

[0002] Lipophilic and hydrophobic (or fat-soluble) vitamin K compounds are mainly vitamins required for the post-translational modification of specific proteins required for blood coagulation (see: CN 102216248 A, published on October 12, 2011); their parent nucleus structure is 2-methyl-1,4-naphthoquinone, and they mainly include the following: vitamin K1, K2, K3 and K4, etc.; among them, vitamin K1 and K2 are mainly naturally occurring vitamins, and vitamin K3 and K4 are mainly artificially synthesized vitamins (see: CN 101092340A, published on December 26, 2007).

[0003] Extensive research has found that vitamin K1 promotes calcification, vitamin K2 has a stronger effect in this regard, and vitamin K3 does not have this effect. In particular, vitamin K2 can inhibit bone resorption, regulate bone metabolism, and effectively prevent fractures. In addition, there are also relevant research reports on vitamin K2 in improving arteriosclerosis and inhibiting liver cancer and leukemia. Therefore, the demand for vitamin K2 is relatively large, and in some cases, there may be a shortage of raw materials, preparations and other products in this area.

[0004] Vitamin K2 represents a series of compounds that appear as light yellow solid or oily liquid. It has various forms depending on the length of the isopentene side chain, represented by MK-n, where n refers to the number of isopentene units on the side chain. Generally, n = 3, 4, 5, 6, 7, 8, 9, 10, etc.; among them, MK4 and MK7 are the most active.

[0005]

[0006] Among them, the synthesis routes of vitamin K2 (MK4) mainly include the following:

[0007] (1) Alkylation reaction: anhydrous zinc chloride, boron trifluoride etherate and cuprous bromide (combination) as catalyst

[0008]

[0009] Vitamin K2 (20) (MK4): n = 3 (see: CN 101092340 A; publication date: 2007.12.26);

[0010] (2) Alkylation reaction: copper, nickel or palladium as catalyst

[0011]

[0012] R is an alkyl group; LG is a leaving group; m is an integer from 0 to 8; n is an integer from 0 to 9; X is hydrogen, a halide, a hydroxyl group or a protected hydroxyl group; the reaction is carried out in the presence of a copper, nickel or palladium catalyst (see: CN 102216248A, publication date: 2011.10.12; and CN 104725205 A, WO2011117324A2, etc.);

[0013] (3) Alkylation reaction: Palladium metal compound or nickel metal compound as catalyst C2

[0014]

[0015] The compound of formula 4 and the long-chain terpene bromide (compound of formula 6) undergo coupling reaction in S2 solvent under the action of base B2 and catalyst C2 (palladium metal compound or nickel metal compound) at temperature T2 to obtain the compound of formula 7 (see: CN112209814 A, publication date: 2021.01.12).

[0016] Fluoroboric acid is an inorganic compound with the chemical formula HBF4. It is a strong inorganic acid and a colorless transparent liquid. It is miscible with water, alcohol, etc. It is mainly used as a cleaner and corrosive agent for oxides and silicate films on metal surfaces (see: Baidu Encyclopedia https: / / baike.baidu.com / item / %E6%B0%9F%E7%A1%BC%E9%85%B8 / 8143614?fr=aladdin).

[0017] So far, no literature has been found that reports on the use of fluoroboric acid or its aqueous solution as a catalyst for alkylation reactions in the preparation of vitamin K2 and / or its intermediates.

[0018] In view of this, the present invention is proposed. Summary of the invention

[0019] In view of the problems and / or deficiencies in the prior art, the purpose of the present invention is to provide a new use of fluoroboric acid or its aqueous solution: as a catalyst in the preparation of a vitamin K2 intermediate (a compound represented by formula II). Using fluoroboric acid or its aqueous solution as a catalyst can improve the reaction selectivity of the compound represented by formula I and geranyl linalool, effectively improve the purity of the compound represented by formula II in the reaction product, reduce the generation of Z-isomer impurities, and can be used to prepare vitamin K2, and a high-yield, high-purity vitamin K2 product can be obtained.

[0020] The present invention provides a new use of fluoroboric acid or its aqueous solution, which is specifically as follows:

[0021] Use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of a compound of formula II; wherein the compound of formula II is produced by the reaction of a compound of formula I with geranyl linalool;

[0022]

[0023] In the formula, R0 is a C1-C4 alkyl group; preferably, R0 is a methyl group.

[0024] In any of the above technical solutions (the use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of the compound represented by formula II), the catalyst is an aqueous solution of fluoroboric acid with a concentration of at least 30 wt%.

[0025] In any of the above technical solutions (the use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of the compound represented by Formula II), the catalyst is a 30wt% to 75wt% (for example, 35wt%, 40wt%, 45wt%, 50wt%, 55wt%, 60wt%, 65wt%, etc.) aqueous solution of fluoroboric acid; preferably, the catalyst is a 45wt% to 60wt% aqueous solution of fluoroboric acid.

[0026] In any of the above technical schemes (the use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of the compound represented by formula II), the molar ratio of the compound represented by formula I to fluoroboric acid is 1:0.05-0.5 (for example, 1:0.1, 1:0.2, 1:0.3, 1:0.4, etc.); preferably, the molar ratio of the compound represented by formula I to fluoroboric acid is 1:0.05-0.3.

[0027] In any of the above technical schemes (the use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of the compound represented by formula II), the molar ratio of the compound represented by formula I to geranyl linalool is 1:0.8-1 (for example, 1:0.8, 1:0.85, 1:0.9, etc.); preferably, the molar ratio of the compound represented by formula I to geranyl linalool is 1:0.8-0.95.

[0028] In any of the above technical schemes (the use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of the compound represented by formula II), the compound represented by formula I and geranyl linalool are reacted under the protection of an inert gas; preferably, the inert gas is nitrogen or argon.

[0029] In any of the above technical schemes (the use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of the compound represented by formula II), the compound represented by formula I undergoes an alkylation reaction with linalool in an organic solvent; preferably, the organic solvent is an aromatic hydrocarbon solvent; and / or the mass volume ratio of the compound represented by formula I to the organic solvent is 1:10 to 20 g / ml; more preferably, the aromatic hydrocarbon solvent is toluene or ethylbenzene; and / or the mass volume ratio of the compound represented by formula I to the organic solvent is 1:10 to 15 g / ml.

[0030] In any of the above technical solutions (the use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of the compound represented by formula II), the reaction temperature of the alkylation reaction is 45-60°C; preferably, the reaction temperature of the alkylation reaction is 48-52°C.

[0031] In any of the above technical solutions (the use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of the compound represented by formula II), the reaction time of the alkylation reaction is 8 to 12 hours; preferably, the reaction time of the alkylation reaction is 9.5 to 11 hours.

[0032] The present invention also provides an application of fluoroboric acid or an aqueous solution thereof in the preparation of vitamin K2. The preparation method of the vitamin K2 comprises the following steps: reacting the compound represented by formula I with geranyl linalool to generate the compound represented by formula II; hydrolyzing the compound represented by formula II in a mixed solvent of an alcohol solvent and n-heptane and in the presence of a hydroxide aqueous solution, then adding hydrochloric acid, and blowing in air or oxygen to generate vitamin K2 (MK-n, n=4); wherein the alcohol solvent is methanol and / or ethanol; the hydroxide is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide;

[0033] Fluoroboric acid or its aqueous solution is used as a catalyst in the preparation of the compound represented by formula II; the preparation of the compound represented by formula II is as described above;

[0034]

[0035] In the formula, R0 is a C1-C4 alkyl group; preferably, R0 is a methyl group.

[0036] Furthermore, the concentration of the hydroxide aqueous solution is 5 wt% to 15 wt% (for example, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, etc.).

[0037] Definition of terms:

[0038] In the present invention, the "inert gas" refers to a gas that generally does not or is difficult to undergo chemical reactions, including nitrogen and Group 0 inert gases, such as nitrogen, argon, etc.

[0039] Without violating the common sense in the art, the above-mentioned preferred conditions can be combined to obtain preferred embodiments of the present invention.

[0040] The positive and progressive effects of the present invention are mainly:

[0041] (1) The present invention uses fluoroboric acid or its aqueous solution as a catalyst to improve the reaction selectivity of the compound represented by formula I and geranyl linalool, effectively improve the purity of the compound represented by formula II in the reaction product, reduce the generation of Z-isomer impurities, and prepare the compound represented by formula II or its n-heptane solution;

[0042] For example, using fluoroboric acid or its aqueous solution as a catalyst, the HPLC purity of the compound represented by Formula II (e.g., Compound 02) is 75.18%, and the impurity content of the Z-isomer is 18.10%. However, using boron trifluoride etherate as a catalyst, the impurity content of the Z-isomer in the obtained product is greatly increased to about 51.4%.

[0043] (2) The present invention uses the compound represented by formula II or its n-heptane solution obtained above to prepare vitamin K2, which can obtain a high-yield and high-purity vitamin K2 product, reducing the material consumption and energy consumption of the unit product of vitamin K2. The process conditions are mild, easy to operate and control, and has good industrial promotion and application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is the HPLC chart of compound 01 obtained in Example 1.

[0045] Figure 2 This is the HPLC chart of compound 02 obtained in Example 1.

[0046] Figure 3 This is the HPLC chart of vitamin K2 obtained in Example 1. DETAILED DESCRIPTION

[0047] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0048] Regarding the definitions of terms used in the present invention, unless otherwise stated, the initial definitions provided for the terms in this document apply to the terms throughout the text; for terms that are not specifically defined herein, the meaning that a person skilled in the art would give them should be given based on the disclosure and / or context.

[0049] Example 1

[0050] ① Preparation of Compound 01

[0051]

[0052] Under nitrogen protection, add 100g (about 0.387mol) vitamin K4 (2-methyl-1,4-naphthalene diol diacetate) and 1000ml methanol to the reaction bottle, then add 53.5g potassium carbonate aqueous solution with a concentration of about 30wt% (potassium carbonate about 0.116mol) and 10.1g hydrosulfite (about 0.058mol sodium dithionite), react at 15℃±5℃ for 8h, and after the reaction is completed (vitamin K4 residual amount ≤0.5%) monitored by TLC or HPLC, add 1022.9 g of hydrochloric acid (containing about 0.233 mol of HCl) with a concentration of about 0.83 wt% was added, stirred and mixed, and methanol was removed by distillation under reduced pressure (50°C, -0.09 MPa). The mixture was cooled to room temperature and filtered. The filter cake was added to 550 ml of a mixed solvent of ethyl acetate-n-heptane (volume ratio 1:10), and slurried at 25°C±5°C for 1 h. The mixture was filtered and dried to obtain compound 01 as an off-white solid with a yield of 89.2% and a HPLC purity of 99.8% (peak area normalization method). Figure 1 shown.

[0053] Compound 01 1 H-NMR and 13 C-NMR spectrum data (solvent CD3OD) are shown in Tables 1 and 2, respectively.

[0054]

[0055] Table 1. Compound 01 1 H-NMR spectrum data

[0056]

[0057] Table 2. Compound 01 13 C-NMR spectrum data

[0058]

[0059] The high performance liquid chromatography (HPLC) detection method of compound 01 is as follows:

[0060]

[0061] Test solution: Weigh about 25 mg of the compound 01 obtained above, place it in a 50 mL brown volumetric flask, add acetonitrile to dissolve and dilute to the mark, shake well, and obtain the solution.

[0062] ② Preparation of Compound 02

[0063]

[0064] Under nitrogen protection, 100 g (about 0.462 mol, HPLC purity ≥ 99.5%) of compound 01, 114.2 g (about 0.393 mol) of geranyl linalool and 1115 ml of toluene were added to the reaction bottle, and then 8.11 g of a 50 wt% aqueous fluoroboric acid solution (containing about 0.046 mol of HBF4 as a catalyst) was added, and the mixture was reacted at 50°C ± 2°C for 10 h. After the reaction was completed by monitoring by TLC or HPLC, the mixture was cooled to room temperature, 250 ml of water was added to quench the reaction, the mixture was allowed to stand, and the organic phase (toluene layer) was taken, washed once with 100 ml of saturated brine, and 560 ml of saturated sodium chloride solution was added. ml water, distill under reduced pressure (40°C, -0.09MPa) to remove toluene, then add 600ml of n-heptane, cool to 5°C, filter to obtain a filtrate, let stand, separate layers, take the organic phase (n-heptane layer), wash once with 100ml of saturated brine, add 300ml of dimethyl sulfoxide (DMSO), let stand, separate layers, take the DMSO layer, add 600ml of n-heptane and 150ml of water, let stand, separate layers, take the n-heptane layer, extract the DMSO / water layer once with 200ml of n-heptane, combine the n-heptane layers, which is the n-heptane solution of compound 02, weighing about 683.3g, and used directly in the next step without separation.

[0065] The n-heptane solution of the above-mentioned compound 02 was subjected to rotary evaporation to remove the solvent n-heptane to obtain an oily substance containing compound 02, which was detected by high performance liquid chromatography (HPLC), as follows:

[0066]

[0067] Test solution: Weigh about 25 mg of the oily substance containing compound 02 obtained above, place it in a 50 mL brown volumetric flask, add acetonitrile to dissolve and dilute to the scale, shake well, and obtain.

[0068] The above oily substance containing compound 02 was tested as follows: the HPLC purity of compound 02 (retention time 36.250 min) was 75.18% (peak area normalization method), and the content of Z-isomer impurity (retention time 37.567 min) was 18.10%. Figure 2 shown.

[0069]

[0070] Compound 02 1 H-NMR and 13 C-NMR spectrum data (solvent CD3OD) are shown in Tables 3 and 4, respectively.

[0071]

[0072] Table 3. Compound 02 1 H-NMR spectrum data

[0073]

[0074] Table 4. Compound 02 13 C-NMR spectrum data

[0075]

[0076]

[0077] ③Preparation of Vitamin K2

[0078]

[0079] Under nitrogen protection, the n-heptane solution of compound 02 obtained in the previous step (about 683.3 g), 600 ml of n-heptane and 150 ml of methanol were added to the reactor, and then 176 g of a sodium hydroxide aqueous solution with a concentration of about 10 wt% (about 0.44 mol of sodium hydroxide) was added, and the mixture was reacted at 20°C ± 5°C for 5 h. After the reaction was completed by monitoring by TLC or HPLC, hydrochloric acid with a concentration of about 2 wt% was added until the pH value of the feed solution was 6.5, and then air was blown in for 1.5 h, allowed to stand, and separated. The aqueous phase was extracted once with 500 ml of n-heptane, the organic phases were combined, and washed once with 200 ml of saturated brine, and the organic phase and 2500 ml of n-heptane were passed through a silica gel column (silica gel 150 g) in turn, and the colorless eluent (about 900 g) in the front was collected separately. ml), then collect the colored product-containing eluate at the back, distill under reduced pressure (30°C, -0.09MPa) until about 400ml remains, add 600ml of anhydrous ethanol, continue to distill under reduced pressure until about 400ml remains, then add 300ml of anhydrous ethanol, continue to distill under reduced pressure until about 400ml remains, then add 600ml of anhydrous ethanol and 100ml of acetone, stir to dissolve, add vitamin K2 solid powder, stir and crystallize at -15±2°C, filter or separate, recrystallize once with anhydrous ethanol, and dry under reduced pressure (25°C±2°C, -0.09MPa) to obtain the vitamin K2 product as a light yellow solid with a yield of 42.3% (based on geranyl linalool) and an HPLC purity of 99.94% (its HPLC spectrum is shown in Figure 3 Peak area normalization method).

[0080] The high performance liquid chromatography (HPLC) detection method of vitamin K2 is as follows:

[0081] Chromatographic columns Tracer Excel ODS-A(4.6mm×150mm, 5μm) Column temperature 40℃ Detection wavelength 270nm Injection volume 20μL Flow rate 1.0ml / min Mobile phase Methanol

[0082] Test solution: Weigh about 25 mg of the vitamin K2 obtained above, place it in a 25 mL brown volumetric flask, add isopropanol to dissolve and dilute to the scale, shake well, and obtain.

[0083] The high performance liquid chromatography (HPLC) detection method for the aforementioned compound 01, compound 02 and vitamin K2 has been verified and complies with the regulations and requirements for methodological validation in the 2020 edition of the "Chinese Pharmacopoeia".

[0084] Example 2. Preparation of Compound 01

[0085] Increase the amount of potassium carbonate to 0.6 equivalents (i.e., the molar ratio of vitamin K4 to potassium carbonate is 1:0.6): under nitrogen protection, add 100g (about 0.387mol) of vitamin K4 (2-methyl-1,4-naphthalene diol diacetate) and 1000ml of methanol to the reaction bottle, then add 107g of a 30wt% potassium carbonate aqueous solution (about 0.232mol of potassium carbonate) and 10.1g of sodium hydrosulfite (about 0.058mol), and react at 15℃±5℃ for 8 hours. h. After the reaction is completed (vitamin K4 residual amount ≤ 0.5%) as monitored by TLC or HPLC, 1022.9 g of hydrochloric acid with a concentration of about 0.83 wt% is added, stirred and mixed, and methanol is removed by vacuum distillation (50°C, -0.09 MPa). The mixture is cooled to room temperature and filtered. The filter cake is added to 550 ml of a mixed solvent of ethyl acetate-n-heptane (volume ratio 1:10), and slurried at 25°C±5°C for 1 h. The mixture is filtered and dried to obtain compound 01 with a yield of 85.4% and a HPLC purity of 98.7%.

[0086] Example 3. Preparation of Compound 01

[0087] Increase the amount of potassium carbonate to 0.8 equivalents: under nitrogen protection, add 100g (about 0.387mol) vitamin K4 (2-methyl-1,4-naphthalene diol diacetate) and 1000ml methanol to the reaction bottle, then add 142.8g of potassium carbonate aqueous solution with a concentration of about 30wt% (potassium carbonate about 0.31mol) and 10.1g of sodium hydrosulfite (about 0.058mol), react at 15℃±5℃ for 8h, and monitor by TLC or HPLC. After the reaction is completed (vitamin K4 residual amount ≤ 0.5%), add 1022.9 g of hydrochloric acid with a concentration of about 0.83 wt%, stir and mix, remove methanol by vacuum distillation (50°C, -0.09 MPa), cool to room temperature, filter, add the filter cake to 550 ml of a mixed solvent of ethyl acetate-n-heptane (volume ratio 1:10), beat at 25°C±5°C for 1 h, filter, and dry to obtain compound 01 with a yield of 78.3% and an HPLC purity of 96.5%.

[0088] Example 4. Preparation of Compound 01

[0089] Without adding insurance powder (sodium dithionite): under nitrogen protection, add 100g (about 0.387mol) of vitamin K4 (2-methyl-1,4-naphthalene diol diacetate) and 1000ml of methanol to the reaction bottle, then add 53.5g of potassium carbonate aqueous solution with a concentration of about 30wt% (about 0.116mol of potassium carbonate), react at 15℃±5℃ for 8h, monitor the completion of the reaction by TLC or HPLC (vitamin K4 residual amount ≤0.5%), add 1022.9g of hydrochloric acid with a concentration of about 0.83wt%, stir and mix, remove methanol by vacuum distillation (50℃, -0.09MPa), cool to room temperature, filter, add the filter cake to 550ml of a mixed solvent of ethyl acetate-n-heptane (volume ratio 1:10), slurry at 25℃±5℃ for 1h, filter, and dry to obtain compound 01 with a yield of 75.6% and an HPLC purity of 95.85%.

[0090] Example 5. Preparation of Vitamin K2

[0091] Reduce the amount of fluoroboric acid to 0.05 equivalents (i.e., the molar ratio of compound 1 to HBF4 is 1:0.05): under nitrogen protection, add 100g (about 0.462mol, HPLC purity ≥99.5%) of compound 01, 114.2g (about 0.393mol) of geranyl linalool and 1115ml of toluene to the reaction bottle, and then add 4.1g of a 50wt% aqueous fluoroboric acid solution (containing about 0.023mol of HBF4 as a catalyst), react at 50℃±2℃ for 10h, monitor the reaction by TLC or HPLC, cool to room temperature, add 250ml of water to quench the reaction, let stand, separate the layers, and take the organic phase (toluene layer), washed once with 100 ml saturated brine, added 560 ml water, and distilled under reduced pressure (40°C, -0.09 MPa) to remove toluene, then added 600 ml n-heptane, cooled to 5°C, filtered to obtain a filtrate, allowed to stand, separated into layers, the organic phase (n-heptane layer) was taken, washed once with 100 ml saturated brine, added 300 ml dimethyl sulfoxide (DMSO), allowed to stand, separated into layers, the DMSO layer was taken, 600 ml n-heptane and 150 ml water were added, allowed to stand, separated into layers, the n-heptane layer was taken, the DMSO / water layer was extracted once with 200 ml n-heptane, the n-heptane layers were combined, i.e., the n-heptane solution of compound 02, which was directly used in the next step without separation.

[0092] Vitamin K2 was prepared in the same manner as in Example 1 to obtain a vitamin K2 product with a yield of 41.7% (based on geranyl linalool) and an HPLC purity of ≥99.5%.

[0093] Examples 6 and 7. Preparation of Vitamin K2

[0094] The amount of fluoroboric acid was increased to 0.2 equivalents and 0.3 equivalents respectively, and other process conditions remained unchanged. Vitamin K2 was prepared in the same manner as in Example 5 to obtain a vitamin K2 product with a yield of ≥40% (based on geranyl linalool) and an HPLC purity of ≥99.5%.

[0095] Example 8. Preparation of Vitamin K2

[0096] The catalyst was changed to boron trifluoride etherate (the amount used was 0.1 equivalent, that is, the molar ratio of compound 1 to boron trifluoride etherate was about 1:0.1), and other process conditions remained unchanged. Vitamin K2 was prepared in the same manner as in Example 5 to obtain a vitamin K2 product with a yield of about 22.5% (based on geranyl linalool) and an HPLC purity of ≥99.5%. Among them, the content of the Z-isomer impurity in the obtained oily substance containing compound 02 was greatly increased to about 51.4%.

[0097] Examples 9 and 10, Preparation of Vitamin K2

[0098] The catalyst was changed to dodecylbenzenesulfonic acid and p-toluenesulfonic acid (in an amount of 0.1 equivalent), and other process conditions remained unchanged, and vitamin K2 was prepared according to the same method as Example 5; the results showed that a large amount of impurities were generated during the reaction, which affected the yield and / or purity of the obtained vitamin K2 product, and their catalytic effects (yield and purity) of the alkylation reaction were not as good as those of boron trifluoride etherate and fluoroboric acid.

[0099] Example 11. Preparation of Vitamin K2

[0100] Under nitrogen protection, 100 g (about 0.462 mol, HPLC purity ≥ 99.5%) of compound 01, 114.2 g (about 0.393 mol) of geranyl linalool and 1115 ml of toluene were added to the reaction bottle, and then 8.11 g of a 50 wt% aqueous fluoroboric acid solution (containing about 0.046 mol of HBF4 as a catalyst) was added, and the mixture was reacted at 50°C ± 2°C for 10 h. After the reaction was completed by TLC or HPLC monitoring, the mixture was cooled to room temperature, 250 ml of water was added to quench the reaction, the mixture was allowed to stand, and the layers were separated. The organic phase (toluene layer) was taken and washed once with 100 ml of saturated brine. Add 560 ml of water, remove toluene by reduced pressure distillation (40°C, -0.09 MPa), then add 600 ml of n-heptane, cool to 5°C, filter to obtain a filtrate, let stand, separate layers, take the organic phase (n-heptane layer), wash once with 100 ml of saturated brine, add 300 ml of dimethyl sulfoxide (DMSO), let stand, separate layers, take the DMSO layer, add 600 ml of n-heptane and 150 ml of water, let stand, separate layers, take the n-heptane layer, extract the DMSO / water layer once with 200 ml of n-heptane, combine the n-heptane layers, which is the n-heptane solution of compound 02, and use it directly in the next step without separation.

[0101] Under nitrogen protection, the n-heptane solution of the aforementioned compound 02, 600 ml of n-heptane and 150 ml of methanol were added to the reactor, and then 246.8 g of a potassium hydroxide aqueous solution with a concentration of about 10 wt% (about 0.44 mol of potassium hydroxide) was added, and the mixture was reacted at 20°C ± 5°C for 5 h. After the reaction was completed by monitoring by TLC or HPLC, hydrochloric acid with a concentration of about 2 wt% was added until the pH value of the feed solution was 6.5, and then air was blown in for 1.5 h, allowed to stand, and separated. The aqueous phase was extracted once with 500 ml of n-heptane, the organic phases were combined, and washed once with 200 ml of saturated brine, and the organic phase and 2500 ml of n-heptane were passed through a silica gel column (silica gel 150 g) in turn, and the colorless liquid in the front was collected separately. The eluate is then collected and the colored eluate is distilled under reduced pressure (30°C, -0.09MPa) until about 400ml remains, 600ml of anhydrous ethanol is added, and the distillation under reduced pressure is continued until about 400ml remains, and then 300ml of anhydrous ethanol is added, and the distillation under reduced pressure is continued until about 400ml remains, and then 600ml of anhydrous ethanol and 100ml of acetone are added, stirred to dissolve, and vitamin K2 solid powder is added, stirred at -15±2°C for crystallization, filtered or separated, recrystallized once with anhydrous ethanol, and dried under reduced pressure (25°C±2°C, -0.09MPa) to obtain a vitamin K2 product with a yield of ≥40% (based on geranyl linalool) and an HPLC purity of ≥99.5%.

[0102] Example 12. Preparation of Vitamin K2

[0103] Under nitrogen protection, 100 g (about 0.462 mol, HPLC purity ≥ 99.5%) of compound 01, 114.2 g (about 0.393 mol) of geranyl linalool and 1115 ml of toluene were added to the reaction bottle, and then 8.11 g of a 50 wt% aqueous fluoroboric acid solution (containing about 0.046 mol of HBF4 as a catalyst) was added, and the mixture was reacted at 50°C ± 2°C for 10 h. After the reaction was completed by TLC or HPLC monitoring, the mixture was cooled to room temperature, 250 ml of water was added to quench the reaction, the mixture was allowed to stand, and the layers were separated. The organic phase (toluene layer) was taken and washed once with 100 ml of saturated brine. Add 560 ml of water, remove toluene by reduced pressure distillation (40°C, -0.09 MPa), then add 600 ml of n-heptane, cool to 5°C, filter to obtain a filtrate, let stand, separate layers, take the organic phase (n-heptane layer), wash once with 100 ml of saturated brine, add 300 ml of dimethyl sulfoxide (DMSO), let stand, separate layers, take the DMSO layer, add 600 ml of n-heptane and 150 ml of water, let stand, separate layers, take the n-heptane layer, extract the DMSO / water layer once with 200 ml of n-heptane, combine the n-heptane layers, which is the n-heptane solution of compound 02, and use it directly in the next step without separation.

[0104] Under nitrogen protection, the n-heptane solution of the aforementioned compound 02 (about 683.3 g), 600 ml of n-heptane and 150 ml of methanol were added to the reactor, and then 105.4 g of a lithium hydroxide aqueous solution (about 0.44 mol of lithium hydroxide) with a concentration of about 10 wt% was added, and the reaction was carried out at 20°C ± 5°C for 5 h. After the reaction was completed by monitoring by TLC or HPLC, hydrochloric acid with a concentration of about 2 wt% was added until the pH value of the feed solution was 6.5, and then air was introduced for 1.5 h, allowed to stand, and separated. The aqueous phase was extracted once with 500 ml of n-heptane, the organic phases were combined, and washed once with 200 ml of saturated brine, and the organic phase and 2500 ml of n-heptane were passed through a silica gel column (silica gel 150 g) in turn, and the front The colorless eluate is collected, and the colored eluate is then collected, and vacuum distilled (30°C, -0.09MPa) until about 400ml remains, 600ml of anhydrous ethanol is added, and the vacuum distillation is continued until about 400ml remains, and then 300ml of anhydrous ethanol is added, and the vacuum distillation is continued until about 400ml remains, and then 600ml of anhydrous ethanol and 100ml of acetone are added, and the solution is stirred to be clear, and vitamin K2 solid powder is added, and the solution is stirred at -15±2°C for crystallization, filtered or separated, and recrystallized once with anhydrous ethanol, and dried under reduced pressure (25°C±2°C, -0.09MPa) to obtain a vitamin K2 product with a yield of ≥40% (based on geranyl linalool) and an HPLC purity of ≥99.5%.

[0105] Of course, the present invention may have many other embodiments. Without violating the spirit and essence of the present invention, those skilled in the art may make various corresponding changes and / or deformations based on the present invention. These corresponding changes and / or deformations should all fall within the scope of protection of the claims attached to the present invention.

Claims

1. Use of fluoroboric acid or its aqueous solution as a catalyst in the preparation of a compound represented by formula II; wherein: The compound represented by formula II is produced by reacting the compound represented by formula I with geranyl linalool; In the formula, R0 is a C1-C4 alkyl group; preferably, R0 is a methyl group.

2. The use according to claim 1, characterized in that: The catalyst is a fluoroboric acid aqueous solution with a concentration of at least 30 wt%.

3. The use according to claim 2, characterized in that: The catalyst is a 30wt% to 75wt% fluoroboric acid aqueous solution; preferably, the catalyst is a 45wt% to 60wt% fluoroboric acid aqueous solution.

4. The use according to any one of claims 1 to 3, characterized in that: The molar ratio of the compound represented by formula I to fluoroboric acid is 1:0.05-0.5; preferably, the molar ratio of the compound represented by formula I to fluoroboric acid is 1:0.05-0.

3.

5. The use according to any one of claims 1 to 3, characterized in that: The molar ratio of the compound represented by formula I to geranyl linalool is 1:0.8-1; preferably, the molar ratio of the compound represented by formula I to geranyl linalool is 1:0.8-0.

95.

6. The use according to any one of claims 1 to 3, characterized in that: The compound represented by formula I is reacted with geranyl linalool under the protection of an inert gas; preferably, the inert gas is nitrogen or argon.

7. The use according to any one of claims 1 to 3, characterized in that: The compound represented by formula I undergoes an alkylation reaction with geranyl linalool in an organic solvent; Preferably, The organic solvent is an aromatic hydrocarbon solvent; and / or the mass volume ratio of the compound represented by formula I to the organic solvent is 1:10-20 g / ml; More preferably, The aromatic hydrocarbon solvent is toluene or ethylbenzene; and / or the mass volume ratio of the compound represented by formula I to the organic solvent is 1:10-15 g / ml.

8. The use according to claim 7, characterized in that: The reaction temperature of the alkylation reaction is 45-60°C; preferably, the reaction temperature of the alkylation reaction is 48-52°C.

9. The use according to claim 7, characterized in that: The reaction time of the alkylation reaction is 8 to 12 hours; preferably, the reaction time of the alkylation reaction is 9.5 to 11 hours.

10. Use of fluoroboric acid or its aqueous solution in the preparation of vitamin K2, characterized in that: The preparation method of vitamin K2 comprises the following steps: reacting the compound represented by formula I with geranyl linalool to generate the compound represented by formula II; hydrolyzing the compound represented by formula II in a mixed solvent of an alcohol solvent and n-heptane and in the presence of a hydroxide aqueous solution, then adding hydrochloric acid, and blowing in air or oxygen to generate vitamin K2; wherein the alcohol solvent is methanol and / or ethanol; the hydroxide is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; Fluoroboric acid or its aqueous solution is used as a catalyst in the preparation of the compound represented by formula II; the preparation of the compound represented by formula II is according to any one of claims 1 to 3; In the formula, R0 is a C1-C4 alkyl group; preferably, R0 is a methyl group.

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