A method for preparing squalene

Abstract

This invention provides a method for preparing squalene. The method involves reacting 1,4-dihalobutane and magnesium powder via a Grignard reaction to obtain the corresponding Grignard reagent, which is then reacted with 5-chloro-2-pentanone via an addition reaction and acidification to prepare 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene. The obtained 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene and magnesium powder are then reacted with the Grignard reagent to obtain the corresponding Grignard reagent, which is then reacted with 6-methyl-5-hepten-2-one via an addition reaction and acidification to prepare squalene. The raw materials used in this invention are inexpensive and readily available. Only two Grignard and addition reactions are required to obtain the target product, making the steps simple. The reaction conditions are mild, the equipment is simple, the cost is low, and it is easy to industrialize. Wastewater generation is low, making it green, safe, and environmentally friendly. The reaction has high selectivity, few byproducts, and high yield and purity of the target product, making it suitable for green industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing squalene, belonging to the field of fine chemical technology. Background Technology

[0002] Squalene (I), chemically known as 2,6,10,15,19,23-hexamethyl-2,6,10,14,18,22-docosahexaene, is a natural oil extracted from shark liver. It possesses significant medicinal value and has been used in influenza vaccines, where it enhances immunity and thus vaccine efficacy. GlaxoSmithKline's commercially available influenza vaccine uses squalene. Environmentalists estimate that approximately 3 million sharks are killed annually for squalene extraction. The applications of squalene are expanding; in May 2020, GlaxoSmithKline announced plans to produce 1 billion squalene adjuvants for use in developing vaccines against COVID-19. Subsequently, a squalene-based vaccine was developed in California, USA, and is expected to undergo clinical trials. However, squalene sources are limited; extracting one ton of squalene requires approximately 300 sharks. The Shark Allies, a shark conservation organization in California, points out that administering two squalene-containing vaccines against COVID-19 to the global population would require the slaughter of approximately 500,000 more sharks, which is detrimental to species conservation. Furthermore, squalene is also used in cosmetics and motor oils, creating a significant and urgent need for non-animal-derived squalene.

[0003] Squalene has the following structure:

[0004]

[0005] Besides its use in vaccines, squalene can effectively inhibit 4-methylnitroso-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors, protect the body's sebum from UV-induced peroxidation, and has antioxidant, UV-damage-resistant, and moisturizing effects, making it widely used as a skin emollient. Squalene is also widely used as a drug sustained-release agent to prolong the drug's half-life. Furthermore, squalene possesses penetrating, diffusing, and bactericidal properties. Whether taken orally or applied topically, it can absorb large amounts of oxygen, enhance cellular metabolism, and relieve fatigue, thus becoming a clearly defined active ingredient widely used in functional foods. In recent years, many countries have included it in their drug classifications; the Chinese Pharmacopoeia lists squalene as an oral nutritional supplement with a dosage of one gram daily. Japan has expanded its use to include oral medications for treating low blood pressure, anemia, diabetes, cirrhosis, cancer, constipation, and tooth decay, as well as topical medications for treating gallstones and bladder stones, tonsillitis, rheumatism, neuralgia, bronchitis, colds, rhinitis, asthma, gout, and gastric and duodenal ulcers. Currently, squalene health foods on the domestic and international markets include various products such as squalene capsules, squalene softgels, and capsules, with each capsule / softgel containing 500–1000 mg of squalene. Furthermore, due to its excellent antioxidant activity, squalene is added to edible vegetable oils such as soybean oil and peanut oil to inhibit or delay oil oxidation, thereby improving the stability of edible vegetable oils and extending product shelf life.

[0006] Currently, squalene is mainly derived from deep-sea shark liver oil, requiring the killing of large numbers of deep-sea sharks, leading to the uncontrolled and excessive hunting of sharks and a decline in their population. Furthermore, the extracted squalene is susceptible to infection by shark pathogens, which can lead to human infection. The lack of a strict and unified production standard also limits the widespread use of squalene. Therefore, the chemical synthesis of squalene has become a hot research topic.

[0007] Currently, there are two main methods for the chemical preparation of squalene:

[0008] Method 1 uses geranylacetone as a raw material, reacts it with sodium acetylenite, and then synthesizes squalene through oxidative coupling, reduction and dehydration. The reaction process is described as follows: reaction route 1.

[0009]

[0010] Reaction route 1

[0011] Method 2 uses dichlorobutane as the starting material. It first reacts with triethyl phosphite via Arbuzov reaction to obtain a phosphonate intermediate. Then, under alkaline conditions, it obtains bipyridyl ether, which is then condensed with two molecules of geranylacetone via Wittig-Horner condensation to obtain squalene. The reaction process is described as follows: Reaction Route 2.

[0012]

[0013] Reaction route 2

[0014] Route 1, with its reductive dehydration process, is prone to over-reduction of carbon-carbon double bonds, producing byproducts that are difficult to remove. Route 2 requires a strong alkali and generates large amounts of phosphorus-containing wastewater, resulting in poor environmental performance. Furthermore, both methods require two molecules of geranylace to obtain one molecule of squalene. Geranylace needs to be prepared from linalool and ethyl acetoacetate under aluminum isopropoxide catalysis, or from linalool and methyl isopropenyl ether, which are cumbersome procedures. Additionally, linalool is expensive, leading to high costs for squalene obtained through these methods and hindering the widespread use of synthetically produced squalene.

[0015] In summary, researching and optimizing a method for preparing squalene from non-animal sources is of great significance for reducing the production cost of artificial synthesis, addressing the shortage of squalene resources, expanding the application scope of squalene, and improving its medical and health benefits. Summary of the Invention

[0016] To address the shortcomings of existing technologies, this invention provides a method for preparing squalene. This method uses 1,4-dihalobutane with the structural formula II as a raw material, and obtains squalene through two Grignard reactions and addition reactions. The raw material is easy to obtain or prepare, the operation method is simple, safe and environmentally friendly, with low wastewater volume, low cost, high yield and selectivity, and few by-products, making it suitable for industrial production.

[0017] Terminology Explanation:

[0018] Compound of Formula II: 1,4-Dihalobutane;

[0019] Compound of Formula III: 5-chloro-2-pentanone;

[0020] Compound of Formula IV: 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene;

[0021] Compound of formula V: 6-methyl-5-hepten-2-one;

[0022] Compound of Formula I: Squalene.

[0023] The compound numbers and structural formula numbers in this specification are completely consistent and have the same referential relationship, based on the compound structural formula.

[0024] The technical solution of the present invention is as follows:

[0025] A method for preparing squalene, comprising the following steps:

[0026] (1) In solvent A, under the action of initiator 1, compound II and magnesium powder undergo a Grignard reaction to obtain the corresponding Grignard reagent; then, compound III is added to and acidified to prepare compound IV.

[0027]

[0028] In the structural formula of compound II, the substituent X is Cl or Br;

[0029] (2) In solvent B, under the action of initiator 2, compound IV and magnesium powder undergo a Grignard reaction to obtain the corresponding Grignard reagent; then squalene is prepared by addition reaction and acidification with compound V.

[0030]

[0031] According to the present invention, preferably, in step (1), the solvent A is one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, methoxycyclopentane, hexane, heptane or toluene; the mass ratio of the solvent A to the compound of formula II is (2-10):1.

[0032] According to the present invention, preferably, in step (1), the initiator 1 is one or a combination of iodine, bromoethane, or 1,2-dibromoethane; the mass of the initiator 1 is 0.5%-5.0% of the mass of the compound of formula II.

[0033] According to the present invention, preferably, in step (1), the molar ratio of magnesium powder, compound III, and compound II is (2.0-2.6):(2.0-3.0):1; preferably, the molar ratio of magnesium powder, compound III, and compound II is (2.1-2.3):(2.1-2.3):1.

[0034] According to the present invention, preferably, in step (1), the compound of formula II is added to the reaction system in two parts, that is: first, 1-10% of the total mass of the compound of formula II is added to the system containing solvent A1, initiator 1 and magnesium powder to initiate the reaction, and then the remaining compound of formula II is added to the system dropwise; the type of solvent A1 is the same as that of solvent A.

[0035] Preferably, after the reaction is initiated, the remaining compound of formula II is diluted with solvent A2 and then added to the system dropwise.

[0036] More preferably, the type of solvent A2 is the same as that of solvent A; the mass ratio of solvent A2 to the residual compound II is 1-10:1, and the total amount of solvent A2 and solvent A1 is equal to the amount of solvent A.

[0037] More preferably, the dropping rate is 1-5 g / min, more preferably 1-3 g / min.

[0038] According to the present invention, preferably, in step (1), the Grignard reaction temperature is 20-100°C; preferably, the Grignard reaction temperature is 40-70°C. The Grignard reaction time is 0.5-3 hours; preferably, the Grignard reaction time is 1-2 hours. The Grignard reaction is carried out under an inert gas atmosphere.

[0039] According to the present invention, preferably, in step (1), the reaction solution obtained by the Grignard reaction of compound II and magnesium powder is not post-treated and is directly carried out in the next step of the reaction.

[0040] According to the present invention, preferably, in step (1), the reaction temperature of the Grignard reagent and the compound of formula III is -20 to 35°C; more preferably, the reaction temperature of the Grignard reagent and the compound of formula III is 5 to 25°C. The reaction time of the Grignard reagent and the compound of formula III is 0.5 to 5 hours, preferably 1 to 3 hours. The reaction of the Grignard reagent and the compound of formula III is carried out under an inert gas atmosphere.

[0041] According to the present invention, preferably, in step (1), the compound of formula III is added to the system containing the Grignard reagent by dropwise addition.

[0042] According to the present invention, preferably, in step (1), the acidification is to adjust the pH of the system to 3-5 using an aqueous solution of ammonium chloride with a mass concentration of 10-30 wt%.

[0043] According to the present invention, in step (1), the post-treatment method of the reaction solution obtained by the addition reaction of Grignard reagent and compound III and acidification is as follows: water and dichloromethane are added to the reaction solution or the residue after the solvent is recovered by vacuum distillation, the pH value is adjusted to 3-5 with ammonium chloride aqueous solution, the layers are separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined, and then washed with saturated sodium chloride aqueous solution; after the solvent is removed by vacuum distillation of the organic phase, further vacuum distillation is carried out to obtain compound IV.

[0044] According to the present invention, preferably, in step (2), the solvent B is one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, methoxycyclopentane, hexane, heptane or toluene; the mass ratio of the solvent B to the compound of formula IV is (2-10):1.

[0045] According to the present invention, preferably, in step (2), the initiator 2 is one or a combination of iodine, bromoethane, or 1,2-dibromoethane; the mass of the initiator 2 is 0.5%-3.0% of the mass of the compound of formula IV.

[0046] According to the present invention, preferably, in step (2), the molar ratio of magnesium powder, compound V and compound IV is (2.0-2.6):(2.0-3.0):1; preferably, the molar ratio of magnesium powder, compound V and compound IV is (2.1-2.3):(2.1-2.3):1.

[0047] According to the present invention, preferably, in step (2), the compound of formula IV is added to the reaction system in two parts, namely: first, 1-10% of the total mass of the compound of formula IV is added to the system containing solvent B1, initiator 2 and magnesium powder to initiate the reaction, and then the remaining compound of formula IV is added to the system dropwise; the type of solvent B1 is the same as that of solvent B.

[0048] Preferably, after the reaction is initiated, the remaining compound of formula IV is diluted with solvent B2 and then added to the system dropwise.

[0049] More preferably, the type of solvent B2 is the same as that of solvent B; the mass ratio of solvent B2 to the residual compound IV is 1-10:1, and the total amount of solvent B2 and solvent B1 is equal to the amount of solvent B.

[0050] More preferably, the dropping rate is 1-5 g / min, more preferably 1-3 g / min.

[0051] According to the present invention, preferably, in step (2), the Grignard reaction temperature is 20-120°C; preferably, the Grignard reaction temperature is 50-80°C. The Grignard reaction time is 0.5-3 hours; preferably, the Grignard reaction time is 1-2 hours. The Grignard reaction is carried out under an inert gas atmosphere.

[0052] According to the present invention, preferably, in step (2), the reaction solution obtained by the Grignard reaction of compound IV and magnesium powder is not post-treated and is directly carried out in the next step of the reaction.

[0053] According to the present invention, preferably, in step (2), the reaction temperature of the Grignard reagent and the compound of formula V is -20 to 40°C; more preferably, the reaction temperature of the Grignard reagent and the compound of formula V is 15 to 35°C. The reaction time of the Grignard reagent and the compound of formula V is 0.5 to 5 hours, preferably 1 to 3 hours. The reaction of the Grignard reagent and the compound of formula V is carried out under an inert gas atmosphere.

[0054] According to the present invention, preferably, in step (2), the compound of formula V is added to the system containing the Grignard reagent by dropwise addition.

[0055] According to the present invention, preferably, in step (2), the acidification is to adjust the pH of the system to 3-5 using an aqueous solution of ammonium chloride with a mass concentration of 10-30 wt%.

[0056] According to the present invention, in step (2), the post-treatment method of the reaction solution obtained by the addition reaction of Grignard reagent and compound of formula V and acidification is as follows: water and dichloromethane are added to the reaction solution or the residue after the solvent is recovered by vacuum distillation, the pH value is adjusted to 3-5 with ammonium chloride aqueous solution, the layers are separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined, and then washed with saturated sodium chloride aqueous solution; after the solvent is removed by vacuum distillation of the organic phase, further vacuum distillation is carried out to obtain squalene.

[0057] The reaction process of this invention is described by the following reaction route 3:

[0058]

[0059]

[0060] Reaction route 3

[0061] In the structural formula of compound II, the substituent X is Cl or Br.

[0062] Technical features and beneficial effects of the present invention:

[0063] 1. This invention provides a low-cost, green method for preparing squalene. The method involves reacting 1,4-dihalobutane and magnesium powder via a Grignard reaction to obtain the corresponding Grignard reagent, which is then reacted with 5-chloro-2-pentanone via an addition reaction and followed by acidification to prepare 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene. The obtained 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene and magnesium powder are then reacted with the Grignard reagent via a Grignard reaction to obtain the corresponding Grignard reagent, which is then reacted with 6-methyl-5-hepten-2-one via an addition reaction and followed by acidification to prepare squalene.

[0064] 2. The raw materials used in the method of this invention are inexpensive and readily available, resulting in low cost; the steps are simple, the reaction conditions are mild, and the target product can be prepared with only two Grignard reactions and addition reactions; the equipment is simple and easy to industrialize; the amount of wastewater generated is small, making it green, safe and environmentally friendly; the raw materials and intermediate products involved are stable, the reaction selectivity is high, the by-products are few, and the yield and purity of the target product are high, making it suitable for green industrial production.

[0065] 3. The Grignard reaction and addition reaction involved in the route of this invention are both classical reaction types. The reaction is easy to operate. The preferred method of di-halogenated material is dilution and dropwise addition, which effectively avoids the coupling side reaction between Grignard reagent and haloalkane. The resulting Grignard reagent has a specific reaction site and suitable Grignard reagent activity. After addition with carbonyl, the carbon-carbon double bond is introduced at a specific position after acidification and dehydration. The reaction has high selectivity and high yield. Detailed Implementation

[0066] The technical concept and essential features of the present invention are described in detail below with reference to embodiments and comparative examples, but this should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made based on the essential features of the present invention are covered within the scope of protection of the present invention.

[0067] All raw materials and reagents used in the examples were commercially available products. All percentages (%) in the examples are weight percentages, unless otherwise specified. All yields in the examples are molar yields.

[0068] Example 1: Preparation of 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene (IV)

[0069] Under nitrogen protection, 150 g of tetrahydrofuran, 26.7 g (1.1 mol) of magnesium powder, 0.5 g of iodine, 1.0 g of 1,2-dibromoethane, and 3.0 g of 1,4-dichlorobutane were added to a 1000 mL four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, and reflux condenser. After initiation at 45-50 °C, a mixed solution of 60.5 g (0.5 mol) of 1,4-dichlorobutane and 250 g of tetrahydrofuran was added dropwise between 45-55 °C over 3 hours. The reaction was then stirred at 55-60 °C for 2 hours to obtain Grignard reagent. The mixture was cooled to 10-15 °C, and under nitrogen protection, 132.5 g (1.1 mol) of 5-chloro-2-pentanone was added dropwise over 1 hour. The reaction was then stirred at 15-20 °C for 2 hours. The solvent was recovered by vacuum distillation at 40-45℃. 200 g of water and 200 g of dichloromethane were added to the residue, and the pH was adjusted to 3-4 with a 20 wt% ammonium chloride aqueous solution. The mixture was stirred at 20-30℃ for 1 hour, resulting in layer separation. The aqueous phase was extracted twice with dichloromethane, 100 g each time. The combined organic phases were washed once with a 100 g saturated sodium chloride aqueous solution. After removing the extractant by vacuum distillation of the organic phase, vacuum distillation (95-105℃ / 2-2.5 mmHg) yielded 121.8 g of a colorless, transparent liquid, 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene, with a gas phase purity of 99.7% and a yield of 92.6%.

[0070] The NMR data of the obtained product are as follows:

[0071] 1 HNMR (400MHz, CDCl3): δppm

[0072] 5.12-5.17(m,2H),3.28(t,4H),1.95-2.06(m,8H),1.61-1.70(m,10H).

[0073] Example 2: Preparation of 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene (IV)

[0074] Under nitrogen protection, 150 g of tetrahydrofuran, 26.7 g (1.1 mol) of magnesium powder, 0.5 g of iodine, 1.0 g of 1,2-dibromoethane, and 3.0 g of 1,4-dibromobutane were added to a 1000 mL four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, and reflux condenser. After initiation at 40-45 °C, a mixed solution of 105.0 g (0.5 mol) of 1,4-dibromobutane and 250 g of tetrahydrofuran was added dropwise between 40-50 °C over 2 hours. The reaction was then stirred at 50-55 °C for 1 hour to obtain Grignard reagent. The mixture was cooled to 10-15 °C, and under nitrogen protection, 132.5 g (1.1 mol) of 5-chloro-2-pentanone was added dropwise over 1 hour. The reaction was then stirred at 15-20 °C for 3 hours. The solvent was recovered by vacuum distillation at 40-45℃. 200 g of water and 200 g of dichloromethane were added to the residue, and the pH was adjusted to 3-4 with a 20 wt% ammonium chloride aqueous solution. The mixture was stirred at 20-30℃ for 1 hour, resulting in layer separation. The aqueous phase was extracted twice with dichloromethane, 100 g each time. The combined organic phases were washed once with a 100 g saturated sodium chloride aqueous solution. After removing the extractant by vacuum distillation of the organic phase, vacuum distillation (95-105℃ / 2-2.5 mmHg) yielded 122.6 g of a colorless, transparent liquid, 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene, with a gas phase purity of 99.8% and a yield of 93.2%.

[0075] Example 3: Preparation of 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene (IV)

[0076] Under nitrogen protection, 150 g of 2-methyltetrahydrofuran, 26.7 g (1.1 mol) of magnesium powder, 0.5 g of iodine, 1.0 g of 1,2-dibromoethane, and 3.0 g of 1,4-dichlorobutane were added to a 1000 mL four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, and reflux condenser. After initiation at 50-60 °C, a mixed solution of 60.5 g (0.5 mol) of 1,4-dichlorobutane and 250 g of tetrahydrofuran was added dropwise between 60-65 °C over 2 hours. The reaction was then stirred at 60-65 °C for 2 hours to obtain Grignard reagent. The mixture was cooled to 10-15 °C, and under nitrogen protection, 132.5 g (1.1 mol) of 5-chloro-2-pentanone was added dropwise over 1 hour. The reaction was then stirred at 15-20 °C for 3 hours. The solvent was recovered by vacuum distillation at 40-45℃. 200 g of water and 200 g of dichloromethane were added to the residue, and the pH was adjusted to 3-4 with a 20 wt% ammonium chloride aqueous solution. The mixture was stirred at 20-30℃ for 1 hour, resulting in layer separation. The aqueous phase was extracted twice with dichloromethane, 100 g each time. The combined organic phases were washed once with a 100 g saturated sodium chloride aqueous solution. After removing the extractant by vacuum distillation of the organic phase, vacuum distillation (95-105℃ / 2-2.5 mmHg) yielded 116.8 g of a colorless, transparent liquid, 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene, with a gas phase purity of 99.3% and a yield of 88.8%.

[0077] Example 4: Preparation of squalene (I)

[0078] Under nitrogen protection, 150 g of tetrahydrofuran, 16.0 g (0.66 mol) of magnesium powder, 0.5 g of iodine, 1.5 g of 1,2-dibromoethane, and 3.0 g of 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene obtained in Example 1 were added to a 1000 mL four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, and reflux condenser. After the reaction was initiated at 45-50 °C, a mixed solution of 75.9 g (0.3 mol) of 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene obtained in Example 1 and 300 g of tetrahydrofuran was added dropwise between 45-55 °C. The addition was completed over 3 hours, and the reaction was then stirred at 60-65 °C for 2 hours to obtain Grignard reagent. Cool to 10-15℃, under nitrogen protection, add 82.0 g (0.65 mol) of 6-methyl-5-hepten-2-one dropwise over 1 hour, stirring at 25-30℃ for 3 hours. Recover the solvent by vacuum distillation at 40-45℃. Add 200 g of water and 200 g of dichloromethane to the residue, adjust the pH to 3-4 with a 20 wt% ammonium chloride aqueous solution, stir at 20-30℃ for 1 hour, and allow the layers to separate. Extract the aqueous phase twice with 100 g of dichloromethane each time. Combine the organic phases and wash once with a 100 g saturated sodium chloride aqueous solution. After removing the extractant by vacuum distillation of the organic phase, perform vacuum distillation (245-265℃ / 2-2.5 mmHg) to obtain 115.2 g of squalene, a colorless oily liquid with a gas phase purity of 99.8% and a yield of 93.5%.

[0079] The NMR data of the obtained product are as follows:

[0080] 1 HNMR (400MHz, CDCl3): δppm

[0081] 5.16-5.26(m,6H),2.02-2.09(m,20H),1.61-1.68(m,18H),1.53-1.58(m,6H).

[0082] Example 5: Preparation of squalene (I)

[0083] Under nitrogen protection, 150 g of tetrahydrofuran, 16.0 g (0.66 mol) of magnesium powder, 0.5 g of iodine, 1.5 g of 1,2-dibromoethane, and 3.0 g of 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene obtained in Example 2 were added to a 1000 mL four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, and reflux condenser. After the reaction was initiated at 45-50 °C, a mixed solution of 75.9 g (0.3 mol) of 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene obtained in Example 2 and 300 g of tetrahydrofuran was added dropwise between 45-55 °C. The addition was completed in 1 hour, and then the reaction was stirred at 60-65 °C for 2 hours to obtain Grignard reagent. Cool to 10-15℃, under nitrogen protection, add 82.0 g (0.65 mol) of 6-methyl-5-hepten-2-one dropwise over 1 hour, stirring at 25-30℃ for 3 hours. Recover the solvent by vacuum distillation at 40-45℃. Add 200 g of water and 200 g of dichloromethane to the residue, adjust the pH to 3-4 with a 20 wt% ammonium chloride aqueous solution, stir at 20-30℃ for 1 hour, and allow the layers to separate. Extract the aqueous phase twice with 100 g of dichloromethane each time. Combine the organic phases and wash once with a 100 g saturated sodium chloride aqueous solution. After removing the extractant by vacuum distillation of the organic phase, perform vacuum distillation (245-265℃ / 2-2.5 mmHg) to obtain 108.2 g of squalene, a colorless oily liquid with a gas phase purity of 99.1% and a yield of 87.8%.

[0084] Example 6: Preparation of 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene (IV)

[0085] Under nitrogen protection, 400 g of tetrahydrofuran, 26.7 g (1.1 mol) of magnesium powder, 0.5 g of iodine, 1.0 g of 1,2-dibromoethane, and 3.0 g of 1,4-dichlorobutane were added to a 1000 mL four-necked flask equipped with a stirrer, thermometer, constant pressure dropping funnel, and reflux condenser. After initiation at 45-50 °C, 60.5 g (0.5 mol) of 1,4-dichlorobutane was added dropwise between 45-55 °C over 1 hour. The reaction was then stirred at 55-60 °C for 2 hours to obtain Grignard reagent. The mixture was cooled to 10-15 °C, and under nitrogen protection, 132.5 g (1.1 mol) of 5-chloro-2-pentanone was added dropwise over 1 hour. The reaction was then stirred at 15-20 °C for 2 hours. The solvent was recovered by vacuum distillation at 40-45℃. 200 g of water and 200 g of dichloromethane were added to the residue, and the pH was adjusted to 3-4 with a 20 wt% ammonium chloride aqueous solution. The mixture was stirred at 20-30℃ for 1 hour, resulting in layer separation. The aqueous phase was extracted twice with dichloromethane, 100 g each time. The combined organic phases were washed once with a 100 g saturated sodium chloride aqueous solution. After removing the extractant by vacuum distillation of the organic phase, vacuum distillation (95-105℃ / 2-2.5 mmHg) yielded 96.3 g of a colorless, transparent liquid, 1,12-dichloro-4,9-dimethyldodecyl-4,8-diene, with a gas phase purity of 97.4% and a yield of 73.2%.

[0086] As demonstrated in this embodiment, maintaining a low concentration of 1,4-dichlorobutane in the system is crucial for the yield and purity of the reaction during the preparation of Grignard reagents. Adding 1,4-dichlorobutane dropwise after diluting it with a solvent ensures a low concentration, which facilitates the timely formation of Grignard reagents, reduces coupling side reactions between 1,4-dichlorobutane and the Grignard reagent, and guarantees a high yield and high purity of the target product.

Claims

1. A method for preparing squalene, comprising the following steps: (1) In solvent A, under the action of initiator 1, compound II and magnesium powder undergo a Grignard reaction to obtain the corresponding Grignard reagent; then, compound III is added to and acidified to prepare compound IV; Compound II is added to the reaction system in two steps: first, 1-10% of the total mass of compound II is added to the system containing solvent A1, initiator 1, and magnesium powder to initiate the reaction; then, the remaining compound II is diluted with solvent A2 and added dropwise to the system. Solvent A is one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, methoxycyclopentane, hexane, heptane, or toluene. Solvents A1 and A2 are the same as solvent A. Initiator 1 is one or a combination of iodine, bromoethane, or 1,2-dibromoethane. Compound III is added dropwise to the system containing Grignard reagents. In the structural formula of compound II, the substituent X is Cl or Br; (2) In solvent B, under the action of initiator 2, compound IV and magnesium powder undergo Grignard reaction to obtain the corresponding Grignard reagent; then squalene is prepared by addition reaction and acidification with compound V. Compound IV is added to the reaction system in two steps: first, 1-10% of the total mass of compound IV is added to the system containing solvent B1, initiator 2, and magnesium powder to initiate the reaction; then, the remaining compound IV is diluted with solvent B2 and added dropwise to the system. Solvent B is one or a combination of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, methoxycyclopentane, hexane, heptane, or toluene. Solvents B1 and B2 are of the same type as solvent B. Initiator 2 is one or a combination of iodine, bromoethane, or 1,2-dibromoethane. Ⅴ。 2. The method for preparing squalene according to claim 1, characterized in that, Step (1) includes one or more of the following conditions: i. The mass ratio of solvent A to compound of formula II is (2-10):1; ii. The mass of initiator 1 is 0.5%-5.0% of the mass of compound II; iii. The molar ratio of the magnesium powder, compound III, and compound II is (2.0-2.6):(2.0-3.0):1; iv. The Grignard reaction temperature is 20-100℃; v. The reaction solution obtained by reacting compound II and magnesium powder with Grignard reaction is directly carried out in the next reaction without post-treatment.

3. The method for preparing squalene according to claim 2, characterized in that, Includes one or more of the following conditions: i. The molar ratio of the magnesium powder, compound III, and compound II is (2.1-2.3):(2.1-2.3):1; ii. The Grignard reaction temperature is 40-70℃.

4. The method for preparing squalene according to claim 1, characterized in that, In step (1), the mass ratio of solvent A2 to the remaining compound II is 1-10:1, the total amount of solvent A2 and solvent A1 is equal to the amount of solvent A; the dropping rate is 1-5 g / min.

5. The method for preparing squalene according to claim 1, characterized in that, Step (1) includes one or more of the following conditions: i. The reaction temperature of the Grignard reagent and the compound of formula III is -20~35℃; ii. The acidification is achieved by adjusting the pH of the system to 3-5 using an aqueous solution of ammonium chloride with a mass concentration of 10-30 wt%.

6. The method for preparing squalene according to claim 5, characterized in that, The reaction temperature of the Grignard reagent and the compound of formula III is 5~25℃.

7. The method for preparing squalene according to claim 1, characterized in that, In step (1), the post-treatment method of the reaction solution obtained by the addition reaction of Grignard reagent and compound III and acidification is as follows: water and dichloromethane are added to the reaction solution or the residue after the solvent is recovered by vacuum distillation. The pH value is adjusted to 3-5 with ammonium chloride aqueous solution. The layers are separated. The aqueous phase is extracted with dichloromethane. The organic phases are combined and then washed with saturated sodium chloride aqueous solution. After the solvent is removed by vacuum distillation of the organic phase, further vacuum distillation is carried out to obtain compound IV.

8. The method for preparing squalene according to claim 1, characterized in that, Step (2) includes one or more of the following conditions: i. The mass ratio of solvent B to compound of formula IV is (2-10):1; ii. The mass of the initiator 2 is 0.5%-3.0% of the mass of the compound of formula IV; iii. The molar ratio of the magnesium powder, compound V, and compound IV is (2.0-2.6):(2.0-3.0):1; iv. The Grignard reaction temperature is 20-120℃; The reaction solution obtained by reacting compound v and magnesium powder with magnesium powder via Grignard reaction is directly carried out in the next reaction without post-treatment.

9. The method for preparing squalene according to claim 8, characterized in that, Includes one or more of the following conditions: i. The molar ratio of magnesium powder, compound V, and compound IV is (2.1-2.3):(2.1-2.3):1; ii. The Grignard reaction temperature is 50-80℃.

10. The method for preparing squalene according to claim 1, characterized in that, In step (2), the mass ratio of solvent B2 to the remaining compound IV is 1-10:1, the total amount of solvent B2 and solvent B1 is equal to the amount of solvent B, and the dropping rate is 1-5 g / min.

11. The method for preparing squalene according to claim 1, characterized in that, Step (2) includes one or more of the following conditions: i. The reaction temperature of the Grignard reagent and the compound of formula V is -20~40℃; ii. Compound V is added dropwise to the system containing Grignard reagent; iii. The acidification is achieved by adjusting the pH of the system to 3-5 using an aqueous solution of ammonium chloride with a mass concentration of 10-30 wt%.

12. The method for preparing squalene according to claim 11, characterized in that, The reaction temperature of the Grignard reagent and compound V is 15~35℃.

13. The method for preparing squalene according to claim 1, characterized in that, In step (2), the post-treatment method of the reaction solution obtained by the addition reaction of Grignard reagent and compound V and acidification is as follows: water and dichloromethane are added to the reaction solution or the residue after the solvent is recovered by vacuum distillation. The pH value is adjusted to 3-5 with ammonium chloride aqueous solution. The layers are separated. The aqueous phase is extracted with dichloromethane. The organic phases are combined and then washed with saturated sodium chloride aqueous solution. After the solvent is removed by vacuum distillation of the organic phase, further vacuum distillation is carried out to obtain squalene.

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