A process for the preparation of setipentol

Abstract

The present application relates to the field of chemical pharmacy, and particularly relates to a preparation method of sertindole, comprising the following steps: taking 1-bromo-3,4-(methylenedioxy) benzene (compound A) and 4,4-dimethyl-1-penten-3-one (compound B) as raw materials, reacting the compound A with zinc powder to obtain an organic zinc reagent, and reacting the compound B with a chloro reagent to obtain a chloro compound with a terminal olefin substituted; then, the organic zinc reagent of the compound A and the chloro compound of the compound B are coupled to obtain an intermediate compound C; finally, the compound C is reduced to obtain sertindole.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceuticals, and specifically to a method for preparing stearyl alcohol. Background Technology

[0002] Lepage et al. described a method for preparing stearyl alcohol from bromopiperidine via the following reaction in the journal J Label Compd Radiopharm 1992, 31(11): 961:

[0003]

[0004] This method uses bromopiperidine as a raw material, which is converted into piperine through carbonyl insertion, reduction, and oxidation. Piperidine is then reacted with methyl tert-butyl ketone to yield stearyl alcohol. This method is cumbersome, and the reagents used, such as butyllithium, lithium aluminum hydride, and chromium trioxide, are highly hazardous. It also requires strict control over reagent storage and reaction procedures.

[0005] The synthesis method of stearyl alcohol reported in US Patent 3910959 is as follows: a mixture of piperine and methyl tert-butyl ketone is dissolved in an ethanol solution with added water and sodium hydroxide, cooled to room temperature, and stirred for 15 days to obtain 4,4-dimethyl-1-[(3,4-methylenedioxy)-phenyl]-1-penten-3-one, which is then reduced in methanol solution with sodium borohydride to obtain stearyl alcohol with a total yield of 63%. This method has a long reaction cycle and the reaction is incomplete. After the reaction is stopped, it is found that there is still a lot of piperine remaining.

[0006] JCMadelmont published an article in the Journal of Lab-elled Compounds and Radiopharmaceuticals, describing a reaction of piperaldehyde and methyl tert-butyl ketone in an ethanol solution with added sodium hydroxide. The mixture was heated under reflux for 4 hours, cooled to room temperature, and stirred at 0°C for 12 hours. After the reaction was completed, the intermediate 4,4-dimethyl-1-[(3,4-methylenedioxy)-phenyl]-1-penten-3-one was obtained. This intermediate was then reduced with sodium borohydride to obtain stearyl alcohol, with a total yield of 40%. Although this method has a short reaction time, the reflux process produces a large amount of piperaldehyde disproportionation products, namely piperol and piperic acid, resulting in a low yield.

[0007]

[0008] The reaction between piperine and methyl tert-butyl ketone is a Claisen-Schmidt reaction, which is slow. If the reaction temperature is increased or the reaction time is extended, the disproportionation byproducts of piperine will increase significantly, affecting the yield and purity of the final product.

[0009] In summary, existing technologies for preparing stearyl alcohol have the following drawbacks: piperine undergoes a disproportionation reaction during the reaction, resulting in a low yield; when using bromopiperidine as a starting material, the reaction steps are lengthy and the route is cumbersome, requiring the use of some highly hazardous and difficult-to-operate reagents; some methods use raw materials that are not readily available, requiring the use of more basic raw materials (piperidine or bromopiperidine) for preparation, and the final product requires column chromatography with a low yield. Summary of the Invention

[0010] To address the problems of the existing technologies, this invention provides a method for preparing stearyl alcohol that is short in route, simple in operation, and highly atom-economical.

[0011] To achieve the above objectives, the present invention provides a method for preparing stearyl alcohol, characterized by comprising the following steps:

[0012]

[0013] Step 1: Under an inert environment, zinc powder is slowly added to the reaction solvent, followed by isopropanol and trimethylchlorosilane in sequence. Stirring is continued until the zinc powder is activated. Then anhydrous lithium chloride is added and stirred. Solution of compound A is slowly added dropwise to obtain organozinc reagent of compound A.

[0014] In step 1), compound A is 1-bromo-3,4-(methylenedioxy)benzene (i.e., bromopiperidine ring);

[0015] In step 1), the molar ratio of compound A to zinc powder is 1:(2-4).

[0016] In step 1), the molar ratio of compound A to lithium chloride is 1:(1.5-2).

[0017] In step 1), the molar ratio of compound A to isopropanol is 1:(0.05-0.1).

[0018] In step 1), the molar ratio of compound A to trimethylchlorosilane (TMSCl) is 1:(0.07-0.1).

[0019] Step 1) needs to be carried out in an inert environment, such as nitrogen or helium, with nitrogen being preferred.

[0020] In step 1), the reaction temperature is 20-50℃, preferably 20-45℃, 30-45℃, and the reaction time is 1-4h, preferably 1-2h.

[0021] In step 1), the solution of compound A needs to be added dropwise slowly (e.g., the reaction solvent can be added). If the reaction is highly exothermic, it can be carried out under ice-water bath conditions.

[0022] In step 1), the reaction solvent is selected from DMF, N-methylpyrrolidone, tetrahydrofuran, DMA, toluene, etc. DMF and tetrahydrofuran are preferred.

[0023] Step 2: Under an inert environment, compound B, nickel catalyst, a catalytic amount of trimethylchlorosilane, and reaction solvent are added sequentially. The reaction solution is cooled, and chlorination reagent is added in batches. The temperature is raised to continue the reaction, and the chlorinated product with the terminal olefin substituted is obtained.

[0024] In step 2), compound B is 4,4-dimethyl-1-penten-3-one.

[0025] Step 2) needs to be carried out in an inert environment, such as nitrogen or helium, with nitrogen being preferred.

[0026] In step 2), the reaction solvent is selected from DMF, N-methylpyrrolidone, tetrahydrofuran, DMA, toluene, etc. DMF and tetrahydrofuran are preferred.

[0027] In step 2), the chlorination reagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), trichloroisocyanuric acid (TCCA), and N-chlorosuccinimide (NCS).

[0028] In step 2), the molar ratio of compound B to the chlorination reagent is 1:(0.5-1.2).

[0029] In step 2), the molar ratio of compound B to the nickel catalyst is 1:(0.03-0.1).

[0030] In step 2), the molar ratio of compound B to trimethylchlorosilane is 1:(0.05-0.15).

[0031] In step 2), the nickel catalyst is selected from nickel acetylacetonate Ni(acac)2, 1,2-bis(diphenylphosphine)ethane nickel dichloride NiCl2(dppe), bis(1,5-cyclooctadiene) nickel Ni(cod)2, and nickel(II) ethylene glycol dimethyl ether (DME) NiCl2.

[0032] The reaction solvent is selected from DMF, N-methylpyrrolidone, tetrahydrofuran, DMA, toluene, etc., with DMF and tetrahydrofuran being preferred.

[0033] In step 2), the reaction solution can be cooled using an ice-water bath, and the reaction temperature is controlled at -10 to 0℃, preferably -5 to 0℃.

[0034] In step 2), the chlorination reagent can be added in batches from 1 to 4 times to control the amount of chlorination reagent added and prevent excessive exothermic reaction.

[0035] In step 2), the temperature is increased to 10-35°C, preferably 10-25°C, after the chlorination reagent has been added in batches. The reaction time is 1-4 hours, preferably 2-4 hours.

[0036] Step 3: Under an inert environment, the chlorinated derivative solution of compound B is added dropwise to the organozinc reagent of compound A. After the addition is complete, the temperature is slowly increased to continue the reaction, and compound C is obtained through coupling.

[0037] Step 3) needs to be carried out in an inert environment, such as nitrogen or helium, with nitrogen being preferred.

[0038] In step 3), the molar ratio of compound A to compound B is 1:(1.2-1.5).

[0039] In step 3), the reaction temperature can be selected from room temperature, for example: 20-25℃;

[0040] In step 3), the heating temperature can be selected from 20-80℃, preferably 60-70℃, and the reaction time is 2-5h, preferably 2-4h.

[0041] In step 3), the same solvent can be used for the preparation of the organozinc reagent of compound A, the preparation of the chlorinated derivative of compound B, and the coupling reaction of the two. The reaction solvent can be selected from DMF, N-methylpyrrolidone, tetrahydrofuran, DMA, toluene, etc., with DMF and tetrahydrofuran being preferred.

[0042] In step 3), the organozinc reagent of compound A is prepared on-site and used immediately to avoid the reduction of the activity of the organozinc reagent of compound A due to prolonged use.

[0043] In step 3), the chloride derivative of compound B does not need to be separated. It can continue to undergo a coupling reaction with the organozinc reagent of compound A in the nickel catalyst reaction system to avoid the decrease in the reactivity of the chloride of compound B due to prolonged reaction.

[0044] After the intermediate reaction in step 3) is completed, the post-processing can be carried out using common methods in the art, which may include the following steps: washing with water / organic solvent in sequence, for example: the organic solvent can be selected from dichloromethane, trichloromethane, ethyl acetate, wherein the volume ratio of water to organic solvent is 1:1, filtering, separating the layers, washing the aqueous layer again with organic solvent, and combining the organic layers.

[0045] After the intermediate reaction in step 3) is completed, some amino acid compounds can be added to the organic layer to effectively remove heavy metal ions remaining in the reaction solvent, such as palladium and nickel. The amino acid compounds are selected from one or more of cysteine, N-acetyl-L-cysteine, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid (sodium salt), and dithiocarbamates.

[0046] In step 3), after treatment with an amino acid solvent, the organic layer is separated, washed with saturated brine, the organic phase is separated, dried, and concentrated to obtain the crude product.

[0047] The crude product in step 3) can be purified and refined by recrystallization. The recrystallization method can be hot-dissolved and cold-precipitated, in which a certain amount of solvent is added to the crude product, heated to reflux, and then cooled to precipitate the solid.

[0048] The solvent used for recrystallization in step 3) is selected from C1-C4 alcohol solvents, such as one or more of methanol, ethanol and isopropanol.

[0049] Step 4: Add compound C and reaction solvent sequentially, then add reducing agent in batches. After the reaction is complete, add acid for post-treatment to obtain stearyl alcohol.

[0050] Step 4) involves reducing compound C to prepare stearyl alcohol.

[0051] In step 4), the molar ratio of compound C to the reducing agent is 1:1-2, preferably 1:1.3-1.5;

[0052] In step 4), the reaction solvent is selected from C1-C4 alcohols, preferably methanol, ethanol, and isopropanol.

[0053] In step 4), the reducing agent is selected from sodium borohydride, potassium borohydride, lithium aluminum hydride, and preferably sodium borohydride or potassium borohydride.

[0054] In step 4), the reducing agent needs to be added in batches to prevent excessive exothermic reaction. The reaction temperature should be controlled at 25-50℃ and the reaction time should be 1-3 hours.

[0055] After the intermediate reaction in step 4) is completed, a small amount of acid needs to be added to treat the excess reducing agent, such as hydrochloric acid, acetic acid, etc.

[0056] After the reaction in step 4) is completed, the post-processing can be carried out using common methods in the art, which may include the following steps: after the reaction is completed, concentrate the solution, add water / organic solvent, for example: the organic solvent can be selected from dichloromethane, trichloromethane, ethyl acetate, wherein the volume ratio of water to organic solvent is 1:1, separate the layers, extract the aqueous layer with the organic solvent, combine the organic layers, wash with saturated brine, dry, concentrate, and obtain the crude product.

[0057] The crude product in step 4) can be purified and refined by recrystallization. The recrystallization method can be hot-dissolved and cold-precipitated, in which a certain amount of solvent is added to the crude product, heated to reflux, and then cooled to precipitate the solid.

[0058] The reagents and raw materials used in this invention are all commercially available.

[0059] The beneficial effects of this invention are as follows:

[0060] 1. This application uses compound A as a starting material, reacting it with zinc powder to prepare the corresponding organozinc reagent. Simultaneously, under the action of a nickel catalyst, compound B reacts with a chlorination reagent to obtain a terminally alkene-substituted compound. The organozinc reagent of compound A and the chlorinated product of compound B then undergo a coupling reaction under the action of a nickel catalyst to obtain intermediate compound C. The chlorination reaction of compound B and the subsequent coupling reaction are carried out in the same reaction vessel, and the nickel catalyst plays an indispensable role in both the chlorination and coupling reactions. Through the "one nickel, two uses" and "one pot, two steps" design, the coupling reaction of compound A and compound B becomes simpler and more efficient, with considerable yield, which is very beneficial to improving the overall yield.

[0061] 2. Avoid using expensive and hard-to-obtain reagents (e.g., 5-vinylbenzo[D][1,3]dioxane) or highly dangerous reagents (e.g., butyllithium, lithium aluminum hydride, and chromium trioxide), thereby simplifying the reaction operation and reducing production and operating costs.

[0062] 3. The raw materials and catalysts used in this invention are inexpensive and readily available. The method is simple, highly atom-economical, and operates under mild reaction conditions, offering significant advantages over the raw materials and methods in the prior art. The entire reaction process yields fewer intermediate byproducts, is easy to process, environmentally friendly, and has industrial potential. Detailed Implementation

[0063] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0064] Example 1

[0065] Step 1: Compound A reacts with compound B to obtain intermediate compound C.

[0066] Place 19.52g of zinc powder and 150ml of DMF in a 1000ml reaction flask under nitrogen protection. Add 0.54g of isopropanol and 1.08g of trimethylchlorosilane. Stir at 20-25℃ for 20 minutes. Add 6.33g of anhydrous lithium chloride. Raise the temperature to 35-40℃. At 35-40℃, add 20g of compound A in 50ml of DMF solution dropwise over 15 minutes. Continue stirring for 1 hour to complete the preparation of the organozinc reagent.

[0067] Separately, 13.4 g of compound B, 1.53 g of nickel acetylacetonate Ni(acac)2, 1.3 g of trimethylchlorosilane, and 130 ml of DMF solution were placed in a 250 ml reaction flask and stirred. Under nitrogen protection, the mixture was cooled to 0 °C, and 16.48 g of 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) was added in portions. After the addition was complete, the temperature was maintained at 15-20 °C for 2 hours until the chlorination reaction was completed.

[0068] Under nitrogen protection and controlled temperature of 20–25 °C, the chlorinated derivative solution of compound B was added dropwise to the zinc reagent of compound A. After the addition was complete, the temperature was slowly increased to 65–70 °C until the reaction was complete. After the reaction was complete, the reaction system was cooled to 0–5 °C, and 1500 ml of water and 500 ml of ethyl acetate were added. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth. The filtrate separated into layers. The aqueous layer was washed with 2 × 100 ml of ethyl acetate. The organic layers were combined and washed with 200 ml of trisodium ethylenediaminetetraacetate solution to separate the ethyl acetate layer. The ethyl acetate layer was then washed with 200 ml of saturated brine to separate the organic phase. The organic phase was dried and concentrated. The crude product was purified with anhydrous ethanol to give 19.64 g of a pale yellow solid, with a yield of 85% and an HPLC purity of 95.8%.

[0069] MS(m / z): 233.11[M+H]+; 1 HNMR(CDCl3,500MHz)δ7.50(dt,J=15.0,1.0

[0070] Hz,1H),7.24–7.18(m,2H),7.15(d,J=8.0Hz,1H),6.76(d,J=15.2Hz,1H),6.07(s,2H),1.31(s,9H).

[0071] Example 2

[0072] Step 1: Compound A reacts with compound B to obtain intermediate compound C.

[0073] Place 29.28g of zinc powder and 200ml of DMF in a 1000ml reaction flask under nitrogen protection. Add 0.81g of isopropanol and 1.62g of trimethylchlorosilane. Stir at 20-25℃ for 20 minutes. Add 10.76g of anhydrous lithium chloride. Raise the temperature to 35-40℃. At 35-40℃, add 30g of compound A in 70ml of DMF solution dropwise over 15 minutes. Continue stirring for 1 hour to complete the preparation of the organozinc reagent.

[0074] Separately, 20.4 g of compound B, 2.88 g of 1,2-bis(diphenylphosphine)ethane nickel dichloride NiCl2 (dppe), 1.95 g of trimethylchlorosilane, and 180 ml of DMF solution were placed in a 250 ml reaction flask and stirred. Under nitrogen protection, the mixture was cooled to 0 °C, and 21.13 g of trichloroisocyanuric acid (TCCA) was added in portions. After the addition was complete, the temperature was maintained at 15-20 °C for 2 hours until the chlorination reaction was completed.

[0075] Under nitrogen protection and controlled temperature of 20–25 °C, the chlorinated derivative solution of compound B was added dropwise to the zinc reagent of compound A. After the addition was complete, the temperature was slowly increased to 65–70 °C until the reaction was complete. After the reaction was complete, the reaction system was cooled to 0–5 °C, and 2000 ml of water and 600 ml of ethyl acetate were added. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth. The filtrate separated into layers. The aqueous layer was washed with 2 × 100 ml of ethyl acetate. The organic layers were combined and washed with 300 ml of trisodium ethylenediaminetetraacetate solution to separate the ethyl acetate layer. The ethyl acetate layer was then washed with 300 ml of saturated brine to separate the organic phase. The organic phase was dried and concentrated. The crude product was purified with anhydrous ethanol to give 28.77 g of a pale yellow solid, with a yield of 83% and an HPLC purity of 95.1%.

[0076] Example 3

[0077] Step 1: Compound A reacts with compound B to give intermediate compound C:

[0078] Place 9.76g of zinc powder and 70ml of DMF in a 500ml reaction flask under nitrogen protection. Add 0.27g of isopropanol and 0.54g of trimethylchlorosilane. Stir at 20-25℃ for 20 minutes. Add 3.165g of anhydrous lithium chloride. Raise the temperature to 35-40℃. At 35-40℃, add 10g of compound A in 25ml of DMF solution dropwise over 5 minutes. Continue stirring for 1 hour to complete the preparation of the organozinc reagent.

[0079] Separately, 7.25 g of compound B, 1.24 g of bis(1,5-cyclooctadiene)nickel Ni(cod)2, 0.65 g of trimethylchlorosilane, and 60 ml of DMF solution were placed in a 100 ml reaction flask and stirred. Under nitrogen protection, the mixture was cooled to 0 °C, and 9.49 g of N-chlorosuccinimide (NCS) was added in portions. After the addition was complete, the temperature was maintained at 10-15 °C for 3 hours until the chlorination reaction was completed.

[0080] Under nitrogen protection and controlled temperature of 20–25 °C, the chlorinated derivative solution of compound B was added dropwise to the zinc reagent of compound A. After the addition was complete, the temperature was slowly increased to 65–70 °C until the reaction was complete. After the reaction was complete, the reaction system was cooled to 0–5 °C, and 700 ml of water and 300 ml of ethyl acetate were added. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth. The filtrate separated into layers. The aqueous layer was washed with 2 × 50 ml of ethyl acetate. The organic layers were combined and washed with 100 ml of trisodium ethylenediaminetetraacetate solution to separate the ethyl acetate layer. The ethyl acetate layer was then washed with 100 ml of saturated brine to separate the organic phase. The organic phase was dried and concentrated. The crude product was purified with anhydrous ethanol to give 10.17 g of a pale yellow solid, with a yield of 88% and an HPLC purity of 96.2%.

[0081] Example 4

[0082] Step 1: Compound A reacts with compound B to give intermediate compound C:

[0083] Place 9.76g of zinc powder and 70ml of DMF in a 500ml reaction flask under nitrogen protection. Add 0.27g of isopropanol and 0.54g of trimethylchlorosilane. Stir at 20-25℃ for 20 minutes. Add 3.165g of anhydrous lithium chloride. Raise the temperature to 35-40℃. At 35-40℃, add 10g of compound A in 25ml of DMF solution dropwise over 5 minutes. Continue stirring for 1 hour to complete the preparation of the organozinc reagent.

[0084] Separately, 7.25 g of compound B, 0.99 g of nickel(II) ethylene glycol dimethyl ether (DME) NiCl2, 0.65 g of trimethylchlorosilane, and 60 ml of DMF solution were placed in a 100 ml reaction flask and stirred. Under nitrogen protection, the mixture was cooled to 0 °C, and 10.35 g of N-chlorosuccinimide (NCS) was added in portions. After the addition was complete, the temperature was maintained at 10-15 °C for 1 hour until the chlorination reaction was completed.

[0085] Under nitrogen protection and controlled temperature of 20–25 °C, the chlorinated derivative solution of compound B was added dropwise to the zinc reagent of compound A. After the addition was complete, the temperature was slowly increased to 65–70 °C until the reaction was complete. After the reaction was complete, the reaction system was cooled to 0–5 °C, and 700 ml of water and 300 ml of ethyl acetate were added. After stirring for 10 minutes, the mixture was filtered through diatomaceous earth. The filtrate was separated into layers. The aqueous layer was washed with 2 × 50 ml of ethyl acetate. The organic layers were combined and washed with 100 ml of trisodium ethylenediaminetetraacetate solution to separate the ethyl acetate layer. The ethyl acetate layer was then washed with 100 ml of saturated brine to separate the organic phase. The organic phase was dried and concentrated. The crude product was purified with anhydrous ethanol to give 9.71 g of a pale yellow solid, with a yield of 84% and an HPLC purity of 96.4%.

[0086] Example 5

[0087] Step 1: Compound A reacts with compound B to give intermediate compound C:

[0088] Place 19.52g of zinc powder and 150ml of tetrahydrofuran in a 1000ml reaction flask under nitrogen protection. Add 0.54g of isopropanol and 1.08g of trimethylchlorosilane. Stir at 20-25℃ for 20 minutes. Add 6.33g of anhydrous lithium chloride. Raise the temperature to 40-45℃. At 40-45℃, add 20g of compound A in 50ml of tetrahydrofuran solution dropwise over 15 minutes. Continue stirring for 2 hours to complete the preparation of the organozinc reagent.

[0089] Separately, 13.4 g of compound B, 1.53 g of nickel acetylacetonate Ni(acac)2, 1.3 g of trimethylchlorosilane, and 130 ml of tetrahydrofuran solution were placed in a 250 ml reaction flask and stirred. Under nitrogen protection, the mixture was cooled to 0 °C, and 16.48 g of 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) was added in portions. After the addition was complete, the temperature was maintained at 15-20 °C for 2 hours until the chlorination reaction was completed.

[0090] Under nitrogen protection and controlled temperature of 20–25 °C, the chlorinated derivative solution of compound B was added dropwise to the zinc reagent of compound A. After the addition was complete, the temperature was slowly increased to reflux until the reaction was complete. After the reaction was complete, the reaction system was cooled to 0–5 °C, 50 ml of water was added, and the mixture was stirred for 3 minutes. The mixture was then filtered through a diatomaceous earth filter. The filtrate was concentrated to remove most of the tetrahydrofuran. 300 ml of water and 300 ml of ethyl acetate were added, and the mixture was extracted and separated. The aqueous layer was washed with 2 × 100 ml of ethyl acetate, and the organic layers were combined. The organic layers were washed with 200 ml of trisodium ethylenediaminetetraacetate solution to separate the ethyl acetate layer. The ethyl acetate layer was then washed with 200 ml of saturated brine to separate the organic phase. The organic phase was dried and concentrated. The crude product was purified with anhydrous ethanol to give 18.48 g of a pale yellow solid, with a yield of 80% and an HPLC purity of 95.1%.

[0091] Example 6

[0092] Step 2, intermediate compound C is reduced to stearyl alcohol:

[0093] Take 15g of intermediate compound C prepared in step 1 and place it in a 250ml reaction flask. Add 150ml of ethanol, stir to dissolve, and heat to 25-30℃. Add 3.66g of sodium borohydride in portions. After the addition is complete, heat to 40-45℃ until the reaction is finished. Cool the reaction system to below 10℃, add 3% dilute hydrochloric acid dropwise to quench excess sodium borohydride, concentrate the ethanol, add 200ml of water and 150ml of dichloromethane, extract and separate the layers. Wash the aqueous layer with 2×70ml of dichloromethane, combine the organic phases, dry and concentrate. The obtained solid is purified with anhydrous ethanol to give 14.37g of white solid, yield 95%, HPLC purity 99.6%.

[0094] MS(m / z): 235.13[M+H]+; 1 H NMR(CDCl3,500MHz)δ7.10–7.01(m,2H),6.89(d,J=7.5Hz,1H),6.57–6.50(m,1H),6.20(dd,J=15. 1,6.1Hz,1H),5.85(s,2H),4.30(ddd,J=6.2,5.0,1.1Hz,1H),2.01(d,J=4.9Hz,1H),0.98(s,9H).

[0095] Example 7

[0096] Step 2, intermediate compound C is reduced to stearyl alcohol:

[0097] Take 25g of intermediate compound C prepared in step 2 and place it in a 500ml reaction flask. Add 250ml of isopropanol, stir to dissolve and heat to 25-30℃. Add 8.7g of potassium borohydride in portions. After the addition is complete, heat to 40-45℃ until the reaction is finished. Cool the reaction system to below 10℃ and add 3% dilute hydrochloric acid dropwise to quench excess potassium borohydride. Concentrate to remove isopropanol, add 300ml of water and 250ml of dichloromethane, extract and separate the layers. Wash the aqueous layer with 2×80ml of dichloromethane. Combine the organic phases, dry and concentrate. Purify the obtained solid with anhydrous ethanol to obtain 24.73g of white solid, yield 92%, HPLC purity 99.7%.

Claims

1. A method for preparing stearyl alcohol, characterized in that, Includes the following steps: Step 1: Under an inert environment, zinc powder is slowly added to the reaction solvent, followed by isopropanol and trimethylchlorosilane in sequence. After the zinc powder is activated, anhydrous lithium chloride is added and stirred. The solution of compound A is then slowly added dropwise to obtain the organozinc reagent of compound A. Step 2: Under an inert environment, compound B, nickel catalyst, a catalytic amount of trimethylchlorosilane, and reaction solvent are added sequentially. The reaction solution is cooled, and chlorination reagent is added in batches. The temperature is raised to continue the reaction, and the chlorinated product with the terminal olefin substituted is obtained. Step 3: Under an inert environment, the chlorinated derivative solution of compound B is added dropwise to the organozinc reagent of compound A. After the addition is complete, the temperature is slowly increased to continue the reaction, and compound C is obtained through coupling. Step 4: Add compound C and reaction solvent sequentially, then add reducing agent in batches. After the reaction is complete, add acid for post-treatment to obtain stearyl alcohol.

2. The method for preparing stearyl alcohol as described in claim 1, characterized in that: In step 1), the molar ratio of compound A to zinc powder is 1:(2-4); the molar ratio of compound A to lithium chloride is 1:(1.5-2); the molar ratio of compound A to isopropanol is 1:(0.05-0.1); and the molar ratio of compound A to trimethylchlorosilane (TMSCl) is 1:(0.07-0.1).

3. The method for preparing stearyl alcohol as described in claim 1, characterized in that: In step 1), the reaction temperature is 20-50℃ and the reaction time is 1-4h.

4. The method for preparing stearyl alcohol as described in claim 1, characterized in that: In step 2), the chlorination reagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), trichloroisocyanuric acid (TCCA), and N-chlorosuccinimide (NCS). The molar ratio of compound B to the chlorination reagent is 1:(0.5-1.2), and the molar ratio of compound B to trimethylchlorosilane is 1:(0.05-0.15).

5. The method for preparing stearyl alcohol as described in claim 1, characterized in that... In step 2), the nickel catalyst is selected from nickel acetylacetone Ni(acac)2, 1,2-bis(diphenylphosphine)ethane nickel dichloride NiCl2(dppe), bis(1,5-cyclooctadiene) nickel Ni(cod)2, and nickel(II) ethylene glycol dimethyl ether (DME) NiCl2, wherein the molar ratio of compound B to the nickel catalyst is 1:(0.03-0.1).

6. The method for preparing stearyl alcohol as described in claim 1, characterized in that... In step 2), the reaction temperature is 10-35℃ and the reaction time is 1-4h.

7. The method for preparing stearyl alcohol as described in claim 1, characterized in that... In step 3), the molar ratio of compound A to compound B is 1:(1.2-1.5).

8. The method for preparing stearyl alcohol as described in claim 1, characterized in that... In step 3), the reaction temperature is 20-80℃ and the reaction time is 2-5h.

9. The method for preparing stearyl alcohol as described in claim 1, characterized in that... The reducing agent mentioned in step 4) is selected from sodium borohydride and potassium borohydride, and the molar ratio of compound C to the reducing agent is 1:(1.5-2).

10. The method for preparing stearyl alcohol as described in claim 1, characterized in that... The solvent mentioned in step 4) is selected from methanol, ethanol, and isopropanol.

11. The method for preparing stearyl alcohol as described in claim 1, characterized in that... In step 4), the reaction temperature is 25-50℃ and the reaction time is 1-3 hours.

12. The method for preparing stearyl alcohol as described in claim 1, characterized in that... The solvents used in steps 1)-2) are selected from DMF, N-methylpyrrolidone, tetrahydrofuran, DMA, and toluene.

Images