Preparation method of farnesyl acetone

Abstract

The invention discloses a preparation method of farnesyl acetone, which comprises the following steps: by taking geranyl acetone as a starting material, carrying out Horner-Wadsworth-Emmons reaction, hydrolyzing, crystallizing and purifying to obtain the farnesyl acetone. By optimizing the process route, the product Z / E selectivity is higher, a single E type product can be obtained, the economy, yield and product purity of the reaction are improved, the use of high-risk and high-pollution chemicals is avoided, and the preparation method is convenient to operate, safe, environmentally friendly, economical in reaction, efficient in preparation and beneficial to industrial implementation.

Description

Technical Field

[0001] The invention relates to a method for preparing farnesyl acetone, and in particular to a method for preparing farnesyl acetone with convenient operation and high reaction efficiency. Background Art

[0002] Farnesyl acetone ((5E,9E)-6,10,14-trimethylpentadeca-5,9,13-trien-2-one) contains three isoprene units and a carbonyl fragment in its chemical structure. It belongs to sesquiterpene compounds and is a natural organic compound. It exists in many essential oils and is widely used in fragrances, medicine and other fields.

[0003]

[0004] Teprenone is a broad-spectrum anti-ulcer drug that has a strong anti-ulcer effect on various experimental ulcers and improves gastric mucosal lesions. It is clinically used to treat acute gastritis and acute exacerbation of chronic gastritis and gastric ulcers.

[0005]

[0006] Farnesyl acetone is an important synthetic intermediate of teprenone. JP2002121165 and CN113666813 disclose a method for preparing farnesyl acetone, wherein trans-nerolidol and acetoacetate or its equivalent compound undergo a Carroll reaction to generate a cis-trans-farnesyl acetone mixture with a Z / E ratio of about 40% / 60%, and then separate the mixture by distillation or freeze crystallization to obtain farnesyl acetone of a single configuration. This method generates 40% of Z-type byproducts, has a low effective utilization rate of raw materials, and is relatively economical. It also needs to be purified by distillation or freeze crystallization, and the operation is cumbersome.

[0007]

[0008] The preparation method disclosed in WO2014107686 is to carry out bromination reaction of farnesol ((E,E)-Farnesol) with phosphorus tribromide, then couple with acetoacetate, and then hydrolyze and decarboxylate to produce farnesyl acetone. Phosphorus tribromide will produce a large amount of phosphorus- and bromine-containing wastewater, which increases the difficulty of waste treatment, and the bromination reaction will produce isomerization byproducts. Even if the more expensive all-trans farnesol is used as the starting material, all-trans farnesyl acetone with a high yield cannot be obtained.

[0009]

[0010] In addition, CN111393275 also discloses a method for obtaining farnesyl acetone by reacting geranyl acetone with a Grignard reagent. This method uses a Grignard reagent to react with geranyl acetone in an affinity addition reaction, and then acidifies to obtain a tertiary alcohol, while removing the ethylene glycol protection to generate a ketone; the tertiary alcohol then undergoes an E1 elimination under acidic conditions to generate the target product. According to the reaction mechanism, the E1 elimination will cause a rearrangement reaction, and the selectivity of the elimination is poor, and the obtained product is generally more mixed. Secondly, the alkyl Grignard reagent is very active and is not conducive to storage and transportation. During the reaction process, concentrated hydrochloric acid needs to be added to quench the Grignard reaction, and then reflux the reaction, which is difficult and dangerous to operate.

[0011]

[0012] In summary, the existing preparation methods of farnesyl acetone are not conducive to industrial production in terms of operability, economy, safety and quality, which limits the preparation of teprenone API. Summary of the invention

[0013] Purpose of the invention: The present invention aims to provide an industrialized method for preparing farnesyl acetone which is convenient to operate, safe, environmentally friendly, economical and efficient.

[0014] Technical solution: The preparation method of farnesyl acetone of the present invention comprises the following steps:

[0015]

[0016] (1) Compound 1 and compound 2 are reacted with an inorganic base to obtain compound 3;

[0017] (2) Compound 3 is deprotected by acid catalysis to obtain compound 4;

[0018] (3) Compound 4 is purified by crystallization to obtain farnesyl acetone 5.

[0019] Preferably, the inorganic base described in step (1) is selected from sodium hydride, potassium hydride, n-butyl lithium, sodium tert-butoxide, potassium tert-butoxide.

[0020] More preferably, the inorganic base is selected from sodium hydride.

[0021] Preferably, the molar ratio of compound 1, compound 2 and the inorganic base in step (1) is 1:(1.05-1.3):(1.1-1.4).

[0022] More preferably, the molar ratio of compound 1, compound 2 and the inorganic base is 1:1.1:1.2.

[0023] Preferably, the reaction solvent of step (1) is selected from toluene, xylene, n-heptane and tetrahydrofuran.

[0024] More preferably, the reaction solvent is selected from toluene.

[0025] Preferably, the reaction temperature of step (1) is 20-40°C.

[0026] More preferably, the reaction temperature is 25-30°C.

[0027] Preferably, the acid in step (2) is selected from hydrochloric acid, trifluoroacetic acid and sulfuric acid.

[0028] More preferably, the acid is selected from 5M hydrochloric acid, concentrated hydrochloric acid, trifluoroacetic acid, and 5M sulfuric acid.

[0029] More preferably, the acid is selected from 5M hydrochloric acid.

[0030] Preferably, the reaction solvent of step (2) is selected from dichloromethane, ethyl acetate and toluene.

[0031] More preferably, the reaction solvent is selected from dichloromethane.

[0032] Preferably, the reaction temperature of step (2) is 0-5°C.

[0033] Preferably, the solvent for the crystallization purification in step (3) is selected from n-heptane, toluene and n-hexane.

[0034] More preferably, the solvent is selected from n-heptane.

[0035] Preferably, the crystallization temperature of the crystallization purification in step (3) is -35 to -65°C.

[0036] More preferably, the crystallization temperature is -40 to -60°C.

[0037] Further preferably, the crystallization purification method is to dissolve compound 4 in n-heptane, crystallize at -40°C, then reduce the temperature to -60°C for crystal growth, separate the crystals, wash them with -60°C n-heptane, and remove the solvent to obtain compound 5.

[0038] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0039] The present invention optimizes the process route to achieve higher product Z / E selectivity, to obtain a single E-form product, thereby improving the economy, yield and product purity of the reaction, and to avoid the use of highly dangerous and highly polluting chemicals, thereby making the preparation method convenient to operate, safe and environmentally friendly, economical to react, and efficient to prepare, and more conducive to industrial implementation. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 GC spectrum for purity detection of the target product in Example 1;

[0041] Figure 2 For the target product of Example 1 1 H-NMR spectrum. DETAILED DESCRIPTION

[0042] Example 1: Preparation of Compound 3

[0043] (1) Reaction 1

[0044] Add 292.9g of compound 2 and 600.0g of toluene to a four-necked bottle, stir to dissolve, cool to 0°C, add 48.0g of sodium hydride in batches, keep warm at 0-5°C for 1h after addition, and then drop 194.3g of compound 1 into the reaction solution. After adding compound 1, keep warm at 0-5°C for 1h, then heat to 25-30°C for 5h, drop saturated aqueous ammonium chloride solution into the reaction bottle to quench the reaction, then separate the liquids, and wash the organic phase with saturated aqueous sodium bicarbonate solution. Concentrate the solvent under reduced pressure until there is basically no fraction, stop concentrating, and obtain 300.0g of compound 3 with a yield of 98.0%.

[0045] (2) Reaction 2

[0046] Add 292.9g of compound 2 and 600.0g of toluene to a four-necked flask, stir to dissolve, cool to -60°C, add 467.5g of 1.6M n-butyl lithium in batches, keep warm at -60°C for 1h after addition, and then drop 194.3g of compound 1 into the reaction solution. After adding compound 1, keep warm at -60°C for 1h, then heat to 25-30°C for 5h, drop saturated ammonium chloride aqueous solution into the reaction flask to quench the reaction, then separate the liquids, and wash the organic phase with saturated sodium bicarbonate aqueous solution. Concentrate the solvent under reduced pressure until there is basically no fraction, stop concentrating, and obtain 296.0g of compound 3 with a yield of 96.7%.

[0047] Example 2: Preparation of Compound 4

[0048] (1) Reaction 1

[0049] Add 300.0g of compound 3 and 800.0g of dichloromethane to the reaction flask, cool to 0°C, add 500g of 5M hydrochloric acid, and keep at 0-5°C for 8h. Separate the liquid to obtain the organic phase, add 1000g of tap water to wash once, and then wash once with 200.0g of saturated sodium chloride solution. Distill under reduced pressure until there is basically no fraction, stop concentrating, and then distill under reduced pressure to obtain 223.5g of compound 4, with a yield of 87.0%.

[0050] (2) Reaction 2

[0051] Add 300.0g of compound 3 and 800g of dichloromethane to the reaction bottle, cool to 0°C, add 334.8g of trifluoroacetic acid, and keep at 0-5°C for 8h. Add 1000g of tap water, stir for 20min, separate the liquids to obtain the organic phase, add 1000.0g of tap water to wash once, and then wash once with 200.0g of saturated sodium chloride solution. Distill under reduced pressure until there is basically no fraction, stop concentrating, and then distill under reduced pressure to obtain 223.5g of compound 4, with a yield of 87.0%.

[0052] Example 3: Preparation of Compound 5

[0053] 200.0 g of compound 4 and 600.0 g of n-heptane were added to a four-necked flask, then cooled to -40°C for crystallization for 1 hour, and then cooled to -60°C for crystallization for 3 hours. The crystals were filtered, and the filter cake was rinsed with 200.0 g of n-heptane at -60°C. The filter cake was melted and the n-heptane was distilled off to obtain 172.0 g of compound 5, with a yield of 86.0% and a purity of 99.78%.

[0054] Table 1 GC purity test results of the final product

[0055]

[0056] 1 H NMR (500MHz, DMSO, TMS): δ = 5.08-5.04 (m, 3H), 2.43 (t, 2H, 3 J=7.5),2.15-2.11(m,2H),2.06(s,3H),2.05-2.00(m,4H),1.94-1.91(m,4H),1.64(s,3H),1.57-1.55(m,9H)ppm.

Claims

1. A method for preparing farnesyl acetone, It is characterized in that The following steps are involved: (1) Compound 1 and compound 2 are reacted with an inorganic base to obtain compound 3; (2) Compound 3 is deprotected by acid catalysis to obtain compound 4; (3) Compound 4 is purified by crystallization to obtain farnesyl acetone 5.

2. The preparation method according to claim 1, It is characterized in that The inorganic base described in step (1) is selected from sodium hydride, potassium hydride, n-butyl lithium, sodium tert-butoxide, potassium tert-butoxide.

3. The preparation method according to claim 1, It is characterized in that The molar ratio of compound 1, compound 2 and the inorganic base in step (1) is 1:(1.05-1.3):(1.1-1.4).

4. The preparation method according to claim 1, It is characterized in that The reaction solvent of step (1) is selected from toluene, xylene, n-heptane and tetrahydrofuran.

5. The preparation method according to claim 1, It is characterized in that The reaction temperature of step (1) is 20-40°C.

6. The preparation method according to claim 1, It is characterized in that The acid described in step (2) is selected from hydrochloric acid, trifluoroacetic acid and sulfuric acid.

7. The preparation method according to claim 1, It is characterized in that The reaction solvent of step (2) is selected from dichloromethane, ethyl acetate and toluene.

8. The preparation method according to claim 1, It is characterized in that The reaction temperature of step (2) is 0-5°C.

9. The preparation method according to claim 1, It is characterized in that The solvent for the crystallization purification in step (3) is selected from n-heptane, toluene and n-hexane.

10. The preparation method according to claim 1, It is characterized in that The crystallization temperature of the crystallization purification in step (3) is -35 to -65°C.

Images