CN102603517A - Synthesis process of 10-HDA (10-hydroxy-2-decenoic acid) - Google Patents

Abstract

The invention relates to a new synthesis process of 10-HDA (10-hydroxy-2-decenoic acid) which comprises the following steps: preparing 8-bromo-1-octanol from 1,8-octanediol and hydrobromic acid under an action of a catalyst with toluene as a solvent; oxidizing 8-bromo-1-octanol with pyridinium chlorochromate in dichloromethane to obtain 8-bromooctanal; reacting obtained 8-bromooctanal with a phosphorus ylides reagent to obtain (2E)-10-bromo-2-decenoic acid; hydrolyzing obtained (2E)-10-bromo-2-decenoic acid in an alkali condition and then acidifying to obtain 10-HDA. The invention provides an industrial synthesis process of 10-HDA, which increases the utilization of atoms, has high purity and yield of 10-HAD and is simple and suitable for industrial production.

Description

Synthetic process of 10-HDA

technical field

The invention relates to a new synthesis process of (2 E )-10-hydroxyl-2-decenoic acid (10-HDA).

Background technique

Drug name: royal jelly acid, chemical name: (2E)-10-hydroxy-2-decenoic acid, English name: (2E)-10-hydroxydec-2-enoic acid, 10-HDA for short. The chemical structure is:

Royal jelly acid is a kind of unsaturated fatty acid, which has antibacterial, antibacterial, anti-ulcer, anti-cancer, anti-tumor, anti-radiation and lipid-lowering effects. In recent years. Experts and scholars at home and abroad have conducted many researches and explorations on the methods of synthesizing 10-HDA. There are many synthetic routes, among which there are mainly the following routes: ① Use suberic acid as raw material and reduce it with LiAlH ₄ to obtain 1,8-HDA Octanediol, then selectively oxidized with Ag ₂ CO ₃ diatomaceous earth to obtain 8-hydroxyoctanal, finally acetylated with acetic anhydride, condensed with malonic acid, and hydrolyzed to obtain 10-HDA; ② 8-hydroxyoctanal is the main Raw materials, Witting-Horner reaction to obtain 10-HDA; ③ Use 1,6-hexanediol as the main raw material, react with dihydropyran through acid-catalyzed reaction, and then undergo alkylation and other processes to obtain 10-HDA; ④ Butadiene is used as the main raw material, palladium is used as the catalyst, and 10-HDA is isolated after hydroboration and oxidation. Several of the above synthetic methods. There are problems such as high cost, harsh reaction conditions and long synthetic routes, and the cumbersome steps directly lead to the reduction of yield. Although these reactions can obtain products, the industrialization feasibility is poor or cannot be realized at all.

Contents of the invention

The present invention aims at overcoming the problems of high cost, harsh reaction conditions and low yield in the above synthesis route, and is a brand new process route. The route uses 1,8-octanediol as the starting material to synthesize 10-HDA through halogenation, oxidation, condensation and hydrolysis. ``

The technical solution adopted by the preparation method of the present invention is: the synthesis technique of 10-HDA comprises the following steps:

1) Using toluene as a solvent, 8-bromo-1-octanol is obtained from 1,8-octanediol and hydrobromic acid under the action of a catalyst; the molar ratio of 1,8-octanediol and hydrobromic acid is 1 :1-1:1.6;

2) Oxidize the 8-bromo-1-octanol obtained in step 1) with pyridinium chlorochromate (PCC) in dichloromethane to 8-bromooctylal; wherein the 8-bromo-1-octanol and pyridinium chlorochromate The molar ratio is 1:1.1-1:1.6;

3) Reaction of 8-bromooctaldehyde obtained in step 2) with phosphorus ylide reagent (triethyl phosphoroacetate) to obtain (2E)-10-bromo-2-decenoic acid; wherein 8-bromooctaldehyde and phosphorus ylide reagent The mol ratio is 1:1-1:1.6; Gained (2E)-10-bromo-2-decenoic acid is hydrolyzed under alkaline conditions and then acidified to obtain (2E)-10-hydroxyl-2-decenoic acid ( 10-HDA).

According to the above scheme, the catalyst described in step 1) is iodine.

The reaction equation involved in the present invention is:

    

    

The invention provides a process for industrially synthesizing 10-HDA, improves the utilization rate of atoms, has simple method, high product purity, high yield of synthesized 10-HDA, and is suitable for industrial production.

Detailed ways

The present invention can be further described by the following examples. However, the invention of the present invention is not limited to the following practice, and these examples do not limit the scope of the present invention in any way. Certain changes and adjustments made by those skilled in the art within the scope of the claims should also be deemed to belong to the scope of the present invention.

Example 1

Synthesis of 8-bromo-1-octanol

 cm^-1: 3410 (OH), 2916, 2862 (C-H), 642 (C-Br); ¹H NMR (CDCL₃): δ: 3.53 ( t, 2 H, H-8 ), 3.35 (t, 2 H, H-1) , 1.75 (m, 2 H, H-7), 1.45 (m, 2 H, H-2), 1.34 (m, 2 H, H-3), 1.24 (m, 6 H, H-(4-6)); ESI-MS m/z 210 [M+H]⁺ (positive mode)。 Add 7.3 g ( 50 mmol) of 1,8-octanediol, 3.3 ml ( 80 mmol) of hydrobromic acid, 0.15 g of iodine (2% of the main material) and 150 ml of toluene to the reaction flask in sequence, and perform a water separation reaction under stirring After 10 h, toluene was recovered to obtain a yellow mixture. The mixture was separated by column chromatography (ф 8 × L 38 cm), eluted with chloroform:methanol (50:1), and evaporated to dryness in the 0.5-1.0 L eluted part to obtain light yellow oil 2, 9.62 g in total, Yield 92.5%. Product detection: yellow oil; IRυ

cm ^-1 : 3410 (OH), 2916, 2862 (CH), 642 (C-Br); ¹ H NMR (CDCL ₃ ): δ: 3.53 ( t, 2 H, H-8 ), 3.35 (t, 2 H, H-1) , 1.75 (m, 2 H, H-7), 1.45 (m, 2 H, H-2), 1.34 (m, 2 H, H-3), 1.24 (m, 6 H, H-(4-6)); ESI-MS m/z 210 [M+H] ⁺ (positive mode).

Synthesis of Bromooctylaldehyde

 cm^-1: 2916, 2862, 1468, 1484 (C-H), 1733 (C=O), 642 (C-Br); ¹H NMR δ: 3.33 ( t, 2 H, H-8 ), 2.37 (t, 2 H, H-2) , 1.80 (m, 2 H, H-7), 1.57 (m, 2 H, H-3), 1.52 (m, 6 H, H-(4-6)); ESI-MS m/z: 208 [M+H]⁺。 Add 6.46 g (30.1 mmol) of 8-bromo-1-octanol and 60 ml of dichloromethane into the reaction flask, add 18.3 g (35 mmol) of PCC into the reaction flask, and react for 2 h while stirring. During this process, the reaction temperature was kept at 20-30°C. After the reaction was completed, silica gel column chromatography was used, and dichloromethane was recovered by distillation under reduced pressure to obtain 5.37 g of yellow oil, with a yield of 84% (calculated on the basis of 8-bromo-1-octanol ). Product detection: yellow oil; IRυ

cm ^-1 : 2916, 2862, 1468, 1484 (CH), 1733 (C=O), 642 (C-Br); ¹ H NMR δ: 3.33 ( t, 2 H, H-8 ), 2.37 (t, 2 H, H-2) , 1.80 (m, 2 H, H-7), 1.57 (m, 2 H, H-3), 1.52 (m, 6 H, H-(4-6)); ESI- MS m/z : 208 [M+H] ⁺ .

Synthesis

 cm^-1: 2916, 2862, 1468, 1484 (C-H), 1703 (C=O); ¹H NMR δ: 1.30-1.54 ( m, 10 H, H-(5-9)), 2.18 (m, 2 H, H-4) , 3.50 (t, 2 H, H-10), 6.02 (d, 1 H, H-2), 7.11 (m, 1 H, H-3); ESI-MS m/z: 187 [M+H]⁺。 Add 6.23 g (30.1 mmol) of 8-bromooctylaldehyde into a 100 ml single-mouth beaker, add 9.07 g (40.5 mmol) of triethyl phosphonoacetate, start stirring vigorously, and then add carbonic acid which is equimolar to 8-bromooctylaldehyde Potassium aqueous solution, react at room temperature for 1.5 h, add 1 mol/L NaOH solution (ethanol: water = 1:1) which is equimolar with bromoaldehyde, maintain 110°C and heat to reflux for 5 h, the reaction ends. Continue to maintain 110°C to distill ethanol and recover it, stop heating and cool down. Slowly add 6 mol/L hydrochloric acid dropwise to the cooled single-necked flask until the pH is 3, extract three times with ether, take the ether layer, and recover the ether by distillation under reduced pressure to obtain the product 10-HDA, namely (2E)-10-hydroxyl- 2.80 g (15.05 mmol) of 2-decenoic acid, with a yield of 44.9% (calculated as 8-bromooctylaldehyde). Product detection: white powder; IRυ

cm ^-1 : 2916, 2862, 1468, 1484 (CH), 1703 (C=O); ¹ H NMR δ: 1.30-1.54 ( m, 10 H, H-(5-9)), 2.18 (m, 2 H, H-4) , 3.50 (t, 2 H, H-10), 6.02 (d, 1 H, H-2), 7.11 (m, 1 H, H-3); ESI-MS m/z : 187 [M+H] ⁺ .

Example 2

Synthesis of 8-bromo-1-octanol

Add 3.85 g (25 mmol) of 1,8-octanediol, 1.5 ml (35 mmol) of hydrobromic acid, 0.07 g of iodine (2% of the main material) and 75 ml of toluene to the reaction flask in sequence, and perform water separation reaction under stirring After 10 h, toluene was recovered to obtain a yellow mixture. The mixture was separated by column chromatography (ф 8 × L 38 cm), eluted with chloroform:methanol (50:1), and evaporated to dryness in the 0.5-1.0 L eluted part to obtain light yellow oil 2, 2.40 g in total, Yield 92.3%.

Synthesis of Bromooctylaldehyde

Add 2.40 g (11.2 mmol) of 1-bromooctanol and 25 ml of methylene chloride in the reaction flask, add 6.80 g (13 mmol) of PCC to the reaction flask, and react for 2 h under stirring, during which Keep the reaction temperature at 20-30°C. After the reaction is completed, use silica gel column chromatography and vacuum distillation to recover dichloromethane to obtain 1.99 g of yellow oil, with a yield of 84% (calculated based on 8-bromo-1-octanol).

Synthesis

Add 1.99 g (9.6 mmol) of 8-bromooctylaldehyde and 2.90 g (13.0 mmol) of triethyl phosphoroacetate into a 100 ml single-mouth beaker, start stirring vigorously, and then add an aqueous solution of potassium carbonate that is equimolar to bromoaldehyde , After reacting at room temperature for 1.5 h, add 1 mol/L NaOH solution (made of ethanol: water = 1:1) with 1 mol/L equimolar bromoaldehyde, maintain 110°C and heat to reflux for 5 h, and the reaction ends. Continue to maintain 110°C to distill ethanol and recover it, stop heating and cool down. Slowly add 6 mol/L hydrochloric acid dropwise to the cooled single-necked flask until the pH is 3, extract three times with ether, take the ether layer, and distill under reduced pressure to recover the ether to obtain the product 10-HDA, namely (2E)-10-hydroxyl- 0.90 g (4.8 mmol) of 2-decenoic acid, the yield is 43.9% (calculated as 8-bromoaldehyde).

Example 3

Synthesis of 8-bromo-1-octanol

Add 385 g (2.5 mol) of 1,8-octanediol, 170 ml (4 mol) of hydrobromic acid, 7 g of iodine (2% of the main material) and 7.5 L of toluene in sequence in the reaction flask, and stir to separate water for 10 h Afterwards, toluene was recovered to obtain a yellow mixture. The mixture was separated by column chromatography (ф 15 × L 3.8 m), eluted with chloroform:methanol (50:1), and evaporated to dryness in the eluted part of 0.5-10 L to obtain light yellow oil 2, 240 g in total, Yield 92.3%.

Synthesis of Bromooctylaldehyde

Add 240 g ( 1.12 mol) of 1-bromooctanol and 2.5L methylene chloride in the reaction flask, add 680 g ( 1.3 mol) of PCC into the reaction flask, and react for 2 h under the condition of stirring, during which Keep the reaction temperature at 20-30°C. After the reaction is completed, use silica gel column chromatography and vacuum distillation to recover dichloromethane to obtain 198 g of yellow oil with a yield of 85% (calculated based on 8-bromo-1-octanol).

Synthesis

Add 198g (0.96 mol) of 8-bromooctyl aldehyde to a 100 ml single-mouth beaker, add 290 g (1.30 mol) of triethyl phosphoroacetate, start stirring vigorously, and then add potassium carbonate equivalent to 8-bromooctyl aldehyde Aqueous solution, after reacting at room temperature for 1.5 h, add 1 mol/L and 8-bromooctanal equimolar NaOH solution (40%, ethanol: water = 1:1), maintain 110°C and heat to reflux for 5 h, the reaction is over . Continue to maintain 110°C to distill ethanol and recover it, stop heating and cool down. Slowly add 6 mol/L hydrochloric acid dropwise to the cooled single-necked flask until the pH is 3, extract three times with ether, take the ether layer, and recover the ether by distillation under reduced pressure to obtain the product 10-HDA, namely (2E)-10-hydroxyl- 2-decenoic acid 90 g (0.48 mol), yield 43.9% (calculated as 8-bromooctylaldehyde).

Claims (2)

The synthesis technique of 1.10-HDA comprises the following steps: 1) Using toluene as a solvent, 8-bromo-1-octanol is obtained from 1,8-octanediol and hydrobromic acid under the action of a catalyst; the molar ratio of 1,8-octanediol and hydrobromic acid is 1 :1-1:1.6; 2) The 8-bromo-1-octanol obtained in step 1) is oxidized to 8-bromooctylal with pyridinium chlorochromate in dichloromethane; wherein the molar ratio of 8-bromo-1-octanol to pyridinium chlorochromate is 1:1.1-1:1.6; 3) Reaction of 8-bromooctaldehyde obtained in step 2) with phosphorus ylide reagent to obtain (2E)-10-bromo-2-decenoic acid; wherein the molar ratio of 8-bromooctaldehyde and phosphorus ylide reagent is 1:1- 1:1.6; The obtained (2E)-10-bromo-2-decenoic acid was hydrolyzed under alkaline conditions and then acidified to obtain (2E)-10-hydroxyl-2-decenoic acid. 2. The synthesis process of 10-HDA according to claim 1, characterized in that the catalyst described in step 1) is iodine.