A preparation method of aldehyde compound

Abstract

The present invention provides a method for preparing an aldehyde compound, specifically, preparing a compound of formula III from a compound of formula I' (a mixture of carboxylic acid and ester) under the action of a reducing agent, and then further preparing a compound of formula IV through an ozone oxidation reaction, wherein R is hydrogen, methyl, ethyl, benzyl or a halogen-substituted alkyl group.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing an aldehyde compound. Background Art

[0002] Aldehyde compounds are widely used in the field of drug synthesis and are often obtained through the following methods. Reduction method: Commonly used reducing agents include lithium aluminum hydride, lithium aluminum hydride, borohydride and other reducing agents. Cracking method: A method of reducing esters to aldehydes by high-temperature decomposition. Acid hydrolysis method: Esters are reacted with water under acidic conditions to decompose into aldehydes and acids. Enzyme catalysis: Esters are decomposed into aldehydes and acids by esterase. However, in the reduction method, the reducing agent used is expensive and prone to over-reduction, resulting in excessive side reactions, low yields, and certain requirements for the purity of the raw materials; the cracking method is very easy to produce excessive acid and toxic gases at high temperatures, which is generally difficult to produce; the acid hydrolysis method is easy to generate excessive acid, resulting in a decrease in yield; the enzyme catalysis method has high costs for enzyme catalysts and equipment.

[0003] In view of the problems existing in the above process when synthesizing aldehyde compounds, it is very necessary to redesign a new route to overcome the above difficulties. Summary of the Invention

[0004] In view of this, the object of the present invention is to provide a method for synthesizing aldehyde compounds, that is, to develop a simple, efficient and low-cost synthesis route that can solve the above-mentioned shortcomings in the prior art.

[0005] In order to solve the above technical problems, the present invention provides a method for preparing an aldehyde compound.

[0006] The method for preparing the aldehyde compound provided by the present invention is specifically, in the presence of a reducing agent, preparing a compound of formula III from a compound of formula I', and then further preparing a compound of formula IV through an oxidation reaction.

[0007]

[0008] Here, R can be hydrogen, methyl, ethyl, benzyl or halogen-substituted alkyl.

[0009] The method comprises the following steps: reducing compound I' to compound III by controlling the material ratio and reaction temperature, quenching, extracting, washing with water, concentrating to obtain compound III oil, and then oxidizing to obtain the target compound.

[0010] The compound of formula I' is composed of a compound of formula I and a compound of formula II,

[0011] The compound of formula I is:

[0012]

[0013] R is methyl, ethyl, benzyl or halogen-substituted alkyl.

[0014] The compound of formula II is:

[0015]

[0016] The molar ratio of compound I to compound II is in the range of 0.1:0.9 to 0.9:0.1.

[0017] The compound I and compound II are reacted with a reducing agent in the presence of THF.

[0018] The above reaction of the present invention is carried out in the presence of a reducing agent, which is Zn(BH4)2.

[0019] The reaction temperature of the present invention is -30 to 30°C.

[0020] The compound III of the present invention is further subjected to oxidation reaction to prepare compound IV.

[0021] The oxidant is O3, and the reaction is carried out under the conditions of N,N-diisopropylethylamine and dimethyl sulfoxide.

[0022] The temperature of the oxidation reaction is -10 to 30° C., and the time is 2 to 12 hours.

[0023] The crystallization solvent is at least one of heptane, cyclohexane, and n-hexane

[0024] The above preparation process of the present invention is carried out in the presence of an organic solvent, and the organic solvent is dimethyl sulfoxide.

[0025] The invention reduces a mixture of an ester and an acid into an alcohol, and then oxidizes the alcohol into an aldehyde using ozone to prepare an aldehyde compound, which is purified by heptane crystallization with a yield of 90%.

[0026] The beneficial effects of the present invention are as follows: the present invention reduces the mixture of ester and acid into alcohol, and then utilizes ozone to oxidize the alcohol into aldehyde. The process has high yield, low cost, is convenient for industrial production, and has certain economic value.

[0027] 1. During ester synthesis, both esters and acids are produced. Using both esters and acids as raw materials offers cost advantages. 2. Reduction to alcohols offers a higher yield. 3. When oxidizing alcohols to aldehydes, we use low-concentration ozone, effectively controlling the reaction to the aldehyde stage and generating less acid. DETAILED DESCRIPTION

[0028] The preferred embodiments of the present invention are described in detail below so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more precise definition of the protection scope of the present invention.

[0029] Example 1:

[0030]

[0031] At room temperature, compound I (50%) and compound II (50%) (31.9 g, 131.0 mmol) were added to 240 mL of dry THF. The mixture was cooled to -10°C under N2 protection, and 1 mol / L Zn(BH4)2 / THF (131 mL, 131.0 mmol) was slowly added, controlling the temperature not to exceed 5°C. After the addition, the mixture was heated to 25°C and allowed to react overnight. After the reaction was completed, 45 mL of methanol was slowly added to quench the mixture, controlling the temperature not to exceed 25°C. The mixture was stirred and kept warm for 0.5 h. The reaction solution was evaporated to dryness, and 150 mL of water was added. The mixture was extracted three times with EA (50 mL x 3). The organic phases were combined, washed with saturated aqueous NaCl solution, and dried over Na2SO4. The organic layer was evaporated to dryness to obtain 27.9 g of compound III as a colorless oily liquid with a yield of 97% and a purity of 98%.

[0032] NMR data: 1 H NMR(400MHz,DMSO-d6)δ4.70(dt,J=11.7,5.6Hz,1H),3.57–3.20(m,4H),2.16–1.94(m ,1H),1.74–1.61(m,2H),1.57–1.47(m,1H),1.38(d,J=4.9Hz,9H),1.23–1.18(m,3H).

[0033] Example 2:

[0034]

[0035] At room temperature, 90 mL of DMSO and 75 mL of DCM were added to the reaction flask. The mixture was cooled to -10°C under N2 protection and stirred for 1 hour. Compound III (30.0 g, 139.3 mmol) and N,N-diisopropylethylamine (54.0 g, 417.8 mmol) were mixed thoroughly and slowly added to the reaction solution. The temperature was maintained below 10°C, and ozone was introduced at 4 g / h for 3 hours. The reaction was then incubated for 2 hours. The reaction solution was then poured into 100 mL of ice water and stirred for 15 minutes. The mixture was then extracted with MTBE (80 mL x 3) until the aqueous layer showed no RMC spot by TLC. The organic layers were combined and adjusted to pH 5-6 with 30% aqueous citric acid. The organic layers were then washed with saturated aqueous NaCl solution and dried over Na2SO4. The organic layer was evaporated to dryness to obtain 29.1 g of compound IV as a light yellow oily liquid with a yield of 95% and a purity of 97%.

[0036] At room temperature, 25.0 g of crude compound IV was dissolved in 30 mL of n-heptane, stirred evenly, and then slowly cooled to -20°C. The mixture was allowed to stand for crystallization for 3-4 h, and 27.0 g of a white solid was obtained by filtration while the mixture was cold. The pure product of the white solid was obtained by drying to obtain 23.1 g of the product, with a yield of 95.2% and a purity of 99%.

[0037] NMR data: 1 H NMR(400MHz,DMSO-d6)δ9.31–9.26(m,1H),3.50–3.34(m,2H),2.00–1.84( m,3H),1.64–1.52(m,1H),1.40(s,4H),1.32(s,5H),1.27(d,J=5.6Hz,3H).

[0038] Example 3:

[0039]

[0040] At room temperature, compound I (50%) and compound II (50%) (30.9 g, 131.0 mmol) were added to 240 mL of dry THF. The mixture was cooled to -10°C under N2 protection, and 1 mol / L Zn(BH4)2 / THF (144 mL, 144.0 mmol) was slowly added, controlling the temperature not to exceed 5°C. After the addition, the mixture was heated to 25°C and allowed to react overnight. After the reaction was completed, 45 mL of methanol was slowly added to quench the mixture, controlling the temperature not to exceed 25°C. The mixture was stirred and kept warm for 0.5 h. The reaction solution was evaporated to dryness, and 150 mL of water was added. The mixture was extracted three times with EA (50 mL x 3). The organic phases were combined, washed with saturated aqueous NaCl solution, and dried over Na2SO4. The organic layer was evaporated to dryness to obtain 28.0 g of compound III as a colorless oily liquid with a yield of 97% and a purity of 97.8%.

[0041] NMR data: 1 H NMR(400MHz,DMSO-d6)δ4.70(dt,J=11.7,5.6Hz,1H),3.57–3.20(m,4H),2.16–1.94(m ,1H),1.74–1.61(m,2H),1.57–1.47(m,1H),1.38(d,J=4.9Hz,9H),1.23–1.18(m,3H).

[0042] At room temperature, 90 mL of DMSO and 75 mL of DCM were added to the reaction flask. The mixture was cooled to -10°C under N2 protection and stirred for 1 hour. Compound III (30.0 g, 139.3 mmol) and N,N-diisopropylethylamine (59.4 g, 459.7 mmol) were mixed thoroughly and slowly added to the reaction solution. The temperature was maintained below 10°C, and ozone was introduced at 3 g / h for 4 hours. The reaction was then incubated for 2 hours. The reaction solution was then poured into 100 mL of ice water and stirred for 15 minutes. The mixture was then extracted with MTBE (80 mL x 3) until the aqueous layer showed no RMC spot by TLC. The organic layers were combined and adjusted to pH 5-6 with 30% aqueous citric acid. The organic layers were then washed with saturated aqueous NaCl solution and dried over Na2SO4. The organic layer was evaporated to dryness to obtain 29.4 g of compound IV as a light yellow oily liquid with a yield of 96% and a purity of 97%.

[0043] At room temperature, 25.0 g of crude compound IV was dissolved in 40 mL of n-heptane, stirred evenly, and then slowly cooled to -25°C. The mixture was allowed to stand for 4 h for crystallization, and 26.5.0 g of a white solid was obtained by filtration while it was cold. The above solid was crystallized again to obtain 22.6 g of pure white solid with a purity of 99.0% and a yield of 93.1%.

[0044] NMR data: 1 H NMR(400MHz,DMSO-d6)δ9.31–9.26(m,1H),3.50–3.34(m,2H),2.00–1.84( m,3H),1.64–1.52(m,1H),1.40(s,4H),1.32(s,5H),1.27(d,J=5.6Hz,3H).

[0045] Example 4:

[0046]

[0047] At room temperature, compound I (70%) and compound II (30%) (32.6 g, 131 mmol) were added to 240 mL of dry THF. The mixture was cooled to -10°C under N2 protection, and 1 mol / L Zn(BH4)2 / THF (118 mL, 118.0 mmol) was slowly added, controlling the temperature not to exceed 5°C. After the addition, the mixture was heated to 25°C and allowed to react overnight. After the reaction was completed, 45 mL of methanol was slowly added to quench the mixture, controlling the temperature not to exceed 25°C. The mixture was stirred and kept warm for 0.5 h. The reaction solution was evaporated to dryness, and 150 mL of water was added. The mixture was extracted three times with EA (50 mL x 3). The organic phases were combined, washed with saturated aqueous NaCl solution, and dried over Na2SO4. The organic layer was evaporated to dryness to obtain 28.3 g of compound III as a colorless oily liquid with a yield of 98% and a purity of 97.5%.

[0048] NMR data:1 H NMR(400MHz,DMSO-d6)δ4.70(dt,J=11.7,5.6Hz,1H),3.57–3.20(m,4H),2.16–1.94(m ,1H),1.74–1.61(m,2H),1.57–1.47(m,1H),1.38(d,J=4.9Hz,9H),1.23–1.18(m,3H).

[0049] At room temperature, 90 mL of DMSO and 75 mL of DCM were added to the reaction flask. The mixture was cooled to -10°C under N2 protection and stirred for 1 hour. Compound III (30.0 g, 139.3 mmol) and DIPEA (54.0 g, 417.3 mmol) were mixed and then slowly added to the reaction solution. The temperature was maintained below 10°C, and ozone was introduced at 2.5 g / h for 5 hours. The reaction was then incubated for 2 hours. The reaction solution was then poured into 100 mL of ice water and stirred for 15 minutes. The mixture was then extracted with MTBE (80 mL x 3) until the aqueous layer showed no RMC spot by TLC. The organic layers were combined and adjusted to pH 5-6 with 30% aqueous citric acid. The organic layers were then washed with saturated aqueous NaCl solution and dried over Na2SO4. The organic layer was evaporated to dryness to obtain 30 g of Compound IV as a pale yellow oily liquid with a yield of 96% and a purity of 95%.

[0050] At room temperature, 30.0 g of crude compound IV was dissolved in 30 mL of n-heptane, stirred evenly, and then slowly cooled to -20°C. The mixture was allowed to stand for crystallization for 3-4 h, and filtered while cold to obtain 28.5.0 g of a white solid. The solid was crystallized again to obtain 27.0 g of a pure white solid, with a yield of 94.7% and a purity of 99%.

[0051] NMR data: 1 H NMR(400MHz,DMSO-d6)δ9.31–9.26(m,1H),3.50–3.34(m,2H),2.00–1.84( m,3H),1.64–1.52(m,1H),1.40(s,4H),1.32(s,5H),1.27(d,J=5.6Hz,3H).

Claims

1. A method for preparing an aldehyde compound, characterized in that: The steps include: (1) Compound Ⅰ' is reduced to generate compound Ⅲ, (2) In the presence of a base, an oxidizing agent is added to compound III to undergo an oxidation reaction to obtain compound IV. The reaction process is as follows: Wherein, R is hydrogen, methyl, ethyl, benzyl or halogen-substituted alkyl, in step (1), the reducing agent is Zn(BH4)2, in step (2), the base is N,N-diisopropylethylamine, and the oxidizing agent is O3.

2. The preparation method according to claim 1, characterized in that The compound of formula I' is composed of a compound of formula I and a compound of formula II. In the step (1), the molar ratio of compound I to compound II is in the range of 0.1-0.9:0.1-0.9, the molar ratio of the reducing agent to compound I' is in the range of 0.5-2:1, and the compound of formula I is R is methyl, ethyl, benzyl or halogen-substituted alkyl, and the compound of formula II is 3. The preparation method according to claim 1, characterized in that In the step (1), the reaction temperature is -30 to 30°C, and the reaction time is 2 to 48 hours.

4. The preparation method according to claim 1, characterized in that In the step (2), the molar ratio of the oxidant to the compound III is in the range of 0.4 to 3:1, and the molar ratio of the base to the compound III is in the range of 2.5 to 6:

1.

5. The preparation method according to claim 1, characterized in that In the step (2), the reaction temperature is -10 to 30°C and the reaction time is 2 to 12 hours.

6. The preparation method according to claim 1, characterized in that In the step (2), the crystallization solvent is at least one of heptane, cyclohexane, and n-hexane.

7. The preparation method according to claim 6, characterized in that The volume to weight ratio of the crystallization solvent is 0.5 to 2:

1.

8. The preparation method according to claim 1, characterized in that In the step (2), the crystallization temperature is -30°C to -5°C.

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