A process for the preparation of (s)-3-cyclohexene-1-carboxylic acid and intermediates thereof

Abstract

The application provides a preparation method of (S)-3-cyclohexene-1-carboxylic acid and an intermediate, and relates to the technical field of chiral synthesis. (S)-3-cyclohexene-1-carboxylic acid IV is prepared by the following steps: propenal I is reacted with 1,3-butadiene II in a first solvent to generate (S)-3-cyclohexene-1-formaldehyde III under the promotion of an organic small molecule catalyst, and then (S)-3-cyclohexene-1-formaldehyde III is oxidized to generate (S)-3-cyclohexene-1-carboxylic acid IV. The method can efficiently and asymmetrically synthesize (S)-3-cyclohexene-1-formaldehyde under the action of the organic small molecule catalyst, and can realize efficient synthesis of (S)-3-cyclohexene-1-carboxylic acid, and the prepared (S)-3-cyclohexene-1-carboxylic acid has good yield and an ee value of up to 99.8%. The preparation method has mild and green reaction conditions, high reaction efficiency, high atom economy and step economy.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chiral synthesis, and particularly relates to a preparation method of (S)-3-cyclohexen-1-carboxylic acid and intermediates. BACKGROUND

[0002] (S)-3-cyclohexen-1-carboxylic acid is an important chemical reagent and organic intermediate as a chiral compound, is widely used in the field of medicine, and plays a very important role in drug research and development, and has shown various drug activities, so that the demand for (S)-3-cyclohexen-1-carboxylic acid also increases year by year, and therefore it is of great significance to develop a green, efficient and simple new synthesis process.

[0003] At present, the synthesis of (S)-3-cyclohexen-1-carboxylic acid mainly adopts chiral source synthesis method and racemate chiral resolution method. Among them, the chiral source synthesis method is greatly limited in synthesizing a specific target product due to the limited types of natural chiral substances, so the non-enantiomeric resolution technology is mainly used in industry to prepare (S)-3-cyclohexen-1-carboxylic acid, and chiral phenethylamine is used as a chiral resolving agent. The non-enantiomeric isomers of racemic 3-cyclohexen-1-carboxylic acid methyl ester and phenethylamine are separated based on the solubility difference of the non-enantiomeric isomers in acetone, and after slow cooling and multiple recrystallization, a product with good chiral purity can be obtained. However, the method is complex to operate, the chiral resolving agent used is expensive and in large quantity, and does not meet the requirements of green chemistry. Therefore, it is necessary to provide a scheme to improve the above problems. SUMMARY

[0004] The purpose of the present application is to provide a preparation method of (S)-3-cyclohexen-1-carboxylic acid and intermediates, which can efficiently and asymmetrically synthesize (S)-3-cyclohexen-1-formaldehyde under the action of an organic small molecule catalyst, realize efficient synthesis of (S)-3-cyclohexen-1-carboxylic acid, and the prepared (S)-3-cyclohexen-1-carboxylic acid has good yield and an ee value of up to 99.8 %. The preparation method has mild and green reaction conditions, high reaction efficiency, high atom economy and step economy.

[0005] The present application provides a preparation method of (S)-3-cyclohexen-1-formaldehyde, which comprises the following steps:

[0006] In a first solvent, propylene aldehyde I and 1,3-butadiene II are reacted in the presence of an organic small molecule catalyst as a promoter to generate (S)-3-cyclohexen-1-formaldehyde III;

[0007]

[0008] The beneficial effects of the preparation method of (S)-3-cyclohexene-1-carboxaldehyde provided by the present invention are that the reaction conditions are mild, enabling efficient synthesis of (S)-3-cyclohexene-1-carboxaldehyde II, with high atom economy and step economy, which is conducive to the further application of (S)-3-cyclohexene-1-carboxaldehyde II in drug synthesis.

[0009] Optionally, when acrolein I reacts with 1,3-butadiene II, the acrolein I is reacted with an excess of the 1,3-butadiene II. The beneficial effect is that it promotes the forward reaction and increases the yield of (S)-3-cyclohexene-1-carboxaldehyde.

[0010] Optionally, when the acrolein I is reacted with an excess of the 1,3-butadiene II, the molar ratio of the acrolein I to the 1,3-butadiene II is 1:(2-4).

[0011] Optionally, when an organic small molecule catalyst is used as a promoter, the organic small molecule catalyst is an organic amine catalyst; the organic amine catalyst includes imidazolidine ketone catalysts. Its advantages lie in the fact that the organic small molecule catalyst is inexpensive, readily available, and highly reactive; it does not contain transition metals, thus avoiding the toxicity of heavy metal elements; and it is stable, facilitating recycling after the reaction, thereby improving the economy and environmental friendliness of the reaction.

[0012] Optionally, when an organic small molecule catalyst is used as a promoter, the molar ratio of the organic small molecule catalyst to acrolein I is (0.01-0.10):1. The advantage is that it can accelerate the reaction at a lower dosage.

[0013] Optionally, when reacting acrolein I with 1,3-butadiene II, the reaction temperature is controlled at 0-40°C. The advantage is that the reaction can be carried out at a lower temperature, resulting in milder reaction conditions.

[0014] Optionally, using an organic small-molecule catalyst as a promoter, acrolein I is reacted with 1,3-butadiene II to generate (S)-3-cyclohexene-1-carboxaldehyde III, followed by purification of (S)-3-cyclohexene-1-carboxaldehyde III and recovery of the organic small-molecule catalyst. The beneficial effect is that separating (S)-3-cyclohexene-1-carboxaldehyde III from the organic small-molecule catalyst facilitates the recovery and reuse of the organic small-molecule catalyst, and improves the synthetic purity of (S)-3-cyclohexene-1-carboxaldehyde III, which is beneficial for its application.

[0015] Optionally, in the process of purifying the (S)-3-cyclohexene-1-formaldehyde III and recovering the small organic molecule catalyst, the following steps are included: after adjusting the pH of the mixed system after the reaction of the acrolein I and the 1,3-butadiene II to 2-4, a first extractant is added to extract and separate the (S)-3-cyclohexene-1-formaldehyde III; and the pH of the mixed system after the separation of the (S)-3-cyclohexene-1-formaldehyde III is adjusted to 10-14, and a second extractant is added to extract and separate the small organic molecule catalyst.

[0016] In a second aspect, the present application provides a method for preparing (S)-3-cyclohexene-1-formic acid, comprising the following steps:

[0017] S1, in a first solvent, acrolein I and 1,3-butadiene II are reacted in the presence of a small organic molecule catalyst to generate (S)-3-cyclohexene-1-formaldehyde III;

[0018] S2, in a second solvent, (S)-3-cyclohexene-1-formaldehyde III generated in step S1 is oxidized to generate (S)-3-cyclohexene-1-formic acid IV;

[0019]

[0020] The method for preparing (S)-3-cyclohexene-1-formic acid provided by the present application has the beneficial effect that (S)-3-cyclohexene-1-formaldehyde III is first synthesized efficiently, and then (S)-3-cyclohexene-1-formaldehyde III is oxidized to (S)-3-cyclohexene-1-formic acid IV, thereby reducing the complexity of the synthesis of (S)-3-cyclohexene-1-formic acid IV, and the reaction conditions are mild and green and environmentally friendly, and the obtained (S)-3-cyclohexene-1-formic acid IV has good yield and high ee value.

[0021] Optionally, in the reaction of (S)-3-cyclohexene-1-formaldehyde III in step S2, the molar ratio of the oxidizing agent to (S)-3-cyclohexene-1-formaldehyde III is (1-5) : 1. This has the beneficial effect that the concentration of the oxidizing agent in the reaction system can be increased, thereby facilitating the oxidation of (S)-3-cyclohexene-1-formaldehyde III to (S)-3-cyclohexene-1-formic acid IV.

[0022] Optionally, after (S)-3-cyclohexene-1-formic acid IV is generated in step S2, (S)-3-cyclohexene-1-formic acid IV is separated and purified. This has the beneficial effect that it is beneficial to separate the unreacted reactants in the system after the reaction is completed, thereby improving the purity of (S)-3-cyclohexene-1-formic acid IV.

[0023] Optionally, when the (S)-3-cyclohexene-1-carboxylic acid IV is separated and purified, the following steps are included: adjusting the pH of the system after the reaction of (S)-3-cyclohexene-1-carboxylic acid IV from (S)-3-cyclohexene-1-carboxaldehyde III to 10-14, separating the first product extraction water phase and the impurity extraction phase after adding the first product extraction agent; adjusting the pH of the first product extraction water phase to 2-4, and separating the product extraction phase after adding the second product extraction agent; purifying the product extraction phase to obtain (S)-3-cyclohexene-1-carboxylic acid IV. DETAILED DESCRIPTION

[0024] To make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of the present application. Unless otherwise defined, the technical terms or scientific terms used herein should be understood as the common meanings of the terms by those of ordinary skill in the art to which the present application belongs. The terms such as “comprise” and the like used herein mean that the elements or objects before the terms encompass the elements or objects listed after the terms and equivalents thereof, and do not exclude other elements or objects.

[0025] The embodiments of the present application provide a preparation method of (S)-3-cyclohexene-1-carboxaldehyde, which comprises the following steps: after propenal I and 1,3-butadiene II are reacted in a first solvent with an organic small molecule catalyst as a promoter, (S)-3-cyclohexene-1-carboxaldehyde III is generated.

[0026]

[0027] In fact, in the process of the reaction of propenal I and 1,3-butadiene II, an asymmetric [4+2] cycloaddition reaction occurs under the action of the organic small molecule catalyst, so that the intermediate (S)-3-cyclohexene-1-carboxaldehyde III is generated in one step, which has high atom economy and step economy.

[0028] In fact, the propenal I, 1,3-butadiene II and the organic small molecule catalyst participating in the reaction are all commercially available conventional products, and can be purified by means known in the art when necessary before use. Further, the propenal I, 1,3-butadiene II and the organic small molecule catalyst used can also be synthesized in a laboratory by means available in the art, and purified when necessary before use.

[0029] In some embodiments, the reaction of propenal I with 1,3-butadiene II can be carried out in an air atmosphere. In fact, the reaction of propenal I with 1,3-butadiene II can be carried out in any gaseous environment.

[0030] In some embodiments, the reaction of propenal I with 1,3-butadiene II can be carried out in a first solvent. In fact, the reaction of propenal I with 1,3-butadiene II can be carried out in any solvent commonly used in organic reactions in the art, which is capable of dissolving the promoter, the product and at least one of the reactants, and which does not react with the promoter, the reactants and the product.

[0031] In some embodiments, the organic small molecule catalyst used in the reaction of propenal I with 1,3-butadiene II can be an organic amine catalyst.

[0032] In further embodiments, when the organic small molecule catalyst is an organic amine catalyst, it can be specifically a proline catalyst, a prolinol or silanol ether catalyst, a cinchona alkaloid catalyst or an imidazolidinone catalyst.

[0033] In further embodiments, when the organic small molecule catalyst is an imidazolidinone catalyst, it can be specifically one of (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4- imidazolinone, (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride, (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone perchlorate, (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone triflate, (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolinone, (5S)-2,2,3-trimethyl-5-benzyl-4- imidazolinone hydrochloride, (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolinone perchlorate and (5S)-2,2,3-trimethyl-5-benzyl-4-imidazolinone triflate.

[0034] In some embodiments, the molar ratio of the organic small molecule catalyst to propenal I in the reaction of propenal I with 1,3-butadiene II is (0.01-0.10): 1.

[0035] In some embodiments, the reaction of propenal I with 1,3-butadiene II is carried out with an excess of 1,3-butadiene II, which is beneficial to promote the reaction to proceed in the forward direction, thereby improving the yield of (S)-3-cyclohexene-1-carboxaldehyde III.

[0036] Specifically, when propenal I is reacted with excess 1,3-butadiene II, the molar ratio of propenal I to 1,3-butadiene II is controlled to be 1:(2-4).

[0037] In some embodiments, when propenal I is reacted with 1,3-butadiene II, the reaction temperature is controlled to be between 0-40℃. In fact, propenal I and 1,3-butadiene II can be reacted at a temperature that does not cause the first solvent to freeze or boil.

[0038] In some embodiments, when propenal I is reacted with 1,3-butadiene II, the reaction system can be stirred to further improve the reaction rate.

[0039] In some embodiments, when propenal I is reacted with 1,3-butadiene II, the reaction time of the reaction system is controlled to be 8-16h.

[0040] In some embodiments, when (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride is selected as the promoter, and the reaction temperature is controlled to be 0-40℃, the reaction of propenal I with 1,3-butadiene II to generate intermediate (S)-3-cyclohexene-1-formaldehyde III is as follows:

[0041]

[0042] In some embodiments, after propenal I is reacted with 1,3-butadiene II to generate (S)-3-cyclohexene-1-formaldehyde III, the obtained product (S)-3-cyclohexene-1-formaldehyde III is purified, and the organic small molecule catalyst is recovered. In this way, the product purity of (S)-3-cyclohexene-1-formaldehyde III is improved, and the recovery of the organic small molecule catalyst facilitates its reuse in the next use, improving the utilization rate and environmental protection.

[0043] In some embodiments, before the obtained product (S)-3-cyclohexene-1-formaldehyde III is purified, distilled water is added to the mixed system after the reaction for quenching treatment.

[0044] In further embodiments, in the process of purifying the product (S)-3-cyclohexene-1-formaldehyde III and recovering the organic small molecule catalyst in the mixed system after the reaction of propenal I with 1,3-butadiene II, the following sub-steps are included:

[0045] D1, adjust the pH of the mixed system to 2-4, after adding the first extractant for extraction, obtain a first extraction aqueous phase and a first extraction phase, concentrate and separate the solutes in the first extraction phase to obtain (S)-3-cyclohexene-1-formaldehyde III;

[0046] D2, adjusting the pH of the first extraction aqueous phase to 10-14, after adding the second extractant for extraction, obtaining a second extraction aqueous phase and a second extraction phase, separating the solute in the second extraction phase, and concentrating and recovering the organic small molecule catalyst.

[0047] In fact, when performing step D1, the first extractant used can be dichloromethane, ethyl acetate or diethyl ether. Specifically, the amount of the first extractant used is 20-100 equivalents of propenal I.

[0048] In fact, when performing step D2, the second extractant used can be dichloromethane, ethyl acetate or diethyl ether. Specifically, the amount of the second extractant used is 20-100 equivalents of propenal I.

[0049] In fact, the first extractant and the second extractant can be the same organic solvent or different organic solvents, so as to be able to extract (S)-3-cyclohexene-1-formaldehyde III and the organic small molecule catalyst in different acid-base environments.

[0050] In some embodiments, in the process of adjusting the pH of the first extraction aqueous phase to 10-14 in step D1, a base is added to the first extraction aqueous phase to adjust the pH to 10-14. Specifically, the base added to the first extraction aqueous phase can be an organic base and / or an inorganic base. More specifically, the organic base can be triethylamine, and the inorganic base can be KOH, NaOH, Na2CO3 or K2CO3. In fact, the base used in step D2 is necessary to be able to adjust the pH of the system and not to react with the solute.

[0051] In some embodiments, in the process of concentrating and separating the solute in the first extraction phase to obtain (S)-3-cyclohexene-1-formaldehyde III in step D1, and in the process of separating the solute in the second extraction phase to concentrate and recover the organic small molecule catalyst in step D2, the concentration and separation operation used is a common operation in the art, such as column chromatography separation, evaporation solvent separation, etc.

[0052] The embodiment of the present application also provides a preparation method of (S)-3-cyclohexene-1-formaldehyde, comprising the following steps:

[0053] S1, in a first solvent, propenal I and 1,3-butadiene II are reacted in the presence of an organic small molecule catalyst as a promoter to generate (S)-3-cyclohexene-1-formaldehyde III;

[0054] S2, in a second solvent, (S)-3-cyclohexene-1-formaldehyde III generated in step S1 is reacted in the presence of an oxidant to generate (S)-3-cyclohexene-1-formaldehyde IV;

[0055]

[0056] In some embodiments, the second solvent used in step S2 can be a mixture of one or more of t-butyl alcohol, tetrahydrofuran and water. In fact, the second solvent used in step S2 can be any solvent commonly used in organic oxidation reactions in the art, which is capable of dissolving the oxidizing agent, the reactant and the product, and does not react with the oxidizing agent, the reactant and the product.

[0057] In some embodiments, the second solvent used in step S2 can further comprise a buffer solution, which is capable of maintaining the pH stability of the reaction system during the reaction. Specifically, the buffer solution can be a sodium phosphate monobasic solution. In fact, the buffer solution used in step S2 can be any buffer solution commonly used in organic reactions in the art, which is capable of maintaining the pH stability and does not react with the oxidizing agent, the reactant and the product.

[0058] In some embodiments, when the second solvent used in step S2 comprises a sodium phosphate monobasic solution, the molar ratio of sodium phosphate monobasic to (S)-3-cyclohexen-1-formaldehyde III is (1-20) : 1.

[0059] In some embodiments, the oxidizing agent used in step S2 can be sodium chlorite. Specifically, the molar ratio of the oxidizing agent to (S)-3-cyclohexen-1-formaldehyde III is (1-5) : 1.

[0060] In some embodiments, the oxidizing agent used in step S2 can be added to the reaction system in the form of an aqueous solution.

[0061] In some embodiments, the reaction in step S2 is controlled to be carried out at a temperature of 0-40°C. In fact, the reaction in step S2 can be carried out at any temperature that does not cause the second solvent to freeze or boil.

[0062] In some embodiments, 2-methyl-2-butene can be further added to the reaction system in step S2, which can prevent the occurrence of side reactions.

[0063] In some embodiments, after (S)-3-cyclohexen-1-formic acid IV is generated in step S2, (S)-3-cyclohexen-1-formic acid IV is separated and purified.

[0064] In further embodiments, when (S)-3-cyclohexen-1-formic acid IV is separated and purified from the reaction system after (S)-3-cyclohexen-1-formic acid IV is generated in step S2, the following steps are included:

[0065] Y1, adjusting the pH of the reaction system to 10-14, and separating the first product aqueous phase and the impurity extraction phase after adding the first product extraction agent;

[0066] Y2, adjusting the pH of the first product aqueous phase to 2-4, adding the second product extractant to separate the product extraction phase;

[0067] Y3, purifying the product extraction phase to obtain (S)-3-cyclohexene-1-carboxylic acid IV.

[0068] Specifically, when performing step Y1 to adjust the pH of the reaction system to 10-14, an organic base or an inorganic base is added to the reaction system, wherein the organic base can be triethylamine, and the inorganic base can be a mixture of one or more of KOH, NaOH, Na2CO3, and K2CO3.

[0069] Specifically, when performing step Y2 to adjust the pH of the reaction system to 2-4, an inorganic acid such as HCl and / or H2SO4 is added to the reaction system.

[0070] Specifically, the first product extractant added when performing step Y1 and the second product extractant added when performing step Y2 can be ethyl acetate, dichloromethane, or diethyl ether, independently.

[0071] Specifically, when performing step Y3 to purify the product extraction phase, the separation and purification method used is a common operation in the art, such as column chromatography separation, solvent evaporation separation, etc.

[0072] Example 1:

[0073] The embodiment 1 of the present application provides a preparation method of (S)-3-cyclohexene-1-formaldehyde III, comprising the following steps:

[0074] S11, 112 g (2.0 mmol) of propylene aldehyde I, 432 g (8 mmol) of 1,3-butadiene II, and 5.6 g (0.02 mmol) of (2S, 5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride are added to a 1000 mL round-bottom flask, 500 mL of water is added, and the reaction is stirred at room temperature under an air atmosphere at 25°C for 8 h;

[0075] S12, 100 mmol of dichloromethane is added to the round-bottom flask in step S11, after stirring and extracting (S)-3-cyclohexene-1-formaldehyde III, the first extraction aqueous phase and the first extraction phase are separated, and the solute in the first extraction phase is separated and purified, to obtain (S)-3-cyclohexene-1-formaldehyde III;

[0076] S13, after adding KOH to the first extraction aqueous phase in step S12 and adjusting the pH of the first extraction aqueous phase to 10-14, 100 mmol of dichloromethane is added to the first extraction aqueous phase, and (2S, 5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone is extracted by stirring, to obtain a second extraction aqueous phase and a second extraction phase, and the solute in the second extraction phase is separated and purified, to obtain (2S, 5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone, and the calculated recovery yield is 95%.

[0077] The reaction formula for generating (S)-3-cyclohexene-1-formaldehyde III in the embodiment 1 of the present application is shown as follows:

[0078]

[0079] Embodiment 2:

[0080] The embodiment 2 provides a method for preparing (S)-3-cyclohexene-1-formic acid IV by using (S)-3-cyclohexene-1-formaldehyde III prepared in the embodiment 1, which comprises the following steps:

[0081] S21, 222 g (2 mmol) of (S)-3-cyclohexene-1-formaldehyde III prepared in the embodiment 1 is added into a 1000 mL round-bottom flask, 150 mL of tert-butyl alcohol, 150 mL of tetrahydrofuran and 50 mL of water are added, and then 1122 g (16 mmol) of 2-methyl-2-butene, 543 g (6 mmol) of sodium dihydrogen phosphate and 360 g (6 mmol) of sodium hydroxide are added, and the reaction is stirred at room temperature in an air atmosphere for 1 h;

[0082] S22, KOH is added to adjust the pH of the reaction system in the round-bottom flask after the reaction in step S21 to 10-14, and then dichloromethane is added for extraction, to separate a first product aqueous phase and an impurity extraction phase;

[0083] S23, HCl is added to adjust the pH of the first product aqueous phase to 2-4, and then dichloromethane is added for extraction, to separate a second product aqueous phase and a product extraction phase;

[0084] S24, (S)-3-cyclohexene-1-formic acid IV in the product extraction phase is purified, and the total yield is calculated to be 85%, and ee = 99.8%.

[0085] The reaction formula for generating (S)-3-cyclohexene-1-formic acid IV in the embodiment 2 is shown as follows:

[0086]

[0087] The spectral characterization of (S)-3-cyclohexene-1-formic acid IV prepared in the embodiment 2 is as follows:

[0088] 1 H NMR (400 MHz, CDCI3) δ 5.72-5.65 (m, 2H), δ 2.65-2.56 (m, 1H), δ 2.29-2.25 (m, 2H), δ 2.18-2.00 (m, 3H), δ 1.76-1.65 (m, 1H). 13 C NMR (101 MHz, CDCI3) δ 182.5, 126.7, 124.9, 39.1, 27.1, 24.8, 24.3.

[0089] As can be seen from Example 1, after the preparation of (S)-3-cyclohexen-1- formic acid IV is promoted by (2S, 5S)-5-benzyl-2-tert-butyl-3-methyl-4- imidazolinone hydrochloride, the (S)-3-cyclohexen-1-formic acid IV can be recovered, so that the utilization rate of (2S, 5S)-5-benzyl-2-tert-butyl-3-methyl-4- imidazolinone hydrochloride can be improved, and the reaction cost can be reduced, and the use of transition metal is avoided, and the toxicity of heavy metal catalyst is avoided.

[0090] As can be seen from Example 1 and Example 2, the method provided by the present application can prepare (S)-3-cyclohexen-1-formic acid IV and its intermediate (S)-3- cyclohexen-1-formaldehyde III in a gram scale, and the preparation reaction conditions are mild and green and environmentally friendly, and the reaction cost is low, which is conducive to the large-scale industrialized preparation of (S)-3-cyclohexen-1-formic acid IV and its intermediate (S)-3-cyclohexen-1-formaldehyde III.

[0091] As can be seen from Example 2, the (S)-3-cyclohexen-1-formic acid IV prepared by the method provided by the present application has good yield and high ee value, which is conducive to the further application of (S)-3-cyclohexen-1-formic acid IV and its intermediate (S)-3-cyclohexen-1-formaldehyde III in the field of drug synthesis and the like.

[0092] Although the embodiments of the present application are described in detail above, it is obvious for those skilled in the art that various modifications and changes can be made to these embodiments. However, it should be understood that such modifications and changes all belong to the scope and spirit of the present application described in the claims. Moreover, the present application described herein can have other embodiments, and can be implemented or realized in various ways.

Claims

1. A method for preparing (S)-3-cyclohexene-1-carboxaldehyde, characterized in that, Includes the following steps: In the first solvent, using (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride as a promoter, acrolein I and 1,3-butadiene II are reacted at 0℃-40℃ to generate (S)-3-cyclohexene-1-carboxaldehyde III. 。 2. The preparation method according to claim 1, characterized in that, When acrolein I reacts with 1,3-butadiene II, the acrolein I is reacted with an excess of the 1,3-butadiene II.

3. The preparation method according to claim 2, characterized in that, When the acrolein I is reacted with an excess of the 1,3-butadiene II, the molar ratio of the acrolein I to the 1,3-butadiene II is 1:(2-4).

4. The preparation method according to claim 1, characterized in that, The molar ratio of (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride to acrolein I is (0.01-0.10):

1.

5. The preparation method according to claim 1, characterized in that, Using (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride as a promoter, acrolein I and 1,3-butadiene II are reacted to generate (S)-3-cyclohexene-1-carboxaldehyde III. The (S)-3-cyclohexene-1-carboxaldehyde III is then purified, and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride is recovered.

6. The preparation method according to claim 5, characterized in that, The process of purifying (S)-3-cyclohexene-1-carboxaldehyde III and recovering (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride includes: After adjusting the pH of the mixture of acrolein I and 1,3-butadiene II to 2-4, the first extractant is added to extract and separate (S)-3-cyclohexene-1-carboxaldehyde III. Adjust the pH of the mixture after separating (S)-3-cyclohexene-1-carboxaldehyde III to 10-14, and add a second extractant to extract and separate (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride.

7. A method for preparing (S)-3-cyclohexene-1-carboxylic acid, characterized in that, Includes the following steps: S1. In the first solvent, using (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-4-imidazolinone hydrochloride as a promoter, acrolein I and 1,3-butadiene II are reacted at 0℃-40℃ to generate (S)-3-cyclohexene-1-carboxaldehyde III. S2. In the second solvent, under the action of an oxidant, (S)-3-cyclohexene-1-carboxaldehyde III generated in step S1 undergoes the following reaction to generate (S)-3-cyclohexene-1-carboxylic acid IV. 。 8. The preparation method according to claim 7, characterized in that, When (S)-3-cyclohexene-1-carboxaldehyde III reacts in step S2, the molar ratio of the oxidant to (S)-3-cyclohexene-1-carboxaldehyde III is (1-5):

1.

9. The preparation method according to claim 7, characterized in that, After performing step S2 to generate (S)-3-cyclohexene-1-carboxylic acid IV, the (S)-3-cyclohexene-1-carboxylic acid IV is separated and purified.

10. The preparation method according to claim 9, characterized in that, The separation and purification of (S)-3-cyclohexene-1-carboxylic acid IV includes the following steps: After adjusting the pH of the system to 10-14 after the reaction of (S)-3-cyclohexene-1-carboxaldehyde III to generate (S)-3-cyclohexene-1-carboxylic acid IV, the aqueous phase of the first product extraction and the impurity extraction phase were separated after adding the first product extractant. Adjust the pH of the aqueous phase of the first product extraction to 2-4, add the second product extractant, and then separate the product extraction phase. The product extract phase was purified to obtain (S)-3-cyclohexene-1-carboxylic acid IV.

Images