A method for refining cyclopentylaldehyde

Abstract

The application discloses a refining method of cyclopentyl formaldehyde, which comprises the following steps: firstly, reacting the cyclopentyl formaldehyde crude product with a lower alcohol, then reacting with sodium bisulfite, separating the sulfonate solid after the reaction, and carrying out a desalting reaction on the sulfonate solid with potassium carbonate to obtain the cyclopentyl formaldehyde fine product. The method improves the separation effect of the cyclopentyl formaldehyde and cyclopentanone, and alcohol is used as the solvent, so that the generated sulfonate is precipitated from the solution, the sulfonate of the cyclopentyl formaldehyde is directly filtered out, and the desalting is carried out with potassium carbonate after water is added for cleaning, so that the finished product is generated, the operation is simple, the effect is good, and the yield is high.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and purification, specifically relating to a method for purifying cyclopentylformaldehyde. Background Technology

[0002] Cyclopentanecarbaldehyde, CAS number 872-53-7, has a molecular weight of 98.14. It is an intermediate in the preparation of ruxolitinib. The structural formula of this product is:

[0003] .

[0004] The most economical synthetic route currently involves first using chlorocyclopentane as a Grignard reagent, then reacting it with DMF to form a Grignard salt, followed by hydrolysis to obtain the product. However, this route produces a specific impurity with a boiling point very close to that of the product, making it difficult to remove by distillation. This impurity has been verified by GC-MS and identified as cyclopentanone by standards. The proposed reaction mechanism is as follows:

[0005]

[0006] The formation of cyclopentanone may be due to the impossibility of completely removing oxygen from the Grignard reaction system. Once the Grignard reagent is formed, it reacts with trace amounts of oxygen in the system to form peroxide, which then hydrolyzes to form cyclopentanone. Its properties are similar to those of the product cyclopentylformaldehyde, and it forms an azeotrope, making distillation virtually ineffective for removal.

[0007] Furthermore, Boucher et al. (Boucher, MM; Furigay, MH; Quach, P.; K.; Brindle, CS* Org. Process Res. Dev. 2017, Article ASAP. DOI: 10.1021 / acs.oprd.7b00231) mentioned in their literature that sodium bisulfite can be used to first form sulfonates with aldehydes and ketones, followed by desalting to purify and separate the two substances. However, in reality, both cyclopentylformaldehyde and cyclopentanone readily form salts with sodium bisulfite, and the salt concentrations are not significantly different, resulting in unsatisfactory separation effects. Summary of the Invention

[0008] The purpose of this invention is to address the aforementioned shortcomings by providing a highly effective and efficient method for purifying cyclopentylformaldehyde, based on existing technologies. The purification scheme of this invention utilizes the slight difference in reactivity between ketones and aldehydes. First, a lower alcohol is used to react with cyclopentylformaldehyde and cyclopentanone to generate a hemiacetal (ketone), thereby increasing the difference in reactivity between the two substances. Cyclopentylformaldehyde can still react with sodium bisulfite to form a sulfonate precipitate, while cyclopentanone is dissolved in water and the mother liquor of alcohols for removal, thus achieving a separation effect.

[0009] The objective of this invention can be achieved through the following measures:

[0010] A method for purifying cyclopentylformaldehyde includes the following steps: first, reacting crude cyclopentylformaldehyde with a lower alcohol, then reacting it with sodium bisulfite, separating the sulfonate solid after the reaction, and then desalting the sulfonate solid with potassium carbonate to obtain refined cyclopentylformaldehyde.

[0011] The crude cyclopentyl formaldehyde of the present invention may contain less than 10% cyclopentanone, preferably less than 5% cyclopentanone, and more preferably less than 3% cyclopentanone.

[0012] The lower alcohols in this invention include any one of methanol and ethanol. The method of this invention is suitable for use with lower alcohols. We have found that using other common solvents can easily lead to various problems such as poor purification effect, low product purity, and low yield.

[0013] In the reaction of crude cyclopentylformaldehyde with lower alcohols, the mass ratio of crude cyclopentylformaldehyde to lower alcohols is 1:1 to 5, preferably 1:1.5 to 4, and more preferably 1:2 to 3.

[0014] The reaction temperature of crude cyclopentylformaldehyde with lower alcohols is 10–40°C, preferably 20–30°C; the reaction time is 1–5 h, preferably 1:1.5–3.5 h.

[0015] In this invention, sodium bisulfite is slowly added to the reaction system in the form of an aqueous solution. Preferably, the concentration of the sodium bisulfite aqueous solution is 20-33%, more preferably 20-25%. The molar ratio of sodium bisulfite to cyclopentylformaldehyde is 1-1.5:1, preferably 1-1.3:1. Experiments have shown that when the amount of sodium bisulfite used is within a suitable range, it can remove 1 / 3 or even more of the cyclopentyl ketone impurity, and the yield of the final product is high. However, when an inappropriate amount of sodium bisulfite is used, such as using 0.9 equivalents of sodium bisulfite, although 2 / 3 or even more of the cyclopentyl ketone impurity can be removed, the final product still has a large residue, and the yield is much lower.

[0016] In the reaction with sodium bisulfite, the reaction temperature is 10–40°C, preferably 20–30°C; the reaction time is 1–5 h, preferably 1:1.5–3.5 h.

[0017] The solvent for the desalting reaction in this invention is water.

[0018] In one embodiment, the molar ratio of potassium carbonate to cyclopentylformaldehyde in the desalination reaction is 2–3:1, preferably 2.1–2.5:1; the temperature of the desalination reaction is 30–40°C, and the reaction time is 2–6 h, preferably 3–5 h.

[0019] In this invention, preferably, after the desalting reaction, the mixture is allowed to stand and separate into layers. The aqueous layer is extracted with methyl tert-butyl ether. The extracted organic phase is washed with pure water and the solvent is removed by vacuum evaporation to obtain the refined cyclopentyl formaldehyde.

[0020] The cyclopentanone content in the refined cyclopentylformaldehyde obtained by the method of the present invention is less than 0.1%, and more preferably less than 0.07%.

[0021] The purification method of the present invention first utilizes the slight difference in activity between ketones and aldehydes by using a lower alcohol to generate a hemiacetal (ketone) with cyclopentylformaldehyde and cyclopentanone, thereby increasing the difference in activity between the two substances.

[0022]

[0023] In the above formula, R is methyl or ethyl.

[0024] Due to the increased steric hindrance of ketones, the acetals of ketones do not react with sodium bisulfite, while the hemiacetals of aldehydes can still react with sodium bisulfite to form sulfonates that precipitate out. Cyclopentanones are removed by dissolving in water and alcohol mother liquors.

[0025]

[0026] Finally, the sulfonate is removed to produce the aldehyde, thus achieving the purpose of purification.

[0027]

[0028] The beneficial effects of this invention are:

[0029] Compared with the prior art, the method of the present invention improves the separation effect of cyclopentylformaldehyde and cyclopentanone. Moreover, the use of alcohol as a solvent causes the generated sulfonate to precipitate from the solution. The sulfonate of cyclopentylformaldehyde is directly filtered out, dissolved in water, and then desalted with potassium carbonate to generate the finished product. The operation is simple, effective, and has a high yield. Attached Figure Description

[0030] Figure 1 This is a liquid phase spectrum of a crude cyclopentylformaldehyde product before purification in Example 1 and Comparative Example 1 of the present invention;

[0031] Figure 2 These are the liquid phase chromatograms of the cyclopentylformaldehyde products before purification in Example 2 and Comparative Example 2 of this invention;

[0032] Figure 3 This is the liquid phase spectrum of cyclopentylformaldehyde after purification in Example 1 of the present invention;

[0033] Figure 4 This is the liquid phase spectrum of cyclopentylformaldehyde after purification in Example 2 of the present invention;

[0034] Figure 5 This is the liquid phase spectrum of cyclopentylformaldehyde purified in Comparative Example 1 of this invention;

[0035] Figure 6 This is the liquid phase spectrum of cyclopentylformaldehyde after purification in Comparative Example 2 of this invention. Detailed Implementation

[0036] The method of the present invention will be further described below with reference to the accompanying drawings and embodiments. However, the scope of protection of the present invention is not limited to the following embodiments.

[0037] Example 1

[0038] Add 200g methanol and 100g cyclopentylcarbaldehyde (0.982mol, 1 equivalent, purity 96.4%, cyclopentanone 2.4%, see [link to reaction flask]) to a 1000ml reaction flask. Figure 1 After stirring for 2 hours, 488 g (1.08 mol) of a 23% sodium bisulfite aqueous solution was added dropwise. After stirring for 2 hours after the addition was complete, the mixture was cooled to 10-15℃ and filtered. The filter cake was washed with a small amount of methanol. The filter cake was then dissolved in 1000 g of pure water under nitrogen protection. 678 g (2.455 mol, 2.5 equivalents) of a 50% potassium carbonate solution was added dropwise. After stirring at 30-40℃ for 4 hours, the mixture was allowed to stand and separate into layers. The aqueous layer was extracted twice with methyl tert-butyl ether (300 g each time). The organic phases were combined and washed with pure water until neutral. The solvent was then evaporated under reduced pressure to obtain 90.1 g of cyclopentyl formaldehyde with a purity of 99.8% and cyclopentanone content less than 0.1%, which is a qualified product (see [link to product description]). Figure 3 The yield was 93.3%.

[0039] Example 2

[0040] Add 300 g of ethanol and 100 g of cyclopentyl formaldehyde (0.992 mol, 1 equivalent, purity 97.38%, cyclopentyl ketone 1.03%, see [link to reaction flask]) to a 1000 ml reaction flask. Figure 2 Stir for 2 hours, then add 493 g (1.09 mol, 1.1 equivalents) of 23% sodium bisulfite aqueous solution dropwise. After the addition is complete, stir for 2 hours, then cool to 10-15℃ and filter. Wash the filter cake with a small amount of methanol. Dissolve the filter cake in 1000 g of pure water under nitrogen protection, and add 685 g (2.48 mol, 2.5 equivalents) of 50% potassium carbonate solution dropwise. Stir at 30-40℃ for 4 hours, then allow to stand and separate into layers. Extract the aqueous layer twice with methyl tert-butyl ether (100 g each time). Combine the organic phases, wash with pure water until neutral, and then evaporate the solvent under reduced pressure to obtain 90.5 g of cyclopentyl formaldehyde with a purity of over 99.8% and cyclopentanone less than 0.1%, yielding a product of 92.7%. See [link to product details]. Figure 4 .

[0041] Comparative Example 1

[0042] 100g of methyl tert-butyl ether, 1000g of pure water, and 100g of cyclopentyl formaldehyde (0.982mol, 1 equivalent, purity 96.4%, cyclopentyl ketone 2.4%) were added to a 2000mL four-necked flask. The liquid chromatography chromatogram is shown below. Figure 1 488 g (1.09 mol, 1.1 equivalent) of 23% sodium bisulfite aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 2 h. The organic layer was separated, and the aqueous layer was extracted twice with 200 g of toluene. Under nitrogen protection, 722 g (2.61 mol) of 50% potassium carbonate solution was added dropwise. The mixture was stirred at 30-40℃ for 4 h, and then allowed to stand to separate the layers. The aqueous layer was extracted twice with methyl tert-butyl ether (100 g each time). The organic phases were combined, washed with pure water until neutral, and the solvent was removed by vacuum evaporation to obtain 90.0 g of cyclopentyl formaldehyde, with a purity of 97.2% and containing 1.7% cyclopentanone, yielding 90.7%. (See [link to product details]). Figure 5 .

[0043] Comparative Example 2

[0044] In a 2000mL four-necked flask, add 100g of 2-methyltetrahydrofuran, 1000g of pure water, 100g of cyclopentylformaldehyde (0.992mol, 1 equivalent) with a purity of 97.38%, and 1.03% cyclopentyl ketone. (See...) Figure 2 403 g (0.893 mol, 0.9 equivalents) of 23% sodium bisulfite aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 2 h. The organic layer was separated, and the aqueous layer was extracted twice with 200 g of 2-methyltetrahydrofuran. The aqueous layer was poured into a 2000 ml four-necked flask, and under nitrogen protection, 685 g (2.48 mol, 2.5 equivalents) of 50% potassium carbonate solution was added dropwise. The mixture was stirred at 30-40 °C for 4 h, and then allowed to stand for separation. The aqueous layer was extracted twice with methyl tert-butyl ether (100 g each time). The organic phases were combined, washed with pure water until neutral, and the solvent was evaporated under reduced pressure to obtain 68.4 g of cyclopentyl formaldehyde, with a purity of 99.34% and containing 0.305% cyclopentanone, yielding 69.8%. (See [link to product details]). Figure 6 .

Claims

1. A method for purifying cyclopentylformaldehyde, characterized in that... The process includes the following steps: first, reacting crude cyclopentylformaldehyde with a lower alcohol, then reacting it with sodium bisulfite, separating the sulfonate solid after the reaction, and then desalting the sulfonate solid with potassium carbonate to obtain refined cyclopentylformaldehyde.

2. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... The crude cyclopentylformaldehyde contains less than 10% cyclopentanone.

3. The method for purifying cyclopentylformaldehyde according to claim 2, characterized in that... The crude cyclopentyl formaldehyde contains less than 5% cyclopentanone.

4. The method for purifying cyclopentylformaldehyde according to claim 3, characterized in that... The crude cyclopentyl formaldehyde contains less than 3% cyclopentanone.

5. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... The lower alcohols include either methanol or ethanol.

6. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... The mass ratio of crude cyclopentylformaldehyde to lower alcohols is 1:1 to 5.

7. The method for purifying cyclopentylformaldehyde according to claim 6, characterized in that... The mass ratio of crude cyclopentylformaldehyde to lower alcohols is 1:1.5 to 4.

8. The method for purifying cyclopentylformaldehyde according to claim 7, characterized in that... The mass ratio of crude cyclopentylformaldehyde to lower alcohols is 1:2-3.

9. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... The reaction temperature of crude cyclopentylformaldehyde with lower alcohols is 10–40℃; the reaction time is 1–5 h.

10. The method for purifying cyclopentylformaldehyde according to claim 9, characterized in that... The reaction temperature of crude cyclopentylformaldehyde with lower alcohols is 20–30 °C; the reaction time is 1.5–3.5 h.

11. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... The sodium bisulfite is slowly added in the form of an aqueous solution, the concentration of which is 20-33%; the molar ratio of sodium bisulfite to cyclopentylformaldehyde is 1-1.5:

1.

12. The method for purifying cyclopentylformaldehyde according to claim 11, characterized in that... The sodium bisulfite is slowly added in the form of an aqueous solution with a concentration of 20-25%; the molar ratio of sodium bisulfite to cyclopentylformaldehyde is 1-1.3:

1.

13. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... The reaction temperature with sodium bisulfite is 10–40℃; the reaction time is 1–5 h.

14. The method for purifying cyclopentylformaldehyde according to claim 13, characterized in that... The reaction temperature with sodium bisulfite is 20–30°C; the reaction time is 1:1.5–3.5 h.

15. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... The solvent for the desalting reaction is water; the molar ratio of potassium carbonate to cyclopentylformaldehyde in the desalting reaction is 2-3:1; the temperature of the desalting reaction is 30-40℃, and the reaction time is 2-6h.

16. The method for purifying cyclopentylformaldehyde according to claim 15, characterized in that... The molar ratio of potassium carbonate to cyclopentylformaldehyde in the desalting reaction is 2.1–2.5:1; the reaction time of the desalting reaction is 3–5 h.

17. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... After the desalting reaction, the mixture was allowed to stand and separate into layers. The aqueous layer was extracted with methyl tert-butyl ether. The organic phase obtained from the extraction was washed with pure water and the solvent was removed by vacuum evaporation to obtain the refined cyclopentyl formaldehyde.

18. The method for purifying cyclopentylformaldehyde according to claim 1, characterized in that... The content of cyclopentanone in the refined cyclopentylformaldehyde is less than 0.1%.

19. The method for purifying cyclopentylformaldehyde according to claim 18, characterized in that... The content of cyclopentanone in the cyclopentylformaldehyde product is less than 0.07%.

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