Synthesis method of methyl cyclopentyl formate
By using the substitution cyclization reaction of 1,4-dihalobutane and dimethyl malonic acid and Krapcho deesterization reaction in the synthesis of methyl cyclopentyl formate, the problem of using expensive catalysts and toxic gases in the prior art is solved, and the low-cost and safe industrial production of methyl cyclopentyl formate is achieved.
Patent Information
- Application Number
- CN202510410290.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-02
- Publication Date
- 2025-06-27
AI Technical Summary
The existing synthesis method of methyl cyclopentyl formate has problems such as the use of expensive metal catalysts, difficult reaction conditions, difficulty in purification, and involvement of toxic gases, and is not suitable for large-scale industrial production.
1,4-dihalobutane was used to perform substitution cyclization reaction with dimethyl malonate and alkaline reagent in solvent, and then Krapcho deesterization reaction was carried out with inorganic salt and water under high temperature conditions to prepare methyl cyclopentyl formate.
The raw materials used in this method are cheap, safe and controllable, with a relatively simple reaction route, suitable for industrial production, reducing process costs and environmental pollution.
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Figure CN120208784A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of the synthesis of organic chemical intermediates, and particularly relates to a method for synthesizing methyl cyclopentanecarboxylate. Background Art
[0002] Methyl cyclopentanecarboxylate is an important pharmaceutical intermediate. For example, it can be used to prepare ruxolitinib. Ruxolitinib, an orally administrable selective JAK1 / JAK2 kinase inhibitor developed by Incyte Corporation of the United States, is the first drug approved by the US FDA in November 2011 for the treatment of myelofibrosis (trade name Jakafi), was granted orphan drug status, and was approved for marketing in the European Union by Novartis in August 2012 (trade name Jakavi).
[0003] There are few published synthesis methods for methyl cyclopentanecarboxylate. The synthesis methods reported in the relevant literature use cyclopentene as the raw material, methanol as the solvent, Pt(acac)2 catalyst and p-toluenesulfonic acid monohydrate, and react with CO under high pressure and high temperature conditions to form the compound methyl cyclopentanecarboxylate. The reaction route is as follows:
[0004]
[0005] The deficiencies of this route are as follows: The raw materials cyclopentene and Pt(acac)2 are expensive, CO is a toxic reagent, and the reaction requires high temperature and high pressure. The post-treatment operation is cumbersome, the process cost is high, the equipment utilization rate is low, resulting in low production capacity, which is not conducive to large-scale industrial production.
[0006] Patent CN115010597 reported using cyclohexanone as the raw material, through chlorination and Favorskii rearrangement reactions to form the target product. The reaction route is as follows:
[0007]
[0008] In this route, it is difficult to obtain a single halogenated product in the chlorination reaction, acid by-products are easily generated during the rearrangement process, and purification is difficult, which is not suitable for industrial production.
[0009] That is, the synthesis routes in the prior art have the following defects: (1) expensive metal catalysts need to be used; (2) the reaction conditions are difficult to control and purification is difficult; (3) problems such as dangerous reagents such as toxic gases and relatively serious environmental pollution are involved, which is not conducive to large-scale industrial production. Summary of the Invention
[0010] Aiming at the deficiencies of the prior art, the present invention provides a method for preparing methyl cyclopentanecarboxylate with low cost and easy industrial production.
[0011] To achieve the above object, the present invention is realized through the following technical solutions:
[0012] A method for synthesizing methyl cyclopentanecarboxylate, the synthesis method comprising the following steps:
[0013] (1) Using 1,4-dihalobutane as the starting material (Compound I), reacting with dimethyl malonate and a basic reagent in a solvent to carry out a substitution cyclization reaction to prepare Compound II;
[0014] (2) Mixing Compound II with inorganic salts and water, and carrying out a Krapcho de-esterification reaction at 120 - 170 °C in a solvent to prepare methyl cyclopentanecarboxylate (Compound III).
[0015] The specific reaction route is as follows:
[0016]
[0017] Among them, X is any one of Cl, Br, and I.
[0018] Preferably, in step (1), the 1,4-dihalobutane is any one of 1,4-dichlorobutane, 1,4-dibromobutane, and 1,4-diiodobutane.
[0019] Preferably, in step (1), the basic reagent is an inorganic base or an organic base.
[0020] Preferably, in step (1), the basic reagent is one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, triethylamine, diisopropylethylamine, piperidine, pyridine, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and lithium diisopropylamide.
[0021] Preferably, in step (1), the molar ratio of 1,4-dihalobutane, dimethyl malonate, and the basic reagent is 1∶1.0 - 3.0∶2.0 - 10.0.
[0022] Preferably, in step (1), the mass ratio of 1,4-dihalobutane to the solvent is 1∶1.0 - 20.0.
[0023] Preferably, in step (2), the inorganic salt is one or more of sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide, sodium cyanide, potassium cyanide, lithium cyanide, sodium iodide, potassium iodide, and lithium iodide.
[0024] Preferably, in step (2), the molar ratio of Compound II, inorganic salt, and water is 1∶0.5 - 10∶0.5 - 20.0.
[0025] Preferably, in the step (2), the mass ratio of the compound II to the solvent is 1:1.0 - 20.0.
[0026] Preferably, the solvent is at least one of dimethyl sulfoxide, dimethylformamide, and dimethylacetamide.
[0027] The present invention provides a method for synthesizing methyl cyclopentanecarboxylate. Compared with the prior art, the advantages are as follows:
[0028] The synthetic route of methyl cyclopentanecarboxylate in the present invention is relatively simple. The raw materials used are all commercially available materials. The raw materials are relatively cheap, safe and controllable, without complex special operation steps, and are suitable for industrial production; it provides a new synthetic scheme for the synthesis of methyl cyclopentanecarboxylate. Description of the Drawings
[0029] Figure 1 1H NMR spectrum of the compound II prepared in Example 1 of the present invention; 1 H spectrum;
[0030] Figure 2 13C NMR spectrum of the compound II prepared in Example 1 of the present invention; 13 C spectrum;
[0031] Figure 3 1H NMR spectrum of the compound III prepared in Example 1 of the present invention; 1 H spectrum;
[0032] Figure 4 13C NMR spectrum of the compound III prepared in Example 1 of the present invention; 13 C spectrum. Detailed Embodiments
[0033] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
[0034] Example 1:
[0035] Methyl cyclopentanecarboxylate was prepared with reference to the following synthetic route:
[0036]
[0037] At room temperature, 1,4-dichlorobutane (0.08 mol, 10.0 g), potassium carbonate (0.31 mol, 43.5 g), and dimethyl sulfoxide (10X, 100.0 g) were added to a clean and dry reaction flask. The temperature was raised to 50 °C, and dimethyl malonate (0.16 mol, 20.8 g) was added dropwise. After stirring for 20 hours, it was cooled to room temperature, filtered, water and ethyl acetate were added to the mother liquor, and extraction and layering were carried out. The organic phase was washed three times with saturated brine and concentrated under reduced pressure to obtain 13.9 g of the product dimethyl 1,1-cyclopentanedicarboxylate (Compound II) in the form of a colorless liquid, with a yield of 95%. The NMR data of Compound II are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 3.68 (s, 6H), 2.15 (m, 4H), 1.65 (m, 4H); 13 C NMR (101 MHz, Chloroform-d) δ 173.22, 60.29, 52.67, 34.65, 25.49.
[0038] At room temperature, dimethyl 1,1-cyclopentanedicarboxylate (Compound II, 0.03 mol, 5.0 g), sodium chloride (0.05 mol, 3.1 g), water (4.5 mL), and dimethyl sulfoxide (45 mL) were added to a clean and dry reaction flask. The temperature was raised to 130 °C, and after stirring for 24 h, it was cooled to room temperature. The product methyl cyclopentanecarboxylate (Compound III, 3.17 g, 92%) was obtained by distillation. The NMR data of Compound III are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 3.64 (s, 1H), 2.78 (tt, J = 8.7, 7.1 Hz, 0H), 1.94 - 1.80 (m, 0H), 1.79 - 1.49 (m, 1H); 13 C NMR (101 MHz, Chloroform-d) δ 176.54, 51.70, 43.35, 29.92, 25.78.
[0039] Example 2:
[0040] Methyl cyclopentanecarboxylate was prepared with reference to the following synthetic route:
[0041]
[0042] At room temperature, 1,4-dibromobutane (0.23 mol, 50.0 g), sodium carbonate (0.46 mol, 48.7 g), and dimethyl sulfoxide (10X, 500.0 g) were added to a clean and dry reaction flask. The temperature was raised to 65 °C, and dimethyl malonate (0.35 mol, 45.5 g) was added dropwise. After stirring for 18 hours, it was cooled to room temperature, filtered, water and ethyl acetate were added to the mother liquor, and extraction was carried out to separate layers. The organic phase was washed three times with saturated brine, and concentrated under reduced pressure to obtain 38.5 g of the product dimethyl 1,1-cyclopentanedicarboxylate (Compound II) in the form of a colorless liquid, with a yield of 90%. The NMR data of the compound are as follows: 1 H NMR(400MHz,Chloroform-d)δ3.68(s,6H),2.15(m,4H),1.65(m,4H); 13 C NMR(101MHz,Chloroform-d)δ173.22,60.29,52.67,34.65,25.49。
[0043] At room temperature, dimethyl 1,1-cyclopentanedicarboxylate (Compound II, 0.21 mol, 38.5 g), sodium chloride (0.42 mol, 26.04 g), water (25 mL), and dimethyl sulfoxide (250 mL) were added to a clean and dry reaction flask. The temperature was raised to 150 °C, and after stirring for 18 h, it was cooled to room temperature. The product methyl cyclopentanecarboxylate (Compound III, 24.2 g, 90%) was obtained by distillation. The NMR data of Compound III are as follows: 1 H NMR(400MHz,Chloroform-d)δ3.64(s,1H),2.78(tt,J=8.7,7.1Hz,0H),1.94-1.80(m,0H),1.79-1.49(m,1H).; 13 C NMR(101MHz,Chloroform-d)δ176.54,51.70,43.35,29.92,25.78。
[0044] Example 3:
[0045] Methyl cyclopentanecarboxylate was prepared according to the following synthetic route:
[0046]
[0047] At room temperature, 1,4-diiodobutane (0.11 mol, 35 g), triethylamine (0.40 mol, 40.4 g), and N,N'-dimethylformamide (10X, 350 g) were added to a clean and dry reaction flask. The temperature was raised to 80 °C, and dimethyl malonate (0.29 mol, 37.2 g) was added dropwise. After stirring for 26 hours, it was cooled to room temperature, filtered, water and ethyl acetate were added to the mother liquor, and extraction was carried out to separate the layers. The organic phase was washed three times with saturated brine, and concentrated under reduced pressure to obtain 18.0 g of the product dimethyl 1,1-cyclopentanedicarboxylate (Compound II) in the form of a colorless liquid, with a yield of 88%. The NMR data of the compound are as follows: 1 H NMR(400MHz,Chloroform-d)δ3.68(s,6H),2.15(m,4H),1.65(m,4H); 13 C NMR(101MHz,Chloroform-d)δ173.22,60.29,52.67,34.65,25.49。
[0048] At room temperature, dimethyl 1,1-cyclopentanedicarboxylate (Compound II, 0.21 mol, 18.0 g), potassium chloride (1.05 mol, 75 g), water (57 mL), and dimethyl sulfoxide (300 mL) were added to a clean and dry reaction flask. The temperature was raised to 145 °C, and after stirring for 9 h, it was cooled to room temperature. The product methyl cyclopentanecarboxylate (Compound III, 23 g, 85%) was obtained by rectification. The NMR data of Compound III are as follows: 1 H NMR(400MHz,Chloroform-d)δ3.64(s,1H),2.78(tt,J=8.7,7.1Hz,0H),1.94-1.80(m,0H),1.79-1.49(m,1H); 13 C NMR(101MHz,Chloroform-d)δ176.54,51.70,43.35,29.92,25.78。
[0049] Example 4:
[0050] Methyl cyclopentanecarboxylate was prepared according to the following synthetic route:
[0051]
[0052] At room temperature, 1,4-dibromobutane (0.69 mol, 150 g), sodium acetate (1.93 mol, 158.4 g) and dimethyl sulfoxide (10X, 1.5 kg) were added to a clean and dry reaction flask. The temperature was raised to 120 °C, and dimethyl malonate (1.449 mol, 194.7 g) was added dropwise. After stirring for 30 hours, it was cooled to room temperature, filtered, water and ethyl acetate were added to the mother liquor, and extraction was carried out to separate layers. The organic phase was washed three times with saturated brine and concentrated under reduced pressure to obtain 119.5 g of the product dimethyl 1,1-cyclopentanedicarboxylate (Compound II) in the form of a colorless liquid, with a yield of 93%. The NMR data of the compound are as follows: 1H NMR (400 MHz, Chloroform-d) δ 3.68 (s, 6H), 2.15 (m, 4H), 1.65 (m, 4H); 13C NMR (101 MHz, Chloroform-d) δ 173.22, 60.29, 52.67, 34.65, 25.49.
[0053] At room temperature, dimethyl 1,1-cyclopentanedicarboxylate (Compound II, 0.64 mol, 119 g), sodium cyanide (1.92 mol, 94 g), water (138 mL) and dimethyl sulfoxide (1300 mL) were added to a clean and dry reaction flask. The temperature was raised to 160 °C, and after stirring for 14 h, it was cooled to room temperature. The product methyl cyclopentanecarboxylate (Compound III, 73 g, 89%) was obtained by distillation. The NMR data of Compound III are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 3.64 (s, 1H), 2.78 (tt, J = 8.7, 7.1 Hz, 0H), 1.94 - 1.80 (m, 0H), 1.79 - 1.49 (m, 1H); 13 13C NMR (101 MHz, Chloroform-d) δ 176.54, 51.70, 43.35, 29.92, 25.78.
[0054] Example 5:
[0055] Methyl cyclopentanecarboxylate was prepared according to the following synthetic route:
[0056]
[0057] At room temperature, 1,4-dichlorobutane (11.8 mol, 1.5 kg), cesium carbonate (23.6 mol, 7.69 kg), and dimethyl sulfoxide (10X, 15 kg) were added to a reaction kettle. The temperature was raised to 120 °C, and dimethyl malonate (17.7 mol, 2.34 kg) was added dropwise. After holding the reaction for 35 hours, it was cooled to room temperature. The filter cake was filtered off and discarded. Water (45 kg) and ethyl acetate (50 kg) were added to the mother liquor, and after stirring for 1 hour, the aqueous layer was separated. The organic phase solution was concentrated under reduced pressure and then distilled under reduced pressure to obtain 2.11 kg of the product dimethyl 1,1-cyclopentanedicarboxylate (Compound II) in the form of a colorless liquid, with a yield of 96%. The NMR data of the compound are as follows: 1 H NMR(400MHz,Chloroform-d)δ3.68(s,6H),2.15(m,4H),1.65(m,4H); 13 C NMR(101MHz,Chloroform-d)δ173.22,60.29,52.67,34.65,25.49。
[0058] At room temperature, dimethyl 1,1-cyclopentanedicarboxylate (Compound II, 11.3 mol, 2.1 kg), sodium chloride (17 mol, 983 g), water (1.62 kg), and dimethyl sulfoxide (2100 L) were added to a reaction kettle. The temperature was raised to 1550 °C, and after stirring for 12 h, the kettle was cooled to 25 °C. The product methyl cyclopentanecarboxylate (Compound III, 1.32 kg, 91%) was obtained by rectification. The NMR data of Compound III are as follows: 1 H NMR(400MHz,Chloroform-d)δ3.64(s,1H),2.78(tt,J=8.7,7.1Hz,0H),1.94-1.80(m,0H),1.79-1.49(m,1H); 13 CNMR(101MHz,Chloroform-d)δ176.54,51.70,43.35,29.92,25.78。
[0059] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for synthesizing methyl cyclopentylcarboxylate, characterized in that: The synthesis method comprises the following steps: (1) using 1,4-dihalobutane as a starting material, mixing it with dimethyl malonate and an alkaline reagent in a solvent to carry out a substitution cyclization reaction to prepare compound II; (2) Compound II is mixed with an inorganic salt and water, and subjected to a Krapcho deesterification reaction at 120-170° C. in a solvent to prepare methyl cyclopentylcarboxylate.
2. The synthesis method according to claim 1, characterized in that: In the step (1), the 1,4-dihalobutane is any one of 1,4-dichlorobutane, 1,4-dibromobutane and 1,4-diiodobutane.
3. The synthesis method according to claim 1, characterized in that: The alkaline agent in step (1) is an inorganic base or an organic base.
4. The synthesis method according to claim 1, characterized in that: In the step (1), the alkaline reagent is one or more of sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, potassium ethoxide, triethylamine, diisopropylethylamine, piperidine, pyridine, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and lithium diisopropylamide.
5. The synthesis method according to claim 1, characterized in that: In the step (1), the molar ratio of 1,4-dihalobutane, dimethyl malonate and alkaline reagent is 1:1.0-3.0:2.0-10.
0.
6. The synthesis method according to claim 1, characterized in that: In the step (1), the mass ratio of 1,4-dihalobutane to the solvent is 1:1.0-20.
0.
7. The synthesis method according to claim 1, characterized in that: The inorganic salt in step (2) is one or more of sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide, sodium cyanide, potassium cyanide, lithium cyanide, sodium iodide, potassium iodide, and lithium iodide.
8. The synthesis method according to claim 1, characterized in that: In the step (2), the molar ratio of compound II, inorganic salt and water is 1:0.5-10:0.5-20.
0.
9. The synthesis method according to claim 1, characterized in that: In the step (2), the mass ratio of compound II to solvent is 1:1.0-20.
0.
10. The synthesis method according to claim 1, characterized in that: The solvent is at least one of dimethyl sulfoxide, dimethylformamide and dimethylacetamide.