A method for separating 3-quinuclidinone

Abstract

The invention discloses a separation method of 3-quinuclidine ketones, comprising the steps of: at a pH of 7.5 to 14 and a pressure of 0.0001MPa to 0.3MPa, at a temperature of 5 to 30 ° C higher than the boiling point of water corresponding to the pressure, the liquid containing water and 3-quinuclidine ketones is distilled to obtain a solution containing 3-quinuclidine ketones. The separation method of 3-quinuclidine ketones in the present application does not need to be extracted using a large amount of organic solvents, thereby saving costs and reducing environmental pollution. In addition, the temperature of the distillation in the method only needs to be carried out at a temperature of 5 to 30 ° C higher than the boiling point of water, which is more energy-saving and environmentally friendly and avoids the side reactions that may be caused by high temperature.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemicals, and in particular to a method for separating 3-quinuclidine. Background Art

[0002] Palonosetron hydrochloride is a 5-HT3 receptor antagonist. It was approved by the U.S. FDA on July 25, 2003, and was first launched in the U.S. by MGI Pharma two months later. The approved indication is the prevention and treatment of acute and delayed nausea and vomiting caused by cancer chemotherapy. (S)-Quinuclide is a key intermediate in the preparation of palonosetron. The chemical structure of palonosetron is shown below:

[0003]

[0004] Solifenacin was originally developed by AstraZeneca, a competitive muscarinic M3 receptor antagonist that inhibits the overactivity of the bladder detrusor muscle by blocking the muscarinic M3 receptors on the bladder smooth muscle. It is mainly used clinically to treat overactive bladder, unstable bladder, and relieve the symptoms of urinary incontinence, frequent urination, and urgency caused by them. It can also be used to relieve the symptoms of frequent urination and urgency caused by prostatitis or prostatic hyperplasia without residual urine. (R)-3-Quinuclidinol is a key intermediate in the preparation of solifenacin. The structure of solifenacin is shown below:

[0005]

[0006] (S)-quinuclidine and (R)-3-quinuclidine alcohol can be prepared from 3-quinuclidine hydrochloride, so 3-quinuclidine hydrochloride is a pharmaceutical intermediate with a broad market.

[0007]

[0008] As reported in patent (CN 101012226A), literature (Daeniker HU, Grob CA. 3-Quinuclidonehydrochloride [J]. Org Synth, 1964, 44: 86-90; Yang Zhijie, Tao Kaiyue, et al. Preparation of 3-quinuclidone [J]. Chinese Pharmaceutical Industry Impurities, 2007, 38 (4).), etc., 3-quinuclidone hydrochloride is generally prepared by Dickmann condensation of 1-ethoxycarbonylmethyl-4-ethoxycarbonylpiperidine as shown in Formula 2, followed by hydrolysis and decarboxylation, adding alkali to the reaction solution to adjust the pH to >7, and then extracting with an organic solvent. After extraction, the mixture is salified with hydrochloric acid or hydrogen chloride and then recrystallized to obtain 3-quinuclidone hydrochloride. The reaction process route is shown below.

[0009]

[0010] However, since 3-quinuclidinone is highly water-soluble, when it is extracted from water with an organic solvent, a large amount of organic solvent is required for multiple extractions (more than 6 times) to barely extract it completely, which is very inconvenient and wastes a lot of solvent, and has a high manufacturing cost.

[0011] In addition, existing literature also records that 3-quinuclidine has a relatively high boiling point, as follows: the literature (Clemo GR, Metcalfe TP. 419. 2-Ketoquinuclidine and a new synthesis of quinuclidine [J]. Journal of the Chemical Society (Resumed), 1937: 1989.) records that the boiling point of 3-quinuclidine is 110° C. at a pressure of 12 mmHg and is 60-80° C. at a pressure of 1 mmHg.

[0012] The literature (Edna O, Bergmann ED. Michael Reactions in the Quinuclidin-3-one Series [J]. Synthesis, 1972.) records that the boiling point of 3-quinuclidinone is 60-70°C at a pressure of 2 mmHg. Summary of the invention

[0013] The technical problem to be solved by the present invention is that in the existing method for separating 3-quinuclidine ketone, a large amount of organic solvent is used for extraction, resulting in a waste of solvent. The present invention provides a method for separating 3-quinuclidine ketone. The method adopts a distillation method when separating 3-quinuclidine ketone, eliminating the extraction step and the recrystallization step which need to consume a large amount of organic solvent and labor, thereby achieving the effect of lower cost and more environmental protection. The temperature during distillation only needs to be 5 to 30°C higher than the boiling point of water, which is more energy-saving and environmentally friendly and avoids the side reactions that may be caused by high temperature.

[0014] The present invention solves the above-mentioned problem through the following technical solutions.

[0015] The invention provides a method for separating 3-quinuclidinone, which comprises the following steps: distilling a liquid containing water and 3-quinuclidinone at a pH of 7.5 to 14 and a pressure of 0.0001 MPa to 0.3 MPa, at an external temperature 5 to 30° C. higher than the boiling point of water corresponding to the pressure, to obtain a solution containing 3-quinuclidinone.

[0016] In the separation method, the pressure is preferably 0.011 MPa to 0.101 MPa.

[0017] In the separation method, the external temperature is preferably 10 to 30° C. higher than the boiling point of water corresponding to the pressure, and more preferably 10 to 20° C. higher.

[0018] In the separation method, the temperature of the external temperature is preferably controlled by an oil bath.

[0019] In the separation method, the liquid containing water and 3-quinuclidine may contain a small amount of substances that azeotrope with water (except 3-quinuclidine, such as toluene, ethanol, propanol, etc.) so as not to affect the above-mentioned distillation, and preferably does not contain substances that azeotrope with water; preferably, the liquid containing water and 3-quinuclidine is obtained by decarboxylation reaction of the compound shown in Formula I;

[0020] The compound described in Formula I is R 2 is C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably ethyl;

[0021] The conditions and steps of the decarboxylation reaction may be the conditions and steps of the decarboxylation reaction conventional in the art.

[0022] In one embodiment, the external temperature is 110° C. and the pressure is 0.101 MPa.

[0023] In one embodiment, the external temperature is 80°C and the pressure is 0.011 MPa.

[0024] In one embodiment, the pH is preferably 8-12, more preferably 8.5-11.

[0025] In one embodiment, the pH can be adjusted using an organic base or an inorganic base, preferably an inorganic base, such as a base that can adjust the pH of the solution to the pH value. The inorganic base generally refers to a substance that is alkaline when dissolved in water. The base is preferably a carbonate, more preferably potassium carbonate or sodium carbonate.

[0026] Distillation in the present application generally refers to a conventional method in the art for separating substances with different boiling points at a specific temperature, including fractional distillation or evaporation.

[0027] The separation method may further comprise the following steps: in water, in the presence of an acid, subjecting the compound represented by formula I to a decarboxylation reaction as described below to obtain a liquid comprising water and 3-quinuclidine;

[0028]

[0029] R 2 It is a C1-C4 alkyl group.

[0030] In the decarboxylation reaction, R 2 It may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably ethyl.

[0031] In the decarboxylation reaction, the acid may be an acid commonly used in this type of decarboxylation reaction in the art, such as hydrochloric acid, sulfuric acid or nitric acid.

[0032] In the decarboxylation reaction, the concentration of the acid in the water may be a conventional concentration for such decarboxylation reactions in the art, preferably 8 to 14 mol / L, more preferably 10 to 12 mol / L.

[0033] In the decarboxylation reaction, the concentration of the compound of formula I in the water may be a conventional concentration for such decarboxylation reactions in the art, preferably 0.2 mol / L to 3 mol / L, more preferably 0.5 mol / L to 1 mol / L.

[0034] In the decarboxylation reaction, the reaction temperature may be a conventional temperature for such decarboxylation reactions in the art, preferably 80 to 130°C, more preferably 104 to 115°C.

[0035] In the decarboxylation reaction, the end point of the decarboxylation reaction is when the compound shown in Formula I disappears or stops reacting. The reaction time is preferably 10 to 30 hours, preferably 17 to 24 hours.

[0036] After the decarboxylation reaction is completed, post-treatment may be further performed, and the post-treatment preferably comprises the following steps: after the decarboxylation reaction is completed, activated carbon is added for decolorization, and a liquid containing water and 3-quinuclidine is obtained by filtration.

[0037] The separation method may further include the following steps: in an organic solvent, in the presence of a base, the compound shown in Formula II undergoes a condensation reaction as shown below to obtain a compound shown in Formula I;

[0038]

[0039] R 1 and R 2 Each independently represents a C1-C4 alkyl group.

[0040] In the condensation reaction, the organic solvent may be an organic solvent conventionally used in this type of condensation reaction in the art, preferably an aromatic hydrocarbon solvent, more preferably toluene.

[0041] In the condensation reaction, the base can be a base conventionally used in this type of condensation reaction in the art, preferably R 3 OM, R 3is a C1-C4 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, preferably tert-butyl), M is an alkali metal (e.g., sodium or potassium), R 3 OM is preferably potassium tert-butoxide.

[0042] In the condensation reaction, the condensation reaction can be carried out in the presence of a conventional protective gas in the art, and the protective gas is preferably nitrogen.

[0043] In the condensation reaction, R 1 It may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, for example ethyl.

[0044] In the condensation reaction, R 2 It may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, for example ethyl.

[0045] In the condensation reaction, the compound shown in Formula II is preferably Correspondingly, the compound shown in formula I is

[0046] In the condensation reaction, the molar ratio of the base to the compound of formula II can be 2:1 to 4:1, preferably 3:1.

[0047] In the condensation reaction, the concentration of the base in the solvent may be a conventional concentration for such condensation reactions in the art, preferably 0.1 mol / L to 5 mol / L, more preferably 0.5 mol / L to 1.5 mol / L (eg 0.9 mol / L).

[0048] In the condensation reaction, the concentration of the compound of formula II in the organic solvent may be a conventional concentration for such condensation reactions in the art, preferably 0.1 mol / L to 2 mol / L, more preferably 0.2 mol / L to 0.5 mol / L (e.g. 0.3 mol / L).

[0049] In the condensation reaction, the reaction temperature may be a conventional reaction temperature for such condensation reactions in the art, preferably 100 to 140°C, more preferably 110 to 120°C.

[0050] In the condensation reaction, the condensation reaction ends when the compound shown in Formula II disappears or stops reacting. The reaction time is preferably 2 to 15 hours, preferably 5 to 7 hours (eg 3 to 4 hours).

[0051] In the condensation reaction, the compound as shown in Formula II is preferably added dropwise to the organic solvent and the base solution, and the dropping time is preferably 1 to 4 hours, more preferably 2 to 3 hours.

[0052] After the condensation reaction is completed, a post-treatment may be further included, and the post-treatment preferably includes the following steps: when the organic solvent and the water layer are separated, the organic solvent is extracted with an acid aqueous solution to obtain an aqueous phase, and the obtained aqueous phase is directly subjected to the decarboxylation reaction as described above; when the base added in the condensation reaction is R 3 OM preferably includes removing R 3 OH then undergoes the above decarboxylation reaction to remove R 3 OH can be prepared by heating at 100°C to 120°C (eg, 115°C) for 1 to 3 hours (eg, 2 hours) in an open air. The acid is preferably hydrochloric acid, more preferably 12 mol / L hydrochloric acid.

[0053] The present invention also provides a method for purifying a salt of 3-quinuclidine, which comprises the following steps: adding acid to the solution containing 3-quinuclidine to adjust the pH to 1-3 and then concentrating to obtain the salt of 3-quinuclidine.

[0054] In the purification method, the acid can be a conventional acid in the art, preferably hydrochloric acid, and accordingly, the salt of 3-quinuclidinone is the hydrochloride of 3-quinuclidinone.

[0055] In addition, the boiling points of water under different pressures can be found in Shen Weidao. Engineering Thermodynamics (Fourth Edition). People's Education Press, 2007. Appendix 1 and Appendix 2 on pages 251-253 and the following Table 1:

[0056] Table 1

[0057] Temperature ℃ PressurePa mbar Temperature ℃ PressurePa mbar Temperature ℃ PressurePa mbar Temperature ℃ PressurePa mbar -40 12.8 0.128 2 705.3 7.053 35 5623.5 56.235 68 28557.7 285.577 -38 16.1 0.161 3 758.6 7.586 36 5940.8 59.408 69 29824.2 298.242 -36 20.1 0.201 4 813.3 8.133 37 5275.5 52.755 70 31157.4 311.574 -34 24.9 0.249 5 871.9 8.719 38 6619.5 66.195 71 32517.3 325.173 -32 30.9 0.309 6 934.6 9.346 39 6991.4 69.914 72 36943.9 369.439 -30 38.4 0.384 7 1001.3 10.013 40 7375.4 73.754 73 35423.8 354.238 -28 47.1 0.471 8 1073.2 10.732 41 7778 77.78 74 36957 369.57 -26 57.2 0.572 9 1147.9 11.479 42 8199.3 81.993 75 38543.5 385.435 -24 70.1 0.701 10 1227.9 12.279 43 8639.3 86.393 76 40183.4 401.834 -22 85.8 0.858 11 1311.9 13.119 44 9100.6 91.006 77 41876.6 418.766 -21 94.4 0.944 12 1402.6 14.026 45 9583.2 95.832 78 43636.4 436.364 -20 102.9 1.029 13 1497.2 14.972 46 10085.8 100.858 79 45462.9 454.629 -19 113.3 1.133 14 1598.5 15.985 47 10612.5 106.125 80 47342.8 473.428 -18 124.6 1.246 15 1705.2 17.052 48 11160.4 111.604 81 49289.3 492.893 -17 136.9 1.369 16 1817.2 18.172 49 11735 117.35 82 51315.8 513.158 -16 150.4 1.504 17 1937.2 19.372 50 12333.7 123.337 83 53408.9 534.089 -15 165 1.65 18 2063.8 20.638 51 12958.9 129.589 84 55568.8 555.688 -14 180.9 1.809 19 2197.2 21.972 52 13612.2 136.122 85 57808.6 578.086 -13 198.1 1.981 20 2328.5 23.285 53 14292.2 142.922 86 60115.1 601.151 -12 216.9 2.169 21 2486.5 24.865 54 14998.8 149.988 87 62488.2 624.882 -11 237.3 2.373 22 2643.8 26.438 55 15732 157.32 88 64941.3 649.413 -10 259.4 2.594 23 2809.1 28.091 56 16505.3 165.053 89 67474.5 674.745 -9 283.3 2.833 24 2983.8 29.838 57 17305.2 173.052 90 70110.9 701.109 -8 309.4 3.094 25 3167.7 31.677 58 18145.2 181.452 91 72807.4 728.074 -7 377.6 3.776 26 3361 33.61 59 19011.8 190.118 92 75593.8 755.938 -6 368.1 3.681 27 3565 35.65 60 19918.4 199.184 93 78473.5 784.735 -5 401 4.01 28 3779.7 37.797 61 20851.6 208.516 94 81446.7 814.467 -4 436.8 4.368 29 4005 40.05 62 21838.2 218.382 95 84513.1 845.131 -3 475.4 4.754 30 4242.3 42.423 63 22851.5 228.515 96 87672.8 876.728 -2 517.2 5.172 31 4492.9 44.929 64 23904.7 239.047 97 90939.2 909.392 -1 562.1 5.621 32 4754.3 47.543 65 24998 249.98 98 94298.9 942.989 0 610 6.1 33 5030.3 50.303 66 26144.5 261.445 99 97752 977.52 1 657.3 6.573 34 5319.6 53.196 67 27331.1 273.311 100 101325 1013.25

[0058] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0059] The reagents and raw materials used in the present invention are commercially available.

[0060] The positive progress of the present invention is that the present application adopts a distillation method when separating 3-quinuclidine ketone, thereby reducing the waste of organic solvents, thereby achieving a lower cost and more environmentally friendly effect, and the temperature during distillation only needs to be 5 to 30° C. higher than the boiling point of water, which is more energy-saving and environmentally friendly and avoids side reactions that may be caused by high temperature. DETAILED DESCRIPTION

[0061] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0062] Example 1 Synthesis of 3-quinuclidinone hydrochloride (Compound 1)

[0063] Add 1000 mL of toluene to a 2L four-necked bottle equipped with a thermometer, a mechanical stirring device, and a reflux tube, replace the air in the reaction bottle with nitrogen, add 128 g (1.141 mol) of potassium tert-butoxide under nitrogen protection, and heat at 120 degrees. When the internal temperature is greater than 100°C, add 91.7 g (0.376 mol) of 1-ethoxycarbonylmethyl-4-ethoxycarbonylpiperidine (as shown in Formula 2, ) 230mL toluene solution, dripping for about 2-3h. After dripping, heat to internal temperature = 110℃, reflux reaction for 3-4h). After the reaction, ice bath to internal temperature = 0-5℃, drip 250mL 12M hydrochloric acid, add 100mL water, stir for 10min, separate the water layer, extract the toluene layer with 150mL 12M hydrochloric acid × 2, and combine the acid and water layers. Heat the water layer at 115 degrees in an open air, install a reflux tube after 2h, heat at 125 degrees to an internal temperature equal to 104℃, reflux for 17h, add 5g activated carbon for decolorization for 40min, and filter while hot. Adjust the filtrate to pH = 8.5 with saturated potassium carbonate solution. The reaction solution was heated at 110°C and distilled to dryness under normal pressure (the oil bath heating temperature was 110°C and the internal temperature was constant at about 98°C). The obtained fraction was adjusted to pH = 1 with hydrochloric acid, and then the solvent was evaporated to dryness to obtain 46.7 g of 3-quinuclidinone hydrochloride as a white solid. Mp>300°C. ESI: m / z, 126.1 [M+H] + . 1 H-NMR (600MHz, DMSO) δ3.97(brs,2H),3.42-3.37(m,2H),3.34-3.29(m,2H),2.62(p,J=3.1Hz,1H),2.21-2.12(m,2H),2.03-1.99(m,2H). 13 C-NMR (151 MHz, DMSO) δ 206.19, 59.42, 46.23, 38.08, 21.18. Purity: 100% (HPLC-ELSD detection).

[0064] Example 2 Synthesis of 3-quinuclidinone hydrochloride (Compound 1)

[0065] Add 1000 mL of toluene to a 2L four-necked bottle equipped with a thermometer, a mechanical stirring device, and a reflux tube, replace the air in the reaction bottle with nitrogen, add 127 g (1.132 mol) of potassium tert-butoxide under nitrogen protection, and heat at 120 degrees. When the internal temperature is greater than 100°C, add 90.7 g (0.373 mol) of 1-ethoxycarbonylmethyl-4-ethoxycarbonylpiperidine (the compound shown in Formula 2, ) 230mL toluene solution, about 2-3h to complete. After the dripping is completed, the temperature is raised to the internal temperature = 110℃, and the reaction is refluxed for 3-4h). After the reaction is completed, ice bath is set to the internal temperature = 0-5℃, 250mL 12M hydrochloric acid is added dropwise, 100mL water is added, stirred for 10min, the water layer is separated, and the toluene layer is extracted with 150mL 12M hydrochloric acid × 2, and the acid water layer is combined. The water layer is heated at 115 degrees for 2h, and then a reflux tube is installed. 125 degrees is added until the internal temperature is equal to 104℃. After reflux for 17h, 5g activated carbon is added for decolorization for 40min, and filtered while hot. The filtrate is adjusted to pH = 8.5 with saturated potassium carbonate solution. The reaction solution is heated at 80℃ and the pressure is 84mm mercury column under reduced pressure distillation to dryness. The obtained fraction is adjusted to pH = 1 with hydrochloric acid, and then the solvent is evaporated to dryness to obtain a white solid, namely 3-quinuclidinone hydrochloride 45.7g. Mp>300℃. ESI: m / z, 126.1 [M+H] + . 1 H-NMR (600MHz, DMSO) δ3.97(brs,2H),3.42-3.37(m,2H),3.34-3.29(m,2H),2.62(p,J=3.1Hz,1H),2.21-2.12(m,2H),2.03-1.99(m,2H). 13 C-NMR (151 MHz, DMSO) δ 206.19, 59.42, 46.23, 38.08, 21.18. Purity: 100% (HPLC-ELSD detection).

Claims

1. A method for separating 3-quinuclidinone, comprising the following steps: distilling a liquid containing water and 3-quinuclidinone at a pH of 7.5 to 8.5 and a pressure of 0.011 MPa to 0.101 MPa, at an external temperature 10 to 30° C. higher than the boiling point of water corresponding to the pressure, to obtain a solution containing 3-quinuclidinone.

2. The method for separating 3-quinuclidinone according to claim 1, wherein The liquid comprising water and 3-quinuclidinone does not contain a substance that forms an azeotrope with water; And / or, the liquid containing water and 3-quinuclidine is a liquid containing water and 3-quinuclidine obtained by decarboxylating a compound as shown in Formula I, wherein the compound as shown in Formula I is R 2 is a C1-C4 alkyl group; And / or, the pH is 8 to 8.5; And / or, the pH is adjusted using an organic base or an inorganic base.

3. The method for separating 3-quinuclidinone according to claim 2, wherein The external temperature is 110° C. and the pressure is 0.101 MPa; or, the external temperature is 80° C. and the pressure is 0.011 MPa.

4. The method for separating 3-quinuclidinone according to claim 2, characterized in that: In the separation method, the external temperature is 10 to 20° C. higher than the boiling point of water corresponding to the pressure; and / or, the R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And / or, the pH is 8.5; And / or, the pH is adjusted using an inorganic base.

5. The method for separating 3-quinuclidinone according to claim 4, characterized in that: The R 2 is methyl; And / or, the inorganic base is a carbonate.

6. The method for separating 3-quinuclidinone according to claim 5, characterized in that: The inorganic base is potassium carbonate or sodium carbonate.

7. The method for separating 3-quinuclidinone according to any one of claims 1 to 3, characterized in that: The separation method further comprises the following steps: in water, in the presence of an acid, subjecting the compound shown in Formula I to a decarboxylation reaction as shown below to obtain a liquid containing water and 3-quinuclidinone; R 2 It is a C1-C4 alkyl group.

8. The method for separating 3-quinuclidinone according to claim 7, characterized in that: In the decarboxylation reaction, R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; and / or, in the decarboxylation reaction, the acid is hydrochloric acid, sulfuric acid or nitric acid; and / or, in the decarboxylation reaction, the concentration of the acid in the water is 8 mol / L to 14 mol / L; And / or, in the decarboxylation reaction, the concentration of the compound of formula I in the water is 0.2 mol / L to 3 mol / L; and / or, in the decarboxylation reaction, the reaction temperature is 80 to 130° C.; And / or, in the decarboxylation reaction, the reaction time is 10 to 30 hours; And / or, the decarboxylation reaction further comprises post-treatment after completion.

9. The method for separating 3-quinuclidinone according to claim 8, characterized in that: In the decarboxylation reaction, R 2 is ethyl; and / or, in the decarboxylation reaction, the concentration of the acid in the water is 10 mol / L to 12 mol / L; And / or, in the decarboxylation reaction, the concentration of the compound of formula I in the water is 0.5 mol / L to 1 mol / L; and / or, in the decarboxylation reaction, the reaction temperature is 104-115° C.; and / or, in the decarboxylation reaction, the reaction time is 17 to 24 hours; And / or, the post-treatment comprises the following steps: after the decarboxylation reaction is completed, adding activated carbon for decolorization, and filtering to obtain a liquid containing water and 3-quinuclidine.

10. The method for separating 3-quinuclidinone according to claim 7, characterized in that: The separation method further comprises the following steps: in an organic solvent, in the presence of a base, the compound shown in formula II undergoes a condensation reaction as shown below to obtain a compound shown in formula I; R 1 It is a C1~C4 alkyl group.

11. The method for separating 3-quinuclidinone according to claim 10, characterized in that: In the condensation reaction, the organic solvent is an aromatic hydrocarbon solvent; And / or, in the condensation reaction, the base is R 3 OM, R 3 is a C1-C4 alkyl group, and M is an alkali metal; and / or, in the condensation reaction, the condensation reaction is carried out in the presence of a protective gas; And / or, in the condensation reaction, R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And / or, in the condensation reaction, R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; And / or, in the condensation reaction, the molar ratio of the base to the compound of formula II is 2:1 to 4:1; and / or, in the condensation reaction, the concentration of the base in the organic solvent is 0.1 mol / L to 5 mol / L; And / or, in the condensation reaction, the concentration of the compound of formula II in the organic solvent is 0.1 mol / L to 2 mol / L; and / or, in the condensation reaction, the reaction temperature is 100 to 140°C; and / or, in the condensation reaction, the reaction time is 2 to 15 hours; And / or, in the condensation reaction, the compound of formula II is added dropwise to the solution of the organic solvent and the base; And / or, after the condensation reaction is completed, post-treatment is further included, and the post-treatment includes the following steps: when the organic solvent and the water layer are separated, the organic solvent is extracted with an acid aqueous solution to obtain a water phase, and the obtained water phase is directly subjected to a decarboxylation reaction.

12. The method for separating 3-quinuclidinone according to claim 11, characterized in that: In the condensation reaction, R 1 is ethyl; And / or, in the condensation reaction, R 2 is ethyl; And / or, in the post-treatment step of the condensation reaction, the acid is hydrochloric acid.

13. The method for separating 3-quinuclidinone according to claim 11, characterized in that: In the condensation reaction, the organic solvent is toluene; And / or, in the condensation reaction, R 3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl; M is sodium or potassium; And / or, in the condensation reaction, the protective gas is nitrogen; And / or, in the condensation reaction, the compound as shown in formula II is Correspondingly, the compound shown in formula I is And / or, in the condensation reaction, the molar ratio of the base to the compound of formula II is 3:1; and / or, in the condensation reaction, the concentration of the base in the organic solvent is 0.5 mol / L to 1.5 mol / L; And / or, in the condensation reaction, the concentration of the compound of formula II in the organic solvent is 0.2 mol / L to 0.5 mol / L; and / or, in the condensation reaction, the reaction temperature is 110-120°C; and / or, in the condensation reaction, the reaction time is 5 to 7 or 3 to 4 hours; And / or, in the condensation reaction, the compound of formula II is added dropwise to the organic solvent and the base solution for 1 to 4 hours; And / or, in the post-treatment, when the base added in the condensation reaction is R 3 OM, the post-treatment removes R 3 OH then undergoes decarboxylation reaction.

14. The method for separating 3-quinuclidinone according to claim 13, characterized in that: In the condensation reaction, R 3 is tert-butyl; R 3 OM is potassium tert-butoxide; and / or, in the condensation reaction, the concentration of the base in the organic solvent is 0.9 mol / L; And / or, in the condensation reaction, the concentration of the compound of formula II in the organic solvent is 0.3 mol / L; And / or, in the condensation reaction, the compound of formula II is added dropwise to the organic solvent and the base solution for 2 to 3 hours; And / or, in said post-treatment, removing R 3 The OH method is to heat in an open air at 100°C to 120°C for 1 to 3 hours.

15. A method for purifying a salt of 3-quinuclidinone, comprising the following steps: obtaining a solution containing 3-quinuclidinone according to the method for separating 3-quinuclidinone according to any one of claims 1 to 14, adding acid to adjust the pH to 1 to 3, and then concentrating to obtain a salt of 3-quinuclidinone.

16. The purification method according to claim 15, characterized in that The acid is hydrochloric acid.

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