PREPARATION METHOD FOR SYNTHESIZING S-NICOTINE FROM GLUTARATE

Abstract

The present invention provides a preparation method for synthesizing S-nicotine from glutarate, including: reacting nicotinate with glutarate in the presence of a base catalyst to obtain 5-carbonyl-5-(pyridin-3-yl)pentanoic acid, reacting with an amination reagent to obtain 5-oxo-5-(pyridin-3-yl)pentanamide, performing Hofmann degradation on to obtain 4-amino-1-(pyridin-3-yl)butanone, reducing a carbonyl group of the 4-amino-1-(pyridin-3-yl)butanone by using (+)-B-diisopinocampheyl chloroborane to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol, performing chlorination and cyclization to obtain S-demethylnicotine, and finally performing amine methylation to obtain S-nicotine.

Claims

1. A preparation method for synthesizing S-nicotine from glutarate, comprising the following steps: step S1: performing a condensation reaction on nicotinate and glutarate in the presence of a base catalyst to obtain 5-carbonyl-5-(pyridin-3-yl)pentanoic acid; step S2: reacting the 5-carbonyl-5-(pyridin-3-yl)pentanoic acid with an amination reagent to obtain 5-oxo-5-(pyridin-3-yl)pentanamide; step S3: performing a Hofmann degradation reaction on the 5-oxo-5-(pyridin-3-yl)pentanamide in the presence of hypochlorite to obtain 4-amino-1-(pyridin-3-yl)butanone; step S4: adding the 4-amino-1-(pyridin-3-yl)butanone and (+)-B-diisopinocampheyl chloroborane into an organic solvent, and reacting at -30 to 10° C. to obtain (S)-4-amino-1-(pyridin-3 -yl)butan-1-ol; step S5: reacting the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol with a chlorination reagent to obtain (S)-4-amino-1-(pyridin-3-yl)chloro-butane; step S6: performing a cyclization reaction on (S)-4-amino-1-(pyridin-3-yl)butyl-1-chloride in the presence of a base to obtain S-demethylnicotine; and step S7. reacting the S-demethylnicotine with an amine methylation reagent to obtain the S-nicotine.

2. The preparation method for synthesizing S-nicotine from glutarate according to claim 1, wherein, at the step S1, a molar ratio of the nicotinate to the glutarate to the base catalyst is 1: (1-1.5): (1.2-2).

3. The preparation method for synthesizing S-nicotine from glutarate according to claim 1, wherein, at the step S2, the amination reagent is one or more selected from a group consisting of ammonium hydroxide, formamide, and acetamide.

4. The preparation method for synthesizing S-nicotine from glutarate according to claim 3, wherein, at the step S2, a molar ratio of the 5-carbonyl-5-(pyridin-3-yl)pentanoic acid to the ammonium hydroxide is 1: (2-4).

5. The preparation method for synthesizing S-nicotine from glutarate according to claim 1, wherein, at the step S3, a molar ratio of the 5-oxo-5-(pyridin-3-yl)pentanamide to the hypochlorite is 1: (1-2).

6. The preparation method for synthesizing S-nicotine from glutarate according to claim 1, wherein, at the step S4, a molar ratio of the 4-amino-1-(pyridin-3-yl)butanone to the (+)-B-diisopino- campheyl chloroborane is 1: (1.2-2).

7. The preparation method for synthesizing S-nicotine from glutarate according to claim 6, wherein, at the step S4, the organic solvent is tetrahydrofuran.

8. The preparation method for synthesizing S-nicotine from glutarate according to claim 6, wherein, a reaction temperature of the step S4 is 0° C.

9. The preparation method for synthesizing S-nicotine from glutarate according to claim 1, wherein, at the step S5, the chlorination reagent is one or more selected from a group consisting of oxaloyl chloride, thionyl chloride, and trichlorophosphorus.

10. The preparation method for synthesizing S-nicotine from glutarate according to claim 9, wherein, at the step S5, a molar ratio of the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol to the oxaloyl chloride is 1: (1-1.5).

11. The preparation method for synthesizing S-nicotine from glutarate according to claim 7, wherein, a reaction temperature of the step S4 is 0° C.

Description

DESCRIPTION OF THE EMBODIMENTS

[0064] The present application will be described in detail below in conjunction with embodiments.

[0065] The raw materials used in the present application can be obtained commercially, and if there is no special description, the raw materials not mentioned in the present application are purchased from Sinopharm Chemical Reagent Co., Ltd.

[0066] Embodiments 1 to 19 provide a preparation method for synthesizing S-nicotine from glutarate, which will be described below by taking Embodiment 1 as an example.

[0067] Embodiment 1 provides a preparation method for synthesizing S-nicotine from glutarate, wherein nicotinate is methyl nicotinate, the glutarate is diethyl glutarate, and a synthetic route is shown as Reaction Formula 2:

##STRReaction formula 2##

[0068] Specific preparation steps were as follows. [0069] Step S1: 48 g (2 mol, 2 eq) of NaH and 282.3 g (1.5 mol, 1.5 eq) of diethyl glutarate were dissolved in 4 L of tetrahydrofuran at 0° C., a reaction was performed at 0° C. for 30 min, 137.1 g (1 mol) of methyl nicotinate was added, and a condensation reaction was performed at 25° C. and monitored by TCL until the end of the reaction to obtain a mixture containing 5-carbonyl-5-(pyridin-3-yl)pentanoic acid. [0070] Step S2: a pH value of the mixture containing 5-carbonyl-5-(pyridin-3-yl)pentanoic acid prepared at Step S1 was adjusted to 4 by using 5 mol/L hydrochloric acid, and 204.36 g of industrial ammonium hydroxide (NH.sub.3: 3 mol, 3 eq) with an NH.sub.3 content of 25 wt% was added, and a reaction was performed at 65° C. for 2 h to obtain a mixture containing 5-oxo-5-(pyridin-3-yl)pentanamide. [0071] Step S3: the mixture containing 5-oxo-5-(pyridin-3-yl)pentanamide obtained at Step S2 was quickly added into 111.7 g (1.5 mol, 1.5 eq) of sodium hypochlorite at 0° C., a reaction was performed at 0° C. for 1 h, the water bath was heated to 71° C., the reaction was continued at 71° C. for 1 h; after the reaction was stopped, the reaction solution was cooled to 25° C., the pH of the system was adjusted to 9 by using a saturated NaOH aqueous solution, after the solution turned black, ethyl acetate-water (a volume ratio of the ethyl acetate to the water was 1: 2) was added for three extractions, and an organic layer was taken, dried over absolute Na.sub.2SO.sub.4, filtered for removing the Na.sub.2SO.sub.4, subjected to rotary evaporation for removing the solvent, and dried under vacuum to obtain 4-amino-1-(pyridin-3-yl)butanone. [0072] Step S4: the 4-amino-1-(pyridin-3-yl)butanone obtained at Step S3 was dissolved in 5 L of tetrahydrofuran at 0° C., 481.1 g (1.5 mol, 1.5 eq) of (+)-B-diisopinocampheyl chloroborane was added, and a reaction was performed at 0° C. for 2 h to obtain a mixture containing (S)-4-amino-1-(pyridin-3-yl)butan-1-ol; [0073] Step S5: 126.9 g (1 mol, 1 eq) of oxalyl chloride was added into the mixture containing (S)-4-amino-1-(pyridin-3-yl)butan-1-ol obtained at Step S4 at 0° C., a reaction was performed at 0° C. for 30 min, after the reaction, extraction was performed by using dichloromethane, and an organic phase was taken and subjected to rotary evaporation for removing the solvent to obtain (S)-4-amino-1-(pyridin-3-yl)chloro-butane. [0074] Step S6: 2 L of tetrahydrofuran was added into the (S)-4-amino-1-(pyridin-3-yl) chloro-butane obtained at Step S5, after the dissolution, 80 g (2 mol, 2 eq) of NaOH was added, and after the dissolution by stirring, a reaction was performed at 60° C. for 2 h to obtain a mixture containing S-demethylnicotine. [0075] Step S7: 170.3 g (1.2 mol, 1.2 eq) of methyl iodide was added into the mixture containing S-demethylnicotine prepared at Step S6, a reaction was performed at 25° C. for 3 h, the pH of the system was adjusted to 6 by using 5 mol/L hydrochloric acid, extraction was performed by using dichloromethane, an organic phase was taken, added with Na.sub.2SO.sub.4 for drying, and concentrated under reduced pressure for removing the solvent to obtain crude S-nicotine; and the crude S-nicotine was further purified once by atmospheric distillation to obtain S-nicotine with a yield of 53%, an ee value of 98%, and a purity of 95%.

[0076] It is worthwhile to note that each mass and specific molar weight in the embodiments of the present application can be selected according to the size of an industrially produced vessel as long as the equivalence ratio of each reaction raw material is consistent.

[0077] A difference between Embodiments 2 to 3 and Embodiment 1 is that: in the reaction of Step S1, the kind of the base catalyst was adjusted as specifically shown in Table 1.

TABLE-US-00001 Effect of selection of base catalyst on the reaction of Step S 1 Serial number Selection of base catalyst Yield of S-nicotine (%) Embodiment 1 NaH 53 Embodiment 2 Sodium tert-butoxide 50 Embodiment 3 Potassium tert-butoxide 50

[0078] A difference between Embodiments 4 to 5 and Embodiment 1 is that: in the reaction of Step S1, the usage amounts of the diethyl glutarate and the NaH were adjusted as specifically shown in Table 2.

TABLE-US-00002 Effect of usage amounts of diethyl glutarate and NaH on the reaction of Step S1 Serial number Equivalent quantity (eq) of diethyl glutarate (eq) Amount of substance of NaH (mol) Yield of S-nicotine (%) Embodiment 1 1.5 2 53 Embodiment 4 1.5 1.2 45 Embodiment 5 1 1.2 48

[0079] A difference between Embodiments 6 to 7 and Embodiment 1 is that: in the reaction of Step S2, the usage amount of the ammonium hydroxide was adjusted as specifically shown in Table 3.

TABLE-US-00003 Effect of usage amount of ammonium hydroxide on the reaction of Step S2 Serial number Equivalent quantity (eq) of ammonium hydroxide Yield of S-nicotine (%) Embodiment 1 3 53 Embodiment 6 2 45 Embodiment 7 4 48

[0080] A difference between Embodiments 8 to 9 and Embodiment 1 is that: in the reaction of Step S4, the usage amount of the (+)-B-diisopinocampheyl chloroborane was adjusted as specifically shown in Table 4.

TABLE-US-00004 Effect of usage amount of (+)-B-diisopinocampheyl chloroborane on the reaction of Step S4 Serial number Equivalent quantity (eq) of (+)-B-diisopinocampheyl chloroborane Yield of S-nicotine (%) Embodiment 1 1.5 53 Embodiment 8 1 49 Embodiment 9 2 51

[0081] A difference between Embodiments 10 to 12 and Embodiment 1 is that: in the reaction of Step S4, the reaction temperature was adjusted as specifically shown in Table 5.

TABLE-US-00005 Effect of reaction temperature on the reaction of Step S4 Serial number Reaction temperature (°C) Yield of S-nicotine (%) Embodiment 1 0 53 Embodiment 10 -10 45 Embodiment 11 10 50 Embodiment 12 5 49

[0082] A difference between Embodiments 13 to 15 and Embodiment 1 is that: in the reaction of Step S4, the kind of the organic solvent was adjusted as specifically shown in Table 6.

TABLE-US-00006 Effect of selection of organic solvent on the reaction of Step S4 Serial number Selection of organic solvent Yield of S-nicotine (%) Embodiment 1 Tetrahydrofuran 53 Embodiment 13 1,4-dioxane 25 Embodiment 14 Methyl tertiary butyl ether 0 Embodiment 15 Absolute ether 0

[0083] A difference between Embodiments 16 to 17 and Embodiment 1 is that: in the reaction of Step S5, the usage amount of the oxalyl chloride was adjusted as specifically shown in Table 7.

TABLE-US-00007 Effect of usage amount of oxalyl chloride on the reaction of Step S5 Serial number Equivalent quantity (eq) of oxalyl chloride Yield of S-nicotine (%) Embodiment 1 1 53 Embodiment 16 1.5 49 Embodiment 17 0.5 41

[0084] A difference between Embodiment 18 and Embodiment 1 is that: at Step S1, the methyl nicotinate was replaced with equimolar ethyl nicotinate, and prepared S-nicotine had a yield of 52%, an ee value of 98%, and a purity of 95%.

[0085] A difference between Embodiment 19 and Embodiment 1 is that: at Step S1, the diethyl glutarate was replaced with equimolar dimethyl glutarate, and prepared S-nicotine had a yield of 54%, an ee value of 98%, and a purity of 95%.

[0086] The specific embodiments are merely an explanation of the present application and are not intended to limit the present application. After reading the present description, those skilled in the art can make modifications to the present embodiments as required without any inventive contribution, and these modifications shall fall within the scope of protection of the present application.