SYNTHESIS METHOD OF CHIRAL (S)-NICOTINE

Abstract

The present application discloses a synthesis method of chiral nicotine from nicotinate and γ-butyrolactone, including the following steps: Step S1: performing condensation under an alkaline condition, and performing ring opening reaction with hydrochloric acid; Step S2: reacting with (+)-B-diisopinocampheyl chloroborane to produce a chiral hydroxyl group; Step S3: performing a chlorination reaction; and Step S4: performing cyclization under an alkaline condition to obtain the chiral nicotine. In the present application, nicotinate and γ-butyrolactone, both cheap and readily available, are used as raw materials, so as to reduce the production cost of (S)-nicotine. (+)-B-diisopinocampheyl chloroborane is used to reduce a carbonyl group of an intermediate to obtain a target chiral center. The (+)-B-diisopinocampheyl chloroborane induces the production of a chiral hydroxyl group, chlorination and cyclization are performed to form chiral (S)-demethylnicotine, and finally amine methylation is performed to obtain (S)-nicotine with photochemical activity.

Claims

1. A synthesis method of chiral nicotine from nicotinate and γ-butyrolactone as raw materials, comprising the following steps: Step S1: performing condensation under an alkaline condition, and performing ring opening reaction with hydrochloric acid; Step S2: reacting with (+)-B-diisopinocampheyl chloroborane to produce a chiral hydroxyl group; Step S3: performing a chlorination reaction; and Step S4: performing cyclization under an alkaline condition to obtain the chiral nicotine.

2. The synthesis method of chiral nicotine according to claim 1, wherein an amination reaction is performed between Step S1 and Step S2, and an amine methylation reaction is performed following the cyclization in Step S4.

3. The synthesis method of chiral nicotine according to claim 1, comprising the following steps: Step A1: performing condensation reaction on nicotinate and Y-butyrolactone, and performing ring opening reaction with hydrochloric acid to obtain 4-chloro-1-(3-pyridinyl)-1-butanone; Step A2: reacting the 4-chloro-1-(3-pyridinyl)-1-butanone with (+)-B-diisopinocampheyl chloroborane to obtain (S)-4-chloro-1-(pyridin-3-yl)butan-1-ol; Step A3: reacting the (S)-4-chloro-1-(pyridin-3-yl)butan-1-ol with a chlorination reagent to obtain (S)-3-(1,4-dichlorobutyl) pyridine; and Step A4: performing cyclization reaction on the (S)-3-(1,4-dichlorobutyl) pyridine using an amination reagent under an alkaline condition to obtain S-demethylnicotine or (S)-nicotine; wherein the S-demethylnicotine is subjected to amine methylation to obtain (S)-nicotine.

4. The synthesis method of chiral nicotine according to claim 2, comprising the following steps: Step B1: adding nicotinate and γ-butyrolactone to organic solvent I and performing condensation at the present of an alkaline catalyst to obtain a condensation product, and subjecting the condensation product to ring opening at the presence of hydrochloric acid to obtain 4-chloro-1-(3-pyridine)-1-butanone; Step B2: reacting 4-chloro-1-(3-pyridine)-1-butanone with an amination reagent under an alkaline condition to obtain 4-amino-1-(3-pyridine)-1-butanone; Step B3: reacting 4-amino-1-(3-pyridine)-1-butanone with (+)-B-diisopinocampheyl chloroborane in an organic solvent H at −30-10° C. to obtain (S)-4-amino-1-(pyridin-3-yl) butan-1-ol; Step B4: reacting (S)-4-amino-1-(pyridin-3-yl) butan-1-ol with a chlorination reagent to obtain (S)-4-amino-1-(pyridin-3-yl) butyl-1-chloride; and Step B5: performing cyclization on (S)-4-amino-1-(pyridin-3-yl) butyl-1-chloride at the presence of a base to obtain (S)-demethylnicotine, and reacting (S)-demethylnicotine with an amine methylation reagent to obtain (S)-nicotine.

5. The synthesis method of chiral nicotine according to claim 3, wherein, in Step A4, the amination reagent is a methylamine salt amination reagent or an amino amination reagent.

6. The synthesis method of chiral nicotine according to claim 5, wherein, in Step A4, when the amination reagent is a methylamine salt amination reagent, (S)-3-(1,4-dichlorobutyl) pyridine is reacted with the amination reagent under an alkaline condition to obtain (S)-nicotine.

7. The synthesis method of chiral nicotine according to claim 6, wherein, in Step A4, when the amination reagent is a methylamine salt amination reagent, a molar ratio of (S)-3-(1,4-dichlorobutyl) pyridine to methylamine salt amination reagent is 1: (1-5).

8. The synthesis method of chiral nicotine according to claim 5, wherein, the methylamine salt amination reagent is any one selected from the group consisting of methylamine hydrochloride, methylamine sulfate and methylamine nitrate.

9. The synthesis method of chiral nicotine according to claim 5, wherein, when the amination reagent is an amino amination reagent, (S)-3-(1,4-dichlorobutyl) pyridine is reacted with the amination reagent under an alkaline condition to obtain (S)-demethylnicotine.

10. The synthesis method of chiral nicotine according to claim 9, wherein, a molar ratio of (S)-3-(1,4-dichlorobutyl) pyridine to amino amination reagent is 1: (3-8).

11. The synthesis method of chiral nicotine according to claim 9, wherein, the amino amination reagent is any one selected from the group consisting of formamide, tert-butyl carbamate and ammonium hydroxide.

12. The synthesis method of chiral nicotine according to claim 4, wherein, in Step B3, a molar ratio of the 4-amino-1-(3-pyridine)-1-butanone to (+)-B-diisopinocampheyl chloroborane is 1:(1-3).

13. The synthesis method of chiral nicotine according to claim 4, wherein, in Step B4, in Step B4, the chlorination reagent is oxalyl chloride, and a molar ratio of (S)-4-amino-1-(pyridin-3-yl) butan-1-ol to oxalyl chloride is 1:(1-3).

14. The synthesis method of chiral nicotine according to claim 4, wherein, in Step B2, the amination reagent is ammonia or formamide.

15. The synthesis method of chiral nicotine according to claim 4, wherein, in Step B2, a molar ratio of the 4-chloro-1-(3-pyridine)-1-butanone to the amination reagent is 1:(1-3).

16. The synthesis method of chiral nicotine according to claim 4, wherein, in Step B1, a mole ratio of nicotinate, γ-butyrolactone and the alkaline catalyst is 1: (1-2): (1.2-3).

17. A synthesis method of chiral nicotine from butyrolactone, comprising the following steps: Step C1: performing condensation reaction on nicotinate and γ-butyrolactone, and performing ring opening reaction with hydrochloric acid to obtain 4-chloro-1-(3-pyridinyl)-1-butanone; Step C2: reacting the 4-chloro-1-(3-pyridinyl)-1-butanone with (+)-B-diisopinocampheyl chloroborane to obtain (S)-4-chloro-1-(pyridin-3-yl)butan-1-ol; Step C3: reacting the (S)-4-chloro-1-(pyridin-3-yl)butan-1-ol with a chlorination reagent to obtain (S)-3-(1,4-dichlorobutyl) pyridine; and Step C4: performing cyclization reaction on the (S)-3-(1,4-dichlorobutyl) pyridine using an amination reagent under an alkaline condition to obtain S-demethylnicotine or (S)-nicotine; wherein the S-demethylnicotine is subjected to amine methylation to obtain (S)-nicotine.

18. The synthesis method of chiral nicotine according to claim 17, wherein, in Step C4, the amination reagent is a methylamine salt amination reagent or an amino amination reagent.

19. The synthesis method of chiral nicotine according to claim 18, wherein, when the amination reagent is a methylamine salt amination reagent, (S)-3-(1,4-dichlorobutyl) pyridine is reacted with the amination reagent under an alkaline condition to obtain (S)-nicotine.

20. The synthesis method of chiral nicotine according to claim 19, wherein, a molar ratio of (S)-3-(1,4-dichlorobutyl) pyridine to methylamine salt amination reagent is 1: (1-5).

Description

DETAILED DESCRIPTION

[0107] The present application will be described in detail below in conjunction with Examples.

EXAMPLES

[0108] When the amination reagent is methylamine salt amination reagent, the method for synthesizing chiral nicotine from butyrolactone provided in the application is shown in reaction formula 1:

##STR00002##

[0109] A method for synthesizing chiral nicotine from butyrolactone is provided in Example 1, in which the amination reagent is methylamine salt amination reagent (specifically methylamine hydrochloride), the synthesis route is shown in reaction formula 1, and the specific preparation steps of (S)-nicotine includes:

[0110] A1: adding 86.1 g (1 mol, 1 eq) γ-butyrolactone to 1 L DMF, stirring at 0° C. for 10 min, adding 48 g (2 mol, 2 eq) NaH to react at 0° C. for 0.5 h, and then adding 137.1 g (1 mol) methyl nicotinate to allow for condensation at 25° C. for 2 h, and TCL monitoring the reaction until the end of the reaction to obtain a condensation product; and adding 0.831 12 mol/L (1 mol, 1 eq) hydrochloric acid to the condensation product, refluxing at 80° C. for 1 h, then extracting with saturated brine, adding sodium bicarbonate to adjust pH of the system to pH 7, extracting with dichloromethane for 3 times, combining organic phases, and spin drying to remove solvent to obtain 4-chloro-1-(3-pyridine)-1-butanone;

[0111] A2: dissolving 4-chloro-1-(3-pyridine)-1-butanone obtained in Step A1 with 5 L tetrahydrofuran, adding 641.5 g (2 mol, 2 eq) (+)-B-diisopino-campheyl chloroborane at 0° C. to react at 0 for 2 h, extracting with dichloromethane for three times, spin drying to remove solvent to obtain (S)-4-chloro-1-(pyridin-3-yl) butan-1-ol;

[0112] A3: adding 2 L 1,4-dioxane to (S)-4-chloro-1-(pyridin-3-yl) butan-1-ol obtained in step A2, mixing, adding 190.4 g (1.5 mol, 1.5 eq) sulfoxide chloride at 0° C., react at 40° C. for 1b, and adding 10 ml water to quench the reaction to obtain a mixture containing (S)-3-(1,4-dichlorobutyl) pyridine; and

[0113] A4: adding 400 g potassium carbonate (3 mol, 3 eq) and 201 g (3 mol, 3 eq) methylamine hydrochloride to the mixture containing (S)-3-(1,4-dichlorobutyl) pyridine obtained in Step A3, reacting under sealing condition at 60° C. for 6 h, adjusting the pH to 6 with 4 mol/L hydrochloric acid after the reaction, extracting with ethyl acetate to obtain an organic phase, spin evaporating to remove the solvent to obtain crude (S)-nicotine; and purifying crude (S)-nicotine by one atmospheric distillation to obtain (S)-nicotine, with a yield of 75%, ee value of 98%, and a purity of 98%.

[0114] Examples 2-3 differ from example 1 only in that, in Step A4, different methylamine salt amination reagents were selected, as shown in Table 1.

TABLE-US-00001 TABLE 1 Effect of selected methylamine salt amination reagents on the yield of (S)-nicotine methylamine salt yield of No. amination reagents (S)-nicotine (%) Example 1 methylamine 75 hydrochloride Example 2 methylamine sulfate 72 Example 3 methylamine nitrate 70

[0115] Examples 4-7 differ from example 1 only in that the use amount of methylamine hydrochloride is varied in Step A4 reaction, as shown in Table 2.

TABLE-US-00002 TABLE 2 Effect of the use amount of methylamine hydrochloride on the yield of (S)-nicotine Eq. of methylamine yield of No. hydrochloride (eq) (S)-nicotine (%) Example 1 3 75 Example 4 1 52 Example 5 2 68 Example 6 4 71 Example 7 5 70

[0116] When the amination reagent is an amino amination reagent, the synthetic route of the method for synthesizing chiral nicotine from butyrolactone provided in the application is shown in reaction formula 2:

##STR00003##

[0117] A method for synthesizing chiral nicotine from butyrolactone was provided in Example 8, in which the amination reagent is an amino amination reagent (specifically ammonium hydroxide), the synthesis route is shown in reaction formula 2, and the specific preparation steps of (S)-nicotine includes:

[0118] A1. adding 86.1 g (1 mol, 1 eq) 7-butyrolactone to 1 L DMF at 0° C., stirring at 0° C. for 10 min, adding 48 g (2 mol, 2 eq) NaH to react at 0° C. for 0.5 h, and then adding 137.1 g (1 mol) methyl nicotinate to allow for condensation at 25° C. for 2 h, and TCL monitoring the reaction until the end of the reaction to obtain a condensation product; and adding 0.831 12 mol/L (1 mol, 1 eq) hydrochloric acid to the condensation product, refluxing at 80° C. for 1 h, then extracting with saturated brine, adding sodium bicarbonate to adjust pH of the system to pH 7, extracting with dichloromethane for 3 times, combining organic phases, and spin drying to remove solvent in the organic phase to obtain 4-chloro-1-(3-pyridine)-1-butanone;

[0119] A2: dissolving 4-chloro-1-(3-pyridine)-1-butanone obtained in Step A1 with 5 L tetrahydrofuran, adding 641.5 g (2 mol, 2 eq) (+)-B-diisopino-campheyl chloroborane at 0° C. to react at 0° C. for 2 h, extracting with dichloromethane for three times, spin drying to remove solvent to obtain (S)-4-chloro-1-(pyridin-3-yl) butan-1-ol;

[0120] A3: adding 2 L 1,4-dioxane to (S)-4-chloro-1-(pyridin-3-yl) butan-1-ol obtained in step A2, mixing, adding 190.4 g (1.5 mol, 1.5 eq) sulfoxide chloride at 0° C., reacting at 40° C. for 1 h, and adding 10 ml water to quench the reaction to obtain a mixture containing (S)-3-(1,4-dichlorobutyl) pyridine;

[0121] A4: adding 400 g potassium carbonate (3 mol, 3 eq) and 140.2 g (4 mol, 4 eq) ammonium hydroxide to the mixture containing (S)-3-(1,4-dichlorobutyl) pyridine, reacting at 60° C. for 5 h, adjusting the pH to 6 with 4 mol/L hydrochloric acid after the reaction, extracting with ethyl acetate to obtain an organic phase, and spin evaporating to remove the solvent to obtain (S)-demethylnicotine; and

[0122] A5: adding 168 g 37 wt % formaldehyde solution and 541 g 88 WT % formic acid solution to the (S)-demethylnicotine obtained in Step A4, reacting at 60° C. for 3 h, adjusting the pH to 6, extracting with a mixed solution of dichloromethane and methanol (the volume ratio of dichloromethane to methanol is 10:1) for three times, combining organic phases, drying the organic phase with Na.sub.2SO.sub.4, concentrating under reduced pressure to remove solvent to obtain crude (S)-nicotine; and purifying (S)-nicotine by one atmospheric distillation to obtain (S)-nicotine, with a yield of 72%, ee value of 98% and purity of 98%.

[0123] Examples 9-10 differ from example 8 only in that different amino amination reagent were selected in Step A4 reaction, as shown in Table 3.

TABLE-US-00003 TABLE 3 Effect of selected amino amination reagents on the yield of (S)-nicotine selected amino amination yield of No. reagents (S)-nicotine (%) Example 8 ammonium hydroxide 72 Example 9 formamide 63 Example 10 tert-butyl carbamate 65

[0124] Examples 11-15 differ from example 8 only in that the use amount of ammonium hydroxide is varied in Step A4 reaction, as shown in Table 4.

TABLE-US-00004 TABLE 4 Effect of the use amount of ammonium hydroxide on the yield of (S)-nicotine eq. of methylamine hydrochloride (eq) yield of No. ammonium hydroxide (eq) (S)-nicotine (%) Example 8 4 72 Example 11 3 60 Example 12 5 71 Example 13 6 70 Example 14 7 68 Example 15 8 67
Example 16 provides a preparation method of (S)-nicotine, in which nicotinate is methyl nicotinate and a synthetic route is shown as Reaction Formula 3:

##STR00004##

[0125] Specific preparation steps were as follows:

[0126] Step B1: adding 86.1 g (1 mol, 1 eq) of γ-butyrolactone (with a CAS No. of 96-48-0) into 1 L of 1,4-dioxane at 0′C, mixing, adding 48 g (2 mol, 2 eq) of sodium hydride, reacting at 0′C for 0.5 h, adding 137.1 g (1 mol) of methyl nicotinate (with a CAS No. of 93-60-7), performing a condensation reaction at 25′C, TLC monitoring the reaction until the end of the reaction to obtain a condensation product, adding 0.083 L of 12 mol/L (1 mol, 1 eq) hydrochloric acid into the condensation product, refluxing at 80′C for 1 h, extracting with saturated salt solution, adding sodium bicarbonate to adjust the pH of the system to pH 7, extracting with dichloromethane for three times, combining organic phases, and spin drying to remove solvent to obtain 4-chloro-1-(pyridin-3-yl)-1-butanone;

[0127] Step B2: dissolving the 4-chloro-1-(pyridin-3-yl)-1-butanone obtained in Step B1 in 1 L of acetonitrile, adding 52 wt % NaOH aqueous solution to adjust pH of the system to pH 9, adding 90.1 g (2 mol, 2 eq) of formamide, reacting at 80° C. for 8 h, adding 4 mol/L hydrochloric acid to adjust the pH to 6, extracting with ethyl acetate to obtain an organic phase, and spin evaporating to remove the solvent to obtain 4-amino-1-(pyridin-3-yl)-1-butanone;

[0128] Step B3: dissolving the 4-amino-1-(pyridin-3-yl)-1-butanone obtained in Step B2 in 5 L of tetrahydrofuran, adding 641.5 g (2 mol, 2 eq) of (+)-B-diisopinocampheyl chloroboraneat 0° C. to react at 0° C. for 2 h, extracting with dichloromethane for three times, and spin drying to remove the solvent to obtain (S)-4-amino-1-(pyridin-3-yl)butan-1-ol;

[0129] Step B4: adding 2 L of 1,4-dioxane into the (S)-4-amino-1-(pyridin-3-yl)butan-1-ol obtained in Step B3, mixing, adding 190.4 g (1.5 mol, 1.5 eq) of oxalyl chloride at 0° C., reacting at 0° C. for 30 min, and quenching the reaction by adding 10 mL of water to obtain a mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chloride; and

[0130] Step B5: adding 80 g (2 mol, 2 eq) of NaOH into the mixture containing (S)-4-amino-1-(pyridin-3-yl)butyl-1-chloride prepared in Step B4, stirring at 60° C. to react for 2 h to obtain a mixture containing (S)-demethylnicotine, adding 170.3 g (1.2 mol, 1.2 eq) of methyl iodide into the mixture containing (S)-demethylnicotine, reacting at 25° C. for 3 h, adjusting the pH of the system to 6 with 12 mol/L hydrochloric acid, extracting with dichloromethane to obtain an organic phase, drying over Na.sub.2SO.sub.4, concentrating under reduced pressure to remove solvent to obtain crude (S)-nicotine, and further purifying the crude (S)-nicotine for one time by atmospheric distillation to obtain (S)-nicotine with a yield of 52%, an ee value of 98%, and a purity o 99%.

[0131] Examples 17-18 differ from example 16 only in that the type of basic catalyst is varied in the Step B1 reaction, as shown in Table 5.

TABLE-US-00005 TABLE 5 Effect of selected base catalyst on the yield of (S)-nicotine yield of No. selected base catalyst (S)-nicotine (%) Example 16 sodium hydride 52 Example 17 sodium tert-butoxide 42 Example 18 potassium tert-butoxide 43

[0132] Example 19 is different from example 16 only in that the type of amination reagent is varied in Step B2 reaction, as shown in Table 6.

TABLE-US-00006 TABLE 6 Effect of selected amination reagents on the yield of (S)-nicotine selected amination yield of No. reagent (S)-nicotine (%) Example 16 formamide 52 Example 19 ammonium 48 hydroxide

[0133] Examples 20-21 differ from example 16 only in that in Step B2 reaction, the use amount of amination reagents is varied, as shown in Table 7.

TABLE-US-00007 TABLE 7 Effect of the use amount of amination reagents on the yield of (S)-nicotine eq. of amination reagents yield of Serial number (eq) (S)-nicotine (%) Example 16 2 52 Example 20 3 48 Example 21 1 45

[0134] Examples 22-24 differ from example 16 only in that the use amount of (+)-B-diisopinocampheyl chloroborane is varied in Step B3 reaction, as shown in Table 8.

TABLE-US-00008 TABLE 8 Effect of the use amount of (+)-B-diisopinocampheyl chloroborane on the yield of (S)-nicotine eq. (eq) of (+)-B-diisopinocampheyl yield of No. chloroborane (S)-nicotine (%) Example 16 2 52 Example 22 1 42 Example 23 3 46 Example 24 1.5 48

[0135] Examples 25-27 differ from example 16 only in that the type of organic solvent II is varied in Step B3 reaction, as shown in Table 9.

TABLE-US-00009 TABLE 9 Effect of selected organic solvent II on the yield of (S)-nicotine yield of No. selected organic solvents II (S)-nicotine (%) Example 16 tetrahydrofuran 52 Example 25 1,4-dioxane 50 Example 26 methyl tert-butyl ether 25 Example 27 absolute ether 48

[0136] Examples 28-30 differ from example 16 only in that the reaction temperature is varied in Step B3 reaction, as shown in table 10.

TABLE-US-00010 TABLE 10 effect of reaction temperature on the yield of (S)-nicotine yield of No. reaction temperature (° C.) (S)-nicotine (%) Example 16 0 52 Example 28 −30 50 Example 29 10 45 Example 30 5 48

[0137] Examples 31-32 differ from example 16 only in that the reaction temperature is varied in Step B4 reaction, as shown in Table 11.

TABLE-US-00011 TABLE 11 effect of reaction temperature on the yield of (S)-nicotine yield of No. reaction temperature (° C.) (S)-nicotine (%) Example 16 0 52 Example 31 10 43 Example 32 −10 48

[0138] Examples 33-34 differ from example 16 only in that the use amount of oxalyl chloride is varied in Step B4 reaction, as shown in Table 12.

TABLE-US-00012 TABLE 12 effect of the use amount of oxalyl chloride on the yield of (S)-nicotine eq. of oxalyl yield of No. chloride (eq) (S)-nicotine (%) Example 16 1.5 52 Example 33 1 48 Example 34 2 35

[0139] A difference between Example 35 and Example 16 is that: in Step B1, the methyl nicotinate was replaced with equimolar ethyl nicotinate (with a CAS No. of 614-18-6), and produced (S)-nicotine had a yield of 52%, an ee value of 98%, and a purity of 99%.

[0140] 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.