CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of international application of PCT application serial no. PCT/CN2021/115386 filed on Aug. 30, 2021, which claims the priority benefit of China application no. 202110860273.3, filed on Jul. 28, 2021. The entirety of each of the above mentioned patent applications is hereby incorporated by reference herein and made a part of this specification.

BACKGROUND
Technical Field

The present application relates to a technical field of chemical synthesis, and in particular to a preparation method for synthesizing a chiral nicotine from a chiral tert-butylsulfenamide.

With the rapid development of the e-cigarette industry, nicotine, as one of the important active components of e-cigarette, is in increasing demand, and, in particular, nicotine with single configuration and optical activity has attracted extensive attention. However, there are few studies on the preparation methods of the chiral nicotine, most of which is basically obtained by chiral resolution, but reagents used in the chiral resolution is expensive, not conducive to industrial production.

China patent publication No. CN104341390A discloses a preparation method of the chiral nicotine, which uses a cyclic imine as a starting raw material, but requires expensive chiral catalysts to induce the formation of a chiral center. China patent publication No. CN111233829A discloses a preparation method of nicotine with optical activity, which uses chiral ligands containing nitrogen or phosphorus to prepare organic metal catalysts, and uses imine derivatives as the starting raw material to prepare the chiral nicotine. Similarly, the organic metal catalysts prepared by chiral ligands containing nitrogen or phosphorus are used as the chiral catalysts to induce the formation of the chiral centers, and the preparation method of the organic metal catalysts is complex and the production cost is high. The applicant found that the use of the chiral catalysts leads to more reaction steps for the whole synthesis of the chiral nicotine, resulting in the lower yield of the chiral nicotine.

The chiral tert-butylsulfenamide is a kind of raw material widely available and inexpensive, but there is no report on the synthesis of the chiral nicotine by using the chiral tert-butylsulfenamide as the raw material at present.

SUMMARY

To reduce reaction steps for preparing a chiral nicotine, the present application provides a preparation method for synthesizing a chiral nicotine from a chiral tert-butylsulfenamide.

In a first aspect, the present application provides the preparation method for synthesizing a chiral nicotine from chiral tert-butylsulfenamide, which is achieved by adopting technical solutions as follows.

The preparation method for synthesizing a chiral nicotine from chiral tert-butylsulfenamide includes steps as follow:

Step S1: condensing 3-pyridinecarboxaldehyde with the chiral tert-butylsulfenamide at the presence of a titanate to obtain a chiral 2-methyl-N-(pyridine-3-yl methylene)propane-2-sulfenamide;

Step S2: reacting the chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide with (1,3-dioxane-2-yl ethyl) magnesium bromide to obtain a chiral N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2-sulfenamide;

Step S3: cyclizing the chiral N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2-sulfenamide under an acidic condition to obtain a chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine; and

Step S4: reducing and amine methylating the chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine to obtain the chiral nicotine.

By adopting the above technical solution, in the present application, the chiral tert-butylsulfenamide is used as a starting raw material, condensed with 3-pyridinecarboxaldehyde, reacted with (1,3-dioxane-2-yl ethyl) magnesium bromide, cyclized under the acidic conditions, and finally reduced and amine methylated to obtain the chiral nicotine. A reaction route for synthesizing the chiral nicotine in the present application is shorter, and the raw materials are easily available and inexpensive, so that the production cost of the chiral nicotine can be reduced. In addition, reaction operations and processing operations in individual steps in the present application are simple, and a yield and an ee value of the chiral nicotine produced by the reaction are high. The preparation method for synthesizing the chiral nicotine from the chiral tert-butylsulfenamide according to the present application is an optimized method for synthesizing the nicotine with single configuration.

Preferably, in Step S1, a mole ratio of 3-pyridinecarboxaldehyde, the chiral tert-butylsul-fenamide to the titanate is 1:1:(1-3); and more preferably, the mole ratio of 3-pyridinecarbox-aldehyde, the chiral tert-butylsulfenamide and the titanate is 1:1:2.

In the present application, the chiral tert-butylsulfenamide can be (S)-tert-butylsulfenamide or (R)-tert-butylsulfenamide, which is determined by the configuration of the final product, that is, the chiral nicotine. When the chiral tert-butylsulfenamide is (S)-tert-butylsulfenamide, the chiral nicotine is (S)-nicotine; and when the chiral tert-butylsulfenamide is (R)-tert-butylsulfenamide, the chiral nicotine is (R)-nicotine.

Preferably, in Step S1, the titanate is one or more selected from the group consisting of tetraethyl titanate, tetrapropyl titanate and tetrabutyl titanate; and more preferably, the titanate is tetraethyl titanate.

Preferably, a solvent used in Step S1 is anhydrous tetrahydrofuran or dimethyl tetrahydrofuran; and preferably, the solvent used in Step S1 is anhydrous tetrahydrofuran.

Preferably, a temperature in Step S1 is 50-90° C.; more preferably, the temperature in Step S1 is 60-80° C.; and most preferably, the temperature in Step S1 is 70° C.

In the present application, a reaction time of step S1 is 1.5-2.5 h; and preferably, the reaction time of step S1 is 2 h.

In the present application, the condensing in Step S1 occurs in a nitrogen atmosphere. The nitrogen atmosphere can improve activity of 3-pyridinecarboxaldehyde, reduce the occurence of other side reactions, and remain the configuration of the chiral tert-butylsulfenamide, thereby increasing the ee value and the yield of 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide.

In the present application, after the condensing in Step S1, a post treatment is performed to obtain the chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide. The post treatment mainly includes subjecting to vigorous stirring in brine, filtrating, washing, liquid separating, extracting, water removing and solvent removing.

Preferably, in Step S2, the mole ratio of the chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide to (1,3-dioxane-2-yl ethyl) magnesium bromide is 1:(1.1-1.3); and more preferably, the mole ratio of the chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide and (1,3-dioxane-2-yl ethyl) magnesium bromide is 1:1.225.

In the present application, the solvent used in Step S2 is tetrahydrofuran.

In the present application, in Step S2, materials are added by: adding the chiral 2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide prepared in Step S1 into tetrahydrofuran, and then adding (1,3-dioxane-2-yl ethyl) magnesium bromide solution dropwise.

In the present application, the reacting of Step S2 include a reaction in nitrogen atmosphere and a reaction under a sealed condition. The temperature of the reaction in nitrogen atmosphere is −30° C., and the reaction time is 30 min. The temperature of the reaction under the sealed conditions is 0° C., and the reaction time is 3 h.

In the present application, after the reaction under the sealed condition in Step S2, the reaction solution is heated to 25° C., and then quenched. A reagent used in the quenching is a mixed solution of saturated NH₄Cl aqueous solution and ethyl acetate, in which a volume ratio of saturated NH₄Cl aqueous solution to ethyl acetate is 5:3.

In the present application, after the quenching in Step S2, a post treatment step is further performed to obtain the chiral N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2-sulfenamide. The post-treatment step mainly includes liquid separating, extracting, washing, water removing and solvent removing.

Preferably, in Step S3, pH of the acidic condition is 2-4; and preferably, the pH of the acidic condition is 3, and the reagent used is a solution of hydrochloric acid in methanol with HCl content of 20 wt %.

In the present application, the chiral N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2-sulfenamide prepared in Step S2 is dissolved in tetrahydrofuran before it is cyclized in the hydrochloric acid methanol solution.

In the present application, the reaction temperature of the cyclizing in Step S3 is 20-30° C. the reaction time is 1.5-2.5 h; and preferably, the reaction temperature of the cyclizing in Step S3 is 25° C., and the reaction time is 2 h.

In the present application, a mixture containing the chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine is obtained by the cyclizing in Step S3.

Preferably, in Step S4, a reducing agent used for the reducing is sodium borohydride. The chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine is reduced to chiral demethylnicotine by the sodium borohydride.

Preferably, in Step S4, a mole ratio of the sodium borohydride to the chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine is (1.5-2.5):1; and more preferably, the mole ratio of the sodium borohydride to the chiral 3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine is 2:1.

In the present application, in Step S4, the reaction temperature of the reducing is (−5)−5° C., and a reaction time is 2.5-3.5 h; and preferably, the reaction temperature of the reducing is 0° C., and the reaction time is 3 h.

In the present application, in Step S4, the pH of system is adjusted to be alkaline before the amine methylating.

In the present application, in Step S4, the amine methylating uses cesium carbonate and methyl iodide.

In the present application, a mole ratio of cesium carbonate and methyl iodide is 1:(1.3-1.8):(1.1-1.3); and more preferably, the mole ratio of cesium carbonate and methyl iodide is 1:1.5:1.2.

In the present application, in Step S4, a reaction temperature of the amine methylating is 20-30° C., preferably 25° C., and a reaction time is 3 h.

In the present application, in Step S4, after the amine methylating, the system is adjusted to a neutral pH by adding acid, extracted to obtain an organic phase, which is dried by Na₂SO₄, and vacuum concentrated to obtain a crude chiral nicotine. Finally, the crude chiral nicotine is subjected to atmospheric distillation purification for one time to obtain the chiral nicotine.

In summary, the embodiments of the present application have the beneficial effects as follow.

The present application provides a new method for synthesizing the chiral nicotine, which uses easily available and inexpensive chiral tert-butylsulfenamide as the starting raw materials. The chiral tert-butylsulfenamide has provided a chiral center, therefore, there is no need for expensive or complex chiral catalyst, and the cost of the raw materials is reduced. Further, the chiral tert-butylsulfenamide is condensed with 3-pyridinecarboxaldehyde, then reacted with (1,3-dioxane-2-yl ethyl) magnesium bromide, cyclized under the acid condition, and finally reduced and amine methylated to obtain chiral nicotine. The whole synthesis involves in a short reaction route, simple operations in each reaction step, the high yield and the ee value of the resulting chiral nicotine, and high purity that can be achieved only by one-time purification, so that the production cost of chiral nicotine is reduced.

DESCRIPTION OF THE EMBODIMENTS

The present application is further described in detail below in combination with examples.

Raw materials used in the present application can be obtained through commercial sale. The raw materials not mentioned in the present application are purchased from Sinopharm Chemical Reagent Co., Ltd., unless otherwise stated.

Examples 1-15 provide a preparation method for synthesizing chiral nicotine from a chiral tert-butylsulfenamide. Example 1 is described below as an example.

Example 1 provides a preparation method for synthesizing chiral nicotine from chiral tert-butylsulfenamide, in which the chiral tert-butylsulfenamide is S-tert-butylsulfenamide, and the chiral nicotine is S-chiral nicotine, and a synthetic route is shown as reaction formula 1:

[Image Omitted]

The specific preparation steps are shown as follows.

Step S1: in a nitrogen atmosphere, 106.7 g (1 mol, 1 eq) 3-pyridinecarboxaldehyde, 121.7 g (1 mol, 1 eq) (S)-tert-butylsulfenamide and 455.5 g (2 mol, 2 eq) tetraethyl titanate were dissolved in 6 L anhydrous tetrahydrofuran, and reacted at 70° C. for 2 h. After the reaction, a reaction solution was poured into 10 L saturated salt water solution, stirred at 1000 rpm for 15 min, and filtered to obtain a filtrate and a filter cake. The filter cake was washed with 3 L ethyl acetate, and the filtrate was collected, and separated to obtain a water layer. The water layer was extracted with 6 L ethyl acetate-water (volume ratio of ethyl acetate to water is 2:1) for 3 times to obtain organic layers. The organic layers were combined, washed with 3 L saturated salt water solution, dried by anhydrous Na₂SO₄and vacuum concentrated to remove solvent to obtain a light yellow oily liquid of (S,E)-2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide.

Step S2: 8 L tetrahydrofuran was added into (S,E)-2-methyl-N-(pyridine-3-yl methylene) propane-2-sulfenamide prepared by Step S1, and mixed uniformly. In the nitrogen atmosphere at −30° C., 2.45 L 0.5 mol/L solution of (1,3-dioxane-2-yl ethyl) magnesium bromide in tetrahydrofuran was added dropwise (in which, (1,3-dioxane-2-yl ethyl) magnesium bromide is 1.225 mol, 1.225 eq), stirred and reacted at −30° C., 400 rpm for 30 min. Then, nitrogen was removed, and the reaction vessel was sealed, the reaction solution was stirred and performed at 0° C., 400 rpm for 3 h. After the reaction, the reaction solution was heated to 25° C., and a mixed solution of 0.5 L saturated NH₄Cl water solution and 0.3 L ethyl acetate were added for a quenching reaction. After the quenching reaction, the reaction solution was separated to obtain an organic layer and a water layer. The water layer was extracted with 10 L ethyl acetate for 3 times, and separated. All the organic layers in the water layer were collected, combined, washed with 15 L saturated salt water, dried with anhydrous magnesium sulfate, filtered and vacuum concentrated to obtain (S,E)-N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2-sulfenamide.

Step S3: 8 L tetrahydrofuran was added into (S,E)-N-(3-(1,3-dioxane-2-yl)-1-(pyridine-3-yl) propylidene)-2-methyl propane-2- sulfenamide prepared by Step S2, and the system was adjusted to a pH of 3 by adding hydrochloric acid methanol solution with HCl content of 20 wt % and reacted at 25° C. for 2 h to obtain a mixture containing (S)-3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine.

Step S4: 75.66 g (2 mol, 2 eq) sodium borohydride was added into the mixture containing (S)-3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine prepared by Step S3, reacted at 0° C. for 3 h. (S)-3-(3,4-dihydro-2H-pyrrol-2-yl) pyridine is reduced to (S)-demethylnicotine, so as to obtain a mixing solution containing (S)-demethylnicotine. The pH of the mixing solution containing (S)-demethylnicotine to 9 with 4 mol/L NaOH, and then 488.3 g (1.5 mol. 1.5 eq) cesium carbonate and 170 g (1.2 mmol, 1.2 eq) methyl iodide were added and reacted at 25° C. for 3 h, and the pH of the system was adjusted to 7 with 5 mol/L HCl, and then the reaction solution was extracted with 15 L saturated salt water and 15 L dichloromethane to obtain an organic phase, which is collected and dried by adding anhydrous Na₂SO₄. The solvent was vacuum concentrated and evaporated to obtain a crude product of (S)-nicotine, which was atmospheric distillation purified to obtain (S)-nicotine, of which a yield is 72%, an ee value is 98%, and a purity is 98%.

Examples 2-3 differ from Example 1 only in that: in Step S1, an amount of the titanate is varied, as specifically shown in table 1.

TABLE 1

Effect of the amount of the titanate on the yield of (S)-nicotine

Equivalence quantity

No.
of titanate(eq)
Yield of (S)-nicotine (%)

Example 1
2
72

Example 2
1
43

Example 3
3
68

Example 4 differs from Example 1 only in that: in Step S1, the type of titanate is varied, as specifically shown in table 2.

TABLE 2

Effect of the selection of titanate on the yield of (S)-nicotine

No.
Selected titanate
Yield of (S)-nicotine (%)

Example 1
tetraethyl titanate
72

Example 4
tetrabutyl titanate
70

Examples 5-7 differ from Example 1 only in that: in Step S1, a reaction temperature is varied, as specifically shown in table 3.

TABLE 3

Effect of the reaction temperature on the yield of (S)-nicotine

No.
Reaction temperature (° C.)
Yield of (S)-nicotine (%)

Example 1
70
72

Example 5
90
65

Example 6
80
68

Example 7
50
54

Example 8-9 differ from Example 1 only in that: in Step S1, the type of the solvent is varied, as specifically shown in table 4.

TABLE 4

Effect of the solvent on the yield of (S)-nicotine

No.
Selection of the solvent
Yield of (S)-nicotine (%)

Example 1
anhydrous tetrahydrofuran
72

Example 8
dimethyl tetrahydrofuran
70

Example 9
dichloromethane
53

Examples 10-11 differ from Example 1 only in that: in Step S2, the amount of (1,3-dioxane-2-yl ethyl) magnesium bromide is varied, as specifically shown in table 5.

TABLE 5

Effect of the amount of (1,3-dioxane-2-yl ethyl)

magnesium bromide on the yield of (S)-nicotine

Equivalence quantity of

(1,3-dioxane-2-yl ethyl)

No.
magnesium bromide (eq)
the yield of (S)-nicotine (%)

Example 1
1.225
72

Example 10
1.1
65

Example 11
1.3
70

Example 12 differs from the Example 1 only in that: in Step S3, acid condition is varied, as specifically shown in table 6.

TABLE 6

Effect of the acid conditions on the yield of (S)-nicotine

No.
the acid conditions
the yield of (S)-nicotine (%)

Example 1
hydrochloric acid
72

methanol solution with

HCl content of 20 wt %

Example 12
90 wt % trifluoroacetic
68

acid aqueous solution

Examples 13-14 differ from the Example 1 only in that: in Step S4, reduction condition is varied, as specifically shown in table 7.

TABLE 7

Effect of the reduction conditions on the yield of (S)-nicotine

No.
the reduction conditions
the yield of (S)-nicotine (%)

Example 1
sodium borohydride
72

Example 13
sodium triacetyl
30

borohydride

Example 14
sodium dithionite
50

The Example 15 differs from the Example 1 only in that: in Step S1, (S)-tert-butylsulfenamide is replaced by (R)-tert-butylsulfenamide in equimolar. The yield of (R)-nicotine is 71%, the ee value is 98%, the purity is 98%.

Comparative Example

The comparative Example 1 differs from the Example 1 only in that: in Step S1, the titanate is replaced by cesium carbonate in equimolar amount. The yield of (S)-nicotine is 28%, the ee value is 97%, the purity is 92%.

What is provided above is merely the preferred embodiments according to the present application, and the protection scope of the present application is not limited to the above embodiments. On the contrary, all the technical solutions obtained based on the concepts of the present application should fall in the protection scope of the present application. It should be noted that, for those skilled in the art, some improvements and modifications can be made without departing from the principles of the present applications, which should be also considered as falling within the protection scope of the present application.