Chiral enrichment method for spontaneous resolution and crystallization of (S)-nicotine

Abstract

The invention relates to the technical field of chiral enrichment of organic compounds, in particular to a chiral enrichment method for spontaneous resolution and crystallization of (S)-nicotine. According to the method, oily (S)-nicotine (the ee value is not lower than 80%) which is obtained through asymmetric synthesis and has relatively low chiral purity reacts with hydrochloric acid to form a nicotine hydrochloride solid, and the obtained nicotine hydrochloride solid is subjected to spontaneous crystallization resolution in a solvent at a certain temperature to obtain enantiomer-enriched (S)-nicotine hydrochloride. After alkalization, (S)-nicotine with high chiral purity can be obtained. The method has the advantages that raw materials with low ee value can be tolerated, the reagent source is convenient, the operation is simple, the loss is less, the ee value of the final product can reach more than 99%, and the method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of chiral enrichment technology of organic compounds, specifically to a ( S A chiral enrichment method for spontaneous resolution crystallization of nicotine. Background Technology

[0002] ( S )-nicotine(( S )-Nicotine), chemical name ( S 3-(1-methylpyrrolidone-2-yl)pyridine, its structure is as follows:

[0003] ( S Nicotine, or L-nicotine, is a chiral amine alkaloid widely found in tobacco plants and various Solanaceae plants. Its unique physiological activities are due to its pyridine and tetrahydropyrrolidine structures. Nicotine's biological activities are mainly divided into two categories: one category consists of activities harmful to the human body, including stimulating effects on the cardiovascular and gastrointestinal systems, addiction, and, at higher doses, neuromuscular disorders and seizures; the other category of physiological activities can be used for disease treatment. Nicotine has shown therapeutic effects on various central nervous system (CNS) diseases, such as Parkinson's syndrome, Alzheimer's disease, attention deficit hyperactivity disorder, cognitive impairment, and schizophrenia, among other CNS disorders. These physiological effects are mainly due to the release of dopamine, acetylcholine, and 5-HT after nicotine binds to nicotinic acetylcholine receptors (nAChRs), thereby exerting a neuroregulatory effect in the central nervous system. Furthermore, existing research has found that... S Nicotine's affinity for acetylcholine receptors is ( R )- 10100 times more potent than nicotine, and more widely used in the market; therefore, a single configuration of ( S Nicotine is of great importance.

[0004] Although at present ( S Various synthetic methods have been developed for the asymmetric synthesis of nicotine, but for those with low enantioselectivity... S Reports on chiral enrichment methods for nicotine remain limited; therefore, there is a need in the art for a method to enrich nicotine with low enantioselectivity. S Nicotine is obtained with high chiral purity through chiral enrichment. S )- The preparation process of nicotine. Summary of the Invention

[0005] The purpose of this invention is to provide a ( SA chiral enrichment method for spontaneous resolution crystallization of nicotine, to address how to address the issue of low enantioselectivity (Chocolate). S The problem of chiral enrichment of nicotine.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: a ( S The chiral enrichment method for spontaneous resolution crystallization of nicotine will yield an oily form with lower chiral purity through asymmetric synthesis. S Nicotine (ee value greater than 80%) forms ( ) under the action of hydrochloric acid. S Nicotine hydrochloride solid was subjected to spontaneous crystallization and recrystallization to obtain enantiomeric enriched ( ) S )-Nicotine hydrochloride, after alkalization, yields a high-chiral-purity ( S - Nicotine (ee value greater than 99%) The reaction formula is shown below: .

[0007] Furthermore, the oily substance with low chiral purity... S Nicotine can be in enantiomeric excess up to 80%, more preferably 90% or more.

[0008] Furthermore, ( S )-Nicole acidification to ( S The reagents used for nicotine hydrochloride are hydrochloric acid solutions with solvents such as methanol, ethanol, isopropanol, propanol, butanol, isobutanol, and 1,4-dioxane.

[0009] Furthermore, the recrystallization solvent is selected from methanol, ethanol, isopropanol, propanol, butanol, isobutanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran, dichloromethane, toluene, xylene, or combinations thereof, more preferably methanol, ethanol, ethyl acetate, or n-hexane.

[0010] Further, the alkali used for alkalization is LiOH, NaOH, KOH, Li2CO3, Na2CO3, K2CO3, Cs2CO3, LiHCO3, NaHCO3, KHCO3, CsHCO3, Na3PO4, Na2HPO4, NaH2PO4, triethylamine, pyridine, 2,6-methylpyridine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, or combinations thereof, more preferably triethylamine, sodium hydroxide, or potassium hydroxide.

[0011] Furthermore, the recrystallization temperature is -78~100℃, more preferably -78~25℃.

[0012] The beneficial effects of this invention are: (1) This invention has successfully developed ( S The chiral enrichment method for nicotine exhibits good stereoselectivity, yields products with high ee values, and is economical, efficient, simple, and reliable, providing high chiral purity. S )-nicotine.

[0013] (2) Extensive experimental studies have demonstrated that this method exhibits very high enantioselectivity, and the obtained ( S Nicotine has an enantioselectivity of up to 99%.

[0014] (3) The chiral enrichment method used in this invention has the characteristics of simple operation, low cost, high atom economy, compliance with green chemistry requirements, and potential for industrial production. Attached Figure Description

[0015] Figure 1 This is a process route diagram of the method of the present invention; Figure 2 This is the nuclear magnetic resonance spectrum after enrichment in Example 1 of the present invention; Figure 3 This is a pre-enrichment detection and analysis diagram from Embodiment 1 of the present invention; Figure 4 This is a detection and analysis diagram after enrichment in Embodiment 1 of the present invention. Detailed Implementation

[0016] The technical solution of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Experimental methods in the embodiments that do not specify specific conditions are generally performed under conventional conditions and conditions described in the manual. Unless otherwise specified, all commercially available reagents and solvents used are directly from the reagent supplier and have not undergone further purification.

[0017] ( S Chiral enrichment method of nicotine like Figure 1 As shown, in this invention ( S Chiral enrichment methods for nicotine include: obtaining an oily form with low chiral purity through asymmetric synthesis. S Nicotine (ee value greater than 80%) forms ( ) under the action of hydrochloric acid. S Nicotine hydrochloride solid was subjected to spontaneous crystallization to obtain enantiomeric enriched ( ) S )-Nicotine hydrochloride, after alkalization, yields a high-chiral-purity ( S The reaction formula for nicotine (ee value greater than 99%) is shown below:

[0018] Example 1 (S Chiral enrichment method of nicotine

[0019] The oily substance obtained by asymmetric synthesis method S Nicotine (1.0g, 96% ee, HPLC detection information as follows) Figure 3 (as shown) reacts with hydrochloric acid to form ( S Nicotine hydrochloride solid, in ethanol / n-hexane ( v / v Under conditions of 1 / 10), spontaneous crystallization resolution was carried out at room temperature, and the recrystallized product was obtained. S Nicotine hydrochloride was dissolved in water and the pH was adjusted to 10-11 with Et3N; after extraction with 10 mL DCM and removal of the solvent under negative pressure, the resulting oily liquid showed improved enantioselectivity. S Nicotine (0.848g, 85% yield, >99% ee).

[0020] like Figure 2 The hydrogen nuclear magnetic resonance spectrum is shown below: 1 H NMR (400 MHz, CDCl3) δ 8.56–8.50 (m, 2H), 7.74–7.70 (m, 1H), 7.30–7.27 (m, 1H), 3.30–3.24 (m, 1H), 3.13–3.08 (m, 1H), 2.37–2.29 (m, 1H), 2.27–2.21 (m, 3H), 2.19 (s, 3H), 2.05–1.94 (m, 1H), 1.90–1.71 (m, 2H).

[0021] Perform HPLC detection, such as Figure 4 The HPLC information is as follows: [DAICEL CHIRALCEL OD-H Column, n -hexane / EtOH (0.1% DEA) = 97 / 3, 254nm, 0.8 mL / min, t major = 7.257 min, t minor = 8.496 min], ee value is >99%.

[0022] Example 2 ( S Chiral enrichment method of nicotine

[0023] The oily substance obtained by asymmetric synthesis method S Nicotine (1.0g, 96% ee) reacts with hydrochloric acid to form ( S Nicotine hydrochloride solid, in ethanol / ether ( v / v Under conditions of 1 / 10), spontaneous crystallization resolution was carried out at room temperature, and the recrystallized product was obtained. S Nicotine hydrochloride was dissolved in water and the pH was adjusted to 10-11 with Et3N; after extraction with 10 mL DCM and removal of the solvent under negative pressure, the resulting oily liquid showed improved enantioselectivity. S Nicotine (0.831g, 83% yield, 98% ee).

[0024] The crude product was analyzed by HPLC, and the HPLC information is as follows: [DAICEL CHIRALCEL OD-H Column, n -hexane / EtOH (0.1% DEA) = 97 / 3, 254nm, 0.8 mL / min, t major = 7.237 min, t minor = 8.506 min], ee value is 98%.

[0025] Example 3 ( S Chiral enrichment method of nicotine

[0026] The oily substance obtained by asymmetric synthesis method S Nicotine (1.0g, 96% ee) reacts with hydrochloric acid to form ( S Nicotine hydrochloride solid, in methanol / ether ( v / v Under conditions of 1 / 10), spontaneous crystallization resolution was carried out at room temperature, and the recrystallized product was obtained. S Nicotine hydrochloride was dissolved in water and the pH was adjusted to 10-11 with Et3N; after extraction with 10 mL DCM and removal of the solvent under negative pressure, the resulting oily liquid showed improved enantioselectivity. S Nicotine (0.809g, 80% yield, 98% ee).

[0027] The crude product was analyzed by HPLC, and the HPLC information is as follows: [DAICEL CHIRALCEL OD-H Column, n-hexane / EtOH (0.1% DEA) = 97 / 3, 254nm, 0.8 mL / min, t major = 7.237 min, t minor = 8.506 min], ee value is 98%.

[0028] Examples 4-22 Examples 4-22 in Table 1 use an oil-based ( S The effect of recrystallization solvent on the reaction results was investigated using nicotine (96% ee) as the raw material at 25°C.

[0029]

[0030] Table 1 Results obtained from Examples 4-22

[0031] Examples 4-22 in Table 1 use an oil-based ( S Nicotine (96% ee) was used as the raw material; as can be seen from Examples 1-22, the type and ratio of solvent used for spontaneous crystallization resolution and the temperature used for recrystallization have an effect on improving ( S )-Nicotine enantioselectivity has different effects when using EtOH / n -hexane( v / v The best results can be obtained by recrystallizing (1 / 50) at -78°C.

[0032] Example 23 ( S Chiral enrichment method of nicotine

[0033] The oily substance obtained by asymmetric synthesis method S Nicotine (1.0g, 80% ee) reacts with hydrochloric acid to form ( S Nicotine hydrochloride solid, in ethanol / n-hexane ( v / v Under conditions of 1 / 50), spontaneous crystallization resolution was carried out at -78℃, and the recrystallized product was obtained. S Nicotine hydrochloride was dissolved in water and the pH was adjusted to 10-11 with Et3N; after extraction with 10 mL DCM and removal of the solvent under negative pressure, the resulting oily liquid showed improved enantioselectivity. S )- Nicotine (0.712g, 71% yield, >99% ee).

[0034] HPLC analysis was performed, and the HPLC information is as follows: [DAICEL CHIRALCEL OD-H Column, n -hexane / EtOH (0.1% DEA) = 97 / 3, 254nm, 0.8 mL / min, t major = 7.257 min, t minor = 8.496 min], ee value is >99%.

[0035] As can be seen from Example 23, spontaneous crystallization under the above-mentioned optimized conditions requires raw materials with a content of not less than 80% ee ( S Recrystallization of nicotine can still yield the target product with an ee of >99%.

[0036] This invention is not limited to the preferred embodiments described above. Anyone can derive other forms of products under the guidance of this invention. However, regardless of any changes made in their shape or structure, any technical solution that is the same as or similar to this application falls within the protection scope of this invention.

Claims

1. A kind of ( S The chiral enrichment method for nicotine is characterized by: An oily substance with lower chiral purity will be obtained through asymmetric synthesis. S Nicotine is acidified to obtain nicotine hydrochloride solid. The obtained nicotine hydrochloride solid is then subjected to spontaneous crystallization to obtain enantiomeric enriched nicotine hydrochloride. S )-Nicotine hydrochloride, after alkalization, yields a high-chiral-purity ( S )-nicotine.

2. The one according to claim 1 ( S The chiral enrichment method for nicotine is characterized by: The aforementioned low-purity, oily substance S The enantiomeric excess of nicotine is not less than 80%.

3. The one according to claim 1 ( S The chiral enrichment method for nicotine is characterized by: The high chiral purity ( S The enantiomeric excess of nicotine is over 99%.

4. The one according to claim 1 ( S The chiral enrichment method for nicotine is characterized by: The acidification process uses a hydrochloric acid solution as a reagent, and the solvents for the hydrochloric acid solution include methanol, ethanol, isopropanol, propanol, butanol, isobutanol, and 1,4-dioxane.

5. The method according to claim 1 ( S The chiral enrichment method for nicotine is characterized by: The solvents for spontaneous crystallization and resolution include one or more of methanol, ethanol, isopropanol, propanol, butanol, isobutanol, ethyl acetate, n-hexane, diethyl ether, tetrahydrofuran, dichloromethane, toluene, and xylene.

6. The method according to claim 1 ( S The chiral enrichment method for nicotine is characterized by: The spontaneous crystallization separation temperature is -78~60℃.

7. The method according to claim 1 ( S The chiral enrichment method for nicotine is characterized by: The alkali used for alkalization includes one or more of the following: LiOH, NaOH, KOH, Li2CO3, Na2CO3, K2CO3, Cs2CO3, LiHCO3, NaHCO3, KHCO3, CsHCO3, Na3PO4, Na2HPO4, NaH2PO4, triethylamine, pyridine, 2,6-methylpyridine, 1,8-diazabicycloundec-7-ene, and 1,4-diazabicyclo[2.2.2]octane.

Images