A preparation method of 2-(5-bromopyridin-3-yl)quinuclidine

Abstract

The invention discloses a preparation method of 2-(5-bromopyridine-3-yl)quinuclidine, which belongs to the field of synthesis technology. The preparation method uses 1-tert-butyloxycarbonyl-4-piperidinylacetic acid as a raw material and prepares the compound described in formula 4 through the following synthetic route, i.e., 2-(5-bromopyridine-3-yl)quinuclidine. The preparation method of the invention has few reaction steps, and the reaction conditions are easy to control. The purity of the prepared 2-(5-bromopyridine-3-yl)quinuclidine is high (99%), and the yield can reach 90%, which is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis, and particularly relates to a method for preparing 2-(5-bromopyridin-3-yl)quinuclidine. Background Art

[0002] The α4β2 nicotinic receptor (nAChR) is a ligand-gated ion channel that is distributed almost throughout the nervous system. It is involved in the regulation and release of neurotransmitters such as acetylcholine, dopamine, γ-aminobutyric acid, and norepinephrine, and plays an important role in the body's learning, memory, cognition, attention, inflammation, and pain. A large number of studies have shown that α4β2 nAChR is an important therapeutic target for neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, depression, nicotine dependence, and pain. It is of great significance for the early diagnosis and efficacy detection of neurodegenerative diseases, mainly Alzheimer's disease (Kong Dewen, Yu Ziru, et al., Research Progress on Nicotinic α4β2 Receptor and Related Diseases and Drugs [J], Acta Pharmaceutica Sinica, 2021, 56(1):1-8).

[0003] At present, many nicotinic receptor-related compounds have been used to treat diseases related to the nervous system. The α4β2 nAChR-related compounds used for treatment mainly include agonists, partial agonists, antagonists and allosteric modulators, including natural compounds extracted from animals and plants, such as geotrichum toxins and cytisine, as well as compounds designed and synthesized according to the structure of natural ligands, and candidate drugs obtained by virtual screening of molecular docking based on the X-ray structure of α4β2 nAChR and efficacy verification. Among them, the combination of aliphatic amines and nitrogen-containing aromatic heterocycles is a common structural feature of the high affinity of compounds to α4β2 nAChR.

[0004] In 2008, Balwinder S. Bhatti published a study on the synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a class of potent nicotinic acetylcholine receptor-ligands. Journal of Organic Chemistry. Chemistry, 73(9), 3497-3507) discloses the structure and preparation method of 2-(5-bromopyridin-3-yl)quinuclidine.

[0005] The main synthetic route of 2-(5-bromopyridin-3-yl)quinuclidine is as follows:

[0006]

[0007] This route has the problem of long reaction steps and difficulty in industrial preparation of the target compound. Summary of the invention

[0008] The invention aims at solving the problems in the prior art and provides a method for preparing 2-(5-bromopyridin-3-yl)quinuclidine. The method has fewer steps, is easy to control reaction conditions, has high yield and is suitable for large-scale industrial production.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] In a first aspect, the present invention provides a method for preparing 2-(5-bromopyridin-3-yl)quinuclidine, which uses 1-tert-butyloxycarbonyl-4-piperidinylacetic acid as a raw material and is prepared through the following synthetic route to obtain a compound of formula 4, namely 2-(5-bromopyridin-3-yl)quinuclidine;

[0011]

[0012] In the above-mentioned synthetic route of the present invention, after each reaction step, a post-treatment step is also included, and the post-treatment includes one or more steps of extracting, washing, drying, purifying and recrystallizing the reactants.

[0013] In some embodiments, in the preparation method, step 1 uses 1-tert-butyloxycarbonyl-4-piperidinylacetic acid to react with dimethylhydroxylamine hydrochloride to obtain an intermediate compound of formula 1;

[0014]

[0015] Preferably, the solvent for the reaction in step S1 is at least one of DMF, N,N-dimethylethylamine, DCM and THF.

[0016] Preferably, the molar ratio of 1-tert-butyloxycarbonyl-4-piperidineacetic acid to dimethylhydroxylamine hydrochloride in step S1 is 1:0.9-1.2; more preferably 1:1.05.

[0017] Preferably, a condensing agent is added to the reaction in step S1, and the condensing agent is at least one of T3P, BOP-Cl and PyBOP.

[0018] Preferably, the molar amount of the condensing agent added is 1-1.5 times that of 1-tert-butyloxycarbonyl-4-piperidinylacetic acid; more preferably, it is 1.3 times.

[0019] In some embodiments, after the reaction in step S1, a post-treatment step is further included, and the post-treatment includes one or more steps of extracting and stratifying the reactants, washing, and drying.

[0020] Preferably, the extractant used in the extraction is ethyl acetate, and the extraction is performed at least once.

[0021] Preferably, the washing is to wash the extracted organic phase at least three times. More preferably, the washing is to wash with 15-30 wt % oxalic acid aqueous solution, saturated sodium bicarbonate and saturated brine in sequence.

[0022] Preferably, the drying is drying the organic phase obtained after washing.

[0023] In some embodiments, in the preparation method, step S2 utilizes 3,5-dibromopyridine to react with the intermediate compound of formula 1 to obtain the intermediate compound of formula 2;

[0024]

[0025] Preferably, the solvent for the reaction in step S2 is at least one of tetrahydrofuran, 2-methyltetrahydrofuran and toluene.

[0026] Preferably, the molar ratio of 3,5-dibromopyridine to the intermediate compound of formula 1 in step S2 is 1:0.9-1.2; more preferably 1:1.

[0027] Preferably, a catalyst is further added to the reaction in step S2, and the catalyst is at least one of isopropylmagnesium chloride, n-butyllithium and magnesium chips.

[0028] Preferably, the added molar amount of the catalyst is 0.9-1.2 times of 3,5-dibromopyridine, and more preferably 1 time.

[0029] In some embodiments, after the reaction in step S2, a post-treatment step is further included, and the post-treatment includes one or more steps of extracting, stratifying, washing, drying, and purifying the reactants.

[0030] Preferably, the extractant used in the extraction is ethyl acetate, and the extraction is performed at least once.

[0031] Preferably, the washing is washing the organic phase after extraction at least once, and more preferably, the washing is washing with saturated brine once.

[0032] Preferably, the drying is drying the organic phase obtained after washing.

[0033] Preferably, the purification is to add ethyl acetate to the dried crude product for pulping, and the amount of ethyl acetate added is 1-5 times the quality of the crude product, and more preferably 2 times.

[0034] In some embodiments, the preparation method, step S3 uses the intermediate compound of formula 2 to react to obtain the intermediate compound of formula 3;

[0035]

[0036] Preferably, the solvent for the reaction in step S3 is at least one of methanol, ethanol, tetrahydrofuran and N,N-dimethylformamide.

[0037] Preferably, a catalyst is further added to the reaction in step S3, and the catalyst is at least one of sodium borohydride, lithium borohydride and borane.

[0038] Preferably, the added molar amount of the catalyst is 1.5-3 times of the intermediate compound of formula 2, and more preferably 2 times.

[0039] In some embodiments, after the reaction in step S3, a post-treatment step is further included, and the post-treatment includes extracting and layering the reactants and drying them.

[0040] Preferably, the extractant used in the extraction is ethyl acetate, and the extraction is performed at least once; preferably three times.

[0041] Preferably, the drying is drying the organic phase obtained after extraction.

[0042] In some embodiments, in the preparation method, step S4 utilizes the intermediate compound of formula 3 to react with trifluoroacetic acid to obtain 2-(5-bromopyridin-3-yl)quinuclidine.

[0043] Preferably, the solvent for the reaction in step S4 is at least one of dichloroethane, dichloromethane, toluene and tetrahydrofuran.

[0044] Preferably, the molar ratio of the intermediate compound of formula 3 to trifluoroacetic acid in step S4 is 1:1.5-3; more preferably 1:2.

[0045] In some embodiments, after the reaction in step S4, a post-treatment step is further included, and the post-treatment includes one or more steps of extracting and stratifying the reactants, drying, and recrystallizing.

[0046] Preferably, the extractant used in the extraction is ethyl acetate, and the extraction is performed at least once.

[0047] Preferably, the drying is drying the organic phase obtained after extraction.

[0048] Preferably, the recrystallization is performed by adding dichloromethane to the dried crude product for recrystallization, and the added amount of dichloromethane is 1-5 times the weight of the crude product, and more preferably 2 times.

[0049] In a second aspect, the present invention provides an intermediate compound, which is any one of the following structural formulas:

[0050]

[0051] The present invention has the following beneficial effects:

[0052] The preparation method of the invention has fewer reaction steps, and the reaction conditions are easy to control. The prepared 2-(5-bromopyridin-3-yl)quinuclidine has high purity (99%) and a yield of up to 90%, and is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0053] The present invention is described below through specific embodiments to make the technical solution of the present invention easier to understand and grasp, but the present invention is not limited thereto, and the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments.

[0054] The endpoints and any value of the scope disclosed in this article are not limited to the accurate scope or value, and these scopes or values ​​should be understood to include values ​​close to these scopes or values. For numerical ranges, between the endpoint values ​​of each scope, between the endpoint values ​​of each scope and a separate point value, and between separate point values, one or more new numerical ranges can be combined with each other, and these numerical ranges should be considered as specifically disclosed in this article. Unless the context clearly indicates otherwise, the singular form "one", "a kind of" and "described" as used herein include singular and plural indicators. The numerical range described by the endpoint is included in all numerical values ​​and fractions within the corresponding range, as well as the described endpoint.

[0055] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention. The experimental methods described in the following embodiments are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0056] The implementation of the sterilization process of the present invention and the technical effects achieved are described in detail below using Gentiana as an example.

[0057] Example 1 Synthesis of intermediate compound of formula 1

[0058] Dissolve 1-tert-butyloxycarbonyl-4-piperidinylacetic acid (10.0 g, 41.1 mmol) in DMF (75 mL), cool to 0°C, then add dimethylhydroxylamine hydrochloride (4.21 g, 43.2 mmol) and N,N-dimethylethylamine (21.5 ml, 123 mmol) in sequence. Keep the internal temperature at 0°C, slowly add T3P / EtOAc (34.0 g, 53.4 mmol) solution to the above reaction solution, stir at 0°C for 2.5 h, and stop the reaction when the raw material disappears after HPLC monitoring. Pour the reaction solution into 300 mL of water and extract three times with 50 mL of ethyl acetate. Wash the organic phase with 40 mL (20% oxalic acid aqueous solution) once, and then wash once with (40 mL) saturated sodium bicarbonate solution. Finally, wash once with saturated brine (40 mL). The organic phase was collected, dried by adding anhydrous sodium sulfate, and concentrated to obtain ethyl acetate to obtain a colorless oil, which was the intermediate compound of formula 1 (9.16 g, yield 78%, purity 99%).

[0059] LCMS(ESI)m / z calcd for C14H26N2O4:286.Found:287(M+1) +. NMR (400MHz, CDCl3) δ4.07 (d, J = 13.2Hz, 2H), 3.67 (s, 3H), 3.18 (s, 3H), 2.73 (t, J = 12.9Hz, 2H), 2 .35(d,J=6.4Hz,2H), 1.93-2.10(m,1H), 1.71(d,J=12.8Hz,2H), 1.45(s,9H), 1.08-1.21(m,2H).

[0060] Example 2 Synthesis of intermediate compound of formula 2

[0061] Dissolve 3,5-dibromopyridine (7.48 g, 31.6 mmol) in tetrahydrofuran (50 mL), cool to -20 ° C, and add isopropylmagnesium chloride tetrahydrofuran solution (2M, 15.8 mL, 31.6 mmol) dropwise while maintaining the internal temperature at -15 ° C to 20 ° C. The reaction mixture is stirred at this temperature for 30 min. Then add the intermediate compound of formula 1 (9.16 g, 31.6 mmol) dissolved in tetrahydrofuran (25 mL) to the above reaction solution, and heat to 10 ° C for two hours. HPLC monitoring shows that the raw material disappears, and a saturated aqueous solution of ammonium chloride is added.

[0062] (100 mL) was quenched. Ethyl acetate (50 mL) was added and extracted three times. The organic phase was washed once with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was slurried with twice the amount of ethyl acetate to obtain a light yellow solid, which was the intermediate compound of formula 2 (10.39 g, yield 85%, purity 98%).

[0063] LCMS(ESI)m / z calcd for C17H23BrN2O3:382.Found:383(M+1) + . NMR (400MHz, CDCl3) δ9.14 (d, J = 1.8 Hz, 1H), 8.89 (d, J = 2.2 Hz, 1H), 8.32 (t, J = 2.0 Hz, 1H), δ 4.17 (d, J = 13.4 Hz, 2H), 2.8 8(t,J=12.5Hz,2H), 2.45(d,J=6.6Hz,2H), 1.96-2.13(m,1H), 1.67(d,J=12.4Hz,2H), 1.45-1.48(m,2H), 1.40(s,9H).

[0064] Example 3 Synthesis of intermediate compound of formula 3

[0065] The intermediate compound of formula 2 (10.39 g, 27.1 mmol) was dissolved in methanol (55 mL) and cooled to 0 ° C. Sodium borohydride (2.05 g, 54.2 mmol) was added in batches, and then the reaction solution was stirred at 0 ° C for 0.5 h. The raw material disappeared after HPLC monitoring, and acetic acid was slowly added to the reaction solution until pH 5-6, and the solvent was concentrated. Water (50 mL) was added to the residue, and ethyl acetate (20 mL) was added and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained light yellow solid crude product was the intermediate compound of formula 3 (9.92 g, yield 95%, purity 98%).

[0066] LCMS(ESI)m / z calcd for C17H25BrN2O3:384.Found:385(M+1) + . NMR (400MHz, CDCl3): δ8.79 (d, J = 2.1Hz 1H), 8.55 (d J = 1.9Hz 1H), 7.98 (t, J = 2.0Hz 1H), 4.90-4.80(m,1H), 3.60(d,J=5.96Hz,1H), 2.75(t,J=12.1Hz,2H), 2.35(d,J=6.3Hz,2H), 1.82-1.97(m,1H), 1.59(d,J=12.1Hz,2H), 1.42-1.47(m,2H), 1.28-1.42(m,2H), 1.22(s,9H).

[0067] Example 4 Synthesis of 2-(5-bromopyridin-3-yl)quinuclidine

[0068] The intermediate compound of formula 3 (9.92g, 25.8mmol) was dissolved in dichloroethane (40mL), cooled to 0°C, trifluoroacetic acid (5.89g, 51.7mmol) was slowly added, and the internal temperature was kept at 0-5°C and stirred for 1h. Then heated to reflux and stirred for 5h. After the disappearance of the raw materials and the intermediates monitored by HPLC, the reaction solution was concentrated. The residue was redissolved in 50mL of water, saturated sodium bicarbonate solution was added, the pH value was adjusted to 8-9, and ethyl acetate (20mL) was added to the aqueous phase and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized with 2 times the amount of dichloromethane to obtain an off-white solid (6.18g, yield 90%, purity 99%), which was 2-(5-bromopyridin-3-yl)quinuclidine.

[0069] LCMS(ESI)m / z calcd for C12H15BrN2:266.Found:267(M+1) +. 1H NMR (400MHz, CD3OD) δ8.65(d,J=1.8Hz,1H), 8.47(d,J=1.8Hz,1H), 8.12(d,J=1.8Hz,1H), 3.88-3.94(t,J=6 .8Hz,1H), 3.66-3.77(m,1H), 3.02-3.18(m,1H), 2.60-2.70(m,2H), 2.00-2.19,(m,3H), 1.54-1.75(m,4H).

[0070] Comparative Example 1 Synthesis of 2-(5-bromopyridin-3-yl)quinuclidine

[0071] The difference between this comparative example and Example 4 is that concentrated hydrochloric acid is used instead of trifluoroacetic acid, specifically:

[0072] The intermediate compound of formula 3 (9.92g, 25.8mmol) was dissolved in dichloroethane (40mL), cooled to 0°C, and concentrated hydrochloric acid (4.3mL, 51.6mmol) was slowly added, and the internal temperature was kept at 0-5°C and stirred for 1h. Then heated to reflux and stirred for 5h. After the disappearance of the raw materials and the intermediates monitored by HPLC, the reaction solution was concentrated. The residue was redissolved in 50mL of water, saturated sodium bicarbonate solution was added, the pH value was adjusted to 8-9, and ethyl acetate (20mL) was added to the aqueous phase and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized with 2 times the amount of dichloromethane to obtain an off-white solid (3.65g, yield 53%, purity 98%), which was 2-(5-bromopyridin-3-yl)quinuclidine.

[0073] Comparative Example 2 Synthesis of 2-(5-bromopyridin-3-yl)quinuclidine

[0074] The difference between this comparative example and Example 4 is that glacial acetic acid is used instead of trifluoroacetic acid, specifically:

[0075] The intermediate compound of formula 3 (9.92g, 25.8mmol) was dissolved in dichloroethane (40mL), cooled to 0°C, and glacial acetic acid (3.09g, 51.6mmol) was slowly added, and the internal temperature was kept at 0-5°C and stirred for 1h. Then heated to reflux and stirred for 5h. After the disappearance of the raw materials and the intermediates monitored by HPLC, the reaction solution was concentrated. The residue was redissolved in 50mL of water, saturated sodium bicarbonate solution was added, the pH value was adjusted to 8-9, and ethyl acetate (20mL) was added to the aqueous phase and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized with 2 times the amount of dichloromethane to obtain an off-white solid (0.56g, yield 8%, purity 96%), which was 2-(5-bromopyridin-3-yl)quinuclidine.

[0076] Comparative Example 3 Synthesis of 2-(5-bromopyridin-3-yl)quinuclidine

[0077] The difference between this comparative example and Example 4 is that hydrobromic acid is used instead of trifluoroacetic acid, specifically:

[0078] The intermediate compound of formula 3 (9.92g, 25.8mmol) was dissolved in dichloroethane (40mL), cooled to 0°C, and hydrobromic acid (6.14g, 51.6mmol) was slowly added, and the internal temperature was kept at 0-5°C and stirred for 1h. Then heated to reflux and stirred for 5h. After the disappearance of the raw materials and the intermediates monitored by HPLC, the reaction solution was concentrated. The residue was redissolved in 50mL of water, saturated sodium bicarbonate solution was added, the pH value was adjusted to 8-9, and ethyl acetate (20mL) was added to the aqueous phase and extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized with 2 times the amount of dichloromethane to obtain an off-white solid (4.04g, yield 59%, purity 98%), which was 2-(5-bromopyridin-3-yl)quinuclidine.

[0079] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 2-(5-bromopyridin-3-yl)quinuclidine, It is characterized in that The compound of formula 4 is prepared by using 1-tert-butyloxycarbonyl-4-piperidinylacetic acid as a raw material through the following synthetic route, namely 2-(5-bromopyridin-3-yl)quinuclidine; Step S1: 1-tert-butyloxycarbonyl-4-piperidinylacetic acid is reacted with dimethylhydroxylamine hydrochloride to obtain an intermediate compound of formula 1; Step S2: using 3,5-dibromopyridine to react with the intermediate compound of formula 1 to obtain the intermediate compound of formula 2; Step S3: using the intermediate compound of formula 2 to react to obtain the intermediate compound of formula 3; Step S4: The intermediate compound of formula 3 is reacted with trifluoroacetic acid to obtain 2-(5-bromopyridin-3-yl)quinuclidine.

2. The preparation method according to claim 1, It is characterized in that The solvent for the reaction in step S1 is at least one of DMF, N,N-dimethylethylamine, DCM and THF; The molar ratio of 1-tert-butyloxycarbonyl-4-piperidinylacetic acid to dimethylhydroxylamine hydrochloride in step S1 is 1:0.9-1.2; In step S1, a condensing agent is added to the reaction, and the condensing agent is at least one of T3P, BOP-Cl, and PyBOP.

3. The preparation method according to claim 2, It is characterized in that The molar ratio of 1-tert-butyloxycarbonyl-4-piperidineacetic acid to dimethylhydroxylamine hydrochloride in step S1 is 1:1.

05.

4. The preparation method according to claim 2, It is characterized in that The molar amount of the condensing agent added in step S1 is 1-1.5 times that of 1-tert-butyloxycarbonyl-4-piperidinylacetic acid.

5. The preparation method according to claim 4, It is characterized in that The molar amount of the condensing agent added in step S1 is 1.3 times that of 1-tert-butyloxycarbonyl-4-piperidinylacetic acid.

6. The preparation method according to claim 1, It is characterized in that The solvent for the reaction in step S2 is at least one of tetrahydrofuran, 2-methyltetrahydrofuran and toluene; The molar ratio of 3,5-dibromopyridine to the intermediate compound of formula 1 in step S2 is 1:0.9-1.2; In step S2, a catalyst is further added to the reaction, wherein the catalyst is at least one of isopropylmagnesium chloride, n-butyllithium and magnesium chips.

7. The preparation method according to claim 6, It is characterized in that The molar ratio of 3,5-dibromopyridine to the intermediate compound of formula 1 in step S2 is 1:

1.

8. The preparation method according to claim 6, It is characterized in that The added molar amount of the catalyst in step S2 is 0.9-1.2 times that of 3,5-dibromopyridine.

9. The preparation method according to claim 8, It is characterized in that The added molar amount of the catalyst in step S2 is 1 times that of 3,5-dibromopyridine.

10. The preparation method according to claim 1, It is characterized in that The solvent for the reaction in step S3 is at least one of methanol, ethanol, tetrahydrofuran and N,N-dimethylformamide.

11. The preparation method according to claim 1, It is characterized in that In step S3, a catalyst is further added to the reaction, and the catalyst is at least one of sodium borohydride, lithium borohydride and borane.

12. The preparation method according to claim 11, It is characterized in that The added molar amount of the catalyst in step S3 is 1.5-3 times of the intermediate compound of formula 2.

13. The preparation method according to claim 12, It is characterized in that The added molar amount of the catalyst in step S3 is twice that of the intermediate compound of formula 2.

14. The preparation method according to claim 1, It is characterized in that The solvent for the reaction in step S4 is at least one of dichloroethane, dichloromethane, toluene and tetrahydrofuran.

15. The preparation method according to claim 1, It is characterized in that In step S4, the molar ratio of the intermediate compound of formula 3 to trifluoroacetic acid is 1:1.5-3.

16. The preparation method according to claim 15, It is characterized in that The molar ratio of the intermediate compound of formula 3 to trifluoroacetic acid in step S4 is 1:2.

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