WO2026077480A1 - Procédé de préparation de 6-bromonicotine - Google Patents

Procédé de préparation de 6-bromonicotine

Info

Publication number
WO2026077480A1
WO2026077480A1 PCT/CN2025/138915 CN2025138915W WO2026077480A1 WO 2026077480 A1 WO2026077480 A1 WO 2026077480A1 CN 2025138915 W CN2025138915 W CN 2025138915W WO 2026077480 A1 WO2026077480 A1 WO 2026077480A1
Authority
WO
WIPO (PCT)
Prior art keywords
reaction
synthesizing
bromonicotinic acid
acid according
organic solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/138915
Other languages
English (en)
Chinese (zh)
Inventor
陈科
姚浩宇
姚继德
康彧
程志杰
王勇翔
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Hangsen Star Technology Co Ltd
Original Assignee
Shenzhen Hangsen Star Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenzhen Hangsen Star Technology Co Ltd filed Critical Shenzhen Hangsen Star Technology Co Ltd
Publication of WO2026077480A1 publication Critical patent/WO2026077480A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 6-bromonicotine Compared with conventional nicotine, 6-bromonicotine not only binds effectively to acetylcholine receptors but also has lower toxicity. In addition, it exhibits extremely high selectivity, accurately targeting receptors associated with neurological diseases. More importantly, 6-bromonicotine can also be chemically converted into other compounds with potential therapeutic effects, thus providing a broader range of possibilities for the treatment of neurological diseases. Therefore, based on its favorable pharmacological properties and potential therapeutic effects, 6-bromonicotinic acid has significant research value and clinical prospects in the treatment of neurological diseases. It may become a key component in the development of novel treatment regimens, providing patients with these diseases with more effective and safer treatment options.
  • the third method involves first converting nicotine oxide into a quaternary ammonium salt, and then using hydrogen bromide gas for nucleophilic substitution to synthesize 6-bromonicotinic acid.
  • this route requires the use of highly corrosive hydrogen bromide gas and a low-temperature environment of -25°C, making it unsuitable for large-scale production.
  • this invention discloses a method for synthesizing 6-bromonicotinic acid using 6-hydroxymaxamine (CAS: 70969-38-9) as a raw material to prepare high-purity, active 6-bromonicotinic acid.
  • This route first converts 6-hydroxymaxamine into compound I through a reduction reaction, followed by aminomethylation and bromination reactions to finally obtain the target product, 6-bromonicotinic acid.
  • the final product has a defined structure and bromine substitution site selectivity, exhibits high yield, is simple to operate, and can be used for industrial production.
  • 6-bromonicotinic acid specifically includes the following steps:
  • This synthesis method is simple to operate, safe and reliable, with high yield, low cost, and product purity of up to 99.0% or more.
  • the organic solvent used in step S1 is at least one of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, and water; preferably, the organic solvent used in the reaction is methanol.
  • the additive used in step S1 may be at least one of formic acid, acetic acid, propionic acid, calcium chloride, lithium chloride, and magnesium chloride; preferably, the additive used in the reaction is acetic acid.
  • the reducing agent used in step S1 may be at least one of sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triethylborohydride, and sodium triacetoxyborohydride; preferably, the reducing agent used in the reaction is sodium borohydride.
  • the temperature of the low-temperature reaction in step S1 is -40 to 10°C; preferably, the temperature of the low-temperature reaction is 0°C.
  • the molar ratio of 6-hydroxymasmin, additives and reducing agents added in step S1 is 1.0:0.1-30:1.0-2.5.
  • the heating temperature in step S2 is 60-90°C.
  • step S2 the addition ratio of compound I, formic acid, and formaldehyde aqueous solution is 1.0g:0.5-0.8g:1.0-10.0g.
  • the organic solvent used in step S3 may be at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, chlorobenzene, dichloromethane, and ethyl acetate; preferably, the organic solvent used in the reaction is acetonitrile.
  • the brominating reagent used in step S3 is selected from at least one of phosphorus tribromooxyphosphine, N-bromosuccinimide, dibromotriphenylphosphine, phosphorus tribromide, and phosphorus pentabromide; preferably, the brominating reagent used in the reaction is phosphorus tribromooxyphosphine.
  • the heating temperature in step S3 is 70–100°C; preferably, the heating temperature is 80°C.
  • the molar ratio of compound II to brominating reagent added in step S3 is 1:1-30.
  • the extraction solvent used in step S3 is dichloromethane and ethyl acetate; preferably, the organic solvent used in the reaction is dichloromethane.
  • the method for synthesizing 6-bromonicotinic acid disclosed in this application is simple to operate, safe and reliable, with high yield and low cost; using 6-hydroxymasmin as a starting material, the purity of the 6-bromonicotinic acid obtained can reach over 99.0%.
  • Figure 1 is a schematic diagram of the synthesis route of the preparation method of this application.
  • Figure 2 is the LC-MS spectrum of the final product obtained in Example 1 of this application.
  • Figure 3 is the 1H NMR spectrum of the final product obtained in Example 1 of this application.
  • Examples 1-6 provide a method for synthesizing 6-bromonicotinic acid, and the following description uses Example 1 as an example.
  • Step S1 In a 1L round-bottom flask, add 32.4g (0.2mol, 1.0eq) of 6-hydroxymaxamine, 3.0g of acetic acid (0.02mol, 0.1eq), and 400mL of anhydrous methanol to obtain a mixed solution. Then cool to 0°C, add 13.8g (0.22mol, 1.1eq) of sodium cyanoborohydride, and stir for 4 hours. After the reaction is completed by TLC monitoring, the mixed solution is restored to room temperature, the reaction is quenched with dilute hydrochloric acid (1.0M solution), extracted with 400mL of dichloromethane, and the organic phase is distilled under reduced pressure to remove the solvent, yielding compound I.
  • dilute hydrochloric acid 1.0M solution
  • Step S2 Compound I obtained in step S1 was mixed with 40% aqueous formaldehyde solution (300.0 g) and formic acid (20.0 g), and then heated to 80°C for 4 hours. After the reaction was completed by TLC monitoring, the mixture was returned to room temperature, and the pH was adjusted to 8 by adding saturated sodium carbonate solution. The mixture was then extracted with 400 mL of dichloromethane, and the solvent was removed by vacuum distillation of the organic phase to obtain compound II.
  • Step S3 Compound II obtained in Step S2 was added to a 500 mL round-bottom flask, followed by 200 mL of acetonitrile and phosphorus tribromooxyphosphate (0.6 mol, 3.0 eq) to obtain a mixed solution.
  • the mixed solution was heated to 80 °C and stirred for 2 hours. After the reaction was complete as monitored by TLC, the mixed solution was returned to room temperature, the solvent was removed by vacuum distillation, the pH was adjusted to 8 with saturated sodium carbonate solution, and then extracted twice with 300 mL of dichloromethane. The organic phases were combined, and the solvent was removed by vacuum distillation to obtain crude 6-bromonicotinic acid.
  • the crude 6-bromonicotinic acid was then distilled under vacuum at 120 °C and 0.1 kPa, and the middle fraction was collected to obtain 21.6 g of high-purity 6-bromonicotinic acid.
  • the overall yield of the three steps was 32%, with a purity of 99.0%.
  • Example 2 The 6-bromonicotinic acid obtained in Example 1 was detected by LC-MS and NMR. The results are shown in Figures 2 and 3. The specific detection data are as follows:
  • Example 1 The difference between Examples 2-4 and Example 1 lies in the type and amount of brominating reagent used in step S3. The specific results are shown in Table 1.
  • Example 5 The difference between Examples 5 and 6 and Example 1 is that the types of organic solvents used in step S3 are different. The specific results are shown in Table 4.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne le domaine de la synthèse chimique organique, et concerne en particulier un procédé de synthèse de 6-bromonicotine. Le procédé de synthèse de 6-bromonicotine utilise la 6-hydroxymyosmine (CAS : 70969-38-9) en tant que matière première, qui subit successivement une réaction de réduction, une réaction de méthylation d'amine et une réaction de bromation, pour finalement obtenir le produit cible 6-bromonicotine. La pureté de produit de la 6-bromonicotine obtenue au moyen de la voie de synthèse peut atteindre 99,0 % ou plus. Le présent procédé de synthèse suit un processus simple et présente un rendement élevé, et est approprié pour une production à l'échelle industrielle.
PCT/CN2025/138915 2024-10-11 2025-12-01 Procédé de préparation de 6-bromonicotine Pending WO2026077480A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202411416202.4 2024-10-11
CN202411416202.4A CN119285607A (zh) 2024-10-11 2024-10-11 一种6-溴烟碱的制备方法

Publications (1)

Publication Number Publication Date
WO2026077480A1 true WO2026077480A1 (fr) 2026-04-16

Family

ID=94168140

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/138915 Pending WO2026077480A1 (fr) 2024-10-11 2025-12-01 Procédé de préparation de 6-bromonicotine

Country Status (2)

Country Link
CN (1) CN119285607A (fr)
WO (1) WO2026077480A1 (fr)

Also Published As

Publication number Publication date
CN119285607A (zh) 2025-01-10

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