A method for the reductive amination synthesis of tetracaine
By using methyl para-aminobenzoate and butyraldehyde as raw materials, combined with borane complex and organic strong base-catalyzed transesterification reaction, tetracaine was synthesized under catalyst-free conditions, solving the problem of catalyst dependence in existing technologies and achieving efficient and mild synthesis results.
Patent Information
- Application Number
- CN202310936752.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-28
- Publication Date
- 2025-12-02
- Estimated Expiration
- 2043-07-28
AI Technical Summary
Existing methods for synthesizing tetracaine rely on catalysts and have limitations. There is a need to develop efficient synthesis methods that do not require catalysts.
Using methyl para-aminobenzoate and butyraldehyde as raw materials, and borane complexes as hydrogen transfer reagents, tetracaine is synthesized by reductive amination under catalyst-free conditions, including an organic strong base-catalyzed transesterification reaction.
This study achieved the synthesis of tetracaine with high yield, mild reaction conditions, and short reaction time, providing an efficient catalyst-free synthesis scheme.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis methodology, including the synthesis of fine chemicals and pharmaceutical intermediates, and specifically relates to a method for the highly selective aldehyde reduction amination synthesis of tertiary and secondary amines under catalyst-free conditions. Technical Background
[0002] Tetracaine is an ester-based local anesthetic that can penetrate mucous membranes for epidural block, subarachnoid block, nerve conduction block, and mucosal surface anesthesia. [Zhang Bimei, Xu Jianchun, Jiang Hong. Transdermal permeation of tetracaine hydrochloride gel [J]. Chinese Journal of Hospital Pharmacy, 2002, 22(6):344-345.] Currently, the main methods for synthesizing tetracaine are metal-catalyzed CN cross-coupling and noble metal-catalyzed high-pressure hydrogenation-reduction amination. [Byun E, Hong B, De Castro KA, et al. One-PotReductive Mono-N-alkylation of Aniline and Nitroarene Derivatives Using Aldehydes [J]. J Org Chem, 2007, 72(25):9815-9817.] These two methods are highly dependent on catalysts and have certain limitations. Therefore, developing a method for the efficient and high-yield synthesis of tetracaine under catalyst-free conditions is of great significance. Summary of the Invention
[0003] This invention uses methyl para-aminobenzoate and butyraldehyde as raw materials, and a borane complex as a hydrogen transfer reagent, to synthesize the medical anesthetic tetracaine via reductive amination. This method has advantages such as no catalyst required, high yield, mild reaction conditions, and short reaction time. Therefore, the method provided by this invention offers an effective approach for the future synthesis of tetracaine.
[0004] Specific steps:
[0005] Methyl p-aminobenzoate (1) and butyraldehyde (2) were reduced-amined with a borane complex (3) as a hydrogen transfer reagent to synthesize methyl 4-(butano)benzoate (4); under the catalysis of an organic strong base (6), compound (4) and 2-(dimethylamino)ethanol (5) were transesterified to generate tetracaine (7).
[0006]
[0007] When synthesizing (4) from (1), (2) and (3), the borane complex (3) is selected from dimethylamine borane complex, tert-butylamine borane complex, ammonia borane complex, triethylamine borane complex or oxazol borane complex.
[0008] When (4) is synthesized from (1), (2) and (3), the molar ratio of (1) and (2) is 1:1 to 1:10, and the molar ratio of (1) and (3) is 1:0.5 to 1:5.
[0009] When synthesizing (4) from (1), (2) and (3), the reaction solvent is selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, butyraldehyde or no solvent, the reaction temperature is 0℃~100℃, and the reaction time is 0.5h~24h.
[0010] Among them: when synthesizing (7) by catalyzing (4) and (5) with organic strong base (6), the organic strong base (6) is selected from sodium methoxide, potassium methoxide, sodium ethoxide or sodium tert-butoxide, and the amount of organic strong base (6) is 1 mol% to 100 mol%.
[0011] Among them, when (7) is synthesized from (4) and (5) by catalysis of organic strong base (6), the molar ratio of (4) and (5) is 1:1 to 1:20.
[0012] The process involves: first, evaporating the solvent to dryness after the reaction, then purifying and separating the components by column chromatography; for column chromatography, 200-300 mesh silica gel or basic alumina can be used as the stationary phase, and a mixture of petroleum ether and ethyl acetate is generally chosen as the eluent. Attached Figure Description
[0013] Figure 1 The 1H NMR and 1C NMR spectra of methyl 4-(butanoamino)benzoate (4) prepared in Example 1;
[0014] Figure 2 The proton and carbon NMR spectra of tetracaine (7) prepared in Example 2; Detailed Implementation
[0015] The technical solution of the present invention will be further described and illustrated below with reference to specific embodiments, but this does not limit the present invention. Simple substitutions or improvements made to the present invention by those skilled in the art are all within the scope of the technical solutions protected by the present invention.
[0016] Example 1: Synthesis of methyl 4-(butanoamino)benzoate (4)
[0017] A stir bar was added to a 10 mL Schlenk tube, and methyl 4-aminobenzoate (1) (1.0 mmol, 151.2 mg, 1 equiv.) and dimethylamine borane complex (3) (2 mmol, 117.8 mg, 2 equiv.) were added under an argon atmosphere. The tube was then cooled to 0 °C in an ice bath, stirred thoroughly, and butyraldehyde (2) (6 mmol, 432.6 mg, 6 equiv.) was slowly added dropwise, with strict control of the dropping rate. During the dropwise addition, there was a violent exothermic reaction and the generation of a colorless gas. When the reaction became very vigorous, the addition of butyraldehyde was stopped, and the addition was resumed only after the reaction subsided. After the addition was complete, the temperature was raised to 70 °C, and the tube was sealed for 24 h of reaction. After the reaction, the product was purified by column chromatography (PE / EA 6:1) to obtain the target product 4-(methoxyformyl)-N-butylaniline (4) (white solid, 159.6 mg, 77% yield).
[0018] The proton and carbon NMR spectra of product methyl 4-(butanoamino)benzoate (4) are as follows: Figure 1 As shown: 1 HNMR(400MHz,Chloroform-d)δ8.04–7.67(m,2H),6.64–6.41(m,2H),4.07(brs,1H),3.84(s,3H), 3.16(t,J=7.1Hz,2H), 1.61(p,J=7.2Hz,2H), 1.44(dt,J=14.9,7.4Hz,2H), 0.96(t,J=7.3Hz,3H). 13 C NMR (151MHz, Chloroform-d) δ167.50,152.27,131.66,118.06,111.40,51.61,43.16,31.51,20.33,13.97.
[0019] Example 2: Synthesis of tetracaine (7)
[0020] A stir bar was added to a 10 mL Schlenk tube, followed by the sequential addition of 4-(methoxyformyl)-N-butylaniline (4) (0.5 mmol, 103.6 mg, 1 equiv.), sodium methoxide (6) (0.1 mmol, 5.4 mg, 0.18 equiv.), and 1.5 mL of 2-dimethylaminoethanol (5). The mixture was heated to 130 °C and reacted for six hours. After the reaction was complete, 8 mL of water was added, followed by extraction with dichloromethane (10 mL × 3). The collected organic phase was then washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and dichloromethane was removed by rotary evaporation under reduced pressure to obtain a yellow oily liquid. Finally, column chromatography (DCM / MeOH 20:1) was used to purify the target product, tetracaine (7) (white solid, 112.3 mg, 85% yield).
[0021] The proton and carbon NMR spectra of the product tetracaine (7) are as follows: Figure 2 As shown: 1 H NMR(400MHz,Chloroform-d)δ7.90–7.80(m,2H),6.56–6.49(m,2H),4.36(t,J=5.9Hz,2H),4.10(brs,1H),3.15(q,J =7.1Hz,2H),2.69(t,J=5.9Hz,2H),2.33(s,6H),1.61(p,J=7.2Hz,2H),1.43(p,J=7.3Hz,2H),0.95(t,J=7.3Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ166.93,152.30,131.75,118.08,111.37,62.46,58.10,45.99,43.16,31.50,20.32,13.96.
Claims
1. A method for synthesizing tetracaine by reductive amination, characterized in that, The method includes the following synthesis process: Methyl p-aminobenzoate and butyraldehyde were reduced-amination with a borane complex as a hydrogen transfer reagent to synthesize methyl 4-(butano)benzoate; under the catalysis of a strong organic base, the methyl 4-(butano)benzoate and 2-(dimethylamino)ethanol underwent transesterification to generate tetracaine. The borane complex is selected from dimethylamine borane complex; When methyl 4-(butano)benzoate is synthesized from methyl p-aminobenzoate, butyraldehyde and borane complex, the molar ratio of methyl p-aminobenzoate to butyraldehyde is 1:6, and the molar ratio of methyl p-aminobenzoate to borane complex is 1:
2. In the synthesis of methyl 4-(butanoamino)benzoate from methyl p-aminobenzoate, butyraldehyde, and borane complex, no solvent was added, the reaction temperature was 70°C, and the reaction time was 24 h. After the reaction, the product was purified by column chromatography, and the eluent used for the column chromatography purification was a mixture of petroleum ether and ethyl acetate in a volume ratio of 6:
1.
2. The method according to claim 1, characterized in that, The organic strong base is selected from sodium methoxide, and the amount of the organic strong base fed is 1 mol% to 100 mol%.
3. The method according to claim 1, characterized in that, The molar ratio of methyl 4-(butanoamino)benzoate to 2-(dimethylamino)ethanol is 1:1 to 1:20.