Synthetic method of trimebutine intermediate and trimebutine maleate
Through the simplified four-step reaction route, the trimebutin intermediate and trimebutin maleate were successfully synthesized, solving the problems of complex synthesis routes, low yields and insufficient purity in the prior art, and achieving an efficient and economical production process.
Patent Information
- Application Number
- CN202411695362.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-25
- Publication Date
- 2025-03-11
AI Technical Summary
The synthesis route of the existing triceptine intermediate is complex, and it uses a low boiling point or toxic solvent. It is complicated to operate, has low overall yield and low product purity, so it is not suitable for industrial production.
Using ethyl phenylacetate as the raw material, the key intermediate 2-(dimethylamino)-2-phenylbutanol is synthesized through four-step reactions, namely esterification, halogenation, nucleophilic substitution and reduction reactions, and then trimebutin maleate is synthesized through transesterification reaction.
The synthesis route is simplified, the yield and purity of the intermediates are improved, the protection and deprotection operations are reduced, the cost is reduced, and the atomic economy is improved.
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Figure CN119591509A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis and relates to a synthesis method of a trimebutine intermediate and trimebutine maleate. Background Art
[0002] Trimebutine Maleate, molecular formula: C 26 H 33 NO9, chemical name (±)-3,4,5-trimethoxybenzoic acid (2-dimethylamino-2-phenyl) butyl ester maleate, structural formula is as formula 8, it can inhibit cell membrane K+ channels, thereby increasing the excitability of smooth muscle; it can also block cell membrane Ca 2+ channels, inhibiting Ca 2+ It can inhibit the excitability of smooth muscles by influx, thereby inhibiting the excitability of smooth muscles; when the gastrointestinal motility is in a low-motility state, it can act on adrenergic receptors to inhibit the release of adrenaline, thereby increasing the motility rhythm; it can also act on opioid agonists of peripheral δ, μ and κ receptors, which can regulate the gastrointestinal motility rhythm, thereby achieving a two-way regulation of gastrointestinal motility. It is clinically suitable for symptoms such as loss of appetite, nausea, vomiting, belching, abdominal distension, abdominal borborygmus, abdominal pain, diarrhea, constipation, etc. caused by gastrointestinal motility disorders and diseases such as irritable bowel syndrome.
[0003]
[0004] In the preparation process of trimebutine maleate raw material, 2-(dimethylamino)-2-phenylbutanol (as shown in Formula 5) is the key intermediate for preparing trimebutine.
[0005]
[0006] Regarding the preparation of the key intermediate of trimebutine, Zhao Yanping reported that DL-phenylglycine was used as the starting material, and the key intermediate 2-(dimethylamino)-2-phenylbutanol was synthesized through six steps of esterification, condensation, alkylation, hydrolysis, reduction, and reductive amination. The synthesis route is as follows ; This route uses low-boiling-point or toxic solvents (ether, dichloromethane), has cumbersome operations, a total yield of less than 25%, and a low product purity, which is not suitable for industrialization.
[0007] CN118930443A discloses a method for synthesizing trimebutine intermediate and trimebutine maleate, which uses DL-phenylglycine as a starting material, synthesizes trimebutine key intermediate 2-(dimethylamino)-2-phenylbutanol through six steps of esterification reaction, condensation reaction, alkylation reaction, hydrolysis reaction, reduction reaction, and reductive amination; synthesizes trimebutine through transesterification reaction; and finally, trimebutine and maleic acid are salified to obtain trimebutine maleate. The synthesis steps are long, the atomic utilization rate is low, and the cost is high. Summary of the invention The invention provides a method for synthesizing a trimebutine intermediate and trimebutine maleate. The synthetic route is short and the yield is high.
[0008] In order to achieve the above objectives, the present invention adopts the following technical scheme: a method for synthesizing a trimebutine intermediate, characterized in that the intermediate is 2-(dimethylamino)-2-phenylbutanol, the specific structural formula is shown in Formula 5, and the synthesis route is shown as follows: ; The specific synthesis includes the following steps: 1) Using ethyl phenylacetate of formula 1 as a raw material, reacting with ethyl bromide in the presence of potassium tert-butoxide and a solvent system to obtain ethyl 2-ethyl phenylacetate of formula 2; 2) ethyl 2-ethylphenylacetate reacts with NBS in azobisisobutyronitrile and chloroform system to obtain ethyl 2-bromo-2-phenylbutyrate, a compound of formula 3; 3) 2-bromo-2-phenylbutyric acid ethyl ester reacts with dimethylamine to obtain a compound of formula 4, 2-(dimethylamino)-2-phenylbutyric acid ethyl ester; 4) 2-(dimethylamino)-2-phenylbutyric acid ethyl ester is subjected to reduction reaction with sodium borohydride to obtain the compound of formula 5, 2-(dimethylamino)-2-phenylbutanol.
[0009] In the optional scheme, step (1) satisfies at least one of the following conditions: the molar ratio of ethyl phenylacetate to ethyl bromide and potassium tert-butoxide is 1:1-1.3:1.2-1.6; the solvent is DMF; the reaction is carried out at 20-30°C for 3-6 hours; after the reaction, water and ethyl acetate are added for extraction, and the organic phase is washed, dried and concentrated to obtain ethyl 2-ethyl phenylacetate.
[0010] Optionally, step 2) satisfies at least one of the following conditions: the molar ratio of ethyl 2-ethyl-phenylacetate to chloroform and azobisisobutyronitrile is 1:2-1.5:0.8-1.1; the reaction temperature is 50-70°C, and the reaction time is 4-8h; after the reaction is completed, the reaction is concentrated under reduced pressure to obtain ethyl 2-bromo-2-phenylbutyrate.
[0011] Optionally, in step 3), after adding THF and K2CO3 to dimethylamine, a THF solution of ethyl 2-bromo-2-phenylbutyrate is added dropwise, and the mixture is reacted at room temperature for 4 to 8 hours, and then filtered under reduced pressure and subjected to column chromatography to obtain ethyl 2-(dimethylamino)-2-phenylbutyrate.
[0012] Optionally, the molar ratio of ethyl 2-bromo-2-phenylbutyrate to dimethylamine is 1:5-6.
[0013] Optionally, step 4) satisfies at least one of the following conditions: ethyl 2-(dimethylamino)-2-phenylbutyrate is dissolved in methanol, sodium borohydride is added, and anhydrous calcium chloride is added in batches under an ice-water bath. After the addition, the temperature is raised to room temperature for reaction, and then water is added to dry the methanol, and the extract is extracted with ethyl acetate. The extract is washed, dried, and then dried to obtain 2-(dimethylamino)-2-phenylbutanol.
[0014] Optionally, the molar ratio of ethyl 2-(dimethylamino)-2-phenylbutyrate to sodium borohydride is 1:2~2.05.
[0015] The present invention also relates to a method for synthesizing trimebutine maleate using the trimebutine intermediate obtained by the synthesis method, characterized in that the synthesis path is as follows: ; Specifically, a compound of formula 5, 2-(dimethylamino)-2-phenylbutanol, and a compound of formula 6, 3,4,5-trimethoxybenzoic acid methyl ester, are used with toluene as a solvent, and a methanol solution of sodium methoxide is added dropwise, and the temperature is increased to carry out an ester exchange reaction to obtain a compound of formula 7, trimebutine; trimebutine and maleic acid are reacted in an isopropanol system at an increased temperature to form a salt to obtain a compound of formula 8, trimebutine maleate.
[0016] Optionally, in the transesterification reaction, the molar ratio of 2-(dimethylamino)-2-phenylbutanol, methyl 3,4,5-trimethoxybenzoate, and sodium methoxide is 1:2~2.1:0.2~0.5; the reaction temperature is 100~120°C, and the reaction time is 2~5 h; the obtained trimebutine is recrystallized and purified in a solvent of one or more of petroleum ether, n-hexane, water, ethyl acetate, methanol, and ethanol.
[0017] Optionally, in the salt-forming reaction, the molar ratio of trimebutine to maleic acid is 1:1.1~1.5, the reaction temperature is 55~70°C, and the reaction time is 2~4 h.
[0018] The present invention has the following beneficial effects: The present invention uses ethyl phenylacetate as a raw material and only needs four steps of reaction to obtain the key intermediate 2-(dimethylamino)-2-phenylbutanol. The route is shortened by 2 steps compared with the previously reported route, and the four-step reaction yield reaches 42.9%. At the same time, the operations of protection and deprotection are reduced, the atom economy is high, and the cost is greatly reduced.
[0019] The present invention uses a tetrahydrofuran solution of dimethylamine when synthesizing compound 4 from compound 3, and can obtain compound 4 with a medium yield, thereby avoiding the use of a methylating agent. The new synthesis method provided by the present invention has simple and readily available reagents, mild reaction conditions, and convenient operation. BRIEF DESCRIPTION OF THE DRAWINGS
[0020] Figure 1 The product obtained in Example 1 1 H NMR spectrum.
[0021] Figure 2 The product obtained in Example 1 13 C NMR spectrum.
[0022] Figure 3 The product obtained in Example 2 1 H NMR spectrum.
[0023] Figure 4 The product obtained in Example 2 13 C NMR spectrum.
[0024] Figure 5 The product obtained in Example 4 1 H NMR spectrum.
[0025] Figure 6 The product obtained in Example 4 13 C NMR spectrum. DETAILED DESCRIPTION
[0026] The present invention provides a method for synthesizing a trimebutine intermediate and trimebutine maleate, and the specific reaction routes thereof are as follows: .
[0027] The reaction steps involved are as follows: 1) Using ethyl phenylacetate of formula 1 as a raw material, reacting with ethyl bromide in the presence of potassium tert-butoxide and a solvent system to obtain ethyl 2-ethyl phenylacetate of formula 2; 2) ethyl 2-ethylphenylacetate reacts with NBS in azobisisobutyronitrile and chloroform system to obtain ethyl 2-bromo-2-phenylbutyrate, a compound of formula 3; 3) 2-bromo-2-phenylbutyric acid ethyl ester reacts with dimethylamine to obtain a compound of formula 4, 2-(dimethylamino)-2-phenylbutyric acid ethyl ester; 4) 2-(dimethylamino)-2-phenylbutyric acid ethyl ester is subjected to reduction reaction with sodium borohydride to obtain the compound of formula 5, 2-(dimethylamino)-2-phenylbutanol.
[0028] 5) 2-(Dimethylamino)-2-phenylbutanol reacts with methyl 3,4,5-trimethoxybenzoate of the compound of formula 6 in the presence of a solvent and a base to obtain trimebutine of the compound of formula 7.
[0029] 6) Trimebutine and maleic acid react in a solvent to obtain a compound of formula 8, namely trimebutine maleate.
[0030] The embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention.
[0031] Example 1, Synthesis of Compound 2: Under nitrogen atmosphere, potassium tert-butoxide (504 mg, 4.5 mmol) and DMF (5 mL) were added to the reaction bottle, stirred at 0°C, ethyl phenylacetate (492 mg, 3 mmol) was slowly added dropwise, stirred for 5-10 min, ethyl bromide (392.4 mg, 3.6 mmol) was slowly added dropwise, and the temperature was slowly raised to 25°C for 4 h. After the reaction was completed, water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 mL * 3). The organic phase was washed with saturated NH4Cl and NaCl (5 mL * 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a light yellow viscous liquid, namely ethyl 2-ethyl-phenylacetate 553.7 mg, with a yield of 96%. Its NMR spectrum is shown in Figure 1 and Figure 2 , 1 H NMR (400 MHz, CDCl3) δ 7.35-7.26 (m, 5H), 4.22 – 4.07 (m, 2H), 3.46 (t, J = 7.2 Hz, 1H), 2.16-2.09 (m, 1H), 1.86-1.78 (m, 1H), 1.23 (t, J =7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 174.1, 139.3,128.5, 127.9, 127.1, 60.6, 53.6, 26.8, 14.2, 12.2. Example 2, synthesis of compound 3: Add ethyl 2-ethyl-phenylacetate (384 mg, 2 mmol), chloroform (4 mL), NBS (540 mg, 2.4 mmol), and azobisisobutyronitrile (0.33 mg, 0.002 mol) to the reaction bottle, heat to 60 °C and react for 5 h. After the reaction is completed, filter and concentrate under reduced pressure to obtain a light yellow viscous liquid, namely 488.1 mg of ethyl 2-bromo-2-phenylbutyrate, with a yield of 90%. Its NMR spectrum is shown in Figure 3 and Figure 4 , 1 H NMR (400 MHz, CDCl3) δ 7.50-7.48 (m, 2H), 7.39-7.28 (m, 3H), 4.29(q, J = 7.2 Hz, 2H), 2.59-2.42 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.2Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 170.5, 139.9, 128.3, 128.1, 127.0, 70.3,62.5, 35.6, 13.9, 10.6. Example 3, Synthesis of Compound 4: Add a tetrahydrofuran solution of dimethylamine (10 mmol, 30%), THF (10 mL), and K2CO3 (552 mg, 4 mmol) to the reaction flask. Stir at room temperature, add a THF solution of ethyl 2-bromo-2-phenylbutyrate (542 mg, 2 mmol, 2 mL) dropwise, react for 4 h to stop the reaction, filter, concentrate under reduced pressure, and obtain 291.8 mg of ethyl 2-(dimethylamino)-2-phenylbutyrate by column chromatography. The yield is 62%.
[0032] Example 4, Synthesis of Compound 5: Dissolve ethyl 2-(dimethylamino)-2-phenylbutyrate (705.9 mg, 3 mmol) in methanol (5 mL) under ice bath conditions, add sodium borohydride (226.8 mg, 6 mmol), add anhydrous calcium chloride (166.5 mg, 1.5 mmol) in batches under ice water bath, and heat to room temperature for 5h (TLC tracking) after the addition is completed. Slowly add 4 mL of water, spin dry to remove part of the methanol, extract with ethyl acetate (4 mL * 3), wash with saturated NaCl solution (4 mL x 3), dry with anhydrous sodium sulfate, spin dry to obtain 463.9 mg of yellow liquid product with a yield of 80%. Its NMR spectrum is shown in Figure 5 and Figure 6 . 1 H NMR (400 MHz, CDCl3) δ 7.38-7.34 (m, 2H), 7.30-7.25 (m, 3H), 4.03 (d, J = 10.4 Hz, 1H), 3.81 (d, J = 10.4 Hz,1H), 3.26 (s, 1H), 2.26 (s, 6H), 2.08-1.88 (m, 2H), 0.74 (t, J = 7.2 Hz, 3H); 13 CNMR (100 MHz, CDCl3) δ 139.5, 128.1, 127.1, 126.9, 65.4, 61.1, 39.1, 26.1, 9.2. Example 5 Synthesis of compound 7: To a 1000 mL reaction bottle, add alcohol compound 5 (20.0 g, 103.5 mmol) and compound 6 (46.8 g, 207.0 mmol) in sequence, add 350 mL of toluene, stir at room temperature to dissolve, add dropwise a methanol solution of sodium methoxide (7.5 g, 41.4 mmol, 30%), and after the addition, heat to 110 °C and install a water separator to react for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to remove toluene, 300 mL of ethyl acetate was added, and the mixture was washed with 5% HCl solution (80 mL×4). The aqueous phases were combined and washed with toluene (50 mL×2). The pH of the aqueous phase was adjusted to 10 with 10% NaOH solution, and the mixture was extracted with ethyl acetate (150 mL×3). The organic phases were combined and washed with saturated NH4Cl solution (150 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a light yellow viscous liquid. The mixture was recrystallized with an appropriate amount of n-hexane, filtered, and dried under vacuum at 50°C overnight to obtain 29.8 g of a white solid powder with a yield of 74.3%.
[0033] Synthesis of compound 8: Add trimebutine (20 g, 51.6 mmol), maleic acid (7.2 g, 61.9 mmol), and 60 mL of isopropanol to the reaction flask, heat to 60°C, and stir to react for 3 h. After the reaction is completed, cool down and crystallize, filter, wash with a small amount of isopropanol, and vacuum dry at 50°C overnight to obtain 21.2 g of trimebutine maleate as a white solid powder with a yield of 81.6%.
[0034] Example 6 Based on Example 3, the synthesis of compound 4 was carried out, except that a dimethylamine aqueous solution was used, and ultimately the target compound 4 could not be obtained.
[0035] The above embodiments describe the preferred implementation of the present invention, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.
Claims
1. A method for synthesizing a trimebutine intermediate, characterized in that: The intermediate is 2-(dimethylamino)-2-phenylbutanol, and its specific structural formula is shown in Formula 5. The synthetic route is shown below: ； The specific synthesis includes the following steps: 1) Using ethyl phenylacetate of formula 1 as a raw material, reacting with ethyl bromide in the presence of potassium tert-butoxide and a solvent system to obtain ethyl 2-ethyl phenylacetate of formula 2; 2) ethyl 2-ethylphenylacetate reacts with NBS in azobisisobutyronitrile and chloroform system to obtain ethyl 2-bromo-2-phenylbutyrate, a compound of formula 3; 3) 2-bromo-2-phenylbutyric acid ethyl ester reacts with dimethylamine to obtain a compound of formula 4, 2-(dimethylamino)-2-phenylbutyric acid ethyl ester; 4) 2-(dimethylamino)-2-phenylbutyric acid ethyl ester is subjected to reduction reaction with sodium borohydride to obtain the compound of formula 5, 2-(dimethylamino)-2-phenylbutanol.
2. The synthesis method according to claim 1, characterized in that Step (1) satisfies at least one of the following conditions: the molar ratio of ethyl phenylacetate to ethyl bromide and potassium tert-butoxide is 1:1-1.3:1.2-1.6; the solvent is DMF; the reaction is carried out at 20-30°C for 3-6 hours; after the reaction, water and ethyl acetate are added for extraction, and the organic phase is washed, dried and concentrated to obtain ethyl 2-ethyl phenylacetate.
3. The synthesis method according to claim 1, characterized in that Step 2) satisfies at least one of the following conditions: the molar ratio of ethyl 2-ethyl-phenylacetate to chloroform and azobisisobutyronitrile is 1:2-1.5:0.8-1.1; the reaction temperature is 50-70°C, and the reaction time is 4-8h; after the reaction is completed, the reaction is concentrated under reduced pressure to obtain ethyl 2-bromo-2-phenylbutyrate.
4. The synthesis method according to claim 1, characterized in that In step 3), after adding THF and K2CO3 to dimethylamine, a THF solution of ethyl 2-bromo-2-phenylbutyrate was added dropwise, and the mixture was reacted at room temperature for 4-8 hours, and then filtered under reduced pressure and subjected to column chromatography to obtain ethyl 2-(dimethylamino)-2-phenylbutyrate.
5. The synthesis method according to claim 4, characterized in that The molar ratio of ethyl 2-bromo-2-phenylbutyrate to dimethylamine is 1:5-6.
6. The synthesis method according to claim 1, characterized in that Step 4) at least one of the following conditions is met: ethyl 2-(dimethylamino)-2-phenylbutyrate is dissolved in methanol, sodium borohydride is added, and anhydrous calcium chloride is added in batches under an ice-water bath. After the addition is complete, the temperature is raised to room temperature for reaction, and water is added to dry the methanol, and the extract is extracted with ethyl acetate. The extract is washed, dried, and then dried to obtain 2-(dimethylamino)-2-phenylbutanol.
7. The synthesis method according to claim 1, characterized in that: The molar ratio of ethyl 2-(dimethylamino)-2-phenylbutyrate to sodium borohydride is 1:2~2.
05.
8. A method for synthesizing trimebutine maleate using a trimebutine intermediate obtained by the synthesis method according to any one of claims 1 to 7, characterized in that: The synthesis path is as follows: ； Specifically, a compound of formula 5, 2-(dimethylamino)-2-phenylbutanol, and a compound of formula 6, 3,4,5-trimethoxybenzoic acid methyl ester, are used with toluene as a solvent, and a methanol solution of sodium methoxide is added dropwise, and the temperature is increased to carry out an ester exchange reaction to obtain a compound of formula 7, trimebutine; trimebutine and maleic acid are reacted in an isopropanol system at an increased temperature to form a salt to obtain a compound of formula 8, trimebutine maleate.
9. The synthesis method according to claim 8, characterized in that: In the transesterification reaction, the molar ratio of 2-(dimethylamino)-2-phenylbutanol, methyl 3,4,5-trimethoxybenzoate and sodium methoxide is 1:2~2.1:0.2~0.5; the reaction temperature is 100~120℃, and the reaction time is 2~5h; the obtained trimebutine is recrystallized and purified in a solvent of one or more of petroleum ether, n-hexane, water, ethyl acetate, methanol and ethanol.
10. The synthesis method according to claim 8, characterized in that: In the salt-forming reaction, the molar ratio of trimebutine to maleic acid is 1:1.1~1.5, the reaction temperature is 55~70°C, and the reaction time is 2~4 h.