CN113444010B - Preparation method of related substance of safinamide - Google Patents
Preparation method of related substance of safinamide Download PDFInfo
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- CN113444010B CN113444010B CN202010232401.5A CN202010232401A CN113444010B CN 113444010 B CN113444010 B CN 113444010B CN 202010232401 A CN202010232401 A CN 202010232401A CN 113444010 B CN113444010 B CN 113444010B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/001—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by modification in a side chain
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- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/367—Halogenated derivatives polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes
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- C07—ORGANIC CHEMISTRY
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
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- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
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Abstract
The invention relates to a preparation method of a substance related to sand fenamide, which has a synthetic route shown as follows. The raw materials and the reagents are cheap and easy to obtain, the reaction operation is simple and convenient, and the synthesis yield is high; the provided compound of formula 7 has high purity and can be used as an impurity reference substance in a raw material drug or a preparation of the safinamide.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a related substance of sand fenamide.
Background
The safinamide is used as a monoamine oxidase inhibitor and is clinically used for the adjuvant treatment of parkinsonism accompanied by the phenomenon of off-period. The structural formula of the sand fenamide is as follows:
the production of (S) -2- ((3- (3-fluorobenzyl) -4- ((3-fluorobenzyl) oxy) benzyl) amino) propanamide (structure shown in formula 7 below) is often accompanied by the production of the impurity (S) -2 during the synthesis of safinamide. According to the report of patent document CN101896456a, this impurity has extremely high toxicity to enzymes of the cytochrome P450 system.
Disclosure of Invention
The invention aims to provide a method for preparing (S) -2- ((3- (3-fluorobenzyl) -4- ((3-fluorobenzyl) oxy) benzyl) amino) propionamide, so as to provide an impurity reference substance with the purity meeting the requirements and further control the quality of the preparation process of the sandfenamide.
In one aspect, the invention provides a process for the preparation of (S) -2- ((3- (3-fluorobenzyl) -4- ((3-fluorobenzyl) oxy) benzyl) amino) propanamide (compound 7), the route being as follows:
wherein X is Br or I; y is Br, cl or I; the method specifically comprises the following steps:
(1) Performing Friedel-crafts acylation reaction on the compound shown in the formula 1 and the compound 2 to prepare a compound shown in the formula 3;
(2) The compound shown in the formula 3 undergoes a reduction reaction to prepare a compound shown in the formula 4;
(3) The compound shown in the formula 4 and the compound shown in the formula 8 undergo substitution reaction to prepare a compound shown in the formula 5;
(4) Formylation of the compound shown in the formula 5 to prepare a compound 6;
(5) Compound 6 is reacted with L-alanyl amide or a salt thereof to prepare compound 7.
In some embodiments, X is Br.
In some embodiments, Y is Br.
In some embodiments, X is Br and Y is Br.
In some embodiments, the catalyst of step (1) is AlCl 3 、FeCl 3 、ZnCl 2 Or SnCl 4 The method comprises the steps of carrying out a first treatment on the surface of the Preferably AlCl 3 Or ZnCl 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably AlCl 3 . In some embodiments, the reaction solvent of step (1) is dichloromethane, nitromethane, or nitrobenzene; dichloromethane is preferred. In some embodiments, the reaction temperature is from room temperature to reflux temperature; reflux is preferred. In some typical embodiments, step (1) is performed under nitrogen blanket. In some more typical embodiments, the post-treatment of step (1) comprises: spin-drying the reaction solvent, adding water, stirring for crystallization, filtering, pulping the filter cake with ethanol, filtering, and drying.
In some embodiments, the reducing system of step (2) is selected from Et 3 SiH/BF 3 ·OEt 2 、Et 3 SiH/CF 3 COOH、NaBH 4 /CF 3 CO 2 H or LiAlH 4 /AlCl 3 The method comprises the steps of carrying out a first treatment on the surface of the Preferably Et 3 SiH/BF 3 ·OEt 2 、Et 3 SiH/CF 3 COOH or NaBH 4 /CF 3 CO 2 H is formed; more preferably Et 3 SiH/BF 3 ·OEt 2 . In some embodiments, the reaction solvent of step (2) is selected from dichloromethane, acetonitrile or diethyl ether or mixtures thereof; preferably dichloromethane or acetonitrile or a mixed solvent thereof; more preferably a mixed solvent of dichloromethane and acetonitrile; most preferably the volume ratio is 2:1 with acetonitrile. In some embodiments, the reaction temperature is from room temperature to reflux temperature; reflux temperature is preferred. In some typical embodiments, step (2) is performed under a nitrogen blanket.
In some embodiments, step (3) is performed in the presence of an acid-binding agent selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium phosphate, or potassium phosphate; sodium carbonate, potassium carbonate or cesium carbonate is preferred. In some embodiments, the reaction solvent of step (3) is selected from DMF, NMP, DMSO or ethanol; DMF is preferred. In some embodiments, the reaction temperature is from room temperature to 100 ℃; preferably 55 ℃. In some typical embodiments, step (3) is performed in the presence of a catalyst KI.
In some embodiments, the formylation reaction of step (4) is performed under n-BuLi/DMF conditions. In some embodiments, the reaction solvent of step (4) is selected from THF or toluene or a mixed solvent thereof; THF is preferred. In some embodiments, the reaction temperature is from-80 to-50 ℃; preferably-65 to-70 ℃. In some typical embodiments, step (4) is performed under nitrogen blanket.
In some embodiments, compound 6 is reacted with L-alanyl amide hydrochloride in step (5) to produce compound 7.
In some embodiments, step (5) is performed in the presence of a base selected from triethylamine or diisopropylethylamine and a reducing agent selected from sodium borohydride or sodium cyanoborohydride; the preferred base is triethylamine; the preferred reducing agent is sodium borohydride. In some embodiments, the reaction solvent of step (5) is methanol or ethanol; methanol is preferred. In some embodiments, the reaction temperature is from 0 ℃ to reflux; preferably 10 to 15 ℃.
In another aspect, the invention provides a compound of the formula,
wherein X is Br or I; preferably, X is Br.
In another aspect, the invention provides a compound of the formula,
wherein X is Br or I; preferably, X is Br.
In another aspect, the invention provides a compound of the formula,
wherein X is Br or I; preferably, X is Br.
The invention has the beneficial effects that the invention provides the preparation method of the related substance of the safinamide shown in the formula 7, the raw materials and the reagents are cheap and easy to obtain, the reaction operation is simple and convenient, and the synthesis yield is high; the provided compound of formula 7 has high purity and can be used as an impurity reference substance in a raw material drug or a preparation of the safinamide.
Detailed Description
The technical scheme of the present invention will be further described with reference to specific examples, but the present invention is not limited thereto.
The analysis method comprises the following steps:
according to high performance liquid chromatography (China pharmacopoeia 2015 edition, ministry of the four general rules 0512), octadecylsilane chemically bonded silica is used as filler [ Welch Xtime C18 (4.6 mm. Times.250 mm,5 μm) or chromatographic column with equivalent efficacy ]; taking 10mmol/L dipotassium hydrogen phosphate buffer (1.74 g of dipotassium hydrogen phosphate is taken, 1000ml of water is added for dissolution, phosphoric acid is used for adjusting the pH value to 6.8) as a mobile phase A, acetonitrile is used as a mobile phase B, and linear gradient elution is carried out according to the following table; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; the detection wavelength was 210nm.
Example 1
(1) Synthesis of Compound (5-bromo-2-hydroxyphenyl) (3-fluorophenyl) methanone (Compound 3, X=Br)
AlCl is added into the reaction bottle 3 (20 g,81mmol,1.5 equiv) and DCM (60 mL), cooling the ice-water bath to 0-10deg.C, slowly dropwise adding 4-bromoanisole (10 g,54mmol,1.0 equiv), dropwise Bi Jiaoban min; compound 2 (10.7 g,67.5mmol,1.25 equiv) was slowly added dropwise under ice bath conditions, and after the addition, the reaction was refluxed for 6h (TLC monitoring reaction was complete). The reaction was cooled to room temperature, concentrated to remove DCM, and the residue was slowly added with 50mL of ice water under ice-bath conditions, stirred for crystallization for 1h, and suction filtered. Pulping the filter cake with hot ethanol at 50deg.C for 30min, stirring with ice bath for 30min, suction filtering, and collecting 20mL waterWashing and airing. 8.5g of product are obtained as yellow powder with a yield of 53.3%. 1 H-NMRδ:6.99(d，J＝10.0Hz，1H)，7.49-7.61(m,6H),10.45(s,1H).
(2) Synthesis of Compound 4-bromo-2- (3-fluorobenzyl) phenol (Compound 4, X=Br)
The compound produced in the step (1) (8.5 g,28.8mmol,1.0 equiv) and Et were reacted 3 SiH (17.0 mL,103.7mmol,3.6 equiv) was dissolved in a mixed solvent of DCM (50 mL)/acetonitrile (25 mL) and BF was slowly added dropwise 3 ·OEt 2 (6.0 mL,50.0mmol,1.74 equiv), and after the addition, the reaction was refluxed for 6h (TLC monitoring the end of the reaction). The reaction was cooled to room temperature, washed with 100mL of water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue purified by column chromatography (ethyl acetate: n-hexane=1:20), and the acceptable fractions were collected to give 4.0g of 4-bromo-2- (3-fluorobenzyl) phenol as a white solid in a yield of 52.4%. 1 H-NMRδ:3.88(s,1H),6.80(d,J＝5.0Hz,1H),7.27～7.07(m,6H),9.78(s,1H).
(3) Synthesis of Compound 4-bromo-2- (3-fluorobenzyl) -1- (3-fluorobenzyloxy) benzene (Compound 5, X=Br)
DMF (50 mL), 4-bromo-2- (3-fluorobenzyl) phenol (4.0 g,14.3mmol,1.0 equiv) and potassium carbonate (2.2 g,15.7mmol,1.1 equiv) were added sequentially to the flask, and the compound 1-bromomethyl-3-fluorobenzene (2.96 g,15.7mmol,1.1 equiv) was added with stirring at room temperature, and the temperature was raised to 55deg.C for 1.5h, whereupon TLC detection reaction ended. The reaction was cooled to room temperature, washed with 100mL of water, extracted with DCM, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue purified by column chromatography (ethyl acetate: n-hexane=1:20), and the acceptable fractions were collected to give 5.0g of 4-bromo-2- (3-fluorobenzyl) -1- (3-fluorobenzyloxy) benzene as a white solid in a yield of 90.0%. 1 H-NMRδ:3.96(s，1H),5.12(s，1H),7.41～7.36，m，3H),7.30～7.26(m，1H),7.17～7.06(m，3H),7.03～6.97(m，4H).
(4) Synthesis of Compound 3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) benzaldehyde (Compound 6)
Under the protection of nitrogen, the product (5.0 g,12.8mmol,1.0 equiv) obtained in the step (3) and dry THF (60 mL) are added into a reaction bottle, the temperature is reduced to below-65 ℃, n-BuLi tetrahydrofuran solution (1.2 equiv) is slowly added dropwise,after dripping, the reaction is carried out for 1h at a constant temperature. Dry DMF (1.0 ml,1.2 equiv) was slowly added dropwise to the system, the reaction was stirred for 30min, and tlc detection was completed. The reaction was quenched with saturated aqueous ammonium chloride, extracted with DCM, dried over anhydrous sodium sulfate, concentrated by filtration, and the residue purified by column chromatography (ethyl acetate: n-hexane=1:20) to yield 2.5g of compound 6 as a white solid in 62.0% yield. 1 H-NMRδ:4.04(s,1H)，5.26(s,1H),6.97～7.44(m，9H),7.77～7.84(m，2H),9.85(s，1H).
(5) Synthesis of Compound (S) -2- [3- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) benzylamino ] propanamide (Compound 7)
MeOH (20 mL), L-alanyl amide hydrochloride (0.63 g,4.07mmol,1.1 equiv) and triethylamine (0.63 mL,4.07mmol,1.1 equiv) were added to the flask, and after stirring and purging at room temperature, compound 6 (1.25 g,3.7mmol,1.0 equiv) was added and reacted at room temperature for 1h; the temperature was lowered to 10-15℃and sodium borohydride (142 mg,3.7mmol,1.0 equiv) was added, and the reaction was continued at room temperature for 1h. The reaction was quenched by adding 100mL of water, extracted with DCM (60 mL x 3), the combined organic phases dried over anhydrous sodium sulfate, concentrated by filtration, the residue purified by column chromatography (ethyl acetate: n-hexane=1:1), the acceptable fractions were collected, concentrated under reduced pressure to dryness to give compound 7 as a white solid 960mg, yield 63.0%, HPLC purity 98.65%.
MS(ESI)m/z:411.2[M+H] + 。
Claims (49)
1. The preparation method of the compound shown in the formula 7 is characterized in that the synthetic route is as follows:
wherein X is Br or I; y is Br, cl or I; the method specifically comprises the following steps:
(1) Performing Friedel-crafts acylation reaction on the compound shown in the formula 1 and the compound 2 to prepare a compound shown in the formula 3;
(2) The compound shown in the formula 3 undergoes a reduction reaction to prepare a compound shown in the formula 4;
(3) The compound shown in the formula 4 and the compound shown in the formula 8 undergo substitution reaction to prepare a compound shown in the formula 5;
(4) Formylation of the compound shown in the formula 5 to prepare a compound 6;
(5) Compound 6 is reacted with L-alanyl amide or a salt thereof to prepare compound 7.
2. The method of claim 1, wherein X is Br.
3. The method of claim 1, wherein Y is Br.
4. The method of claim 1, wherein X is Br and Y is Br.
5. The process of claim 1 wherein the catalyst used in step (1) is AlCl 3 、FeCl 3 、ZnCl 2 Or SnCl 4 。
6. The process of claim 5, wherein the catalyst used in step (1) is AlCl 3 Or ZnCl 2 。
7. The process of claim 6, wherein the catalyst used in step (1) is AlCl 3 。
8. The process according to claim 1, wherein the reaction solvent in step (1) is methylene chloride, nitromethane or nitrobenzene.
9. The process of claim 8, wherein the reaction solvent of step (1) is methylene chloride.
10. The process according to claim 1, wherein the reaction temperature in the step (1) is room temperature to reflux temperature.
11. The process of claim 10, wherein the reaction temperature in step (1) is reflux temperature.
12. The method according to claim 1, wherein step (1) is performed under nitrogen atmosphere.
13. The method of claim 1, wherein the post-treatment of step (1) comprises: spin-drying the reaction solvent, adding water, stirring for crystallization, filtering, pulping the filter cake with ethanol, filtering, and drying.
14. The process according to claim 1, wherein the reducing system of step (2) is selected from Et 3 SiH/BF 3 ·OEt 2 、Et 3 SiH/CF 3 COOH、NaBH 4 /CF 3 CO 2 H or LiAlH 4 /AlCl 3 。
15. The process of claim 14, wherein the reducing system of step (2) is selected from Et 3 SiH/BF 3 ·OEt 2 、Et 3 SiH/CF 3 COOH or NaBH 4 /CF 3 CO 2 H。
16. The process of claim 15, wherein the reduction system of step (2) is Et 3 SiH/BF 3 ·OEt 2 。
17. The process according to claim 1, wherein the reaction solvent in the step (2) is selected from dichloromethane, acetonitrile or diethyl ether or a mixed solvent thereof.
18. The process according to claim 17, wherein the reaction solvent in step (2) is selected from dichloromethane or acetonitrile or a mixed solvent thereof.
19. The method according to claim 18, wherein the reaction solvent in the step (2) is a mixed solvent of dichloromethane and acetonitrile.
20. The process of claim 19, wherein the reaction solvent in step (2) is present in a volume ratio of 2:1 with acetonitrile.
21. The process according to claim 1, wherein the reaction temperature in the step (2) is room temperature to reflux temperature.
22. The process of claim 21, wherein the reaction temperature of step (2) is reflux temperature.
23. The method according to claim 1, wherein the step (2) is performed under nitrogen atmosphere.
24. The process according to claim 1, wherein step (3) is carried out in the presence of an acid-binding agent selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium phosphate or potassium phosphate.
25. The process according to claim 24, wherein step (3) is carried out in the presence of an acid-binding agent selected from sodium carbonate, potassium carbonate or cesium carbonate.
26. The process according to claim 1, wherein the reaction solvent of step (3) is selected from DMF, NMP, DMSO and ethanol.
27. The method of claim 26, wherein the reaction solvent in step (3) is DMF.
28. The process according to claim 1, wherein the reaction temperature in step (3) is room temperature to 100 ℃.
29. The process of claim 28, wherein the reaction temperature in step (3) is 55 ℃.
30. The process according to claim 1, wherein step (3) is carried out in the presence of a catalyst KI.
31. The process according to claim 1, wherein the formylation reaction of step (4) is carried out under n-BuLi/DMF conditions.
32. The process according to claim 1, wherein the reaction solvent in the step (4) is selected from THF, toluene or a mixed solvent thereof.
33. The process of claim 32, wherein the reaction solvent in step (4) is THF.
34. The process according to claim 1, wherein the reaction temperature in step (4) is-80 to-50 ℃.
35. The process of claim 34, wherein the reaction temperature in step (4) is from-65 ℃ to-70 ℃.
36. The method according to claim 1, wherein step (4) is performed under nitrogen atmosphere.
37. The process of claim 1 wherein compound 6 is reacted with L-alanyl amide hydrochloride in step (5) to produce compound 7.
38. The process according to claim 1, wherein step (5) is carried out in the presence of a base selected from triethylamine or diisopropylethylamine and a reducing agent selected from sodium borohydride or sodium cyanoborohydride.
39. The process of claim 38, wherein the base of step (5) is triethylamine; the reducing agent is sodium borohydride.
40. The method according to claim 1, wherein the reaction solvent in the step (5) is methanol or ethanol.
41. The process of claim 40 wherein the reaction solvent in step (5) is methanol.
42. The process according to claim 1, wherein the reaction temperature in step (5) is from 0℃to reflux.
43. The process of claim 42, wherein the reaction temperature in step (5) is 10 to 15 ℃.
44. A compound of the formula (I) wherein,
wherein X is Br or I.
45. The compound of claim 44, wherein X is Br.
46. A compound of the formula (I) wherein,
wherein X is Br or I.
47. The compound of claim 46, wherein X is Br.
48. A compound of the formula (I) wherein,
wherein X is Br or I.
49. The compound of claim 48, wherein X is Br.
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| CN1636984A (en) * | 1999-09-04 | 2005-07-13 | 葛兰素集团有限公司 | Benzophenones as inhibitors of reverse transcriptase |
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| CN106365966A (en) * | 2015-07-24 | 2017-02-01 | 上海医药集团股份有限公司 | Preparation method of benzyl aryl ether |
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| CN113195502A (en) * | 2018-10-10 | 2021-07-30 | 詹森生物制药有限公司 | Macrocyclic influenza endonuclease inhibitors |
| CN112028754A (en) * | 2020-06-17 | 2020-12-04 | 浙江美诺华药物化学有限公司 | Preparation method of safinamide mesylate intermediate |
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| CN1636984A (en) * | 1999-09-04 | 2005-07-13 | 葛兰素集团有限公司 | Benzophenones as inhibitors of reverse transcriptase |
| WO2002089738A2 (en) * | 2001-05-08 | 2002-11-14 | Yale University | Proteomimetic compounds and methods |
| CN101896456A (en) * | 2007-12-11 | 2010-11-24 | 纽朗制药有限公司 | Process for the production of 2-[4-(3- or 2-fluorobenzyloxy)benzylamino]propanamides with high purity degree |
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