CN114773352B - Process for preparing substituted nicotinamides - Google Patents
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- CN114773352B CN114773352B CN202210694131.9A CN202210694131A CN114773352B CN 114773352 B CN114773352 B CN 114773352B CN 202210694131 A CN202210694131 A CN 202210694131A CN 114773352 B CN114773352 B CN 114773352B
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- methoxymethyl
- isoxazol
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The present application relates to a process for the preparation of substituted nicotinamide of formula (1), comprising the steps of:
Description
Technical Field
The invention relates to a synthesis process of N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazole [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide.
Background
N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide is an antagonist of the α 5-GABAA receptor and is described in chinese patent application CN 2019101857359.
Antagonists of the α 5-GABAA receptor have recently been identified as useful for the treatment of pain, particularly neuropathic pain (WO), and N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazole [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide has been identified as a candidate drug with a structure according to formula (1):
the prior art methods for preparing N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide are low in yield and cumbersome in steps. Accordingly, there is a need in the art for a high yield, simple procedure process for the preparation of N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide of formula (1).
Disclosure of Invention
The invention provides a method for preparing N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide of formula (1), which has the advantages of simple and convenient steps, high production efficiency, mild conditions, simple post-treatment and/or high yield. The method comprises the following steps:
step 1): using 1,4-dichlorophthalazine of formula (I), 5- (methoxymethyl) isoxazole-3-carbonyl hydrazide of formula (II) and methyl 6- (hydroxymethyl) nicotinate of formula (IV) as starting materials, and reacting in the presence of a base in a protic or aprotic solvent to obtain methyl 6- (((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl nicotinate of formula (V);
preferably, in the step 1), the reaction temperature is from 10 to 150 ℃, preferably from 30 to 90 ℃, more preferably from 40 to 80 ℃, and most preferably from 50 to 60 ℃;
preferably, in step 1), the reaction time is from 1 to 72 hours, preferably from 3 to 48 hours;
preferably, in step 1), the protic or aprotic solvent is: ethyl acetate, methanol, ethanol, N-propanol, isopropanol, acetone, acetonitrile, acetic acid, diethyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or a combination thereof.
Preferably, in step 1), the base is an inorganic base or an organic base. Preferably, the base is an inorganic base, preferably selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal acetates, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal phosphates, alkaline earth metal acetates, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, ammonium phosphate, ammonium acetate or combinations thereof; more preferably, the inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, barium hydroxide, calcium hydroxide, ammonium carbonate, ammonium bicarbonate, ammonium phosphate, ammonium acetate, or combinations thereof; or the organic base is a nitrogen-containing organic base compound, such as triethylamine and pyridine.
Specifically, step 1 is a two-step reaction carried out in a one-pot process. Reacting 1,4-dichlorophthalazine of formula (I), 5- (methoxymethyl) isoxazole-3-carbonyl hydrazide of formula (II) in the presence of a base in a protic or aprotic solvent to form intermediate 3- (6-chloro- [1,2,4] triazolo [3,4-a ] phthalazin-3-yl) -5- (methoxymethyl) isoxazole of formula (III), which is then substituted with 6- (hydroxymethyl) nicotinic acid methyl ester of formula (IV) to form 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [ 24 zxft 3924 ] triazolo [ 3534-a ] phthalazin-6-yl) oxymethyl ester of formula (V);
synthetic route to
Step 2): 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methylnicotinic acid methyl ester of formula (V) is saponified in a protic or aprotic solvent in the presence of an inorganic base to give 6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methylnicotinic acid of formula (VI);
preferably, in the step 2), the reaction temperature is 10 to 90 ℃, preferably 30 to 60 ℃, and more preferably 50 to 60 ℃;
preferably, in step 2), the reaction time is 1 to 10 hours, preferably 3~8 hours;
preferably, in step 2), the protic or aprotic solvent is: ethyl acetate, methanol, ethanol, N-propanol, isopropanol, acetone, acetonitrile, acetic acid, diethyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or a mixture thereof.
Preferably, in step 2), the inorganic base is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, alkali metal acetates, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal phosphates, alkaline earth metal acetates, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, ammonium phosphate, ammonium acetate or combinations thereof; more preferably, the inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, barium hydroxide, calcium hydroxide, ammonium carbonate, ammonium bicarbonate, ammonium phosphate, ammonium acetate, or combinations thereof;
step 3): reacting 6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methylnicotinic acid of formula (VI) with isopropylamine in the presence of a protic or aprotic solvent and a condensing agent to give N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazole [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide of formula (1);
preferably, in the step 3), the reaction temperature is 10 to 80 ℃, preferably 20 to 60 ℃, and more preferably 30 to 50 ℃;
preferably, in step 3), the reaction time is 1 to 10 hours, preferably 3~8 hours;
preferably, in step 3), the protic or aprotic solvent is: ethyl acetate, methanol, ethanol, N-propanol, isopropanol, acetone, acetonitrile, acetic acid, diethyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or a combination thereof.
Preferably, in step 3), the condensing agent is selected from carbonium Hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HBTU), O- (5-chlorobenzotriazol-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HCTU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium tetrafluoroborate (TBTU), O- (N-succinimidyl) -bis (dimethylamino) carbonium tetrafluoroborate (TSTU), O- (N-endo-5-norbornene-2,3-carbodiimide) -bis (dimethylamino) carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy-tris (tetrahydropyrrole) phosphonium hexafluorophosphate (PyBOP) and 7-azabenzotriazol-1-yloxy-tris (tetrahydropyrrole) phosphonium hexafluorophosphate (pypc), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-ethyl-tris (O) -carbodiimide (ci-7-dimethylamino) carbodiimide (ci-1-dimethylamino) or combinations thereof.
Detailed Description
The following definitions, unless otherwise indicated, are provided to illustrate and define the meaning and scope of the various terms used herein to describe the invention.
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.
Any feature disclosed in this specification may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.
It should be understood that the above detailed description of the invention and the following examples are intended only to limit the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art in light of the above teachings are within the scope of the invention. The specific parameters and the like in the above embodiments are also only one example of suitable ranges, that is, suitable ranges can be selected by those skilled in the art through the description herein, and are not limited to the specific values and specific steps in the following embodiments.
Example 1
Step 1:
at room temperature, 31.73kg of acetonitrile is added into a reaction kettle, 2.00kg of 1, 4-dichlorophthalazine I and 1.81kg of 5- (methoxymethyl) isoxazole-3-carbonyl hydrazide II are added under stirring, and the temperature is raised to reflux (80 ℃) under stirring for reaction for 2 hours. Cooling to below 40 deg.C, adding 31.73kg acetonitrile and 1.77kg 6- (hydroxymethyl) nicotinic acid methyl ester IV, stirring for 15-30 min, adding 8.53kg potassium phosphateHeating to 45-55 deg.C, stirring for 20-24 hr, adding water, stirring, filtering, and oven drying the filter cake at 50-60 deg.C to obtain 3.85kg 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4)]Triazolo [3,4-a]Phthalazin-6-yl) oxy) methyl nicotinate V in 85.9% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.39 (s, 3H) 3.89 (s, 3H), 4.71 (s, 2H) 5.81 (s, 2H) 7.15 (s, 1H) 7.89 (d, J =8.00 Hz, 1H) 7.98-8.05 (M, 1H) 8.10-8.18 (M, 1H) 8.35 (dd, J =7.83, 1.96 Hz, 1H) 8.39 (d, J =7.83 zxft 3524, 1 zxft 3754) 8.59, 7.59J =7.83, 4984 zxft 7972, 3 zxft 5272 (M, 1 zxft 5224): [ M + H ]] + ＝447。
Step 2:
water was added to the reaction vessel, and 3.82kg of 6- (((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4) was added with stirring]Triazolo [3,4-a]Daizin-6-yl) oxy) methyl nicotinate V and tetrahydrofuran, dripping lithium hydroxide aqueous solution at 30 ℃, heating to 50 ℃ for reaction for 1-hour, adding water into the reaction liquid after the reaction is finished, filtering, and drying a filter cake in a vacuum oven to obtain 3.18kg of 6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4)]Triazolo [3,4-a]Phthalazin-6-yl) oxy) methylnicotinic acid VI in 85.9% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.39 (s, 3H) 4.71 (s, 2H) 5.81 (s, 2H) 7.15 (s, 1H) 7.87 (d, J =8.00 Hz, 1H) 7.98-8.05 (M, 1H) 8.10-8.18 (M, 1H) 8.33 (dd, J =7.83, 1.96 Hz, 1H) 8.40 (d, J =7.83, hz, 1H) 8.60 (d, J =7.83, hz, 4972 zxft 7945 H.72, 5232 zxft 799 H.72, 5232 zxft 7942H 7942, 1.32, 9, and 5 g.9 H.5 H.32] + ＝433。
And step 3:
DMF and 3.12kg of 6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4) were added to the reaction vessel]Triazolo [3,4-a]Phthalazin-6-yl) oxy) methylnicotinic acid VI and 4.10kg HBTU, 1.28kg isopropylamine was added dropwise with stirring, the temperature was kept at 30 ℃, stirring was continued for 1 hour after the dropwise addition, water was added after the reaction was completed, and the filter cake was collected by filtration. Oven drying the filter cake to obtain 3.27kg white solid N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4)]Triazole [3,4-a]Phthalazin-6-yl) oxy) methyl) nicotinamide (1) in 85.8% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.28 (d, J=6.85 Hz, 6 H) 3.52 (s, 3 H) 4.30 (dq, J=13.57, 6.56 Hz, 1 H) 4.69 (s, 2 H) 5.78 (s, 2 H) 6.17 (d, J=6.85 Hz, 1 H) 7.03 (s, 1 H) 7.79 - 7.86 (m, 2 H) 7.96 (t, J=7.34 Hz, 1 H) 8.15 (dd, J=7.83, 1.96 Hz, 1 H) 8.31 (d, J=7.83 Hz, 1 H) 8.66 (d, J=7.83 Hz, 1 H) 8.91 - 9.02 (m, 1 H),LC-MS:m/z(ES+) [M+H] + =474。
The synthesis route (II) is as follows:
comparative example 1
Step 1: at room temperature, adding 80 mL acetonitrile into a reaction kettle, adding 3.98 g of 1, 4-dichlorophthalazine I and 3.42 g of 5- (methoxymethyl) isoxazole-3-carbonyl hydrazide II under stirring, heating to reflux (80 ℃) to react for 2 hours under stirring, cooling the system to below 40 ℃ to precipitate a solid, filtering, and drying to obtain a light yellow solid product (III) 5.9 g with the yield of 93.7%.
Step 2: at room temperature, 32 mL acetonitrile is added into a reaction kettle, 1.58 g of the product (III) in the previous step, 0.84 g of methyl 6- (hydroxymethyl) nicotinate IV is stirred for 15 to 30 minutes, 4.04 g potassium phosphate is added, the temperature is increased to 45 to 55 ℃, stirring is carried out for 20 to 24 hours, water is added, stirring and filtering are carried out, and a filter cake is placed in an oven to be dried at 50 to 60 ℃ to obtain 2.02 g of methyl 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methylnicotinate V, wherein the yield is 90.5%.
The synthesis route (II) is a two-step reaction to obtain the key compound V, but compared with the synthesis route (I) which is a one-pot method, the synthesis process route has the defects of complicated process operation, long time and lower yield.
The synthetic route I is verified by an amplification process and has strong operability and good process stability. The synthesis scale is more than kilogram level, so the method is more suitable for industrial production. The synthesis scale of the synthesis route (II) is gram-scale, and the synthesis stability is poor.
In conclusion, the method has the advantages of simple and convenient steps, high production efficiency, mild conditions, simple post-treatment and/or high yield and the like, and is suitable for industrial production of N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazole [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide.
Claims (1)
1. A process for the preparation of N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide of formula (1) comprising the steps of:
step 1): at room temperature, adding 31.73kg of acetonitrile into a reaction kettle, adding 2.00kg of 1, 4-dichlorophthalazine I and 1.81kg of 5- (methoxymethyl) isoxazole-3-carbonyl hydrazide II under stirring, and heating to 80 ℃ under stirring for reflux reaction for 2 hours; cooling the system to below 40 ℃, adding 31.73kg of acetonitrile and 1.77kg of 6- (hydroxymethyl) methyl nicotinate IV, stirring for 15-30 minutes, adding 8.53kg of potassium phosphate, heating to 45-55 ℃, stirring for 20-24 hours, adding water, stirring, filtering, putting a filter cake into a 50-60 ℃ oven for drying to obtain 3.85kg of 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] oxazin-6-yl) oxy) methyl nicotinate V, wherein the yield is 85.9%;
step 2): adding water into a reaction kettle, adding 3.82kg of methyl 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl nicotinate V and tetrahydrofuran under stirring, dripping aqueous lithium hydroxide solution at 30 ℃, heating to 50 ℃ for reaction for 1 hour, adding water into the reaction solution after the reaction is finished, filtering, drying a filter cake in a vacuum oven to obtain 3.18kg of 6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl nicotinic acid VI with the yield of 85.9 percent;
step 3): DMF, 3.12kg of 6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methylnicotinic acid VI and 4.10kg of HBTU were added to the reaction vessel, 1.28kg of isopropylamine was added dropwise with stirring, 30 ℃ was maintained, stirring was continued for 1 hour after the completion of the dropwise addition, water was added after the completion of the reaction, the filter cake was filtered and collected, and the filter cake was oven-dried to obtain 3.27kg of N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide (1) as a white solid in a yield of 85.8%.
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