CN114773352A - Process for preparing substituted nicotinamides - Google Patents
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Abstract
The present application relates to a process for the preparation of substituted nicotinamides 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] triazolo [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, in particular neuropathic pain (WO), and N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [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 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 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 steps, high production efficiency, mild conditions, simple post-treatment, high yield and the like. The method comprises the following steps:
step 1): starting with 1, 4-dichlorophthalazine of formula (I), 5- (methoxymethyl) isoxazole-3-carbonyl hydrazide of formula (II) and 6- (hydroxymethyl) nicotinic acid methyl ester of formula (IV), in a protic or aprotic solvent in the presence of a base to give 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 10-150 ℃, preferably 30-90 ℃, more preferably 40-80 ℃, and most preferably 50-60 ℃;
preferably, in the step 1), the reaction time is 1 to 72 hours, and preferably 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) and 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), and then substituting the intermediate 3- (6-chloro- [1,2,4] triazolo [3,4-a ] phthalazin-3-yl) -5- (methoxymethyl) isoxazole of formula (III) with 6- (hydroxymethyl) nicotinic acid methyl ester of formula (IV) to obtain 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [ 1) of formula (V), 2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl nicotinate;
synthetic route to
Step 2): saponification of methyl 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methylnicotinate of formula (V) 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 10-90 ℃, preferably 30-60 ℃, and more preferably 50-60 ℃;
preferably, in the step 2), the reaction time is 1-10 hours, and 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] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide of formula (1);
preferably, in the step 3), the reaction temperature is 10-80 ℃, preferably 20-60 ℃, and more preferably 30-50 ℃;
preferably, in the step 3), the reaction time is 1-10 hours, and 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 the group consisting of 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-dicarbonimide) -bis (dimethylamino) carbonium tetrafluoroborate (TNTU), benzotriazol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate (PyBOP) and 7- Azabenzotriazol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate (PyAOP), Dicyclohexylcarbodiimide (DCC), Diisopropylcarbodiimide (DIC) and 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), O- (7-azabenzotriazol-1-yl) -bis (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 of 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, 2.00 kg of 1, 4-dichlorophthalazine I and 1.81 kg 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 the system to below 40 deg.C, adding 31.73kg acetonitrile, 1.77kg 6- (hydroxymethyl) methyl nicotinate IV, stirring for 15-30 min, adding 8.53 kg potassium phosphate, heating 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 3.85 kg 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) delta 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 Hz, 1H) 8.59 (d, J =7.83 Hz, 1H) 9.10-9.13 (M, 1H) LCM: [ M + H ] LCM]+＝447。
Step 2:
water was added to the reaction vessel, and 3.82 kg of 6- (((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] z-ox-y-l) 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] isoxazole-3-yl) - [1,2,4] of]Triazolo [3,4-a ]]Phthalazin-6-yl) oxy) methylnicotinic acid VI in 85.9% yield. 1H NMR(400 MHz, CHLOROFORM-d) δppm 3.39 (s, 3 H) 4.71 (s, 2 H) 5.81 (s, 2 H) 7.15 (s, 1 H) 7.87 (d, J=8.00 Hz, 1 H) 7.98 – 8.05 (m, 1 H) 8.10 –8.18 (m, 1 H) 8.33 (dd, J=7.83, 1.96 Hz, 1 H) 8.40 (d, J=7.83 Hz, 1 H) 8.60 (d, J=7.83 Hz, 1 H)9.09 - 9.13 (m, 1 H) 13.46(s,1H) LCMS:[M+H]+＝433。
And step 3:
DMF and 3.12 kg of 6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] methyl) ethyl acetate are added to the reaction kettle]Triazolo [3,4-a]Phthalazin-6-yl) oxy) methylnicotinic acid VI and 4.10 kg HBTU, 1.28 kg isopropylamine is added dropwise with stirring, the temperature is kept at 30 ℃, stirring is continued for 1 hour after the dropwise addition is finished, water is added after the reaction is finished, and the filter cake is collected by filtration. The filter cake was oven dried to give 3.27 kg of a white solid, N-isopropyl-6- (((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] z-ole) - [1]Triazole [3,4-a ]]Phthalazin-6-yl) oxy) methyl) nicotinamide (1) in 85.8% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (d, J =6.85 Hz, 6H) 3.52 (s,3H) 4.30 (dq, J =13.57, 6.56 Hz, 1H) 4.69 (s, 2H) 5.78 (s, 2H) 6.17 (d, J =6.85 Hz, 1H) 7.03 (s, 1H) 7.79-7.86 (M, 2H) 7.96 (t, J =7.34 Hz, 1H) 8.15 (dd, J =7.83, 1.96 Hz, 1H) 8.31 (d, J =7.83 Hz, 1H) 8.66 (d, J =7.83 Hz, 1H) 8.91-9.02 (M, 1H), LC-MS: [ M + H ]/(ES +) [ M + H + ], 1H + ]]+=474。
The synthesis route (II) is as follows:
comparative example 1
Step 1: at room temperature, adding 80 mL of 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, stirring and heating to reflux (80 ℃) for reacting for 2 hours, cooling the system to below 40 ℃, separating out a solid, filtering, and drying to obtain 5.9 g of a light yellow solid product (III), wherein the yield is 93.7%.
And 2, step: adding 32 mL of acetonitrile into a reaction kettle at room temperature, adding 1.58 g of the product (III) in the last step and 0.84 g of methyl 6- (hydroxymethyl) nicotinate IV, stirring for 15-30 minutes, adding 4.04 g of potassium phosphate, heating to 45-55 ℃, stirring for 20-24 hours, adding water, stirring, filtering, and drying a filter cake in an oven at 50-60 ℃ 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, thus being 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 disclosed by the invention has the advantages of simple 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] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide.
Claims (13)
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): starting from 1, 4-dichlorophthalazine of formula (I), 5- (methoxymethyl) isoxazol-3-carbonyl hydrazide of formula (II) and methyl 6- (hydroxymethyl) nicotinate of formula (IV) in a protic or aprotic solvent in the presence of a base, to give methyl 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methylnicotinate of formula (V);
step 2): saponification of methyl 6- ((((3- (5- (methoxymethyl) isoxazol-3-yl) - [1,2,4] triazolo [3,4-a ] phthalazin-6-yl) oxy) methylnicotinate of formula (V) 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);
and 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] triazolo [3,4-a ] phthalazin-6-yl) oxy) methyl) nicotinamide of formula (1).
2. The process according to claim 1, characterized in that in steps 1), 2) and 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.
3. The method according to claim 1, wherein in step 1), the base is an inorganic base or an organic base.
4. The process according to claim 3, characterized in that in step 1) the inorganic base is 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.
5. The method of claim 3, wherein in step 1), the inorganic base is selected from the group consisting of 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 a combination thereof.
6. The method according to claim 3, wherein in step 1), the organic base is a nitrogen-containing organic base compound.
7. The process according to claim 3, wherein in step 1), the organic base is triethylamine or pyridine.
8. The method of claim 1, wherein in step 1), the reaction temperature is 10 to 150 ℃.
9. The method according to claim 1, wherein the reaction temperature in step 2) is 10 to 90 ℃.
10. The process of claim 1, wherein in step 2) the inorganic base is 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.
11. The method of claim 1, wherein in step 2) the inorganic base is selected from the group consisting of 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.
12. The method of claim 1, wherein in step 3), the reaction temperature is 10 to 80 ℃.
13. The method according to claim 1, wherein in step 3), the condensing agent is selected from the group consisting of carbenium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbenium hexafluorophosphate, O- (5-chlorobenzotriazol-1-yl) -bis (dimethylamino) carbenium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbenium tetrafluoroborate, O- (N-succinimidyl) -bis (dimethylamino) carbenium tetrafluoroborate, O- (N-endo-5-norbornene-2, 3-dicarbonimide) -bis (dimethylamino) carbenium tetrafluoroborate, benzotriazol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate and 7-azabenzotriazo Oxazol-1-yloxy-tris (tetrahydropyrrolyl) phosphonium hexafluorophosphate, dicyclohexylcarbodiimide, diisopropylcarbodiimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino), or combinations thereof.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286636A (en) * | 2022-10-08 | 2022-11-04 | 上海赛默罗生物科技有限公司 | Nicotinamide crystal form and preparation method and application thereof |
| CN116008443A (en) * | 2023-03-28 | 2023-04-25 | 上海赛默罗生物科技有限公司 | Method for detecting related substances in alpha 5-GABAA receptor modulator medicines |
| CN116046958A (en) * | 2023-03-28 | 2023-05-02 | 上海赛默罗生物科技有限公司 | Method for detecting related substances in phthalazine isoxazoles |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998050385A1 (en) * | 1997-05-08 | 1998-11-12 | Merck Sharp & Dohme Limited | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
| GB2352631A (en) * | 1999-05-20 | 2001-02-07 | Merck Sharp & Dohme | Inverse agonist of GABA-A alpha-5 receptor subtype & spheron disruption inhibitor combination for treating neurodegenerative conditions eg Alzheimer's disease |
| US20120283248A1 (en) * | 2009-08-25 | 2012-11-08 | Centre National De La Recherche Scientifique - Cnrs | Composition and method for treating cognitive impairments in down syndrom subjects |
| CN110256440A (en) * | 2018-03-12 | 2019-09-20 | 上海赛默罗生物科技有限公司 | Phthalazines isoxazole alkoxyl derivatives, preparation method, pharmaceutical composition and purposes |
| WO2021121294A1 (en) * | 2019-12-16 | 2021-06-24 | 上海赛默罗生物科技有限公司 | Triazolopyridazine derivative, preparation method therefor, pharmaceutical composition thereof, and use thereof |
-
2022
- 2022-06-20 CN CN202210694131.9A patent/CN114773352B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998050385A1 (en) * | 1997-05-08 | 1998-11-12 | Merck Sharp & Dohme Limited | SUBSTITUTED 1,2,4-TRIAZOLO[3,4-a]PHTHALAZINE DERIVATIVES AS GABA ALPHA 5 LIGANDS |
| GB2352631A (en) * | 1999-05-20 | 2001-02-07 | Merck Sharp & Dohme | Inverse agonist of GABA-A alpha-5 receptor subtype & spheron disruption inhibitor combination for treating neurodegenerative conditions eg Alzheimer's disease |
| US20120283248A1 (en) * | 2009-08-25 | 2012-11-08 | Centre National De La Recherche Scientifique - Cnrs | Composition and method for treating cognitive impairments in down syndrom subjects |
| CN110256440A (en) * | 2018-03-12 | 2019-09-20 | 上海赛默罗生物科技有限公司 | Phthalazines isoxazole alkoxyl derivatives, preparation method, pharmaceutical composition and purposes |
| WO2021121294A1 (en) * | 2019-12-16 | 2021-06-24 | 上海赛默罗生物科技有限公司 | Triazolopyridazine derivative, preparation method therefor, pharmaceutical composition thereof, and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| 薛永强 等: "《现代有机合成方法与技术》", 31 May 2003, 化学工业出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286636A (en) * | 2022-10-08 | 2022-11-04 | 上海赛默罗生物科技有限公司 | Nicotinamide crystal form and preparation method and application thereof |
| CN116008443A (en) * | 2023-03-28 | 2023-04-25 | 上海赛默罗生物科技有限公司 | Method for detecting related substances in alpha 5-GABAA receptor modulator medicines |
| CN116046958A (en) * | 2023-03-28 | 2023-05-02 | 上海赛默罗生物科技有限公司 | Method for detecting related substances in phthalazine isoxazoles |
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Denomination of invention: Method for preparing substituted nicotinamide Effective date of registration: 20230814 Granted publication date: 20230317 Pledgee: China Minsheng Banking Corp Shanghai branch Pledgor: SHANGHAI SIMR BIOTECHNOLOGY Co.,Ltd.|Shanghai Semerode Biotechnology Co.,Ltd.|RUDONG SIMR BIOTECH Co.,Ltd. Registration number: Y2023310000463 |