CN111285798A - Synthesis method of (3-cyclopropylpyridine-2-yl) methylamine hydrochloride - Google Patents
Synthesis method of (3-cyclopropylpyridine-2-yl) methylamine hydrochloride Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
Abstract
The invention provides a synthetic method of (3-cyclopropyl pyridine-2-yl) methylamine hydrochloride, belonging to the technical field of synthesis of organic chemical intermediates. The method comprises the following steps: under the protection of nitrogen, 3-bromo-2-cyanopyridine reacts with cyclopropylboronic acid, phosphine ligand, alkali and catalyst, then reacts with hydrogen under the action of the catalyst, reacts with di-tert-butyl dicarbonate and alkali, and finally reacts with an organic solvent of hydrogen chloride to obtain the target product (3-cyclopropylpyridin-2-yl) methylamine hydrochloride. Wherein, the 3-bromo-2-cyanopyridine is prepared by taking 3-bromopyridine as a raw material and performing nitrogen oxidation and cyanation reactions. The invention has reasonable process design, simple experimental operation and easy control.
Description
Technical Field
The invention relates to the technical field of synthesis of organic chemical intermediates, in particular to a method for synthesizing (3-cyclopropyl pyridine-2-yl) methylamine hydrochloride.
Background
Heterocyclic compounds, particularly pyridine heterocyclic compounds, are important compounds in pharmaceutical chemistry, are used as important fine chemical raw materials, and derivatives of the heterocyclic compounds mainly comprise aminopyridine, halogenated pyridine, cyanopyridine and the like, and are mainly applied to the fields of novel pesticides, medicines and the like.
Since the chemical structure of cyclopropyl group is different from that of linear aliphatic hydrocarbon and other multiple aliphatic rings, it is often used in the design of drug molecules, which can enhance the drug effect, metabolic stability, affinity to receptors, etc. of drugs. Therefore, cyclopropyl and methylamino are introduced into the pyridine ring, so that the biological activity of the pyridine compound is improved. Therefore, the synthesis research of the polypeptide has great practical significance.
Disclosure of Invention
The invention aims to provide a method for synthesizing (3-cyclopropyl pyridine-2-yl) methylamine hydrochloride. Mainly solves the technical problem that no literature reports the synthesis method of the compound.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a synthetic method of (3-cyclopropyl pyridine-2-yl) methylamine hydrochloride comprises the following steps:
the synthesis method is realized by the following steps:
(1) dissolving the compound C in an organic solvent, and reacting with cyclopropyl boric acid, a phosphine ligand, alkali and a catalyst under the protection of nitrogen to obtain a compound D;
(2) dissolving the compound D in an organic solvent, and reacting with hydrogen under the action of a catalyst to obtain a compound E;
(3) dissolving the compound E in an organic solvent, and reacting with di-tert-butyl dicarbonate and alkali to obtain a compound F;
(4) and dissolving the compound F in an organic solvent, and reacting with an organic solvent of hydrogen chloride to obtain a compound G.
Preferably, in the step (1), the organic solvent is toluene, the alkali is potassium phosphate, the reaction temperature is 80-110 ℃, and the reaction time is 5-30 hours.
Preferably, in the step (1), the phosphine ligand is tricyclohexylphosphine, the catalyst is palladium acetate, and the molar ratio of the compound C, the cyclopropylboronic acid, the tricyclohexylphosphine, the potassium phosphate and the palladium acetate is 1: 1.3: 0.15: 3.5: 0.03 to 0.1.
Preferably, in the step (1), the phosphine ligand and the catalyst are all tetrakis (triphenylphosphine) palladium, and the molar ratio of the compound C, the cyclopropylboronic acid, the potassium phosphate and the tetrakis (triphenylphosphine) palladium is 1: 1.3: 3.5: 0.03 to 0.1.
Preferably, the organic solvent in the step (2) is methanol, the reaction temperature is 10-35 ℃, and the reaction time is 3-25 hours.
Preferably, in the step (2), under the condition of ammonia water, the catalyst is raney nickel, and the mass ratio of the compound D to the raney nickel is 1: 0.5; under 0.5-1.0 Mpa, the catalyst is palladium carbon with the content of 10%, and the mass ratio of the compound D to the palladium carbon with the content of 10% is 1: 0.05 to 0.1.
Preferably, in the step (3), the organic solvent is dichloromethane, the base is sodium carbonate or potassium carbonate, the reaction temperature is 10-35 ℃, the reaction time is 1-10 hours, and the molar ratio of the compound E, the di-tert-butyl dicarbonate and the base is 1: 1.5: 2.
preferably, the organic solvent in the step (4) is ethyl acetate or dioxane, the organic solvent of hydrogen chloride is 2mol/L ethyl acetate solution of hydrogen chloride or 4mol/L dioxane solution of hydrogen chloride, the reaction temperature is 15-50 ℃, and the reaction time is 3-25 hours.
Preferably, the compound C is prepared by taking 3-bromopyridine as a raw material, and the synthetic route is as follows:
the synthesis steps are as follows: dissolving the compound A in dichloromethane, adding m-chloroperoxybenzoic acid in batches under an ice salt bath, and reacting for 3 hours at 20 ℃ to obtain a compound B; and dissolving the compound B in acetonitrile, adding trimethylsilyl cyanide and triethylamine under the protection of nitrogen, and reacting at 75 ℃ for 15 hours to obtain a compound C.
Preferably, the m-chloroperoxybenzoic acid is 67 mass percent of wet solids, and the molar ratio of the compound A to the m-chloroperoxybenzoic acid is 1: 1.5, the mol ratio of the compound B, the trimethylsilyl cyanide and the triethylamine is 1: 3: 2.
the Chinese explanation of the invention: boc2O: di-tert-butyl dicarbonate, wherein Boc is tert-butyloxycarbonyl; m-CPBA: m-chloroperoxybenzoic acid; TMSCN: tri-component of Chinese Tri-componentCyanosilane; TEA: triethylamine.
The invention has the beneficial effects that:
the invention provides a synthetic method of (3-cyclopropylpyridine-2-yl) methylamine hydrochloride for the first time, and provides theoretical basis and experimental data for preparing the (3-cyclopropylpyridine-2-yl) methylamine hydrochloride; the synthesis method disclosed by the invention is reasonable in design, simple in experimental operation and easy to control.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.
Example 1
(1) Synthesis of Compound C
3-bromopyridine (23.7g, 150mmol, 1eq.) was dissolved in 350ml dichloromethane and 67% by mass m-chloroperoxybenzoic acid (58g, 225mmol, 1.5eq.) was added portionwise under an ice salt bath. After the completion of the addition, the reaction was carried out at 20 ℃ for 3 hours.
After the reaction, 140ml of a saturated aqueous sodium bicarbonate solution was added under ice-cooling, and the mixture was stirred for half an hour. The mixture was extracted with a mixture of dichloromethane and methanol (volume ratio 8: 1), and the resulting organic phase was dried, concentrated, and purified by column chromatography to give 24.3g of 3-bromopyridine-N-oxide as a pale red oil in 93% yield.
3-bromopyridine-N-oxide (24.3g, 139.5mmol, 1eq.) was dissolved in 360ml acetonitrile, and trimethylsilyl cyanide (41.5g, 418.5mmol, 3eq.) and triethylamine (28.2g, 279mmol, 2eq.) were added in that order under nitrogen protection, and the reaction was carried out at 75 ℃ for 15 hours.
After the reaction was completed, the reaction solution was cooled and then added to an ice saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing the organic phase with saturated sodium chloride, drying, and purifying by column chromatography to obtain 22.5g white solid 3-bromo-2-cyanopyridine with yield of 88%.
(2) Synthesis of Compound D
3-bromo-2-cyanopyridine (22.5g, 122.8mmol, 1eq.) was dissolved in 1400ml of toluene, cyclopropylboronic acid (13.7g, 159.6mmol, 1.3eq.) was added, tricyclohexylphosphine (5.2g, 18.4mmol, 0.15eq.) was added in that order, potassium phosphate (91.2g, 429.7mmol, 3.5eq.) was added, palladium acetate (2.1g, 9.2mmol, 0.075eq.) and 14ml of water, and the mixture was heated to 98 ℃ under nitrogen protection, and the reaction was held for 15 hours.
After the reaction is finished, water is added after the reaction liquid is cooled. Extracting with ethyl acetate, drying the organic phase, concentrating, and purifying by column chromatography to obtain 15.9g white solid 3-cyclopropylpyridine-2-carbonitrile with a yield of 90%.
(3) Synthesis of Compound E
3-Cyclopropylpyridine-2-carbonitrile (15.9g, 110.5mmol, 1eq.) was dissolved in 200ml of methanol, followed by addition of 8g of Raney nickel and 40ml of aqueous ammonia in this order, hydrogen gas was introduced, and the reaction was carried out at 22 ℃ for 16 hours.
After the reaction, suction filtration was carried out. The filter cake was washed with methanol and the filtrate was concentrated. The resulting concentrated residue was 15.1g (3-cyclopropylpyridin-2-yl) methylamine as a light black oil in 92% yield.
(4) Synthesis of Compound F
(3-Cyclopropylpyridin-2-yl) methylamine (15.1g, 101.7mmol, 1eq.) was dissolved in 500ml dichloromethane and di-tert-butyl dicarbonate (33.3g, 152.5mmol, 1.5eq.) was added. Sodium carbonate (21.5g, 203.3mmol, 2eq.) was dissolved in 130ml of water and added to the above reaction system. The reaction was carried out at 25 ℃ for 5 hours.
After the reaction, water was added. Extraction was carried out with dichloromethane and the organic phase was washed with saturated sodium chloride, concentrated and purified by column chromatography to give 23.5g of methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate as an oily substance in 93% yield.
(5) Synthesis of Compound G
Methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate (23.5g, 94.5mmol, 1eq.) was dissolved in 160ml of ethyl acetate and 260ml of a 2mol/L solution of hydrogen chloride in ethyl acetate were added. The reaction was carried out at 28 ℃ for 10 hours.
After the reaction, the reaction mixture was cooled to 5 ℃ and filtered to obtain the final product (3-cyclopropylpyridin-2-yl) methylamine hydrochloride (15.7 g in total) in a yield of 90%.
1H NMR(d6-DMSO)：8.80(s,3H),8.54(d,J＝4.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(dd,J＝7.7,5.1Hz,1H),4.43(d,J＝4.4Hz,2H),2.19-2.03(m,1H),1.11-0.94(m,2H),0.85–0.68(m,2H)。
Example 2
(1) Synthesis of Compound C
3-bromopyridine (28.4g, 180mmol, 1eq.) was dissolved in 420ml dichloromethane and 67% by mass of m-chloroperoxybenzoic acid (69.5g, 270mmol, 1.5eq.) was added portionwise under an ice salt bath. After the completion of the addition, the reaction was carried out at 20 ℃ for 3 hours.
After the reaction, 170ml of a saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling, and the mixture was stirred for half an hour. The mixture was extracted with a mixture of dichloromethane and methanol (volume ratio 8: 1), and the resulting organic phase was dried, concentrated, and purified by column chromatography to give 29.1g of 3-bromopyridine-N-oxide as a pale red oil in 93% yield.
3-bromopyridine-N-oxide (29.1g, 167.4mmol, 1eq.) was dissolved in 430ml of acetonitrile, and trimethylsilyl cyanide (49.8g, 502.2mmol, 3eq.) and triethylamine (33.9g, 334.8mmol, 2eq.) were added in this order under nitrogen protection, and the reaction was carried out at 75 ℃ for 15 hours.
After the reaction was completed, the reaction solution was cooled and then added to an ice saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing the organic phase with saturated sodium chloride, drying, and purifying by column chromatography to obtain 26.4g of white solid 3-bromo-2-cyanopyridine with yield of 86%.
(2) Synthesis of Compound D
3-bromo-2-cyanopyridine (26.4g, 144mmol, 1eq.) was dissolved in 1600ml of toluene, cyclopropylboronic acid (16.1g, 187.2mmol, 1.3eq.) was added to the solution, tricyclohexylphosphine (6.1g, 21.6mmol, 0.15eq.) was added to the solution, potassium phosphate (107g, 503.9mmol, 3.5eq.) was added to the solution, palladium acetate (3.2g, 14.4mmol, 0.1eq.) was added to the solution, and the solution was heated to 110 ℃ under nitrogen protection and then allowed to react for 5 hours with incubation.
After the reaction is finished, water is added after the reaction liquid is cooled. Extracting with ethyl acetate, drying the organic phase, concentrating, and purifying by column chromatography to obtain 17g white solid 3-cyclopropylpyridine-2-carbonitrile with a yield of 82%.
(3) Synthesis of Compound E
3-Cyclopropylpyridine-2-carbonitrile (17g, 118.1mmol, 1eq.) was dissolved in 210ml of methanol, followed by addition of 8.5g of Raney nickel and 40ml of aqueous ammonia in this order, hydrogen gas was introduced, and the reaction was carried out at 10 ℃ for 25 hours.
After the reaction, suction filtration was carried out. The filter cake was washed with methanol and the filtrate was concentrated. The resulting concentrated residue was 14.7g (3-cyclopropylpyridin-2-yl) methylamine as a light black oil, 84% yield.
(4) Synthesis of Compound F
(3-Cyclopropylpyridin-2-yl) methylamine (14.7g, 99.2mmol, 1eq.) was dissolved in 480ml dichloromethane and di-tert-butyl dicarbonate (32.5g, 148.7mmol, 1.5eq.) was added. Potassium carbonate (27.4g, 198.4mmol, 2eq.) was dissolved in 150ml of water and added to the reaction system. The reaction was carried out at 35 ℃ for 1 hour.
After the reaction, water was added. Extraction was carried out with dichloromethane and the organic phase was washed with saturated sodium chloride, concentrated and purified by column chromatography to give 17.2g of methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate as an oily substance in a yield of 70%.
(5) Synthesis of Compound G
Methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate (17.2g, 69.4mmol, 1eq.) was dissolved in 120ml dioxane and 95ml dioxane solution of 4mol/L hydrogen chloride was added. The reaction was carried out at 15 ℃ for 25 hours.
After the reaction, the reaction mixture was cooled to 5 ℃ and filtered to obtain the final product (3-cyclopropylpyridin-2-yl) methylamine hydrochloride (10.6g in total) in 83% yield.
1H NMR(d6-DMSO)：8.80(s,3H),8.54(d,J＝4.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(dd,J＝7.7,5.1Hz,1H),4.43(d,J＝4.4Hz,2H),2.19-2.03(m,1H),1.11-0.94(m,2H),0.85–0.68(m,2H)。
Example 3
(1) Synthesis of Compound C
3-bromopyridine (19g, 120mmol, 1eq.) was dissolved in 280ml dichloromethane and 67% by mass of m-chloroperoxybenzoic acid (46.4g, 180mmol, 1.5eq.) was added portionwise under an ice salt bath. After the completion of the addition, the reaction was carried out at 20 ℃ for 3 hours.
After completion of the reaction, 110ml of a saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling, and the mixture was stirred for half an hour. The mixture of dichloromethane and methanol (volume ratio 8: 1) is used for extraction, the obtained organic phase is dried and concentrated, and then the mixture is purified by column chromatography to obtain 19.2g of light red oily 3-bromopyridine-N-oxide with yield of 92%.
3-bromopyridine-N-oxide (19.2g, 110.4mmol, 1eq.) was dissolved in 280ml of acetonitrile, and trimethylsilyl cyanide (32.9g, 331.2mmol, 3eq.) and triethylamine (22.3g, 220.8mmol, 2eq.) were added in this order under nitrogen protection, and the reaction was carried out at 75 ℃ for 15 hours.
After the reaction was completed, the reaction solution was cooled and then added to an ice saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing the organic phase with saturated sodium chloride, drying, and purifying by column chromatography to obtain 18g of white solid 3-bromo-2-cyanopyridine with a yield of 89%.
(2) Synthesis of Compound D
3-bromo-2-cyanopyridine (18g, 98.3mmol, 1eq.) was dissolved in 1100ml of toluene, cyclopropylboronic acid (11g, 127.7mmol, 1.3eq.) was added in this order, tricyclohexylphosphine (4.1g, 14.7mmol, 0.15eq.), potassium phosphate (73g, 343.9mmol, 3.5eq.), palladium acetate (0.7g, 3mmol, 0.03eq.) and 11ml of water, and the mixture was heated to 80 ℃ under nitrogen protection, and the reaction was allowed to proceed for 30 hours.
After the reaction is finished, water is added after the reaction liquid is cooled. Extraction is carried out by ethyl acetate, organic phase is dried and concentrated, and then 10.9g white solid 3-cyclopropyl pyridine-2-carbonitrile is obtained by column chromatography purification, the yield is 77%.
(3) Synthesis of Compound E
3-Cyclopropylpyridine-2-carbonitrile (10.9g, 75.7mmol, 1eq.) was dissolved in 140ml of methanol, 7.6g of 10% palladium on carbon was added, hydrogen was introduced, and the reaction was carried out at 20 ℃ under 0.75MPa for 15 hours.
After the reaction, suction filtration was carried out. The filter cake was washed with methanol and the filtrate was concentrated. The resulting concentrated residue was 10.2g (3-cyclopropylpyridin-2-yl) methylamine as a light black oil, 91% yield.
(4) Synthesis of Compound F
(3-Cyclopropylpyridin-2-yl) methylamine (10.2g, 68.9mmol, 1eq.) was dissolved in 330ml dichloromethane and di-tert-butyl dicarbonate (22.5g, 103.3mmol, 1.5eq.) was added. Sodium carbonate (15g, 137.8mmol, 2eq.) was dissolved in 90ml of water and added to the above reaction system. The reaction was carried out at 10 ℃ for 10 hours.
After the reaction, water was added. Extraction was carried out with dichloromethane and the organic phase was washed with saturated sodium chloride, concentrated and purified by column chromatography to give 14.9g of methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate as an oil in 87% yield.
(5) Synthesis of Compound G
Methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate (14.9g, 59.9mmol, 1eq.) was dissolved in 100ml of ethyl acetate and 160ml of a 2mol/L solution of hydrogen chloride in ethyl acetate were added. The reaction was carried out at 50 ℃ for 3 hours.
After the reaction is finished, the reaction product is cooled to 5 ℃ and filtered, and the final product (3-cyclopropyl pyridine-2-yl) methylamine hydrochloride is obtained, wherein the total amount of the hydrochloride is 8g, and the yield is 72%.
1H NMR(d6-DMSO)：8.80(s,3H),8.54(d,J＝4.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(dd,J＝7.7,5.1Hz,1H),4.43(d,J＝4.4Hz,2H),2.19-2.03(m,1H),1.11-0.94(m,2H),0.85–0.68(m,2H)。
Example 4
(1) Synthesis of Compound C
3-bromopyridine (23.7g, 150mmol, 1eq.) was dissolved in 350ml dichloromethane and 67% by mass m-chloroperoxybenzoic acid (58g, 225mmol, 1.5eq.) was added portionwise under an ice salt bath. After the completion of the addition, the reaction was carried out at 20 ℃ for 3 hours.
After the reaction, 140ml of a saturated aqueous sodium bicarbonate solution was added under ice-cooling, and the mixture was stirred for half an hour. The mixture was extracted with a mixture of dichloromethane and methanol (volume ratio 8: 1), and the resulting organic phase was dried, concentrated, and purified by column chromatography to give 24.3g of 3-bromopyridine-N-oxide as a pale red oil in 93% yield.
3-bromopyridine-N-oxide (24.3g, 139.5mmol, 1eq.) was dissolved in 360ml acetonitrile, and trimethylsilyl cyanide (41.5g, 418.5mmol, 3eq.) and triethylamine (28.2g, 279mmol, 2eq.) were added in that order under nitrogen protection, and the reaction was carried out at 75 ℃ for 15 hours.
After the reaction was completed, the reaction solution was cooled and then added to an ice saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing the organic phase with saturated sodium chloride, drying, and purifying by column chromatography to obtain 22.5g white solid 3-bromo-2-cyanopyridine with yield of 88%.
(2) Synthesis of Compound D
3-bromo-2-cyanopyridine (22.5g, 122.8mmol, 1eq.) was dissolved in 1400ml of toluene, cyclopropylboronic acid (13.7g, 159.6mmol, 1.3eq.) was added to this, potassium phosphate (91.2g, 429.7mmol, 3.5eq.) was added to this, tetrakis (triphenylphosphine) palladium (9.9g, 8.6mmol, 0.07eq.) was added to this, and the mixture was heated to 100 ℃ under nitrogen protection, and the reaction was allowed to proceed for 14 hours with heat preservation.
After the reaction is finished, water is added after the reaction liquid is cooled. Extraction is carried out by ethyl acetate, organic phase is dried and concentrated, and then 15.8g white solid 3-cyclopropyl pyridine-2-carbonitrile is obtained by column chromatography purification, the yield is 89%.
(3) Synthesis of Compound E
3-Cyclopropylpyridine-2-carbonitrile (15.8g, 109.3mmol, 1eq.) was dissolved in 200ml of methanol, followed by addition of 7.9g of Raney nickel and 40ml of aqueous ammonia in this order, hydrogen gas was introduced, and the reaction was carried out at 35 ℃ for 3 hours.
After the reaction, suction filtration was carried out. The filter cake was washed with methanol and the filtrate was concentrated. The resulting concentrated residue was 11.5g (3-cyclopropylpyridin-2-yl) methylamine as a light black oil, yield 71%.
(4) Synthesis of Compound F
(3-Cyclopropylpyridin-2-yl) methylamine (11.5g, 77.6mmol, 1eq.) was dissolved in 380ml dichloromethane and di-tert-butyl dicarbonate (25.4g, 116.4mmol, 1.5eq.) was added. Potassium carbonate (21.4g, 155.1mmol, 2eq.) was dissolved in 120ml of water and added to the above reaction system. The reaction was carried out at 25 ℃ for 4 hours.
After the reaction, water was added. Extraction was carried out with dichloromethane and the organic phase was washed with saturated sodium chloride, concentrated and purified by column chromatography to give 17.3g of methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate as an oily substance in 90% yield.
(5) Synthesis of Compound G
Methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate (17.3g, 69.8mmol, 1eq.) was dissolved in 120ml dioxane and 100ml dioxane solution of 4mol/L hydrogen chloride was added. The reaction was carried out at 28 ℃ for 10 hours.
After the reaction, the reaction mixture was cooled to 5 ℃ and filtered to obtain (3-cyclopropylpyridin-2-yl) methylamine hydrochloride as a final product in an amount of 11.6g with a yield of 90%.
1H NMR(d6-DMSO)：8.80(s,3H),8.54(d,J＝4.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(dd,J＝7.7,5.1Hz,1H),4.43(d,J＝4.4Hz,2H),2.19-2.03(m,1H),1.11-0.94(m,2H),0.85–0.68(m,2H)。
Example 5
(1) Synthesis of Compound C
3-bromopyridine (28.4g, 180mmol, 1eq.) was dissolved in 420ml dichloromethane and 67% by mass of m-chloroperoxybenzoic acid (69.5g, 270mmol, 1.5eq.) was added portionwise under an ice salt bath. After the completion of the addition, the reaction was carried out at 20 ℃ for 3 hours.
After the reaction, 170ml of a saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling, and the mixture was stirred for half an hour. The mixture was extracted with a mixture of dichloromethane and methanol (volume ratio 8: 1), and the resulting organic phase was dried, concentrated, and purified by column chromatography to give 29.1g of 3-bromopyridine-N-oxide as a pale red oil in 93% yield.
3-bromopyridine-N-oxide (29.1g, 167.4mmol, 1eq.) was dissolved in 430ml of acetonitrile, and trimethylsilyl cyanide (49.8g, 502.2mmol, 3eq.) and triethylamine (33.9g, 334.8mmol, 2eq.) were added in this order under nitrogen protection, and the reaction was carried out at 75 ℃ for 15 hours.
After the reaction was completed, the reaction solution was cooled and then added to an ice saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing the organic phase with saturated sodium chloride, drying, and purifying by column chromatography to obtain 26.4g of white solid 3-bromo-2-cyanopyridine with yield of 86%.
(2) Synthesis of Compound D
3-bromo-2-cyanopyridine (26.4g, 144mmol, 1eq.) was dissolved in 1600ml of toluene, cyclopropylboronic acid (16.1g, 187.2mmol, 1.3eq.) was added to each of potassium phosphate (107g, 503.9mmol, 3.5eq.), tetrakis (triphenylphosphine) palladium (16.6g, 14.4mmol, 0.1eq.) and 16ml of water in this order, and the mixture was heated to 110 ℃ under nitrogen protection, and the reaction was allowed to proceed for 5 hours with incubation.
After the reaction is finished, water is added after the reaction liquid is cooled. Extraction is carried out by ethyl acetate, the organic phase is dried and concentrated, and then the white solid 3-cyclopropyl pyridine-2-carbonitrile of 17.2g is obtained by column chromatography purification, with the yield of 83%.
(3) Synthesis of Compound E
3-Cyclopropylpyridine-2-carbonitrile (17.2g, 119.5mmol, 1eq.) was dissolved in 210ml of methanol, 8.6g of 10% palladium on carbon was added, hydrogen was introduced, and the reaction was carried out at 35 ℃ under 1.0MPa for 3 hours.
After the reaction, suction filtration was carried out. The filter cake was washed with methanol and the filtrate was concentrated. The resulting concentrated residue was 13.5g (3-cyclopropylpyridin-2-yl) methylamine as a light black oil, yield 76%.
(4) Synthesis of Compound F
(3-Cyclopropylpyridin-2-yl) methylamine (13.5g, 90.8mmol, 1eq.) was dissolved in 450ml dichloromethane and di-tert-butyl dicarbonate (29.7g, 136.2mmol, 1.5eq.) was added. Potassium carbonate (25.1g, 181.6mmol, 2eq.) was dissolved in 150ml of water and added to the above reaction system. The reaction was carried out at 10 ℃ for 10 hours.
After the reaction, water was added. Extraction was carried out with dichloromethane and the organic phase was washed with saturated sodium chloride, concentrated and purified by column chromatography to give 19.4g of methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate as an oily substance in 86% yield.
(5) Synthesis of Compound G
Methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate (19.4g, 78.1mmol, 1eq.) was dissolved in 130ml of ethyl acetate and 210ml of a 2mol/L solution of hydrogen chloride in ethyl acetate were added. The reaction was carried out at 28 ℃ for 10 hours.
After the reaction, the reaction mixture was cooled to 5 ℃ and filtered to obtain the final product (3-cyclopropylpyridin-2-yl) methylamine hydrochloride in an amount of 12.8g, with a yield of 89%.
1H NMR(d6-DMSO)：8.80(s,3H),8.54(d,J＝4.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(dd,J＝7.7,5.1Hz,1H),4.43(d,J＝4.4Hz,2H),2.19-2.03(m,1H),1.11-0.94(m,2H),0.85–0.68(m,2H)。
Example 6
(1) Synthesis of Compound C
3-bromopyridine (19g, 120mmol, 1eq.) was dissolved in 280ml dichloromethane and 67% by mass of m-chloroperoxybenzoic acid (46.4g, 180mmol, 1.5eq.) was added portionwise under an ice salt bath. After the completion of the addition, the reaction was carried out at 20 ℃ for 3 hours.
After completion of the reaction, 110ml of a saturated aqueous sodium hydrogencarbonate solution was added under ice-cooling, and the mixture was stirred for half an hour. The mixture of dichloromethane and methanol (volume ratio 8: 1) is used for extraction, the obtained organic phase is dried and concentrated, and then the mixture is purified by column chromatography to obtain 19.2g of light red oily 3-bromopyridine-N-oxide with yield of 92%.
3-bromopyridine-N-oxide (19.2g, 110.4mmol, 1eq.) was dissolved in 280ml of acetonitrile, and trimethylsilyl cyanide (32.9g, 331.2mmol, 3eq.) and triethylamine (22.3g, 220.8mmol, 2eq.) were added in this order under nitrogen protection, and the reaction was carried out at 75 ℃ for 15 hours.
After the reaction was completed, the reaction solution was cooled and then added to an ice saturated sodium bicarbonate solution. Extracting with ethyl acetate, washing the organic phase with saturated sodium chloride, drying, and purifying by column chromatography to obtain 18g of white solid 3-bromo-2-cyanopyridine with a yield of 89%.
(2) Synthesis of Compound D
3-bromo-2-cyanopyridine (18g, 98.3mmol, 1eq.) was dissolved in 1100ml of toluene, cyclopropylboronic acid (11g, 127.7mmol, 1.3eq.) was added to the solution in this order, potassium phosphate (73g, 343.9mmol, 3.5eq.) was added to the solution, tetrakis (triphenylphosphine) palladium (3.4g, 3mmol, 0.03eq.) was added to the solution, and the solution was heated to 80 ℃ under nitrogen protection and then allowed to react for 30 hours with heat preservation.
After the reaction is finished, water is added after the reaction liquid is cooled. Extraction is carried out by ethyl acetate, organic phase is dried and concentrated, and then 10.6g white solid 3-cyclopropyl pyridine-2-carbonitrile is obtained by column chromatography purification, the yield is 75%.
(3) Synthesis of Compound E
3-Cyclopropylpyridine-2-carbonitrile (10.6g, 73.7mmol, 1eq.) was dissolved in 140ml of methanol, 10.6g of 10% palladium on carbon was added thereto, hydrogen was introduced thereinto, and the reaction was carried out at 10 ℃ under 0.5MPa for 25 hours.
After the reaction, suction filtration was carried out. The filter cake was washed with methanol and the filtrate was concentrated. The resulting concentrated residue was 9g of (3-cyclopropylpyridin-2-yl) methylamine as a light black oil in 82% yield.
(4) Synthesis of Compound F
(3-Cyclopropylpyridin-2-yl) methylamine (9g, 60.4mmol, 1eq.) is dissolved in 300ml dichloromethane and di-tert-butyl dicarbonate (19.8g, 90.6mmol, 1.5eq.) is added. Sodium carbonate (12.8g, 120.8mmol, 2eq.) was dissolved in 80ml of water and added to the above reaction system. The reaction was carried out at 35 ℃ for 1 hour.
After the reaction, water was added. Extraction was carried out with dichloromethane, and the organic phase was washed with saturated sodium chloride, concentrated and purified by column chromatography to give 10.7g of methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate as an oily substance in 71% yield.
(5) Synthesis of Compound G
Methyl tert-butyl (3-cyclopropylpyridin-2-yl) carbamate (10.7g, 42.9mmol, 1eq.) was dissolved in 70ml dioxane and 60ml dioxane solution of 4mol/L hydrogen chloride was added. The reaction was carried out at 28 ℃ for 10 hours.
After the reaction is finished, the reaction product is cooled to 5 ℃ and filtered by suction to obtain the final product (3-cyclopropyl pyridine-2-yl) methylamine hydrochloride which accounts for 7g, and the yield is 88%.
1H NMR(d6-DMSO)：8.80(s,3H),8.54(d,J＝4.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.53(dd,J＝7.7,5.1Hz,1H),4.43(d,J＝4.4Hz,2H),2.19-2.03(m,1H),1.11-0.94(m,2H),0.85–0.68(m,2H)。
Claims (10)
1. A synthetic method of (3-cyclopropyl pyridine-2-yl) methylamine hydrochloride is characterized by comprising the following steps:
the method comprises the following steps:
(1) dissolving the compound C in an organic solvent, and reacting with cyclopropyl boric acid, a phosphine ligand, alkali and a catalyst under the protection of nitrogen to obtain a compound D;
(2) dissolving the compound D in an organic solvent, and reacting with hydrogen under the action of a catalyst to obtain a compound E;
(3) dissolving the compound E in an organic solvent, and reacting with di-tert-butyl dicarbonate and alkali to obtain a compound F;
(4) and dissolving the compound F in an organic solvent, and reacting with an organic solvent of hydrogen chloride to obtain a compound G.
2. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride according to claim 1, wherein the organic solvent in step (1) is toluene, the base is potassium phosphate, the reaction temperature is 80 to 110 ℃, and the reaction time is 5 to 30 hours.
3. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride as claimed in claim 2, wherein in step (1) the phosphine ligand is tricyclohexylphosphine, the catalyst is palladium acetate, and the molar ratio of compound C, cyclopropylboronic acid, tricyclohexylphosphine, potassium phosphate, palladium acetate is 1: 1.3: 0.15: 3.5: 0.03 to 0.1.
4. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride according to claim 2, wherein the phosphine ligand and the catalyst in step (1) are tetrakis (triphenylphosphine) palladium, and the molar ratio of compound C, cyclopropylboronic acid, potassium phosphate and tetrakis (triphenylphosphine) palladium is 1: 1.3: 3.5: 0.03 to 0.1.
5. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride according to claim 1, wherein the organic solvent in step (2) is methanol, the reaction temperature is 10 to 35 ℃, and the reaction time is 3 to 25 hours.
6. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride according to claim 5, wherein in step (2), under the condition of ammonia water, the catalyst is Raney nickel, and the mass ratio of the compound D to the Raney nickel is 1: 0.5; under 0.5-1.0 Mpa, the catalyst is palladium carbon with the content of 10%, and the mass ratio of the compound D to the palladium carbon with the content of 10% is 1: 0.05 to 0.1.
7. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride according to claim 1, wherein in step (3), the organic solvent is dichloromethane, the base is sodium carbonate or potassium carbonate, the reaction temperature is 10 to 35 ℃, the reaction time is 1 to 10 hours, and the molar ratio of the compound E, di-tert-butyl dicarbonate and base is 1: 1.5: 2.
8. the method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride according to claim 1, wherein the organic solvent in step (4) is ethyl acetate or dioxane, the organic solvent of hydrogen chloride is 2mol/L ethyl acetate solution of hydrogen chloride or 4mol/L dioxane solution of hydrogen chloride, the reaction temperature is 15 to 50 ℃, and the reaction time is 3 to 25 hours.
9. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride according to claim 1, wherein compound C is prepared from 3-bromopyridine as the starting material by the following synthetic route:
the synthesis steps are as follows: dissolving the compound A in dichloromethane, adding m-chloroperoxybenzoic acid in batches under an ice salt bath, and reacting for 3 hours at 20 ℃ to obtain a compound B; and dissolving the compound B in acetonitrile, adding trimethylsilyl cyanide and triethylamine under the protection of nitrogen, and reacting at 75 ℃ for 15 hours to obtain a compound C.
10. The method for synthesizing (3-cyclopropylpyridin-2-yl) methylamine hydrochloride according to claim 9, wherein m-chloroperoxybenzoic acid is 67% by mass of wet solids, and the molar ratio of compound a to m-chloroperoxybenzoic acid is 1: 1.5, the mol ratio of the compound B, the trimethylsilyl cyanide and the triethylamine is 1: 3: 2.
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| CN112707831A (en) * | 2021-02-05 | 2021-04-27 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3- (1-aminocyclopropyl) methyl benzoate |
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| CN101835777A (en) * | 2007-10-25 | 2010-09-15 | 尔察祯有限公司 | Carbacephem beta-lactam antibiotics |
| CN107106558A (en) * | 2014-11-18 | 2017-08-29 | 默沙东公司 | With A2AThe Aminopyrazine compound of antagonist properties |
| WO2020014332A1 (en) * | 2018-07-10 | 2020-01-16 | Nikang Therapeutics, Inc. | Adenosine receptor binding compounds |
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| CN101835777A (en) * | 2007-10-25 | 2010-09-15 | 尔察祯有限公司 | Carbacephem beta-lactam antibiotics |
| CN107106558A (en) * | 2014-11-18 | 2017-08-29 | 默沙东公司 | With A2AThe Aminopyrazine compound of antagonist properties |
| WO2020014332A1 (en) * | 2018-07-10 | 2020-01-16 | Nikang Therapeutics, Inc. | Adenosine receptor binding compounds |
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| CN112707831A (en) * | 2021-02-05 | 2021-04-27 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3- (1-aminocyclopropyl) methyl benzoate |
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