CN110563643A - synthesis method of (5-bromo-3-methyl-pyridin-2-yl) -methylamine - Google Patents
synthesis method of (5-bromo-3-methyl-pyridin-2-yl) -methylamine 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a synthesis method of (5-bromo-3-methyl-pyridin-2-yl) -methylamine. The (5-bromo-3-methyl-pyridin-2-yl) -methylamine is obtained by bromination, diazotization, bromination and methylamine reaction of 2-amino-3-methylpyridine serving as an initial raw material. The method designs a brand new synthetic route, has mild reaction conditions and high product purity, and the starting material 2-amino-3-methylpyridine is easy to obtain and is easy for industrial production.
Description
Technical Field
the invention belongs to the field of chemistry or pharmaceutical chemistry, and particularly relates to a synthetic method of (5-bromo-3-methyl-pyridin-2-yl) -methylamine.
Background
The (5-bromo-3-methyl-pyridin-2-yl) -methylamine is an important intermediate for synthesizing Ozenoxacin (Ozenoxacin), the Ozenoxacin is a novel broad-spectrum antibacterial medical compound of quinolones with excellent antibacterial activity, and a novel topoisomerase inhibitor with topoisomerase characteristics, which is created by effectively overcoming antibacterial resistance clinically, has the characteristics of reliability, high efficiency, broad spectrum, low toxicity and the like, and is mainly used for treating systemic diseases such as urinary tract, digestive tract, respiratory tract and the like caused by bacterial infection. The chemical formula of ozenoxacin is as follows:
on 28.9.2015, Maruho Co., Ltd, Ozenoxacin was approved for sale in Japan under the trade name Zebiax ゼ ビ ア ッ ク ス ロ ー シ ョ ン 2%, NDA No. 22700AMX01000000, and the dosage form was a lotion or a rinse with a specification of 2%/10 g.
Currently, the synthetic route for (5-bromo-3-methyl-pyridin-2-yl) -methylamine is as follows:
1) patent WO2009/16460 reports the reaction of 5-bromo-3-methylpyridin-2-amine with methyl iodide to form (5-bromo-3-methyl-pyridin-2-yl) -methylamine with tetrahydrofuran as solvent, sodium hydride as acid-binding agent, the reaction equation is as follows:
The process is a primary amine alkylation reaction, so that dimethylamine is easily generated as a side reaction, the purity is low, and the yield is only 57.8%.
2) patent US6335447 reports the reaction of 5-bromo-2-chloro-3-methylpyridine with aqueous methylamine at 180 ℃ to form (5-bromo-3-methyl-pyridin-2-yl) -methylamine with water as solvent, the reaction equation being as follows:
The process has harsh reaction conditions, the reaction temperature is up to 180 ℃, and the raw material 5-bromo-2-chloro-3-methylpyridine is not easy to obtain and is difficult to realize industrial production.
in view of the above-mentioned disadvantages of the current synthesis process of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, the development of a synthesis method of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, which has mild reaction conditions, high yield, high purity and is suitable for production, is still in need of further research and study.
Disclosure of Invention
in view of the disadvantages of the above-mentioned routes, the present invention aims to provide a synthesis method of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, which has mild reaction conditions, few steps, high yield and is suitable for production, and the specific technical scheme is as follows:
A method of synthesizing (5-bromo-3-methyl-pyridin-2-yl) -methylamine via the following chemical reaction equation:
the reaction equation is prepared by the following steps:
(1) Bromination: 2-amino-3-methylpyridine is taken as an initial raw material, organic acid is taken as a solvent, and bromine is dripped to carry out bromination reaction under the catalysis of a small amount of iodine; quenching the reaction solution by water, adjusting the pH to 9-10 by using liquid caustic soda, and stirring for 1 hour under heat preservation; filtering, washing with water to neutrality, and drying at 45-50 deg.C to obtain 5-bromo-2-amino-3-methylpyridine;
(2) diazotization and bromination: dripping bromine and then sodium nitrite aqueous solution in hydrobromic acid of 5-bromo-2-amino-3-methylpyridine, keeping the temperature at 15-25 ℃, stirring for 3 hours, cooling to below 0 ℃, adjusting the pH to 7-8 by using 30% liquid alkali, performing suction filtration, washing a filter cake by using methanol, and drying at 40-45 ℃ to obtain 2, 5-dibromo-3-methylpyridine;
(3) methylamino: using N, N-Dimethylformamide (DMF) as a solvent, cooling to 10 ℃, adding an organic base, stirring for dissolving, adding N-methylformamide and 2, 5-dibromo-3-methylpyridine, heating to 80-100 ℃, keeping the temperature for reaction for 1-5 hours, cooling to 20-40 ℃, adding water, adjusting the pH value to 1 by using 30% hydrochloric acid, extracting and removing impurities by using toluene, separating a lower water layer, adjusting the pH value of the water layer to 9.5-10.5 by using 30% liquid caustic soda, extracting by using isopropyl acetate, washing an upper organic layer by using 0.5-8% diluted hydrochloric acid until the pH value is 7-8, removing the lower water layer, distilling the isopropyl acetate to dryness under reduced pressure by using the upper organic layer, adding n-hexane, cooling to 0-10 ℃ for crystallization to obtain a flaky crystal, performing suction filtration, washing a filter cake, and drying at 80 ℃ to obtain (5-bromo-3-methyl-pyridin-2-yl) -methylamine.
Wherein in the reaction step (1), the organic acid is at least one of formic acid, acetic acid and propionic acid, and the amount of the organic acid is 3-6 times of the weight of the 2-amino-3-methylpyridine; the iodine amount is 5-10% of the weight of the 2-amino-3-methylpyridine; controlling the dropping temperature of bromine to be-5-20 ℃, wherein the dropping time is 1-3 hours, and after the completion of the dropping of the bromine, carrying out heat preservation reaction for 1-2 hours at the temperature of-5-20 ℃; the water quenching dosage is 2 to 5 times of the weight of the 2-amino-3-methylpyridine, and the quenching time is 10 minutes to 1 hour; the dropping temperature of the liquid caustic soda is 15-25 ℃.
in the reaction step (2), the dosage of hydrobromic acid is 3-8 times of the weight of 5-bromo-2-amino-3-methylpyridine; the molar ratio of bromine to 5-bromo-2-amino-3-methylpyridine is 1.1-1.5: 1, controlling the dropping temperature of bromine to be-15-0 ℃, and the dropping time to be 0.5-2 hours; the concentration of the sodium nitrite aqueous solution is 35.0-45.0%, the molar ratio of the sodium nitrite to the 5-bromo-2-amino-3-methylpyridine is 1.5-3.0: 1, controlling the dropping temperature of a sodium nitrite aqueous solution to be-15-0 ℃, and dropping for 1-2 hours; the dosage of the washing methanol is 0.2 to 2 times of the weight of the 5-bromo-2-amino-3-methylpyridine, and the washing times are 1 to 2 times.
in the reaction step (3), the dosage of DMF is 2-5 times of the weight of 2, 5-dibromo-3-methylpyridine; the organic base is at least one of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, sodium hydride, potassium hydride, butyl lithium and tert-butyl lithium, and the molar ratio of the organic base to the 2, 5-dibromo-3-methylpyridine is 1.05-1.5, preferably 1.1-1.3: 1: 1; the molar ratio of the N-methylformamide to the 2, 5-dibromo-3-methylpyridine is 1.05-1.5: 1, preferably the molar ratio is 1.1-1.3; the reaction temperature is 80-100 ℃, and the preferable reaction temperature is 80-90 ℃; the reaction time is 1 to 5 hours, and the preferable reaction time is 3 to 4 hours; the water addition amount is 3 to 6 times of the weight of the 2, 5-dibromo-3-methylpyridine; the dosage of the toluene is 2 to 4 times of the weight of the 2, 5-dibromo-3-methylpyridine; the dosage of the isopropyl acetate is 4 to 8 times of the weight of the 2, 5-dibromo-3-methylpyridine; the temperature for distilling the isopropyl acetate under reduced pressure is 45-60 ℃, and the vacuum degree is-0.1 to-0.06 MPa; the dosage of n-hexane for crystallization is 2-4 times of the weight of 2, 5-dibromo-3-methylpyridine, and the dosage of n-hexane for washing is 0.3-1 time of the weight of 2, 5-dibromo-3-methylpyridine.
The invention has the beneficial effects that:
1) The invention provides a synthesis method of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, which designs a brand new synthesis route, has mild reaction conditions, easily obtains the starting material 2-amino-3-methylpyridine and is easy for industrial production.
2) the invention provides a synthesis method of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, which avoids the generation of dimethylamino byproducts, has an HPLC content of more than 99.5 percent and a single impurity of less than 0.2 percent, achieves a total yield of more than 70.0 percent, and has a stable process.
Drawings
FIG. 1 is a nuclear magnetic carbon spectrum of 2, 5-dibromo-3-methylpyridine.
FIG. 2 is a nuclear magnetic hydrogen spectrum of 2, 5-dibromo-3-methylpyridine.
FIG. 3 is a mass spectrum of 2, 5-dibromo-3-methylpyridine.
Figure 4 is a mass spectrum of (5-bromo-3-methyl-pyridin-2-yl) -methylamine.
Detailed Description
The present invention is described in detail by the following specific examples, which are provided for the purpose of illustration and are not to be construed as limiting the invention.
Example 1
(1) Preparation of 5-bromo-2-amino-3-methylpyridine
108.1g (1mol) of 2-amino-3-methylpyridine, 324.4g of formic acid and 5.4g of iodine are added into a 2L four-neck flask, stirring is started, and the temperature is reduced to below 10 ℃; 163.0g (1.02mol) of bromine is dripped, the dripping temperature is controlled to be-5-0 ℃, and the dripping time is 1-2 h; after the dropwise addition is finished, stirring for 2 hours at the temperature of minus 5-0 ℃; after the heat preservation is finished, adding 250ml of water, and stirring for 30 min; dripping 30% liquid alkali to adjust the pH to 9-10, and controlling the dripping temperature to 15-25 ℃; after the dropwise addition, stirring for 1h at the temperature of 15-25 ℃; filtering, washing with water to neutrality, and drying at 45-50 deg.C to obtain dried product 177.7g, with yield 95.0% and HPLC content 98.1%.
(2) preparation of 2, 5-dibromo-3-methylpyridine
93.5g (0.5mol) of 5-bromo-2-amino-3-methylpyridine and 281g of hydrobromic acid are added into a 1L four-neck flask, stirring is started, and the temperature is reduced to below-10 ℃; dripping 87.9g (0.55mol) of bromine, controlling the dripping temperature to be-15-0 ℃, and the dripping time to be 1-2 h; then dropwise adding a solution prepared from 51.8g (0.75mol) of sodium nitrite and 96.0g of water, controlling the dropwise adding temperature to be-15-0 ℃, and controlling the dropwise adding time to be 1.5-2 h; after the dropwise addition is finished, stirring for 3 hours at 15-25 ℃; cooling to below 0 deg.C, and adjusting pH to 7-8 with liquid alkali; suction filtration, washing twice with 50 ml/methanol, drying at 40-45 deg.C to obtain 113.5g of 2, 5-dibromo-3-methylpyridine with yield of 90.5%, HPLC content of 99.2%, 5-bromo-2-amino-3-methylpyridine content of 0.3%, 2, 3-bromo-5-methylpyridine content of 0.2%.
WNMR-I-500MHz type nuclear magnetic resonance instrument nuclear magnetic hydrogen spectrum detection, the data is as follows:
1H NMR(CDCl3)δ：2.37(s,3H),7.64(d,1H),8.25-8.26(d,1H)。
The liquid quality detection [ M ] was 251.70 (theoretical molecular weight 250.92).
(3) Preparation of (5-bromo-3-methyl-pyridin-2-yl) -methylamine
adding DMF105g into a 1L four-neck flask, cooling to 10 ℃, adding sodium methoxide 16.2g (0.3mol), stirring for dissolving, adding N-methylformamide 17.7g (0.3mol) and 2, 5-dibromo-3-methylpyridine 50.2g (0.2mol), heating to 95 ℃, keeping the temperature for reaction for 5 hours, cooling to 20-40 ℃, adding water 200g, adjusting the pH to 1 with 30% hydrochloric acid, extracting and removing impurities with 120g of toluene, separating out a lower water layer, adjusting the pH of the water layer to 9.5-10.5 with 30% liquid alkali, extracting with 200g of isopropyl acetate, washing an upper organic layer with 0.5% diluted hydrochloric acid until the pH is 7-8, removing the lower water layer, distilling isopropyl acetate under reduced pressure in the upper organic layer until the isopropyl acetate is dry, distilling the isopropyl acetate under reduced pressure at the temperature of 45-50 ℃, and the vacuum degree of-0.09 to-0.08 MPa; adding 150g of N-hexane, cooling to 0-10 ℃, crystallizing to obtain a flaky crystal, performing suction filtration, washing with 20ml of N-hexane, and drying at 80 ℃ to obtain 33.5g of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, wherein the yield is 83.3%, the HPLC content is 99.7%, the benzoic acid content is 0.05%, the N- (3-bromo-5-methylpyridin-2-yl) -N-methylbenzamide content is 0.02%, and the residual single impurity content is less than 0.2%.
The liquid quality detection [ M ] was 202.75 (theoretical molecular weight 201.06).
Example 2:
(1) Preparation of 5-bromo-2-amino-3-methylpyridine
108.1g (1mol) of 2-amino-3-methylpyridine, 324.4g of acetic acid and 8.6g of iodine are added into a 2L four-neck flask, stirring is started, and the temperature is reduced to below 10 ℃; 175.8.0g (1.1mol) of bromine is dripped, the dripping temperature is controlled to be 0-5 ℃, and the dripping time is 1-2 h. After the dropwise addition is finished, stirring for 2 hours at the temperature of 0-5 ℃. After the heat preservation is finished, adding 300ml of water, and stirring for 15 min; 30 percent liquid caustic soda is dripped to adjust the pH value to 9-10, and the dripping temperature is controlled at 15-20 ℃. After the dropwise addition, stirring for 1h at the temperature of 15-20 ℃. Filtering, washing with water to neutrality, and drying at 45-50 deg.C to obtain 178.1g dried product with yield 95.2% and HPLC content 98.0%;
(2) preparation of 2, 5-dibromo-3-methylpyridine
93.5g (0.5mol) of 5-bromo-2-amino-3-methylpyridine and 281g of hydrobromic acid are added into a 1L four-neck flask, stirring is started, and the temperature is reduced to below-10 ℃; dropwise adding 119.9g (0.75mol) of bromine, controlling the dropwise adding temperature to be-15 to-5 ℃, the dropwise adding time to be 1-2h, dropwise adding a solution prepared from 69.0g (1.0mol) of sodium nitrite and 85.0g of water, controlling the dropwise adding temperature to be-15 to-5 ℃, the dropwise adding time to be 1-1.5h, stirring for 3h at 15-25 ℃ after the dropwise adding is finished, cooling to be below 0 ℃, adjusting the pH to be 7-8 by using liquid alkali, carrying out suction filtration, washing by 120ml of methanol once, and drying at 40-45 ℃ to obtain 114.2g of 2, 5-dibromo-3-methylpyridine, wherein the yield is 91.0%, the HPLC content is 99.1%, the 5-bromo-2-amino-3-methylpyridine content is 0.2%, and the 2, 3-bromo-5-methylpyridine content is 0.3%;
(3) preparation of (5-bromo-3-methyl-pyridin-2-yl) -methylamine
Adding DMF150g into a 1L four-neck flask, cooling to 10 ℃, adding 16.3g (0.24mol) of sodium ethoxide, stirring for dissolving, adding 14.2g (0.24mol) of N-methylformamide and 50.2g (0.2mol) of 2, 5-dibromo-3-methylpyridine, heating to 90 ℃, preserving heat for reaction for 4 hours, cooling to 20-40 ℃, adding 300g of water, adjusting the pH to 1 with 30% hydrochloric acid, extracting and removing impurities with 120g of toluene, separating out a lower water layer, adjusting the pH of the water layer to 9.5-10.5 with 30% liquid alkali, extracting with 200g of isopropyl acetate, washing an upper organic layer with 0.5% diluted hydrochloric acid until the pH is 7-8, separating out the lower water layer, distilling isopropyl acetate under reduced pressure in an upper organic layer until the isopropyl acetate is dry, distilling the isopropyl acetate under reduced pressure at a temperature of 55-60 ℃, keeping a vacuum degree of-0.1 to-0.08 MPa, adding 200g of N-hexane, cooling to 0-10 ℃ for crystallization to obtain a flaky crystal, suction filtration, washing with 50ml of N-hexane, drying at 80 ℃ to obtain 32.9g of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, with a yield of 81.8%, an HPLC content of 99.6%, a benzoic acid content of 0.1%, an N- (3-bromo-5-methylpyridin-2-yl) -N-methylbenzamide content of 0.03%, and less than 0.2% of the remaining single impurities.
Example 3:
(1) Preparation of 5-bromo-2-amino-3-methylpyridine
108.1g (1mol) of 2-amino-3-methylpyridine, 324.4g of propionic acid and 5.4g of iodine are added into a 2L four-neck flask, stirring is started, and the temperature is reduced to below 10 ℃; 163.0g (1.02mol) of bromine is dripped, the dripping temperature is controlled to be 5-10 ℃, and the dripping time is 1-2 h; after the dropwise addition is finished, stirring for 2 hours at the temperature of 5-10 ℃; after the heat preservation is finished, adding 400ml of water, and stirring for 30 min; dripping 30% liquid alkali to adjust the pH to 9-10, and controlling the dripping temperature to be 20-25 ℃; after the dropwise addition, stirring for 1h at the temperature of 20-25 ℃; filtering, washing with water to neutrality, and drying at 45-50 deg.C to obtain dried product 177.3g with yield of 94.8% and HPLC content of 98.4%;
(2) preparation of 2, 5-dibromo-3-methylpyridine
93.5g (0.5mol) of 5-bromo-2-amino-3-methylpyridine and 281g of hydrobromic acid are added into a 1L four-neck flask, stirring is started, and the temperature is reduced to below-10 ℃; 119.8g (0.75mol) of bromine is dripped, the dripping temperature is controlled to be-15-0 ℃, and the dripping time is 1-2 h; then dropwise adding a solution prepared from 51.8g (0.75mol) of sodium nitrite and 96.0g of water, controlling the dropwise adding temperature to be-15-0 ℃, and controlling the dropwise adding time to be 1.5-2 h; after the dropwise addition is finished, stirring for 3 hours at the temperature of 20-25 ℃; cooling to below 0 deg.C, and adjusting pH to 7-8 with liquid alkali; suction filtration, washing with 175ml of methanol once, and drying at 40-45 ℃ to obtain 113.9g of 2, 5-dibromo-3-methylpyridine, wherein the yield is 90.8%, the HPLC content is 99.5%, the content of 5-bromo-2-amino-3-methylpyridine is 0.1%, and the content of 2, 3-bromo-5-methylpyridine is 0.1%;
(3) Preparation of (5-bromo-3-methyl-pyridin-2-yl) -methylamine
Adding DMF200g into a 1L four-neck flask, cooling to 10 ℃, adding 28.8g (0.3mol) of sodium tert-butoxide, stirring for dissolution, adding 15.4g (0.26mol) of N-methylformamide and 50.2g (0.2mol) of 2, 5-dibromo-3-methylpyridine, heating to 85 ℃, keeping the temperature for reaction for 3.5h, cooling to 20-40 ℃, adding 250g of water, adjusting the pH to 1 with 30% hydrochloric acid, extracting and removing impurities with 120g of toluene, separating out a lower water layer, adjusting the pH of the water layer to 9.5-10.5 with 30% liquid alkali, extracting with 200g of isopropyl acetate, washing an upper organic layer with 0.5% diluted hydrochloric acid until the pH is 7-8, separating out the lower water layer, distilling the isopropyl acetate under reduced pressure to dryness in the upper organic layer, distilling the isopropyl acetate under reduced pressure at a temperature of 55-60 ℃, a vacuum degree of-0.08 to-0.06 MPa, adding 180g of N-hexane to 0-10 ℃ for crystallization to obtain a flaky crystal, suction filtration, washing with 40ml of N-hexane, drying at 80 ℃ to obtain 33.0g of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, with a yield of 82.1%, an HPLC content of 99.8%, a benzoic acid content of 0.02%, N- (3-bromo-5-methylpyridin-2-yl) -N-methylbenzamide which was not detected, and less than 0.2% of the remaining single impurities.
Example 4:
(1) preparation of 5-bromo-2-amino-3-methylpyridine
108.1g (1mol) of 2-amino-3-methylpyridine, 324.4g of formic acid and 5.4g of iodine are added into a 2L four-neck flask, stirring is started, and the temperature is reduced to below 10 ℃; 191.7g (1.2mol) of bromine is dripped, the dripping temperature is controlled to be 0-5 ℃, and the dripping time is 1-2 h; after the dropwise addition is finished, stirring for 2 hours at the temperature of 0-5 ℃; after the heat preservation is finished, 325ml of water is added, and the mixture is stirred for 30 min; dripping 30% liquid alkali to adjust the pH to 9-10, and controlling the dripping temperature to 15-25 ℃; after the dropwise addition, stirring for 1h at the temperature of 15-25 ℃; filtering, washing with water to neutrality, and drying at 45-50 deg.C to obtain dried product 176.8g with yield of 94.5% and HPLC content of 97.3%;
(2) preparation of 2, 5-dibromo-3-methylpyridine
93.5g (0.5mol) of 5-bromo-2-amino-3-methylpyridine and 300g of hydrobromic acid are added into a 1L four-neck flask, stirring is started, and the temperature is reduced to below-10 ℃; dropwise adding 103.9g (0.65mol) of bromine, controlling the dropwise adding temperature to be-15 to-10 ℃, and controlling the dropwise adding time to be 1 to 2 hours; then dropwise adding a solution prepared from 103.5g (1.5mol) of sodium nitrite and 155.0g of water, controlling the dropwise adding temperature to be-15 to-10 ℃, and controlling the dropwise adding time to be 1.5 to 2 hours; after the dropwise addition is finished, stirring for 3 hours at 15-20 ℃; cooling to below 0 deg.C, and adjusting pH to 7-8 with liquid alkali; suction filtration, washing with 120ml methanol once, and drying at 40-45 ℃ to obtain 115.2g of 2, 5-dibromo-3-methylpyridine, with the yield of 91.8%, the HPLC content of 99.0%, the 5-bromo-2-amino-3-methylpyridine content of 0.2%, and the 2, 3-bromo-5-methylpyridine content of 0.2%;
(3) preparation of (5-bromo-3-methyl-pyridin-2-yl) -methylamine
Adding DMF125g into a 1L four-neck flask, cooling to 10 ℃, adding 5.1g (0.21mol) of sodium hydride, stirring for dissolving, adding 12.4g (0.21mol) of N-methylformamide and 50.2g (0.2mol) of 2, 5-dibromo-3-methylpyridine, heating to 100 ℃, preserving heat for reaction for 3 hours, cooling to 20-40 ℃, adding 250g of water, adjusting the pH to 1 with 30% hydrochloric acid, extracting and removing impurities with 130g of toluene, separating out a lower water layer, adjusting the pH of the water layer to 9.5-10.5 with 30% liquid alkali, extracting with 200g of isopropyl acetate, washing an upper organic layer with 0.5% diluted hydrochloric acid until the pH is 7-8, removing the lower water layer, distilling isopropyl acetate under reduced pressure from the upper organic layer until the isopropyl acetate is dry, distilling the isopropyl acetate under reduced pressure at the temperature of 45-50 ℃, and the vacuum degree of-0.1 to-0.09 MPa; adding 120g of N-hexane, cooling to 0-10 ℃, crystallizing to obtain a flaky crystal, performing suction filtration, washing with 35ml of N-hexane, and drying at 80 ℃ to obtain 33.8g of (5-bromo-3-methyl-pyridin-2-yl) -methylamine, wherein the yield is 84.2%, the HPLC content is 99.7%, the benzoic acid content is not detected, the N- (3-bromo-5-methylpyridin-2-yl) -N-methylbenzamide content is 0.05%, and the residual single impurity content is less than 0.2%.
The present invention is not limited to the above-described embodiments, and any simple, equivalent changes or modifications made to the above-described embodiments in accordance with the technical spirit of the present invention fall within the technical scope of the present invention.
Claims (5)
1. A method for synthesizing (5-bromo-3-methyl-pyridin-2-yl) -methylamine, characterized in that: prepared via the following chemical reaction equation:
The reaction equation is prepared by the following steps:
(1) Bromination: 2-amino-3-methylpyridine is taken as an initial raw material, organic acid is taken as a solvent, and bromine is dripped to carry out bromination reaction under the catalysis of a small amount of iodine; quenching the reaction solution by water, adjusting the pH to 9-10 by using liquid caustic soda, and stirring for 1 hour under heat preservation; filtering, washing with water to neutrality, and drying at 45-50 deg.C to obtain 5-bromo-2-amino-3-methylpyridine;
(2) Diazotization and bromination: dripping bromine and then sodium nitrite aqueous solution in hydrobromic acid of 5-bromo-2-amino-3-methylpyridine, keeping the temperature at 15-25 ℃, stirring for 3 hours, cooling to below 0 ℃, adjusting the pH to 7-8 by using 30% liquid alkali, performing suction filtration, washing a filter cake by using methanol, and drying at 40-45 ℃ to obtain 2, 5-dibromo-3-methylpyridine;
(3) Methylamino: using N, N-Dimethylformamide (DMF) as a solvent, cooling to 10 ℃, adding an organic base, stirring for dissolving, adding N-methylformamide and 2, 5-dibromo-3-methylpyridine, heating to 80-100 ℃, keeping the temperature for reaction for 1-5 hours, cooling to 20-40 ℃, adding water, adjusting the pH value to 1 by using 30% hydrochloric acid, extracting and removing impurities by using toluene, separating a lower water layer, adjusting the pH value of the water layer to 9.5-10.5 by using 30% liquid caustic soda, extracting by using isopropyl acetate, washing an upper organic layer by using 0.5-8% diluted hydrochloric acid until the pH value is 7-8, removing the lower water layer, distilling the isopropyl acetate to dryness under reduced pressure by using the upper organic layer, adding n-hexane, cooling to 0-10 ℃ for crystallization to obtain a flaky crystal, performing suction filtration, washing a filter cake, and drying at 80 ℃ to obtain (5-bromo-3-methyl-pyridin-2-yl) -methylamine.
2. A process for the synthesis of (5-bromo-3-methyl-pyridin-2-yl) -methylamine as claimed in claim 1, wherein: in the reaction step (1), the organic acid is at least one of formic acid, acetic acid and propionic acid, and the amount of the organic acid is 3-6 times of the weight of the 2-amino-3-methylpyridine; the iodine dosage is 5-10% of the weight of the 2-amino-3-methylpyridine; the dosage of the bromine is 1.02 to 1.2 times of the molar ratio of the 2-amino-3-methylpyridine; the dropping temperature of the bromine is controlled to be-5-20 ℃, the dropping time is 1-3 hours, and after the dropping of the bromine is finished, the bromine is subjected to heat preservation reaction for 1-2 hours at the temperature of-5-20 ℃; the water quenching dosage is 2 to 5 times of the weight of the 2-amino-3-methylpyridine, and the quenching time is 10 minutes to 1 hour; the dropping temperature of the liquid caustic soda is 15-25 ℃.
3. A process for the synthesis of (5-bromo-3-methyl-pyridin-2-yl) -methylamine as claimed in claim 1, wherein: in the reaction step (2), the dosage of the hydrobromic acid is 3-8 times of the weight of the 5-bromo-2-amino-3-methylpyridine; the molar ratio of the bromine to the 5-bromo-2-amino-3-methylpyridine is 1.1-1.5: 1, controlling the dropping temperature of bromine to be-15-0 ℃, and the dropping time to be 0.5-2 hours; the concentration of the sodium nitrite aqueous solution is 35.0-45.0%, the molar ratio of the sodium nitrite to the 5-bromo-2-amino-3-methylpyridine is 1.5-3.0: 1, controlling the dropping temperature of a sodium nitrite aqueous solution to be-15-0 ℃, and dropping for 1-2 hours; the dosage of the washing methanol is 0.2 to 2 times of the weight of the 5-bromo-2-amino-3-methylpyridine, and the washing times are 1 to 2 times.
4. A process for the synthesis of (5-bromo-3-methyl-pyridin-2-yl) -methylamine as claimed in claim 1, wherein: in the reaction step (3), the dosage of DMF is 2-5 times of the weight of 2, 5-dibromo-3-methylpyridine; the organic base is at least one of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, sodium hydride, potassium hydride, butyl lithium and tert-butyl lithium, and the molar ratio of the organic base to the 2, 5-dibromo-3-methylpyridine is 1.05-1.5: 1; the molar ratio of the N-methylformamide to the 2, 5-dibromo-3-methylpyridine is 1.05-1.5: 1; the water addition amount is 3 to 6 times of the weight of the 2, 5-dibromo-3-methylpyridine; the dosage of the toluene is 2-4 times of the weight of the 2, 5-dibromo-3-methylpyridine; the dosage of the isopropyl acetate is 4 to 8 times of the weight of the 2, 5-dibromo-3-methylpyridine; the temperature for distilling the isopropyl acetate under reduced pressure is 45-60 ℃, and the vacuum degree is-0.1 to-0.06 MPa; the dosage of the n-hexane for crystallization is 2-4 times of the weight of 2, 5-dibromo-3-methylpyridine, and the dosage of the n-hexane for washing is 0.3-1 time of the weight of 2, 5-dibromo-3-methylpyridine.
5. A process for the synthesis of (5-bromo-3-methyl-pyridin-2-yl) -methylamine as claimed in claim 1, wherein: in the reaction step (3), the molar ratio of the organic base to the 2, 5-dibromo-3-methylpyridine is preferably 1.1 to 1.3: 1; the mol ratio of the N-methylformamide to the 2, 5-dibromo-3-methylpyridine is preferably 1.1-1.3: 1; the reaction temperature in the reaction step (3) is preferably 80-90 ℃, and the reaction time is preferably 3-4 hours.
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| CN113666865A (en) * | 2021-09-07 | 2021-11-19 | 杭州科耀医药科技有限公司 | Synthetic method of 2-isopropyl-3-amino-4-methylpyridine |
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