CN109651241B - Synthesis method of 4-bromo-6-chloronicotinaldehyde - Google Patents
Synthesis method of 4-bromo-6-chloronicotinaldehyde Download PDFInfo
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- 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
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Abstract
The invention provides a synthesis method of 4-bromo-6-chloronicotinaldehyde, which relates to the field of pharmaceutical chemistry, and comprises the synthetic route of reacting 4, 6-dichloronicotinic acid ethyl ester with 4-methoxybenzylamine to obtain 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester, reacting 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester with trifluoroacetic acid to obtain 4-amino-6-chloronicotinic acid ethyl ester, reacting 4-amino-6-chloronicotinic acid ethyl ester with tert-butyl nitrite and benzyl triethyl ammonium bromide to obtain 4-bromo-6-chloronicotinic acid ethyl ester, reacting 4-bromo-6-chloronicotinic acid ethyl ester with diisobutyl aluminum hydride under a certain condition to obtain 4-bromo-6-chloronicotinol, the 4-bromo-6-chloronicotinyl alcohol further reacts under the catalysis of manganese dioxide to obtain a target product, namely 4-bromo-6-chloronicotinaldehyde; the synthesis method disclosed by the invention has the advantages of mild reaction conditions, reduction in production cost and suitability for large-scale industrial production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and in particular relates to a preparation method of 4-bromo-6-chloronicotinaldehyde.
Background
A selective inhibitor of the FGFR4 enzyme (tyrosine kinase) for use in the treatment of a disease caused by FGFR4 or FGF 19. FGFR4 has obvious selective inhibition effect and wide application prospect in the treatment of tumors such as liver cancer, gastric cancer, renal cell carcinoma, sarcoma, cholangiocarcinoma, colon cancer, prostatic cancer, ovarian cancer, breast cancer and the like. 4-bromo-6-chloro-nicotinaldehyde is an important intermediate of FGFR4 enzyme selective inhibitor, the yield of the original production synthesis process is only 35%, the operation is complex, the process steps are long, the reaction is difficult, the yield is low, and the economic benefit and the environmental impact are poor.
Disclosure of Invention
The invention aims to provide a synthesis method of 4-bromo-6-chloronicotinaldehyde, which has mild reaction conditions, effectively improves the process yield and is suitable for industrial mass production.
In order to achieve the above purpose, the invention provides the following technical scheme: a synthetic method of 4-bromo-6-chloronicotinaldehyde comprises the following synthetic route:
the specific synthetic process is as follows:
1)4, 6-Dichloronicotinic acid ethyl ester and 4-methoxybenzylamine at a reaction temperature T1T is less than or equal to 0 DEG C1Stirring at the temperature of less than or equal to 60 ℃ until the reaction is finished, pouring the reaction solution into ice water, extracting by ethyl acetate in sequence, separating an organic phase, backwashing for three times by using water, backwashing by using saturated salt water, drying, and eluting by column chromatography to obtain a compound (1), namely 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate;
2) adding 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate of the compound (1) into trifluoroacetic acid, heating reaction liquid to 50-60 ℃, fully reacting, distilling off part of the trifluoroacetic acid, pouring the reaction liquid into ice water after the reaction is finished, adjusting the reaction liquid to show alkalinity by adopting an alkaline reagent, and sequentially performing extraction, backwashing, drying and column chromatography elution to obtain the 4-amino-6-chloroethyl nicotinate of the compound (2); the alkaline agent includes sodium bicarbonate, sodium carbonate, etc.;
3) adding the 4-amino-6-chloronicotinic acid ethyl ester of the compound (2) into dichloromethane, adding tert-butyl nitrite and benzyltriethylammonium bromide, reacting at room temperature, pouring a reaction solution into water after the reaction is finished, and sequentially performing extraction, backwashing, drying and column chromatography elution to obtain a compound (3), namely 4-bromo-6-chloronicotinic acid ethyl ester;
4) adding the compound (3) 4-bromo-6-chloronicotinic acid ethyl ester into a dichloromethane solvent, wherein dichloromethane can at least completely dissolve the compound (3) 4-bromo-6-chloronicotinic acid ethyl ester; under the protection of argon, cooling the reaction solution to-60 to-70 ℃, slowly adding diisobutylaluminum hydride, stirring for 30 minutes, heating to 0 ℃, stirring until the reaction is complete, adding the reaction solution into ice dilute hydrochloric acid, sequentially extracting with DCM, separating an organic phase, backwashing, drying and eluting by column chromatography to obtain a compound (4), namely 4-bromo-6-chloronicotinyl alcohol;
5) adding the compound (4) 4-bromo-6-chloronicotinyl alcohol into dichloromethane, adding manganese dioxide as a catalyst, filtering the reaction solution by using kieselguhr after complete reaction at room temperature, and obtaining the target product compound (5) 4-bromo-6-chloronicotinyl aldehyde after removing dichloromethane by reduced pressure distillation after filtering.
Further, the mass ratio of the 4, 6-dichloro nicotinic acid ethyl ester to the 4-methoxybenzylamine in the step 1) is 1: (1-4).
Further, the mass ratio of the compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate to trifluoroacetic acid in the step 2) is 1: (20-40).
Further, the mass ratio of the compound (2) ethyl 4-amino-6-chloronicotinate to tert-butyl nitrite in the step 3) is 1: (1.5-10), wherein the mass ratio of the 4-amino-6-chloronicotinic acid ethyl ester of the compound (2) to the benzyltriethylammonium bromide is 1: (2-6).
Further, the eluent for column chromatography elution in the step 3) is petroleum ether: ethyl acetate 100: 1.
Further, the mass ratio of the compound (3) ethyl 4-bromo-6-chloronicotinate to diisobutylaluminum hydride in the step 4) is 1: (1-4).
Further, the mass ratio of the compound (4) 4-bromo-6-chloronicotinyl alcohol to manganese dioxide in the step 5) is 1: (2-10).
According to the technical scheme, the synthesis method of the 4-bromo-6-chloronicotinaldehyde provided by the technical scheme of the invention has the following beneficial effects:
compared with the prior art, the synthesis method of 4-bromo-6-chloronicotinaldehyde disclosed by the invention optimizes the reaction conditions of the synthesis process, particularly the selection of a reaction solvent and a reactant; specifically, 4, 6-dichloro ethyl nicotinate and 4-methoxybenzylamine are reacted to obtain 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate; reacting 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate with trifluoroacetic acid to obtain 4-amino-6-chloroethyl nicotinate; 4-amino-6-chloronicotinic acid ethyl ester reacts with tert-butyl nitrite and benzyl triethyl ammonium bromide to obtain 4-bromo-6-chloronicotinic acid ethyl ester; 4-bromo-6-chloronicotinyl alcohol is obtained by reacting 4-bromo-6-chloronicotinyl ethyl ester with diisobutylaluminum hydride at a reaction temperature of-60 ℃ to-70 ℃ under a certain condition; the 4-bromo-6-chloronicotinyl alcohol further reacts under the catalysis of manganese dioxide to obtain a target product, namely 4-bromo-6-chloronicotinaldehyde; the synthesis route has mild reaction conditions, greatly simplifies the reaction process and the post-treatment process, is simple to operate and greatly reduces the production cost.
The comprehensive yield of the target product of the synthesis method disclosed by the invention under the preferable reaction condition is more than 80% through research and calculation; in addition, compared with the prior art, the consumption of the reaction solvent is greatly reduced, specifically, the reaction solvent with the volume of at least 50% is reduced, and the method plays a very important role in reducing environmental pollution, saving energy and reducing emission; the invention is beneficial to environmental protection and is suitable for large-scale industrial production.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a nuclear magnetic spectrum of compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate in the synthetic route of the present invention;
FIG. 2 is a nuclear magnetic spectrum of compound (2), ethyl 4-amino-6-chloronicotinate, of the synthetic route of the present invention;
FIG. 3 is a nuclear magnetic spectrum of compound (3), ethyl 4-bromo-6-chloronicotinate, of the synthetic route of the present invention;
FIG. 4 is a nuclear magnetic spectrum of compound (4), 4-bromo-6-chloronicotinyl alcohol, of the synthetic route of the present invention;
FIG. 5 is a nuclear magnetic spectrum of compound (5), 4-bromo-6-chloronicotinaldehyde, of the synthetic route of the present invention.
Detailed Description
In order to better understand the technical content of the present invention, specific embodiments are described below with reference to the accompanying drawings.
In this disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not necessarily intended to include all aspects of the invention. It should be appreciated that the various concepts and embodiments described above, as well as those described in greater detail below, may be implemented in any of numerous ways, as the disclosed concepts and embodiments are not limited to any one implementation. In addition, some aspects of the present disclosure may be used alone, or in any suitable combination with other aspects of the present disclosure.
Based on the phenomena that the method for synthesizing 4-bromo-6-chloro nicotinaldehyde in the prior art has long process steps, the overall process route has low target product yield, uses a large amount of solvent and is not friendly to the environment, the invention aims to disclose a method for synthesizing 4-bromo-6-chloro nicotinaldehyde, which has the advantages of simple operation, high target product yield, small solvent usage amount and environment friendliness.
The raw materials and reagents used in the present invention are commercially available; in the present document, "at room temperature conditions" means a temperature range of 10 ℃ to 30 ℃.
The invention discloses a synthesis method of 4-bromo-6-chloronicotinaldehyde, which comprises the following specific synthetic route and specific synthetic process:
firstly, 4, 6-dichloro nicotinic acid ethyl ester and 4-methoxybenzylamine are reacted at a reaction temperature T1Lower, 0 deg.C≤T1Stirring at the temperature of less than or equal to 60 ℃ until the reaction is finished, pouring the reaction solution into ice water, extracting by ethyl acetate in sequence, separating an organic phase, backwashing for three times by using water, backwashing by using saturated salt water, drying, and eluting by column chromatography to obtain a compound (1), namely 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate; wherein the mass ratio of the 4, 6-dichloro nicotinic acid ethyl ester to the 4-methoxybenzylamine is 1:1 to 1: 4, combining the specific examples, when the mass ratio of the 4, 6-dichloro-nicotinic acid ethyl ester to the 4-methoxybenzylamine is 1:1, when the reaction temperature is 40 ℃, the yield of the product compound (1), namely 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate, is high. The compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate, has a nuclear magnetic spectrum as shown in fig. 1, and 1H NMR (600MHz, CDCl3), δ 8.69(s,1H),8.48(s,1H),7.24(d, J ═ 8.6Hz,2H),6.90(d, J ═ 8.6Hz,2H),6.56(s,1H),4.34(dd, J ═ 7.9,6.4Hz,4H),3.81(s,3H),1.38(t, J ═ 7.1Hz, 3H).
Secondly, adding the compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate, into trifluoroacetic acid, wherein the trifluoroacetic acid can at least completely dissolve the compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate; heating the reaction solution to 50-60 ℃, fully reacting, distilling off part of trifluoroacetic acid, pouring the reaction solution into ice water after the reaction is finished, adjusting the reaction solution to show alkalinity by adopting an alkaline reagent, sequentially extracting by using ethyl acetate, separating an organic phase, backwashing by using saturated salt water, drying, and carrying out column chromatography elution to obtain a compound (2), namely 4-amino-6-chloronicotinic acid ethyl ester; wherein the mass ratio of the compound (1) 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate to trifluoroacetic acid is 1: (20-40), wherein the alkaline reagent comprises sodium bicarbonate, sodium carbonate and the like; with reference to the specific examples, when the mass ratio of the compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester to trifluoroacetic acid, is 1: when 33, the yield of the product compound (2), ethyl 4-amino-6-chloronicotinate, is high. The nuclear magnetic spectrum of compound (2), ethyl 4-amino-6-chloronicotinate, is shown in fig. 2, 1H NMR (600MHz, CDCl3) δ 8.69(s,1H),6.57(s,1H),4.36(q, J ═ 7.1Hz,2H),1.40(t, J ═ 7.1Hz, 3H).
Thirdly, adding the compound (2) 4-amino-6-chloronicotinic acid ethyl ester into a dichloromethane solvent, wherein dichloromethane can at least completely dissolve the compound (2) 4-amino-6-chloronicotinic acid ethyl ester, adding tert-butyl nitrite and benzyl triethyl ammonium bromide, and reacting at room temperature; after the reaction is finished, pouring the reaction liquid into water, sequentially extracting by dichloromethane, separating an organic phase, backwashing by using saturated saline solution, drying, and carrying out column chromatography elution to obtain a compound (3), namely 4-bromo-6-chloronicotinic acid ethyl ester; wherein the mass ratio of the compound (2) 4-amino-6-chloronicotinic acid ethyl ester to the tert-butyl nitrite is 1: (1.5-10), wherein the mass ratio of the 4-amino-6-chloronicotinic acid ethyl ester of the compound (2) to the benzyltriethylammonium bromide is 1: (2-6); with reference to the specific examples, when the mass ratio of the compound (2) ethyl 4-amino-6-chloronicotinate to tert-butyl nitrite is 1:10, the weight ratio of the compound (2) ethyl 4-amino-6-chloronicotinate to the benzyltriethylammonium bromide is 1: when 5, the yield of the product compound (3), ethyl 4-bromo-6-chloronicotinate, is high. The nuclear magnetic spectrum of compound (3), ethyl 4-bromo-6-chloronicotinate, is shown in fig. 3, 1H NMR (600MHz, CDCl3) δ 8.80(s,1H),7.68(s,1H), 4.47-4.39 (m,2H),1.42(t, J ═ 7.1Hz, 3H).
Further, adding 4-bromo-6-chloronicotinic acid ethyl ester of a compound (3) into a dichloromethane solvent, wherein dichloromethane can at least completely dissolve the 4-bromo-6-chloronicotinic acid ethyl ester of the compound (3), cooling to-60 to-70 ℃ under the protection of argon, slowly adding diisobutyl aluminum hydride, uniformly stirring, heating to 0 ℃, stirring till the reaction is complete, adding a reaction solution into ice dilute hydrochloric acid, sequentially extracting with DCM, separating an organic phase, backwashing by using a saturated sodium bicarbonate aqueous solution and a saturated salt solution, drying, and performing petroleum ether: the volume ratio of ethyl acetate is 100: the mixed solvent of 1 is used as eluent for column chromatography elution to obtain a compound (4), 4-bromo-6-chloronicotinyl alcohol; wherein the mass ratio of the compound (3) ethyl 4-bromo-6-chloronicotinate to diisobutylaluminum hydride is 1: (1 to 4), according to the specific embodiment, the mass ratio of the compound (3), ethyl 4-bromo-6-chloronicotinate to diisobutylaluminum hydride is 1: and 3, the product yield is higher. The NMR spectrum of 4-bromo-6-chloronicotinyl alcohol (4) is shown in FIG. 4, 1H NMR (600MHz, CDCl3) delta 8.45(s,1H),7.57(s,1H),4.79(s, 2H).
Finally, adding the compound (4) 4-bromo-6-chloronicotinyl alcohol into a dichloromethane solvent, wherein dichloromethane can at least completely dissolve the compound (4) 4-bromo-6-chloronicotinyl alcohol, adding manganese dioxide as a catalyst, and completely reacting at room temperature; filtering the reaction solution by using kieselguhr after the reaction, and obtaining a target product compound (5), namely 4-bromo-6-chloronicotinaldehyde after removing dichloromethane by reduced pressure distillation after the filtration; wherein the mass ratio of the compound (4), 4-bromo-6-chloronicotinyl alcohol and manganese dioxide is 1: (2-10) and in combination with the examples, when the mass ratio of the compound (4), 4-bromo-6-chloronicotinyl alcohol, to manganese dioxide, is 1: 2-10, and the yield of the target product compound (5), 4-bromo-6-chloronicotinaldehyde, is highest. The NMR spectrum of 4-bromo-6-chloronicotinaldehyde (5) is shown in FIG. 5, 1H NMR (600MHz, CDCl3) delta 10.33(s,1H),8.80(s,1H),7.69(s, 1H).
The synthesis method of 4-bromo-6-chloronicotinaldehyde according to the present invention will be further described with reference to the accompanying drawings and specific examples.
Example 1
First step synthesis of compound (1) ethyl 6-chloro-4- ((4-methoxybenzyl) amino) nicotinate:
150g of ethyl 4, 6-dichloronicotinate (0.68mol) and 93.5g of 4-methoxybenzylamine (0.68mol) were added to a 3000ml dry three-necked flask, mechanically stirred, heated to 40 ℃, stirred overnight, after completion of the reaction by Thin Layer Chromatography (TLC), added to ice water, extracted 3 times with ethyl acetate, backwashed 1 time with saturated saline, dried by adding anhydrous sodium sulfate, and eluted in the column layer [ eluent: (petroleum ether: ethyl acetate ═ 40: 1) ] 196g of the compound ethyl 6-chloro-4- ((4-methoxybenzyl) amino) nicotinate (1) were obtained in a yield of 90%.
Second step synthesis of compound (2) ethyl 4-amino-6-chloronicotinate:
196g of compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester (0.61mol), was added to 1500ml of trifluoroacetic acid (20mol), heated to 50 ℃ to 60 ℃ for overnight reaction, after completion of TLC detection reaction, most of the trifluoroacetic acid was distilled off under reduced pressure, added to ice water while hot, adjusted to alkali with sodium bicarbonate solid, extracted with ethyl acetate 3 times, backwashed 1 time with saturated saline, dried with anhydrous sodium sulfate, and eluted at the column layer [ eluent: (petroleum ether: ethyl acetate ═ 8: 1) ] 110g of ethyl 4-amino-6-chloronicotinate of the compound (2) was obtained in a yield of 90%.
The third step is the synthesis of a compound (3), 4-bromo-6-chloronicotinic acid ethyl ester:
30g of compound (2), ethyl 4-amino-6-chloronicotinate (0.15mol), was added to 600ml of dichloromethane, 154.2g of tert-butyl nitrite (1.5mol) and 203.6g of benzyltriethylammonium bromide (0.75mol) were added to the system, and the reaction was allowed to react overnight at room temperature, and after completion of the TLC detection reaction, the reaction solution was poured into water, dichloromethane was extracted 3 times, saturated saline was backwashed 1 time, and elution by chromatography of silicon [ eluent: (petroleum ether: ethyl acetate ═ 100: 1) ] 30g of ethyl 4-bromo-6-chloronicotinate of the compound (3) were obtained in a yield of 75%.
The fourth step synthesis of compound (4) (4-bromo-6-chloropyridin-3-yl) methanol:
adding 30g of compound (3), 4-bromo-6-chloronicotinic acid ethyl ester (0.11mol) into 600ml of dichloromethane, reducing the temperature to-60 ℃ under the protection of argon, slowly adding 340.3ml of diisobutylaluminum hydride (1M/L and 0.33mol), stirring for reacting for 30 minutes, removing dry ice, raising the temperature of a reaction system to 0 ℃, stirring for reacting for 30 minutes, detecting by TLC, completely reacting, adding a reaction solution into 1.5M of ice dilute hydrochloric acid, extracting with DCM for 3 times, adding a saturated sodium bicarbonate aqueous solution for backwashing for 2 times, backwashing with a saturated saline solution for 1 time, adding anhydrous sodium sulfate for drying, and carrying out silica chromatography elution [ eluent: (petroleum ether: ethyl acetate ═ 10: 1) ] 19g of the compound (4), 4-bromo-6-chloronicotinyl alcohol, were obtained in 80% yield.
The fifth step is the synthesis of a compound (5), namely 4-bromo-6-chloronicotinaldehyde:
19g of the compound (4), 4-bromo-6-chloronicotinyl alcohol (0.085mol) was added to 200ml of dichloromethane, 74.3g of manganese dioxide (0.85mol) was added, the reaction was allowed to proceed overnight at room temperature, TLC detection was carried out, the reaction was completed, the reaction solution was filtered through celite, and the obtained filtrate was subjected to distillation under reduced pressure to remove dichloromethane, whereby 16.8g of the objective compound, 4-bromo-6-chloronicotinyl alcohol (5), was obtained in a yield of 90% and a purity of 98%.
Example 2
First step synthesis of compound (1) ethyl 6-chloro-4- ((4-methoxybenzyl) amino) nicotinate:
150g of ethyl 4, 6-dichloronicotinate (0.68mol) and 93.5g of 4-methoxybenzylamine (0.68mol) were added to a 3000ml dry three-necked flask, mechanically stirred at room temperature for overnight reaction, checked by TLC, the starting material did not react completely, added to ice water, extracted 3 times with ethyl acetate, back-washed 1 time with saturated saline, dried with anhydrous sodium sulfate, and column-eluted [ eluent: (petroleum ether: ethyl acetate ═ 40: 1) ] 120g of the compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester, were obtained in 55% yield.
Second step synthesis of compound (2) ethyl 4-amino-6-chloronicotinate:
120g of compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester (0.37mol), was added to 600ml of trifluoroacetic acid (8.07mol), heated to 50 ℃ to 60 ℃ for reaction overnight, subjected to TLC detection, most of the trifluoroacetic acid was distilled off under reduced pressure, added to ice water while hot, adjusted to alkali with sodium bicarbonate solid, extracted with ethyl acetate 3 times, backwashed with saturated saline 1 time, dried by adding anhydrous sodium sulfate, and eluted in the column layer [ eluent: (petroleum ether: ethyl acetate ═ 8: 1) ] 63g of ethyl 4-amino-6-chloronicotinate of the compound (2) was obtained in 80% yield.
The third step is the synthesis of a compound (3), 4-bromo-6-chloronicotinic acid ethyl ester:
30g of ethyl 4-amino-6-chloronicotinate (2) (0.15mol) was added to 600ml of dichloromethane, 30.9g of tert-butyl nitrite (0.3mol) and 81.6g of benzyltriethylammonium bromide (0.3mol) were added to the system, and the mixture was reacted at room temperature overnight, detected by TLC, the reaction solution was poured into water, dichloromethane was extracted 3 times, saturated saline was backwashed 1 time, and elution by chromatography on silicon [ eluent: (petroleum ether: ethyl acetate ═ 100: 1) ] 4g of ethyl 4-bromo-6-chloronicotinate of the compound (3) were obtained in a yield of 10%.
The fourth step synthesis of compound (4) (4-bromo-6-chloropyridin-3-yl) methanol:
adding 4g of compound (3), 4-bromo-6-chloronicotinic acid ethyl ester (0.015mol) into 80ml of dichloromethane, reducing the temperature to-70 ℃ under the protection of argon, slowly adding 15ml of diisobutylaluminum hydride (1M/L and 0.015mol), stirring for reaction for 30 minutes, removing dry ice, raising the temperature of a reaction system to 0 ℃, stirring for reaction for 30 minutes, detecting by TLC (thin layer chromatography), completely reacting, adding a reaction solution into 1.5M of ice dilute hydrochloric acid, extracting with DCM for 3 times, adding a saturated sodium bicarbonate aqueous solution for backwashing for 2 times, backwashing with a saturated saline solution for 1 time, adding anhydrous sodium sulfate for drying, and carrying out silica chromatography elution [ eluent: (petroleum ether: ethyl acetate ═ 10: 1) ] 2g of the compound (4), 4-bromo-6-chloronicotinyl alcohol, was obtained in a yield of 60%.
The fifth step is the synthesis of a compound (5), namely 4-bromo-6-chloronicotinaldehyde:
2g of the compound (4), 4-bromo-6-chloronicotinyl alcohol (0.009mol), was added to 20ml of dichloromethane, 3.9g of manganese dioxide (0.045mol) was added, the reaction was allowed to react overnight at room temperature, detected by TLC, the reaction solution was filtered through celite, and the resulting filtrate was chromatographed [ eluent: (petroleum ether: ethyl acetate ═ 5: 1) ], to give 1.6g of the target compound, 4-bromo-6-chloronicotinaldehyde (5), in a yield of 80% and a purity of 98%.
Example 3
First step synthesis of compound (1) ethyl 6-chloro-4- ((4-methoxybenzyl) amino) nicotinate:
150g of ethyl 4, 6-dichloronicotinate (0.68mol) and 187g of 4-methoxybenzylamine (1.36mol) were added to a 3000ml dry three-necked flask, mechanically stirred, heated to a reaction temperature of 60 ℃, stirred overnight, checked by TLC, reacted completely, added to ice water, extracted 3 times with ethyl acetate, back-washed 1 time with saturated saline, dried with anhydrous sodium sulfate, and column layer eluted [ eluent: (petroleum ether: ethyl acetate ═ 40: 1) ] 109g of the compound ethyl 6-chloro-4- ((4-methoxybenzyl) amino) nicotinate were obtained in 50% yield.
Second step synthesis of compound (2) ethyl 4-amino-6-chloronicotinate:
109g of compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester (0.34mol), was added to 1010ml of trifluoroacetic acid (13.59mol), heated to 50 ℃ to 60 ℃ for reaction overnight, subjected to TLC detection, most of the trifluoroacetic acid was distilled off under reduced pressure, added to ice water while hot, adjusted to alkali with sodium bicarbonate solid, extracted with ethyl acetate 3 times, backwashed with saturated saline 1 time, dried with anhydrous sodium sulfate, and eluted from the column layer [ eluent: (petroleum ether: ethyl acetate ═ 8: 1) ] 51.2g of ethyl 4-amino-6-chloronicotinate compound (2) were obtained in a yield of 75%.
The third step is the synthesis of a compound (3), 4-bromo-6-chloronicotinic acid ethyl ester:
30g of compound (2), ethyl 4-amino-6-chloronicotinate (0.15mol), was added to 600ml of dichloromethane, 46.4g of tert-butyl nitrite (0.45mol) and 136.1g of benzyltriethylammonium bromide (0.45mol) were added to the system, and the reaction was allowed to react overnight at room temperature, detected by TLC, the reaction solution was poured into water, extracted with dichloromethane 3 times, backwashed with saturated saline water 1 time, and eluted by chromatography on silicon [ eluent: (petroleum ether: ethyl acetate ═ 100: 1) ] 15.8g of ethyl 4-bromo-6-chloronicotinate of the compound (3) were obtained in a yield of 40%.
The fourth step synthesis of compound (4) (4-bromo-6-chloropyridin-3-yl) methanol:
adding 15.8g of compound (3), 4-bromo-6-chloronicotinic acid ethyl ester (0.06mol), into 300ml of dichloromethane, under the protection of argon, cooling to-65 ℃, slowly adding 120ml of diisobutylaluminum hydride (1M/L, 0.12mol), stirring for reaction for 30 minutes, removing dry ice, raising the temperature of a reaction system to 0 ℃, stirring for reaction for 30 minutes, detecting by TLC, completely reacting, adding a reaction solution into 1.5M of ice dilute hydrochloric acid, extracting with DCM for 3 times, adding a saturated sodium bicarbonate aqueous solution for backwashing for 2 times, backwashing with a saturated salt water for 1 time, adding anhydrous sodium sulfate for drying, and carrying out silica chromatography elution [ eluent: (petroleum ether: ethyl acetate ═ 10: 1) ] 9.3g of the compound (4), 4-bromo-6-chloronicotinyl alcohol, was obtained in a yield of 70%.
The fifth step is the synthesis of a compound (5), namely 4-bromo-6-chloronicotinaldehyde:
9.3g of compound (4), 4-bromo-6-chloronicotinyl alcohol (0.04mol) was added to 100ml of dichloromethane, 3.9g of manganese dioxide (0.08mol) was added, the reaction was allowed to react overnight at room temperature, detection was performed by TLC, the reaction solution was filtered through celite, and the resulting filtrate was chromatographed [ eluent: (petroleum ether: ethyl acetate ═ 5: 1) ], 5.3g of the target compound, 4-bromo-6-chloronicotinaldehyde, was obtained in a yield of 60% and a purity of 98%.
Example 4
First step synthesis of compound (1) ethyl 6-chloro-4- ((4-methoxybenzyl) amino) nicotinate:
150g of 4, 6-dichloronicotinic acid ethyl ester (0.68mol) and 373.1g of 4-methoxybenzylamine (2.72mol) were added to a 3000ml dry three-necked flask, mechanically stirred, cooled to a reaction temperature of 0 ℃, stirred for overnight reaction, detected by TLC, reacted completely, added to ice water, extracted with ethyl acetate 3 times, back washed with saturated saline 1 time, dried by adding anhydrous sodium sulfate, and column layer eluted [ eluent: (petroleum ether: ethyl acetate ═ 40: 1) ] 98.2g of ethyl 6-chloro-4- ((4-methoxybenzyl) amino) nicotinate, compound (1), were obtained in 45% yield.
Second step synthesis of compound (2) ethyl 4-amino-6-chloronicotinate:
98.2g of compound (1), 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester (0.306mol), was added to 909ml of trifluoroacetic acid (12.24mol), heated to 50 ℃ to 60 ℃ for reaction overnight, checked by TLC, most of the trifluoroacetic acid was distilled off under reduced pressure, added to ice water while hot, adjusted to alkali with sodium bicarbonate solid, extracted with ethyl acetate 3 times, backwashed with saturated saline 1 time, dried by adding anhydrous sodium sulfate, and eluted in the column layer [ eluent: (petroleum ether: ethyl acetate ═ 8: 1) ] 46g of ethyl 4-amino-6-chloronicotinate of the compound (2) was obtained in a yield of 75%.
The third step is the synthesis of a compound (3), 4-bromo-6-chloronicotinic acid ethyl ester:
30g of ethyl 4-amino-6-chloronicotinate (2) (0.15mol) as a compound was added to 600ml of dichloromethane, 77.34g of tert-butyl nitrite (0.75mol) and 245g of benzyltriethylammonium bromide (0.9mol) were added to the system, and the mixture was reacted at room temperature overnight, detected by TLC, poured into water, extracted with dichloromethane 3 times, backwashed with saturated saline solution 1 time, and eluted by chromatography on silicon [ eluent: (petroleum ether: ethyl acetate ═ 100: 1) ] 21.8g of ethyl 4-bromo-6-chloronicotinate of the compound (3) were obtained in 55% yield.
The fourth step synthesis of compound (4) (4-bromo-6-chloropyridin-3-yl) methanol:
adding 21.8g of compound (3), 4-bromo-6-chloronicotinic acid ethyl ester (0.082mol) into 300ml of dichloromethane, protecting with argon, cooling to-60 ℃, slowly adding 330ml of diisobutylaluminum hydride (1M/L, 0.33mol), stirring for reaction for 30 minutes, removing dry ice, raising the temperature of the reaction system to 0 ℃, stirring for reaction for 30 minutes, detecting by TLC, completely reacting, adding the reaction solution into 1.5M of ice-dilute hydrochloric acid, extracting with DCM for 3 times, adding saturated sodium bicarbonate aqueous solution for backwashing for 2 times, backwashing with saturated salt water for 1 time, adding anhydrous sodium sulfate for drying, and carrying out silica chromatography elution [ eluent: (petroleum ether: ethyl acetate ═ 10: 1) ] 13.76g of the compound (4), 4-bromo-6-chloronicotinyl alcohol, was obtained in a yield of 75%.
The fifth step is the synthesis of a compound (5), namely 4-bromo-6-chloronicotinaldehyde:
13.76g of compound (4), 4-bromo-6-chloronicotinyl alcohol (0.062mol) was added to 100ml of methylene chloride, 53.9g of manganese dioxide (0.62mol) was added, the reaction was allowed to react overnight at room temperature, detection was performed by TLC, the reaction solution was filtered through celite, and the resulting filtrate was chromatographed [ eluent: (petroleum ether: ethyl acetate: 5: 1) ], 12.3g of the target compound, 4-bromo-6-chloronicotinaldehyde, was obtained in 85% yield and 98% purity.
The synthesis method disclosed by the invention has the advantages that the comprehensive yield of the target product under the preferable reaction condition is more than 80%, the reaction condition is mild, the operation is simple, large-scale process devices are not involved, and the yield of the synthesized target product is improved compared with the prior art; in addition, the consumption of the reaction solvent is greatly reduced compared with the prior art, and the use of the reaction solvent with the volume of at least 50% is reduced by combining with the specific use condition, so that the method plays a very important role in improving the reduction of environmental pollution, energy conservation and emission reduction, is beneficial to environmental friendliness, and is also suitable for large-scale industrial production.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (7)
1. The synthesis method of the 4-bromo-6-chloronicotinaldehyde is characterized by comprising the following synthetic route:
the specific synthesis steps comprise:
1)4, 6-Dichloronicotinic acid ethyl ester and4-methoxybenzylamine at the reaction temperature T1Stirring the mixture at 40 ℃ until the reaction is finished under the condition that the mass ratio of the substances is 1 (1-4); pouring the reaction solution into ice water, and sequentially carrying out extraction, backwashing, drying and column chromatography elution to obtain a compound (1), namely 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate;
2) adding a compound (1), namely 6-chloro-4- ((4-methoxybenzyl) amino) ethyl nicotinate into trifluoroacetic acid, and heating reaction liquid to 50-60 ℃ for full reaction; after the reaction is finished, part of trifluoroacetic acid is evaporated; pouring the residual reaction solution into ice water, and adjusting the reaction solution to show alkalinity by adopting an alkaline reagent; then the compound (2) 4-amino-6-chloronicotinic acid ethyl ester is obtained by sequentially carrying out extraction, backwashing, drying and column chromatography elution;
3) adding the compound (2) 4-amino-6-chloronicotinic acid ethyl ester into dichloromethane, adding tert-butyl nitrite and benzyl triethyl ammonium bromide, wherein the mass ratio of the compound (2) 4-amino-6-chloronicotinic acid ethyl ester, the tert-butyl nitrite and the benzyl triethyl ammonium bromide is 1:10:5, and reacting at room temperature; after the reaction is finished, pouring the reaction liquid into water, and sequentially carrying out extraction, backwashing, drying and column chromatography elution to obtain a compound (3), namely 4-bromo-6-chloronicotinic acid ethyl ester;
4) completely dissolving the compound (3), namely 4-bromo-6-chloronicotinyl ethyl ester in dichloromethane, and reacting with diisobutylaluminum hydride at the temperature of minus 60 ℃ to minus 70 ℃ under the protection of argon to obtain a compound (4), namely 4-bromo-6-chloronicotinyl alcohol;
5) the compound (4), 4-bromo-6-chloronicotinyl alcohol, is completely dissolved in dichloromethane and reacts under the catalytic action of manganese dioxide to obtain the target product, 4-bromo-6-chloronicotinyl aldehyde, 5.
2. The method for synthesizing 4-bromo-6-chloronicotinaldehyde according to claim 1, wherein the mass ratio of the compound (1) 6-chloro-4- ((4-methoxybenzyl) amino) nicotinic acid ethyl ester to trifluoroacetic acid in the step 2) is 1: (20-40).
3. The method for synthesizing 4-bromo-6-chloronicotinaldehyde according to claim 1, wherein the eluent eluted by column chromatography in step 3) is petroleum ether: ethyl acetate = 100: 1.
4. The method for synthesizing 4-bromo-6-chloronicotinaldehyde according to claim 1, wherein the specific process of the step 4) is as follows: adding the compound (3), namely 4-bromo-6-chloronicotinic acid ethyl ester into dichloromethane, cooling to minus 60 to minus 70 ℃ under the protection of argon, slowly adding diisobutylaluminum hydride, uniformly stirring, heating to 0 ℃, and stirring until complete reaction; adding the reaction solution into ice dilute hydrochloric acid, and then sequentially carrying out extraction, backwashing, drying and column chromatography elution to obtain the compound (4), namely the 4-bromo-6-chloronicotinyl alcohol.
5. The method for synthesizing 4-bromo-6-chloronicotinaldehyde according to claim 1, wherein the mass ratio of the compound (3) ethyl 4-bromo-6-chloronicotinate to diisobutylaluminum hydride in the step 4) is 1: (1-4).
6. The method for synthesizing 4-bromo-6-chloronicotinaldehyde according to claim 1, wherein the specific process of the step 5) is as follows: adding the compound (4) 4-bromo-6-chloronicotinyl alcohol into dichloromethane, adding manganese dioxide as a catalyst, filtering the reaction solution by using kieselguhr after complete reaction at room temperature, and obtaining the target product compound (5) 4-bromo-6-chloronicotinyl aldehyde after removing dichloromethane by reduced pressure distillation after filtering.
7. The method for synthesizing 4-bromo-6-chloronicotinaldehyde according to claim 6, wherein the mass ratio of the compound (4) 4-bromo-6-chloronicotinyl alcohol to manganese dioxide in the step 5) is 1: (2-10).
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