CN112341351B - Preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide - Google Patents
Preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide Download PDFInfo
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- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
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- C07C51/15—Preparation of carboxylic acids or their salts, halides or anhydrides by reaction of organic compounds with carbon dioxide, e.g. Kolbe-Schmitt synthesis
Abstract
The invention discloses a preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, which comprises the following steps: (1) introducing carbon dioxide into the compound (II) under the condition of hydrogen abstraction by butyl lithium to generate a compound (III); (2) nitrifying the compound (III) by concentrated sulfuric acid and nitric acid to generate a compound (IV); (3) reacting the compound (IV) with acyl chloride to generate a compound (V); (4) reacting the compound (V) with ammonia water to generate an amide compound (VI); (5) reducing the amide compound (VI) by iron powder to obtain a compound (VII); (6) carrying out Sandemal reaction on the compound (VII) to obtain a compound (VIII); (7) and (3) reacting the compound (VIII) through ammonia gas at high pressure to generate the compound (I). The preparation method has higher yield.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide.
Background
2-amino-4-bromo-3-fluoro-5-iodobenzamide is a class of key intermediates, WO2018143315 and US20180015087 disclose the following routes to synthesize 2-amino-4-bromo-3-fluoro-5-iodobenzamide compounds I:
in the synthesis method, the price of the starting material 2-fluoro-3-bromonitrobenzene is very expensive in the process of synthesizing the 2-amino-4-bromo-3-fluoro-5-iodobenzamide compound I, and the yield of the 2-amino-4-bromo-3-fluoro-5-iodobenzamide obtained by condensation of the condensing agent in the last step is low, so that the 2-amino-4-bromo-3-fluoro-5-iodobenzamide needs to be purified by a column method and is not beneficial to industrial amplification generation.
Disclosure of Invention
In view of the above problems in the prior art, the present applicant provides a method for preparing 2-amino-4-bromo-3-fluoro-5-iodobenzamide. The preparation method has higher yield.
The technical scheme of the invention is as follows:
a process for the preparation of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, said process being carried out according to the following route:
the method comprises the following specific steps:
(1) introducing carbon dioxide into the compound (II) under the condition of hydrogen abstraction by butyl lithium to generate a compound (III);
(2) nitrifying the compound (III) by concentrated sulfuric acid and nitric acid to generate a compound (IV);
(3) reacting the compound (IV) with acyl chloride to generate a compound (V);
(4) reacting the compound (V) with ammonia water to generate an amide compound (VI);
(5) reducing the amide compound (VI) by iron powder to obtain a compound (VII);
(6) carrying out Sandemal reaction on the compound (VII) to obtain a compound (VIII);
(7) and (3) reacting the compound (VIII) through ammonia gas at high pressure to generate the compound (I).
In the step (1), the molar ratio of the compound (II) to butyl lithium is 1: 1.0-1.25; the reaction conditions are as follows: the temperature is-78 ℃, and the reaction time is 1-2 h.
In the step (2), the solvent is concentrated sulfuric acid; the molar ratio of the compound (III) to the nitric acid is 1: 1.0-1.5; the weight-volume ratio of the compound (III) to concentrated sulfuric acid is 1:5 g/ml; the reaction conditions are as follows: the temperature is 0-30 ℃, and the reaction time is 2-6 h.
In the step (2), the mass concentration of the concentrated sulfuric acid is 98%; the mass concentration of the nitric acid is 68 percent;
in the step (3), the solvent is one or more of toluene, dichloromethane and chloroform; the acyl chloride is thionyl chloride or oxalyl chloride; the molar ratio of the compound (VII) to the acyl chloride is 1: 1.0-5.0; the reaction conditions are as follows: the temperature is 60-110 ℃, and the reaction time is 3-10 h.
In the step (4), the solvent is 28% of strong ammonia water; the molar ratio of the compound (V) to 28% concentrated ammonia water is 1: 1.0-5.0; the reaction conditions are as follows: the temperature is-10 to 20 ℃, and the reaction time is 1 to 2 hours.
In the step (5), the solvent is a mixed solvent of acetic acid, ethanol and water; the molar ratio of the compound (VI) to the iron powder is 1: 1.0-5.0; the reaction conditions are as follows: the temperature is 80-100 ℃, and the reaction time is 6-10 h.
In the step (6), the compound (VII) is subjected to diazotization reaction with sodium nitrite, diazonium salt is replaced by halogen under the catalysis of cuprous iodide or potassium iodide to carry out Sandmell reaction, and the solvent in the process is water or N, N-dimethylformamide; the iodinating agent is potassium iodide or cuprous iodide; the molar ratio of the compound (VII) to the sodium nitrite to the potassium iodide is 1: 1.0-1.5: 4.0-6.0; the diazotization reaction conditions are as follows: the temperature is-10 to 0 ℃, and the reaction time is 0.5 to 3 hours; the reaction conditions of the sandwort reaction are as follows: the temperature is 60-80 ℃, and the reaction time is 0.5-3 h.
In the step (7), the solvent is one or more of methanol, ethanol, isopropanol, N-dimethylformamide and dimethyl sulfoxide; the ammonia is ammonia gas or ammonia water; the high pressure conditions were: the pressure is 0.1 MPa-2 MPa; the reaction conditions are as follows: the temperature is 30-120 ℃, and the reaction time is 1-10 h.
The beneficial technical effects of the invention are as follows:
the invention adopts the 2, 3-difluorobromobenzene as the starting material, avoids using expensive starting material in the process of the total synthesis route, is easy to process the reaction in each step, does not need complicated operations such as column-passing purification and the like, and has the lowest yield of 82 percent and the total yield of about 53.7 percent in each step. Low cost and high yield, and is very suitable for industrial production.
Drawings
FIG. 1 is a 1H-NMR spectrum of 2-amino-4-bromo-3-fluoro-5-iodobenzamide obtained in example 1;
FIG. 2 is a GC spectrum of 2-amino-4-bromo-3-fluoro-5-iodobenzamide obtained in example 1.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1
A method for preparing 2-amino-4-bromo-3-fluoro-5-iodobenzamide, said method comprising the steps of:
(1) synthesis of Compound III
193g (1mol) of 2, 3-difluorobromobenzene and 1000ml of tetrahydrofuran are added into a reaction bottle, 2.5M butyl lithium 500ml is dropwise added when the temperature is reduced to-78 ℃, the mixture is stirred for 30min after the dropwise addition, carbon dioxide is introduced, the temperature is kept for reacting for 1 hour, and the HPLC tracking reaction is carried out until the 2, 3-difluorobromobenzene is completely reacted; adding 1000ml of water for quenching reaction, layering by 1000ml of ethyl acetate, adjusting the pH value of an aqueous layer to 3, precipitating a solid, filtering and drying to obtain 222g of a compound III, wherein the molar yield is as follows: 93.6 percent.
(2) Synthesis of Compound IV
Adding 200g (843.9mmol) of compound III and 1000ml of 98% concentrated sulfuric acid into a reaction bottle, cooling to 0 ℃, dropwise adding 118.7g (1266mmol) of 68% concentrated nitric acid, stirring for 6h at 0 ℃, and carrying out HPLC tracking reaction until the compound III is completely reacted; cooling, quenching to 3000ml of water, filtering the solid, pulping by ethyl acetate and purifying to obtain 225g of a compound IV, wherein the molar yield is as follows: 94.5 percent.
(3) Synthesis of Compound V
Adding 141g (500mmol) of compound IV, 500ml of toluene and 36.1ml (500mmol) of thionyl chloride into a reaction bottle, heating to 110 ℃, refluxing for 10h, and carrying out HPLC tracking reaction until the compound IV is completely reacted; the reaction solution was concentrated to give 136g of compound V, molar yield: 91 percent
(4) Synthesis of Compound VI
Adding 36ml of 28% ammonia water (500mmol) into a reaction bottle, cooling to-10 ℃, slowly adding 150g (500mmol) of the compound V, controlling the reaction temperature to-10 ℃, stirring for 2 hours, and carrying out HPLC tracking reaction until the compound V completely reacts; filtering, pulping with 1000ml of water, filtering and drying to obtain 107.4g of a compound VI with the molar yield: 84 percent
(5) Synthesis of Compound VII
Adding 100g (355.9mmol) of compound VI, 800ml of ethanol, 200ml of water and 100ml of acetic acid into a reaction bottle, heating to 80 ℃, adding 20g (355.9mmol) of iron powder in a small amount for multiple times, heating, refluxing and stirring for 10 hours after the addition is finished, and carrying out HPLC tracking reaction until the compound VI is completely reacted; cooling to 5 ℃, filtering, concentrating the filtrate, adding 1200ml of methanol, filtering and drying to obtain 73.6g of a compound VII with a molar yield: 82.4 percent
(6) Synthesis of Compound VIII
Adding 66.5g (265mmol) of compound VII, 500ml of 40% sulfuric acid aqueous solution and 100ml of N, N-dimethylformamide into a reaction bottle, cooling to 0 ℃, dropwise adding 50ml of prepared 18.2g (265mmol) of sodium nitrite aqueous solution, stirring for 3h at 0 ℃, dropwise adding 500ml of prepared 177g (1.06mol) of potassium iodide solution, heating to 60 ℃, stirring for 3h, and performing HPLC tracking reaction until the compound VII is completely reacted; adding 1000ml ethyl acetate for extraction, washing an organic layer by saturated sodium chloride, drying and concentrating a reaction solution, pulping by isopropanol to obtain 78.6g of a compound VIII, wherein the molar yield is as follows: 82 percent of
(7) Synthesis of Compound I
Adding 70g (193.3mmol) of compound VIII, 400ml of N, N-dimethylformamide into a reaction bottle, introducing ammonia gas, heating to 120 ℃, reacting for 10 hours under the pressure of 0.1Mpa by stirring, and carrying out HPLC tracking reaction until the compound VIII is completely reacted; concentrating the reaction solution to dryness, recrystallizing and drying by methanol to obtain 62g of a compound I, wherein the molar yield is as follows: 88.5 percent.
FIG. 1 shows the hydrogen spectrum of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, 1H-NMR (400MHz, DMSO-d)6)δ:8.04～7.95(d,2H，CONH2),7.42(s,1H，H-6),6.85(br,2H，NH2)。
Fig. 2 is a gas chromatogram of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, and it can be seen that the purity of 2-amino-4-bromo-3-fluoro-5-iodobenzamide compound I is greater than 98%.
Example 2
A method for preparing 2-amino-4-bromo-3-fluoro-5-iodobenzamide, said method comprising the steps of:
(1) synthesis of Compound III
193g (1mol) of 2, 3-difluorobromobenzene and 1000ml of tetrahydrofuran are added into a reaction bottle, 2.5M butyl lithium 400ml is dropwise added when the temperature is reduced to-78 ℃, the mixture is stirred for 30min after the dropwise addition, carbon dioxide is introduced, the temperature is kept for reacting for 2h, and the HPLC tracking reaction is carried out until the 2, 3-difluorobromobenzene is completely reacted; adding 1000ml of water for quenching reaction, layering by 1000ml of ethyl acetate, adjusting the pH value of an aqueous layer to 3, precipitating a solid, filtering and drying to obtain 201.8g of a compound III, wherein the molar yield is as follows: 85.1 percent.
(2) Synthesis of Compound IV
Adding 200g (843.9mmol) of compound III and 1000ml of concentrated sulfuric acid into a reaction bottle, cooling to 30 ℃, dropwise adding 98.9g (1055mmol) of 68% concentrated nitric acid, slowly stirring for 2h at 30 ℃ after dropwise adding is finished, and carrying out HPLC tracking reaction until the compound III completely reacts; cooling, quenching to 3000ml water, filtering the solid, pulping and purifying by ethyl acetate to obtain 214.3g of compound IV, the molar yield: 90 percent.
(3) Synthesis of Compound V
Adding 141g (500mmol) of compound IV, 500ml of dichloromethane and 180.5ml (2.5mol) of thionyl chloride into a reaction bottle, heating to 40 ℃, refluxing for 3h, and carrying out HPLC tracking reaction until the compound IV is completely reacted; the reaction solution was concentrated to obtain 150g of compound V, molar yield: 100 percent
(4) Synthesis of Compound VI
Adding 90ml of 28% ammonia water (1.25mol) into a reaction bottle, cooling to 0 ℃, slowly adding 150g (500mmol) of the compound V, controlling the reaction temperature to 0 ℃, stirring for 1.5 hours, and carrying out HPLC tracking reaction until the compound V is completely reacted; filtering, pulping with 1000ml water, filtering, drying to obtain 112.8g of compound VI, the molar yield: 88.2 percent
(5) Synthesis of Compound VII
Adding 100g (355.9mmol) of compound VI, 800ml of ethanol, 200ml of water and 100ml of acetic acid into a reaction bottle, heating to 90 ℃, adding 50g (890mmol) of iron powder in a small amount for multiple times, heating, refluxing and stirring for 8 hours after the addition is finished, and carrying out HPLC tracking reaction until the compound VI is completely reacted; cooling to 5 ℃, filtering, concentrating the filtrate, adding 1200ml of methanol, filtering and drying to obtain 77.3g of a compound VII with a molar yield: 86.5 percent
(6) Synthesis of Compound VIII
Adding 66.5g (265mmol) of compound VII, 500ml of 40% sulfuric acid aqueous solution and 100ml of N, N-dimethylformamide into a reaction bottle, cooling to-5 ℃, dropwise adding 50ml of prepared 22.75g (331mmol) of sodium nitrite aqueous solution, stirring for 1.5h at the temperature of-5 ℃, dropwise adding 500ml of prepared 220g (1.32mol) of potassium iodide solution, heating to 70 ℃, stirring for 1.5h, and carrying out HPLC tracking reaction until the compound VII is completely reacted; adding 1000ml ethyl acetate for extraction, washing an organic layer by saturated sodium chloride, drying and concentrating a reaction solution, pulping by isopropanol to obtain 82.5g of a compound VIII, wherein the molar yield is as follows: 86.1 percent
(7) Synthesis of Compound I
Adding 70g (193.3mmol) of compound VIII and 400ml of methanol into a reaction bottle, introducing ammonia gas, heating to 30 ℃, reacting for 5 hours under the pressure of 1Mpa, and carrying out HPLC tracking reaction until the compound VIII completely reacts; concentrating the reaction solution to dryness, recrystallizing and drying by methanol to obtain 60g of a compound I, wherein the molar yield is as follows: 85.6 percent.
Example 3
A method for preparing 2-amino-4-bromo-3-fluoro-5-iodobenzamide, said method comprising the steps of:
(1) synthesis of Compound III
193g (1mol) of 2, 3-difluorobromobenzene and 1000ml of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to-78 ℃, 440ml of 2.5M butyl lithium is dropwise added, the mixture is stirred for 30min after the dropwise addition, carbon dioxide is introduced, the temperature is kept for reacting for 1.5h, and the HPLC tracking reaction is carried out until the 2, 3-difluorobromobenzene is completely reacted; adding 1000ml of water for quenching reaction, layering by 1000ml of ethyl acetate, adjusting the pH value of an aqueous layer to 3, precipitating a solid, filtering and drying to obtain 211.4g of a compound III with a molar yield: 89.1 percent.
(2) Synthesis of Compound IV
Adding 200g (843.9mmol) of compound III and 1000ml of concentrated sulfuric acid into a reaction bottle, cooling to 15 ℃, dropwise adding 79.2g (843.9mmol) of 68% concentrated nitric acid, slowly returning to 15 ℃ after dropwise adding, stirring for 4h, and carrying out HPLC tracking reaction until the compound III is completely reacted; cooling, quenching to 3000ml of water, filtering the solid, pulping by ethyl acetate and purifying to obtain 204.5g of a compound IV, wherein the molar yield is as follows: 85.9 percent.
(3) Synthesis of Compound V
Adding 141g (500mmol) of compound IV, 500ml of chloroform and 90.25ml (1.25mol) of thionyl chloride into a reaction bottle, heating to 60 ℃, refluxing for 6h, and carrying out HPLC tracking reaction until the compound IV is completely reacted; the reaction solution was concentrated to obtain 150g of compound V, molar yield: 100 percent
(4) Synthesis of Compound VI
Adding 180ml of 28% ammonia water (2.5mol) into a reaction bottle, cooling to 20 ℃, slowly adding 150g (500mmol) of the compound V, controlling the reaction temperature to 20 ℃, stirring for 1 hour, and carrying out HPLC tracking reaction until the compound V completely reacts; filtering, pulping with 1000ml of water, filtering and drying to obtain 130g of a compound VI, wherein the molar yield is as follows: 92.5 percent
(5) Synthesis of Compound VII
Adding 100g (355.9mmol) of compound VI, 800ml of ethanol, 200ml of water and 100ml of acetic acid into a reaction bottle, heating to 80 ℃, adding 100g (1.78mol) of iron powder in a small amount for multiple times, heating, refluxing and stirring for 6 hours, and performing HPLC tracking reaction until the compound VI completely reacts; cooling to 5 ℃, filtering, concentrating the filtrate, adding 1200ml of methanol, filtering and drying to obtain 81g of a compound VII with a molar yield: 90.6 percent
(6) Synthesis of Compound VIII
Adding 66.5g (265mmol) of compound VII, 500ml of 40% sulfuric acid aqueous solution and 100ml of N, N-dimethylformamide into a reaction bottle, cooling to-10 ℃, dropwise adding 50ml of 27.3g (397.5mol) of sodium nitrite aqueous solution prepared in advance, stirring for 0.5h at the temperature of-10 ℃, dropwise adding 500ml of 177g (1.06mol) of potassium iodide solution prepared in advance, heating to 80 ℃, stirring for 0.5h, and carrying out HPLC tracking reaction until the compound VII is completely reacted; adding 1000ml ethyl acetate for extraction, washing an organic layer by saturated sodium chloride, drying and concentrating a reaction solution, pulping by isopropanol to obtain 76.6g of a compound VIII, wherein the molar yield is as follows: 80 percent of
(7) Synthesis of Compound I
Adding 70g (193.3mmol) of compound VIII and 400ml of ethanol into a reaction bottle, introducing ammonia gas, heating to 70 ℃, reacting for 1 hour under the pressure of 1Mpa, and carrying out HPLC tracking reaction until the compound VIII completely reacts; concentrating the reaction solution to dryness, recrystallizing and drying by methanol to obtain 59g of a compound I, wherein the molar yield is as follows: 84.2 percent.
Claims (9)
1. A preparation method of 2-amino-4-bromo-3-fluoro-5-iodobenzamide, which is characterized by comprising the following steps:
the method comprises the following specific steps:
(1) introducing carbon dioxide into the compound (II) under the condition of hydrogen abstraction by butyl lithium to generate a compound (III);
(2) nitrifying the compound (III) by concentrated sulfuric acid and nitric acid to generate a compound (IV);
(3) reacting the compound (IV) with acyl chloride to generate a compound (V);
(4) reacting the compound (V) with ammonia water to generate an amide compound (VI);
(5) reducing the amide compound (VI) by iron powder to obtain a compound (VII);
(6) carrying out Sandemal reaction on the compound (VII) to obtain a compound (VIII);
(7) and (3) reacting the compound (VIII) through ammonia gas at high pressure to generate the compound (I).
2. The preparation method according to claim 1, wherein in the step (1), the molar ratio of the compound (II) to the butyllithium is 1:1.0 to 1.25; the reaction conditions are as follows: the temperature is-78 ℃, and the reaction time is 1-2 h.
3. The method according to claim 1, wherein in the step (2), the solvent is concentrated sulfuric acid; the molar ratio of the compound (III) to the nitric acid is 1: 1.0-1.5; the weight-volume ratio of the compound (III) to concentrated sulfuric acid is 1:5 g/ml; the reaction conditions are as follows: the temperature is 0-30 ℃, and the reaction time is 2-6 h.
4. The preparation method according to claim 3, wherein in the step (2), the mass concentration of the concentrated sulfuric acid is 98%; the mass concentration of the nitric acid is 68 percent.
5. The preparation method according to claim 1, wherein in the step (3), the solvent is one or more of toluene, dichloromethane and chloroform; the acyl chloride is thionyl chloride or oxalyl chloride; the molar ratio of the compound (VII) to the acyl chloride is 1: 1.0-5.0; the reaction conditions are as follows: the temperature is 60-110 ℃, and the reaction time is 3-10 h.
6. The method according to claim 1, wherein in the step (4), the solvent is 28% concentrated ammonia water; the molar ratio of the compound (V) to 28% concentrated ammonia water is 1: 1.0-5.0; the reaction conditions are as follows: the temperature is-10 to 20 ℃, and the reaction time is 1 to 2 hours.
7. The production method according to claim 1, wherein in the step (5), the solvent is a mixed solvent of acetic acid, ethanol and water; the molar ratio of the compound (VI) to the iron powder is 1: 1.0-5.0; the reaction conditions are as follows: the temperature is 80-100 ℃, and the reaction time is 6-10 h.
8. The preparation method according to claim 1, wherein in the step (6), the compound (VII) is subjected to diazotization with sodium nitrite, the diazonium salt is substituted by halogen under the catalysis of cuprous iodide or potassium iodide to carry out Sandmell reaction, and the solvent in the process is water or N, N-dimethylformamide; the iodinating agent is potassium iodide or cuprous iodide; the molar ratio of the compound (VII) to the sodium nitrite to the potassium iodide is 1: 1.0-1.5: 4.0-6.0; the diazotization reaction conditions are as follows: the temperature is-10 to 0 ℃, and the reaction time is 0.5 to 3 hours; the conditions of the Sandemall reaction are as follows: the temperature is 60-80 ℃, and the reaction time is 0.5-3 h.
9. The preparation method according to claim 1, wherein in the step (7), the solvent is one or more of methanol, ethanol, isopropanol, N-dimethylformamide and dimethyl sulfoxide; the ammonia is ammonia gas or ammonia water; the high pressure conditions were: the pressure is 0.1 MPa-2 MPa; the reaction conditions are as follows: the temperature is 30-120 ℃, and the reaction time is 1-10 h.
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