CN113698310B - Preparation method of enzalutamide diester intermediate - Google Patents
Preparation method of enzalutamide diester intermediate Download PDFInfo
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- CN113698310B CN113698310B CN202110959547.4A CN202110959547A CN113698310B CN 113698310 B CN113698310 B CN 113698310B CN 202110959547 A CN202110959547 A CN 202110959547A CN 113698310 B CN113698310 B CN 113698310B
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
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Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an enzalutamide diester intermediate, and more particularly relates to a preparation method of 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] methyl benzoate, which comprises the steps of taking 2-fluoro-4-bromobenzoic acid, 2-aminoisobutyric acid, N-dimethylformamide, potassium carbonate, water and dimethyl sulfate as raw materials, generating an intermediate potassium salt in the reaction process, and directly participating in the subsequent esterification reaction to obtain a target product. The preparation method provided by the invention adopts a one-step method, does not need to carry out step by step, directly utilizes the intermediate potassium salt for esterification, is simple and efficient, reduces the use of acid, ethyl acetate extractant and the like in the reaction process, improves the production efficiency, and is more environment-friendly.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of an enzalutamide diester intermediate, and more particularly relates to a preparation method of 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] methyl benzoate.
Background
Methyl 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] benzoate is an important intermediate for synthesizing enzalutamide diester. In the prior art, 2-fluoro-4-bromobenzoic acid, 2-aminoisobutyric acid, N-Dimethylformamide (DMF), ethyl Acetate (EA), isopropyl acetate (IPAc) and the like are generally used as raw materials, and are prepared in multiple steps including coupling reaction, esterification reaction and the like, and meanwhile, in the preparation process, acid is used for adjusting the pH of a solution to acidity, then an intermediate product 4- (1-carboxyl-1-methyl-ethylamino) -2-fluoro-benzoic acid is solidified, purified and then subjected to esterification reaction, so that the overall reaction process is complex, a large amount of acidic wastewater is generated in the preparation process, and the wastewater treatment difficulty and cost are increased. The development of a simple, efficient and environment-friendly preparation method is urgently needed.
Disclosure of Invention
In view of the above drawbacks or needs for improvement of the prior art, the present invention provides a method for preparing an enzalutamide diester intermediate, which is methyl 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] benzoate. The preparation method provided by the invention adopts a one-step method, does not need to carry out step by step, directly utilizes the intermediate potassium salt for esterification, is simple and efficient, reduces the use of acid, ethyl acetate extractant and the like in the reaction process, improves the production efficiency, and is more environment-friendly.
In order to achieve the above object, the present invention provides a method for preparing an enzalutamide diester intermediate, comprising: sequentially adding 2-fluoro-4-bromobenzoic acid, 2-aminoisobutyric acid and N, N-dimethylformamide into a reaction bottle, adding potassium carbonate and primary water while stirring, vacuumizing and replacing nitrogen, adding cuprous chloride, keeping the nitrogen protection, carrying out high-temperature heat preservation reaction for 10-20h, cooling after the reaction is finished, dropwise adding dimethyl sulfate, carrying out heat preservation reaction for 1.5-2.5h at the temperature, adding secondary water after the reaction is finished, stirring and crystallizing for 1-1.5h, filtering to obtain a crude product, adding the crude product into methanol, heating and refluxing for 1-2h, cooling and crystallizing, filtering, and drying to obtain a target compound methyl 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] benzoate, wherein the reaction formula is as follows:
wherein, the compound of formula (I) is intermediate potassium salt. The one-step method is adopted in the technical scheme for preparation, the intermediate potassium salt is dipotassium salt, can directly participate in the subsequent esterification reaction, does not need to adjust the reaction solution to be acidic by acid and extract by ethyl acetate, and is high in reaction speed and purity.
Further, in the technical scheme, before the dimethyl sulfate is dropwise added, the N, N-dimethylformamide is added and stirred. Further, potassium carbonate may be added in an amount of 0 to 3.5% based on the total amount of potassium carbonate.
Further, the high temperature range in the above technical scheme is 130-140 ℃. In the technical scheme, the temperature is strictly controlled, when the reaction temperature is too high, byproducts are increased, the purity is low, and when the reaction temperature is too low, the reaction time is prolonged, and the reaction efficiency is low.
Further, in the reaction of the technical scheme, the molar ratio of the 2-fluoro-4-bromobenzoic acid to the potassium carbonate is 1. The potassium carbonate in the technical scheme can be added at one time, and can also be added at the later stage accounting for 0-3.5% of the total amount. However, the total reaction amount cannot be less than 2.5 times of the molar amount of the 2-fluoro-4-bromobenzoic acid, otherwise the reaction time is prolonged and the reaction speed is slow.
Further, in the reaction of the technical scheme, the molar ratio of the 2-fluoro-4-bromobenzoic acid to the 2-aminoisobutyric acid is 1.4-1.8.
Further, in the reaction of the technical scheme, the molar ratio of the 2-fluoro-4-bromobenzoic acid to the N, N-dimethylformamide is 1.
Further, in the reaction of the technical scheme, the molar ratio of the 2-fluoro-4-bromobenzoic acid to the dimethyl sulfate is 1.8-2.2.
Further, in the reaction of the technical scheme, the molar ratio of the 2-fluoro-4-bromobenzoic acid to the cuprous chloride is 1.
Further, in the reaction of the technical scheme, the mass-volume ratio (kg/L) of the 2-fluoro-4-bromobenzoic acid to the total water amount is 1; wherein the mass volume ratio (kg/L) of the 2-fluoro-4-bromobenzoic acid to the primary water amount is 1. In the technical scheme, the amount of the first water addition is relatively small, and the main purpose is to provide conditions for the reaction of the N, N-dimethylformamide; the amount of the second water addition is relatively large, and the main purpose is to prevent salt residues in the reaction product.
Further, in the technical scheme, the crystallization temperature is 0-5 ℃.
Compared with the prior art, the invention has the following beneficial effects:
1. the preparation method adopts a one-step method, takes 2-fluoro-4-bromobenzoic acid, 2-aminoisobutyric acid, N-dimethylformamide, potassium carbonate, water and dimethyl sulfate as raw materials, generates an intermediate potassium salt in the reaction process, does not need to dissociate, omits the operations of acidification, extraction, layering, drying, distillation and the like, and simplifies the process;
2. the intermediate dipotassium salt can be separated or not separated and directly enters an esterification procedure, so that the use of an acid-binding agent (potassium carbonate) in the esterification procedure is reduced or not used;
3. according to the invention, the reaction liquid does not need to be adjusted to be acidic, the use of acid, ethyl acetate extractant and the like is reduced, the occupation of multiple devices in production is avoided, and the production efficiency is improved; meanwhile, no acidic waste liquid is generated, the waste liquid is simple to treat, and the cost is low;
4. the invention has the advantages that the reaction conditions are reasonably controlled, the reaction speed is high, and the purity of the obtained target product is high;
5. the invention adopts one-step synthesis, and has the advantages of simple method, high efficiency and environmental protection.
Detailed Description
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials in the following examples are all ordinary commercial products and can be obtained by commercial purchase, unless otherwise specified.
The above-mentioned technical features of the present invention and those described in detail below (e.g., in the embodiments) can be combined with each other to form a new or preferred embodiment.
Example 1
At room temperature, sequentially adding 2-fluoro-4-bromobenzoic acid (50 g), 2-aminoisobutyric acid (36 g) and N, N-dimethylformamide (225 g) into a reaction bottle, adding potassium carbonate (82 g) and water (10 mL) under stirring, vacuumizing, replacing with nitrogen, adding cuprous chloride (5 g), maintaining nitrogen protection, heating to 130 ℃, keeping the temperature for reaction for 12 hours, after the reaction is finished, cooling to 30 ℃, dropwise adding dimethyl sulfate (57.5 g), keeping the temperature for reaction for 2 hours, after the reaction is finished, adding water (600 mL), stirring, crystallizing for 1 hour, filtering to obtain a crude product, adding the crude product into methanol (65 mL), heating and refluxing for 2 hours, cooling to 0 ℃, crystallizing, filtering and drying to obtain 55g of a target compound, wherein the molar yield is 81.4%, and the purity is 99.68% by an HPLC method.
Example 2
At room temperature, sequentially adding 2-fluoro-4-bromobenzoic acid (50 g), 2-aminoisobutyric acid (40 g) and N, N-dimethylformamide (235 g) into a reaction bottle, adding potassium carbonate (90 g) and water (20 mL) under stirring, vacuumizing, replacing with nitrogen, adding cuprous chloride (5.5 g), maintaining nitrogen protection, heating to 140 ℃, keeping warm, reacting for 15 hours, cooling to 40 ℃ after reaction, dropwise adding dimethyl sulfate (55.2 g), keeping warm at the temperature, reacting for 2.5 hours, adding water (650 mL) after reaction, stirring, crystallizing for 1.5 hours, discharging, centrifuging to obtain a crude product, adding the crude product into methanol (68 mL), heating, refluxing for 1 hour, cooling to 5 ℃ for crystallizing, filtering and drying to obtain a target compound 47.6g, wherein the molar yield is 80.8%, and the purity is 99.91% by an HPLC method.
Example 3
At room temperature, sequentially adding 2-fluoro-4-bromobenzoic acid (50 g), 2-aminoisobutyric acid (36 g) and N, N-dimethylformamide (225 g) into a reaction bottle, adding potassium carbonate (82 g) and water (30 mL) under stirring, vacuumizing and replacing with nitrogen, adding cuprous chloride (5 g), maintaining the nitrogen protection, heating to 130 ℃, keeping the temperature and reacting for 12 hours, cooling the materials to 90 ℃ after the reaction is finished, filtering, stirring and cooling the filtrate to 30 ℃ for crystallization for 1 hour, putting the obtained intermediate into the reaction bottle again after filtering, adding N, N-dimethylformamide (110 g), dropwise adding dimethyl sulfate (57.5 g), keeping the temperature and reacting for 2 hours at the temperature, adding water (600 mL) after the reaction is finished, stirring and crystallizing for 1 hour, filtering to obtain a crude product, adding the crude product into methanol (65 mL), heating and refluxing for 2 hours, cooling to 0 ℃ for crystallization, filtering and drying to obtain 55g of a target compound, wherein the molar yield is 89.5%, and the purity is 99.92% determined by an HPLC method.
Example 4
At room temperature, sequentially adding 2-fluoro-4-bromobenzoic acid (500 g), 2-aminoisobutyric acid (370 g) and N, N-dimethylformamide (2300 g) into a reaction bottle, adding potassium carbonate (825 g) and water (400 mL) under stirring, vacuumizing, replacing with nitrogen, adding cuprous chloride (50 g), maintaining the nitrogen protection, heating to 140 ℃, carrying out heat preservation reaction for 17 hours, cooling to 90 ℃ after the reaction is finished, filtering, stirring and cooling the filtrate to 40 ℃ for crystallization for 1 hour, putting the obtained intermediate into the reaction bottle again after filtering, adding N, N-dimethylformamide (1150 g), dropwise adding dimethyl sulfate (575 g), carrying out heat preservation reaction for 2.5 hours at the temperature, adding water (6L) after the reaction is finished, stirring for crystallization for 1.5 hours, filtering to obtain a crude product, adding the crude product into methanol (650 mL), heating and refluxing for 1.5 hours, cooling to 5 ℃ for crystallization, filtering and drying to obtain 559g of a target compound, wherein the molar yield is 91.0%, and the purity is 99.90% by adopting an HPLC method.
Comparative example 1
2-fluoro-4-bromobenzoic acid (50 g), 2-aminoisobutyric acid (36 g) and N, N-dimethylformamide (225 g) were sequentially charged into a reaction flask at room temperature, potassium carbonate (82 g) was added with stirring, the system was thick at this time, cuprous chloride (5 g) was added after vacuum nitrogen replacement, the system was diluted, and the system gradually thickened after about 20 min. Maintaining the nitrogen protection, heating to 130 ℃, keeping the temperature for reaction for 12h, after the reaction is finished, cooling to 30 ℃, thickening the materials, increasing the stirring force, dropwise adding dimethyl sulfate (57.5 g), gradually thinning the system, keeping the temperature for reaction for 2h, after the reaction is finished, adding water (600 mL), stirring and crystallizing for 1h, filtering to obtain a crude product, adding the crude product into methanol (65 mL), heating and refluxing for 2h, cooling to 0 ℃, crystallizing, filtering, drying to obtain 45g of a target compound, wherein the molar yield is 73.3%, and the purity is 99.7% by HPLC (high performance liquid chromatography).
Comparative example 2
At room temperature, sequentially adding 2-fluoro-4-bromobenzoic acid (50 g), 2-aminoisobutyric acid (36 g) and N, N-dimethylformamide (225 g) into a reaction bottle, adding potassium carbonate (82 g) and methanol (10 mL) under stirring, vacuumizing, replacing with nitrogen, adding cuprous chloride (5 g), maintaining nitrogen protection, heating to 120 ℃, keeping the temperature, reacting for 12 hours, cooling to 30 ℃ after the reaction is finished, dropwise adding dimethyl sulfate (57.5 g), keeping the temperature, reacting for 2 hours, adding water (600 mL), stirring, crystallizing for 1 hour after the reaction is finished, filtering to obtain a crude product, adding the crude product into methanol (65 mL), heating, refluxing for 2 hours, cooling to 0 ℃, crystallizing, filtering, drying to obtain a target compound 46.5g, wherein the molar yield is 75.7%, and the purity is 99.60% by an HPLC method.
Comparative example 3
At room temperature, 2-fluoro-4-bromobenzoic acid (50 g), 2-aminoisobutyric acid (36 g) and isopropyl acetate (225 g) were sequentially added to a reaction flask, potassium carbonate (82 g) and water (10 mL) were added with stirring, and after vacuum nitrogen replacement, cuprous chloride (5 g) was added, and while maintaining nitrogen protection, the temperature was raised to 80 ℃ and the reaction was maintained for 12 hours, followed by continuous TLC, and the compound (I) formation was not observed even after 24 hours of reaction.
Comparative example 4 (prepared by the method of patent WO 2011/106570A 1)
To a reaction flask was charged 2-fluoro-4-bromobenzoic acid (50 g), 2-aminoisobutyric acid (36 g) and potassium carbonate (78.8 g), followed by DMF (250 mL), H 2 O (30 mL), vacuum-pumping nitrogen for three times under stirring, then rapidly adding CuCl (5 g), heating to above 90 ℃ and keeping the temperature for reaction for 16h. After the reaction, water and ethyl acetate were added, the layers were washed and separated, and 1M citric acid was added to the aqueous layer to adjust the pH to 3-4. Then, ethyl acetate (200 mL. Times.3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate was added, and the filtrate was distilled to dryness under reduced pressure to give 45g of light brown 4- [ (1-carboxy-1-methylethyl) amino group]-2-fluorobenzoic acid solid in 81.7% molar yield and 99.0% HPLC purity.
Adding light brown 4- [ (1-carboxyl-1-methylethyl) amino ] -2-fluorobenzoic acid solid (45 g) and DMF (135 mL) into a reaction bottle, stirring to dissolve, adding potassium carbonate (62 g), dropwise adding dimethyl sulfate (47 g) at room temperature, keeping the temperature for 1-2h after dropwise adding, and monitoring by TLC until the raw materials disappear. After the reaction is finished, adding water (600 mL), heating to 60 ℃, keeping the temperature for more than 1h (destroying residual DMS), cooling to room temperature, crystallizing for 2h, filtering, rinsing with water to obtain a wet product of 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] methyl benzoate, and drying at 55-60 ℃ to obtain 46.2g of a target compound with the molar yield of 92.0% and the purity of 99.37% by liquid phase HPLC, wherein the comprehensive molar yield of the two steps is 75.2%.
And (4) comprehensive conclusion:
from the results of examples 1 and 2 and examples 3 and 4, it can be seen that when methyl 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] benzoate was synthesized in a one-step process with a purity as high as 99.92% and the yields of examples 3 and 4 were slightly higher than those of examples 1 and 2, it was demonstrated that the yield of the desired product could be improved by properly crystallizing the intermediate potassium salt.
As can be seen from the results of example 1 and comparative examples 1 to 3, when no water was added to the initial reaction, the product yield was low; when methanol is used for replacing water in the initial reaction, the product yield is low; when IPAc is used for replacing DMF and water in the initial reaction, the reaction can not be carried out, which shows that the effect of adopting DMF and water in the initial reaction is better.
From the results of examples 1 and 3 and comparative example 4, it can be seen that comparative example 4, which uses the coupling reaction method of WO 2011/106570A1, example 9B in combination with the esterification reaction method described herein, to prepare methyl 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] benzoate in two steps, appears to have a high single-step yield, but has a combined yield of only 75.2%, lower than those of examples 1 and 3, and has a significant difference from that of example 3; it is also slightly lower in purity than the inventive examples. The methyl 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] benzoate prepared by the one-step method has high yield and purity.
Finally, it should be emphasized that the above-described preferred embodiments of the present invention are merely examples of implementations, rather than limitations, and that many variations and modifications of the invention are possible to those skilled in the art, without departing from the spirit and scope of the invention.
Claims (7)
1. A preparation method of an enzalutamide diester intermediate is characterized by comprising the following steps: sequentially adding 2-fluoro-4-bromobenzoic acid, 2-aminoisobutyric acid and N, N-dimethylformamide into a reaction bottle, adding potassium carbonate and primary water while stirring, vacuumizing, replacing with nitrogen, adding cuprous chloride, keeping the nitrogen protection, keeping at high temperature for 10-20h, cooling to 20-60 ℃ after the reaction is finished, dropwise adding dimethyl sulfate, keeping at the temperature for 1.5-2.5h, adding secondary water after the reaction is finished, stirring for crystallization for 1-1.5h, filtering to obtain a crude product, adding the crude product into methanol, heating for reflux for 1-2h, cooling for crystallization, filtering, and drying to obtain a target compound methyl 2-fluoro-4- [ (1-methoxy-2-methyl-1-oxo-2-propyl) amino ] benzoate, wherein the reaction formula is as follows:
wherein, the compound of formula (I) is intermediate potassium salt;
in the reaction, the molar ratio of the 2-fluoro-4-bromobenzoic acid to the dimethyl sulfate is 1.8-2.2;
in the reaction, the mass volume ratio kg/L of the 2-fluoro-4-bromobenzoic acid to the total water amount is 1; wherein the mass volume ratio kg/L of the 2-fluoro-4-bromobenzoic acid to the primary water amount is 1;
in the reaction, the molar ratio of 2-fluoro-4-bromobenzoic acid to 2-aminoisobutyric acid is 1.4 to 1.8.
2. The method for preparing the enzalutamide diester intermediate according to claim 1, wherein N, N-dimethylformamide is added and stirred before the dimethyl sulfate is added dropwise.
3. The method for preparing enzalutamide diester intermediate as claimed in claim 1, wherein the elevated temperature is in the range of 130-140 ℃.
4. The method for preparing the enzalutamide diester intermediate as claimed in claim 1, wherein the molar ratio of 2-fluoro-4-bromobenzoic acid to potassium carbonate in the reaction is 1.
5. The method for preparing the enzalutamide diester intermediate as claimed in claim 1, wherein the molar ratio of 2-fluoro-4-bromobenzoic acid to N, N-dimethylformamide in the reaction is 1.
6. The method for preparing the enzalutamide diester intermediate according to claim 1, wherein the molar ratio of 2-fluoro-4-bromobenzoic acid to cuprous chloride in the reaction is 1.
7. The method for preparing the enzalutamide diester intermediate as claimed in claim 1, wherein the temperature for crystallization is 0-5 ℃.
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