CN112094253A - Synthetic method for preparing SGLT inhibitor intermediate - Google Patents
Synthetic method for preparing SGLT inhibitor intermediate Download PDFInfo
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- CN112094253A CN112094253A CN202010948961.0A CN202010948961A CN112094253A CN 112094253 A CN112094253 A CN 112094253A CN 202010948961 A CN202010948961 A CN 202010948961A CN 112094253 A CN112094253 A CN 112094253A
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- dihydrobenzofuran
- dibromo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
Abstract
A process for preparing compound 1 and compound 2, compound 1 and compound 2 having the structures shown below, said process comprising the steps of:
Description
Technical Field
The invention belongs to the field of organic chemical synthesis of medical intermediates, and particularly relates to a method for synthesizing an SGLT inhibitor by using an independently designed and innovative intermediate.
Background
Diabetes is one of the major diseases that challenge human health in the 21 st century. In 2019, China estimates that 1.16 million adults have diabetes, a patient also faces the risk of life-threatening complications. In the estimated 1.16 million people, over 6500 million people have not been diagnosed yet and face extremely high risk. Worldwide, 4.63 million adults are predicted to have diabetes, and 1.63 million people are in the western pacific region alone.
Sodium-glucose cotransporter (SGLT) inhibitors are a new class of oral therapeutic agents for diabetes that act to lower blood glucose levels by increasing glucose excretion in the urine.
U.S. patent publication No. 2015/0152075 discloses a diphenylmethane derivative compound having an inhibitory activity against SGLT, which has an effect on the treatment of diabetes mellitus, and is capable of significantly reducing urine glucose excretion in animals, as compared with the star drug dapagliflozin.
Chinese patent CN109311861A discloses a preparation method of the above compound and its key intermediate, the specific route is as follows:
according to the above route, 22 steps of reaction are required from the starting material to the diphenylmethane derivative, and 14 and 15 steps of reaction are required from the starting material to the key intermediate compound 1 and the key intermediate compound 2, respectively, so that the overall operation is complex, the production cost is high, and the requirements of the pharmaceutical industry are difficult to meet.
Disclosure of Invention
Aiming at the characteristics of long synthetic route, complex operation and high production cost of the existing diphenylmethane derivative, the invention provides an improved method for preparing a compound 1 and a compound 2.
The invention provides a method for preparing a compound 1 and a compound 2, which comprises the following steps:
compound 1:
1-1, taking 2, 3-dihydrobenzofuran-7-aniline as a raw material, and carrying out selective double bromination by using a bromination reagent to obtain 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline;
performing Sandmeyer reaction (Sandmeyer reaction) on 1-2, 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline to obtain 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran;
1-3, 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran selectively uses strong base to selectively extract bromine, and then a formylation reagent is added to obtain a compound 1;
the synthetic route is as follows:
compound 2:
selectively removing bromine from 2-1, 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran by using strong base, and then reacting with 4-cyclopropylbenzaldehyde to obtain a compound 2;
the synthetic route is as follows:
wherein, in the step 1-1, the brominating agent comprises one of bromine, N-bromosuccinimide (NBS) and dibromohydantoin, and preferably N-bromosuccinimide;
further, in step 1-2, the reagent used in Sandmeyer reaction (Sandmeyer reaction) includes one of hydrochloric acid/sodium nitrite/cuprous chloride system, isoamyl nitrite/copper chloride system, and tert-butyl nitrite/copper chloride system;
further, in steps 1-3, the strong base comprises one or two of n-butyllithium, tert-butyllithium and isopropyl magnesium chloride, preferably isopropyl magnesium chloride; the reason why isopropyl magnesium chloride is preferred is that isopropyl magnesium chloride is highly safe.
Further, in the step 1-3, the formylation reagent comprises one of N, N-dimethylformamide, N-formylmorpholine and ethyl formate, preferably N, N-dimethylformamide;
further, in step 2-1, the strong base comprises one or two of n-butyllithium, tert-butyllithium and isopropyl magnesium chloride, and isopropyl magnesium chloride.
Compared with the existing synthetic route, the invention has the following advantages:
1. the preparation method of the compound 1 and the compound 2 has the advantages that the total yield is more than 50%, and the preparation method has the characteristics of short route, relatively mild reaction conditions and the like.
2. The synthetic route provided by the invention has the advantages of easily available raw materials, low cost, no special operation process and low requirement on equipment, and is suitable for large-scale industrial production.
Detailed Description
The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more clearly understand the advantages and features of the present invention and to clearly define the scope of the present invention.
Example 1: synthesis of 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline
In a 1000mL reaction flask, 8.7g of 2, 3-dihydrobenzofuran-7-aniline and 200mL of ethyl acetate are added, and then 41.4g of bromine is dropwise added at a temperature of between 10 and 20 ℃ (the addition of the bromine is the result of experimental optimization, if the addition of the bromine is too small, the reaction is incomplete, if the addition of the bromine is too large, the system is complicated, byproducts are increased, and the reaction temperature is controlled mainly to prevent the byproducts from being increased). After the dropwise addition, filtration was carried out. Adding the filter cake into a mixed solvent of 100mL of water and 100mL of ethyl acetate, dropwise adding a 10% sodium hydroxide solution, and adjusting the pH to be between 8 and 10 (the system is acidic after the reaction, part of the product is salified, and the adjustment of the pH to be 8-10 is used for dissociation, the pH is too low, the dissociation is incomplete, and the alkali is consumed too much when the pH is too high). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 15.73g of 4, 6-dibromo-2, 3-dihydrobenzofuran-7-ylamine in 83.4% yield as a white solid.
Example 2: synthesis of 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline
5g of 2, 3-dihydrobenzofuran-7-aniline and 100mL of N, N-dimethylformamide are added into a 100mL reaction bottle, the reaction bottle is cooled to a temperature between minus 5 ℃ and 0 ℃, 13.17g N-bromosuccinimide (the N-bromosuccinimide has the advantages that the N-bromosuccinimide is solid and is easy to calculate and control, bromine is corrosive liquid and is irritant and inconvenient to weigh and use) is dropwise added in batches, and the reaction bottle is stirred for 30 minutes. The reaction solution was poured into 200mL of water, extracted twice with ethyl acetate, and the combined organic phases were washed with 10% sodium hydroxide, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 8.47g of 4, 6-dibromo-2, 3-dihydrobenzofuran-7-phenylamine in 78.2% yield.
Example 3: synthesis of 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran
10g of 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline and 50mL of concentrated hydrochloric acid are added into a 250mL reaction bottle, the temperature is reduced to 0-5 ℃, and a sodium nitrite solution (2.47g is dissolved in 8mL of water) is dropwise added under the condition of heat preservation. After the dropwise addition, the reaction was carried out for 30 minutes while maintaining the temperature, and then 6.76g of cuprous chloride was added in portions and allowed to warm to room temperature for 2 hours. Ethyl acetate was added for extraction, and the organic layer was washed with 5% sodium hydroxide solution and concentrated to give a crude product, which was subjected to silica gel column chromatography to give 9.01g of 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran in a yield of 84.5% as a white solid.
Example 4: synthesis of 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran
In a 250mL reaction flask were added 10g of 4, 6-dibromo-2, 3-dihydrobenzofuran-7-ylamine, 100mL of acetonitrile, 9.18g of copper chloride, and heated at 50 ℃ to add 8.0g of isoamyl nitrite dropwise. After the dropwise addition, the reaction was carried out for 30 minutes under heat preservation. Cooling to room temperature, concentrating to remove the solvent, adding ethyl acetate, filtering, washing the filtrate with 5% sodium hydroxide solution, concentrating to obtain a crude product, and performing silica gel column chromatography to obtain 8.78g of 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran, wherein the yield is 82.3%, and the white solid is obtained.
Example 5: synthesis of Compound 1
A100 mL reaction flask was charged with 3.5g of 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran and 35mL of tetrahydrofuran, and 18mL of a 2.5M solution of isopropyl magnesium chloride in tetrahydrofuran was added dropwise under nitrogen. After the dropwise addition, stirring is carried out for 1 hour under the condition of heat preservation, then 5mL of N, N-dimethylformamide is dropwise added under the condition of heat preservation, and the reaction is carried out for 30 minutes under the condition of heat preservation. The reaction solution was poured into 3M hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give 2.73g of compound 1 in 93.2% yield as a white solid.
Example 6: synthesis of Compound 2
Into a 100mL reaction flask were charged 3.5g of 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran and 35mL of tetrahydrofuran, and the mixture was cooled to-30 ℃ under nitrogen atmosphere, and 2.25mL of a 2.5M solution of isopropyl magnesium chloride in tetrahydrofuran was added dropwise, followed by 4.6mL of a 2.5M solution of n-butyl lithium in n-hexane. After the completion of the dropwise addition, stirring was carried out for 30 minutes under heat, and then a solution of 1.96g of 4-cyclopropylbenzaldehyde in tetrahydrofuran (10mL) was added dropwise under heat. After the dropwise addition, the reaction was continued for 30 minutes under heat preservation. The reaction solution was poured into 3M hydrochloric acid, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography to give 3.70g of compound 2, yield 86.9%.
Claims (10)
1. A process for preparing compound 1 and compound 2, said compound 1 and compound 2 having the structures shown below, said process comprising the steps of:
1) taking 2, 3-dihydrobenzofuran-7-aniline as a raw material, and carrying out selective double bromination by using a bromination reagent to obtain 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline;
2) performing Sandmeyer reaction (Sandmeyer reaction) on the 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline obtained in the step 1) to perform chlorination to obtain 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran;
3-1) selectively removing bromine from the 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran obtained in the step 2) by using strong base, and then adding a formylation reagent to obtain a compound 1;
3-2) selectively removing bromine from the 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran obtained in the step 2) by using strong base, and then reacting with 4-cyclopropylbenzaldehyde to obtain a compound 2.
2. The method of claim 1, wherein: in the step 1), the brominating agent comprises at least one of bromine, N-bromosuccinimide (NBS) and dibromohydantoin, preferably N-bromosuccinimide;
preferably, the reaction temperature of the selective dibromo is controlled to be 10-20 ℃.
3. The method of claim 1, wherein: in the step 2), the reagent used in the sandmeyer reaction comprises at least one of a hydrochloric acid/sodium nitrite/cuprous chloride system, an isoamyl nitrite/cupric chloride system, and a tert-butyl nitrite/cupric chloride system.
4. The method of claim 1, wherein:
in the step 3-1), the strong base comprises at least one of n-butyllithium, t-butyllithium and isopropylmagnesium chloride, preferably isopropylmagnesium chloride.
5. The method of claim 1, wherein:
in the step 3-1), the formylation reagent comprises one of N, N-dimethylformamide, N-formylmorpholine and ethyl formate, and preferably N, N-dimethylformamide.
6. The method of claim 1, wherein:
in the step 3-2), the strong base is selected from at least one of the genera n-butyllithium, tert-butyllithium and isopropylmagnesium chloride.
7. The method of claim 2, wherein: in the step 1), after the double bromination reaction, filtering, adding a filter cake into a mixed solvent of water and ethyl acetate, dropwise adding a sodium hydroxide solution, adjusting the pH value to be between 8 and 10, separating an organic layer, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline; further preferably, in the mixed solvent of water and ethyl acetate, the volume ratio of water to ethyl acetate is 1: 1, wherein the mass concentration of the sodium hydroxide is 10%.
8. The method of claim 3, wherein: the step 2) comprises the following steps: adding 4, 6-dibromo-2, 3-dihydrobenzofuran-7-aniline and concentrated hydrochloric acid into a reaction bottle, cooling to 0-5 ℃, preserving heat, dropwise adding a sodium nitrite solution, preserving heat, reacting for 20-60 minutes, then adding cuprous chloride in batches, heating to room temperature, reacting for 1-3 hours, adding ethyl acetate for extraction, washing an organic layer with a sodium hydroxide solution, concentrating to obtain a crude product, and separating and purifying to obtain the 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran.
9. The method of claim 3, wherein: the step 3-1) comprises the following steps: adding 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran and tetrahydrofuran into a reaction bottle, dropwise adding a tetrahydrofuran solution of isopropyl magnesium chloride under the protection of nitrogen, keeping the temperature and stirring for 0.5-1.5 hours after dropwise adding, then keeping the temperature and dropwise adding N, N-dimethylformamide, continuing keeping the temperature and reacting for 20-60 minutes, pouring the reaction solution into hydrochloric acid, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, concentrating and separating to obtain a compound 1.
10. The method of claim 6, wherein: the step 3-2) comprises the following steps: adding 4, 6-dibromo-7-chloro-2, 3-dihydrobenzofuran and tetrahydrofuran into a reaction bottle, cooling to-30 ℃ under the protection of nitrogen, dropwise adding a tetrahydrofuran solution of isopropyl magnesium chloride, dropwise adding an n-hexane solution of n-butyllithium, keeping the temperature and stirring for 20-60 minutes after dropwise adding is finished, then keeping the temperature and dropwise adding a tetrahydrofuran solution of 4-cyclopropylbenzaldehyde, continuously keeping the temperature and reacting for 20-60 minutes after dropwise adding is finished, pouring the reaction liquid into hydrochloric acid, extracting with ethyl acetate, drying an organic layer with anhydrous sodium sulfate, concentrating, separating and purifying to obtain a compound 2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022051980A1 (en) * | 2020-09-10 | 2022-03-17 | 广东莱佛士制药技术有限公司 | Synthesis method for preparing sglt inhibitor intermediate |
| WO2023136617A1 (en) * | 2022-01-14 | 2023-07-20 | 주식회사 대웅제약 | Method for producing intermediate useful for synethesis of sglt inhibitor |
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