CN110028443B - Preparation method of tricyclic compound drug intermediate for regulating FXR activity - Google Patents
Preparation method of tricyclic compound drug intermediate for regulating FXR activity 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
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/64—One oxygen atom attached in position 2 or 6
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Abstract
The invention discloses a preparation method of a tricyclic compound drug intermediate for regulating FXR activity. The method firstly 4-Carrying out esterification reaction on bromosalicylic acid and methanol to obtain 4-bromosalicylic acid methyl ester; then, under the catalysis of common alkali, 4-bromosalicylic acid methyl ester and 3-bromo-6-methoxy-2-methylpyridine undergo nucleophilic substitution reaction to obtain 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone; reducing carbonyl to obtain tricyclic compound medicine intermediate 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl for regulating FXR activity]Phenol. The method adopts the 4-bromosalicylic acid and the 3-bromo-6-methoxy-2-methylpyridine which are simple, easy to obtain and easy to store as starting materials, adopts the common alkali for preparing the compound (4b), has mild reaction conditions, reduces the risk of the process, and is easy for industrial production.
Description
Technical Field
The invention relates to a preparation method of a tricyclic compound drug intermediate for regulating FXR activity, belonging to the technical field of drug synthesis.
Background
Farnesoid X Receptor (FXR) is a member of the nuclear hormone receptor superfamily and is expressed primarily in the liver, kidney and intestine. It functions as a heterodimer with the retinoic acid x receptor (RXR), binding to response elements in the promoter of the target gene to regulate gene transcription.
CN105884758 discloses the synthesis of a novel class of tricyclic compounds which bind to FXR and act as modulators of FXR activity and their use in medicine, and is described in detail. A key intermediate of this patent, 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl]Phenol (compound (28b), wherein k is 1, j is 0, and T is1-T4，T6、T7Are all CH, T6＝N，R8＝Q＝Br，Pg＝CH3，Z1H), the structure is as follows:
CN105884758 discloses that this intermediate a can further prepare tricyclic compounds that modulate FXR activity, as shown below (synthesis method 4 of CN 105884758).
On the basis of the above, bromine in the target product can be further converted into carboxyl to prepare the typical compound 5 in CN 105884758.
The synthetic route of the drug intermediate is simply disclosed in CN105884758 (synthetic method 4 of CN 105884758), and detailed process research is not carried out, and the synthetic route is as follows:
the intermediate (a) of the medicine takes the (1a) and the (2a) as initial raw materials in the preparation, the two initial raw materials are very products, are not easy to purchase, have poor stability and storage, the raw material (1a) is easy to oxidize and needs protection of inert gas for storage, and the raw material (2a) is decomposed in water to generate toxic gas, so the intermediate is not suitable for industrial production. The two starting materials are prepared from strong alkali such as sodium tert-butoxide, sodium hydride and the like to obtain the compound (3a), the reaction conditions of the strong alkali are very harsh, the reaction is violent, more generated impurities are generated, the post-treatment is difficult, and the industrial production is difficult. And deprotection and benzenesulfonyl hydrazide reduction are adopted to prepare the compound (4a), the reducing agent has foaming risk in reaction, is easy to generate material spraying phenomenon, and is not easy for industrial production.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of a tricyclic compound drug intermediate (5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl ] phenol) for regulating FXR activity. The method adopts the 4-bromosalicylic acid (1b) and the 3-bromo-6-methoxy-2-methylpyridine (3b) which are simple, easy to obtain and easy to store as starting materials, and the preparation of the compound (4b) adopts the common alkali, so that the reaction condition is mild, the risk of the process is reduced, and the industrial production is easy.
The technical scheme of the invention is as follows: a preparation method of a tricyclic compound drug intermediate for regulating FXR activity is characterized by comprising the following steps:
1) 4-bromosalicylic acid and methanol are subjected to esterification reaction to obtain 4-bromosalicylic acid methyl ester (2 b);
2) carrying out nucleophilic substitution reaction on 4-bromosalicylic acid methyl ester (2b) and 3-bromo-6-methoxy-2-methylpyridine (3b) under the catalysis of common base to obtain 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone (4 b);
3) the carbonyl in 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone (4b) is reduced to give 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl ] phenol (a).
The chemical reaction equation is as follows:
the esterification reaction in the step 1) adopts sulfuric acid and thionyl chloride as catalysts.
The common alkali in the step 2) is potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, sodium amide, sodium salt of amines with substituent groups, lithium salt and the like. The organic solvent is tetrahydrofuran, acetonitrile, dioxane, etc.
The reducing agent in the step 3) is sodium borohydride, potassium borohydride and sodium borohydride and potassium borohydride with other boron elements containing substituent groups. The solvent adopted in the step 3) is tetrahydrofuran, water and a mixture thereof.
The reaction temperature of the step 1) is 30-70 ℃, and the reaction time is 1-5 hours. The dosage of the sulfuric acid or the thionyl chloride is 0.05-0.2g/g based on the mass of the 4-bromosalicylic acid; the amount of methanol is 3.0-10.0 g/g.
The reaction temperature in the step 2) is 0-60 ℃, the reaction time is 2-10 hours, and the molar ratio of (2b) to (3b) is 0.8-1.2:1, preferably 0.9-1.1: 1. The molar ratio of the customary base to (3b) is from 1.0 to 4.0:1, preferably from 1.1 to 2.0: 1.
The reaction temperature of the step 3) is 0-50 ℃, the reaction time is more than 1 hour, the preferable reaction temperature is 0-20 ℃, and the reaction time is 2-10 hours. The molar ratio of the reducing agent to (4b) is 1.2-5.0: 1.
Specifically, the method comprises the following steps:
1) adding methanol and 4-bromosalicylic acid into a reaction vessel, adding sulfuric acid or thionyl chloride while stirring, heating to 30-65 ℃, keeping the temperature for reaction for 1-5 hours, adding water into a reaction bottle after the reaction is finished, stirring, filtering and drying to obtain 4-bromosalicylic acid methyl ester;
2) adding an organic solvent and 3-bromo-6-methoxy-2-methylpyridine into a reaction vessel at room temperature, adding alkali in batches while stirring, heating to 20-60 ℃, stirring for 0.5-1 hour, slowly dropwise adding a tetrahydrofuran solution of 4-bromosalicylic acid methyl ester, controlling the temperature to 20-60 ℃, preserving heat, stirring and reacting for 3-6 hours; cooling after complete reaction, pouring the reaction liquid into water, filtering, and drying to obtain 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone;
3) adding a solvent and 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone into a reaction vessel, cooling to 0-20 ℃, slowly adding a reducing agent while stirring, controlling the temperature to 0-20 ℃ for reaction for 2-10 hours, adding water after the reaction is completed, adding methyl tert-butyl ether for extraction, combining organic phases, washing, decompressing, evaporating the solvent, adding a refined solvent for refining, filtering and drying to obtain the 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl ] phenol.
The refined solvent in the step 3): petroleum ether, cyclohexane, n-hexane, n-heptane and the like in an amount of 0.25 to 5.0ml/g, preferably 0.5 to 2.0ml/g, based on the mass of (4 b).
The invention has the beneficial effects that:
1. the invention takes 4-bromosalicylic acid (1b) and 3-bromo-6-methoxy-2-methylpyridine (3b) as initial raw materials, and the two raw materials are common materials, are easy to purchase, have good stability, are easy to store, and are suitable for industrial production;
2. in the nucleophilic substitution reaction for preparing the compound (4b), common alkali such as sodium hydroxide, potassium hydroxide, tetrabutyl ammonium hydroxide and the like is adopted, so that the danger of the reaction is greatly reduced, the reaction condition is mild, and the industrial production is easy to realize;
in conclusion, the method has the advantages of simple and easily obtained raw materials, simple operation steps, mild reaction conditions, safe and environment-friendly process, high product yield and easy industrial production.
Drawings
FIG. 1 shows a tricyclic compound drug intermediate 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl group for regulating FXR activity]Process for preparing phenol1HNMR map.
Detailed Description
Example 1:
1) preparation of methyl 4-bromosalicylate (2b)
Adding 450g of methanol and 90g of 4-bromosalicylic acid into a three-necked flask at room temperature, slowly adding 9g of sulfuric acid while stirring, heating to 65 ℃ for refluxing, keeping the temperature and stirring for 1 hour, and detecting by TLC (thin layer chromatography) to complete the reaction. 450g of water was added to the reaction flask, stirred for 20 minutes, filtered with suction, and dried at 70 ℃ to obtain 91.0 g. Yield 95.0%, purity: 98.7 percent.
2) Preparation of 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone (4b)
Adding 300g of acetonitrile into a three-necked bottle at room temperature, adding 85g of 3-bromo-6-methoxy-2-methylpyridine, adding 28.2g of potassium hydroxide in batches under stirring, heating to 30 ℃, stirring for 1 hour, slowly dropwise adding a mixed solution of 97.2g of methyl 4-bromosalicylate and 97.2g of tetrahydrofuran, controlling the temperature to be 30 ℃, keeping the temperature, stirring and reacting for 6 hours, and detecting by TLC to complete the reaction. And cooling, pouring the reaction liquid into 1L of water, performing suction filtration, and drying to obtain 149.0 g. Yield 88.5%, purity: 96.3 percent.
3) Preparation of 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl ] phenol (a)
At room temperature, 1300g of tetrahydrofuran, 50g of water and 130g of 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone are added into a three-necked bottle, the temperature is reduced to 0 ℃, 14.7g of sodium borohydride is slowly added under stirring, the temperature is controlled to be 0 ℃, the reaction is carried out for 8 hours, and the reaction is completely detected by TLC. 1300g of water was added, 1300g of methyl tert-butyl ether was added and extracted twice, the organic phases were combined, washed once with saturated sodium chloride, the solvent was evaporated under reduced pressure, 65 g of petroleum ether was added, stirred at room temperature for 1 hour, filtered and dried to give 110.1g of an off-white solid. The yield is 89.6%, and the purity is 98.8%.
1HNMR(400MHz,CDCL3-d6) δ — 3.03-3.05 (m,2H), 3.18-3.20 (m,2H),3.97(s,3H),6.54(d, J ═ 5.6Hz 1H), 6.95-6.97 (m,1H), 7.00-7.04 (m,1H),7.26(s,1H),7.70(d, J ═ 5.6Hz 1H),8.58(s, 1H). As shown in fig. 1.
The molecular weight of this compound was further confirmed to be 385 by mass spectrometry.
Example 2:
1) preparation of methyl 4-bromosalicylate (2b)
Adding 300g of methanol and 90g of 4-bromosalicylic acid into a three-necked flask at room temperature, slowly adding 6g of thionyl chloride while stirring, heating to 30 ℃, keeping the temperature and stirring for 5 hours, and detecting by TLC to completely react. 300g of water was added to the reaction flask and stirred for 20 minutes. Suction filtration and drying at 70 ℃ gave 93.8 g. Yield 98.0%, purity: 98.2 percent.
2) Preparation of 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone (4b)
Adding 250g of tetrahydrofuran and 85g of 3-bromo-6-methoxy-2-methylpyridine into a three-necked flask at room temperature, adding 25.2g of sodium hydroxide in batches under stirring, heating to 60 ℃, stirring for 40 minutes, slowly dropwise adding a mixed solution of 97.2g of methyl 4-bromosalicylate and 97.2g of tetrahydrofuran, controlling the temperature to be 60 ℃, keeping the temperature, stirring and reacting for 6 hours, and detecting the reaction by TLC (thin layer chromatography). And cooling, pouring the reaction liquid into 1L of water, performing suction filtration, and drying to obtain 153.6 g. Yield 91.2%, purity: 96.0 percent.
3) Preparation of 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl ] phenol (a)
Adding 390g of water and 130g of 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone into a three-necked bottle at room temperature, cooling to 0 ℃, slowly adding 87.38g of potassium borohydride while stirring, controlling the temperature to be 20 ℃, reacting for 2 hours, and detecting the reaction to be complete by TLC. 390g of water is added, 390g of methyl tert-butyl ether is added for extraction twice, organic phases are combined and washed once by saturated sodium chloride, 130g of n-hexane is added after the solvent is evaporated under reduced pressure, and the mixture is washed by slurry at room temperature for 1 hour, filtered and dried to obtain 104.0g of off-white solid. The yield is 85.0 percent, and the purity is 99.0 percent.
Claims (8)
1. A preparation method of a tricyclic compound drug intermediate for regulating FXR activity is characterized by comprising the following steps:
1) 4-bromosalicylic acid and methanol are subjected to esterification reaction to obtain 4-bromosalicylic acid methyl ester;
2) carrying out nucleophilic substitution reaction on 4-bromosalicylic acid methyl ester and 3-bromo-6-methoxy-2-methylpyridine under the catalysis of common base to obtain 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone;
3) reducing carbonyl in 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone to obtain a tricyclic compound drug intermediate 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl ] phenol for adjusting FXR activity;
the common alkali in the step 2) is any one of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide and sodium amide;
the reducing agent adopted in the reduction of the step 3) is any one of sodium borohydride and potassium borohydride.
2. The process for preparing a tricyclic compound as claimed in claim 1, wherein the esterification in step 1) is carried out using sulfuric acid or thionyl chloride as a catalyst.
3. The process for producing the tricyclic compound intermediate for FXR activity regulation according to claim 1 or 2, wherein the reaction temperature in step 1) is 30 to 70 ℃ and the reaction time is 1 to 5 hours.
4. The process for producing the tricyclic compound intermediate for FXR activity regulation according to claim 1 or 2, wherein the reaction temperature in step 2) is 0 to 60 ℃ and the reaction time is 2 to 10 hours.
5. The process for producing the tricyclic compound intermediate for FXR activity regulation according to claim 1 or 2, wherein the reaction temperature in the step 3) is 0 to 50 ℃ and the reaction time is 1 hour or more.
6. The process for producing the tricyclic compound as an intermediate for FXR activity-modulating according to claim 5, wherein the reaction temperature in the step 3) is 0 to 20 ℃ and the reaction time is 2 to 10 hours.
7. The process for producing the tricyclic compound intermediate for FXR activity regulation according to claim 1 or 2, wherein,
1) adding methanol and 4-bromosalicylic acid into a reaction vessel, adding sulfuric acid or thionyl chloride while stirring, heating to 30-65 ℃, keeping the temperature for reaction for 1-5 hours, adding water into a reaction bottle after the reaction is finished, stirring, filtering and drying to obtain 4-bromosalicylic acid methyl ester;
2) adding an organic solvent and 3-bromo-6-methoxy-2-methylpyridine into a reaction vessel at room temperature, adding common alkali in batches while stirring, heating to 20-60 ℃, stirring for 0.5-1 hour, dropwise adding a tetrahydrofuran solution of 4-bromosalicylic acid methyl ester, controlling the temperature to 20-60 ℃, preserving heat, stirring and reacting for 3-6 hours; cooling to room temperature after complete reaction, pouring the reaction liquid into water, performing suction filtration and drying to obtain 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone; the organic solvent is tetrahydrofuran, acetonitrile or dioxane;
3) adding a solvent and 1- (4-bromo-2-hydroxyphenyl) -2- (3-bromo-6-methoxy-pyridin-2-yl) -ethanone into a reaction vessel, cooling to 0-20 ℃, adding a reducing agent while stirring, controlling the temperature to 0-20 ℃ to react for 2-10 hours, adding water after the reaction is completed, adding methyl tert-butyl ether for extraction, combining organic phases, washing, decompressing, evaporating the solvent, adding a refined solvent for refining, filtering, and drying to obtain 5-bromo-2- [2- (3-bromo-6-methoxy-pyridin-2-yl) -ethyl ] phenol; the solvent is tetrahydrofuran, water or a mixture of the tetrahydrofuran and the water.
8. The process for producing the tricyclic compound as an intermediate for FXR activity-modulating according to claim 7, wherein the solvent for purification in the step 3) is: petroleum ether, cyclohexane, n-hexane or n-heptane.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080319022A1 (en) * | 2004-04-21 | 2008-12-25 | In2Gen Co., Ltd. | 2-Pyridyl substituted imidazoles as ALK5 and/or ALK4 inhibitors |
| CN105884758A (en) * | 2015-02-13 | 2016-08-24 | 广东东阳光药业有限公司 | Tricyclic compound and application thereof to drugs |
| CN107686486A (en) * | 2016-08-05 | 2018-02-13 | 广东东阳光药业有限公司 | Tricyclic nitrogen containing compounds and its application in medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080319022A1 (en) * | 2004-04-21 | 2008-12-25 | In2Gen Co., Ltd. | 2-Pyridyl substituted imidazoles as ALK5 and/or ALK4 inhibitors |
| CN105884758A (en) * | 2015-02-13 | 2016-08-24 | 广东东阳光药业有限公司 | Tricyclic compound and application thereof to drugs |
| CN107686486A (en) * | 2016-08-05 | 2018-02-13 | 广东东阳光药业有限公司 | Tricyclic nitrogen containing compounds and its application in medicine |
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