CN113880720A - Preparation method of mirabegron key intermediate - Google Patents
Preparation method of mirabegron key intermediate Download PDFInfo
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- CN113880720A CN113880720A CN202111336074.9A CN202111336074A CN113880720A CN 113880720 A CN113880720 A CN 113880720A CN 202111336074 A CN202111336074 A CN 202111336074A CN 113880720 A CN113880720 A CN 113880720A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
Abstract
The invention provides a preparation method of a mirabegron key intermediate compound shown in formula (III), which is simple, convenient and safe to operate, free of harsh reaction conditions, high in reaction purity and yield, low in process cost which is about 40% of that of palladium-carbon and other metal catalysts, suitable for large-scale production and in line with the green chemical principle. The intermediate compound shown in formula (III) prepared by the method is used for continuously preparing a mirabegron finished product so as to meet the existing requirements.
Description
1. Field of the invention
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of a mirabegron key intermediate.
2. Background of the invention
Mirabegron (Mirabegron) tablets were developed by the pharmaceutical company of austele (astella) japan, and clinical trials were started in japan in 2005, and were first approved in japan (trade name: Betanis, 25mg, 50mg) on day 7 and 1 in 2011 and then marketed in japan on day 16 and 9. On 28/6/2012, mirabegron was approved by the U.S. FDA for the treatment of adult overactive bladder (trade name: Myrbetriq, 25mg, 50 mg). The 12 th month in 2012 and the 3 rd month in 2013 were approved for marketing in the european union (trade name: Betmiga) and canada (trade name: Myrbetriq).
The chemical name of mirabegron (compound of formula (I)) is: 2- (2-amino-1, 3-thiazol-4-yl) -N- [4- [2- [ [ (2R) -2-hydroxy-2-phenylethyl ] ethyl]Amino group]Ethyl radical]Phenyl radical]Acetamide with molecular formula C21H24N4O2S, molecular weight 396.51, CAS registry number 223673-61-8, structure shown below.
Now, various preparation methods of mirabegron are disclosed, and the following routes are the main production routes of the product at present through comprehensive analysis:
(R) -2- { [2- (4-aminophenyl) ethyl ] amino } -1-phenylethanol (CAS: 521284-22-0, compound of formula III) is a key intermediate for the preparation of mirabegron, the most common method for the preparation presently disclosed for this intermediate is the reduction of (R) -2- { [2- (4-nitrophenyl) ethyl ] amino } -1-phenylethanol (compound of formula IV) hydrochloride to give:
WO2014132270A2 discloses a preparation method of the mirabegron intermediate compound shown in the formula (III), which adopts 10% palladium-carbon as a catalyst and adopts hydrogen to reduce nitro under pressure. The method has the advantages of less by-products, simple post-treatment and purification and high yield. However, high-pressure equipment is needed for hydrogenation pressurization, hydrogen is flammable and explosive, potential safety hazards are large, and requirements on equipment and equipment operation are high; and the adopted metal catalyst palladium causes higher production cost. In conclusion, the method is not beneficial to realizing large-scale production and has limited wide application.
Patent WO2014132270A2 also discloses another preparation method of the mirabegron intermediate compound shown as formula (III), which is reduction by adopting an iron powder/hydrochloric acid system. The method well solves the defects of metal catalytic hydrogenation reduction, avoids using special high-pressure equipment and using flammable and explosive hydrogen, but uses a large amount of iron powder, generates a large amount of waste residues and is not environment-friendly; in addition, the iron powder has high density and is easy to settle, and the reaction process has higher requirements on stirring and mixing of equipment and is also the difficult point of enlarging the process. There are natural drawbacks in large-scale production.
In order to solve the problem that the palladium-carbon hydrogenation pressurized catalytic reaction of the milbeuron intermediate compound (III) adopts high-pressure equipment, the Chinese patent CN108947853A adopts a method for preparing the intermediate by adopting a microchannel reactor and adopting low-pressure palladium-carbon hydrogenation, although the method avoids the use of the high-pressure equipment, a noble metal catalyst and flammable and explosive hydrogen are still required to be used, in addition, the reaction also needs to independently customize the reaction equipment of the microchannel reactor, the production cost is high, and the production safety risk is still not effectively solved.
Chinese patent CN105481705A discloses a preparation method of the mirabegron intermediate compound shown in formula (III), palladium carbon/ammonium formate or ammonium acetate is used as a reduction system to prepare the intermediate, and the method adopts ammonium formate or ammonium acetate to replace hydrogen as a hydrogen donor, so that the use of high-pressure equipment and flammable and explosive hydrogen can be avoided. However, the inventors of the present invention have studied on the preparation method, and found that formamide can also participate in the reaction when palladium-carbon or ammonium formate is used in the reduction method, so that formylation series impurities (compounds of formula (VIII) to compounds of formula (X)) are easily generated, and the impurities are difficult to remove, participate in subsequent reactions to derive finished products, and are difficult to remove, thereby affecting the API quality; in addition, the method has strong dependence on stirring speed, equipment height-diameter ratio, reaction system loading capacity and the like, is not easy to control, is easy to cause low conversion rate, and has great limitation on scale-up production.
In summary, in the currently reported synthesis method of the mirabegron key intermediate (R) -2- { [2- (4-aminophenyl) ethyl ] amino } -1-phenylethanol, nitro reduction preparation is carried out by adopting different reduction systems, and various problems exist, such as use of palladium-carbon or platinum-carbon metal catalysts and higher cost; the hydrogen is used for pressurization and reduction, the potential safety hazard of a pressurization device is large, and the amplification production is limited. The iron powder is used for reduction, a large amount of iron powder waste residues are generated, the requirement on equipment stirring is high, the amplification is difficult, the difficulty in post-treatment, separation and purification is high, and the amplification production is limited. The hydrogen sources such as ammonium formate and the like are used for reduction, so that impurities such as formylation and the like can be generated, the product purity is low, the purification is difficult, the subsequent reaction is involved, the quality of the mirabegron finished product is influenced, and the mirabegron finished product needs to be refined for many times; in addition, the scale production is enlarged, the dependence on equipment is strong, and the realization difficulty of production amplification is high. Under the restriction of the above conditions, the nitro reduction preparation of the intermediate is difficult to realize large-scale production, so that the research on a method for preparing the key intermediate of mirabegron, which is simple, convenient and safe to operate, low in cost, high in product purity and suitable for large-scale production, is an urgent problem to be solved in the field.
3. Summary of the invention
The invention aims to solve the problems in the prior art, provides a preparation method of the mirabegron key intermediate, which is simple, convenient and safe to operate, has no harsh reaction conditions, high reaction purity and yield, low process cost which is about 40 percent of that of palladium-carbon and other metal catalysts, is suitable for large-scale production and accords with the green chemical principle, and continuously prepares the mirabegron finished product so as to meet the existing requirements.
Specifically, the invention provides a preparation method of a mirabegron key intermediate compound shown as a formula (III), which comprises the following steps:
reducing the compound of the formula (IV) under the conditions of hydrazine hydrate, ferric chloride hexahydrate and activated carbon to prepare a key intermediate compound of the formula (III);
wherein the content of the first and second substances,
the usage amount of the hydrazine hydrate is 4.0-8.0 mol, preferably 6.0 mol; the using amount of the ferric chloride hexahydrate is 0.1-0.6 molar mass, and preferably 0.1 molar mass; the using amount of the active carbon is 0.1-0.6 times of the mass, and preferably 0.3 time of the mass; the reaction temperature is 55-75 ℃, preferably 65 ℃; the reaction solvent is one or more of absolute ethyl alcohol, methanol, isopropanol, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, and preferably methanol.
The invention also provides a preparation method of the mirabegron, which comprises the following steps:
(1) adding EDCI, 1-hydroxybenzotriazole and triethylamine into a compound of a formula (VII) and a compound of a formula (VI), and controlling the temperature to be 20-30 ℃ to react to obtain a compound of a formula V;
(2) adding 2mol/L borane dimethyl sulfide complex into the compound shown in the formula (V), and controlling the temperature to be 60-70 ℃ for reaction to obtain a compound shown in the formula IV;
(3) reducing the compound of the formula (IV) under the conditions of hydrazine hydrate, ferric chloride hexahydrate and activated carbon to prepare a compound of a formula III; the usage amount of the hydrazine hydrate is 4.0-8.0 mol, preferably 6.0 mol; the using amount of the ferric chloride hexahydrate is 0.1-0.6 molar mass, and preferably 0.1 molar mass; the using amount of the active carbon is 0.1-0.6 times of the mass, and preferably 0.3 time of the mass; the reaction temperature is 55-75 ℃, preferably 65 ℃; the reaction solvent is one or more of absolute ethyl alcohol, methanol, isopropanol, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, and preferably methanol;
(4) EDCI and hydrochloric acid are added into the compound of the formula (III) and the compound of the formula (II) to react at a controlled temperature of 5-15 ℃ to prepare the mirabegron.
The invention has the beneficial effects that:
(1) the invention provides a key intermediate of mirabegron and a preparation method thereof, and the mirabegron is prepared, and the preparation method does not use a precious metal catalyst and has low cost; flammable and explosive hydrogen is not used, and the safe production coefficient is high;
(2) the catalytic amount of ferric chloride hexahydrate is adopted, and activated carbon is used as a carrier for suspension, so that the dependence of amplification on stirring and mixing is solved, and the scale amplification is easy; and the amount of the generated waste residues is small, and the method is environment-friendly.
(3) The reaction reagent and the catalyst used in the reduction system are common and easy to obtain, the cost is low, the conversion rate is high, the selectivity is good, the reaction produced impurities are few, the post-treatment separation and purification are simple, and the product purity and the yield are high.
(4) The chromatogram of the key intermediate compound of the mirabegron prepared by the preparation method of the invention, namely the compound of the formula (III), shows that the impurity compound of the formula (VIII), the impurity compound of the formula (IX) and the impurity compound of the formula (X) are not detected.
(5) The preparation method provided by the invention has the advantages of mild reaction conditions, simple and safe operation and easy control, and the adopted solvents are conventional solvents, so that the preparation method is suitable for large-scale production.
4. Description of the drawings
FIG. 1 shows the spectrum of the compound of formula (III) prepared in example 3.
FIG. 2 shows the spectrum of the compound of formula (III) prepared in comparative example 1.
FIG. 3 is a mass spectrum of the compound of formula (III) prepared in example 3.
FIG. 4 is a nuclear magnetic hydrogen spectrum of the compound of formula (III) prepared in example 3.
5. Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the present invention is provided for illustrative purposes only and is not intended to limit the scope of the present invention.
Example 1: preparation of the Compound of formula (V)
200g of the compound of the formula (VII) and 286g of the compound of the formula (VI) were put in 1.6kg of N, N-dimethylformamide, and 132g of triethylamine, 178g of 1-hydroxybenzotriazole and 264g of EDCI were added thereto at room temperature. Controlling the temperature to be room temperature, stirring and reacting for 1h, adding 1.6kg of purified water, stirring and crystallizing for 2h, filtering and drying; 371g of the compound of formula (V) was obtained in 93.7% yield.
Example 2: preparation of the Compound of formula (IV)
300g of the compound of the formula (V) are introduced into 1.5kg of tetrahydrofuran and 675g of borane dimethylsulfide complex is slowly added thereto. After the addition, the temperature is raised to reflux reaction for 3 hours, and the reaction is finished. After the temperature is reduced to room temperature, 120g of methanol and 200g of hydrochloric acid are added. The temperature was raised to 60 ℃ and stirred for 1 hour. The solvent was evaporated under reduced pressure, 1.2kg of methanol was added after concentration, stirred for 2 hours, filtered under suction, and dried by forced air at 50 + -5 deg.C to obtain 300g of the compound of formula (IV) with a yield of 93.2%.
Example 3: preparation of the Compound of formula (III)
Adding 200g of the compound shown in the formula (IV) into 1600g of methanol, adding 16.8g of hexahydrate and ferric chloride and 60.0g of activated carbon; keeping the temperature and stirring for 30 minutes, slowly adding 234g of hydrazine hydrate, after the dropwise addition is finished, heating to reflux, keeping the temperature and reacting for 5 hours, after the reaction is finished, cooling to 25 +/-5 ℃, and performing suction filtration to obtain filtrate; adding the filtrate into a reaction bottle, slowly adding 3.0kg of purified water, and gradually separating out solids; keeping the temperature at 10 +/-5 ℃ for 2 hours for crystallization, and performing suction filtration and drying to obtain 151g of a compound shown in the formula (III); the yield thereof was found to be 94.9%. As shown in fig. 1 and table 1, the compound of impurity formula (VIII), the compound of impurity formula (IX) and the compound of impurity formula (X) were not detected.
TABLE 1 chromatographic Peak results for Compound of formula (III) prepared in example 3
| Retention time | Area of | % area | Peak height | Number of theoretical plates | Degree of separation | Tailing factor | Integral type | |
| X | 18.479 | ND | ND | ND | ND | ND | ND | ND |
| Ⅷ | 20.865 | ND | ND | ND | ND | ND | ND | ND |
| Ⅸ | 23.282 | ND | ND | ND | ND | ND | ND | ND |
| III | 25.725 | 13383048 | 99.960 | 793462 | 46511 | 1.33 | BV | |
| 27.087 | 3879 | 0.029 | 270 | 73520 | 3.03 | VB | ||
| 28.097 | 509 | 0.004 | 53 | 195007 | 5.42 | 1.24 | BB | |
| 30.033 | 1002 | 0.007 | 84 | 100382 | 3.83 | 0.90 | BB | |
| Sum | 13388438 |
Example 4: preparation of Compounds of formula (I)
100g of the compound of the formula (III) are added to 1.5kg of purified water; adding 40.0g of hydrochloric acid, stirring for 15 minutes, adding 83.6g of a compound of the formula (II), adjusting the pH of the system to 5-6 by using hydrochloric acid, adding 90.8g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide, stirring at room temperature for reaction, reacting for 1 hour, after the reaction is finished, adding a sodium hydroxide solution to adjust the pH to 9-10, stirring and crystallizing for 1 hour, filtering, washing and drying to obtain 145g of a product of the formula (I), wherein the yield is 93.5%.
Comparative example 1: preparation of the Compound of formula (III)
4.0kg of ammonium formate and 5.2kg of the compound of the formula (IV) were added to 61.8kg of methanol, and 519g of palladium on carbon was added. The temperature is controlled to be 30 ℃, the reaction is slowly stirred for 5.5 hours, and the reaction is finished. After the reaction is finished, filtering, and leaching a filter cake with a proper amount of methanol. The solvent was distilled off under reduced pressure, and 77.9kg of purified water was added thereto, followed by stirring until it was clear. And (3) controlling the temperature to be room temperature, slowly adding a sodium hydroxide solution (obtained by adding 1.04kg of sodium hydroxide into 2.44kg of purified water and stirring and dissolving), adjusting the pH value to 9-10, and continuously stirring for 1 hour. Centrifuging and drying to obtain 3.31kg of the compound shown in the formula (III) with the yield of 80.0%. As shown in fig. 2 and table 2, the compounds of formula (III) prepared include the compound of impurity formula (VIII), the compound of impurity formula (IX) and the compound of impurity formula (X).
TABLE 1 chromatographic Peak results for Compound of formula (III) prepared in comparative example 1
Claims (6)
1. A preparation method of a compound of a key intermediate formula (III) of mirabegron is characterized by comprising the following steps:
the compound of formula (IV) is reduced under the conditions of hydrazine hydrate, ferric chloride hexahydrate and activated carbon to prepare the key intermediate compound of formula (III).
2. The method for preparing the mirabegron key intermediate compound shown in the formula (III) according to claim 1,
the usage amount of the hydrazine hydrate is 4.0-8.0 molar weight;
the dosage of the ferric chloride hexahydrate is 0.1-0.6 molar weight;
the using amount of the active carbon is 0.1-0.6 times of the mass;
the reaction temperature is 55-75 ℃;
the reaction solvent is one or more of absolute ethyl alcohol, methanol, isopropanol, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
3. The method for preparing the mirabegron key intermediate compound shown in the formula (III) according to claim 2,
the usage amount of the hydrazine hydrate is 6.0 molar weight;
the dosage of the ferric chloride hexahydrate is 0.1 molar weight;
the using amount of the active carbon is 0.3 time of the mass;
the reaction temperature is 65 ℃;
the reaction solvent is methanol.
4. The preparation method of mirabegron is characterized by comprising the following steps:
(1) adding EDCI, 1-hydroxybenzotriazole and triethylamine into a compound of a formula (VII) and a compound of a formula (VI), and controlling the temperature to be 20-30 ℃ to react to obtain a compound of a formula V;
(2) adding 2mol/L borane dimethyl sulfide complex into the compound shown in the formula (V), and controlling the temperature to be 60-70 ℃ for reaction to obtain a compound shown in the formula IV;
(3) reducing the compound of the formula (IV) under the conditions of hydrazine hydrate, ferric chloride hexahydrate and activated carbon to prepare a compound of a formula III;
(4) EDCI and hydrochloric acid are added into the compound of the formula (III) and the compound of the formula (II) to react at a controlled temperature of 5-15 ℃ to prepare the mirabegron.
5. The method of preparing mirabegron as claimed in claim 4, wherein: in the step (3), the step (c),
the usage amount of the hydrazine hydrate is 4.0-8.0 molar weight;
the dosage of the ferric chloride hexahydrate is 0.1-0.6 molar weight;
the using amount of the active carbon is 0.1-0.6 times of the mass;
the reaction temperature is 55-75 ℃;
the reaction solvent is one or more of absolute ethyl alcohol, methanol, isopropanol, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
6. The method of preparing mirabegron as claimed in claim 5, wherein:
the usage amount of the hydrazine hydrate is 6.0 molar weight;
the dosage of the ferric chloride hexahydrate is 0.1 molar weight;
the using amount of the active carbon is 0.3 time of the mass;
the reaction temperature is 65 ℃;
the reaction solvent is methanol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539084A (en) * | 2020-11-24 | 2022-05-27 | 威智医药有限公司 | Preparation method of mirabegron and intermediate thereof |
| CN114560779A (en) * | 2022-01-25 | 2022-05-31 | 杭州华东医药集团浙江华义制药有限公司 | Synthesis method of mirabegron key intermediate |
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| CN103387500A (en) * | 2012-05-11 | 2013-11-13 | 上海医药工业研究院 | Preparation methods for mirabegron and intermediate thereof |
| CN104230840A (en) * | 2014-09-05 | 2014-12-24 | 安徽联创药物化学有限公司 | Synthesis method of mirabegron |
| CN106748970A (en) * | 2016-12-01 | 2017-05-31 | 陕西师范大学 | The deoxidization nojirimycin derivative of N aryl 1 and its application in treatment diabetes medicament is prepared |
| CN113816864A (en) * | 2020-06-18 | 2021-12-21 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenylethylamine |
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- 2021-11-12 CN CN202111336074.9A patent/CN113880720A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103387500A (en) * | 2012-05-11 | 2013-11-13 | 上海医药工业研究院 | Preparation methods for mirabegron and intermediate thereof |
| CN104230840A (en) * | 2014-09-05 | 2014-12-24 | 安徽联创药物化学有限公司 | Synthesis method of mirabegron |
| CN106748970A (en) * | 2016-12-01 | 2017-05-31 | 陕西师范大学 | The deoxidization nojirimycin derivative of N aryl 1 and its application in treatment diabetes medicament is prepared |
| CN113816864A (en) * | 2020-06-18 | 2021-12-21 | 南京正大天晴制药有限公司 | Preparation method of (R) -2-hydroxy-N- [2- (4-aminophenyl) ethyl ] -2-phenylethylamine |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114539084A (en) * | 2020-11-24 | 2022-05-27 | 威智医药有限公司 | Preparation method of mirabegron and intermediate thereof |
| CN114560779A (en) * | 2022-01-25 | 2022-05-31 | 杭州华东医药集团浙江华义制药有限公司 | Synthesis method of mirabegron key intermediate |
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Application publication date: 20220104 |