A preparation method of 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid

Abstract

The invention discloses a method for preparing 3'-amino-2'-hydroxy-biphenyl-3-formic acid. The 3'-amino-2'-hydroxy-biphenyl-3-formic acid prepared in this scheme has no obvious color change after 48 hours of exposure, indicating that it has good light stability; no obvious degradation is observed after 6 months of storage at room temperature, indicating that it has good long-term storage stability and is easy to store; under the temperature condition of 150°C, its weight loss rate is within 10%, indicating that it has good thermal stability. The above-mentioned 3'-amino-2'-hydroxy-biphenyl-3-formic acid has good stability in all aspects, which is of great significance for improving the industrial production efficiency of Eltrombopag.

Description

Technical Field

[0001] The present invention relates to the field of preparation of 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid, and more specifically, to a method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid. Background Art

[0002] 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid is an important intermediate in the synthesis of Eltrombopag, and its structural formula is shown in the following formula (1):

[0003]

[0004] Currently, 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid is mostly synthesized by hydrogenation, which is highly dangerous and not suitable for large-scale production. Therefore, developing a relatively stable, easy to store and transport, and relatively safe 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid is of great significance for improving the industrial production efficiency of Eltrombopag. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid, so as to solve the technical problems existing in the above-mentioned background technology.

[0006] The technical solution of the present invention provides a method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid, comprising the following steps:

[0007] S1: Add 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid and an appropriate amount of solvent into a corrosion-resistant reaction bottle and stir evenly;

[0008] S2: Then, add an excess of hydrazine hydrate and a catalytic additive, heat the reaction system to 80-100°C, and keep stirring evenly during the reaction until the reaction is completed;

[0009] S3: After the reaction is completed, the reaction bottle is removed from the heating source and cooled naturally to room temperature. The catalyst is removed by a vacuum filter, and then extracted, concentrated and recrystallized to obtain 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid.

[0010] In a preferred embodiment, the solvent added in S1 is one of ethanol, deionized water, and a mixed solvent of ethanol and water.

[0011] In a preferred embodiment, the reaction time in S2 is 4-8 hours, and the stirring rate is 30-60 r / min.

[0012] In a preferred embodiment, the catalyst added to S2 is a 10-20% palladium / carbon catalyst.

[0013] In a preferred embodiment, the extraction process in S3 is: transfer the reaction mixture to a separatory funnel, add an appropriate amount of deionized water, shake gently to transfer the reaction product to the aqueous phase, and perform three extractions to recover the target product to the maximum extent.

[0014] In a preferred embodiment, the concentration process in S3 is: using a rotary evaporator to remove water and other volatile solvents by low-pressure evaporation at 60-70° C., and concentrating until the residue is nearly dry to avoid product degradation caused by high temperature.

[0015] In a preferred embodiment, the recrystallization process in S3 is: dissolving the crude product in hot ethanol at 50-70° C., and then cooling it to precipitate crystals.

[0016] The beneficial effects of the technical solution of the present invention are:

[0017] The 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid prepared in this scheme has no obvious color change after exposure for 48 hours, indicating that it has good light stability; it has no obvious degradation after storage for 6 months at room temperature, indicating that it has good long-term storage stability and is easy to store; under the temperature condition of 150°C, its weight loss rate is within 10%, indicating that it has good thermal stability. The above 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid has good stability in all aspects, which is of great significance for improving the industrial production efficiency of Eltrombopag. DETAILED DESCRIPTION

[0018] The present invention is further described in detail below. The embodiments of the present invention are provided for the purpose of illustration and description, and are not intended to be exhaustive or to limit the present invention to the disclosed forms. Many modifications and variations will be apparent to those of ordinary skill in the art. The embodiments are selected and described to better illustrate the principles and practical applications of the present invention, and to enable those of ordinary skill in the art to understand the present invention and design various embodiments with various modifications suitable for specific uses.

[0019] Example 1

[0020] The technical solution of the present invention provides a method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid, comprising the following steps:

[0021] S1: Add 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid and an appropriate amount of solvent into a corrosion-resistant reaction bottle and stir evenly;

[0022] S2: Then, add an excess of hydrazine hydrate and a catalytic additive, heat the reaction system to 80°C, and keep stirring evenly during the reaction until the reaction is completed;

[0023] S3: After the reaction is completed, the reaction bottle is removed from the heating source and cooled naturally to room temperature. The catalyst is removed by vacuum filter, and then extracted, concentrated and recrystallized to obtain 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid.

[0024] The solvent added in S1 is ethanol. The reaction time in S2 is 4 hours, and the stirring rate is 30 r / min. The catalyst added in S2 is 10% palladium / carbon catalyst.

[0025] The extraction process in S3 is: transfer the reaction mixture to a separatory funnel, add an appropriate amount of deionized water, shake gently to transfer the reaction product to the aqueous phase, and perform three extractions to recover the target product to the maximum extent. The concentration process in S3 is: use a rotary evaporator to evaporate water and other volatile solvents at low pressure at 60°C, and concentrate until the residue is nearly dry to avoid product degradation caused by high temperature. The recrystallization process in S3 is: dissolve the crude product in hot ethanol at 50°C, and wait for it to cool and precipitate crystals.

[0026] Example 2

[0027] The technical solution of the present invention provides a method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid, comprising the following steps:

[0028] S1: Add 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid and an appropriate amount of solvent into a corrosion-resistant reaction bottle and stir evenly;

[0029] S2: Then, an excess of hydrazine hydrate and a catalytic additive are added, and the reaction system is heated to 100° C. During the reaction, uniform stirring is maintained until the reaction is completed;

[0030] S3: After the reaction is completed, the reaction bottle is removed from the heating source and cooled naturally to room temperature. The catalyst is removed by vacuum filter, and then extracted, concentrated and recrystallized to obtain 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid.

[0031] The solvent added in S1 is deionized water. The reaction time in S2 is 8 hours, and the stirring rate is 60 r / min. The catalyst added in S2 is 20% palladium / carbon catalyst.

[0032] The extraction process in S3 is: transfer the reaction mixture to a separatory funnel, add an appropriate amount of deionized water, shake gently to transfer the reaction product to the aqueous phase, and perform three extractions to recover the target product to the maximum extent.

[0033] The concentration process in S3 is: using a rotary evaporator, evaporating at low pressure at 70°C to remove water and other volatile solvents, and concentrating until the residue is nearly dry to avoid product degradation caused by high temperature. The recrystallization process in S3 is: dissolving the crude product in hot ethanol at 70°C, and cooling it to precipitate crystals.

[0034] Example 3

[0035] The technical solution of the present invention provides a method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid, comprising the following steps:

[0036] S1: Add 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid and an appropriate amount of solvent into a corrosion-resistant reaction bottle and stir evenly;

[0037] S2: Then, add an excess of hydrazine hydrate and a catalytic additive, heat the reaction system to 90°C, and keep stirring evenly during the reaction until the reaction is completed;

[0038] S3: After the reaction is completed, the reaction bottle is removed from the heating source and cooled naturally to room temperature. The catalyst is removed by vacuum filter, and then extracted, concentrated and recrystallized to obtain 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid.

[0039] The solvent added in S1 is a mixed solvent of ethanol and water. The reaction time in S2 is 5 hours, and the stirring rate is 40 r / min. The catalyst added in S2 is a 15% palladium / carbon catalyst.

[0040] The extraction process in S3 is: transfer the reaction mixture to a separatory funnel, add an appropriate amount of deionized water, shake gently to transfer the reaction product to the aqueous phase, and perform three extractions to recover the target product to the maximum extent.

[0041] The concentration process in S3 is: using a rotary evaporator, evaporating at low pressure at 65°C to remove water and other volatile solvents, and concentrating until the residue is nearly dry to avoid product degradation caused by high temperature. The recrystallization process in S3 is: dissolving the crude product in hot ethanol at 55°C, and cooling it to precipitate crystals.

[0042] Example 4

[0043] The technical solution of the present invention provides a method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid, comprising the following steps:

[0044] S1: Add 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid and an appropriate amount of solvent into a corrosion-resistant reaction bottle and stir evenly;

[0045] S2: Then, add an excess of hydrazine hydrate and a catalytic additive, heat the reaction system to 95°C, and keep stirring evenly during the reaction until the reaction is completed;

[0046] S3: After the reaction is completed, the reaction bottle is removed from the heating source and cooled naturally to room temperature. The catalyst is removed by vacuum filter, and then extracted, concentrated and recrystallized to obtain 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid.

[0047] The solvent added in S1 is one of ethanol, deionized water, and a mixed solvent of ethanol and water.

[0048] The reaction time in S2 is 7 hours, the stirring rate is 50 r / min, and the catalyst added in S2 is 10-20% palladium / carbon catalyst.

[0049] The extraction process in S3 is: transfer the reaction mixture to a separatory funnel, add an appropriate amount of deionized water, shake gently to transfer the reaction product to the aqueous phase, and perform three extractions to recover the target product to the maximum extent.

[0050] The concentration process in S3 is: using a rotary evaporator, evaporating at low pressure at 65°C to remove water and other volatile solvents, and concentrating until the residue is nearly dry to avoid product degradation caused by high temperature. The recrystallization process in S3 is: dissolving the crude product in hot ethanol at 60°C, and cooling it to precipitate crystals.

[0051] 1. Performance Testing

[0052] The 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid prepared in Examples 1-4 was subjected to performance tests, including light stability, storage stability, and thermal stability. The results are shown in Table 1 below.

[0053] Photostability test: Expose the sample to ultraviolet light or visible light and observe its photochemical stability for 48 hours.

[0054] Storage stability test: Determine the degradation rate after storing at room temperature for 6 months;

[0055] Thermal stability test: Use a thermogravimetric analyzer to measure the mass change of the sample under 150°C treatment conditions.

[0056] Table 1

[0057]

[0058]

[0059] As shown in Table 1 above, the 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid prepared in this scheme has no obvious color change after exposure for 48 hours, indicating that it has good light stability; it has no obvious degradation after storage for 6 months at room temperature, indicating that it has good long-term storage stability and is easy to store; under the temperature condition of 150°C, its weight loss rate is within 10%, indicating that it has good thermal stability. The above 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid has good stability in all aspects, which is of great significance for improving the industrial production efficiency of Eltrombopag.

[0060] Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field and related fields without creative work should fall within the scope of protection of the present invention. The structures, devices and operating methods not specifically described and explained in the present invention are implemented according to the conventional means in the field unless otherwise specified and limited.

Claims

1. A method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid, characterized in that: The steps include: S1: Add 2'-hydroxy-3'-nitrobiphenyl-3-carboxylic acid and an appropriate amount of solvent into a corrosion-resistant reaction bottle and stir evenly; S2: Then, add an excess of hydrazine hydrate and a catalytic additive, heat the reaction system to 80-100°C, and keep stirring evenly during the reaction until the reaction is completed; S3: After the reaction is completed, the reaction bottle is removed from the heating source and cooled naturally to room temperature. The catalyst is removed by vacuum filter, and then extracted, concentrated and recrystallized to obtain 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid.

2. The method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid according to claim 1, characterized in that: The solvent added in S1 is one of ethanol, deionized water, and a mixed solvent of ethanol and water.

3. The method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid according to claim 1, characterized in that: The reaction time in S2 is 4-8 hours, and the stirring rate is 30-60 r / min.

4. The method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid according to claim 1, characterized in that: The catalyst added in S2 is a 10-20% palladium / carbon catalyst.

5. The method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid according to claim 1, characterized in that: The extraction process in S3 is: transfer the reaction mixture to a separatory funnel, add an appropriate amount of deionized water, shake gently to transfer the reaction product to the aqueous phase, and perform three extractions to recover the target product to the maximum extent.

6. The method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid according to claim 1, characterized in that: The concentration process in S3 is: using a rotary evaporator, evaporating at low pressure at 60-70°C to remove water and other volatile solvents, and concentrating until the residue is nearly dry to avoid product degradation caused by high temperature.

7. The method for preparing 3'-amino-2'-hydroxy-biphenyl-3-carboxylic acid according to claim 1, characterized in that: The recrystallization process in S3 is as follows: the crude product is dissolved in hot ethanol at 50-70°C, and crystals are precipitated after cooling.

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