A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid

Abstract

The invention discloses a method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid, specifically comprising the following steps: step 1: bromoadamantane and magnesium metal react to generate a Grignard reagent; step 2: the Grignard reagent reacts with acetonitrile, and then hydrolyzes in an acidic aqueous solution to obtain 1-adamantanone; step 3: 1-adamantanone is oxidized with potassium permanganate in an alkaline aqueous solution to obtain adamantanone acid; step 4: adamantanone acid reacts in a mixed solvent of concentrated nitric acid and concentrated sulfuric acid and then hydrolyzes to obtain 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid of the present invention has fewer steps, high yield, simple and easy-to-obtain raw materials, and simple operation of the synthetic method.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid. Background Art

[0002] Saxagliptin, trade name Onglyza, chemical name (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]-hexane-3-carbonitrile, was jointly developed by Bristol-Myers Squibb and AstraZeneca and approved by FDA for marketing in July 2009. Saxagliptin is a highly selective, reversible, competitive dipeptidyl peptidase IV (DPP-IV) inhibitor with good tolerance and no obesity, and is clinically used to treat type 2 diabetes.

[0003] 2-(3-Hydroxy-1-adamantyl)-2-oxoacetic acid is an important intermediate for the synthesis of saxagliptin. Its CAS registration number is 709031-28-7 and its structural formula is:

[0004]

[0005] Letters in Organic Chemistry, 2012, 9(5), 347-350 The prepared adamantane carboxyl chloride is reacted with sodium salt of diethyl malonate, and then hydrolyzed and decarboxylated to obtain acetyladantane, which is then oxidized and hydroxylated with potassium permanganate to obtain 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid;

[0006]

[0007] Among them, the synthesis of acetyladamantane requires three steps of reaction, the route is long and the yield is low. Summary of the invention

[0008] 1. Technical problems to be solved:

[0009] In view of the above technical problems, the present invention provides a method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid.

[0010] 2. Technical solution:

[0011] A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid, the route of the synthetic method is as follows:

[0012]

[0013] The specific steps include:

[0014] Step 1: Bromoadamantane reacts with magnesium metal to generate a Grignard reagent;

[0015] Step 2: The Grignard reagent reacts with acetonitrile, and then hydrolyzes in an acidic aqueous solution to obtain 1-adamantanone;

[0016] Step 3: 1-adamantanone is oxidized with potassium permanganate in an alkaline aqueous solution to obtain adamantanone acid;

[0017] Step 4: Adamantane keto acid is reacted in a mixed solvent of concentrated nitric acid and concentrated sulfuric acid and then hydrolyzed to obtain 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid.

[0018] Furthermore, the reaction solvent of step 1 is tetrahydrofuran or diethyl ether.

[0019] Furthermore, the molar ratio of bromoadamantane to metallic magnesium in step 1 is 1:1.1-1.3.

[0020] Furthermore, the molar ratio of the acetonitrile in step 2 to the bromoadamantane in step 1 is 1.5-3:1.

[0021] Furthermore, the acidic aqueous solution in step 2 is dilute hydrochloric acid.

[0022] Furthermore, tert-butyl alcohol can be added in step 3 as a co-solvent.

[0023] Furthermore, the alkaline aqueous solution in step 3 is an aqueous solution of sodium hydroxide or potassium hydroxide.

[0024] Furthermore, the volume ratio of concentrated nitric acid to concentrated sulfuric acid in step 4 is 1:10-15.

[0025] 3. Beneficial effects:

[0026] The synthetic method of 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid provided by the invention has fewer steps, high yield, simple and easily available raw materials and simple synthetic method operation. DETAILED DESCRIPTION

[0027] The present invention is described in detail below.

[0028] Example 1

[0029] A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid comprises the following steps:

[0030]

[0031] Step 1: Add Mg (1.3 g, 53.5 mmol) to dry tetrahydrofuran (10 mL), and under nitrogen protection, prepare the mixture according to the conventional Grignard reagent, stir vigorously, raise the temperature to 40°C, dissolve bromoadamantane (10 g, 46.5 mmol) in dry tetrahydrofuran (100 mL), and add the mixture dropwise to the solution, during which a weak reflux is formed. After the addition is completed, reflux for 1 hour, and cool to room temperature to form a Grignard reagent tetrahydrofuran solution.

[0032]

[0033] Step 2: Dry acetonitrile (3.8 g, 92.6 mmol) was diluted with 40 ml of tetrahydrofuran, cooled to -68 °C, and the Grignard reagent prepared in step 1 was slowly added dropwise to the solution. The addition time was controlled within 2 h. After the addition was completed, the reaction was continued at this temperature for 4 h. 2 mol / L dilute hydrochloric acid was slowly added dropwise until the pH was below 7, and stirring was continued for 1 h. The tetrahydrofuran was partially removed by concentration under reduced pressure, and the mixture was extracted three times with 50 ml of ethyl acetate. The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and the crude product was crystallized and purified with dichloromethane: n-hexane (1:10) to obtain 1-adamantanone (7.2 g, 40.4 mmol). The yield of steps 1-2 was 86.9%.

[0034]

[0035] Step 3: Add 100 ml of 2% KOH solution and 20 ml of tert-butyl alcohol to 1-adamantanone (5.0 g, 28 mmol), heat to 40°C, add potassium permanganate (8 g, 50.6 mmol) in batches within 1 hour, keep the reaction at 40°C for 5 hours, and add 20 ml of 10% sodium sulfite solution to quench the reaction. Filter while hot, and wash the filter cake with 15 ml of hot water. The filtrate is cooled to room temperature, adjusted to pH = 1 with concentrated hydrochloric acid, extracted with ethyl acetate three times, the combined organic layers are washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to an oily substance, which is crystallized with ethyl acetate: n-hexane (1:1) to obtain 5.3 g of a white solid of adamantanone acid, with a yield of 90.74%.

[0036]

[0037] Step 4: Add adamantane acid (5 g, 24 mmol) in batches to a mixture of 65% nitric acid (2.5 mL) and 95% sulfuric acid (27 mL) at 0°C to 5°C, keeping the temperature not higher than 25°C. Then react at room temperature for 3 hours, the reaction solution turns dark yellow, the reaction mixture is poured into ice water, and the organic layer is extracted with ethyl acetate (50 mL × 3). The organic layers are combined and washed with saturated brine, concentrated to obtain a crude product, and the crude product is recrystallized with ethyl acetate: n-hexane (1:3) to obtain 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid (4.0 g, 17.8 mmol), with a yield of 74.3%.

[0038] Although the present invention has been disclosed as above in terms of preferred embodiments, they are not intended to limit the present invention. Anyone skilled in the art can make various changes or modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection defined by the claims of this application.

Claims

1. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid, characterized in that: The route of the synthetic method is as follows: The specific steps include: Step 1: Bromoadamantane reacts with magnesium metal to generate a Grignard reagent; Step 2: The Grignard reagent reacts with acetonitrile, and then hydrolyzes in an acidic aqueous solution to obtain 1-adamantanone; Step 3: 1-adamantanone is oxidized with potassium permanganate in an alkaline aqueous solution to obtain adamantanone acid; Step 4: Adamantane keto acid is reacted in a mixed solvent of concentrated nitric acid and concentrated sulfuric acid and then hydrolyzed to obtain 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid.

2. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid according to claim 1, characterized in that: The reaction solvent of step 1 is tetrahydrofuran or diethyl ether.

3. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid according to claim 1, characterized in that: The molar ratio of bromoadamantane to metallic magnesium in step 1 is 1:1.1-1.

3.

4. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid according to claim 2 or 3, characterized in that: The molar ratio of the acetonitrile in step 2 to the bromoadamantane in step 1 is 1.5-3:

1.

5. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid according to claim 4, characterized in that: The acidic aqueous solution in step 2 is dilute hydrochloric acid.

6. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid according to claim 5, characterized in that: In step 3, tert-butyl alcohol can also be added as a co-solvent.

7. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid according to claim 6, characterized in that: The alkaline aqueous solution in step 3 is an aqueous solution of sodium hydroxide or potassium hydroxide.

8. A method for synthesizing 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid according to claim 7, characterized in that: The volume ratio of concentrated nitric acid to concentrated sulfuric acid in step 4 is 1:10-15.

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