CN115894207A - Synthesis method of 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid - Google Patents

Abstract

The invention discloses a synthesis method of 2-(3-hydroxyl-1-adamantane)-2-oxoacetic acid, specifically comprising the following steps: Step 1: reacting bromoadamantane and metal magnesium to generate Grignard reagent; Step 2: Grignard reagent reacts with acetonitrile, and then hydrolyzes in acidic aqueous solution to obtain 1-adamantanyl ketone; Step 3: 1-adamantanyl ketone is oxidized with potassium permanganate in alkaline aqueous solution to obtain adamantanonic acid; Step 4: adamantanone acid is reacted in a mixed solvent of concentrated nitric acid and concentrated sulfuric acid and then hydrolyzed to obtain 2-(3-hydroxyl-1-adamantane)-2-oxoacetic acid. The synthesis method of 2-(3-hydroxyl-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 synthesis method.

Description

A kind of synthetic method of 2-(3-hydroxyl-1-adamantane)-2-oxoacetic acid

technical field

The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a synthesis method of 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid.

Background technique

Saxagliptin, trade name Onglyza, chemical name (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]decane -1-yl)acetyl]-2-azabicyclo[3.1.0]-hexane-3-carbonitrile, jointly developed by Bristol-Myers Squibb and AstraZeneca, approved by FDA in July 2009. Saxagliptin is a highly selective and reversible competitive dipeptidyl peptidase Ⅳ (DPP-Ⅳ) inhibitor, which is well tolerated and does not cause obesity. It is clinically used for the treatment of type Ⅱ diabetes.

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

Letters in Organic Chemistry, 2012, 9(5), 347-350 reacts the prepared adamantanecarbonyl chloride with the sodium salt of diethyl malonate, hydrolyzes and decarboxylates to obtain acetyladamantane, and then oxidizes it with potassium permanganate , hydroxylation to obtain 2-(3-hydroxyl-1-adamantyl)-2-oxoacetic acid;

Among them, the synthesis of acetyladamantane requires three steps of reaction, the route is longer and the yield is lower.

Contents of the invention

1. Technical problems to be solved:

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

2. Technical solution:

A kind of synthetic method of 2-(3-hydroxyl-1-adamantane)-2-oxoacetic acid, the route of described synthetic method is as follows:

Specifically, the following steps are included:

Step 1: bromoadamantane reacts with metal magnesium to generate Grignard reagent;

Step 2: Grignard reagent reacts with acetonitrile, and then hydrolyzes in acidic aqueous solution to obtain 1-adamantanyl ketone;

Step 3: 1-adamantanone ketone is oxidized with potassium permanganate in alkaline aqueous solution to obtain adamantanonic acid;

Step 4: reacting adamantanone acid in a mixed solvent of concentrated nitric acid and concentrated sulfuric acid and then hydrolyzing it to obtain 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid.

Further, the reaction solvent in step 1 is tetrahydrofuran or diethyl ether.

Further, the molar ratio of bromoadamantane and metal magnesium in step 1 is 1:1.1-1.3.

Further, the molar ratio of the acetonitrile in step 2 to the bromoadamantane in step 1 is 1.5-3:1.

Further, the acidic aqueous solution in step 2 is dilute hydrochloric acid.

Further, in step 3, tert-butanol can also be added as a cosolvent.

Further, the alkaline aqueous solution in step 3 is an aqueous solution of sodium hydroxide or potassium hydroxide.

Further, the volume ratio of concentrated nitric acid and concentrated sulfuric acid in step 4 is 1:10-15.

3. Beneficial effects:

The synthesis method of 2-(3-hydroxyl-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 synthesis method.

Detailed ways

The present invention will be specifically described below.

Example 1

A kind of synthetic method of 2-(3-hydroxyl-1-adamantane)-2-oxoacetic acid, comprises the following steps:

Step 1: Add Mg (1.3g, 53.5mmol) into dry tetrahydrofuran (10mL), under the protection of nitrogen, prepare according to the conventional Grignard reagent, stir vigorously, heat up to 40°C, and bromoadamantane (10g, 46.5mmol) was dissolved in dry tetrahydrofuran (100mL), and added dropwise to the solution, during which a weak reflux was formed. After the dropwise addition, the solution was refluxed for 1h and cooled to room temperature to form a Grignard reagent tetrahydrofuran solution.

Step 2: Dried acetonitrile (3.8g, 92.6mmol) was diluted with 40ml of tetrahydrofuran, cooled to -68°C, and the Grignard reagent prepared in step 1 was slowly added dropwise to the solution, and the dropping time was controlled at 2h. After the end, continue to react at this temperature for 4 hours, slowly add 2 mol/L dilute hydrochloric acid dropwise until the pH is below 7, and continue stirring for 1 hour. Concentrate under reduced pressure to remove part of tetrahydrofuran, extract three times with 50 ml of ethyl acetate, combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and dichloromethane: n-hexane (1: 10) Purification by crystallization to obtain 1-adamantanyl ketone (7.2 g, 40.4 mmol), the yield of step 1-2 is 86.9%.

Step 3: Add 100ml 2% KOH solution, 20ml tert-butanol to 1-adamantanyl ketone (5.0g, 28mmol), heat to 40°C, add potassium permanganate (8g, 50.6mmol) in batches within 1 hour , kept at 40° C. for 5 hours, and added 20 mL of 10% sodium sulfite solution to quench the reaction. Suction filtration while hot, and the filter cake was washed with 15ml of hot water. The filtrate was cooled to room temperature, adjusted to pH = 1 with concentrated hydrochloric acid, extracted three times with ethyl acetate, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to an oil, and washed with ethyl acetate: n-hexane ( 1:1) crystallization to obtain 5.3 g of white solid of adamantanonic acid, yield 90.74%.

Step 4: Add adamantanonic 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 reacted at room temperature for 3 hours, and the reaction solution turned dark yellow. The reaction mixture was poured into ice water, and the organic layer was extracted with ethyl acetate (50 mL×3). The organic layers were combined and washed with saturated brine, and concentrated to obtain a crude product, which was recrystallized from ethyl acetate:n-hexane (1:3) to obtain 2-(3-hydroxy-1-adamantane)-2-oxoacetic acid (4.0g , 17.8mmol), yield 74.3%.

Although the present invention has been disclosed as above with preferred embodiments, they are not intended to limit the present invention. Any skilled person can make various changes or modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be defined by the protection scope of the claims of the present application.

Claims (8)

1. A synthetic method of 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid is characterized in that the route of the synthetic method is as follows:

the method specifically comprises the following steps:

step 1: reacting bromoadamantane and magnesium metal to generate a Grignard reagent;

step 2: reacting the Grignard reagent with acetonitrile, and hydrolyzing in an acidic aqueous solution to obtain 1-adamantane ketone;

step 5363, oxidizing the 3:1-adamantane ketone in an alkaline aqueous solution by using potassium permanganate to obtain adamantane keto acid;

and 4, step 4: reacting adamantane acid in a mixed solvent of concentrated nitric acid and concentrated sulfuric acid, and hydrolyzing to obtain 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid.

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

3. The synthesis method of 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid according to claim 1, wherein the molar ratio of bromoadamantane and magnesium metal in step 1 is 1.1-1.3.

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

5. The 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 diluted hydrochloric acid.

6. The method for synthesizing 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid according to claim 5, wherein tert-butanol is further added as a cosolvent in step 3.

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

8. The method for synthesizing 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid according to claim 7, wherein the volume ratio of the concentrated nitric acid and the concentrated sulfuric acid in the step 4 is 1.