CN115894207A

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

Info

Publication number: CN115894207A
Application number: CN202211573194.5A
Authority: CN
Inventors: 黄陈赛; 吴�荣
Original assignee: Nanjing Kanglirui Biotechnology Co ltd
Current assignee: Nanjing Kanglirui Biotechnology Co ltd
Priority date: 2022-12-08
Filing date: 2022-12-08
Publication date: 2023-04-04

Abstract

The invention discloses a synthetic method of 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid, which 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 3:1-adamantane ketone is oxidized by potassium permanganate in an alkaline aqueous solution 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. The synthetic method of the 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid has the advantages of fewer steps, high yield, simple and easily available raw materials and simple operation.

Description

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

Technical Field

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

Background

Saxagliptin (saxagliptin), trade name of oglza, chemical name (1s, 3s, 5s) -2- [ (2S) -2-amino-2- (3-hydroxytricyclo [3.3.1.13,7] decan-1-yl) acetyl ] -2-azabicyclo [3.1.0] -hexane-3-carbonitrile, developed by Bristol-Myers Squibb corporation in association with astrzeneca corporation, approved by FDA in 2009 on the market at 7 months. Saxagliptin is a highly selective, reversible competitive dipeptidyl peptidase IV (DPP-IV) inhibitor, has good tolerance and does not cause obesity, and is clinically used for treating type II diabetes.

2- (3-hydroxy-1-adamantyl) -2-oxoacetic acid is an important intermediate for synthesizing saxagliptin, and the CAS registration number is as follows: 709031-28-7, having the formula:

letters in Organic Chemistry,2012,9 (5), 347-350 react the prepared adamantane formyl chloride with sodium salt of diethyl malonate, and then are hydrolyzed and decarboxylated to obtain acetylamantane, and then are oxidized and hydroxylated by potassium permanganate to obtain 2- (3-hydroxy-1-adamantyl) -2-oxoacetic acid;

wherein, the synthesis of the acetylamantane requires three steps of reaction, the route is longer, and the yield is lower.

Disclosure of Invention

1. The technical problem to be solved is as follows:

aiming at the technical problems, the invention provides a synthesis method of 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid.

2. The technical scheme is as follows:

a synthetic method of 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid comprises the following steps:

the method specifically comprises the following steps:

step 1: reacting bromoadamantane and metal magnesium 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.

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

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

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

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

Furthermore, tertiary butanol can be added as a cosolvent in the step 3.

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

Further, the volume ratio of the concentrated nitric acid to the concentrated sulfuric acid in the step 4 is 1.

3. Has the beneficial effects that:

the synthetic method of the 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid has the advantages of fewer steps, high yield, simple and easily available raw materials and simple operation.

Detailed Description

The present invention will be described in detail below.

Example 1

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

step 1: mg (1.3 g,53.5 mmol) is added into dry tetrahydrofuran (10 mL), under the protection of nitrogen, after the initiation is carried out according to the preparation of a conventional Grignard reagent, vigorous stirring is carried out, the temperature is raised to 40 ℃, bromoadamantane (10g, 46.5 mmol) is dissolved in dry tetrahydrofuran (100 mL), dropwise addition is carried out on the solution, weak reflux is formed in the process, after the dropwise addition is finished, the reflux reaction is carried out for 1h, and the solution is cooled to room temperature, so that the Grignard reagent tetrahydrofuran solution is formed.

Step 2: dried acetonitrile (3.8g, 92.6mmol) was diluted with tetrahydrofuran (40 ml), cooled to-68 ℃, and the Grignard reagent prepared in step 1 was slowly added dropwise to the solution over a period of 2 hours, and after the addition was completed, the reaction was continued at this temperature for 4 hours, and 2mol/L of dilute hydrochloric acid was slowly added dropwise until the pH was below 7, and the stirring was continued for 1 hour. After partial tetrahydrofuran was removed by concentration under reduced pressure, extracted three times with ethyl acetate 50ml, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by dichloromethane: n-hexane (1.

And step 3: 100mL of a 2% KOH solution and 20mL of t-butanol were added to 1-adamantanemenone (5.0g, 28mmol), the mixture was heated to 40 ℃ and potassium permanganate (8g, 50.6 mmol) was added in portions over 1 hour, the mixture was allowed to react at 40 ℃ for 5 hours, and 20mL of a 10% sodium sulfite solution was added to quench the reaction. The mixture is filtered off with suction while hot and the filter cake is washed with 15ml of hot water. The filtrate was cooled to room temperature, the pH was adjusted to =1 with concentrated hydrochloric acid, ethyl acetate was extracted three times, the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to an oily substance, which was crystallized from ethyl acetate: n-hexane (1: 1) to obtain 5.3g of a white solid of adamantanone acid with a yield of 90.74%.

And 4, step 4: adamantanone acid (5g, 24mmol) was added in portions to a mixture of 65% nitric acid (2.5 mL) and 95% sulfuric acid (27 mL) at 0 ℃ to 5 ℃ with the temperature maintained at not higher than 25 ℃. Then, the reaction mixture was poured into ice-water, and the organic layer was extracted with ethyl acetate (50 mL. Times.3). The organic layers were combined and washed with saturated brine and concentrated to give a crude product which was purified with ethyl acetate: n-hexane (1:3) was recrystallized to give 2- (3-hydroxy-1-adamantane) -2-oxoacetic acid (4.0g, 17.8mmol) in a yield of 74.3%.

Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

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;

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.