CN112898303A

CN112898303A - Synthetic method of linagliptin chloro intermediate

Info

Publication number: CN112898303A
Application number: CN201911229723.8A
Authority: CN
Inventors: 叶俊涛
Original assignee: JIANGSU ZHENGDA QINGJIANG PHARMACEUTICAL CO Ltd
Current assignee: JIANGSU ZHENGDA QINGJIANG PHARMACEUTICAL CO Ltd
Priority date: 2019-12-04
Filing date: 2019-12-04
Publication date: 2021-06-04

Abstract

The invention discloses a synthesis method of a linagliptin intermediate, which comprises the steps of reacting 1-methyluracil, urea, NCS and the like with an oxidant under the combined action of acid catalysis and a high-pressure mercury lamp to obtain a compound A; and then carrying out substitution reaction on the compound A and 1-bromo-2-butyne to obtain a compound B, namely the linagliptin intermediate. The method provided by the invention has the advantages of easily available raw materials, few steps, high yield and mild reaction conditions, and is suitable for industrial production.

Description

Synthetic method of linagliptin chloro intermediate

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthetic method of a linagliptin intermediate.

Background

Diabetes is caused by the increase of blood sugar due to absolute or relative insufficiency of insulin, which in turn causes metabolic disturbance of the body

And (4) disordering. Today, diabetes has become the third leading killer threatening human health following cardiovascular disease and tumors. Generally, diabetes can be classified into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes). Among them, type 2 diabetes is the most common, accounting for more than 90% of patients with diabetes. The anti-carbohydrate drugs currently on the market include insulin, biguanides, sulfonylureas, glycosidase inhibitors and thiazolidinediones. However, the conventional anti-sugar drugs generally have problems such as weight gain, side effects such as hypoglycemia, and gradual decrease in drug efficacy. However, linagliptin, as a DPP-iv inhibitor, can effectively promote the secretion of insulin and inhibit the level of glucagon, thereby improving the ability of the body to control blood glucose level, and also has the function of protecting beta cell, and does not cause the side effects of hypoglycemia and weight gain, so that linagliptin has become a research and development hotspot of drugs for treating type 2 diabetes.

At present, the synthesis process of linagliptin is mainly shown in the following route:

we have found that with reference to the route, the compound bromobutylkyne is an important intermediate in the synthesis of linagliptin, and now the synthetic process route for the compound is mainly seen in route two (CN 104211702, CN 102807568, Journal of medical Chemistry, 52(20), 6433-: the method uses 6-amino-1-methyl uracil as initial material, firstly reacts with sodium nitrite to obtain corresponding compound of last nitroso, and then the compound of corresponding formula II is obtained after one time of reduction, cyclization, iodination and substitution. The method has long route, uses explosive nitrite compounds, has low yield and limits the industrial application of the method to a certain extent.

Disclosure of Invention

The purpose of the invention is as follows: in order to solve the problems in the prior art, the invention provides a linagliptin

The synthesis method of the intermediate can avoid using dangerous chemical reagents, has mild reaction, economy, environmental protection, simple process and higher yield, and is suitable for industrial production.

The technical scheme is as follows: the synthesis method of the linagliptin intermediate comprises the following steps:

(1) carrying out photochemical reaction on 1-methyl uracil, urea, NCS and an oxidant under the conditions of acid catalysis and irradiation of a high-pressure mercury lamp to obtain a compound A;

(2) carrying out substitution reaction on the compound A and 1-bromo-2-butyne to obtain a compound B, namely a linagliptin intermediate;

the reaction in the step (1) is an oxidative coupling cyclization reaction.

The reaction of step (1) is a reaction driven and involved by NCS, and the molar ratio of 1-methyluracil to NCS is preferably 1.0: 2.0.

The reaction in the step (1) is an oxidation reaction in which an oxidant participates, wherein the oxidant is one or more of hydrogen peroxide and TBHP, and TBHP is preferred; the molar ratio of 1-methyluracil to oxidizing agent is preferably 2.0;

the reaction in the step (1) is carried out under the catalysis of acid, and the acid catalyst is one or more of sulfuric acid, hydrochloric acid, boric acid and C1-C4 carboxylic acid, preferably sulfuric acid; wherein the concentration of the hydrochloric acid is 37 wt%; the concentration of sulfuric acid is 98 wt%; the carboxylic acid of C1-C4 may be, for example, formic acid, acetic acid, propionic acid, etc.; the molar ratio of 1-methyluracil to acid is preferably 1.0: 0.1.

In step (1), the molar ratio of 1-methyluracil to urea is preferably 1.0: 2.0.

In the step (1), the reaction solvent is one or more of dioxane, DMF, NMP and ethylene glycol dimethyl ether, and dioxane is preferred; the reaction temperature is preferably 85 ℃; the reaction time is 16-20 h.

Adding alkali as an acid-binding agent due to acid generation in the step (2), wherein the alkali is one or more of sodium carbonate, potassium carbonate, triethylamine, N-diisopropylethylamine, DABCO and DBU, and preferably N, N-diisopropylethylamine; the molar ratio of the compound A to the base is 1.0 to (1.2-3.0), preferably 1.0 to 1.5.

In step (2), the molar ratio of compound A to 1-bromo-2-butyne is preferably 1.0: 1.5.

In the step (2), the reaction solvent is one or more of acetone, acetonitrile, 1, 2-dichloroethane and DMF, preferably acetone; the reaction temperature is 50-70 ℃, preferably 65 ℃; the reaction time is 4-6 h.

The beneficial effects of the synthetic route of the compound shown in the formula II of the invention are as follows: the method provided by the invention has the advantages of easily available raw materials, few steps, high yield and mild reaction conditions, and is suitable for industrial production.

The present invention will be described in further detail below by way of examples, but it should not be construed that the scope of the subject matter of the present invention is limited to the following examples. Such alterations and modifications are intended to be included herein by the scope of this disclosure, and such modifications are intended to be within the meaning of those skilled in the art.

Example 1 preparation of Compounds of formula I

In a 50 m L single neck bottle, 1-methyluracil (1.26 g, 10m o l), urea (1.20 g,

20mmol), NCS (2.6g, 20mmol), TBHP (70%, 2.83 g, 22mmol), sulfuric acid (98% strength by weight, 49mg, 0.5 mmol), 20mL of dioxane, then raised to 75 ℃ and stirred for 18 h. Then, 80mL of ethyl acetate was added to dilute the mother liquor, washed three times with a saturated aqueous sodium sulfite solution, once with a saturated aqueous sodium chloride solution, and finally once again with water, and ethyl acetate was rotary-distilled off under reduced pressure to obtain a crude product. The crude product was recrystallized from dichloromethane and cyclohexane to give 2.6g of compound a in 82% yield and 99% purity.

Example 2 preparation of Compound B

[ in a 100mL single-necked flask, the compound of formula (2.6g, ca. 10mmol), N, N-diisopropylethylamine (1.94 g, 15mmol), 1-bromo-2-butyne (1.98 g, 15mmol), and 30mL of acetone were sequentially added, the temperature was raised to 50 ℃ and the reaction was refluxed for 5 hours. And (3) cooling the reaction, cooling to room temperature, carrying out suction filtration, washing a filter cake with methanol to obtain a crude product, namely a light yellow solid, and recrystallizing the crude product with dichloromethane and cyclohexane to obtain 3.58 g of a compound B, wherein the yield is 96% and the purity is 99%.

Claims

1. A synthetic method of a linagliptin intermediate is characterized by comprising the following steps:

(1) reacting 1-methyl uracil, urea, NCS and an oxidant in the presence of acid catalysis and irradiation of a high-pressure mercury lamp to obtain a compound A;

(2) and carrying out substitution reaction on the compound A and 1-bromo-2-butyne to obtain a compound B, namely the linagliptin intermediate.

2. The method for synthesizing linagliptin intermediate as claimed in claim 1, wherein in step (1), the molar ratio of 1-methyluracil to NCS is 1.0: 2.0-3.0.

3. The method for synthesizing linagliptin intermediates according to claim 1, wherein in the step (1), the oxidant is hydrogen peroxide, TBHP, one or more; the mol ratio of the 1-methyl uracil to the oxidant is 1.0 to (2.0-3.0).

4. The method for synthesizing the linagliptin intermediate according to claim 1, characterized in that in the step (1), the acid catalyst is one or more of sulfuric acid, hydrochloric acid, boric acid, and carboxylic acids of C1-C4; the mol ratio of the 1-methyl uracil to the acid is 1.0 to (0.1-0.2).

5. The method for synthesizing linagliptin intermediate as claimed in claim 1, wherein in step (1), the molar ratio of 1-methyluracil to urea is 1.0 to (1.05-2.0).

6. The method for synthesizing linagliptin intermediates according to claim 1, characterized in that in the step (1), the reaction solvent is one or more of dioxane, DMF, NMP, and ethylene glycol dimethyl ether; the reaction temperature is 70-90 ℃.

7. The method for synthesizing linagliptin intermediate according to claim 1, wherein the step (2) is performed under alkaline conditions, and the base is one or more of sodium carbonate, potassium carbonate, triethylamine, N-diisopropylethylamine, DABCO, and DBU; the mol ratio of the compound A to the alkali is 1.0 to (1.2-2.0).

8. The method for synthesizing the linagliptin intermediate as claimed in claim 1, wherein the molar ratio of the compound A to the 1-bromo-2-butyne in the step (2) is 1.0 to (2.0-3.0).

9. The method for synthesizing the linagliptin intermediate according to claim 1, characterized in that in the step (2), the reaction solvent is one or more of acetone, acetonitrile, 1, 2-dichloroethane and DMF; the reaction temperature is 50-70 ℃.