CN113149991A - Synthesis method of sitagliptin free base and sitagliptin phosphate monohydrate - Google Patents

US6699871B2 discloses for the first time sitagliptin and pharmaceutically acceptable salts thereof and the corresponding preparation process, the synthetic route of which is shown in figure 1. In the method, (R) -3- (tert-butoxycarbonylamino) -4- (2,4, 5-trifluorophenyl) butyric acid (a compound of formula 2) is condensed with 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride (a compound of formula 3) by adding 1-hydroxybenzotriazole (abbreviated as HOBt in English) to methylene chloride, and purification is carried out by preparative thin layer chromatography to obtain tert-butyl (R) - (4-oxo-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) -1- (2,4, 5-trifluorophenyl) butan-2-yl) carbamate (a compound of formula 4), the yield was only 33%. The compound of

4 was reacted with hydrochloric acid in methanol to produce (3R) -3-amino-1- [3- (trifluoromethyl) -5,6,7, 8-tetrahydro-1, 2, 4-triazolo [4,3-a ] pyrazin-7-yl ] -4- (2,4, 5-trifluorophenyl) butan-1-one hydrochloride (compound of

5, sitagliptin hydrochloride) in 85.8% yield.

The above process requires the use of chromatographic techniques to purify the intermediates, resulting in very low yields; furthermore, explosive dry HOBt needs to be used, and thus the method is not suitable for commercial production. In addition, impurities (compounds of

7, compounds of formula 8) are also easily generated using methanol and hydrochloric acid in the reaction process of the compounds of

4 to compounds of

5, and the reaction steps are shown in fig. 2, affecting the purity of the product.

International patent application WO2009064476a1 discloses a process for the preparation of sitagliptin free base by reaction of a compound of

2 with a compound of

3 in DMF solvent with DCC, DMAP and TEA to produce a compound of

4, the reaction scheme being shown in figure 3. After the reaction was completed, separation was performed using ethyl acetate and isopropanol solvents, yield 85%. The compound of

4 was reacted in concentrated hydrochloric acid (HCl) and isopropanol solvent at 40 ℃ to give the compound (R) -3-amino-1- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazin-7 (8H) -yl) -4- (2,4, 5-trifluorophenyl) butan-1-one (compound of

6, sitagliptin free base) in 77% yield.

The above preparation process requires the isolation of the compound of

4 using various solvents including DMF (12.5 times by volume), ethyl acetate (35 times by volume) and isopropanol (7.5 times by volume), and it is not feasible to use DMF in too large a volume in terms of cost and recovery rate, so that the process is not suitable for commercial production.

Similarly, during the reaction of the compound of

4 to the compound of

5, which uses isopropanol and hydrochloric acid, impurities (compound of

7, compound of formula 9) are also easily generated, and the reaction steps are shown in fig. 4, affecting the purity of the product.

(2) washing and layering the reaction system obtained in the step (1), separating an organic layer, distilling to obtain a compound of a

4,

(4) adding an anti-solvent into the residue obtained in the step (3) for reaction, filtering and separating solid to obtain a target product, namely a compound shown as a

6,

(a) adding the compound of the

6 into isopropanol and water at the temperature of 20-30 ℃, adding phosphoric acid, and heating;

(b) adding the compound of

1 into the reaction system in the step (a), and keeping for 1.5-3 h;

Preferably, in step (b), after slowly cooling to 68-70 ℃, the compound of

1 is added, and after the addition is finished, slowly cooling to 60-65 ℃ for 2 h.

Compared with the prior art, the invention has the advantages that: according to the invention, by removing dried HOBt or changing the dried HOBt into HOBt hydrate, DMF (dimethyl formamide) solvent is removed in the process and a simple solvent which is easy to recover is used in the production process, so that the production cost is reduced and the reaction safety is improved; the in-situ process from the compound of

2 to the compound of

6 of the present invention can improve the yield and reduce the operation steps, and other solvents are used to replace methanol or isopropanol IPA, thereby avoiding the generation of impurities shown in

7,

8 and

9, and greatly improving the purity and yield of the product, and the HPLC purity of the sitagliptin free base is more than 99%.

FIG. 2 is a diagram of a reaction procedure for producing a compound of

7, a compound of

8 in the background art;

FIG. 4 is a diagram of the reaction steps in the prior art to produce compounds of

7 and 9.

B. Preparation of Compounds of

6 from Compounds of

2

adding 40mL of methanol and 20mL of concentrated hydrochloric acid into the crude compound of

4, and stirring at 25-27 ℃ until the reaction is carried out;

after the reaction was complete, vacuum distillation was carried out at 50 ℃, 40mL of water was added to the residue and the pH was adjusted to 10-12 using 2M sodium hydroxide solution, the product was extracted twice with 50mL of dichloromethane, the combined organic layers were washed with 50mL of water, the organic layer was vacuum distilled at 45 ℃, 70mL of methyl tert-butyl ether (MTBE) was added to the residue and slowly cooled to 20-26 ℃, the solid was filtered, washed with MTBE, and the wet product was vacuum dried at 45 ℃ to give the dry product. Yield 84.84%, HPLC purity 99.46%, impurity content 0.42% as shown in

8.

the preparation method of the compound of the

2 comprises the following steps:

after obtaining the compound of

4, 300mL of dichloromethane and 6mL of concentrated hydrochloric acid are added to 60g of (R) - (4-oxo-4- (3- (trifluoromethyl) -5, 6-dihydro- [1,2,4] triazolo [4,3-a ] pyrazine-7 (8H) -) -1- (2,4, 5-trifluorophenyl) but-2-yl) carbamate, and the reaction temperature is maintained at 20-30 ℃ until the reaction is completed;

slowly cooling to 68-70 deg.C, adding 250mg of compound of

1, slowly cooling to 60-65 deg.C, holding for 2 hr, slowly cooling to 10-15 deg.C within 5-7 hr, stirring for 10-12 hr, filtering, washing with 50ml isopropanol, and vacuum drying wet cake at 30-35 deg.C to obtain compound of

1. The yield was 93.76%, the HPLC purity was 100%, and the water content was 3.5%.

1. A synthetic method of sitagliptin free base is characterized by comprising the following steps:

(1) reacting a compound of formula 2 with a compound of formula 3 in the presence of a coupling agent, a base, a condensing agent and a solvent,

(2) washing and layering the reaction system obtained in the step (1), separating an organic layer, distilling to obtain a compound of a formula 4,

(3) adding concentrated hydrochloric acid into the reaction system in the step (2) for reaction, after the reaction is finished, carrying out vacuum distillation, adding water into the residue, adjusting the pH to 10-12 with alkali liquor, extracting the system with an organic solvent, concentrating the organic solvent, and carrying out vacuum distillation;

(4) adding an anti-solvent into the residue obtained in the step (3) for reaction, filtering and separating solid to obtain a target product, namely a compound shown as a formula 6,

2. the method of synthesizing sitagliptin free base according to claim 1, characterized in that: the coupling agent in the step (1) is N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, and the condensing agent is 1-hydroxybenzotriazole hydrate.

3. The method of synthesizing sitagliptin free base according to claim 1, characterized in that: the alkali in the step (1) is selected from triethylamine, diisopropylethylamine, N-methylmorpholine or N-methylpyrrolidine, and the solvent is dichloromethane; the organic solvent in the step (3) is dichloromethane.

4. The method of synthesizing sitagliptin free base according to claim 1, characterized in that: the reaction temperature of the step (1) is 0-30 ℃, and the reaction temperature of the step (3) is 20-35 ℃.

5. The method of synthesizing sitagliptin free base according to claim 1, characterized in that: the alkali liquor in the step (3) is 2M sodium hydroxide solution.

6. The method of synthesizing sitagliptin free base according to claim 1, characterized in that: in the step (4), the anti-solvent is methyl tert-butyl ether, and the reaction temperature is 20-26 ℃.

7. A synthetic method of sitagliptin phosphate monohydrate is characterized by comprising the following steps:

(a) adding a compound of formula 6 as defined in any one of claims 1 to 6 to isopropanol and water at 20 to 30 ℃, adding phosphoric acid, and heating;

(b) adding the compound of formula 1 into the reaction system in the step (a), and keeping for 1.5-3 h;

(c) and (b) slowly cooling the reaction system in the step (b), filtering and drying to obtain a target product (3R) -3-amino-1- [3- (trifluoromethyl) -5,6,7, 8-tetrahydro-1, 2, 4-triazolo [4,3-a ] pyrazin-7-yl ] -4- (2,4, 5-trifluorophenyl) butan-1-one phosphate monohydrate.

8. The method of synthesizing sitagliptin phosphate monohydrate according to claim 7, characterized in that: heating to 78-80 ℃ in the step (a), wherein the volume concentration of the phosphoric acid is 85%.

9. The method of synthesizing sitagliptin phosphate monohydrate according to claim 7, characterized in that: in the step (b), slowly cooling to 68-70 ℃, then adding the compound of the formula 1, slowly cooling to 60-65 ℃ after adding, and keeping for 2 h.

10. The method of synthesizing sitagliptin phosphate monohydrate according to claim 7, characterized in that: in the step (c), the reaction system is slowly cooled to 10-15 ℃ within 5-7h, stirred for 10-12 h, and then filtered, washed and dried.