阅读说明：本技术 一种西格列汀游离碱单体的制备方法 (Preparation method of sitagliptin free base monomer ) 是由 徐巧巧 梅杰 郭必豹 徐肃然 于 2018-08-24 设计创作，主要内容包括：本发明属于化工制药技术领域,具体涉及一种西格列汀游离碱单体的制备方法。所述方法为西格列汀盐酸盐或其他水溶性盐,在水中溶解后,用氢氧化钠溶液或其他无机碱调pH,温度为20-45℃条件下反应,反应完毕,抽滤,洗涤,干燥后制备得到。这种晶型制备方法稳定性高,操作简单,成本低,能够得到高产量的西格列汀游离碱单体,适用于工业化生产,具有很高的经济效益。(The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method of a sitagliptin free alkali monomer. The method comprises the steps of dissolving sitagliptin hydrochloride or other water-soluble salts in water, adjusting the pH value with a sodium hydroxide solution or other inorganic bases, reacting at the temperature of 20-45 ℃, filtering, washing and drying after the reaction is finished to obtain the sitagliptin hydrochloride or other water-soluble salts. The crystal form preparation method has the advantages of high stability, simple operation and low cost, can obtain the sitagliptin free alkali monomer with high yield, is suitable for industrial production, and has high economic benefit.)

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

a. sitagliptin hydrochloride or other water-soluble salts react with water under the conditions that the pH value is adjusted by inorganic salt and the temperature is 20-45 ℃,

wherein, the reaction of the sitagliptin hydrochloride or other water-soluble salts in the water in the step a is as follows:

b. after the alkali adjustment is finished, solidifying the materials, and then crushing part of the blocky materials;

c. filtering, and oven drying at 70-80 deg.C.

2. The method for preparing sitagliptin free base monomer according to claim 1, characterized by comprising the steps of: a. adjusting the pH of sitagliptin hydrochloride or other water-soluble salt or sitagliptin hydrochloride or other water-soluble salt known in the prior art and water in an inorganic base at the temperature of 20-45 ℃; b. curing the material obtained in the step a, and crushing part of the blocky material; c. filtering, and oven drying at 70-80 deg.C.

3. The method according to claim 1 or 2, wherein the water-soluble salt is a phosphate, tartrate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, dodecylsulfate, sulfate, hydrobromide, methanesulfonate, acetate, benzoate, oxalate, succinate, mandelate, fumarate, lactate, malate, glycolate, maleate, citrate, D-gluconate, thiocyanate, aspartate, ethanedisulfonate, pyroglutamate, glutarate, dibenzoyltartrate, D-glucuronate, hydrogen sulfate, quinic acid salt, formate, orotate, sodium bisulfate, potassium bisulfate, ammonium bisulfate, cesium bisulfate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, or ammonium dihydrogen phosphate, Cesium dihydrogen phosphate double salt, tromethamine hydrogen sulfate double salt, aminopropanediol hydrogen sulfate double salt, aminoethanol hydrogen sulfate double salt, glucosamine hydrogen sulfate double salt, arginine dihydrogen phosphate double salt, ornithine dihydrogen phosphate double salt, citrulline dihydrogen phosphate double salt, lysine hydrogen sulfate double salt, nitrate, picolinate, cinnamate, stearate, palmitate, xanthinol hydrochloride, laurate, gentisate, adipate, trifluoroacetate, 4-methyl salicylate, myristate, isophthalate, isonicotinate, caffeate, ferulate, coumarate, pterostilbene phosphate, lipoate, isethionate, naphthalenesulfonate.

4. The preparation method according to claim 1 or 2, wherein the mass ratio of sitagliptin hydrochloride or other water-soluble salt to water is 1-25.

5. The method according to claim 1 or 2, wherein the inorganic base is sodium hydroxide or potassium hydroxide.

6. The method of claim 1 or 2, wherein the inorganic base is dosed based on pH.

7. The production method according to claim 1 or 2, wherein the inorganic base is adjusted to a pH of 7.5 to 10.5.

8. The method according to claim 1 or 2, wherein the curing time is 0.5 to 4.5 hours.

Technical Field

The invention relates to a preparation method of a sitagliptin free base monomer.

Background

Sitagliptin is (R) -7- (1-oxo-3- ((R) -amino) -4- (2,4, 5-trifluorophenyl) butyl) -3- (trifluoromethyl) -5,6,7, 8-tetrahydro-1, 2, 4-triazolo [4,3-a ] pyrazine, represented by the following structural formula.

Sitagliptin belongs to a dipeptidyl peptidase-4 (DPP-4) inhibitor, can be independently applied or can be used for treating type 2 diabetes by other oral hypoglycemic drugs to form compound drugs, and has the advantages of good safety and low incidence of adverse reactions such as hypoglycemia and weight gain.

US6699871 discloses a class of β -aminotetrahydrotriazolo [4,3-a ] pyrazines which are potent inhibitors of DPP-IV and are therefore useful in the treatment of type II diabetes, US6699871 specifically discloses sitagliptin, and also discloses methods for preparing sitagliptin and related compounds.

International application WO2004/085661 discloses a process for the preparation of sitagliptin using S-phenylglycinamide as a chiral auxiliary to form an intermediate, which is then used to form sitagliptin.

International application WO2004/087650 discloses another method for enantioselectively synthesizing N-protected 3- ((R) -amino) -4- (2,4, 5-trifluorophenyl) butanoic acid, condensing with pyrazine intermediate and deprotecting to prepare sitagliptin.

Although the prior art reports several methods for the preparation of sitagliptin, most use hazardous reagents, expensive reagents and extensive protection and deprotection steps.

Crystalline salts of sitagliptin are known. International application WO2005/072530 discloses various crystalline salts of sitagliptin, and international application WO2006/033848 discloses a non-crystalline form of sitagliptin dihydrogen phosphate. International application WO2005/020920 discloses two anhydrous crystalline forms (form I and form III) and a desolvated, dehydrated crystalline form II of the dihydrogen phosphate salt of sitagliptin. International application WO2005/030127 discloses the dehydrated crystalline form IV of the dihydrogen phosphate salt of sitagliptin. International application WO2005/072530 discloses crystalline hydrochloride, besylate, p-toluenesulfonate, 10-camphorsulfonate and tartrate salts of sitagliptin. International application WO2007/035198 discloses lauryl sulfate salts of sitagliptin.

US patent US8334385 discloses the preparation of sitagliptin free base monomers using dichloromethane as solvent. There are some drawbacks that still need to be further improved. Such as the properties of solid sitagliptin, such as stability, flowability, vapor impermeability, purity, solubility, bioavailability and the like.

Disclosure of Invention

The preparation method of the invention improves the solvent, uses water as the solvent, is more environment-friendly, has lower cost and simple operation, is beneficial to industrial production and has high economic benefit.

In order to realize the technical purpose of the invention, the invention provides the following technical scheme:

firstly, the invention provides a sitagliptin free base monomer, and the prepared sitagliptin salt free base monomer is detected by adopting X-ray powder diffraction, so that an XRD (X-ray diffraction) spectrum shown as an attached figure 1 is obtained.

An X-ray powder diffraction pattern expressed by 2 θ ± 0.2 ° has characteristic peaks at 7.229,9.301,11.418,14.531,14.972,15.290,16.604,17.531,17.911,18.721,21.281,21.319,21.622,22.346,22.584,23.025,24.040,24.361,24.421,25.115,26.882,28.410,28.612,29.914,30.848,32.040,32.909,32.982,33.698,34.434,36.841,39.055, 39.255.

The invention further provides a preparation method of the sitagliptin free base monomer, which comprises the following steps:

a. reacting sitagliptin hydrochloride or other water-soluble salts with water under the conditions that the pH is adjusted by inorganic base and the temperature is 20-45 ℃, wherein the reaction of the sitagliptin hydrochloride or other water-soluble salts in the water in the step a is as follows:

b. after the alkali adjustment is finished, solidifying the materials, and then crushing part of the blocky materials;

c. filtering, and oven drying at 70-80 deg.C.

The water-soluble salt is phosphate, tartrate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, dodecyl sulfate, hydrobromide, methanesulfonate, acetate, benzoate, oxalate, succinate, mandelate, fumarate, lactate, malate, glycolate, maleate, citrate, D-gluconate, thiocyanate, aspartate, ethanedisulfonate, pyroglutamate, glutarate, dibenzoyl tartrate, D-glucuronate, hydrogen sulfate, quinic acid, formate, orotate, sodium bisulfate, potassium bisulfate, ammonium bisulfate, cesium bisulfate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, cesium dihydrogen phosphate, tromethamine bisulfate, aminopropanediol bisulfate, dihydrogensulfate, potassium bisulfate, ammonium bisulfate, cesium bisulfate, ammonium dihydrogen phosphate, potassium bisulfate, ammonium dihydrogen phosphate, cesium bisulfate, tromethamine bisulfate, aminopropanediol bisulfate, or a salt of bisulfate, potassium bisulfate, or a salt of, Aminoethanol hydrogen sulfate double salt, glucosamine hydrogen sulfate double salt, arginine dihydrogen phosphate double salt, ornithine dihydrogen phosphate double salt, citrulline dihydrogen phosphate double salt, lysine hydrogen sulfate double salt, nitrate, picolinate, cinnamate, stearate, palmitate, xanthinol hydrochloride, laurate, gentisate, adipate, trifluoroacetate, 4-methyl salicylate, myristate, isophthalate, isonicotinate, caffeate, ferulate, coumarate, pterostilbene phosphate, lipoate, isethionate, naphthalenesulfonate.

The mass ratio of sitagliptin hydrochloride or other water-soluble salts to water is 1-25, preferably 1: 6;

the inorganic alkali feeding amount is based on pH;

the pH value adjusted by the inorganic base is 7.5-10.5, and preferably 8-9;

the inorganic alkali is sodium hydroxide and potassium hydroxide, preferably sodium hydroxide;

the curing time is from 0.5 to 4.5 hours, preferably from 2 to 3 hours.

In the step a of the preparation method of the invention, the following steps can be carried out: sitagliptin hydrochloride or other water-soluble salt or sitagliptin hydrochloride or other water-soluble salt known in the prior art and water are reacted at the temperature of 20-45 ℃ under the condition that the pH is adjusted by inorganic base,

the mass ratio of sitagliptin hydrochloride or other water-soluble salts to water is 1-25, preferably 1: 6;

the inorganic alkali feeding amount is based on pH;

the inorganic base is used for adjusting the pH value to be 7.5-10.5, and preferably 8-9.

The preparation method provided by the invention has the advantages of high stability, simple operation and low cost, can obtain high-yield sitagliptin free alkali monomers, is suitable for industrial production, and has very high economic benefits.

Drawings

Fig. 1 is a powder X-ray diffraction pattern of sitagliptin free base monomer prepared in example 1.

Detailed Description

For further understanding of the present invention, the following examples are provided to illustrate the preparation of sitagliptin free base monomer by the method provided by the present invention. It is to be understood that these examples are described merely to illustrate the features of the present invention in further detail, and not as limitations of the invention or of the scope of the claims appended hereto.

The detection conditions used in the present invention are:

x-ray powder diffraction detection XPRD:

the instrument comprises the following steps: bruker D2 Phaser X-ray diffraction powder diffractometer;

x-ray target Cu K α (1.54184A);

pipe pressure: 30 kV;

pipe flow: 10 mA;

2 θ scanning range: 4 to 40 degrees;

scan rate (step time): 0.2 s/step;

step length: 0.02 degree.