CN111574463A

CN111574463A - Riagliptin intermediate compound IV

Info

Publication number: CN111574463A
Application number: CN201910122790.3A
Authority: CN
Inventors: 张贵民; 王本利; 黄文波
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2019-02-19
Filing date: 2019-02-19
Publication date: 2020-08-25
Anticipated expiration: 2039-02-19
Also published as: CN111574463B

Abstract

The invention belongs to the field of pharmaceutical chemicals, and discloses a linagliptin intermediate IV

And a new route for synthesizing the important intermediate of linagliptin by utilizing the intermediate IV of linagliptin

Description

Riagliptin intermediate compound IV

Technical Field

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

Background

Linagliptin (linagliptin) with the chemical name 8- [ (3R) -3-amino-1-piperidinyl]-7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl group]-1H-purine-2, 6-dione; the molecular formula is as follows: c₂₅H₂₈N₈O₂(ii) a Molecular weight: 472.54, respectively; CAS registry number 668270-12-0, structural formula as follows:

linagliptin is an oral hypoglycemic drug developed by the pharmaceutical company of German Brigg Yiger, is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, is approved by the U.S. FDA to be marketed in 5.2nd.2011, and has a trade name of Tradjenta and 4.2013, and is approved by the national food and drug administration (CFDA) to be sold in China.

At present, linagliptin is mainly synthesized by using 3-methyl-8-halogenated xanthine or 8-halogenated-7- (2-butynyl) -3-methylxanthine as a basic parent nucleus, connecting a quinazoline ring at a nitrogen atom at the 1 position and connecting (R) -3-aminopiperidine at a carbon atom at the 8 position in sequence. Most researches are carried out at home and abroad on the synthesis method of linagliptin, and a synthesis route of linagliptin is disclosed in documents (Chinese medicinal chemical impurities, vol 21, page 5, 408; J Med Chem, 2007, 58(26): 6450-: the linagliptin is prepared by 3 times of substitution reaction and hydrolysis reaction of a 3-methyl-8-bromo xanthine raw material, and the synthetic route is as follows:

during the synthesis process of the Chinese patent CN105503872A according to the process, new unknown impurities are found, and the impurities are not intermediates of the reaction.

Patent documents WO200551950, WO2015004599, CA2586938, CN104496989A and CN104387390A respectively disclose an industrial preparation process of linagliptin, which uses 8-bromo-7- (2-butynyl) -3-methylxanthine (compound a) as a starting material, and undergoes nucleophilic substitution reaction with 2-chloromethyl-4-methylquinazoline (compound B) under alkaline conditions to generate 8-bromo-7- (2-butynyl) -3-methyl-1- [ (4-methyl-2-quinazoline) methyl ] -1H-purine-2, 6-dione (compound C), and a piperidine derivative (compound D) protected by a group replaces the 8-position bromine atom of compound C to generate compound E, and finally, after removing a protecting group, the final product linagliptin is refined to obtain an linagliptin refined product, the synthetic route is as follows:

the process has long reaction period and complex operation, the intermediate A is easy to couple by itself, and the debromination is easy at high temperature, which brings difficulty to subsequent purification and is not suitable for industrialized mass production.

Patent document WO2014/097314a1 uses 3-methylxanthine as a starting material, 8-bromo-3-methylxanthine is generated through bromination, and then reacts with 1-bromo-2-butyne in the presence of an acid-binding agent N, N-diisopropylethylamine to generate a compound a (8-bromo-7- (2-butynyl) -3-methylxanthine), the compound a and a compound B (2-chloromethyl-4-methylquinazoline) react in a DMSO solution with potassium carbonate as an acid-binding agent and tetrabutylammonium bromide as a phase transfer catalyst to prepare an intermediate D (8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-diketone), then potassium carbonate is used as an acid binding agent, potassium iodide is used as a catalyst, and the potassium iodide reacts with a compound C ((R) -3-tert-butoxycarbonylaminopiperidine) to prepare an intermediate E (1- [ (4-methyl-quinazoline-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-diketone-2, 3,6, 7-tetrahydro-1H-purine), and finally, the linagliptin is obtained by deprotection of trifluoroacetic acid, wherein the synthetic route is as follows:

the operation steps of the process are complicated, products in each step are purified and then put into the next step for reaction, 1-bromo-2-butyne is easily coupled with 1-bit N atom of 8-bromo-3-methylxanthine to generate new impurities, and the intermediate A still has self coupling to generate dimeric impurities.

Liuxiangsheng, etc. in the synthesis of linagliptin, ([ J ] (J) (J of Chinese medicine Industrial journal, 2016.47(1):4-7), methylurea and ethyl cyanoacetate are used as raw materials, and 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -dione (8) is obtained by condensation ring closure, nitrosation, reduction, ring closure, bromination and nucleophilic substitution reaction with 1-bromo-2-butyne, then is subjected to alkylation reaction with 2-chloromethyl-4-methyl quinazoline (2), and finally is subjected to nucleophilic substitution reaction with (R) -3-aminopiperidine dihydrochloride to obtain linagliptin, wherein the synthetic route is as follows:

the method has a long route, and the explosive nitrite compound is used, so that the yield is not high, the final total yield is only 27%, and the industrial application of the method is limited to a certain extent.

After researching the synthetic route of linagliptin, the compound 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -diketone (8) is found to be a very key intermediate in the synthesis of linagliptin; however, in the reaction, 1-bromo-2-butyne is easily coupled with 1-site nitrogen atom of 3-methyl-8-bromoxanthine (7) to generate new impurities, and 8-site active bromine of the compound 7 is easily subjected to nucleophilic substitution reaction with 1-site N to generate dimer impurities.

In order to solve the above problems, patent document CN104844602A discloses a method for preparing linagliptin, which comprises reacting compound a (8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione) with compound C ((R) -3-aminopiperidine) in the presence of potassium carbonate salt or sodium carbonate, using an inorganic salt containing iodine as a catalyst, using N-methyl-2-pyrrolidone or N, N-dimethylformamide as a solvent, at 30-80 ℃, and directly adding compound B (2-chloromethyl-4-methylquinazoline) without separation after the reaction is finished to generate compound E (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8- [ (R) -3- (tert-butyloxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine), and deprotection of the compound E to obtain linagliptin, wherein the synthetic route is as follows:

the process improves the yield by changing the reaction sequence and implementing the one-pot method, but the process still cannot completely avoid the self-coupling reaction of the compound A, and in order to improve the purity of the linagliptin, the process uses an iodine-containing inorganic salt as a catalyst, which undoubtedly increases the production cost.

In conclusion, the linagliptin preparation methods in the prior art have problems, or have many impurities and are difficult to remove, and have low yield and low purity; or high technical requirements, serious environmental pollution and high production cost; therefore, the problem to be solved at present is to explore a process route for linagliptin synthesis, which is simple and convenient to operate, short in production period, high in yield and more suitable for industrial production.

Disclosure of Invention

Aiming at solving the problems that in the prior art, the linagliptin preparation process has many impurities and is difficult to remove, the yield is low and the purity is low; or the technical requirement is high, the environmental pollution is serious, the production cost is high, and the like, the invention provides a linagliptin intermediate IV and a preparation method of the compound; and the compound is used for synthesizing an important linagliptin intermediate 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione I.

The invention is realized by the following technical scheme:

a linagliptin intermediate compound represented by formula IV:

a preparation method of a linagliptin intermediate compound IV comprises the following steps: adding 2-chloromethyl-4-methyl quinazoline II and 1-methyl uracil III into an organic solvent, heating and stirring until the solid is completely dissolved, slowly adding alkali under the condition of temperature control for reaction to obtain an intermediate IV, wherein the reaction route is as follows:

preferably, the base is selected from an organic base or an inorganic base, wherein the organic base is selected from one or two of Triethylamine (TEA), N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU); the inorganic base is one or two of potassium carbonate, sodium bicarbonate and disodium hydrogen phosphate; among them, Triethylamine (TEA) is particularly preferable.

In a preferable embodiment, the feeding molar ratio of the compound II to the compound III to the alkali is 1: 1.1-2.5, and particularly preferably 1:1.2: 1.8.

Preferably, the organic solvent is selected from one or a combination of DMSO, NMP, DMF, 1, 4-dioxane and toluene.

In a preferred scheme, the reaction temperature of the reaction is 70-100 ℃, and particularly preferably 80-85 ℃.

In a preferable scheme, after the post-treatment operation, after the reaction is finished, slowly adding ethanol and purified water (V/V is 1:2), stirring at a controlled temperature, carrying out suction filtration, washing a filter cake by using a mixed solvent of ethanol and purified water, and drying to obtain an intermediate IV.

The application of the compound IV in preparing linagliptin intermediates.

The compound IV is used for preparing an important linagliptin intermediate 8- [ (3R) -3-tert-butyloxycarbonylamino-1-piperidyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione I, and the preparation method comprises the following steps:

step 1: adding the compound IV, urea and an iodine source into an organic solvent, and adding a catalyst and active carbon for reaction to obtain an intermediate V;

step 2: carrying out nucleophilic substitution reaction on the intermediate V and 1-bromo-2-butyne under an alkaline condition to obtain an intermediate VI;

and step 3: the intermediate VI reacts with R-3- (Boc-amino) piperidine under the action of alkali to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione I, and the synthetic route is as follows:

preferably, the above steps are described in further detail in the following sections:

step 1 preparation of compound v:

the preparation method of the compound V comprises the following steps: and adding the compound IV, urea and an iodine source into an organic solvent, adding a catalyst and active carbon under the condition of controlling the temperature, and continuously stirring until the reaction is finished to obtain an intermediate V.

Preferably, the catalyst is selected from TMSI, TMSOTf, CoCl₂One or two of HSiW, HPW and HPM, and particularly preferred is HSiW.

Preferably, the amount of the catalyst is 1.0-10%, particularly preferably 7.0% of the mass of the compound IV.

Preferably, the iodine source is selected from one or two of potassium iodide, sodium iodide and tetrabutylammonium iodide, and potassium iodide is particularly preferred.

Preferably, the feeding molar ratio of the compound IV, the urea and the iodine source is as follows: 1: 1.05-2.5, especially 1:1.1: 1.1.

Preferably, the dosage of the activated carbon is 3.0-10%, particularly preferably 6.0% of the total mass of the compound IV, the urea and the iodine source.

Preferably, the organic solvent is selected from one or a mixture of DMSO, NMP, DMF, 1, 4-dioxane and toluene, and DMF is particularly preferred.

In a preferred scheme, the reaction temperature is 70-100 ℃, and particularly preferably 80-85 ℃.

In a preferred scheme, after the reaction is finished, post-treatment operation is required, specifically, after the reaction is finished, the temperature is reduced, the reaction liquid is added with an organic solvent for extraction, the extract liquid is subjected to suction filtration, washing and concentration until the volume is one half of the volume of the added extraction solvent, and the organic solvent is added for crystallization to obtain a compound V; the extraction solvent is one or a mixture of benzene, toluene and xylene; the crystallization solvent is selected from one or a mixed solution of petroleum ether, acetone, n-heptane, n-hexane and cyclohexane, and cyclohexane is particularly preferred.

Step 2 preparation of Compound VI:

the preparation method of the compound VI comprises the following steps: and adding the intermediate compound V, 1-bromo-2-butyne and alkali into an organic solvent, heating to 70-75 ℃, stirring for reaction, cooling reaction liquid after TLC detection reaction, performing suction filtration, washing a filter cake, and drying to obtain an intermediate compound VI.

Preferably, the reaction base is one or two selected from potassium carbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine, and N, N-diisopropylethylamine is particularly preferred.

Preferably, the reaction organic solvent is selected from one of toluene, N-dimethylformamide, N-dimethylacetamide, xylene, 1, 4-dioxane or a mixture thereof, and N, N-dimethylformamide is particularly preferred.

In a preferred scheme, the feeding molar ratio of the reaction compound V, the 1-bromo-2-butyne and the alkali is as follows: 1: 1.01-2.5, and particularly preferably 1:1.02: 1.05.

In a preferred scheme, after the reaction is finished, post-treatment operation is required, specifically, after the reaction is finished, the temperature of a reaction solution is reduced to 20-25 ℃, the reaction solution is kept at the temperature and stirred, the reaction solution is subjected to suction filtration, and a filter cake is subjected to pulping, washing and drying to obtain an intermediate compound VI; the solvent used for washing is selected from one or a mixture of methanol, ethanol, isopropanol, tetrahydrofuran and acetone, and ethanol is particularly preferred.

Step 3 preparation of compound I:

adding a compound VI and R-3- (Boc-amino) piperidine into toluene, heating to 60-65 ℃, stirring until the solid is completely dissolved, adding alkali under the protection of inert gas, washing, drying, concentrating and crystallizing the reaction solution after the reaction is finished to obtain a compound I.

Preferably, the base of the reaction is selected from one or a mixture of butyl lithium, lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and particularly preferred is lithium bis (trimethylsilyl) amide.

In a preferred embodiment, the compound VI, the R-3- (Boc-amino) piperidine and the base are fed in a molar ratio of 1: 1.1-2.0, and particularly preferably 1:1.4: 1.3.

In a preferred scheme, after the reaction is finished, post-treatment operation is required, specifically, after the reaction is finished, the temperature of the reaction is reduced to 20-25 ℃, the reaction liquid is washed by purified water and saturated salt solution, dried and concentrated to one fourth of a toluene solvent, and then an organic solvent is added for crystallization; the crystallization solvent is selected from one or a mixed solution of petroleum ether, acetone, n-heptane, n-hexane and cyclohexane, and cyclohexane is particularly preferred.

In the present invention, nitrogen and argon are generally selected as the inert gas, and argon is particularly preferred.

Compared with the prior art, the invention has the following technical effects:

1. the method provides a linagliptin intermediate compound IV and a new method for preparing an important linagliptin intermediate 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione I by using the compound simply, conveniently and efficiently, and the whole synthesis method has the advantages of simple operation, high reaction yield and high purity of the obtained product;

2. 1-methyl uracil is used as a starting material, and no dimeric impurity is generated in a subsequent substitution reaction of an obtained new intermediate 1-methyl-3- ((4-methyl quinazoline-2-yl) methyl) pyrimidine-2, 4(1H,3H) -diketone IV;

3. in the synthesis of the compound V, iodine-containing salt is used as an iodinating reagent, and compared with the traditional iodinating reagent such as iodine simple substance, the iodinating reagent has the advantages of low toxicity, mild use conditions and high conversion rate; the traditional TBHP and concentrated sulfuric acid catalysts with strong oxidizing property are replaced by relatively mild catalysts, so that the synthesis method is more economical and environment-friendly, meanwhile, the corrosion to reaction equipment is avoided, the post-treatment is simple, and the method is more suitable for industrial production;

4. in the reaction with R-3- (Boc-amino) piperidine, milder organic alkali is used to replace inorganic alkali, so that the reaction is milder, economic and environment-friendly, and the yield is higher.

In conclusion, the invention provides a new compound and a new method for synthesizing a linagliptin intermediate 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione I by using the compound, the method avoids using dangerous chemical reagents, the synthesized intermediate cannot generate self coupling, the generation of impurities is reduced, a green catalyst is used for replacing a traditional catalyst, the reaction is milder, the economy and the environmental protection are realized, the yield is higher, and the method is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.

The structure of the novel compound obtained by the invention is confirmed:

spectral data for compound IV: ESI-HRMS: M/z 283.1160[ M + H ]]⁺；¹H-NMR(400MHz,DMSO-d₆)：8.03-8.05(d,J＝8.0Hz,1H),7.85(t,J＝8.8Hz,1H),7.81(d,J＝7.8Hz,1H),7.66(d,J＝7.2Hz,1H),6.76(d,J＝4.4Hz,1H),6.64(d,J＝5.6Hz,1H),4.98(s,2H),2.81(s,3H),1.81(s,3H)；¹³C NMR(400MHz,DMSO-d₆):170.66,162.55,161.21,152.11,149.24,142.16,132.83,131.73,128.54,123.22,122.98,103.13,49.87,35.62,24.11.

Spectral data for compound V: ESI-HRMS: M/z 449.0178[ M + H ]]⁺；¹H-NMR(400MHz,DMSO-d₆):8.02-8.04(d,J＝8.0Hz,1H)，7.86-7.88(t,J＝8.0Hz,1H)，7.79-7.81(d,J＝8.0Hz，1H)，7.53-7.57(d,J＝8.0Hz,1H)，5.01(s，2H)，3.31(s，1H)，2.84(s，3H)，1.83(s，3H)；¹³C NMR(400MHz,DMSO-d₆)：170.68,161.24,155.10,152.13,150.33,149.26,145.16,132.85,131.92,128.55,123.23,122.96,114.63,49.86,32.62,23.41.

Preparation of Compound IV

Example 1

19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline II, 13.24g (105mmol) of 1-methyl uracil III and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80-85 ℃, stirred and dissolved, 18.21g (180mmol) of triethylamine is slowly dripped, the temperature is controlled to 80-85 ℃, the mixture is stirred and reacted for 3-4 h, after TLC detection reaction is finished, the temperature is reduced to 50-55 ℃, ethanol (60ml) and purified water (120ml) are slowly added, the temperature is controlled to 20-25 ℃, the mixture is stirred and reacted for 1.5-2 h, crystallization is complete, suction filtration is carried out, a filter cake is washed by a mixed solvent of ethanol (20ml) and purified water (40ml), and dried for 8h under the vacuum degree of 50 ℃, and then the compound IV is obtained, the molar yield is 93.6%, the purity is 99.9%, and the maximum single.

Example 2

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly dropwise adding 11.13g (110mmol) of triethylamine, controlling the temperature to be 80-85 ℃, stirring for reacting for 3-4 h, after TLC detection reaction is finished, cooling to 50-55 ℃, slowly adding 60ml of ethanol and 120ml of purified water, controlling the temperature to be 20-25 ℃, stirring for reacting for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of 20ml of ethanol and 40ml of purified water, drying at 50 ℃ under vacuum degree for 8h to obtain a compound IV, wherein the molar yield is 93.0%, the purity is 99.9%, and the maximum single impurity is 0.01%.

Example 3

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly adding 25.30g (250mmol) of triethylamine, controlling the temperature to 80-85 ℃, stirring for reacting for 3-4 h, after TLC detection reaction is finished, cooling to 50-55 ℃, slowly adding ethanol (60ml) and purified water (120ml), controlling the temperature to 20-25 ℃, stirring for reacting for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of ethanol (20ml) and purified water (40ml), drying at 50 ℃ under a vacuum degree for 8h to obtain a compound IV, wherein the molar yield is 93.5%, the purity is 99.8%, and the maximum single impurity content is 0.02%.

Example 4

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly dropwise adding 10.12g (100mmol) of triethylamine, controlling the temperature to be 80-85 ℃, stirring for reacting for 3-4 h, after TLC detection reaction is finished, cooling to 50-55 ℃, slowly adding ethanol (60ml) and purified water (120ml), controlling the temperature to be 20-25 ℃, stirring for reacting for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of ethanol (20ml) and purified water (40ml), drying at the vacuum degree of 50 ℃ for 8h to obtain a compound IV, wherein the molar yield is 92.5%, the purity is 99.9%, and the maximum single impurity content is 0.01%.

Example 5

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly dropwise adding 26.31g (260mmol) of triethylamine, controlling the temperature to 80-85 ℃, stirring for reacting for 4-5 h, after TLC detection reaction is finished, cooling to 50-55 ℃, slowly adding ethanol (60ml) and purified water (120ml), controlling the temperature to 20-25 ℃, stirring for reacting for 2-3 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of ethanol (20ml) and purified water (40ml), and drying at 50 ℃ in vacuum for 8h to obtain a compound IV, wherein the molar yield is 93.6%, the purity is 99.7%, and the maximum single impurity content is 0.02%.

Example 6

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 70-75 ℃, stirring for dissolving, slowly adding 23.26g (180mmol) of N, N-diisopropylethylamine dropwise, controlling the temperature to be 70-75 ℃ after finishing dropping, stirring for reacting for 3-4 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding 60ml of ethanol and 120ml of purified water, controlling the temperature to be 20-25 ℃, stirring for reacting for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of 20ml of ethanol and 40ml of purified water, and drying at the vacuum degree of 50 ℃ for 8h to obtain a compound IV, wherein the molar yield is 93.4%, the purity is 99.8% and the maximum single impurity is 0.01%.

Example 7

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 95-100 ℃, stirring for dissolving, slowly adding 22g (180mmol) of 4-dimethylamino pyridine, controlling the temperature to be 95-100 ℃, stirring for reaction for 3-4 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding 60ml of ethanol and 120ml of purified water, controlling the temperature to be 20-25 ℃, stirring for reaction for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of 20ml of ethanol and 40ml of purified water, and drying for 8h at a vacuum degree of 50 ℃ to obtain a compound IV, wherein the molar yield is 93.4%, the purity is 99.8% and the maximum single impurity content is 0.02%.

Example 8

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 65-70 ℃, stirring for dissolving, slowly dropwise adding DBU27.40g (180mmol), controlling the temperature to 65-70 ℃ after finishing dripping, stirring for reacting for 3-4 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding ethanol (60ml) and purified water (120ml), controlling the temperature to 20-25 ℃, stirring for reacting for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of ethanol (20ml) and purified water (40ml), drying at the vacuum degree of 50 ℃ for 8h to obtain a compound IV, wherein the molar yield is 93.3%, the purity is 99.8%, and the maximum single impurity content is 0.01%.

Example 9

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 90ml of dimethyl sulfoxide into a three-neck flask, heating to 100-105 ℃, stirring for dissolving, slowly adding 19.08g (180mmol) of sodium carbonate, controlling the temperature to 100-105 ℃, stirring for reaction for 3-4 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding ethanol (60ml) and purified water (120ml), controlling the temperature to 20-25 ℃, stirring for reaction for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake with a mixed solvent of ethanol (20ml) and purified water (40ml), drying for 8h at the vacuum degree of 50 ℃ to obtain a compound IV, wherein the molar yield is 93.2%, the purity is 99.7%, and the maximum single impurity content is 0.03%.

Example 10

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline and 13.24g (105mmol) of 1-methyl uracil into a three-neck flask, heating 85ml of N, N-dimethylformamide to 80-85 ℃, stirring for dissolving, slowly adding 17.67g (180mmol) of potassium acetate, controlling the temperature to 80-85 ℃, stirring for reacting for 3-4 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding 60ml of ethanol and 120ml of purified water, controlling the temperature to 20-25 ℃, stirring for reacting for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of 20ml of ethanol and 40ml of purified water, drying for 8h at the temperature of 50 ℃ under the vacuum degree, and obtaining a compound IV, wherein the molar yield is 93.5%, the purity is 99.8%, and the maximum single impurity content is 0.02%

Example 11

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105mmol) of 1-methyl uracil and 70ml of 1, 4-dioxane into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly adding 15.1g (180mmol) of sodium bicarbonate, controlling the temperature to 80-85 ℃, stirring for reacting for 3-4 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding 60ml of ethanol and 120ml of purified water, controlling the temperature to 20-25 ℃, stirring for reacting for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of 20ml of ethanol and 40ml of purified water, and drying at 50 ℃ in vacuum for 8h to obtain a compound IV, wherein the purity is 93.0%, the molar yield is 99.9% and the maximum single impurity is 0.01%.

Example 12

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 13.9g (110mmol) of 1-methyl uracil and 90ml of toluene into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly adding 24.88g (180mmol) of potassium carbonate, controlling the temperature to 80-85 ℃, stirring for reaction for 3-4 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding ethanol (60ml) and purified water (120ml), controlling the temperature to 20-25 ℃, stirring for reaction for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake with a mixed solvent of ethanol (20ml) and purified water (40ml), drying at the vacuum degree of 50 ℃ for 8h to obtain a compound IV, wherein the molar yield is 93.1%, the purity is 99.8%, and the maximum single impurity content is 0.01%.

Example 13

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 31.5g (250mmol) of 1-methyl uracil and 70ml of N, N-dimethylformamide into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly adding 24.50g (180mmol) of sodium acetate, controlling the temperature to 80-85 ℃, stirring for reacting for 4-5 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding 60ml of ethanol and 120ml of purified water, controlling the temperature to 20-25 ℃, stirring for reacting for 2-2.5 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of 20ml of ethanol and 40ml of purified water, drying at 50 ℃ under a vacuum degree for 8h to obtain a compound IV, wherein the molar yield is 93.6%, the purity is 99.8%, and the maximum single impurity content is 0.02%.

Example 14

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 12.6g (100mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly adding 25.56g (180mmol) of disodium hydrogen phosphate, controlling the temperature to 80-85 ℃, stirring for reacting for 3-4 h, cooling to 50-55 ℃ after TLC detection reaction is finished, slowly adding ethanol (60ml) and purified water (120ml), controlling the temperature to 20-25 ℃, stirring for reacting for 1.5-2 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of ethanol (20ml) and purified water (40ml), and drying at the vacuum degree of 50 ℃ for 8h to obtain a compound IV, wherein the purity is 92.8%, the purity is 99.9% and the maximum single impurity is 0.01%.

Example 15

Adding 19.26g (100mmol) of 2-chloromethyl-4-methyl quinazoline, 32.8g (260mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 80-85 ℃, stirring for dissolving, slowly adding 21.60g (180mmol) of disodium hydrogen phosphate, controlling the temperature to 80-85 ℃, stirring for reacting for 4-5 h, after TLC detection reaction is finished, cooling to 50-55 ℃, slowly adding ethanol (60ml) and purified water (120ml), controlling the temperature to 20-25 ℃, stirring for reacting for 2-2.5 h, completely crystallizing, performing suction filtration, washing a filter cake by using a mixed solvent of ethanol (20ml) and purified water (40ml), and drying at the vacuum degree of 50 ℃ for 8h to obtain a compound IV, wherein the purity is 93.5%, the purity is 99.7% and the maximum single impurity is 0.03%.

Preparation of Compound V

Example 16

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 130ml of N, N-dimethylformamide into a three-neck flask, heating to 80-85 ℃, adding 3g of activated carbon and 1.75g of HSiWs, continuously stirring for reacting for 8-9 h, cooling to 25-30 ℃ after TLC detection reaction is finished, adding 150ml of toluene, stirring, performing suction filtration, adding purified water into filtrate for washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate, and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.8 percent, the purity is 99.9 percent, and the maximum single impurity content is 0.01 percent.

Example 17

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 130ml of N, N-dimethylformamide into a three-neck flask, heating to 80-85 ℃, adding 3g of activated carbon and 0.25g of HSiW, continuing stirring for reaction for 8-9 h, cooling to 25-30 ℃ after TLC detection reaction is finished, adding 150ml of toluene, stirring, performing suction filtration, adding purified water into filtrate for washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate, and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 93.9 percent and the purity is 99.9 percent. Maximum single hetero 0.01%.

Example 18

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 140ml of dimethyl sulfoxide into a three-neck flask, heating to 80-85 ℃, adding 3g of activated carbon and 2.5g of HSiW, continuously stirring for reacting for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, carrying out suction filtration, adding purified water into filtrate for washing for three times, washing with saturated saline, collecting organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.7 percent, the purity is 99.8 percent, and the maximum single impurity content is 0.02 percent.

Example 19

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 130ml of N-methyl-2-pyrrolidone into a three-neck flask, heating to 80-85 ℃, adding 3g of activated carbon and 0.225g of HSiWs, continuing stirring for reaction for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, carrying out suction filtration, adding purified water into filtrate for washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 93.5%, purity 99.9%, maximum single impurity 0.01%.

Example 20

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 130ml of toluene into a three-neck flask, heating to 80-85 ℃, adding 3g of activated carbon and 2.75g of HSiWs, continuously stirring for reacting for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, carrying out suction filtration, adding purified water into filtrate for washing three times, washing with saturated saline, collecting organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of n-hexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, carrying out suction filtration, leaching a filter cake with ethanol, carrying out suction filtration, and drying at 50 ℃ under a vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.7 percent, the purity is 99.7 percent, and the maximum single impurity content is 0.02 percent.

Example 21

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 18.10g (97.35mmol) of sodium iodide and 140ml of 1, 4-dioxane into a three-neck flask, heating to 80-85 ℃, adding 2.9g of activated carbon and 1.75g of TMSOTf, continuing stirring for reaction for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, performing suction filtration, adding purified water into filtrate, washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate, and drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 60ml of petroleum ether, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, carrying out suction filtration, leaching a filter cake with ethanol, carrying out suction filtration, and drying at 50 ℃ under vacuum for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.6 percent, the purity is 99.8 percent, and the maximum single impurity content is 0.01 percent.

Example 22

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 35.96g (97.35mmol) of tetrabutylammonium iodide and 100ml of dimethyl sulfoxide solution into a three-neck flask, heating to 80-85 ℃, adding 4.0g of activated carbon and 1.75g of HPWs, continuously stirring for reacting for 8-9 h, cooling to 25-30 ℃, adding 120ml of benzene, stirring, carrying out suction filtration, adding purified water into filtrate, washing for three times, washing with saturated sodium chloride, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate, and drying. Filtering out a drying agent, concentrating under reduced pressure to about 60ml, adding 60ml of acetone, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.8 percent, the purity is 99.8 percent, and the maximum single impurity content is 0.02 percent.

Example 23

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 110ml of N-methylpyrrolidone into a three-neck flask, heating to 70-75 ℃, adding 2.8g of activated carbon and 1.75g of HPMto react for 8-9 h under continuous stirring, cooling to 25-30 ℃, adding 160ml of p-xylene, stirring, carrying out suction filtration, adding purified water into filtrate to wash for three times, washing with saturated sodium chloride, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering out a drying agent, concentrating under reduced pressure to about 80ml, adding 40ml of n-heptane, cooling to 0-5 ℃, stirring for crystallization for about 2h, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum for 10h to obtain a compound V, wherein the molar yield is as follows: 94.5 percent, the purity is 99.8 percent, and the maximum single impurity content is 0.02 percent.

Example 24

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 15.42g (92.93mmol) of potassium iodide and 130ml of N, N-dimethylformamide into a three-neck flask, heating to 80-85 ℃, adding 2.9g of activated carbon and 1.75g of heteropoly acid HSiWs, continuously stirring and reacting for 8-9 h, cooling to 25-30 ℃, adding 160ml of m-xylene, stirring, performing suction filtration, adding purified water into filtrate, washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate, and drying. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.3 percent, the purity is 99.9 percent, and the maximum single impurity content is 0.01 percent.

Example 25

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 36.73g (221.25mmol) of potassium iodide and 130ml of N, N-dimethylformamide into a three-neck flask, heating to 80-85 ℃, adding 4.0g of activated carbon and 1.75g of heteropoly acid HSiWs, continuously stirring and reacting for 8-9 h, cooling to 25-30 ℃, adding 150ml of o-xylene, stirring, carrying out suction filtration, adding purified water into filtrate for washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.8 percent, the purity is 99.9 percent, and the maximum single impurity content is 0.01 percent.

Example 26

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 14.69g (88.5mmol) of potassium iodide and 130ml of N, N-dimethylformamide into a three-neck flask, heating to 80-85 ℃, adding 2.8g of activated carbon and 1.75g of heteropoly acid HSiWs, continuously stirring and reacting for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, carrying out suction filtration, adding purified water into filtrate, washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 93.8 percent, the purity is 99.9 percent, and the maximum single impurity content is 0.01 percent.

Example 27

Adding 25.0g (88.5mmol) of compound IV, 5.85g (97.35mmol) of urea, 38.20g (230.1mmol) of potassium iodide and 130ml of N, N-dimethylformamide into a three-neck flask, heating to 80-85 ℃, adding 4.1g of activated carbon and 1.75g of heteropoly acid HSiW1, continuing stirring for reaction for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, carrying out suction filtration, adding purified water into filtrate, washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.8 percent, the purity is 99.9 percent, and the maximum single impurity content is 0.01 percent.

Example 28

Adding 25.0g (88.5mmol) of compound IV, 5.58g (92.93mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 140ml of 1.4-dioxane into a three-neck flask, heating to 95-100 ℃, adding 2.1g of activated carbon and 1.75g of heteropoly acid HSiWs, continuing stirring for reaction for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, performing suction filtration, adding purified water into filtrate, washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate, and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.7 percent, the purity is 99.8 percent, and the maximum single impurity content is 0.02 percent.

Example 29

Adding 25.0g (88.5mmol) of compound IV, 13.29g (221.25mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 100ml of toluene into a three-neck flask, heating to 65-70 ℃, adding 5.6g of activated carbon and 1.75g of heteropoly acid HSiWs, continuing stirring for reaction for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, carrying out suction filtration, adding purified water into filtrate for washing for three times, washing with saturated sodium chloride, collecting organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.4 percent, the purity is 99.7 percent, and the maximum single impurity content is 0.02 percent.

Example 30

Adding 25.0g (88.5mmol) of compound IV, 5.36g (88.5mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 130ml of N, N-dimethylformamide into a three-neck flask, heating to 100-105 ℃, adding 1.0g of activated carbon and 1.75g of heteropoly acid HSiW1, continuing stirring for reaction for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, performing suction filtration, adding purified water into filtrate, washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate, and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.5 percent, the purity is 99.7 percent, and the maximum single impurity content is 0.02 percent.

Example 31

Adding 25.0g (88.5mmol) of compound IV, 13.82g (230.1mmol) of urea, 16.16g (97.35mmol) of potassium iodide and 130ml of N, N-dimethylformamide into a three-neck flask, heating to 80-85 ℃, adding 6.2g of activated carbon and 1.75g of heteropoly acid HSiWs, continuously stirring and reacting for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, carrying out suction filtration, adding purified water into filtrate, washing for three times, washing with saturated saline, collecting the organic phase, adding a proper amount of anhydrous sodium sulfate and drying. Filtering a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 3 hours, performing suction filtration, leaching a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10 hours to obtain a compound V, wherein the molar yield is as follows: 94.8 percent, the purity is 99.7 percent, and the maximum single impurity content is 0.02 percent.

Preparation of Compound VI

Example 32

Adding 35.0g (78.1mmol) of compound V, 10.60g (79.7mmol) of 1-bromo-2-butyne, 10.60g (82.0mmol) of N, N-diisopropylethylamine and 200ml of N, N-dimethylformamide into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction is finished, keeping the temperature, stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10h to obtain compound VI, wherein the molar yield is 97.7%, the purity is 99.9%, and the maximum single impurity is 0.01%.

Example 33

Adding 35.0g (78.1mmol) of compound V, 10.60g (79.7mmol) of 1-bromo-2-butyne, 10.19g (78.9mmol) of N, N-diisopropylethylamine and 200ml of N, N-dimethylformamide into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction is finished, keeping the temperature, stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10h to obtain compound VI, wherein the molar yield is 97.1%, the purity is 99.8%, and the maximum single impurity is 0.01%.

Example 34

Adding 35.0g (78.1mmol) of compound V, 10.60g (79.7mmol) of 1-bromo-2-butyne, 25.23g (195.25mmol) of N, N-diisopropylethylamine and 210ml of N, N-dimethylacetamide into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction is finished, keeping the temperature, stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing filter cakes with tetrahydrofuran, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10h to obtain compound VI, wherein the molar yield is 97.7%, the purity is 99.7% and the maximum single impurity is 0.02%.

Example 35

Adding 35.0g (78.1mmol) of compound V, 10.60g (79.7mmol) of 1-bromo-2-butyne, 10.09g (78.1mmol) of N, N-diisopropylethylamine and 180ml of toluene into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction is finished, keeping the temperature and stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing a filter cake with isopropanol, performing suction filtration, and drying at 50 ℃ under vacuum for 10h to obtain compound VI, wherein the molar yield is 96.6%, the purity is 99.9%, and the maximum single impurity content is 0.01%.

Example 36

Adding 35.0g (78.1mmol) of compound V, 10.60g (79.7mmol) of 1-bromo-2-butyne, 26.24g (203.6mmol) of N, N-diisopropylethylamine and 200ml of 1.4-dioxane into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction is finished, keeping the temperature, stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing a filter cake with methanol, performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10h to obtain compound VI, wherein the molar yield is 97.7%, the purity is 99.7%, and the maximum single impurity is 0.02%.

Example 37

Adding 35.0g (78.1mmol) of compound V, 10.49g (78.89mmol) of 1-bromo-2-butyne, 11.33g (82mmol) of potassium carbonate and 220ml of m-xylene into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, after TLC detection reaction is finished, cooling to 20-25 ℃, preserving heat, stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing a filter cake with methanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10h to obtain compound VI, wherein the molar yield is 97.2%, the purity is 99.8%, and the maximum single impurity content is 0.01%.

Example 38

Adding 35.0g (78.1mmol) of compound V, 25.97g (195.25mmol) of 1-bromo-2-butyne, 6.89g (82mmol) of sodium bicarbonate and 200ml of p-xylene into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction, preserving heat, stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing a filter cake with isopropanol, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10h to obtain compound VI, wherein the molar yield is 97.8%, the purity is 99.7%, and the maximum single impurity content is 0.02%.

Example 39

Adding 35.0g (78.1mmol) of compound V, 10.39g (78.1mmol) of 1-bromo-2-butyne, 8.30g (82mmol) of triethylamine and 180ml of o-xylene into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction is finished, preserving heat, stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing a filter cake with acetone, performing suction filtration, and drying at 50 ℃ under vacuum degree for 10h to obtain compound VI, wherein the molar yield is 96.9%, the purity is 99.8%, and the maximum single impurity content is 0.01%.

Example 40

Adding 35.0g (78.1mmol) of compound V, 27.0g (203.06mmol) of 1-bromo-2-butyne, 10.60g (82.0mmol) of N, N-diisopropylethylamine and 200ml of N, N-dimethylformamide into a three-neck flask, heating to 70-75 ℃, stirring for reaction for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction is finished, keeping the temperature, stirring for reaction for 1.0-1.5 h, performing suction filtration, pulping and washing a filter cake with ethanol, performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10h to obtain compound VI, wherein the molar yield is 97.8%, the purity is 99.6%, and the maximum single impurity content is 0.02%.

Preparation of Compound I

EXAMPLE 41

Adding 35.0g (70.0mmol) of a compound VI, 19.6g (98.0mmol) of R-3- (Boc-amino) piperidine and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 15.3g (91.0mmol) of lithium bis (trimethylsilyl) amide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150ml multiplied by 2) to wash, washing with 150ml of saturated saline, and adding a proper amount of anhydrous sodium sulfate into an organic phase to dry. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2H, performing suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 97.8%, the purity is 99.9%, and the maximum single impurity is 0.01%.

Example 42

Adding 35.0g (70.0mmol) of a compound VI, 19.6g (98.0mmol) of R-3- (Boc-amino) piperidine and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 12.9g (77.0mmol) of lithium bis (trimethylsilyl) amide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150ml multiplied by 2) to wash, washing with 150ml of saturated saline, and adding a proper amount of anhydrous sodium sulfate into an organic phase to dry. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2H, performing suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 96.7%, the purity is 99.9%, and the maximum single impurity is 0.01%.

Example 43

Adding 35.0g (70.0mmol) of a compound VI, 19.6g (98.0mmol) of R-3- (Boc-amino) piperidine and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 23.4g (140mmol) of lithium bis (trimethylsilyl) amide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150ml multiplied by 2) to wash, washing with 150ml of saturated saline solution, adding a proper amount of anhydrous sodium sulfate into an organic phase, and drying. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2H, performing suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 97.8%, the purity is 99.8%, and the maximum single impurity is 0.01%.

Example 44

Adding 35.0g (70.0mmol) of a compound VI, 19.6g (98.0mmol) of R-3- (Boc-amino) piperidine and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 11.71g (70mmol) of lithium bis (trimethylsilyl) amide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150ml multiplied by 2) to wash, washing with 150ml of saturated saline solution, adding a proper amount of anhydrous sodium sulfate into an organic phase, and drying. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2H, performing suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 96.4%, the purity is 99.9%, and the maximum single impurity is 0.01%.

Example 45

Adding 35.0g (70.0mmol) of a compound VI, 19.6g (98.0mmol) of R-3- (Boc-amino) piperidine and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 24.60g (147mmol) of lithium bis (trimethylsilyl) amide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150ml multiplied by 2) to wash, washing with 150ml of saturated saline solution, adding a proper amount of anhydrous sodium sulfate into an organic phase, and drying. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring for crystallization for about 2H, performing suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 97.8%, the purity is 99.7%, and the maximum single impurity is 0.02%.

Example 46

Adding 35.0g (70.0mmol) of a compound VI, 25.24g (126.0mmol) of R-3- (Boc-amino) piperidine and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 15.3g (91.0mmol) of lithium bis (trimethylsilyl) amide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150ml multiplied by 2) to wash, washing with 150ml of saturated saline, adding a proper amount of anhydrous sodium sulfate into an organic phase, and drying. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 110ml of n-heptane, cooling to 0-5 ℃, stirring for crystallization for about 2H, performing suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 96.8%, the purity is 99.9%, and the maximum single impurity is 0.01%.

Example 47

Adding 35.0g (70.0mmol) of a compound VI, 28.04g (140mmol) of R-3- (Boc-amino) piperidine and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 15.3g (91.0mmol) of lithium bis (trimethylsilyl) amide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150ml multiplied by 2) to wash, washing with 150ml of saturated saline solution, adding a proper amount of anhydrous sodium sulfate into an organic phase, and drying. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 120ml of n-hexane, cooling to 0-5 ℃, stirring and crystallizing for about 2H, carrying out suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), carrying out suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 97.8%, the purity is 99.7%, and the maximum single impurity content is 0.02%.

Example 48

Adding 35.0g (70.0mmol) of a compound VI, 14.02g (70mmol) of R-3- (Boc-amino) piperidine (70mmol) and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 5.8g (91mmol) of butyllithium under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding 150ml of purified water (150ml multiplied by 2) for washing, washing with 150ml of saturated saline, adding a proper amount of anhydrous sodium sulfate into an organic phase, and drying. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 140ml of petroleum ether, cooling to 0-5 ℃, stirring and crystallizing for about 2H, carrying out suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), carrying out suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 96.5%, the purity is 99.9%, and the maximum single impurity is 0.01%.

Example 49

Adding 35.0g (70.0mmol) of a compound VI, 29.44g (147.0mmol) of R-3- (Boc-amino) piperidine and 280ml of toluene into a three-neck flask, heating to 60-65 ℃, stirring to dissolve, adding 9.7g (91mmol) of lithium diisopropylamide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring to react for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150ml multiplied by 2) to wash, washing with 150ml of saturated saline, adding a proper amount of anhydrous sodium sulfate into an organic phase, and drying. Filtering a drying agent, concentrating under reduced pressure to about 80ml, adding 130ml of acetone, cooling to 0-5 ℃, stirring for crystallization for about 2H, performing suction filtration, pulping and washing a filter cake by using ethanol (50ml multiplied by 2), performing suction filtration, and drying at 50 ℃ under a vacuum degree for 10H to obtain 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, wherein the molar yield is 97.8%, the purity is 99.7%, and the maximum single impurity is 0.02%.

Preparation of linagliptin

Example 50

Adding 31.71g of 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, 100ml of methanol, 60ml of water and stirring under a nitrogen environment, heating to reflux reaction for 6-9H, cooling to room temperature, and precipitating a solid. Filtering, washing a filter cake with a small amount of methanol, and drying to obtain linagliptin with the molar yield of 96.8%, the purity of 99.9% and the maximum single impurity of 0.01%.

Comparative example 1

Into a 2L three-necked flask, 908g (3.7mol) of 8-bromo-3-methylxanthine, 574.1g (4.442mol) of N, N-Diisopropylethylamine (DIEA), 591.1g (4.445mol) of 1-bromo-2-butyne, and 12L of acetone were added. Starting stirring, heating to reflux reaction, and finishing the reaction after 4-6 hours. Cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake with 4L of methanol to obtain a light yellow solid, and drying to obtain the 3-methyl-7- (2-butyn-L-yl) -8-bromo-xanthine, wherein the yield is 97.4%, the purity is 91.7%, and the maximum single impurity content is 2.5%.

550g (1.851mol) of the product of the above step 463.3g (2.405mol) of 2-chloromethyl-4-methylquinazoline, 332.6g (2.407mol) of potassium carbonate and 6L of Dimethylacetamide (DMAC) were charged into a 10L reactor. Stirring, heating to 75-95 ℃ for reaction, finishing the reaction after 7-10 h, cooling to below 65 ℃, adding 3L of methanol, stirring for 0.5-1 h, filtering, and washing a filter cake with 1L of methanol. The obtained filter cake is pulped by 2L of water and filtered, the filter cake is washed by 1L of water and 1L of methanol to obtain a yellow filter cake, and the yellow filter cake is dried to obtain the 1- [ (4-methyl quinazoline-2-yl) methyl ] -3-methyl-7- (2-butyn-1-yl) -8-bromine xanthine with the yield of 79.4 percent, the purity of 93.5 percent and the maximum single impurity of 2.7 percent.

To a 10L reactor was added 700g (1.54mol) of the product of the above step, 464.1g (2.32mol) (R) -3-Boc-aminopiperidine, 854g (6.18mol) of potassium carbonate and 3.5L acetonitrile. Starting stirring, heating to reflux (micro reflux), reacting at the temperature of 80-85 ℃, and finishing the reaction after 28-35 h. 4.5L of hot water with the temperature of 70 ℃ is slowly added, stirred at room temperature and slowly cooled, and solid is separated out. And (5) filtering. And pulping the solid obtained by filtering with 8L of hot water at 65-75 ℃, slowly cooling to room temperature, and filtering. The filter cake was washed with water and the dried pale yellow 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione, yield 80.6%, purity 94.6%, maximum single hetero 2.2%.

Comparative example 2

54g (0.182mol) of the compound 8-bromo-7- (2-butynyl) -3-methylxanthine, 40g (0.2mol) of the compound 2-chloromethyl-4-methylquinazoline, 50g (0.364mol) of potassium carbonate and 0.6g (0.04mol) of potassium iodide were charged into a 2L reaction flask, followed by addition of NMP270 ml. Stirring and heating to 40-50 ℃, and stirring for 2-3 h. After TLC detection reaction is finished, 36.5g (0.192mol) of compound R-3- (Boc-amino) piperidine is added for continuous reaction for 3-4 h. After completion of the TLC detection (DCM: MeOH ═ 20:1), the heating was stopped and the temperature was reduced to room temperature.

And (3) post-treatment: 540ml of methylene chloride and 1080ml of water were added and stirred until the solid dissolved. The layers were separated and the aqueous layer was extracted with (270ml × 2) DCM and the organic phases were combined; adding 500ml of 1% acetic acid aqueous solution, washing for 1 time, and washing for 1 time with saturated sodium chloride to obtain an organic phase. Evaporating an organic phase to dryness to obtain a light yellow solid, adding 300ml of ethanol, heating until the mixture is dissolved in a reflux manner, slowly dripping 300ml of water, cooling to 20-30 ℃, stirring for 2 hours, performing suction filtration, and washing a filter cake with 20ml of anhydrous ethanol. And (3) drying by blowing at 60-70 ℃ for 5-6 h. The compound 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione was obtained in 86.7% yield, 93.5% HPLC purity, maximum single hetero 2.8%.

Comparative example 3

Into a reaction flask were charged 150ml of dimethyl sulfoxide, 10g of the compound 8-bromo-7- (2-butynyl) -3-methylxanthine, 7.13g of the compound 2-chloromethyl-4-methylquinazoline, 9.30g of potassium carbonate, and 0.61g of tetrabutylammonium bromide. Heating to 60 ℃ under stirring, and reacting for 6h to obtain a first reaction solution. 8.2g of the compound R-3- (Boc-amino) piperidine is added to the first reaction solution, and the reaction is finished after the temperature is raised to 75-80 ℃ for 16 hours. Dropwise adding 200ml of water into the reaction system, cooling to 25 ℃ after dropwise adding, and stirring for 2 hours; filtration and vacuum drying of the resulting solid at 45 ℃ gave the compound 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione in 85.4% molar yield and purity: 90.7 percent and maximum single impurity 2.1 percent.

Comparative example 4

Sodium (23.0g, 1.0mol) and absolute ethanol (500ml) were added to a 2L reaction flask, stirred at room temperature for 1h, methylurea (37.1g, 0.50mol) and ethyl cyanoacetate (34.9ml, 0.50mol) were added, and heated under reflux for 6 h. The reaction mixture was cooled to room temperature, and ethanol was recovered under reduced pressure. Dissolving the residue with distilled water (100ml), dropwise adding 4mol/L hydrochloric acid (200ml) to adjust the pH to 7, stirring in ice bath for 1h, filtering, recrystallizing the filter cake with water to obtain white crystal 6-amino-1-methyl uracil, wherein the molar yield is 90.2%, and the purity is as follows: 94.7 percent and maximum single impurity 2.5 percent;

6-amino-1-methyluracil (60.0g, 430.0mmol), distilled water (300ml) and acetic acid (120ml) were charged into a 1L reaction flask, followed by dropwise addition of a prepared aqueous solution (240ml) of sodium nitrite (43.5g, 0.63mol), and the reaction was stirred at 50 ℃ for 1 hour. Cooling the reaction solution to room temperature, continuously stirring for reaction for 1h, filtering, washing a filter cake with ice water (100ml) and glacial ethanol (500ml) in sequence, and drying under reduced pressure to obtain purple solid 6-amino-5-nitroso-1-methyl uracil with the molar yield of 91.5% and the purity: 92.5 percent and maximum single impurity 2.3 percent;

adding 6-amino-5-nitroso-1-methyl uracil (60.0g, 0.35mol) and 25% ammonia water (600ml) into a 2L reaction bottle, adding sodium hydrosulfite (215.0g, 1.23mol) in batches, stirring at 50 ℃ for reaction for 1h, cooling the reaction liquid to room temperature, continuing stirring for reaction for 8h, filtering, washing a filter cake with ice water (100ml) and glacial ethanol (500ml) in sequence, and drying under reduced pressure to obtain light yellow solid 5, 6-diamino-1-methyl uracil with the molar yield of 70.4% and the purity: 94.9 percent and maximum single impurity 2.1 percent;

adding 5, 6-diamino-1-methyl uracil (40.0g, 0.26mol) and distilled water (1L) into a 2L reaction bottle, dropwise adding formic acid (29.5ml, 0.77mol), heating and refluxing for 3H under the protection of nitrogen, cooling to room temperature, adding an aqueous solution of sodium hydroxide (51.2g, 1.28mol), continuously refluxing for 1H, cooling the reaction liquid to room temperature, adding 2mol/L hydrochloric acid (300ml) to adjust the pH to 7, stirring for 1H in an ice bath, filtering, washing the obtained filter cake with ice water (100ml) and glacial ethanol (200ml) in sequence, and drying under reduced pressure to obtain a light yellow solid, namely 3-methyl-1H-purine-2, 6(3H,7H) -dione, wherein the molar yield is 71.2%, and the purity: 93.7 percent and maximum single impurity 2.8 percent;

adding 3-methyl-1H-purine-2, 6(3H,7H) -diketone (30.0g, 0.18mol), sodium acetate (29.6g, 0.36mol) and glacial acetic acid (460ml) into a 1L reaction bottle, dropwise adding bromine (11.1ml, 0.22mol), heating to 65 ℃, stirring for reaction for 2H, cooling to room temperature, filtering, washing a filter cake with acetic acid (50ml) and water (100ml) in sequence, and drying under reduced pressure to obtain a white solid 3-methyl-8-bromo-1H-purine-2, 6(3H,7H) -diketone with the molar yield of 78.0 percent and the purity: 91.2 percent and maximum single impurity 2.6 percent;

3-methyl-8-bromo-1H-purine-2, 6(3H,7H) -dione (30.0g, 0.12mol), N-diisopropylethylamine (DIEPA, 26.3ml, 0.16mol) and DMF (360ml) were added to a 1L reaction flask, 1-bromo-2-butyne (11.8ml, 0.13mol) was added dropwise, stirred at room temperature for 12H, distilled water (300ml) was added and stirred for 0.5H, filtered, and the filter cake was washed with ice water (100ml) and glacial ethanol (100ml) in sequence, dried under reduced pressure to give 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -dione as a white solid in 79.0% molar yield: 94.6 percent and maximum single impurity 2.4 percent;

A1L reaction flask was charged with 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -dione (20.0g, 67.0mmol), DMF (300ml), anhydrous potassium carbonate (18.6g, 135.0mmol) and 2-chloromethyl-4-methyl quinazoline (13.0g, 67.0mmol), and the reaction was stirred at 90 ℃ for 6H. After cooling to room temperature, anhydrous potassium carbonate (27.9g, 0.20mol) and (R) -3-aminopiperidine dihydrochloride (17.3g, 0.1mol) were added, and the reaction was stirred at 80 ℃ for 8 hours. Cooled to room temperature, DMF was evaporated under reduced pressure, dichloromethane (100ml) was added, stirring was carried out for 0.5h, filtration was carried out and the filter cake was washed with dichloromethane (50 ml). The filtrate was concentrated, 10% glacial acetic acid (300ml) was added, stirred for 0.5h and washed with dichloromethane (100 ml. times.3). The aqueous phase was taken and 10% sodium carbonate solution (200ml) was adjusted to pH8, extracted with dichloromethane (100 ml. times.2), concentrated under reduced pressure, the resulting crude product was dissolved in dichloromethane, activated carbon (10% to 25%) was added, reflux was applied under heating for 1h, the activated carbon was removed by filtration while hot, the filtrate was concentrated, and dichloromethane was added to the residue: stirring and pulping for 1h by using a mixed solvent of petroleum ether (1:10), filtering, and drying a filter cake at 45 ℃ to obtain white solid linagliptin, wherein the molar yield is 57.0%, and the purity is as follows: 95.7 percent and the maximum single impurity is 2.3 percent.

Comparative example 5

400ml of acetic acid, 100g of 3-methyl-xanthine (0.6019mol) and 74g of sodium acetate (0.90mol) are introduced at 25-30 ℃ into a round-bottomed flask equipped with a stirrer. The mixture is stirred for 5-10 minutes and cooled to l 0-15 ℃. Slowly adding 144.2g of liquid bromine (0.90mol) dropwise to the reaction mixture for about 60 minutes and raising the temperature to 60-65 ℃; keeping for 3-4 hours. After the reaction was complete, the reaction mixture was cooled to 15-20 ℃ and 800ml of DMF in water was slowly added. The reaction mixture is kept stirring for 2-3 hours. The solid obtained was filtered and washed with DMF water. A slurry wash of DMF water was added to the wet material and the wet material was fed into a round bottom flask. Adding 700ml of methanol to the wet material and raising the temperature to 60-65 ℃; and kept at 60-65 ℃ for 60 minutes. The reaction mixture was cooled to 40-45 ℃ and held for 60 minutes. The resulting solid was filtered and washed with methanol. And (3) drying the wet material at 40-45 ℃ for 5-8 hours in vacuum to obtain the target compound 8-bromo-3-methyl-xanthine with the molar yield of 88%, the purity of 92.3% and the maximum single impurity of 2.8%.

1000ml of DMF, 62g of N, N-diisopropylethylamine (0.6128 moles) and 100g of 8-bromo-3-methyl-xanthine (0.4081 moles) were added at 20-30 ℃ to a 5 liter round bottom flask equipped with an overhead stirrer, hot bag and dropping funnel and stirred for 5-10 minutes to obtain a clear solution. To the reaction mixture was slowly added 81.45g of 1-bromo-2-butyne (0.6128 moles) at 25-30 ℃ and the reaction mixture was maintained at the same temperature for 3-4 hours. After the reaction was complete, 2000ml of cooled DMF water was slowly added to the reaction mixture and stirred at 25-30 ℃ for 1-2 hours. The solid was filtered and washed with 100ml of DMF water. The wet material was fed to a round bottom flask and 700ml of methanol was fed and the temperature was raised to 60-65 ℃ and held for 60 minutes. The reaction mixture was cooled to 40-45 ℃ and held for 60 minutes. The solid was filtered and washed with 100ml of methanol; drying at 40-45 ℃ for 5-8 hours to obtain the 3-methyl-7- (2-butyn-l-yl) -8-bromo-xanthine with the molar yield of 80.2%, the purity of 95.3% and the maximum single impurity of 3.5%.

700ml of DMSO, 77.8g of 2- (chloromethyl) -4-methyl-quinazoline (0.4038 mol), 100g of 3-methyl-7- (2-butyn-l-yl) -8-bromo-xanthine (0.3365 mol), 0.5g of tetrabutylammonium bromide and 55.8g of anhydrous potassium carbonate (0.4038 mol) were added at 20-30 ℃ to a 5 liter round bottom flask equipped with an overhead stirrer and a hot bag and the temperature was raised to 75-80 ℃. The reaction mixture is maintained at 75-80 ℃ for 2-3 hours. After the reaction was complete, the reaction mixture was cooled to 45-50 ℃. To the reaction mixture was slowly added 600ml of methanol and stirred at 45-50 ℃ for 60 minutes. The solid was filtered and washed with 200ml of methanol followed by a DMF water slurry. The wet material was fed to a round bottom flask and 700ml of methanol was fed to the round bottom flask; the temperature was raised to 65 ℃ and held for 60 minutes. The reaction mass was cooled to 40-45 ℃ and held for 60 minutes. The solid was filtered and washed with 200ml methanol. Drying the wet material at 40-45 ℃ for 5-8 hours to obtain l- [ (4-methyl-quinazoline-2 yl) methyl ] -3-methyl-7- (2-butyn-l-yl) -8-bromo-xanthine, wherein the molar yield is 79.6%, the purity is 96.5%, and the maximum single impurity content is 2.7%.

800ml of DMSO, 53.2g of (R) 3-Boc-aminopiperidine (0.2654 moles), 100g of 1- [ (4-methyl-quinazolin-yl) methyl ] -3-methyl-7- (2-butyn-l-yl) -8-bromo-xanthine (0.2212 moles), 0.5g of potassium iodide and 91.5g of potassium carbonate (0.6620 moles) are fed at 20-30 ℃ to a 5 liter round-bottomed flask equipped with an overhead stirrer and a hot bag. The temperature of the reaction mixture is raised to 80-85 ℃ and maintained at the same temperature for 4-5 hours. After the reaction is complete, the reaction mixture is cooled to 30-35 ℃, 1600ml of cooled DMF water is slowly added and stirred at 25-35 ℃ for 60 minutes. The solid was filtered and washed with 200ml of DM water. The wet material was washed again with DMF water. The wet material was charged to a round bottom flask and 700ml of dichloromethane was charged, stirred for 3 minutes and the layers were separated. The organic layer was washed with DMF water and treated with activated carbon, followed by filtration through hyflo (celite) and washing with dichloromethane. Distilling off the solvent at 35-40 ℃, slowly adding 800ml of hexane/cyclohexane and the dichloromethane solution at 35-40 ℃ into another round-bottom flask, and stirring for 30-60 minutes at 30-35 ℃. The solid was filtered and washed with 200ml of hexane/cyclohexane. The wet material was dried under vacuum at 40 to 45 ℃ for 5 to 8 hours to obtain l- [ (4-methyl-quinazolin-2 yl) methyl ] -3-methyl-7- (2-butyn-l-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-l-yl ] -xanthine in a molar yield of 85.5%, a purity of 93.5% and a maximum mono-impurity of 3.2%.

Claims

1. A linagliptin intermediate compound shown as a formula IV:

2. the intermediate compound IV according to claim 1, which is prepared by a process comprising the steps of: under the action of alkali, 2-chloromethyl-4-methyl quinazoline II and 1-methyl uracil III react in an organic solvent under the condition of controlling the temperature to obtain an intermediate IV, and the reaction route is as follows:

3. the process according to claim 2, wherein the base is selected from an organic base or an inorganic base, wherein the organic base is selected from one or two of triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene; the inorganic base is one or two selected from potassium carbonate, sodium carbonate, potassium acetate, sodium bicarbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.

4. The preparation method according to claim 2, wherein the organic solvent is one or a combination of DMSO, NMP, DMF, 1, 4-dioxane and toluene; the reaction temperature is 70-100 ℃.

5. Use of the compound iv according to claim 1 for the preparation of linagliptin.

6. A process for preparing 8- [ (3R) -3-tert-butoxycarbonylamino-1-piperidinyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione I, which is an important intermediate of linagliptin, from the compound IV according to claim 1, comprising the following steps:

and step 3: under the action of alkali, the intermediate VI reacts with R-3- (Boc-amino) piperidine to obtain 8- [ (3R) -3-tert-butyloxycarbonylamino-1-piperidyl ] -7- (2-butyn-1-yl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione I, and the synthetic route is as follows:

7. the process of claim 6, wherein the catalyst in step 1 is selected from the group consisting of TMSI, TMSOTf, CoCl₂One or two of HSiW, HPW and HPM.

8. The method according to claim 6, wherein the iodine source in step 1 is one or two selected from potassium iodide, sodium iodide, and tetrabutylammonium iodide.

9. The method according to claim 6, wherein the base used in step 2 is one or two selected from potassium carbonate, sodium bicarbonate, triethylamine, and N, N-diisopropylethylamine.

10. The method according to claim 6, wherein the base used in step 3 is one or two selected from the group consisting of butyllithium, lithium diisopropylamide and lithium bis (trimethylsilyl) amide.