CN111574520A - Riagliptin intermediate compound V - Google Patents

Riagliptin intermediate compound V Download PDF

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CN111574520A
CN111574520A CN201910122786.7A CN201910122786A CN111574520A CN 111574520 A CN111574520 A CN 111574520A CN 201910122786 A CN201910122786 A CN 201910122786A CN 111574520 A CN111574520 A CN 111574520A
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CN111574520B (en
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张贵民
王本利
黄文波
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Lunnan Better Pharmaceutical Co ltd
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of pharmaceutical chemicals, and provides a linagliptin intermediate compound V

Description

Riagliptin intermediate compound V
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a linagliptin intermediate compound V.
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:
Figure BDA0001972527960000011
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 FDA in the United states and marketed in 5.2.2011, has the trade name of Tradjenta, 4.2013, and is approved to be sold in China by the national food and drug administration (CFDA) of linagliptin.
At present, a large number of patents and literature reports on the synthesis of linagliptin are published, for example, 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 to perform 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), a piperidine derivative (compound D) with a protected group replaces the 8-position bromine atom of the compound C to generate compound E, finally, after removing protecting groups, the final product linagliptin is generated and refined to obtain a linagliptin refined product, and the synthetic route is as follows:
Figure BDA0001972527960000021
the process has long reaction period and complex operation, and the intermediate A is easy to debrominate at high temperature, which brings difficulty to subsequent purification and is not suitable for industrial mass production.
In WO2014/097314A1, 3-methylxanthine is used 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 under the conditions that potassium carbonate is used as an acid agent and tetrabutylammonium bromide is used as a phase-binding 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:
Figure BDA0001972527960000022
the process has complicated operation steps, tetrabutylammonium bromide is used as a phase transfer catalyst in the production, potassium iodide is used as a catalyst, the production cost is increased, 1-bromo-2-butyne is easily coupled with an intermediate 8-bromo-3-methylxanthine 1-bit N atom to generate new impurities, and the intermediate A is easily coupled with itself to generate dimer impurities.
Chinese patent document CN104844602A discloses a preparation method of linagliptin, which comprises the steps of reacting a compound A (8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1H-purine-2, 6-dione) with a compound C ((R-3-aminopiperidine compound) in the presence of potassium carbonate or sodium carbonate and an iodine-containing inorganic salt as a catalyst and N-methyl-2-pyrrolidone or N, N-dimethylformamide as a solvent under heating, and directly adding a compound B (2-chloromethyl-4-methyl quinazoline) without separation after the reaction is finished to generate a compound E (1- [ (4-methyl-quinazolin-2-yl) methyl ] -3-methyl-7- (2-butyn-1) -yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidin-1-yl ] -2, 6-dione-2, 3,6, 7-tetrahydro-1H-purine), deprotection of compound E gives linagliptin, the synthetic route is as follows:
Figure BDA0001972527960000031
the process improves the yield by changing the reaction sequence and implementing the one-pot method, but the process uses a catalyst, namely an iodine-containing inorganic salt, in order to improve the purity of the linagliptin, thereby undoubtedly increasing the production cost.
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 through condensation ring-closing, nitrosation, reduction, ring-closing, 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. The process has the advantages of complicated operation steps, 27 percent of final total yield and the following synthetic route:
Figure BDA0001972527960000032
research on the synthetic route of the linagliptin shows that the linagliptin is mainly synthesized by using 3-methyl-8-halogenated xanthine or 8-7- (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, so that the linagliptin serving as an important intermediate 7 (3-methyl-8-bromoxanthine) plays a vital role in the whole preparation of the linagliptin.
For the synthesis of the intermediate, chinese patents CN104211702A, CN102807568A disclose that 6-amino-1-methyluracil is used as the starting material, and first reacts with sodium nitrite to obtain the corresponding compound of the last nitroso group, and then the corresponding compound of formula I is obtained through reduction, cyclization, and iodination in sequence. The method has a long route, uses explosive nitrite compounds, has low yield, and limits the industrial application of the method to a certain extent, and the synthetic route is as follows:
Figure BDA0001972527960000041
chinese patent document CN107936023A discloses a method for preparing compound I by reacting 1-methyl uracil and urea as raw materials with potassium iodide as an iodine source under TBHP, a concentrated sulfuric acid catalyst and an oxidant. The process takes TBHP with strong oxidizing property and concentrated sulfuric acid as catalysts, the oxidant seriously pollutes the environment, the corrosion to equipment is strong, the post-treatment is complex, the operation is not suitable, and the synthetic route is as follows:
Figure BDA0001972527960000042
in conclusion, the linagliptin preparation methods have problems, or have many impurities which are difficult to remove, 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 problems of high technical requirement, serious environmental pollution, high production cost and the like are solved, and the invention provides a linagliptin intermediate V 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 V:
Figure BDA0001972527960000051
the preparation method of the compound V comprises the following steps: adding a 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 for reaction until the reaction is finished to obtain an intermediate V, wherein the reaction route is as follows:
Figure BDA0001972527960000052
preferably, the catalyst is selected from TMSI, TMSOTf and 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 3-10%, particularly preferably 6% of the total mass of the compound IV, the urea and the iodine source.
Preferably, the organic solvent is selected from one or a combination of DMSO, NMP, DMF, 1, 4-dioxane and toluene.
In a preferable 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, an organic layer 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.
The preparation method of the 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, and stirring for reaction to obtain an intermediate IV, wherein the reaction route is as follows:
Figure BDA0001972527960000061
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 selected from potassium carbonate, sodium carbonate, potassium acetate, sodium bicarbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate; triethylamine (TEA) is particularly preferred.
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 the preferable scheme, the reaction temperature of the reaction is 70-100 ℃, and particularly preferably 80-85 ℃.
In a preferable scheme, after the reaction is finished, post-treatment operation is required, specifically, after the reaction is finished, ethanol and purified water (V/V is 1:2) are slowly added, stirring is carried out at a controlled temperature, suction filtration is carried out, a filter cake is washed by a mixed solvent of ethanol and purified water, and drying is carried out, so as to obtain an intermediate IV.
Use of compound v for the preparation of linagliptin.
The application of the compound V in preparing an important 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 of linagliptin comprises the following steps: nucleophilic substitution is carried out on the compound V and 1-bromo-2-butyne in the step 1 under an alkaline environment to obtain an intermediate VI; step 2, under the action of alkali, the intermediate VI reacts with R-3- (Boc-amino) piperidine 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:
Figure BDA0001972527960000071
preferably, the above steps are described in further detail in the following sections:
step 1 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 feeding molar ratio of the reaction compound V, the 1-bromo-2-butyne and the alkali is 1: 1.01-2.5, and particularly preferably 1:1.02: 1.05.
Preferably, the reaction solvent is selected from one or a mixture of toluene, N-dimethylformamide, N-dimethylacetamide, xylene and 1,4 dioxane, and N, N-dimethylformamide is particularly preferred.
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 2 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 butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide or one or two thereof, with lithium bis (trimethylsilyl) amide being particularly preferred.
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 V 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 is simple and convenient to operate, high in reaction yield and high in purity of the obtained product;
2. urea is used as a raw material to synthesize an intermediate 3-methyl-8-iodine-1H-purine-2, 6(3H,7H) -diketone V for the first time, and the new compound V has no dimeric impurity in the subsequent substitution reaction;
3. the compound V is synthesized by taking the iodized salt as an iodinating reagent, and compared with the traditional iodinating reagent such as iodine simple substance, the compound V has the advantages of low toxicity, mild use condition 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. the organic base is used for catalyzing the substitution reaction of R-3- (Boc-amino) piperidine, and compared with inorganic base, the reaction condition is mild, economic and environment-friendly, and the yield is higher.
In conclusion, the invention provides a new compound 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, the method avoids using dangerous chemical reagents, avoids generating larger impurities in the production process, replaces the traditional catalyst with a green catalyst, has milder reaction, is economic and environment-friendly, has higher yield and 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:
Figure BDA0001972527960000091
high resolution mass spectrum of 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.
Figure BDA0001972527960000092
High resolution mass spectrum of 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)；13CNMR(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 a 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 a 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, namely 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 a white solid 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -dione in 79.0% molar yield, purity: 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 a white solid linagliptin with the molar yield of 57.0 percent and the purity of: 95.7 percent and the maximum single impurity is 2.3 percent.
Comparative example 5
In a 50mL single-necked flask, 1-methyluracil (1.26g, 10mmol), urea (1.20g, 20mmol), potassium iodide (1.83g, 11mmol), TBHP (70%, 2.83g, 22mmol), sulfuric acid (98 wt% concentration, 49mg, 0.5mmol), 20mL of dioxane were added in this order, and then the temperature was raised to 75 ℃ and stirred for 18 h. Then, 80mL of ethyl acetate was added to dilute the mother liquor, washed three times with a saturated aqueous sodium sulfite solution, once with a saturated aqueous sodium chloride solution, and finally once again with water, and ethyl acetate was rotary-distilled off under reduced pressure to obtain a crude product. The crude product was recrystallized from dichloromethane and cyclohexane to give the compound 3-methyl-8-iodo-1H-purine-2, 6(3H,7H) -dione in 74.8% molar yield, 92.5% purity and 2.4% maximum single hetero.
In a 100mL single-necked flask, 3-methyl-8-iodo-1H-purine-2, 6(3H,7H) -dione (2.92g, 10mmol), N, N-diisopropylethylamine (1.94g, 15mmol), 1-bromo-2-butyne (1.98g, 15mmol), and 30mL of acetone were sequentially added, and the reaction was refluxed at 50 ℃ for 5 hours. The reaction is cooled, cooled to room temperature, filtered, and the filter cake is washed with methanol to obtain a crude product, namely a light yellow solid, and the crude product is recrystallized by dichloromethane and cyclohexane to obtain 3.23g of a compound, namely 8-iodo-7- (2-butynyl) -3-methyl-1H-purine-2, 6(3H,7H) -dione, wherein the molar yield is 76.5%, the purity is 97.4%, and the maximum single impurity content is 2.5%.
Example 6
6-amino-1-methyluracil (10.00g,70.9mmol) was dissolved in a mixed solution of 50mL of water and 20mL of glacial acetic acid, and an aqueous solution (40mL) of sodium nitrite (7.138g,103.5mmol) was added at 25 ℃ at room temperature, stirred at room temperature for 0.5h, then warmed to 50 ℃ and stirred for 1h, and finally moved to room temperature and stirred overnight. After completion of the TLC detection reaction, stirring was stopped, filtration was carried out, and the filter cake was washed with water (100mL) and 95% ethanol (50mL) to give intermediate 6-amino-5-nitroso-1-methyluracil as a purple solid in 75.3% yield, 93.5% purity, and 2.2% maximum single impurity.
6-amino-5-nitroso-1-methyluracil (11.50g,67.6mmol) was dissolved in 200mL of aqueous ammonia (25%), and sodium dithionite (41.20g, 236.6mmol) was added thereto at room temperature of 25 ℃ and stirred. The temperature in the reaction flask was gradually increased to 35 ℃. When the temperature in the bottle does not rise any more, the bottle is heated to 60 ℃ and stirred for 1 hour. The reaction was then allowed to warm to room temperature and stirred for 6 h. After the reaction was completed, the stirring was stopped, the mixture was filtered, and the filter cake was washed with ice water and dried under vacuum. The intermediate 5, 6-diamino-1-methyl uracil is obtained in the yield of 77.5%, the purity of 92.4% and the maximum single impurity of 2.5%.
5, 6-diamino-1-methyl uracil (10.00g,64.0mmol) is dissolved in a mixed solvent of formic acid (3.305mL) and water (74.74mL), heated and refluxed at 105 ℃ for 3h, then cooled to 20 ℃, added with a solution of sodium hydroxide (5.12g,128.1mmol) in water (6.40mL), and heated and refluxed at 105 ℃ for 1h, and then the reaction is completed. Cooling to 0 ℃, adjusting the pH value to 4 by glacial acetic acid, separating out a yellowish white solid, filtering, washing a filter cake by ice water, and drying in vacuum to obtain the intermediate 3-methyl-1H-2, 6-dicarbonylpurine, wherein the yield is 77%, the purity is 90.7%, and the maximum single impurity content is 2.7%.

Claims (10)

1. A linagliptin intermediate compound represented by formula V:
Figure FDA0001972527950000011
2. the process for the preparation of intermediate compound v according to claim 1, characterized in that it comprises the following steps: adding the compound IV, urea and an iodine source into an organic solvent, and adding a catalyst and active carbon under the condition of controlling the temperature to react to obtain an intermediate V:
Figure FDA0001972527950000012
3. the process of claim 2 wherein the catalyst is selected from the group consisting of TMSI, TMSOTf, CoCl2One or two of HSiW, HPW and HPM; the dosage of the catalyst is 1.0-10% of the mass of the compound IV.
4. The method of claim 2, wherein the iodine source is one or two of potassium iodide, sodium iodide, and tetrabutylammonium iodide.
5. The preparation method according to claim 2, wherein the amount of the activated carbon is 3 to 10 percent of the total mass of the compound IV, the urea and the iodine source.
6. 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 ℃.
7. The preparation method according to claim 2, wherein the compound IV is prepared by the following steps: under the alkaline condition, 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:
Figure FDA0001972527950000013
8. the process of claim 7, wherein the base is selected from the group consisting of organic bases and inorganic bases, wherein the organic base is selected from one or two of triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine, and 1, 8-diazabicyclo [5.4.0] undec-7-ene; the inorganic base is one or two of potassium carbonate, sodium bicarbonate and disodium hydrogen phosphate.
9. Use of compound v according to claim 1 for the preparation of linagliptin.
10. Use of compound v according to claim 1 for the preparation of the important 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, linagliptin, the preparation method comprising the following steps: in the step 1, nucleophilic substitution is carried out on the intermediate V and 1-bromo-2-butyne under an alkaline condition to obtain an intermediate VI; step 2, under the action of alkali, the intermediate VI reacts with R-3- (Boc-amino) piperidine 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:
Figure FDA0001972527950000021
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