CN111574463B - Rivastigmine intermediate compound IV - Google Patents

Rivastigmine intermediate compound IV Download PDF

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CN111574463B
CN111574463B CN201910122790.3A CN201910122790A CN111574463B CN 111574463 B CN111574463 B CN 111574463B CN 201910122790 A CN201910122790 A CN 201910122790A CN 111574463 B CN111574463 B CN 111574463B
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CN111574463A (en
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张贵民
王本利
黄文波
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • 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 chemical industry and discloses a linagliptin intermediate IV
Figure RE-310589DEST_PATH_IMAGE001
And a novel route for synthesizing linagliptin important intermediate by utilizing linagliptin intermediate IV

Description

Rivastigmine 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 (chemical name 8- [ (3R) -3-amino-1-piperidinyl)]-7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl]-1H-purine-2, 6-dione; the molecular formula: c (C) 25 H 28 N 8 O 2 The method comprises the steps of carrying out a first treatment on the surface of the Molecular weight: 472.54; CAS registry number 668270-12-0, having the following structural formula:
Figure BDA0001972530200000011
the linagliptin is an oral hypoglycemic drug developed by the pharmaceutical company Bolin and Yingan in Germany, is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, is approved by the United states FDA for marketing in 5 th month and 2 days in 2011, has the trade name of Tradjenta, and is approved by the national food and drug administration (CFDA) for marketing in China in 4 th month of 2013, and clinical results show that the drug has good hypoglycemic effect, high selectivity, long-acting and oral effectiveness, and good safety and tolerance.
At present, the synthesis of linagliptin mainly takes 3-methyl-8-halogenated xanthine or 8-halogenated-7- (2-butynyl) -3-methylxanthine as basic parent nucleus, and is obtained by connecting quinazoline ring with 1-nitrogen atom and connecting (R) -3-aminopiperidine with 8-carbon atom in sequence. The synthesis method of linagliptin is studied more at home and abroad, and the synthesis route of linagliptin is disclosed in documents (Chinese medicinal chemistry impurity, 2011, volume 21, page 5, 408; J Med Chem,2007, 58 (26): 6450-6453; CN105936634A): 3-methyl-8-bromoxanthine is used as raw material, and Li Geli is prepared through 3 times of substitution reaction and hydrolysis reaction, and the synthetic route is as follows:
Figure BDA0001972530200000021
chinese patent CN105503872a, during the synthesis according to the above process, found a new unknown impurity which is not an intermediate of the above reaction.
Patent documents WO200551950, WO2015004599, CA2586938 and CN104496989A, CN104387390A respectively disclose an industrial preparation process of linagliptin, wherein 8-bromo-7- (2-butynyl) -3-methylxanthine (compound A) is used as a starting material, nucleophilic substitution reaction is carried out on the 8-bromo-7- (2-butynyl) -3-methyl-1- [ (4-methyl-2-quinazoline) methyl ] -1H-purine-2, 6-dione (compound C) and 2-chloromethyl-4-methylquinazoline (compound B) under alkaline conditions, 8-bromine atoms of the compound C are replaced by a piperidine derivative (compound D) with protected groups to generate a compound E, and finally, the compound E is subjected to deprotection to generate a final product linagliptin, and then refined to obtain a linagliptin fine product, wherein the synthetic route is as follows:
Figure BDA0001972530200000022
The process has long reaction period, complicated operation, easy self coupling of the intermediate A, easy debromination at high temperature, difficult subsequent purification and unsuitability for industrialized mass production.
Patent document WO2014/097314A1 uses 3-methylxanthine as a starting material, 8-bromo-3-methylxanthine is generated by bromination, then 1-bromo-2-butyne is reacted 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) are reacted in DMSO solution, potassium carbonate is used as an acid-binding agent, tetrabutylammonium bromide is used as a phase transfer catalyst, intermediate D (8-bromo-7- (2-butynyl) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione) is prepared by reacting with potassium carbonate as an acid-binding agent, potassium iodide is used as a catalyst, and compound C ((R) -3-tert-butoxycarbonylaminopiperidine) is reacted to obtain intermediate E (4-methyl-quinazolin-3-methyl ] -3-methyl-7- (2-butynyl) -3-methyl-7-t-butynyl-2, 6-butanedione, finally, the linagliptin is obtained by deprotection of trifluoroacetic acid, and the synthetic route is as follows:
Figure BDA0001972530200000031
the process has complicated operation steps, each step of product is purified and then put into the next reaction, 1-bromo-2-butyne is very easy to be coupled with 1-N atom of 8-bromo-3-methylxanthine to generate new impurities, and the intermediate A is still coupled with itself to generate dimeric impurities.
Liu Xiangsheng in the synthesis of linagliptin, ([ J ] (J) journal of pharmaceutical industry, 2016.47 (1): 4-7), methyl urea and ethyl cyanoacetate are used as raw materials, and undergo condensation ring closure, nitrosylation, reduction, ring closure, bromination and nucleophilic substitution reaction with 1-bromo-2-butyne to obtain 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6 (3H, 7H) -dione (8), and then undergo alkylation reaction with 2-chloromethyl-4-methyl quinazoline (2), and finally undergo nucleophilic substitution reaction with (R) -3-aminopiperidine dihydrochloride to obtain linagliptin, wherein the synthetic route is as follows:
Figure BDA0001972530200000032
the method has long route, and the explosive nitrous acid compound is used, so that the yield is not high, and the final total yield is only 27%, so that the industrialized application of the method is limited to a certain extent.
After studying the above synthetic route of linagliptin, the compound 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6 (3H, 7H) -dione (8) was found to be a very critical intermediate in the synthesis of linagliptin; however, in the reaction, the 1-bromo-2-butyne compound is very easy to couple with the 1-nitrogen atom of the 3-methyl-8-bromoxanthine compound (7) to generate new impurities, and meanwhile, the 8-active bromine of the compound 7 is very easy to generate nucleophilic substitution reaction with the 1-N to generate dimer impurities.
In order to solve such problems, patent document CN104844602a discloses a preparation method of linagliptin, which comprises the steps of 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 or sodium carbonate and using an iodine-containing inorganic salt as a catalyst and N-methyl-2-pyrrolidone or N, N-dimethylformamide as a solvent at 30-80 ℃, directly adding compound B (2-chloromethyl-4-methylquinazoline) without isolation to form 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), and deprotecting compound E to obtain the following synthetic route:
Figure BDA0001972530200000041
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 the process uses iodine-containing inorganic salt as a catalyst for improving the purity of the linagliptin, which definitely increases the production cost.
In summary, the preparation methods of linagliptin in the prior art have problems, or have more impurities which are difficult to remove, low yield and low purity; or has high technical requirements, serious environmental pollution and high production cost; therefore, the research on a process route which is simple and convenient to operate, short in production period, higher in yield and more suitable for industrial production for linagliptin synthesis is still a problem to be solved at present.
Disclosure of Invention
In order to solve the problems of the prior art that the linagliptin is high in impurity content, difficult to remove, low in yield and low in purity in the preparation process; or the problems of high technical requirements, serious environmental pollution, high production cost and the like, the invention provides a linagliptin intermediate IV and a preparation method of the compound; and a novel method for synthesizing an important 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 of linagliptin by using the compound, wherein the method avoids the generation of larger impurities in the reaction process, replaces the traditional catalyst with a green catalyst, has milder reaction, economy, environmental protection and high yield, and is suitable for industrial production.
The invention is realized by the following technical scheme:
a linagliptin intermediate compound of formula IV:
Figure BDA0001972530200000051
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, and slowly adding alkali under the condition of temperature control to react to obtain an intermediate IV, wherein the reaction route is as follows:
Figure BDA0001972530200000052
Preferably, the base is selected from organic base or inorganic base, wherein the organic base is selected from one or two of Triethylamine (TEA), N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP) and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU); the inorganic base is one or two selected from potassium carbonate, sodium bicarbonate and disodium hydrogen phosphate; among them, triethylamine (TEA) is particularly preferable.
In a preferred embodiment, the molar ratio of the compound II to the compound III to the base is 1:1.1 to 2.5:1.1 to 2.5, 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.
Preferably, the reaction temperature of the reaction is from 70℃to 100℃and particularly preferably from 80℃to 85 ℃.
In a preferred scheme, the post-treatment operation is carried out, after the reaction is finished, ethanol and purified water (V/V=1:2) are slowly added, the temperature is controlled, the stirring is carried out, the suction filtration is carried out, and the filter cake is washed and dried by using a mixed solvent of ethanol and purified water, thus obtaining the intermediate IV.
The use of the compound IV for preparing an linagliptin intermediate.
The application of the compound IV in preparing an important intermediate 8- [ (3R) -3-tert-butyloxycarbonylamino-1-piperidinyl ] -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:
Step 1: adding the compound IV, urea and an iodine source into an organic solvent, and adding a catalyst and activated carbon for reaction to obtain an intermediate V;
step 2: nucleophilic substitution reaction is carried out on the intermediate V and 1-bromo-2-butyne under alkaline conditions to obtain an intermediate VI;
step 3: intermediate VI is reacted with R-3- (Boc-amino) piperidine under the action of a base to give 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 synthesized by the following route:
Figure BDA0001972530200000061
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: adding the compound IV, urea and iodine sources into an organic solvent, adding a catalyst and activated carbon under the temperature control condition, and continuously stirring until the reaction is finished to obtain an intermediate V.
Preferably, the catalyst is selected from TMSI, TMSOTf, coCl 2 One or both of HSiW, HPW, HPM, HSiW is particularly preferred.
Preferably, the catalyst is used in an amount of 1.0% to 10% by mass, particularly preferably 7.0% by mass, based on 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 particularly preferably potassium iodide.
In a preferred scheme, the feeding mole ratio of the compound IV to urea to iodine source is as follows: 1:1.05 to 2.5:1.05 to 2.5, particularly preferably 1:1.1:1.1.
Preferably, the dosage of the activated carbon is 3.0-10% of the total mass of the compound IV, urea and iodine source, and particularly preferably 6.0%.
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.
Preferably, the reaction temperature is from 70℃to 100℃and particularly preferably from 80℃to 85 ℃.
In a preferred scheme, after the reaction is finished, the post-treatment operation is needed, specifically, after the reaction is finished, the temperature is reduced, the reaction solution is added with an organic solvent for extraction, the extraction solution is subjected to suction filtration, washing and concentration to a volume which is half of that of the 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 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: adding the intermediate compound V, 1-bromo-2-butyne and alkali into an organic solvent, heating to 70-75 ℃ and stirring for reaction, cooling the reaction liquid after TLC detection reaction, carrying out suction filtration, washing and drying a filter cake to obtain the intermediate compound VI.
Preferably, the reaction base is selected from one or two of potassium carbonate, sodium bicarbonate, triethylamine and N, N-diisopropylethylamine, and particularly preferably N, N-diisopropylethylamine.
Preferably, the reaction organic solvent is selected from one or a mixture of toluene, N-dimethylformamide, N-dimethylacetamide, xylene and 1, 4-dioxane, and particularly preferably N, N-dimethylformamide.
Preferably, the feeding mole ratio of the reaction compound V to the 1-bromo-2-butyne to the alkali is as follows: 1:1.01 to 2.5:1.01 to 2.5, particularly preferably 1:1.02:1.05.
In a preferred scheme, after the reaction is finished, the post-treatment operation is needed, specifically, the temperature of the reaction liquid is reduced to 20-25 ℃ after the reaction is finished, the reaction is carried out by heat preservation and stirring, suction filtration is carried out, and a filter cake is pulped, washed and dried 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 the compound VI and the 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 and concentrating the reaction liquid after the reaction is finished, and crystallizing to obtain the compound I.
Preferably, the base of the reaction is selected from one or a mixture of butyllithium, lithium diisopropylamide and lithium bis (trimethylsilyl) amide, particularly preferably lithium bis (trimethylsilyl) amide.
In a preferred embodiment, the molar ratio of the compound VI, R-3- (Boc-amino) piperidine and base is 1:1.1 to 2.0:1.1 to 2.0, particularly preferably 1:1.4:1.3.
In a preferred scheme, post-treatment operation is needed after the reaction is finished, specifically, the temperature is reduced to 20-25 ℃ after the reaction is finished, and the reaction liquid is washed by purified water and saturated saline water, dried and concentrated to one fourth of toluene solvent, and then added with organic solvent for crystallization; the crystallization solvent is selected from one or mixed solution of petroleum ether, acetone, n-heptane, n-hexane and cyclohexane, and cyclohexane is particularly preferred.
In the present invention, the inert gas is usually nitrogen or argon, and among them, argon is particularly preferable.
Compared with the prior art, the invention has the technical effects that:
1. provides a linagliptin intermediate compound IV, and provides a novel method for simply, conveniently and efficiently 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, wherein the whole synthesis method is simple and convenient to operate, high in reaction yield and high in purity of the obtained product;
2. Taking 1-methyluracil as a starting material, and the obtained novel intermediate 1-methyl-3- ((4-methylquinazolin-2-yl) methyl) pyrimidine-2, 4 (1H, 3H) -diketone IV does not generate dimerization impurity in subsequent substitution reaction;
3. in the synthesis of the compound V, iodized salt is used as an iodizing reagent, and compared with the traditional iodizing reagent such as iodine simple substance, the iodized salt has the advantages of low toxicity, mild use condition and high conversion rate; the relatively mild catalyst is used for replacing the traditional strong-oxidability TBHP and concentrated sulfuric acid catalyst, 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 milder organic base is used for replacing inorganic base in the reaction with R-3- (Boc-amino) piperidine, and the reaction is milder, economical and environment-friendly and has higher yield.
In summary, the invention provides a novel compound and a novel method for synthesizing the 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, which avoids using dangerous chemical reagents, and the synthesized intermediate does not generate self coupling, reduces impurity generation, replaces the traditional catalyst with a green catalyst, has milder reaction, economy and environmental protection and higher yield, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
The structure of the novel compound obtained by the invention is confirmed:
Figure BDA0001972530200000091
spectrogram data for compound IV: ESI-HRMS m/z=283.1160 [ M+H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 )：δ8.03-8.05(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)； 13 C NMR(400MHz,DMSO-d 6 ):δ170.66,162.55,161.21,152.11,149.24,142.16,132.83,131.73,128.54,123.22,122.98,103.13,49.87,35.62,24.11.
Figure BDA0001972530200000092
Spectrogram data for compound V: ESI-HRMS m/z=449.0178 [ M+H ]] + ； 1 H-NMR(400MHz,DMSO-d 6 ):δ8.02-8.04(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)； 13 C NMR(400MHz,DMSO-d 6 )：δ170.68,161.24,155.10,152.13,150.33,149.26,145.16,132.85,131.92,128.55,123.23,122.96,114.63,49.86,32.62,23.41.
Preparation of Compound IV
Example 1
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline II, 13.24g (105 mmol) of 1-methyl uracil III, 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80-85 ℃ and stirred for dissolution, 18.21g (180 mmol) of triethylamine is slowly added dropwise, the temperature is controlled to 80-85 ℃ after the dripping is finished, the mixture is stirred for 3-4 h, after the TLC detection reaction is finished, the temperature is reduced to 50-55 ℃, 60ml of ethanol and 120ml of purified water are slowly added, the temperature is controlled to 20-25 ℃ for 1.5-2 h, the mixture is stirred for complete crystallization, suction filtration is carried out, a filter cake is washed by a mixed solvent of 20ml of ethanol and 40ml of purified water, and the mixture is dried for 8h at 50 ℃ in vacuum, and the compound IV is obtained, wherein the molar yield is 93.6%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 2
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80 to 85 ℃ and stirred for dissolution, 11.13g (110 mmol) of triethylamine is slowly added dropwise, the temperature is controlled to 80 to 85 ℃ after the dripping is finished, the mixture is stirred for 3 to 4 hours, after the TLC detection reaction is finished, the temperature is reduced to 50 to 55 ℃, 60ml of ethanol and 120ml of purified water are slowly added, the temperature is controlled to 20 to 25 ℃ and the mixture is stirred for 1.5 to 2 hours, the crystallization is complete, the mixture is filtered by suction, a filter cake is washed by a mixed solvent of 20ml of ethanol and 40ml of purified water, and the mixture is dried for 8 hours at 50 ℃ under vacuum degree, and the compound IV is obtained, wherein the molar yield is 93.0%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 3
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80 to 85 ℃ and stirred for dissolution, 25.30g (250 mmol) of triethylamine is slowly added dropwise, the temperature is controlled to 80 to 85 ℃ after the dripping is finished, the mixture is stirred for 3 to 4 hours, after the TLC detection reaction is finished, the temperature is reduced to 50 to 55 ℃, 60ml of ethanol and 120ml of purified water are slowly added, the temperature is controlled to 20 to 25 ℃ and the mixture is stirred for 1.5 to 2 hours, the crystallization is complete, the mixture is filtered by suction, a filter cake is washed by a mixed solvent of 20ml of ethanol and 40ml of purified water, and the mixture is dried for 8 hours at 50 ℃ under vacuum degree, and the compound IV is obtained, wherein the molar yield is 93.5%, the purity is 99.8%, and the maximum single impurity is 0.02%.
Example 4
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80 to 85 ℃ and stirred for dissolution, 10.12g (100 mmol) of triethylamine is slowly added dropwise, the temperature is controlled to 80 to 85 ℃ after the dripping is finished, the mixture is stirred for 3 to 4 hours, after the TLC detection reaction is finished, the temperature is reduced to 50 to 55 ℃, 60ml of ethanol and 120ml of purified water are slowly added, the temperature is controlled to 20 to 25 ℃, the mixture is stirred for 1.5 to 2 hours, the crystallization is complete, the mixture is filtered by suction, a filter cake is washed by a mixed solvent of 20ml of ethanol and 40ml of purified water, and is dried for 8 hours at 50 ℃ under vacuum, and the compound IV is obtained, wherein the molar yield is 92.5%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 5
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80 to 85 ℃ and stirred for dissolution, 26.31g (260 mmol) of triethylamine is slowly added dropwise, the temperature is controlled to 80 to 85 ℃ after the dripping is finished, the mixture is stirred for 4 to 5 hours, after the TLC detection reaction is finished, the temperature is reduced to 50 to 55 ℃, 60ml of ethanol and 120ml of purified water are slowly added, the temperature is controlled to 20 to 25 ℃ and the mixture is stirred for 2 to 3 hours, crystallization is completed, suction filtration is carried out, a filter cake is washed by a mixed solvent of 20ml of ethanol and 40ml of purified water, and the mixture is dried for 8 hours at 50 ℃ under vacuum degree, so that the compound IV is obtained, the molar yield is 93.6%, the purity is 99.7%, and the maximum single impurity is 0.02%.
Example 6
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 70 to 75 ℃, stirred and dissolved, 23.26g (180 mmol) of N, N-diisopropylethylamine is slowly added dropwise, the temperature is controlled to 70 to 75 ℃, the mixture is stirred and reacted for 3 to 4 hours, after TLC detection reaction is completed, the temperature is reduced to 50 to 55 ℃, ethanol (60 ml) and purified water (120 ml) are slowly added, the temperature is controlled to 20 to 25 ℃, the mixture is stirred and reacted for 1.5 to 2 hours, crystallization is complete, suction filtration is carried out, a filter cake is washed by a mixed solvent of ethanol (20 ml) and purified water (40 ml), and the mixture is dried in vacuum at 50 ℃ for 8 hours, so that the compound IV is obtained, the molar yield is 93.4%, the purity is 99.8%, and the maximum single impurity is 0.01%.
Example 7
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 95 to 100 ℃, stirred and dissolved, 22g (180 mmol) of 4-dimethylaminopyridine is slowly added, the temperature is controlled to 95 to 100 ℃, the stirring reaction is carried out for 3 to 4 hours, after TLC detection is finished, the temperature is reduced to 50 to 55 ℃, ethanol (60 ml) and purified water (120 ml) are slowly added, the temperature is controlled to 20 to 25 ℃, the stirring reaction is carried out for 1.5 to 2 hours, crystallization is completed, suction filtration is carried out, a filter cake is washed by a mixed solvent of ethanol (20 ml) and purified water (40 ml), and the mixture is dried for 8 hours at 50 ℃ under vacuum degree, thus obtaining the compound IV, the molar yield is 93.4%, the purity is 99.8%, and the maximum single impurity is 0.02%.
Example 8
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 65 to 70 ℃ and stirred for dissolution, 27.40g (180 mmol) of DBU is slowly added dropwise, the temperature is controlled to 65 to 70 ℃ after the completion of the dropwise addition, the mixture is stirred for 3 to 4 hours, after the TLC detection reaction is completed, the temperature is reduced to 50 to 55 ℃, 60ml of ethanol and 120ml of purified water are slowly added, the temperature is controlled to 20 to 25 ℃, the mixture is stirred for 1.5 to 2 hours, the crystallization is completed, the mixture is filtered by suction, a filter cake is washed by a mixed solvent of 20ml of ethanol and 40ml of purified water, and the mixture is dried for 8 hours at 50 ℃ under vacuum degree, so that the compound IV is obtained, the molar yield is 93.3%, the purity is 99.8%, and the maximum single impurity is 0.01%.
Example 9
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil, 90ml of dimethyl sulfoxide, heating to 100-105 ℃, stirring for dissolution, slowly adding 19.08g (180 mmol) of sodium carbonate, controlling the temperature to 100-105 ℃, stirring for reaction for 3-4 h, cooling to 50-55 ℃ after TLC detection is finished, slowly adding 60ml of ethanol and 120ml of purified water, controlling the temperature to 20-25 ℃, stirring for reaction for 1.5-2 h, crystallizing completely, filtering, 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 the compound IV, wherein the molar yield is 93.2%, the purity is 99.7%, and the maximum single impurity is 0.03%.
Example 10
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 85ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80 to 85 ℃ and stirred for dissolution, 17.67g (180 mmol) of potassium acetate is slowly added, the temperature is controlled to 80 to 85 ℃, the mixture is stirred for reaction for 3 to 4 hours, after TLC detection is finished, the temperature is reduced to 50 to 55 ℃, ethanol (60 ml) and purified water (120 ml) are slowly added, the temperature is controlled to 20 to 25 ℃, the mixture is stirred for reaction for 1.5 to 2 hours, crystallization is complete, suction filtration is carried out, a filter cake is washed by a mixed solvent of ethanol (20 ml) and purified water (40 ml), and the mixture is dried for 8 hours at 50 ℃ in vacuum to obtain the compound IV, the molar yield of 93.5%, the purity of 99.8% and the maximum single impurity of 0.02%
Example 11
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.24g (105 mmol) of 1-methyl uracil and 70ml of 1, 4-dioxane are added into a three-neck flask, the mixture is heated to 80-85 ℃ and stirred for dissolution, 15.1g (180 mmol) of sodium bicarbonate is slowly added, the temperature is controlled to 80-85 ℃, the mixture is stirred for reaction for 3-4 h, after TLC detection is finished, the temperature is reduced to 50-55 ℃, ethanol (60 ml) and purified water (120 ml) are slowly added, the temperature is controlled to 20-25 ℃, the mixture is stirred for reaction for 1.5-2 h, crystallization is complete, suction filtration is carried out, a filter cake is washed by a mixed solvent of ethanol (20 ml) and purified water (40 ml), and the mixture is dried for 8h at 50 ℃ in vacuum, so that the compound IV is obtained, the molar yield is 93.0%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 12
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 13.9g (110 mmol) of 1-methyl uracil, 90ml of toluene, heating to 80-85 ℃, stirring for dissolution, slowly adding 24.88g (180 mmol) 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 60ml of ethanol and 120ml of purified water, controlling the temperature to 20-25 ℃, stirring for reaction for 1.5-2 h, crystallizing completely, filtering, 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 the compound IV, wherein the molar yield is 93.1%, the purity is 99.8%, and the maximum single impurity is 0.01%.
Example 13
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 31.5g (250 mmol) of 1-methyl uracil and 70ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80-85 ℃ and stirred for dissolution, 24.50g (180 mmol) of sodium acetate is slowly added, the temperature is controlled to 80-85 ℃, the mixture is stirred for reaction for 4-5 h, after TLC detection is finished, the temperature is reduced to 50-55 ℃, ethanol (60 ml) and purified water (120 ml) are slowly added, the temperature is controlled to 20-25 ℃, the mixture is stirred for reaction for 2-2.5 h, crystallization is complete, suction filtration is carried out, a filter cake is washed by a mixed solvent of ethanol (20 ml) and purified water (40 ml), and the mixture is dried for 8h at 50 ℃ in vacuum, so that the compound IV is obtained, the molar yield is 93.6%, the purity is 99.8%, and the maximum single impurity is 0.02%.
Example 14
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 12.6g (100 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80 to 85 ℃, 25.56g (180 mmol) of disodium hydrogen phosphate is slowly added, the temperature is controlled to 80 to 85 ℃, the mixture is stirred and reacted for 3 to 4 hours, after TLC detection is finished, the temperature is reduced to 50 to 55 ℃, 60ml of ethanol and 120ml of purified water are slowly added, the temperature is controlled to 20 to 25 ℃, the mixture is stirred and reacted for 1.5 to 2 hours, crystallization is complete, suction filtration is carried out, a filter cake is washed by a mixed solvent of 20ml of ethanol and 40ml of purified water, and the mixture is dried for 8 hours at 50 ℃ under vacuum degree, so that the compound IV is obtained, the molar yield is 92.8%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 15
19.26g (100 mmol) of 2-chloromethyl-4-methyl quinazoline, 32.8g (260 mmol) of 1-methyl uracil and 80ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80 to 85 ℃, stirring is carried out for dissolution, 21.60g (180 mmol) of disodium hydrogen phosphate is slowly added, the temperature is controlled to 80 to 85 ℃, stirring is carried out for 4 to 5 hours, after TLC detection is finished, the temperature is reduced to 50 to 55 ℃, ethanol (60 ml) and purified water (120 ml) are slowly added, the temperature is controlled to 20 to 25 ℃, stirring is carried out for 2 to 2.5 hours, crystallization is complete, suction filtration is carried out, a filter cake is washed by a mixed solvent of ethanol (20 ml) and purified water (40 ml), and the mixture is dried for 8 hours at 50 ℃ under vacuum, thus obtaining the compound IV with the molar yield of 93.5%, the purity of 99.7%, and the maximum single impurity of 0.03%.
Preparation of Compound V
Example 16
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 130ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80-85 ℃, 3g of active carbon and 1.75g of HSiW1.75g of N-dimethylformamide are added, the reaction is continuously stirred for 8-9 h, the temperature is reduced to 25-30 ℃ after the TLC detection reaction is finished, 150ml of toluene is added, the mixture is stirred and filtered, the filtrate is washed three times by adding purified water, the saturated saline is washed, and an organic phase is collected and added with a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.8%, purity 99.9% and maximum single impurity 0.01%.
Example 17
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 130ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80-85 ℃, 3g of active carbon and 0.25g of HSiW are added, the reaction is continuously stirred for 8-9 h, the temperature is reduced to 25-30 ℃ after the TLC detection reaction is finished, 150ml of toluene is added, the mixture is stirred and filtered, the filtrate is washed three times by adding purified water, the saturated saline is washed, and an organic phase is collected and added with a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 93.9% and the purity is 99.9%. The maximum single impurity is 0.01%.
Example 18
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 140ml of dimethyl sulfoxide, heating to 80-85 ℃, adding 3g of active carbon and 2.5g of HSiW, continuing to stir and react for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, filtering, adding purified water into the filtrate to wash for three times, washing with saturated saline solution, collecting an 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 cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.7%, purity 99.8%, maximum single impurity 0.02%.
Example 19
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 130ml of N-methyl-2-pyrrolidone are added into a three-neck flask, the mixture is heated to 80 to 85 ℃, 3g of active carbon and 0.225g of HSiW0.225g are added into the mixture, the mixture is continuously stirred for reaction for 8 to 9 hours, the temperature is reduced to 25 to 30 ℃, 150ml of toluene is added into the mixture, the mixture is stirred and filtered, the filtrate is washed three times by adding purified water, the saturated saline is washed, and an organic phase is collected and added into a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 93.5%, purity 99.9%, maximum single impurity 0.01%.
Example 20
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 130ml of toluene, heating to 80-85 ℃, adding 3g of activated carbon and 2.75g of HSiW2.75g, continuously stirring and reacting for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, filtering, adding purified water into filtrate for three times, washing with saturated saline solution, collecting an 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 normal hexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.7%, purity 99.7% and maximum single impurity 0.02%.
Example 21
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 18.10g (97.35 mmol) of sodium iodide, 140ml of 1, 4-dioxane, is added into a three-neck flask, the mixture is heated to 80-85 ℃, 2.9g of active carbon and 1.75g of TMSOTF are added, the mixture is continuously stirred for reaction for 8-9 h, the temperature is reduced to 25-30 ℃, 150ml of toluene is added, stirring and suction filtration are carried out, the filtrate is added into purified water for three times, saturated saline water is used for washing, and an organic phase is collected and added into a proper amount of anhydrous sodium sulfate for 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, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.6%, purity 99.8%, maximum single impurity 0.01%.
Example 22
Into a three-neck flask, 25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 35.96g (97.35 mmol) of tetrabutylammonium iodide, 100ml of dimethyl sulfoxide solution, heating to 80-85 ℃, adding 4.0g of active carbon and 1.75g of HPW, continuously stirring for reaction for 8-9 h, cooling to 25-30 ℃, adding 120ml of benzene, stirring, suction filtering, adding purified water into filtrate for washing three times, washing with saturated saline, collecting an 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 and crystallizing for about 2 hours, carrying out suction filtration, leaching a filter cake by ethanol, carrying out suction filtration, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.8%, purity 99.8%, maximum single impurity 0.02%.
Example 23
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 110ml of N-methylpyrrolidone are added into a three-neck flask, the mixture is heated to 70-75 ℃, 2.8g of active carbon and 1.75g of HPM are added, the mixture is continuously stirred for reaction for 8-9 h, the temperature is reduced to 25-30 ℃, 160ml of paraxylene is added, the mixture is stirred and filtered, the filtrate is washed three times by adding purified water, the saturated saline is washed, and an organic phase is collected and added with a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 80ml, adding 40ml of n-heptane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.5%, purity 99.8%, maximum single impurity 0.02%.
Example 24
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 15.42g (92.93 mmol) of potassium iodide, 130ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80-85 ℃, 2.9g of active carbon and 1.75g of heteropolyacid HSiW1.75g are added, the mixture is continuously stirred for reaction for 8-9 h, the temperature is reduced to 25-30 ℃, 160ml of m-xylene is added, stirring and suction filtration are carried out, the filtrate is added into purified water for three times, saturated saline water is used for washing, and an organic phase is collected and added into a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 80ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.3%, purity 99.9% and maximum single impurity 0.01%.
Example 25
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 36.73g (221.25 mmol) of potassium iodide, 130ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80-85 ℃, 4.0g of activated carbon and 1.75g of heteropolyacid HSiW1.75g are added, the mixture is continuously stirred for reaction for 8-9 h, the temperature is reduced to 25-30 ℃, 150ml of o-xylene is added, stirring and suction filtration are carried out, the filtrate is added into purified water for three times, saturated saline water is used for washing, and an organic phase is collected and added into a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.8%, purity 99.9% and maximum single impurity 0.01%.
Example 26
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 14.69g (88.5 mmol) of potassium iodide, 130ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80-85 ℃, 2.8g of active carbon and 1.75g of heteropolyacid HSiW1.75g are added, the mixture is continuously stirred for reaction for 8-9 h, the temperature is reduced to 25-30 ℃, 150ml of toluene is added, stirring and suction filtration are carried out, the filtrate is added into purified water for three times, saturated saline water is used for washing, and an organic phase is collected and added into a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 93.8%, purity 99.9%, maximum single impurity 0.01%.
Example 27
25.0g (88.5 mmol) of compound IV, 5.85g (97.35 mmol) of urea, 38.20g (230.1 mmol) of potassium iodide, 130ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80-85 ℃, 4.1g of activated carbon and 1.75g of heteropolyacid HSiW1.75g are added, the mixture is continuously stirred for reaction for 8-9 h, the temperature is reduced to 25-30 ℃, 150ml of toluene is added, stirring and suction filtration are carried out, the filtrate is added into purified water for three times, saturated saline water is used for washing, and an organic phase is collected and added with a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.8%, purity 99.9% and maximum single impurity 0.01%.
Example 28
25.0g (88.5 mmol) of compound IV, 5.58g (92.93 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 140ml of 1.4-dioxane, 2.1g of active carbon and 1.75g of heteropolyacid HSiW1.75g are added into a three-neck flask, the mixture is continuously stirred and reacted for 8 to 9 hours, cooled to 25 to 30 ℃, 150ml of toluene is added, stirring and suction filtration are carried out, the filtrate is added into purified water for three times, saturated saline water is used for washing, and an organic phase is collected and added into a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.7%, purity 99.8%, maximum single impurity 0.02%.
Example 29
25.0g (88.5 mmol) of compound IV, 13.29g (221.25 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 100ml of toluene, heating to 65-70 ℃, adding 5.6g of activated carbon, 1.75g of heteropolyacid HSiW1.75g, continuing to stir and react for 8-9 h, cooling to 25-30 ℃, adding 150ml of toluene, stirring, filtering, adding purified water into filtrate to wash for three times, washing with saturated saline, collecting an 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 cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.4%, purity 99.7% and maximum single impurity 0.02%.
Example 30
25.0g (88.5 mmol) of compound IV, 5.36g (88.5 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 130ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 100 to 105 ℃, 1.0g of active carbon and 1.75g of heteropolyacid HSiW1.75g are added, the mixture is continuously stirred for reaction for 8 to 9 hours, the temperature is reduced to 25 to 30 ℃, 150ml of toluene is added, stirring and suction filtration are carried out, the filtrate is added into purified water for three times, saturated saline water is used for washing, and an organic phase is collected and added into a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.5%, purity 99.7% and maximum single impurity 0.02%.
Example 31
25.0g (88.5 mmol) of compound IV, 13.82g (230.1 mmol) of urea, 16.16g (97.35 mmol) of potassium iodide, 130ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 80-85 ℃, 6.2g of activated carbon and 1.75g of heteropolyacid HSiW1.75g are added, the mixture is continuously stirred for reaction for 8-9 h, the temperature is reduced to 25-30 ℃, 150ml of toluene is added, stirring and suction filtration are carried out, the filtrate is added into purified water for three times, saturated saline water is used for washing, and an organic phase is collected and added into a proper amount of anhydrous sodium sulfate for drying. Filtering out a drying agent, concentrating under reduced pressure to about 75ml, adding 40ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 3 hours, leaching a filter cake with ethanol, leaching, and drying at a vacuum degree of 50 ℃ for 10 hours to obtain a compound V with a molar yield: 94.8%, purity 99.7% and maximum single impurity 0.02%.
Preparation of Compound VI
Example 32
35.0g (78.1 mmol) of compound V, 10.60g (79.7 mmol) of 1-bromo-2-butyne, 10.60g (82.0 mmol) of N, N-diisopropylethylamine and 200ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 70 to 75 ℃, stirred for 1.5 to 2h, after TLC detection is finished, the temperature is reduced to 20 to 25 ℃, the mixture is kept at a temperature and stirred for 1.0 to 1.5h, suction filtration is carried out, a filter cake is pulped and washed by ethanol, suction filtration is carried out, and the filter cake is dried for 10h at a vacuum degree of 50 ℃ to obtain the compound VI, wherein the molar yield is 97.7%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 33
35.0g (78.1 mmol) of compound V, 10.60g (79.7 mmol) of 1-bromo-2-butyne, 10.19g (78.9 mmol) of N, N-diisopropylethylamine, 200ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 70 to 75 ℃, the reaction is stirred for 1.5 to 2h, after TLC detection is finished, the temperature is reduced to 20 to 25 ℃, the reaction is kept at the temperature for 1.0 to 1.5h, suction filtration is carried out, a filter cake is pulped and washed by ethanol, suction filtration is carried out, and the filter cake is dried for 10h at the vacuum degree of 50 ℃ to obtain the compound VI, the molar yield is 97.1%, the purity is 99.8%, and the maximum single impurity is 0.01%.
Example 34
35.0g (78.1 mmol) of compound V, 10.60g (79.7 mmol) of 1-bromo-2-butyne, 25.23g (195.25 mmol) of N, N-diisopropylethylamine, 210ml of N, N-dimethylacetamide are added into a three-neck flask, the mixture is heated to 70 to 75 ℃, stirred for 1.5 to 2h, cooled to 20 to 25 ℃ after TLC detection reaction is finished, stirred for 1.0 to 1.5h at a temperature, pumped and filtered, a filter cake is beaten and washed by tetrahydrofuran, pumped and filtered, and dried for 10h at a vacuum degree of 50 ℃ to obtain the compound VI, wherein the molar yield is 97.7%, the purity is 99.7%, and the maximum single impurity is 0.02%.
Example 35
35.0g (78.1 mmol) of compound V, 10.60g (79.7 mmol) of 1-bromo-2-butyne, 10.09g (78.1 mmol) of N, N-diisopropylethylamine, 180ml of toluene are added into a three-neck flask, the mixture is heated to 70-75 ℃, the mixture is stirred for 1.5-2 h, after TLC detection is finished, the temperature is reduced to 20-25 ℃, the mixture is kept at the temperature for 1.0-1.5 h, suction filtration is carried out, a filter cake is pulped and washed by isopropanol, suction filtration is carried out, and the mixture is dried at the vacuum degree of 50 ℃ for 10h, thus obtaining the compound VI, the molar yield is 96.6%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 36
35.0g (78.1 mmol) of compound V, 10.60g (79.7 mmol) of 1-bromo-2-butyne, 26.24g (203.6 mmol) of N, N-diisopropylethylamine, 200ml of 1.4-dioxane are added into a three-neck flask, the mixture is heated to 70 to 75 ℃, the reaction is stirred for 1.5 to 2h, after TLC detection is finished, the temperature is reduced to 20 to 25 ℃, the reaction is kept at the temperature for 1.0 to 1.5h, suction filtration is carried out, a filter cake is pulped and washed by methanol, suction filtration is carried out, and the vacuum degree at 50 ℃ is dried for 10h, thus obtaining the compound VI, the molar yield is 97.7%, the purity is 99.7%, and the maximum single impurity is 0.02%.
Example 37
35.0g (78.1 mmol) of compound V, 10.49g (78.89 mmol) of 1-bromo-2-butyne, 11.33g (82 mmol) of potassium carbonate, 220ml of meta-xylene, heating to 70-75 ℃, stirring for 1.5-2 h, cooling to 20-25 ℃ after TLC detection reaction is finished, preserving heat, stirring for 1.0-1.5 h, suction filtering, pulping and washing a filter cake with methanol, suction filtering, and drying at 50 ℃ in vacuum for 10h to obtain the compound VI, wherein the molar yield is 97.2%, the purity is 99.8%, and the maximum single impurity is 0.01%.
Example 38
35.0g (78.1 mmol) of compound V, 25.97g (195.25 mmol) of 1-bromo-2-butyne, 6.89g (82 mmol) of sodium bicarbonate and 200ml of paraxylene are added into a three-neck flask, the mixture is heated to 70-75 ℃ and stirred for 1.5-2 h, after TLC detection reaction is finished, the temperature is reduced to 20-25 ℃, the mixture is kept at a temperature and stirred for 1.0-1.5 h, suction filtration is carried out, a filter cake is pulped and washed by isopropanol, suction filtration is carried out, and the mixture is dried for 10h at a vacuum degree of 50 ℃ to obtain the compound VI, wherein the molar yield is 97.8%, the purity is 99.7%, and the maximum single impurity is 0.02%.
Example 39
35.0g (78.1 mmol) of compound V, 10.39g (78.1 mmol) of 1-bromo-2-butyne, 8.30g (82 mmol) of triethylamine, 180ml of o-xylene are added into a three-neck flask, the mixture is heated to 70-75 ℃ and stirred for 1.5-2 h, after TLC detection reaction is finished, the temperature is reduced to 20-25 ℃, the mixture is kept at a temperature and stirred for 1.0-1.5 h, suction filtration is carried out, a filter cake is pulped and washed by acetone, suction filtration is carried out, and the mixture is dried for 10h at a vacuum degree of 50 ℃ to obtain the compound VI, wherein the molar yield is 96.9%, the purity is 99.8%, and the maximum single impurity is 0.01%.
Example 40
35.0g (78.1 mmol) of compound V, 27.0g (203.06 mmol) of 1-bromo-2-butyne, 10.60g (82.0 mmol) of N, N-diisopropylethylamine, 200ml of N, N-dimethylformamide are added into a three-neck flask, the mixture is heated to 70 to 75 ℃, the reaction is stirred for 1.5 to 2h, after TLC detection is finished, the temperature is reduced to 20 to 25 ℃, the reaction is kept at the temperature for 1.0 to 1.5h, suction filtration is carried out, a filter cake is pulped and washed by ethanol, suction filtration is carried out, and the filter cake is dried for 10h at the vacuum degree of 50 ℃ to obtain the compound VI, wherein the molar yield is 97.8%, the purity is 99.6%, and the maximum single impurity is 0.02%.
Preparation of Compound I
Example 41
35.0g (70.0 mmol) of compound VI, 19.6g (98.0 mmol) of R-3- (Boc-amino) piperidine, 280ml of toluene, heating to 60-65 ℃, stirring until the compound VI is dissolved, 15.3g (91.0 mmol) of lithium bis (trimethylsilyl) amide is added under the protection of nitrogen, the temperature is continuously controlled to 60-65 ℃, stirring and reacting for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150 ml multiplied by 2) for washing, 150ml of saturated saline solution for washing, and adding a proper amount of anhydrous sodium sulfate into an organic phase for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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
35.0g (70.0 mmol) of compound VI, 19.6g (98.0 mmol) of R-3- (Boc-amino) piperidine, 280ml of toluene, heating to 60-65 ℃, stirring until the compound VI is dissolved, 12.9g (77.0 mmol) of lithium bis (trimethylsilyl) amide is added under the protection of nitrogen, the temperature is continuously controlled to 60-65 ℃, stirring and reacting for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150 ml multiplied by 2) for washing, 150ml of saturated saline solution for washing, and adding a proper amount of anhydrous sodium sulfate into an organic phase for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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
35.0g (70.0 mmol) of compound VI, 19.6g (98.0 mmol) of R-3- (Boc-amino) piperidine, 280ml of toluene, heating to 60-65 ℃, stirring until the compound VI is dissolved, 23.4g (140 mmol) of lithium bis (trimethylsilyl) amide is added under the protection of nitrogen, the temperature is continuously controlled to 60-65 ℃, stirring and reacting for 5-6 h, after the TLC detection reaction is finished, cooling to 20-25 ℃, adding purified water (150 ml multiplied by 2) for washing, 150ml of saturated saline for washing, and adding a proper amount of anhydrous sodium sulfate into an organic phase for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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
35.0g (70.0 mmol) of compound VI, 19.6g (98.0 mmol) of R-3- (Boc-amino) piperidine, 280ml of toluene, heating to 60-65 ℃, stirring until the compound VI is dissolved, adding 11.71g (70 mmol) of lithium bis (trimethylsilyl) amide under the protection of nitrogen, continuously controlling the temperature to 60-65 ℃, stirring for reaction for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150 ml multiplied by 2) for washing, washing with saturated saline water (150 ml), and adding a proper amount of anhydrous sodium sulfate into an organic phase for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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
35.0g (70.0 mmol) of compound VI, 19.6g (98.0 mmol) of R-3- (Boc-amino) piperidine, 280ml of toluene, heating to 60-65 ℃, stirring until the compound VI is dissolved, 24.60g (147 mmol) of lithium bis (trimethylsilyl) amide is added under the protection of nitrogen, the temperature is continuously controlled to 60-65 ℃, stirring and reacting for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150 ml multiplied by 2) for washing, 150ml of saturated saline for washing, and adding a proper amount of anhydrous sodium sulfate into an organic phase for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 100ml of cyclohexane, cooling to 0-5 ℃, stirring and crystallizing for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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
35.0g (70.0 mmol) of compound VI, 25.24g (126.0 mmol) of R-3- (Boc-amino) piperidine, 280ml of toluene, heating to 60-65 ℃, stirring until the compound VI is dissolved, 15.3g (91.0 mmol) of lithium bis (trimethylsilyl) amide is added under the protection of nitrogen, the temperature is continuously controlled to 60-65 ℃, stirring and reacting for 5-6 h, after the TLC detection reaction is finished, cooling to 20-25 ℃, adding purified water (150 ml multiplied by 2) for washing, 150ml of saturated saline for washing, and adding a proper amount of anhydrous sodium sulfate into an organic phase for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 110ml of n-heptane, cooling to 0-5 ℃, stirring and crystallizing for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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 96.8%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 47
35.0g (70.0 mmol) of compound VI, 28.04g (140 mmol) of R-3- (Boc-amino) piperidine, 280ml of toluene, heating to 60-65 ℃, stirring until the compound VI is dissolved, 15.3g (91.0 mmol) of lithium bis (trimethylsilyl) amide is added under the protection of nitrogen, the temperature is continuously controlled to 60-65 ℃, stirring and reacting for 5-6 h, after TLC detection is finished, cooling to 20-25 ℃, adding purified water (150 ml multiplied by 2) for washing, 150ml of saturated saline for washing, and adding a proper amount of anhydrous sodium sulfate into an organic phase for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 120ml of n-hexane, cooling to 0-5 ℃, stirring for crystallization for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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 48
35.0g (70.0 mmol) of compound VI, 14.02g (70 mmol) of R-3- (Boc-amino) piperidine (70 mmol) and 280ml of toluene are added into a three-neck flask, the mixture is heated to 60 to 65 ℃ and stirred until the mixture is dissolved, 5.8g (91 mmol) of butyllithium is added under the protection of nitrogen, the temperature is continuously controlled to 60 to 65 ℃, the mixture is stirred and reacted for 5 to 6 hours, after the TLC detection reaction is finished, the temperature is reduced to 20 to 25 ℃, purified water (150 ml multiplied by 2) is added for washing, saturated saline water is added for washing 150ml, and an organic phase is added with a proper amount of anhydrous sodium sulfate for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 140ml of petroleum ether, cooling to 0-5 ℃, stirring and crystallizing for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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 96.5%, the purity is 99.9%, and the maximum single impurity is 0.01%.
Example 49
35.0g (70.0 mmol) of compound VI, 29.44g (147.0 mmol) of R-3- (Boc-amino) piperidine, 280ml of toluene, heating to 60-65 ℃, stirring until the compound VI is dissolved, 9.7g (91 mmol) of lithium diisopropylamide is added under the protection of nitrogen, continuing to control the temperature to 60-65 ℃, stirring and reacting for 5-6 h, cooling to 20-25 ℃ after TLC detection reaction is finished, adding purified water (150 ml multiplied by 2) for washing, saturated saline water for washing 150ml, and adding a proper amount of anhydrous sodium sulfate into an organic phase for drying. Filtering out the drying agent, concentrating under reduced pressure to about 80ml, adding 130ml of acetone, cooling to 0-5 ℃, stirring for crystallization for about 2H, suction filtering, pulping and washing a filter cake by ethanol (50 ml multiplied by 2), suction filtering, and drying at 50 ℃ under vacuum 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
31.71g of 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, 100ml of methanol, 60ml of water and nitrogen were added to the reaction flask, stirring was started under nitrogen atmosphere, and the mixture was heated to reflux for 6 to 9 hours, and then cooled to room temperature to precipitate a solid. Filtering, washing filter cake with a small amount of methanol, and drying to obtain linagliptin with a molar yield of 96.8%, a purity of 99.9% and a maximum single impurity of 0.01%.
Comparative example 1
Into a 2L three-necked flask, 908g (3.7 mol) of 8-bromo-3-methylxanthine, 574.1g (4.442 mol) of N, N-Diisopropylethylamine (DIEA), 591.1g (4.445 mol) of 1-bromo-2-butyne and 12L of acetone were charged. Stirring is started, heating is carried out until reflux reaction is carried out, and the reaction is finished after 4-6 hours. The reaction solution is cooled to room temperature, pumped and filtered, and filter cakes are washed by 4L of methanol to obtain pale yellow solid, and 3-methyl-7- (2-butyn-L-yl) -8-bromo-xanthine is obtained after drying, the yield is 97.4%, the purity is 91.7%, and the maximum single impurity is 2.5%.
550g (1.851 mol) of the product of the above step 463.3g (2.405 mol) of 2-chloromethyl-4-methylquinazoline, 332.6g (2.407 mol) of potassium carbonate and 6L (dimethylacetamide, DMAC) were charged into a 10L reaction vessel. Stirring, heating to 75-95 ℃ for reaction, cooling to below 65 ℃ after the reaction is finished for 7-10 hours, adding 3L of methanol, stirring for 0.5-1 hour, filtering, and washing a filter cake with 1L of methanol. The obtained filter cake is pulped by 2L of water, filtered, washed by 1L of water and 1L of methanol to obtain a yellow filter cake, and dried to obtain 1- [ (4-methyl quinazoline-2-yl) methyl ] -3-methyl-7- (2-butine-1-yl) -8-bromoxanthine, wherein the yield is 79.4%, the purity is 93.5%, and the maximum single impurity is 2.7%.
To a 10L reactor was added 700g (1.54 mol) of the product of the above step 464.1g (2.32 mol) (R) -3-Boc-aminopiperidine, 854g (6.18 mol) of potassium carbonate and 3.5L of acetonitrile. Stirring is started, heating is carried out until reflux (micro reflux), the reaction temperature is 80-85 ℃, and the reaction is finished after 28-35 hours. 4.5L of hot water at 70 ℃ is slowly added, and the mixture is stirred at room temperature and slowly cooled, so that solid is separated out. And (5) filtering. The solid obtained by filtration is beaten by 8L hot water at 65-75 ℃, slowly cooled to room temperature and filtered. The filter cake was washed with water and dried to give 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 in 80.6% yield, 94.6% purity, maximum mono-impurity 2.2%.
Comparative example 2
54g (0.182 mol) of 8-bromo-7- (2-butynyl) -3-methylxanthine, 40g (0.2 mol) of 2-chloromethyl-4-methylquinazoline, 50g (0.364 mol) of potassium carbonate and 0.6g (0.04 mol) of potassium iodide were introduced into a 2L reactor, followed by 270ml of NMP. Stirring and heating to 40-50 ℃, and stirring for 2-3 h. After completion of the TLC detection, 36.5g (0.192 mol) of R-3- (Boc-amino) piperidine was added thereto, and the reaction was continued for 3 to 4 hours. After TLC detection (DCM: meoh=20:1) was completed, heating was stopped and cooled to room temperature.
Post-treatment: 540ml of methylene chloride and 1080ml of water were added, and the mixture was stirred until the solid was dissolved. The aqueous layer was separated, extracted with (270 ml×2) DCM and the organic phases combined; 500ml of 1% acetic acid aqueous solution was added to wash 1 time, and the mixture was washed 1 time with saturated sodium chloride to obtain an organic phase. The organic phase is evaporated to dryness and is added with 300ml of ethanol, heated to reflux and dissolved, slowly added with 300ml of water dropwise, cooled to 20-30 ℃, stirred for 2 hours, filtered by suction, and the filter cake is washed with 20ml of absolute 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 with an HPLC purity of 93.5% and a maximum mono-impurity of 2.8%.
Comparative example 3
150ml of dimethyl sulfoxide, 10g of 8-bromo-7- (2-butynyl) -3-methylxanthine, 7.13g of 2-chloromethyl-4-methylquinazoline, 9.30g of potassium carbonate and 0.61g of tetrabutylammonium bromide were added to the reaction flask. Heating to 60 ℃ under stirring, and reacting for 6 hours to obtain a first reaction liquid. 8.2g of compound R-3- (Boc-amino) piperidine is added into the first reaction solution, the temperature is raised to 75 ℃ to 80 ℃ for reaction for 16 hours, and the reaction is finished. 200ml of water is dripped into the reaction system, the temperature is reduced to 25 ℃ after the dripping is finished, and the mixture is stirred for 2 hours; filtration and drying of the resulting solid at 45℃under vacuum gives 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 a molar yield of 85.4%, purity: 90.7% and the maximum single impurity is 2.1%.
Comparative example 4
Sodium (23.0 g,1.0 mol) and absolute ethanol (500 ml) were added to a 2L reaction flask, stirred at room temperature for 1h, methyl urea (37.1 g,0.50 mol) and ethyl cyanoacetate (34.9 ml,0.50 mol) were added, and heated under reflux for 6h. The reaction solution was cooled to room temperature, and ethanol was recovered under reduced pressure. Distilled water (100 ml) is added into the residue to dissolve, 4mol/L hydrochloric acid (200 ml) is added dropwise to adjust the pH to 7, ice bath stirring is carried out for 1h, filtration is carried out, a filter cake is recrystallized by water, and white crystal 6-amino-1-methyl uracil is obtained, the molar yield is 90.2 percent, and the purity is: 94.7% and the maximum single impurity is 2.5%;
6-amino-1-methyluracil (60.0 g,430.0 mmol), distilled water (300 ml) and acetic acid (120 ml) were added to a 1L reaction flask, and then an aqueous solution (240 ml) of the prepared sodium nitrite (43.5 g,0.63 mol) was added dropwise thereto, and the reaction was stirred at 50℃for 1 hour. The reaction solution is cooled to room temperature, the stirring reaction is continued for 1h, the filtration is carried out, the filter cake is washed by ice water (100 ml) and ice ethanol (500 ml) in sequence, and the purple solid 6-amino-5-nitroso-1-methyl uracil is obtained after decompression and drying, the molar yield is 91.5 percent, and the purity is: 92.5 percent, the maximum single impurity is 2.3 percent;
6-amino-5-nitroso-1-methyl uracil (60.0 g,0.35 mol) and 25% ammonia water (600 ml) are added into a 2L reaction bottle, sodium dithionite (215.0 g,1.23 mol) is added in batches, the reaction is stirred for 1h at 50 ℃, the reaction liquid is cooled to room temperature, the stirring reaction is continued for 8h, filtration is carried out, a filter cake is washed by ice water (100 ml) and ice ethanol (500 ml) in sequence, and the filter cake is dried under reduced pressure to obtain light yellow solid 5, 6-diamino-1-methyl uracil with 70.4 mol yield and purity: 94.9% of the total amount of single impurities 2.1%;
5, 6-diamino-1-methyl uracil (40.0 g,0.26 mol) and distilled water (1L) are added into a 2L reaction bottle, formic acid (29.5 ml,0.77 mol) is added dropwise, heating reflux is carried out for 3H under the protection of nitrogen, cooling is carried out to room temperature, sodium hydroxide (51.2 g,1.28 mol) aqueous solution is added, reflux is continued for 1H, reaction liquid is cooled to room temperature, 2mol/L hydrochloric acid (300 ml) is added to adjust to pH7, ice bath stirring is carried out for 1H, filtration is carried out, the obtained filter cake is washed by ice water (100 ml) and ice ethanol (200 ml) in sequence, decompression drying is carried out, light yellow solid 3-methyl-1H-purine-2, 6 (3H, 7H) -dione is obtained, molar yield is 71.2 percent, purity: 93.7%, maximum single impurity 2.8%;
To a 1L reaction flask were added 3-methyl-1H-purine-2, 6 (3H, 7H) -dione (30.0 g,0.18 mol), sodium acetate (29.6 g,0.36 mol) and glacial acetic acid (460 ml), bromine (11.1 ml,0.22 mol) was added dropwise, the mixture was stirred at 65℃for 2 hours, cooled to room temperature, filtered, and the filter cake was washed successively with acetic acid (50 ml) and water (100 ml), dried under reduced pressure to give 3-methyl-8-bromo-1H-purine-2, 6 (3H, 7H) -dione as a white solid, molar yield 78.0%, purity: 91.2 percent, the maximum single impurity is 2.6 percent;
3-methyl-8-bromo-1H-purine-2, 6 (3H, 7H) -dione (30.0 g,0.12 mol), N-diisopropylethylamine (DIEPA, 26.3ml,0.16 mol) and DMF (360 ml) were added to a 1L reaction flask, 1-bromo-2-butyne (11.8 ml,0.13 mol) was added dropwise, stirred at room temperature for 12H, distilled water (300 ml) was added, stirred for 0.5H, filtered, and the filter cake was washed sequentially with ice water (100 ml) and ice-ethanol (100 ml), 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 a molar yield of 79.0% purity: 94.6% and the maximum single impurity is 2.4%;
in a 1L reaction flask were charged 8-bromo-7- (2-butynyl) -3-methyl-1H-purine-2, 6 (3H, 7H) -dione (20.0 g,67.0 mmol), DMF (300 ml), anhydrous potassium carbonate (18.6 g,135.0 mmol) and 2-chloromethyl-4-methyl quinazoline (13.0 g,67.0 mmol), and the mixture was stirred at 90℃for 6 hours. Cooled to room temperature, anhydrous potassium carbonate (27.9 g,0.20 mol) and (R) -3-aminopiperidine dihydrochloride (17.3 g,0.1 mol) were added, and the temperature was raised to 80℃and the reaction was stirred for 8 hours. Cooled to room temperature, DMF was evaporated under reduced pressure, dichloromethane (100 ml) was added, stirred for 0.5h, filtered and the filter cake was washed with dichloromethane (50 ml). The filtrate was concentrated, 10% glacial acetic acid (300 ml) was added thereto, stirred for 0.5h, and washed with dichloromethane (100 ml. Times.3). Adding 10% sodium carbonate solution (200 ml) to water, adjusting pH to 8, extracting with dichloromethane (100 ml×2), concentrating under reduced pressure, dissolving the crude product in dichloromethane, adding active carbon (10% -25%), refluxing under heating for 1h, filtering to remove active carbon while hot, concentrating the filtrate, and adding dichloromethane into the residue: mixing petroleum ether (1:10) mixed solvent, stirring and pulping for 1h, filtering, drying filter cake at 45 ℃ to obtain white solid linagliptin with the molar yield of 57.0% and the purity: 95.7% and the maximum single impurity is 2.3%.
Comparative example 5
400ml of acetic acid, 100g of 3-methyl-xanthine (0.6019 mol) and 74g of sodium acetate (0.90 mol) were charged at 25 to 30℃into a round-bottomed flask equipped with a stirrer. The mixture was stirred for 5-10 minutes and cooled to l 0-15 ℃. 144.2g of liquid bromine (0.90 mol) was slowly added dropwise to the reaction mixture for about 60 minutes and the temperature was raised to 60-65 ℃; the mixture is kept for 3 to 4 hours. After the reaction was completed, the reaction mixture was cooled to 15 to 20 ℃ and 800ml of DMF aqueous solution was slowly added. The reaction mixture was kept stirred for 2 to 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 to a round bottom flask. 700ml of methanol is added to the wet material and the temperature is raised to 60-65 ℃; and maintained 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 rinsed with methanol. The wet material is dried in vacuum at 40-45 ℃ for 5-8 hours to obtain the target compound 8-bromo-3-methyl-xanthine with a molar yield of 88%, a purity of 92.3% and a maximum mono-impurity of 2.8%.
1000ml of DMF, 62g of N, N-diisopropylethylamine (0.6128 mol) and 100g of 8-bromo-3-methyl-xanthine (0.4081 mol) were added at 20-30℃to a 5 liter round bottom flask equipped with overhead stirrer, hot bag and dropping funnel and stirred for 5-10 minutes to obtain a clear solution. 81.45g of 1-bromo-2-butyne (0.6128 mol) was slowly added to the reaction mixture at 25-30℃and the reaction mixture was maintained at the same temperature for 3-4 hours. After the reaction was completed, 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 moist material was fed to a round-bottomed 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 rinsed with 100ml of methanol; drying at 40-45 deg.c for 5-8 hr to obtain 3-methyl-7- (2-butyn-l-yl) -8-bromo-xanthine with molar yield of 80.2%, purity of 95.3% and 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 to 30℃to a 5 liter round bottom flask equipped with an overhead stirrer and a hot bag, and the temperature was raised to 75 to 80 ℃. The reaction mixture is maintained at 75-80℃for 2-3 hours. After the reaction was completed, the reaction mixture was cooled to 45 to 50 ℃. 600ml of methanol was slowly added to the reaction mixture and stirred at 45-50℃for 60 minutes. The solid was filtered and washed with 200ml of methanol followed by DMF aqueous slurry. Feeding the moist material to a round-bottomed flask, and feeding 700ml of methanol to the round-bottomed flask; the temperature was raised to 65 ℃ and maintained for 60 minutes. The reaction mass was cooled to 40-45 ℃ and held for 60 minutes. The solid was filtered and rinsed with 200ml methanol. The wet material is dried for 5 to 8 hours at the temperature of 40 to 45 ℃ to obtain l- [ (4-methyl-quinazoline-2-yl) methyl ] -3-methyl-7- (2-butine-l-yl) -8-bromine-xanthine, the molar yield is 79.6 percent, the purity is 96.5 percent, and the maximum single impurity is 2.7 percent.
800ml of DMSO, 53.2g of (R) 3-Boc-aminopiperidine (0.2654 mol), 100g of 1- [ (4-methyl-quinazolin-yl) methyl ] -3-methyl-7- (2-butyn-l-yl) -8-bromo-xanthine (0.2212 mol), 0.5g of potassium iodide and 91.5g of potassium carbonate (0.6620 mol) were fed at 20-30℃to a 5 liter round bottom flask equipped with an overhead stirrer and a hot bag. The temperature of the reaction mixture was raised to 80-85 ℃ and maintained at the same temperature for 4-5 hours. After the reaction was completed, the reaction mixture was cooled to 30-35 ℃, 1600ml of cooled DMF water was slowly added and stirred at 25-35 ℃ for 60 minutes. The solid was filtered and rinsed with 200ml DM water. The wet material was again rinsed with DMF water. The moist material was fed to a round-bottomed flask and 700ml of dichloromethane were fed, stirred for 3 minutes and the layers separated. The organic layer was washed with DMF water and treated with activated carbon, followed by filtration through hyflo (celite) and washing with dichloromethane. The solvent was distilled off at 35-40℃and in a further round-bottomed flask 800ml of hexane/cyclohexane and the above dichloromethane solution were slowly added at 35-40℃and stirred for 30-60 minutes at 30-35 ℃. The solid was filtered and washed with 200ml of hexane/cyclohexane. The wet material is dried in vacuum at 40-45 ℃ for 5-8 hours to obtain l- [ (4-methyl-quinazoline-2-yl) methyl ] -3-methyl-7- (2-butine-l-yl) -8- [ (R) -3- (tert-butoxycarbonylamino) -piperidine-l-yl ] -xanthine, the molar yield is 85.5%, the purity is 93.5%, and the maximum mono-impurity is 3.2%.

Claims (6)

1. A linagliptin intermediate compound of formula IV:
Figure QLYQS_1
。
2. the process for the preparation of intermediate compound iv according to claim 1, characterized in that it comprises 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 temperature control condition to obtain an intermediate IV, wherein the reaction route is as follows:
Figure QLYQS_2
。
3. the process according to claim 2, wherein the base is selected from the group consisting of organic bases selected from triethylamine,N,N-diisopropylethylamine, 4-dimethylaminopyridine, 1, 8-diazabicyclo [5.4.0]One or two of undec-7-ene, potassium acetate and sodium acetate; the inorganic base is one or two selected from potassium carbonate, sodium bicarbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate.
4. The method according to claim 2, wherein the organic solvent is selected from one or a combination of DMSO, NMP, DMF, 1, 4-dioxane and toluene; the reaction temperature is 70-100 ℃.
5. Use of compound iv according to claim 1 for the preparation of linagliptin.
6. A process for the preparation of the 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 of compound IV according to claim 1, comprising the steps of:
Step 1: adding the compound IV, urea and an iodine source into an organic solvent, and adding a catalyst and activated carbon for reaction to obtain an intermediate V;
step 2: nucleophilic substitution is carried out on the intermediate V and 1-bromo-2-butyne under alkaline conditions to obtain an intermediate VI;
step 3: intermediate VI is reacted with R-3- (Boc-amino) piperidine under the action of a base to give 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 synthesized by the following route:
Figure QLYQS_3
catalyst selection TMSI, TMSOTf, coCl in step 1 2 One or two of HSiW and HPW;
in the step 1, the iodine source is selected from one or two of potassium iodide, sodium iodide and tetrabutylammonium iodide;
the base used in step 2 is selected from potassium carbonate, sodium bicarbonate, triethylamine,N,N-one or both of diisopropylethylamine;
the alkali used in the step 3 is selected from one or two of butyl lithium, diisopropyl lithium amide and di (trimethylsilyl) lithium amide.
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