CN110054626B

CN110054626B - Preparation method of pyridopyrimidine derivative

Info

Publication number: CN110054626B
Application number: CN201810048437.0A
Authority: CN
Inventors: 戚聿新; 范岩森; 刘月盛; 刘会锋
Original assignee: Xinfa Pharmaceutical Co Ltd
Current assignee: Xinfa Pharmaceutical Co Ltd
Priority date: 2018-01-18
Filing date: 2018-01-18
Publication date: 2020-04-28
Anticipated expiration: 2038-01-18
Also published as: CN110054626A

Abstract

The invention discloses a preparation method of a pyridopyrimidine derivative, which comprises the steps of preparing 1-cyclopentyl-4-methylpyridine-2, 6- (1H,5H) -diketone by amidation condensation of 3-methyl-2-glutaconic acid diester and cyclopentylamine, and then condensing the 1-cyclopentyl-4-methylpyridine-2, 6- (1H,5H) -diketone with a methylene reagent (N, N-dimethylformamide diol) and urea in a one-pot method to obtain 2-hydroxy-5-methyl-8-cyclopentylpyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone. Then preparing 2-chloro-5-methyl-6-bromo-8-cyclopentyl pyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone through chlorination reaction and bromination reaction. The method does not use trihalopyrimidine with higher price, palladium salt catalyst and 3-boric acid ester substituted ethyl crotonate, and has the advantages of cheap and easily obtained raw materials, easy operation, stable reaction yield, less three wastes, high reaction atom economy, low cost and easy green industrial production.

Description

Preparation method of pyridopyrimidine derivative

Technical Field

The invention relates to a preparation method of a key intermediate pyridopyrimidine derivative of palbociclib, in particular to a preparation method of 2-chloro-5-methyl-6-bromo-8-cyclopentyl pyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone, belonging to the technical field of medical chemistry.

Background

Palbociclib (VII), the trade name of which is Ibrance and the English name of which is Palbociclib and the Chinese name of which is Palbociclib or Palbociclib, is a breakthrough breast cancer drug developed by the company Perey, is approved by the United states FDA on 2/3 days 2015, is used for selectively inhibiting cyclin-dependent kinases 4 and 6(CDK4/6), restoring cell cycle control and blocking tumor cell proliferation, and is combined with an aromatase inhibitor letrozole for first-line treatment of ER +/HER 2-postmenopausal metastatic breast cancer. Palbociclib is the first CDK4/6 inhibitor to market worldwide. The CAS number of Pabociclib is [571190-30-2], and the chemical name is: 6-acetyl-8-cyclopentyl-5-methyl-2- [ [5- (piperazin-1-yl) pyridin-2-yl ] amino ] -8H-pyrido [2,3-D ] pyrimidin-7-one. In the research and development route reported by the original research company, 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridino [2,3-d ] pyrimidine-8-hydro-7-one (I) is used as a key intermediate to prepare palbociclib, and the related chemical structural formula is as follows:

WO2008032157, US20160002223, CN105130986 and CN105622638 all use 2-chloro-5-methyl-6-bromo-8-cyclopentyl pyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone (II) to prepare Pabociclib, and describe in detail the preparation method of compound II, namely using 2, 4-dichloro-5-bromo (iodo) pyrimidine as raw material, carrying out 4-position substitution reaction with cyclopentylamine to obtain 2-chloro-4-cyclopentylamino-5-bromo (iodo) pyrimidine, then carrying out Suzuki reaction coupling and lactamization with 3-boric acid ester substituted ethyl crotonate under the catalysis of palladium salt to obtain 2-chloro-5-methyl-8-cyclopentyl pyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone, then NBS or bromine is used for preparing 2-chloro-5-methyl-6-bromo-8-cyclopentyl pyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone through bromination reaction, the total yield is 35.9 percent to 60.6 percent, and the reaction process is described as a synthetic route 1.

The raw material 2, 4-dichloro-5-bromo (iodo) pyrimidine used in the preparation route is high in price and not easy to obtain, the palladium salt catalyst and the 3-boric acid ester substituted ethyl crotonate are high in price, the yield is unstable, the reaction atom economy is low, and the green industrial production and cost reduction of the intermediate I are not facilitated.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a preparation method of a key intermediate pyridopyrimidine derivative required by the preparation of palbociclib by using cheap and easily available raw materials and a simplified process flow, namely a preparation method of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridino [2,3-d ] pyrimidine-8-hydro-7-one (I).

The technical scheme of the invention is as follows:

a process for the preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] pyrimidin-8-hydro-7-one (I) comprising the steps of:

(1) preparing 1-cyclopentyl-4-methylpyridine-2, 6- (1H,5H) -diketone (III) by amidation condensation of 3-methyl-2-pentenedioic acid diester (II) and cyclopentylamine in the presence of a solvent and a catalyst; condensing the obtained compound (III) and a methylene reagent in a solvent to prepare 1-cyclopentyl-4-methyl-5-dialkyl amino methylene pyridine-2, 6- (1H,5H) -diketone (IV), and condensing with urea to obtain 2-hydroxy-5-methyl-8-cyclopentyl pyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone (V);

(2) reacting 2-hydroxy-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one (V) with a chlorinating agent in the presence of a solvent or an excess of the chlorinating agent to prepare 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidin-8-hydro-7-one (VI);

(3) 2-chloro-5-methyl-8-cyclopentylpyridino [2,3-d ] pyrimidine-8-hydro-7-one (VI) is subjected to bromination reaction in a solvent to prepare 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridino [2,3-d ] pyrimidine-8-hydro-7-one (I).

Wherein R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl or sec-butyl; r' is methyl or ethyl.

According to the method of the invention, the preferable process conditions and the material dosage ratio in each step are as follows:

preferably, in the step (1), the solvent is one of toluene, xylene, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and chlorobenzene or a combination thereof, and the mass ratio of the solvent to the compound of the formula II is (2-20): 1;

preferably, the catalyst in step (1) is one of piperidine, 4-methylpiperidine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] -5-nonene (DBN) or a combination thereof; the mass ratio of the dosage of the catalyst to the compound of the formula II is 0.3-5%;

preferably, the molar ratio of the compound II to the cyclopentylamine in the step (1) (0.9-3.0) is 1; carrying out amidation reaction at a programmed temperature for 2-8 hours at 50-100 ℃, and then for 2-8 hours at 80-150 ℃;

preferably, the methylene reagent in the step (1) is N, N-dimethylformamide acetal, and further preferably N, N-dimethylformamide dimethyl acetal and N, N-dimethylformamide dimethyl acetal; the molar ratio of the methylene reagent to the compound of the formula II is (1.0-3.0): 1;

preferably, the temperature of the methylene reaction in the step (1) is 80-130 ℃, and the condensation reaction time is 3-10 hours;

preferably, the molar ratio of the urea to the compound of formula II in step (1) is (1.0-3.0): 1; the cyclization reaction temperature of the urea condensed pyrimidine is 40-110 ℃, and the reaction time is 3-8 hours; further preferably, stirring and reacting for 2-3 hours at the temperature of 60-95 ℃;

preferably, in the step (2), the solvent is one of toluene, xylene, 1, 2-dichloroethane and acetonitrile or a combination thereof, and the mass ratio of the solvent to the compound of the formula V is (0-8): 1;

preferably, the chlorinating reagent in the step (2) is one of phosphorus oxychloride, phosphorus pentachloride, solid phosgene, diphosgene, phosgene and thionyl chloride or a combination thereof, and the molar ratio of the chlorinating reagent to the compound of the formula V is (2.0-8.0): 1;

preferably, the chlorination reaction temperature in the step (2) is 20-120 ℃, the reaction time is 2-18 hours, and further preferably, the chlorination reaction temperature is 60-100 ℃, and the reaction time is 4-8 hours;

preferably, the solvent in the step (3) is N, N-Dimethylformamide (DMF), acetic acid, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, dioxane or a combination thereof, and the mass ratio of the solvent to the compound of the formula VI is (5-15: 1;

preferably, the brominating agent in the step (3) is one of bromine, N-bromosuccinimide (NBS) or a combination thereof, and the molar ratio of the brominating agent to the compound of the formula VI is (1.0-3.0): 1;

preferably, the bromination reaction temperature in the step (3) is 20-120 ℃, the reaction time is 2-20 hours, and further preferably, the bromination reaction temperature is 60-100 ℃, and the reaction time is 3-11 hours.

The invention prepares 1-cyclopentyl-4-methylpyridine-2, 6- (1H,5H) -diketone (III) by amidation condensation of 3-methyl-2-pentenedioic acid diester (II) and cyclopentylamine in the presence of solvent and catalyst, then condensing with a methylene reagent (N, N-dimethylformamide glycol) to prepare 1-cyclopentyl-4-methyl-5-dialkyl amino methylene pyridine-2, 6- (1H,5H) -diketone (IV), and condensing with urea to obtain 2-hydroxy-5-methyl-8-cyclopentyl pyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone (V), wherein the process is finished by a one-pot method. The obtained 2-hydroxy-5-methyl-8-cyclopentylpyridino [2,3-d ] pyrimidine-8-hydrogen-7-ketone (V) is subjected to chlorination reaction and bromination reaction in sequence to prepare 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridino [2,3-d ] pyrimidine-8-hydrogen-7-ketone (I), and can be used for preparing palbociclib. The process of the present invention employs the following reaction scheme 2:

The invention has the beneficial effects that:

1. the method does not use trihalogenated pyrimidine with higher price and 3-boric acid ester substituted ethyl crotonate, and the used raw materials are cheap and easy to obtain and operate.

2. The method does not use a palladium salt catalyst, is favorable for avoiding heavy metal residues of products, utilizes cyclopentylamine amidation, is favorable for the stability of intermediates in each step, and is favorable for the specificity of functional groups for carrying out target reaction, so that the obtained products have high purity, stable yield, purity of over 99 percent, total yield of 71 percent, less three wastes, high reaction atom economy, and are favorable for the cost reduction and green industrial production of the intermediate I.

Drawings

FIG. 1 is an HPLC chart of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] pyrimidin-8-hydro-7-one (I) prepared in example 1.

Detailed Description

The following examples are provided to fully illustrate the technical aspects of the present invention in detail, but the present invention is not limited to the following examples. Any non-inventive arrangements or embodiments derived from the embodiments of the present invention or any variations of the non-inventive implementation sequences based on the embodiments of the present invention by those skilled in the art are within the scope of the present invention.

The 3-methyl-2-pentenedioic acid diester used in the examples is provided by the medical company of Jinan Ruihui, and the content is more than 99.0%, wherein the impurity content of the 3-methyl-2-glutaric acid diester is less than 0.5%, the impurity content of the 3-methyl-3-hydroxy-2-glutaric acid diester is less than 0.2%, and the rest of the raw materials and reagents are commercial products. In the examples, "%" is a mass percentage unless otherwise specified.

Example 1: preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] opyrimidin-8-hydro-7-one (I)

Step (1): preparation of 2-hydroxy-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidin-8-hydro-7-one (V)

Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a distillation apparatus were charged 120 g of N, N-dimethylformamide, 17.2 g (0.1 mol) of dimethyl 3-methyl-2-pentenedioate, 8.6 g (0.1 mol) of cyclopentylamine, 0.2 g of DBU, and the mixture was stirred at 80 to 85 ℃ for 4 hours and at 110 to 115 ℃ for 4 hours while distilling off the formed methanol. Cooling to 50-60 ℃, adding 14.3 g (0.12 mol) of N, N-dimethylformamide dimethyl acetal (DMF-DMA), reacting at 110-115 ℃ for 5 hours, cooling to 50-60 ℃, adding 10.0 g (0.17 mol) of urea, reacting at 80-85 ℃ for 5 hours, decompressing, distilling and recovering part of solvent (80-85 g of solvent), cooling to room temperature, adding 300 g of water, filtering, washing a filter cake with 20 g of isopropanol, and drying to obtain 21.7 g of white solid 2-hydroxy-5-methyl-8-cyclopentylpyridin [2,3-d ] pyrimidine-8-hydro-7-one, wherein the yield is 88.6% and the liquid phase purity is 99.7%.

Step (2): preparation of 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidin-8-hydro-7-one (VI)

42.5 g (0.3 mol) of phosphorus oxychloride and 12.3 g (0.05 mol) of 2-hydroxy-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one are added into a 250 ml four-neck flask with a thermometer and mechanical stirring, the mixture is stirred and reacted for 4 hours at 120 ℃, the excess phosphorus oxychloride is recovered under reduced pressure, the temperature is reduced to 60 to 65 ℃, the obtained viscous liquid is slowly poured into 300 g of ice water, filtered, the filter cake is washed by 20 g of methyl tert-butyl ether and dried, and 12.3 g of 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one are obtained, the yield is 93.2 percent and the liquid phase purity is 99.8 percent.

And (3): preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] opyrimidin-8-hydro-7-one (I)

Adding 85 ml of DMF, 13.2 g (0.05 mol) of 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one into a 250 ml four-neck flask with a thermometer and a mechanical stirrer, dissolving 13.36 g (0.075 mol) of NBS in 25 ml of DMF, dropwise adding the DMF solution of NBS into the reaction flask at room temperature, heating to 60 ℃, stirring for reaction for 5 hours, adding 10% sodium bisulfite aqueous solution (5 g of sodium sulfite in 45 ml of water), cooling to 0-5 ℃, stirring for 3 hours, filtering, pulping and washing the crude product with 60 ml of isopropanol, filtering, drying to obtain 14.8 g of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one, the yield was 86.1% and the purity was 99.6%.

The nuclear magnetic data of the product obtained are as follows:

¹HNMR(400MHz，DMSO-d6)δ：

9.19(s,1H),5.86–5.77(m,1H),2.64(s,3H),2.17–1.99(m,4H),1.90–1.82(m,2H),1.69–1.59(m,2H)。

the HPLC profile is shown in FIG. 1:

peak watch

Detector A280nm

Peak number	Retention time	Area of	Height	Percentage of area
					1	4.360	1290	122	0.036
2	4.988	1381	167	0.039
					3	5.720	3538017	361500	99.693
4	6.955	1719	148	0.048
					5	8.000	6537	413	0.184
Total of		3548944	362349	100.000

Example 2: preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] opyrimidin-8-hydro-7-one (I)

Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a distillation apparatus, 150 g of toluene, 20.0 g (0.1 mol) of diethyl 3-methyl-2-pentenedioate, 8.6 g (0.1 mol) of cyclopentylamine, 0.2 g of DBU were charged, and the mixture was stirred at 80 to 85 ℃ for 4 hours and at 100 to 105 ℃ for 4 hours while distilling off the formed ethanol. Cooling to 50-60 ℃, adding 14.3 g (0.12 mol) of N, N-dimethylformamide dimethyl acetal (DMF-DMA), reacting at 100-105 ℃ for 7 hours, cooling to 50-60 ℃, adding 10.0 g (0.17 mol) of urea, reacting at 85-90 ℃ for 7 hours, carrying out reduced pressure distillation to recover the solvent, cooling to room temperature, adding 300 g of water, filtering, washing a filter cake with 20 g of isopropanol, and drying to obtain 20.5 g of white solid 2-hydroxy-5-methyl-8-cyclopentylpyridine [2,3-d ] pyrimidine-8-hydrogen-7-ketone, wherein the yield is 83.7% and the liquid phase purity is 99.3%.

150 g of toluene, 35.5(0.3 mol) of thionyl chloride, 12.3 g (0.05 mol) of 2-hydroxy-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one were placed in a 500 ml four-neck flask equipped with a thermometer and mechanically stirred to react at 70-75 ℃ for 7 hours, the excess thionyl chloride and toluene were recovered under reduced pressure, the temperature was reduced to 40-45 ℃, the resulting viscous liquid was slowly poured into 300 g of ice water, filtered, the filter cake was washed with 20 g of methyl t-butyl ether and dried to obtain 12.1 g of 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one with a yield of 91.8% and a liquid phase purity of 99.6%.

200 ml of chloroform, 39.6 g (0.15 mol) of 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidin-8-hydro-7-one are added to a 500 ml four-neck flask equipped with a thermometer and mechanically stirred, stirred uniformly, 14.61 ml (45.6 g, 0.285 mol) of bromine is added dropwise to the reaction flask, stirred at 50 ℃ for 8 hours, after the reaction is finished, 30% sodium bisulfite aqueous solution (22 g of sodium sulfite dissolved in 52 ml of water) is added to the reaction flask, the organic phase is evaporated and the solvent is recovered, the remaining solid is separated by layers, slurried and washed with isopropanol to obtain 45.3 g of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one, the yield was 88.0% and the purity was 99.7%.

Example 3: preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] opyrimidin-8-hydro-7-one (I)

Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a distillation apparatus were charged 120 g of N, N-dimethylformamide, 25.5 g (0.1 mol) of di-tert-butyl 3-methyl-2-pentenedioate, 8.6 g (0.1 mol) of cyclopentylamine, 0.3 g of DBU, and the mixture was stirred at 90 to 95 ℃ for 4 hours and at 120 to 125 ℃ for 4 hours, while the resulting tert-butanol was distilled off. Cooling to 50-60 ℃, adding 14.3 g (0.12 mol) of N, N-dimethylformamide dimethyl acetal (DMF-DMA), reacting at 110-115 ℃ for 5 hours, cooling to 50-60 ℃, adding 10.0 g (0.17 mol) of urea, reacting at 90-95 ℃ for 5 hours, decompressing, distilling and recovering part of solvent (80-85 g of solvent), cooling to room temperature, adding 300 g of water, filtering, washing a filter cake with 20 g of isopropanol, and drying to obtain 21.2 g of white solid 2-hydroxy-5-methyl-8-cyclopentylpyridin [2,3-d ] pyrimidine-8-hydro-7-one, wherein the yield is 86.5% and the liquid phase purity is 99.6%.

50 g of toluene, 21.5 g (0.15 mol) of phosphorus oxychloride, 12.3 g (0.05 mol) of 2-hydroxy-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one and 105 ℃ are added into a 250 ml four-neck flask with a thermometer and mechanical stirring, the mixture is stirred and reacted for 6 hours at 110 ℃, the excessive toluene and the phosphorus oxychloride are recovered under reduced pressure, the temperature is reduced to 60 to 65 ℃, the obtained viscous liquid is slowly poured into 300 g of ice water, filtered, the filter cake is washed by 20 g of methyl tertiary butyl ether and dried to obtain 12.1 g of 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one, the yield is 91.7 percent and the liquid phase purity is 99.5 percent.

100 ml of chloroform, 13.2 g (0.05 mol) of 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one, 10.7 g (0.06 mol) of NBS and stirring at 55-60 ℃ for 6 hours are added into a 250 ml four-neck flask which is provided with a thermometer and is mechanically stirred, 30 g of 10% sodium bisulfite aqueous solution is added after the reaction is finished, the mixture is cooled to 0-5 ℃, stirred for 3 hours and filtered, 60 ml of isopropanol is used for pulping and washing the crude product, and 15.1 g of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one is obtained after filtration and drying, the yield is 88.0 percent and the purity is 99.4 percent.

Claims

1. A process for the preparation of 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] pyrimidin-8-hydro-7-one (I) comprising the steps of:

(3) preparing 2-chloro-5-methyl-6-bromo-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one (I) by bromination reaction of 2-chloro-5-methyl-8-cyclopentylpyridin [2,3-d ] opyrimidine-8-hydro-7-one (VI) in a solvent;

2. A process for the preparation of a compound of formula i as claimed in claim 1, wherein step (1) comprises either or both of the following conditions:

A1) the solvent is one of toluene, xylene, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide and chlorobenzene or a combination thereof, and the mass ratio of the solvent to the compound of the formula II is (2-20) to 1;

A2) the catalyst is one of piperidine, 4-methylpiperidine, 4-dimethylaminopyridine, 1, 8-diazabicycloundecen-7-ene, 1, 5-diazabicyclo [4.3.0] -5-nonene or a combination thereof; the mass ratio of the dosage of the catalyst to the compound of the formula II is 0.3-5%.

3. A process for the preparation of a compound of formula i as claimed in claim 1, wherein step (1) comprises either or both of the following conditions:

B1) the molar ratio (0.9-3.0) of the compound II to the cyclopentylamine is 1;

B2) the amidation reaction is carried out at a programmed temperature, the reaction time is 2-8 hours at 50-100 ℃, and then the reaction time is 2-8 hours at 80-150 ℃.

4. A process for the preparation of a compound of formula i as claimed in claim 1, wherein step (1) comprises any one or more of the following conditions:

C1) the methylene reagent is N, N-dimethylformamide diol;

C2) the molar ratio of the methylene reagent to the compound of the formula II is (1.0-3.0): 1;

C3) the temperature of the methylene reaction is 80-130 ℃, and the time of the condensation reaction is 3-10 hours.

5. The process for the preparation of a compound of formula i according to claim 4, wherein the transmethylating agent is N, N-dimethylformamide dimethyl acetal, N-dimethylformamide dimethyl acetal.

6. A process for the preparation of a compound of formula i as claimed in claim 1, wherein step (1) comprises either or both of the following conditions:

D1) the molar ratio of the urea to the compound shown in the formula II is (1.0-3.0): 1;

D2) the cyclization reaction temperature of the urea condensed pyrimidine is 40-110 ℃, and the reaction time is 3-8 hours.

7. The process for preparing a compound of formula I as claimed in claim 6, wherein the reaction temperature of the cyclization reaction of urea condensed pyrimidine is 60-95 ℃ and the reaction time of stirring is 2-3 hours.

8. The process for preparing a compound of formula I according to claim 1, wherein in step (2), the solvent is one of toluene, xylene, 1, 2-dichloroethane, acetonitrile or a combination thereof, and the mass ratio of the solvent to the compound of formula V is (0-8): 1.

9. The method for preparing the compound of formula I according to claim 1, wherein the chlorinating reagent in step (2) is one of phosphorus oxychloride, phosphorus pentachloride, phosgene solid, diphosgene, phosgene, thionyl chloride or a combination thereof, and the molar ratio of the chlorinating reagent to the compound of formula V is (2.0-8.0): 1.

10. The process for preparing a compound of formula I as claimed in claim 1, wherein the chlorination reaction in step (2) is carried out at a temperature of 20 to 120 ℃ for 2 to 18 hours.

11. A process for the preparation of a compound of formula i according to claim 10, wherein the chlorination reaction is carried out at a temperature of 60 ℃ to 100 ℃ for a time of 4 to 8 hours.

12. A process for the preparation of a compound of formula i as claimed in claim 1, wherein step (3) comprises either or both of the following conditions:

E1) the solvent is one or the combination of N, N-dimethylformamide, acetic acid, acetonitrile, dichloromethane, chloroform, tetrahydrofuran and dioxane, and the mass ratio of the solvent to the compound shown in the formula VI is (5-15): 1;

E2) the reagent used in the bromination reaction is one or the combination of bromine and N-bromosuccinimide, and the molar ratio of the reagent used in the bromination reaction to the compound shown in the formula VI is (1.0-3.0): 1.

13. The process for preparing a compound of formula i according to claim 1, wherein the bromination reaction in the step (3) is carried out at a temperature of 20 to 120 ℃ for 2 to 20 hours.

14. A process for the preparation of a compound of formula i according to claim 13, wherein the bromination is carried out at a temperature of 60 ℃ to 100 ℃ for a period of 3 to 11 hours.