CN104788482A - A method of preparing 2-aminopyrimidine-5-boronic acid pinacol ester - Google Patents

Abstract

The invention discloses a method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester. Starting from the raw material 2-chloropyrimidine, under the catalysis of BF ₃ -Et ₂ O, bromination occurs with NBS to obtain 2-chloro- 5-bromopyrimidine; then react this intermediate with n-Bu ₃ MgLi at -20～-10°C, and then add methoxyboronic acid pinacol ester or isopropoxyboronic acid pinacol ester to obtain 2 -Chloropyrimidine-5-boronic acid pinacol ester; then add ammonia water or ammonia methanol solution, seal reaction at 80-100°C to obtain 2-aminopyrimidine-5-boronic acid pinacol ester. The synthesis process of the invention has mild conditions, avoids ultra-low temperature reaction, and the reaction can be carried out continuously, and the pure product can be obtained only by simple recrystallization in the final product.

Description

A method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester

technical field

The invention relates to a method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester, which belongs to the field of synthesis of pharmaceutical intermediates.

technical background

The type I PI3K inhibitor Apitolisib and the kinase inhibitor Votrient, known to be on the market or under research, both contain a 2-aminopyrimidine group, and more studies still regard this fragment as an important structural unit. As one of the key intermediates, 2-aminopyrimidine-5-boronic acid pinacol ester has a synthetic method with public information: mainly including 1) using 2-amino-5-iodopyrimidine and pinacol borane in Pd( PPh) _catalyzed by (reference: Org.Biomol.Chem., 2011, 9, 3139) or 2-amino-5-bromopyrimidine and biboronic acid pinacol ester coupling in the presence of PdCl ₂ dppf (reference: WO 2012 /109423 A1); 2) After using the same raw material to protect the amino group with Boc (reference: CN102399235A and CN102367260A) or diphenylmethylene (reference: US 2008/0269523 A1), (or directly without protection, reference: Eur .J.Org.Chem.2007, 5712) using butyllithium/triisopropyl borate/ultra-low temperature reaction at -78°C to form boric acid first, then after deprotection, then react with pinacol to form ester.

The above method: 1) the amount of coupling catalyst is large, the cost is high, and the product has heavy metal residues; 2) when the amino group is protected by benzophenone, the condensation product cannot be obtained according to the first step of the patent method, and Boc protection needs to be used. The nitrogen is completely protected; the yield of the direct reaction method without protection of the amino group is unstable and the reproducibility is poor, and all such methods have the disadvantage of requiring ultra-low temperature reaction.

Contents of the invention

The technical problem to be solved by this invention is to provide a new method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester, comprising the following steps:

In the first step, under the catalysis of BF ₃ -Et ₂ O, 2-chloropyrimidine and NBS are refluxed in acetonitrile or ethylene glycol dimethyl ether solvent to obtain 2-chloro-5-bromopyrimidine;

In the second step, 2.5M n-BuLi was added to n-BuMgBr by keeping the temperature at -20～-10°C to prepare n-Bu ₃ MgLi, and then the 2-chloro-5- Bromopyrimidine was dissolved in tetrahydrofuran and dropped into the above solution, kept warm for 1 hour, added dropwise methoxy pinacol borate or isopropoxy borate pinacol ester, kept warm for 1 hour, the solution rose to room temperature, stirred overnight, added Saturated ammonium chloride quenched, extracted with ethyl acetate, and evaporated to dryness to obtain 2-chloropyrimidine-5-boronic acid pinacol ester;

The third step is to add the 2-chloropyrimidine-5-boronic acid pinacol ester obtained in the second step into ammonia water or ammonia methanol in the autoclave, and react at 80-100°C for 6 hours, spin the solution to dry and add tetrahydrofuran or acetic acid The ethyl ester was dissolved and filtered, and the solvent was evaporated to dryness again, and methanol was added to recrystallize to obtain 2-aminopyrimidine-5-boronic acid pinacol ester.

Further, in the first step, the molar ratio of 2-chloropyrimidine to NBS and BF ₃ -Et ₂ O is 1:1-1.5:0.05-0.3.

Further, in the second step, the molar ratio of n-BuLi to n-BuMgBr is 2:1 _; The molar ratio of propoxy borate pinacol ester is 1:0.4-0.5:1.1-1.5.

Further, in the third step, the molar ratio of 2-chloropyrimidine-5-boronic acid pinacol ester to ammonia water or ammonia methanol is 1:2-5.

The reaction formula is as follows:

Beneficial effects of the invention

The synthesis process of the invention has mild conditions, avoids ultra-low temperature reaction, and the reaction can be carried out continuously, and the pure product can be obtained only by simple recrystallization in the final product.

Detailed ways

Example 1

A method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester, comprising the following steps:

Add 11.5g (0.1mol) of 2-chloropyrimidine, 21.3g (0.12mol) of brominating reagent NBS and 80mL of acetonitrile into the reaction flask, add catalytic amount of BF ₃ -Et ₂ O 2.8g (0.02mol) at room temperature, and complete the addition After that, the temperature was raised to reflux for 5-8 hours. After the reaction was detected by TLC, the temperature was lowered, and the insoluble solid was filtered off. After the solvent was distilled under reduced pressure, ethyl acetate was added _to dissolve, and then 45 mL of saturated _Na2CO3 solution was added dropwise to wash, and the The organic layer was taken out, and 60 mL of ethyl acetate was added to the aqueous layer. After layering again, the organic layers were combined, washed with saturated brine, and spin-dried to obtain 14.1 g of light yellow 2-chloro-5-bromopyrimidine solid, which was directly used in the next step. Reacting. ¹ H-NMR (400 MHz, CDCl3): 8.70 (s, 2H).

Under the protection of nitrogen, add 29.2mL n-BuMgBr solution (1M tetrahydrofuran solution) prepared in advance to the reaction flask and cool to -20°C, then maintain the internal temperature at -20～-10°C and add 23.4mL n-BuLi (2.5 M hexane solution), after the dropwise addition was completed and incubated and stirred for 30 minutes, the 2-chloro-5-bromopyrimidine 14.1g (73mmol) and anhydrous tetrahydrofuran 40mL obtained in the first step were incubated for 1 hour after the dropwise addition, and TLC detected that the exchange was complete , then maintain this temperature dropwise anhydrous tetrahydrofuran solution of methoxy borate pinacol ester 13.3g (84mmol), keep warm for 1 hour, the solution naturally rises to room temperature, stir overnight, add saturated ammonium chloride to quench and adjust the pH to be 4 -5, extracted with 70 mL of ethyl acetate, combined the organic layers and evaporated to dryness to obtain 12.1 g of solid crude product of 2-chloropyrimidine-5-boronic acid pinacol ester, the GC content was greater than 95%, and the yield was 69%, which could be directly used in the next reaction ; ¹ H-NMR (400 MHz, CDCl3): 8.60 (s, 2H), 1.29 (s, 12H).

In a 100mL autoclave, 12.1g (50mmol) of 2-chloropyrimidine-5-boronic acid pinacol ester obtained in the second step was added to 22.5g 28% ammonia water (180mmol), and the reaction was sealed at 100°C for 6 hours, and the solution was spin-dried Then add 150mL of ethyl acetate to dissolve and filter, evaporate the solvent again and add methanol to recrystallize to obtain 8.6g of white crystalline solid 2-aminopyrimidine-5-boronic acid pinacol ester with a yield of 78%. ¹ H-NMR (400MHz, CDCl3): 8.58(s, 2H), 5.80(s, 2H), 1.32(s, 12H);

Example 2

A method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester, comprising the following steps:

Add 11.5g (0.1mol) of 2-chloropyrimidine, 21.3g (0.12mol) of brominating reagent NBS and 80mL of ethylene glycol dimethyl ether into the reaction flask, and add catalytic amount of BF ₃ -Et ₂ O 4.2g (0.03 mol), after the addition was completed, the temperature was raised to reflux for 5-8 hours. After the reaction was detected by TLC, the temperature was lowered, and the insoluble solid was filtered off. After the solvent was distilled under reduced pressure, ethyl acetate was added to dissolve, and then 45 mL of saturated Na ₂ CO was added dropwise. _3. The solution was washed, the organic layer was separated, and 60 mL of ethyl acetate was added to the aqueous layer. After layering again, the organic layers were combined, washed with saturated saline, and spin-dried to obtain 13.2 g of light yellow 2-chloro-5-bromopyrimidine solid. used directly in the next reaction. ¹ H-NMR (400 MHz, CDCl3): 8.70 (s, 2H).

Under the protection of nitrogen, under the protection of nitrogen, add 29.2mL of n-BuMgBr solution (1M tetrahydrofuran solution) prepared in advance to the reaction bottle and cool it to -20°C, then maintain the internal temperature at -20～-10°C and add 23.4mL n-BuMgBr dropwise -BuLi (2.5M hexane solution), after the dropwise addition was completed and incubated and stirred for 30 minutes, 14.1g (73mmol) of 2-chloro-5-bromopyrimidine obtained in the first step and 40mL of anhydrous tetrahydrofuran were incubated for 1 hour after the dropwise addition. TLC detects that the exchange is complete, then maintains the temperature and drips anhydrous tetrahydrofuran solution of 15.6 g (84 mmol) of isopropoxy pinacol borate ester, and keeps warm for 1 hour. The solution naturally rises to room temperature, stirs overnight, and quenches with saturated ammonium chloride. The pH was adjusted to 4-5, extracted with 80 mL of ethyl acetate, and the combined organic layers were evaporated to dryness to obtain 10.5 g of solid crude product of 2-chloropyrimidine-5-boronic acid pinacol ester, the GC content was greater than 96%, and the yield was 64%, which could be directly Into the next reaction; ¹ H-NMR (400MHz, CDCl3): 8.60 (s, 2H), 1.29 (s, 12H).

In a 100mL autoclave, 7.2g (30mmol) of 2-chloropyrimidine-5-boronic acid pinacol ester obtained in the second step was added to 9.42mL 7M ammonia methanol solution (66mmol), and the reaction was sealed at 80°C for 8 hours, and the solution was spun After drying, add 100mL tetrahydrofuran to dissolve, filter, evaporate the solvent again, and add methanol to recrystallize to obtain 4.4g of white crystalline solid 2-aminopyrimidine-5-boronic acid pinacol ester, with a yield of 66%. ¹ H-NMR (400 MHz, CDCl3): 8.58 (s, 2H), 5.80 (s, 2H), 1.32 (s, 12H).

Claims (4)

1. a method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester, is characterized in that comprising the following steps: In the first step, under the catalysis of BF ₃ -Et ₂ O, 2-chloropyrimidine and NBS are refluxed in acetonitrile or ethylene glycol dimethyl ether solvent to obtain 2-chloro-5-bromopyrimidine; In the second step, 2.5M n-BuLi was added to n-BuMgBr by keeping the temperature at -20～-10°C to prepare n-Bu ₃ MgLi, and then the 2-chloro-5- Bromopyrimidine was dissolved in tetrahydrofuran and dropped into the above solution, kept warm for 1 hour, added dropwise methoxy pinacol borate or isopropoxy borate pinacol ester, kept warm for 1 hour, the solution rose to room temperature, stirred overnight, added Saturated ammonium chloride quenched, extracted with ethyl acetate, and evaporated to dryness to obtain 2-chloropyrimidine-5-boronic acid pinacol ester; The third step is to add the 2-chloropyrimidine-5-boronic acid pinacol ester obtained in the second step into ammonia water or ammonia methanol solution in the autoclave, and react at 80-100°C for 6 hours. After the solution is spin-dried, add tetrahydrofuran Or dissolve in ethyl acetate and filter, evaporate the solvent again and add methanol for recrystallization to obtain 2-aminopyrimidine-5-boronic acid pinacol ester. 2. A method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester according to claim 1, characterized in that: in the first step, 2-chloropyrimidine and NBS, BF ₃ -Et ₂ O The molar ratio is 1:1-1.5:0.05-0.3. 3. a kind of method for preparing 2-aminopyrimidine-5-boronic acid pinacol ester according to claim 1, is characterized in that: in the described second step, the mol ratio of described n-BuLi and n-BuMgBr is 2:1; the molar ratio of 2-chloro-5-bromopyrimidine to n-Bu ₃ MgLi, pinacol methoxy borate or pinacol isopropoxy borate is 1:0.4-0.5:1.1 -1.5. 4. a kind of method for preparing 2-aminopyrimidine-5-boric acid pinacol ester according to claim 1, is characterized in that: in the described 3rd step, 2-chloropyrimidine-5-boric acid pinacol ester and The molar ratio of ammonia water or ammonia to methanol is 1:2-5.