Preparation methods for palbociclib free base crystal form A and crystal form B

Abstract

Disclosed is a preparation method for a Palbociclib free base crystal form A as shown in Formula I, comprising the following steps: treating a Palbociclib free base and/or a Palbociclib salt compound by using an inorganic base in a water solvent at the temperature of 35 to 100C. to obtain a Palbociclib free base crystal form A, the water solvent being water or mixed solvent obtained by water and an organic solvent capable of being mixed and disclosed in the water. Also disclosed is a preparation method for a Palbociclib free base crystal form B, comprising the following steps: treating a Palbociclib salt compound by using an inorganic base in a water solvent at the temperature of 0 to 20 C. to obtain a Palbociclib free crystal form B, the water solvent being water or a mixed solvent obtained by water and an organic solvent capable of being mixed and dissolved in the water. The method is safe and convenient in operation and low in pollution, and facilitates industrial production.

Claims

1. A method for preparing crystal form B of palbociclib of the Formula I: the method comprising: ##STR00002## treating a pharmaceutically acceptable salt of palbociclib with a base selected from the group consisting of ammonia, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate in an aqueous solvent selected from the group consisting of water and a co-solvent mixture consisting of water and a water-miscible organic solvent selected from the group consisting of methanol, ethanol, isopropanol and tetrahydrofuran, at a temperature in the range of 0 C. to 20 C., to obtain crystal form B of palbociclib; wherein crystal form B of palbociclib exhibits an X-ray powder diffraction pattern comprising characteristic peaks having 2 angles selected from the group consisting of 6.094, 6.692, 11.049, 12.154, 12.940, 16.498, 19.879, 22.684, and 26.778.

2. The method according to claim 1, wherein the pharmaceutically acceptable salt of palbociclib is selected from the group consisting of palbociclib isethionate, palbocklib hydrochloride, palbociclib sulfate, and palbociclib methane sulfonate or a combination thereof.

3. The method according to claim 1, wherein the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

4. The method according to claim 1, wherein the water-miscible organic solvent is selected from the group consisting of methanol, ethanol and isopropanol.

5. The method according to claim 1, wherein the volume ratio of water and the water-miscible organic solvent in the aqueous solvent is 1:0 to 1:20.

6. The method according to claim 1, wherein the volume ratio of water and the water-miscible organic solvent in the aqueous solvent is 1:0 to 1:2.

7. The method according to claim 1, wherein the treatment is performed at a pH greater than 8.0.

8. The method according to claim 1, wherein the treatment is performed at a pH greater than 10.0.

9. The method according to claim 1, wherein the treatment is performed at a temperature in the range of 5 C. to 15 C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) In order to illustrate the examples of the present invention and the technical solutions of the prior arts more clearly, the drawings used in the examples and the prior art. are briefly described below. Obviously, the drawings in the following description are only some examples of the present invention, For those ordinary skilled in the art, other drawings can be also obtained according to these drawings without any creative work.

(2) FIG. 1 shows an X-ray powder diffraction pattern of a crystal form A of palbociclib.

(3) FIG. 2 shows an X-ray powder diffraction pattern of a crystal form B of palbociclib.

DETAILED DESCRIPTION OF THE INVENTION

(4) To illustrate the purposes, technical solutions and advantages of the present invention, the present invention will be further described in detail with the following accompanying drawings and examples. Obviously, the described examples are only a part of the examples of the present invention, rather than all of the examples. All other examples obtained by an ordinary skilled person in the art based on the examples of the present invention without creative efforts shall be within the scope of the present invention.

(5) X-Ray Powder Diffraction (XRPD) Analysis Conditions: BRUKER D8 Advance Measurement (Luke Corporation) is used with specific voltage and current: 40 kV, 40 mA. Goniometer: vertical goniometer, radius 280 mm; slit: DS=2, SS=, mask=15 mm, RS=5.0 mm; detector: LYNXEYE detector; scan mode: continuous scan; scan range: 3 to 40; count time per step: 0.2 seconds; total scan time: 390 seconds.

EXAMPLE 1

(6) Preparation of palbociclib isethionate: 1.00 g of tert-butyl 4-[6-[(6-(1-butoxyvinyl)-8-cyclopentyl-7,8-dihydro-5-methyl-7-oxopyridino [2,3-D]pyrimidin-2-yl)amino]-3-pyridyl]-1-piperazine carboxylate was added into a 2 L three-necked flask, and then 1.0 L methanol, 90.4 g isethionic acid and 50 ml water were added. The mixture was heated to 60-65 C. and stirred for 3-4 hours. The system was then cooled to 0-5 C., crystallized, and suction filtrated to obtain a yellow solid. The resulting solid was purified via recrystallization from a methanol/water mixed solvent, dried to obtain 94.5 g (yield: 81.5%) yellow fluffy solid, with HPLC purity of 99.8%

EXAMPLE 2

(7) Preparation of palbociclib hydrochloride: 100 g tert-butyl 4-[6-[(6-(1-butoxyvinyl)-8-cyclopentyl-7,8-dihydro-5-methyl -7-oxopyridino [2,3-D]pyrimidin-2-yl)amino]-3-pyridyl]-1-piperazine carboxylate was added into a 2 L three-necked flask, and then 1.0 L methanol, 41.5 ml hydrochloric acid and 100 ml water were added. The mixture was heated to 60-65 C. and stirred for 3-4 hours. The system was then cooled to 0-5 C., crystallized, and suction filtrated to obtain a yellow solid. The resulting solid was purified via recrystallization from a methanol/water mixed solvent, dried to obtain 63.4 g (yield: 72.4%) yellow fluffy solid, with HPLC purity of 99.8%,

EXAMPLE 3

(8) Preparation of palbociclib free base: 40.0 g palbociclib isethionate (prepared in example 1) was dissolved into 700 ml water to form palbociclib isethionate solution. 20.0 g sodium carbonate was dissolved into 320 ml water and stirred at 30 C., and then palbociclib isethionate solution was added dropwise into the solution of sodium carbonate with stirring, and a yellow solid was precipitated. After that, the mixture was stirred at a constant temperature of 30 C. for 1 hour. Suction filtration and drying was introduced. to obtain 0.97 g (yield: 97.0%) yellow solid, with HPLC purity of 99.8%.

EXAMPLE 4

(9) Preparation of a crystal form A of palbociclib free base: 92.0 g palbociclib isethionate (prepared in example 1) was dissolved in 1.8 L water to form palbociclib isethionate solution. 13.1 g sodium hydroxide was dissolved into 1.8 L water and stirred at 50 C.-60 C., and then the palbociclib isethionate solution was added dropwise into the solution of sodium hydroxide with stirring, and a yellow solid was precipitated. After that (sample was taken and monitored by XRPD, a crystal form A had been formed), the mixture was stirred at a constant temperature of 50 C.-60 C. for 2 hours. Suction filtration and drying was introduced to obtain 55.7 g (yield: 94.7%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 5

(10) Preparation of a crystal form A of palbociclib free base: 1.0 g palbociclib free base (prepared in example 3) and 0.7 g isethionic acid were dissolved into 24 ml mixed solvent of water and methanol to form a solution of palbociclib isethionate. 0.43 g sodium carbonate was dissolved in 32 ml water with stirring at 35 C., and the solution of the palbociclib isethionate was added dropwise into the solution of sodium carbonate with stirring, then a yellow solid was precipitated. After that (sample was taken and monitored by XRPD, crystal form A had been formed), the mixture was stirred at a constant temperature of 35 C. for 1 hour. Suction filtration and drying was introduced to give 0.97 g (yield: 97.0%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 6

(11) Preparation of a crystal form A of palbociclib free base: 1.6 g palbociclib hydrochloride (prepared in example 2) was dissolved into 40 ml water to form palbociclib hydrochloride solution. 0.38g sodium hydroxide was dissolved in 30 ml water and stirred at 100 C., and the palbociclib hydrochloride solution was added dropwise into the solution of sodium hydroxide with stirring, then a yellow solid was precipitated. After that, suction filtration and drying was introduced to obtain 1.32 g (yield: 96%) yellow solid, with HPLC purity of 99.9%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 7

(12) Preparation of a crystal form A of palbociclib free base: 1.0 g palbociclib free base (prepared in example 3) and 0.3 g sulfuric acid were dissolved into 25 ml mixed solvent of water and ethanol to form a solution of palbociclib sulfate. 0.51 g potassium carbonate was dissolved in 32 ml water with stirring at 40 C., and the solution of the palbociclib sulfate was added dropwise into the potassium carbonate solution with stirring, then a yellow solid was precipitated. After that, the mixture was stirred at a constant temperature of 40 C. for 1 hour. Suction filtration and drying was introduced to obtain 0.96 g (yield: 96.0%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 8

(13) Preparation of a crystal form A of palbociclib free base: 1.0 g palbociclib free base (prepared in example 3) and 0.45 g methane sulfonic acid were dissolved into 25 ml mixed solvent of water and isopropyl alcohol to form a solution of palbociclib methanesulfonate. 0.21 g potassium hydroxide was dissolved in 30 ml water with stirring at 55 C., and the solution of the palbociclib methanesulfonate was added dropwise into the potassium hydroxide solution with stirring, then a yellow solid was precipitated. After that, suction filtration and drying was introduced to obtain 0.95 g (yield: 95.0%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 9

(14) Preparation of a crystal form A of palbociclib free base: 8.0 g palbociclib isethionate (prepared in example 1), 2.0 g palbociclib hydrochloride (prepared in example 2) and 3 g palbociclib free base (prepared in example 3) were dissolved into 250 ml mixed solvent of water and tetrahydrofuran to form a mixed palbociclib solution. 10 g ammonia was dissolved in 150 ml water with stirring at 35 C., and the mixed palbociclib solution was added dropwise to the aqueous ammonia solution with stirring, then a yellow solid was precipitated. After that, the mixture was stirred at a constant temperature of 35 C. for 0.5 hour. Suction filtered and drying was introduced to obtain 9.1 g (yield: 92.4%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 10

(15) Preparation of a crystal form B of palbociclib free base: 1.0 g palbociclib isethionate (prepared in example 1) was dissolved into 9 ml water to form a mixture, and the mixture was slowly added dropwise to a solution of 0.22 g sodium hydroxide and 32 ml water. The temperature was controlled at 20 C. and an orange-yellow solid was precipitated (the sample was taken and monitored by XRPD, crystal form B had been formed). The mixture was stirred at 20 C. overnight, then suction filtration, rinsing with water, and drying was introduced to obtain 0.60 g (yield: 93.9%) yellow solid. The product was analyzed by XRPD as the crystal form B.

EXAMPLE 11

(16) Preparation of a crystal form B of palbociclib free base: 1.0 g palbociclib free base (prepared in example 3) and 0.7 g isethionic acid were dissolved into 24 ml mixed solvent of water and methanol to form a solution of palbociclib isethionate, 0.45 g sodium carbonate was dissolved in 40 ml water with stirring at 0 C., and the solution of palbociclib isethionate was added dropwise to the sodium carbonate solution with stirring, then a yellow solid was precipitated. The mixture was stirred at a constant temperature of 0 C. for 1 hour. Suction filtration and drying was introduced to obtain 0.97 g (yield: 97.0%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form B.

EXAMPLE 12

(17) Preparation of a crystal form B of palbociclib free base: A mixture of 130 g palbociclib isethionate (prepared in example 1) and 22.5 g palbociclib hydrochloride (prepared in example 2) was dissolved into 1.5 L water and transferred into a 5 L four-necked flask. 150 g ammonia water and 1.5 L water was mixed and added dropwise into the above mixture at 25 C. A large amount of solids precipitated. Stirring for 3 hours, suction filtration, rinsing with water and drying was introduced to obtain 96.1 g (yield: 93.6%) yellow solid, with HPLC purity of 99.9%. The product was analyzed by XRPD as the crystal form B.

EXAMPLE 13

(18) Preparation of a crystal form B of palbociclib free base: 0.80 g palbociclib hydrochloride (prepared in example 2) and 0.3 g palbociclib free base (prepared in example 3) were dissolved into 25 ml mixed solvent of water and isopropyl alcohol to form a mixed palbociclib solution. 0.19 g sodium hydroxide was dissolved in 15 ml water with stirring at 10 C., and the mixed palbociclib solution was added dropwise into solution of sodium hydroxide with stirring, then a yellow solid was precipitated. After that, suction filtration and drying was introduced to obtain 0.85 g (yield: 85.8%) yellow solid, with HPLC purity of 99.9%. The product was analyzed by XRPD as the crystal form B.

EXAMPLE 14

(19) Preparation of a crystal form B of palbociclib free base: 2.0 g palbociclib free base (prepared in example 3) and 0.7 g sulfuric acid were dissolved into 50 ml mixed solvent of water and ethanol to form a solution of palbociclib sulfate. 1.0 g potassium carbonate was dissolved in 35 ml water with stirring at 15 C., and the solution of palbociclib sulfate was added dropwise to the potassium carbonate solution with stirring, then a yellow solid was precipitated. After that, the mixture was stirred at a constant temperature of 15 C. for 1 hour. Suction filtration and drying was introduced to obtain 1.85 g (yield: 92.50%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form B.

EXAMPLE 15

(20) Preparation of a crystal form B of palbociclib free base: 1.0 g palbociclib free base (prepared in example 3) and 0.45 g methane sulfonic acid were dissolved into 25 ml mixed solvent of water and tetrahydrofuran (volume ratio of 1:0.15) to form a solution of palbociclib methanesulfonate. 0.25 g potassium hydroxide was dissolved in 30 ml water with stirring at 15 C., and the solution of palbociclib methanesulfonate was added dropwise to the potassium hydroxide solution with stirring, then a yellow solid was precipitated, After that, suction filtration and drying was introduced to obtain 0.94 g (yield: 94.0%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form B.

EXAMPLE 16

(21) Preparation of a crystal form A of palbociclib free base: 150 g palbociclib isethionate (prepared in example 1) was dissolved into 1.51. water and transferred into a 5 L four-necked flask. 150 g ammonia water and 1.5 L water was mixed and added dropwise into the four-necked flask at 25 C. A large amount of solids were precipitated, stirred for 3 hours (the sample was taken and monitored by XRPD, crystal form B had been formed). The mixture was heated to 50 C.-60 C. and stirred for 4 hours, then suction filtration, rinsing with water and drying was introduced to obtain 89.3 g (yield: 93.2%) yellow solid, with HPLC purity of 99.9%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 17

(22) Preparation of a crystal form A of palbociclib free base: 0.5 g sodium hydroxide was dissolved into 20 ml water and heated to 100 C. 1.0 g crystal form B (prepared in example 12) was added thereto and stirred for 1 hour. Suction filtration and drying was introduced to obtain 0.97g (yield: 97.0%) yellow solid, with HPLC purity of 99.8%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 18

(23) Preparation of a crystal form A of palbociclib free base: 0.5 g sodium carbonate was dissolved into 20 ml mixed solvent of water and methanol (volume ratio 1:2) and heated to 50 C. 1.0 g crystal form B (prepared in example 12) was added thereto and stirred for 1 hour. Suction filtration and drying was introduced to obtain 0.98 g (yield: 98.0%) yellow solid, with HPLC purity of 99.9%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 19

(24) Preparation of a crystal form A of palbociclib free base: 0.5 g potassium carbonate was dissolved into 30 ml mixed solvent of water and ethanol (volume ratio 1:1) and heated to 60 C. 1.0 g crystal form B (prepared in example 12) was added thereto and stirred for 1 hour. Suction filtration and drying was introduced to obtain 0.99 g (yield: 99.0%) yellow solid, with HPLC purity of 99.9%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 20

(25) Preparation of a crystal form A of palbociclib free base: 5 g potassium hydroxide was dissolved into 300 ml mixed solvent of water and isopropyl alcohol (volume ratio 1:0.2) and heated to 35 C. 10.0 g crystal form B (prepared in example 12) was added thereto, and 0.2 g crystal form A (prepared in example 4) was added as seed crystal. The mixture was stirred for 3 hours. Suction filtration and drying was introduced to obtain 10.0 g (yield: 98.0%) yellow solid, with HPLC purity of 99.9%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 21

(26) Preparation of a crystal form A of palbociclib free base: 5 g ammonia water was dissolved into 300 ml mixed solvent of water and tetrahydrofuran (volume ratio 1:0.1) and heated to 35 C. A mixture of 10.0 g crystal form. B (prepared in example 12) and crystal form A (prepared in example 4) was added thereto and stirred for 3 hours. Suction filtration and drying was introduced to obtain 9.9 g (yield: 99.0%) yellow solid, with HPLC purity of 99.9%. The product was analyzed by XRPD as the crystal form A.

EXAMPLE 22

(27) Characteristic peaks of a crystal form A of palbociclib free base: The X-ray powder diffraction pattern of a crystal form A of palbociclib free base (prepared in example 4) was detected by using Cu-K radiation. The 20 angles and relative intensities of the characteristic peaks are shown in Table 1.

(28) TABLE-US-00002 TABLE 1 Characteristic peaks of a crystal form A of palbociclib free base 2 relative intensities 4.966 12.8% 7.912 14.5% 10.193 100% 11.479 5.4% 14.023 12.1%

EXAMPLE 23

(29) Characteristic peaks of a crystal form B of palbociclib free base: The X-ray powder diffraction pattern of a crystal form B of palbociclib free base (prepared in example 10) was detected by using Cu-K radiation. The 29 angles and relative intensities of the characteristic peaks are shown in Table 1.

(30) TABLE-US-00003 TABLE 2 Characteristic peaks of palbociclib free base crystal form B 2 relative intensities 6.094 100.0% 6.692 16.7% 11.049 21.4% 12.154 13.1% 12.940 18.3% 16.498 14.1% 19.879 19.0% 22.684 11.0% 26.778 12.9%

COMPARATIVE EXAMPLE 1

(31) Preparation of a crystal form A of palbociclib free base: according to the method disclosed in WO2014128588A1, 1.0 eq. palbociclib free base in n-butanol (320 ml, 16 ml/g) and anisole (480 ml, 24 ml/g) was heated to 95-100 C. and remained insoluble. The seed crystal of crystal form A was required to be added into the reaction system to obtain a crystal form A of palbociclib free base.

COMPARATIVE EXAMPLE 2

(32) Preparation of a crystal form B of palbociclib free base: according to the method disclosed in WO2014128588A1, in the case of adding seed crystal, stable crystal form B cannot be obtained.

(33) It can be seen from the above examples and comparative examples that the preparation method of crystal form A and crystal form B of palbociclib free base provided according to the present invention can be performed in a solvent of water or a mixed solvent of water and water-miscible organic solvent to obtain crystal form A and crystal form B of palbociclib free base, with a high yield and a high purity under milder experimental conditions. The method provided by the present invention has the advantages of mild condition, easy to control, and stable scaling up. Stable crystal form A and crystal form B can be obtained, and solids in both crystal forms can realize industrial production.

(34) The above are only the preferred examples of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention should be included in the protection scope of the present invention.