CN113004279B

CN113004279B - Method for controlling water content of PARP inhibitor-containing sesquihydrate product

Info

Publication number: CN113004279B
Application number: CN202110181423.8A
Authority: CN
Inventors: 掌子龙; 蒋群; 刘军涛; 王卫娟; 杜争鸣
Original assignee: Baiji Shenzhou Suzhou Biotechnology Co ltd
Current assignee: Baiji Shenzhou Suzhou Biotechnology Co ltd
Priority date: 2019-05-10
Filing date: 2019-05-10
Publication date: 2023-01-06
Anticipated expiration: 2039-05-10
Also published as: CN111171031A; CN113004279A; CN111171031B

Abstract

The invention relates to a method for controlling the water content of a product containing PARP inhibitor (R) -2-fluoro-10 a-methyl-7,8,9, 10, 10a, 11-hexahydro-5, 6,7a, 11-tetraazacycloheptatrieno [ def ] cyclopenta [ a ] fluorene-4 (5H) -ketone sesquihydrate, wherein an alcohol solvent and water are used as solvents for recrystallization, the volume of a reaction solvent is reduced, the production flux is improved, the distillation time is shortened, the production efficiency is improved, a certain humidity is provided during product drying to realize water absorption balance, the loss of crystal water of the sesquihydrate in the drying process is reduced, the change of crystal form is inhibited, and the water content of the product is controlled to be between 8.0 and 9.5 percent.

Description

Method for controlling water content of PARP inhibitor-containing sesquihydrate product

Technical Field

The invention discloses a method for controlling the water content of a product containing PARP inhibitor sesquihydrate, in particular to a method for controlling the water content of a product containing (R) -2-fluoro-10 a-methyl-7,8,9, 10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluorene-4 (5H) -ketone sesquihydrate.

Background

WO2013/097225A1 discloses inhibitors as poly (ADP-ribosyl) transferases (PARPs) and specifically compounds

I.e. (R) -2-fluoro-10 a-methyl-7,8,9, 10, 10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def]Cyclopenta [ a ]]Fluoren-4 (5H) -one (BGB 290, hereinafter "compound a"), which can be prepared in the manner disclosed in WO2017/032289 A1. The compound is an inhibitor of poly Adenosine Diphosphate (ADP) ribose polymerase (PARP), has high selectivity to PARP-1/2, and can effectively inhibit BRCA1/2 mutation or other HR deficiencyProliferation of trapped cell lines, significantly induced tumor regression in BRCA1 mutant breast cancer xenograft models at much lower doses than olaparib, a compound with excellent DMPK properties and significant brain permeability. WO2017/032289A1 discloses (R) -2-fluoro-10 a-methyl-7,8,9, 10, 10a, 11-hexaoxy-5,6,7a, 11-tetrahydroheterocycloheptatrienoo [ def]A sesquihydrate of cyclopenta [ a1 fluoren-4 (5H) -one having the structure:

the sesquihydrate has excellent chemical stability, particularly long-term chemical/physical stability, which makes it a suitable API candidate for formulation and clinical use, i.e. the sesquihydrate of compound a has a solubility of about 0.04mg/mL in water. In a low pH aqueous environment such as simulated gastric fluid (pH 1.2), rapid dissolution is possible and good absorption of the drug in animals and humans is obtained. The low solubility in water and high crystalline stability make the compound a sesquihydrate crystalline form particularly suitable for wet granulation and coating processes in pharmaceutical product manufacture.

WO2017/032289A1 discloses a process for the preparation of compound a sesquihydrate (form C) which employs isopropanol-water as the recrystallization solvent to produce compound a sesquihydrate, however, isopropanol is less soluble in compound a. Complete dissolution of the crude compound a is required before crystallization, and if isopropanol is used, a larger volume of solvent (greater than 50 times the mass) is required, resulting in reduced throughput, reduced efficiency and increased cost.

The inventor surprisingly found that the ethanol is used as a solvent for recrystallization, and only 12-18 times of the mass-to-volume ratio of the ethanol relative to the compound A is needed, so that the reaction volume is greatly reduced, and the production flux is improved. In the subsequent reduced pressure distillation (solvent replacement), the distillation time is greatly shortened and the production efficiency is improved because the added amount of the organic solvent is less. In addition, the inventor also finds that when the sesquihydrate of the compound A is dried at a higher temperature, the sesquihydrate is easy to lose crystal water, so that the crystal form is changed. The boiling point of ethanol is lower than that of isopropanol, so that the ethanol is easier to remove under the existing drying condition at a lower temperature, and the crystal form maintenance and the dissolution residue control of the raw material medicines are facilitated.

The inventor finds out through creative experiments that the crystal form of the sesquihydrate is form C, and when the water content (KF) is less than 8.0%, the crystal form can be transformed; and the water content is higher than 9.5%, more free water is contained, and the product is easy to adhere and agglomerate, so that the subsequent preparation production is influenced. When drying the sesquihydrate-containing product, it is an important process step to control the water content of the product to 8.0-9.5%.

The inventor discovers that in the drying process of the compound A sesquihydrate, drying is carried out under the condition of keeping certain humidity so as to realize moisture absorption balance, and can ensure that a product with the water content of 8.0-9.5% can be stably produced, and the crystal form meets the requirements.

Disclosure of Invention

The present invention relates to a process for controlling the water content of the product of (R) -2-fluoro-10 a-methyl-7,8,9, 10, 10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] cyclopenta [ a ] fluoren-4 (5H) -one (compound a) sesquihydrate, which comprises the steps of:

(i) Reacting a compound A: (R) -2-fluoro-10 a-methyl-7,8,9, 10, 10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def]Cyclopenta [ a ]]Fluoren-4 (5H) -ones

Dissolving the crude product of (a) in a mixed solvent of alcohol and water;

(ii) Supplementing water and seed crystals, and inducing crystallization;

(iii) Distilling under reduced pressure to remove the solvent, filtering and collecting the solid;

(iv) Optionally providing a humidity, drying the solid, taking a sample, determining the percentage of moisture content in the solid:

(a) When the moisture content percentage is less than 8.0 weight percent, drying under the condition of providing certain humidity to realize moisture absorption balance, and obtaining a product with the moisture content percentage ranging from 8.0 to 9.5 weight percent;

(b) When the water content percentage is more than 9.5 percent by weight, drying the mixture until a product with the water content percentage ranging from 8.0 to 9.5 percent by weight is obtained;

(c) When the water content percentage is between 8.0 and 9.5 weight percent, the solid is the product.

Preferably, the percentage moisture content is determined using the karl fischer volumetric method. When the stated percentage of moisture content is determined by the Karl Fischer volumetric method, the percentage of moisture content is also expressed as KF.

Thus, preferably, step (iv) is optionally provided with or without humidity, drying the solids, sampling, determining the percentage of moisture content (KF) in the solids:

(a) When KF is less than 8.0 wt%, drying the solid under the condition of providing certain humidity to realize moisture absorption balance, and obtaining a product with KF in the range of 8.0-9.5%;

(b) When KF is greater than 9.5 wt%, drying the solid to obtain a product with KF ranging from 8.0 to 9.5 wt%;

(c) When the water content percentage is between 8.0 and 9.5 weight percent, the product is directly obtained.

Preferably, the weight to volume ratio of the crude compound A to the alcohol is 1: 5-40 (w/v, g/ml), preferably 1: 12-18 (w/v, g/ml), more preferably 1: 15-16 (w/v, g/ml).

Preferably, the weight to volume ratio of the crude compound A to the water for dissolving the compound A is 1: 1.0-10.0 (w/v, g/ml), preferably 1: 3.0-6.0 (w/v, g/ml), more preferably 1: 4.0-5.0 (w/v, g/ml).

Preferably, the temperature in step (i) is in the range of 40 to 80 ℃, preferably 50 to 60 ℃.

Preferably, the alcohol in step (i) is preferably ethanol and methanol, most preferably ethanol. Preferably, in step (iv), the means for providing a certain humidity includes, but is not limited to, placing water or an aqueous solution in a drying container; or bubbling water vapor or other means of maintaining humidity.

Preferably, the drying of the solid of step (iv) is vacuum drying.

Preferably, the temperature selected for drying the solid in step (iv) is in the range of 25 to 45 ℃.

Preferably, the time selected for drying the solid in step (iv) is from 2 to 240 hours; more preferably 2 to 120 hours; more preferably 2 to 8 hours.

Preferably, the means of providing a degree of humidity in step (iv) (a) includes, but is not limited to, placing water or an aqueous solution in a drying vessel; or bubbling water vapor or other means of maintaining humidity.

Preferably, the aqueous solution is a non-volatile aqueous inorganic salt solution.

Preferably, the inorganic salt is selected from, but not limited to, sodium chloride, potassium chloride, sodium sulfate, potassium sulfate.

Preferably, the humidity is > 50%.

Preferably, the temperature of drying at equilibrium of moisture uptake in step (iv) (a) is from 25 to 45 ℃.

Preferably, the drying at equilibrium of moisture absorption described in step (iv) (a) is oven atmospheric drying or closed environment drying.

Preferably, the time for equilibrium of moisture absorption in step (iv) (a) is from 24 to 120 hours.

Preferably, the drying of step (iv) (b) is vacuum drying.

Preferably, the drying temperature in step (iv) (b) is from 25 to 35 ℃.

Preferably, the drying time in step (iv) (b) is from 1 to 5 hours.

The moisture content of 8.0 to 9.5 wt.% as referred to herein means the sum of all forms of water content in the sample (product), which contains crystal water and a part of trace amount of free water.

Preferably, the water content is determined by KF method using a mettler-toledo karl fischer volumetric water titrator, and the results of the water content tested include crystallized water and a small amount of free water.

The control method of the present invention is a process useful for mass production of a product comprising a sesquihydrate of compound a. There are several innovations to this approach:

(a) The ethanol is adopted to replace isopropanol in the prior art, so that the volume of a reaction solvent is reduced, the production flux is improved, the distillation time is shortened, and the production efficiency is improved.

(b) Compared with isopropanol, ethanol is adopted as a recrystallization solvent, the drying temperature is lower, the loss of crystallization water in the drying process is reduced, and the change of crystal form is inhibited.

(c) It was found by investigation that controlling the water content of the sesquihydrate to 8.0 to 9.5% by weight is an important process condition when drying the sesquihydrate.

(d) And drying (such as placing water or aqueous solution in a drying container or blowing water vapor and the like) under the condition of keeping a certain humidity so as to realize moisture absorption balance, so that a product with the water content of 8.0-9.5 weight percent can be stably produced, and the crystal form meets the requirement.

Drawings

FIG. 1 is an X-ray powder diffraction (XRPD) pattern of Compound A sesquihydrate

Detailed Description

The crude product of compound a used herein is obtained according to the process disclosed in WO2017/032289A1, the entire content of which is incorporated herein by reference.

As used herein, "percent moisture content" refers to the percentage of moisture in a solid (including crystalline water and small amounts of free water) by mass of the solid.

The following is intended to be illustrative and is intended to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for within the knowledge of one skilled in the art. Unless otherwise specified, temperatures are in degrees Celsius. The conditions not specified hereinafter are those conventionally used or those suggested by the manufacturer.

Example 1

The crude compound A (10 g) was completely dissolved in a mixed solution of 155mL of ethanol and 45mL of water at 55 ℃. After the solution was cooled to room temperature, water and seed crystals were added to obtain a suspension. After aging the suspension under stirring for a certain period of time, water was added, ethanol was removed by concentration, and the solid obtained after filtration was washed with water. The washed solid was dried under vacuum at 35 ℃ for 8 hours in the presence of water (KF =10.29%, w/w), and then at 30 ℃ for 2 hours to obtain the target product (determined by KF =8.65%, w/w, yield 98.46%), the XRPD pattern of compound a sesquihydrate is shown in fig. 1, and its characteristic peaks are consistent with the spectrum of compound a sesquihydrate form C in WO2017/032289A1, fig. 7A.

Example 2

The crude compound A (10 g) was completely dissolved in a mixed solution of 155mL ethanol and 60mL water at 55 ℃. After the solution was cooled to room temperature, water and seed crystals were added. After the suspension was aged for a while with stirring, water was added, ethanol was removed by concentration, and the solid obtained after filtration was washed with water. The wet cake was dried in the presence of water under vacuum at 35 ℃ for 8 hours (KF =11.30%, w/w), and 30 ℃ for 2 hours to obtain the target product (determined KF =8.93%, yield 93.00%).

In addition, the TGA results were compared to form C in table 14 of the specification of WO2017/032289A1 with a TGA weight loss measurement of increasing the temperature to 150 ℃ at 25.8 ℃ and a sample weight loss (water yield) of 8.94% ^＊ The characterization data of the crystal forms are consistent.

Example 3

The crude compound A (10 g) was completely dissolved in a mixed solution of 155mL of ethanol and 45mL of water at 65 ℃. After the solution was cooled to room temperature, water and seed crystals were added. After aging the suspension under stirring for a certain period of time, water was added, the ethanol was removed by concentration, and the solid obtained after filtration was washed with water. The wet cake and water were dried under vacuum at 35 ℃ for 8 hours to obtain the target product (determined KF =8.52%, w/w, yield 93.71%).

Example 4

The crude compound A (60 g) was completely dissolved in a mixed solution of 930mL of ethanol and 270mL of water at 55 ℃. After the solution was cooled to room temperature, water and seed crystals were added. After aging the suspension under stirring for a certain period of time, water was added, the ethanol was removed by concentration, and the solid obtained after filtration was washed with water. The wet cake was divided into two portions, one portion was vacuum dried in the presence of water at 25 ℃ for 4 hours (KF =10.75%, w/w), after which vacuum dried at 35 ℃ for 2 hours to obtain BGB290 sesquihydrate (KF =8.89%, w/w). Another portion was dried under vacuum in the presence of water at 45 ℃ for 120 hours to obtain the target product (KF =8.76%, w/w, as determined).

Example 5

The crude compound A (60 g) was completely dissolved in a mixed solution of 930mL of ethanol and 270mL of water at 55 ℃. After the solution was cooled to room temperature, water and seed crystals were added. After aging the suspension under stirring for a certain period of time, water was added, the ethanol was removed by concentration, and the solid obtained after filtration was washed with water. The wet cake was dried under vacuum at 50 ℃ for 8 hours (KF =4.5% w/w), followed by atmospheric drying at 45 ℃ for 120 hours in the presence of water to perform moisture absorption equilibration to obtain the target product (determined KF =8.72%, w/w).

Example 6

The crude compound A (60 g) was completely dissolved in a mixed solution of 930mL of ethanol and 270mL of water at 55 ℃. After the solution was cooled to room temperature, water and seed crystals were added. After aging the suspension under stirring for a certain period of time, water was added, the ethanol was removed by concentration, and the solid obtained after filtration was washed with water. The wet cake was vacuum dried in the presence of water at 35 ℃ for 2 hours (KF =10.07%, w/w), and then divided into two portions, one portion was vacuum dried at 25 ℃ for 1 hour to obtain compound a sesquihydrate (KF =8.78%, w/w), and the other portion was vacuum dried at 35 ℃ for 3 hours to obtain the target product (KF =8.58%, w/w, measured).

Comparative example 1

The crude compound A (30 g) was completely dissolved in a mixed solution of 465mL of ethanol and 135mL of water at 55 ℃. After the solution was cooled to room temperature, water and seed crystals were added. After aging the suspension under stirring for a certain period of time, water was added, the ethanol was removed by concentration, and the solid obtained after filtration was washed once with water. The wet cake was dried at 40 ℃ for 40h to give the target product (KF =5.41%, w/w as determined).

Comparative example 2

Compound a sesquihydrate (5 g) dried at 70 ℃ for 5h to give compound a anhydrous (KF =0.8% w/w).

From examples 1 to 6, it is clear that, in either case of drying with water in the wet cake drying (example 3) or without water initially and then with water equilibration (example 5), a product containing the sesquihydrate of compound a with KF between 8.0% and 9.5% by weight is finally obtained. In comparative example 1, however, no water balance was used for the wet cake and no humidity was subsequently provided to achieve water balance, and the final product had a KF value of only 5.41% (w/w). Comparative example 2 shows that the water of crystallization of the product is lost to an anhydrate upon drying at elevated temperature (70 ℃) without humidification.

The invention has been described in detail with respect to the general description, specific embodiments and experiments, and it is intended that modifications or improvements can be made without departing from the spirit of the invention and within the scope of the claims.

Claims

1. A method for controlling the activity of (R) -2-fluoro-10 a-methyl-7,8,9, 10, 10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def ] containing PARP inhibitor]Cyclopenta [ a ]]Fluorene-4 (5H) -one sesquihydrate

The method of producing a water content of the product of (a), wherein the production method comprises the steps of:

(i) Reacting a compound A: (R) -2-fluoro-10 a-methyl-7,8,9, 10, 10a, 11-hexahydro-5, 6,7a, 11-tetraazacyclohepta [ def]Cyclopenta [ a ] s]Fluoren-4 (5H) -ones

Dissolving the crude product of the compound A in a mixed solvent of ethanol and water, wherein the weight-to-volume ratio of the crude product of the compound A to the ethanol is 1: 5-40 (w/v, g/ml); and the weight-to-volume ratio of the crude compound A to the water for dissolving the compound A is 1: 1.0-10.0 (w/v, g/ml);

(ii) Supplementing water and seed crystals, and inducing crystallization;

(iv) Providing a humidity, drying the solid, sampling, and determining the moisture content percentage in the solid, wherein the humidity is more than 50 percent:

(a) When the moisture content percentage is less than 8.0 wt%, drying the solid under the humidity to realize moisture absorption balance, and obtaining a product with the moisture content percentage ranging from 8.0 to 9.5 wt%;

(b) Drying the solids when the moisture content percentage is greater than 9.5 wt% to obtain a product having a moisture content percentage in the range of 8.0 to 9.5 wt%;

2. The method of claim 1, wherein the percent moisture content is determined using the karl fischer volumetric method; when the stated percentage of moisture content is determined by the Karl Fischer volumetric method, the percentage of moisture content is also expressed as KF.

3. The process of any one of claims 1-2, wherein the weight to volume ratio of the crude compound a to ethanol is from 1: 12 to 18 (w/v, g/ml).

4. The process of claim 3, wherein the weight to volume ratio of the crude compound A to ethanol is 1: 15 to 16 (w/v, g/ml).

5. The process according to any one of claims 1-2, wherein the weight to volume ratio of the crude compound a to the water used to dissolve compound a is 1: 3.0 to 6.0 (w/v, g/ml).

6. The process according to claim 5, wherein the weight to volume ratio of the crude compound A to the water used for dissolving compound A is 1: 4.0-5.0 (w/v, g/ml).

7. The process of any one of claims 1-2, wherein the temperature of dissolving the crude product of step (i) is 40-80 ℃.

8. The process of claim 7, wherein the temperature of dissolving the crude product in step (i) is 50-60 ℃.

9. The method according to any one of claims 1-2, wherein in step (iv), the manner of providing a certain humidity is selected from placing water or an aqueous solution in a drying vessel; or other means of bubbling water vapor or maintaining humidity, and any combination thereof.

10. The process of any one of claims 1-2, wherein the drying the solid in step (iv) is vacuum drying; and/or the temperature selected for drying the solid of step (iv) is from 25 to 45 ℃; and/or the time selected for drying the solid in step (iv) is from 2 to 240 hours.

11. The process according to claim 10, wherein the time selected for drying the solid in step (iv) is between 2 and 120h.

12. The process according to claim 11, wherein the time selected for drying the solid in step (iv) is between 2 and 8h.

13. The method of any one of claims 1-2, wherein the means for providing a humidity in step (iv) (a) comprises placing water or an aqueous solution in a drying vessel; or other means of bubbling water vapor or maintaining humidity, and any combination thereof.

14. The process of any one of claims 1-2, wherein in step (iv) (a), the temperature of drying at equilibrium of moisture uptake is from 25 to 45 ℃; and/or the duration of drying described in step (iv) (a) is from 24 to 120 hours; and/or in step (iv) (a), the drying is oven drying under normal pressure or drying in a closed environment.

15. The method of any one of claims 1-2, wherein the drying temperature in step (iv) (b) is from 25 to 35 ℃; and/or the drying time is 1-5 hours; and/or the drying described in step (iv) (b) is vacuum drying.