WO2019056163A1 - N-formyl palbociclib and preparation method therefor and use thereof, and palbociclib preparation and quality control method therefor - Google Patents

Abstract

Disclosed are a degradable impurity, i.e. N-formyl palbociclib, in a palbociclib solid preparation, a preparation method therefor, and a use thereof in prescription studies and impurity detection for the palbociclib solid preparation. Also provided are a stabilized palbociclib solid preparation and a preparation method therefor. The product yield of the preparation method of N-formyl palbociclib may exceed 50% and the purity may exceed 90%, and the preparation method has the advantages of having a simple process, a high product purity and a shorter production period, and is suitable for rapid laboratory preparation and large-scale preparation, etc. The obtained palbociclib solid preparation has an improved stability, and after being placed under conditions of 60ºC and 75% of relative humidity for 10 days, the N-formyl palbociclib impurity in the palbociclib solid preparation also does not increase.

Description

N-formyl Paboxini and preparation method and use thereof, and Pabsini preparation and quality control method thereof Technical field

The invention relates to the technical field of pharmaceutical manufacture, in particular to N-formyl Paboxini and its preparation method and use as well as the Pabsini preparation and its quality control method.

Background technique

该药由美国辉瑞(Pfizer)制药公司开发，其化学名为6-乙酰基-8-环戊基-5-甲基-2-[5-(1-哌嗪基)-2-吡啶基]氨基]吡啶并[2，3-d]嘧啶-7(8H)-酮，分子式C₂₄H₂₉N₇O₂，分子量为447.53，其结构式如下式：Palbociclib, trade name

The drug was developed by Pfizer Pharmaceuticals, USA, and its chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(1-piperazinyl)-2-pyridyl] Amino]pyrido[2,3-d]pyrimidin-7(8H)-one, molecular formula C ₂₄ H ₂₉ N ₇ O ₂ , molecular weight 447.53, the structural formula is as follows:

是近年来美国FDA批准的与内分泌治疗相关的第二个靶向治疗药物，同时也是美国FDA批准的第一个CDKs抑制剂。Palbociclib was approved by the US FDA in February 2015 and is used in combination with letrozole for the treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor (HER2)-negative Breast cancer patients, and used as a first-line treatment for breast cancer. After Ivemus,

It is the second targeted therapy for endocrine therapy approved by the US FDA in recent years, and it is also the first CDK inhibitor approved by the US FDA.

As an oral targeting drug, Pabsini selectively inhibits cyclin-dependent kinases 4 and 6 (CDK4/6), restores cell cycle control, and blocks tumor cell proliferation. Preclinical data indicate that dual inhibition of CDK4/6 and ER signaling has a synergistic effect and is capable of inhibiting G1 ER-positive (ER+) breast cancer cell growth.

Due to the good efficacy of Pabsini in the treatment of breast cancer, many analysts in the pharmaceutical industry are pre- Measuring annual sales can reach more than $3 billion, so a number of large multinational generic companies have conducted extensive imitation research on their prescriptions.

Summary of the invention

The inventors unexpectedly discovered in the prescription study of the Pabsini capsule and the Pabsini sustained-release capsule that if the prescription contains reducing sugar excipients, N-formyl Palbocini will be produced. Impurities, and become one of the most important degradation impurities in tablet prescriptions, especially when the formulation parameters of the formulation are not well controlled, the content can even reach 0.5% or more, exceeding the limit of the individual impurities of the preparation product not exceeding 0.20%. . However, reducing sugar excipients are commonly used in most solid formulation formulations, so it is important to control such degradation impurities in the formulation process.

The present inventors have unexpectedly discovered that when the formulation contains reducing saccharide adjuvants such as glucose, fructose, galactose, lactose, maltose, etc., since the Pabsini molecule contains an unsubstituted capped piperazine ring secondary amine group, The secondary amine atom in the group readily undergoes a Maillard reaction with the reducing saccharide excipient in the formulation to attach a formyl group to the secondary amine group to produce an N-formyl Paboxini impurity.

The inventors have conducted a large number of experiments to prove that the degradation impurity produced in the prescription is N-formyl Paboxini, and its structure is characterized as follows:

The obtained target impurity was detected by high resolution mass spectrometry (HRMS), and its [M+H ⁺ ] exact molecular weight was 476.2408 with a matching error of 0.5 ppm. The matching formula was C ₂₅ H ₂₉ N ₇ O ₃ , and N-formyl Pabo The theoretical precise molecular weight of the Sini [M+H ⁺ ] 475.2405 is almost identical, as shown in Figure 1.

The target impurity was determined to be N-Formyl Palbociclib by nuclear magnetic ¹ H-NMR and ¹³ C-NMR data (data summary is shown in Table 1 and Table 2). The confirmed structural formula is as follows:

The nuclear magnetic ¹ H-NMR and ¹³ C-NMR spectra of the target compound are shown in Fig. 2 and Fig. 3, and the compound numbers are shown in Fig. 4.

Table 1. N-formyl Paboxini nuclear magnetic resonance data

Chemical shift (ppm) Peak type Ownership H number Number of protons 1.11 m H-3 1 1.70, 2.07 t H-19/20 4 1.90, 2.33 q H-18/21 4 2.37 t H-24 3 2.55 q H-23 3 3.15, 3.19 t H-13/16 4 3.58, 3.76 t H-14/15 4 7.36 Dd H-10 1 8.02 s H-25 1 8.05 d H-12 1 8.12 s N-H 1 8.21 d H-9 1 8.81 s H-7 1

Table 2. N-formyl Paboxini nuclear magnetic resonance carbon spectrum data

Chemical shift (ppm) C atom type C number Ownership C number 14.14 CH ₃ 1 C-24

25.95, 29.52 CH ₃ 2 C-19/20 28.25, 29.85 CH ₂ 2 C-18/21 31.39 CH 1 C-17 31.68 CH ₃ 1 C-23 39.99, 45.56 CH ₂ 2 C-14/15 49.40, 50.98 CH 2 C-13/16 108.13 C 1 C-3 113.66 CH 1 C-9 127.34 CH 1 C-10 131.10 C 1 C-2 137.88 CH 1 C-12 141.81 C 1 C-4 143.35 C 1 C-11 146.03 C 1 C-8 155.63 C 1 C-5 157.30 CH 1 C-7 158.09 C 1 C-6 160.88 C 1 C-25 161.51 C 1 C-1 202.78 C 1 C-22

Accordingly, a first aspect of the present invention provides N-formyl Paboxini, which is a degradation impurity in a Pabsini solid preparation and has a chemical structure as shown in Formula I:

In a preferred embodiment of the first aspect of the present invention, the purity of the N-formyl Paboxini is 90% or more, preferably 95% or more, and more preferably 99% or more.

In addition, in the development process of the formulation prescription analysis method and the routine monitoring of the finished product QC, a large amount of N-formyl Paboxini is required as an impurity standard to locate and quantify the impurity in the prescription.

Accordingly, a second aspect of the present invention provides a process for the preparation of N-formyl Paboxini, which comprises the steps of:

(a) adding a salt of paboxinis free base or paboxininic acid to the reaction solvent and a formylating agent;

(b) heating to a temperature of 30 to 150 ° C, preferably 90 to 120 ° C to carry out the reaction;

(c) After completion of the reaction, the target product N-formylparcosonib was isolated.

Then, the target product is separated by a conventional separation method such as column chromatography or recrystallization, and a high-purity N-formyl Paboxini sample can be obtained at one time.

In a preferred embodiment of the second aspect of the invention, in step a), the acid forming a salt with paboxini is selected from the group consisting of isethionethane, hydrobromic acid, hydrochloric acid, sulfuric acid, sulfuric acid, methanesulfonic acid, lemon Acid, tartaric acid, maleic acid, malic acid, fumaric acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid and palmitic acid.

In another preferred embodiment of the second aspect of the present invention, in the step (a), the reaction solvent is water, a polar organic solvent or a mixed solvent thereof, wherein the polar organic solvent is preferably formic acid, N, N- Dimethylformamide and dimethyl sulfoxide.

In another preferred embodiment of the second aspect of the present invention, in the step (a), the formylating agent is formic acid, methyl formate, ethyl formate, propyl formate, isopropyl formate, A N-butyl acrylate, isobutyl formate, tert-butyl formate, benzyl formate, C1-C5 linear or branched alkyl-substituted benzyl formate, phenolic formate, C1-C5 linear or branched alkyl formic acid Phenolic esters, or formic acid with acetic anhydride, trifluoroacetic anhydride, methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, tert-butyl chloroformate or chloroformic acid A mixture of benzyl esters is preferably formic acid, methyl formate, ethyl formate, benzyl formate, or a mixture of formic acid and acetic anhydride.

In a preferred embodiment of the second aspect of the present invention, in the step (a), when the formylating agent is formic acid, the formylating agent is combined with Pabsinib free base or Pabsini The acid formed salt volume mass ratio is from 0.1 to 100:1 ml/g, preferably from 5 to 50:1 ml/g, more preferably from 25 to 50:1 ml/g; when the formylating agent is selected from methyl formate, formic acid B Ester, propyl formate, isopropyl formate, n-butyl formate, isobutyl formate, tert-butyl formate, benzyl formate, C1-C5 linear or branched alkyl-substituted benzyl formate, phenolic formate, formic acid C1-C5 linear or branched alkyl substituted phenol ester, or formic acid with acetic anhydride, trifluoroacetic anhydride, methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, chloroformic acid In the case of a mixture of butyl ester, tert-butyl chloroformate or benzyl chloroformate, the molar ratio of the formylating agent to the Pabsini molecule is from 0.2 to 100:1, preferably from 3 to 40:1.

A third aspect of the invention provides the use of N-formyl paboxinis as an impurity control in the detection of the impurity of the Pabusini preparation.

In the research and development of new drugs, the quality of drugs is an important criterion for measuring the quality of drugs. The impurities present in drugs directly affect the efficacy of drugs and may cause toxic side effects. Therefore, impurity detection is a very important one in drug quality control. In the link, the impurities produced by the interaction between the API (pharmaceutical active ingredient) and other raw materials in the formulation research are the key factors affecting the quality of the prescription drug, especially the content of the active ingredient and the toxic side effects. The inventors determined by appropriate structural characterization methods. Impurity structure, further analysis of its possible causes, and then the synthesis of a simple operation, easy to obtain raw materials and low cost N-formyl Paboxini sample, using the impurities in the Pabusini preparation impurities The use as an impurity control during the test makes it possible to design a reliable and efficient analytical method.

A fourth aspect of the present invention provides a stabilized paposini solid preparation comprising pabosini or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, the excipient not comprising Reducing sugar substances, such as glucose, fructose, galactose, lactose, maltose, etc., placed at 60 ° C, 75% relative humidity for 10 days, the content of N-formyl Paboxini does not exceed the Pabusini marker 0.2%.

In a preferred embodiment of the fourth aspect of the invention, the N-formyl Paboxini is present in an amount of no more than 0.1% of the Pabsini label at 60 ° C, 75% relative humidity for 10 days. .

The paposini solid preparation according to the present invention includes tablets, capsules, granules and the like.

A fifth aspect of the invention provides a method of preparing a Pabsini solid preparation comprising the steps of:

1) uniformly blending Pabsini or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the excipient does not contain a reducing saccharide;

2) dry granulating the mixture of step 1) and granulating to obtain granules containing paboxini;

3) The granules are compressed into tablets or filled into capsules.

In addition, the N-formyl Paboxini found in the present invention makes it possible to more easily and intuitively control the quality of the Pabsini solid preparation. A preferred quality control method comprises the steps of: weighing an appropriate amount of N-formyl Paboxini in a diluent to prepare an appropriate concentration of an impurity reference solution; followed by reverse phase liquid chromatography on the Pabsini solid The N-formyl Paboxini impurity contained in the preparation sample was subjected to qualitative or quantitative study.

At least the following technical effects are achieved by the present invention:

1. The inventors have unexpectedly discovered that in the solid preparation of Pabsini, the Maillard reaction of Pabsini with the original excipients produces a new impurity of N-formyl Paboxini and spectral analysis of the experimental data. The structure of the compound was confirmed and proved to be a major degradation impurity of the Pabsini solid preparation. The compound can be used as an impurity reference for the detection of impurities in the Pabsini solid preparation, and can effectively and reliably monitor impurities in the solid preparation of Pabsini, thereby effectively controlling the quality of the solid preparation of Pabsini to ensure the quality of the Pabsini solid preparation. The safety and efficacy of clinical use of Bosini solid preparations.

2. The preparation method of N-formyl Paboxini provided by the invention, the method has low process cost, easy control, easy availability of raw materials; and the obtained product has stable quality and high yield; In the preparation process, the preparation cycle is short, no special equipment is needed, and the preparation efficiency is greatly improved, and is particularly suitable for rapid preparation in the laboratory.

3. The Pabsini solid preparation provided by the present invention contains almost no N-formyl Paboxini degradation impurities, and the solid preparation is kept at 60 ° C, 75% relative humidity for 10 days, and no N- is observed. Formyl Pabsini reduces the growth of impurities and is more advantageous in the production and storage process. Lower impurity content and less degradation of the main drug help to improve the safety and effectiveness of the product.

DRAWINGS

Figure 1 is a high resolution mass spectrometry data (HRMS) of N-formyl Pabusini standard prepared according to the present invention.

FIG 2 N- formyl基帕博西尼standard 1H NMR, spectrum ⁽¹ H-NMR) prepared in the present invention.

Figure 3 is a nuclear magnetic carbon spectrum ( ^13C -NMR) of the N-formyl Paboxini standard prepared according to the present invention.

Figure 4 is a chart showing the N-formyl Paboxini structural formula atom number of the present invention.

Detailed ways

The invention is further illustrated by way of example below.

Example 1

1 g of Pabsini free base was added to 30 mL of formic acid, heated to 105 ° C for 20 hours, and the reaction liquid was monitored by HPLC. The purity of the target compound was 75%, and then the formic acid was distilled off by a rotary evaporator. The analytical method [HP-Silica normal phase silica gel, eluent: dichloromethane:methanol = (10:1, V/V)] was used to isolate the target product to obtain 0.72 g of N-formyl Paboxini, HPLC purity. 99.5%, yield 68%.

Example 2

1 g of Pabsini free base was added to 35 mL of formic acid, and the mixture was heated to 110 ° C for 18 hours, and the reaction liquid was monitored by HPLC. The purity of the target compound was 82%, and then the formic acid was removed by a lyophilizer, and the residue was 30 mL. Recrystallization of methanol to obtain N-formyl Pabo Sini 0.69 g, HPLC purity 95.7%, yield 65%.

Example 3

1 g of Pabsini free base was added to 30 mL of formic acid, and the mixture was heated to 90 ° C for 25 hours, and the reaction liquid was monitored by HPLC. The purity of the target compound was 71%, and then most of the formic acid was distilled off by a rotary evaporator. Then, the residue was diluted with 80 mL of water, and the pH was adjusted to about 9 with sodium carbonate. At this time, solid precipitation was observed, followed by column chromatography [HP-Silica normal phase silica gel, eluent was dichloromethane:methanol = ( 12:1, V/V)] The title product was separated to give N-formyl paposinis (0.47 g), HPLC purity 99.6%, yield 57%.

Example 4

1 g of paboxinis hydrochloride was added to 50 mL of water-formic acid (1:1, V/V), and the mixture was heated to 100 ° C for 20 hours, and the reaction solution was monitored by HPLC. The purity of the target compound was 74%, and then used. After distilling off most of the formic acid by rotary evaporator, the residue was diluted with 80 mL of water, and the pH was adjusted to about 9 with sodium carbonate. At this time, solids were observed, and the solid was recrystallized from 40 mL of ethanol to obtain N-formyl Bosini 0.51 g, HPLC purity 93.8%, yield 52%.

Example 5

1 g (Paboxini free base was added to 50 mL of N,N-dimethylformamide, then 5 mL of methyl formate was added, and the mixture was heated to 100 ° C for 24 hours, and the reaction solution was monitored by HPLC to obtain the purity of the target compound. 65%, then remove N,N-dimethylformamide and unreacted methyl formate by lyophilization, using column chromatography [HP-Silica normal phase silica gel, eluent is dichloromethane: methanol = (9:1, V/V)] The title product was separated to obtain 0.56 g of N-formyl papossini, HPLC purity 98.2%, yield 53%.

Example 6

1 g of Pabsini free base was added to 80 mL of N,N-dimethylformamide, then 3 mL of ethyl formate was added, and the mixture was heated to 90 ° C for 20 hours, and the reaction liquid was monitored by HPLC. The purity of the target compound was 67%, then N,N-dimethylformamide and unreacted ethyl formate were removed by lyophilization, and the solid was recrystallized from 40 mL of ethanol-water (1:1, V/V) to obtain N- Formyl paposinis 0.57 g, HPLC purity 91.3%, yield 54%.

Example 7

1 g of Pabsini free base was added to 75 mL of dimethyl sulfoxide, then 3 mL of benzyl formate was added, and the mixture was heated to 120 ° C for 22 hours, and the reaction solution was monitored by HPLC. The purity of the target compound was 73%, and then used. The lyophilizer removes dimethyl sulfoxide and unreacted benzyl formate by column chromatography [HP-Silica normal phase silica gel, eluent is dichloromethane: methanol = (10:1, V/V)] The target product was isolated to obtain 0.70 g of N-formylparsopinis, HPLC purity 99.5%, yield 66%.

Example 8

1 g of Pabsini free base was added to 90 mL of N,N-dimethylformamide, then 4 mL of benzyl formate was added, and the mixture was heated to 115 ° C for 20 hours, and the reaction solution was monitored by HPLC. The purity of the target compound was 70%, then N,N-dimethylformamide and unreacted benzyl formate were removed by lyophilization, and the solid was recrystallized from 30 mL of ethanol to obtain 0.57 g of N-formylparcosinib. HPLC purity 90.6%, yield 54%.

Example 9

1 g of paboxinis hydrochloride was added to 25 mL of formic acid, then 8 mL of acetic anhydride was added, and the mixture was heated to 110 ° C for 19 hours, and the reaction solution was monitored by HPLC. The purity of the target compound was 67%, and then the formic acid was removed by a lyophilizer. And acetic anhydride, the solid was recrystallized from 15 mL of N,N-dimethylformamide to obtain 0.50 g of the N-formyl Paboxini sample, the HPLC purity was 91.7%, and the yield was 51%.

Example 10

1 g of paboxinis hydrochloride was added to 30 mL of formic acid, then 10 mL of acetic anhydride was added, and the mixture was heated to 90 ° C for 24 hours, and the reaction solution was monitored by HPLC. The purity of the target compound was 63%, and then the formic acid was removed by a lyophilizer. And acetic anhydride, using a thin layer chromatography method [HP-Silica normal phase silica gel, eluent is dichloromethane: methanol = (15:1, V / V)] to separate the target product to obtain N-formyl Pa Bosini 0.54 g, HPLC purity 99.1%, yield 55%.

Example 11

1 g of pacloxil malate was added to 10 mL of N,N-dimethylformamide, and then 2.0 mL of phenolic formate was added, and the mixture was heated to 150 ° C for heating for 18 hours, and the reaction solution was subjected to HPLC. The purity of the target compound was monitored to be 64%, and then the formic acid and the unreacted phenolic formate were removed by a lyophilizer, followed by column chromatography [HP-Silica normal phase silica gel, and the eluent was dichloromethane:methanol. = (9:1, V/V)] The title product was separated to give 0.43 g of N-formyl paspoxini, HPLC purity 98.8%, yield 52%.

Example 12

1 g of paboxinis mesylate was added to 10 mL of formic acid, first cooled to 0 ° C, then slowly added 2.5 mL of a mixture of formic acid and methyl chloroformate (1:1, V / V), heated to 30 after heating °C, reaction for 15 hours. The reaction solution was monitored by HPLC, and the purity of the target compound was 72%. Then, the formic acid and the unreacted formic acid and ethyl chloroformate were removed by a lyophilizer, and then subjected to column chromatography [HP-Silica normal phase silica gel, The eluent was dichloromethane:methanol = (10:1, V/V). The title product was isolated from the residue to give N-formyl paposinis 0.51 g, HPLC purity 99.2%, yield 57 %.

Example 13

According to Table 3, the prescribed amount of paboxini was uniformly mixed with microcrystalline cellulose, mannitol, sodium carboxymethyl starch and silica, and the granulation mechanism was carried out by roll-pressing dry granulation, and the granules were obtained by granulation. The dry granules of Sini are mixed with magnesium stearate and filled into capsules.

table 3

Pabotini 125mg Microcrystalline cellulose 250mg Mannitol 50mg Carboxymethyl starch sodium 16mg Silica 4mg Magnesium stearate 5mg total 450mg

Example 14

According to Table 4, the prescription amount of Pabsini was mixed with polyethylene glycol, mannitol, croscarmellose sodium and silica, and the pellets were obtained by roll-pressing dry granulation mechanism and obtained by granulation. The dry granules containing Pabsini are mixed and added with magnesium stearate and then filled into capsules.

Table 4

Pabotini 125mg Polyethylene glycol 50mg Mannitol 240mg Croscone sodium 27mg Silica 4mg Magnesium stearate 4mg total 450mg

Comparative Example 1

According to Table 5, the prescribed amount of paboxini was uniformly mixed with lactose, microcrystalline cellulose, sodium carboxymethyl starch and silica, and the pellet was granulated by a roll-pressing dry granulation method, and the granules were obtained by granulating. The dry granules of nicotine are mixed and added with magnesium stearate and then filled into capsules.

table 5

Pabotini 125mg lactose 250mg Microcrystalline cellulose 50mg Carboxymethyl starch sodium 16mg Silica 4mg Magnesium stearate 5mg total 450mg

The samples of Example 13, Example 14 and Comparative Example 1 were placed at 60 ° C, 75% relative humidity, and samples were taken at 5 days and 10 days to determine N-formyl Paboxini, and with 0 day sample. For comparison, the results are shown in Table 6 below:

Table 6:

N.D means not detected, RL is the reporting limit, RL=0.05%

According to the results in Table 6, when the prescription contains reducing sugar excipients such as lactose, the Pabsini solid preparation is prone to produce N-formyl Paboxini impurities, and with the extension of the standing time, N-formyl Pabo The content of Sini impurities is constantly increasing. On the other hand, in the formulations of Example 13 and Example 14, the N-formyl Paboxini impurity was not detected, and after standing for 10 days at 60 ° C and 75% relative humidity, the N-formyl group in the solid preparation of Pabsini was prepared. Pabosini impurities have not seen growth.

Example 15

A method for controlling the quality of a Pabsini solid preparation using N-formyl paboxini as an impurity reference:

Chromatographic conditions:

Instrument: High performance liquid chromatograph equipped with UV detector

Column: Waters Xterra MS C18, 150 x 4.6 mm, 3.5 μm

Mobile phase A: 0.1% aqueous solution of trifluoroacetic acid (volume ratio)

Mobile phase B: acetonitrile

Detection wavelength: 240nm

Flow rate: 1.0mL/min

Injection volume: 10μL

Column temperature: 45 ° C

Running time: 65min

Mobile phase gradient:

Diluent: acetonitrile: water: trifluoroacetic acid = (50:50:0.1, V/V/V).

Blank solution: same dilution.

Preparation of N-formyl Paboxini control solution: 1 mg of N-formylparcosoni was weighed and dissolved in 1 ml of the dilution.

Specific steps:

The Pebsini capsule prepared according to Comparative Example 1 was subjected to a sample of a sample placed under high temperature and high humidity conditions (60 ° C, 75% relative humidity) for 10 days, decapsuleized, weighed and added to a corresponding volumetric volumetric flask. Add the diluent to a volume of about 2/3 volumetric flask, shake for 1 hour to disperse, then continue to sonicate for 10 min to dissolve the paboxini, cool to room temperature, dilute the dilution to the mark, shake well, let stand for a while, precision transfer In a 5 mL to 50 mL volumetric flask, dilute to the mark with the diluted solution, shake well, filter with a 0.45 μm PTFE needle filter, and take the filtrate as the test solution. The test solution was detected by the above HPLC method and positioned and quantified with a N-formyl Paboxini control solution, which was placed under high temperature and high humidity conditions (60 ° C, 75% relative humidity) of the Pabusini capsule. The content in the day sample was 0.24%.

The impurity compound N-formyl Paboxini in the paboxini preparation proposed by the present invention, its preparation method, use and stabilized Pabsini solid preparation have been described by the examples, and the relevant skilled person can obviously The technology of the present invention can be implemented by modifying or appropriately changing and combining the technical solutions described herein without departing from the scope of the present invention. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the spirit, scope and content of the invention.

Claims (14)

A compound having a chemical structure as shown in Formula I:

The compound according to claim 1, which has a purity of 90% or more, preferably 95% or more, and more preferably 99% or more. The method of preparing a compound according to claim 1, wherein the method comprises the steps of: (a) adding a reaction solvent and a formylating reagent to the salt of pabsini free base or paboxini with an acid; (b) heating to a temperature of 30 to 150 ° C, preferably 90 to 120 ° C to carry out the reaction; (c) After completion of the reaction, N-formylparcosonib was isolated. The preparation method according to claim 3, wherein in the step a), the acid forming a salt with paboxini is selected from the group consisting of isethionethane, hydrobromic acid, hydrochloric acid, sulfuric acid, sulfuric acid, methanesulfonic acid, Citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, p-toluenesulfonic acid, formic acid, acetic acid, propionic acid and palmitic acid are preferably hydrochloric acid. The preparation method according to claim 3 or 4, wherein in the step (a), the reaction solvent is water, a polar organic solvent or a mixed solvent thereof, wherein the polar organic solvent is preferably formic acid, N, N-dimethylformamide and dimethyl sulfoxide. The preparation method according to any one of claims 3 to 5, wherein in the step (a), the formylating agent is formic acid, methyl formate, ethyl formate, propyl formate or formic acid. Propyl ester, n-butyl formate, isobutyl formate, tert-butyl formate, benzyl formate, C1-C5 linear or branched alkyl substituted benzyl formate, phenolic formate, C1-C5 linear or branched formate Alkyl substituted phenol ester, or formic acid with acetic anhydride, trifluoroacetic anhydride, methyl chloroformate, ethyl chloroformate, chloroformic acid a mixture of n-propyl ester, isopropyl chloroformate, n-butyl chloroformate, tert-butyl chloroformate or benzyl chloroformate, preferably formic acid, methyl formate, ethyl formate, benzyl formate, or formic acid and acetic anhydride. mixture. The preparation method according to any one of claims 3 to 6, wherein in the step (a), when the formylating agent is formic acid, the formylating agent is separated from the Paboxini The volume ratio of the salt formed by the base or paboxini to the acid is from 0.1 to 100:1 ml/g, preferably from 5 to 50:1 ml/g, more preferably from 25 to 50:1 ml/g; when the formylation reagent is selected From methyl formate, ethyl formate, propyl formate, isopropyl formate, n-butyl formate, isobutyl formate, tert-butyl formate, benzyl formate, C1-C5 linear or branched alkyl substituted benzyl Ester, phenolic formate, C1-C5 linear or branched alkyl substituted phenolic ester, or formic acid with acetic anhydride, trifluoroacetic anhydride, methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, chloroformic acid When a mixture of isopropyl ester, n-butyl chloroformate, tert-butyl chloroformate or benzyl chloroformate, the molar ratio of the formylating agent to the Pabsini molecule is 0.2 to 100:1, preferably 3 to 40:1. Use of the compound of claim 1 as an impurity control in the detection of the impurity of the Pabsini preparation. A solid preparation of Pabsini containing Pabsini or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient characterized by being placed at 60 ° C, 75% relative humidity for 10 days, N - The content of formyl paboxini is not more than 0.2% of the Pabsini label. The Pabsini solid preparation according to claim 9, wherein the content of the N-formyl Paboxini is not more than Pabsini at a temperature of 60 ° C and 75% relative humidity for 10 days. 0.1% of the indicated amount. The paposinis solid preparation according to claim 9, wherein the adjuvant does not contain a reducing saccharide, preferably glucose, fructose, galactose, lactose or maltose. A method of preparing a Pabsini solid preparation according to any one of claims 9-11, comprising the steps of: 1) mixing the paboxinis or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant; 2) dry granulating the mixture of step 1) and granulating to obtain granules containing paboxini; 3) The granules are compressed into tablets or filled into capsules. A method for controlling the quality of a Pabsini solid preparation, characterized in that N-formyl Paboxini is used as an impurity control. The method of claim 13 comprising the steps of: Weighing an appropriate amount of N-formyl Paboxini in a dilution to prepare an appropriate concentration of the impurity reference solution; followed by liquid chromatography on the N-formyl Pabo contained in the sample of the Pabsini solid preparation Sini impurities are qualitatively or quantitatively studied.

Images