CN108864145B - Purification method of oxabipyridine derivative - Google Patents

Purification method of oxabipyridine derivative Download PDF

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CN108864145B
CN108864145B CN201811079076.2A CN201811079076A CN108864145B CN 108864145 B CN108864145 B CN 108864145B CN 201811079076 A CN201811079076 A CN 201811079076A CN 108864145 B CN108864145 B CN 108864145B
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monohydrochloride
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CN108864145A (en
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李小羿
戴向荣
韩可余
李刚
殷雷
凌娟
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Zhaoke Guangzhou Tumour Medicament Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Abstract

A method for purifying an oxabipyridine derivative: the method comprises the following steps: converting the oxydopyrimidine derivative from 2HCl to monohydrochloride, adding 2P-4P pyridine solution, stirring at 70-90 deg.C for 2-5 hr, and adding 5P-Extracting and filtering 7P purified water to obtain a mixture, adding 21P-24P methanol water solution (4:1, V/V), uniformly mixing at 50 ℃, adding 50% of silames @ Thiol metal scavenger based on the weight of a sample to remove heavy metal Ru, stirring for 18 hours, filtering, washing with 2 times of methanol, concentrating the filtrate at 40 ℃, concentrating to 15P, stirring at 26 ℃ for 23 hours, and filtering to obtain a finished product.

Description

Purification method of oxabipyridine derivative
Technical Field
The invention belongs to the field of medicines, and particularly relates to a purification method of an oxabipyridine derivative.
Background
TG-02, developed by Tragara, which has progressed to clinical stage II abroad, TG02 hydrochloride is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. It dose-dependently inhibits the signaling pathways of CDKs, JAK2 and FLT3 in tumor cells, the main target of which is CDKs. TG02 has antiproliferative effects in a wide range of tumor cell lines, inducing G1 cell cycle arrest and apoptosis.
Synthesis procedure of TG02
1) Will be provided with
Figure BDA0001800769460000011
By a reaction of
Figure BDA0001800769460000012
2) Will be provided with
Figure BDA0001800769460000013
Olefin generation with GRUBBS second generation catalystsMetathesis cyclization reaction to obtain crude TG02 product
Figure BDA0001800769460000014
Grubbs second generation catalysts, the structural formula of which is shown below.
Figure BDA0001800769460000021
Heavy metal ruthenium detection method
ICP-MS instrument parameters:
parameter(s) Numerical value Parameter(s) Numerical value
Plasma gas flow rate 20L/min Depth of sampling 10mm
Flow rate of carrier gas 1.5L/min Number of measurement points 4
Radio frequency power 1800W Analysis ofTime 0.1S
Temperature of the atomization chamber 3.0℃ Number of repetitions 3 times of
Microwave digestion procedure:
time/min Temperature/. degree.C Pressure/atm
0-2 100 10
2-5 120 20
5-10 150 30
10-20 250 30
Solution preparation:
precisely weighing 0.1g of sample, placing the sample in a polytetrafluoroethylene digestion tank, adding 5ml of nitric acid, shaking up, sealing the digestion tank, placing the digestion tank in a microwave digestion instrument, and digesting according to the temperature rising program of microwave digestion; after the program is operated, transferring the digestion solution to a 50ml measuring flask, and fixing the volume by using purified water to obtain a test solution; 5ng/ml, 20ng/ml and 40ng/ml Ru standard solutions are prepared to serve as control solution.
Basis of control of Ru Limit
According to the requirements of ChP, FDA and ICHQ3, Ru belongs to 2B heavy metal elements, and the control limit of Ru is 10ug/g in combination with the dosage form requirement of the preparation.
A series of Scavengers such as SiliMets Metal Scavengers and the like (such as SiliMets @ DMT, SiliMets @ cysteine, SiliMets @ Thiol) are made of high-purity silica gel of SiliCycle company, various metals such as Pd, Pt, Sn, Ru, Rh, Ni and Cr can be effectively eliminated through simple filtration, the synthesis mode of the APIS is greatly improved, the Scavengers of the SiliMets Metal Scavengers with different types are mainly different in loading capacity, and the most suitable scavenger is selected according to needs.
The purification of API from the remaining metal by conventional methods such as activated carbon, distillation, recrystallization, ultrafiltration or reverse osmosis often leads to problems such as high cost, time consumption, low efficiency and even loss of API, and the conventional heavy metal treatment method is difficult to control RU within a limited range in the synthesis process of TG 02.
Disclosure of Invention
The method for removing heavy metals in the raw material synthesis process is characterized in that acetylcysteine, kieselguhr and active carbon are mainly used for reaction or adsorption in the conventional method so as to achieve the purpose of effectively controlling the limit of heavy metals, and the TG02 raw material is difficult to control ruthenium (Ru) in the limit range according to the conventional heavy metal removal method in the synthesis process, so that the requirements of high-purity raw materials, low pollution and wide application are met; the invention aims to provide a method for removing heavy metals by using oxabipyridine derivatives. The method has the advantages of simple operation, mild reaction conditions, no high-toxicity and high-corrosion reagent, easily available raw materials, and suitability for industrial production of medicaments, and various starting raw materials can meet production requirements. The method comprises the following steps:
a method for purifying an oxabipyridine derivative, the method comprising the steps of:
1) converting the double hydrochloride of the oxabipyrimidine derivative into mono hydrochloride of the oxabipyrimidine derivative, and extracting and purifying the mono hydrochloride;
2) adding a metal adsorbent into the oxy-bipyrimidine derivative monohydrochloride purified in the step 1) for purification again;
3) concentrating and purifying the oxy-bipyrimidine derivative monohydrochloride purified in the step 2) to obtain a final finished product.
Further, the conversion of the bis-hydrochloride salt of the oxydicamidine derivative to the mono-hydrochloride salt of the oxydicamidine derivative is carried out in step 1) by adding a polybasic weak base.
Further, the weak polybasic base in the step 1) is one of pyridine solution, triethylamine solution or dimethylamine solution.
Further, the conversion temperature in step 1) is 70 ℃ to 90 ℃.
Further, the conversion time in step 1) is 2 to 5 hours.
Further explaining, the extraction and purification in the step 1) is pure water extraction, and the mass of the required pure water is 5-7 times of that of the raw materials. The extracted water amount is very important, if the water amount is large, the double waste of water source and raw material can be caused, and if the water amount is small, the incomplete removal of heavy metal can be caused.
Further, in the step 2), a methanol aqueous solution is added for purification, and the concentration of the methanol aqueous solution is 5: 1-3: 1. The proportion of the methanol aqueous solution plays an important role in removing heavy metals, if too much or too little methanol in the proportion influences the removal of the heavy metals, too much methanol can cause resource waste and can cause partial product loss, and too little methanol can cause partial heavy metals not to be removed.
Further indicates that the mass of the methanol water solution in the step 2) is 21-24 times of that of the raw material.
Further, the mass of the metal adsorbent in the step 2) accounts for 40-60% of the mass of the sample.
Further explaining, the concentration process in the step 3) is divided into two stages, wherein the concentration temperature in the first stage is 30-50 ℃, and the concentration temperature in the second stage is 28-20 ℃.
The invention has the beneficial effects that: the purification of API (target product) from the remaining metal by conventional methods such as activated carbon, distillation, recrystallization, ultrafiltration or reverse osmosis often leads to problems such as high cost, time consumption, low efficiency, and even loss of API (target product), and it is difficult to control RU within a limited range by conventional heavy metal treatment methods during the synthesis of the oxabipyrimidine derivative.
Detailed Description
The present invention is described in further detail below with reference to specific examples. It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The examples are illustrative and are not to be construed as limiting the invention. In addition, all reagents used in the following examples are commercially available or can be synthesized according to methods herein or known, and are readily available to those skilled in the art for reaction conditions not listed, if not explicitly stated.
The invention will be further described by the following technical solutions
Referring to the following formula, in the following examples, the invention proceeds according to the following reaction:
a series of synthetic steps are carried out to obtain crude TG02 product 2Hcl, the crude product is subjected to salification treatment and metal scavenger removal to achieve the purpose of controlling heavy metal Ru, and the specific steps are as follows:
step 1,
Figure BDA0001800769460000061
From 2Hcl to Hcl.
Push button
Figure BDA0001800769460000062
2HCl and 2P-4P pyridine solution are stirred for 2 to 5 hours at the temperature of 70 to 90 ℃, and finally 5P-7P purified water is used for extraction and filtration to obtain
Figure BDA0001800769460000063
Hcl, this step can control R below 100 ppm.
Step 2,
Figure BDA0001800769460000064
Hcl uses a siliamets @ Thiol metal scavenger to remove the heavy metal Ru.
Push button
Figure BDA0001800769460000065
Hcl and 21P-24P methanol water solution (4:1, V/V) are mixed evenly at 50 ℃, then 50 percent of metal scavenger of the weight of the sample is added, stirred for 18 hours, filtered, washed by 2P methanol, the filtrate is concentrated at 40 ℃, concentrated to 15P, stirred for 23 hours at 26 ℃, filtered and dried, and the finished product is obtained.
Example 1:
20g of crude TG 02-2 HCl, 500mL of methylene chloride were added to a suitable reaction flask and the pH of the solution was adjusted to 11-12 with 1% NaOH solution. And standing the solution for layering to obtain an organic layer. 10g of CWPN-16-3560 was added to the organic layer, and the mixture was stirred at 20 to 30 ℃ for 48 hours. The mixture was then filtered through celite and the filtrate was concentrated to 5P (100 g). 200mL of n-heptane was added to the concentrate, and the mixture was stirred at 20-25 ℃ for 1 hour. The mixture was filtered and the filter cake dried at 40 ℃ under reduced pressure to give 13.44g of sample, 757ppm ruthenium. .
Example 2:
0.5g TG02 (ruthenium 4742.8ppm), 25mL methylene chloride were added to a suitable reaction flask, followed by 50% wt CMPN-16-11660, stirred at 25 ℃ for 24 hours, filtered, and dried to give the product as a heavy metal for determination of ruthenium: 1026 ppm.
Example 3:
2g of crude TG02 HCl (ruthenium-1000 ppm), 45mL of 80% aqueous methanol was added to a suitable reaction flask, the mixture was heated to 50 ℃ until clear, 1.0g of CMPN-16-11660 scavenger was added to the solution and stirred at 50 ℃ for 18 hours. The mixture was then filtered and washed with 2P methanol. And the filtrate was concentrated to about 30mL at 40 ℃ under reduced pressure, with significant solids precipitated. The mixture was allowed to stand at room temperature for 23 hours, then filtered, and the filter cake was dried at 50 ℃ under reduced pressure for 5 hours to give 1.37g of a sample, yield 68.5%, ruthenium 13.1 ppm.
And (4) analyzing results:
the results of examples 1, 2 and 3 show that the removal of heavy metals is carried out in crude dihydrochloride, monohydrochloride and free state of TG02, and surprisingly it was found that the best removal is achieved in the state of TG02 monohydrochloride. In the experiment, how to form the monohydrochloride by the TG2 is also unexpectedly found by various experiments, and finally, the three solutions are found to be capable of stably producing the monohydrochloride, wherein the salt forming rate reaches 99 percent and the structure of the raw material is not damaged.
Example 4:
2.0g of crude TG02 HCl (ruthenium-1000 ppm), 45mL of 80% aqueous methanol was added to a suitable reaction flask and the mixture was heated to 50 ℃ and the solution was essentially clear. 0.2g of Charcol was added to the reaction flask and stirred at 50 ℃ for one hour. The mixture was filtered and the filter cake was washed with 80% aqueous methanol. The filtrate and the washing solution were combined, and 2.0g of Amberlite 743 was added thereto, and stirred with heating at 50 ℃ for 2 hours. The mixture was filtered and washed with 80% aqueous methanol, and the filtrate was concentrated to 30mL under reduced pressure at 40 ℃ with a solid precipitated out, and the mixture was left at room temperature for 18 hours. The concentrate was then filtered and dried at 50 ℃ under reduced pressure to give 1.02g of a sample, yield 51%, ruthenium 92.9 ppm.
Example 5:
2g of crude TG 02.2HCl (ruthenium-1000 ppm), 45mL of 80% aqueous methanol was added to a suitable reaction flask, the mixture was heated to 50 ℃ until clear, 1.0g of siliamets @ DMT scavenger was added to the solution and stirred at 50 ℃ for 18 hours. The mixture was then filtered and washed with 2P methanol. And the filtrate was concentrated to about 30mL at 40 ℃ under reduced pressure, with significant solids precipitated. The mixture was allowed to stand at room temperature for 23 hours, then filtered, and the filter cake was dried at 50 ℃ under reduced pressure for 5 hours to give a sample of 1.3g, yield 65%, ruthenium 14.9 ppm.
Example 6:
2g of crude TG 02.2HCl (ruthenium-1000 ppm), 45mL of 80% aqueous methanol was added to a suitable reaction flask, the mixture was heated to 50 ℃ until clear, 1.0g of siliamets @ Thiol scavenger was added to the solution and stirred at 50 ℃ for 18 hours. The mixture was then filtered and washed with 2P methanol. And the filtrate was concentrated to about 30mL at 40 ℃ under reduced pressure, with significant solids precipitated. The mixture was allowed to stand at room temperature for 23 hours, then filtered, and the filter cake was dried at 50 ℃ under reduced pressure for 5 hours to give 1.37g of a sample, yield 68.5%, ruthenium 14.1 ppm.
And (4) analyzing results:
comparing the test results of examples 3, 4, 5 and 6, the adsorption effect of different metal adsorbents in the state of crude monohydrochloride TG02 was poor except that the adsorption effect of example 4, and the removal rates of other metals were more than 98%. Therefore, we chose siiliames @ Thiol as a scavenger of ruthenium, a heavy metal, in general. The metal scavenger is safe and has low consumption.
Example 7:
2g of crude TG 02-2 HCl (containing ruthenium-1000 ppm) was added to a 2.5P pyridine solution and stirred at 70 ℃ for 5 hours, and finally extracted with 7P purified water and filtered to obtain crude TG 02-Hcl (ruthenium-73 ppm).
Example 8:
2g of crude compound A, 2HCl (ruthenium-1000 ppm) was added to 2.5P pyridine solution and stirred at 70 ℃ for 5 hours, and finally extracted and filtered with 7P purified water to obtain crude compound A, HCl (ruthenium-81 ppm). The structure of compound A:
Figure BDA0001800769460000091
example 8:
2g of crude compound B, 2HCl (ruthenium-1000 ppm) was added to 2.5P pyridine solution and stirred at 70 ℃ for 5 hours, and finally extracted and filtered with 7P purified water to obtain crude compound B, HCl (ruthenium-86 ppm). The structure of compound B:
Figure BDA0001800769460000101
and (4) analyzing results:
comparing the test results of examples 7, 8 and 9, the crude TG02 and TG02 derivative form monohydrochloride, and the heavy metal removal can be effectively realized.
Example 10:
weighing 2g of TG02 crude product 2HCl (containing ruthenium to 1000ppm), adding a 4P triethylamine N, N dimethylformamide (1:1v/v) mixed solution, stirring for 5 hours at 70 ℃, and finally extracting and filtering by using 7P purified water to obtain TG02 crude product monohydrochloride, wherein the content of heavy metal is 96 ppm. 2gTG02 monohydrochloride and 45mL of 80% aqueous methanol were added to a suitable reaction flask, the mixture was heated to 50 ℃ until clear, 1.0g of siliamets @ Thiol scavenger was added to the solution, and the mixture was stirred at 50 ℃ for 18 hours. The mixture was then filtered and washed with 2P methanol. And the filtrate was concentrated to about 30mL at 40 ℃ under reduced pressure, with significant solids precipitated. The mixture was allowed to stand at room temperature for 23 hours, then filtered, and the filter cake was dried at 50 ℃ under reduced pressure for 5 hours to give 1.35g of a sample, yield 67.5%, ruthenium 14.3 ppm.
Example 11:
weighing 2g of TG02 crude product 2HCl (containing ruthenium to 1000ppm), adding a 4P dimethylamine N, N dimethylformamide (1:1v/v) mixed solution, stirring for 5 hours at 70 ℃, and finally extracting and filtering by using 7P purified water to obtain TG02 crude product monohydrochloride, wherein the content of heavy metal is 82 ppm. 2gTG02 monohydrochloride and 45mL of 80% aqueous methanol were added to a suitable reaction flask, the mixture was heated to 50 ℃ until clear, 1.0g of siliamets @ Thiol scavenger was added to the solution, and the mixture was stirred at 50 ℃ for 18 hours. The mixture was then filtered and washed with 2P methanol. And the filtrate was concentrated to about 30mL at 40 ℃ under reduced pressure, with significant solids precipitated. The mixture was allowed to stand at room temperature for 23 hours, then filtered, and the filter cake was dried at 50 ℃ under reduced pressure for 5 hours to give a sample of 1.38g, yield 69%, ruthenium 14.2 ppm.
Examples 12, 13, 14, 15:
2g of crude TG02 product 2HCl (containing ruthenium-1000 ppm) is added with 2P-4P pyridine solution to be stirred for 2-5 hours at the temperature of 70-90 ℃, and finally 5P-7P purified water is used for extraction and filtration to obtain crude TG02 product monohydrochloride.
The implementation conditions are shown in Table 1
Table 1:
example 12 Example 13 Example 14 Example 15
Temperature of 60℃ 70℃ 80℃ 90℃
Time of stirring 3h 3h 4h 5h
Volume of purified water 5P 6P 6P 7P
Ru content (ppm) 256ppm 87ppm 75ppm 147ppm
And (4) analyzing results:
comparing the test results of examples 12, 13, 14, 15, crude monohydrochloride TG02 was formed under different conditions with no removal rates by metal adsorbent adsorption. It is unexpectedly found that the process of forming the monohydrochloride has strong effect of removing heavy metals, and the removal effect of the monohydrochloride is better than that of a part of metal scavenger.

Claims (8)

1. A method for purifying an oxydyrimidine derivative monohydrochloride, the method comprising the steps of:
1) converting the double hydrochloride of the oxabipyrimidine derivative into mono hydrochloride of the oxabipyrimidine derivative, and extracting and purifying the mono hydrochloride;
2) adding a metal adsorbent into the oxy-bipyrimidine derivative monohydrochloride purified in the step 1) for purification again;
3) concentrating and purifying the oxy-bipyrimidine derivative monohydrochloride purified in the step 2) to obtain a final finished product;
the oxabipyridine derivative is: TGO2, structural formula:
Figure DEST_PATH_IMAGE001
the metal adsorbent is selected from: sillimets @ DMT, sillimets @ Thiol;
in the step 1), the conversion from the double hydrochloride of the oxydicamidine derivative to the single hydrochloride of the oxydicamidine derivative is carried out by adding a polybasic weak base, wherein the polybasic weak base is one of pyridine solution, triethylamine solution or dimethylamine solution.
2. The method for purifying the monohydrochloride of an oxydyrimidine derivative according to claim 1, wherein the temperature for the conversion in step 1) is 70 ℃ to 90 ℃.
3. The method for purifying the monohydrochloride of an oxydyrimidine derivative according to claim 1, wherein the conversion time in step 1) is 2 to 5 hours.
4. The method for purifying the monohydrochloride of an oxydyrimidine derivative as claimed in claim 1, wherein the extraction purification in the step 1) is an extraction with purified water, and the mass of the purified water is 5 to 7 times that of the raw material.
5. The method for purifying an oxydicamidine derivative monohydrochloride as claimed in claim 1, characterized in that the purification in step 2) is carried out by adding methanol aqueous solution with concentration of 5: 1-3: 1.
6. The method for purifying an oxydicamidine derivative monohydrochloride as claimed in claim 5, characterized in that the mass of the methanol aqueous solution in step 2) is 21-24 times that of the raw material.
7. The method for purifying the monohydrochloride of an oxydyrimidine derivative according to claim 1, wherein the amount of the metal adsorbent used in the step 2) is 40 to 60% by mass based on the mass of the sample.
8. The method for purifying the monohydrochloride of an oxydyrimidine derivative as claimed in claim 1, wherein the concentration in the step 3) is carried out in two stages, the concentration temperature in the first stage being from 30 ℃ to 50 ℃ and the concentration temperature in the second stage being from 20 ℃ to 28 ℃.
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