CN111943904B - Refining method of key intermediate of neurokinin 1 receptor antagonist - Google Patents

Refining method of key intermediate of neurokinin 1 receptor antagonist Download PDF

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CN111943904B
CN111943904B CN201910401615.8A CN201910401615A CN111943904B CN 111943904 B CN111943904 B CN 111943904B CN 201910401615 A CN201910401615 A CN 201910401615A CN 111943904 B CN111943904 B CN 111943904B
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CN111943904A (en
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王晓飞
陈俊
郑礼康
柴雨柱
王华萍
徐丹
朱春霞
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Jiangsu Purun Biopharmaceutical Co ltd
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D265/00Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/281,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/301,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/321,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention provides a refining method of a key intermediate of a neurokinin 1 receptor antagonist, which adopts a proper solvent and anti-solvent system and an optimized recrystallization process to obviously reduce the content of an impurity compound B in an intermediate compound II (lower than 0.05 percent), further obviously reduce the content of an impurity compound A in a final product compound I, and the refining method with high yield has simple operation, easy industrial production and obvious progress.

Description

Refining method of key intermediate of neurokinin 1 receptor antagonist
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a refining method of a key intermediate of a high-purity human substance P neurokinin 1 (NK 1) receptor antagonist.
Background
5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ]]Ethoxy group]-3- (4-fluorophenyl) -4-morpholinyl]Methyl group]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one (compound of formula I) is a human substance P neurokinin 1 (NK 1) receptor selective high affinity antagonist developed by merck corporation, and is used clinically mainly for the prevention of acute delayed nausea and vomiting occurring during the initial and repeated treatment of highly emetic antitumor chemotherapies. The structure is as follows
Figure BDA0002059946410000011
In 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ]]Ethoxy group]-3- (4-fluorophenyl) -4-morpholinyl]Methyl group]In the preparation process of the-1, 2-dihydro-3H-1, 2, 4-triazole-3-ketone, a main impurity A exists, and the structural formula is as follows:
Figure BDA0002059946410000012
in the quality standard (EP, USP, JP) of the compound I, the content of the impurity A is strictly controlledThe standard prescribes that the impurity A is less than or equal to 0.15 percent and the total impurity is less than or equal to 0.20 percent. It follows that impurity A is the main impurity in the production of compound I and requires strict control.
In intermediate compound II
Figure BDA0002059946410000013
In the course of the preparation of (2), impurity compounds B are often produced
Figure BDA0002059946410000014
Brands K M J in 2006 at "Understanding the Origin of Unusual Stepwise Hydrogenation Kinetics in the Synthesis of the- (4-Fluorophenyl) morpholine Moiety of NK 1 Receptor Antagonist Aprepitant,Organic Process Research&The Development,2006,10:109-117 "reports that the reaction of compound II to compound I is a heterogeneous reaction, which produces impurity B, whereas the removal of impurity B by recrystallisation of compound II is difficult, and the formation of impurity B is reduced only by providing a large amount of H donor in the reaction.
Disclosure of Invention
In one aspect, the present invention provides a method for refining a compound of formula II: recrystallizing a compound of formula II in a protic solvent, wherein the compound of formula II has the structure:
Figure BDA0002059946410000021
in some embodiments, the protic solvent is selected from alcoholic solvents; preferably methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; more preferably methanol, ethanol or isopropanol; more preferably ethanol.
In some embodiments, the present invention provides a method of refining a compound of formula II: the compound of the formula II is dissolved in a proton solvent, and then an aprotic solvent is added for crystallization.
In some embodiments, the aprotic solvent is selected from one or a combination of more than two of n-hexane, n-heptane, n-pentane; preferably n-hexane or n-heptane.
In some embodiments, the volume ratio of the protic solvent to the aprotic solvent is from 3:7 to 15; preferably 3:10.
In some embodiments, the temperature at which the aprotic solvent is added is from 60 ℃ to 120 ℃; preferably 60-90 ℃; more preferably 65-75deg.C.
In some embodiments, the temperature of crystallization is from-5 ℃ to 10 ℃; preferably 0-10 ℃.
In some embodiments, the time for crystallization is from 1 to 3 hours.
In some embodiments, the invention provides a refining method of a compound of a formula II, which is characterized in that the compound of the formula II is dissolved in ethanol, then n-hexane or n-heptane is added, stirring is carried out for 40 minutes at 70 ℃, the temperature is reduced to 0-10 ℃, stirring crystallization is carried out for 1-3 hours, and then a refined product of the compound II is obtained.
In another aspect, the present invention provides a process for the preparation of compound I, comprising the steps of:
(1) Dissolving a compound of the formula II in a proton solvent, and adding an aprotic solvent for crystallization;
(2) Reacting the recrystallized compound of formula II with a compound of formula III to obtain a compound of formula I
Figure BDA0002059946410000022
Wherein step (1) is the same as the method for purifying the compound of formula II.
The content of the invention is mass fraction.
The invention adopts a proper solvent and antisolvent system and an optimized recrystallization process to obviously reduce the content of the impurity compound B in the intermediate compound II (lower than 0.05 percent), and further obviously reduce the content of the impurity compound A in the final product compound I.
Detailed description of the preferred embodiments
In order to facilitate understanding of the present invention by those skilled in the art, the synthetic route of the present invention will be specifically described below by way of specific examples.
The compound I, the impurity A and the impurity B can be measured by adopting the following HPLC analysis method:
test solution: taking a test sample, precisely weighing, adding a diluent to dissolve and dilute the test sample to prepare a solution containing about 0.5mg of compound I in each 1ml, and taking the solution as the test sample solution, wherein the diluent is acetonitrile with the volume ratio of 50:50: a mixed solution of water.
Control solution: taking a proper amount of the compound I reference substance, adding a diluent for dissolving and diluting to prepare a solution containing about 0.5 mug of the compound I reference substance per 1ml, and taking the solution as a reference substance solution.
Mobile phase a: mixing with 0.1% phosphoric acid solution (1 ml phosphoric acid, 1000ml water, and mixing well)
Mobile phase B: acetonitrile
The HPLC column was: octadecylsilane chemically bonded silica is filler [ ACE Excel 3C18-PFP (4.6mm. Times.150 mm,3.5 μm) or chromatographic column with equivalent efficacy; the flow rate is 1.0ml per minute; the column temperature is 30 ℃; detection wavelength: 210nm; elution was performed according to the following table gradient.
Figure BDA0002059946410000031
Example 1
100g of compound II (containing 0.11% of impurity compound B) and 210ml of absolute ethyl alcohol are added into a 2000ml three-necked flask, the temperature is raised and the reflux is carried out for 0.5 hour until the compound II is completely dissolved and clarified, 700ml of normal hexane is slowly added at the temperature of 70 ℃, the mixture is stirred for 40 minutes at the temperature of 70 ℃ after the addition, the temperature is reduced to 0-10 ℃, and the mixture is stirred and crystallized for 1-3 hours after the temperature is reached, thus 95.3g of refined product of the compound II is obtained, wherein the content of the impurity compound B is reduced to 0.02%.
Wherein compound II: 1 HNMR(500M,DMSO-d6)ppm:1.48-1.50(3H,d);3.34-3.39(2H,m);3.88-3.91(1H,dd);4.24-4.30(1H,td);4.62-4.64(1H,d);4.75-4.76(1H,d);5.03-5.07(1H,q);7.19-7.23(2H,t);7.54(2H,s);7.61-7.64(2H,m);7.89(1H,s);10.24(1H,s);10.62(1H,s)
example 2
100g of compound II (containing 0.11% of impurity compound B) and 210ml of absolute ethyl alcohol are added into a 2000ml three-necked flask, the temperature is raised and the reflux is carried out for 0.5 hour until the compound II is completely dissolved and clarified, 700ml of n-heptane is slowly added at the temperature of 70 ℃, the mixture is stirred for 40 minutes at the temperature of 70 ℃ after the addition, the temperature is reduced to 0-10 ℃, and the mixture is stirred and crystallized for 1-3 hours after the temperature is reached, 93.5g of refined product of the compound II is obtained, wherein the content of the impurity compound B is reduced to 0.03%.
Example 3
100g of compound II (containing 0.11% of impurity compound B) and 150ml of absolute ethyl alcohol are added into a 2000ml three-necked flask, the temperature is raised and the reflux is carried out for 0.5 hour until the compound II is completely dissolved and clarified, 700ml of n-heptane is slowly added under the temperature of 65 ℃, the mixture is stirred for 40 minutes at 70 ℃ after the addition, the temperature is reduced to 0-10 ℃, the mixture is stirred and crystallized for 1-3 hours after the temperature is reached, 90.7g of refined product of the compound II is obtained, and the content of the impurity compound B is reduced to 0.04%.
Example 4
100g of compound II (containing 0.11% of impurity compound B) and 210ml of absolute ethyl alcohol are added into a 2000ml three-necked flask, the temperature is raised and the reflux is carried out for 0.5 hour until the compound II is completely dissolved and clarified, the mixture is stirred for 40 minutes at 70 ℃, the temperature is reduced to 0-10 ℃, the mixture is stirred and crystallized for 1-3 hours after the temperature is reached, and 81.5g of refined compound II is obtained, wherein the content of the impurity compound B is reduced to 0.01%.
Example 5
100g of compound II (containing 0.11% of impurity compound B) and 150ml of absolute ethyl alcohol are added into a 2000ml three-necked bottle, the temperature is raised and the reflux is carried out for 0.5 hour until the compound II is completely dissolved and clarified, the mixture is stirred for 40 minutes at 65 ℃, the temperature is reduced to 0-10 ℃, the mixture is stirred and crystallized for 1-3 hours after the temperature is reached, 78.6g of refined product of the compound II is obtained, and the content of the impurity compound B is reduced to 0.02%.
Example 6
450ml of N, N-dimethylformamide and 50g of refined product of the compound II (containing 0.02% of the impurity compound B) are added into a 2000ml three-necked bottle, stirred and dissolved until the mixture is clear, the temperature is controlled to be 5-15 ℃, 220ml of 8% potassium carbonate aqueous solution is dropwise added, 30min of reaction is completed after the dropwise addition, 750ml of water is added after the HPLC detection reaction is completed, the temperature is controlled to be 5-10 ℃ and stirred for 1h, the mixture is filtered and dried, 45g of the compound I is obtained, the yield is 90%, and the content of the impurity compound A is 0.02%.
Wherein compound I:1HNMR (500M, DMSO-d 6) ppm:1.39-1.40 (3H, d); 2.40-2.46 (1H, m); 2.78-2.81 (1H, d); 2.87-2.89 (1H, d); 3.39-3.41 (1H, d); 3.51-3.52 (1H, d); 3.64-3.66 (1H, d); 4.14-4.18 (1H, t); 4.37-4.38 (1H, d); 4.94-4.98 (1H, q); 7.06-7.10 (2H, t); 7.39 (2H, s); 7.53 (2H, m); 7.82 (1H, s); 11.27 (1H, s); 11.37 (1H, s).
Comparative example 1
100g of Compound II (containing 0.11% of impurity compound B) and 200ml of n-hexane were put into a 2000ml three-necked flask, and the mixture was refluxed for 0.5 hour at a temperature elevated, whereby Compound II was not dissolved and the subsequent crystallization step was not performed.
Comparative example 2
100g of Compound II (containing 0.11% of impurity compound B) and 200ml of ethyl acetate were put into a 2000ml three-necked flask, and the mixture was refluxed for 0.5 hour at a temperature, whereby Compound II was not dissolved and the subsequent crystallization step was not performed.
Comparative example 3
100g of Compound II (containing 0.11% of impurity compound B) and 200ml of acetonitrile were put into a 2000ml three-necked flask, and the mixture was refluxed for 0.5 hour at a temperature, whereby Compound II was not dissolved and the subsequent crystallization step was not performed.
Comparative example 4
100g of compound II (containing 0.11% of impurity compound B) and 210ml of absolute ethyl alcohol are added into a 2000ml three-necked flask, the temperature is raised and the reflux is carried out for 0.5 hour until the compound II is completely dissolved and clarified, 700ml of ethyl acetate is slowly added at the temperature of 70 ℃, the mixture is stirred for 40 minutes at the temperature of 70 ℃ after the addition, the temperature is reduced to 0-10 ℃, and the mixture is stirred and crystallized for 1-3 hours after the temperature is reached, thus 95.3g of refined compound II is obtained, wherein the impurity compound B is 0.10%.
Comparative example 5
100g of compound II (containing 0.11% of impurity compound B) and 210ml of absolute ethyl alcohol are added into a 2000ml three-necked flask, the temperature is raised and the reflux is carried out for 0.5 hour until the compound II is completely dissolved and clarified, 700ml of acetone is slowly added at the temperature of 70 ℃, the mixture is stirred for 40 minutes at the temperature of 70 ℃ after the addition, the temperature is reduced to 0-10 ℃, and the mixture is stirred and crystallized for 1-3 hours after the temperature is reached, 93.7g of refined compound II is obtained, wherein the impurity compound B is 0.11%.

Claims (4)

1. A process for the purification of a compound of formula II: recrystallizing a compound of formula II in a protic solvent, wherein the compound of formula II has the structure:
Figure FDA0004054246550000011
the compound of the formula II is dissolved in a proton solvent, and then an aprotic solvent is added for crystallization; the aprotic solvent is ethanol, and the aprotic solvent is n-hexane or n-heptane; the volume ratio of the proton solvent to the aprotic solvent is 3:7-15; the temperature of the aprotic solvent is 65-75 ℃; the crystallization temperature is 0-10 ℃; the crystallization time is 1-3 h.
2. The refining method according to claim 1, wherein the volume ratio of the protic solvent to the aprotic solvent is 3:10.
3. The refining method according to claim 1, wherein the compound of formula II is dissolved in ethanol, then n-hexane or n-heptane is added, stirring is performed for 40 minutes at 70 ℃, cooling is performed to 0-10 ℃, and stirring crystallization is performed for 1-3 hours, so that the refined product of the compound II is obtained.
4. A process for the preparation of compound I, comprising the steps of:
(1) Dissolving a compound of the formula II in a proton solvent, and adding an aprotic solvent for crystallization; the aprotic solvent is ethanol, and the aprotic solvent is n-hexane or n-heptane; the volume ratio of the proton solvent to the aprotic solvent is 3:7-15; the temperature of the aprotic solvent is 65-75 ℃; the crystallization temperature is 0-10 ℃; the crystallization time is 1-3 h;
(2) Reacting the recrystallized compound of formula II with a compound of formula III to obtain a compound of formula I
Figure FDA0004054246550000012
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009116081A2 (en) * 2008-03-03 2009-09-24 Msn Laboratories Limited An improved process for the preparation of aprepitant
CN102850339A (en) * 2012-10-17 2013-01-02 上海博志研新药物技术有限公司 New neurokinin (NK-1) receptor antagonist crystal form and preparation method thereof
CN109467552A (en) * 2019-01-14 2019-03-15 成都晶富医药科技有限公司 The preparation process of Aprepitant

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009116081A2 (en) * 2008-03-03 2009-09-24 Msn Laboratories Limited An improved process for the preparation of aprepitant
CN102850339A (en) * 2012-10-17 2013-01-02 上海博志研新药物技术有限公司 New neurokinin (NK-1) receptor antagonist crystal form and preparation method thereof
CN109467552A (en) * 2019-01-14 2019-03-15 成都晶富医药科技有限公司 The preparation process of Aprepitant

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Understanding the Origin of Unusual Stepwise Hydrogenation Kinetics in the Synthesis of the 3-(4-Fluorophenyl)morpholine Moiety of NK1 Receptor Antagonist Aprepitant;Brands, Karel M. J. et al;《Organic Process Research & Development》;20061231;第10卷(第1期);第110、115页 *
方亮.药剂学.《药剂学》.中国医药科技出版社,2016,(第3版), *

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