CN111943904A - Method for refining key intermediate of neurokinin 1 receptor antagonist - Google Patents
Method for refining key intermediate of neurokinin 1 receptor antagonist Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000007670 refining Methods 0.000 title claims abstract description 6
- 229940123821 Neurokinin 1 receptor antagonist Drugs 0.000 title abstract description 3
- PFPSZGPAQFBVHZ-UHFFFAOYSA-N n-(3-chlorophenyl)-2-[(4-phenyl-5-pyridin-4-yl-1,2,4-triazol-3-yl)sulfanyl]acetamide Chemical compound ClC1=CC=CC(NC(=O)CSC=2N(C(C=3C=CN=CC=3)=NN=2)C=2C=CC=CC=2)=C1 PFPSZGPAQFBVHZ-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000002904 solvent Substances 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 11
- 239000000010 aprotic solvent Substances 0.000 claims description 10
- 239000003586 protic polar solvent Substances 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 31
- 229940126062 Compound A Drugs 0.000 abstract description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 abstract description 3
- 239000012296 anti-solvent Substances 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000001816 cooling Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- 102100024304 Protachykinin-1 Human genes 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- -1 (1R) -1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy Chemical group 0.000 description 1
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- LZTSCEYDCZBRCJ-UHFFFAOYSA-N 1,2-dihydro-1,2,4-triazol-3-one Chemical compound OC=1N=CNN=1 LZTSCEYDCZBRCJ-UHFFFAOYSA-N 0.000 description 1
- 101001131829 Homo sapiens P protein Proteins 0.000 description 1
- 101500027611 Homo sapiens Substance P Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- ATALOFNDEOCMKK-OITMNORJSA-N aprepitant Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](C)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC1=NNC(=O)N1 ATALOFNDEOCMKK-OITMNORJSA-N 0.000 description 1
- 229960001372 aprepitant Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 102000047119 human OCA2 Human genes 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic 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
- C07D413/06—Heterocyclic 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
-
- Y—GENERAL 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for refining 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) and further obviously reduce the content of an impurity compound A in a final product compound I.
Description
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 P substance neurokinin 1(NK1) receptor antagonist.
Background
5- [ [ (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] phenyl]Ethoxy radical]-3- (4-fluorophenyl) -4-morpholinyl]Methyl radical]-1, 2-dihydro-3H-1, 2, 4-triazol-3-one (compound of formula I) is a selective high affinity antagonist of the neurokinin 1(NK1) receptor of the human substance P developed by Merck and used clinically mainly for the prevention of the first and second course of treatment of highly emetic antitumor chemotherapyAcute delayed nausea and vomiting. The structural formula is
At 5- [ [ (2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl]Ethoxy radical]-3- (4-fluorophenyl) -4-morpholinyl]Methyl radical]During the preparation of 1, 2-dihydro-3H-1, 2, 4-triazol-3-one, a major impurity A is present, having the formula:
in the quality standards (EP, USP, JP) of the compound I, the content of the impurity A is strictly controlled, and the standards specify 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 can be seen that impurity a is the main impurity in the production of compound I and needs to be strictly controlled.
In the intermediate compound II
During the preparation process, the impurity compound B is often generated
In 2006 Brands K M J at "underlying the orientation of the inferior Stepwise Hydrogenation Kinetics in the Synthesis of the 3- (4-Fluorophenyl) morphology of NK1Receptor Antagonist Aprepitant，Organic Process Research&Development,2006,10: 109-.
Disclosure of Invention
In one aspect, the present invention provides a method for purifying a compound of formula II: recrystallizing the compound of formula II in a protic solvent, wherein the compound of formula II has the structure:
in some embodiments, the protic solvent is selected from alcoholic solvents; preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; more preferably methanol, ethanol or isopropanol; ethanol is more preferred.
In some embodiments, the present invention provides a method of purifying a compound of formula II: dissolving the compound of the formula II in a protic solvent, and adding an aprotic solvent for crystallization.
In some embodiments, the aprotic solvent is selected from one or a combination of two or more of n-hexane, n-heptane, n-pentane; n-hexane or n-heptane is preferred.
In some embodiments, the volume ratio of protic solvent to aprotic solvent is 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 to 90 ℃; more preferably from 65 to 75 ℃.
In some embodiments, the temperature of the crystallization is from-5 ℃ to 10 ℃; preferably 0-10 deg.C.
In some embodiments, the time for crystallization is 1 to 3 hours.
In some embodiments, the invention provides a refining method of a compound shown in formula II, which is characterized in that the compound shown in formula II is dissolved in ethanol, n-hexane or n-heptane is added, the mixture is stirred for 40 minutes at 70 ℃, the temperature is reduced to 0-10 ℃, and the mixture is stirred and crystallized for 1-3 hours, so that a refined product of the compound II is obtained.
In another aspect, the present invention provides a method for preparing compound I, comprising the steps of:
(1) dissolving the compound of the formula II in a protic solvent, and adding an aprotic solvent for crystallization;
(2) reacting the recrystallized compound of formula II with the compound of formula III to obtain the compound of formula I
Wherein, the step (1) is the same as the purification method of the compound of the formula II.
The contents are mass fractions.
The invention adopts a proper solvent and anti-solvent 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
The synthetic routes of the present invention are specifically illustrated below by specific examples in order to facilitate the understanding of the present invention by those skilled in the art.
The compound I, the impurity A and the impurity B can be determined by the following HPLC analysis method:
test solution: taking a test sample, precisely weighing, adding a diluent, dissolving and diluting to prepare a solution containing about 0.5mg of the compound I in each 1ml of the test sample solution, wherein the diluent is acetonitrile in a volume ratio of 50: a mixed solution of water.
Control solution: taking a proper amount of a compound I reference substance, adding a diluent to dissolve and dilute the compound I reference substance to prepare a solution containing about 0.5 mu g of the compound I per 1ml, and using the solution as a reference substance solution.
Mobile phase A: adding 0.1% phosphoric acid solution (1 ml phosphoric acid, 1000ml water, mixing)
Mobile phase B: acetonitrile
The HPLC chromatographic column comprises: octadecylsilane chemically bonded silica is filler [ ACE Excel 3C18-PFP (4.6mm × 150mm, 3.5 μm) or chromatographic column with equivalent efficiency; the flow rate was 1.0ml per minute; the column temperature is 30 ℃; detection wavelength: 210 nm; the gradient elution was performed according to the following table.
Example 1
Adding 100g of compound II (containing 0.11% of impurity compound B) and 210ml of absolute ethyl alcohol into a 2000ml three-necked bottle, heating and refluxing for 0.5 hour until the compound II is completely dissolved and clarified, slowly adding 700ml of n-hexane at the temperature of 70 ℃, stirring for 40min at the temperature of 70 ℃ after the addition is finished, cooling to 0-10 ℃, and stirring for crystallization for 1-3 hours after the temperature is reached to obtain 95.3g of a refined product of the compound II, wherein the content of the impurity compound B is reduced to 0.02%.
Wherein the compound II:1HNMR(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
Adding 100g of compound II (containing 0.11 percent of impurity compound B) and 210ml of absolute ethyl alcohol into a 2000ml three-necked bottle, heating and refluxing for 0.5 hour until the compound II is completely dissolved and clarified, slowly adding 700ml of n-heptane at the temperature of 70 ℃, stirring for 40min at the temperature of 70 ℃ after the addition is finished, cooling to 0-10 ℃, and stirring for crystallization for 1-3 hours after the temperature is reached to obtain 93.5g of a refined product of the compound II, wherein the content of the impurity compound B is reduced to 0.03 percent.
Example 3
Adding 100g of compound II (containing 0.11 percent of impurity compound B) and 150ml of absolute ethyl alcohol into a 2000ml three-necked bottle, heating and refluxing for 0.5 hour until the compound II is completely dissolved and clarified, slowly adding 700ml of n-heptane at the temperature of 65 ℃, stirring for 40min at 70 ℃ after the addition is finished, cooling to 0-10 ℃, stirring and crystallizing for 1-3 hours after the temperature is reached to obtain 90.7g of a refined product of the compound II, wherein the content of the impurity compound B is reduced to 0.04 percent.
Example 4
Adding 100g of compound II (containing 0.11% of impurity compound B) and 210ml of absolute ethyl alcohol into a 2000ml three-necked bottle, heating and refluxing for 0.5 hour until the compound II is completely dissolved and clarified, stirring for 40min at 70 ℃, cooling to 0-10 ℃, stirring and crystallizing for 1-3 hours after reaching the temperature to obtain 81.5g of a refined product of the compound II, wherein the content of the impurity compound B is reduced to 0.01%.
Example 5
Adding 100g of compound II (containing 0.11% of impurity compound B) and 150ml of absolute ethyl alcohol into a 2000ml three-necked bottle, heating and refluxing for 0.5 hour until the compound II is completely dissolved and clarified, stirring for 40min at 65 ℃, cooling to 0-10 ℃, stirring and crystallizing for 1-3 hours after reaching the temperature to obtain 78.6g of a refined product of the compound II, wherein the content of the impurity compound B is reduced to 0.02%.
Example 6
Adding 450ml of N, N-dimethylformamide and 50g of refined product of the compound II (containing 0.02% of the impurity compound B) into a 2000ml three-necked bottle, stirring and dissolving to be clear, controlling the temperature to be 5-15 ℃, dropwise adding 220ml of 8% potassium carbonate aqueous solution, reacting for 30min after finishing dropwise adding, after the HPLC detection reaction is finished, adding 750ml of water, controlling the temperature to be 5-10 ℃, stirring for 1h, filtering, and drying to obtain 45g of the compound I, wherein the yield is 90%, and the content of the impurity compound A is 0.02%.
Wherein the compound I: 1HNMR (500M, DMSO-d6) 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 the compound II (containing 0.11% of the impurity compound B) and 200ml of n-hexane were put into a 2000ml three-necked flask, and heated and refluxed for 0.5 hour, whereby the compound II was not dissolved and the subsequent crystallization step could not be carried out.
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 at elevated temperature for 0.5 hour, whereby the compound II was not dissolved and the subsequent crystallization step could not be carried out.
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 at elevated temperature for 0.5 hour, whereby the compound II was not dissolved and the subsequent crystallization step could not be carried out.
Comparative example 4
Adding 100g of compound II (containing 0.11 percent of impurity compound B) and 210ml of absolute ethyl alcohol into a 2000ml three-necked bottle, heating and refluxing for 0.5 hour until the compound II is completely dissolved and clarified, slowly adding 700ml of ethyl acetate at the temperature of 70 ℃, stirring for 40min at the temperature of 70 ℃ after the addition is finished, cooling to 0-10 ℃, and stirring for crystallization for 1-3 hours after the temperature is reached to obtain 95.3g of a refined product of the compound II, wherein the impurity compound B is 0.10 percent.
Comparative example 5
Adding 100g of compound II (containing 0.11 percent of impurity compound B) and 210ml of absolute ethyl alcohol into a 2000ml three-necked bottle, heating and refluxing for 0.5 hour until the compound II is completely dissolved and clarified, slowly adding 700ml of acetone at the temperature of 70 ℃, stirring for 40min at the temperature of 70 ℃ after the addition is finished, cooling to 0-10 ℃, and stirring and crystallizing for 1-3 hours after the temperature is reached to obtain 93.7g of a refined product of the compound II, wherein the impurity compound B is 0.11 percent.
Claims (9)
1. A method of purifying a compound of formula II: recrystallizing the compound of formula II in a protic solvent, wherein the compound of formula II has the structure:
2. the purification process according to claim 1, wherein the protic solvent is selected from the group consisting of alcoholic solvents; preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol; more preferably methanol, ethanol or isopropanol; ethanol is more preferred.
3. The purification process according to claim 1, wherein the compound of formula II is dissolved in a protic solvent, followed by addition of an aprotic solvent for crystallization; the aprotic solvent is one or a composition of more than two of n-hexane, n-heptane and n-pentane; n-hexane or n-heptane is preferred.
4. The purification process according to claim 3, wherein the volume ratio of the protic solvent to the aprotic solvent is 3:7 to 15; preferably 3: 10.
5. The purification process according to claim 3, wherein the temperature at which the aprotic solvent is added is 60 to 120 ℃; preferably 60 to 90 ℃; more preferably from 65 to 75 ℃.
6. The method according to claim 3, wherein the temperature of the crystallization is from-5 ℃ to 10 ℃; preferably 0-10 deg.C.
7. The purification process according to claim 3, wherein the time for crystallization is 1 to 3 hours.
8. The refining method of claim 3, wherein the compound of formula II is dissolved in ethanol, and n-hexane or n-heptane is added, and the mixture is stirred at 70 ℃ for 40 minutes, cooled to 0-10 ℃, and stirred for crystallization for 1-3 hours to obtain the refined compound II.
9. A process for the preparation of compound I, comprising the steps of:
(1) dissolving the compound of the formula II in a protic solvent, and adding an aprotic solvent for crystallization;
(2) reacting the recrystallized compound of formula II with the compound of formula III to obtain the compound of formula I
Priority Applications (1)
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Citations (3)
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| 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 |
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| 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 |
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| Title |
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| BRANDS, KAREL M. J. ET AL: "Understanding the Origin of Unusual Stepwise Hydrogenation Kinetics in the Synthesis of the 3-(4-Fluorophenyl)morpholine Moiety of NK1 Receptor Antagonist Aprepitant", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| 方亮: "《药剂学》", 31 March 2016, 中国医药科技出版社 * |
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