CN111943904B - Refining method of key intermediate of neurokinin 1 receptor antagonist - Google Patents
Refining method of key intermediate of neurokinin 1 receptor antagonist Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000007670 refining Methods 0.000 title claims abstract description 10
- 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 35
- 239000002904 solvent Substances 0.000 claims abstract description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 239000000010 aprotic solvent Substances 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- 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
- 239000003586 protic polar solvent Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 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
- 238000001953 recrystallisation Methods 0.000 abstract description 3
- 239000012296 anti-solvent Substances 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-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
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- 101500027611 Homo sapiens Substance P Proteins 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 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 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 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
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000007865 diluting 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
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011259 mixed solution Substances 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
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 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 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
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
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:
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
In the course of the preparation of (2), impurity compounds B are often produced
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:
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
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.
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:
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
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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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| 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 * |
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