CN107722007B - Preparation method of apixaban impurity - Google Patents
Preparation method of apixaban impurity Download PDFInfo
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- CN107722007B CN107722007B CN201711125644.3A CN201711125644A CN107722007B CN 107722007 B CN107722007 B CN 107722007B CN 201711125644 A CN201711125644 A CN 201711125644A CN 107722007 B CN107722007 B CN 107722007B
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- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 229960003886 apixaban Drugs 0.000 title claims abstract description 14
- 239000012535 impurity Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- -1 4- ((5-amino-5-oxopentyl) amino) phenyl Chemical group 0.000 claims abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- 229940126214 compound 3 Drugs 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229940125904 compound 1 Drugs 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229940125898 compound 5 Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 abstract 2
- 239000007858 starting material Substances 0.000 abstract 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 abstract 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000003828 vacuum filtration Methods 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 240000004460 Tanacetum coccineum Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- RAVVJKCSZXAIQP-UHFFFAOYSA-N methyl 5-bromopentanoate Chemical compound COC(=O)CCCCBr RAVVJKCSZXAIQP-UHFFFAOYSA-N 0.000 description 1
- JAVHFVJOWIQHII-UHFFFAOYSA-N methyl 5-chloropentanoate Chemical compound COC(=O)CCCCCl JAVHFVJOWIQHII-UHFFFAOYSA-N 0.000 description 1
- LTRHTLMOPUYPRM-UHFFFAOYSA-N methyl 5-iodopentanoate Chemical compound COC(=O)CCCCI LTRHTLMOPUYPRM-UHFFFAOYSA-N 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides an apixaban impurity 6- (4- ((5-amino-5-oxopentyl) amino) phenyl) -1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-1H-pyrazole [3, 4-c)]The preparation method of pyridine-3-formamide (compound 7) takes compounds 1 and 2 as starting materials, and compounds 7 are obtained by 4 steps of substitution, N-terminal Boc protection, cyclization and alkaline hydrolysis:
Description
The technical field is as follows:
the invention relates to a preparation method of apixaban impurities, belonging to the technical field of medicines.
Background of the invention:
apixaban (Apixaban) is an orally available, highly selective, reversible, competitive inhibitor of coagulation by factor Xa in diameter developed by behmeet-schnobarbape and feverfew for the prevention and treatment of thrombosis. The clinical application is mainly used for preventing Venous Thrombosis (VTE) formation of adult patients who undergo phase-selective hip or knee replacement surgery. The FDA approved treatment for the treatment of non-valvular atrial fibrillation in 2012 and also had a positive effect on preventing stroke in patients with Acute Coronary Syndrome (ACS).
6- (4- ((5-amino-5-oxopentyl) amino) phenyl) 1- (4-methoxyphenyl) -7-oxo-4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4-c ] pyridine-3-carboxamide (Compound 7) is a by-product of the alkaline decomposition of apixaban:
the impurities can be obviously increased along with the increase of alkali concentration and the prolonging of reaction time in the synthesis process, and are difficult to remove by column chromatography, recrystallization method and other purification means due to the similarity of the structure of the impurities and apixaban, and no related preparation method report is seen at present.
With the advancement of the national research work on drug consistency, the preparation method of the impurity compound 7 is determined, a qualified reference substance is provided, and the quality control of apixaban can be positively performed.
The invention content is as follows:
the invention aims to provide a preparation method of an apixaban impurity compound 7.
The technical scheme of the invention is to provide a preparation method of an apixaban impurity compound 7, which is characterized by sequentially comprising the following reaction steps:
a, the compound 1 and the compound 2 are subjected to alkali action to obtain a compound 3;
b, reacting the compound 3 with di-tert-butyl dicarbonate to obtain a compound 4;
c, reacting the compound 4 with the compound 5 under the action of alkali, and then acidifying to obtain a compound 6;
d, under the action of formamide and metal alkali salt, obtaining a compound 7 by using the compound 6;
wherein, X in the compound 2 is halogen selected from chlorine, bromine and iodine.
According to the invention, the base in the step a is selected from one of triethylamine, sodium carbonate, potassium carbonate and cesium carbonate; the solvent is one of N, N-dimethylformamide, acetonitrile and toluene.
According to the present invention, preferably, the molar ratio of compound 1 to compound 2 in step a is 1: 0.5 to 5.0.
According to the invention, the reaction of the step b is carried out under the action of a base, wherein the base is one of triethylamine, N-diisopropylethylamine, sodium carbonate and potassium carbonate; the solvent used in the reaction is selected from one of ethyl acetate, isopropyl acetate, toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol and tert-butanol.
According to the invention, the base in the step c is selected from one of triethylamine, sodium carbonate and potassium carbonate; the acid used for acidification is selected from one of hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid; the reaction solvent is selected from one of ethyl acetate, isopropyl acetate, toluene, dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol and tert-butanol.
According to the invention, the metal base salt in the step d is selected from one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydrogen and sodium amide; the solvent used in the reaction is selected from one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, methanol, ethanol, N-propanol, isopropanol, tert-butanol, N-butanol, ethylene glycol, propylene glycol and acetonitrile.
The invention has the advantages that the compound 7 is obtained by 4 steps of reaction from the compounds 1 and 2, and the high-purity product can be obtained by column chromatography purification, thereby providing a reliable impurity reference substance for the quality control research of apixaban.
The attached drawings of the specification:
FIG. 1 preparation of Compound 6 in example 11H NMR chart;
FIG. 2 preparation of Compound 7 in example 11H NMR chart.
The specific implementation mode is as follows:
for a better understanding of the present invention, reference will now be made to the following examples, which are set forth to illustrate, but are not to be construed as the limit of the present invention.
Example 1
a: compound 1(10.0g), methyl 5-bromovalerate (8.5g), and triethylamine (2.7g) were added to DMF (20mL), and the mixture was stirred at 80-90 ℃ until compound 1 reacted completely. After cooling to 20-30 ℃, the reaction solution is slowly poured into 200mL of water, and the precipitated white solid is collected by vacuum filtration and dried to obtain 10.3g of compound 3.
b: compound 3(5.0g), di-tert-butyl dicarbonate (3.4g) and triethylamine (2.6g) were added to ethyl acetate (30mL), and the mixture was incubated at 50-60 ℃ until compound 3 reacted completely. After cooling to 20-30 ℃, the reaction solution is slowly poured into 60mL of water, standing and layering are carried out, an upper organic phase is collected, dried by sodium sulfate and concentrated under reduced pressure to obtain 5.2g of compound 4.
c: adding toluene (50mL) into a compound 4(5.0g), a compound 3(3.2g) and triethylamine (4.2g), keeping the temperature at 90-100 ℃, stirring for 6 hours, cooling to 10-20 ℃, dropping 15mL of dilute hydrochloric acid, keeping the temperature at 10-20 ℃, stirring for 2 hours, carrying out suction filtration under reduced pressure to collect light yellow solid, and drying to obtain 5.5g of a compound 6.
1HNMR(600MHz，DMSO-d6)δ：7.47-7.51(m,2H),7.33-7.34(m,2H),7.23-7.24(m,2H), 7.00-7.03(m,2H),4.33-4.37(q,J＝6.0Hz,2H),4.07-4.08(t,J＝6.0Hz,2H),3.81(s,3H),3.57-3.59 (t,J＝6.0Hz,2H),3.34(s,3H),3.21-3.34(t,J＝7.2Hz,2H),2.31-2.33(t J＝6.0Hz,2H),1.40-1.52 (m,4H),1.38(s,9H),1.18-1.19(t,J＝6.0Hz,3H)。
d: adding a compound 6(5.7g) and formamide (5.7g) into DMF (20mL), then adding sodium methoxide (2.1g), keeping the temperature at 50-60 ℃, stirring until the compound completely reacts, then dripping water (20mL), keeping the temperature at 50-60 ℃, stirring for 2 hours, cooling the reaction liquid to room temperature, pouring the reaction liquid into 100mL, carrying out reduced pressure suction filtration to collect precipitated white solid, and carrying out column chromatography separation on the solid to obtain 3.2g of a compound 7.
1HNMR(600MHz，DMSO-d6)δ：7.66(s,1H),7.52–7.45(m,2H),7.40(s,1H),7.26(s,1H), 7.05–6.95(m,4H),6.69(s,1H),6.58–6.47(m,2H),5.60(t,J＝5.6Hz,1H),3.93(t,J＝6.7Hz, 2H),3.81(s,3H),3.17(d,J＝6.7Hz,2H),2.99(dd,J＝12.6,6.6Hz,2H),2.09(t,J＝7.3Hz,2H), 1.64–1.46(m,4H)。
Example 2:
a: compound 1(10.0g), methyl 5-chloropentanoate (27.6g), a catalytic amount of potassium iodide and cesium carbonate (17.8g) were added to acetonitrile (100mL), and stirred at 70-80 ℃ until completion of the reaction of Compound 1. After cooling to 0-5 ℃, slowly pouring the reaction solution into 500mL of water, carrying out vacuum filtration to collect precipitated white solid, and drying to obtain 3.8g of a compound 3.
b: compound 3(5.0g), di-tert-butyl dicarbonate (3.4g) and sodium carbonate (2.2g) were added to dichloromethane (50mL), and the reflux was maintained until completion of the reaction of compound 3. After cooling to 20-30 ℃, the reaction solution is slowly poured into 60mL of water, standing and layering are carried out, a lower organic phase is collected, dried by sodium sulfate and concentrated under reduced pressure to obtain 4.2g of compound 4.
c: adding ethyl acetate (50mL) into compound 4(5.0g), compound 3(3.2g) and sodium carbonate (2.6g), keeping the temperature at 70-80 ℃, stirring for 6 hours, cooling to 10-20 ℃, carrying out vacuum filtration to remove inorganic salts, collecting filtrate, then dripping 15mL of dilute acetic acid, keeping the temperature at 10-20 ℃, stirring for 2 hours, carrying out vacuum filtration to collect light yellow solid, and drying to obtain 4.5g of compound 6.
d: adding a compound 6(5.7g) and formamide (5.7g) into N, N-dimethylacetamide (20mL), adding potassium tert-butoxide (3.1g), keeping the temperature at 50-60 ℃, stirring until the compound completely reacts, then dripping water (20mL), keeping the temperature at 50-60 ℃, stirring for 2 hours, cooling the reaction liquid to room temperature, pouring into 100mL, carrying out vacuum filtration to collect precipitated white solid, and carrying out column chromatography separation on the solid to obtain 3.2g of the compound 7.
Example 3:
a: compound 1(10.0g), methyl 5-iodovalerate (4.4g) and potassium carbonate (10.1g) were added to toluene (20mL), and the mixture was stirred at 80-90 ℃ until compound 1 reacted completely. After concentration under reduced pressure, 200mL of the residue was added, and the precipitated white solid was collected by suction filtration under reduced pressure and dried to obtain 11.5g of Compound 3.
b: compound 3(5.0g), di-tert-butyl dicarbonate (3.4g) and N, N-diisopropylethylamine (20mL) were added to ethanol (50mL) and the mixture was incubated at 50-60 ℃ until compound 3 reacted completely. The organic solvent was distilled off under reduced pressure, then 60mL of water and then methylene chloride (50mL) were added to the residue, and after stirring and standing, the lower organic phase was separated, collected, dried over sodium sulfate, and concentrated under reduced pressure to give 4.3g of Compound 4.
c: adding toluene (50mL) into a compound 4(5.0g), a compound 3(3.2g) and potassium carbonate (2.8g), keeping the temperature at 90-100 ℃, stirring for 6 hours, cooling to 10-20 ℃, carrying out vacuum filtration to remove inorganic salts, collecting filtrate, dripping 15mL of dilute sulfuric acid, keeping the temperature at 10-20 ℃, stirring for 2 hours, carrying out vacuum filtration to collect light yellow solid, and drying to obtain 6.2g of a compound 6.
d: adding a compound 6(5.7g) and formamide (5.7g) into tetrahydrofuran (50mL), then adding sodium ethoxide (1.8g), keeping the temperature at 50-60 ℃, stirring until the compound completely reacts, then dripping water (20mL), keeping the temperature at 50-60 ℃, stirring for 2 hours, cooling the reaction liquid to room temperature, pouring the reaction liquid into 100mL, carrying out reduced pressure suction filtration to collect precipitated white solid, and carrying out column chromatography separation on the solid to obtain 3.8g of a compound 7.
Claims (4)
1. A preparation method of apixaban impurity shown as a compound 7 is characterized in that,
wherein X in the compound 2 is halogen selected from chlorine, bromine and iodine, and the method sequentially comprises the following reaction steps:
a, obtaining a compound 3 from a compound 1 and a compound 2 under the action of alkali, wherein the alkali is selected from one of triethylamine, sodium carbonate, potassium carbonate and cesium carbonate; the solvent is one of N, N-dimethylformamide, acetonitrile and toluene;
b, reacting the compound 3 with di-tert-butyl dicarbonate to obtain a compound 4;
c, reacting the compound 4 with the compound 5 under the action of alkali, and then acidifying to obtain a compound 6;
the compound d 6 is reacted with formamide and alkali metal salt to obtain compound 7.
2. The process according to claim 1, wherein the molar ratio of compound 1 to compound 2 in step a is 1: 0.5 to 5.0.
3. The preparation method according to claim 1, wherein the solvent used in step c is selected from one of ethyl acetate and toluene; the alkali is selected from one of triethylamine, sodium carbonate and potassium carbonate; the acid used in acidification is selected from one of hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid.
4. The method according to claim 1, wherein the solvent used in step d is one selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, and acetonitrile; the metal alkali salt is selected from one of sodium methoxide, sodium ethoxide and potassium tert-butoxide.
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| CN106928220A (en) * | 2017-03-10 | 2017-07-07 | 南京正科医药股份有限公司 | One group of Eliquis impurity |
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| CN106928220A (en) * | 2017-03-10 | 2017-07-07 | 南京正科医药股份有限公司 | One group of Eliquis impurity |
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