CN107722007A - The preparation method of Eliquis impurity - Google Patents
The preparation method of Eliquis impurity Download PDFInfo
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- CN107722007A CN107722007A CN201711125644.3A CN201711125644A CN107722007A CN 107722007 A CN107722007 A CN 107722007A CN 201711125644 A CN201711125644 A CN 201711125644A CN 107722007 A CN107722007 A CN 107722007A
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- alkali
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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
- 229940047562 eliquis Drugs 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000012535 impurity Substances 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group 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 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 229940126214 compound 3 Drugs 0.000 claims description 11
- 238000006243 chemical reaction Methods 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
- 229940125904 compound 1 Drugs 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 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
- 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001447 alkali salts Chemical class 0.000 claims description 2
- 239000002585 base Substances 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
- 229910052799 carbon 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 group 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000000052 vinegar Substances 0.000 claims description 2
- 235000021419 vinegar Nutrition 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- 239000013558 reference substance Substances 0.000 abstract description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- BFJMHTOBRRZELQ-UHFFFAOYSA-N 3-iodo-2h-pyrazolo[3,4-c]pyridine Chemical compound N1=CC=C2C(I)=NNC2=C1 BFJMHTOBRRZELQ-UHFFFAOYSA-N 0.000 abstract 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 abstract 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 14
- 239000007787 solid Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 9
- 230000006837 decompression Effects 0.000 description 9
- 238000009413 insulation Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 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
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- -1 hydrogen furans Chemical class 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 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
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YZWKKMVJZFACSU-UHFFFAOYSA-N 1-bromopentane Chemical compound CCCCCBr YZWKKMVJZFACSU-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 229960003886 apixaban Drugs 0.000 description 1
- 238000011882 arthroplasty Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- YKYMGFHOJJOSEB-UHFFFAOYSA-N butan-1-ol;potassium Chemical compound [K].CCCCO YKYMGFHOJJOSEB-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001112 coagulating effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000004394 hip joint Anatomy 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
- 210000003127 knee Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 238000001556 precipitation Methods 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
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003908 quality control method Methods 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
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
Abstract
The invention provides a kind of Eliquis impurity 6 (4 ((oxopentyl of 5 amino 5) amino) phenyl) 1 (4 methoxyphenyl) 7 oxo 4; 5; 6; 7 tetrahydrochysene 1H pyrazoles [3; 4 c] pyridine 3 formamide (compound 7) preparation method; it is starting material with compound 1,2, is substituted, N ends Boc is protected, be cyclized, the step of alkaline hydrolysis 4 reacts to obtain compound 7：
Description
Technical field：
The present invention relates to a kind of preparation method of Eliquis impurity, belong to pharmaceutical technology field.
Background of invention：
Eliquis (Apixaban) is a kind of orally available, high selection researched and developed jointly by Mei-Shi Guibao when hundred and Pfizer
Property, invertibity, emulative Xa follow diameter Coagulative inhibitors agent, for preventing and treating thrombus.Clinic is mainly used in prevention and connect
By phlebothrombosis (VTE) formation of the adult patients of select a time hip joint or replacement knee in arthroplasty.FDA in 2012 ratifies to be used to control
The treatment of NVAF is treated, and also has good effect to prevention acute coronary syndrome (ACS) patient's palsy.
6- (4- ((5- amino-5-oxos amyl group) amino) phenyl) 1- (4- methoxyphenyls) -7- oxos -4,5,6,7- tetra-
Hydrogen -1H- pyrazoles [3,4-c] pyridine-3-carboxamide (compound 7) is accessory substance of the Eliquis in alkaline decomposition：
The impurity in building-up process with alkali concn increase and the reaction time extend can substantially increase, due to its structure with
Eliquis is similar, it is difficult to which the means of purification such as used column chromatography or recrystallization method removes, and has no related preparation method at present
Report.
With the propulsion that country works medicine agreement, the preparation method of impurity compound 7 is determined, there is provided qualified
Reference substance, the quality control of Eliquis can be played a positive role.
The content of the invention：
It is an object of the invention to provide a kind of preparation method of Eliquis impurity compound 7.
The technical scheme is that for a kind of preparation method of Eliquis impurity compound 7, it is characterised in that successively
Including following reactions steps：
A compounds 1 obtain compound 3 with compound 2 under alkali effect；
B compounds 3 react to obtain compound 4 with di-tert-butyl dicarbonate；
C compounds 4 are reacted with compound 5 under alkali effect, rear acidifying, obtain compound 6；
D compounds 6 obtain compound 7 under formamide, metal base salt action；
Wherein, X is halogen in compound 2, selected from chlorine, bromine, iodine.
According to the present invention, the one kind of alkali in triethylamine, sodium carbonate, potassium carbonate, cesium carbonate described in step a；It is used
The one kind of solvent in DMF, acetonitrile, toluene.
, according to the invention it is preferred to, the mol ratio of compound 1 and compound 2 is 1 in step a：0.5~5.0.
According to the present invention, step b reacts under alkali effect, and described alkali is selected from triethylamine, DIPEA, carbon
One kind in sour sodium, potassium carbonate；React solvent for use and be selected from ethyl acetate, isopropyl acetate, toluene, dichloromethane, acetonitrile, four
One kind in hydrogen furans, methanol, ethanol, isopropanol, the tert-butyl alcohol.
According to the present invention, the one kind of alkali in triethylamine, sodium carbonate, potassium carbonate described in step c；Acidifying acid used
One kind in hydrochloric acid, sulfuric acid, acetic acid, trifluoracetic acid；Reaction dissolvent is selected from ethyl acetate, isopropyl acetate, toluene, dichloro
One kind in methane, acetonitrile, tetrahydrofuran, methanol, ethanol, isopropanol, the tert-butyl alcohol.
According to the present invention, the metal alkali salt described in step d is selected from sodium methoxide, caustic alcohol, potassium tert-butoxide, sodium hydrogen, Sodamide
In one kind；React solvent for use and be selected from DMF, DMA, 1-METHYLPYRROLIDONE, four
One kind in hydrogen furans, methanol, ethanol, normal propyl alcohol, isopropanol, the tert-butyl alcohol, n-butanol, ethylene glycol, propane diols, acetonitrile.
The beneficial effects of the invention are as follows from compound 1,2s, react to obtain compound 7 through 4 steps, purifying through column chromatography can
To obtain the product of high-purity, reliable impurity reference substance is provided for the quality controling research of Eliquis.
Figure of description：
Compound 6 in Fig. 1 embodiments 11H NMR scheme；
Compound 7 in Fig. 2 embodiments 11H NMR scheme.
Embodiment：
Content for a better understanding of the present invention, it is described further with reference to specific embodiment, but not only office of the invention
It is limited to this.
Embodiment 1
a：Compound 1 (10.0g), 5- bromo pentane acid A esters (8.5g), triethylamine (2.7g) are added in DMF (20mL), protected
Warm 80-90 DEG C of stirring to compound 1 reacts complete.After being cooled to 20-30 DEG C, reaction solution is poured slowly into 200mL water, depressurized
The white solid that collected by suction separates out, 10.3g compounds 3 are obtained after drying.
b：Compound 3 (5.0g), di-tert-butyl dicarbonate (3.4g) and triethylamine (2.6g) are added into ethyl acetate
In (30mL), 50-60 DEG C of insulation reacts complete to compound 3.After being cooled to 20-30 DEG C, reaction solution is poured slowly into 60mL water
In, stratification, upper organic phase is collected, sodium sulphate is dried, and is concentrated under reduced pressure to give 5.2g compounds 4.
c：Compound 4 (5.0g), compound 3 (3.2g), triethylamine (4.2g) are added into toluene (50mL), are incubated 90-100
After DEG C stirring 6 hours, it is cooled to 10-20 DEG C, instills 15mL watery hydrochloric acid, after being incubated 10-20 DEG C of stirring 2 hours, decompression, which filters, receives
Collect light yellow solid, 5.5g compounds 6 are obtained after drying.
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：Compound 6 (5.7g), formamide (5.7g) are added in DMF (20mL), sodium methoxide (2.1g) is then added and protects
Warm 50-60 DEG C of stirring is complete to compound reaction, then instills water (20mL), continues 50-60 DEG C of insulation and stirs 2 hours, will be anti-
After answering liquid to be cooled to room temperature, pour into 100mL, the white solid that decompression collected by suction separates out, the solid is subjected to column chromatography point
From obtaining 3.2g compounds 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).
Embodiment 2：
a：Compound 1 (10.0g), 5- chloro pentane acids methyl esters (27.6g), catalytic amount KI and cesium carbonate (17.8g) are added
Enter in acetonitrile (100mL), be incubated 70-80 DEG C of stirring to compound 1 and react complete.After being cooled to 0-5 DEG C, reaction solution is slowly fallen
Enter in 500mL water, the white solid that decompression collected by suction separates out, 3.8g compounds 3 are obtained after drying.
b：Compound 3 (5.0g), di-tert-butyl dicarbonate (3.4g) and sodium carbonate (2.2g) are added into dichloromethane
In (50mL), maintain the reflux for reacting complete to compound 3.After being cooled to 20-30 DEG C, reaction solution is poured slowly into 60mL water,
Stratification, lower floor's organic phase is collected, sodium sulphate is dried, and is concentrated under reduced pressure to give 4.2g compounds 4.
c：Compound 4 (5.0g), compound 3 (3.2g), sodium carbonate (2.6g) are added into ethyl acetate (50mL), insulation
After 70-80 DEG C is stirred 6 hours, 10-20 DEG C is cooled to, decompression, which filters, removes inorganic salts, collects filtrate, then the instillation dilute vinegar of 15mL
Acid, after 10-20 DEG C of insulation stirring 2 hours, collected by suction light yellow solid is depressurized, 4.5g compounds 6 are obtained after drying.
d：Compound 6 (5.7g), formamide (5.7g) are added in DMA (20mL), then add uncle
Butanol potassium (3.1g) is incubated 50-60 DEG C of stirring to compound and reacts complete, then instills water (20mL), continues 50-60 DEG C of insulation
Stirring 2 hours, after reaction solution is cooled into room temperature, is poured into 100mL, the white solid that decompression collected by suction separates out, this is consolidated
Body carries out column chromatography for separation, obtains 3.2g compounds 7.
Embodiment 3：
a：Compound 1 (10.0g), 5- iodine methyl valerate (4.4g), potassium carbonate (10.1g) are added in toluene (20mL),
80-90 DEG C of stirring to compound 1 of insulation reacts complete.After being concentrated under reduced pressure, 200mL is added into residue, depressurizes collected by suction
The white solid of precipitation, 11.5g compounds 3 are obtained after drying.
b：By compound 3 (5.0g), di-tert-butyl dicarbonate (3.4g), N, N- diisopropylethylamine (20mL) adds ethanol
In (50 mL), 50-60 DEG C of insulation reacts complete to compound 3.Decompression is steamed in organic solvent, is then added into residue
60mL water, dichloromethane (50mL) is then added, stratification after stirring, collects lower floor's organic phase, sodium sulphate is dried, decompression
It is concentrated to give 4.3g compounds 4.
c：Compound 4 (5.0g), compound 3 (3.2g), potassium carbonate (2.8g) are added into toluene (50mL), are incubated 90-100
After DEG C stirring 6 hours, 10-20 DEG C is cooled to, decompression, which filters, removes inorganic salts, collects filtrate, instills 15mL dilute sulfuric acids, insulation
After 10-20 DEG C is stirred 2 hours, collected by suction light yellow solid is depressurized, 6.2g compounds 6 are obtained after drying.
d：Compound 6 (5.7g), formamide (5.7g) are added in tetrahydrofuran (50mL), then add caustic alcohol
(1.8g) is incubated 50-60 DEG C of stirring to compound and reacts complete, then instills water (20mL), continues 50-60 DEG C of stirring 2 of insulation
Hour, after reaction solution is cooled into room temperature, pour into 100mL, the white solid that decompression collected by suction separates out, the solid is carried out
Column chromatography for separation, obtain 3.8g compounds 7.
Claims (5)
- A kind of 1. preparation method of the Eliquis impurity shown in compound 7, it is characterised in thatWherein, X is halogen in compound 2, selected from chlorine, bromine, iodine, successively including following reactions steps：A compounds 1 obtain compound 3 with compound 2 under alkali effect；B compounds 3 react to obtain compound 4 with di-tert-butyl dicarbonate；C compounds 4 are reacted with compound 5 under alkali effect, rear acidifying, obtain compound 6；D compounds 6 obtain compound 7 under formamide, metal base salt action.
- 2. preparation method according to claim 1, it is characterised in that the mol ratio of compound 1 and compound 2 in step a For 1：0.5~5.0.
- 3. preparation method according to claim 1, it is characterised in that alkali described in step a is selected from triethylamine, sodium carbonate, carbon One kind in sour potassium, cesium carbonate；The one kind of solvent for use in DMF, acetonitrile, toluene.
- 4. preparation method according to claim 1, it is characterised in that solvent for use is selected from ethyl acetate, toluene in step c In one kind；The one kind of the alkali in triethylamine, sodium carbonate, potassium carbonate；Acid used is selected from hydrochloric acid, sulfuric acid, vinegar during acidifying One kind in acid, trifluoracetic acid.
- 5. preparation method according to claim 1, it is characterised in that solvent for use is selected from N, N- dimethyl methyls in step d One kind in acid amides, DMA, acetonitrile；The metal alkali salt is in sodium methoxide, caustic alcohol, potassium tert-butoxide It is a kind of.
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Citations (2)
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| CN105566242A (en) * | 2016-01-12 | 2016-05-11 | 江苏豪森药业集团有限公司 | Preparing method for linezolid and intermediate thereof |
| 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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| CN105566242A (en) * | 2016-01-12 | 2016-05-11 | 江苏豪森药业集团有限公司 | Preparing method for linezolid and intermediate thereof |
| 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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| 梁兴运: "阿哌沙班的合成及工艺优化", 《河南大学硕士学位论文》 * |
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