CN101128442A - Processes for the preparation of linezolid intermediate - Google Patents
Processes for the preparation of linezolid intermediate Download PDFInfo
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- CN101128442A CN101128442A CNA2006800058491A CN200680005849A CN101128442A CN 101128442 A CN101128442 A CN 101128442A CN A2006800058491 A CNA2006800058491 A CN A2006800058491A CN 200680005849 A CN200680005849 A CN 200680005849A CN 101128442 A CN101128442 A CN 101128442A
- Authority
- CN
- China
- Prior art keywords
- linezolid
- oxazolidinyl
- oxo
- fluorophenyl
- morpholinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229960003907 linezolid Drugs 0.000 title claims abstract description 157
- 238000000034 method Methods 0.000 title claims abstract description 149
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 title claims abstract description 109
- 238000002360 preparation method Methods 0.000 title claims description 23
- 150000001412 amines Chemical class 0.000 claims abstract description 23
- 239000006227 byproduct Substances 0.000 claims abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 94
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 41
- DDJRIWWXSQVYHW-UHFFFAOYSA-N CNC1NCCO1 Chemical compound CNC1NCCO1 DDJRIWWXSQVYHW-UHFFFAOYSA-N 0.000 claims description 40
- 239000011541 reaction mixture Substances 0.000 claims description 39
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 37
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 34
- 230000002829 reductive effect Effects 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 28
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 25
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- 238000006722 reduction reaction Methods 0.000 claims description 25
- 239000003054 catalyst Substances 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 229910000510 noble metal Inorganic materials 0.000 claims description 17
- 239000003960 organic solvent Substances 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 14
- 239000012535 impurity Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 9
- 230000002051 biphasic effect Effects 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 7
- 239000000908 ammonium hydroxide Substances 0.000 claims description 7
- 150000002191 fatty alcohols Chemical class 0.000 claims description 7
- 238000012544 monitoring process Methods 0.000 claims description 7
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 150000001555 benzenes Chemical class 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 5
- 229910052763 palladium Inorganic materials 0.000 claims description 5
- 229910052725 zinc Inorganic materials 0.000 claims description 5
- 239000011701 zinc Substances 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000005660 chlorination reaction Methods 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 3
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 claims description 2
- 239000013583 drug formulation Substances 0.000 claims 2
- 238000010268 HPLC based assay Methods 0.000 claims 1
- -1 gac Chemical compound 0.000 claims 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 6
- 238000004587 chromatography analysis Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract 1
- KZYMHNDGSFJVMU-ZEQRLZLVSA-N n,n-bis[[(5s)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound C([C@@H](OC1=O)CN(C(=O)C)C[C@@H]2OC(=O)N(C2)C=2C=C(F)C(N3CCOCC3)=CC=2)N1C(C=C1F)=CC=C1N1CCOCC1 KZYMHNDGSFJVMU-ZEQRLZLVSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- 239000013078 crystal Substances 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000011010 flushing procedure Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 230000005587 bubbling Effects 0.000 description 4
- TYZROVQLWOKYKF-CYBMUJFWSA-N n-[[(5r)-3-(3-fluoro-4-morpholin-4-ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide Chemical compound O=C1O[C@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-CYBMUJFWSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- WDGCBNTXZHJTHJ-UHFFFAOYSA-N 2h-1,3-oxazol-2-id-4-one Chemical group O=C1CO[C-]=N1 WDGCBNTXZHJTHJ-UHFFFAOYSA-N 0.000 description 1
- UYGKMSUDBLULNG-UHFFFAOYSA-N 3-[(2-oxo-1,3-oxazolidin-5-yl)methyl]thiophene-2-carboxamide Chemical class S1C=CC(CC2OC(=O)NC2)=C1C(=O)N UYGKMSUDBLULNG-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- VVNCNSJFMMFHPL-VKHMYHEASA-N D-penicillamine Chemical compound CC(C)(S)[C@@H](N)C(O)=O VVNCNSJFMMFHPL-VKHMYHEASA-N 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 208000008745 Healthcare-Associated Pneumonia Diseases 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
Abstract
The present invention provides improved methods of converting R-N-(4-morpholiyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) to the intermediate S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) that involve the production of fewer by-products than previous methods. The amine (II) may then be converted into linezolid (I) of high chemical purity with respect to the inactive R-enantiomer and bis-linezolid (IV), and is in high yield, without the need for tedious, complicated purification steps, such as chromatography.
Description
The cross reference of related application
The sequence number that the application has required on February 24th, 2005 to submit to is 60/656, the sequence number of submitting on February 24th, 778,2005 is that the sequence number of submitting on June 14th, 60/656,646 and 2005 is 60/690, the rights and interests of 822 provisional application, it incorporates this paper by reference into.
Invention field
The present invention relates to intermediate R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing is converted into improving one's methods of intermediate S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine, and the purposes of described method in the preparation Linezolid.
Background of invention
Linezolid [(S) N-[[3-(3-fluoro-4-morpholinyl) phenyl]-2-oxo-5- oxazolidinyl] methyl] ethanamide] be biocide.Linezolid is the (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides, and empirical formula is C
16H
20FN
3O
4, have the structure of following formula (I):
Described Linezolid in the Merck index (13th edition, Monograph number:05526, CASRegistry Number:165800-03-3), be white crystal, fusing point is 181.5-182.5 ℃.In U.S. Patent No. 5,688,792 (embodiment 5), European patent No.717738, Israel patent No.110,802, Canadian Patent No.2,168,560 and international monopoly open
WOLinezolid and preparation method thereof is disclosed in 95/07271.
This oxazolidone is by Pfizer, and Inc. as injection liquid, tablet and oral administration mixed suspension listing, is called ZYVOX in the U.S..It is mainly used in, and treatment nosocomial pneumonia, skin and skin histology infect and resistance of vancomycin property of medicine enterococcus faecalis infects.
U.S. Patent No. 5,688,792 is called ' 792 patents hereinafter, has required Linezolid and has been used for the treatment of the rights and interests of infected by microbes purposes.This patent also discloses but has not required following preparation method's rights and interests:
Scheme 1
Bricker, et al., J.Med.Chem., 39673-679 also discloses this preparation method in (1996), and wherein it states that above-mentioned path avoids using phosgene to prepare the carbamate precursor of oxazolidone ring.Its author also discloses by using potassium phthalimide to slough phthalic imidine by all methylamine aqueous solution then and has avoided using NaN
3
In above-mentioned synthesizing, will have the intermediate amine of following structure (II), S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine:
Obtain ethanamide as the oily product or in solution with acetic anhydride, Linezolid (I) without separating.Then according to (col.15, the 11.22-28) method of described separation Linezolid have wherein been described the separation method of chromatography and required flow point, and evaporation and grinding product obtain pure Linezolid then in ' 792 patents.Handle owing to reclaim required necessity, so the productive rate of Linezolid is lower.
In above-mentioned synthesizing, with the intermediate triazo-compound, R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III)
In the presence of palladium/carbon catalyst, in ethyl acetate solvent, be reduced to its corresponding amine by catalytic hydrogenation, S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).These reaction conditionss have caused the generation of the byproduct of reaction of undesirable level, thereby produce undesirable high-caliber pair-Linezolid (IV) when intermediate amine (II) acetyl turns to Linezolid (I).
Need simple, effective, industrialized method produce pure intermediate (II), be used to prepare Linezolid (I) then and need not before last grinding or recrystallization, to adopt complicated and purification process consuming time, as column chromatography.The invention provides such method.
The invention summary
In an enforcement side of the present invention, described reduction reaction is undertaken by catalytic hydrogenation, and described method comprises:
(a) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) be selected from the following organic solvent except that ethyl acetate and mix: C
1-C
8The straight or branched Fatty Alcohol(C12-C14 and C12-C18), C
6-C
12Aromatic hydrocarbon, single-, two-or three-C
1-C
4Alkyl replaces or unsubstituting phenenyl, the C except that ethyl acetate
1-C
4Alkyl ester and chlorination aromatic hydrocarbon obtain mixture;
(b) induce the catalytic hydrogenation of trinitride (III) mixture to obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
In another embodiment of the present invention, the method that R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) is reduced to S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) is provided, and described method comprises:
(a) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and straight or branched fat C
1-C
8Alcohol or biphasic solvent system are mixed, and obtain reaction mixture; With
(b) carry out reduction reaction with the reductive agent that is selected from formic acid and its salt, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
In another embodiment again, the invention provides the method that R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) is reduced to S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).This method comprises:
(a) mix R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and C
1-C
4Alkyl ester;
(b) in the presence of alkali metal base, carry out reduction reaction with the reductive agent that is selected from hydroborate and its mixture, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
In particularly preferred embodiments, used ester is an ethyl acetate.Preferably, described reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE.Preferably, used alkali is alkaline earth metal hydroxides, more preferably, is sodium hydroxide.
Preferably, described reduction reaction proceeds to fully, analyzes by regular TLC or HPLC and determines when described reduction reaction is monitored fully.
In another embodiment again, the invention provides the method that R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) is reduced to S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).This method comprises:
(a) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and C
1-C
8The straight or branched Fatty Alcohol(C12-C14 and C12-C18), single-, two-or three-C
1-C
4Alkyl replaces or unsubstituted benzene or C
1-C
4Alkyl ester mixes; With
(b) carry out reduction reaction with triethyl-phosphite (triethyl phosphite) as reductive agent and obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
In another aspect of this invention, the method for preparing Linezolid (I) is provided, described method comprises one of above-described method that trinitride (III) is reduced to amine (II), by method as known in the art amine (II) further is reduced to Linezolid then.The Linezolid of gained has high chemical purity with respect to the R-enantiomorph of non-activity and two-Linezolid (IV), and is high yield, need not tediously long and complicated purification step, as chromatography.
By method of the present invention, can make two-Linezolid (IV) foreign matter content less than about 3.2%, preferably less than about 1%, be more preferably less than about 0.10%, most preferably less than about 0.05% Linezolid (I).
In addition, by method of the present invention, can make the highly purified Linezolid (I) that need not to carry out the chromatography purification program.By adopting method disclosed herein, with respect to byproduct of reaction impurity, the purity of Linezolid (I) is preferably greater than 98% greater than 95%, most preferably greater than 99%.
The present invention also provides preparation to comprise with the HPLC peak area method and has measured the method for two-Linezolid (IV) content less than the pharmaceutical preparation of about 3.2% Linezolid (I), and described method comprises:
A) obtain one or more samples of one or more batches Linezolid (I);
B) measure two-Linezolid (IV) level in each sample;
C) according to the mensuration of each batch sample, select with the HPLC peak area method measure two-Linezolid (IV) level less than about 3.2% batch Linezolid (I); With
D) comprise with the HPLC peak area method with selected batch of preparation and measure the pharmaceutical preparation of two-Linezolid (IV) content less than about 3.2% Linezolid (I).
Detailed Description Of The Invention
Room temperature used herein is meant about 25 ℃ of about 18-, about 22 ℃ of preferably about 20-.
Biphasic solvent used herein system can be organic solvent and aequeous solvent mixture.Preferably, described aqueous solvent is a water.Organic solvent: the ratio of water is about 0.1: about 10: 1 of 1-is preferably about 1: 1.Described consisting of phase-transferring agent can be selected from various known consisting of phase-transferring agent, comprises bromination tetrabutylammonium (TBAB).
The present invention relates to R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) is reduced to the novel improved method of its corresponding amine S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
As used herein, by reduction reaction with trinitride (N
3) groups converted is amine (NH
2) group.In context, described reduction reaction can comprise catalytic hydrogenation, as, referring to Sheradsky, T.in The Chemistry of the Azido Group, Patai, S.Ed., IntersciencePress (1971), Chapter 6, p.331, or use other reductive agent.
The disclosed method for preparing Linezolid in ' 792 patent working examples 5 wherein adopts ethyl acetate by hydrogenization corresponding trinitride (III) to be reduced to corresponding amine (II) as solvent.In contrast, the hydrogenization in the method for reducing disclosed by the invention is for to carry out in the presence of no ethyl acetate solvent, or carries out in all kinds of SOLVENTS or solvent systems as reductive agent with ammonium formiate.
In an enforcement side of the present invention, reduction process is undertaken by catalytic hydrogenation, and described method comprises:
(a) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) be selected from the following organic solvent except that ethyl acetate and mix: C
1-C
8The straight or branched Fatty Alcohol(C12-C14 and C12-C18), C
6-C
12Aromatic hydrocarbon, and single-, two-, three-C
1-C
4Alkyl replaces or unsubstituted benzene, the C except that ethyl acetate
1-C
4Alkyl ester and chlorination aromatic hydrocarbon obtain mixture;
(b) induce the catalytic hydrogenation of described trinitride (III) mixture to obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
In the method, ethyl acetate does not exist with the amount that can be used as solvent or cosolvent.No ethyl acetate exists and does not comprise that ethyl acetate brings into play existing on a small quantity of solvent function with trace or being not enough to.Most preferred organic solvent is a toluene in the step (a).In order to obtain to dissolve fully, preferably, the amount of described organic solvent is about 40 volumes of about 28-, more preferably about 35 volumes (g/mL).These volumes are less than ' volume mentioned in 792 patents, therefore have advantage.
Preferably, when in step (a), mixing trinitride and organic solvent, reach dissolving fully.
Generally speaking, the catalytic hydrogenation of triazo-compound as known in the art is usually by with nitrogen wash reaction mixture 3 times, carries out for 3 times with the hydrogen flushing reaction mixture of 1.5atm, and keeping temperature simultaneously is-5 ℃-Yue 35 ℃ of pacts, is preferably room temperature.Described catalytic hydrogenation proceeds to fully preferably and monitors by analyzing with regular TLC or HPLC.
This reduction reaction is carried out in the presence of catalyzer.Catalyst system therefor is for the duty metal catalyst, as platinum, palladium.Preferably, described noble metal catalyst is a palladium.Described noble metal catalyst can be as carbon, gac or aluminum oxide (alumina) on inert support.Preferably, described noble metal catalyst is palladium carbon Pd/C.Preferably, the amount of described noble metal catalyst is about 2-20% of triazo-compound.
Preferably, described catalytic hydrogenation comprises the aqueous solution and gas form, water, C at any type of ammonium
1-C
2Alcohol, water or sodium hydroxide carry out under existing, and it joins in the reaction mixture in step (a).Preferably, in step (a), make ammonia bubbling in reaction mixture feed or ammonium hydroxide is mixed in the reaction mixture.
In a single day in step (b), obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II), can reclaim by any method as known in the art.Preferably, reclaim by filtration, more preferably, by diatomaceous earth filter and except that desolvating.
In another embodiment of the present invention, a kind of method is provided, wherein R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) has been reduced to S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine by following method:
(a) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and straight or branched fat C
1-C
8Alcohol or biphasic solvent system are mixed, and obtain reaction mixture; With
(b) carry out reduction reaction with the reductive agent that is selected from formic acid and its salt, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
Preferably, the amount of described organic solvent is about 25 volumes of about 10-, more preferably about 15 volumes (g/mL).In known prior art method, be with relatively large solvent to reach dissolving fully.
Most preferred solvent is ethanol or butanols in the step (a).Preferably, described reductive agent is an ammonium formiate.
This reduction reaction is carried out in the presence of catalyzer.Catalyst system therefor is zinc or noble metal catalyst, as platinum, palladium.Preferably, described noble metal catalyst is a palladium.Described noble metal catalyst can be as carbon, gac or aluminum oxide on inert support.Preferably, described noble metal catalyst is palladium carbon Pd/C.Preferably, the amount of described noble metal catalyst is about 2-20% of triazo-compound, and the amount of zinc is about 1-2 equivalent of triazo-compound.
Preferably, described reduction reaction proceeds to fully, analyzes with regular TLC or HPLC and judges.
In a single day obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) in step (b), available any method known in the art reclaims.Preferably, by filtered and recycled, more preferably, by diatomaceous earth filter and except that desolvating.
In another embodiment again, the invention provides the method that R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) is reduced to S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (11).This method comprises:
(a) mix R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and C
1-C
4Alkyl ester;
(b) in the presence of alkali metal base, carry out reduction reaction with the reductive agent that is selected from hydroborate and its mixture, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
In particularly preferred embodiments, used ester is an ethyl acetate.Preferably, described reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE.Preferably, used alkali is alkaline earth metal hydroxides, more preferably, is sodium hydroxide.
Preferably, by adopting regular TLC or HPLC to analyze reduction reaction is carried out fully, and judge when described reaction is carried out fully.
In another embodiment again, the invention provides the method that R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) is reduced to S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).This method comprises:
(a) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and C
1-C
8The straight or branched Fatty Alcohol(C12-C14 and C12-C18), single-, two-, three-C
1-C
4Alkyl replaces or unsubstituted benzene or C
1-C
4Alkyl ester mixes.
(b) carry out reduction reaction with triethyl-phosphite as reductive agent, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
Preferably, R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) is mixed with toluene, benzene or ethyl acetate, toluene is preferred.
Preferably, by adopting regular TLC or HPLC to analyze reduction reaction is carried out fully, and judge when described reaction is carried out fully.
In another aspect of this invention, provide the method for preparing Linezolid, it comprises one of above-described method that trinitride (III) is reduced to amine (II), uses method as known in the art further amine (II) to be reduced to Linezolid then.With respect to the R-enantiomorph and the two-Linezolid of non-activity, the gained Linezolid has high chemical purity and high yield, need not to adopt tediously long and complicated purification step such as chromatography.
In present method embodiment preferred, a pot process (one pot process) is provided, wherein amine (II) is not settled out from the reduction reaction mixture, but directly is converted into Linezolid by acetylizing in solution.Even without the precipitating action of amine (II) and/or be further purified, also can produce the Linezolid (I) of the impurity that does not contain undesirable level, thereby not need with method purifying resemble the chromatography.
When producing Linezolid (I) with method of the present invention, it is highly purified, and is substantially free of the impurity such as the two-Linezolid of by product and undesirable level.In addition, the ability of producing pure intermediate amine (II) by method of the present invention has been avoided the needs to purification step tediously long, expensive and consuming time.In the disclosed program of preparation Linezolid, after the acetylize step that amine is converted into Linezolid, need purification step.This just need tediously long chromatography program with to the separating of required flow point, then evaporation and grinding product with obtain pure Linezolid (referring to, as U.S. Patent No. 5,688,792, at col.15,11.22-28).This working method is consuming time, expensive and reduce output inevitably.
Adopt method of the present invention, can obtain two-Linezolid foreign matter content less than about 3.2%, preferably less than about 1%, be more preferably less than about 0.10%, most preferably less than about 0.05% Linezolid (I).
In addition, adopt method of the present invention, can obtain highly purified Linezolid (I) and need not to carry out the chromatography purification program.By adopting method disclosed herein, can obtain with respect to byproduct of reaction impurity purity be higher than about 95%, preferably be higher than about 98%, most preferably be higher than about 99% Linezolid (I).
The present invention also provides preparation to comprise with the HPLC peak area method and has measured the method for two-Linezolid (IV) content less than the pharmaceutical preparation of about 3.2% Linezolid (I), and described method comprises:
(a) obtain one or more samples (I) of one or more batches Linezolid;
(b) measure in each sample the level of two-Linezolid (IV);
(c) according to the mensuration of each batch sample, select with the HPLC peak area method measure pair-Linezolid (IV) level be lower than about 3.2% Linezolid (I) batch; With
(d) prepare with the HPLC peak area method with selected batch and measure the pharmaceutical preparation of two-Linezolid (IV) content less than about 3.2% Linezolid (I).
Preferably, measure two-Linezolid (IV) content less than about 0.25% with the HPLC peak area method.More preferably, less than about 0.10%, most preferably less than about 0.05%.
Be higher than 3.2% if measure two-Linezolid content with the HPLC peak area method in the step (b), can be by reducing from the ethyl acetate crystallization.
Described the present invention with reference to specific embodiment, those skilled in the art can understand other embodiments from specification sheets.The present invention also does further qualification by the embodiment of reference following detailed preparation of compositions and the inventive method purposes.Those skilled in the art be it is evident that, can improve many raw materials and method and do not depart from scope of the present invention.
Embodiment
Embodiment 1-comparing embodiment is according to U.S. Patent No. 5,688,792
By catalytic hydrogenation from trinitride (III) intermediate preparation Linezolid
In the 1L reactor, add 6g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and 150ml ethyl acetate, add 0.6g Pd/C then.With nitrogen wash 3 times of this system, with hydrogen flushing 3 times.The pressure of hydrogen is made as 1.5atm.Reaction mixture is stirred under RT, react until reacting completely with regular TLC or HPLC monitoring.By the diatomite filtration reaction mixture, under RT, in the presence of triethylamine, handle gained solution with diacetyl oxide.Leach precipitation, drying obtains containing Linezolid (I) form IV of two-Linezolid (IV) 3.2%.
Embodiment 2-by catalytic hydrogenation from trinitride (III) intermediate preparation Linezolid
In the 1L reactor, add 9g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and 150ml toluene, add 0.6g Pd/C and 20ml ammonium hydroxide then.With nitrogen wash 3 times of this system, with hydrogen flushing 3 times.The pressure of hydrogen is made as 1.5atm.Reaction mixture is stirred under RT, react until reacting completely with regular TLC or HPLC monitoring.Use the diatomite filtration reaction mixture, gained solution is handled with the normal diacetyl oxide of 1.5-5 under RT.Leach the precipitation of formation, drying obtains Linezolid (I).Do not detect the vestige of two-Linezolid (4), show wherein to contain the two-Linezolid (4) that is no more than 0.01% (w/w).
Embodiment 3-does not contain the Linezolid of (R)-Linezolid enantiomorph from trinitride (III) intermediate preparation by catalytic hydrogenation and ammonium hydroxide
In the 10L reactor, add 150g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), add the solution of 15g Pd/C in 5L toluene then.At last, add 500ml ammonium hydroxide.With nitrogen wash 3 times of this system, with hydrogen flushing 3 times.The pressure of hydrogen is made as 1.5atm.Reaction mixture is stirred under RT, react until reacting completely with regular TLC or HPLC monitoring.By the diatomite filtration reaction mixture.
Dropwise add diacetyl oxide (2 equivalent) in the solution that comprises (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) of Xing Chenging upward.Reaction mixture was stirred 4 hours under RT.During this period, be settled out Linezolid (I) crystal.Filter this crystal, drying.(the R-enantiomorph of % Linezolid: 0.6% (w/w).
Embodiment 4-does not contain the Linezolid of (R)-Linezolid enantiomorph from trinitride (III) intermediate preparation with catalytic hydrogenation and ammonia (ammonium gas)
In the 10L reactor, add 150g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and 5L toluene, add 15g Pd/C (10%Pd/C that contains 52% water) then.This system was fed 2 hours with the ammonia bubbling, use nitrogen wash then 3 times, with hydrogen flushing 3 times.The pressure of hydrogen is made as 1.5arm.Reaction mixture is stirred under RT, until reacting completely.By the diatomite filtration reaction mixture, under RT, handle gained solution with the 60ml diacetyl oxide.Leach precipitation, drying, obtain Linezolid (I) form IV (purity: 99.5%, productive rate: 91%).
Embodiment 5-prepares intermediate amine (II) by catalytic hydrogenation
In the 10L reactor, add 150g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), add the solution of 15g Pd/C in 5L toluene then.Add 500ml ammonium hydroxide at last.With nitrogen wash 3 times of this system, with hydrogen flushing 3 times.The pressure of hydrogen is made as 1.5atm.Reaction mixture is stirred under RT, react until reacting completely with regular TLC or HPLC monitoring.By the diatomite filtration reaction mixture.Leave standstill and/or cool off and be settled out S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) white solid, filter, 50 ℃ of following dried overnight.(crystal C, total purity of measuring with HPLC is 98.6%).
Embodiment 6-by catalytic hydrogenation from trinitride (III) intermediate preparation Linezolid
In the 10L reactor, add 150g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and 5L toluene, add 15g Pd/C (10%Pd/C that contains 52% water) then.This system was fed 2 hours with the ammonia bubbling, use nitrogen wash then 3 times, with hydrogen flushing 3 times.The pressure of hydrogen is made as 1.5atm.Reaction mixture is stirred under RT, react until reacting completely with regular TLC or HPLC monitoring.By the diatomite filtration reaction mixture, under RT, handle gained solution with the 60ml diacetyl oxide.Leach precipitation, drying, obtain crystal Linezolid (I) (purity: 99.5%, productive rate: 91%).
Embodiment 7-by catalytic hydrogenation from trinitride (III) intermediate preparation Linezolid
In the 10L reactor, add 150g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing, add the solution of 7.5g Pd/C in 5.25L toluene then.At last, fed 1 hour with the ammonia bubbling.With nitrogen wash 3 times of this system, with hydrogen flushing 3 times.The pressure of hydrogen is made as 1.7atm.Reaction mixture is stirred under RT, and then reaction is until reacting completely.Filter reaction mixture.Steam toluene to doing.
The 4.5L ethyl acetate is joined in the residue of (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine.This mixture heating up to dissolving, is filtered.In this solution, dropwise add diacetyl oxide (at least 2.5 equivalent).2 hours (, if desired, adding more diacetyl oxide again) of stirred reaction mixture under RT until reacting completely.During this period, be settled out Linezolid.Filter crystal, dry (form IV).Need not to be further purified.
Embodiment 8-prepares intermediate amine (II) with ammonium formiate
In three-necked flask, add 6.4g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), add 2.5g ammonium formiate, 23ml ethanol and 2.6g zinc powder then.Reaction mixture is stirred under RT, react until reacting completely with regular TLC or HPLC monitoring.Add 60ml acetone then.Filter reaction mixture, evaporation obtains solid S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) (crystal form A, measuring total purity with HPLC is 96.5%).
Embodiment 9-reductive agent: ammonium formiate (and ammonium hydroxide) does not contain the Linezolid of (R)-Linezolid enantiomorph from trinitride (III) intermediate preparation
In three-necked flask, add 6.4g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), add 100ml butanols, 2.5g ammonium formiate and 1.3g10% palladium carbon then.Reaction mixture was stirred 6 hours down at 80 ℃.Filter reaction mixture.In this organic solution, add the 4ml triethylamine, mixture is chilled to 0 ℃.Dropwise add the 4.7ml diacetyl oxide.Leach the Linezolid (I) that from reaction mixture, is settled out.Obtain 2.45g exsiccant Linezolid (I) form IV (purity: 93.2%; 50% productive rate).
Embodiment 10-reductive agent: ammonium formiate is from trinitride (III) intermediate preparation Linezolid
In three-necked flask, add 6.4g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), add 2.5g ammonium formiate, 2.6g zinc powder, 0.6gTBAB and 1: 1 ethyl acetate of 100ml then: water mixture.Reaction mixture was stirred 2 hours under RT, and reflux is 10 hours then.Filter reaction mixture.Separate each phase, with water ethyl acetate extraction 2 times.Merge all organic phases, add the 4ml triethylamine, this mixture is chilled to 0 ℃.Dropwise add the 4.7ml diacetyl oxide.The reaction mixture stirring is spent the night.Obtain dry Linezolid (the I) (purity: 98.7%, 54% productive rate) of 3.6g.
Embodiment 11-reductive agent: sodium borohydride is from trinitride (III) intermediate preparation Linezolid
In three-necked flask, add 10g R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), under nitrogen, add 1g TBAB, 2g NaBH then
4, 1g NaOH particle and 100ml ethyl acetate.Reaction mixture remained under 55 ℃ spend the night.Add entry, separate each phase.Water washs 2 times with ethyl acetate.Merge organic phase.In solution, add triethylamine (10ml), add the 10ml diacetyl oxide then.Solution stirring is spent the night.Add the 30ml sherwood oil, induce Linezolid (I) crystal settling.Obtain 2.6g white crystal (purity: 96.2% productive rate: 35%).
Embodiment 12-with diacetyl oxide from amine (II) intermediate preparation Linezolid
In the flask that 29g crystal (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) is housed, adding 200ml toluene under 25 ℃.Dropwise add diacetyl oxide (2.5 equivalent).The reaction mixture stirring is spent the night.The Linezolid that filtration is settled out from reaction mixture (I).Gained is deposited in the baking oven 50 ℃ of following dried overnight.The gained crystal is analyzed through PXRD and is shown as Linezolid (I) form IV.Productive rate is 84.9%, (R)-and Linezolid enantiomorph content is 0.03%.In addition, do not detect the vestige of two-Linezolid (IV), show that the content of two-Linezolid (IV) is lower than 0.01% (w/w).
Embodiment 13-does not contain the Linezolid of two-Linezolid (IV) and (R)-Linezolid enantiomorph from amine (II) intermediate preparation with diacetyl oxide
In the solution that comprises gained (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II), dropwise add diacetyl oxide (2 equivalent).Reaction mixture was stirred 4 hours under RT.During this period, be settled out crude product Linezolid (I).Filter crystal, dry (the R-enantiomorph of % Linezolid: 0.6% (w/w).
Embodiment 14-with ethyl acetate from amine (II) intermediate preparation Linezolid
3g S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) is mixed with the 50ml ethyl acetate.Add the 3ml triethylamine, the gained mixture is chilled to 0 ℃.Dropwise add the 2.5ml diacetyl oxide.The reaction mixture stirring is spent the night.Obtain dry Linezolid (I) form IV of 2.5g (purity: 98.3% productive rate: 70%).
Embodiment 15-batch method
(110ml 66V) mixes also reflux with ethyl acetate with Linezolid (1.7g contains 3.15% pair-Linezolid).This turbid solution of filtered while hot obtains settled solution.Be chilled to room temperature, filter crystal, drying.Obtain 1.22g (71.3% productive rate), and analyze its pair-Linezolid content.Two-Linezolid content is 0.02%.
(450ml 30V) mixes also reflux with ethyl acetate with Linezolid (15g contains 0.16% pair-Linezolid).This turbid solution of filtered while hot obtains settled solution.Be chilled to room temperature, filter crystal, drying.Obtain 12.5g (83.3% productive rate) and analyze its pair-Linezolid content, do not detect two-Linezolid.
The HPLC method
Column Hypersil Gold 150×4.6，5μ
Detectability: 0.1%
Eluent: 0.01M K
2HPO
4: MeOH A:80: 20 B:50: 50
Table 1
| Time | A | B | Flow velocity |
| 0 | 100 | 0 | 1.5 |
| 15 | 57 | 43 | 2 |
| 25 | 35 | 65 | 2 |
Claims (64)
1. one kind prepares the method for S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) by catalytic hydrogenation from R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), and described method comprises:
(a) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) be selected from the following organic solvent except that ethyl acetate and mix: C
1-C
8The straight or branched Fatty Alcohol(C12-C14 and C12-C18), C
6-C
12Aromatic hydrocarbon, single-, two-or three-C
1-C
4Alkyl replaces or unsubstituted benzene, three-C except that ethyl acetate
1-C
4Alkyl ester and chlorination aromatic hydrocarbon obtain mixture; With
(b) induce the catalytic hydrogenation of described trinitride (III) mixture, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
2. the process of claim 1 wherein that being mixed in the step (a) walk to dissolving fully.
3. claim 1 or 2 method, wherein the organic solvent in the step (a) is a toluene.
4. claim 1,2 or 3 method, the amount of wherein said organic solvent is about 40 volumes of about 28-(g/mL).
5. claim 1-3 or 4 method, the amount of wherein said organic solvent is about 35 volumes (g/mL).
6. the process of claim 1 wherein that catalytic hydrogenation proceeds to fully monitors by adopting regular TLC or HPLC to analyze.
7. claim 1 or 6 method, wherein catalytic hydrogenation is carried out in the presence of noble metal catalyst.
8. the method for claim 7, wherein said noble metal catalyst is platinum, palladium.
9. the method for claim 7, wherein catalytic hydrogenation is carried out in the presence of the noble metal catalyst that is stated from inert support such as carbon, gac or the aluminum oxide.
10. the method for claim 9, wherein said noble metal catalyst is palladium carbon Pd/C.
11. the method for claim 7, the amount of wherein said noble metal catalyst are about 2-about 20% of triazo-compound.
12. the method for claim 1-5 or 6, wherein catalytic hydrogenation comprises the aqueous solution and gas form, water, sodium hydroxide or C at any type of ammonium
1-C
2Carry out under the existence of alcohol, water or sodium hydroxide.
13. the method for claim 12, wherein catalytic hydrogenation is carried out in the presence of ammonia or ammonium hydroxide.
14. the method for claim 1-12 or 13 also comprises amine (II) is converted into Linezolid (I).
15. the method for claim 14, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 3.2%.
16. the method for claim 14, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 1%.
17. the method for claim 14, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 0.1%.
18. the method for claim 14, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 0.05%.
19. the method for claim 14, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 95%.
20. the method for claim 14, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 98%.
21. the method for claim 14, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 99%.
22. one kind prepares the method for S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) by catalytic hydrogenation from R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), described method comprises: mix the fatty C of R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and straight or branched
1-C
8Alcohol or biphasic solvent system obtain reaction mixture; Reduce described trinitride (III) with the reductive agent that is selected from formic acid and its salt, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
23. the method for claim 22, wherein said alcohol are ethanol or butanols.
24. the method for claim 22 or 23, the amount of wherein said alcohol are about 10 volumes-Yue 25 volumes of described triazo-compound.
25. claim 22,23 or 24 method, the amount of wherein said alcohol is about 15 volumes (g/mL) of described triazo-compound.
26. the method for claim 22-24 or 25, the aqueous solvent of wherein said biphasic solvent are water.
27. the method for claim 22-25 or 26, the organic solvent of wherein said biphasic solvent are ethyl acetate.
28. the method for claim 22-26 or 27, the organic solvent of wherein said biphasic solvent: the ratio of water is about 0.1: about 10: 1 of 1-
29. the method for claim 28, the organic solvent of wherein said biphasic solvent: the ratio of water is about 1: 1.
30. the method for claim 22, wherein said method comprises consisting of phase-transferring agent, and described consisting of phase-transferring agent is bromination tetrabutylammonium (TBAB) or Aliquot 336.
31. the method for claim 22, wherein said reductive agent are ammonium formiate.
32. the method for claim 22, wherein reduction reaction zinc or be stated from inert support such as carbon, gac, aluminum oxide or zinc on noble metal catalyst in the presence of carry out.
33. the method for claim 32, wherein said noble metal catalyst are palladium carbon Pd/C.
34. the method for claim 22, the amount of wherein said noble metal catalyst are about 2-20% of described triazo-compound.
35. the method for claim 32, wherein the amount of zinc is about 1-2 equivalent of described triazo-compound.
36. proceeding to fully, the method for claim 32, wherein said reduction reaction judge by adopting regular TLC or HPLC to analyze.
37. the method for claim 22 also comprises described amine (II) is converted into Linezolid.
38. the method for claim 37, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 3.2%.
39. the method for claim 38, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 1%.
40. the method for claim 39, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 0.1%.
41. the method for claim 37, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 0.05%.
42. the method for claim 37, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 95%.
43. the method for claim 37, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 98%.
44. the method for claim 43, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 99%.
45. one kind prepares the method for S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) by reduction reaction from R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), described method comprises:
(a) mix R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and C
1-C
4Alkyl ester; With
(b) in the presence of alkali metal base, carry out reduction reaction with the reductive agent that is selected from hydroborate and its mixture, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
46. the method for claim 45, wherein said ester are ethyl acetate.
47. the method for claim 45, wherein said reductive agent are sodium borohydride or POTASSIUM BOROHYDRIDE.
48. proceeding to fully, the method for claim 45, wherein said reduction reaction judge by adopting regular TLC or HPLC to analyze.
49. the method for claim 1 also comprises amine (II) is converted into Linezolid (I).
50. the method for claim 49, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 3.2%.
51. the method for claim 49, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 1%.
52. the method for claim 49, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 0.1%.
53. the method for claim 49, wherein the Linezolid of being produced (I) comprises and is less than two-Linezolid (IV) of about 0.05%.
54. the method for claim 49, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 95%.
55. the method for claim 49, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 98%.
56. the method for claim 49, the pure Linezolid of wherein being produced (I) with respect to the purity of byproduct of reaction impurity greater than about 99%.
57. one kind is reduced to the method for S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III), described method comprises:
(a) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and C
1-C
8The straight or branched Fatty Alcohol(C12-C14 and C12-C18), single-, two-, three-C
1-C
4Alkyl replaces or unsubstituted benzene or C
1-C
4Alkyl ester mixes;
(b) carry out reduction reaction with triethyl phosphate as reductive agent and obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II).
58. the method for claim 57 is wherein mixed R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) with toluene, benzene or ethyl acetate.
59. the method for claim 57 is wherein mixed R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) with toluene.
60. the method for claim 57, wherein reduction reaction being proceeded to completely, monitoring method is when to proceed to fully by regular TLC or HPLC assay determination reaction.
61. one kind prepares to comprise with the HPLC peak area method and measures the method for two-Linezolid content less than the pharmaceutical preparation of about 3.2% Linezolid, described method comprises:
A) obtain one or more samples of one or more batches Linezolid;
B) measure in each sample the level of two-Linezolid;
C) according to the mensuration of each batch sample, the level of selecting to measure two-Linezolid with the HPLC peak area method less than about 3.2% batch Linezolid; With
D) comprise with the HPLC peak area method with selected batch of preparation and measure the pharmaceutical preparation of two-Linezolid content less than about 3.2% Linezolid.
62. the method for claim 61, wherein when the level of measuring with the HPLC peak area method in the step b) be higher than about 3.2% the time, with the crystallization from ethyl acetate of described Linezolid.
63. one kind prepares to comprise with the HPLC peak area method and measures the method for two-Linezolid content less than the pharmaceutical preparation of about 3.2% Linezolid, described method comprises:
A) obtain one or more samples of one or more batches Linezolid;
B) measure in each sample the amount of two-Linezolid;
Whether the amount of two-Linezolid of measuring with the HPLC peak area method c) determining step b) is less than about 3.2%; With
D) if the amount of two-Linezolid of measuring with the HPLC peak area method in the step b) is about 3.2% or higher, then come purifying by crystallization from ethyl acetate, less than about 3.2%, and come useful in preparing drug formulations until the amount of measuring two-Linezolid with the HPLC peak area method with Linezolid through such purifying; Or
E) if the amount of two-Linezolid of measuring with the HPLC peak area method in the step b) less than about 3.2%, is then come useful in preparing drug formulations with this Linezolid.
64. a method for preparing Linezolid (I), described method comprises:
(a) by following method R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) is reduced to S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II), described method comprises:
(i) with R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) be selected from the following organic solvent except that ethyl acetate and mix: C
1-C
8The straight or branched Fatty Alcohol(C12-C14 and C12-C18), C
6-C
12Aromatic hydrocarbon, single-, two-or three-C
1-C
4Alkyl replaces or unsubstituted benzene, three-C except that ethyl acetate
1-C
4Alkyl ester and chlorination aromatic hydrocarbon obtain mixture; Induce the catalytic hydrogenation of described trinitride (III) mixture, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II); Or
(ii) mix R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and straight or branched fat C
1-C
8Alcohol or biphasic solvent system obtain reaction mixture; Reduce described trinitride (III) with the reductive agent that is selected from formic acid and its salt, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II); Or
(iii) mix R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-triazo-methane thing (III) and C
1-C
4Alkyl ester; In the presence of alkali metal base, carry out reduction reaction with the reductive agent that is selected from hydroborate and its mixture, obtain S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5- oxazolidinyl-methylamine (II);
With
(b) with top step (i), the amine (II) that produces in (ii) or (iii) is converted into Linezolid (I).
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65677805P | 2005-02-24 | 2005-02-24 | |
| US60/656,778 | 2005-02-24 | ||
| US60/656,646 | 2005-02-24 | ||
| US60/690,822 | 2005-06-14 |
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| Publication Number | Publication Date |
|---|---|
| CN101128442A true CN101128442A (en) | 2008-02-20 |
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ID=39096016
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800058491A Pending CN101128442A (en) | 2005-02-24 | 2006-02-23 | Processes for the preparation of linezolid intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103119040A (en) * | 2010-08-11 | 2013-05-22 | 斯索恩有限公司 | Process for making linezolid |
| CN109265407A (en) * | 2018-10-23 | 2019-01-25 | 扬子江药业集团北京海燕药业有限公司 | A kind of synthetic method of double Linezolids |
-
2006
- 2006-02-23 CN CNA2006800058491A patent/CN101128442A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103119040A (en) * | 2010-08-11 | 2013-05-22 | 斯索恩有限公司 | Process for making linezolid |
| CN103140487A (en) * | 2010-08-11 | 2013-06-05 | 斯索恩有限公司 | Process for making linezolid |
| CN109265407A (en) * | 2018-10-23 | 2019-01-25 | 扬子江药业集团北京海燕药业有限公司 | A kind of synthetic method of double Linezolids |
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