OA16374A - Reinforcement element for casting comprising ring shaped portions and reinforcement with such reinforcement elements. - Google Patents
Reinforcement element for casting comprising ring shaped portions and reinforcement with such reinforcement elements. Download PDFInfo
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- OA16374A OA16374A OA1201300144 OA16374A OA 16374 A OA16374 A OA 16374A OA 1201300144 OA1201300144 OA 1201300144 OA 16374 A OA16374 A OA 16374A
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- Prior art keywords
- hydrochloride
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- dimethyl
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- 230000002787 reinforcement Effects 0.000 title abstract 5
- 238000005266 casting Methods 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 20
- KZVVGZKAVZUACK-BJILWQEISA-N rilpivirine hydrochloride Chemical compound Cl.CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 KZVVGZKAVZUACK-BJILWQEISA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- 229960004481 rilpivirine hydrochloride Drugs 0.000 claims description 17
- ODGCEQLVLXJUCC-UHFFFAOYSA-N tetrafluoroborate Chemical compound F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-N 0.000 claims description 17
- DHBOHGCHPDMVOD-BJILWQEISA-N (E)-3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile;hydrochloride Chemical compound Cl.CC1=CC(\C=C\C#N)=CC(C)=C1N DHBOHGCHPDMVOD-BJILWQEISA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M Sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 9
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- NLHHRLWOUZZQLW-UHFFFAOYSA-N acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- -1 éthanol Chemical compound 0.000 claims description 6
- KGJZTOFHXCFQIV-UHFFFAOYSA-N Sodium tetrafluoroborate Chemical compound [Na+].F[B-](F)(F)F KGJZTOFHXCFQIV-UHFFFAOYSA-N 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 229910001495 sodium tetrafluoroborate Inorganic materials 0.000 claims description 5
- DJEKCSMPNQGMSE-UHFFFAOYSA-N 4-amino-1-(anilinomethyl)-2,6-dimethylcyclohexa-2,4-diene-1-carboxylic acid Chemical compound CC1C=C(N)C=C(C)C1(C(O)=O)CNC1=CC=CC=C1 DJEKCSMPNQGMSE-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin dichloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 claims description 4
- NSBSVUUVECHDDX-UHFFFAOYSA-N 2,6-dimethyl-4-nitroaniline Chemical compound CC1=CC([N+]([O-])=O)=CC(C)=C1N NSBSVUUVECHDDX-UHFFFAOYSA-N 0.000 claims description 3
- 230000000875 corresponding Effects 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 229940113088 dimethylacetamide Drugs 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- AKEBROIVCDHVSD-UHFFFAOYSA-N potassium;tetrafluoroborate Chemical compound [K+].F[B-](F)(F)F AKEBROIVCDHVSD-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000001119 stannous chloride Substances 0.000 claims description 2
- 229940013123 stannous chloride Drugs 0.000 claims description 2
- 235000011150 stannous chloride Nutrition 0.000 claims description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N Benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims 2
- ZCXOSDRICFIHTA-UHFFFAOYSA-N N-methylaniline;hydrochloride Chemical compound [Cl-].C[NH2+]C1=CC=CC=C1 ZCXOSDRICFIHTA-UHFFFAOYSA-N 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 description 14
- 229960002814 rilpivirine Drugs 0.000 description 14
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 230000002194 synthesizing Effects 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- QXCHAADSAYQDHL-UHFFFAOYSA-N 4-[(4-chloropyrimidin-2-yl)amino]benzonitrile Chemical compound ClC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 QXCHAADSAYQDHL-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- JNRBSZUSHVFWIK-UHFFFAOYSA-N 3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile Chemical compound CC1=CC(C=CC#N)=CC(C)=C1N JNRBSZUSHVFWIK-UHFFFAOYSA-N 0.000 description 4
- KVYIHCOHAXPDSK-UHFFFAOYSA-N 4-(aminomethyl)-2,6-dimethylbenzoic acid;nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1.CC1=CC(CN)=CC(C)=C1C(O)=O KVYIHCOHAXPDSK-UHFFFAOYSA-N 0.000 description 4
- YQLHQZLTGRFHJZ-UHFFFAOYSA-N CC1C(CNC2=CC=CC=C2)(C(=CC(=C1)C=CC#N)C)C(=O)O Chemical compound CC1C(CNC2=CC=CC=C2)(C(=CC(=C1)C=CC#N)C)C(=O)O YQLHQZLTGRFHJZ-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DHBOHGCHPDMVOD-UHFFFAOYSA-N 3-(4-amino-3,5-dimethylphenyl)prop-2-enenitrile;hydrochloride Chemical compound Cl.CC1=CC(C=CC#N)=CC(C)=C1N DHBOHGCHPDMVOD-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000001187 sodium carbonate Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000707 stereoselective Effects 0.000 description 3
- BIAWTEWJLFFLTI-UHFFFAOYSA-N 3-anilinoprop-2-enenitrile Chemical compound N#CC=CNC1=CC=CC=C1 BIAWTEWJLFFLTI-UHFFFAOYSA-N 0.000 description 2
- BBNOJNASJQRRSH-UHFFFAOYSA-N 4-[(6-oxo-1H-pyrimidin-2-yl)amino]benzonitrile Chemical compound N1C(=O)C=CN=C1NC1=CC=C(C#N)C=C1 BBNOJNASJQRRSH-UHFFFAOYSA-N 0.000 description 2
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 2
- QGLAYJCJLHNIGJ-UHFFFAOYSA-N 4-bromo-2,6-dimethylaniline Chemical compound CC1=CC(Br)=CC(C)=C1N QGLAYJCJLHNIGJ-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 235000012970 cakes Nutrition 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- 238000006170 formylation reaction Methods 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000002588 toxic Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- FLQBDHPWSUNFBU-UHFFFAOYSA-N 4-(aminomethyl)-2,6-dimethylbenzoic acid;aniline;hydrochloride Chemical compound Cl.NC1=CC=CC=C1.CC1=CC(CN)=CC(C)=C1C(O)=O FLQBDHPWSUNFBU-UHFFFAOYSA-N 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N Anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- GHDOZKADEWILGC-UHFFFAOYSA-M CCC(CC)(OP([O-])=O)C#N Chemical compound CCC(CC)(OP([O-])=O)C#N GHDOZKADEWILGC-UHFFFAOYSA-M 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N Dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M Tetra-n-butylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
- FMWBITALBGNLPY-UHFFFAOYSA-M [O-]P(=O)OCC#N Chemical class [O-]P(=O)OCC#N FMWBITALBGNLPY-UHFFFAOYSA-M 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- ARPLQAMUUDIHIT-UHFFFAOYSA-M cyanomethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC#N)C1=CC=CC=C1 ARPLQAMUUDIHIT-UHFFFAOYSA-M 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- STVBVOVJMOPCKS-PHEILAHGSA-N methyl (2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanoate;hydrochloride Chemical compound Cl.C1([C@]2(C)CCN(C[C@@H]2C)C[C@@H](C(=O)OC)CC=2C=CC=CC=2)=CC=CC(O)=C1 STVBVOVJMOPCKS-PHEILAHGSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- SAALQYKUFCIMHR-UHFFFAOYSA-N propan-2-ol;2-propan-2-yloxypropane Chemical compound CC(C)O.CC(C)OC(C)C SAALQYKUFCIMHR-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Abstract
Reinforcement element for being positioned within a cast to elastically withstand tensile loads thereon, said reinforcement element comprising a plane sheet- or plate-shaped body of at least one row of consecutively coupled ring-shaped portions.
Description
AN IMPROVED RILPIVIRINE PROCESS
FIELD OF THE INVENTION
The présent invention relates to a novel, cost effective and stereoselective process for the synthesis of Rilpivirine hydrochloride. Typically, the invention relates to a stereoselective synthesis of a key Rilpivirine intermediate namely, (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride wherein the desired E isomer is selectively obtained with the undesired Z isomer less than 0.5% and thereby assists in obtaining Rilpivirine hydrochloride having Z-isomer less than 0.1%.
BACKGROUND OF THE INVENTION
Rilpivirine, which is chemically known as 4-{[4-({4-[(1E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino) pyrimidin-2-yl]amino}benzonitrile, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and exhibits human îmmunodeficiency virus (HIV) réplication inhibiting properties. Rilpivirine is used as its hydrochloride sait in the anti-HIV formulations.
Rilpivirine hydrochloride (I)
Conventionally, various processes followed for the synthesis of Rilpivirine hydrochloride (I), generally involve préparation of the key intermediate, (E)-4-(2-cyanoethenyl)-2,6dimethylphenylamine hydrochloride of formula (II).
(E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II)
WO 03/016306 first disclosed the synthesis of Rilpivirine involving different routes for synthesis of 4-(2-cyanoethenyl)-2,6-dimethylphenylamine. The first route involved protection of the amino group of 4-bromo-2,6-dimethylphenylamine by converting to Ν,Ν-dimethylmethanimidamide, followed by formylation involving n-butyl lithium and dimethylformamide. The resulting formyl dérivative was treated with diethyl(cyanomethyl) phosphonate to give the cyanoethenyl compound which was deprotected using zinc chloride to yield the cyanoethenylphenylamine intermediate having an undisclosed E/Z ratio. This route involved an elaborate sequence of synthesis comprising protection of amine by its conversion into imide, use of a highly moisture sensitive and pyrophoric base such as butyl lithium and a low ytelding formylation reaction. Ail these factors made the process highly unviable on industrial scale.
The second route disclosed in WO 03/016306 employed 4-iodo-2,6-di methyl phenyl ami ne as a starting material for synthesis of cyanoethenylphenylamine intermediate, which involved reaction of the dimethylphenylamine dérivative with acrylonitrile for atleast 12 hours at 130*0 in presence of sodium acetate and a heterogeneous catalyst such as palladium on carbon. Isolation ofthe desired compound involved solvent treatment with multiple solvents followed by évaporation. This route also does not give any details of the E/Z ratio of the unsaturated intermediate product. Although this route avoids use of phosphine ligands but lengthy reaction time and problem of availability of pure halo-phenylamine dérivatives coupled with moderate yields hampers the commercial usefulness of this route.
The third route disclosed in WO 03/016306 involved reaction of 4-bromo-2,6-dimethylphenylamine with acrylamide in presence of palladium acetate, tris(2-methylphenyl)phosphine and N.Ndiethylethanamine. The resulting amide was dehydrated using phosphoryl chloride to give 4-(2cyanoethenyl)-2,6-dimethylphenylamine in a moderate yield of 67% without mentioning the E/Z ratio.
Although the E/Z isomer ratio for the cyanoethenyl dérivative obtained from these routes is not specifically disclosed in the patent, however, reproducibility of the abovementioned reactions were found to provide an E/Z ratio between 70/30 and 80/20.
Various other methods have also been reported in the literature for introduction of the cyanoethenyl group in Rilpivirine. The Journal of Médicinal Chemistry (2005), 48, 2072-79 discloses Wittig or Wadsworth-Emmons reaction of the corresponding aldéhyde with cyanomethyl triphenylphosphonium chloride to provide a product having an E/Z isomer ratio of 80/20. An alternate method of Heck reaction comprising reaction of aryl bromide with acrylonitrile in presence of tri-o-tolylphosphine and palladium acetate gave the same cornpound with a higher E/Z isomer ratio of 90/10. The method required further purification in view of the presence of a significant proportion of the Z isomer in the unsaturated intermediate.
A similar method was disclosed in Organic Process Research and Development (2008), 12, 530536. However, the E/Z ratio of 4-(2-cyanoethenyl)-2,6-dimethylphenylamîne was found to be 80/20, which was found to improve to 98/2 (E/Z) after the cornpound was converted to its hydrochloride sait utilizing éthanol and isopropanol mixture.
It would be évident from the foregoing that prior art methods are associated with the following drawbacks:
a) High proportion of Z isomer, which requires elaborate purification by utilizing column chromatographie techniques, crystallization, or successive treatment with multiple solvents, which decreases the overall yield,
b) Introduction of cyanoethenyl group to the formylated benzenamine dérivatives involves a moisture sensitive reagent like n-butyl lithium, which is not preferred on industrial scale. Further, the method utilizes cyanomethyl phosphonate esters and is silent about the proportion of the Z isomer and the higher percentage of impurities which requires elaborate purification and ultimately lowers the yield,
c) Prior art routes involve use of phosphine ligands which are expensive, environmentally toxic for large scale operations,
d) Prior art methods utilize phase transfer catalysts such as tetrabutyl ammonium bromide in stoichiometric amounts and the reactions are carried out at very high températures of upto 140-150°C.
Thus, there is a need to develop an improved, convenient and cost effective process for préparation of (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II) having
Z-isomer less than 0.5%, without involving any purification and does not involve use of phosphine reagent and which subsequently provides Rilpivirine hydrochloride (I) conforming to regulatory spécifications.
The présent inventors hâve developed a process for stereoselective synthesîs of the key Rilpivirine intermediate, (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II), comprising diazotization of 2,6-dimethyl-4-amino-1-carboxybenzyl phenylamine followed by treatment with alkali tetrafluoroborate to provide the tetrafluoroborate sait of the diazonium ion which îs followed by reaction with acrylonitrile in presence of palladium (II) acetate and subséquent deprotection of the amino group with an acid followed by treatment with hydrochloric acid to give the desired E isomer 10 of compound (II) having Z isomer content less than 0.5% and with a yield of 75-80%. The compound (II) was subsequently converted to Rilpivirine hydrochloride of formula (I) with Z isomer content less than 0.1%.
OBJECT OF THE INVENTION
An objective of the présent invention is to provide (E)-4-(2-cyanoethenyl)-2,6-dimethyl phenylamine hydrochloride (II) having Z isomer less than 0.5% by a convenient, cost-effective, industrially viable process which does not involve use of environmentally toxic phosphine reagents.
Another object of the invention is to provide a process which is amenable for synthesîs on a 20 commercial scale and in which the E isomer of 4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II) is selectively synthesized by utilizing reagents which are not hazardous and moisture sensitive.
Yet another object of the présent invention is to provide an efficient and cost-effective process for 25 préparation of Rilpivirine hydrochloride (I) with Z-isomer content less than 0.1% by utilizing (E)-4-(2cyanoethenyl)-2,6-dimethyl phenylamine hydrochloride of formula (II) having undesired Z isomer less than 0.5%.
SUMMARY OF THE INVENTION
The présent invention relates to a novel method for synthesîs of (E)-4-(2-cyanoetheny))-2,6dimethylphenylamine hydrochloride of formula (II) having desired purity.
An aspect of the invention relates to a novel and cost-effective process for préparation of (E)-4-(2cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II) having Z-isomer less than 0.5%, by a 35 process comprising reaction of 2,6-dimethyl-4-amino-1-carboxybenzyl phenylamine (V) with sodium nitrite in hydrochloric acid, followed by treatment of the diazotized compound with sodium tetrafluoroborate to give the corresponding tetrafluoroborate sait of formula (VI), which on reaction with acrylonitrile in presence of palladium acetate and a solvent gives compound (VII), which after deprotection with an acid followed by treatment with hydrochloric acid gave compound (II),
Another aspect of the invention relates to a novel and cost-effective process for préparation of Rilpivirine hydrochloride (I) having Z isomer less than 0.1%, comprising reaction of (E)-4-(2cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II) with 4-[(4-chloro-2pyrimidinyl)amino] benzonitrile of formula (XI), in acetonitrile as solvent, isolating Rilpivirine free base at alkaline pH, optionally purifying with acetone, dissolving in dimethyl sulphoxide, heating the mixture to 50-55°C and adding hydrochloric acid followed by water and isolating Rilpivirine hydrochloride having Z isomer less than 0.1% at a température of 25-30°C.
The objectives of the présent invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The présent inventors hâve surprisingly found that (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II), having Z isomer less than 0.5% can be prepared in 75-80% yield by the palladium acetate catalyzed reaction of acrylonitrile with diazonium tetrafluoroborate sait of 2,6dimethyl-4-amino-1-carboxybenzyl phenylamine. Further, Rilpivirine hydrochloride obtained from compound (II) was found to hâve Z isomer less than 0.1% (Scheme 1).
HN
NH2
NaNO21 HCl (V)
Sodium tetrafluoro borate 1 water 15-20°C
(VI)
3,5-d im ethy I -4-(ca rboxy benzylamine)-phenyl-1diazonium tetrafluoroborate
(VII)
2,6-dimethyl-4-(2-cyanc ethenyl)-phenyl-1-carboxy benzylamine
3,5-dimethyl-4-(carboxy be nzyl am ine) -1 -p heny la m i n e Hydrochloride sait (Va)
hydrochloride
Scheme 1: Method embodied in the présent invention for the préparation of Rilpivirine hydrochloride (I)
The compound of formula (V) was prepared by réaction of 2,6-dimethyl-4-nitroaniline (III) with benzylchloroformate to give 3,5-dimethyl-4-carboxybenzylamine-1-nitrobenzene (IV), which was then converted to 3,5-dimethyl-4-carboxybenzylamine-1-phenylamine hydrochloride (Va) by réduction with stannous chloride in methanol as solvent.
In an embodiment, 3,5-dimethyl-4-carboxybenzylamine-1-benzeneamine hydrochloride of formula (Va) was treated with sodium nitrite in presence of hydrochloric acid in an aqueous medium at 0 to 25*C to give the diazonium compound. After completion of the reaction as monitored by HPLC, the reaction mixture was treated with aqueous tetrafluoroborate solution to yield 3,5-dimethyl-4carboxybenzylamino-1-diazonium tetrafluoroborate (VI).
The aqueous tetrafluoroborate solution was prepared by dissolving an alkali tetrafluoroborate such as sodium tetrafluoroborate or potassium tetrafluoroborate în water to obtain a 30-50% aqueous solution.
The arenediazonium tetrafluoro borate sait of formula (VI), which separated out was filtered and dried. An organic solvent was added to the compound of formula (V).
The organic solvent was selected from the group comprising of éthanol, methanol, isopropanol, dimethyl formamide, dim ethyl acetamide and tetrahydrofuran.
Acrylonitrile was gradually added to the mixture in presence of palladium acetate and stirred at ambient température till completion of reaction. The reaction mass was filtered and concentrated to provide a residue containing 2,6-dimethyl-4-(2-cyanoethenyl)-1-carboxybenzyl phenylamine (VII),
An organic or inorganic acid but preferably an organic acid such as trifluoroacetic acid was employed for deprotection of compound (VII).
Trifluoroacetic acid was added to the residue and stirred at 40-60°C till completion of reaction as monîtored by TLC. The reaction mass was quenched with water and neutralized with liquid ammonia. The mixture was extracted with a water-immiscible solvent like toluene. The organic layer was concentrated and treated with a mixture of an alcohol like isopropanol and ether like diisopropyl ether. Hydrochloric acid dissolved in isopropanol was then added to the mixture to separate out (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II).
It îs pertinent to note that compound (II) was obtained with a yield of 75-80% and was found to hâve Z isomer less than 0.5% which was easily reduced to below 0.1% in Rilpivirine hydrochloride.
This is in stark contrast to prior art methods wherein (£)-4-(2-cyanoethenyl)-2,6dimethylphenylamine hydrochloride (II) is isolated with Z isomer more than 2% and requires repeated purification for obtaining Z isomer below the desired limits in Rilpivirine hydrochloride (I).
(£)-4-(2-Cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II) was then dissolved in acetonitrile and after addition of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (XI), the resulting mixture was heated at 70 to 90'C till completion of reaction as monitored by HPLC. The reaction mixture was then cooled to 40°C and Rilpivirine base started to separate out when the reaction mixture was made alkaline with an aqueous solution of an inorganic base like sodium carbonate.
Rilpivirine free base was then purified by refluxing in an organic solvent like acetone and after optional carbon treatment was partially concentrated, cooled and filtered.
The wet cake having Z-isomer = 0.6% was dried, dissolved in dimethyl sulphoxide, and after mixing gradually with hydrochloric acid at 50-55°C was diluted with water at same température.
The final product, which had separated out was filtered at 25 to 30°C and washed with water to provide Rilpivirine hydrochloride having Z-isomer less than 0.1%. It was observed that the filtration température was critical for obtaining the finished product with Z isomer content less than 0.1%.
The inventors found that no further purification was required thereby obviating any chance of loss in yield.
The compound of formula (XI) required for préparation of rilpivirine free base was obtained as disclosed in Scheme-2.
(XI) (IX) (X)
4-hydroxy-2-th kxnethyl pyrtmidine
CVIII)
Scheme 2: Préparation of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (XI)
4-Hydroxy-2-thiomethylpyrimidine of formula (VIII) was treated with 4-aminobenzonitrile of formula (IX) in the température range of 170 to 190°C and in absence of a solvent to provide 4-[(4-hydroxy2-pyrimidinyl)amino]benzonitrile of formula (X) of desired purity.
Compound (X) was further treated with phosphorous oxychloride to yield 4-[(4-chloro-2pyrimidinyl)amino] benzonitrile of formula (XI). The reaction was carried out in the température range of 60 to 80°C, using toluene as a solvent.
The following examples are meant to be illustrative of the présent invention. These examples exemplify the invention and are not to be construed as limitîng the scope ofthe invention.
EXAMPLES
Example 1:
Synthesis of 3,5-dimethyl-4-carboxybenzylamine-phenyl-1-diazonium tetrafluoroborate (VI) 3,5-Dimethyl-4-carboxybenzylamine-1-phenylamine hydrochloride (150gms) was added to water (1500ml) and the reaction mixture was cooied to 10 to 15°C. Concentrated hydrochloric acid (150ml) was slowly added to the reaction mass, followed by addition of 50% aqueous sodium nitrite solution (102ml) and stirred at same température. After completion of the reaction as monitored by
TLC, a 50% aqueous solution of sodium tetrafluoroborate (323ml) was added to the reaction mass and stirred. The tetrafluoroborate sait separating out from the reaction mass was filtered and dried to yield 3,5-dimethyl-4-carboxybenzylamine-phenyl-1-diazonium tetrafluoroborate.
Yield = 165 gms % Yield: 91%
Example 2:
Synthesis of 2,6-dimethyl-4-(2-cyanoethenyl)-1-carboxybenzyl phenylamine (VII)
Acrylonitriie (43.1 gms) was gradually added to 3,5-dimethyl’4-carboxybenzylamine-phenyl-1diazonium tetrafluoroborate (200gms) in méthanol (2000ml). Palladium acetate (5gms) was added to the reaction mass under stirring at 25 to 30°C and the reaction mass was stirred till completion of the reaction. Upon completion, the reaction mass was filtered, and concentrated to give a residue containing 2,6-dimethyl-4-(2-cyanoethenyl)-1-carboxybenzylphenylamine (VII) which was utilized for next reaction.
Yield = 161 gms
Example 3:
Synthesis of 2,6-dimethyl-4-(2-cyanoethenyl) phenylamine hydrochloride (II)
Trifluoroacetic acid (600 ml) was slowly added to the residue of 2,6-dimethyl-4-(2-cyanoethenyl)-1carboxybenzyl phenylamine obtained from example 2 (161gms) at 25 to 30°C and the reaction mass was stirred at 45-60°C till completion of reaction as monitored by TLC. After completion of the reaction, water (1800 ml) was added to the reaction mass, neutralized with aqueous ammonia and extracted with toluene. The organic layer was separated and concentrated to give 2,6-dimethyl-4(2-cyanoethenyl)phenylamine. The residue was admixed with 1:1 mixture of isopropanol and diisopropyl ether (1000ml) and treated with HCl dissolved in isopropanol to yield 2,6-dimethyl’4-(2cyanoethenyl)phenylamine hydrochloride sait (II) which was cooled to 25-30°C, filtered and dried. Yield = 90 g % Yield: 80% (based on compound VI)
Example 4:
Synthesis of 3,5-dimethyl-4-carboxybenzylamine-1-nitrobenzene (IV)
A solution of benzylchloroformate (1027 gms; 50% solution in toluene) was slowly added to a suspension of 2,6-dimethyl-4-nitroaniline (100gms) in toluene (1000ml) at 25 to 30°C. The mixture was refluxed till completion of the reaction. The reaction mixture was cooled at 10-15°C, filtered and dried to give 3,5-dimethyl-4-carboxybenzylamine-1-nitrobenzene (IV).
Yield: 160 g % Yield; 88%
Example 5:
Synthesis of 3,5-dimethyl-4-carboxybenzylamine-1-phenylamine hydrochloride (Va)
Stannous chloride dihydrate (394 gms) was added to a mixture of 3,5-dimethyl-4carboxybenzylamine-1-nitrobenzene (150gms) and methanol (1500ml). The reaction mass was heated at 60 to 65°C and stirred till completion of the reaction, as monitored by HPLC. The reaction mixture was concentrated and the residue was diluted with water (750ml). A 20% solution of sodium hydroxide (2000ml) was added slowly with stirring at 15 to 20‘C. The mixture was extracted with dichloromethane and the organic layer was stirred with hydrochloric acid at 10'15°C to separate 3,5-dimethyl-4-carboxybenzylamine-1-phenylamine hydrochloride sait (Va), which was filtered and dried.
Yield = 145 gms % Yield: 94%
Example 6:
Synthesis of 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (X)
A mixture of 4-hydroxy-2-thiomethylpyrimidine (VIII) (500gms) and 4-aminobenzonitrile (IX; 1246.5 g) was heated slowly to 100 to 125°C, with stirring, followed by further heating at 180 to 185°C which was continued till the reaction was complété, as monitored by HPLC. The reaction mass was then cooled to 100-110°C and toluene (2000ml) was added to it. The reaction mass was stirred at 100 to 110°C, cooled to ambient température, filtered and dried to give 4-[(4-hydroxy-2pyrimidinyl)amino]benzonitrile. Toluene (2500ml) was added to it and phosphorus oxychloride (434.5gms) was slowly added to the mixture at 50 to 70°C. The reaction mass was stirred at 70 to 75°C till completion of reaction and cooled to 10-20°C, quenched with water and neutralized by adding sodium carbonate solution, filtered at 10-20°C and dried to give 4-[(4-chloro-2pyrimidinyl)amino]benzonitrile (X).
Yield = 450 g % Yield: 83%
Example 7:
Synthesis of Rilpivirine hydrochloride
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (100gms) and 2,6-dimethyl-4-(2-cyanoethenyl) phenylamine hydrochloride (90.65gms) were mixed with acetonitrile (800ml) in an inert atmosphère and heated at 85-90°C till completion of the reaction, as monitored by HPLC. The reaction mixture was cooled to 40°C and pH of the reaction mass was adjusted to = pH 10 with 20% sodium carbonate solution. The reaction mass was fîltered at 5 to 10°C and dried to yield Rilpivirine (110 g ms).
Rilpivirine thus obtained was dissolved in acetone (3600ml) and after optional charcoal treatment 5 was concentrated to 500ml and was fîltered at 5-10°C, dried to give Rilpivirine (80gms), which was then added to dimethyl sulfoxide (338 ml) and heated to 70-75°C. The mixture was cooled to 50 to 55°C and mixed with hydrochloric acid (25ml) with constant stirring. Water (1350 ml) was added to the mixture at 40 to 45°C, which was stirred and cooled further. The reaction mass was fîltered at 25 to 30°C and the wet cake was dried to give 90gms of Rilpivirine hydrochloride (I) having Z 10 isomer less than 0.1 %.
Claims (9)
- WE CLAIM,1. A process for the préparation of (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride of formula (II) comprising reaction of 2,6-dimethyl-4-amino-1-carboxybenzyl phenylamine (V) with sodium nitrite in hydrochloric acid, followed by treatment of the diazotized compound with alkali tetrafluoroborate to give the corresponding tetrafluoroborate sait of formula (VI), which on reaction with acrylonitrile in presence of palladium acetate and a solvent gave compound (VII), which after deprotection with an acid followed by treatment with hydrochloric acid gave compound (II) having Z-isomer less than 0.5%.
- 2. The method as claimed in claim 1, wherein the solvent is selected from the group comprising of methanol, éthanol, isopropanol, dimethyl formamide, dimethyl acetamide and tetrahydrofuran.
- 3. The method as claimed in claim 1, wherein the deprotection of compound (VII) is carried out with an organic acid and an inorganic acid.
- 4. The method as claimed in claim 3, wherein the acid is preferably an organic acid and is trifluoroacetic acid.
- 5. The method as claimed in claim 2, wherein the alkali tetrafluoroborate selected from the group comprising of sodium tetrafluoroborate and potassium tetrafluoroborate.
- 6. A process for préparation of Rilpivirîne hydrochloride (I) having Z isomer less than 0.1%, comprising reaction of (E)-4-(2-cy a noethenyl)-2,6-di methyl phenylamine hydrochloride of formula (II) with 4-[(4’Chloro-2-pyrimidinyl)amino] benzonitrile of formula (XI), in acetonitrile as solvent, isolating Rilpivirîne free base at alkaline pH, optionally purifying with acetone, dissolving in dimethyl sulphoxide, heating the mixture to 50-55°C, adding hydrochloric acid followed by water and isolating Rilpivirîne hydrochloride having Z isomer less than 0.1% at a température of 25-30°C.
- 7. The method as claimed in claim 1, wherein the compound of formula (V) is prepared by a process comprising reaction of 2,6-dimethyl-4-nitroaniline (III) with benzyl chlorofomnate to give compound of formula (IV) which is then treated with stannous chloride.
- 8. (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II) having Z isomer less than 0.5%.A
- 9. Use of (E)-4-(2-cyanoethenyl)-2,6-dimethylphenylamine hydrochloride (II) having Z-isomer less than 0.5% for the préparation of Rilpivirine hydrochloride of formula (I).
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SE1001005-6 | 2010-10-12 |
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