GB2463736A - Process for the preparation of ortho amino-substituted aromatic carboxylic acids - Google Patents
Process for the preparation of ortho amino-substituted aromatic carboxylic acids Download PDFInfo
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- GB2463736A GB2463736A GB0817909A GB0817909A GB2463736A GB 2463736 A GB2463736 A GB 2463736A GB 0817909 A GB0817909 A GB 0817909A GB 0817909 A GB0817909 A GB 0817909A GB 2463736 A GB2463736 A GB 2463736A
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- -1 amino-substituted aromatic carboxylic acids Chemical class 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 150000002431 hydrogen Chemical class 0.000 claims abstract 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 239000000460 chlorine Substances 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 abstract description 6
- WIFCKLPZYYALGY-UHFFFAOYSA-N 1h-pyrrole-2,3-dione Chemical compound O=C1NC=CC1=O WIFCKLPZYYALGY-UHFFFAOYSA-N 0.000 abstract 1
- PNVYBJKUNISJRL-UHFFFAOYSA-N 6-amino-5-methyl-1h-indazole-7-carboxamide Chemical compound NC(=O)C1=C(N)C(C)=CC2=C1NN=C2 PNVYBJKUNISJRL-UHFFFAOYSA-N 0.000 abstract 1
- SAWNFCCPPRARBZ-UHFFFAOYSA-N 6-amino-5-methyl-1h-indazole-7-carboxylic acid Chemical compound OC(=O)C1=C(N)C(C)=CC2=C1NN=C2 SAWNFCCPPRARBZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000002917 insecticide Substances 0.000 abstract 1
- 125000002560 nitrile group Chemical group 0.000 abstract 1
- 239000002243 precursor Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical class NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- JLXXLCJERIYMQG-UHFFFAOYSA-N phenylcyanamide Chemical compound N#CNC1=CC=CC=C1 JLXXLCJERIYMQG-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000006062 fragmentation reaction Methods 0.000 description 2
- 150000002443 hydroxylamines Chemical class 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the preparation of an insecticide of formula (I), wherein X is a bivalent group selected from X1-X8; R1is C1-C4alkyl or halogen; and R2and R3are hydrogen, C1-C4alkyl, C1-C4alkoxy, cyano, nitro or halogen. The process is depicted below and comprises (a) reacting a pyrroline dione of formula (II) with a source of hydroxylamine, preferably hydroxylamine hydrochloride, to give a compound of formula (III); (b) converting the intermediate (III) into the ortho amino-substituted aromatic cyano compound of formula (IV) by heating; and (c) hydrolysing the nitrile group of precursor (IV) to obtain the product of formula (I). A particular example is the synthesis of 6-amino-5-methyl-1H-indazole-7-carboxylic acid. The preparation of 6-amino-5-methyl-1H-indazole-7-carboxamide is also outlined. Compounds of formula (IV) are claimed separately.
Description
Process for the rreparation of ortho amino-substituted aromatic carboxylic acids The present invention relates to a novel process for the preparation of ortho amino-substituted aromatic carboxylic acid derivatives, useful for the preparation of insecticidafly active anthranilamides and to novel intermediates for use in that process.
Processes for the preparation of anthranilamide derivatives are described, for example, in WO 03/015519, WO 2004067528, W02005/085234 and W02006/040113. A process for the preparation of certain anthranilamide derivatives using 6-amino-i H-indazole-7-carboxylic acids as intermediates is described, for example, in WO 2007/093402.
It is known from WO 2007/093402 to prepare 6-amino-i H-indazole-7-carboxylic acid of formula Bi NH2 -.--0 (Bi), G;t1 OH wherein G1 to G4 together with the phenyl ring forms a 1 H-indazole moiety, by reacting a compound of formula Al
H I 0
G4: (Al), G&;t31 0 wherein G1 to G4 together with the phenyl ring forms a 1 H-indazole moiety, with hydrogen peroxide in a protic solvent in the presence of a base to a compound of formula Bi (page 19, reaction scheme 6 and page 42, example 3). However, such process has the disadvantage that yield and especially purity (side-products) of the product is unsatisfactory for a multi-step, large scale industrial process for the preparation of insecticidally active anthranilamide derivatives.
It is therefore the object of the present invention to provide a process for the preparation of ortho amino-substituted aromatic carboxylic acids in high yield and purity.
The present invention accordingly relates to a process for the preparation of compounds of formula I (I), wherein X is a bivalent group selected from (X1), R (X2), (X3), RN (X4), R2 (X5), (X6), (X7) and R2 -NH (X8); R1 is C1-C4alkyl or halogen; and R2 and R3 independently from each other, are hydrogen, C1-C4alkyl, C1-C4alkoxy, cyano, nitro or halogen; which process comprises a) reacting a compound of formula II (II), wherein X is as defined under formula I, with a hydroxylamine source to give a compound of formula Ill xQ: (Ill), wherein X is as defined under formula I; b) converting said compound of formula Ill by heating into a compound of formula IV X (IV), wherein X is as defined under formula I; and C) converting said compound of formula IV under hydrolysirig conditions to the compound of formula I. The alkyl groups occurring in the definitions of the substituents can be straight-chain or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl or tert-butyl. Halogen is generally fluorine, chlorine, bromine or iodine. Alkoxy groups preferably have a preferred chain length of from 1 to 4 carbon atoms. Alkoxy is, for example, methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy; preferably methoxy and ethoxy.
The process of the present invention is advantageous for the preparation of compounds of formula I, selected from the group consisting of the compounds of formula I wherein a) R1 is methyl, R2 is CN and X is X1; b) R1 is methyl, R2 is Cl and X is X1; C) R1 is methyl, R2 is Cl and X is X1; d) R1 is methyl, R2 is CN and X is X1; e) R1 is methyl, R2 is CN and X is X1; f) R1 is methyl, R2 is hydrogen and X is X8; g) R1 is chlorine, R2 is hydrogen and X is X8; h) R1 is methyl, R2 is hydrogen and X is X8; i) R1 is methyl, R2 is CN and X is X1; andj) R1 is methyl, R2 is Cl and X is X1.
The process according to the present invention is characterised by steps with high yield and selectivity with a minimum of side-products, giving intermediates which can be easily isolated in high purity.
Reaction step a): Preferred hydroxylamine sources are hydroxylamine itself or hydroxylamine hydrochloride in a solvent such as an alcohol, e.g. methanol, ethanol or isopropanol or aqueous alcohols.
The reaction may be optionally conducted in the presence of a base such as sodium hydroxide or sodium acetate, or an agent which can extract water, such as a catalytic amount of an organic or inorganic acid, such as para-toluene sulfonic acid, or sulphuric acid.
The temperature may be from ambient temperature up to the reflux temperature of the reaction solvent, preferably at the reflux temperature.
The work up of the reaction is an essential advantage of the invention over the prior art process. Compounds of formula Ill are generally high-melting solids because of the strong intramolecular hydrogen bond. This leads to insolubility, and therefore compounds of formula Ill can be simply isolated by removing the reaction solvent, washing with water, whereby all the inorganic salts and by-products are dissolved in the water, giving highly pure compounds of formula Ill after filtration and drying.
Reaction step b): This reaction can be effected by simply heating or melting compounds of formula Ill, to achieve a thermal fragmentation reaction as described by Grob and Schiess (Angew. Chem. Int. Ed., 6 (1967) 1-15). Alternatively a base and solvent may be used. Bases can be sodium alkoxides or metal carbonates and may be used in catalytic, in equivalent amounts or in excess. Solvents can be an alcohol, like methanol or ethanol or a high boiling solvent such as ethylene glycol or sulfolane.
Alternatively, by converting the hydroxy group in compounds of formula Ill into a leaving group, the fragmentation may be conducted under milder conditions again using a base in a solvent. Such leaving groups may be acetate, phosphate, sulfonate, mesylate, or triflate, and the base may be a pyridine base, a piperidine base, or a tertiary base such as triethylamine or DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). Solvents may be typical solvents such as tetrahydrofurane or methylenechforide, and the reaction temperature may be from ambient temperature up to 30° C. Reaction step C): This reaction may be accomplished using hydrolysing conditions under acidic or basic conditions, using at elevated temperatures, preferably of from 50 to 150°C. Optionally, the reaction may also be performed under diazotization conditions, for example in the presence of NaNO2 and an acid, for example a water solution of HCI, or an aliphatic nitrite such as t-butyl-nitrite or isopentyl-nitrite. Optionally, the reaction may also be conducted in the presence of an oxidizing agent, for example in the presence of hydrogen peroxide, a hypochlorite or a perchlorate. Preferably, the reaction may also be conducted in the presence of a mixture of a base and an oxidizing agent, for example NaOH or KOH or LiOH in the presence of a water solution of hydrogen peroxide.
Conversion of the compound of formula IV into the compound of formula I may be performed in one step or as illustrated below, in two steps.
Step 1: converting the compound of formula IV under hydrolysing conditions, optionally in the presence of an oxidizing agent to give a compound of formula V x02 (V).
Step 2: converting said compound of formula V under hydrolysing conditions, optionally in the presence of an oxidizing agent to the compound of formula I. Compounds of formula II and their preparation are described for example in WO 2007/093402.
Compounds of formula Ill and their preparation are described for example in GB patent application No. 0716414.8.
Compounds of formula IV are novel, are especially developed for the process according to the present invention and therefore constitute a further object of the present invention.
Especially preferred are compounds of formula IV, wherein X is X8.
The compounds of formula IV selected from the group consisting of the compounds of formula IV wherein a) R1 is methyl, R2 is CN and X is X1; b) R1 is methyl, R2 is Cl and X is X1; C) R1 is methyl, R2 is CI and X is X1; d) R1 is methyl, R2 is CN and X is X1; e) R1 is methyl, R2 is CN and X is X1; f) R1 is methyl, R2 is hydrogen and X is X8; g) R1 is chlorine, R2 is hydrogen and X is X8; h) R1 is methyl, R2 is hydrogen and X is X8; i) R1 is methyl, R2 is CN and X is X1; andj) R1 is methyl, R2 is Cl and X is X1 are especially preferred for the use in the process of the invention.
The process according to the invention is explained in greater detail by the following
Examples.
Example P1:
a) Preparation of compound B:
N-NH N-NH
A B
151.83 g isatin derivative A was suspended in 2000 ml ethanol and 100 g hydroxylamine hydrochloride was added. The mixture was heated to a temperature of 80°C for a period of hours after which time LCMS showed all starting material had been consumed. The reaction mixture was allowed to cool to 50°C and filtered at this temperature. The filtrate was evaporated under reduced pressure and the solid residue was dried under vacuum. The crude product was stirred in 2000 ml water, filtered and the solid again dried under vacuum to give 128.6 g of hydroxylamine derivative B as a light brown solid with melting point> 250°C. M+1: 217 (79%).
b) Preparation of compound C: CH3 CH HNOH5c 5.41 g of hydroxylamine derivative B was suspended in 50 ml of DMF and 3.38 g of sodium methoxide was added. The reaction mixture was heated to a temperature of 110°C for one hour, whereby as the temperature reached 50°C the suspension dissolved to form a brown solution. LCMS showed consumption of starting material. After cooling to ambient temperature, the reaction mixture was diluted with 25 ml of ethyl acetate and the reaction mixture was filtered through silica gel and Hyflo. The filtrate was evaporated under reduced pressure and the solid residue was dried under vacuum to give the cyano-aniline C as a beige solid with melting point >250°C (86%). M+1: 173.
c) Preparation of compound D:
HO
345 mg of cyanoaniline derivative C was suspended in 4.7 ml of 30% potassium hydroxide solution and 0.3 ml of 30% hydrogen peroxide solution was added. The mixture was heated to 130°C for a period of 20 hours after which time TLC showed disappearance of both starting material and intermediate amide. The reaction mixture was then allowed to cool, diluted with water and 4N hydrochloric acid was added to bring the pH to 5.6 as measured by an electrode. The beige precipitate was then filtered and the filtered solid dried under vacuum to give anthranilic acid D as a brownish solid. M+1:193 (54%).
d) Preparation of compound E: HN 3:H:H2 mg of cyanoaniline C was suspended in 2 ml of concentrated sulphuric acid and the mixture was heated to a temperature of 90°C for a period of four hours. The mixture was allowed to cool to ambient temperature and poured onto 5 ml water, aqueous 4N sodium hydroxide was added to make the mixture basic, and the product was extracted into ethy' acetate. The organic phase was dried, filtered and evaporated to give anthranilic amide E as a brownish solid with a melting point of 172-174°C (89%).
Claims (5)
- I -9.-What is claimed is: 1. A process for the preparation of compounds of formula I NH2 xQo (I),OHwherein X is a bivalent group selected from R1 R1 R1 (X1), R/h' (X2), (X3),R
- 2 R2 R1 R1 R1(), (X5), (X6), R1 R1 (X7) and (X8);-NHR1 is C1-C4alkyl or halogen; and R2 and R3 independently from each other, are hydrogen, C1-C4alkyl, C1-C4alkoxy, cyano, nitro, or halogen; which process comprises a) reacting a compound of formula II -10-xQo (II), wherein X is as defined under formula I, with a hydroxylamine source to give a compound of formula Ill (Ill), wherein X is as defined under formula I; b) converting said compound of formula Ill by heating into a compound of formula IV X (IV), wherein X is as defined under formula I; and c) converting said compound of formula IV under hydrolysing conditions to the compound of formula I. 2. A process according to claim 1 for the preparation of compounds of formula I selected from the group consisting of the compounds of formula I wherein a) R1 is methyl, R2 is CN and X is X1; b) R1 is methyl, R2 is Cl and X is X1; C) R, is methyl, R2 is Cl and X is X1; d) R1 is methyl, R2 is CN and X is X1; e) R1 is methyl, R2 is CN and X is X1; f) R1 is methyl, R2 is hydrogen and X is X5;g) R1 is chlorine, R2 is hydrogen and X is X8; h) R1 is methyl, R2 is hydrogen and X is X8; i) R1 is methyl, R2 is CN and X is X1; andj) R1 is methyl, R2 is Cl and X is X1.
- 3. A compound of formula IV -11 -X (IV), wherein X is as defined under formula I in claim 1.
- 4. A compound of formula IV according to claim 3, X (IV), selected from the group consisting of the compounds of formula IV wherein a) R1 is methyl, R2 is CN and X is X1; b) R1 is methyl, R2 is Cl and X is X1; c) R1 is methyl, R2 is CI and X is X1; d) R1 is methyl, R2 is CN and X is X1; e) R1 is methyl, R2 is CN and X is X1; f) R1 is methyl, R2 is hydrogen and X is X8; g) R1 is chlorine, R2 is hydrogen and X is X6; h) R1 is methyl, R2 is hydrogen and X is X8; i) R1 is methyl, R2 is CN and X is X1; andj) R, is methyl, R2 is Cl and X is X1.
- 5. A compound of formula IV according to claim 3, wherein X is X8.
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