HRP20020634A2 - Method for the preparation of 5-cyanophthalide - Google Patents
Method for the preparation of 5-cyanophthalide Download PDFInfo
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- HRP20020634A2 HRP20020634A2 HRP20020634A HRP20020634A2 HR P20020634 A2 HRP20020634 A2 HR P20020634A2 HR P20020634 A HRP20020634 A HR P20020634A HR P20020634 A2 HRP20020634 A2 HR P20020634A2
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- cyanophthalide
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- dehydrating agent
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- 238000000034 method Methods 0.000 title claims description 28
- XEEGWTLAFIZLSF-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carbonitrile Chemical compound N#CC1=CC=C2C(=O)OCC2=C1 XEEGWTLAFIZLSF-UHFFFAOYSA-N 0.000 title claims description 19
- 238000002360 preparation method Methods 0.000 title claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000012024 dehydrating agents Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 230000003197 catalytic effect Effects 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- QTWUWCFGWYYRRL-UHFFFAOYSA-N 1-oxo-3h-2-benzofuran-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2C(=O)OCC2=C1 QTWUWCFGWYYRRL-UHFFFAOYSA-N 0.000 claims description 5
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 5
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 5
- PCCDWPAOUMBBAI-UHFFFAOYSA-N 5-(4,5-dihydro-1,3-oxazol-2-yl)-3h-2-benzofuran-1-one Chemical compound C=1C=C2C(=O)OCC2=CC=1C1=NCCO1 PCCDWPAOUMBBAI-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 150000002978 peroxides Chemical class 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 4
- 239000002243 precursor Substances 0.000 claims description 4
- 230000007017 scission Effects 0.000 claims description 4
- 125000003003 spiro group Chemical group 0.000 claims description 4
- 150000003511 tertiary amides Chemical class 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 229910019213 POCl3 Inorganic materials 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- -1 4-fluorophenyl magnesium halide Chemical class 0.000 description 7
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 229960001653 citalopram Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 3
- 238000005979 thermal decomposition reaction Methods 0.000 description 3
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 2
- ISMUWQMUWFPFBZ-UHFFFAOYSA-N 5-amino-3h-2-benzofuran-1-one Chemical compound NC1=CC=C2C(=O)OCC2=C1 ISMUWQMUWFPFBZ-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-N Terephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- HNWLPTIKBKJXOX-UHFFFAOYSA-N n-(1-hydroxy-2-methylpropan-2-yl)-1-oxo-3h-2-benzofuran-5-carboxamide Chemical compound OCC(C)(C)NC(=O)C1=CC=C2C(=O)OCC2=C1 HNWLPTIKBKJXOX-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- ARCGXLSVLAOJQL-UHFFFAOYSA-N trimellitic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1 ARCGXLSVLAOJQL-UHFFFAOYSA-N 0.000 description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 1
- DNEVVXBMQZYGEI-UHFFFAOYSA-N 2-benzofuran-1-carbonitrile Chemical compound C1=CC=CC2=C(C#N)OC=C21 DNEVVXBMQZYGEI-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical group O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 150000007860 aryl ester derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003112 inhibitor Substances 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
- 239000007788 liquid Substances 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
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 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
- 229940076279 serotonin Drugs 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- 150000003549 thiazolines Chemical class 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Ovaj se izum odnosi na novi postupak priprave 5-cijanoftalida koji predstavlja intermedier u uporabi pri proizvodnji dobro poznatog depresiva citaloprama, 1-[3-(dimetilamino)propil]-1-(4-fluorofenil)-1,3-dihidro-5-izobenzofurankarbonitrila. This invention relates to a new process for the preparation of 5-cyanophthalide, which is an intermediate used in the production of the well-known depressant citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5- of isobenzofurancarbonitrile.
Pozadina izuma Background of the invention
Citalopram je poznati depresiv koji se već nekoliko godina nalazi na tržištu i koji ima sljedeću strukturu: Citalopram is a well-known antidepressant that has been on the market for several years and has the following structure:
[image] [image]
To je selektivni, centralno djelujući inhibitor ponovne pohrane serotonina (5-hidroksitriptamin; 5-HT), pa prema tome ima antidepresivno djelovanje. Antidepresivno djelovanje ovog spoja opisan je nekoliko publikacija, npr. J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982., 6, 277-295 i A. Graven, Acta Psychiatr. Scand., 1987., 75, 478-486. It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, and therefore has an antidepressant effect. The antidepressant effect of this compound is described in several publications, eg J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A. Graven, Acta Psychiatr. Scand., 1987, 75, 478-486.
Citalopram se pripravlja prema postupku opisanom u SAD patentu br. 4,650,884, prema kojem se 5-cijanoftalid podvrgava dvjema uzastopnim Grignardovim reakcijama, tj. s 4-fluorofenil magnezijevim halogenidom, odnosno N,N-dimetilaminopropil magnezijevim halogenidom, a dobiveni spoj formule Citalopram is prepared according to the procedure described in US patent no. 4,650,884, according to which 5-cyanophthalide is subjected to two consecutive Grignard reactions, i.e. with 4-fluorophenyl magnesium halide and N,N-dimethylaminopropyl magnesium halide, and the obtained compound of the formula
[image] [image]
podvrgava se reakciji zatvaranja prstena dehidracijom jakom sumpornom kiselinom. undergoes a ring-closing reaction by dehydration with strong sulfuric acid.
Enantiomeri citaloprama mogu se pripraviti na način opisan u SAD patentu br. 4,943,590, tj. separacijom enantiomera intermediera formule II i zatvaranjem enantioselektivnog prstena radi dobivanja željenog enantiomera. Citalopram enantiomers can be prepared as described in US Pat. No. 4,943,590, i.e. by separating the enantiomers of the intermediate of formula II and closing the enantioselective ring to obtain the desired enantiomer.
Tako je 5-cijanoftalid značajan intermedier za proizvodnju citaloprama i važno je da bude adekvatno kvalitetno proizveden, odgovarajućim postupkom i na rentabilan način. Thus, 5-cyanophthalide is an important intermediate for the production of citalopram, and it is important that it be produced in an adequate quality, with an appropriate process and in a cost-effective manner.
Način priprave 5-cijanoftalida ranije je opisan u Bull. Soc. Sci. Bretagne, 1951., 26, 35 i u Levy i Stephen, J. Chem. Soc., 1931., 867. Prema tom načinu, 5-aminoftalid se diazotacijom konvertira u odgovarajući 5-cijanoftalid, nakon čega slijedi reakcija s CuCN. 5-Aminoftalid je dobiven iz 4-aminoftalimida kroz dvostepeni reduktivni postupak. The method of preparation of 5-cyanophthalide was previously described in Bull. Soc. Sci. Bretagne, 1951, 26, 35 and in Levy and Stephen, J. Chem. Soc., 1931, 867. According to this method, 5-aminophthalide is converted into the corresponding 5-cyanophthalide by diazotization, followed by reaction with CuCN. 5-Aminophthalide was obtained from 4-aminophthalimide through a two-step reductive process.
Sinteza stanovitih alkil- i fenilnitrila iz kiselih klorida opisana je u Tetrahedron Letters, 1982., 23, 14, 1505-1508 i u Tetrahedron, 1998., 54, 9281. The synthesis of certain alkyl- and phenylnitriles from acid chlorides is described in Tetrahedron Letters, 1982, 23, 14, 1505-1508 and in Tetrahedron, 1998, 54, 9281.
Nađeno je da se 5-cijanoftalid može pripravljati u visokom iskorištenju prikladnim, rentabilnim postupkom iz 2-(1-okso-1,3-dihidroizobenzofuran-5-il)oksazolinskih ili -tiazolinskih intermediera formule IV. It was found that 5-cyanophthalide can be prepared in high yield by a suitable, cost-effective process from 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline or -thiazoline intermediates of formula IV.
Opis izuma Description of the invention
Dakle, ovaj izum predstavlja novi način priprave 5-cijanoftalida koji uključuje tretiranje spoja formule IV Thus, this invention represents a new way of preparing 5-cyanophthalide, which includes treating the compound of formula IV
[image] [image]
gdje X predstavlja O ili S; where X represents O or S;
R1 - R2 su svaki neovisno odabrani iz vodika i C1-6 alkila ili R1 i R2 zajedno čine C2-5alkilenski lanac, tvoreći tako spiro-prsten; R3 je odabran iz vodika i C1-6 alkila, R4 je odabran iz vodika, C1-6 alkila, karboksi grupe ili zato prethodničke grupe, ili R3 i R4 zajedno čine C2-5 alkilenski lanac, tvoreći tako spiro-prsten; s dehidracijskim agensom ili alternativno, kad X znači S, termalnim cijepanjem tiazolinskog prstena ili tretiranjem s radikalnim inicijatorom poput peroksida ili sa svjetlom, radi dobivanja 5-cijanoftalida koji ima formulu R 1 - R 2 are each independently selected from hydrogen and C 1-6 alkyl or R 1 and R 2 together form a C 2-5 alkylene chain, thus forming a spiro ring; R 3 is selected from hydrogen and C 1-6 alkyl, R 4 is selected from hydrogen, C 1-6 alkyl, carboxy or precursor groups, or R 3 and R 4 together form a C 2-5 alkylene chain, thus forming a spiro ring; with a dehydrating agent or alternatively, when X is S, by thermal cleavage of the thiazoline ring or by treatment with a radical initiator such as peroxide or with light to give 5-cyanophthalide having the formula
[image] [image]
Dehidracijski agens može biti fosforoksitriklorid, tionilklorid, fosforpentaklorid, PPA (polifosforna kiselina) i P4O10. Reakcija može biti provedena uz prisutnost organske baze poput piridina ili katalitičke količine tercijarnog amida. The dehydrating agent can be phosphorus oxytrichloride, thionyl chloride, phosphorus pentachloride, PPA (polyphosphoric acid) and P4O10. The reaction can be carried out in the presence of an organic base such as pyridine or a catalytic amount of a tertiary amide.
Preferirano, spoj formule IV tretira se sa SOCl2 kao dehidrirajućim agensom, a reakcija se provodi u toluenu uključujući katalitičku količinu N,N-dimetilformamida. Preferably, the compound of formula IV is treated with SOCl 2 as a dehydrating agent and the reaction is carried out in toluene including a catalytic amount of N,N-dimethylformamide.
Alternativno, dehidracijski agens može biti Vilsmeierov reagens, tj. spoj koji nastaje reakcijom klorirajućeg agensa, preferirano kiselog klorida, npr. fozgena, oksalil klorida, tionil klorida, fosforoksi klorida, forsforpentaklorida, triklorometil kloroformata, koji se također kratko naziva "difozgenom", ili di(triklorometil) karbonata, koji se također kratko naziva "trifozgenom", s tercijarnim amidom poput N,N-dimetilformamida ili N,N-dialkilalkanamida, npr. N,N-dimetilacetamida. Klasični Vilsmeierov reagens je klorometilendimetiliminium klorid. Vilsmeierov reagens se preferirano pripravlja in situ dodavanjem klorirajućeg agensa mješavini koja sadrži početni derivat oksazolina ili tiazolina formule IV i tercijarni amid. Alternatively, the dehydrating agent may be Vilsmeier's reagent, i.e., a compound formed by the reaction of a chlorinating agent, preferably an acid chloride, e.g., phosgene, oxalyl chloride, thionyl chloride, phosphoroxy chloride, phosphorpentachloride, trichloromethyl chloroformate, also called "diphosgene" for short, or of di(trichloromethyl) carbonate, also called "triphosgene" for short, with a tertiary amide such as N,N-dimethylformamide or N,N-dialkylalkanamide, eg N,N-dimethylacetamide. The classic Vilsmeier reagent is chloromethylenedimethyliminium chloride. The Vilsmeier reagent is preferably prepared in situ by adding a chlorinating agent to a mixture containing the starting oxazoline or thiazoline derivative of formula IV and a tertiary amide.
Kad X znači S i kad se konverzija tiazolinske grupe u cijano grupu provodi termalnom transformacijom, termalno raspadanje spoja IV preferirano se provodi u bezvodnom organskom otapalu, još bolje u aprotičkom polarnom otapalu poput N,N-dimetilformamida, N,N-dimetilacetamida, dimetilsulfoksida ili acetonitrila. Temperatura na kojoj termalno raspadanje 2-tiazolilnu grupu pretvara u cijano grupu kreće se između 60°C i 140°C. Termalna dekompozicija može prikladno biti provedena refluksom u odgovarajućem otapalu, preferirano acetonitrilu. Termalno cijepanje može se prikladno provesti uz prisutnost kisika ili oksidacijskog agensa. Spojevi formule IV u kojoj X znači S, a R4 je karboksi grupa ili prethodnik karboksi grupe, mogu se također konvertirati u citalopram tretiranjem s radikalnim inicijatorom poput svjetla ili peroksida. When X means S and when the conversion of the thiazoline group to the cyano group is carried out by thermal transformation, the thermal decomposition of compound IV is preferably carried out in an anhydrous organic solvent, even better in an aprotic polar solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide or acetonitrile. The temperature at which thermal decomposition converts the 2-thiazolyl group into a cyano group ranges between 60°C and 140°C. Thermal decomposition may conveniently be carried out by refluxing in a suitable solvent, preferably acetonitrile. Thermal cleavage may conveniently be carried out in the presence of oxygen or an oxidizing agent. Compounds of formula IV wherein X is S and R 4 is a carboxy group or precursor of a carboxy group may also be converted to citalopram by treatment with a radical initiator such as light or peroxide.
U specifikacijama i patentnim zahtjevima C1-6 alkil odnosi se na razgranatu ili nerazgranatu grupu koja ima jedan do uključivo šest atoma ugljika, kao što su metil, etil, 1-propil, 2-propil, 1-butil, 2-butil, 2-metil-2-propil, 2,2-dimetil-1-etil i 2-metil-1-propil. In the specification and claims, C1-6 alkyl refers to a branched or unbranched group having one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2- methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.
Dakle, postupkom prema ovom izumu dobiva se 5-cijanoftalid u visokom prinosu, a sam je postupak mnogo prikladniji od poznatih postupaka. To je takozvani robustan postupak. Nema primjene CuCN, čime se količina neželjenih nusproizvoda svodi na minimum, a sam je postupak ekološki prihvatljiv. Thus, the process according to this invention yields 5-cyanophthalide in high yield, and the process itself is much more suitable than known processes. This is the so-called robust procedure. There is no application of CuCN, which reduces the amount of unwanted by-products to a minimum, and the process itself is environmentally friendly.
U daljnjem aspektu, ovaj se izum odnosi na način priprave intermediera formule IV, koji podrazumijeva: In a further aspect, this invention relates to a method of preparing intermediates of formula IV, which includes:
a) reakciju funkcionalnog derivata 5-karboksiftalida formule V a) reaction of the functional derivative 5-carboxyphthalide of formula V
[image] [image]
s 2-hidroksi- ili 2-merkaptoetanaminom formule VI with 2-hydroxy- or 2-mercaptoethanamine of formula VI
[image] [image]
gdje su H, R1 - R4 prema ranijoj definiciji, where H, R1 - R4 are according to the earlier definition,
b) podvrgavanje amida tako dobivene formule VII b) subjecting the thus obtained amide of formula VII
[image] [image]
gdje su X, R1 - R4 prema ranijoj definiciji, zatvaranju prstena dehidracijom; where X, R 1 - R 4 are as defined earlier, ring closure by dehydration;
i na taj način dobivanjem 2-(1-okso-1,3-dihidroizobenzofuran-5-il)oksazolina ili -tiazolina formule IV and thus obtaining 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline or -thiazoline of formula IV
[image] [image]
Preferirano, funcionalni derivat upotrijebljen u fazi a) je ester, poput alkilestera, arilestera ili derivata alkilarilestera 5-karboksiftalida, ili derivat kiselog halida 5-karboksiftalida. Preferably, the functional derivative used in step a) is an ester, such as an alkyl ester, aryl ester or alkyl aryl ester derivative of 5-carboxyphthalide, or an acid halide derivative of 5-carboxyphthalide.
Preferirano, dehidrirajući agens upotrijebljen u fazi b) je SOCl2, POCl3 i PCl5, najbolje SOCl2. Preferably, the dehydrating agent used in step b) is SOCl 2 , POCl 3 and PCl 5 , preferably SOCl 2 .
Reakcija iz faze b) provodi se bez vode ili u prikladnom otapalu, poput toluena, sulfolana ili acetonitrila. Osim toga, kad se koristi otapalo mogla bi biti potrebna katalitička količina N,N-dimetilformamida, osobito ako je dehidrirajući agens SOCl2. Preferirano, kao otapalo se koristi toluen, po potrebi uz prisutnost katalitičke količine N,N-dimetilformamida. The reaction from phase b) is carried out without water or in a suitable solvent, such as toluene, sulfolane or acetonitrile. Additionally, when a solvent is used, a catalytic amount of N,N-dimethylformamide may be required, especially if the dehydrating agent is SOCl 2 . Preferably, toluene is used as the solvent, if necessary with the presence of a catalytic amount of N,N-dimethylformamide.
Reakcija iz faze b) provodi se na povišenoj temperaturi, preferirano na temperaturi refluksa otapala. The reaction from phase b) is carried out at an elevated temperature, preferably at the reflux temperature of the solvent.
Vrijeme reakcije nije značajno i stručnjak ga može lako odrediti. The reaction time is not significant and can be easily determined by an expert.
5-karboksiftalid koji se koristi kao početni materijal može se dobiti na načine opisane u SAD patentu br. 3,607,884 ili njemačkom patentu br. 2630927, tj. reakcijom koncentrirane otopine tereftalne kiseline s formaldehidom u tekućem SO3 ili elektrokemijskom hidrogenacijom trimelitične kiseline. The 5-carboxyphthalide used as starting material can be obtained by methods described in US Pat. No. 3,607,884 or German patent no. 2630927, i.e. by the reaction of a concentrated solution of terephthalic acid with formaldehyde in liquid SO3 or by the electrochemical hydrogenation of trimellitic acid.
U preferiranoj izvedbi ovog izuma R3 je metil ili etil. In a preferred embodiment of the present invention, R 3 is methyl or ethyl.
5-cijanoftalid može biti izoliran na konvencionalan način, npr. dodavanjem vode, filtriranjem i zatim ispiranjem kristala. Daljnje pročišćavanje može se, po želji, provesti rekristalizacijom. 5-Cyanophthalide can be isolated in a conventional manner, eg by adding water, filtering and then washing the crystals. Further purification can, if desired, be carried out by recrystallization.
Dakle, postupkom prema ovom izumu 5-cijanoftalid se dobiva novom uporabom 2-(1-okso-1,3-dihidroizobenzofuran-5-il)oksazolinskih ili -tiazolinskih intermediera formule IV kao reagensa. Pomoću tih reagensa uvjeti postupka su mnogo prikladniji od ranije opisanih uvjeta poznatog postupka za pripravu 5-cijanoftalida, osobito uz primjenu SOCl2 kao dehidrirajućeg agensa. Thus, by the process according to this invention, 5-cyanophthalide is obtained by the new use of 2-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline or -thiazoline intermediates of formula IV as a reagent. Using these reagents, the process conditions are much more suitable than the previously described conditions of the known process for the preparation of 5-cyanophthalide, especially with the use of SOCl2 as a dehydrating agent.
Primjeri Examples
Ovaj se izum u nastavku ilustrira sljedećim primjerima. This invention is further illustrated by the following examples.
Primjer 1 Example 1
Priprava 2-[[(1-okso-1,3-dihidroizobenzofuran-5-il)karbonil]amino]-2-metil-1-propanola Preparation of 2-[[(1-oxo-1,3-dihydroisobenzofuran-5-yl)carbonyl]amino]-2-methyl-1-propanol
5-karboksiftalid (267 g, 1,5 mol) se dodaje tionil kloridu (950 mL), a zatim se kap po kap dodaje N,N-dimetilformamid (12 mL). Mješavina se 1 sat grije na refluksu i tionil klorid se izdestilira pod smanjenim tlakom, nakon čega slijede sukcesivna uparavanja s toluenom (2 x50 mL) radi dobivanja krutog taloga. Zatim se sirovi kiseli klorid spaja s 100 mL tetrahidrofurana. Otopini 2-amino-2-metil-1-propanola (400,5 g, 4,5 mol) u tetrahidrofuranu (500 mL), ohlađenoj na +5°C, kap po kap se dodaje otopina kiselog klorida, uz održavanje temperature na +5→+10°C. Nakon završetka dodavanja hlađenje prestaje i mješavina se preko noći miješa na sobnoj temperaturi. Zatim se mješavina ulijeva u deioniziranu vodu (2000 mL), a organsko otapalo se odstranjuje pod smanjenim tlakom na 50°C. Nakon hlađenja i dvosatnog miješanja kruti se proizvod profiltrira i ispere deioniziranom vodom (2 x 100 mL). Dobiveni proizvod suši se 36 sati na 70°C pod smanjenim tlakom. Iskorištenje: 285,3 g (76%) bjelkastog proizvoda čistoće (HPLC, vršno područje) = 90%. 1H NMR (DMSO d-6, 500 MHz): 1,18 (3H, s); 1,32 (3H, s); 3,55 (2H, s); 5,45 (2H, s), 7,88 - 7,98 (3H, m); 8,07 (1H, s). 5-Carboxyphthalide (267 g, 1.5 mol) was added to thionyl chloride (950 mL), followed by dropwise addition of N,N-dimethylformamide (12 mL). The mixture is heated at reflux for 1 hour and the thionyl chloride is distilled off under reduced pressure, followed by successive evaporations with toluene (2 x 50 mL) to give a solid precipitate. The crude acid chloride is then combined with 100 mL of tetrahydrofuran. To a solution of 2-amino-2-methyl-1-propanol (400.5 g, 4.5 mol) in tetrahydrofuran (500 mL), cooled to +5°C, acid chloride solution was added dropwise, while maintaining the temperature at +5→+10°C. After the addition is complete, cooling is stopped and the mixture is stirred overnight at room temperature. The mixture is then poured into deionized water (2000 mL), and the organic solvent is removed under reduced pressure at 50°C. After cooling and stirring for two hours, the solid product is filtered and washed with deionized water (2 x 100 mL). The obtained product is dried for 36 hours at 70°C under reduced pressure. Yield: 285.3 g (76%) of a whitish product of purity (HPLC, peak area) = 90%. 1H NMR (DMSO d-6, 500 MHz): 1.18 (3H, s); 1.32 (3H, s); 3.55 (2H, s); 5.45 (2H, s), 7.88 - 7.98 (3H, m); 8.07 (1H, s).
Primjer 2 Example 2
Priprava 4,4-dimetil-1-(1-okso-1,3-dihidroizobenzofuran-5-il)oksazolina Preparation of 4,4-dimethyl-1-(1-oxo-1,3-dihydroisobenzofuran-5-yl)oxazoline
Tionil kloridu (130 ml), ohlađenom na -10°C, u porcijama se, uz miješanje, dodaje 2-[[(1-okso-1,3-dihidroizo-benzofuran-5-il)carbonil]amino]-2-metil-1-propanol (85 g, 0,34 mol). Temperatura se 1,5 sat održava na -10→ -5°C, nakon čega hlađenje prestaje i reakcija se preko noći miješa na sobnoj temperaturi. Zatim se hladi na 0°C i kap po kap se dodaje tetrahidrofuran (860 mL), uz održavanje temperature ispod +8°C. Dobivena suspenzija se još dva sata miješa na 5°C, a zatim profiltrira i dobiveni se kristali isperu tetrahidrofuranom (150 mL). Mokra krutina otopi se u deioniziranoj vodi (400 mL) te se pH podesi na 9,1 dodavanjem 25%-tne vodene otopine amonijaka. Krutina se profiltrira, ispere deioniziranom vodom i 14 sati suši na 50°C pod smanjenim tlakom. Iskorištenje: 62,8 g (80%) bijelog proizvoda čistoće (HPLC, vršno područje) = 94%. 1H NMR (DMSO d-6, 500 MHz): 1,31 (6H, s); 4,18 (2H, s); 5,44 (2H, s); 7,9 (1H, d, J=11,3 Hz); 8,01 (1H, d, J=11,3 Hz); 8,12 (1H, s). To thionyl chloride (130 ml), cooled to -10°C, 2-[[(1-oxo-1,3-dihydroiso-benzofuran-5-yl)carbonyl]amino]-2- methyl-1-propanol (85 g, 0.34 mol). The temperature is maintained at -10→ -5°C for 1.5 hours, after which the cooling stops and the reaction is stirred overnight at room temperature. It is then cooled to 0°C and tetrahydrofuran (860 mL) is added dropwise, keeping the temperature below +8°C. The resulting suspension is stirred for another two hours at 5°C, then filtered and the resulting crystals are washed with tetrahydrofuran (150 mL). The wet solid was dissolved in deionized water (400 mL) and the pH was adjusted to 9.1 by adding 25% aqueous ammonia. The solid is filtered, washed with deionized water and dried for 14 hours at 50°C under reduced pressure. Yield: 62.8 g (80%) white product purity (HPLC, peak area) = 94%. 1H NMR (DMSO d-6, 500 MHz): 1.31 (6H, s); 4.18 (2H, s); 5.44 (2H, s); 7.9 (1H, d, J=11.3 Hz); 8.01 (1H, d, J=11.3 Hz); 8.12 (1H, s).
Primjer 3 Example 3
Priprava 5-cijanoftalida Preparation of 5-cyanophthalide
Suspenziji 4,4-dimetil-2-(1-okso-1,3-dihidroizobenzofuran-5-il)oksazolina (23,1 g, 0,1 mol) u tionil kloridu (36 mL) polako se dodaje N,N-dimetilformamid (5 ml). Otopina se 1 sat grije na refluksu i zatim preko 3 sata ostavi da se ohladi na sobnu temperaturu. Zatim se dodaje toluen (150 mL) i suspenzija se profiltrira i ispere toluenom (2 x 50 mL). Mokri se kristali stavljaju u deioniziranu vodu (150 mL), a pH se pomoću 25%-tne vodene otopine amonijaka podešava na 8,0. Krutina se profiltrira i ispere deioniziranom vodom (2 x 50 mL) i suši na 60°C pod smanjenim tlakom. Iskorištenje: 11,9 g (75%) bjelkastog proizvoda čistoće (HPLC, vršno područje) = 92%. Analitički čist uzorak dobiva se kristalizacijom iz octene kiseline ili toluena. 1H NMR (DMSO d-6, 500 MHz): 5,48 (2H, s); 8,04 (2H, s+s); 8,22 (1H, s). N,N- dimethylformamide (5 ml). The solution is heated at reflux for 1 hour and then allowed to cool to room temperature over 3 hours. Toluene (150 mL) is then added and the suspension is filtered and washed with toluene (2 x 50 mL). The wet crystals are placed in deionized water (150 mL), and the pH is adjusted to 8.0 using a 25% aqueous ammonia solution. The solid is filtered and washed with deionized water (2 x 50 mL) and dried at 60°C under reduced pressure. Yield: 11.9 g (75%) of a whitish product purity (HPLC, peak area) = 92%. An analytically pure sample is obtained by crystallization from acetic acid or toluene. 1H NMR (DMSO d-6, 500 MHz): 5.48 (2H, s); 8.04 (2H, s+s); 8.22 (1H, s).
Claims (10)
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