HRP20010616A2 - Method for producing derivatives of biphenyl-2-carboxylic acid - Google Patents
Method for producing derivatives of biphenyl-2-carboxylic acid Download PDFInfo
- Publication number
- HRP20010616A2 HRP20010616A2 HR20010616A HRP20010616A HRP20010616A2 HR P20010616 A2 HRP20010616 A2 HR P20010616A2 HR 20010616 A HR20010616 A HR 20010616A HR P20010616 A HRP20010616 A HR P20010616A HR P20010616 A2 HRP20010616 A2 HR P20010616A2
- Authority
- HR
- Croatia
- Prior art keywords
- substituted
- phenyl
- hydroxy
- alkoxy
- methyl
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 17
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical class OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 title claims description 15
- -1 oxazolin-2-yl residue Chemical group 0.000 claims description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- 238000000034 method Methods 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 238000007127 saponification reaction Methods 0.000 claims description 9
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Chemical group 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical group 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 claims description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 3
- ZSTUEICKYWFYIC-UHFFFAOYSA-N 2-(4-methylphenyl)benzoic acid Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1C(O)=O ZSTUEICKYWFYIC-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 2
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical group [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000011651 chromium Chemical group 0.000 claims description 2
- 229910052804 chromium Inorganic materials 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000006286 aqueous extract Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- UABFDXDSFKGWJM-UHFFFAOYSA-N 2-(2-methoxyphenyl)-4,5-dihydro-1,3-oxazole Chemical class COC1=CC=CC=C1C1=NCCO1 UABFDXDSFKGWJM-UHFFFAOYSA-N 0.000 description 2
- JUNZDJNCZJUDRU-UHFFFAOYSA-N 4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5h-1,3-oxazole Chemical group C1=CC(C)=CC=C1C1=CC=CC=C1C1=NC(C)(C)CO1 JUNZDJNCZJUDRU-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- YEBXJRBNPTUQKG-UHFFFAOYSA-N 1,1'-biphenyl;4,5-dihydro-1,3-oxazole Chemical compound C1CN=CO1.C1=CC=CC=C1C1=CC=CC=C1 YEBXJRBNPTUQKG-UHFFFAOYSA-N 0.000 description 1
- AZQQFCSRBIOXMN-UHFFFAOYSA-N 2-(2-phenylphenyl)-4,5-dihydro-1,3-oxazole Chemical group O1CCN=C1C1=CC=CC=C1C1=CC=CC=C1 AZQQFCSRBIOXMN-UHFFFAOYSA-N 0.000 description 1
- MUFNIUXQTXCXFN-UHFFFAOYSA-N 4,4-dimethyl-2-(2-phenylphenyl)-5h-1,3-oxazole Chemical group CC1(C)COC(C=2C(=CC=CC=2)C=2C=CC=CC=2)=N1 MUFNIUXQTXCXFN-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Izum se odnosi na postupak za proizvodnju derivata bifenil-2-karboksilne kiseline formule (I) The invention relates to a process for the production of biphenyl-2-carboxylic acid derivatives of the formula (I)
[image] [image]
koji se može primijeniti u tehničkom mjerilu, pri čemu R1 i R2 mogu imati značenje navedeno u opisu i u patentnim zahtjevima. which can be applied in a technical scale, whereby R1 and R2 can have the meaning specified in the description and in the patent claims.
Pozadina izuma Background of the invention
Bifenil-2-karbonkiseline formule (I) su kao međuproizvodi značajne pri proizvodnji farmaceutski zanimljivih aktivnih tvari, posebno pri proizvodnji farmaceutskih aktivnih tvari koje se mogu upotrijebiti kao angiotenzin-IL-antagonisti. Biphenyl-2-carboxylic acids of formula (I) are important as intermediates in the production of pharmaceutically interesting active substances, especially in the production of pharmaceutical active substances that can be used as angiotensin-IL antagonists.
Postupci za proizvodnju bifenil-2-karboksilnih kiselina i njihovih derivaten (I) poznati su iz stanja tehnike. Jedan, za pozadinu izuma važan, postupak provodi se povezivanjem aromatskog Grignardovog spoja (II) s prema porebi supstituiranim (2-metoksifenil)-2-oksazolinom (III) prema shemi 1, a koji su opisli Meyers et al. (npr. u Tetrahedron (1985), sv. 41, 837-860), pri čemu se najprije dobije odgovarajući (2-oksazolinil)-2-bifenilni derivat (IV). Processes for the production of biphenyl-2-carboxylic acids and their derivatives (I) are known from the state of the art. One, important for the background of the invention, procedure is carried out by connecting an aromatic Grignard compound (II) with an optionally substituted (2-methoxyphenyl)-2-oxazoline (III) according to scheme 1, which was described by Meyers et al. (eg in Tetrahedron (1985), vol. 41, 837-860), whereby the corresponding (2-oxazolinyl)-2-biphenyl derivative (IV) is first obtained.
[image] [image]
Shema 1: Scheme 1:
Pri tome, ostatak R0x predstavlja prema potrebi supstituirani oksazolin-2-ilni ostatak. Definicija ostataka R1 i R2 data je u kasnijem dijelu opisa kao i u patentnim zahtjevima. Saponifikacijom oksazolina (IV) dolazi se do odgovarajuće kemijske promjene u odgovarajuću karboksilnu kiselinu formule (I). Ta saponifikacija spoja (IV) može se, formalno razmatrajući, provesti na dva reakcijski različita načina. Na shemi 2 prikazani su ti načini provedbe reakcije putevi na primjeru proizvodnje bifenil-2-karboksilne kiseline, počevši od bifenil-oksazolina nesupstituiranog na oksazolinskom ostataku (tj R1 i R2 = vodik; R0x = oksazolin-2-il). In this case, the residue R0x represents an optionally substituted oxazolin-2-yl residue. The definition of residues R1 and R2 is given in the later part of the description as well as in the patent claims. Saponification of oxazoline (IV) leads to a corresponding chemical change in the corresponding carboxylic acid of formula (I). This saponification of compound (IV) can, formally considered, be carried out in two reactionally different ways. Scheme 2 shows these ways of carrying out the reaction, using the example of the production of biphenyl-2-carboxylic acid, starting from biphenyl-oxazoline unsubstituted on the oxazoline residue (ie R1 and R2 = hydrogen; R0x = oxazolin-2-yl).
[image] [image]
Shema 2: Scheme 2:
Saponifikacija oksazolina, prema reakcijskim uvjetima poznatim iz stanja tehnike, u prvom stupnju dovodi do tvorbe amino estera (Vb) (Meyers et al., J. Org. Chem. (1974) Vol. 39, 2787-2793). Amino ester (Vb) može se zatim, u drugom reakcijskom stupnju, npr. višesatnim kuhanjem u 10 - 25%-tnoj natrijevoj lužini, saponificirani u karboksilnu kiselinu (I). Saponification of oxazoline, according to reaction conditions known from the state of the art, in the first step leads to the formation of amino ester (Vb) (Meyers et al., J. Org. Chem. (1974) Vol. 39, 2787-2793). The amino ester (Vb) can then, in the second reaction stage, for example by boiling for several hours in 10-25% sodium alkali, saponified into carboxylic acid (I).
Za proizvodni postupak u velikom tehničkom mjerilu poželjno je prije svega provoditi postupak saponifikacije kao postupak u jednoj posudi. Međutim, kad se polazeći od postupka poznatog iz stanja tehnike, kiselu saponifikaciju provodi u jednoj posudi (npr. prema EP59983), ona u velikom tehničkom mjerilu dovodi samo do nezadovoljavajućih rezultata. For the production process on a large technical scale, it is preferable to carry out the saponification process as a one-pot process. However, when starting from a process known from the state of the art, acid saponification is carried out in one vessel (eg according to EP59983), it only leads to unsatisfactory results on a large technical scale.
Opaženo je da se zbog neznatne topivosti u otapalu koje se upotrebljava prema stanju tehnike (npr. vodena solna kiselina prema EP 59983) amino ester (Vb) djelomično izlučuje nakon njegovog stvaranja. Na mješalici kao i na stijenkama reakcijske posude se stvara talog (Vb). To dovodi do toga da se amino ester (Vb) sukcesivno izvlači iz reakcijske otopine i zbog neznatne topivosti nakon toga on praktički više nije raspoloživ za daljnju reakciju za željeni ciljni spoj (I). Do velikog smanjenja iskorištenja dolazi zbog uključka proizvoda (I) u iskristalizirom i stvarno zgrudanom amino esteru (Vb). It was observed that due to the low solubility in the solvent used according to the state of the art (eg aqueous hydrochloric acid according to EP 59983), the amino ester (Vb) is partially excreted after its formation. A deposit (Vb) forms on the mixer as well as on the walls of the reaction vessel. This leads to the fact that the amino ester (Vb) is successively extracted from the reaction solution and, due to its low solubility, it is practically no longer available for further reaction for the desired target compound (I). A large decrease in utilization occurs due to the inclusion of product (I) in the crystallized and actually coagulated amino ester (Vb).
Prethodno navedeni nedostaci dovode do povišenih troškova u industrijskoj proizvodnji spoja (1), jer se u okviru obrade i čišćenja krajnjeg proizvoda mora izvrštiti odvajanje amino estera (Vb), a zbog pretvorbe izlučenog amino estera (Vb) u krajnji proizvod, mora se izvršiti i zaseban korak sinteze. The aforementioned disadvantages lead to increased costs in the industrial production of compound (1), because within the processing and cleaning of the final product, the separation of the amino ester (Vb) must be carried out, and due to the conversion of the secreted amino ester (Vb) into the final product, it must also be carried out a separate synthesis step.
Zbog toga je cilj i zadatak predloženog izuma dati postupak za proizvodnju derivata/homologa bifenil-2-karboksilne kiseline koji se može primijeniti u industrijskoj proizvodnji i u kojem su prevladani nedostaci koji se pojavljuju u postupku poznatom iz stanja tehnike. Therefore, the aim and task of the proposed invention is to provide a process for the production of derivatives/homologues of biphenyl-2-carboxylic acid that can be applied in industrial production and in which the shortcomings that appear in the process known from the state of the art are overcome.
Opis izuma u pojedinostima Description of the invention in detail
Iznenađujuće je pronađeno da se nedostaci koji se pojavljuju u proizvodnom postupku za derivate bifenil-2-karboksilne kiseline poznatom iz stanja tehnike mogu izbjeći ako se saponifikaciju oksazolina (IV) provodi sa solnom kiselinom pri povišenoj temperaturi, pod tlakom i u prisutnosti inertnog organskog orapala koje se ne miješa s vodom. It was surprisingly found that the defects that appear in the production process for biphenyl-2-carboxylic acid derivatives known from the state of the art can be avoided if the saponification of oxazoline (IV) is carried out with hydrochloric acid at elevated temperature, under pressure and in the presence of an inert organic solvent which does not mix with water.
Predloženi izum odnosi se stoga na postupak koji se može primijeniti u industrijskom mjerilu za proizvodnju derivata bifenil-2-karboksilne kiseline opće formele (I) The proposed invention therefore relates to a process that can be applied on an industrial scale for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I)
[image] [image]
u kojoj where
R1 i R2, jednaki ili različiti, predstavljaju vodik, C1-C6-alkil, koji prema potrebi može biti substituiran s halogenim, C1-C6-alkoksi, C1-C6-acil, C1-C6-alkoksikarbonil, COOH, fenil, benzil, halogen, hidroksi, nitro ili amino, ili u kojoj R1 and R2, the same or different, represent hydrogen, C1-C6-alkyl, which can be substituted with halogen, C1-C6-alkoxy, C1-C6-acyl, C1-C6-alkoxycarbonyl, COOH, phenyl, benzyl, halogen, hydroxy, nitro or amino, or in which
R1 i R2 zajedno sa susjednim ugljikovim atomima fenilnog prstena tvore zasićen ili nezasićen 5- ili 6-člani karbocikl koji prema potrebi može biti supstituiran sa C1-C4-alkilom, halogenim, COOH, fenilom ili s hidroksi; koji je naznačen time, da se (2-oksazolinil)-2-bifenilni derivat opće formule (IV) R1 and R2 together with the adjacent carbon atoms of the phenyl ring form a saturated or unsaturated 5- or 6-membered carbocycle which can be substituted with C1-C4-alkyl, halogen, COOH, phenyl or hydroxy if necessary; which is indicated by the fact that the (2-oxazolinyl)-2-biphenyl derivative of the general formula (IV)
[image] [image]
u kojoj where
R1 i R2 imaju gore navedeno značenje i R1 and R2 have the above meaning and
R0x predstavlja oksazolin-2-ilni ostatak, koji je prema potrebi jednostruko, dvostruko, trostruko ili četverostruko supstituiran s jednim ili više ostataka C1-C6-alkila koji prema potrebi može biti supstituiran s halogenim, hidroksi ili sa C1-C4-alkoksi, C1-C6-alkoksi, fenil koji prema potrebi može biti supstituiran sa C1-C4-alkilom, C1-C4-alkoksi, hidroksi, nitro ili amino, benzil, piridil ili C1-C6-alkoksikarbonil, saponificira sa solnom kiselinom pri povišenoj temperaturi pod tlakom i u prisutnosti inertnog organskog otapala koje se ne miješa s vodom. R0x represents an oxazolin-2-yl residue, which is, if necessary, singly, doubly, triply or quadruply substituted with one or more C1-C6-alkyl residues, which can be substituted with halogen, hydroxy or with C1-C4-alkoxy, C1 -C6-Alkoxy, phenyl which, if necessary, can be substituted with C1-C4-alkyl, C1-C4-Alkoxy, hydroxy, nitro or amino, benzyl, pyridyl or C1-C6-Alkoxycarbonyl, saponified with hydrochloric acid at elevated temperature under pressure and in the presence of an inert, water-immiscible organic solvent.
Prema izumu prednost se daje se postupku za proizvodnju derivata bifenil-2-karboksilne kiseline opće formule (I), u kojoj According to the invention, preference is given to the process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I), in which
R1 i R2 jednaki ili različiti, predstavljaju vodik, C1-C4-alkil, koji prema potrebi može biti supstituiran s fluorom, klorom ili s bromom, C1-C4-alkoksi, C1-C4-acil, C1-C4-alkoksikarbonil, COOH, fenil, benzil, fluor, klor, brom, hidroksi, nitro ili amino, ili u kojoj R1 and R2, the same or different, represent hydrogen, C1-C4-alkyl, which can be substituted with fluorine, chlorine or bromine, if necessary, C1-C4-alkoxy, C1-C4-acyl, C1-C4-alkoxycarbonyl, COOH, phenyl, benzyl, fluoro, chloro, bromo, hydroxy, nitro or amino, or in which
R1 i R2 zajedno sa susjednim ugljikovim atomima fenilnog prstena tvore nezasićen 6-člani karbocikl, koji prema potrebi može biti supstituiran sa C1-C4-alkilom, fluorom, klorom, bromom, COOH, fenilom ili s hidroksi; koji je naznačen time, da se (2-oksazolinil)-2-bifenilni derivat opće formule (IV) u kojoj R1 and R2, together with the adjacent carbon atoms of the phenyl ring, form an unsaturated 6-membered carbocycle, which, if necessary, can be substituted with C1-C4-alkyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy; which is indicated by the fact that the (2-oxazolinyl)-2-biphenyl derivative of the general formula (IV) in which
R1 i R2 imaju gore navedeno značenje, i R1 and R2 have the above meaning, i
R0x predstavlja oksazolin-2-ilni ostatak, koji prema potrebi može biti jednostruko ili dvostruko substituiran s jednim ili više ostataka C1-C4-alkila, koji prema potrebi može biti supstituiran s fluorom, klorom, bromom, hidroksi ili sa C1-C4-alkoksi, C1-C4-alkoksi, fenil, koji prema potrebi može biti supstituiran sa C1-C4-alkilom, C1-C4-alkoksi, hidroksi, nitro ili amino, benzil ili C1-C4-alkoksikarbonil, saponificira sa solnom kiselinom pri povišenoj temperaturi, pod tlakom i u prisutnosti inertnog organskog otapala koje se ne miješa s vodom. R0x represents an oxazolin-2-yl radical, which can be singly or doubly substituted with one or more C1-C4-alkyl radicals, which can be optionally substituted with fluorine, chlorine, bromine, hydroxy or with C1-C4-alkoxy . under pressure and in the presence of an inert organic solvent that does not mix with water.
Prema izumu posebnu prednost se daje postupku za proizvodnju derivata bifenil-2-karboksilne kiseline opće formule (I), u kojoj According to the invention, a special advantage is given to the process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I), in which
R1 i R2, jednaki ili različiti, predstavljaju vodik, metil, etil, n-propil, izo-propil, n-butil, terc-butil, CF3, metoksi, etoksi, COOH, fenil, benzil, fluor, klor, brom, hidroksi, nitro ili amino, ili u kojoj R1 and R2, the same or different, represent hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, CF3, methoxy, ethoxy, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy , nitro or amino, or in which
R1 i R2 zajedno sa susjednim ugljikovim atomima fenilnog prstena tvore anelirani fenilni prsten koji prema potrebi može biti supstituiran s metilom, etilom, n-propilom, izo-propilom, terc-butilom, fluorom, klorom, kromom, COOH, fenilom ili s hidroksi, R1 and R2 together with the adjacent carbon atoms of the phenyl ring form an annelized phenyl ring which, if necessary, can be substituted with methyl, ethyl, n-propyl, iso-propyl, tert-butyl, fluorine, chlorine, chromium, COOH, phenyl or with hydroxy,
koji je naznačen time, da se (2-oksazolinil)-2-bifenilni derivat opće formule (IV) u kojoj which is indicated by the fact that the (2-oxazolinyl)-2-biphenyl derivative of the general formula (IV) in which
R1 i R2 imaju gore navedeno značenje, i R1 and R2 have the above meaning, i
R0x predstavlja oksazolin-2-ilni ostatak, koji prema potrebi može biti jednostruko ili dvostruko substituiran s jednim ili više ostataka iz skupine koju čine metil, etil, n-propil, izo-propil, n-butil, terc-butil, metoksimetil, hidroksimetil, metoksi, etoksi, fenil, koji prema potrebi može biti supstituiran s metilom, etilom, n-propilom, izo-propilom, n-butilom, terc-butilom, metoksi, etoksi ili s hidroksi, benzil, metoksikarbonil ili etoksikarbonil, saponificira sa solnom kiselinom pri povišenoj temperaturi, pod tlakom i u prisutnosti inertnog organskog otapala koje se ne miješa s vodom. R0x represents an oxazolin-2-yl residue, which can be singly or doubly substituted as needed with one or more residues from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, methoxymethyl, hydroxymethyl , methoxy, ethoxy, phenyl, which can be substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, methoxy, ethoxy or with hydroxy, benzyl, methoxycarbonyl or ethoxycarbonyl, saponified with salt acid at elevated temperature, under pressure and in the presence of an inert organic solvent that does not mix with water.
Nadalje, prema izumu značajan je postupak za proizvodnju derivata bifenil-2-karboksilne kiseline opće formule (I), u kojoj Furthermore, according to the invention, a process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I) is significant, in which
R1 i R2, jednaki ili različiti predstavljaju vodik, metil, CF3, COOH, fenil, fluor ili hidroksi, ili u kojoj R1 and R2, the same or different, represent hydrogen, methyl, CF3, COOH, phenyl, fluorine or hydroxy, or in which
R1 i R2 zajedno sa susjednim ugljikovim atomima fenilnog prstena tvore anelirani fenilni prsten, koji je naznačen time da se (2-oksazolinil)-2-bifenilni derivat opće formule (IV), u kojoj R1 and R2 together with the adjacent carbon atoms of the phenyl ring form an fused phenyl ring, which is indicated by the fact that the (2-oxazolinyl)-2-biphenyl derivative of the general formula (IV), in which
R1 i R2 imaju gore navedeno značenje, i R1 and R2 have the above meaning, i
R0x predstavlja oksazolin-2-ilni ostatak, koji je prema potrebi jednostruko ili dvostruko supstituiran s jednim ili više ostataka iz skupine koju čine metil, etil, metoksi, etoksi, fenil ili benzil, saponificira sa solnom kiselinom pri povišenoj temperaturi, pod tlakom i u prisutnosti inertnog organskog otapala koje se ne miješa s vodom. R0x represents an oxazolin-2-yl residue, which, as necessary, is singly or doubly substituted with one or more residues from the group consisting of methyl, ethyl, methoxy, ethoxy, phenyl or benzyl, saponified with hydrochloric acid at elevated temperature, under pressure and in the presence an inert organic solvent that does not mix with water.
Posebno značenje daje se postupku za proizvodnju derivata bifenil-2-karboksilne kiseline opće formule (I), u kojoj Special significance is given to the process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I), in which
R1 i R2, jednaki ili različiti, predstavljaju vodik, metil ili CF3, koji je naznačen time da se (2-Oksazolinil)-2-bifenilni derivat opće formule (IV), u kojoj R1 and R2, the same or different, represent hydrogen, methyl or CF3, which is indicated by the fact that the (2-Oxazolinyl)-2-biphenyl derivative of the general formula (IV), in which
R1 i R2 imaju prethodno navedeno značenje i R1 and R2 have the aforementioned meaning and
R0x predstavlja oksazolin-2-ilni ostatak, koji prema potrebi može biti jednostruko ili dvostruko substituiran s metilom, saponificira sa solnom kiselinom pri povišenoj temperaturi, pod tlakom i u prisutnosti inertnog organskog otapala koje se ne miješa s vodom. R0x represents an oxazolin-2-yl residue, which can be singly or doubly substituted with methyl if necessary, saponified with hydrochloric acid at elevated temperature, under pressure and in the presence of an inert organic solvent that does not mix with water.
Prema izumu, posebno povoljan oblik i način izvedbe provodi se kako slijedi. U reakcijsku posudu odgovarajuće veličine stavi se 0,08-0,8, prednosno 0,15-0,5, posebno prednosno pribl. 0,2 l vode i 3,0-6,0 mola, prednosno 3,5 -5,0 molova, posebno prednosno pribl. 4,0 mola solne kiseline po molu oksazolin-2-il-bifenila (IV). Prednosno se vrši dodavanje prethodno navedene solne kiseline u obliku vodene otopine, posebno prednosno u obliku 36,5%-tne vodene otopine, tako da se dobije koncentraciju solne kiseline od 20 - 30%, posebno prednosno od pribl. 24%. According to the invention, a particularly advantageous form and method of execution is carried out as follows. 0.08-0.8, preferably 0.15-0.5, especially preferably approx. 0.2 l of water and 3.0-6.0 moles, preferably 3.5-5.0 moles, especially preferably approx. 4.0 moles of hydrochloric acid per mole of oxazolin-2-yl-biphenyl (IV). Preferably, the aforementioned hydrochloric acid is added in the form of an aqueous solution, especially preferably in the form of a 36.5% aqueous solution, so that a hydrochloric acid concentration of 20 - 30% is obtained, especially preferably of approx. 24%.
Nakon stvaranja inertne atmosfere sa zaštitnim plinom, ponajprije s dušikom, reakcijsku posudu se evakuira (na pribl. 50 mbara) i po molu upotrijebljenog polaznog spoja (IV) pomiješa se s 0,05-0,2, prednosno 0,08-0,15, posebno prednsno s pribl. 0,1 l inertnog organskog otapala. Kao inertna organska otapala prema izumu u obzir dolaze alifatski ili aromatski ugljikovodici i aromatski kloruljikovodici koji imaju 6-10 C-atoma. Prednosni su alifatski ili aromatski ugljikovodici koji imaju 7-8 C-atoma. Kao otapala koja se mogu upotrijebiti prema izumu kao prednosna se mogu navesti toluol, ksilol, klorbenzol i metilcikloheksan. Posebnu prednost daje se metil-cikloheksanu. After creating an inert atmosphere with a protective gas, preferably with nitrogen, the reaction vessel is evacuated (at approx. 50 mbar) and per mole of the starting compound (IV) used is mixed with 0.05-0.2, preferably 0.08-0, 15, especially the front with approx. 0.1 l of inert organic solvent. As inert organic solvents according to the invention, aliphatic or aromatic hydrocarbons and aromatic hydrogen chlorides having 6-10 C-atoms come into consideration. Aliphatic or aromatic hydrocarbons having 7-8 carbon atoms are preferred. Solvents that can be used according to the invention are preferably toluene, xylene, chlorobenzene and methylcyclohexane. Particular preference is given to methyl-cyclohexane.
Nakon dodatka inertnog organskog otapala, reakcijsku otopinu grije se pri temperaturu u području od 120-160°C, prednosno 130-150°C, posebno prednosno 140-145°C. Pri konstantnoj temperaturi miješa se daljnjih 3-10 h, prednosno 4-8 sati. Pri tome, aparatura je zatvorena (u pogonu primjerice zatvaranjem zaklopca za suparu), tako da se pomoću prethodno spomenutog grijanja reakcijske otopine unutar aparaturure uspostavi tlak od 3-6 bara (= bara nadtlaka), prednosno od 4-5 bara. Ovisno o vrelištu upotrijebljenog otapala temperaturu se može mijenjati, čime se uspostavlja gore navedeni unutarnji tlak. Time se prema izumu dobije prednost da se mogu upotrijebiti i konvencionalni uređaji, kao što su primjerice DIN emajlirane aparature (stupanj tlaka od 6 bara). After the addition of an inert organic solvent, the reaction solution is heated to a temperature in the range of 120-160°C, preferably 130-150°C, especially preferably 140-145°C. At a constant temperature, it is stirred for a further 3-10 hours, preferably 4-8 hours. At the same time, the apparatus is closed (in operation, for example by closing the steam valve), so that a pressure of 3-6 bar (= bar overpressure), preferably 4-5 bar, is established inside the apparatus by means of the previously mentioned heating of the reaction solution. Depending on the boiling point of the solvent used, the temperature can be changed, which establishes the internal pressure mentioned above. Thus, according to the invention, the advantage is obtained that conventional devices can be used, such as for example DIN enameled devices (pressure level of 6 bar).
Zatim se reakcijsku posudu ohladi na temperaturu pri kojoj aparatura ima maksimalan atmosferski tlak (20 50°C). Potlak se prema potrebi izravnava pomoću inertnog plina. Za obradu, reakcijsku smjesu se pomiješa s prikladnim otapalom ili s mješavinom otapala koja omogućuje odvajanje vodene faze solne kiseline bez gubitka proizvoda. Povoljna je upotreba toluola, ksilola ili metilcikloheksana u mješavini s tetrahidrofuranom. Posebno povoljna je mješavina toluola i tetrahidrofurana u omjeru od otprilike 1:1. Po molu upotrijebljenog polaznog spoja (IV) stavi se između 0,1-1 l gore navedenog organskog otapala ili mješavine otapala. Upotrebljava se prednosno 0,2-0,5 l prethodno navedenog organskog otapala ili mješavine otapala po molu upotrijebljenog oksazolina (IV). Posebno prednosno se upotrebljava pribl. 0,3-0,35 l organskog otapala ili mješavine otapala po molu upotrijebljenog oksazolina (IV). Then the reaction vessel is cooled to the temperature at which the apparatus has maximum atmospheric pressure (20 50°C). If necessary, the pressure is equalized using an inert gas. For workup, the reaction mixture is mixed with a suitable solvent or with a mixture of solvents that allows separation of the aqueous phase of hydrochloric acid without loss of product. It is advantageous to use toluene, xylene or methylcyclohexane in a mixture with tetrahydrofuran. A mixture of toluene and tetrahydrofuran in a ratio of approximately 1:1 is particularly advantageous. Between 0.1-1 l of the above-mentioned organic solvent or solvent mixture is placed per mole of the starting compound (IV) used. Preferably, 0.2-0.5 l of the aforementioned organic solvent or mixture of solvents is used per mole of oxazoline (IV) used. It is particularly preferred to use approx. 0.3-0.35 l of organic solvent or mixture of solvents per mole of oxazoline (IV) used.
Vodenu dolnju fazu se zatim odvoji i zaostalu gornju fazu se ekstrahira s vodom još nekoliko puta, prednosno 2-3 puta, posebno prednosno 2 puta. Količina upotrijebljene vode za ispiranje prema izumu za jednu ekstrakciju je u rasponu od 0,05-0,5 l po molu upotrijebijenog oksazolina (IV). Prednosno se za jedan stupanj ekstrakcije upotrebljava 0,1-0,2 l vode po molu upotrijebijenog polaznog spoja (IV). The aqueous lower phase is then separated and the remaining upper phase is extracted with water several more times, preferably 2-3 times, especially preferably 2 times. The amount of water used for rinsing according to the invention for one extraction is in the range of 0.05-0.5 l per mole of oxazoline (IV) used. Preferably, for one stage of extraction, 0.1-0.2 l of water is used per mole of the starting compound (IV) used.
Tako ispranu organsku gornju fazu se zatim zaluži. U tu svrhu mogu se prema izumu upotrijebiti vodene otopine hidroksida alkalijskih ili zemno alkalijskih metala. Prednosno se upotrebljava litijev, natrijev ili kalijev hidroksid. Po molu polaznog spoja (IV) upotrebljava se 0,7-1 mol baze, prednosno 0,8-0,9 mola baze. The organic upper phase washed in this way is then made alkaline. For this purpose, according to the invention, aqueous solutions of hydroxides of alkali or alkaline earth metals can be used. Lithium, sodium or potassium hydroxide is preferably used. 0.7-1 mol of base is used per mol of starting compound (IV), preferably 0.8-0.9 mol of base.
Dolnju fazu se nakon provedenog rastavljanja faza ispušta u drugu reakcijsku posudu. Zaostalu gornju fazu se zatim ponovno podvrgava gore spomenutom zaluživanju. Pri tome, prema izumu se dodaje u svakom slučaju samo još pribl. 10% masa/masa količne baze upotrijebljene u prvom stupnju zaluživanja. Nakon ponovnog odvajanja dolnje faze, sjedinjeni vodeni eksrakti se destilacijom oslobode od otapala pokupljenog ispiranjem. Po molu upotrijebijenog polaznog spoja (IV) izdestilira otprilike 0,05-0,5 l vode, prednosno između 0,07 i 0,2 l, posebno prednosno pribl. 0,1 l vode. Kad se ohladi na temperaturu ispod 40°C, prednosno na temperaturu u području od 20-30°C, posebno prednosno na 25°C, po molu upotrijebi jenog polaznog spoja doda se 0,1-0,5 l, prednosno pribl. 0,2 l vode i zatim se zakiseli s 1-5 molova, prednosno 2-4 mola, posebno prednosno pribl. 3,5 mola solne kiseline. After phase separation, the lower phase is discharged into another reaction vessel. The residual upper phase is then again subjected to the above-mentioned leaching. At the same time, according to the invention, only approx. 10% mass/mass of the colic base used in the first stage of alkalization. After separating the lower phase again, the combined aqueous extracts are freed from the solvent collected by washing by distillation. Per mole of the starting compound (IV) used, it distils approximately 0.05-0.5 l of water, preferably between 0.07 and 0.2 l, especially preferably approx. 0.1 l of water. When it cools down to a temperature below 40°C, preferably to a temperature in the range of 20-30°C, especially preferably to 25°C, 0.1-0.5 l is added per mole of starting compound used, preferably approx. 0.2 l of water and then acidified with 1-5 moles, preferably 2-4 moles, especially preferably approx. 3.5 moles of hydrochloric acid.
Izlučeni proizvod se odvoji centrifugiranjem, ispere s vodom i osuši. The secreted product is separated by centrifugation, washed with water and dried.
Slijedeći primjeri služe za ilustraciju provedbe postupka sinteze prema izumu za proizvodnju derivata bifenil-2-karboksilne kiseline opće formule (I). Oni se podrazumijevaju samo kao mogući primjeri prikazanog postupka i izum se ne ograničava na njihov sadržaj. The following examples serve to illustrate the implementation of the synthesis procedure according to the invention for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I). They are understood only as possible examples of the presented process and the invention is not limited to their content.
Primjer 1 Example 1
U emajliranu mješalicu od 1200 l stavi se 265 kg 4'-metil-2-(4',4-dimetil-oksazolin-2-il)bifenil, 205 l vode i 400 kg 36,5%-tne solne kiseline. Zatim se atmosferu učini inertnom pomoću dušika i evakuira na pribl. 50 mbara i tada se doda 102,5 l metilcikloheksana. Zaklopac za suparu se zatvori i kroz otprilike l sat zagrije se na pribl. 140°C i miješa se još 4 do 8 sati pri 140 - 145°C. Pri tome se uspostavi nunutarnji tlak od 4-5 bara. Nakon toga se ohladi na 20 - 30°C, tlak dušika se namjesti na atmosferski tlak i doda se 175 l toluola i 150 l THF-a. Vodenu dolnju fazu se odvoji i zaostalu organsku fazu se još jednom ekstrahira s 205 l i zatim sa 103 l vode. U gornju fazu se doda daljnjih 512 l vode i 80 kg 45%-tne natrijeve lužine i nakon odvajanja, dolnju fazu se ispusti u drugu emajliranu mješalicu od 1200 1. Taj postupak se ponovi sa 103 l vode i 8,9 kg 45%-tne natrijeve lužine. 265 kg of 4'-methyl-2-(4',4-dimethyl-oxazolin-2-yl)biphenyl, 205 l of water and 400 kg of 36.5% hydrochloric acid are placed in a 1200 l enameled mixer. The atmosphere is then made inert with nitrogen and evacuated to approx. 50 mbar and then 102.5 l of methylcyclohexane are added. The steam valve is closed and in about 1 hour it heats up to approx. 140°C and mixed for another 4 to 8 hours at 140 - 145°C. In doing so, an internal pressure of 4-5 bar is established. After that, it is cooled to 20 - 30°C, the nitrogen pressure is adjusted to atmospheric pressure and 175 l of toluene and 150 l of THF are added. The aqueous lower phase is separated and the residual organic phase is extracted once again with 205 l and then with 103 l of water. A further 512 l of water and 80 kg of 45% sodium lye are added to the upper phase, and after separation, the lower phase is discharged into another enameled mixer of 1200 1. This procedure is repeated with 103 l of water and 8.9 kg of 45%- tne sodium alkali.
Iz sjedinjenih vodenih ekstrakata izdestilira se najprije pribl. 103 l, a kad se ohladi na 25°C doda se 205 l vode i zatim 97 kg 36,5%-tne solne kiseline. Proizvod se odvoji cenrifugiranjem, ispere s vodom i osuši. Iskorištenje: 190 kg 4'-metilbifenil-2-karboksilne kiseline (90%). From the combined aqueous extracts, approx. 103 l, and when it cools down to 25°C, add 205 l of water and then 97 kg of 36.5% hydrochloric acid. The product is separated by centrifugation, washed with water and dried. Yield: 190 kg of 4'-methylbiphenyl-2-carboxylic acid (90%).
Primjer 2 Example 2
U emajliranu mješalicu od 1200 l stavi se 251 kg 2-(4, 4-dimetiloksazolin-2-il)bifenila, 205 l vode i 400 kg 36,5%-tne solne kiseline. Atmosferu se učini inertnom s dušikom i zatim se evakuira na pribl. 50 mbara i zatim se doda još 102,5 l metilcikloheksana. Kad se zatvori zaklopac za suparu zagrije se kroz otprilike l sat na pribl. 140°C i miješa se još daljnjih 4 do 8 sati pri 140-145°C. Pri tome se uspostavi unutarnji tlak od 4-5 bara. Zatim se ohladi na 20 - 30°C, s dušikom se namjesti na atmosferski tlak i doda se 175 l toluola i 150 l THF-a. Vodenu fazu se odvoji i preostalu organsku fazu se još jednom ekstrahira s 205 l i zatim sa 103 l vode. U gornju fazu se doda daljnjih 512 l vode i 80 kg 45%-tne natrijeve lužine i kad se dolnja faza odvoji ispusti ju se u drugu emajliranu mješalicu od 1200 1. Taj postupak se ponovi sa 103 l vode i 8,9 kg 45%-tne natrijeve lužina. Iz sjedinjenih vodenih ekstrakata izdestilira se najprije pribl. 103 l, a kad se ohladi na 25°C doda se 205 l vode i zatim 97 kg 36,5%-tne solne kiseline. Proizvod se odvoji cetrifugiranjem, ispere s vodom i osuši. Iskorištenje: 180 kg bifenil-2-karboksilne kiseline (91%). 251 kg of 2-(4, 4-dimethyloxazolin-2-yl)biphenyl, 205 l of water and 400 kg of 36.5% hydrochloric acid are placed in a 1200 l enameled mixer. The atmosphere is made inert with nitrogen and then evacuated to approx. 50 mbar and then another 102.5 l of methylcyclohexane is added. When the steam valve is closed, it heats up in about 1 hour to approx. 140°C and mixed for a further 4 to 8 hours at 140-145°C. In doing so, an internal pressure of 4-5 bar is established. It is then cooled to 20 - 30°C, adjusted to atmospheric pressure with nitrogen and 175 l of toluene and 150 l of THF are added. The aqueous phase is separated and the remaining organic phase is extracted once again with 205 l and then with 103 l of water. A further 512 l of water and 80 kg of 45% sodium lye are added to the upper phase, and when the lower phase is separated, it is dropped into another enameled mixer of 1200 1. This procedure is repeated with 103 l of water and 8.9 kg of 45% -tne sodium lye. From the combined aqueous extracts, approx. 103 l, and when it cools down to 25°C, add 205 l of water and then 97 kg of 36.5% hydrochloric acid. The product is separated by centrifugation, washed with water and dried. Yield: 180 kg of biphenyl-2-carboxylic acid (91%).
Usporedbeni primjer Comparative example
U emajliranu mješalicu od 1200 l stavi se 265 kg 4'-metil-2-(4,4-dimetil-oksazolin-2-il)bifenila, 205 l vode i 400 kg 36,5%-tne solne kiseline. Atmosferu se učini inertnom s dušikom, zatim se evakuira na pribl. 50 mbara i zaklopac za suparu se zatvori. Nakon toga se tijekom otprilike l sata unutrašnjost uređaja zagrije na pribl. 140°C i miješa se još daljnjih 4 do 8 sati pri 140-145°C, pri čemu se uspostavi unutarnji tlak od 4 - 5 bara. Nakon toga se ohladi na 20 - 30°C, s dušikom se namjesti na atmosfeski tlak i doda se 175 l toluola i 150 l THF-a. Dolnju vodenu fazu se doda otpadnoj vodi, a preostalu organsku gornju fazu se još jednom ekstrahira s 205 l i zatim sa 103 l vode. U gornju fazu doda se daljnjih 512 l vode i 80 kg45%-tne natrijeve lužine i dolnju fazu se odvoji i ispusti u drugu emajliranu mješalicu od 1200 1. Taj se postupak ponovi sa 103 l vode i 8,9 kg 45%-tne natrijeve lužine. Iz sjedinjenih vodenih ekstrakata izdestilira najprije pribl. 103 l, a kad se ohladi na 25°C, doda se 205 l vode i zatim 97 kg 36,5%-tne solne kiseline. Proizvod se odvoji centrifugiranjem, ispere s vodom i osuši. 265 kg of 4'-methyl-2-(4,4-dimethyl-oxazolin-2-yl)biphenyl, 205 l of water and 400 kg of 36.5% hydrochloric acid are placed in a 1200 l enameled mixer. The atmosphere is made inert with nitrogen, then evacuated to approx. 50 mbar and the fuel flap closes. After that, for about 1 hour, the inside of the device heats up to approx. 140°C and mixed for a further 4 to 8 hours at 140-145°C, during which an internal pressure of 4-5 bar is established. After that, it is cooled to 20 - 30°C, adjusted to atmospheric pressure with nitrogen and 175 l of toluene and 150 l of THF are added. The lower aqueous phase is added to the waste water, and the remaining organic upper phase is extracted once again with 205 l and then with 103 l of water. A further 512 l of water and 80 kg of 45% caustic soda are added to the upper phase and the lower phase is separated and discharged into another enameled mixer of 1200 l. This procedure is repeated with 103 l of water and 8.9 kg of 45% caustic soda alkalis. From the combined water extracts, he first distills approx. 103 l, and when it cools down to 25°C, add 205 l of water and then 97 kg of 36.5% hydrochloric acid. The product is separated by centrifugation, washed with water and dried.
Iskorištenje: 100 kg 4'-metilbifenil-2-karboksilne kiseline (47%). Yield: 100 kg of 4'-methylbiphenyl-2-carboxylic acid (47%).
Claims (13)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19908504A DE19908504C2 (en) | 1999-02-26 | 1999-02-26 | Large-scale process for the preparation of derivatives of biphenyl-2-carboxylic acid by saponifying a (2-oxazolinyl) -2-biphenyl derivative with hydrochloric acid |
PCT/EP2000/001162 WO2000051961A1 (en) | 1999-02-26 | 2000-02-12 | Method for producing derivatives of biphenyl-2-carboxylic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
HRP20010616A2 true HRP20010616A2 (en) | 2002-08-31 |
Family
ID=7899061
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HR20010616A HRP20010616A2 (en) | 1999-02-26 | 2001-08-23 | Method for producing derivatives of biphenyl-2-carboxylic acid |
Country Status (34)
Country | Link |
---|---|
EP (1) | EP1169289B1 (en) |
JP (1) | JP4558946B2 (en) |
KR (1) | KR100683432B1 (en) |
CN (1) | CN1222500C (en) |
AR (1) | AR022772A1 (en) |
AT (1) | ATE253034T1 (en) |
AU (1) | AU781070B2 (en) |
BG (1) | BG105780A (en) |
BR (1) | BR0008483B1 (en) |
CA (1) | CA2364862C (en) |
CO (1) | CO5160249A1 (en) |
CZ (1) | CZ299385B6 (en) |
DE (2) | DE19908504C2 (en) |
DK (1) | DK1169289T3 (en) |
EA (1) | EA003948B1 (en) |
EE (1) | EE200100448A (en) |
ES (1) | ES2208284T3 (en) |
HK (1) | HK1042289B (en) |
HR (1) | HRP20010616A2 (en) |
HU (1) | HU227949B1 (en) |
IL (2) | IL144619A0 (en) |
NO (1) | NO20014045D0 (en) |
NZ (1) | NZ514365A (en) |
PE (1) | PE20001490A1 (en) |
PL (1) | PL198060B1 (en) |
PT (1) | PT1169289E (en) |
SK (1) | SK12142001A3 (en) |
TR (1) | TR200102476T2 (en) |
TW (1) | TWI274051B (en) |
UA (1) | UA58631C2 (en) |
UY (1) | UY26035A1 (en) |
WO (1) | WO2000051961A1 (en) |
YU (1) | YU60401A (en) |
ZA (1) | ZA200105925B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100355717C (en) * | 2005-12-09 | 2007-12-19 | 浙江工业大学 | Method for synthesizing diphenyl-2-carboxylic acid |
RU2484117C2 (en) * | 2011-03-30 | 2013-06-10 | Учреждение Российской Академии Наук Институт Проблем Химической Физики Ран (Ипхф Ран) | Using 4-biphenyl carboxylic acid derivatives as organic mechanoluminescent material and mechanoluminescent composition |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5223058A (en) * | 1975-08-15 | 1977-02-21 | Sankyo Co Ltd | Preparation of indanylpropionic acid derivatives |
GB1592161A (en) * | 1976-08-13 | 1981-07-01 | Secr Defence | Biphenyl carboxylic esters and their use as liquid crystal materials |
US4710513A (en) * | 1979-08-17 | 1987-12-01 | Merck & Co., Inc. | Substituted pyranone inhibitors of cholesterol synthesis |
GB2095663B (en) * | 1981-03-11 | 1985-03-27 | Wellcome Found | Substituted diaryl compounds |
JPH051002A (en) * | 1991-02-15 | 1993-01-08 | Nikko Kyodo Co Ltd | Production of alpha-amino acid |
JPH0761952A (en) * | 1993-06-17 | 1995-03-07 | Eisai Kagaku Kk | Production of halomethylbiphenylcarboxylic acid ester derivative |
JP3420321B2 (en) * | 1994-02-03 | 2003-06-23 | 北陸製薬株式会社 | Method for producing 2,4,5-trihalogeno-3-methylbenzoic acid |
ATE209626T1 (en) * | 1996-05-30 | 2001-12-15 | Aventis Pharma Inc | ALKYLOXYAMINE SUBSTITUTED FLUORENONE DERIVATIVES AND THEIR USE AS PROTEIN KINASE C INHIBITORS |
DE19632643C1 (en) * | 1996-08-13 | 1998-01-22 | Great Lakes Chem Konstanz Gmbh | Catalyzed coupling of aryl magnesium halides and bromoarylcarboxylic acid compounds to produce biphenylcarboxylic acids |
AU2362399A (en) * | 1998-04-21 | 1999-10-28 | Rohm And Haas Company | Metal salt catalyzed process to oxazolines and subsequent formulation of chloroketones |
-
1999
- 1999-02-26 DE DE19908504A patent/DE19908504C2/en not_active Expired - Fee Related
-
2000
- 2000-02-12 DE DE50004257T patent/DE50004257D1/en not_active Expired - Lifetime
- 2000-02-12 CZ CZ20013080A patent/CZ299385B6/en not_active IP Right Cessation
- 2000-02-12 HU HU0200271A patent/HU227949B1/en not_active IP Right Cessation
- 2000-02-12 NZ NZ514365A patent/NZ514365A/en not_active IP Right Cessation
- 2000-02-12 DK DK00907558T patent/DK1169289T3/en active
- 2000-02-12 PT PT00907558T patent/PT1169289E/en unknown
- 2000-02-12 CN CNB008042160A patent/CN1222500C/en not_active Expired - Fee Related
- 2000-02-12 EE EEP200100448A patent/EE200100448A/en unknown
- 2000-02-12 WO PCT/EP2000/001162 patent/WO2000051961A1/en active IP Right Grant
- 2000-02-12 ES ES00907558T patent/ES2208284T3/en not_active Expired - Lifetime
- 2000-02-12 AU AU29110/00A patent/AU781070B2/en not_active Ceased
- 2000-02-12 EP EP00907558A patent/EP1169289B1/en not_active Expired - Lifetime
- 2000-02-12 JP JP2000602190A patent/JP4558946B2/en not_active Expired - Lifetime
- 2000-02-12 AT AT00907558T patent/ATE253034T1/en active
- 2000-02-12 YU YU60401A patent/YU60401A/en unknown
- 2000-02-12 SK SK1214-2001A patent/SK12142001A3/en unknown
- 2000-02-12 IL IL14461900A patent/IL144619A0/en active IP Right Grant
- 2000-02-12 BR BRPI0008483-2A patent/BR0008483B1/en not_active IP Right Cessation
- 2000-02-12 EA EA200100831A patent/EA003948B1/en not_active IP Right Cessation
- 2000-02-12 TR TR2001/02476T patent/TR200102476T2/en unknown
- 2000-02-12 CA CA002364862A patent/CA2364862C/en not_active Expired - Fee Related
- 2000-02-12 PL PL349464A patent/PL198060B1/en unknown
- 2000-02-12 KR KR1020017010739A patent/KR100683432B1/en not_active IP Right Cessation
- 2000-02-23 CO CO00012756A patent/CO5160249A1/en unknown
- 2000-02-24 PE PE2000000152A patent/PE20001490A1/en not_active Application Discontinuation
- 2000-02-25 AR ARP000100847A patent/AR022772A1/en active Pending
- 2000-02-25 UY UY26035A patent/UY26035A1/en unknown
- 2000-02-25 TW TW089103323A patent/TWI274051B/en not_active IP Right Cessation
- 2000-12-02 UA UA2001096607A patent/UA58631C2/en unknown
-
2001
- 2001-07-18 ZA ZA200105925A patent/ZA200105925B/en unknown
- 2001-07-30 IL IL144619A patent/IL144619A/en not_active IP Right Cessation
- 2001-08-03 BG BG105780A patent/BG105780A/en active Pending
- 2001-08-20 NO NO20014045A patent/NO20014045D0/en not_active Application Discontinuation
- 2001-08-23 HR HR20010616A patent/HRP20010616A2/en not_active Application Discontinuation
-
2002
- 2002-05-22 HK HK02103840.4A patent/HK1042289B/en not_active IP Right Cessation
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5091929B2 (en) | Method for producing benzoic acids | |
CN107141246B (en) | A kind of preparation method of Isatine derivatives | |
HU222121B1 (en) | Process for preparing benzoic acid derivatives | |
HRP20010616A2 (en) | Method for producing derivatives of biphenyl-2-carboxylic acid | |
CN1330065A (en) | Intermediate for preparing enantiomorph pure indol-carbocylic acids and its active derivative | |
NO314303B1 (en) | Process for the synthesis of quinoline derivatives | |
WO2017094031A2 (en) | Novel process for preparation of apremilast | |
JP2005526112A (en) | Method for preparing 4-methyl-thiazole-5-carbaldehyde intermediate. | |
CN109535140A (en) | A method of double indoles substituted-dihydro pyrrolones derivatives are constructed based on oxime ester and indoles | |
KR20070010794A (en) | Synthetic method of optically pure (s)-3-hydroxypyrrolidine | |
US2701251A (en) | Process of producing indoleacetic acids and new indoleacetic acids produced thereby | |
US6369271B1 (en) | Process for preparing derivatives of biphenyl-2-carboxylic acid | |
US6184394B1 (en) | Process for the preparation of 3-furoate esters and novel intermediate compounds | |
Kulka et al. | Cyclodehydration of o-Phenoxyphenylacetic Acids to Dihydrodibenz (b, f) oxepinones | |
CN110862325B (en) | Preparation method of (1R,3S) -3-amino-1-cyclopentanol and salt thereof | |
Anacardio et al. | Palladium-Catalyzed Selective Carbonylation of Vinyl Triflates in the Presence of 2-Iodophenols: A New Route to 3-Spiro-Fused Benzofuran-2 (3H)-ones | |
CH635588A5 (en) | PROCESSES FOR THE PREPARATION OF THIENO (2,3-C) AND THIENO (3,2-C) PYRIDINES. | |
CN108383705A (en) | A kind of preparation method of 3,7- diethyl nonane -4,6- diketone | |
CN115215780B (en) | Method for preparing heterobifunctional crosslinking agent SMCC by using N, N-disuccinimidyl carbonate | |
JP2010037237A (en) | Method for producing carboxylic acid ester | |
Xu et al. | Rongalite-promoted synthesis of β-keto sulfones via radical cascade reaction | |
MXPA01008564A (en) | Method for producing derivatives of biphenyl-2-carboxylic acid | |
US3484438A (en) | Phenthiazine derivatives | |
JPH0140832B2 (en) | ||
RU2316545C1 (en) | METHOD FOR PREPARING PROTECTED CYCLIC 2,3-DEHYDRO-α-AMINO ACIDS |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A1OB | Publication of a patent application | ||
ARAI | Request for the grant of a patent on the basis of the submitted results of a substantive examination of a patent application | ||
PNAN | Change of the applicant name, address/residence |
Owner name: BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG., DE |
|
OBST | Application withdrawn |