ZA200105925B - Method for producing derivatives of biphenyl-2-carboxylic acid. - Google Patents
Method for producing derivatives of biphenyl-2-carboxylic acid. Download PDFInfo
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- ZA200105925B ZA200105925B ZA200105925A ZA200105925A ZA200105925B ZA 200105925 B ZA200105925 B ZA 200105925B ZA 200105925 A ZA200105925 A ZA 200105925A ZA 200105925 A ZA200105925 A ZA 200105925A ZA 200105925 B ZA200105925 B ZA 200105925B
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- optionally
- phenyl
- hydroxy
- substituted
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- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 42
- 229910052799 carbon Inorganic materials 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- -1 oxazolin-2-yl group Chemical group 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 239000011737 fluorine Substances 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 239000000460 chlorine Chemical group 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 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
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 238000007127 saponification reaction Methods 0.000 claims description 9
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 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
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 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
- 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
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 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
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 5
- GRFOHUBBUMAJMM-UHFFFAOYSA-N 3-(2-aminoquinolin-3-yl)-n-cyclohexyl-n-methylpropanamide Chemical compound C=1C2=CC=CC=C2N=C(N)C=1CCC(=O)N(C)C1CCCCC1 GRFOHUBBUMAJMM-UHFFFAOYSA-N 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 26
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 14
- 239000000243 solution Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- 210000003298 dental enamel Anatomy 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000006286 aqueous extract Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 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
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 238000005580 one pot 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
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000002918 oxazolines Chemical class 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 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
1 g 4 ® WO 00/51961 - 1 - PCT/EP00/01162 75961pct . Jer] . f bin 1-0. 1 acid
The invention relates to a process which can be used on an industrial scale for preparing biphenyl-2-carboxylic acid derivatives (I)
HOOC
D0.
R' (1), wherein R' and R? may have the meanings given in the specification and claims. oft] .
Biphenyl-2-carboxylic acids of formula (I) are very important as intermediate products in the production of pharmaceutically valuable active substances, particularly in the production of pharmaceutical substances which may be used as angiotensin-II-antagonists.
Processes for preparing biphenyl-2-carboxylic acid and the derivatives (I) thereof are known from the prior art. One method essential to the background of the invention is the coupling of aromatic Grignard compounds (II) with optionally substituted (2-methoxyphenyl) -2-oxazolines (III) according to Diagram 1, as described by Meyers et al. (e.g. Tetrahedron (1985) Vol. 41, 837-860), in which the corresponding (2-oxazolinyl)-2-biphenyl derivatives (IV) are obtained to begin with.
t ’ A] [
Rr? R® . Oya a [we] - 3
R' : 2 ox 2 OH { | R (1) RR © no) (IV) 0 (1
Diagram 1:
The group R*™ denotes an optionally substituted oxazolin- 2-yl group. The definition of the groups R!' and R® can be found in the later part of the specification and in the claims. Conversion into the corresponding carboxylic acids of formula (I) is effected by saponification of the oxazolines (IV). This saponification of (IV) can be carried out by two different reaction methods, from a formal point of view. In Diagram 2 these reaction methods are illustrated by way of example with reference to the preparation of biphenyl-2-carboxylic acid, starting from biphenyl-oxazoline unsubstituted at the oxazoline group (i.e. R! and R? = hydrogen; R™ = oxazolin-2-yl).
' . ® WO 00/51961 - 3 - B PCT/EP00/01162
OH a
CoN
Ng (IV) No yd 0 oO
Diagram 2: (Vb)
The saponification of the oxazoline under reaction conditions known in the art leads in the first step to the formation of the aminoester (Vb) (Meyers et al. J. Org.
Chem. (1974) Vol. 39, 2787-2793). The aminoester (Vb) can then be saponified to the carboxylic acid (I) in a second reaction step, e.g. by boiling for several hours in 10 - 25 % sodium hydroxide solution.
For a large-scale manufacturing process, however, it is desirable to carry out the saponification process as a one-pot process.
The acid saponification by a one-pot process (e.g. according to EP59983) carried out using the methods known from the prior art, however, led to unsatisfactory results when done on a large scale.
It was observed that because of the low solubility in the solvents which are used according to the prior art (e.g. aqueous hydrochloric acid according to EP 59983) amino- ester (Vb) is partially precipitated after being formed. A precipitate of (Vb) is formed on the stirring mechanism and on the walls of the reaction vessel. This causes aminoester (Vb) to be removed successively from the reaction solution and, because of the poor solubility, it is then virtually no longer available for further reaction to form the desired end compound (I). A further reduction in yield occurs as a result of the inclusion of product (I) in the crystallised aminoester (Vb) which is clumping normally.
The abovementioned disadvantages lead to an increased cost in the large-scale production of (I), since within the scope of the working up and processing of the end product, on the one hand, the aminoester (Vb) has to be separated off and, on the other hand, a separate synthesis step has to take place for reacting the precipitated aminoester (Vb) to form the end product.
The aim and objective of the present invention is therefore to provide a process for preparing derivatives/homologues of biphenyl-2-carboxylic acid on a large scale which overcomes the disadvantages of the processes known from the prior art.
I led d Cs ft .
Surprisingly, it has been found that the disadvantages encountered in the methods of preparing biphenyl-2- carboxylic acid derivatives known from the prior art can be avoided if the saponification of the oxazoline (IV) is carried out with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
The present invention is consequently directed to a large- scale process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I)
: HOOC 0
R' (1), wherein
R' and R’* which may be identical or different denote hydrogen, C;-Ci-alkyl, which may optionally be substituted by halogen, C,-Ci-alkoxy, C,-C¢-acyl, C,-C,-alkoxycarbonyl,
COOH, phenyl, benzyl, halogen, hydroxy, nitro or amino, or wherein
R' and R’ together with adjacent carbon atoms of the phenyl ring form a saturated or unsaturated 5- or 6- membered carbocyclic group which may optionally be substituted by C,-C,-alkyl, halogen, COOH, phenyl or hydroxy; characterised in that a (2-oxazolinyl)-2-biphenyl derivative of general formula (IV)
Rx 0)
R' (Iv), wherein
R' and R? are as hereinbefore defined and
R*™ denotes an oxazolin-2-yl group, which may optionally be mono-, di-, tri- or tetra-substituted by one or more of the groups C,-C,-alkyl, which may optionally be substituted by halogen, hydroxy or C,-C,-alkoxy, C,-C,- alkoxy, phenyl, which may optionally be substituted by C,-
C,-alkyl, C,-C,-alkoxy, hydroxy, nitro or amino, benzyl, pyridyl or C,-C.-alkoxycarbonyl, is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
[J WO 00/51961 - 6 - 3 PCT/EP00/01162
A preferred process according to the invention is a process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I) wherein
R' and R?, which may be identical or different, denote hydrogen, C,-C,~alkyl, which may optionally be substituted by fluorine, chlorine or bromine, C,-C,-alkoxy, C,-C,-acyl,
C,-C,~alkoxycarbonyl, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, nitro or amino, or wherein
R' and R® together with adjacent carbon atoms of the phenyl ring form an unsaturated 6-membered carbocyclic group which may optionally be substituted by C,-C,-alkyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy; characterised in that a (2-oxazolinyl)-2-biphenyl derivative of general formula (IV), wherein
R' and R® are as hereinbefore defined and
R denotes an oxazolin-2-yl group, which may optionally be mono- or disubstituted by one or more of the groups C,-
C,-alkyl, which may optionally be substituted by fluorine, chlorine, bromine, hydroxy or C,-C,-alkoxy, C,-C,-alkoxy, phenyl, which may optionally be substituted by C,-C,- alkyl, C,-C,-alkoxy, hydroxy, nitro or amino, benzyl or C,-
C,-alkoxycarbonyl, is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
Particularly preferred is a process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I), wherein
R' and R®* which may be identical or different, denote hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, CF,, methoxy, ethoxy, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, nitro or amino, or wherein
R' and R® together with adjacent carbon atoms of the phenyl ring form an anellated phenyl ring which may optionally be substituted by methyl, ethyl, n-propyl,
isopropyl, tert.-butyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy, characterised in that a (2-oxazolinyl)-2-biphenyl derivative of general formula (IV) wherein
R!' and R® are as hereinbefore defined and
R%* denotes an oxazolin-2-yl group, which may optionally be mono- or disubstituted by one or more of the groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl, methoxymethyl, hydroxymethyl, methoxy or ethoxy, or phenyl, which may optionally be substituted by methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl, methoxy, ethoxy or hydroxy, or benzyl, methoxycarbonyl or ethoxycarbonyl, is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
Also of importance according to the invention is a process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I), wherein
R' and R* which may be identical or different, denote hydrogen, methyl, CF,, COOH, phenyl, fluorine or hydroxy, or wherein
R' and R? together with adjacent carbon atoms of the phenyl ring form an anellated phenyl ring, characterised in that a (2-oxazolinyl)-2-biphenyl derivative of general formula (IV), wherein
R' and R® are as hereinbefore defined and
Ro denotes an oxazolin-2-yl group, which may optionally be mono- or disubstituted by one or more of the groups methyl, ethyl, methoxy, ethoxy, phenyl or benzyl, is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
Of particular importance is a process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I), wherein
R' and R® which may be identical or different, denote hydrogen, methyl or CF,, characterised in that a (2-oxazolinyl)-2-biphenyl derivative of general formula (IV), wherein
R' and R’ are as hereinbefore defined and
R%* denotes an oxazolin-2-yl group optionally mono- or disubstituted by methyl, is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
It is particularly preferable according to the invention to operate as follows. 0.08-0.8, preferably 0.15-0.5, most preferably about 0.2 1 water and 3.0-6.0 mol, preferably 3.5 - 5.0 mol, most preferably about 4.0 mol hydrochloric acid per mol of oxazolin-2-yl-biphenyl (IV)are placed in a reaction vessel of suitable size. Preferably, the abovementioned hydrochloric acid is added in the form of aqueous solutions, most preferably in the form of 36.5% aqueous solution, so that a hydrochloric acid concentration of 20 - 30 %, most preferably about 24 % is produced.
After rendering inert with protective gas, preferably nitrogen, the reaction vessel is evacuated (to about 50 mbar) and 0.05-0.2, preferably 0.08-0.15, most preferably about 0.1 litre of an inert organic solvent is added per mol of starting compound (IV) used. According to the invention, aliphatic or aromatic hydrocarbons and aromatic chlorohydrocarbons with 6-10 carbon atoms may be used as inert organic solvents. Aliphatic or aromatic hydrocarbons with 7-8 carbon atoms are preferred. The solvents which may be used according to the invention are preferably
¢ WO 00/51961 - 9 - B PCT/EP00/01162 toluene, xylene, chlorobenzene and methylcyclohexane.
Methylcyclohexane is particularly preferred.
After the addition of the inert organic solvent the reaction solution is heated to a temperature in the range from 120-160°C, preferably 130-150°C, most preferably 140- 145°C. At constant temperature the mixture is stirred for a further 3-10 h, preferably 4-8 hours. The apparatus is sealed (in practice by closing the vapour seal valve), so that the heating of the reaction solution mentioned above produces an internal pressure of 3-6 baro (= bars overpressure), preferably 4-5 baro within the apparatus.
The temperature can be varied depending on the boiling point of the solvent used, so that the abovementioned internal pressure is built up. This results in the additional advantage according to the invention that conventional apparatus such as DIN enamel apparatus (to pressure level 6 baro) can be used.
The reaction vessel is then cooled to a temperature at which the apparatus is at maximum atmospheric pressure (20 - 50°C). Any underpressure is optionally equalised with inert gas. For working up, the reaction mixture is combined with a suitable solvent or mixture of solvents which enables the aqueous hydrochloric acid phase to be separated off without loss of product. It is preferable to use toluene, xylene or methylcyclohexane in admixture with tetrahydrofuran. A mixture of toluene and tetrahydrofuran in a ratio of about 1:1 is particularly preferred. Between 0.1 and 1 litre of the above mentioned organic solvent or mixture of solvents are used per mol of starting compound (IV) used. Preferably, 0.2-0.5 1 of the above mentioned organic solvent or mixture of solvents are used per mol of oxazoline (IV) put in. Most preferably, about 0.3 to 0.35 1 of the organic solvent or mixture of solvents are used per mol of oxazoline (IV) put in.
The aqueous lower phase is then separated off and the remaining upper phase is extracted several times, preferably 2-3 times, most preferably twice with water.
According to the invention, the amount of washing water used for each extraction process is within a range of from 0.05-0.5 1 water per mol of oxazoline (IV) used.
Preferably, in each extraction step, 0.1-0.2 litres of water are used per mol of starting compound (IV) put in.
The washed organic upper phase is then made alkaline. This may be done according to the invention with aqueous solutions of alkali metal or alkaline earth metal hydroxides. Preferably, aqueous solutions of lithium, sodium or potassium hydroxide are used. According to the invention, aqueous sodium hydroxide solution is particularly preferred as the base. 0.7-1 mol of base, preferably 0.8-0.9 mol of base are used per mol of starting compound (IV).
After the phase separation has taken place the lower phase is decanted into another reaction vessel. The upper phase remaining is then subjected to the above mentioned alkalisation. According to the invention, however, only about 10% w/w of the quantity of base used in the first alkalisation step are added. Once the lower phase has been separated off, the combined aqueous extracts are freed from any entrained solvent by distillation. About 0.05-0.5 1 water, preferably between 0.07 and 0.2 1, most preferably about 0.1 litres of water are distilled off per mol of starting compound (IV) used. After cooling to a temperature below 40°C, preferably to a temperature in the range from 20-30°C, most preferably to 25°C, 0.1-0.5 1, preferably about 0.2 1 of water are added per mol of starting compound put in and the mixture is then made acidic with 1-5 mol, preferably, 2-4 mol, most preferably about 3.5 mol hydrochloric acid.
The product precipitated is centrifuged, washed with water and dried.
The Examples which follow serve to illustrate some methods of synthesising derivatives of biphenyl-2-carboxylic acid of general formula (I) carried out by way of example, according to the invention. They should be understood as being purely possible procedures described by way of example, without restricting the invention to their contents.
Example 1 265 kg of 4'-methyl-2-(4,4-dimethyloxazolin-2-yl)biphenyl, 205 1 of water and 400 kg of 36.5 % hydrochloric acid are placed in a 1200 1 enamel stirring apparatus. After it has been rendered inert with nitrogen it is evacuated to about 50 mbar and then 102.5 1 of methylcyclohexane are added.
After the vapour seal valve has been closed the apparatus is heated to about 140°C within about 1 h and then stirred for a further 4 to 8 h at 140 - 145 °C. An internal pressure of 4 - 5 baro is built up. Then the apparatus is cooled to 20 - 30°C, adjusted to atmospheric pressure with nitrogen and 175 1 of toluene and 150 1 of THF are added.
The aqueous lower phase is separated off and the organic upper phase remaining is extracted with 205 1 and then with 103 1 of water. A further 512 1 of water and 80 kg of 45 % sodium hydroxide solution are added to the upper phase and, after settling, the lower phase is drained off into another 1200 1 enamel stirring apparatus. This operation is repeated with 103 litres of water and 8.9 kg of 45 % sodium hydroxide solution. To begin with, about 103 1 are distilled off from the combined aqueous extracts and after cooling to 25°C, 205 litres of water and then 97 kg of 36.5 % hydrochloric acid are added. The product is centrifuged, washed with water and dried.
Yield : 190 kg of 4'-methylbiphenyl-2-carboxylic acid
Example 2 251 kg of 2-(4,4-dimethyloxazolin-2-yl)biphenyl, 205 1 of water and 400 kg of 36.5 % hydrochloric acid are placed in a 1200 1 enamel stirring apparatus. After it has been rendered inert with nitrogen it is evacuated to about 50 mbar and then 102.5 1 of methylcyciohexane are added.
After the vapour seal valve has been closed the apparatus is heated to about 140°C within about 1 h and then stirred for a further 4 to 8 h at 140 - 145 °C. An internal pressure of 4 - 5 baro is built up. Then the apparatus is cooled to 20 - 30°C, adjusted to atmospheric pressure with nitrogen and 175 1 of toluene and 150 1 of THF are added.
The aqueous lower phase is separated off and the organic upper phase remaining is extracted with 205 1 and then with 103 1 of water. A further 512 1 of water and 80 kg of 45 % sodium hydroxide solution are added to the upper phase and, after settling, the lower phase is drained off into another 1200 1 enamel stirring apparatus. This operation is repeated with 103 litres of water and 8.9 kg of 45 % sodium hydroxide solution. To begin with, about 103 1 are distilled off from the combined aqueous extracts and after cooling to 25°C, 205 litres of water and then 97 kg of 36.5 % hydrochloric acid are added. The product is centrifuged, washed with water and dried.
Yield : 180 kg of biphenyl-2-carboxylic acid (91%)
Comparison example: 265 kg of 4'-methyl-2-(4,4-dimethyloxazolin-2-yl)biphenyl, 205 1 of water and 400 kg of 36.5 % hydrochloric acid are placed in a 1200 1 enamel stirring apparatus. After it has been rendered inert with nitrogen, evacuated to about 50 mbar and the vapour seal valve has been closed, the contents of the apparatus are heated to about 140°C within about 1 h and then stirred for a further 4 to 8 h at 140 -
145 °C, during which time an internal pressure of 4 - S baro is built up. Then the apparatus is cooled to 20 - 30°C, adjusted to atmospheric pressure with nitrogen and 175 1 of toluene and 150 1 of THF are added. The aqueous lower phase is added to the waste water and the organic upper phase remaining is extracted with 205 1 and then with 103 1 of water. A further 512 1 of water and 80 kg of 45 % sodium hydroxide solution are added to the upper phase and, after settling, the lower phase is drained off into another 1200 1 enamel stirring apparatus. This operation is repeated with 103 litres of water and 8.9 kg of 45 % sodium hydroxide solution. To begin with, about 103 1 are distilled off from the combined aqueous extracts and after cooling to 25°C, 205 litres of water and then 97 kg of 36.5 % hydrochloric acid are added. The product is centrifuged, washed with water and dried.
Yield : 100 kg of 4'-methylbiphenyl-2-carboxylic acid
Claims (13)
- o WO 00/51961 - 14 - B PCT/EP00/01162 Patent Claims 1) Process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I)HOOC 0 R' (1), wherein R' and R® which may be identical or different denote hydrogen, C,;-C.,-alkyl, which may optionally be substituted by halogen, C,-Cg-alkoxy, C,-C;-acyl, C,-C,-alkoxycarbonyl, COCH, phenyl, benzyl, halogen, hydroxy, nitro or amino, or wherein R' and R? together with adjacent carbon atoms of the phenyl ring form a saturated or unsaturated 5- or 6- membered carbocyclic group which may optionally be substituted by C,-C,-alkyl, halogen, COOH, phenyl or hydroxy; characterised in that a (2-oxazolinyl) -2-biphenyl derivative of general formula (IV) RX 0) R' (Tv), wherein R' and R® are as hereinbefore defined and RY denotes an oxazolin-2-yl group, which may optionally be mono-, di-, tri- or tetra-substituted by one or more of the groups C,-C,-alkyl, which may optionally be substituted by halogen, hydroxy or C,-C,-alkoxy, C,-C.- alkoxy, phenyl, which may optionally be substituted by C;- C,-alkyl, C,-C,-alkoxy, hydroxy, nitro or amino, benzyl, pyridyl or C,-C,-alkoxycarbonyl,is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
- 2) Process according to claim 1, wherein R' and R?, which may be identical or different, denote hydrogen, C,-C,-alkyl, which may optionally be substituted by fluorine, chlorine or bromine, C,-C,- alkoxy, C,-C,-acyl, C,-C,-alkoxycarbonyl, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, nitro or amino, or wherein R' and R? together with adjacent carbon atoms of the phenyl ring form an unsaturated 6-membered carbocyclic group which may optionally be substituted by C,-C,-alkyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy, and R denotes an oxazolin-2-yl group, which may optionally be mono- or disubstituted by one or more of the groups C,- C,-alkyl, which may optionally be substituted by fluorine, chlorine, bromine, hydroxy or C,-C,-alkoxy, C,-C,-alkoxy, phenyl, which may optionally be substituted by C,-C,- alkyl, C,-C,-alkoxy, hydroxy, nitro or amino, benzyl or C,- C,~alkoxycarbonyl. 3) Process according to claim 1 or 2, wherein R' and R?, which may be identical or different, denote hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, CF,, methoxy, ethoxy, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, nitro or amino, or wherein R' and R? together with adjacent carbon atoms of the phenyl ring form an anellated phenyl ring which may optionally be substituted by methyl, ethyl, n-propyl, isopropyl, tert.-butyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy, and
- R™ denotes an oxazolin-2-yl group, which may optionally be mono- or disubstituted by one or more of the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, tert.butyl, methoxymethyl, hydroxymethyl, methoxy or ethoxy, or phenyl, which may optionally be substituted by methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl, methoxy, ethoxy or hydroxy, or benzyl, methoxycarbonyl or ethoxycarbonyl.
- 4) Process according to one of claims 1 to 3, whereinR' and R?, which may be identical or different,denote hydrogen, methyl, CF,, COOH, phenyl, fluorine or hydroxy, or wherein R' and R®’ together with adjacent carbon atoms of the phenyl ring form an anellated phenyl ring, and R%* denotes an oxazolin-2-yl group, which may optionally be mono- or disubstituted by one or more of the groups methyl, ethyl, methoxy, ethoxy, phenyl or benzyl.
- 5) Process according to one of claims 1 to 4, whereinR' and R®> which may be identical or different, denote hydrogen, methyl or CF,,and R™ denotes an oxazolin-2-yl group which may optionally be mono- or disubstituted by methyl.
- 6) Process according to one of claims 1 to 5,characterised in that saponification is carried out at a pressure of 4-5 baro.
- 7) Process according to one of claims 1 to 6, characterised in that 3.0 - 6.0 mol of hydrochloric acid are used for the saponification per mol of starting compound of general formula (IV).} .® WO 00/51961 - 17 - 3 PCT/EP00/01162
- 8) Process according to one of claims 1 to 7, characterised in that 3.5 - 5.0 mol of hydrochloric acid are used for the saponification per mol of starting compound of general formula (IV).
- 9) Process according to one of claims 1 to 8, characterised in that aliphatic or aromatic hydrocarbons or aromatic chlorohydrocarbons with 6-10 carbon atoms are used as the organic solvent.
- 10) Process according to one of claims 1 to 9, characterised in that aliphatic or aromatic hydrocarbons with 7-8 carbon atoms or chlorobenzene are used as the organic solvent.
- 11) Process according to one of claims 1 to 10, characterised in that toluene, xylene, chlorobenzene and methylcyclohexane are used as the organic solvent.
- 12) Process according to one of claims 1 to 11, characterised in that methylcyclohexane is used as the organic solvent.
- 13) Process for preparing 4'-methylbiphenyl-2-carboxylic acid according to one of claims 1 to 12.
Applications Claiming Priority (1)
| 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 |
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| ZA200105925B true ZA200105925B (en) | 2003-01-07 |
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| ZA200105925A ZA200105925B (en) | 1999-02-26 | 2001-07-18 | Method for producing derivatives of biphenyl-2-carboxylic acid. |
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| EP (1) | EP1169289B1 (en) |
| JP (1) | JP4558946B2 (en) |
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| CO (1) | CO5160249A1 (en) |
| CZ (1) | CZ299385B6 (en) |
| DE (2) | DE19908504C2 (en) |
| DK (1) | DK1169289T3 (en) |
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| 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 |
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| 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 |
| DK104382A (en) * | 1981-03-11 | 1982-09-12 | Wellcome Found | PROCEDURE FOR PREPARING SUBSTITUTED BIPHENYL 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 |
| NZ332597A (en) * | 1996-05-30 | 2000-08-25 | Hoechst Marion Roussel Inc | Alkyloxyamino substituted fluoren-9-ones 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 |
| CN1215047C (en) * | 1998-04-21 | 2005-08-17 | 陶氏益农有限责任公司 | Method for preparing oxazoline catalyzed by metallic salt and method for preparing chloroone therefrom |
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