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WO1995030764A1 - Formation of and dehydraton of hydroxylated diphenylacetylenes - Google Patents

Formation of and dehydraton of hydroxylated diphenylacetylenes Download PDF

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Publication number
WO1995030764A1
WO1995030764A1 PCT/US1995/001958 US9501958W WO9530764A1 WO 1995030764 A1 WO1995030764 A1 WO 1995030764A1 US 9501958 W US9501958 W US 9501958W WO 9530764 A1 WO9530764 A1 WO 9530764A1
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formula
compound
cis
dihydrodiol
hydroxy
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Inventor
Alan Douglas Grund
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BIO-TECHNICAL RESOURCES LP
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BIO-TECHNICAL RESOURCES LP
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Priority claimed from US08/240,125 external-priority patent/US5420361A/en
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Priority to AU18453/95A priority Critical patent/AU1845395A/en
Publication of WO1995030764A1 publication Critical patent/WO1995030764A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/06—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic

Definitions

  • the present invention relates to the production of the cis dihydrodiol derivative of diphenyl acetylenes and the dehydration thereof to form the corresponding meta-substituted phenol derivative.
  • X and Y may be the same or different, and represent hydrogen, halogen, ceryl, or cyano groups except that X and Y cannot both be hydrogen, using strains ofPseudomonasputida.
  • U. S. Patent No. 4,532,209 discloses the production of p-cresol by the acidification of an aqueous solution of 4-methylcyclohexa-3,5-diene-l,2-diol-l- carboxylic acid.
  • (+)-cis-2,3-dihydroxy-l-methylcyclohexa-4,6-diene is disclosed by D.T. Gibson et al., Biochemistry, pp. 1626-1630, Vol. 9, (1970) along with the acid catalyzed dehydration of (+)-cis-2,3-dihydroxy-l-methylcyclohexa -4,6-diene.
  • U.K. Patent No. 2,203,150 B discloses preparing fluorophenols by dehydrating l,2-dihydroxy-3-fluorocyclohexa-3,5-diene in the presence of base and subsequently recovering 2 and/or 3-fluorophenol. The use of base does not make the reaction overly selective for 3-fluorophenol.
  • R 3 is selected from the group consisting of hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxy substituted cycloalkyl, hydroxy substituted phenyl, hydroxy substituted phenalkyl, amino substituted alkyl and alkyl substituted by the group alkyl
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, phenalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxy cycloalkyl, hydroxyalkenyl, hydroxy cycloalkyl, hydroxy substituted phenyl, hydroxy substituted phenalkyl, amino alkyl and alkyl substituted by the group alkyl.
  • n and o are individually 1 or 0 with the proviso that both m and o may not be 0, n is 0, 1 or 2; and X is phenyl, divalent oxygen, sulfur, sulfinyl, sulfonyl, carbonyl, amino or alkylamino or X is a divalent alkylene, alkenylene or alkynylene chain which may optionally include one or more divalent oxygen, sulfur, sulfinyl, sulfonyl, carbonyl, amino or alkylamino moieties in any combination by enzymatically biotransforming the corresponding biphenyl compound with a microorganism.
  • U.S. 4,772,755 discloses compounds of the formula wherein X is hydroxy, alkoxy or alkanoyloxy, Ar 1 is an organic group such as phenyl which may be independently substituted by one or more of alkyl, alkoxy, alkylthio, dialkylamino, halogen etc. and R is an unsubstituted or substituted alkyl group.
  • EP 400,779 Al discloses production of meta-hydroxypheny-acetylenes from phenyl substituted ketal or acetal precursors.
  • the present invention relates to the preparation of 3-hydroxy- diphenylacetylene or less preferably 2-hydroxydiphenylacetylene.
  • the first step in the process is the preparation of diphenylacetylene dihydrodiol by the microbial oxidation of diphenylacetylene.
  • the diphenylacetylene dihydrodiol is then dehydrated with a base at an elevated temperature to produce 3-hydroxy- diphenylacetylene.
  • the diphenylacetylene dihydrodiol can be dehydrated with an acid to produce 2-hydroxydiphenylacetylene.
  • the first aspect of the present involves the production of diphenylacetylene dihydrodiol from diphenylacetylene. This is done by microbial oxidation using a suitable bacteria.
  • a bacterium is isolated by enrichment technique from the environment or obtained from a depository.
  • the first criteria for the bacterium is that it is capable of growth on biphenyl as the sole carbon and energy source.
  • suitable bacteria are of the genus Pseudomonas and, more specifically, are mutants of Pseudomonas Strain 73.
  • Strain 73 is a mobile, anaerobic bacterium having a rod morphology (1 x 3 microns).
  • the organism is negative for the production of pigments, accumulation of poly- ⁇ -hydroxybutyrate (PHB), hydrolysis of gelatin, or formation of nitrogen from nitrate.
  • PHB poly- ⁇ -hydroxybutyrate
  • the organism has no requirement for specific growth factors and does not grow at 41°C.
  • the starting strain is then treated with N-methyl-N'-nitro-N- nitrosoquanidine or ultraviolet light in the known manner to effect mutagenesis to obtain mutants which are unable to grow on biphenyl. Certain of these mutants will be found which lack a functional dihydrodiol dehydrogenase.
  • UV absorbance maximum 321 nm.
  • This UV absorbing metabolite is the cis-2,3-dihydrodiol of diphenyl acetylene, and can accumulate in the growth medium at concentrations of from 100 parts per million (ppm) to 1,000 pp or even higher, depending on growth conditions. This dihydrodiol can then be dehydrated either to the 2 or 3-hydroxydiphenyl acetylene phenol as described below.
  • ATCC strain number 55272 is a Pseudomonas Strain 73-4, a mutant of
  • Pseudomonas Strain 73 described above. This mutant possesses all of the characteristics of a Pseudomonas Strain 73, with the exception that the bacterium is incapable of growth on biphenyl and that it lacks the diol dehydrogenase activity which converts aromatic cis-dihydrodiols to catechols.
  • the strain was received by the American Type Culture Collection, 12301
  • a cell free aqueous broth containing the cis-2,3- diol of diphenylacetylene at a concentration of 100 to 5,000 ppm is used.
  • the broth is quickly heated to 50° to 120°C, preferably from 75° to 100°C.
  • a solution of base at the elevated temperature is quickly added and mixed.
  • the final concentration of base is at least 0.1N, preferably 1.0N or higher up to 8.0N.
  • the solution is held at the elevated temperature for at least 15 minutes, preferably for longer times of 1 to 10 hours.
  • the mixture is then cooled to 20° to 30°C and the phenols recovered such as by extraction with organic solvents.
  • the preferred bases are sodium hydroxide, potassium hydroxide and cesium hydroxide, with sodium hydroxide preferred because of cost.
  • the conversion to the 3-hydroxydiphenylacetylene isomer is 100% when the process is operated under optimum conditions.
  • the compounds produced by the present invention are useful as intermediates for producing polymeric materials.
  • reaction schemes I, II or III Generally the reactions of the present invention can be represented by the following reaction schemes I, II or III.
  • the composition of the minimal salts (MS) medium used in the following Example 1 in grams per liter was as follows: NH-jCl, 1.0; NaNO 3 , 1.0; MgSO 4 , 0.16; FeSO 4 .7H 2 O, 0.004; K 2 HPO 4 , 4.4; KH 2 PO 4 , 3.4; trace salts (TS) solution, 2 ml; and distilled water, 1 liter.
  • the pH of the medium was adjusted to 7.0 using HCl as required.
  • the trace salts solution consisted in grams per liter: concentrated HCl, 10ml; CuSO 4 .5H 2 O, 0.063; CoCl 2 .6H 2 O, 0.16; H 3 BO 3 , 0.91; ZnSO .7H 2 O, 1.8; MnSO 4 .H 2 O, 1.2; NaMoO 4 .2H 2 O, 0.048; CaCl 2 .2H 2 O, 11.4, VSO 4 .2H 2 O, 0.08, Ni(NO 3 ) 2 .6H 2 O, 0.04; Na 2 SeO 3 , 0.04; and distilled water, 980 ml. Carbon sources were added from sterile stock solutions to autoclaved media (1% final concentration).
  • Pseudomonas strain 73-4 ATCC 55272, a mutant of Pseudomonas strain 73, lacking a functional diol dehydrogenase, was grown in the MS medium described above plus 1% succinic acid as carbon source.
  • the organism was grown in 100 ml of medium in a 500 ml shake flask agitated at 150 RPM at 30°C.
  • Diphenylacetylene was provided as solid crystals added to the growth medium. After 16 hours incubation the cells were removed by centrifugation and the broth assayed for the diol of diphenylacetylene by gas chromatography. The compound was present at 320 ppm.
  • Pseudomonas strain 73-4 was grown in the MS medium as described in Example 1, but with glucose as the sole carbon and energy source. Exposure to diphenylacetylene for 16 hours resulted in formation of diphenylacetylene- cis-2,3-dihydrodiol at a concentration of 125 ppm.
  • Diphenylacetylene dihydrodiol was produced to a concentration of 150 ppm using a microorganism isolated from the environment and a process similar to that described in Example 1. Following removal of the cells by centrifiigation, the crude broth containing the dihydrodiol was divided into four portions and treated as described in the Table below.

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Abstract

The production of cis-dihydrodiol compounds of formula (1) where n is 0 or 1 (preferably 0) by the microbial oxidation of a compound of formula (2) using a mutant of a Pseudomonas bacteria at 25 °C to 35 °C and pH 6-8 is disclosed. Further treatment of the cis-dihydrodiol compound with an aqueous basic solution will produce the corresponding 3-dihydrodiphenylacetylene whereas further treatment of the cis-dihydrodiol compound with an aqueous acidic solution will produce the corresponding 2-hydroxy acetylene.

Description

FORMATION OF AND DEHYDRATION OF HYDROXYLATED DIPHENYLACETYLENES
The present invention relates to the production of the cis dihydrodiol derivative of diphenyl acetylenes and the dehydration thereof to form the corresponding meta-substituted phenol derivative. Use of alkali, preferably at elevated temperature, optimizes production of 3-hydroxydiphenylacetylene over 2-hydroxydiphenylacetylene.
Compounds of the general formula
Figure imgf000003_0001
have been chemically dehydrated to phenols by acidification. In general, the 2- hydroxy isomer predominates, or is the exclusive product of the reaction. More recently, U.S. Patent Application serial number 07/623,581, filed December 7, 1990, discloses the use of a base to optimize production of the 3- hydroxy isomer of certain such compounds.
U. S. Patent No. 4,508,822 discloses the preparation of compounds of the general formula
X
Figure imgf000003_0002
wherein X and Y may be the same or different, and represent hydrogen, halogen, ceryl, or cyano groups except that X and Y cannot both be hydrogen, using strains ofPseudomonasputida. U. S. Patent No. 4,532,209 discloses the production of p-cresol by the acidification of an aqueous solution of 4-methylcyclohexa-3,5-diene-l,2-diol-l- carboxylic acid.
The formation of (+)-cis-2,3-dihydroxy-l-methylcyclohexa-4,6-diene from toluene by Pseudomonas putia, is disclosed by D.T. Gibson et al., Biochemistry, pp. 1626-1630, Vol. 9, (1970) along with the acid catalyzed dehydration of (+)-cis-2,3-dihydroxy-l-methylcyclohexa -4,6-diene.
U.K. Patent No. 2,203,150 B discloses preparing fluorophenols by dehydrating l,2-dihydroxy-3-fluorocyclohexa-3,5-diene in the presence of base and subsequently recovering 2 and/or 3-fluorophenol. The use of base does not make the reaction overly selective for 3-fluorophenol.
Initial Reactions in the Oxidation of Ethylbenzene by Pseudomonas putida, by D. T. Gibson et al., Biochemistry, pp. 1520-1527, Vol. 12, No. 8, (1973) discloses the oxidation of ethyl benzene to (+)-cis-3-ethyl-3,5- cyclohexadiene-l,2-diol and (+)-cis-3-( -hydroxy-ethyl)-3,5-cyclohexadiene- 1,2-diol by Pseudomonas putida as well as the oxidation of acetophenone to cis-3-(l' oxoethyl)-3,5-cyclohexadiene-l,2-diol. The reference also discloses the acid catalyzed dehydration of (+)-cis-3-ethyl-3,5-cyclohexa-diene-l,2-diθl.
Biodegradations Yield Novel Intermediates For Chemical Synthesis, D. W. Ribbons et al., Biotechnology and Biodegradations, pp. 213-245, London discloses the use of mutants of . putida to form compounds of the formula
Figure imgf000004_0001
where R1 = R2 = H; R1 = Cl, R2 = H; R1 = F, R2 = H; R1 = CH3, R2 = H; R1 = Ph, R2 = H; R1 = CF3, R2 =H; R1 = C2H5, R2 = H; R1 = HC=CH2, R2 = H; R1 = C=CH, R2 = H; R1 = CH3, R2 = F; R1 = CH3, R2 = Cl; R1 = CH3, R2 = Br.
U.S. Patent No. 4,081,468 discloses acetylenic compounds of the formula
R3 - C = C - R4
where R3 is selected from the group consisting of hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxy substituted cycloalkyl, hydroxy substituted phenyl, hydroxy substituted phenalkyl, amino substituted alkyl and alkyl substituted by the group alkyl, and R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, phenalkyl, hydroxyalkyl, hydroxyalkenyl, hydroxy cycloalkyl, hydroxyalkenyl, hydroxy cycloalkyl, hydroxy substituted phenyl, hydroxy substituted phenalkyl, amino alkyl and alkyl substituted by the group alkyl.
U.S. 4,153,509 discloses preparing compounds of the formula
Figure imgf000005_0001
wherein, m and o are individually 1 or 0 with the proviso that both m and o may not be 0, n is 0, 1 or 2; and X is phenyl, divalent oxygen, sulfur, sulfinyl, sulfonyl, carbonyl, amino or alkylamino or X is a divalent alkylene, alkenylene or alkynylene chain which may optionally include one or more divalent oxygen, sulfur, sulfinyl, sulfonyl, carbonyl, amino or alkylamino moieties in any combination by enzymatically biotransforming the corresponding biphenyl compound with a microorganism.
U.S. 4,772,755 discloses compounds of the formula
Figure imgf000006_0001
wherein X is hydroxy, alkoxy or alkanoyloxy, Ar1 is an organic group such as phenyl which may be independently substituted by one or more of alkyl, alkoxy, alkylthio, dialkylamino, halogen etc. and R is an unsubstituted or substituted alkyl group.
EP 400,779 Al discloses production of meta-hydroxypheny-acetylenes from phenyl substituted ketal or acetal precursors.
The present invention relates to the preparation of 3-hydroxy- diphenylacetylene or less preferably 2-hydroxydiphenylacetylene. The first step in the process is the preparation of diphenylacetylene dihydrodiol by the microbial oxidation of diphenylacetylene. The diphenylacetylene dihydrodiol is then dehydrated with a base at an elevated temperature to produce 3-hydroxy- diphenylacetylene. Alternatively, the diphenylacetylene dihydrodiol can be dehydrated with an acid to produce 2-hydroxydiphenylacetylene.
The first aspect of the present involves the production of diphenylacetylene dihydrodiol from diphenylacetylene. This is done by microbial oxidation using a suitable bacteria. Generally, a bacterium is isolated by enrichment technique from the environment or obtained from a depository. The first criteria for the bacterium is that it is capable of growth on biphenyl as the sole carbon and energy source. Generally, suitable bacteria are of the genus Pseudomonas and, more specifically, are mutants of Pseudomonas Strain 73. Strain 73 is a mobile, anaerobic bacterium having a rod morphology (1 x 3 microns). It is gram negative strain reaction, is catalase and oxidase positive, and utilizes glucose strictly in an oxidative manner. The organism is negative for the production of pigments, accumulation of poly-β-hydroxybutyrate (PHB), hydrolysis of gelatin, or formation of nitrogen from nitrate. The organism has no requirement for specific growth factors and does not grow at 41°C. The starting strain is then treated with N-methyl-N'-nitro-N- nitrosoquanidine or ultraviolet light in the known manner to effect mutagenesis to obtain mutants which are unable to grow on biphenyl. Certain of these mutants will be found which lack a functional dihydrodiol dehydrogenase. When such mutants are grown on a defined minimal salts medium containing a carbon source such as glucose or succinate and exposed to diphenylacetylene, a colorless metabolite accumulates in the growth medium with an ultraviolet light (UV) absorbance maximum at 321 nm. This UV absorbing metabolite is the cis-2,3-dihydrodiol of diphenyl acetylene, and can accumulate in the growth medium at concentrations of from 100 parts per million (ppm) to 1,000 pp or even higher, depending on growth conditions. This dihydrodiol can then be dehydrated either to the 2 or 3-hydroxydiphenyl acetylene phenol as described below.
ATCC strain number 55272 is a Pseudomonas Strain 73-4, a mutant of
Pseudomonas Strain 73, described above. This mutant possesses all of the characteristics of a Pseudomonas Strain 73, with the exception that the bacterium is incapable of growth on biphenyl and that it lacks the diol dehydrogenase activity which converts aromatic cis-dihydrodiols to catechols. The strain was received by the American Type Culture Collection, 12301
Parklawn Drive, Rockville, Maryland on January 6, 1992 and was designated ATCC number 55272.
Generally, a cell free aqueous broth containing the cis-2,3- diol of diphenylacetylene at a concentration of 100 to 5,000 ppm is used. To optimize dehydration to the meta-phenol (3-hydroxydiphenylacetylene) the broth is quickly heated to 50° to 120°C, preferably from 75° to 100°C. Then a solution of base at the elevated temperature is quickly added and mixed. The final concentration of base is at least 0.1N, preferably 1.0N or higher up to 8.0N. The solution is held at the elevated temperature for at least 15 minutes, preferably for longer times of 1 to 10 hours. The mixture is then cooled to 20° to 30°C and the phenols recovered such as by extraction with organic solvents. The preferred bases are sodium hydroxide, potassium hydroxide and cesium hydroxide, with sodium hydroxide preferred because of cost. The conversion to the 3-hydroxydiphenylacetylene isomer is 100% when the process is operated under optimum conditions.
The compounds produced by the present invention are useful as intermediates for producing polymeric materials.
Generally the reactions of the present invention can be represented by the following reaction schemes I, II or III.
Scheme I
Figure imgf000008_0001
73-4 A with HCl or
B with NaOH
Figure imgf000008_0002
PHENYL DIPHENYL- 2-HYDROXY- 3-HYDROXY- ACETYLENE ACETYLENE- DIPHENYL- DIPHENYL- CIS-2,3- ACETYLENE ACETYLENE DfflYDRODIOL Scheme II
Figure imgf000009_0001
2-HYDROXY- 2'-HYDROXY- 2,2'-DIHYDROXY- 2,3'-DΠΓYDROXY
DIPHENYL DIPHENYL- DIPHENYL- DIPHENYL¬
ACETYLENE ACETYLENE- ACETYLENE ACETYLENE CIS-2,3-
DIHYDRODIOL
Scheme III
Figure imgf000009_0002
3-HYDROXY- 3'-HYDROXY- 2,3'-DIHYDROXY- 3,3'-DIHYDROXY
DIPHENYL DIPHENYL- DIPHENYL- DIPHENYL¬
ACETYLENE ACETYLENE- ACETYLENE ACETYLENE
CIS-2,3-
DIHYDRODIOL The composition of the minimal salts (MS) medium used in the following Example 1 in grams per liter was as follows: NH-jCl, 1.0; NaNO3, 1.0; MgSO4, 0.16; FeSO4.7H2O, 0.004; K2HPO4, 4.4; KH2PO4, 3.4; trace salts (TS) solution, 2 ml; and distilled water, 1 liter. The pH of the medium was adjusted to 7.0 using HCl as required. The trace salts solution consisted in grams per liter: concentrated HCl, 10ml; CuSO4.5H2O, 0.063; CoCl2.6H2O, 0.16; H3BO3, 0.91; ZnSO .7H2O, 1.8; MnSO4.H2O, 1.2; NaMoO4.2H2O, 0.048; CaCl2.2H2O, 11.4, VSO4.2H2O, 0.08, Ni(NO3)2.6H2O, 0.04; Na2SeO3, 0.04; and distilled water, 980 ml. Carbon sources were added from sterile stock solutions to autoclaved media (1% final concentration).
EXAMPLE 1
Pseudomonas strain 73-4, ATCC 55272, a mutant of Pseudomonas strain 73, lacking a functional diol dehydrogenase, was grown in the MS medium described above plus 1% succinic acid as carbon source. The organism was grown in 100 ml of medium in a 500 ml shake flask agitated at 150 RPM at 30°C. Diphenylacetylene was provided as solid crystals added to the growth medium. After 16 hours incubation the cells were removed by centrifugation and the broth assayed for the diol of diphenylacetylene by gas chromatography. The compound was present at 320 ppm.
EXAMPLE 2
Pseudomonas strain 73-4 was grown in the MS medium as described in Example 1, but with glucose as the sole carbon and energy source. Exposure to diphenylacetylene for 16 hours resulted in formation of diphenylacetylene- cis-2,3-dihydrodiol at a concentration of 125 ppm.
EXAMPLE 3
Diphenylacetylene dihydrodiol was produced to a concentration of 150 ppm using a microorganism isolated from the environment and a process similar to that described in Example 1. Following removal of the cells by centrifiigation, the crude broth containing the dihydrodiol was divided into four portions and treated as described in the Table below.
TABLE
Treatment of Products of Dehydration
Diphenylacetylene 2-hydroxydiphenylacetylene 3 -hydroxydiphenylacetylene dihvdrodiol % %
1.0N HCl/25°C/l hour 93 7
1.0N HCl/75°C/l hour 65 35
1.0N NaOH/25°C/l hour 86 14
1.0N NaOH/75°C/l hour 0 100
Having thus described and exemplified the invention with a certain degree of particularity, it should be appreciated that the following claims are not to be so limited but are to be afforded a scope commensurate with the wording of each element of the claim and equivalents thereof.

Claims

Claims
Claim 1. A process for the production of a product compound of the formula
Figure imgf000012_0001
Figure imgf000012_0002
, comprising growing Pseudomonas ATCC No. 52272 in a growth medium at 25°C to 35°C and at a pH in the range of 6 to 8, supplying a compound of the formula
Figure imgf000012_0003
to the growing strain, to produce the product compound of the formula:
Figure imgf000013_0001
Figure imgf000013_0002
, and recovering the product compound from the medium.
Claim 2. A process comprising treating a starting compound of the formula
Figure imgf000013_0003
where n is 0 or 1, at a temperature of 50°C to 120°C with an aqueous basic solution at about the same temperature to bring the normality of the resulting basic solution to at least 1.0 and maintaining about the same for at least 15 minutes and producing a compound of the formula
Figure imgf000014_0001
Figure imgf000014_0002
Claim 3. The process of Claim 2 wherein the starting compound has the formula
Figure imgf000014_0003
Figure imgf000014_0004
and the product compound has the formula
Figure imgf000015_0001
Claim 4. The process of Claim 3, wherein the resulting solution contains at least about 1.0N base.
Claim 5. The process of Claim 4, wherein the base is sodium hydroxide, potassium hydroxide or cesium hydroxide.
Claim 6. The process of Claim 5, wherein the temperature is from about 75°C to 100°C.
Claim 7. The process of Claim 6, wherein the basic solution is held at 75°C to 100°C for about 1 to about 10 hours.
Claim 8. The process of Claim 6, wherein from 100 to 5,000 ppm of the starting compound is present.
Claim 9. Diphenyl-cis-2,3-dihydrodiol.
Claim 10. A compound of the formula
Figure imgf000016_0001
Figure imgf000016_0002
where n is 0 or 1.
Claim 11. A compound of Claim 10 having the formula
Figure imgf000016_0003
Figure imgf000016_0004
Claim 12. A compound of the formula
Figure imgf000017_0001
Figure imgf000017_0002
where n is 0 or 1.
Claim 13. A compound of Claim 12 having the formula
r^^
Figure imgf000017_0003
PCT/US1995/001958 1994-05-10 1995-02-15 Formation of and dehydraton of hydroxylated diphenylacetylenes Ceased WO1995030764A1 (en)

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US08/240,125 US5420361A (en) 1992-02-05 1994-05-10 Formulation of and dehydration of hydroxylated diphenyl acetylenes
US08/286,900 US5470728A (en) 1992-02-05 1994-08-08 Formation of and dehydration of hydroxylated diphenyl acetylenes using Pseudomonas ATCC 55272
US08/286,900 1994-08-08

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4153509A (en) * 1977-10-17 1979-05-08 Union Carbide Corporation Microbial production of hydroxylated biphenyl compounds
US4508822A (en) * 1981-10-06 1985-04-02 Imperial Chemical Industries, Plc Biochemical process
US4652584A (en) * 1984-07-13 1987-03-24 Mcneilab, Inc. Acetylenic phenoxypropanol derivatives and pharmaceutical compositions for the treatment of hypertension
GB2203150A (en) * 1987-04-09 1988-10-12 Shell Int Research Preparation of fluorophenols
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