- Enantioselective synthesis of (S)-phenylephrine by whole cells of recombinant Escherichia coli expressing the amino alcohol dehydrogenase gene from Rhodococcus erythropolis BCRC 10909
-
(R)-phenylephrine [(R)-PE] is an α1-adrenergic receptor agonist that is widely used in over-the-counter drugs to treat the common cold. We found that Rhodococcus erythropolis BCRC 10909 can convert detectable level of 1-(3-hydroxyphenyl)-2-(methylamino) ethanone (HPMAE) to (S)-PE by high performance liquid chromatography tandem mass spectrometry analysis. An amino alcohol dehydrogenase gene (RE_AADH) which possesses the ability to convert HPMAE to (S)-PE was then isolated from R. erythropolis BCRC 10909 and expressed in Escherichia coli NovaBlue. The purified RE_AADH, tagged with 6×His, had a molecular mass of approximately 30kDa and exhibited a specific activity of 0.19μU/mg to HPMAE in the presence of NADPH, indicating this enzyme could be categorized as NADP+-dependent short-chain dehydrogenase reductase. E. coli NovaBlue cell expressing the RE_AADH gene was able to convert HPMAE to (S)-PE with more than 99% enantiomeric excess (ee), 78% yield and a productivity of 3.9mmol(S)-PE/Lh in 12h at 30°C and pH 7. The (S)-PE, recovered from reaction mixture by precipitation at pH 11.3, could be converted to (R)-PE (ee>99%) by Walden inversion reaction. This is the first reported biocatalytic process for the production of (S)-PE from HPMAE.
- Lin, Wei-De,Chen, Chien-Yu,Chen, Huei-Chung,Hsu, Wen-Hwei
-
-
Read Online
- Whole-cell yeast-mediated preparation of (R)-2-chloro-1-(3-nitrophenyl) ethanol as a synthetic precursor for (R)-phenylephrine
-
The incubated whole-cell biocatalyst of Pichia minuta JCM 3622 reduced 2-chloro-1-(3-nitrophenyl)ethanone to provide (R)-2-chloro-1-(3-nitrophenyl) ethanol with 99.2% ee in 87% isolated yield in the presence of Amberlite XAD-7 as a reservoir for the hydrophobic, crystalline and toxic substrate. The product was transformed to (R)-1-(3-hydroxyphenyl)-2-methylaminoethanol (phenylephrine, 1a), a selective α1-adrenergic receptor agonist, in 98.0% ee over five steps.
- Tokoshima, Daisuke,Hanaya, Kengo,Shoji, Mitsuru,Sugai, Takeshi
-
-
- PROCESS FOR RESOLUTION OF 1-(3-HYDROXYPHENYL)-2-METHYLAMINO ETHANOL
-
Resolution of the title compound to its active isomer (R)-1-(3-hydroxyphenyl)-2-methylamino ethanol with (R)-naproxen as a resolving agent.
- -
-
Page/Page column 4
(2012/05/07)
-
- Recyclable Cu(II)-macrocyclic salen complexes catalyzed nitroaldol reaction of aldehydes: A practical strategy in the preparation of (R)-phenylephrine
-
Chiral macrocyclic salen ligands 1′-3′ derived from 1R,2R-(-)-1,2-diaminocyclohexane, 1R,2R-(+)-1,2-diphenyl-1,2-diaminoethane and (R)-(+)-1,1′-binaphthyl-2,2′-diamine with trigol bis aldehyde were prepared and characterized by microanalysis, 1H NMR, UV/Vis. spectroscopy, optical rotation and mass spectroscopy. Highly enantioselective nitroaldol reaction of various aromatic and aliphatic aldehydes with nitromethane in presence of several bases were carried out in the presence of in situ generated Cu(I)/Cu(II) complexes with chiral macrocyclic salen ligands 1′-3′ at RT. Excellent yields (up to 92% with respect to the aldehyde) of β-nitroalcohols with high enantioselectivity (ee, ～95%) was achieved in case of 3-methoxy- and 4-nitrobenzaldehyde in ca. 30 h with the use of chiral macrocyclic salen ligands 3′ with CuCl2· 2H2O in presence of 2,6-lutidine as a base. Chiral macrocyclic salen catalyst 3 mediated nitroaldol process is recyclable (up to 8 cycles with no significant loss in its performance). This protocol is also used for the synthesis of enantiomerically pure (R)-phenylephrine (α1-adrenergic receptor agonist) via asymmetric nitroaldol reaction of 3-methoxybenzaldehyde in three steps.
- Kureshy, Rukhsana I.,Dangi, Balchand,Das, Anjan,Khan, Noor-Ul H.,Abdi, Sayed H.R.,Bajaj, Hari C.
-
-
- METHOD FOR PRODUCING L-PHENYLEPHRINE USING AN ALCOHOL DEHYDROGENASE OF AROMATOLEUM AROMATICUM EBN1 (AZOARCUS SP. EBN1)
-
The present invention relates to a multi-stage process for producing substituted, optically active alcohols, comprising an enzyme-catalyzed synthesis step, in particular a synthesis step which is catalyzed by an alcohol dehydrogenase. The inventive method is particularly suitable for producing phenylephrine, i.e. 3-[(1R)-1-hydroxy-2-methylamino-ethyl]-phenol.
- -
-
-
- A feasibility study on the synthesis of phenylephrine via ruthenium-catalyzed homogeneous asymmetric hydrogenation
-
We report a feasibility study on a new route to (R)-phenylephrine, based on the ruthenium-catalyzed asymmetric hydrogenation of an aminoketone precursor. The direct and fast asymmetric reduction of aminoketones or their hydrochloride salts is achievable at low catalyst loadings (molar substrate to catalyst ratio, S/C, >25,000/1, TOF up to 25,000 h-1) with high enantioselectivity (>95% ee), without the need for N-protection nor isolation of the free base prior to reaction.
- McGarrity, John F.,Zanotti-Gerosa, Antonio
-
experimental part
p. 2479 - 2486
(2011/02/22)
-
- SYNTHESIS OF ENANTIOMERICALLY PURE 2-HYDROXY-2-ARYL-ETHYLAMINES
-
The present invention relates to an improved process for preparing enantiomerically pure 2-hydroxy-2-aryl-ethylamines, and their pharmaceutically acceptable salts, by transition metal catalyzed asymmetric hydrogenation preferably using a ruthenium transition metal catalyst system having as a chiral, bidentate phosphine ligand ((R)-I -diphenylphosphino-2- [(S)-α-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl] ferrocene), such as Chiralyst LM 1010 RS available from Umicore AG and Co., KG.
- -
-
Page/Page column 14-17
(2009/08/14)
-
- PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE 2-AMINO-1-PHENYLETHANOLS
-
Optically active 2-amino-l-phenylethanols of formula (I) or its mirror image, wherein R1 is hydrogen, C1-6alkyl or aryl-substituted C1-6alkyl and R2 through R6 are independently hydrogen, hydroxy or C1-6alkoxy, or salts thereof are prepared by asymmetric hydrogenation of the corresponding 2-aminoacetophenones in the presence of a ruthenium complex catalyst comprising a chiral phosphine ligand.
- -
-
Page/Page column 10-11
(2008/12/06)
-
- 2-t-butyl-3 alkyl-5-(m-hydroxyphenyl)-1,3-oxazolidines having mydriatic effect
-
An oxazolidine derivative of phenylephrine, and the non-toxic pharmaceutically acceptable salt forms thereof. The prodrug is much quicker absorbed across the cornea of the eye, does not induce the same unwanted side effects as phenylephrine, and can produce the same mydriatic effect as phenylephrine at dosage levels of approximately one-tenth the level of phenylephrine.
- -
-
-
- Pharmaceutical formula
-
The present invention concerns a pharmacological vehicle or carrier system, which makes possible administration of the active ingredient with a high absorption thereof in the blood circulation of the patient treated therewith, in particular also in the case of oral administration. The pharmacological vehicle system according to the invention comprises ultrafine particles of a reaction product of a reactive derivative of an at least dibasic inorganic acid or an alkane-carboxylic acid having 2 or 3 carboxyl groups and optionally one or two hydroxy groups, wherein one bond of the dibasic inorganic acid or one carboxy group of the alkane-carboxylic acid is bonded to a pharmacological active ingredient containing a hydroxy group, SH group and/or a primary or secondary amino group having a ractive hydrogen atom on this group, and the other bond is bonded to the free hydroxy group of a glycerolipid having at least one free hydroxy group on the glycerol. The invention further concerns these reaction products and a process for the preparation of ultrafine particles of these reaction products.
- -
-
-
- Phenylephrine prodrug useful as mydriatic agent
-
An oxazolidine derivative of phenylephrine, and the non-toxic pharmaceuticlaly acceptable salt forms thereof. The prodrug is much quicker absorbed across the cornea of the eye, does not induce the same unwanted side effects as phenylephrine, and can produce the same mydriatic effect as phenylephrine at dosage levels of approximately one-tenth the level of phenylephrine.
- -
-
-
- Oil suspended phenylephrine
-
An oil suspension, preferably sesame seed oil suspension, of the base form of phenylephrine as an opthalmic medicament. Surprisingly, the base form of phenylephrine is much quicker absorbed into the eye than the conventional acid salt form. As a result, lower dosage levels can be used to achieve the same mydriatic effect, thus reducing the risk of adverse side effects from systemic absorption.
- -
-
-
