37178-37-3

Usage

Uses

Used in Antiparkinsonian Applications:
Ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate is used as a therapeutic agent for the treatment of Parkinson's disease (PD). It serves as a precursor to dopamine, a neurotransmitter that is deficient in the brains of PD patients. By increasing dopamine levels, it helps alleviate the motor symptoms associated with the disease, such as tremors, rigidity, and bradykinesia.
Used in Neuroprotective Studies:
In the field of neuroscience, ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate is used as a research tool to study the protective effects of various compounds on neurodegenerative diseases. For instance, it has been used to investigate the neuroprotective effects of piperlongumine (PLG) on rotenone-induced Parkinson's disease models. This application aids in understanding the underlying mechanisms of neurodegeneration and the development of novel therapeutic strategies.
Used in Drug Delivery Systems:
Ethyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate can also be employed in the development of drug delivery systems, particularly for targeted delivery to the central nervous system. Its chemical properties allow for potential conjugation with various carriers, such as nanoparticles or liposomes, to enhance its bioavailability and therapeutic efficacy in treating neurological disorders.

Biochem/physiol Actions

L-Dopa ethyl ester is a prodrug of levodopa that has greater gastric solubility. The drug is rapidly hydrolyzed to levodopa by nonspecific esterases in the gastrointestinal tract. L-Dopa ethyl ester (etilevodopa)-carbidopa treatment was well tolerated but did not demonstrate better efficacy compared with standard levodopa-carbidopa treatment. L-Dopa ethyl ester should have a significant brain penetration following an administration by injection.

InChI:InChI=1/C11H15NO4/c1-2-16-11(15)8(12)5-7-3-4-9(13)10(14)6-7/h3-4,6,8,13-14H,2,5,12H2,1H3/t8-/m0/s1

Synthetic route

ethanol (64-17-5) + levodopa (59-92-7) → L-DOPA ethyl ester (37178-37-3)

Conditions	Yield
With hydrogenchloride Fischer esterification;	100%
With hydrogenchloride Fisher esterfication;	100%
With thionyl chloride 1.) 0 deg C, 2 h, 2.) room temperature, overnight;
With thionyl chloride for 24h; Reflux;

levodopa (59-92-7) + ascorbic acid (50-81-7) → L-DOPA ethyl ester (37178-37-3)

Conditions	Yield
With thionyl chloride; 2,6-di-tert-butyl-4-methyl-phenol; sodium hydrogencarbonate; sodium sulfate In ethanol; water	88%
With thionyl chloride; 2,6-di-tert-butyl-4-methyl-phenol; sodium hydrogencarbonate; sodium sulfate In ethanol; water	88%

di-tert-butyl dicarbonate (24424-99-5) + L-DOPA ethyl ester (37178-37-3) → N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-L-phenylalanine ethyl ester (203398-44-1)

Conditions	Yield
With triethylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	97%
With triethylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	97%
With triethylamine In N,N-dimethyl-formamide 1.) 0 deg C, 2 h, 2.) room temperature, 48 h;	42.1 g

L-DOPA ethyl ester (37178-37-3) → levodopa (59-92-7)

Conditions	Yield
With water; sodium chloride In dimethyl sulfoxide at 37℃; Rate constant; also human plasma as reagent;

3-Bromoindan-1-one (40774-41-2) + L-DOPA ethyl ester (37178-37-3) → 3-(3,4-dihydroxyphenyl)-2-(3-oxoindan-1-ylamino)propionic acid ethyl ester

Conditions	Yield
With triethylamine In dichloromethane at 0℃;

L-DOPA ethyl ester (37178-37-3) → N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-6-iodo-L-phenylalanine ethyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 42.1 g / triethylamine / dimethylformamide / 1.) 0 deg C, 2 h, 2.) room temperature, 48 h 2: 43 percent Turnov. / CF3CO2Ag, I2 / CH2Cl2 / 24 h / Ambient temperature View Scheme

L-DOPA ethyl ester (37178-37-3) → carbidopa monohydrate

L-DOPA ethyl ester (37178-37-3) → ethyl 3-(3,4-(dibenzyloxy)phenyl)-2-(tert-butoxycarbonylamino)propanoate (69344-36-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / tetrahydrofuran / 16 h / 20 °C 2: potassium carbonate / acetone / 48 h / Reflux View Scheme

L-DOPA ethyl ester (37178-37-3) → ethyl 2-amino-3-(3,4-(dibenzyloxy)phenyl)propanoate (69295-27-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydrogencarbonate / tetrahydrofuran / 16 h / 20 °C 2: potassium carbonate / acetone / 48 h / Reflux 3: trifluoroacetic acid / dichloromethane / 26 h / 0 - 20 °C View Scheme

L-DOPA ethyl ester (37178-37-3) → C23H22N2O3

Conditions	Yield
Multi-step reaction with 6 steps 1.1: sodium hydrogencarbonate / tetrahydrofuran / 16 h / 20 °C 2.1: potassium carbonate / acetone / 48 h / Reflux 3.1: trifluoroacetic acid / dichloromethane / 26 h / 0 - 20 °C 4.1: toluene / 24 h / Reflux 5.1: acetic acid; nitric acid / 1.5 h / 0 °C 5.2: 1.5 h / 80 °C 6.1: hydrazine hydrate / ethanol / 40 h / Reflux View Scheme

L-DOPA ethyl ester (37178-37-3) → C23H24N2O2

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium hydrogencarbonate / tetrahydrofuran / 16 h / 20 °C 2.1: potassium carbonate / acetone / 48 h / Reflux 3.1: trifluoroacetic acid / dichloromethane / 26 h / 0 - 20 °C 4.1: toluene / 24 h / Reflux 5.1: acetic acid; nitric acid / 1.5 h / 0 °C 5.2: 1.5 h / 80 °C 6.1: hydrazine hydrate / ethanol / 40 h / Reflux 7.1: dimethyl sulfide borane / tetrahydrofuran / 30 h / Reflux View Scheme

L-DOPA ethyl ester (37178-37-3) → ethyl 3-(3,4-bis(benzyloxy)phenyl)-2-(1,3-dioxoisoindolin-2-yl)propanoate

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydrogencarbonate / tetrahydrofuran / 16 h / 20 °C 2: potassium carbonate / acetone / 48 h / Reflux 3: trifluoroacetic acid / dichloromethane / 26 h / 0 - 20 °C 4: toluene / 24 h / Reflux View Scheme

L-DOPA ethyl ester (37178-37-3) → (S)-2-(6,7-bis(benzyloxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)isoindoline-1,3-dione

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydrogencarbonate / tetrahydrofuran / 16 h / 20 °C 2.1: potassium carbonate / acetone / 48 h / Reflux 3.1: trifluoroacetic acid / dichloromethane / 26 h / 0 - 20 °C 4.1: toluene / 24 h / Reflux 5.1: acetic acid; nitric acid / 1.5 h / 0 °C 5.2: 1.5 h / 80 °C View Scheme

L-DOPA ethyl ester (37178-37-3) → tert-butyl ((S)-3-(benzyloxy)-1-(((S)-6,7-bis(benzyloxy)-1,2,3,4-tetrahydroquinolin-3-yl)amino)-1-oxopropan-2-yl)carbamate

Conditions

Yield

Multi-step reaction with 8 steps 1.1: sodium hydrogencarbonate / tetrahydrofuran / 16 h / 20 °C 2.1: potassium carbonate / acetone / 48 h / Reflux 3.1: trifluoroacetic acid / dichloromethane / 26 h / 0 - 20 °C 4.1: toluene / 24 h / Reflux 5.1: acetic acid; nitric acid / 1.5 h / 0 °C 5.2: 1.5 h / 80 °C 6.1: hydrazine hydrate / ethanol / 40 h / Reflux 7.1: dimethyl sulfide borane / tetrahydrofuran / 30 h / Reflux 8.1: benzyl chloroformate; 4-methyl-morpholine / dichloromethane / 6 h / -78 - 20 °C View Scheme

di-tert-butyl dicarbonate (24424-99-5) + L-DOPA ethyl ester (37178-37-3) → N-(tert-butoxycarbonyl)-3,4-(dihydroxy)-L-phenylalanine ethyl ester (1313214-06-0)

Conditions	Yield
With sodium hydrogencarbonate In tetrahydrofuran at 20℃; for 16h;

Upstream product

• 59-92-7 levodopa 
• 50-81-7 ascorbic acid 
• 64-17-5 ethanol 

Downstream Products

• 1313214-06-0 N-(tert-butoxycarbonyl)-3,4-(dihydroxy)-L-phenylalanine ethyl ester 
• 69295-27-8 ethyl 2-amino-3-(3,4-(dibenzyloxy)phenyl)propanoate 
• 69344-36-1 ethyl 3-(3,4-(dibenzyloxy)phenyl)-2-(tert-butoxycarbonylamino)propanoate 
• 38821-49-7 carbidopa monohydrate 
• 203398-44-1 N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-L-phenylalanine ethyl ester 
• 59-92-7 levodopa 

Relevant academic research and scientific papers

An alternative approach to the synthesis of the three fragments of anachelin H

The synthesis of the fully protected peptide, polyketide and alkaloid fragments of anachelin H is presented. The peptide fragment was prepared using a liquid phase peptide synthesis; the polyketide fragment was synthetized using a cross metathesis and an intramolecular oxa-Michael reaction as the key steps to introduce the desired stereochemistry; finally, the alkaloid fragment was obtained by an oxidative cyclization of a catechol derivative using potassium ferricyanide. The synthesis of all fragments was based on the use of natural amino acids as sources of asymmetry. The independent synthesis of the three fragments should allow more efficient biological studies on the fragments instead of the whole natural product. Experiments to illustrate the coupling of fragments and the effectiveness of the convergent strategy are also described.

NUCLEOPHILIC FLUORINATION OF AROMATIC COMPOUNDS

Iodylbenzene derivatives substituted with electron donating as well as electron withdrawing groups on the aromatic ring are used as precursors in aromatic nucleophilic substitution reactions. The iodyl group (IO2) is regiospecifically substituted by nucleophilic fluoride to provide the corresponding fluoroaryl derivatives. No-carrier-added [F-18] fluoride ion derived from anhydrous [F- 18]KF/Kryptofix, [F-18]CsF or a quaternary ammonium fluoride (e.g., Me4NF, Et4NF, n-Bu4NF, (PhCH2)4NF) exclusively substitutes the iodyl moiety in these derivatives and provides high specific activity F- 18 labeled fluoroaryl analogs. Iodyl derivatives of a benzothiazole analog and 6-iodyl-L-dopa derivatives have been synthesized as precursors and have been used in the preparation of no-carrier-added [F-18]fluorobenzothiazole as well as 6-[F-18]fluoro-L-dopa.

NO-CARRIER-ADDED NUCLEOPHILIC [F-18] FLUORINATION OF AROMATIC COMPOUNDS

Phenyliodonium ylide derivatives substituted with electron donating as well as electron withdrawing groups on the aromatic ring are shown for use as precursors in aromatic nucleophilic substitution reactions. The iodonium ylide group is substituted by nucleophiles such as halide ions to provide the corresponding haloaryl derivatives. No- carrier-added [F-18]fluoride ion exclusively substitutes the iodonium ylide moiety in these derivatives and provides high specific activity F- 18 labeled fluoro derivatives. Protected L-dopa-6-iodonium ylide derivative have been synthesized as a precursors for the preparation of no-carrier-added 6-[F- 18]fluoro-L-dopa. The iodonium ylide group in this L-dopa.derivative is nucleophilically substituted by no-carrier-added [F-18]fluoride ion to provide a [F-18]fluoro intermediates which upon acid hydrolysis yielded 6-[F- 18]fluoro-L-dopa.

6-[18F]Fluoro-L-DOPA by radiofluorodestannylation : A short and simple synthesis of a new labelling precursor

This paper describes a short and simple synthesis of a new fully protected stannylated precursor, namely N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-6-trimethylstannyl-L -phenylalanine ethyl ester, for the preparation of 6-[18F]fluoro-L-DOPA, used routinely in our Positron Emission Tomography program on neurodegenerative diseases as a tracer of the cerebral dopamine metabolism. The chemical pathway described for the total synthesis of our labelling precursor uses a straightforward protection sequence. This 4-step chemical synthesis allows the rapid preparation of several grammes of pure material in good overall yield. Regioselective radiofluorodestannylation using [18F]fluorine ([18F]F2, cyclotron-produced isotope, half-life : 110 min) gave pure 6-[18F]fluoro-L- DOPA (8) in good radiochemical yield (26% decay-corrected, based on starting [18F]fluorine recovered from the target) in 45-50 min after the End of Bombardment. The product was found to be >99% chemically, radiochemically and enantiomerically pure.

L-DOPA ethyl ester to treat Parkinson's disease

Patients suffering from Parkinson's disease are treated by administering a composition which contains an active ingredient and a pharmaceutically acceptable carrier. The active ingredient comprises L-DOPA ethyl ester in an amount which is at least 97% by weight of the active ingredient and L-DOPA in an amount which is less than 1% by weight of the active ingredient.

Process for preparing ethyl ester of L-DOPA

A composition which comprises a pharmaceutically acceptable carrier and an active ingredient, such active ingredient comprising L-DOPA ethyl ester in an amount which is at least 97%, by weight, of the active ingredient, and L-DOPA in an amount which is less than 1% by weight of such active ingredient is provided by this invention. This invention also provides a process for preparing such a composition. Further, this invention provides a method of treating a patient suffering from Parkinson's disease which comprises administering to a patient a pharmaceutical composition comprising a therapeutically effective amount of L-DOPA ethyl ester and a pharmaceutically acceptable carrier.