79416-27-6

Usage

Biochem/physiol Actions

Methyl δ-aminolevulinate (methyl-ALA, MAL) and 5-Aminolevulinic acid (5-ALA) are commonly used in photosentizer reagents for photodynamic therapy to treat conditions such as Acne vulgaris and hypertrophic scarring.

InChI:InChI=1/C6H11NO3.ClH/c1-10-6(9)3-2-5(8)4-7;/h2-4,7H2,1H3;1H

Synthetic route

methanol (67-56-1) + 5-aminolevulinic acid hydrochloride (5451-09-2) → methyl aminolevulinate (79416-27-6)

Conditions	Yield
With thionyl chloride at 20℃; for 30h;	86.3%
With thionyl chloride at 20℃; for 48h;	81%
With thionyl chloride at 0 - 20℃;
With thionyl chloride

methanol (67-56-1) + ALA (106-60-5) → methyl aminolevulinate (79416-27-6)

Conditions	Yield
With thionyl chloride at 60℃; for 5h;

methyl 5-bromo-4-oxopentanoate (53856-93-2) → methyl aminolevulinate (79416-27-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) K2CO3 / 1.) DMFA, 20 deg C, 20 min, 2.) 72 h, 3.) water, 20 deg C, 24 h 2: 1.) conc. HCl, 2.) conc. HCl / 1.) water, reflux, 10 h, 2.) acetone, 60-70 deg C 3: 81 percent / SOCl2 / 48 h / 20 °C View Scheme

methyl 5-(1,3-dioxoisoindolin-2-yl)-4-oxopentanoate (109258-71-1) → methyl aminolevulinate (79416-27-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) conc. HCl, 2.) conc. HCl / 1.) water, reflux, 10 h, 2.) acetone, 60-70 deg C 2: 81 percent / SOCl2 / 48 h / 20 °C View Scheme

levulinic acid (123-76-2) + phosphorus pentasulfide → methyl aminolevulinate (79416-27-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: 10.7 g / Br2, urea / 48 h / 20 °C 2: 1.) K2CO3 / 1.) DMFA, 20 deg C, 20 min, 2.) 72 h, 3.) water, 20 deg C, 24 h 3: 1.) conc. HCl, 2.) conc. HCl / 1.) water, reflux, 10 h, 2.) acetone, 60-70 deg C 4: 81 percent / SOCl2 / 48 h / 20 °C View Scheme

2,2-dimethyl-4,6-dioxo-5-(3-phthalimido-2-oxopropyl)-1,3-dioxane (114681-18-4) → methyl aminolevulinate (79416-27-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) conc. HCl, 2.) conc. HCl / 1.) water, reflux, 10 h, 2.) acetone, 60-70 deg C 2: 81 percent / SOCl2 / 48 h / 20 °C View Scheme

5-aminolevulinic acid hydrochloride (5451-09-2) → methyl aminolevulinate (79416-27-6)

Conditions	Yield
With hydrogenchloride In methanol
With hydrogenchloride In methanol

methyl aminolevulinate (79416-27-6) + (2S,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (203866-13-1) → 5-[(1-tert-butoxycarbonyl-(4S)-fluoro-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester (871979-17-8)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	100%

methyl aminolevulinate (79416-27-6) + (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid (83624-01-5) → 5-[(1-tert-butoxycarbonyl-(4R)-methoxy-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester (871979-27-0)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	100%

1-(tert-butoxycarbonyl)-L-proline (15761-39-4) + methyl aminolevulinate (79416-27-6) → N-(N-tert-butoxycarbonyl-L-prolyl)-5-aminolaevulinic acid methyl ester (871979-33-8)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	100%

methyl aminolevulinate (79416-27-6) + (2S,3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid (109523-13-9) → 5-[(1-tert-butoxycarbonyl-(2S)-octahydroindolyl)carbonylamino]levulinic acid methyl ester (871980-14-2)

Conditions	Yield
With benzotriazol-1-ol; 1,2-dichloro-ethane; triethylamine In dichloromethane; water	100%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	100%

(1-tert-butoxycarbonyl-(4S)-isopropoxy-(2S)-pyrrolidinyl)carboxylic acid (871810-88-7) + methyl aminolevulinate (79416-27-6) → 5-[(1-tert-butoxycarbonyl-(4S)-isopropoxy-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester (871979-48-5)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	100%

(1-tert-butoxycarbonyl-(4S)-cyclobutoxy-(2S)-pyrrolidinyl)carboxylic acid (871810-91-2) + methyl aminolevulinate (79416-27-6) → 5-[(1-tert-butoxycarbonyl-(4S)-isopropoxy-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester (871979-48-5)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	100%

methyl aminolevulinate (79416-27-6) + (2S,4R)-4-acetoxy-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (361483-69-4) → 5-[(4R)-acetoxy-1-tert-butoxycarbonyl-(2S)-pyrrolidinylcarbonylamino]levulinic acid methyl ester (871979-67-8)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	100%

(1-tert-butoxycarbonyl-(5S)-methoxymethyl-(2S)-pyrrolidinyl)carboxylic acid + methyl aminolevulinate (79416-27-6) → 5-[(1-tert-butoxycarbonyl-(5S)-methoxymethyl-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester (871979-99-6)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	100%

methyl aminolevulinate (79416-27-6) + (2S,4S)-1-[(tert-butoxy)carbonyl]-4-methoxypyrrolidine-2-carboxylic acid (83623-93-2) → 5-[(1-tert-butoxycarbonyl-(4S)-methoxy-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester (871978-92-6)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	99%

t-butyloxycarbonyl-O-benzyl-L-tyrosine hydroxysuccinimide ester (27601-29-2) + methyl aminolevulinate (79416-27-6) → N-(N(α)-tert-butoxycarbonyl-O-(benzyl)-L-tyrosyl)-5-aminolaevulinic acid methyl ester (1166835-65-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	98%

O1-(2,5-dioxopyrrolidin-1-yl)-O4-tert-butyl-(2S)-2-(tert-butoxycarbonylamino)-butanedioate (50715-50-9) + methyl aminolevulinate (79416-27-6) → N-(N(α)-tert-butoxycarbonyl-O(γ)-tert-butyl-L-aspartyl)-5-aminolaevulinic acid methyl ester

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	98%

2,5-dioxopyrrolidin-1-yl N-(tert-butoxycarbonyl)-L-tryptophanate (3392-11-8) + methyl aminolevulinate (79416-27-6) → N-(N-tert-butoxycarbonyl-L-tryptophyl)-5-aminolaevulinic acid methyl ester (1166835-63-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	97%

methyl aminolevulinate (79416-27-6) + pyropheophorbide a (24533-72-0) → C39H43N5O5

Conditions	Yield
Stage #1: pyropheophorbide a With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 2h; Stage #2: methyl aminolevulinate With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h; Inert atmosphere;	96.1%

succinimido (tert-butyloxycarbony) serinate (39747-65-4) + methyl aminolevulinate (79416-27-6) → N-(N-tert-butoxycarbonyl-L-seryl)-5-aminolaevulinic acid methyl ester (1166835-60-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	96%

benzyl [(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]carbamate (5241-56-5, 17324-88-8, 53562-23-5, 4801-80-3) + methyl aminolevulinate (79416-27-6) → methyl 5-((2'-benzyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoate

Conditions	Yield
Stage #1: benzyl [(2S)-1-amino-1-oxo-3-phenylpropan-2-yl]carbamate; methyl aminolevulinate With benzotriazol-1-ol; 1-n-butyl-3-methylimidazolim bromide; dicyclohexyl-carbodiimide In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	96%

tertbutoxycarbonyl-L-methionine N-hydroxysuccinimide ester (3845-64-5) + methyl aminolevulinate (79416-27-6) → N-(N-tert-butoxycarbonyl-L-methionyl)-5-aminolaevulinic acid methyl ester (1166835-59-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	95%

methyl aminolevulinate (79416-27-6) + Nα-Boc-D-tryptophan-N-hydroxysuccinimide ester (22220-11-7) → N-(N-tert-butoxycarbonyl-D-tryptophyl)-5-aminolaevulinic acid methyl ester (1166835-64-8)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	95%

methyl aminolevulinate (79416-27-6) + Boc-Phe-ONSu (3674-06-4) → methyl 5-((2'-tert-butyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoate (321837-83-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	95%

methyl aminolevulinate (79416-27-6) + pyropheophorbide a acid → 173-[N-(2-oxo-4-methoxycarbonylbutyl)]pyropheophorbide amide

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6h;	94.9%

(S)-5-tert-butyl 1-(2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl)amino)pentanedioate (32886-55-8) + methyl aminolevulinate (79416-27-6) → N-(N(α)-tert-butoxycarbonyl-O(δ)-tert-butyl-L-glutamyl)-5-aminolaevulinic acid methyl ester

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	94%

tert-butoxycarbonyl-L-proline N-hydroxysuccinimide ester (3392-10-7) + methyl aminolevulinate (79416-27-6) → N-(N-tert-butoxycarbonyl-L-prolyl)-5-aminolaevulinic acid methyl ester (871979-33-8)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	94%

benzoyl chloride (98-88-4) + methyl aminolevulinate (79416-27-6) → methyl 5-(N-benzoyl)amino-4-oxopentanoate (37061-97-5)

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;	94%
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	91%

2-furancarbonyl chloride (527-69-5) + methyl aminolevulinate (79416-27-6) → methyl 5-(furan-2-carboxamido)-4-oxopentanoate

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	94%

2-Thiophenecarbonyl chloride (5271-67-0) + methyl aminolevulinate (79416-27-6) → methyl 4-oxo-5-(thiophene-2-carboxamido)pentanoate

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	94%

(1-tert-butoxycarbonyl-(5S)-ethoxymethyl-(2S)-pyrrolidinyl)carboxylic acid + methyl aminolevulinate (79416-27-6) → 5-[(1-tert-butoxycarbonyl-(5S)-ethoxymethyl-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester (871979-84-9)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃;	93%

(1-tert-butoxycarbonyl-(5S)-ethoxymethyl-(2S)-pyrrolidinyl)carboxylic acid + methyl aminolevulinate (79416-27-6) → 5-[(1-tert-butoxycarbonyl-(5S)-ethoxymethyl-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester

Conditions	Yield
With benzotriazol-1-ol; 1,2-dichloro-ethane In water	93%

methyl aminolevulinate (79416-27-6) → δ-aminolevulinic acid methyl ester phosphate (920538-42-7)

Conditions	Yield
With phosphoric acid; triethylamine In water at 0 - 20℃; for 0.166667h;	93%

N-tertiarybutoxycarbonyl-D-alanine N-hydroxysuccinimide ester (34404-33-6) + methyl aminolevulinate (79416-27-6) → N-(N-tert-butoxycarbonyl-D-alanyl)-5-aminolaevulinic acid methyl ester (1166835-54-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	93%

Boc-Lys(Z)-OSu (34404-36-9) + methyl aminolevulinate (79416-27-6) → N-(N(α)-tert-butoxycarbonyl-N(ε)-(benzyloxycarbonyl)-L-lysyl)-5-aminolaevulinic acid methyl ester (861982-91-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	93%

2,5-dioxopyrrolidin-1-yl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N6-(tert-butoxycarbonyl)-L-lysinate (132307-50-7) + methyl aminolevulinate (79416-27-6) → N-(N(α)-(9-fluorenylmethoxycarbonyl)-N(ε)-(tert-butoxycarbonyl)-L-lysyl)-5-aminolaevulinic acid methyl ester (1166835-52-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	93%

Upstream product

• 67-56-1 methanol 
• 5451-09-2 5-aminolevulinic acid hydrochloride 
• 106-60-5 ALA 
• 114681-18-4 2,2-dimethyl-4,6-dioxo-5-(3-phthalimido-2-oxopropyl)-1,3-dioxane 
• 109258-71-1 methyl 5-(1,3-dioxoisoindolin-2-yl)-4-oxopentanoate 
• 53856-93-2 methyl 5-bromo-4-oxopentanoate 
• 123-76-2 levulinic acid 

Downstream Products

• 379691-83-5 5-((S)-2-Benzyloxycarbonylamino-4-methyl-pentanoylamino)-4-oxo-pentanoic acid methyl ester 
• 900795-41-7 methyl 5-(4-methylphenylsulfonamido)-4-oxopentanoate 
• 871979-07-6 5-[(1-benzyloxycarbonyl-(4S)-methoxy-(2S)-pyrrolidinyl)carbonylamino]levulinic acid methyl ester 
• 929630-72-8 13-cyclohexyl-6-[(5-methoxy-2,5-dioxopentyl)amino]carbonyl-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid methyl ester 
• 1166835-66-0 N-(N(α)-tert-butoxycarbonyl-N(τ)-(trityl)-L-histidyl)-5-aminolaevulinic acid methyl ester 
• 1166835-61-5 N-(N-tert-butoxycarbonyl-D-phenylalanyl)-5-aminolaevulinic acid methyl ester 
• 861982-91-4 N-(N(α)-tert-butoxycarbonyl-N(ε)-(benzyloxycarbonyl)-L-lysyl)-5-aminolaevulinic acid methyl ester 
• 1166835-65-9 N-(N(α)-tert-butoxycarbonyl-O-(benzyl)-L-tyrosyl)-5-aminolaevulinic acid methyl ester 
• 321837-83-6 methyl 5-((2'-tert-butyloxycarbonylamino)-L-phenylpropionyl)amino-4-oxopentanoate 
• 865620-62-8 5-[2-(4-methoxy-benzyloxy)-propionylamino]-4-oxo-pentanoic acid methyl ester 
• 929630-74-0 methyl 13-cyclohexyl-3-(methyloxy)-6-(((5-(methyloxy)-2,5-dioxopentyl)amino)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate 
• 1407814-85-0 2-(2-fluorophenyl)-N-[(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)methyl]acetamide 
• 1407814-88-3 2-(2-fluorophenyl)-N-[(6-oxo-1,6-dihydropyridazin-3-yl)methyl]acetamide 
• 1352906-01-4 2-chloro-7-(2-fluorobenzyl)imidazo[1,5-b]pyridazine 

Relevant academic research and scientific papers

Synthesis and evaluation of new 5-aminolevulinic acid derivatives as prodrugs of protoporphyrin for photodynamic therapy

Protoporphyrin IX (PpIX) is used as a photosensitizer in the photodynamic diagnosis (PDD) and photodynamic therapy (PDT) of cancer and is synthesized intracellularly from 5-aminolevulinic acid (5-ALA) precursors. Thirteen novel 5-ALA derivatives were designed and synthesized appropriately with tailored hydrophilicity and lipophilicity. The generation of PpIX was detected and their antitumor activity in vitro and in vivo was also investigated. It was shown that compounds 9b-c, 11b-c and 13a displayed a characteristic long wavelength absorption peak at 593 nm after 5 h incubation in mice fibrosarcoma S180 cells. After being exposed to 600 nm laser light irradiation, these compounds can inhibit cell proliferation in S180 cells in vitro. The growth of S180 cell tumors in Kunming mice was significantly inhibited by these compounds in vivo. Among these compounds, 13a has low dark toxicity and high phototoxicity, which makes it an effective and promising prodrug for PDT.

5-[(PIPERAZIN-1-YL)-3-OXO-PROPYL]-IMIDAZOLIDINE-2,4-DIONE DERIVATIVES AS ADAMTS INHIBITORS FOR THE TREATMENT OF OSTEOARTHRITIS

The present invention discloses compounds according to Formula (I), wherein R, R2, R3a, R3b, and Cy are as defined herein. The present invention discloses compounds inhibiting ADAMTS, methods for their production, pharmaceutical compositions comprising the same and methods for the prophylaxis and/or treatment of inflammatory conditions and/or diseases involving degradation of cartilage and/or disruption of cartilage homeostasis.

Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy

The present invention relates to compounds being esters of 5-aminolevulinic acids or pharmaceutically acceptable salts thereof, including compounds of formula (I) R22N—CH2COCH2-CH2CO—OR1 (wherein R1 may represent alkyl optionally substituted by hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, oxo or fluoro groups and optionally interrupted by oxygen, nitrogen, sulphur or phosphorus atoms; and R2 represents a hydrogen atom or a group R1, and both R2 groups may be the identical or different), and their use in diagnosis and photochemotherapy of disorders or abnormalities of external or internal surfaces of the body, and products and kits for performing the invention.

The synthesis and applications of 5-aminolevulinic acid (ALA) derivatives in photodynamic therapy and photodiagnosis

A route has been developed to high-purity precursors, viz., ALA esters, to be used in photodiagnosis and photodynamic therapy. Hexyl, butyl and methyl 5-aminolevulinates are similar to the ALA acid in chemical stability and efficacy in producing the appropriate photosensitizer PpIX. Tests carried out on animal models showed the method based on the esters to be the more selective.

The effects of 5-aminolevulinic acid esters on protoporphyrin IX production in human adenocarcinoma cell lines

Photodynamic diagnosis (PDD) and photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PPIX) is an interesting approach to detect and treat dysplasia and early cancers in the gastrointestinal tract. Because of low lipophi

Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy

PCT No. PCT/GB96/00553 Sec. 371 Date Dec. 5, 1997 Sec. 102(e) Date Dec. 5, 1997 PCT Filed Mar. 8, 1996 PCT Pub. No. WO96/28412 PCT Pub. Date Sep. 19, 1996The invention provides a pharmaceutical compositions comprising a compound of formula I:R22N-CH2COCH2-CH2CO-OR1(I)wherein, R1 and R2 have any of the values defined in the specification; or a salt thereof; and a pharmaceutically acceptable carrier or excipient. The invention also provides a method for the diagnosis or photochemotherapeutic treatment of disorders or abnormalities of external or internal surfaces of the body using such compounds or salts.