58016-28-7

Basic information

• Product Name: methyl 2,4-dihydroxy-6-pentylbenzoate
• Synonyms: methyl 2,4-dihydroxy-6-pentylbenzoate;Methyl olivetolate
• CAS NO: 58016-28-7
• Molecular Formula: C₁₃H₁₈O₄
• Molecular Weight: 238.29
• Mol File: 58016-28-7.mol
• Article Data: 5

Chemical Properties

• Melting Point: 105-106 °C(Solv: benzene (71-43-2))
• Boiling Point: 409.3±30.0 °C(Predicted)
• Appearance: /
• Density: 1.153±0.06 g/cm3(Predicted)
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: Dichloromethane; Ethyl Acetate
• PKA: 8.30±0.23(Predicted)
• CAS DataBase Reference: methyl 2,4-dihydroxy-6-pentylbenzoate(CAS DataBase Reference)
• NIST Chemistry Reference: methyl 2,4-dihydroxy-6-pentylbenzoate(58016-28-7)
• EPA Substance Registry System: methyl 2,4-dihydroxy-6-pentylbenzoate(58016-28-7)

Safety Data

• Hazardous Substances Data: 58016-28-7(Hazardous Substances Data)

Usage

Uses

Methyl Olivetolate is an intermediate in synthesizing Δ9-Tetrahydrocannabinolic Acid (Acid A & B) (T293235). It is one of the substances screened for in meconium drug testings for medicinal opiods among addicted mothers. Δ9-Tetrahydrocannabinolic Acid has been shown to protect dopaminergic neurons against 1-methyl-4-Ph pyridinium (MPP+) induced cell death.

Synthesis Reference(s)

Tetrahedron Letters, 23, p. 2935, 1982 DOI: 10.1016/S0040-4039(00)87498-5

Synthetic route

1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene (74590-73-1) + (2-Pentyl-[1,3]dioxolan-2-yl)-acetyl chloride (83578-33-0) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
With titanium tetrachloride In dichloromethane	55%

1-(1-imidazolyl)-1-hexanone (60988-34-3) + 1,3,5-tris(trimethylsiloxy)-1-methoxyhexa-1,3,5-triene (102342-54-1) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
With titanium(IV) isopropylate; titanium tetrachloride In dichloromethane 1.) -78 deg C, 5 h, 2.) RT, overnight;	52%

N,N-dimethylhexanamide (5830-30-8) + 3,5-dioxohexanoic acid methyl ester (29736-80-9) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
With lithium diisopropyl amide In tetrahydrofuran at -20℃; for 5h;	36%

Hexanoyl chloride (142-61-0) + 1,3,5-tris(trimethylsiloxy)-1-methoxyhexa-1,3,5-triene (102342-54-1) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
With titanium(IV) isopropylate; titanium tetrachloride In dichloromethane 1.) -78 deg C, 2-3 h, 2.) RT, overnight;	21%

2,4-nonanedione (6175-23-1) + malonic acid dimethyl ester (108-59-8) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
With sodium hydride; lithium diisopropyl amide In tetrahydrofuran; hexane for 48h; Heating;	10%

diazomethane (186581-53-3, 908094-01-9) + 2,4-dihydroxy-6-pentylbenzoic acid (491-72-5) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
With diethyl ether

methanol (67-56-1) + anziaic acid (641-68-9) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

N,N-dimethylhexanamide (5830-30-8) + carbonic acid dimethyl ester (616-38-6) + acetylacetone (123-54-6) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
Yield given. Multistep reaction;

anziaic acid methyl ester → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
With sulfuric acid

2-hydroxy-4-(2-hydroxy-4-methoxy-6-pentylbenzoyloxy)-6-pentylbenzoic acid (529-47-5) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: methanol. KOH-solution 2: diethyl ether View Scheme

2,4-dihydroxy-6-pentylbenzaldehyde (855875-40-0) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: acetone; pyridine / Erwaermen des Reaktionsprodukts mit Kaliumpermanganat in wss. Aceton 2: aqueous ammonia 3: diethyl ether View Scheme

2,4-bis-ethoxycarbonyloxy-6-pentyl-benzoic acid → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: aqueous ammonia 2: diethyl ether View Scheme

(E)-non-3-en-2-one (18402-83-0) + malonic acid dimethyl ester (108-59-8) → methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7)

Conditions	Yield
Stage #1: (E)-non-3-en-2-one; malonic acid dimethyl ester With sodium In methanol at 0℃; for 8h; Reflux; Stage #2: With bromine In N,N-dimethyl-formamide at 0 - 80℃; for 17h;
Stage #1: (E)-non-3-en-2-one; malonic acid dimethyl ester With sodium In methanol for 8h; Reflux; Stage #2: With bromine In N,N-dimethyl-formamide at 0 - 80℃; for 17h;

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → Olivetol (500-66-3)

Conditions	Yield
With water; potassium hydroxide at 50 - 100℃;	94%

4-dimethylamino-1-butanol (13330-96-6) + methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → C18H29NO4

Conditions	Yield
With potassium hydroxide at 130℃; for 4h; Inert atmosphere;	83%

6-(N,N-dimethylamino)-1-hexanol (1862-07-3) + methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → C20H33NO4

Conditions	Yield
With potassium hydroxide at 130℃; for 4h; Inert atmosphere;	81%

2-(dipropylamino)ethanol (3238-75-3) + methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → C20H33NO4

Conditions	Yield
With potassium hydroxide at 130℃; for 4h; Inert atmosphere;	81%

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) + benzyl bromide (100-39-0) → methyl 4-benzyloxy-2-hydroxy-6-pentylbenzoate (94103-01-2)

Conditions	Yield
With potassium carbonate In acetone for 24h; Heating;	77%
With potassium carbonate In acetone for 22h; Heating;	43%

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) + (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (861892-40-2) → methyl (1'R,2'R)-2,6-dihydroxy-5'-methyl-4-pentyl-2'-(prop-1 -en-2- yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate (55658-71-4)

Conditions	Yield
Stage #1: methyl 2,6-dihydroxy-6-pentylbenzoate; (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol With boron trifluoride diethyl etherate In chlorobenzene at 22℃; Stage #2: With sodium hydrogencarbonate In chlorobenzene at 20℃; for 0.333333h;	70%
With boron trifluoride diethyl etherate In chlorobenzene at 20℃; for 1h; Reagent/catalyst; Temperature; Solvent;	70%
Stage #1: methyl 2,6-dihydroxy-6-pentylbenzoate; (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol With boron trifluoride diethyl etherate In chlorobenzene at 22℃; Flow reactor; Stage #2: With sodium hydrogencarbonate In chlorobenzene at 22℃; for 0.333333h;
With boron trifluoride diethyl etherate In chlorobenzene at 20℃; for 1h; Solvent;

2-(N,N-dimethylamino)ethanol (108-01-0) + methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → C16H25NO4

Conditions	Yield
With potassium hydroxide at 130℃; for 4h; Inert atmosphere;	70%

(1S,4R)-p-mentha-2,8-dien-1-ol (22972-51-6) + methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → Methyl tetrahydrocannabinolate (16850-65-0)

Conditions	Yield
With boron trifluoride diethyl etherate; magnesium sulfate In dichloromethane at 0℃; for 1.5h;	55%

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → 2-hydroxy-4-methoxy-6-pentylbenzoic acid (52189-68-1)

Conditions	Yield
With potassium carbonate; methyl iodide weiteres Reagens: Aceton; Behandeln des Reaktionsprodukts mit wss. Alkalilauge;
With silver(l) oxide; methyl iodide weiteres Reagens: Aceton; Behandeln des Reaktionsprodukts mit wss. Alkalilauge;

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) + isopropyl bromide (75-26-3) → methyl 2-hydroxy-4-isopropyloxy-6-pentylbenzoate (78135-63-4)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 24h; Heating;	15.7 g

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → methyl 4-benzyloxy-2,5-dihydroxy-6-pentylbenzoate (113487-78-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 43 percent / potassium carbonate / acetone / 22 h / Heating 2: 19 percent / potassium persulfate, 20percent sodium hydroxide, dimethyl sulfoxide / 24 h / 10 - 20 °C View Scheme

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → 8-hydroxy-3-methoxy-6-pentyl-1propyl-11-oxo-11H-dibenzo<1,4>dioxepin-7-carboxylic acid (stenosporonic acid) (103538-04-1)

Conditions

Yield

Multi-step reaction with 7 steps 1: 43 percent / potassium carbonate / acetone / 22 h / Heating 2: 19 percent / potassium persulfate, 20percent sodium hydroxide, dimethyl sulfoxide / 24 h / 10 - 20 °C 3: 76 percent / trifluofoacetic anhydride / toluene / 2 h / Ambient temperature 4: 13 percent / potassium carbonate / dimethylsulfoxide / 75 - 76 °C 5: 36 percent / potassium hydroxide / dimethylsulfoxide / 8 h / 90 - 95 °C 6: 98 percent / H2 / 10percent Pd/C / ethyl acetate / 15 h 7: 26 percent / trifluoroacetic anhydride / toluene / 2 h / Ambient temperature View Scheme

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → 2-(5'-carboxy-2',4'-dihydro-6'-pentylphenoxy)-4-methoxy-6-propylbenzoic acid (113487-85-7)

Conditions

Yield

Multi-step reaction with 6 steps 1: 43 percent / potassium carbonate / acetone / 22 h / Heating 2: 19 percent / potassium persulfate, 20percent sodium hydroxide, dimethyl sulfoxide / 24 h / 10 - 20 °C 3: 76 percent / trifluofoacetic anhydride / toluene / 2 h / Ambient temperature 4: 13 percent / potassium carbonate / dimethylsulfoxide / 75 - 76 °C 5: 36 percent / potassium hydroxide / dimethylsulfoxide / 8 h / 90 - 95 °C 6: 98 percent / H2 / 10percent Pd/C / ethyl acetate / 15 h View Scheme

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → methyl 4-benzyloxy-3-(2'-hydroxy-4'-methoxy-6'-propylbenzoyloxy)-6-hydroxy-2-pentylbenzoate (113487-80-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 43 percent / potassium carbonate / acetone / 22 h / Heating 2: 19 percent / potassium persulfate, 20percent sodium hydroxide, dimethyl sulfoxide / 24 h / 10 - 20 °C 3: 76 percent / trifluofoacetic anhydride / toluene / 2 h / Ambient temperature View Scheme

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → 2-(2'-benzyloxy-5'-carboxy-4'-hydroxy-6'-pentylphenoxy)-4-methoxy-6-propylbenzoic acid (113500-97-3)

Conditions

Yield

Multi-step reaction with 5 steps 1: 43 percent / potassium carbonate / acetone / 22 h / Heating 2: 19 percent / potassium persulfate, 20percent sodium hydroxide, dimethyl sulfoxide / 24 h / 10 - 20 °C 3: 76 percent / trifluofoacetic anhydride / toluene / 2 h / Ambient temperature 4: 13 percent / potassium carbonate / dimethylsulfoxide / 75 - 76 °C 5: 36 percent / potassium hydroxide / dimethylsulfoxide / 8 h / 90 - 95 °C View Scheme

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → 2-(2'-benzyloxy-4'-hydroxy-5'-mrthoxycarbonyl-6'-pentylphenoxy)-4-methoxy-6-propylbenzoic acid (113487-82-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 43 percent / potassium carbonate / acetone / 22 h / Heating 2: 19 percent / potassium persulfate, 20percent sodium hydroxide, dimethyl sulfoxide / 24 h / 10 - 20 °C 3: 76 percent / trifluofoacetic anhydride / toluene / 2 h / Ambient temperature 4: 13 percent / potassium carbonate / dimethylsulfoxide / 75 - 76 °C View Scheme

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → methyl 4-benzyloxy-3-formyl-6-methoxy-2-pentylbenzoate (122849-76-7)

Conditions	Yield
Multi-step reaction with 5 steps 1: 15.7 g / K2CO3 / dimethylformamide / 24 h / Heating 2: 15.7 g / K2CO3 / acetone / 20 h / Heating 3: tin(IV) chloride / CH2Cl2 / 4 h / 0 °C 4: 7.3 g / TiCl4 / CH2Cl2 / 3 h / 0 °C 5: 10.3 g / K2CO3 / dimethylformamide / 18 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1: 77 percent / potassium carbonate / acetone / 24 h / Heating 2: 89 percent / potassium carbonate / acetone / Heating 3: 80 percent / phosphoryl chloride / 24 h / 70 °C View Scheme

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → 6-benzyloxy-4-methoxy-3-methoxycarbonyl-2-pentylbenzoic acid (78135-68-9)

Conditions	Yield
Multi-step reaction with 6 steps 1: 15.7 g / K2CO3 / dimethylformamide / 24 h / Heating 2: 15.7 g / K2CO3 / acetone / 20 h / Heating 3: tin(IV) chloride / CH2Cl2 / 4 h / 0 °C 4: 7.3 g / TiCl4 / CH2Cl2 / 3 h / 0 °C 5: 10.3 g / K2CO3 / dimethylformamide / 18 h / Ambient temperature 6: 7.5 g / tetrabutylammonium permanganate, pyridine / 5 h View Scheme
Multi-step reaction with 4 steps 1: 77 percent / potassium carbonate / acetone / 24 h / Heating 2: 89 percent / potassium carbonate / acetone / Heating 3: 80 percent / phosphoryl chloride / 24 h / 70 °C 4: 97 percent / sodium chlorite, sulphamic acid / H2O; dioxane / 0.67 h View Scheme

methyl 2,4-dihydroxy-6-pentylbenzoate (58016-28-7) → methyl 3-(2,4-dihydroxy-6-pentylbenzoyl)-4-hydroxy-6-methoxy-2-pentylbenzoate (78135-69-0)

Conditions

Yield

Multi-step reaction with 8 steps 1: 15.7 g / K2CO3 / dimethylformamide / 24 h / Heating 2: 15.7 g / K2CO3 / acetone / 20 h / Heating 3: tin(IV) chloride / CH2Cl2 / 4 h / 0 °C 4: 7.3 g / TiCl4 / CH2Cl2 / 3 h / 0 °C 5: 10.3 g / K2CO3 / dimethylformamide / 18 h / Ambient temperature 6: 7.5 g / tetrabutylammonium permanganate, pyridine / 5 h 7: trifluoroacetic anhydride / CH2Cl2 / 2 h / Ambient temperature 8: 3.65 g / H2 View Scheme

Upstream product

• 18402-83-0 (E)-non-3-en-2-one 
• 108-59-8 malonic acid dimethyl ester 
• 855875-40-0 2,4-dihydroxyl-6-pentylbenzaldehyde 
• 529-47-5 2-hydroxy-4-(2-hydroxy-4-methoxy-6-pentylbenzoyloxy)-6-pentylbenzoic acid 
• 6175-23-1 2,4-nonanedione 
• 5830-30-8 N,N-dimethylhexanamide 
• 616-38-6 carbonic acid dimethyl ester 
• 123-54-6 acetylacetone 
• 142-61-0 Hexanoyl chloride 
• 102342-54-1 1,3,5-tris(trimethylsiloxy)-1-methoxyhexa-1,3,5-triene 
• 74590-73-1 1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene 
• 83578-33-0 (2-Pentyl-[1,3]dioxolan-2-yl)-acetyl chloride 
• 29736-80-9 3,5-dioxohexanoic acid methyl ester 
• 60988-34-3 1-(1-imidazolyl)-1-hexanone 

Downstream Products

• 63953-93-5 (E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzoic acid methyl ester 
• 23978-85-0 tetrahydrocannabinolic acid 
• 1244-58-2 cannabidiolic acid 
• 2969-22-4 (+)-CBD methyl ester 
• 55658-71-4 methyl (1'R,2'R)-2,6-dihydroxy-5'-methyl-4-pentyl-2'-(prop-1 -en-2- yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-3-carboxylate 
• 500-66-3 Olivetol 
• 95001-70-0 2-(3,7-dimethylocta-2,6-dien-1-yl)-5-pentylbenzene-1,3-diol 
• 2808-41-5 Cannabigerolinsaeure-methylester 
• 74219-29-7 (1'S,2'S)-5'-methyl-4-pentyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol 
• 1972-08-3 dronabinol 

Relevant articles and documents

SYNTHESIS OF PHYTOCANNABINOIDS INCLUDING A DECARBOXYLATION STEP

method for decarboxylating a carboxylated phytocannabinoid compound of Formula I to form a phytocannabinoid compound of Formula II: Formula I Formula II wherein: R1 is selected from the group consisting of: substituted or unsubstituted C1-C5 alkyl; R2 is selected from the group consisting of: OH or O, and R3 is selected from the group consisting of: a substituted or unsubstituted cyclohexene, a substituted or unsubstituted C2-C8 alkene, or a substituted or unsubstituted C2-C8 dialkene; or R2 is O, and R2 and R3 together form a ring structure in which R2 is an internal ring atom; wherein the method includes heating a reaction mixture comprising the carboxylated phytocannabinoid compound and a polar aprotic solvent in the presence of a LiCl for a time sufficient to decarboxylate at least a portion of the carboxylated phytocannabinoid compounds and form the phytocannabinoid compound.

Chemistry of 1,3,5-Tris(trimethylsiloxy)-1-methoxyhexa-1,3,5-triene, a β-Tricarbonyl Trianion Equivalent

The title compound has been synthesized and its chemistry studied.Condensation with orthoesters, acid chlorides, or imidazolides gave aromatic compounds in a 5C + 1C condensation.A formal synthesis of lasiodiplodin has been completed.

Convenient Syntheses of Alkyl β-Resorcylate Derivatives

Syntheses of methyl 2,4-dihydroxy-6-methyl- (1a) and -3,6-dimethylbenzoates (1b) and methyl 2,4-dihydroxy-6-pentylbenzoate (1c) are described.Condensation reactions of dimethyl sodiomalonate with the dianion derived from pentane-2,4-dione or the dimerisation of the methyl acetoacetate dianion or the acetylation of the trianion derived from methyl 3,5,7-trioxo-octanoate gave (1a) (78percent) after work-up at pH 9.Analogous convenient, short, optimised syntheses of (1b and c) are given in detail.