85006-31-1

Basic information

• Product Name: Methyl 3-amino-4-methylthiophene-2-carboxylate
• Synonyms: M3A4MT2C;METHYL 3-AMINO-4-METHYLTHIOPHENE-2-CARBOXYLATE;Methyl 3-amino-4-methyl-2-thenoate;METHYL 3-AMINO-4-METHYL-2-THIOPHENECARBOXYLATE;LABOTEST-BB LT00453517;3-AMINO-4-METHYL-2-THIOPHENECARBOXYLIC ACID METHYL ESTER;3-AMINO-4-METHYLTHIOPHENE-2-CARBOXYLIC ACID METHYL ESTER;3-AMINO-4-METHYLTHIOPHENECARBOXYLIC ACID METHYL ESTER
• CAS NO: 85006-31-1
• Molecular Formula: C₇H₉NO₂S
• Molecular Weight: 171.22
• EINECS: 285-060-8
• Product Categories: Esters;Thiophenes & Benzothiophenes;Thiophene&Benzothiophene;Organic acids;API intermediates;Thiophen;Thiophenes & Benzothiophenes;Building Blocks;C7 to C9;Chemical Synthesis;Heterocyclic Building Blocks;Thiophenes
• Mol File: 85006-31-1.mol
• Article Data: 4

Chemical Properties

• Melting Point: 85-88 °C(lit.)
• Boiling Point: 318.6 °C at 760 mmHg
• Flash Point: >100°C
• Appearance: white to light yellow crystal powder
• Density: 1.264 g/cm³
• Vapor Pressure: 0.000357mmHg at 25°C
• Refractive Index: 1.586
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 1.71±0.10(Predicted)
• Water Solubility: 1g/L at 35℃
• BRN: 973196
• CAS DataBase Reference: Methyl 3-amino-4-methylthiophene-2-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: Methyl 3-amino-4-methylthiophene-2-carboxylate(85006-31-1)
• EPA Substance Registry System: Methyl 3-amino-4-methylthiophene-2-carboxylate(85006-31-1)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36-24/25-22
• WGK Germany: 2
• Hazardous Substances Data: 85006-31-1(Hazardous Substances Data)

Usage

Chemical Properties

white to light yellow crystal powder

Uses

Methyl 3-Amino-4-methylthiophene-2-carboxylate is a versatile reactant used in various syntheses. It is used in the preparation of (oxalylamino)benzoic acids and (carboxyheteroarylamino)oxalic acids as selective and orally bioavailable nonpeptide inhibitors of protein-tyrosine phosphatase 1B.

Application

methyl 3-amino-4-methylthiophene-2-carboxylate is the starting material used in the synthesis of the local anesthetic articaine. 7-Methylthieno[3,2-d]pyrimidin-4(3H)-one was prepared using methyl 3-amino-4-methylthiophene-2-carboxylate.The reaction of 4-bromotoluene (0.171 g, 1 mmol), methyl 3-amino-4-methylthiophene-2-carboxylate(0.342 g, 2 mmol) and KOAc (0.196 g, 2 mmol) in the presence of PdCl(C3H5)(dppb) (12.2 mg, 0.02mmol) in DMAc at 120 °C affords the corresponding Methyl 3-amino-4-methyl-5-p-tolylthiophene-2-carboxylate in 81% (0.212 g) isolated yield.

InChI:InChI=1/C7H9NO2S/c1-4-3-11-6(5(4)8)7(9)10-2/h3H,8H2,1-2H3

Synthetic route

4-methyl-3-oxotetrahydro-2-thiophencarboxylic acid methyl ester (2689-70-5) → 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1)

Conditions	Yield
Stage #1: 4-methyl-3-oxotetrahydro-2-thiophencarboxylic acid methyl ester With iron(III) chloride; 1,3,5-trichloro-2,4,6-triazine; hydroxylamine hydrochloride In N,N-dimethyl-formamide at 70 - 90℃; for 4h; Stage #2: With ammonium hydroxide for 0.5h; Reagent/catalyst; Temperature;	96.5%
With MH2OH*HCl In acetonitrile for 5h; Heating;	64%
With hydroxylamine hydrochloride In acetonitrile

3-amino-2-carbomethoxy-4-methyl-4,5-dihydrothiophene (125089-02-3) → 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1)

Conditions	Yield
With dihydrogen peroxide In ethyl acetate; isopropyl alcohol

di-tert-butyl dicarbonate (24424-99-5) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → tert‐butyl N‐(4‐methylthiophen‐3‐yl)carbamate (1097629-78-1)

Conditions	Yield
Stage #1: 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester With potassium hydroxide In water at 20 - 80℃; for 0.5h; Stage #2: With hydrogenchloride In water at 50 - 60℃; for 0.25h; Stage #3: di-tert-butyl dicarbonate With potassium hydroxide In hexane; water; acetone at -10 - 20℃;	100%
Stage #1: 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester With water; potassium hydroxide at 20 - 80℃; Inert atmosphere; Stage #2: With hydrogenchloride In water at 50 - 60℃; Stage #3: di-tert-butyl dicarbonate With potassium hydroxide In water at 5 - 20℃; Inert atmosphere;	81%

N-(benzyloxycarbonyl)glycyl chloride (15050-24-5) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 3-((benzyloxycarbonyl)glycyl)amino-2-methoxycarbonyl-4-methylthiophene (135429-76-4)

Conditions	Yield
In N,N,N,N,N,N-hexamethylphosphoric triamide; acetonitrile Ambient temperature;	99.3%

formic acid (64-18-6) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-formamido-4-methylthiophene-2-carboxylate (443762-03-6)

Conditions	Yield
Stage #1: formic acid With acetic anhydride at 0℃; Stage #2: 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester at 0 - 20℃; for 4h;	97%
With (1-methyl-3-(3-sulfopropyl)-1H-imidazol-3-ium)3[PW12O403-] In neat (no solvent) at 70℃; for 1h; Green chemistry;	88%
Stage #1: formic acid; 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester In acetic anhydride at 0 - 20℃; for 18h; Stage #2: for 0.5h;	81%

trifluoroacetic anhydride (407-25-0) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 4-methyl-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (1000409-43-7)

Conditions	Yield
With pyridine In acetonitrile at 0 - 20℃;	96%
With pyridine In acetonitrile at 0 - 20℃; for 2h;	96%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;	95%

3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 2,4-dimethyl-3-amino-thiophene (87685-15-2)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 80℃; for 3h; Inert atmosphere;	96%
With lithium aluminium tetrahydride In tetrahydrofuran for 3.5h; Cooling with ice; Reflux;	60.6%
Stage #1: 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester With lithium aluminium tetrahydride In tetrahydrofuran for 3.5h; Cooling with ice; Reflux; Stage #2: With sodium hydroxide In tetrahydrofuran; water at 0℃; for 1h;	60.6%
With sodium bis(2-methoxyethoxy)aluminum dihydride In potassium hydroxide; toluene
With sodium bis(2-methoxyethoxy)aluminum dihydride In potassium hydroxide; toluene

chloroformic acid ethyl ester (541-41-3) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 3-Ethoxycarbonylamino-4-methyl-thiophene-2-carboxylic acid methyl ester (118252-13-4)

Conditions	Yield
In toluene for 3h; Heating;	94%

2,6-difluorobenzoylchloride (18063-02-0) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 3-(2,6-difluoro-benzylamino)-4-methyl-thiophene-2-carboxylic acid methyl ester

Conditions	Yield
With pyridine at 20℃; for 168h;	94%

urea (57-13-6) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 7-methylthieno<3,2-d>pyrimidine-2,4-dione (35265-81-7)

Conditions	Yield
In N,N-dimethyl-formamide for 2.5h; Heating / reflux;	93.7%
for 1.5h; Heating;	90%
In N,N-dimethyl-formamide at 200℃; for 1.5h;	77%
at 160 - 200℃;	61%

3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 7-methylthieno<3,2-d>pyrimidine-2,4-dione (35265-81-7)

Conditions	Yield
With urea In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide	93.7%
With potassium cyanate; sodium hydroxide; acetic acid In water	84%
Multi-step reaction with 2 steps 1: H2O / 12 h / Ambient temperature 2: 5percent aq. NaOH / 2 h View Scheme
Multi-step reaction with 3 steps 1: dichloromethane / 0.37 h / -78 - 20 °C 2: hydrogenchloride; water / 2 h / Heating / reflux 3: methanol; sodium hydroxide; water / 2 h / Heating / reflux View Scheme

3-bromo-1-trifluoromethylbenzene (401-78-5) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-4-methyl-5-(3-trifluoromethylphenyl)-thiophene-2-carboxylate (1246226-63-0)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	92%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	92%

cis,trans-2,5-dimethoxytetrahydrofuran (696-59-3) + 4-chlorpyridine hydrochloride (7379-35-3) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 4-methyl-3-(pyrrol-1-yl)thiophene-2-carboxylate (179751-31-6)

Conditions	Yield
In 1,4-dioxane; water	91%

formamide (77287-34-4, 77287-35-5, 60100-09-6) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 7-methyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (175137-13-0)

Conditions	Yield
at 200℃; for 24h;	91%
at 200℃; for 24h;	91%
at 20℃;	60%

o-cyanobromobenzene (2042-37-7) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-5-(2-cyanophenyl)-4-methylthiophene-2-carboxylate (1246226-66-3)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	90%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	90%

3-cyanobromobenzene (6952-59-6) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-5-(3-cyanophenyl)-4-methylthiophene-2-carboxylate (1393718-85-8)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	90%

para-bromoacetophenone (99-90-1) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 5-(4-acetylphenyl)-3-amino-4-methylthiophene-2-carboxylate (1393718-78-9)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	90%

4-bromopyridine hydrochloride (19524-06-2) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-4-methyl-5-pyridin-4-ylthiophene-2-carboxylate (1246226-68-5)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	89%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	89%

1-Bromo-4-fluorobenzene (460-00-4) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-5-(4-fluorophenyl)-4-methyl-thiophene-2-carboxylate (691394-01-1)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	89%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	89%

o-trifluoromethylphenyl bromide (392-83-6) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-4-methyl-5-(2-trifluoromethylphenyl)-thiophene-2-carboxylate (1393718-90-5)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	88%

2-bromobenzoic acid methyl ester (610-94-6) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-5-(2-methoxycarbonylphenyl)-4-methylthiophene-2-carboxylate (1246226-65-2)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	87%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	87%

4-bromobenzenecarbonitrile (623-00-7) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-5-(4-cyanophenyl)-4-methylthiophene-2-carboxylate (1246226-62-9)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	87%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	87%

4-bromo-benzaldehyde (1122-91-4) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-5-(4-formylphenyl)-4-methylthiophene-2-carboxylate (1246226-60-7)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	87%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	87%

4'-Bromopropiophenone (10342-83-3) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-4-methyl-5-(4-propionylphenyl)-thiophene-2-carboxylate (1246226-61-8)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	86%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	86%

Ethyl oxalyl chloride (4755-77-5) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 3-(ethoxyoxalylamino)-4-methylthiophene-2-carboxylic acid methyl ester

Conditions	Yield
In tetrahydrofuran at 20℃; for 0.25h;	84%

bromochlorobenzene (106-39-8) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-5-(4-chlorophenyl)-4-methylthiophene-2-carboxylate (691394-00-0)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	84%

1-bromo-3-chlorobenzene (108-37-2) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → 3-amino-5-(3-chlorophenyl)-4-methyl-thiophene-2-carboxylic acid methyl ester (1293119-61-5)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	84%

3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → (3-amino-4-methylthiophen-2-yl)methanol

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 4h; Cooling with ice;	83.9%

para-nitrophenyl bromide (586-78-7) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-4-methyl-5-(4-nitrophenyl)-thiophene-2-carboxylate (725234-25-3)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	83%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	83%

m-bromobenzoic aldehyde (3132-99-8) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-5-(3-formylphenyl)-4-methylthiophene-2-carboxylate (1393718-83-6)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	83%

p-trifluoromethylphenyl bromide (402-43-7) + 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester (85006-31-1) → methyl 3-amino-4-methyl-5-(4-trifluoromethylphenyl)-thiophene-2-carboxylate (1246226-56-1)

Conditions	Yield
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	82%
With PdCl(C3H5)(dppb); potassium acetate In N,N-dimethyl acetamide at 120℃; for 20h; Inert atmosphere;	82%

Upstream product

• 2689-70-5 4-methyl-3-oxotetrahydro-2-thiophencarboxylic acid methyl ester 
• 125089-02-3 3-amino-2-carbomethoxy-4-methyl-4,5-dihydrothiophene 

Downstream Products

• 35265-81-7 7-methylthieno<3,2-d>pyrimidine-2,4-dione 
• 87685-15-2 2,4-dimethyl-3-amino-thiophene 
• 35265-81-7 7-methylthieno[3,2-d]pyrimidine-2,4-diol 
• 1394371-75-5 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide 
• 953044-73-0 1-(4-(2-(5-(3-methylthieno[3,2-b]pyridin-7-ylthio)-3-phenoxypyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone 
• 953045-90-4 3-methylthieno[3,2-b]pyridin-7-ol 
• 953045-91-5 7-chloro-3-methylthieno[3,2-b]pyridine 

Relevant articles and documents

Preparation method of articaine hydrochloride intermediate

The invention relates to a preparation method of an articaine hydrochloride intermediate. The method is characterized by comprising the steps of dissolving 2-methoxycarbonyl-4-methyl-3-oxotetrahydrothiophene into a solvent; then, sequentially adding a catalyst, cyanuric chloride and hydroxylamine hydrochloride; then, carrying out a reaction under the condition of heat preservation; after the reaction is finished, evaporating solvent under reduced pressure, and adding ammonia water into the obtained residue for neutralizing; after that, filtering to obtain a filter cake, washing the filter cakewith water, and then drying to obtain the finished product 3-amino-4-methyl-2-methyl-thiophenecarboxylate. The method has the advantage that the yield of the prepared articaine hydrochloride intermediate, i.e., 3-amino-4-methyl-2-thiophene methyl formate is high and reaches 90% or above.

Process for the preparation of thiophene derivatives and also new dihydrothiophene 1-oxides

Process for the preparation of thiophene derivatives and also new dihydrothiophene 1-oxides. Thiophene derivatives having an--optionally substituted--amino group on the thiophene ring are prepared by dehydrogenating dihydrothiophenes, substituted in a manner identical to that of the desired thiophene derivatives, by means of H2 O2, the dihydrothiophenes being reacted with H2 O2 in a first reaction stage in a neutral medium to give the corresponding sulfoxides, which are then rearranged into the thiophene derivatives by means of acid in the second reaction stage. The dihydrothiophene 1-oxides formed as intermediates in this reaction are new compounds. Like the thiophene derivatives formed from them by rearrangement with acid, they are intermediates, mainly in the sector of plant protection agents and pharmaceuticals.