49844-90-8

Basic information

• Product Name: 4-Chloro-2-methylthiopyrimidine
• Synonyms: 4-Chloro-2-(methylmercapto)pyrimidine;4-CHLORO-2-METHYLSULFANYL-PYRIMIDINE;4-Chloro-2-(methylthio)pyrimidine 97%;2-methylthio-4-chloropyrimine;2-(Methylthio)-4-chloropyrimidine;4-Chloro-2-(methylthio)pyrimidine ,98%;4-Chloro-2-methylthiopyrimidine,97%;4-Chloro-2-(Methylthio)py...
• CAS NO: 49844-90-8
• Molecular Formula: C5H5ClN2S
• Molecular Weight: 160.62
• EINECS: 256-500-6
• Product Categories: Halides;Pyrazines, Pyrimidines & Pyridazines;Pyrimidine;Pyrazines, Pyrimidines & Pyridazines;Building Blocks;Halogenated Heterocycles;Heterocyclic Building Blocks;Pyrimidines;PyrimidinesHeterocyclic Building Blocks;Heterocycle-Pyrimidine series
• Mol File: 49844-90-8.mol
• Article Data: 9

Chemical Properties

• Melting Point: −2 °C(lit.)
• Boiling Point: 139-140 °C36 mm Hg(lit.)
• Flash Point: >230 °F
• Appearance: /liquid
• Density: 1.381 g/mL at 25 °C(lit.)
• Vapor Pressure: 0.0511mmHg at 25°C
• Refractive Index: n20/D 1.6(lit.)
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• PKA: -0.56±0.20(Predicted)
• Water Solubility: Not miscible or difficult to mix in water.
• Sensitive: Hygroscopic
• BRN: 118042
• CAS DataBase Reference: 4-Chloro-2-methylthiopyrimidine(CAS DataBase Reference)
• NIST Chemistry Reference: 4-Chloro-2-methylthiopyrimidine(49844-90-8)
• EPA Substance Registry System: 4-Chloro-2-methylthiopyrimidine(49844-90-8)

Safety Data

• Hazard Codes: C
• Statements: 34
• Safety Statements: 26-36/37/39-45
• RIDADR: UN 1760 8/PG 2
• WGK Germany: 3
• F: 10-13-23
• HazardClass: 8
• PackingGroup: III
• Hazardous Substances Data: 49844-90-8(Hazardous Substances Data)

Usage

Chemical Properties

Clear yellow to brown liquid

Uses

Different sources of media describe the Uses of 49844-90-8 differently. You can refer to the following data:
1. It finds it application as a building block used in medicinal chemistry synthesis. 4-Chloro-2-methylthiopyrimidine is used in the total synthesis of the marine alkaloid variolin B1 and 2-hydroxy-4-pyrimidinecarboxylic acid. It is also used in the synthesis of 2,4-disubstituted pyrimidines, a novel class of KDR kinase inhibitors.
2. 4-Chloro-2-methylthiopyrimidine was used in the total synthesis of the marine alkaloid variolin B1 and 2-hydroxy-4-pyrimidinecarboxylic acid. It was used in the synthesis of 2,4-disubstituted pyrimidines, a novel class of KDR kinase inhibitors. It was used as building block in medicinal chemistry synthesis.

InChI:InChI=1/C5H5ClN2S/c1-9-5-7-3-2-4(6)8-5/h2-3H,1H3

Synthetic route

2-(methylsulfanyl)pyrimidin-4-ol (5751-20-2) → 4-Chloro-2-methylthiopyrimidine (49844-90-8)

Conditions	Yield
Stage #1: 2-(methylsulfanyl)pyrimidin-4-ol With trichlorophosphate In N,N-dimethyl-formamide; toluene at 20℃; for 0.5h; Stage #2: With thionyl chloride In N,N-dimethyl-formamide; toluene at 20 - 80℃; for 1h; Time; Solvent; Reagent/catalyst;	88.3%
With trichlorophosphate at 80℃;
With trichlorophosphate In neat (no solvent) at 80℃; for 7h; Inert atmosphere;

2-Methylthiouracil (5751-20-2) → 4-Chloro-2-methylthiopyrimidine (49844-90-8)

Conditions	Yield
With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 40℃; for 3h;	87.6%
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 40℃; for 3h;	87.6%
With trichlorophosphate
With trichlorophosphate

2-methylthio-1H-pyrimidin-4-one (5751-20-2) → 4-Chloro-2-methylthiopyrimidine (49844-90-8)

Conditions	Yield
With trichlorophosphate 1) reflux, 1.75 h, 2) r.t., overnight;

4-oxy-2-methylsulfanyl-pyrimidine hydrochloride → 4-Chloro-2-methylthiopyrimidine (49844-90-8)

Conditions	Yield
With phosphorus pentachloride; trichlorophosphate

4-Chloro-2-methylthiopyrimidine (49844-90-8) → 4-chloro-2-methanesulfonylpyrimidine (97229-11-3)

Conditions	Yield
With hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide In ethanol; water at 0℃; for 24h; Inert atmosphere;	99%
With chromium(VI) oxide; periodic acid In ethyl acetate; acetonitrile at 0℃; for 1.75h;	94%
With hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide In ethanol at 0 - 20℃; Inert atmosphere;	85.7%

4-Chloro-2-methylthiopyrimidine (49844-90-8) → 4-iodo-2-(methylthio)pyrimidine (1122-74-3)

Conditions	Yield
With hydrogen iodide In water at 20℃; for 8h;	99%
With hydrogen iodide In water at 20℃; for 16h;	98%
With hydrogen iodide In water at 20℃; for 72h;	95%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 2,6-dimethylbenzene boronic acid (100379-00-8) → 4-(2,6-dimethylphenyl)-2-(methylthio)pyrimidine

Conditions	Yield
With potassium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) In water; toluene for 12h; Suzuki-Miyaura cross-coupling; Heating;	99%
With potassium carbonate; PdCl2[P(tBu)2(p-Me2NC6H4)]2 In water; toluene at 100℃; Suzuki-Miyaura cross-coupling;	99%

benzoimidazole (51-17-2) + 4-Chloro-2-methylthiopyrimidine (49844-90-8) → 1-(2-(methylthio)pyrimidin-4-yl)-1H-benzo[d]imidazole

Conditions	Yield
With triethylamine In neat (no solvent) at 80℃; for 0.166667h; Microwave irradiation; Green chemistry;	99%
With NaH In N,N-dimethyl-formamide
With NaH In N,N-dimethyl-formamide
With triethylamine In N,N-dimethyl-formamide at 60 - 120℃; Microwave irradiation;

1,2,3-Benzotriazole (95-14-7) + 4-Chloro-2-methylthiopyrimidine (49844-90-8) → C11H9N5S*ClH

Conditions	Yield
In neat (no solvent) at 80℃; for 0.0833333h; Microwave irradiation; Green chemistry;	99%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 2-cyclobutyl-4-(methylsulfonyl)aniline → N-(2-cyclobutyl-4-(methylsulfonyl)phenyl)-2-(methylthio)pyrimidin-4-amine

Conditions	Yield
With toluene-4-sulfonic acid In isopropyl alcohol at 70℃; for 22.6667h; Inert atmosphere;	99%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 4-Phenylimidazole (670-95-1) → C14H12N4S (1244039-66-4)

Conditions	Yield
Stage #1: 4-Phenylimidazole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1.16667h; Stage #2: 4-Chloro-2-methylthiopyrimidine In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h;	98.4%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 1-(2-hydroxybenzyl)-3-(3-t-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (940875-00-3) → 1-(2-(2-(methylthio)pyrimidin-4-yloxy)benzyl)-3-(3-t-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (940870-62-2)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 22h;	98%

4-Chloro-2-methylthiopyrimidine (49844-90-8) → 4-azido-2-(methylthio)pyrimidine

Conditions	Yield
With sodium azide In N,N-dimethyl-formamide at 20℃; for 72h;	98%
With sodium azide In N,N-dimethyl-formamide

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 5-nitroindole (6146-52-7) → 1-(2-(methylthio)pyrimidin-4-yl)-5-nitro-1H-indole

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃;	98%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 5-chloro-2-methoxyphenyl boronic acid (89694-48-4) → 4-(5-chloro-2-methoxyphenyl)-2-methylsulfanylpyrimidine (1262148-80-0)

Conditions	Yield
With potassium carbonate; tetrakis(triphenylphosphine) palladium(0) In ethanol; toluene for 1h; Suzuki Coupling; Reflux;	97%

4-Chloro-2-methylthiopyrimidine (49844-90-8) → 4-bromo-2-methylsulfanylpyrimidine (959236-97-6)

Conditions	Yield
With trimethylsilyl bromide In acetonitrile at 40℃; for 30h;	96%
With trimethylsilyl bromide In acetonitrile at 40℃; for 24h; Inert atmosphere;	96%
With trimethylsilyl bromide In acetonitrile at 40℃; for 24h; Inert atmosphere;	95%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + phenylpropyolic acid (637-44-5) → C13H10N2S

Conditions	Yield
With bis[dicyclohexyl(2,4,6-triisopropyl-[1,1':3',1''-terphenyl]-2-yl)phosphane]palladium(II) dichloride; caesium carbonate In tetrahydrofuran at 80℃; for 7h;	96%

4-Chloro-2-methylthiopyrimidine (49844-90-8) → 4-chloro-2-(methylsulfinyl)pyrimidine (97229-10-2)

Conditions	Yield
With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 24h;	95%
With manganese(II) triflate; 1-Adamantanecarboxylic acid; C32H38N4O2; dihydrogen peroxide In acetonitrile at -30℃; for 0.5h; enantioselective reaction;	85%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 25℃; Cooling with ice;

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 4-methoxyphenylboronic acid (5720-07-0) → 4-(4-methoxyphenyl)-2-(methylsulfanyl)pyrimidine (148990-17-4)

Conditions	Yield
With potassium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) In water; toluene for 12h; Suzuki-Miyaura cross-coupling; Heating;	95%
With potassium carbonate; PdCl2[P(tBu)2(p-Me2NC6H4)]2 In water; toluene at 100℃; Suzuki-Miyaura cross-coupling;	95%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 3,4-dinitophenol (577-71-9) → 4-(3,4-dinitro-phenoxy)-2-methylsulfanyl-pyrimidine (952490-61-8)

Conditions	Yield
at 150℃; for 2h;	95%
at 150℃; for 2h;

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 2,3,4-trimethoxyphenylboronic acid (118062-05-8) → C14H16N2O3S (634611-62-4)

Conditions	Yield
Stage #1: 4-Chloro-2-methylthiopyrimidine; 2,3,4-trimethoxyphenylboronic acid With sodium carbonate In 1,4-dioxane; water at 20℃; for 0.0833333h; Stage #2: tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 110℃; for 16h;	95%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + phenylacetylene (536-74-3) → C13H10N2S

Conditions	Yield
With potassium phosphate; bis[dicyclohexyl(2,4,6-triisopropyl-[1,1':3',1''-terphenyl]-2-yl)phosphane]palladium(II) dichloride In acetonitrile at 90℃; for 6h; Sonogashira Cross-Coupling;	95%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 3‐cyclopropyl‐2‐propynoic acid (7358-93-2) → C10H10N2S

Conditions	Yield
With bis[dicyclohexyl(2,4,6-triisopropyl-[1,1':3',1''-terphenyl]-2-yl)phosphane]palladium(II) dichloride; caesium carbonate In tetrahydrofuran at 80℃; for 5h;	95%

tetrahydropyran-4-carboxylic acid methyl ester (110238-91-0) + 4-Chloro-2-methylthiopyrimidine (49844-90-8) → methyl 4-(2-(methylthio)pyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylate

Conditions	Yield
With lithium hexamethyldisilazane In tetrahydrofuran at 30℃; for 0.0833333h;	95%
With lithium hexamethyldisilazane In tetrahydrofuran at 30℃; for 0.0833333h;	95%
With lithium hexamethyldisilazane In tetrahydrofuran at 30℃; for 0.0833333h;	95%
With lithium hexamethyldisilazane In tetrahydrofuran at 30℃; for 0.0833333h;	95%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + trimethylamine (75-50-3) → Trimethyl-4-(2-methylthiopyrimidinyl)ammoniumchlorid (6622-64-6)

Conditions	Yield
In benzene 1) 0 deg C; 2) room temperature, 1h;	94%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 4-cyanophenylboronic acid (126747-14-6) → 4-(2-methylsulfanylpyrimidin-4-yl)benzonitrile (874778-91-3)

Conditions	Yield
With potassium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) In water; toluene for 12h; Suzuki-Miyaura cross-coupling; Heating;	94%
With potassium carbonate; PdCl2[P(tBu)2(p-Me2NC6H4)]2 In water; toluene at 100℃; Suzuki-Miyaura cross-coupling;	94%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + phenol (108-95-2) → 2-methylthio-4-phenoxypyrimidine + (E)-methyl 2-[2-(4-phenoxypyrimidin-2-yloxy)phenyl]-3-methoxypropenoate (131860-90-7)

Conditions	Yield
In N,N-dimethyl-formamide	A 94% B n/a

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 4-nitro-phenol (100-02-7) → 2-methylsulfanyl-4-(4-nitrophenoxy)-pyrimidine (307309-31-5)

Conditions	Yield
Stage #1: 4-nitro-phenol With sodium hydride at 0℃; for 0.5h; Stage #2: 4-Chloro-2-methylthiopyrimidine at 70 - 80℃; for 16h;	94%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 4-aminoindazole (41748-71-4) → N-(2-methylsulfanylpyrimidin-4-yl)-1H-indazol-4-amine (945396-85-0)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane; butan-1-ol at 80℃; for 4h;	93%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 2-ethoxy-4-fluorobenzenamine (178993-28-7) → N-(2-ethoxy-4-fluorophenyl)-2-(methylthio)pyrimidin-4-amine

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 80℃; for 4h;	93%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + tri-n-butyl(vinyl)tin (7486-35-3) → 2-methylthio-4-vinylpyrimidine (131467-05-5)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In 1,2-dichloro-ethane at 70℃; for 48h;	92%
With tetrakis(triphenylphosphine) palladium(0) In 1,2-dichloro-ethane at 70℃; for 48h; Stille Cross Coupling;	92%
With tetrakis(triphenylphosphine) palladium(0) In 1,2-dichloro-ethane at 70℃; for 48h; Stille Cross Coupling;	92%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + (2-fluoro-pyridin-3-yl)boronic acid (174669-73-9) → 4-(2-fluoropyridin-3-yl)-2-(methylthio)pyrimidine

Conditions	Yield
With potassium hydrogencarbonate; PdCl2[P(tBu)2(p-Me2NC6H4)]2 In water; acetonitrile at 100℃; Suzuki-Miyaura cross-coupling;	92%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere;	73%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + 5-methoxy-1H-indazole (94444-96-9) → 5-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-1H-indazole

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide at 0℃; for 2h; Inert atmosphere;	92%

4-Chloro-2-methylthiopyrimidine (49844-90-8) + tert-butyl 4-(4-(((tert-butyldimethylsilyl)oxy)-methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate → tert-butyl 4-(4-(((tert-butyldimethylsilyl)oxy)-methyl)-5-(2-(methylthio)pyrimidin-4-yl)-1H-1,2,3-triazol-1-yl)-piperidine-1-carboxylate

Conditions

Yield

Stage #1: tert-butyl 4-(4-(((tert-butyldimethylsilyl)oxy)-methyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate With n-butyllithium In tetrahydrofuran; hexane Cooling with acetone-dry ice; Stage #2: With zinc(II) chloride In tetrahydrofuran; hexane Cooling with acetone-dry ice; Stage #3: 4-Chloro-2-methylthiopyrimidine With (2‑dicyclohexylphosphino‑2′,6′‑dimethoxybiphenyl)[2‑(2′‑amino‑1,1′‑biphenyl)]palladium(II) methanesulfonate In tetrahydrofuran; hexane at 60℃; for 18h; Cooling with acetone-dry ice;

92%

Upstream product

• 5751-20-2 2-(methylsulfanyl)pyrimidin-4-ol 
• 5751-20-2 2-methylthio-1H-pyrimidin-4-one 
• 5751-20-2 2-Methylthiouracil 

Downstream Products

• 259541-93-0 4-(2-methylsulfanylpyrimidin-4-yl)benzoic acid ethyl ester 
• 3934-20-1 2,6-Dichloropyrimidine 
• 17119-73-2 4-chloro-6-methyl-2-methylthiopyrimidine 
• 913722-68-6 3-benzyl-N-methyl-N-(2-(methylthio)pyrimidin-4-yl)-7-phenyl-3H-benzo[d]imidazol-5-amine 
• 913722-47-1 N,3-dimethyl-N-(2-(methylthio)pyrimidin-4-yl)-7-phenyl-3H-benzo[d]imidazol-5-amine 
• 175836-60-9 2-methylthio-4-[3-(trifluoromethyl)phenoxy]pyrimidine 
• 317828-04-9 2-[(S)-1-Phenylethylamino]-4-[5-(2-methylthiopyrimidin-4-yl)benzimidazol-1-yl]pyrimidine 
• 306297-34-7 1-(2-methylsulfanylpyrimidin-4-yl)-2-(3-trifluoromethylphenyl)-1H-imidazole-4-carboxylic acid ethyl ester 
• 317824-35-4 2-[(S)-1-Phenylethylamino]-4-[2-methylbenzimidazol-1-yl]pyrimidine 
• 317824-41-2 2-[(S)-1-Phenylethylamino]-4-[5-methylbenzotriazol-1-yl]pyrimidine 
• 317824-37-6 2-[(S)-1-Phenylethylamino]-4-[5,6-dimethylbenzimidazol-1-yl]pyrimidine 
• 894792-12-2 1-(2-(methylmercapto)-pyrimidin-4-yl)-7-phenyl-1,2,3,4-tetrahydro-1,8-naphthyridine 
• 894791-64-1 1-(2-(methylthio)pyrimidin-4-yl)-7-phenyl-1,2,3,4-tetrahydro-1,6-naphthyridine 
• 894792-69-9 8-(2-(methylthio)pyrimidin-4-yl)-2-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine 

Relevant articles and documents

Synthesis method of 4-chloro-2-methylthiopyrimidine

The invention belongs to the technical field of organic synthesis, in particular to a synthesis method of 4-chloro-2-methylthiopyrimidine. The method includes taking 2-thiouracil as a raw material, dimethyl sulfate as a methylation reagent, thionyl chloride and phosphorus oxychloride as a chlorination reagent, and synthesizing the 4-chloro-2-methylthiopyrimidine through methylation and chlorination.The dimethyl sulfate is taken as the methylation reagent to replace methyl bromide or methyl iodide, and thus the safety of the reaction is increased, and the cost is decreased; sodium hydroxide istaken as alkali to replace sodium methoxide or butyl lithium, and thus the safety of the reaction is increased, and the cost is reduced; toluene is taken as a reaction solvent, and thus the dosage ofthe chlorinated reagent is greatly reduced, the reaction safety is greatly improved, the cost is reduced, and the post-treatment operation is simplified; and the sulfoxide chloride and the phosphorusoxychloride are taken as the mixed chlorinating reagent, and thus the reaction yield is greatly improved.

A new route for the synthesis of Palbociclib

Abstract: In this paper, a novel synthetic method for Palbociclib was reported. It was synthesized in eight steps from 2-(methylthio) pyrimidin-4-(3H)-one with approximately 10% overall yield. This protocol started material 2-(methylthio) pyrimidin-4-(3H)-one, involved nucleophilic substitution by thionyl chloride, bromination, nucleophilic substitution by cyclopentylamine, a one pot-two step method (Heck reaction, ring close sequence), oxidation and bromination, cross-coupling reaction, Heck reaction, aqueous workup to afford Palbociclib. This synthetic route used inexpensive raw material and reagents, involved readily controllable reaction conditions and reduced environmental hazards. Graphic abstract: Synthesis of Palbociclib, a small molecule CDK inhibitor, starting from 2-(methylthio) pyrimidin-4-(3H)-one by 8 steps reaction. This method afforded the Palbociclib in 10% yield. [Figure not available: see fulltext.].

Synthesis of N,N-dialkyl-1-(2-alkylthiopyrimidin-4-yl)piperidin- 4-amines as potential heat shock protein inhibitors

A new efficient method for synthesizing promising heat shock protein inhibitors, N,N-dialkyl- 1-(2-alkylthiopyrimidin-4-yl)piperidin-4-amines, by the reaction of 2-alkyl-4-chlorothiouracils with 4-(N-alkyl-N-methylamino)piperidines was developed. 2-Alkyl-4-chlorothiouracils were synthesized by alkylation of 2-thiouracil with alkyl iodides and subsequent treatment of the intermediates with POCl3. 4-(N-Alkyl-N-methylamino)piperidines were prepared by reductive amination of 1-(tert-butoxycarbonyl)-4-piperidinone with methylamine followed by treatment of the intermediate with the appropriate aldehydes.