58-08-2

Usage

Uses

Used in Pharmaceutical Industry:
Caffeine is used as a mild vasoconstrictor for relieving headaches, particularly migraines. It is also used in medications to treat apnea in premature infants, stimulating the underdeveloped area of the brain controlling respiration.
Used in Dietary and Athletic Supplements:
The combination of caffeine and ephedrine is used as an appetite suppressant and energy booster in dietary and athletic supplements.
Used in Cosmetics:
Caffeine has a lipolytic effect on fatty cells, breaking down lipids and releasing fatty acids. It is used for skin firming and tightening, often incorporated into body product formulations targeting cellulite and slimming, as well as in eye creams that claim to reduce puffiness.
Used in Food and Beverage Industry:
Caffeine is consumed in coffee, tea, cocoa, chocolate, and soft drinks. It is used as a food additive in soft drinks for its mildly stimulating effect and distinctive taste note. It is also used in cola-type beverages and is optional in other soft drinks up to 0.02%.
Used in Medicine:
Caffeine is used as a cardiac and respiratory stimulant, as well as a diuretic. It is found in many drugs and acts as a reversible acetylcholinesterase inhibitor.
Used in Sun Protection:
Caffeine has been demonstrated to induce apoptosis in DNA damaged epidermal cells and tumors while sparing normal tissue. It also has a sunscreen-like effect and inhibits the formation of UVB-induced thymine dimers and sunburn skin lesions.

Originator

Caffedrine,Thompson Med.

History

Runge isolated caff eine from coffee in 1819. Caffeine derives its name from the Kaffa region of Ethiopia. Caffeine comes from the German kaffeine, which in turn is derived from the German word for coffee, kaffee. In 1827, a compound isolated from tea was named theine, but this was eventually shown to be caffeine.

Indications

This product is included in the Pharmacopoeia of the People’s Republic of China (2015), the British Pharmacopoeia (2017), the United States Pharmacopeia (40), the Japanese Pharmacopoeia (17th ed.), the European Pharmacopoeia (9.0th ed.), the Indian Pharmacopoeia (2010), and the International Pharmacopoeia (5th ed.). Commonly used dosage forms of caffeine include tablet, powder, and injection. Mainly used dosage forms in the market include caffeine citrate tablets, amidopyrine caffeine tablets, amidopyrine caffeine, children acetaminophen aspirin caffeine tablets, ergotamine caffeine tablets, caffeine sodium benzoate injection, cafe bromine agent, etc.

Manufacturing Process

Caffeine was synthesized by the reaction N-chloromethylation of theophylline by action dimethylsulphate in dimethylsulfoxide.

Therapeutic Function

Neurotropic, Central stimulant

Air & Water Reactions

Efflorescent in air. Water soluble.

Reactivity Profile

Caffeine may be hygroscopic. Aqueous solutions (1.12 mg/mL) are stable for three weeks at 41° F if protected from light. In normal room lighting and at room temperature, solutions are stable for 3 days. Solutions of Caffeine in water, DMSO, 95% ethanol or acetone should be stable for 24 hours under normal lab conditions. REACTIVITY: Caffeine may react with strong oxidizing agents. Caffeine is also incompatible with iodine, silver salts and tannins. Caffeine is a very weak base. Caffeine is decomposed by strong solutions of caustic alkalis.

Hazard

One grain or more is toxic, 200 μg/m L has been found to inhibit activity of the enzyme DNA polymerase. Use in soft drinks not to exceed 0.02%. Questionable carcinogen.

Health Hazard

Caffeine is a stimulant of the central nervoussystem. It eliminates fatigue and drowsiness. However, high doses cause gastrointestinal motility, restlessness, sleeplessness,nervousness, and tremor. Acute poisoningeffects include nausea, vomiting, headache,excitability, tremor, and sometimes, convulsive coma. Other symptoms may be respiratory depression, muscle contraction, distortedperception, and hallucination. Ingestion of15–20 g may be fatal to humans.LD50 value, oral (mice): 127 mg/kgLD50 value, oral (rabbits): 224 mg/kgAnimal studies indicate that caffeine athigh doses produces adverse reproductiveeffects, causing developmental abnormalities. It tested negative in the histidine reversion–Ames and TRP reversion tests.

Fire Hazard

Flash point data for Caffeine are not available; however, Caffeine is probably combustible.

Biological Activity

Central nervous system stimulant. Antagonist at A 1 and A 2A adenosine receptors and inhibitor of cyclic nucleotide phosphodiesterases. Mobilises calcium from intracellular stores and inhibits benzodiazepine binding to GABA receptors.

Clinical Use

The commonly used clinical preparations include caffeine sodium benzoate and ergotamine caffeine. The preparation of caffeine sodium benzoate (injection) is constituted of 0.12?g/ml of caffeine, 0.13?g/ml of sodium benzoate, and cafe bromine mixture (oral liquid). Clinically, it can be used for migraine headaches, cerebral artery dilated headache, or headache caused by histamine. However, it is invalid in the prevention of headaches. The adverse reactions include nausea, vomiting, abdominal pain, and fatigue. Other common symptoms include numbness and tingling of the hands, toes, and face and swelling of the foot and lower limb. Overdose causes severe poisoning, mental disorder, ataxia, convulsions, gray chills of the hand and foot, sensory disturbance, and even death due to coma and respiratory paralysis. Caffeine citrate preparation, including injection and oral solution, is the only internationally approved drug for the treatment of premature infant apnea.

Safety Profile

A human poison by ingestion. An experimental poison by ingestion, subcutaneous, intraperitoneal, intramuscular, rectal, and intravenous routes. Human systemic effects: ataxia, blood pressure elevation, change in heart rate, changes in tubules, convulsions or effect on seizure threshold, dtarrhea, distorted perceptions, hallucinations, hypermotility, muscle contraction, musculoskeletal tumors, nausea or vomiting, toxic psychosis, tremors. A human teratogen causing developmental abnormalities of the craniofacial and musculoskeletal systems, pregnancy termination (abortion), and stillbirth. Human maternal effects include an unspecified effect on labor or chddbirth. Human mutation data reported. An experimental teratogen. Other experimental reproductive effects. Questionable carcinogen with experimental carcinogenic data. Large doses (above 1.0 g> cause palpitation, excitement, insomnia, dtzziness, headache, and vomiting. Continued excessive use of caffeine in tea or coffee may lead to digestive disturbances, constipation, palpitations, shortness of breath, and depressed mental states. It is also implicated in cardiac disorders under those condttions. When heated to decomposition it emits toxic fumes of NOx

Synthesis

Usually obtained from tea dust in which it is present up to 5% or as a by-product from the manufacture of caffeine-free coffee; synthetically prepared starting with dimethylurea and malonic acid.

Environmental Fate

Caffeine can have profound effects on the cardiovascular system. At least four mechanisms have been proposed for the pro-arrhythmic potential of caffeine in overdose. First, caffeine increases circulating catecholamines. Second, caffeine inhibits phosphodiesterase. Increased circulating catecholamines after caffeine overdose increase b1-receptor stimulation. Stimulation of b1-receptors increases intracellular cAMP by G protein stimulation of adenylate cyclase. The activity of cAMP is prolonged due to its decreased metabolism as phosphodiesterase is inhibited by caffeine. Subsequently, b1-receptor effects are exaggerated and tachydysrhythmias are induced. Third, caffeine increases myocardial intracellular calcium. Caffeine both induces release of calcium from the sarcoplasmic reticulumand blocks calcium’s reuptake into the sarcoplasmic reticulum. This resulting increase in cytosolic calcium may provoke dysrhythmias. Fourth, caffeine blocks cardiac adenosine receptors, which have been shown to be antiarrhythmic.The hypotension that has been noted with overdoses of caffeine is due primarily to two mechanisms. First, caffeineinduced tachydysrhythmias lead to inadequate filling of the heart and subsequent decrease in cardiac output. Second, caffeine augments β2-effects and causes subsequent vasodilation with resulting hypotension.

Purification Methods

Caffeine crystallises from water or absolute EtOH. [Beilstein 26 III/IV 2338.]

Toxicity evaluation

Caffeine’s production and widespread use as an additive to food and as a stimulant may result in release to the environment through waste systems. It has an estimated vapor pressure of 7.3×10-9 mmHg (25°C), which indicates that it will exist as particulate in the atmosphere. Caffeine is not susceptible to photolysis and if released into soil it has a high mobility based on the Koc of 22.

InChI:InChI=1/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3

Synthetic route

methyl bromide (74-83-9) + xanthin (69-89-6) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With solution aqueuse d'hydroxide de sodium; tetrabutylammomium bromide In dichloromethane 1)room temp. 12h 2)reflux 3h;	100%

2,6-dimethoxy-7,9-dimethylpurinium iodide → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
In xylene at 140℃; for 0.75h; Rearrangement;	100%

theophylline sodium salt (3485-82-3) + carbonic acid dimethyl ester (616-38-6) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In water; ethylene glycol at 135℃; for 4h; Autoclave; Green chemistry;	98.4%
With PEG 400 In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 12h; Solvent; Concentration; Temperature; Reagent/catalyst;	94.9%
With NaY (Y-type sodium zeolite catalyst); turkey red oil In water for 5h; Reflux;

methyl bromide (74-83-9) + theophylline (58-55-9) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 3-benzyladenine (7280-81-1)

Conditions	Yield
With solution aqueuse d'hydroxide de sodium; tetrabutylammomium bromide In dichloromethane 1)20 deg C, 12h 2)40 deg C, 3h;	A 98% B n/a

Methyl formate (107-31-3) + 1,3-Dimethylxanthine potassium salt (57533-87-6) → theophylline (58-55-9) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
In methanol	A 97.5% B n/a

methanol (67-56-1) + 1,3-Dimethylxanthine potassium salt (57533-87-6) → Methyl formate (107-31-3) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With carbon monoxide at 140℃; under 37503 Torr; for 20h;	A n/a B 97%

theophylline (58-55-9) + methyl iodide (74-88-4) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With sodium hydride In dimethyl sulfoxide for 0.75h;	95%
With sodium hydride In dimethyl sulfoxide at 20℃; for 24h; Reagent/catalyst;	90%

methyl bromide (74-83-9) + theobromine / (83-67-0) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 3-benzyladenine (7280-81-1)

Conditions	Yield
With solution aqueuse d'hydroxide de sodium; tetrabutylammomium bromide In dichloromethane 1)20 deg C, 12h 2)40 deg C, 3h;	A 94% B n/a

3-methylxanthine (1076-22-8) + dimethyl sulfate (77-78-1) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With tetramethyl ammoniumhydroxide; potassium carbonate In methanol; water at 65 - 70℃;	92.5%

theobromine / (83-67-0) + dimethyl sulfate (77-78-1) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
potassium fluoride on basic alumina In acetonitrile for 24h; Ambient temperature;	92%
With sodium hydroxide

theophylline (58-55-9) + carbonic acid dimethyl ester (616-38-6) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With cetyltrimethylammonium bromide; N-ethyl-N,N-diisopropylamine In toluene at 140℃; for 9h; Solvent; Concentration; Reagent/catalyst; Temperature;	90.7%
With 18-crown-6 ether In N,N-dimethyl-formamide at 90℃; for 12h;	67%
With DABCO-NaY (1:1 DABCO Y-type sodium zeolite catalyst); turkey red oil In water for 5h; Reagent/catalyst; Reflux;

theophylline (58-55-9) + methyl iodide (74-88-4) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 3-benzyladenine (7280-81-1)

Conditions	Yield
With solution aqueuse d'hydroxide de sodium; tetrabutylammomium bromide In dichloromethane 1)20 deg C, 12h 2)40 deg C, 3h;	A 90% B n/a

theophylline (58-55-9) + dimethyl sulfate (77-78-1) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
potassium fluoride on basic alumina In acetonitrile for 24h; Ambient temperature;	88%
With sodium hydroxide
With sodium hydroxide
With potassium hydroxide; Aliquat 336 1.) 20 deg C, 2 h, 2.) 1 h; Yield given. Multistep reaction;

theophylline (58-55-9) + diphenylmethylsulfonium tetrafluoroborate (10504-60-6) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With potassium hydroxide In water; N,N-dimethyl-formamide at 20℃; for 3h;	88%

Trimethylsulfonium Fluoride (353-39-9) + Theophylline (58-55-9) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
In N,N-dimethyl-formamide at 100℃; for 1h;	86%

xanthin (69-89-6) + N,N'-dicyclohexyl-O-methyl isourea (6257-10-9) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
In N,N-dimethyl-formamide at 100℃; for 48h;	85%

theophylline (58-55-9) + acetic acid (64-19-7) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With copper(I) thiophene-2-carboxylate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(5-methyl-2-(4-fluorophenyl)pyridine(-1H))-iridium(III) hexafluorophosphate; N,N,N′,N′-tetramethyl-N″-tert-butylguanidine; bathophenanthroline; iodomesitylene diacetate In 1,4-dioxane at 20℃; for 1h; Inert atmosphere; Irradiation; regioselective reaction;	82%

4--1-methyl-5-methylaminocarbonylimidazole (107605-83-4) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With sodium hydride In ethanol for 1.5h; Heating;	81%

theobromine / (83-67-0) + carbonic acid dimethyl ester (616-38-6) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With 18-crown-6 ether In N,N-dimethyl-formamide at 90℃; for 12h;	78%

1-methyl-9-aminoxanthine potassium salt (113613-79-9) + methyl iodide (74-88-4) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
In N,N-dimethyl-formamide at 100℃; for 3h;	76%

carbonic acid dimethyl ester (616-38-6) + xanthin (69-89-6) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With 18-crown-6 ether In N,N-dimethyl-formamide at 90℃; for 12h;	74%

8-bromocaffeine (10381-82-5) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With copper In N,N-dimethyl-formamide for 2h; Heating;	72%

1-methyl-9-aminoxanthine (113613-76-6) + methyl iodide (74-88-4) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
In N,N-dimethyl-formamide at 100℃; for 1h;	71%

4-(N-trichloroacetyl-N-methylamino)-1-methyl-5-methylaminocarbonylimidazole (107605-87-8) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With sodium hydride In ethanol for 2h; Heating;	66%

7-(2-hydroxyethyl)theophylline (519-37-9) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With cerium(III) chloride; 9,10-diphenylanthracene; 1,2-bis(2,4,6-triisopropylphenyl)disulfane; tetrabutyl-ammonium chloride In acetonitrile for 168h; Irradiation; Inert atmosphere;	63%

dimethyl sulfate (77-78-1) + xanthin (69-89-6) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
potassium fluoride on basic alumina In acetonitrile for 24h; Ambient temperature;	61%
With alkaline solution
With sodium hydroxide

theobromine / (83-67-0) + methyl iodide (74-88-4) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 3-benzyladenine (7280-81-1)

Conditions	Yield
With solution aqueuse d'hydroxide de sodium; tetrabutylammomium bromide In dichloromethane 1)20 deg C, 12h 2)40 deg C, 3h;	A 56% B n/a

1,3,7,9-tetramethylxanthinium methyl sulfate (18623-34-2) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
at 260℃; for 15h;	25%

theophylline (58-55-9) + methyl p-toluene sulfonate (80-48-8) → 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2)

Conditions	Yield
With sodium hydroxide

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 8-chlorocaffeine (4921-49-7)

Conditions	Yield
With chlorine In chloroform	100%
With chlorine In chloroform at 50℃; for 2h;	100%
With trichloroisocyanuric acid; brilliant green carbocation In acetonitrile at 20℃; for 2h; Irradiation; regioselective reaction;	78%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 8-bromocaffeine (10381-82-5)

Conditions	Yield
With N-Bromosuccinimide In dichloromethane; water for 120h;	100%
With N-Bromosuccinimide In dichloromethane; water for 120h;	99%
With N-Bromosuccinimide In dichloromethane; water for 120h;	99%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 8-deuterio-1,3,7-trimethylxanthine

Conditions	Yield
With [(N,N’-bis(1R,2R,3R,5S)-(−)-isopinocampheyl-1,2-ethanediimine-radical)NiI(μ2-H)]2; deuterium In tetrahydrofuran at -196 - 45℃; under 760.051 Torr; for 24h; Sealed tube;	100%
With deuteromethanol; silver carbonate; johnphos In dichloromethane at 50 - 80℃;	98%
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; deuterium In tetrahydrofuran at 55℃; under 750.075 Torr; for 22h; Inert atmosphere;	92%
With palladium 10% on activated carbon; hydrogen; water-d2 at 90℃; for 1.5h;	86.9%
With water-d2 at 150℃; for 0.25h; Microwave irradiation;

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + para-chlorotoluene (106-43-4) → 1,3,7-trimethyl-8-(4-methylphenyl)-1H-purine-3,7-dihydro-2,6-dione

Conditions	Yield
With palladium diacetate; caesium carbonate; tricyclohexylphosphine tetrafluoroborate In toluene at 20 - 130℃; for 24h; Inert atmosphere;	99%
With potassium phosphate; palladium diacetate In 1-methyl-pyrrolidin-2-one at 125℃; for 24h;	86%

1-bromo-4-methoxy-benzene (104-92-7) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 1,3,7-trimethyl-8-(p-methoxyphenyl)-xanthine (439927-43-2)

Conditions	Yield
With potassium phosphate; palladium diacetate; Trimethylacetic acid In N,N-dimethyl-formamide at 20 - 120℃; for 7.16667h; Inert atmosphere;	99%
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In 5,5-dimethyl-1,3-cyclohexadiene; N,N-dimethyl-formamide at 20 - 140℃; for 36.1667h; Inert atmosphere; regioselective reaction;	98%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + diphenyl acetylene (501-65-5) → (E)-8-(1,2-Diphenylethenyl)-3,7-dihydro-1,3,7-trimethyl-1H-purin-2,6-dion (99765-12-5)

Conditions	Yield
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; cesium acetate; 1,2-bis-(diphenylphosphino)ethane In toluene at 120℃; for 24h; Sealed vial; optical yield given as %de; stereoselective reaction;	99%
With bis(dibenzylideneacetone)-palladium(0); tricyclohexylphosphine; Trimethylacetic acid In N,N-dimethyl acetamide at 130℃; for 14h; Inert atmosphere; Glovebox; stereoselective reaction;	69%

tert-butyl N-(thiophen-2-ylmethyl)carbamate (401485-19-6) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → tert-butyl N-((5-(1,3,7-trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl) thiophen-2-yl)methyl)carbamate (1403938-43-1)

Conditions	Yield
With pyridine; palladium diacetate; copper(II) acetate monohydrate; copper(l) chloride In 1,4-dioxane at 120℃; for 20h; Schlenk technique; Inert atmosphere;	99%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 2-iodonaphthalene (612-55-5) → 1,3,7-trimethyl-8-(naphthalen-2-yl)-xanthine (1257390-78-5)

Conditions	Yield
With (1-(2-(tert-butylamino)ethyl)-3-mesityl-2,3-dihydro-1H-imidazol-2-yl)copper(I) iodide; lithium tert-butoxide In N,N-dimethyl-formamide at 140℃; for 8h; Glovebox;	99%

NH-pyrazole (288-13-1) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 1,3,7-trimethyl-4,5,8-tri(1H-pyrazol-1-yl)-3,4,5,7-tetrahydro-1H-purine-2,6-dione

Conditions	Yield
With tetrabutylammonium tetrafluoroborate In acetonitrile at 45℃; for 10h; Temperature; Inert atmosphere; Electrochemical reaction; Green chemistry; diastereoselective reaction;	99%

4-bromo-1H-pyrazole (2075-45-8) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 4,5,8-tris(4-bromo-1H-pyrazol-1-yl)-1,3,7-trimethyl-3,4,5,7-tetrahydro-1H-purine-2,6-dione

Conditions	Yield
With tetrabutylammonium tetrafluoroborate In acetonitrile at 45℃; for 10h; Inert atmosphere; Electrochemical reaction; Green chemistry; diastereoselective reaction;	99%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 4-bromo-3-methyl-1H-pyrazole (13808-64-5) → 4,5,8-tris(4-bromo-3-methyl-1H-pyrazol-1-yl)-1,3,7-trimethyl-3,4,5,7-tetrahydro-1H-purine-2,6-dione

Conditions	Yield
With tetrabutylammonium tetrafluoroborate In acetonitrile at 45℃; for 10h; Inert atmosphere; Electrochemical reaction; Green chemistry; diastereoselective reaction;	99%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + oxalic acid (144-62-7) → oxalic acid caffeine, oxalic acid

Conditions	Yield
In methanol; cyclohexane at 17 - 22℃; under 724.572 - 782.178 Torr; for 0.5h;	98.3%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 2,6-dithiocaffeine (32061-73-7)

Conditions	Yield
With Lawessons reagent; aluminum oxide for 0.1h; microwave irradiation;	98%
With Lawessons reagent In toluene for 25h; Reflux;	75%
With bis(1,5-cyclooctadiylboryl)sulfide In 1,3,5-trimethyl-benzene for 336h; Heating;	62%
With kerosine

d6-dimethyl sulfate (15199-43-6) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → C9H10(2)H3N4O2(1+)*C(2)H3O4S(1-)

Conditions	Yield
In nitrobenzene at 90 - 100℃; for 25h;	98%

ethanol (64-17-5) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 8-(1-hydroxyethyl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (32086-89-8)

Conditions	Yield
With tert.-butylhydroperoxide In decane at 120℃; for 0.333333h; Reagent/catalyst; Solvent; Temperature; Time; Microwave irradiation; Green chemistry;	98%
With di-tert-butyl peroxide In water at 20℃; Inert atmosphere; UV-irradiation;	96%
With benzophenone Ambient temperature; Irradiation;

bromobenzene (108-86-1) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 1,3,7-trimethyl-8-phenylxanthine (6439-88-9)

Conditions	Yield
With potassium phosphate; palladium diacetate; Trimethylacetic acid In N,N-dimethyl-formamide at 20 - 120℃; for 7.16667h; Inert atmosphere;	98%
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In 5,5-dimethyl-1,3-cyclohexadiene; N,N-dimethyl-formamide at 20 - 140℃; for 36.1667h; Inert atmosphere; regioselective reaction;	93%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 9-bromophenanthrene (573-17-1) → 3,7-Dihydro-1,3,7-trimethyl-8-(9-phenanthryl)-1H-purin-2,6-dion (99765-06-7)

Conditions	Yield
With potassium phosphate; palladium diacetate; Trimethylacetic acid In N,N-dimethyl-formamide at 20 - 120℃; for 7.16667h; Inert atmosphere;	98%
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In 5,5-dimethyl-1,3-cyclohexadiene; N,N-dimethyl-formamide at 20 - 140℃; for 36.1667h; Inert atmosphere; regioselective reaction;	95%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 8-deuterio-1,3,7-tris(trideuteriomethyl)xanthine (1220356-33-1)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen; water-d2 at 160℃; for 24h;	98%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + trimethoxonium tetrafluoroborate (420-37-1) → 1,3,7,9-tetramethylxanthinium tetrafluoroborate

Conditions	Yield
Stage #1: 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione; trimethoxonium tetrafluoroborate In acetonitrile at 20℃; for 0.0833333h; Inert atmosphere; Schlenk technique; Stage #2: With sodium carbonate In acetonitrile at 20℃; for 0.916667h;	97%
In 1,2-dichloro-ethane at 100℃; for 1h;	66%
In 1,2-dichloro-ethane Inert atmosphere; Schlenk technique; Reflux;

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + para-iodoanisole (696-62-8) → 1,3,7-trimethyl-8-(p-methoxyphenyl)-xanthine (439927-43-2)

Conditions	Yield
With (1-(2-(tert-butylamino)ethyl)-3-mesityl-2,3-dihydro-1H-imidazol-2-yl)copper(I) iodide; lithium tert-butoxide In N,N-dimethyl-formamide at 140℃; for 8h; Glovebox;	97%
With potassium phosphate; palladium diacetate; Trimethylacetic acid In N,N-dimethyl-formamide at 20 - 120℃; for 7.16667h; Inert atmosphere;	92%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 4-iodo-3-methyl-1H-pyrazole (15802-75-2) → 4,5,8-tris(4-iodo-3-methyl-1H-pyrazol-1-yl)-1,3,7-trimethyl-3,4,5,7-tetrahydro-1H-purine-2,6-dione

Conditions	Yield
With tetrabutylammonium tetrafluoroborate In acetonitrile at 45℃; for 10h; Inert atmosphere; Electrochemical reaction; Green chemistry; diastereoselective reaction;	97%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + para-bromotoluene (106-38-7) → 1,3,7-trimethyl-8-(4-methylphenyl)-1H-purine-3,7-dihydro-2,6-dione

Conditions	Yield
With potassium phosphate; palladium diacetate; Trimethylacetic acid In N,N-dimethyl-formamide at 20 - 120℃; for 7.16667h; Inert atmosphere;	96%
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In 5,5-dimethyl-1,3-cyclohexadiene; N,N-dimethyl-formamide at 20 - 140℃; for 36.1667h; Inert atmosphere; regioselective reaction;	96%
With 2-ethyl-[1,2,4] triazolo[4,3-a]pyridin-2-ium tetrafluoroborate; palladium diacetate; potassium carbonate In N,N-dimethyl-formamide at 115℃; for 22h; Inert atmosphere;	94%

3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) + 2-methylphenyl bromide (95-46-5) → 1,3,7-trimethyl-8-(o-tolyl)-xanthine (1137486-72-6)

Conditions	Yield
With potassium phosphate; palladium diacetate; Trimethylacetic acid In N,N-dimethyl-formamide at 20 - 120℃; for 7.16667h; Inert atmosphere;	96%
With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline In 5,5-dimethyl-1,3-cyclohexadiene; N,N-dimethyl-formamide at 20 - 140℃; for 36.1667h; Inert atmosphere; regioselective reaction;	88%

2-Methylthiophene (554-14-3) + 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione (58-08-2) → 1,3,7-trimethyl-8-(5-methylthiophen-2-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione (1207995-92-3)

Conditions	Yield
Stage #1: 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione With pyridine; palladium diacetate; copper(II) acetate monohydrate In 1,4-dioxane at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 2-Methylthiophene In 1,4-dioxane at 120℃; for 20h; Inert atmosphere;	96%
With pyridine; palladium diacetate; copper(II) acetate monohydrate In 1,4-dioxane at 120℃; for 24h; Schlenk technique; Inert atmosphere;	92%
With pyridine; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; oxygen; copper(II) acetate monohydrate In 1,4-dioxane at 140℃; under 760.051 Torr; for 30h; Schlenk technique; Green chemistry;	89%

Upstream product

• 58-55-9 theophylline 
• 80-48-8 methyl p-toluene sulfonate 
• 77-78-1 dimethyl sulfate 
• 67-56-1 methanol 
• 74-88-4 methyl iodide 
• 10184-00-6 6-amino-5-formylamino-1H-pyrimidine-2,4-dione 
• 74-87-3 methylene chloride 
• 123-39-7 N-Methylformamide 
• 7150-04-1 6-amino-5-bromo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione 
• 1076-22-8 3-methylxanthine 
• 6632-68-4 6-amino-1,3-dimethyl-5-nitroso-1H-pyrimidine-2,4-dione 
• 7597-60-6 1,3-dimethyl-4-amino-5-(formylamino)uracil 
• 141-52-6 sodium ethanolate 
• 4921-49-7 8-chlorocaffeine 

Downstream Products

• 108074-37-9 4,5-dimethoxy-1,3,7-trimethyl-tetrahydro-purine-2,6,8-trione 
• 6336-13-6 8-acetoxymercuri-caffeine 
• 20041-90-1 caffeidine 
• 2757-85-9 1,3-dimethylalloxan 
• 525601-89-2 (+/-)-3,6-dimethyl-1-oxa-3,6,8-triazaspiro[4,4]nonane-2,4,7,9-tetraone 
• 598-50-5 N-Methylurea 
• 107-97-1 sarcosine 
• 16404-16-3 2,6,8-trichloro-7-methylpurine 
• 13182-58-6 6-Thiocoffein 
• 4921-49-7 8-chlorocaffeine 
• 10381-82-5 8-bromocaffeine 
• 5415-41-8 8-iodo-1,3,7-trimethyl-3,7-dihydro-1 H-purine-2,6-dione 
• 10381-83-6 7-chloromethyl-8-chloro-1,3-dimethyl-7H-purine-2,6-(1H,3H)-dione 
• 42297-40-5 1,3,7-trimethyl-2,6-dioxo-8-nitro-1H,3H,7H-xanthine 

Relevant academic research and scientific papers

SERS multiplexing of methylxanthine drug isomersviahost-guest size matching and machine learning

Multiplexed detection and quantification of structurally similar drug molecules, methylxanthine MeX, incl. theobromine TBR, theophylline TPH and caffeine CAF, have been demonstratedviasolution-based surface-enhanced Raman spectroscopy (SERS), achieving highly reproducible SERS signals with detection limits down to ～50 nM for TBR and TPH, and ～1 μM for CAF. Our SERS substrates are formed by aqueous self-assembly of gold nanoparticles (Au NPs) and supramolecular host molecules, cucurbit[n]urils (CBn,n= 7, 8). We demonstrate that the binding constants can be significantly increased using a host-guest size matching approach, which enables effective enrichment of analyte molecules in close proximity to the plasmonic hotspots. The dynamic range and the robustness of the sensing scheme can be extended using machine learning algorithms, which shows promise for potential applications in therapeutic drug monitoring, food processing, forensics and veterinary science.

Green synthesis of caffeine based on methylating reagent dimethyl carbonate and environmental friendly separating method

In this paper, a green process for the synthesis and separation of caffeine was reported. Theophylline sodium is used as the raw material, diazabicyclo[5.4.0]undec-7-ene as the catalyst, and Turkey red oil as the solvent, particularly, dimethyl carbonate was adopted in place of high toxic dimethyl sulfate to form a mixture of caffeine and by-product sodium bicarbonate. After converting sodium bicarbonate to sodium carbonate, the solubility difference between caffeine and sodium carbonate at 40°C was for the first time utilized to achieve the purpose of separating caffeine with an excellent yield of 98.4% and a purity of greater than 99.0%. Furthermore, both the reaction mother liquor and separation mother liquor can be recycled and reused during the reaction and separation processes, respectively, with little caffeine loss. No industrial waste was discharged in the process of the improved synthesis and separation, which is therefore environmental friendly.

Method for synthesizing caffeine

The invention discloses a method for synthesizing caffeine, and relates to the technical field of preparation of heterocyclic compounds containing purine ring systems. The preparation method comprisesthe following steps: mixing cyanoacetic acid and acetic anhydride at 30-80 DEG C for reaction, adding a solvent and dimethylurea, cooling to room temperature after reflux reaction is finished, filtering, concentrating filtrate, combining solids to obtain dimethylacetamide, adding liquid caustic soda to adjust the pH to 8-11, and reacting at 80-100 DEG C to generate dimethyl 4AU; the method comprises the following steps: completely dissolving dimethyl 4AU in formic acid, adding sodium nitrite, reacting at room temperature, adding a catalyst, keeping the temperature at 30-70 DEG C, recovering the catalyst after the reaction is finished, and concentrating mother liquor to recover formic acid, thereby obtaining dimethyl FAU; adding water and liquid caustic soda into dimethyl FAU, and carryingout a ring-closure reaction to obtain theophylline sodium salt; the theophylline sodium salt is subjected to methylation reaction and refining to obtain caffeine. The method has the advantages of accessible raw materials, mild and controllable reaction conditions, fewer steps, high yield and greatly higher product quality, is simple to operate, and can easily implement industrial production.

Dehydroxymethylation of alcohols enabled by cerium photocatalysis

Dehydroxymethylation, the direct conversion of alcohol feedstocks as alkyl synthons containing one less carbon atom, is an unconventional and underexplored strategy to exploit the ubiquity and robustness of alcohol materials. Under mild and redox-neutral reaction conditions, utilizing inexpensive cerium catalyst, the photocatalytic dehydroxymethylation platform has been furnished. Enabled by ligand-to-metal charge transfer catalysis, an alcohol functionality has been reliably transferred into nucleophilic radicals with the loss of one molecule of formaldehyde. Intriguingly, we found that the dehydroxymethylation process can be significantly promoted by the cerium catalyst, and the stabilization effect of the fragmented radicals also plays a significant role. This operationally simple protocol has enabled the direct utilization of primary alcohols as unconventional alkyl nucleophiles for radical-mediated 1,4-conjugate additions with Michael acceptors. A broad range of alcohols, from simple ethanol to complex nucleosides and steroids, have been successfully applied to this fragment coupling transformation. Furthermore, the modularity of this catalytic system has been demonstrated in diversified radical-mediated transformations including hydrogenation, amination, alkenylation, and oxidation.

Dehydroxymethylation of Alcohols Enabled by Cerium Photocatalysis

Dehydroxymethylation, the direct conversion of alcohol feedstocks as alkyl synthons containing one less carbon atom, is an unconventional and underexplored strategy to exploit the ubiquity and robustness of alcohol materials. Under mild and redox-neutral reaction conditions, utilizing inexpensive cerium catalyst, the photocatalytic dehydroxymethylation platform has been furnished. Enabled by ligand-to-metal charge transfer catalysis, an alcohol functionality has been reliably transferred into nucleophilic radicals with the loss of one molecule of formaldehyde. Intriguingly, we found that the dehydroxymethylation process can be significantly promoted by the cerium catalyst, and the stabilization effect of the fragmented radicals also plays a significant role. This operationally simple protocol has enabled the direct utilization of primary alcohols as unconventional alkyl nucleophiles for radical-mediated 1,4-conjugate additions with Michael acceptors. A broad range of alcohols, from simple ethanol to complex nucleosides and steroids, have been successfully applied to this fragment coupling transformation. Furthermore, the modularity of this catalytic system has been demonstrated in diversified radical-mediated transformations including hydrogenation, amination, alkenylation, and oxidation.

Room-temperature palladium-catalyzed direct 2-alkenylation of azole derivatives with alkenyl bromides

Pd-catalyzed direct C2-alkenylation of azole derivatives proceeds efficiently under mild conditions, and the reaction of substituted benzoxazoles, oxazole and benzothiazole occurred even at room temperature. The substrate scope of the reaction was turned out to include mono-, di- and trisubstituted alkenyl bromides. To validate the scalability of this method, 5-Methyl-2-(prop-1-en-2-yl)benzoxazole (3c) was prepared on one-gram scale at room temperature.

Decarboxylative sp 3 C-N coupling via dual copper and photoredox catalysis

Over the past three decades, considerable progress has been made in the development of methods to construct sp 2 carbon-nitrogen (C-N) bonds using palladium, copper or nickel catalysis 1,2 . However, the incorporation of alkyl substrates to form sp 3 C-N bonds remains one of the major challenges in the field of cross-coupling chemistry. Here we demonstrate that the synergistic combination of copper catalysis and photoredox catalysis can provide a general platform from which to address this challenge. This cross-coupling system uses naturally abundant alkyl carboxylic acids and commercially available nitrogen nucleophiles as coupling partners. It is applicable to a wide variety of primary, secondary and tertiary alkyl carboxylic acids (through iodonium activation), as well as a vast array of nitrogen nucleophiles: nitrogen heterocycles, amides, sulfonamides and anilines can undergo C-N coupling to provide N-alkyl products in good to excellent efficiency, at room temperature and on short timescales (five minutes to one hour). We demonstrate that this C-N coupling protocol proceeds with high regioselectivity using substrates that contain several amine groups, and can also be applied to complex drug molecules, enabling the rapid construction of molecular complexity and the late-stage functionalization of bioactive pharmaceuticals.

A synthesis method of caffeine

The invention relates to the field of synthesis of organic chemistry, and discloses a synthetic method of caffeine. The method comprises that in the presence of a phase-transfer catalyst, theophylline or sodium theophylline and a methylation reagent of di

Mechanistic Insight into Caffeine-Oxalic Cocrystal Dissociation in Formulations: Role of Excipients

Caffeine-oxalic acid cocrystal, widely reported to be stable under high humidity, dissociated in the presence of numerous pharmaceutical excipients. In cocrystal-excipient binary systems, the water mediated dissociation reaction occurred under pharmaceutically relevant storage conditions. Powder X-ray diffractometry was used to identify the dissociated products obtained as a consequence of coformer-excipient interaction. The proposed cocrystal dissociation mechanism involved water sorption, dissolution of cocrystal and excipient in the sorbed water, proton transfer from oxalic acid to the excipient, and formation of metal salts and caffeine hydrate. In compressed tablets with magnesium stearate, the cocrystal dissociation was readily discerned from the appearance of peaks attributable to caffeine hydrate and stearic acid. Neutral excipients provide an avenue to circumvent the risk of water mediated cocrystal dissociation.

Preparation process for environment-friendly semisynthetic caffeine

The invention relates to a preparation process for environment-friendly semisynthetic caffeine. According to the preparation process, preparation is carried out under the specific conditions like a temperature range of 90 to 160 DEG C, usage of an alkalin