320-67-2

Basic information

• Product Name: 5-Azacytidine
• Synonyms: Antibiotic U 18496-15N4;Azacitidine-15N4;Azacytidine-15N4;LadakaMycin-15N4;LedakaMycin-15N4;Mylosar-15N4;NSC 102816-15N4;NSC 103-627-15N4
• CAS NO: 320-67-2
• Molecular Formula: C₈H₁₂N₄O₅
• Molecular Weight: 244.2
• EINECS: 206-280-2
• Product Categories: Epigenetics;Pyrimidine purine;5-azacytidine, Mylosar, Ladakamycin;CORVATON;Inhibitors;Nucleosides and their analogs;Nucleosides, Nucleotides & Related Reagents;Bases & Related Reagents;Nucleotides;Carbohydrates & Derivatives;API intermediates;Antitumors for Research and Experimental Use;Biochemistry;Chemical Reagents for Pharmacology Research
• Mol File: 320-67-2.mol
• Article Data: 26

Chemical Properties

• Melting Point: 226-232 °C (dec.)(lit.)
• Boiling Point: 387.12°C (rough estimate)
• Flash Point: 277 °C
• Appearance: White to Off-white/lyophilized powder
• Density: 1.4287 (rough estimate)
• Vapor Pressure: 1.18E-13mmHg at 25°C
• Refractive Index: 1.6590 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Soluble in DMSO (up to 25 mg/ml), or in Water (up to 12 mg/ml).
• PKA: 13.46±0.70(Predicted)
• Water Solubility: 0.5-1.0 g/100 mL at 21 ºC
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20° for up to 1 month.
• Merck: 14,887
• BRN: 620461
• CAS DataBase Reference: 5-Azacytidine(CAS DataBase Reference)
• NIST Chemistry Reference: 5-Azacytidine(320-67-2)
• EPA Substance Registry System: 5-Azacytidine(320-67-2)

Safety Data

• Hazard Codes: T
• Statements: 45-46-22
• Safety Statements: 53-22-36/37/39-45
• WGK Germany: 3
• RTECS: XZ3017500
• F: 10-23
• Hazardous Substances Data: 320-67-2(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 320-67-2 differently. You can refer to the following data:
1. Azacytidine also referred to as Azacytidine and 5-azacytidine (brand name: Vidaza) is an anti-cancer chemotherapy medication. The drug is classified as demethylation and antimetabolite agent. Azacytidine acts by inhibiting the growth and proliferation of cancer cells in the body. The drug is indicated for the treatment of specific types of blood cell disorders and bone marrow cancers.
2. 5-Azacytidine is an analog of the nucleoside cytidine which can be incorporated into DNA and RNA. 5-Azacytidine acts as an epigenetic modifier by incorporating into DNA where it irreversibly binds to DNA methyltransferases, thus inhibiting their activity.Azacitidine is an antineoplastic agent launched for the treatment of myelodysplastic syndrome (MDS). MDS is a group of closely related diseases caused by abnormal blood-forming stem cells of the bone marrow. Azacitidine is indicated for the treatment of all five subtypes of MDS, which consist of refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia.

Indication

Azacytidine is prescribed for treating patients with secondary types of myelodysplastic syndrome, including refractory anemia that presents in the form of ringed sideroblasts (especially if it necessitates transfusion), or it presents itself alongside thrombocytopenia or neutropenia. Also, it is used in treating refractory anemia accompanied by excess blasts, refractory anemia characterized by excess blasts in transition (currently classified as chronic myelogenous leukemia that is accompanied by multilineage dysplasia), and acute myelomonocytic leukemia.

Contraindications

Azacytidine is contraindicated in patients who have acute malignant hepatic tumors or known hypersensitivity to the drug or mannitol.

Dosage

For treatment of patients with myelodysplastic syndrome, the initial dose is 75mg/m2 administered intravenously or subcutaneously in daily doses for 7 days in 4-week intervals. The recommended maintenance dose may be increased to 100mg/m2 if there are no noteworthy effects after 2 treatment cycles and if the patient does not experience additional toxicity other than vomiting and nausea. Patients should undergo treatment that lasts for a minimum of 4 cycles. However, a partial or complete response may necessitate additional cycles other than the recommended 4 cycles. Treatment should not be discontinued if the patient is experiencing positive outcomes from the therapy.

Mechanism of Action

5-Azacytidine is a chemical analog that is closely linked with the cytosine nucleoside in ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Azacytidine influences antineoplastic activity through two main mechanisms; suppression of DNA methyltransferase when administered in low doses, which results in hypomethylation of DNA, and unmediated cytotoxicity in anomalous hematopoietic cells present in the bone marrow by its integration into RNA and DNA at high doses which causes the death of the cells. Since Azacytidine is considered a ribonucleoside, it integrates itself into RNA to a greater extent than DNA. The integration into RNA results in the dissimulation of malfunctioning methylation, polyribosomes, and recipient function of replicated RNA, and suppression of protein production. The integration of Azacytidine into DNA results in a covalent bond that is characterized by DNA methyltransferases, which inhibits DNA synthesis and resultant cytotoxicity.

Elimination

Intravenous administration of the radioactive form of the drug to cancer patients results in 85% elimination of Azacytidine through urinary excretion. Fecal excretion of the radioactive dose takes place in <1% of the administered drug in 3 days. The mean elimination of radioactivity through urine accounts for 50% of 14C-azacytidine administration.

Adverse reactions

Common side effects associated with Azacytidine in more than 30% of the patients include low white blood cell count, fever, vomiting, low platelet count, anemia, and nausea. At nadir, 10-17days of chemotherapy cycles, one may also experience petechiae, ecchymosis, constipation, redness at the injection site and fatigue. Other side effects associated with Azacytidine in about 10-29% of the patients may include insomnia, depression, itching, upper respiratory infection, hypokalemia, anxiety, skin rash, abdominal pain, weight loss, nosebleed, chest pain, swelling on the ankles, dizziness, confusion, back pain, sore throat, poor appetite, headache, myalgia and arthralgia, pain at the injection site, chills, weakness, shortness of breath and coughs. It is important to contact health care provider if one is experiencing diarrhea (4-6 episodes in 24 hours). A patient should also contact the doctor in case he/she has nausea that interferes with their ability to eat. If one has bloodstained urine, constipation that persists regardless of laxative use, extreme fatigue, tarry or bloodstained stools, vomiting (4-5 episodes in a span of 24 hours), signs of infection such as productive coughs or painful urination, and inability to eat or take fluids for more than 24 hours.

Precautions

A patient should notify their healthcare provider if they are taking any other medications which may include herbal remedies, vitamins, and over-the-counter medications before receiving an Azacytidine prescription. A patient should not receive any vaccination or immunization while they are on Azacytidine treatment. Breastfeeding is not recommended while one is taking this drug. A patient should also inform their healthcare provider if they are pregnant or intending to get pregnant before starting Azacytidine treatment. Azacytidine may cause neutropenia, anemia, and thrombocytopenia. Since the drug may result in hepatotoxicity amongst patients with acute hepatic impairment, caution should be taken during the administration of Azacytidine in patients with liver disease. Renal toxicity that may range from renal failure to increased serum creatinine and death has been reported amongst patients who have been accorded intravenous treatment with Azacytidine in combination treatment with other chemotherapeutic medications for nonMDS cases. The drug may also result in acute tumor lysis syndrome for patients with MDS. Azacytidine poses a threat to a developing embryo/fetus based on its mechanism of action.

Chemical Properties

White crystalline solid or powder. Soluble in dimethyl sulfoxide, slightly soluble in ethanol:water (50:50), propylene glycol, polyethylene glycol; slightly soluble in water, saturated octanol aqueous solution, 5% glucose injection, N-methyl-2-pyrrolidone, 0.9% sodium chloride injection and 5% polysorbate 80 aqueous solution; insoluble in acetone, ethanol and methyl ethyl ketone.

Originator

Pharmion (US)

Uses

Different sources of media describe the Uses of 320-67-2 differently. You can refer to the following data:
1. A potent growth inhibitor and cytotoxic agent. It acts as a demethylating agent by inhibiting DNA methyltransferase
2. Antineoplastic;'Antimetabolite
3. 5-Azacytidine, its incorporation into RNA alters RNA synthesis and processing, and results in inhibition of protein synthesis. It has been used as a cancer chemotherapeutic agent. It is a powerful bacteriostatic, antitumor, and mutagenic agent; it also exhibits immunosuppressive, antimitotic, radioprotective, and virostatic effects.

Definition

ChEBI: A N-glycosyl-1,3,5-triazine that is 4-amino-1,3,5-triazin-2(1H)-one substituted by a beta-D-ribofuranosyl residue via a N-glycosidic linkage.

Manufacturing Process

A mixture of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-4-methylthio-1,2- dihydro-1,3,5-triazin-2-one (0.5875 g), absolute methanol (5 ml) and a normal methanolic sodium methoxide solution (1.2 ml) is stirred at room temperature with the exclusion of atmospheric moisture (a guard tube filled with potassium hydroxide pellets is fitted to the reaction vessel). The starting compound passes into solution in the course of 5 min. The resulting solution is allowed to stand at room temperature for 45 min and then the cations are removed by passage of the solution through a column packed with 10 ml of a weakly acidic cation exchange resin in the H+ form prewashed with water and methanol. The methanolic effluent (60 ml) is evaporated under reduced pressure at 30°C, the residue is dissolved in methanol (20 ml) and the solution once again is evaporated and the 1-β-D-ribofuranosyl-4-methoxy-1,2- dihydro-1,3,5-triazin-2-one was obtained. The residual crude crystalline 1β-D-ribofuranosyl-4-methoxy-1,2-dihydro- 1,3,5-triazin-2-one is dissolved in a 10% solution of dry ammonia in absolute methanol (4 ml) and the whole reaction mixture is allowed to stand in a stoppered flask for 30 min at room temperature (the product begins to deposit in the course of 5 min) and for 12 h in a refrigerator at -10°C. The resulting 5-azacytidine is collected with suction, washed with methanol and dried under reduced pressure. A yield of 0.216 g (88.6%) of 5-azacytidine, that is [1-β-D-ribofuranosyl-4-amino-1,3,5-triazin-2(1H)-one], melting point 232°-234°C (dec.), is obtained.

Brand name

Vidaza (Pharmion).

Therapeutic Function

Antineoplastic

Biological Functions

Azacitidine is given subcutaneously for the treatment of myelodysplastic syndrome, and serum levels generally are maximized within 30 minutes. The parent drug and its metabolites are excreted in the urine. Azacitidine is carcinogenic and teratogenic in rodents, and leukopenia, thrombocytopenia, and neutropenia are the most common reasons for drug discontinuation or dosage reduction.

General Description

White crystalline powder.

Air & Water Reactions

Slightly water soluble. Unstable in solution.

Reactivity Profile

5-Azacytidine is sensitive to light (may discolor). 5-Azacytidine is sensitive to oxidation. 5-Azacytidine is unstable in solution. 5-Azacytidine undergoes hydrolysis in aqueous buffers. 5-Azacytidine is incompatible with strong oxidizers.

Fire Hazard

Flash point data for 5-Azacytidine are not available; however, 5-Azacytidine is probably combustible.

Biological Activity

DNA methyltransferase inhibitor. Incorporates into DNA forming covalent adducts with cellular DNMT1, depleting enzyme activity. Induces demethylation and reactivation of silenced genes. Improves the efficiency of reprogramming of stem cells.

Biochem/physiol Actions

5-Azacytidine is a deoxycytidine analog and a demethylating agent. It acts as a potential antineoplastic agent for acute myelogenous leukemia. 5-Azacytidine activates repressed genes by inhibiting DNA methylation. 5-Azacytidine also affects protein synthesis by altering the RNA function and stability.

Clinical Use

Antineoplastic agent: Treatment of people not eligible for stem cell transplants with myelodysplastic syndromes, chronic myelomonocytic leukaemia or acute myeloid leukaemia

Safety Profile

Confirmed carcinogen with experimental carcinogenic, neoplastigenic, tumorigenic data. Poison by ingestion, intravenous, and intraperitoneal routes. Human systemic effects by intravenous route: nausea, vomiting and dlarrhea, reduction in white cell count (luekopenia and agranulocytosis). An experimental teratogen. Other experimental reproductive effects. Human mutation data reported. A skin irritant. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

The triazine ring of azacitidine is sensitive to water; this characteristic has made the synthesis of azacitidine a challenge, especially in manufacturing at commercial scale. A number of reports have appeared in order to avoid the use of water; however, these methods all have additional problems that render them undesirable for the large scale synthesis. A recent improved synthesis is depicted in the Scheme. 5- Azacytosine (1) was bis-silylated with HMDS in the presence of (NH4)SO4 to furnish trimethylsilylated azacytosine (2) in greater than 90% yield. Coupling of silylated azacytosine 2 with 1,2,3,5-tetra-O-acetyl-b-Dribofuranose (3) in DCM in the presence of TMS-triflate provided protected 5-azacitidine 4. The acetyl groups were then removed by using NaOMe in MeOH at rt. The crude azacitidine was crystallized from DMSO/MeOH to provide pure azacitidine (I).

Potential Exposure

A growth inhibitor (DNA methyltransferase inhibitor). A cytotoxic agent and chemotherapeutic agent used to treat angina pectoris, an ischemic heart disease symptom. Occupational exposure to azacitidine could occur among health professionals and support staff (including custodians) by dermal contact, inhalation, or accidental ingestion during drug preparation or administration or cleanup of medical waste, including disposal of excretions from treated patients (Zimmerman et al. 1981, NIOSH 2004). The National Occupational Exposure Survey (conducted from 1981 to 1983) estimated that 1069 healthservices workers, including 698 women, potentially were exposed to azacitidine. Azacitidine may be produced synthetically or isolated from the bacterium Streptoverticillium ladakanus . Incompatibilities: Azacitidine is Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Contact with alkali metals, nitrides, and strong reducing agents such as hydrides may form flammable and/or toxic gases. May react with anhydrides forming acids and esters, generating noticeable heat, and also with oxoacids and carboxylic acids to form esters plus water, but the heat of reaction in the latter case typically is low. Keep away from isocyanates and epoxides; may initiate their polymerization. Azacitidine is sensitive to light and oxidation and unstable in solution. It undergoes hydrolysis in aqueous buffers.

Drug interactions

Potentially hazardous interactions with other drugs None known

Carcinogenicity

Azacitidine is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

Metabolism

Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. Following IV administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the radioactive dose. Faecal excretion accounted for <1% of administered radioactivity over three days. Mean excretion of radioactivity in urine following SC administration of [14C]-azacitidine was 50%.

Shipping

UN3249 Medicine, solid, toxic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials.

Incompatibilities

Azacitidine is Incompatible with oxidizers (chlorates, nitrates, peroxides, permanganates, perchlorates, chlorine, bromine, fluorine, etc.); contact may cause fires or explosions. Keep away from alkaline materials, strong bases, strong acids, oxoacids, epoxides. Contact with alkali metals, nitrides, and strong reducing agents such as hydrides may form flammable and/or toxic gases. May react with anhydrides forming acids and esters, generating noticeable heat, and also with oxoacids and carboxylic acids to form esters plus water, but the heat of reaction in the latter case typically is low. Keep away from isocyanates and epoxides; may initiate their polymerization. Azacitidine is sensitive to light and oxidation and unstable in solution. It undergoes hydrolysis in aqueous buffers.

Waste Disposal

It is inappropriate and possibly dangerous to the environment to dispose of expired or waste drugs and pharmaceuticals by flushing them down the toilet or discarding them to the trash. Household quantities of expired or waste pharmaceuticals may be mixed with wet cat litter or coffee grounds, double-bagged in plastic, discard in trash. Larger quantities shall carefully take into consideration applicable DEA, EPA, and FDA regulations. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

References

1) Giraldo et al. (2011), Inhibition of DNA Methylation in somatic cells ; Methods Mol. Biol., 791 145 2) Brueckner et al. (2005), Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA Methyltransferases; Cancer Res., 65 6305 3) Mikkelsen et al. (2008), Dissecting direct reprogramming through integrative genomic analysis; Nature, 454 49 4) Qian et al. (2011), 5-Azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extra cellular regulated kinase; Stem Cells Dev., 21 67 5) Kiziltepe et al. (2007), 5-Azacytidine, a DNA Methyltranserase inhibitor, induces ATR-mediated DNA double-strand break responses, apoptosis, and synergistic cytotoxicity with doxorubicin and bortezomib against multiple myeloma cells; Mol. Cancer Ther., 6 1718

InChI:InChI=1/C8H12N4O5/c9-7-10-2-12(8(16)11-7)6-5(15)4(14)3(1-13)17-6/h2-6,13-15H,1H2,(H2,9,11,16)/t3-,4+,5+,6?/m1/s1

Synthetic route

5-azacytidine mono-hydrochloride → 5-azacytidine (320-67-2)

Conditions	Yield
With triethylamine In methanol at 25 - 30℃; for 2h; Product distribution / selectivity; Inert atmosphere;	99.13%

p-chlorobenzoyl azacitidine → 5-azacytidine (320-67-2)

Conditions	Yield
With ammonia In methanol for 2h;	89.2%
With sodium methylate In methanol for 2h; Inert atmosphere;	74.4%

2,3,5-tri-O-acetyl-β-D-ribofuranose-4-amino-1,3,5-triazine (10302-78-0) → 5-azacytidine (320-67-2)

Conditions	Yield
With sodium methylate In methanol for 2h; Inert atmosphere;	80.2%
With methanol; sodium methylate at 20 - 25℃; for 1.58333h; Product distribution / selectivity;	75%
With sodium methylate In methanol for 3h; Solvent;	38.8%

4-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,3,5-triazin-2(1H)-one (28998-36-9) → 5-azacytidine (320-67-2)

Conditions	Yield
With sodium methylate In methanol for 2h; Inert atmosphere;	75.9%
With ammonia In methanol at 0 - 20℃; for 7h;	60%

2',3',5'-tri-O-acetylcytidine (56787-28-1) → 5-azacytidine (320-67-2)

Conditions	Yield
With N-butylamine In methanol at 65℃; for 1h;	75.3%

1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (6974-32-9) + 2-(trimethylsilylamino)-4-(trimethylsilyloxy)-s-triazine (52523-35-0) → 5-azacytidine (320-67-2)

Conditions	Yield
Stage #1: 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose; 2-(trimethylsilylamino)-4-(trimethylsilyloxy)-s-triazine; trifluorormethanesulfonic acid In acetonitrile at 55℃; for 12.5h; Industry scale; Stage #2: With methanol; sodium methylate In dimethyl sulfoxide; acetonitrile at 22 - 23℃; for 3.75h;	71%

1,2,3,5-tetraacetylribose (13035-61-5) → 5-azacytidine (320-67-2)

Conditions	Yield
Stage #1: 5-azacytosine With chloro-trimethyl-silane; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile for 20h; Heating / reflux; Stage #2: 1,2,3,5-tetraacetylribose With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 20℃; for 20h; Stage #3: With sodium methylate; sodium hydrogencarbonate more than 3 stages;	41.3%
Stage #1: 5-azacytosine With chloro-trimethyl-silane; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile for 20h; Heating / reflux; Stage #2: 1,2,3,5-tetraacetylribose With trimethylsilyl trifluoromethanesulfonate In acetonitrile at 20℃; for 20h; Stage #3: With sodium methylate; sodium hydrogencarbonate more than 3 stages;

N-(Formylamidino)-N'-β-D-ribofuranosylharnstoff (65126-88-7) → 5-azacytidine (320-67-2)

Conditions	Yield
at 37℃; Rate constant; pH 9.5; other temperature, pH; decomposition of 5-aza-2'-deoxycytidine and 5-azacytidine on alkali and neutral solutions, HPLC study;

C17H26N4O8Si → 5-azacytidine (320-67-2)

Conditions	Yield
With sodium methylate In methanol

2-(trimethylsilylamino)-4-(trimethylsilyloxy)-s-triazine (52523-35-0) + 1,2,3,5-tetraacetylribose (13035-61-5) → 5-azacytidine (320-67-2)

Conditions	Yield
Stage #1: 2-(trimethylsilylamino)-4-(trimethylsilyloxy)-s-triazine; 1,2,3,5-tetraacetylribose With tin(IV) chloride In 1,2-dichloro-ethane at 5 - 20℃; for 2.25h; Stage #2: With water; sodium hydrogencarbonate In 1,2-dichloro-ethane at 15 - 20℃; for 0.5h; Product distribution / selectivity;

5-azacytosine (931-86-2) + 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (14215-97-5) → 5-azacytidine (320-67-2)

Conditions	Yield
Stage #1: 5-azacytosine With N,O-Bis(trimethylsilyl)trifluoroacetamide In dichloromethane for 1.5h; Reflux; Stage #2: 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose; trimethylsilyl trifluoromethanesulfonate In dichloromethane for 2.16667h; Reflux; Stage #3: With methanol; sodium methylate at 50℃; for 1h;
Stage #1: 5-azacytosine With N,O-Bis(trimethylsilyl)trifluoroacetamide In dichloromethane for 1.5h; Reflux; Stage #2: 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose In dichloromethane for 2h; Reflux; Stage #3: With methanol; sodium methylate at 50℃; for 1h; Product distribution / selectivity;

5-azacytosine (931-86-2) + 1,2,3,5-tetra-O-acetyl-D-ribofuranose (28708-32-9) → 5-azacytidine (320-67-2)

Conditions	Yield
Stage #1: 5-azacytosine With N,O-Bis(trimethylsilyl)trifluoroacetamide In dichloromethane for 1.5h; Reflux; Stage #2: 1,2,3,5-tetra-O-acetyl-D-ribofuranose; trimethylsilyl trifluoromethanesulfonate In dichloromethane for 2.16667h; Reflux; Stage #3: With methanol; sodium methylate at 50℃; for 1h; Product distribution / selectivity;
Stage #1: 5-azacytosine With N,O-Bis(trimethylsilyl)trifluoroacetamide In dichloromethane for 1.5h; Reflux; Stage #2: 1,2,3,5-tetra-O-acetyl-D-ribofuranose With trimethylsilyl trifluoromethanesulfonate In dichloromethane for 2h; Reflux; Stage #3: With methanol; sodium methylate at 50℃; for 1h; Product distribution / selectivity;

C17H23N3O6 → 5-azacytidine (320-67-2)

Conditions	Yield
With methanol; sodium methylate at 20℃; for 12h;	10.3 g

C32H34N4O7Si → 5-azacytidine (320-67-2)

Conditions	Yield
With methanol; sodium methylate In dichloromethane at 20℃; for 12h;	8 g

maleic acid (110-16-7) + 5-azacytidine (320-67-2) → 5-azacytidine maleic acid

Conditions	Yield
In methanol; water for 0.333333h;	99%

nicotinamide (98-92-0) + 5-azacytidine (320-67-2) → 5-azacytidine nicotinamide

Conditions	Yield
In methanol; water for 0.333333h;	99%

5-azacytidine (320-67-2) → 5-azacytidine zinc chloride

Conditions	Yield
With zinc(II) chloride In methanol; water for 0.333333h;	98%

5-azacytidine (320-67-2) → 4-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5,6-dihydro-1,3,5-triazin-2(1H)-one (62488-57-7)

Conditions	Yield
With sodium tetrahydroborate In water at 20℃; for 1.5h;	97%

5-azacytidine (320-67-2) → 5-azacytidine mono-hydrochloride

Conditions	Yield
With hydrogenchloride In methanol; isopropyl alcohol at 25 - 30℃; for 4h; Product distribution / selectivity; Inert atmosphere;	93.29%

toluene-4-sulfonic acid (104-15-4) + 5-azacytidine (320-67-2) → 2’, 3’-O-isopropyl-5-N-cytidine (65370-90-3)

Conditions	Yield
In acetone for 24h; Inert atmosphere;	90%

5-azacytidine (320-67-2) → 5-azacytidine hemisulfate

Conditions	Yield
With sulfuric acid In methanol at 25 - 30℃; for 2.5h; Product distribution / selectivity; Inert atmosphere;	87.7%

5-azacytidine (320-67-2) → 5-azacytidine mono-hydrobromide (1401238-97-8)

Conditions	Yield
With hydrogen bromide In methanol; acetic acid at 25 - 30℃; for 12.5h; Product distribution / selectivity; Inert atmosphere;	67%

tert-butyldimethylsilyl chloride (18162-48-6) + 5-azacytidine (320-67-2) → C26H54N4O5Si3

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 15h; Cooling with ice;	67%

chloro-trimethyl-silane (75-77-4) + 5-azacytidine (320-67-2) → 2',3',5'-tri(trimethylsilyl)-5-azacytidine

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1h; Cooling with ice;	64%
In pyridine Yield given;

4,4'-dimethoxytrityl chloride (40615-36-9) + 5-azacytidine (320-67-2) → 5'-O-(4,4'-dimethoxytrityl)-5-azacytidine (107036-45-3)

Conditions	Yield
With pyridine	59%
In pyridine	2.89 g (59%)

methanesulfonic acid (75-75-2) + 5-azacytidine (320-67-2) → 5-azacytidine mesylate (879492-75-8)

Conditions	Yield
In methanol at 25 - 30℃; for 2h; Product distribution / selectivity; Inert atmosphere;	52.7%

5-azacytidine (320-67-2) + tert-butylchlorodiphenylsilane (58479-61-1) → C24H30N4O5Si

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 15 - 30℃; for 2h; Cooling with ice;	48%

elaidoyl chloride (112-77-6, 7378-94-1, 7459-35-0) + 5-azacytidine (320-67-2) → 5-azacytidine 5'-elaidic acid ester (1137569-06-2)

Conditions	Yield
Stage #1: 5-azacytidine With hydrogenchloride In diethyl ether; ISOPROPYLAMIDE at 20℃; Stage #2: elaidoyl chloride In ISOPROPYLAMIDE at 20 - 30℃; Stage #3: With water; sodium hydrogencarbonate In ethyl acetate	43%

benzyltrimethylsilane (770-09-2) + 5-azacytidine (320-67-2) → 5’-O-(t-butyldimethylsilyl)-5-azacytidine

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 17h; Cooling with ice;	23%

5-azacytidine (320-67-2) + 2-(1-bromo-1-methylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane → C17H29BN4O7

Conditions	Yield
Stage #1: 5-azacytidine With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Inert atmosphere; Stage #2: 2-(1-bromo-1-methylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; regioselective reaction;	18%

5-azacytidine (320-67-2) + chlorophosphoric acid diphenyl ester (2524-64-3) → C20H21N4O8P

Conditions	Yield
With pyridine at 0℃; for 0.1h;	16%

chloro-trimethyl-silane (75-77-4) + 5-azacytidine (320-67-2) → 5'-O-trimethylsilyl-5-azacytidine

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 15 - 30℃; for 1h; Cooling with ice;	14%

5-azacytidine (320-67-2) + benzyl alcohol (100-51-6) → C22H25N4O8P

Conditions	Yield
Stage #1: 5-azacytidine With triethyl phosphate; trichlorophosphate at 0℃; for 0.1h; Stage #2: benzyl alcohol With pyridine at 0℃; for 1h;	13%

tert-butyldimethylsilyl chloride (18162-48-6) + 5-azacytidine (320-67-2) → 5'-O-(t-butyldimethylsilyl)-5-azacytidine

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 3h; Cooling with ice;	12%

5-azacytidine (320-67-2) → 4,5-dihydro-1,2-dideoxy-α-D-ribofuranoso[1,2-d]-1,3-oxazol-2-one (2508-81-8)

Conditions	Yield
In water Heating;

Upstream product

• 65126-88-7 N-(Formylamidino)-N'-β-D-ribofuranosylharnstoff 
• 13035-61-5 1,2,3,5-tetraacetylribose 
• 931-86-2 5-azacytosine 
• 14215-97-5 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose 
• 28708-32-9 1,2,3,5-tetra-O-acetyl-D-ribofuranose 
• 62402-31-7 5,6-dihydro-5-azacytidine hydrochloride 
• 22432-98-0 1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-5-azacytosine 
• 71084-43-0 5,6-dihydro-1-β-D-arabinofuranosyl-5-azacytosine 
• 28998-36-9 4-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-1,3,5-triazin-2(1H)-one 
• 56787-28-1 2',3',5'-tri-O-acetylcytidine 
• 6974-32-9 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose 
• 52523-35-0 2-(trimethylsilylamino)-4-(trimethylsilyloxy)-s-triazine 
• 10302-78-0 2,3,5-tri-O-acetyl-β-D-ribofuranose-4-amino-1,3,5-triazine 

Downstream Products

• 107036-45-3 5'-O-(4,4'-dimethoxytrityl)-5-azacytidine 
• 62488-57-7 5,6-dihydro-5-azacytidine 
• 65370-90-3 2’, 3’-O-isopropyl-5-N-cytidine 
• 107036-50-0 Imidazole-1-carbothioic acid O-{(2R,3R,5S)-2-(4-amino-2-oxo-2H-[1,3,5]triazin-1-yl)-5-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-tetrahydro-furan-3-yl} ester 
• 107036-49-7 Imidazole-1-carbothioic acid O-{(2R,3S,5R)-5-(4-amino-2-oxo-2H-[1,3,5]triazin-1-yl)-2-[bis-(4-methoxy-phenyl)-phenyl-methoxymethyl]-tetrahydro-furan-3-yl} ester 
• 107036-46-4 5'-O-(4,4'-dimethoxytrityl)-5-azacytidine 2',3'-O-(cyclic thiocarbonate) 
• 107036-48-6 5'-O-(4,4'-dimethoxytrityl)-3'-deoxy-5-azacytidine 
• 107036-47-5 5'-O-(4,4'-dimethoxytrityl)-2'-deoxy-5-azacytidine 

Relevant articles and documents

An improved and scalable process for the synthesis of 5-azacytidine: An antineoplastic drug

An improved, practical, and scalable process for the manufacture of antineoplastic drug, 5-azacytidine (1), is described. A thorough understanding of the reaction parameters and stability of the reaction intermediates led us to the development of a robust process. The challenges in the isolation and systematic approach used to streamline the process into a very robust and practical manufacturing process are described.

Azacytidine methylate substance and preparation method, pharmaceutical composition and application thereof

The invention discloses an azacytidine methylate substance and a preparation method, a pharmaceutical composition and application thereof. The molar ratio of azacytidine to methanol in the azacytidinemethylate substance is 1 to (0.4 to 1.0), preferably, the molar ratio is 1 to (0.4 to 0.8), much preferably, the molar ratio is 1 to (0.4 to 0.6), and especially and preferably, the molar ratio of 1to 0.5. The azacytidine methylate substance has high solubility and is soluble in water and can be used as a raw drug for azacytidine freeze-dried preparations.

Method for preparing azacitidine by high-purity and low-calcination residue

The invention relates to the field of a pharmaceutical synthesis technology, and discloses a method for synthesizing azacitidine. The method improves the quality and product purity of azacitidine, andthe reaction conditions are easy to control and reduce the production cost, and the method is suitable for industrial preparation.

A new process for deprotection of acetyl and benzoyl groups in synthesis of azacitidine

4-Amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one or azacitidine is a promising DNA demethylation inhibitor used for the treatment of myloneplastic, bone cancer and breast cancer. An efficient, cost-effective and convenient manufacturing process for the synthesis of azacitidine is described. The present research relates to the synthesis, deprotection, isolation and purification of azacitidine (1). In this process, more particularly 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is used as deprotection reagent for deprotection of O-acetyl, O-benzoyl to acquire azacitidine (1). The new process allows for the reliable and efficient production of drug substance similar overall yield. The new improved process has merits including enantiomeric purity, better crystallization and the product complies with the requirements of USP30.