Cytarabine hydrochloride

Cytarabine hydrochloride is an antimetabolic agent and DNA synthesis inhibitor with IC50 of 16 nM.

Crystals (from aqueous ethanol) or fluffy white powder. (NTP, 1992)

Crystals (from aqueous ethanol) or fluffy white powder. (NTP, 1992)|Cytarabine Hydrochloride is the hydrochloride form of cytarabine, an antimetabolite analogue of cytidine with a modified sugar moiety (arabinose instead of ribose). Cytarabine is converted to the triphosphate form within the cell and then competes with cytidine for incorporation into DNA. Because the arabinose sugar sterically hinders the rotation of the molecule within DNA, DNA replication ceases, specifically during the S phase of the cell cycle. This agent also inhibits DNA polymerase, resulting in a decrease in DNA replication and repair.|A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)

Method 1. Preparation of 5'-cytidine-phosphate (5'-CMP) as raw material cytosine nucleoside hydrochloride 100g of 5'-cytidine-phosphate is suspended in 800ml of distilled water, and about 50ml of concentrated ammonia is added to adjust the pH value It is 8-9, the insoluble matter can be removed by filtration. After diluting to 1L, add 1L of lanthanum hydroxide gel, heat up to 90℃ and stir to hydrolyze (the end point of the reaction can be determined by electrophoresis analysis of lanthanum hydroxide gel during hydrolysis), When the 5'-cytidine-phosphate spots on the electrophoresis paper disappeared and cytosine spots appeared (about 25h), the reaction was over, centrifuged to obtain the supernatant, the precipitate was washed twice with 6L distilled water and centrifuged, and the washing solution Mix with the supernatant. Concentrate under reduced pressure, filter to remove insolubles during concentration, stop after concentrating to about 0.2L, cool down, adjust pH to 2.5-3 with 6mol/L hydrochloric acid, that is, white crystals will precipitate out, add 100ml 95% ethanol, cool overnight in refrigerator Filter and wash with dilute alcohol and absolute ethanol to obtain the product. Preparation of 5'-cytidine-phosphate [ammonia, lanthanum hydroxide]→[pH8-9, 90℃, 25h] cytosine nucleoside hydrochloride and cytosine arabinoside 30ml of cold distilled water, with the release of hydrochloric acid gas, after 5 minutes, put the reaction solution in an ice salt bath for 30 minutes. Add 2L of ethyl acetate and 40g of cytosine nucleoside hydrochloride, and reflux in a hot water bath at 80°C for about 40-50 minutes. The reaction solution was poured into 4L of distilled water, and ethyl acetate was evaporated under reduced pressure at 50°C. Adjust the pH of the concentrated solution to 3-3.5 with sodium hydroxide solution, add concentrated ammonia, hydrolyze at 80°C for 10 minutes, and filter to remove insoluble materials. Adjust the pH of the filtrate to 2.5-3, load it on an activated carbon column, and elute with distilled water at pH 3 and 50% ethanol-1% ammonia water at 60°C. Concentrate the eluate to about 20ml, adjust the pH to 3, and add ethanol to cool Crystallize and filter to obtain the product. Cytosine nucleoside hydrochloride [phosphorus oxychloride, ethyl acetate, water]→[0-80℃, 40-50min] 2, 2'-oxygen bridge-3', 5'-diacetyl cytosine nucleus Glycoside hydrochloride [ammonia] → [80℃, 10min] Preparation of cytarabine cytarabine hydrochloride Add 22g cytarabine cytarabine to 2% hydrochloric acid-methanol 440ml and methanol 220ml, and heat to dissolve in a water bath at 50℃. The activated carbon was decolorized for half an hour, filtered, concentrated, cooled overnight in the refrigerator, filtered to obtain a crude product, and recrystallized with 30 times methanol to obtain a pure product. Cytarabine [hydrochloric acid, methanol]→[50℃, 30min] Cytarabine hydrochloride Method 2. Preparation of D-arabinose using calcium gluconate as raw material The feed is calcium gluconate (m): iron sulfate ( m): Anhydrous barium acetate (m): water (V): hydrogen peroxide (V)=1:0.077:0.14:13:1.2-1.3. After the calcium gluconate is heated and dissolved in water, add the pre-prepared mixture of barium acetate solution and ferric sulfate solution, stir and raise the temperature to 95°C, filter to remove insolubles, and add half the amount of hydrogen peroxide to the filtrate and react at 40-56°C for 30 minutes , Let stand for 30min, then add the remaining hydrogen peroxide at 40℃ to react for 30min, add oxalic acid and filter to remove calcium oxalate, the filtrate is concentrated under 50℃ under vacuum, add anhydrous methanol to dissolve the crystals, filter to obtain crude product, methanol recrystallization to obtain pure product . Calcium gluconate [barium acetate, iron sulfate, hydrogen peroxide]→[40-56℃, 1.5 h] D-arabinose 2-amino-D-arabinose-oxazoline preparation feed ratio is D-arabinose ( m): Cyanamide (m): Ammonia (V): Methanol (V)=1:0.56:0.3-0.35:3-4. Dissolve cyanamide in methanol to make a 15%-20% solution, add D-arabinose and ammonia, slowly heat to an internal temperature of 51-62°C (about 1h) with stirring, keep it warm for 30min and then stir and leave for 2h. Leave it overnight and filter to obtain the product. D-arabinose [cyanamide, ammonia, methanol] → [57-62℃, 30min] 2-amino-D-arabinose-oxazoline cytarabine hydrochloride, the feed ratio is propynyl cyanide (m ): 2-Amino-D-arabinose-oxazoline (m): dimethylacetamide (m): ammonia (1 mol/L, V)=1:3.25:10:40-50. Mix 2-amino-D-arabinose-oxazoline and dimethylacetamide, cool to 5℃ under stirring, add dropwise a mixture of propargyl cyanide and a small amount of dimethylacetamide, control the dropping speed so that the temperature does not change When the temperature is over 10℃, after dripping, stir the reaction at 25℃ for 30min, filter, add ammonia water and stir for 10min at 60℃ for the filtrate, distill under reduced pressure below 60℃ to remove water, and adjust the pH to the concentrated solution with hydrochloric acid methanol solution (3%-5%) 4. Cool to precipitate crystals, filter to obtain crude product, refine with 20-50 times methanol, add activated carbon to decolorize, obtain cytarabine hydrochloride. 2-Amino-D-arabinose-oxazoline [propynyl cyanide, dimethylacetamide]→[25℃, 30min] cyclocytidine [ammonia, hydrochloric acid-methanol solution]→[pH4]arabinoside Acid salt.

Used for acute leukemia, also used for head and neck squamous cell carcinoma, externally for viral keratitis and epidemic conjunctivitis, etc.

Molecular Weight:279.68
Hydrogen Bond Donor Count:5
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:279.0621982
Monoisotopic Mass:279.0621982
Topological Polar Surface Area:129
Heavy Atom Count:18
Complexity:383
Defined Atom Stereocenter Count:4
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes