TROXACITABINE троксацитабин , تروكساسيتابين , 曲沙他滨 ,

Troxacitabine

CAS 145918-75-8

• Molecular FormulaC₈H₁₁N₃O₄
• Average mass213.191 Da

Hmd-cytosine; NCGC00183848-01; Beta-L-Dioxolane-cytidine; 4-amino-1-[(2S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]pyrimidin-2-one; 2R(-)-cis-Hmd-cytosine, (-)-ODDC

4-amino-1-[(2S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]pyrimidin-2-one

Troxacitabine (brand name Troxatyl) is a nucleoside analogue with anticancer activity. Its use is being studied in patients with refractory lymphoproliferative diseases.^[1]

Troxacitabine (brand name Troxatyl) is a nucleoside analogue with anticancer activity. Its use is being studied in patients with refractory lymphoproliferative diseases.

PATENT

https://www.google.com/patents/WO1992018517A1?cl=en

WO 9218517

SYNTHESIS

WO 2016030335

PATENT

WO 2016030335

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016030335&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

PATENT

WO-2017031994

MACHINE TRANSLATED FROM CHINESE, BEAWARE OF FUNNY NAMES

Chinese Patent Application No. 201310275643.2 discloses a method for the synthesis of tricatadine, which uses a L-menthol ester of dihydroxyacetic acid as a raw material and undergoes condensation reaction with hydroxyacetaldehyde, and then the hydroxyl group is halogenated to obtain a halide , The halide is coupled with cytosine to obtain the coupling, and the conjugate is reduced to obtain tricatadine. However, the present inventors have found that the method requires a four-step reaction, such as condensation, halogenation, coupling and reduction, which is required to be carried out in different reaction systems. The steps are long and cumbersome, and in particular, the intermediate product is required to be separated and replaced Containers, and not suitable for amplification, it is not suitable for industrial production.

the present invention provides a process for the synthesis of a compound of formula III, wherein the synthesis reaction formula is as follows:

Example 1 Synthesis of tricatadine

The synthetic route is as follows:

Step 1: Preparation of Formula II

18.0 g of methylene chloride was added to the reaction kettle, and the mixture of the formula I was homogeneously added. After the temperature was lowered to 0 ± 3 ° C under the protection of nitrogen, 1.5 g of trimethyl iodosilane was slowly added; (V / v), and R _f = 0.5 at the point of disappearance). The reaction was carried out under nitrogen atmosphere for 2.5 ± 0.5 hours until the reaction was complete (sampling TLC test: developing solvent: petroleum ether: ethyl acetate = 4: 1 (v / v) Subsequently, the temperature of the autoclave was kept at 0 ± 3 ° C, and 3.64 g of hexamethyldisilazane and 1.15 g of N ⁴ -acetyl cytosine were slowly added dropwise . After the completion of the addition, the temperature of the control kettle was 0 ± 3 ℃, and the reaction was carried out under the protection of nitrogen for 3.5 ± 0.5 hours until the reaction was complete (sampling TLC test: developing agent: petroleum ether: ethyl acetate = 4: 1 (v / v), R _F = 0.2 points disappear).

Then, the temperature was maintained at 22 ± 3 ° C, and 10 %% (w / w) aqueous sodium thiosulfate solution was slowly added dropwise. After adding 5 g of aqueous sodium thiosulfate solution, 0.5 g of diatomaceous earth was added, hour. Filter, filter cake washed with methylene chloride 3 times, filter cake collection stand-by. The filtrate and the washing liquid were combined into the kettle, the aqueous phase and the organic phase were separated. The organic phase was washed once with 11.3 g of saturated brine. The organic phase was separated and dried overnight with anhydrous sodium sulfate to remove the water. Remove the sodium sulfate solid, the filtrate into the rotary evaporator, steaming temperature does not exceed 45 ℃, until the end of distillation. The residue obtained by steaming was transferred to a reaction vessel, 11.2 g of acetone and 18.5 g of isopropyl acetate were added, and the mixture was heated to reflux (68 ± 3 ° C) and stirred for 1 hour. Within 2.5 ± 0.5 hours, slowly cool down until the kettle temperature is 22 ± 3 ° C. The filter was filtered in a vacuum oven at about 40 ° C and dried overnight under vacuum to give a white solid (formula II).

The diatomaceous earth cake obtained by the above-mentioned filtration was transferred to a reaction vessel, heated to 27 ± 3 ° C, 18.0 g of methylene chloride was added, and the mixture was stirred and stirred for 2 hours. The filtrate was filtered and the filtrate was transferred to a rotary evaporator. The steaming temperature did not exceed 45 ° C until the distillation was completed. The crude solid obtained by steaming (the crude product of formula II) and the white solid used in the previous step were combined and transferred to a reaction kettle, and an isopropyl acetate: acetone = 3: 2 (v / v) mixed solvent was added (1 g of crude (13.3 g of isopropyl acetate + 7.9 g of acetone) was added and heated to reflux (68 ± 3 ° C), and the mixture was stirred for 1 hour. In 2.5 ± 0.5 hours, slow down to the kettle temperature of 22 ± 3 ℃. Quickly filter the filter cake with cold acetone 1.5g once. The filter cake was placed in a vacuum oven at about 40 ° C and dried overnight under vacuum to give the formula II.

Step 2: Preparation and purification of formula III

Take the type II boutique 1g added to the four bottles, add methanol 5.0g, stir the solid dispersed evenly. And 0.045 g of sodium methoxide was weighed, and the mixture was added to 0.135 g of methanol and stirred to dissolve sodium methoxide. The methanol solution of sodium methoxide was added dropwise to a four-necked flask. The incubation was carried out at 22.5 ± 2.5 ° C for 1 hour until the reaction was complete (sampling TLC: developing solvent: dichloromethane: methanol = 4: 1 (v / v) and R _f = 0.8).

After completion of the reaction, the pH of the system was adjusted to 6.5 ± 0.5 with ice acetic acid under ice bath. And then adding 200-300 mesh silica gel (available from Qingdao Ocean Chemical Plant) 10 g of sand, filling the column, the column chromatography, which was dichloromethane: methanol = 4: 1 (v / V), collecting the fraction containing tricatropa, and steaming to dryness. The steamed solid was transferred to a three-necked flask, 3.0 g of absolute ethanol was added, and the mixture was uniformly dispersed (suspended) and heated to 78 ± 2 ° C for 0.5 hour. After completion of the reflux, slowly (2.5 ± 0.5 hours) was cooled to room temperature and stirred at room temperature for 12 hours. Continue to cool down to 2.5 ± 2.5 ℃, at this temperature holding 4.5 ± 0.5 hours. Filter, filter cake with 1.0g cold ethanol washing once, thoroughly filter, the filtrate abandoned. The filter cake was transferred to a vacuum oven and dried at 38 ± 2 ° C until constant weight to obtain a purity of the formula III.

The above method can be equal to the proportion of stable amplification, for example, can be directly amplified about 60 to 180 times, that is, I feed 61.7g ~ 185.97g (other reactants equal ratio increase), after amplification of the final product (formula III) HPLC detection purity To 99.3% ~ 99.8%, the yield of 65 ~ 85%, fully meet the tricatitabine medicinal industrial needs.

PATENT

CN 104861067

PATENT

CN 105503838

PAPER

In vitro optimization of non-small cell lung cancer activity with troxacitabine, L-1,3-dioxolane-cytidine, prodrugs
Journal of medicinal chemistry (2007), 50, (9), 2249-53.

l-1,3-Dioxolane-cytidine, a potent anticancer agent against leukemia, has limited efficacy against solid tumors, perhaps due to its hydrophilicity. Herein, a library of prodrugs were synthesized to optimize in vitro antitumor activity against non-small cell lung cancer. N⁴-Substituted fatty acid amide prodrugs of 10−16 carbon chain length demonstrated significantly improved antitumor activity over l-1,3-dioxolane-cytidine. These in vitro results suggest that the in vivo therapeutic efficacy of l-1,3-dioxolane-cytidine against solid tumors may be improved with prodrug strategies.

PAPER

• Kim, Hea O.; Schinazi, Raymond F.; Shanmuganathan, Kirupathevy; Jeong, Lak S.; Beach, J. Warren; Nampalli, Satyanarayana; Cannon, Deborah L.; Chu, Chung K.
• From Journal of Medicinal Chemistry (1993), 36(5), 519-28.

PAPER

• Jin, Haolun; Tse, Allan Tse; Evans, Colleen A.; Mansour, Tarek S.; Beels, Christopher M.; Ravenscroft, Paul; Humber, David C.; Jones, Martin F.; Payne, Jeremy J.; Ramsay, Michael V. J.
• From Tetrahedron:  Asymmetry (1993), 4(2), 211-14

PAPER

• Belleau, Bernard R.; Evans, Colleen A.; Tse, H. L. Allan; Jin, Haolun; Dixit, Dilip M.; Mansour, Tarek S.
• From Tetrahedron Letters (1992), 33(46), 6949-52.

PAPER

http://pubs.acs.org/doi/pdf/10.1021/jm00089a007

J. Med. Chem. 1992,35,1987-1995 Asymmetric Synthesis of 1,3-Dioxolane-Pyrimidine Nucleosides and Their Anti-HIV Activity

References

Troxacitabine

Identifiers
IUPAC name[show]
CAS Number	145918-75-8
PubChem CID	151173
ChemSpider	399955
UNII	60KQZ0388Y
ChEMBL	CHEMBL359164
Chemical and physical data
Formula	C8H11N3O4
Molar mass	213.19 g/mol
3D model (Jmol)	Interactive image
SMILES[hide] O=C1/N=C(/N)\C=C/N1[C@H]2O[C@H](OC2)CO

//////////////TROXACITABINE, троксацитабин , تروكساسيتابين , 曲沙他滨 , Hmd-cytosineM,  NCGC00183848-01, Beta-L-Dioxolane-cytidine,   2R(-)-cis-Hmd-cytosine, (-)-ODDC