154361-50-9 Usage
Uses
Used in Anticancer Applications:
Capecitabine is used as an antineoplastic agent for the treatment of various types of cancer. It is particularly effective against breast cancer and colorectal cancer. The drug modulates several oncological signaling pathways, exerting inhibitory effects on tumor growth and progression. Additionally, it demonstrates synergistic anticancer effects when combined with conventional chemotherapeutic drugs, enhancing chemo-sensitivity and efficacy in resistant cases.
Used in Drug Delivery Systems:
Capecitabine is also used in the development of novel drug delivery systems to enhance its applications and efficacy against cancer cells. Various organic and metallic nanoparticles have been employed as carriers for Capecitabine delivery, aiming to improve its delivery, bioavailability, and therapeutic outcomes.
Used in Pharmaceutical Industry:
Capecitabine is used as an antiproliferative 5-fluorouracil releasing compound in the pharmaceutical industry. It is a prodrug of doxifluridine (5-FU) and is activated by a cascade of three enzymes, resulting in the selective release of 5-FU at the tumor site. This selective release offers a prolonged tumor exposure to 5-FU, making Capecitabine a more effective treatment option for various types of cancer.
Indications and Uses
Capecitabine is a new form of oral fluorinated pyrimidine drug. Capecitabine was developed by Roche Pharmaceuticals, and its commercial name is Xeloda. Capecitabine can change in vivo into 5- FU, an anti-metabolizim fluorine pyrimidine deoxynucleoside carbamate drug that targets cancer cells to inhibit cell division and disrupt RNA and protein synthesis. Its effects are significantly tied to the level of TP enzyme expression in neoplastic tissue and to DPD enzyme in vivo expression. It is suitable as further treatment for advanced primary or metastatic breast cancer patients who have not responded to paclitaxel or anthracycline antibiotics. As an anticancer drug, it is mostly used to treat advanced primary or metastatic breast cancer, as well as in treatment for non-small cell lung cancer, pancreatic cancer, bladder cancer, rectal cancer, colon cancer, gastric cancer, and other solid tumors. Many drugs such as taxanes (paclitaxel, docetaxel, mitomycin, cisplatin, etc.) can increase TP enzyme expression in neoplastic tissues and also have curative effects on gastric cancer. When used in combination with Capecitabine, these drugs can also improve Capecitabine’s anticancer abilities and produce synergistic effects.
Clinical trials
Analyses of nearly 400 randomized comparisons of clinical outcomes show that a combination of adriamycin, cisplatin or oxaliplatin with 5-FU, compared to a combination of these drugs with Capecitabine, has a two-fold difference in curative efficacy and lowers toxicty. A large-scale Chinese clinical trial of Capecitabine in combination with DDP in the treatment of stage II gastric cancer also proves its advantages of high efficacy, low toxicity, and affordability.
Drug interactions
Currently, there are no side effects of clinical significance when used in combination with antihistamines, NSAIDs, morphine, paracetamol, aspirin, antiemetic drugs, and H2 receptor antagonist drugs.
Capecitabine’s binding rate with serum protein is relatively low (64%), and its possibility of interacting through substitution with drugs that bind closely with proteins is currently unknown. In external experiments, Capecitabine has not shown any influence on human liver microsomal P450 enzyme.
If any phenytoin and coumarin derivatives anticoagulants are used in combination with Capecitabine, dosages should be lowered.
Drug interactions
Potentially hazardous interactions with other drugs
Allopurinol: avoid concomitant use.
Anticoagulants: possibly enhances effect of
coumarins.
Antiepileptics: reported toxicity with fosphenytoin
and phenytoin, due to increased phenytoin levels.
Antipsychotics: avoid with clozapine - increased risk
of agranulocytosis.
Folic acid: toxicity of capecitabine increased - avoid.
Adverse effects
Common adverse reactions include nausea, vomiting, oral ulcers, abdominal pain, diarrhea, loss of appetite, and skin changes. There have also been reports of some patients experiencing transient myelosuppression, hair loss, tears, headache, and dizziness.
Warnings and precautions
Capecitabine is a bone marrow inhibitor; a blood exam must be administered before every usage to monitor blood cell and platelet count.
This product poses toxic side effects to the liver, so liver functions must be routinely examined. Additionally, heart functions should also be monitored to prevent irreversible toxic reactions. If venous transfusion of the drug is required, the aforementioned organ functions should be tested for suitability before administration. Capecitabine may cause damage to embryos, thus making it unsuitable for pregnant women. Women using this drug are also not suitable for pregnancy. Even after treatment is ended, this drug may have some impact on fertility.
Originator
Roche (Switzerland)
Manufacturing Process
5-Deoxy-5-fluoro-N4-((n-pentyloxy)carbonyl)cytidine may be prepared
according to US Patent No. 6,114,520.From 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluorocytidine and n-pentylchloroformate in dichloromethane and pyridine may be obtained 2',3'-
bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluoro-N4-((pentyloxy)carbonyl)
cytidine.From 2',3'-bis-O-(tert-butyldimethylsilyl)-5'-deoxy-5-fluoro-N4-
((pentyloxy)carbonyl)cytidineand tetrabutylammonium fluoride in
tetrahydrofuran at room temperature for 2 hours may be prepared the
product which by hydrolyses may be converted to 5-deoxy-5-fluoro-N4-
((pentyloxy)carbonyl)cytidine. Purification of the product may be carried out
by silica gel chromatography (using dichloromethane:methanol = 20:1 as an
eluent).
Therapeutic Function
Antitumor
Biochem/physiol Actions
Capecitabine is an anti-cancer drug, a prodrug of doxifluridine, metabolized to 5-fluorouracil at the tumor site. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5′-Deoxy-5-fluorocytidine (5′-DFCR) and 5′-Deoxy-5-fluorouridine (5′-DFUR), to form 5-fluorouracil.
Clinical Use
Capecitabine is indicated for use as first-line therapy in patients with colorectal cancer. It also is used alone or in combination with docetaxel in patients with metastatic breast cancer who have experienced disease progression or recurrence after anthracycline therapy. Given b.i.d. in tablet form, the total daily dose is calculated based on patient body surface area and is taken 30 minutes after eating to avoid food-induced decreases in absorption. In addition to bone marrow suppression, nausea, and vomiting, the drug can induce severe diarrhea and a potentially disabling disorder termed “hand-and-foot syndrome” (palmar-plantar erythrodysethesia). Capecitabine inhibits CYP2C9 and, along with competition for serum protein binding sites, results in clinically significant drug–drug interactions with both warfarin and phenytoin.
in vitro
in antiproliferative assays, both ls174t wt and ls174t-c2 cells were more sensitive to capecitabine when cultivated in the same plates as hepg2 hepatoma. in ls174t wt alone and cultivated with hepg2, ic50values of capecitabine were 890 ± 48 and 630 ± 14 μm respectively. the ic50fell from 330 ± 4 down to 89 ± 6 μmin ls174t-c2 subline when cultivated in the same plates as hepatoma cells.in the ls174t-c2 subclone, whereas little cell death occurred in cells exposed to capecitabine, both early and late apoptosis were increased by 244 and 262%, respectively [1]. furthermore, capecitabine induces apoptosis in a fas-dependent manner, and shows a 7-fold higher cytotoxicity and markedly stronger apoptotic potential in thymidine phosphorylase (tp)-transfected ls174t-c2 cells [2].
in vivo
capecitabine was effective in a wider dose range in cxf280, hct116, colo205, and widr human colon cancer xenograft models [2]. in highly metastatic nude mice model, capecitabine inhibited tumor growth and metastatic recurrence after resection of hcc attributed to the high expression of pd-ecgf in tumors [3].
Metabolism
Although capecitabine is a carbamylated analogue of cytidine , the drug actually is another 5-fluoro-dUMP prodrug. Given orally, it is extensively metabolized to fluorouracil, which is then converted to the active fluorinated deoxyribonucleotide as previously described. Thymidine phosphorylase, an enzyme involved in this biotransformation, is much more active in tumors than in normal tissue, which improves the tumor-selective generation of fluorouracil. Levels of active drug in the tumor can be up to 3.5-fold higher than in surrounding tissue, leading to a lower incidence of side effects compared to fluorouracil therapy. Because capecitabine is biotransformed to fluorouracil, it follows the same catabolic and elimination pathways reported for 5-fluorouracil.
references
[1]. ishikawa t, utoh m, sawada n, et al. tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts[j]. biochemical pharmacology, 1998, 55(7): 1091-1097.[2]. ishikawa t, utoh m, sawada n, et al. tumor selective delivery of 5-fluorouracil by capecitabine, a new oral fluoropyrimidine carbamate, in human cancer xenografts[j]. biochemical pharmacology, 1998, 55(7): 1091-1097.[3]. zhou j, tang z y, fan j, et al. capecitabine inhibits postoperative recurrence and metastasis after liver cancer resection in nude mice with relation to the expression of platelet-derived endothelial cell growth factor[j]. clinical cancer research, 2003, 9(16): 6030-6037.
Check Digit Verification of cas no
The CAS Registry Mumber 154361-50-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,4,3,6 and 1 respectively; the second part has 2 digits, 5 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 154361-50:
(8*1)+(7*5)+(6*4)+(5*3)+(4*6)+(3*1)+(2*5)+(1*0)=119
119 % 10 = 9
So 154361-50-9 is a valid CAS Registry Number.
InChI:InChI=1/C9H12FN3O4/c1-3-5(14)6(15)8(17-3)13-2-4(10)7(11)12-9(13)16/h2-3,5-6,8,14-15H,1H3,(H2,11,12,16)/t3-,5-,6-,8-/m1/s1
154361-50-9Relevant articles and documents
Synthesis of the antitumoral nucleoside capecitabine through a chemo-enzymatic approach
Ciceri, Samuele,Ciuffreda, Pierangela,Grisenti, Paride,Ferraboschi, Patrizia
, p. 5909 - 5913 (2015)
Capecitabine is a 5′-deoxynucleoside endowed with antitumoral activity. We planned a new approach to its synthesis: a cross linked enzyme aggregate subtilisin (Alcalase CLEA)-catalyzed alcoholysis allowed the selective deprotection of primary acetyl ester of the N1-(2′,3′,5′-tri-O-acetyl-β-d-ribofuranosyl)-5-fluoro-N4-(n-pentyloxycarbonyl)cytosine affording the corresponding 5′-hydroxyderivative; the 5′-alcohol was transformed into the methyl group of capecitabine after a careful investigation about the best reducing agent and reaction conditions.
Continuous-Flow Sequential Schotten-Baumann Carbamoylation and Acetate Hydrolysis in the Synthesis of Capecitabine
Miranda, Leandro S. De M.,De Souza, Rodrigo O. M. A.,Lea?, Raquel A. C.,Carneiro, Paula F.,Pedraza, Sergio F.,De Carvalho, Otavio V.,De Souza, Stefania P.,Neves, Rebeca V.
, p. 2516 - 2520 (2019)
Capecitabine is an important anticancer drug whose synthesis comprises late-stage carbamoylation and ester hydrolysis. Herein we report the use of the Schotten-Baumann reaction in order to perform these transformation in one pot both in batch and under continuous flow. In batch, capecitabine was obtained in 82% yield in 5 h, while under continuous flow it was obtained in 81% yield in 30 min. This one-pot reaction reduces the chemical waste produced, labor, time, and cost and additionally comprises the use of environmentally friendly solvents and reagents as well as energy-efficient and safe methods, all of which fulfill the requirements of a green process.
Preparation of capecitabine intermediate
-
Paragraph 0025-0028, (2021/09/01)
The invention belongs to the field of medicine synthesis, and provides a preparation method of capecitabine intermediate, in particular to a compound of the formula I II in the presence of a ketone solvent and an organic base.
Cytidine derivative and method for preparing capecitabine medicines through derivative
-
Paragraph 0065-0069, (2020/05/14)
The invention discloses a 5-deoxy-D-ribofuranose 1-[2-(1-styyl) benzoate] derivative as shown in a general formula (I) and a preparation method of the derivative, and a method for preparing a N4-deoxycarbonyl cytidine derivative and antitumor medicines namely capecitabine by using the general formula (I) as a raw material, wherein the structure of the general formula (I) is as shown in the description. The 5-deoxy-D-ribofuranose 1-[2-(1-styyl) benzoate] derivative as the raw material of a reaction is used as a glycosyl donor and can be activated under the condition of Lewis acid trimethylsilyl trifluoromethanesulfonate and N-lodosuccinimide in catalysis quantity, so that Lewis acid in traditional use equivalent or excessive quantity is avoided, and a reaction system is mild, free from occurrence of other side reactions and efficient.
A capecitabine synthetic method
-
Paragraph 0020; 0023; 0026; 0027; 0029, (2018/06/21)
The invention belongs to the technical field of medicine preparation and relates to a synthetic method of capecitabine. The method comprises the following steps: 1) condensation reaction: reacting 2', 3'-bi-O-acetyl-5'-deoxy-5-fluoro-cytidine with halo n-amyl formate in the presence of an acid applying agent and a dimethylamino-pyridine catalyst to prepare N-pentyloxy carbonyl-2' 3'-bi-O-actyl-5'-deoxy-5-fluoro-cytidine; and 2) hydrolysis reaction: carrying out hydrolysis reaction on N-pentyloxy carbonyl-2' 3'-bi-O-actyl-5'-deoxy-5-fluoro-cytidine in the presence of an inorganic base to prepare the final product capecitabine. Compared with the prior art, the method provided by the invention has the advantages that by taking the inorganic base as the acid applying agent, use of a lot of organic bases is avoided and therefore the yield is improved, the production cost lowered, the environmental pollution is reduced, the physical health of the worker is ensured, and industrial production is facilitated.
A capecitabine synthetic method
-
, (2017/07/14)
The invention discloses a synthesis method for capecitabine. The method comprises the following five steps of (1) carrying out reaction on D-ribose and acetic anhydride so as to prepare a compound V; (2) carrying out reaction on the compound V and 5-FC so as to prepare a compound IV; (3) hydrolyzing the compound IV so as to prepare a compound III; (4) hydroxylating the compound III so as to prepare a compound II; and (5) deprotecting so as to prepare the capecitabine (a compound I) finally. The synthesis method has simple operation steps and mild reaction conditions, is easy to extract and separate the product, has high yield, greatly lowers the production cost, and is beneficial to industrial production.
Method for preparing capecitabine from capecitabine waste water extract
-
Paragraph 0039; 0044; 0045, (2017/07/20)
The invention discloses a method for preparing capecitabine from capecitabine waste water extract. The method comprises the following steps: extracting 5'-deoxy-5-gemcitabine from capecitabine waste water, introducing isopropylidene at hydroxy of a saccharide structure part of a compound for protection, further introducing acryl at an amino group, and eliminating the isopropylidene protection from the saccharide structure part to obtain capecitabine. By adopting the method, not only is the waste water harmlessly treated, but also the reutilization of impurities in the waste water is realized, the production cost is decreased, the operation is convenient, raw materials needed for preparation are easy to obtain, and the industrialized production is facilitated (shown in the description).
For a continuously operated synthetic capecitabine method
-
Paragraph 0025-0026, (2017/08/31)
The invention discloses a method for synthesizing capecitabine by continuous operations. The method comprises the following steps: acylating 5'-deoxy-2', 3'-2-O-acetyl-5-gemcitabine to obtain 5'-deoxy-2',3'-2-O-acetyl-N-[(pentyl acetal) carbonyl]-5-fluorine cytidine methylene chloride solution; then directly adding an alkaline aqueous solution; adding alcohol, and hydrolyzing and synthesizing capecitabine. The method disclosed by the invention is short in reaction time to more than ten minutes, fewer in treatment steps, simple to operate, low in cost and small in pollution.
Preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine
-
, (2017/08/28)
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine; the method comprises: reacting a compound of formula IV as a raw material with n-amyl chloroformate under the action of K3PO4 to obtain the compound of formula V, 2',3'-bis-O-acetyl-5'-deoxy-5-fluorine-N4-[(pentyloxy)carbonyl]cytidine. The invention also provides application of the method in the preparation of capecitabine. The preparation method has the advantages that reaction yield can be significantly increased, product purity is high, reaction conditions are mild, the use of pyridine is avoided, pyridine residue in the product is avoided, and the method is suitable for industrial production of medicine.
Capecitabine and wherein the intermediate preparation method
-
, (2017/02/09)
The invention discloses a preparation method of capecitabine. The method comprises the following steps: based on D-ribose serving as a starting raw material, carrying out hydroxyl protection, 5-site tosylation, iodine substitution, hypophosphorous acid deiodination and acetylation so as to obtain the key intermediate 12,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose; carrying out glycosylation on the key intermediate and 5-fluorocytosine; and finally, carrying out N-4 site acylation and deprotection so as to obtain the capecitabine. In the method, a metal catalyst dose not need to be used for participating in reaction, the reaction condition is mild, and the yield is high, thus the method is economical and effective as well as suitable for industrial production on a large scale.
