Thalidomide

Base Information

• Chemical Name: Thalidomide
• CAS No.: 50-35-1
• Deprecated CAS: 14088-68-7,731-40-8
• Molecular Formula: C13H10N2O4
• Molecular Weight: 258.233
• Hs Code.: 29337900
• European Community (EC) Number: 200-031-1
• NSC Number: 758479,527179,91730,91729,66847
• UN Number: 2811
• UNII: 4Z8R6ORS6L
• DSSTox Substance ID: DTXSID9022524
• Nikkaji Number: J4.101G
• Wikipedia: Thalidomide
• Wikidata: Q203174
• NCI Thesaurus Code: C870
• RXCUI: 10432
• Pharos Ligand ID: RFRZDXFY6BYS
• Metabolomics Workbench ID: 145766
• ChEMBL ID: CHEMBL468
• Mol file: 50-35-1.mol

Synonyms:Sedoval;Thalidomide;Thalomid

Chemical Property of Thalidomide

Chemical Property:

• Appearance/Colour: white solid
• Vapor Pressure: 1.65E-10mmHg at 25°C
• Melting Point: 269-271 °C
• Refractive Index: 1.646
• Boiling Point: 509.7 °C at 760 mmHg
• PKA: 10.70±0.40(Predicted)
• Flash Point: 262.1 °C
• PSA: 83.55000
• Density: 1.503 g/cm³
• LogP: 0.35450
• Storage Temp.: Store at RT
• Solubility.: 45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: 0.6 mg/mL
• Water Solubility.: <0.1 g/100 mL at 22℃
• XLogP3: 0.3
• Hydrogen Bond Donor Count: 1
• Hydrogen Bond Acceptor Count: 4
• Rotatable Bond Count: 1
• Exact Mass: 258.06405680
• Heavy Atom Count: 19
• Complexity: 449
• Transport DOT Label: Poison

Purity/Quality:

99%Min ^*data from raw suppliers

Thalidomide ^*data from reagent suppliers

Safty Information:

• Pictogram(s): T
• Hazard Codes: T
• Statements: 46-61-21-25-62-22
• Safety Statements: 53-22-26-36/37/39-45

MSDS Files:

SDS file from LookChem

Useful:

• Drug Classes: Antineoplastic Agents
• Canonical SMILES: C1CC(=O)NC(=O)C1N2C(=O)C3=CC=CC=C3C2=O
• Recent ClinicalTrials: UARK 2006-66, Total Therapy 3B: An Extension of UARK 2003-33 Total Therapy
• Recent EU Clinical Trials: A MULTICENTER, OPEN LABEL, RANDOMIZED PHASE II STUDY COMPARING DARATUMUMAB
• Recent NIPH Clinical Trials: None
• Uses: It is used as sedative and has certain efficacy in treating various types of leprosy reactions such as fever, erythema nodosum, neuralgia, joint pain, and swollen lymph nodes but has no treatment effect on leprosy. Inhibits FGF-induced angiogenesis. Inhibits replication of human immunodeficiency virus type 1. Teratogenic sedative. There is now a growing clinical interest in Thalidomide, and it is introduced as an immunomodulatory agent used primarily in combination with dexamethasone to treat multiple myeloma. Thalidomide was prescribed as an anti-nausea agent to help pregnant women with morning sickness in the late 1950s. It was found to be a potent teratogen, causing many different forms of birth defects and was withdrawn from the market. Thalidomide and synthetic analogs have recently been proven effective in treating inflammation associated with diseases such as leprosy, arthritis and Crohn’s disease, and in cancers such as multiple myeloma. The direct target for the teratogenicity of thalidomide was not discovered until 2010, when it was found that it interacts directly with the protein cereblon (CRBN; IC50 = 8.5 nM), a ubiquitously-expressed E3 ligase. Binding of thalidomide analogs to CRBN-DNA damage binding protein-1 complexes account for the immunomodulatory and antiproliferative effects of these compounds.[Cayman Chemical] Thalidomide was formerly used as a sedative-hypnotic drug. It is used in the treatmentof leprosy. Recent studies indicate that thecompound may be effective against cancer.
• Description: Thalidomide is a glutamic acid derivative first synthesized in 1953 by Swiss Pharmaceuticals; however, due to lack of pharmacological effects, the development was discontinued. In 1954, Chemie Grünenthal, a German company, undertook the development of thalidomide and, in 1957, thalidomide was marketed as an anticonvulsant for the treatment of epilepsy. Since the drug caused drowsiness, it was also marketed as a sedative. Thalidomide was considered a safe and effective drug that caused deep sleep with no hangover, and by the end of the 1950s, 14 pharmaceutical firms were marketing the drug in countries of Europe, Asia, Australia, the Americas, and Africa. However, the drug was never approved for use in the United States due to concerns about the safety of the drug raised by Frances Kelsey, MD, a drug reviewer at Food and Drug Administration (FDA). The approval process was delayed due to her repeated requests for additional safety information from William S. Merrell Company, the licensee of Chemie Grünenthal that applied to market thalidomide in the United States. Dr Kelsey’s concerns were mostly related to thalidomideinduced neuropathy. Previous research had shown that drugs that irritated nerves in adult rabbits could have adverse effects on growth and cause deformities in fetal rabbits. During this time, the use of the drug became widespread and, because it was effective in alleviating morning sickness, it became popular among pregnant women. In 1961, two physicians, William G. McBride, MD of Australia and Widulind Lenz, MD of Germany, associated the increase in malformation of the limbs (phocomelia) and other congenital abnormalities with the use of thalidomide by pregnant women. By late 1961, birth defects in more than 12 000 children were associated with thalidomide use, which forced companies to withdraw the drug worldwide. The birth defects were due to thalidomide teratogenecity: mainly phocomelia and malformation of ears, often accompanied by malformation of the internal organ. In 1965, an experimental use of thalidomide in patients with lepromatous leprosy proved to be effective in treating painful skin lesions that resulted from the inflammatory complications of leprosy. In fact, experimental use of thalidomide had been extended to a variety of diseases with various degrees of success, including refractory rheumatoid arthritis, Crohn’s disease, human immunodeficiency virus (HIV)-1 associated Kaposi’s sarcoma, cutaneous lupus, prostate cancer, and colorectal cancer. In 1998, the FDA approved Thalomid as a therapy for erythema nodosum leprosum (ENL), or leprosy. Subsequently in 2006, Thalomid in combination with dexamethasone was approved for treatment of multiple myeloma. (±)-Thalidomide is an immunomodulatory compound with diverse biological activities, including anticancer, anti-inflammatory, and teratogenic properties. It prevents polymorphonuclear leukocyte (PMN) chemotaxis when used at concentrations of 1, 10, and 100 μg/ml. (±)-Thalidomide increases IL-2-induced proliferation and IFN-γ production in primary human T cells in vitro. It enhances natural killer (NK) cell-mediated cytotoxicity in MM.1S multiple myeloma cells. Thalidomide (4 mg/animal) reduces lung IL-6, TGF-β, VEGF, angiopoietin-1, angiopoietin-2, and collagen type Iα1 expression, inhibits pulmonary angiogenesis, and attenuates fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis. It induces apoptosis in primary human embryonic fibroblasts (EC50 = 8.9 μM) and induces limb and eye defects in chicken embryos (EC50 = 50 μg/kg egg weight). Formulations containing thalidomide have been used in the treatment of multiple myeloma and erythema nodosum leprosum (ENL) in non-pregnant individuals.
• Indications: Thalidomide (Thalomid) is a derivative of glutamic acid that is chemically related to glutethimide. It exerts a number of biological effects as an immunosuppressive, antiinflammatory, and antiangiogenic agent, yet its mechanisms of action have not been fully elucidated. Thalidomide potently inhibits production of tumor necrosis factor (TNF) and interleukin (IL) 12, and its effect on these and other cytokines may account for some of its clinical effects.
• Therapeutic Function: Sedative, Hypnotic, Antiarthritic
• Clinical Use: Thalidomide is approved for use in the United States for the treatment of cutaneous manifestations of erythema nodosum leprosum, a potentially lifethreatening systemic vasculitis that occurs in some patients with leprosy.Although not approved for other indications, thalidomide has also been shown to be very effective in the management of Beh?et’s disease, HIVrelated mucosal ulceration (aphthosis), and select cases of lupus erythematosus.
• Drug interactions: Potentially hazardous interactions with other drugs Thalidomide enhances the effects of barbiturates, alcohol, chlorpromazine and reserpine. Use with caution with other drugs that can cause peripheral neuropathy.

Technology Process of Thalidomide

There total 36 articles about Thalidomide which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 95.0%

phthalic anhydride (85-44-9) + rac-α-aminoglutarimide hydrochloride (24666-56-6,2686-86-4) → thalidomide (50-35-1)

Guidance literature:

With acetic acid; triethylamine; for 3h; Temperature; Reagent/catalyst; Concentration; Reflux;

Reference yield: 91.0%

phthalic anhydride (85-44-9) + (RS)-(2,6-dioxopiperidin-3-yl)carbamic acid tert-butyl ester (31140-42-8) → thalidomide (50-35-1)

Guidance literature:

With 2,2,2-trifluoroethanol; at 150 ℃; for 2h; Reagent/catalyst; Microwave irradiation;

DOI:10.1002/cmdc.201800271

Reference yield: 91.0%

(S)-2-phthalimidoglutaramic acid (3343-29-1,2110-19-2,174591-46-9) → thalidomide (50-35-1)

Guidance literature:

With dmap; 1,1'-carbonyldiimidazole; In tetrahydrofuran; for 16h; Reflux; Inert atmosphere;

DOI:10.1021/op980201b

upstream raw materials:

acetic anhydride

2-phthalimidoglutaramic acid

urea

N-phthaloylglutamic acid anhydride

Downstream raw materials:

2-(1-benzyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

2-[1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione

Refernces

• 1、 Tang, Kai-Wei,Hsu, Wen-Li,Chen, Cheng-Ru,Tsai, Ming-Hsien,Yen, Chia-Jung,Tseng, Chih-Hua. "Discovery of triazolyl thalidomide derivatives as anti-fibrosis agents". . p. 3589 - 3599. Retrieved 2021/03/03.
• 2、 Vu, Binh Duong,Ho Ba, Ngoc Minh,Phan, Dinh Chau. "Facile Synthesis of Thalidomide". supporting information. p. 1374 - 1377. Retrieved 2019/08/12.