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85622-93-1 Usage

Description

Temozolomide is an oral alkylating agent and antitumor drug, which is a 3-methyl analog of mitozolomide and is converted to cytotoxic triazene MTIC. It is a prodrug for MTIC, formed by spontaneous hydrolysis in the body, and is used for the treatment of newly diagnosed malignant glioblastoma multiforme (concomitantly with radiotherapy) and malignant melanoma. It is a potent inhibitor of the enzyme O6-alkylguanine-DNA alkyltransferase (OGAT) involved in DNA repair activity.
Used in Antineoplastic Applications:
Temozolomide is used as an antineoplastic agent for its potent activity in the treatment of recurrent gliomas or glioblastoma, a type of tumor that affects the brain or spine. It is effective against paclitaxel-resistant tumors and induces apoptosis, causing arrest at the G2/M cell cycle checkpoint.
Used in Cancer Research:
Temozolomide is used for analyzing drug resistance mechanisms in glioblastoma cell lines, aiding in the understanding of cancer resistance and the development of more effective treatments.
Used in Oncology:
Temozolomide is used as an imidazotetrazine alkylating agent in the treatment of malignant gliomas, such as relapsed anaplastic astrocytoma and advanced metastatic melanoma. It has been approved for further applications in oncology.
Used in Pharmaceutical Industry:
Temozolomide is used as an active pharmaceutical ingredient in the development of cancer treatments, specifically for brain tumors and melanoma. It is marketed under the brand names Temodar (Schering) and Temodal.
Chemical Properties:
Temozolomide is an off-white to light-pink crystalline solid, with a melting point of 212 °C (decomposition) and a UV maximal absorption wavelength of 327 nm in 95% ethanol. It can be crystallized from dichloromethane.

Anticancer drugs

Temozolomide is the first effective orally-taken imidazole and tetrazine-class anticancer drug which belongs to the second generation of an alkylating agent with antitumor activity without liver metabolic activation after oral administration. It is characterized by easily penetration through the blood-brain barrier, good tolerance and being not superimposed with other drugs toxicity, and having synergistic effect with radiotherapy which is suitable for treating malignant glioma recurrence after conventional treatment such as glioblastoma multiforme tumors or degenerative astrocytoma. It is first-line drug for treatment of metastatic melanoma. Temozolomide had been first synthesized by Cancer Research UK Group, and then be transferred to the Schering-Plough Company (United States) for development. The drug is different from the existing Antineoplastic drug. It has a novel chemical structure and belongs to a four-imidazole derivative. Temozolomide does not play a direct role. At physiological pH, it is first quickly converted into active compound MTIC [5-(3-methyl-triazene-1-) imidazole-4-carboxamide] via non-enzymatically way. People think that the cytotoxicity of MTIC is mainly due to its DNA alkylation (methylation) effect. Alkylation mainly occurs in the O6 and N7 position of guanine. Basic and clinical studies of temozolomide have confirmed that it is effective in treating some of the most common glioma cells. In 1999, it has been approved for enter into market in EU and the US wherein the permitted indication in United States is mainly for second-line treatment of glioblastoma multiforme and degenerative star gliomas and approved indications of EU is for treating developing or relapsing glioblastoma multiforme which has already been subject to conventional therapy. The efficacy of temozolomide on treating glioblastoma multiforme has received more recognition in Europe.

Pharmacokinetics

This medicine can be completely oral absorbed and has a nearly 100% availability. It can exhibit a broad spectrum of activity in murine tumor model systems and can penetrate through the human blood-brain barrier. The toxic effects of temozolomide cells originate from its role in strong methylation of DNA bases. Under alkaline conditions, temozolomide can quickly be broken for formation of active methyl diazonium ion. Since the brain has a higher basicity than the surrounding tissue, so that the activation of this drug can relatively concentrate and occur at the tumor site. It has a strong anti-tumor effect with certain selectivity with its side-effect profile being alleviated, small bone marrow toxicity and improved patient tolerance.

Toxicological effects

Genetic Toxicity: Temozolomide has in vitro mutagenesis effect on bacteria (Ames test), and can cause the collapse of mammalian cell chromosomes (human peripheral blood lymphocytes clear test). Reproductive toxicity: There currently have been no reproductive toxicity performed for temozolomide, but the toxicity study of repeated medication test of rat and dog have shown that when the administered doses of 50mg/m2 and 125mg/m2, for rat and dog, respectively (calculated by body surface area, equivalent to approximately 1/4 and 5/8 of maximum recommended dosage, respectively), this product is toxic to animal testicles exhibited as syncytial cells (i.e. immature sperm) occurs and testicular atrophy. Carcinogenicity: There have been no conventional carcinogenicity studies about temozolomide yet. Giving 125 mg/m2 of temozolomide to rats in a cycle of 5 consecutive days per 28 days to (according to calculation of body surface area, it is comparable to the maximum recommended daily amount for human) for three cycles can produce breast cancer for both male and female rats. According to calculation of 25, 50, 125mg/m2 (according to the calculation of body surface area, it is roughly equivalent to 1/8 to 1/2 of the maximum recommended dosage) after administration of 6 cycles, the animals in all the dose group got breast cancer: at high-dose group, fibrosarcoma occurs in the heart, eyes, seminal vesicles, salivary glands, abdomen, uterus and prostate tissue. It is also appeared in seminal vesicle cancer, heart, nerve sheath tumors, optic nerve cancer, and Bernhard's adenocarcinoma. Moreover, adenoid tumor also occurs in other visible tissues such as animal skin, lung, pituitary, and thyroid.

The treatment of recurrent glioblastoma multiforme tumor

The treatment of Temozolomide for recurrent glioblastoma multiforme trials have confirmed upon clinical assays to be safe and effective. A randomized controlled trial in phase II have showed that 225 cases of glioblastoma multiforme patients suffering the first reoccurrence of pleomorphic glioblastoma who have been treated by temozolomide or procarbazine (every 56 days once every 28 d, oral administration of 125~150 mg/m2 per day) for 6 months, respectively, the temozolomide group of patients have got no disease deterioration with survival and overall survival rate being 21% and 60%, respectively. This was significantly higher than that in procarbazine group (8% and 44%). The average survival time and overall survival time for patients in the temozolomide group with no disease progression was 2.9 and 7.3 months, respectively, which were significantly higher than that in procarbazine group that was 1.9 and 5.8 months, respectively. The Experimental have also evaluated the health-related quality of life in both the first 3 months and 6 months after the starting of the treatment, the results also have confirmed that temozolomide group had more patients with quality of life being improved or remaining stable. The main side effect for temozolomide is transient and non-retention bone marrow suppression which is both predictable and easy to handle with a trials incidence of 24%. Temozolomide is also prone to cause moderate nausea and vomiting in patients, however these adverse reactions can be prevented with conventional antiemetic therapy. The efficacy of temozolomide for treating recurrent glioblastoma multiforme efficacy and its property of adverse reaction were significantly better than the existing standard drug procarbazine.

Clinical evaluation

Temozolomide is effective in treating newly diagnosed glioblastoma multiforme cell tumor. A small II trial results has shown that 33 cases of such patients who had been subject to temozolomide (200mg/m2) treatment where 17 patients had achieved complete or partial remission, and other four patients were in stable condition. The average time from the disease remission to disease progression for 17 patients was seven months, and was two months for the treatment of non-responders with their average survival time being 12 months and 6 months. But the effect of temozolomide in treating newly diagnosed degenerative astrocytomas remains unclear. Temozolomide is of high efficacy on glioma cells, especially has a significant effect on the most common pleomorphic glioblastoma. No matter in tumor response rates, or in patient survival and tolerability it all has a good effect. More importantly, the quality of patients’ life is significantly better than the existing standard drug procarbazine, moving a big step toward the treatment of tumors using this kind of drug. The first-line position of Temozolomide in treatment of progressive metastatic melanoma has been affirmed in clinical assays. Applications for applying it widely in Europe and the United States are being conducted. A recent randomized controlled trial results in III phase have shown about the 305 cases of these patients who subjected to temozolomide (200 mg/m2) and dacarbazine (every 21 days once a 5d, 250 mg/m2 per day) treatment, temozolomide group of patients had a overall survival and treatment response rates of 7.9 months and 13.5%, respectively, which was better than that of 5.7 months and 12.1% as observed in dacarbazine group. Patients in Temozolomide group had a better tolerance than dacarbazine group with its life-qualify evaluation (reflected by reduced physiological function) also significantly better than dacarbazine group (the rate of decline was 18% and 42% after three months of treatment, respectively). Melanoma skin tumors are rare skin cancer, even though it accounts for only about 4% of all skin cancers, but the mortality rate accounted for about 79% of all skin cancer. The current standard drug for treating it is still dacarbazine. Temozolomide has exhibited high clinical efficacy towards glial cells and melanoma, and thus is worthy of attention. The above information is edited by the lookchem of Dai Xiongfeng.

Patent No

DE 3237255; US 5260921

Production methods

Amino-4-carboxamido-imidazole is first subject to nitrite diazotization, and has reaction with methyl isocyanate in dichloromethane for cyclization to obtain ammonium temozolomide.

Originator

CRC Technology (UK)

Manufacturing Process

Reaction of 1H-imidazole-4-carboxilic acid amide with nitrous acid leads to the diazonium salt (5-diazenyl-1-H-imidazole-4-carboxilic acid amide). Condensation of the diazonium salt with methylisocyanate leads to initial formation of unstable urea which cyclizes under the reaction condition to give 3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide (temozolomide).

Therapeutic Function

Antineoplastic

Biological Activity

DNA methylating, chemotherapeutic agent. Displays antitumor activity against a board spectrum of tumors, including leukemias, lymphomas and solid tumors (IC 50 = 5.0 μ M for cytotoxicity against mouse TLX5 lymphoma cells).

Biochem/physiol Actions

Temozolomide is a DNA methylating agent and drug resistance-modifying agent; anti-tumor and anti-angiogenic. Temozolomide induces G2/M arrest and apoptosis through adduction of a methyl group to O6 position of guanine in genomic DNA and functional inactivation of DNA repair protein O(6)-alkylguanine DNA alkyltransferase (AGT) in base excision repair (BER) pathway.

Clinical Use

This imidazolotetrazine derivative is administered orally in capsule form for the treatment of glioblastoma multiforme or in patients with anaplastic astrocytoma who have not responded to procarbazine or the nitrosoureas.

Metabolism

Oral absorption is rapid and complete. The CYP450 enzymes are not extensively involved in temozolomide metabolism, and less than 6% of the drug is excreted unchanged in the urine. Women clear the drug less effectively than men and have a higher incidence of severe neutropenia and thrombocytopenia in the initial therapy cycle. Food decreases temozolomide absorption, and myelosuppression is the most significant adverse effect.

References

1) Kurzen et al. (2003), Inhibition of angiogenesis by non-toxic doses of temozolomide; Anticancer Drugs, 14 515 2) Gunther et al. (2003), Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids; Br. J. Cancer, 88 463 3) Danson et al. (2001), Temozolomide: a novel oral alkylating agent; Curr. Opin. Expert Rev. Anticancer Ther., 10 13 4) Natsumeda et al. (2011), Induction of autophagy in temozolomide treated malignant gliomas; Neuropathology, 31 486

Check Digit Verification of cas no

The CAS Registry Mumber 85622-93-1 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 8,5,6,2 and 2 respectively; the second part has 2 digits, 9 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 85622-93:
(7*8)+(6*5)+(5*6)+(4*2)+(3*2)+(2*9)+(1*3)=151
151 % 10 = 1
So 85622-93-1 is a valid CAS Registry Number.
InChI:InChI=1/C6H6N6O2/c1-11-6(14)12-2-8-3(4(7)13)5(12)9-10-11/h2H,1H3,(H2,7,13)

85622-93-1 Well-known Company Product Price

  • Brand
  • (Code)Product description
  • CAS number
  • Packaging
  • Price
  • Detail
  • TCI America

  • (T2744)  Temozolomide  >98.0%(HPLC)

  • 85622-93-1

  • 500mg

  • 990.00CNY

  • Detail
  • TCI America

  • (T2744)  Temozolomide  >98.0%(HPLC)

  • 85622-93-1

  • 5g

  • 3,990.00CNY

  • Detail
  • Sigma-Aldrich

  • (PHR1437)    pharmaceutical secondary standard; traceable to USP

  • 85622-93-1

  • PHR1437-1G

  • 1,293.67CNY

  • Detail
  • Sigma

  • (T2577)  Temozolomide  ≥98% (HPLC)

  • 85622-93-1

  • T2577-25MG

  • 1,855.62CNY

  • Detail
  • Sigma

  • (T2577)  Temozolomide  ≥98% (HPLC)

  • 85622-93-1

  • T2577-100MG

  • 4,722.12CNY

  • Detail
  • USP

  • (1643543)  Temozolomide  United States Pharmacopeia (USP) Reference Standard

  • 85622-93-1

  • 1643543-200MG

  • 10,869.30CNY

  • Detail

85622-93-1SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 12, 2017

Revision Date: Aug 12, 2017

1.Identification

1.1 GHS Product identifier

Product name Temozolomide

1.2 Other means of identification

Product number -
Other names temodar

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:85622-93-1 SDS

85622-93-1Synthetic route

methyl isocyanate
624-83-9

methyl isocyanate

5-diazoimidazole-4-carboxamide
7008-85-7

5-diazoimidazole-4-carboxamide

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
In dichloromethane at 25℃; for 480h;98%
In 1,4-dioxane at 50℃;76.5%
In dimethyl sulfoxide at 25℃;
ethyl 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylate

ethyl 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylate

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
With ammonium hydroxide; copper(II) sulfate at 100℃; for 6h; Reagent/catalyst; Temperature;92%
8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one hydrochloride

8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one hydrochloride

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
With Lewatit Mono Plus MP-64 In acetone at 60 - 63℃; styrene-divinylbenzene (macroporous); Purification / work up;90.3%
With acetic acid In water; acetone for 0.166667h; Purification / work up; Heating / reflux;88%
With acetic acid In water; acetonitrile at 60 - 63℃; for 0.166667h; Purification / work up;86.7%
With acetic acid In tetrahydrofuran; water for 0.166667h; Purification / work up; Heating / reflux;70%
5-{3-methyl-3-[(phenyloxy)carbonyl]triazen-1-yl}imidazole-4-carboxamide

5-{3-methyl-3-[(phenyloxy)carbonyl]triazen-1-yl}imidazole-4-carboxamide

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
In methanol; acetone at 20℃; for 1h; UV-irradiation;79%
8-carbamoyl-3-trimethylsilylmethylimidazo<5,1-d>-1,2,3,5-tetrazin-4(3H)-one

8-carbamoyl-3-trimethylsilylmethylimidazo<5,1-d>-1,2,3,5-tetrazin-4(3H)-one

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
With tetrabutyl ammonium fluoride In acetic acid; acetonitrile at 25℃; for 24h;78%
With tetrabutyl ammonium fluoride; acetic acid In acetonitrile at 25℃;78%
5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide
188612-53-5

5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Stage #1: 5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide With lithium chloride hydrate; acetic acid In water at 20℃; for 0.5h;
Stage #2: With iodine; sodium nitrite In water at -10 - 20℃; for 3h;
76%
Stage #1: 5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide With acetic acid; lithium bromide In water at 20℃; for 1h;
Stage #2: With sodium nitrite In water at -10 - 20℃; for 6h;
Stage #3: With sodium thiosulfate In water for 0.333333h; Product distribution / selectivity;
64%
Stage #1: 5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide With sodium nitrite In water at 0℃; for 0.333333h;
Stage #2: With tartaric acid In water at 0 - 60℃; for 4h;
47%
N-tert-butyl-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide
442534-20-5

N-tert-butyl-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
With sulfuric acid at 15 - 20℃; for 3h;52%
5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide
188612-53-5

5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide

A

temozolomide
85622-93-1

temozolomide

B

2-Azahypoxanthine
4656-86-4

2-Azahypoxanthine

Conditions
ConditionsYield
With hydrogenchloride; sodium nitrite at 5 - 25℃;A 35%
B 15%
3-N-hydroxymethyl temozolomide
1161825-88-2

3-N-hydroxymethyl temozolomide

methyl iodide
74-88-4

methyl iodide

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile22%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 25℃;22%
(8-Carbamoyl-4-oxo-imidazo[5,1-d][1,2,3,5]tetrazin-3-yl)-acetic acid 2-thioxo-2H-pyridin-1-yl ester
157467-00-0

(8-Carbamoyl-4-oxo-imidazo[5,1-d][1,2,3,5]tetrazin-3-yl)-acetic acid 2-thioxo-2H-pyridin-1-yl ester

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In N,N-dimethyl-formamide at 25℃; Irradiation; Yield given;
With 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride In N,N-dimethyl-formamide for 0.5h; Ambient temperature; Irradiation; Yield given;
dimethyl sulfate
77-78-1

dimethyl sulfate

4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide

4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
With triethylamine In dimethyl sulfoxide at 25℃; Yield given;
5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide
188612-53-5

5-amino-N1-methyl-1H-imidazole-1,4-dicarboxamide

A

temozolomide
85622-93-1

temozolomide

B

9-(N-methylcarbamoyl)-2-azahypoxanthine

9-(N-methylcarbamoyl)-2-azahypoxanthine

Conditions
ConditionsYield
With tartaric acid; sodium nitrite In water at 0℃; for 1h;A 45 % Chromat.
B n/a
5-{3-methyl-3-[(phenyloxy)carbonyl]triazen-1-yl}imidazole-4-carbonitrile

5-{3-methyl-3-[(phenyloxy)carbonyl]triazen-1-yl}imidazole-4-carbonitrile

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 74 percent / aq. HCl / acetic acid / 0.42 h / Heating
2: 79 percent / acetone; methanol / 1 h / 20 °C / UV-irradiation
View Scheme
C17H18N6O3
1025840-09-8

C17H18N6O3

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 2.05 g / TFA / acetic acid; methanol / 5 h / 20 °C
2: 74 percent / aq. HCl / acetic acid / 0.42 h / Heating
3: 79 percent / acetone; methanol / 1 h / 20 °C / UV-irradiation
View Scheme
5-Amino-4-carbamoyl-imidazole-1-carboxylic acid 4-nitro-phenyl ester
196806-10-7

5-Amino-4-carbamoyl-imidazole-1-carboxylic acid 4-nitro-phenyl ester

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 48 percent / tetrahydrofuran; ethanol / 25 °C
2: 45 percent Chromat. / NaNO2, tartaric acid / H2O / 1 h / 0 °C
View Scheme
8-carbamoyl-3,4-dihydro-4-oxoimidazo<5,1-d>-1,2,3,5-tetrazin-3-ylacetic acid
157466-98-3

8-carbamoyl-3,4-dihydro-4-oxoimidazo<5,1-d>-1,2,3,5-tetrazin-3-ylacetic acid

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: N-methylmorpholine / dimethylformamide / 0.17 h / -15 - -10 °C
2: Et3N / dimethylformamide / 0.5 h / -15 - -10 °C
3: AIBN, Bu3SnH / dimethylformamide / 0.5 h / Ambient temperature; Irradiation
View Scheme
Multi-step reaction with 3 steps
1: N-methylmorpholine / dimethylformamide / -15 °C
2: Et3N / -15 °C
3: Bu3SnH, AIBN / dimethylformamide / 25 °C / Irradiation
View Scheme
ethyl (8-carbamoyl-3,4-dihydro-4-oxoimidazo<5,1-d>-1,2,3,5-tetrazin-3-yl)acetate
157466-97-2

ethyl (8-carbamoyl-3,4-dihydro-4-oxoimidazo<5,1-d>-1,2,3,5-tetrazin-3-yl)acetate

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: 80 percent / aq. HCl / 4 h / 40 - 45 °C
2: N-methylmorpholine / dimethylformamide / 0.17 h / -15 - -10 °C
3: Et3N / dimethylformamide / 0.5 h / -15 - -10 °C
4: AIBN, Bu3SnH / dimethylformamide / 0.5 h / Ambient temperature; Irradiation
View Scheme
Multi-step reaction with 4 steps
1: 80 percent / 5M aq. HCl / 45 °C
2: N-methylmorpholine / dimethylformamide / -15 °C
3: Et3N / -15 °C
4: Bu3SnH, AIBN / dimethylformamide / 25 °C / Irradiation
View Scheme
C12H14N6O6
157466-99-4

C12H14N6O6

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: Et3N / dimethylformamide / 0.5 h / -15 - -10 °C
2: AIBN, Bu3SnH / dimethylformamide / 0.5 h / Ambient temperature; Irradiation
View Scheme
Multi-step reaction with 2 steps
1: Et3N / -15 °C
2: Bu3SnH, AIBN / dimethylformamide / 25 °C / Irradiation
View Scheme
[(5-Amino-4-carbamoyl-imidazole-1-carbonyl)-amino]-acetic acid ethyl ester
157466-96-1

[(5-Amino-4-carbamoyl-imidazole-1-carbonyl)-amino]-acetic acid ethyl ester

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: 93 percent / 2N aq. NCl, NaNO2 / 0 °C
2: 80 percent / 5M aq. HCl / 45 °C
3: N-methylmorpholine / dimethylformamide / -15 °C
4: Et3N / -15 °C
5: Bu3SnH, AIBN / dimethylformamide / 25 °C / Irradiation
View Scheme
5-amino-1H-imidazole-4-carboxamide monohydrochloride
72-40-2

5-amino-1H-imidazole-4-carboxamide monohydrochloride

4-Nitrophenyl chloroformate
7693-46-1

4-Nitrophenyl chloroformate

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
With triethylamine In dichloromethane
4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide

4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide

methyl iodide
74-88-4

methyl iodide

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Stage #1: 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.05h;
Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2.5h;
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 5h;
5-diazoimidazole-4-carboxiamide
865071-35-8

5-diazoimidazole-4-carboxiamide

methyl isocyanate
624-83-9

methyl isocyanate

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
In N,N-dimethyl-formamide at 20℃; for 72h; Industry scale;
tert-butyl (8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)methylcarbamate
1332700-58-9

tert-butyl (8-carbamoyl-4-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)methylcarbamate

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: hydrogenchloride / water / 15 h / 4 - 20 °C / Darkness
2: sodium hydride / N,N-dimethyl-formamide / 5 h / 0 - 20 °C
View Scheme
8-carbamoyl-3-(2-trimethylsilylethoxy)methylimidazo<5,1-d>-1,2,3,5-tetrazin-4(3H)-one

8-carbamoyl-3-(2-trimethylsilylethoxy)methylimidazo<5,1-d>-1,2,3,5-tetrazin-4(3H)-one

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: boron trifluoride diethyl etherate / chloroform / 2 h / 0 - 20 °C
2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile
View Scheme
Multi-step reaction with 2 steps
1: boron trifluoride / chloroform / 0 °C
2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 25 °C
View Scheme
1,1'-carbonyldiimidazole
530-62-1

1,1'-carbonyldiimidazole

temozolomide
85622-93-1

temozolomide

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: acetonitrile; N,N-dimethyl-formamide / 2 h / 20 °C
2.1: acetonitrile / 6 h / 55 - 60 °C
3.1: sodium nitrite / water / 0.33 h / 0 °C
3.2: 4 h / 0 - 60 °C
View Scheme
temozolomide
85622-93-1

temozolomide

3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrahydro-8-carboxylic acid
113942-30-6

3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrahydro-8-carboxylic acid

Conditions
ConditionsYield
With sulfuric acid; sodium nitrite100%
With sulfuric acid; water; sodium nitrite at 15 - 20℃;98.6%
With sulfuric acid; sodium nitrite In water at 0℃;80%
temozolomide
85622-93-1

temozolomide

methyl (Z)-2-((3R,4S,5S,8S,9S,10S,11R,13R,14S,16S)-16-acetoxy-3,11-dihydroxy-4,8,10,14-tetramethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-ylidene)-6-methylhept-5-enoate
21157-24-4

methyl (Z)-2-((3R,4S,5S,8S,9S,10S,11R,13R,14S,16S)-16-acetoxy-3,11-dihydroxy-4,8,10,14-tetramethylhexadecahydro-17H-cyclopenta[a]phenanthren-17-ylidene)-6-methylhept-5-enoate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;97%
temozolomide
85622-93-1

temozolomide

telmisatran
144701-48-4

telmisatran

4'-[[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid methyl ester
528560-93-2

4'-[[4-methyl-6-(1-methyl-1H-benzimidazol-2-yl)-2-propyl-1H-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid methyl ester

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;95%
isosteviol
27975-19-5

isosteviol

temozolomide
85622-93-1

temozolomide

isosteviol methyl ester
30217-41-5

isosteviol methyl ester

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;95%
temozolomide
85622-93-1

temozolomide

hesperetin
520-33-2

hesperetin

C6H6N6O2*C16H14O6

C6H6N6O2*C16H14O6

Conditions
ConditionsYield
In ethanol for 1h;94%
[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid
53-86-1

[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid

temozolomide
85622-93-1

temozolomide

indomethacin methyl ester
1601-18-9

indomethacin methyl ester

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;93%
1,1-Diphenylethylene
530-48-3

1,1-Diphenylethylene

temozolomide
85622-93-1

temozolomide

1,1-diphenylcyclopropane
3282-18-6

1,1-diphenylcyclopropane

Conditions
ConditionsYield
With meso-tetraphenylporphyrin iron(III) chloride; potassium hydroxide In water at 23℃; for 4h; Sealed tube;93%
4-Methoxystyrene
637-69-4

4-Methoxystyrene

temozolomide
85622-93-1

temozolomide

4-methoxyphenylcyclopropane
4030-17-5

4-methoxyphenylcyclopropane

Conditions
ConditionsYield
With meso-tetraphenylporphyrin iron(III) chloride; potassium hydroxide In water at 23℃; for 4h; Catalytic behavior; Reagent/catalyst; Solvent; Sealed tube;91%
temozolomide
85622-93-1

temozolomide

methyl (4R,4aS,6aR,9S,11aR,11bS)-9-hydroxy-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate
14364-16-0

methyl (4R,4aS,6aR,9S,11aR,11bS)-9-hydroxy-4,11b-dimethyl-8-methylenetetradecahydro-6a,9-methanocyclohepta[a]naphthalene-4-carboxylate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;90%
4-isopropylidene cyclohex-1-enyl methanol
110299-94-0

4-isopropylidene cyclohex-1-enyl methanol

temozolomide
85622-93-1

temozolomide

(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic acid-4-isopropenylcyclohex-1-enylmethyl ester

(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic acid-4-isopropenylcyclohex-1-enylmethyl ester

Conditions
ConditionsYield
Stage #1: temozolomide With oxalyl dichloride In 1,2-dichloro-ethane at 10℃; for 3h; Swern Oxidation; Inert atmosphere; Reflux;
Stage #2: 4-isopropylidene cyclohex-1-enyl methanol In 1,2-dichloro-ethane at 20℃; for 14h; Time; Reflux;
89%
oxalyl dichloride
79-37-8

oxalyl dichloride

(-)-perillyl alcohol
536-59-4, 18457-55-1

(-)-perillyl alcohol

temozolomide
85622-93-1

temozolomide

(3-methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)carbamic acid-4-isopropenyl cyclohex-1-enylmethyl ester

(3-methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)carbamic acid-4-isopropenyl cyclohex-1-enylmethyl ester

Conditions
ConditionsYield
Stage #1: oxalyl dichloride; temozolomide In 1,2-dichloro-ethane at 20℃; for 3h; Inert atmosphere;
Stage #2: (-)-perillyl alcohol In 1,2-dichloro-ethane at 20℃; for 14h; Inert atmosphere;
89%
androst-4-en-3-one-17β-carboxylic acid
302-97-6

androst-4-en-3-one-17β-carboxylic acid

temozolomide
85622-93-1

temozolomide

3-oxo-androst-4-ene-17β-carboxylic acid methyl ester
2681-55-2

3-oxo-androst-4-ene-17β-carboxylic acid methyl ester

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 4h; Sealed tube;89%
p-N,N-dimethylaminobenzoic acid
619-84-1

p-N,N-dimethylaminobenzoic acid

temozolomide
85622-93-1

temozolomide

methyl 4-(N,N-dimethylamino)benzoate
1202-25-1

methyl 4-(N,N-dimethylamino)benzoate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;88%
temozolomide
85622-93-1

temozolomide

N,N'-di-tert-butyloxycarbonylpiperazine-2-carboxylic acid
181955-79-3

N,N'-di-tert-butyloxycarbonylpiperazine-2-carboxylic acid

O1,O4-di-tert-butyl O2-methyl piperazine-1,2,4-tricarboxylate
171504-98-6

O1,O4-di-tert-butyl O2-methyl piperazine-1,2,4-tricarboxylate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;88%
2-(6-chloro-carbazol-2-yl)-propionic acid
53716-49-7

2-(6-chloro-carbazol-2-yl)-propionic acid

temozolomide
85622-93-1

temozolomide

methyl (2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate
52263-88-4

methyl (2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;88%
N-Fmoc L-Phe
35661-40-6

N-Fmoc L-Phe

temozolomide
85622-93-1

temozolomide

methyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenylalaninate
129397-81-5

methyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-phenylalaninate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;87%
3-methoxystyrene
626-20-0

3-methoxystyrene

temozolomide
85622-93-1

temozolomide

1-cyclopropyl-3-methoxybenzene
54134-93-9

1-cyclopropyl-3-methoxybenzene

Conditions
ConditionsYield
With meso-tetraphenylporphyrin iron(III) chloride; potassium hydroxide In water at 23℃; for 4h; Sealed tube;87%
all-trans-retinoic-acid
302-79-4

all-trans-retinoic-acid

temozolomide
85622-93-1

temozolomide

all-trans-methyl retinoate
339-16-2

all-trans-methyl retinoate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;86%
epigibberic acid
5937-49-5

epigibberic acid

temozolomide
85622-93-1

temozolomide

(4bR,7S,9aS,10R)-1,7-dimethyl-8-oxo-4b,6,7,8,9,10-hexahydro-5H-7,9a-methanobenzo[a]azulene-10-carboxylate
43207-02-9

(4bR,7S,9aS,10R)-1,7-dimethyl-8-oxo-4b,6,7,8,9,10-hexahydro-5H-7,9a-methanobenzo[a]azulene-10-carboxylate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;86%
temozolomide
85622-93-1

temozolomide

3-[(S)-2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyl]indole-1-carboxylic acid tert-butyl ester
143824-78-6

3-[(S)-2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyl]indole-1-carboxylic acid tert-butyl ester

tert-butyl (S)-3-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate
405555-31-9

tert-butyl (S)-3-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;85%
temozolomide
85622-93-1

temozolomide

3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide
301323-33-1

3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide

Conditions
ConditionsYield
With 2,4-(4-phenoxyphenyl)-1,3-dithia-2λ(5),4λ(5)-diphosphetane 2,4-disulfides In dichloromethane Reflux;84%
With Lawessons reagent In dichloromethane Reflux; Inert atmosphere;80%
4-methoxybenzoic acid
100-09-4

4-methoxybenzoic acid

temozolomide
85622-93-1

temozolomide

methyl 4-methoxybenzoate
121-98-2

methyl 4-methoxybenzoate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;83%
4-<(tetrahydropyran-2-yloxy)methyl>benzoic acid
104292-82-2

4-<(tetrahydropyran-2-yloxy)methyl>benzoic acid

temozolomide
85622-93-1

temozolomide

methyl 4-<(tetrahydropyran-2-yloxy)methyl>benzoate
104292-97-9

methyl 4-<(tetrahydropyran-2-yloxy)methyl>benzoate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 4h; Sealed tube;83%
4-Methoxyphenylacetic acid
104-01-8

4-Methoxyphenylacetic acid

temozolomide
85622-93-1

temozolomide

4-methoxy-phenyl acetic acid methyl ester
23786-14-3

4-methoxy-phenyl acetic acid methyl ester

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;83%
1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid
26171-23-3

1-methyl-5-(p-toluoyl)pyrrole-2-acetic acid

temozolomide
85622-93-1

temozolomide

methyl 1-Methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate
33369-52-7

methyl 1-Methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;81%
temozolomide
85622-93-1

temozolomide

gibberellic acid

gibberellic acid

(1R,2S,4aR,4bR,7S,9aS,10S)-2,7-dihydroxy-1-methyl-8-methylene-13-oxo-1,2,4b,5,6,7,8,9,10,10a-decahydro-4a,1-(epoxymethano)-7,9a-methanobenzo[a]azulene-10-carboxylate
510-50-9, 25274-38-8, 76675-42-8

(1R,2S,4aR,4bR,7S,9aS,10S)-2,7-dihydroxy-1-methyl-8-methylene-13-oxo-1,2,4b,5,6,7,8,9,10,10a-decahydro-4a,1-(epoxymethano)-7,9a-methanobenzo[a]azulene-10-carboxylate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;81%
temozolomide
85622-93-1

temozolomide

4-hydroxy-benzoic acid
99-96-7

4-hydroxy-benzoic acid

methyl 4-hydroxylbenzoate
99-76-3

methyl 4-hydroxylbenzoate

Conditions
ConditionsYield
With sodium carbonate In 1,4-dioxane; water at 60℃; for 6h; Sealed tube;80%

85622-93-1Relevant articles and documents

Alternative syntheses of the antitumour drug temozolomide avoiding the use of methyl isocyanate

Wang,Stevens,Thomson

, p. 1687 - 1688 (1994)

Ethyl (8-carbamoyl-3,4-dihydro-4-oxoimidazo[5,1-d] -1,2,3,5-tetrazin-3-yl)acetate 5 can be prepared by two routes starting from 5-aminoimidazole-4-carboxamide 2; hydrolysis of 5 to the corresponding carboxylic acid 6 followed by Barton radical decarboxylation gives the antitumour imidazotetrazinone temozolomide 1.

Preparation method of temozolomide

-

Paragraph 0101-0104, (2021/10/13)

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of temozolomide, which comprises the following steps: reacting a nitrosoimidazole compound with methylhydrazine to generate an azo compound IV, further hydrolyzing the compound IV to obtain an intermediate V, and further performing nucleophilic substitution on the compound V and p-nitrophenyl chloroformate to obtain a new intermediate VII; and carrying out intermediate VIIcyclization to obtain temozolomide. According to the method, the use of methyl isocyanate with high toxicity and the process of instable diazo compound intermediates are avoided, the synthesized intermediates do not generate dimerization impurities, a green catalyst is used for replacing a traditional catalyst, the reaction is milder, the method is economical and environmentally friendly, the yield is high, and the method is suitable for industrial production.

Temozolomide intermediate compound IV

-

Paragraph 0026; 0090-0098, (2021/10/13)

The invention belongs to the field of pharmaceutical chemical engineering, and particularly relates to a IV novel method for synthesizing temozolomide by reacting a nitroimidazole type substrate with methylhydrazine, and the method IV avoids the use of dangerous chemical reagents, and the synthesized intermediate does not generate new impurities. The method is economical, environment-friendly, high in yield and suitable for industrial production.

PROCESS FOR PREPARING HIGHLY PURE TEMOZOLOMIDE

-

Page/Page column 17, (2020/10/18)

The present invention provides a commercially viable process for preparation of highly pure Temozolomide (VI), which is useful in the treatment of cancer. The invention also provides an economically viable process for an intermediate compound of formula III useful in the process for preparing Temozolomide.

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