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Suvorexant
Cas No: 1030377-33-3
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Suvorexant CAS NO.1030377-33-3
Cas No: 1030377-33-3
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Suvorexant
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5-Chloro-2-[(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)-benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole
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Factory Price API 99% Suvorexant 1030377-33-3 GMP Manufacturer
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Suvorexant
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suvorexant
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1030377-33-3 Usage

Hypnotic drugs

Suvorexant is a new hypnotic drug developed by the US pharmaceutical giant Merck. Unlike other hypnotics, instead of being administrated on demand like general hypnotics (that is, they are taken only when needed), Merck's Suvorexant is a therapeutic drug, should be subject to long-term administration. The drug can block Orexins (neuropeptides) to send messages. Orexins (neuropeptides) usually transduces a variety of sobering messages for the human body, being the culprit leading to insomnia. Professor Andrew Krystal from the Center for Medical Research at Duke University said Merck's drug would become a new drug favored by patients. Darryle Schoepp, the head of neurology and ophthalmology at Merck, says the drug is especially suitable for patients who have been unable to sleep all night and have received little benefit from existing medications. ?“More than 2,000 patients with insomnia that not caused by other medical problems have participated in the two post-trials of Suvorexant,”Said by Merck. The most common side effects of the drug are fatigue and headache. On August 13, 2014, the US Food and Drug Administration (FDA) approved the release of Belsomra (Suvorexant) from Merck for the treatment of patients who fall asleep and have difficulty sleeping (insomnia). Belsomra is an orexin receptor antagonist and is the first approved drug in this class of drugs. Orexin is a kind of chemical substances that participate into the regulation of sleep wake-up period, playing an important role in maintaining human awakening. Belsomra can alter the information behavior of orexins in the brain. Figure 1 structure of the Suvorexant.

side effects

Suvorexant (BELSOMRA) has possible side effects. Before you begin treatment, it’s important to know what these side effects are and to discuss the risks and benefits of taking BELSOMRA with your doctor. Below is a list of the most commonly reported adverse events that occurred in 3-month clinical trials: placebo (n=767) BELSOMRA 15 mg or 20 mg (n=493) Diarrhea (placebo 1%, BELSOMRA 2%) Dry mouth (placebo 1%, BELSOMRA 2%) Upper respiratory tract infection (placebo 1%, BELSOMRA 2%) Headache (placebo 6%, BELSOMRA 7%) Next-day drowsiness (placebo 3%, BELSOMRA 7%) Dizziness (placebo 2%, BELSOMRA 3%) Abnormal dreams (placebo 1%, BELSOMRA 2%) Cough (placebo 1%, BELSOMRA 2%) Side effects that you should report to your doctor or health care professional as soon as possible: allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue confusion depressed mood feeling faint or lightheaded, falls hallucinations inability to move or speak for up to several minutes while you are going to sleep or waking up memory loss periods of leg weakness lasting from seconds to a few minutes problems with balance, speaking, walking restlessness, excitability, or feelings of agitation unusual activities while asleep like driving, eating, making phone calls Side effects that usually do not require medical attention (Report these to your doctor or health care professional if they continue or are bothersome.): abnormal dreams daytime drowsiness diarrhea dizziness headache

Feature

The regulation of dual OX antagonist on sleep is currently in phase III clinical trials.

Dosage

The recommended dosage is 10 mg, to be taken orally no more than once per night, within 30 min of going to bed and with at least 7 h remaining until the planned awaken time. If this dosage is well tolerated but not effective, the dosage can be increased up to a maximum of 20 mg once daily; the lowest effective dosage should be used. Patients taking concomitant moderate cytochrome P450 (CYP) 3A4 inhibitors should receive a reduced dose of 5 mg.

Pharmacokinetics

In fasting conditions, the median time to maximum plasma concentration of suvorexant is 2 h. For suvorexant 10 mg, the mean absolute bioavailability is 82 %. Administration of suvorexant with a high-fat meal had no clinically significant on systemic drug exposure, but delayed tmax by 1.5 h. Steady state is achieved within 3 days. The mean volume of distribution of suvorexant is 49 L. Suvorexant is extensively bound to plasma proteins, including albumin and a1-acid glycoprotein, and does not preferentially distribute into the red blood cells.? Suvorexant is primarily metabolized by CYP3A, with a minor contribution by CYP2C19. The main circulating compounds are the unchanged drug and a hydroxyl metabolite, which is not expected to be pharmacologically active. Suvorexant is primarily eliminated in the faeces.

Biological activity

Suvorexant (MK-4305) is a potent OX receptor antagonist, acting on the OX1 receptor and the OX2 receptor with a Ki being 0.55 nM and 0.35 nM, respectively. Phase III.

Clinical evaluation

The US Food and Drug Administration (FDA) have approved a new remedy for the treatment of insomnia, suvorexant (Belsomra), which is an orexin receptor antagonist. Suvorexant is the first approved orexin receptor antagonist that inhibits the neuronal activation of the wake-up system by blocking the binding of the neuropeptides, orelectins A and B, to the orexin receptors. According to suvorexant producer Merck, the FDA recommended its inclusion in the control substance, to which DEA proposed earlier this year that it should be classified as a Category IV control substance under the Controlled Substances law. At the end of 2012, Merck submitted its listing application to the US Food and Drug Administration (FDA). In May 2013, FDA's Peripheral and CNS Drugs Committee questioned the safety of the initial dose proposed by the company. A few months later, the FDA recommended that the initial dose for most patients should be set at 10 mg. The company had not prepared the formulation of this dosage, thus have redesigned and produced of several new formulations. "The FDA has approved four specifications-5, 10, 15, and 20 mg of Belsomra," said by Dr. Ellis Unger who is the director of the FDA's Center for Drug Evaluation and Evaluation. Dr. Unger said in a statement, "using the smallest effective doses can reduce the risk of side effects, such as drowsiness in the morning.” FDA and Merck said that: it is only needed to administrate 1 tablet of Suvorexant at a time of between half an hour before sleeping every night to at least 7 hours before getting up at least 7 hours, no more than 20 mg per day. Drowsiness is the most common side effect. In the next day driving behavior study, which was required by the FDA, the capability of the patients who have administrated 20 mg were impaired. The FDA warned that patients subjecting to a 20 mg dosage should be warned not to engage in driving or any other activity requiring vigilance the next day. The drug may also lead to what the FDA calls "complex behaviors upon sleepy driving and other non-complete arousal state", including cooking and eating, phone calls, or sexual activity. If this behavior occurs, the patient and his family should inform the doctor. Suvorexant is distributed together with a patient medication guide, which contains detailed safety information. The FDA said that although three trials were conducted on the drug, none were compared with other approved hypnotic drugs, so the comparative effectiveness of the drug remains unknown. Information on the indications, dosage and pharmacological effects of new hypnotic drug suvorexant (Belsomra) are edited by Tongtong from the ChemicalBook.

description

Suvorexant (Belsomra? ) is a novel sedative hypnotic drug that is prescribed to promote sleep in patients with insomnia. It is the first of a new class of drugs classified as dual orexin receptor antagonists (DORAs) and is currently approved for the treatment of insomnia in the United States and Japan. It is a CNS depressant and blocks the binding of wake-promoting neuropeptides orexin A and orexin B to the two orexin receptors (OX1R and OX2R) thus, altering the signaling (action) of orexin in the brain and suppressing the sleep-wake drive. Suvorexant is a central nervous system (CNS) depressant and can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur in the absence of symptoms, and may not be reliably detected by ordinary clinical exam. CNS depressant effects may persist in some patients for up to several days after discontinuing Suvorexant. Belsomra (Suvorexant) can impair driving skills and may increase the risk of falling asleep while driving. Discontinue or decrease the dose in patients who drive if daytime somnolence develops. Caution patients taking Belsomra 20 mg against next-day driving and other activities requiring full mental alertness. Caution patients taking lower doses of Belsomra as well, because there is individual variation in sensitivity to Belsomra.

Description

Suvorexant, a dual orexin receptor antagonist marketed under the trade name Belsomra?, discovered and developed by Merck for the treatment of insomnia, was approved by the US FDA in August 2014 and became available in Japan in November of the same year. The drug’s mechanism of action operates through the competitive blockade of wake-promoting neuropeptides orexin A and orexin B toward receptors orexin receptor type 1 and orexin receptor type 2, which are believed to modulate sleep-wake cycles.

Chemical Synthesis

Commercially available acid 240 was first subjected to a copper-assisted substitution reaction involving 1,2,3-triazole in DMF at elevated temperatures. Although these conditions resulted in an excellent yield of a triazole-substituted product, an approximate 4:1 ratio of the desired 2-arylated triazole 241 and the undesired 1-arylated triazole byproduct were recovered from the reaction. The mixture was then treated with N,Ndimethylethylenediamine in acid to sequester copper. Next, the mixture of arylated triazoles was carefully subjected to sodium tbutoxide in DMF and ethyl acetate to form the corresponding sodium salts, and interestingly it was found that the desired sodium salt of 241 could be isolated based on its solubility profile under these conditions. Acidification of the desired carboxylate salt using dilute HCl gave rise to acid 241 in 60% yield across the fourstep sequence. Next, subjection of this acid to oxalyl chloride in chilled DMF generated the acid chloride 242 in excellent yield. This crude acid chloride was used immediately in the next step of the synthetic sequence. For the preparation of the diazepine-containing portion of suvorexant, the synthesis commenced with the condensation of commercial 2-amino-4-chlorophenol (243) with thiophosgene (244) to furnish benzoxazole 245. Next, thiol 245 was converted to the corresponding chloride prior to exposure to Boc-protected ethylenediamine 246 under basic conditions. This was followed by a Michael addition of the resulting aminobenzoxazole and methyl vinyl ketone (MVK). The result of this sequence of reactions delivered aminobenzoxazole ketone 247 in 75% yield over the three steps. Next, subjection of the carbamate to methanesulfonic acid removed the Boc functionality and this was followed by an intramolecular reductive amination sequence to construct the diazaepine ring. Acid–base workup ultimately provided the racemic diazepine 248 in 92% yield from 247. Next, salt formation with a benzoyl tartaric acid and subsequent recrystallization upgrade using isopropyl acetate and methanol at ambient temperature was used to resolve racemic 248 into the tartrate salt 249 in 27% yield and excellent enantiomeric excess. Finally, salt 249 was freebased using sodium hydroxide prior to exposure to the crude acid chloride 242 under basic conditions to ultimately deliver suvorexant (XXX) in 95% yield and 99% ee across the twostep sequence.

Mechanism of action

Suvorexant is a dual antagonist of orexin receptors OX1R and OX2R. It exerts its pharmacological effect by inhibiting binding of neuropeptides orexin A and B, also known as hypocretin 1 and 2, that are produced by neurons in the lateral hypothalamus. These neurons control the wake-promoting centers of the brain and are active during wakefulness, especially during motor activities, and stop firing during sleep. By inhibiting the reinforcement of arousal systems, suvorexant use causes a decrease in arousal and wakefulness, rather than having a direct sleep-promoting effect. References https://www.drugbank.ca/drugs/DB09034

Definition

ChEBI: An aromatic amide obtained by formal condensation of the carboxy group of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid with the secondary amino group of 5-chloro-2-[(5R)-5-methyl-1,4-diazepan-1-yl]-1,3-benzoxazole. An rexin receptor antagonist used for the management of insomnia.

In vivo studies

In rats, Suvorexant has excellent passive permeability and oral bioavailability, and is conducive to sleep. In addition, suvorexant significantly and dose-dependently decreased the motor activity of rats (10, 30, and 100 mg/kg), dogs (1 and 3 mg/kg), and monkeys (10 mg/kg), while promoting their sleep.

1030377-33-3SDS

SAFETY DATA SHEETS

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

Version: 1.0

Creation Date: Aug 20, 2017

Revision Date: Aug 20, 2017

1.Identification

1.1 GHS Product identifier

Product name suvorexant

1.2 Other means of identification

Product number -
Other names Suvorexant

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:1030377-33-3 SDS

1030377-33-3Synthetic route

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid
956317-36-5

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole
1266975-27-2

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; Reagent/catalyst; Solvent; Temperature;97%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃;97%
Stage #1: 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 10℃; for 1h; Industry scale;
Stage #2: 5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole With triethylamine In dichloromethane at 15℃; for 1h;
95%
With triethylamine; chloroacetyl chloride In dichloromethane at 0 - 20℃;83%
2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid
956317-36-5

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole
1266975-27-2

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

C13H16ClN3O*C18H14O8
1276666-14-8

C13H16ClN3O*C18H14O8

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Stage #1: C13H16ClN3O*C18H14O8 With sodium hydroxide In dichloromethane; water at 20℃; for 1h;
Stage #2: 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 10℃; for 1h;
Stage #3: 5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole With triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 15℃; for 1h; optical yield given as %ee;
95%
2,5-dichloro-1,3-benzoxazole
3621-81-6

2,5-dichloro-1,3-benzoxazole

1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone
1030377-32-2

1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With triethylamine In N,N-dimethyl-formamide at 75℃;94%
With triethylamine In N,N-dimethyl-formamide at 75℃; for 2h;93.02%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Reagent/catalyst; Autoclave; Large scale;93.5%
5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole
1266975-27-2

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

5-methyl-2-(1H-1,2,3-triazol-2-yl)benzoic acid

5-methyl-2-(1H-1,2,3-triazol-2-yl)benzoic acid

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Stage #1: 5-methyl-2-(1H-1,2,3-triazol-2-yl)benzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 10℃; for 1h;
Stage #2: 5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole With triethylamine In dichloromethane at -10 - -5℃; for 1h;
92%
2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid
956317-36-5

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid

5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride
1266664-66-7

5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3h;91%
With triethylamine; chloroacetyl chloride In dichloromethane at 0℃;88%
Stage #1: 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In Isopropyl acetate at 20 - 25℃; Inert atmosphere;
Stage #2: 5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride With triethylamine In Isopropyl acetate; acetonitrile at 20 - 40℃; Product distribution / selectivity;
Stage #1: 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid With oxalyl dichloride; Isopropyl acetate In N,N-dimethyl-formamide at 20 - 25℃; for 1h; Inert atmosphere;
Stage #2: 5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride With Isopropyl acetate; potassium carbonate In water; N,N-dimethyl-formamide at 0 - 5℃; for 1.25h; Concentration; Solvent; Reagent/catalyst;
14.4 g
5-chloro-2-mercaptobenzoxazole
22876-19-3

5-chloro-2-mercaptobenzoxazole

(R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

(R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Stage #1: 5-chloro-2-mercaptobenzoxazole With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.916667h;
Stage #2: (R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride With triethylamine In N,N-dimethyl-formamide at 20 - 37℃; for 0.5h;
76%
5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl chloride
1104546-96-4

5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl chloride

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole
1266975-27-2

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

A

Suvorexant
1030377-33-3

Suvorexant

B

C23H23ClN6O2

C23H23ClN6O2

Conditions
ConditionsYield
With triethylamine In dichloromethane at 5 - 10℃; for 1.5h;A 68%
B n/a
1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone
1030377-32-2

1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone

5-chloro-benzoxazole
17200-29-2

5-chloro-benzoxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With acetic acid In acetonitrile at 20℃; for 8h; Electrolysis;64.66%
With oxygen; copper diacetate; acetic acid In acetonitrile at 70℃; for 4h;3.3 g
2-iodoyl-5-methylbenzoic acid
52548-14-8

2-iodoyl-5-methylbenzoic acid

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: copper(l) iodide; potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 40 °C
1.2: 20 °C
2.1: sodium hydroxide / dichloromethane; water / 1 h / 20 °C
2.2: 1 h / 0 - 10 °C
2.3: 1 h / 0 - 15 °C
View Scheme
Multi-step reaction with 3 steps
1.1: potassium carbonate / tetrahydrofuran; water / 3 h / 22 - 25 °C / Inert atmosphere
1.2: 19 h / 21 - 23 °C / Inert atmosphere
2.1: oxalyl dichloride / Isopropyl acetate; N,N-dimethyl-formamide / 3 h / 20 - 25 °C / Inert atmosphere
3.1: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 2 steps
1.1: potassium carbonate / copper(l) iodide / N,N-dimethyl-formamide; tetrahydrofuran / 40 - 65 °C / Industry scale
1.2: 20 °C
2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1 h / 0 - 10 °C / Industry scale
2.2: 1 h / 15 °C
View Scheme
Multi-step reaction with 4 steps
1: potassium carbonate; copper(l) iodide / N,N-dimethyl-formamide
2: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C
3: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C
4: triethylamine / N,N-dimethyl-formamide / 2 h / 75 °C
View Scheme
2-bromo-5-chlorobenzo[d]oxazole
1251033-26-7

2-bromo-5-chlorobenzo[d]oxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: acetonitrile / Inert atmosphere
2: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
3: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
4: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
5: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 5 steps
1: acetonitrile / Inert atmosphere
2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 23 °C / Inert atmosphere
3: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
4: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
5: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
2-[(5-chloro-1,3-benzoxazol-2-yl)amino]ethanol
1356342-15-8

2-[(5-chloro-1,3-benzoxazol-2-yl)amino]ethanol

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
2: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
3: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
4: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 4 steps
1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 23 °C / Inert atmosphere
2: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
3: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
4: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 3 steps
1.1: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
1.2: 1.25 h / 0 - 10 °C
2.1: isopropylamine hydrochloride; triethanolamine; pyridoxal 5'-phosphate; isopropylamine mesylate / water; dimethyl sulfoxide / 11 h / 40 °C / pH 8.5 / Enzymatic reaction
3.1: oxalyl dichloride; Isopropyl acetate / N,N-dimethyl-formamide / 1 h / 20 - 25 °C / Inert atmosphere
3.2: 1.25 h / 0 - 5 °C
View Scheme
C13H15ClN2O3
1383717-09-6

C13H15ClN2O3

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
2: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
3: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
methanesulfonic acid 2-[(5-chloro-benzooxazol-2-yl)-(3-oxo-butyl)amino]ethyl ester
1383717-11-0

methanesulfonic acid 2-[(5-chloro-benzooxazol-2-yl)-(3-oxo-butyl)amino]ethyl ester

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
2: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 2 steps
1.1: isopropylamine hydrochloride; triethanolamine; pyridoxal 5'-phosphate; isopropylamine mesylate / water; dimethyl sulfoxide / 11 h / 40 °C / pH 8.5 / Enzymatic reaction
2.1: oxalyl dichloride; Isopropyl acetate / N,N-dimethyl-formamide / 1 h / 20 - 25 °C / Inert atmosphere
2.2: 1.25 h / 0 - 5 °C
View Scheme
5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl chloride
1104546-96-4

5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl chloride

5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride
1266664-66-7

5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With potassium carbonate In Isopropyl acetate; water at 0℃; for 1.25h; Inert atmosphere;14.4 g
2-hydroxy-5-chloro-aniline
95-85-2

2-hydroxy-5-chloro-aniline

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1.1: toluene-4-sulfonic acid / tetrahydrofuran / 60 °C / Inert atmosphere
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2.83 h / -25 - -15 °C / Inert atmosphere
2.2: 3.33 h / -20 - -15 °C / Inert atmosphere
3.1: acetonitrile / Inert atmosphere
4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 23 °C / Inert atmosphere
5.1: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
6.1: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
7.1: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 7 steps
1.1: toluene-4-sulfonic acid / tetrahydrofuran / 60 °C / Inert atmosphere
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2.83 h / -25 - -15 °C / Inert atmosphere
2.2: 3.33 h / -20 - -15 °C / Inert atmosphere
3.1: acetonitrile / Inert atmosphere
4.1: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
5.1: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
6.1: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
7.1: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 4 steps
1.1: water; methanol / 0 - 5 °C / Industry scale
2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1.75 h / 25 °C / Industry scale
2.2: 2.5 h / 10 - 20 °C
2.3: 10 h / 20 °C
3.1: hydrogenchloride; water / 10 h / 20 - 30 °C
3.2: 35 °C / pH > 10
3.3: 24 h / -5 °C / Inert atmosphere
4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1 h / 0 - 10 °C / Industry scale
4.2: 1 h / 15 °C
View Scheme
2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid
956317-36-5

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole
1266975-27-2

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃; Reagent/catalyst; Solvent; Temperature;97%
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0 - 20℃;97%
Stage #1: 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 10℃; for 1h; Industry scale;
Stage #2: 5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole With triethylamine In dichloromethane at 15℃; for 1h;
95%
With triethylamine; chloroacetyl chloride In dichloromethane at 0 - 20℃;83%
2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid
956317-36-5

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole
1266975-27-2

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

C13H16ClN3O*C18H14O8
1276666-14-8

C13H16ClN3O*C18H14O8

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Stage #1: C13H16ClN3O*C18H14O8 With sodium hydroxide In dichloromethane; water at 20℃; for 1h;
Stage #2: 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 10℃; for 1h;
Stage #3: 5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole With triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 15℃; for 1h; optical yield given as %ee;
95%
2,5-dichloro-1,3-benzoxazole
3621-81-6

2,5-dichloro-1,3-benzoxazole

1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone
1030377-32-2

1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With triethylamine In N,N-dimethyl-formamide at 75℃;94%
With triethylamine In N,N-dimethyl-formamide at 75℃; for 2h;93.02%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Reagent/catalyst; Autoclave; Large scale;93.5%
5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole
1266975-27-2

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

5-methyl-2-(1H-1,2,3-triazol-2-yl)benzoic acid

5-methyl-2-(1H-1,2,3-triazol-2-yl)benzoic acid

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Stage #1: 5-methyl-2-(1H-1,2,3-triazol-2-yl)benzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 10℃; for 1h;
Stage #2: 5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole With triethylamine In dichloromethane at -10 - -5℃; for 1h;
92%
2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid
956317-36-5

2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid

5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride
1266664-66-7

5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 3h;91%
With triethylamine; chloroacetyl chloride In dichloromethane at 0℃;88%
Stage #1: 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid With oxalyl dichloride; N,N-dimethyl-formamide In Isopropyl acetate at 20 - 25℃; Inert atmosphere;
Stage #2: 5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride With triethylamine In Isopropyl acetate; acetonitrile at 20 - 40℃; Product distribution / selectivity;
Stage #1: 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid With oxalyl dichloride; Isopropyl acetate In N,N-dimethyl-formamide at 20 - 25℃; for 1h; Inert atmosphere;
Stage #2: 5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride With Isopropyl acetate; potassium carbonate In water; N,N-dimethyl-formamide at 0 - 5℃; for 1.25h; Concentration; Solvent; Reagent/catalyst;
14.4 g
5-chloro-2-mercaptobenzoxazole
22876-19-3

5-chloro-2-mercaptobenzoxazole

(R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

(R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Stage #1: 5-chloro-2-mercaptobenzoxazole With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.916667h;
Stage #2: (R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone hydrochloride With triethylamine In N,N-dimethyl-formamide at 20 - 37℃; for 0.5h;
76%
5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl chloride
1104546-96-4

5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl chloride

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole
1266975-27-2

5-chloro-2-[(5R)-hexahydro-5-methyl-1H-1,4-diazepin-1-yl]benzoxazole

A

Suvorexant
1030377-33-3

Suvorexant

B

C23H23ClN6O2

C23H23ClN6O2

Conditions
ConditionsYield
With triethylamine In dichloromethane at 5 - 10℃; for 1.5h;A 68%
B n/a
1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone
1030377-32-2

1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone

5-chloro-benzoxazole
17200-29-2

5-chloro-benzoxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With acetic acid In acetonitrile at 20℃; for 8h; Electrolysis;64.66%
With oxygen; copper diacetate; acetic acid In acetonitrile at 70℃; for 4h;3.3 g
2-iodoyl-5-methylbenzoic acid
52548-14-8

2-iodoyl-5-methylbenzoic acid

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: copper(l) iodide; potassium carbonate / tetrahydrofuran; N,N-dimethyl-formamide / 0.5 h / 40 °C
1.2: 20 °C
2.1: sodium hydroxide / dichloromethane; water / 1 h / 20 °C
2.2: 1 h / 0 - 10 °C
2.3: 1 h / 0 - 15 °C
View Scheme
Multi-step reaction with 3 steps
1.1: potassium carbonate / tetrahydrofuran; water / 3 h / 22 - 25 °C / Inert atmosphere
1.2: 19 h / 21 - 23 °C / Inert atmosphere
2.1: oxalyl dichloride / Isopropyl acetate; N,N-dimethyl-formamide / 3 h / 20 - 25 °C / Inert atmosphere
3.1: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 2 steps
1.1: potassium carbonate / copper(l) iodide / N,N-dimethyl-formamide; tetrahydrofuran / 40 - 65 °C / Industry scale
1.2: 20 °C
2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1 h / 0 - 10 °C / Industry scale
2.2: 1 h / 15 °C
View Scheme
Multi-step reaction with 4 steps
1: potassium carbonate; copper(l) iodide / N,N-dimethyl-formamide
2: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C
3: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C
4: triethylamine / N,N-dimethyl-formamide / 2 h / 75 °C
View Scheme
2-bromo-5-chlorobenzo[d]oxazole
1251033-26-7

2-bromo-5-chlorobenzo[d]oxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: acetonitrile / Inert atmosphere
2: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
3: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
4: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
5: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 5 steps
1: acetonitrile / Inert atmosphere
2: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 23 °C / Inert atmosphere
3: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
4: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
5: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
2-[(5-chloro-1,3-benzoxazol-2-yl)amino]ethanol
1356342-15-8

2-[(5-chloro-1,3-benzoxazol-2-yl)amino]ethanol

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
2: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
3: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
4: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 4 steps
1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 23 °C / Inert atmosphere
2: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
3: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
4: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 3 steps
1.1: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
1.2: 1.25 h / 0 - 10 °C
2.1: isopropylamine hydrochloride; triethanolamine; pyridoxal 5'-phosphate; isopropylamine mesylate / water; dimethyl sulfoxide / 11 h / 40 °C / pH 8.5 / Enzymatic reaction
3.1: oxalyl dichloride; Isopropyl acetate / N,N-dimethyl-formamide / 1 h / 20 - 25 °C / Inert atmosphere
3.2: 1.25 h / 0 - 5 °C
View Scheme
C13H15ClN2O3
1383717-09-6

C13H15ClN2O3

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
2: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
3: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
methanesulfonic acid 2-[(5-chloro-benzooxazol-2-yl)-(3-oxo-butyl)amino]ethyl ester
1383717-11-0

methanesulfonic acid 2-[(5-chloro-benzooxazol-2-yl)-(3-oxo-butyl)amino]ethyl ester

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
2: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 2 steps
1.1: isopropylamine hydrochloride; triethanolamine; pyridoxal 5'-phosphate; isopropylamine mesylate / water; dimethyl sulfoxide / 11 h / 40 °C / pH 8.5 / Enzymatic reaction
2.1: oxalyl dichloride; Isopropyl acetate / N,N-dimethyl-formamide / 1 h / 20 - 25 °C / Inert atmosphere
2.2: 1.25 h / 0 - 5 °C
View Scheme
5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl chloride
1104546-96-4

5-methyl-2-(2Η-1,2,3-triazol-2-yl)benzoyl chloride

5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride
1266664-66-7

5-chloro-2-((R)-5-methyl-[1,4]diazepan-1-yl)benzooxazole hydrochloride

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With potassium carbonate In Isopropyl acetate; water at 0℃; for 1.25h; Inert atmosphere;14.4 g
2-hydroxy-5-chloro-aniline
95-85-2

2-hydroxy-5-chloro-aniline

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1.1: toluene-4-sulfonic acid / tetrahydrofuran / 60 °C / Inert atmosphere
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2.83 h / -25 - -15 °C / Inert atmosphere
2.2: 3.33 h / -20 - -15 °C / Inert atmosphere
3.1: acetonitrile / Inert atmosphere
4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 23 °C / Inert atmosphere
5.1: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
6.1: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
7.1: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 7 steps
1.1: toluene-4-sulfonic acid / tetrahydrofuran / 60 °C / Inert atmosphere
2.1: lithium hexamethyldisilazane / tetrahydrofuran / 2.83 h / -25 - -15 °C / Inert atmosphere
2.2: 3.33 h / -20 - -15 °C / Inert atmosphere
3.1: acetonitrile / Inert atmosphere
4.1: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
5.1: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
6.1: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
7.1: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 4 steps
1.1: water; methanol / 0 - 5 °C / Industry scale
2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1.75 h / 25 °C / Industry scale
2.2: 2.5 h / 10 - 20 °C
2.3: 10 h / 20 °C
3.1: hydrogenchloride; water / 10 h / 20 - 30 °C
3.2: 35 °C / pH > 10
3.3: 24 h / -5 °C / Inert atmosphere
4.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1 h / 0 - 10 °C / Industry scale
4.2: 1 h / 15 °C
View Scheme
5-chloro-benzoxazole
17200-29-2

5-chloro-benzoxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2.83 h / -25 - -15 °C / Inert atmosphere
1.2: 3.33 h / -20 - -15 °C / Inert atmosphere
2.1: acetonitrile / Inert atmosphere
3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 23 °C / Inert atmosphere
4.1: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
5.1: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
6.1: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 6 steps
1.1: lithium hexamethyldisilazane / tetrahydrofuran / 2.83 h / -25 - -15 °C / Inert atmosphere
1.2: 3.33 h / -20 - -15 °C / Inert atmosphere
2.1: acetonitrile / Inert atmosphere
3.1: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
4.1: triethylamine / Isopropyl acetate / 1.25 h / 0 - 10 °C / Inert atmosphere
5.1: sitagliptin transaminase CDX-017; triethanolamine; pyridoxal 5'-phosphate; isopropylamine hydrochloride / water; dimethyl sulfoxide / 11 h / 40 °C / pH 9.5 / Inert atmosphere
6.1: potassium carbonate / Isopropyl acetate; water / 1.25 h / 0 °C / Inert atmosphere
View Scheme
Multi-step reaction with 4 steps
1.1: 1,1,1,3,3,3-hexamethyl-disilazane; n-butyllithium / tetrahydrofuran; hexane / 4.73 h / -52 - 12.5 °C / Inert atmosphere
1.2: 3.33 h / -25 - 20 °C
1.3: 20 - 27 °C
2.1: sodium hydroxide / N,N-dimethyl-formamide / 6 h / Inert atmosphere
2.2: 1.25 h / 0 - 10 °C
3.1: isopropylamine hydrochloride; triethanolamine; pyridoxal 5'-phosphate; isopropylamine mesylate / water; dimethyl sulfoxide / 11 h / 40 °C / pH 8.5 / Enzymatic reaction
4.1: oxalyl dichloride; Isopropyl acetate / N,N-dimethyl-formamide / 1 h / 20 - 25 °C / Inert atmosphere
4.2: 1.25 h / 0 - 5 °C
View Scheme
Multi-step reaction with 3 steps
1: acetic acid / acetonitrile / 6 h / 20 °C / Electrolysis
2: hydrogenchloride / 1,4-dioxane; water / 3 h / 20 °C
3: 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 3 h / 20 °C
View Scheme
5-chloro-2-mercaptobenzoxazole
22876-19-3

5-chloro-2-mercaptobenzoxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1.75 h / 25 °C / Industry scale
1.2: 2.5 h / 10 - 20 °C
1.3: 10 h / 20 °C
2.1: hydrogenchloride; water / 10 h / 20 - 30 °C
2.2: 35 °C / pH > 10
2.3: 24 h / -5 °C / Inert atmosphere
3.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1 h / 0 - 10 °C / Industry scale
3.2: 1 h / 15 °C
View Scheme
Multi-step reaction with 4 steps
1.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1.75 h / 25 °C / Industry scale
1.2: 2.5 h / 10 - 20 °C
1.3: 10 h / 20 °C
2.1: tetrahydrofuran / 25 - 60 °C / Industry scale
3.1: potassium carbonate / dichloromethane; water / -5 - 20 °C / Industry scale; Inert atmosphere
3.2: 16.5 h / -10 - -5 °C
3.3: 0 °C / pH > 11
4.1: oxalyl dichloride / N,N-dimethyl-formamide / Isopropyl acetate / 20 - 25 °C / Inert atmosphere
4.2: 20 - 40 °C
View Scheme
Multi-step reaction with 2 steps
1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1.83 h / 20 °C
2: triethylamine / N,N-dimethyl-formamide / 39 h / 20 - 90 °C
View Scheme
4-[(2-amino-ethyl)-(5-chlorobenzoxazol-2-yl)amino]butan-2-one-bis-methanesulfonic acid salt

4-[(2-amino-ethyl)-(5-chlorobenzoxazol-2-yl)amino]butan-2-one-bis-methanesulfonic acid salt

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: potassium carbonate / dichloromethane; water / -5 - 20 °C / Industry scale; Inert atmosphere
1.2: 16.5 h / -10 - -5 °C
1.3: 0 °C / pH > 11
2.1: oxalyl dichloride / N,N-dimethyl-formamide / Isopropyl acetate / 20 - 25 °C / Inert atmosphere
2.2: 20 - 40 °C
View Scheme
{2-[(5-chlorobenzooxazol-2-yl)-(3-oxobutyl)amino]ethyl}carbamic acid tert-butyl ester
1276666-10-4

{2-[(5-chlorobenzooxazol-2-yl)-(3-oxobutyl)amino]ethyl}carbamic acid tert-butyl ester

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: hydrogenchloride; water / 10 h / 20 - 30 °C
1.2: 35 °C / pH > 10
1.3: 24 h / -5 °C / Inert atmosphere
2.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 1 h / 0 - 10 °C / Industry scale
2.2: 1 h / 15 °C
View Scheme
Multi-step reaction with 3 steps
1.1: tetrahydrofuran / 25 - 60 °C / Industry scale
2.1: potassium carbonate / dichloromethane; water / -5 - 20 °C / Industry scale; Inert atmosphere
2.2: 16.5 h / -10 - -5 °C
2.3: 0 °C / pH > 11
3.1: oxalyl dichloride / N,N-dimethyl-formamide / Isopropyl acetate / 20 - 25 °C / Inert atmosphere
3.2: 20 - 40 °C
View Scheme
C21H30N2O

C21H30N2O

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 8 steps
1: sodium hydroxide / 1,4-dioxane; water / 2.5 h / 0 - 20 °C
2: hydrogen; 20% palladium hydroxide-activated charcoal / methanol / 20 h / 760.05 Torr
3: sodium hydrogencarbonate / tetrahydrofuran; water / 23 h / 0 °C
4: triphenylphosphine; azodicarboxylic acid bis(2-methoxyethyl) ester / toluene / 17 h / 20 °C
5: potassium carbonate; thiophenol / acetonitrile / 17 h / 60 °C
6: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / N,N-dimethyl-formamide / 16 h / 20 °C
7: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
8: potassium carbonate / acetonitrile / 5 h / 20 - 65 °C
View Scheme
C11H24N2O3

C11H24N2O3

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: sodium hydrogencarbonate / tetrahydrofuran; water / 23 h / 0 °C
2: triphenylphosphine; azodicarboxylic acid bis(2-methoxyethyl) ester / toluene / 17 h / 20 °C
3: potassium carbonate; thiophenol / acetonitrile / 17 h / 60 °C
4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / N,N-dimethyl-formamide / 16 h / 20 °C
5: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
6: potassium carbonate / acetonitrile / 5 h / 20 - 65 °C
View Scheme
1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone
1030377-32-2

1-(7(R)-methyl-1,4-diazepan-1-yl)-1-[5-methyl-2-(2H-1,2,3-triazole-2-yl)phenyl]methanone

2-bromo-5-chlorobenzo[d]oxazole
1251033-26-7

2-bromo-5-chlorobenzo[d]oxazole

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
With potassium carbonate In acetonitrile at 20 - 65℃; for 5h;
(3R)-3-[benzyl((1R)-1-phenylethyl)amino]-N-(2-hydroxyethyl)butyramide

(3R)-3-[benzyl((1R)-1-phenylethyl)amino]-N-(2-hydroxyethyl)butyramide

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 9 steps
1: lithium aluminium tetrahydride / tetrahydrofuran / 1 h / Reflux
2: sodium hydroxide / 1,4-dioxane; water / 2.5 h / 0 - 20 °C
3: hydrogen; 20% palladium hydroxide-activated charcoal / methanol / 20 h / 760.05 Torr
4: sodium hydrogencarbonate / tetrahydrofuran; water / 23 h / 0 °C
5: triphenylphosphine; azodicarboxylic acid bis(2-methoxyethyl) ester / toluene / 17 h / 20 °C
6: potassium carbonate; thiophenol / acetonitrile / 17 h / 60 °C
7: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / N,N-dimethyl-formamide / 16 h / 20 °C
8: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
9: potassium carbonate / acetonitrile / 5 h / 20 - 65 °C
View Scheme
(3R)-{3-[benzyl((1R)-1-phenylethyl)amino]butyl}(2-hydroxyethyl)carbamic acid tert-butyl ester

(3R)-{3-[benzyl((1R)-1-phenylethyl)amino]butyl}(2-hydroxyethyl)carbamic acid tert-butyl ester

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1: hydrogen; 20% palladium hydroxide-activated charcoal / methanol / 20 h / 760.05 Torr
2: sodium hydrogencarbonate / tetrahydrofuran; water / 23 h / 0 °C
3: triphenylphosphine; azodicarboxylic acid bis(2-methoxyethyl) ester / toluene / 17 h / 20 °C
4: potassium carbonate; thiophenol / acetonitrile / 17 h / 60 °C
5: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / N,N-dimethyl-formamide / 16 h / 20 °C
6: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
7: potassium carbonate / acetonitrile / 5 h / 20 - 65 °C
View Scheme
(2-hydroxyethyl)[(R)-3-(2-nitrobenzenesulfonylamino)butyl]carbamic acid tert-butyl ester

(2-hydroxyethyl)[(R)-3-(2-nitrobenzenesulfonylamino)butyl]carbamic acid tert-butyl ester

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: triphenylphosphine; azodicarboxylic acid bis(2-methoxyethyl) ester / toluene / 17 h / 20 °C
2: potassium carbonate; thiophenol / acetonitrile / 17 h / 60 °C
3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / N,N-dimethyl-formamide / 16 h / 20 °C
4: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
5: potassium carbonate / acetonitrile / 5 h / 20 - 65 °C
View Scheme
(R)-5-methyl-4-(2-nitrobenzenesulfonyl)[1,4]diazepane-1-carboxylic acid tert-butyl ester

(R)-5-methyl-4-(2-nitrobenzenesulfonyl)[1,4]diazepane-1-carboxylic acid tert-butyl ester

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: potassium carbonate; thiophenol / acetonitrile / 17 h / 60 °C
2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / N,N-dimethyl-formamide / 16 h / 20 °C
3: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
4: potassium carbonate / acetonitrile / 5 h / 20 - 65 °C
View Scheme
(5R)-5-methyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester

(5R)-5-methyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole; 4-methyl-morpholine / N,N-dimethyl-formamide / 16 h / 20 °C
2: trifluoroacetic acid / dichloromethane / 1 h / 20 °C
3: potassium carbonate / acetonitrile / 5 h / 20 - 65 °C
View Scheme
(R)-methyl-2-(N-benzyl-3-((tert-butoxycarbonyl)amino)butyramido)acetate

(R)-methyl-2-(N-benzyl-3-((tert-butoxycarbonyl)amino)butyramido)acetate

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: hydrogenchloride / ethyl acetate / 4 h
2: sodium methylate / methanol / 20 °C / Inert atmosphere
3: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C
4: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C
5: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C
6: triethylamine / N,N-dimethyl-formamide / 2 h / 75 °C
View Scheme
Multi-step reaction with 5 steps
1: hydrogenchloride / ethyl acetate / 4 h / 25 °C
2: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 25 °C / Cooling with ice
3: benzotriazol-1-ol; triethylamine / N,N-dimethyl-formamide; 1,2-dichloro-ethane / 2 h / 50 °C
4: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 25 °C
5: triethylamine / N,N-dimethyl-formamide / 2 h / 75 °C
View Scheme
(R)-4-benzyl-7-methyl-1,4-diazepane-2,5-dione

(R)-4-benzyl-7-methyl-1,4-diazepane-2,5-dione

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 20 °C
2: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C
3: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C
4: triethylamine / N,N-dimethyl-formamide / 2 h / 75 °C
View Scheme
Multi-step reaction with 4 steps
1: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 25 °C / Cooling with ice
2: benzotriazol-1-ol; triethylamine / N,N-dimethyl-formamide; 1,2-dichloro-ethane / 2 h / 50 °C
3: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 25 °C
4: triethylamine / N,N-dimethyl-formamide / 2 h / 75 °C
View Scheme
(R)-1-benzyl-5-methyl-1,4-diazepane

(R)-1-benzyl-5-methyl-1,4-diazepane

Suvorexant
1030377-33-3

Suvorexant

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: benzotriazol-1-ol; triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 2 h / 20 °C
2: palladium 10% on activated carbon; hydrogen / methanol / 4 h / 20 °C
3: triethylamine / N,N-dimethyl-formamide / 2 h / 75 °C
View Scheme
Multi-step reaction with 3 steps
1: benzotriazol-1-ol; triethylamine / N,N-dimethyl-formamide; 1,2-dichloro-ethane / 2 h / 50 °C
2: 10% palladium hydroxide on charcoal; hydrogen / methanol / 4 h / 25 °C
3: triethylamine / N,N-dimethyl-formamide / 2 h / 75 °C
View Scheme
Multi-step reaction with 3 steps
1: / dichloromethane / 18 - 25 °C / Large scale
2: LACTIC ACID / methanol / 30 - 35 °C / Inert atmosphere; Large scale
3: triethylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C / Autoclave; Large scale
View Scheme
Suvorexant
1030377-33-3

Suvorexant

C23H20(2)H3ClN6O2

C23H20(2)H3ClN6O2

Conditions
ConditionsYield
With deuterium In tetrahydrofuran under 1500.15 Torr; for 24h; Glovebox; Heating;99%
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