150683-30-0

Basic information

• Product Name: Tolvaptan
• Synonyms: N-[4-(9-chloro-6-hydroxy-2-azabicyclo[5.4.0]undeca-8,10,12-triene-2-carbonyl)-3-methyl-phenyl]-2-methyl-benzamide;N-[4-[(5R)-7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1-benzazepine-1-carbonyl]-3-methylphenyl]-2-methylbenzamide;Tolvaptan;OPC 41061;OPC-41061;SaMsca;Tolvaptan Tablets;N-(4-(7-Chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)-3-Methylphenyl)-2-MethylbenzaMide
• CAS NO: 150683-30-0
• Molecular Formula: C₂₆H₂₅ClN₂O₃
• Molecular Weight: 448.94
• EINECS: 1308068-626-2
• Product Categories: APIs;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Isotope Labelled Compounds;Tolvaptan;Samsca;Other APIs;Inhibitors
• Mol File: 150683-30-0.mol

Chemical Properties

• Melting Point: 219-222°C
• Boiling Point: 594.4 °C at 760 mmHg
• Flash Point: 313.3 °C
• Appearance: white to tan/
• Density: 1.311 g/cm³
• Vapor Pressure: 5.64E-15mmHg at 25°C
• Refractive Index: 1.663
• Storage Temp.: Refrigerator
• Solubility: DMSO: ≥15mg/mL
• PKA: 13.00±0.70(Predicted)
• CAS DataBase Reference: Tolvaptan(CAS DataBase Reference)
• NIST Chemistry Reference: Tolvaptan(150683-30-0)
• EPA Substance Registry System: Tolvaptan(150683-30-0)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 150683-30-0(Hazardous Substances Data)

Usage

Uses

1. Used in Pharmaceutical Industry:
Tolvaptan is used as a therapeutic agent for the treatment of hyponatremia, particularly in cases caused by congestive heart failure, various edematous diseases, cirrhosis, and SIADH. It helps in increasing the plasma sodium concentration and promoting water excretion without disturbing the electrolyte balance.
2. Used in Cardiovascular Applications:
Tolvaptan is used as a diuretic agent to reduce left ventricular end-systolic volumes and improve left ventricular ejection fraction in a rat model of myocardial infarction.
3. Used in Nephrology:
Tolvaptan is used as a selective V2 receptor antagonist to promote water excretion in patients with impaired renal function, contributing to the management of hyponatremia.
4. Used in Oncology:
Although not explicitly mentioned in the provided materials, tolvaptan has been studied for its potential use in oncology, particularly in the treatment of certain types of cancer by targeting the arginine vasopressin V2 receptor.
5. Used in Drug Delivery Systems:
Tolvaptan can be formulated in various drug delivery systems to enhance its bioavailability, therapeutic outcomes, and patient compliance.

Synthesis

Fugure 1: Synthesis of Tolvaptan

Synthesis

Tolvaptan may be prepared in 11 steps starting from 5chloro- 2-nitrobenzoic acid. Following esterification, reduction of the nitro moiety with tin(II) chloride, subsequent protection (tosylation) and alkylation of the resulting aniline, and a Dieckmann cyclization with potassium tert-butoxide generate the benzazepinone core that is ultimately decarboxylated by heating with hydrochloric acid in acetic acid. After deprotection of the amine group, condensation with 2methyl- 4-nitrobenzoyl chloride affords another nitro handle that is reduced with tin(II) chloride. This aniline is coupled with 2-methylbenzoyl chloride to give the penultimate intermediate. In the final step, reduction of the ketone functionality with sodium borohydride provides racemic tolvaptan that is formulated into 15- and 30-mg tablets for oral administration.

Precautions

Tolvaptan(SAMSCA) should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Tolvaptan(SAMSCA) is contraindicated in the following conditions: Urgent need to raise serum sodium acutely Inability of the patient to sense or appropriately respond to thirst Hypovolemic hyponatremia Concomitant use of strong CYP 3A inhibitors Anuric patients Hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or its components

References

https://www.samsca.com/dosing-and-administration https://en.wikipedia.org/wiki/Tolvaptan

Originator

Otsuka Pharmaceutical (US)

Biochem/physiol Actions

Tolvaptan (OPC 41061) is a potent, orally active non-peptide vasopressin V2 selective antagonist. IC50 = 3 nM at the rat V2 receptor; 29 times more selective for the V2 than for V1a. Tolvaptan has also been shown to inhibit the development of polycystic kidney disease in several animal models.

Clinical Use

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Otsuka Pharmaceutical licensed tolvaptan under the trade name Samsca after the FDA approved the drug in May 2009. Tolvaptan has also shown efficacy against polycystic kidney disease. In a 2004 trial, tolvaptan administered with traditional diuretics was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia (decreased blood levels of potassium). The drug also exhibited no adverse effect on kidney function.

Side effects

The most common adverse events were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. The recommended starting dose is 15 mg daily with a daily 15-mg adjustment to a maximum of 60 mg daily to raise serum sodium concentration. Initiation should be in a hospital setting where serum sodium and volume status may be monitored since too rapid correction of hyponatremia (>12 mEq/L/24 h) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, spastic quadriparesis, seizures, coma, and death. In addition to avoiding concomitant use of strong CYP3A4 inhibitors, tolvaptan is contraindicated in settings of urgent need to raise serum sodium acutely, in patients with an inability to sense or appropriately respond to thirst, in hypovolemic hyponatremia conditions, and in anuric patients.

references

[1] miyazaki t, fujiki h, yamamura y, et al. tolvaptan, an orally active vasopressin v2-receptor antagonist-pharmacology and

InChI:InChI=1/C26H25ClN2O3/c1-16-6-3-4-7-20(16)25(31)28-19-10-11-21(17(2)14-19)26(32)29-13-5-8-24(30)22-15-18(27)9-12-23(22)29/h3-4,6-7,9-12,14-15,24,30H,5,8,13H2,1-2H3,(H,28,31)/t24-/m1/s1

Synthetic route

MOP-21826 (137973-76-3) → tolvaptan (150683-30-0)

Conditions	Yield
With methanol; sodium tetrahydroborate at 0℃; for 2h;	96%
With methanol; sodium tetrahydroborate at 20℃; for 5h;	94%
With sodium bis(2-methoxyethoxy)aluminium dihydride In tetrahydrofuran at -5 - 20℃; Solvent;	94.2%

MOP-21826 (137973-76-3) → C34H32ClN3O4 + C42H36ClN3O5 + C42H38ClN3O5 + C42H38ClN3O5 + tolvaptan (150683-30-0)

Conditions	Yield
Stage #1: MOP-21826 With sodium tetrahydroborate In methanol for 1h; Stage #2: With hydrogenchloride In methanol; water at 20℃;	A n/a B n/a C n/a D n/a E 90%

(±)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol + 2-methyl-4-(2-methylbenzoylamino)benzoic acid chloride (331947-69-4) → tolvaptan (150683-30-0)

Conditions	Yield
With 2,6-dimethylpyridine In N,N-dimethyl acetamide; water at 0℃; for 2h; Reagent/catalyst;	72%

2,2-dimethyl-propionic acid 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester → tolvaptan (150683-30-0)

Conditions	Yield
With sodium hydroxide In ethanol; water at 50℃; for 2h;
With sodium hydroxide; ethanol; water at 50℃; for 2h;

(rac)-7-chloro-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl pivalate (804498-94-0) → tolvaptan (150683-30-0)

Conditions

Yield

Multi-step reaction with 8 steps 1: 96 percent / hydroxylamine hydrochloride; sodium acetate / ethanol; H2O / 2 h / Heating 2: PCl5 / CH2Cl2 / 2 h / 20 °C 3: acetic acid; Zn / 0.5 h / Heating 4: BH3*THF / tetrahydrofuran / 0.5 h / Heating 5: 98 percent / triethylamine / CH2Cl2 / 1 h / 20 °C 6: 82 percent / hydrochloric acid; SnCl2 / ethanol / 2 h / Heating 7: triethylamine / CH2Cl2 / 1 h / 20 °C 8: NaOH / ethanol; H2O / 2 h / 50 °C View Scheme

2,2-dimethylpropionic acid 7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester (863762-10-1) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 98 percent / triethylamine / CH2Cl2 / 1 h / 20 °C 2: 82 percent / hydrochloric acid; SnCl2 / ethanol / 2 h / Heating 3: triethylamine / CH2Cl2 / 1 h / 20 °C 4: NaOH / ethanol; H2O / 2 h / 50 °C View Scheme

2,2-dimethyl-propionic acid 7-chloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: BH3*THF / tetrahydrofuran / 0.5 h / Heating 2: 98 percent / triethylamine / CH2Cl2 / 1 h / 20 °C 3: 82 percent / hydrochloric acid; SnCl2 / ethanol / 2 h / Heating 4: triethylamine / CH2Cl2 / 1 h / 20 °C 5: NaOH / ethanol; H2O / 2 h / 50 °C View Scheme

2,2-dimethylpropionic acid 4-[(E)-hydroxyimino]-7-chloro-1,2,3,4-tetrahydronaphthalen-1-yl ester (863762-02-1) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 7 steps 1: PCl5 / CH2Cl2 / 2 h / 20 °C 2: acetic acid; Zn / 0.5 h / Heating 3: BH3*THF / tetrahydrofuran / 0.5 h / Heating 4: 98 percent / triethylamine / CH2Cl2 / 1 h / 20 °C 5: 82 percent / hydrochloric acid; SnCl2 / ethanol / 2 h / Heating 6: triethylamine / CH2Cl2 / 1 h / 20 °C 7: NaOH / ethanol; H2O / 2 h / 50 °C View Scheme

2,2-dimethyl-propionic acid 3,3,7-trichloro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: acetic acid; Zn / 0.5 h / Heating 2: BH3*THF / tetrahydrofuran / 0.5 h / Heating 3: 98 percent / triethylamine / CH2Cl2 / 1 h / 20 °C 4: 82 percent / hydrochloric acid; SnCl2 / ethanol / 2 h / Heating 5: triethylamine / CH2Cl2 / 1 h / 20 °C 6: NaOH / ethanol; H2O / 2 h / 50 °C View Scheme

2,2-dimethylpropionic acid 7-chloro-1-(4-amino-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester (863762-24-7) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / CH2Cl2 / 1 h / 20 °C 2: NaOH / ethanol; H2O / 2 h / 50 °C View Scheme

2,2-dimethylpropionic acid 7-chloro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester (863762-20-3) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 82 percent / hydrochloric acid; SnCl2 / ethanol / 2 h / Heating 2: triethylamine / CH2Cl2 / 1 h / 20 °C 3: NaOH / ethanol; H2O / 2 h / 50 °C View Scheme

4-chlorobenzenesulfonyl chloride (5202-89-1) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: 85 percent / pyridine / 20 °C 2.1: 94 percent / K2CO3 / dimethylformamide / 4 h / 120 °C 3.1: t-BuOK / toluene / 0.5 h / Heating 3.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 4.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 5.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 6.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 7.1: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 8.1: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1: sodium carbonate / acetonitrile / 5 h / 80 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 3: potassium tert-butylate / toluene / 1 h / 120 °C 4: acetic acid; hydrogenchloride / water / 6 h / 100 °C 5: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C 6: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C 7: sodium tetrahydroborate; methanol / 2 h / 0 °C View Scheme

5-chloro-2-nitrobenzoic acid (2516-95-2) → tolvaptan (150683-30-0)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: 100 percent / K2CO3 / acetone / 0.5 h / Heating 2.1: SnCl2*2H2O; conc. HCl / ethanol / 20 °C 3.1: 85 percent / pyridine / 20 °C 4.1: 94 percent / K2CO3 / dimethylformamide / 4 h / 120 °C 5.1: t-BuOK / toluene / 0.5 h / Heating 5.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 6.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 7.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 8.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 9.1: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 10.1: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme

2-methyl-4-nitrobenzoyl chloride (30459-70-2) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 2: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 3: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 4: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / dichloromethane; water / pH 7 - 8 2.1: tin(ll) chloride / methanol / 16 h / 20 °C 3.1: sodium hydrogencarbonate / dichloromethane / 0 - 5 °C / pH 7 - 8 4.1: sodium tetrahydroborate; methanol / 1 h / 20 °C 4.2: pH 6 - 7 View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 2.1: tin(IV) chloride / methanol / 16 h / 20 °C 3.1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 4.1: sodium tetrahydroborate / methanol / 1 h / 20 °C 4.2: pH 6.0 - 7.0 View Scheme
Multi-step reaction with 4 steps 1.1: magnesium hydroxide / acetonitrile / 0.5 h / 10 °C 1.2: 5 h 2.1: methanol; tin(II) chloride dihdyrate / 23 h / 10 °C 3.1: magnesium hydroxide / dichloromethane; water / 0.5 h / 10 °C 3.2: 3 h 4.1: sodium tetrahydroborate; methanol / 1 h View Scheme

2-methyl-4-nitrobenzoic acid (1975-51-5) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: SOCl2 2: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 3: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 4: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 5: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme

methyl 5-chloro-2-nitrobenzoate (51282-49-6) → tolvaptan (150683-30-0)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: SnCl2*2H2O; conc. HCl / ethanol / 20 °C 2.1: 85 percent / pyridine / 20 °C 3.1: 94 percent / K2CO3 / dimethylformamide / 4 h / 120 °C 4.1: t-BuOK / toluene / 0.5 h / Heating 4.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 5.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 6.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 7.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 8.1: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 9.1: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme

7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one (160129-45-3) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 2: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 3: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 4: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / dichloromethane; water / pH 7 - 8 2.1: tin(ll) chloride / methanol / 16 h / 20 °C 3.1: sodium hydrogencarbonate / dichloromethane / 0 - 5 °C / pH 7 - 8 4.1: sodium tetrahydroborate; methanol / 1 h / 20 °C 4.2: pH 6 - 7 View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 2.1: tin(IV) chloride / methanol / 16 h / 20 °C 3.1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 4.1: sodium tetrahydroborate / methanol / 1 h / 20 °C 4.2: pH 6.0 - 7.0 View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate; triphenylphosphine; palladium diacetate / N,N-dimethyl-formamide; water / 8 h / 120 °C / 22502.3 Torr / Autoclave 2: iron; ammonium chloride / water; methanol / 6 h / 35 - 40 °C 3: pyridine / dichloromethane / 2 h / 0 - 10 °C 4: sodium tetrahydroborate; methanol / 1 h / 15 - 30 °C View Scheme
Multi-step reaction with 4 steps 1.1: magnesium hydroxide / acetonitrile / 0.5 h / 10 °C 1.2: 5 h 2.1: methanol; tin(II) chloride dihdyrate / 23 h / 10 °C 3.1: magnesium hydroxide / dichloromethane; water / 0.5 h / 10 °C 3.2: 3 h 4.1: sodium tetrahydroborate; methanol / 1 h View Scheme

N-p-toluenesulfonyl-5-chloro-anthranilic acid methyl ester (247237-38-3) → tolvaptan (150683-30-0)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: 94 percent / K2CO3 / dimethylformamide / 4 h / 120 °C 2.1: t-BuOK / toluene / 0.5 h / Heating 2.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 3.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 4.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 5.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 6.1: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 7.1: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme

7-chloro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one (193686-76-9) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 2: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 3: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 4: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 5: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme

1-(4-amino-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137977-97-0) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 2: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 2.1: sodium tetrahydroborate / methanol / 1 h / 20 °C 2.2: pH 6.0 - 7.0 View Scheme

1-(4-nitro-2-methylbenzoyl)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (137982-91-3) → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 2: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 3: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: tin(ll) chloride / methanol / 16 h / 20 °C 2.1: sodium hydrogencarbonate / dichloromethane / 0 - 5 °C / pH 7 - 8 3.1: sodium tetrahydroborate; methanol / 1 h / 20 °C 3.2: pH 6 - 7 View Scheme
Multi-step reaction with 3 steps 1.1: tin(IV) chloride / methanol / 16 h / 20 °C 2.1: sodium hydrogencarbonate / water; dichloromethane / 0 - 5 °C / pH 7.0 - 8.0 3.1: sodium tetrahydroborate / methanol / 1 h / 20 °C 3.2: pH 6.0 - 7.0 View Scheme

methyl 5-chloro-2-[N-(3-ethoxycarbonyl)propyl-N-p-toluenesulfonyl]aminobenzoate (247237-43-0) → tolvaptan (150683-30-0)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: t-BuOK / toluene / 0.5 h / Heating 1.2: 60 percent / conc. HCl / acetic acid / 5 h / Heating 2.1: 81 percent / polyphosphoric acid / 1.5 h / 80 - 100 °C 3.1: 32 percent / Et3N / CH2Cl2 / 2 h / 20 °C 4.1: 39 percent / SnCl2*2H2O; conc. HCl / ethanol / 20 °C 5.1: 53 percent / Et3N / CH2Cl2 / 1.5 h / 20 °C 6.1: 30 percent / NaBH4 / methanol / 1 h / 20 °C View Scheme

C13H16ClNO4 → tolvaptan (150683-30-0)

Conditions

Yield

Multi-step reaction with 6 steps 1: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C 2: potassium tert-butylate / toluene / 1 h / 120 °C 3: acetic acid; hydrogenchloride / water / 6 h / 100 °C 4: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C 5: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C 6: sodium tetrahydroborate; methanol / 2 h / 0 °C View Scheme

C21H21ClN2O7 → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: potassium tert-butylate / toluene / 1 h / 120 °C 2: acetic acid; hydrogenchloride / water / 6 h / 100 °C 3: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C 4: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C 5: sodium tetrahydroborate; methanol / 2 h / 0 °C View Scheme

C20H17ClN2O6 → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: acetic acid; hydrogenchloride / water / 6 h / 100 °C 2: hydrogenchloride; tin(II) chloride dihdyrate / ethanol / 4 h / 20 °C 3: N-ethyl-N,N-diisopropylamine / dichloromethane / 2 h / 20 °C 4: sodium tetrahydroborate; methanol / 2 h / 0 °C View Scheme

C18H16Cl2N2O4 → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: dichloromethane / 4.5 h / 20 °C / Reflux 2: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C 3: triethylamine / dichloromethane / 2.25 h / 20 °C 4: sodium tetrahydroborate; methanol / 5 h / 20 °C View Scheme

4-chloro-aniline (106-47-8) → tolvaptan (150683-30-0)

Conditions

Yield

Multi-step reaction with 8 steps 1: sodium carbonate / acetonitrile / 4 h / 80 °C 2: triethylamine / dichloromethane / 3 h / 20 °C 3: sodium hydroxide / 1.5 h / 50 °C 4: thionyl chloride / dichloromethane / 2 h / 20 °C / Reflux 5: dichloromethane / 4.5 h / 20 °C / Reflux 6: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C 7: triethylamine / dichloromethane / 2.25 h / 20 °C 8: sodium tetrahydroborate; methanol / 5 h / 20 °C View Scheme

ethyl 4-(4-chlorophenylamino)butanoate → tolvaptan (150683-30-0)

Conditions

Yield

Multi-step reaction with 7 steps 1: triethylamine / dichloromethane / 3 h / 20 °C 2: sodium hydroxide / 1.5 h / 50 °C 3: thionyl chloride / dichloromethane / 2 h / 20 °C / Reflux 4: dichloromethane / 4.5 h / 20 °C / Reflux 5: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C 6: triethylamine / dichloromethane / 2.25 h / 20 °C 7: sodium tetrahydroborate; methanol / 5 h / 20 °C View Scheme

C20H21ClN2O5 → tolvaptan (150683-30-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: sodium hydroxide / 1.5 h / 50 °C 2: thionyl chloride / dichloromethane / 2 h / 20 °C / Reflux 3: dichloromethane / 4.5 h / 20 °C / Reflux 4: hydrogenchloride; tin(II) chloride dihdyrate / water; ethanol / 3 h / 20 °C 5: triethylamine / dichloromethane / 2.25 h / 20 °C 6: sodium tetrahydroborate; methanol / 5 h / 20 °C View Scheme

Dibenzyl N,N-diisopropylphosphoramidite (108549-23-1) + tolvaptan (150683-30-0) → C40H38ClN2O6P

Conditions	Yield
Stage #1: Dibenzyl N,N-diisopropylphosphoramidite; tolvaptan With 1H-tetrazole In dichloromethane at 20℃; for 2h; Stage #2: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -40 - 0℃; for 1h;	97.2%
Multi-step reaction with 2 steps 1: 2H-tetrazole / dichloromethane / 2 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / -40 - 0 °C View Scheme

tolvaptan (150683-30-0) → C26H26ClN2O6P (942619-74-1)

Conditions	Yield
Stage #1: tolvaptan With triethylamine; trichlorophosphate In 1,2-dimethoxyethane at -15 - -12℃; for 2h; Stage #2: With sodium hydroxide; water In 1,2-dimethoxyethane; toluene at 0 - 50℃; Stage #3: With hydrogenchloride; water at 10℃; Product distribution / selectivity;	97%
Multi-step reaction with 3 steps 1: 2H-tetrazole / dichloromethane / 2 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / -40 - 0 °C 3: 5%-palladium/activated carbon; hydrogen / ethanol / 0.17 h View Scheme
Multi-step reaction with 2 steps 1.1: 1H-tetrazole / dichloromethane / 2 h / 20 °C 1.2: 1 h / -40 - 0 °C 2.1: 5%-palladium/activated carbon; hydrogen / ethanol View Scheme

methanol (67-56-1) + tolvaptan (150683-30-0) → C27H28ClN2O5P (942619-87-6)

Conditions	Yield
Stage #1: tolvaptan With pyridine; diphenyl hydrogen phosphite at 0 - 20℃; for 0.5h; Stage #2: methanol at 20℃; for 0.5h;	91%

tolvaptan (150683-30-0) → fluorodeoxytolvaptan

Conditions	Yield
With 1,3-bis(2,6-diisopropylphenyl)-2-fluoroimidazolium tetrafluoroborate; cesium fluoride In toluene at 80℃; for 17h; Inert atmosphere; Schlenk technique; Sealed tube;	86%

tolvaptan (150683-30-0) → C26H24ClN2O6P(2-)*2Na(1+)

Conditions	Yield
Stage #1: tolvaptan With triethylamine; trichlorophosphate In 1,2-dimethoxyethane at -18 - -13℃; for 2h; Inert atmosphere; Large scale; Stage #2: With water; sodium hydroxide In 1,2-dimethoxyethane at -3 - 30℃; for 0.5h; Inert atmosphere; Large scale;	86%
Multi-step reaction with 4 steps 1: 2H-tetrazole / dichloromethane / 2 h / 20 °C 2: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / -40 - 0 °C 3: 5%-palladium/activated carbon; hydrogen / ethanol / 0.17 h 4: sodium hydroxide / methanol; water / 0.08 h / Cooling with ice View Scheme
Multi-step reaction with 3 steps 1.1: 1H-tetrazole / dichloromethane / 2 h / 20 °C 1.2: 1 h / -40 - 0 °C 2.1: 5%-palladium/activated carbon; hydrogen / ethanol 3.1: sodium hydroxide / methanol; water / 0.08 h / Cooling with ice View Scheme

3-Hydroxypropionitrile (109-78-4) + tolvaptan (150683-30-0) → C29H29ClN3O5P

Conditions	Yield
Stage #1: tolvaptan With pyridine; diphenyl hydrogen phosphite at 20℃; for 0.5h; Stage #2: 3-Hydroxypropionitrile at 20℃; for 0.5h;	75%

tolvaptan (150683-30-0) + n-hexadecanoyl chloride (112-67-4) → {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} hexadecanoate (1094837-35-0)

Conditions	Yield
With pyridine In dichloromethane at 20℃;	74%

tolvaptan (150683-30-0) → C26H26ClN2O5P

Conditions	Yield
Stage #1: tolvaptan With triethylamine; phosphorus trichloride In tetrahydrofuran at -10℃; for 2h; Stage #2: With sodium hydroxide; water In tetrahydrofuran at 0℃; Product distribution / selectivity;	60%
Stage #1: tolvaptan With pyridine; diphenyl hydrogen phosphite at 20℃; for 1h; Stage #2: With water at 20℃; for 0.5h; Product distribution / selectivity;	24%

ethanol (64-17-5) + tolvaptan (150683-30-0) → C28H30ClN2O5P

Conditions	Yield
Stage #1: tolvaptan With pyridine; diphenyl hydrogen phosphite at 0 - 20℃; for 1h; Stage #2: ethanol at 20℃; for 0.5h;	38%

methanol (67-56-1) + tolvaptan (150683-30-0) → C28H30ClN2O6P

Conditions	Yield
Stage #1: tolvaptan With triethylamine; trichlorophosphate In tetrahydrofuran for 0.5h; Cooling with ice/methanol; Stage #2: methanol With triethylamine In tetrahydrofuran for 0.5h;	33%

glycolic acid methyl ester (96-35-5) + tolvaptan (150683-30-0) → C29H30ClN2O7P

Conditions	Yield
Stage #1: tolvaptan With pyridine; diphenyl hydrogen phosphite at 20℃; for 1h; Stage #2: glycolic acid methyl ester at 20℃; for 12h;	20%

Upstream product

• 137973-76-3 MOP-21826 
• 804498-94-0 (rac)-7-chloro-4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl pivalate 
• 863762-10-1 2,2-dimethylpropionic acid 7-chloro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester 
• 863762-02-1 2,2-dimethylpropionic acid 4-[(E)-hydroxyimino]-7-chloro-1,2,3,4-tetrahydronaphthalen-1-yl ester 
• 863762-24-7 2,2-dimethylpropionic acid 7-chloro-1-(4-amino-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester 
• 863762-20-3 2,2-dimethylpropionic acid 7-chloro-1-(2-methyl-4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl ester 
• 5202-89-1 4-chlorobenzenesulfonyl chloride 
• 2516-95-2 5-chloro-2-nitrobenzoic acid 
• 30459-70-2 2-methyl-4-nitrobenzoyl chloride 
• 1975-51-5 2-methyl-4-nitrobenzoic acid 
• 51282-49-6 methyl 5-chloro-2-nitrobenzoate 
• 160129-45-3 7-chloro-1,2,3,4-tetrahydro-5H-benzo[b]azepin-5-one 
• 247237-38-3 N-p-toluenesulfonyl-5-chloro-anthranilic acid methyl ester 
• 193686-76-9 7-chloro-1-(4-methylbenzenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one 

Downstream Products

• 942619-74-1 C₂₆H₂₆ClN₂O₆P 
• 1056613-08-1 C₃₄H₄₂ClN₂O₅P 
• 1056613-14-9 C₄₀H₃₈ClN₂O₅P 
• 1094837-24-7 {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} succinate 
• 1094837-55-4 {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}(2-chloroethyl)carbamate 
• 1094837-35-0 {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} hexadecanoate 
• 1094837-49-6 chloromethyl {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} carbonate 
• 1094837-42-9 7-chloro-1-(2-methyl-4-(2-methylbenzamido)benzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-chlorobutyrate 
• 1094837-36-1 {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} chloroacetate 
• 1094837-41-8 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-dimethylaminobutyrate hydrochloride 
• 1094837-46-3 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrate 
• 1094837-31-6 {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yloxycarbonylmethylthio} acetic acid 
• 942619-87-6 C₂₇H₂₈ClN₂O₅P 
• 1316312-24-9 7-chloro-2,3-dihydro-1H-benzo[b]azepine 

Relevant articles and documents

Preparation method of high-purity tolvaptan

The invention provides a preparation method of high-purity tolvaptan. Specifically, the quality of an intermediate N-(4-(7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-1H-benzo[b]aza-1-ylcarbonyl)-3-methylphenyl)-2-methylbenzamide is controlled through crystallization and purification, so that the high-purity intermediate is obtained, and the high-purity tolvaptan is obtained by controlling the process conditions of reducing the intermediate to obtain the tolvaptan and subsequently purifying the tolvaptan. The method is low in cost, simple in preparation process and mild in reaction condition, the purity of the prepared tolvaptan reaches 99.9% or above, the yield reaches 80% or above, and industrial production is facilitated.

INTERMEDIATES AND METHODS FOR THE PREPARATION OF TOLVAPTAN AND ITS DERIVATIVES

The present invention relates to new intermediates for the synthesis of tolvaptan and its derivatives, as well as a method for its preparation involving said intermediates.

MANUFACTURING METHOD OF TOLVAPTAN, SALT THEREOF AND SOLVATE

PROBLEM TO BE SOLVED: To provide a manufacturing method of high purity and high yield tolvaptan, a salt thereof, or a solvate thereof without using a solvent with large environmental load, and having enhanced operability of a reaction. SOLUTION: There is provided a manufacturing method of tolvaptan, a salt thereof, or a solvate thereof, including a process for reacting following a described carboxylic acid derivative (I) with a chlorination agent such as thionyl chloride to convert it to a corresponding acid chloride (I), in which the reaction process is conducted in a presence of a solvent having relative dielectric constant of 10 or more and donor number of 20 or more, and represented by N,N-dimethyl acetamide, N-methyl-2-pyrrolidone, N.N'-dimethyl propylene urea or N,N,N',N'-tetramethyl urea. SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT

IMPROVED METHODS OF PRODUCING SYNTHETIC INTERMEDIATES OF TOLVAPTAN

PROBLEM TO BE SOLVED: To provide improved methods of producing 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. SOLUTION: The present invention provides methods of producing 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine and 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine, which are synthetic intermediates of tolvaptan, by condensing an amino group and a carboxyl group in the presence of magnesium hydroxide. SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT

Preparation method of high-purity tolvaptan

The invention discloses a preparation method of high-purity tolvaptan. The preparation method comprises the step of reducing N-[4-[(5R)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1-benazepine-1-formyl]-3-methyl phenyl]-2-methyl benzamide with sodium bis(2-methoxyethoxy) aluminumhydride, thereby obtaining the high-purity tolvaptan with the purity higher than or equal to 99.95%. The preparation method disclosed by the invention has the advantages that sodium bis(2-methoxyethoxy) aluminumhydride is adopted as a reducing agent for preparing tolvaptan by reducing N-[4-[(5R)-7-chloro-5-oxo-2,3,4,5-tetrahydro-1-benazepine-1-formyl]-3-methyl phenyl]-2-methyl benzamide, the production of a dechlorination impurity IV can be extremely effectively inhibited, and finally the high-purity tolvaptan with the purity higher than or equal to 99.95% can be obtained, and high yield being 90% or above can be obtained while tetrahydrofuran or methyltetrahydrofuran is adopted as a reaction solvent.

Preparation method of tolvaptan

The invention discloses a preparation method of tolvaptan. According to the preparation method, 7-chloro-1,2,3,4-tetrahydrobenzo[b]azepine-5-one and 4-nitro-2-methyl bromobenzene are taken as the primary raw materials; high purity tolvaptan is obtained after steps of carbonyl inserting reactions, reduction reactions, and acylation reactions, and the yield is high. The preparation method has the advantages that no bromine or tin dichloride is used; the preparation method does not generate a large amount of industrial waste water, and the environment is protected. At the same time, the generation of impurities namely a compound V and a compound VIII is avoided, and the purification becomes easier. No explosive, flammable, and toxic solvent such as chloroform, ether, and the like, is used, the requirements on the protection of workers are lowered, and the safe production is guaranteed. Moreover, the route design is novel, the raw materials are easily available, the operation of the technology is simple and feasible, and a simple and feasible method is provided for the massive industrial production of tolvaptan.

Preparation method for cardiovascular disease treatment drug

The invention provides a preparation method for a cardiovascular disease treatment drug. Specifically, the invention provides a compound represented by a formula (IV) shown in the description and a method for preparing Tolvaptan from the compound represented by the formula (IV). The method provided by the invention has the advantages of being environment-friendly, being easy in raw material obtaining and high in total yield, and the like, thereby being applicable to the industrialized preparation of Tolvaptan.

Preparation method of high-efficiency low-toxicity pitressin antagonist

The invention provides a preparation method of a high-efficiency low-toxicity pitressin antagonist. Specifically, the invention provides a compound having the formula A shown in the description, and a method for preparing tolvaptan through the compound having the formula A. All groups in the formula are defined in the description. The method has advantages of environmental protection, available raw materials, and high overall yield, and is suitable for industrial preparation of tolvaptan.

PROCESS FOR THE PREPARATION OF A BENZAZEPINE DERIVATIVE

Provided is an industrially scalable process for the preparation of a benzazepine derivative, namely, 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (generically referred as Tolvaptan).

PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES

The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.