41570-61-0

Basic information

• Product Name: Tulobuterol
• Synonyms: TULOBUTEROL;TULOBUTEROL BASE;alpha-[(tert-butylamino)methyl]-o-chlorobenzyl alcohol;TulobuterolHcl56776-01-3/Base;Tulobuterol(baseandorunspecifiedsalt);2-Chloro-a-[[(1,1-dimethylethyl)amino]methyl]benzenemethano;Benzenemethanol, 2-chloro-a-[[(1,1-dimethylethyl)amino]methyl]- (9CI);HN 078
• CAS NO: 41570-61-0
• Molecular Formula: C₁₂H₁₈ClNO
• Molecular Weight: 227.73
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Amines;Aromatics;API
• Mol File: 41570-61-0.mol
• Article Data: 10

Chemical Properties

• Melting Point: 89-91°C
• Boiling Point: 338.2 °C at 760 mmHg
• Flash Point: 158.3 °C
• Appearance: Crystalline Solid
• Density: 1.098 g/cm³
• Vapor Pressure: 3.9E-05mmHg at 25°C
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 13.62±0.20(Predicted)
• CAS DataBase Reference: Tulobuterol(CAS DataBase Reference)
• NIST Chemistry Reference: Tulobuterol(41570-61-0)
• EPA Substance Registry System: Tulobuterol(41570-61-0)

Safety Data

• Safety Statements: 24/25
• RTECS: DA4734170
• Hazardous Substances Data: 41570-61-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Tulobuterol is used as a transdermal patch for increasing normal diaphragm muscle strength. As a β-adrenergic receptor agonist, it helps in managing respiratory conditions by enhancing muscle strength and improving breathing efficiency.
Used in Respiratory Treatment:
Tulobuterol is used as a sympathomimetic drug for treating respiratory conditions, particularly those involving the diaphragm muscle. Its agonistic action on β-adrenergic receptors aids in improving muscle strength and overall respiratory function.

InChI:InChI=1/C12H18ClNO.ClH/c1-12(2,3)14-8-11(15)9-6-4-5-7-10(9)13;/h4-7,11,14-15H,8H2,1-3H3;1H

Synthetic route

1-(2-chlorophenyl)-2-hydroxyethanone (27993-71-1) + tert-butylamine (75-64-9) → tulobuterol (41570-61-0)

Conditions	Yield
With methanol; sodium tetrahydroborate at 15 - 20℃;	94.1%
Stage #1: 1-(2-chlorophenyl)-2-hydroxyethanone; tert-butylamine In 1,2-dichloro-ethane at 25℃; for 2h; Stage #2: With sodium tetrahydroborate In 1,2-dichloro-ethane at 0℃; for 2h;	73%

o-chlorostyrene oxide (62717-50-4) + tert-butylamine (75-64-9) → tulobuterol (41570-61-0)

Conditions	Yield
In methanol at 40 - 50℃; for 9h; Concentration;	93%
In water at 20℃; for 48h;	59%
In ethanol; toluene at 150℃; under 6000.6 - 6750.68 Torr; for 0.833333h; Flow reactor; regioselective reaction;	162 mg

2-Bromo-1-(2-chlorophenyl)ethan-1-ol (72702-57-9) + tert-butylamine (75-64-9) → tulobuterol (41570-61-0)

Conditions	Yield
In ethanol for 6h; Reflux; Large scale;	89%
In ethanol at 20 - 80℃; for 3h; Temperature;	85%
for 8h; Reflux; Inert atmosphere;	68%

1-(2-chlorophenyl)ethanone (2142-68-9) + tert-butylamine (75-64-9) → tulobuterol (41570-61-0)

Conditions	Yield
Stage #1: 1-(2-chlorophenyl)ethanone With N-Bromosuccinimide; toluene-4-sulfonic acid In dichloromethane for 6h; Reflux; Stage #2: tert-butylamine With magnesium sulfate In methanol at 30℃; for 4h; Inert atmosphere; Stage #3: With potassium borohydride In ethanol at -10 - 10℃; for 6.5h; Solvent; Reagent/catalyst; Temperature; Reflux;	79%

2-Chlorobenzyl alcohol (17849-38-6) → tulobuterol (41570-61-0)

Conditions

Yield

Multi-step reaction with 3 steps 1: sodium hypochlorite; potassium bromide; sodium hydrogencarbonate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / water; toluene / 0 °C / Flow reactor 2: sodium hydroxide; tetra-(n-butyl)ammonium iodide / water; toluene / 0.4 h / 90 °C / 750.08 - 1500.15 Torr / Flow reactor 3: ethanol; toluene / 0.83 h / 150 °C / 6000.6 - 6750.68 Torr / Flow reactor View Scheme

2'-chloro-sec-phenethyl alcohol (13524-04-4) → tulobuterol (41570-61-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium hydrogensulfate; hydroquinone / 3 h / 200 - 205 °C 2: sodium hydrogencarbonate; 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / Reflux 3: methanol / 9 h / 40 - 50 °C View Scheme

1-(2-chlorophenyl)ethanone (2142-68-9) → tulobuterol (41570-61-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: iodine; dimethyl sulfoxide / 120 °C 2.1: 1,2-dichloro-ethane / 2 h / 25 °C 2.2: 2 h / 0 °C View Scheme
Multi-step reaction with 3 steps 1: bromine / water / 0.75 h / 20 °C / Large scale 2: potassium borohydride / water; ethanol / 0.25 h / 20 °C / Cooling with ice; Large scale 3: ethanol / 6 h / Reflux; Large scale View Scheme

2-chloro-benzaldehyde (89-98-5) → tulobuterol (41570-61-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium tert-butylate / dimethyl sulfoxide / 0.5 h / 5 - 20 °C 2: water / 48 h / 20 °C View Scheme

3-(tert-butyloxycarbonylamino)propionic acid (3303-84-2) + tulobuterol (41570-61-0) → C20H31ClN2O4

Conditions	Yield
With dmap In dichloromethane at 0 - 20℃; for 3h;	98%

tulobuterol (41570-61-0) → Tulobuterol hydrochloride (56776-01-3)

Conditions	Yield
With hydrogenchloride In diethyl ether; isopropyl alcohol	91%

tulobuterol (41570-61-0) → β-alanyl-tulobuterol

Conditions	Yield
Multi-step reaction with 2 steps 1: dmap / dichloromethane / 3 h / 0 - 20 °C 2: hydrogenchloride / tetrahydrofuran; ethyl acetate / 2 h / 0 - 20 °C View Scheme

tulobuterol (41570-61-0) → tulobuterol + tulobuterol

Conditions	Yield
With ammonium acetate; triethylamine In water; acetonitrile pH=5;

Upstream product

• 89-98-5 2-chloro-benzaldehyde 
• 2142-68-9 1-(2-chlorophenyl)ethanone 
• 75-64-9 tert-butylamine 
• 72702-57-9 2-Bromo-1-(2-chlorophenyl)ethan-1-ol 
• 27993-71-1 1-(2-chlorophenyl)-2-hydroxyethanone 
• 13524-04-4 2'-chloro-sec-phenethyl alcohol 
• 17849-38-6 2-Chlorobenzyl alcohol 
• 62717-50-4 o-chlorostyrene oxide 

Downstream Products

• 56776-01-3 Tulobuterol hydrochloride 

Relevant articles and documents

Tulobuterol crystal form and preparation method thereof

The invention provides a tulobuterol crystal form and a preparation method thereof. The preparation method comprises the following steps of: dissolving tulobuterol in ethyl acetate and other good solvents, dropwisely adding n-heptane and other poor solvents into the system, filtering, taking the filter cake, and drying the filter cake to obtain the tulobuterol crystal form crystal. The crystal form is high in purity and good in stability, has superiority in process production, and is suitable for long-term storage in the preparation process.

Synthesis of the β2-Agonist Tulobuterol and Its Metabolite 4-Hydroxytulobuterol

Abstract: Alternative methods have been developed for the synthesis of theβ2-agonist tulobuterol and its metabolite4-hydroxytulobuterol with a similar activity. The proposed procedures utilizeavailable reagents, and the key stage in the synthesis is the formation ofintermediate oxirane according to the Corey–Chaykovsky reaction, followed byopening of the oxirane ring by the action of excess tert-butylamine. In the synthesis of 4-hydroxytulobuterol, thehydroxy group was protected by benzylation, and the protecting group was removedin the final stage by hydrogenation over carbon-supported palladium.

Preparation method of tulobuterol

The invention provides a preparation method of tulobuterol. The technical problems of potential safety hazard, complicated post-treatment and the like in the existing method are solved. According to the method, a compound 1-(2-chlorphenyl)-2-tert-butylaminoethanol is synthesized from industrially available 2-chlorostyrene through a two-step reaction. The method is short in reaction step, mild in reaction condition, simple and convenient to operate, high in yield and good in application and development prospect, and can be used for preparing tulobuterol.

Process for preparing beta-aminoalcohol from terminal olefin

The invention provides a method for preparing beta-aminoalcohol from terminal olefin. The method comprises the following steps: with the terminal olefin as a raw material, adding dibromohydantoin, conducting stirring, and then adding organic amine to obtain corresponding beta-aminoalcohol. The method has the advantages of mild conditions, easy operation, cheap raw materials, and wide application prospect.

Method for synthesizing tulobuterol

The invention discloses a method for synthesizing tulobuterol. According to the method, 1-(2-chlorophenyl)-2-bromoethanone (compound 3) and 1-(2-chlorophenyl)-2,2-dibromoethanone (compound 10) can besimultaneously utilized to synthesize the tulobuterol. In an original route, the compound 10 is a by-product of synthesis of the compound 3, and about 10-15% of the compound 10 is not fully utilized.The method provided by the invention can improve the synthesis yield of the tulobuterol, is simple to operate, is environmentally friendly, is low in cost and is suitable for industrial production.

Method for industrial production of tulobuterol

The invention discloses a method for industrial production of tulobuterol. The method comprises the following steps of 1, preparation of an intermediate II, wherein chloroacetophenone and an oxidant containing DMSO are added into a reaction kettle in sequence, a reaction is carried out for 1-1.5 hours under the condition of heat preservation, stirring is conducted until the reaction is completelyfinished, and through quenching, extraction, washing and concentration, the intermediate II is prepared; 2, preparation of a crude tulobuterol product, wherein the intermediate II, tert-butylamine, analcohol solvent and sodium borohydride are added into the reaction kettle in sequence and stirred, the reaction temperature is controlled, stirring is conducted until the reaction is completely finished, after concentration, extraction, washing and drying with a drying agent, filtration is conducted, and a filtrate is concentrated and recrystallized to obtain the crude tulobuterol product I; 3, refining of the tulobuterol, wherein the crude tulobuterol product I, an organic solvent and activated carbon for refinement of injection are recrystallized to obtain the refined tulobuterol. The industrial production method is green in reaction and simple in step and causes little pollution to the environment, the purity of the product is up to 99.95% or above, and the tulobuterol contains few impurities.

Method for preparing beta-arylamino alcohol drugs such as tulobuterol, clorprenaline, dichloroisoprenaline and sotalol

The invention provides a method for preparing beta-arylamino alcohol drugs such as tulobuterol, clorprenaline, dichloroisoprenaline and sotalol. The beta-arylamino alcohol drugs have a chemical structure represented by a formula 4 shown in the description. The method comprises the following steps: (1) reacting arylethanone represented by a formula 1 shown in the description with a halogenating agent and sulfoxide to obtain arylglyoxal represented by a formula 2 shown in the description and or 1,1-dihydroxyarylethanone represented by a formula 3 shown in the description; and (2) performing a nucleophilic addition reaction on the arylglyoxal represented by the formula 2 and/or the 1,1-dihydroxyarylethanone represented by the formula 3 and an amine compound having a chemical formula of R1-NH2, and performing a reductive amination reaction in the presence of a reducing agent to obtain the beta-arylamino alcohol drugs.

Synthesis method for compound tulobuterol

The invention relates to a synthesis method for compound tulobuterol. The technical problems that potential safety hazards exist in an existing method, and cost is high are solved. The method includes the following steps of a, an olefination reaction, wherein 1-(2-chlorphenyl)-1-ethyl alcohol serves as an initial raw material, and in the presence of a catalyst and acid, a heating reaction is conducted to generate 2-chloro-styrene; b, a cyclization reaction, wherein 2-chloro-styrene serves as a raw material, and in the presence of alkali and an oxidizing agent, an epoxidation reaction is conducted to obtain 2-(2-chlorphenyl) ethylene oxide; c, a ring-opening reaction, wherein 2-(2-chlorphenyl) ethylene oxide serves as a raw material and reacts with tert-butylamine to obtain compound 1-(2-chlorphenyl)-2-tert-butylamino ethanol. The synthesis method can be used for preparing tulobuterol.

Continuous and convergent access to vicinyl amino alcohols

Five active pharmaceutical ingredients (APIs) containing the vicinyl amino alcohol moiety were synthesized using a convergent chemical assembly system. The continuous system is composed of four flow reaction modules: biphasic oxidation, Corey-Chaykovsky epoxidation, phenol alkylation, and epoxide aminolysis. Judicious choice of reagents and module order allowed for two classes of β-amino alcohols, aryl and aryloxy, to be synthesized in good (27-69%) overall yields.

Combined doses

The present invention discloses a method and a pharmaceutical dry powder combined dose for the prophylaxis or treatment of a respiratory disorder in a mammalian host by inhalation of a metered dry powder combined dose of finely divided dry medication powders. At least one dry powder medicament is selected from a first group of bronchodilating medicaments and at least one dry powder medicament from a second group of anti-inflammatory medicaments. A metered dry powder medicinal combined dose comprising separately metered deposits of medicinally suitable quantities of each of the selected medicaments is prepared, in which the sum of the metered deposits constitutes the metered quantities of powder of the combined dose and the medicinal combined dose is introduced into an adapted inhaler device for a generally simultaneous delivery of the medicinal combined dose during the course of a single inhalation by a user, such that the delivered medicinal combined dose is composed of a high proportion of mixed de-aggregated fine particles of the selected medicaments, whereby an desired therapeutic or treating effect to the user is achieved.