78613-35-1

Basic information

• Product Name: Amorolfine
• Synonyms: (+/-)-cis-2,6-dimethyl-4-[2-methyl-3-(p-tert-pentylphenyl)propyl]morpholine;SYLIMARIN;4-(3-(4-(1,1-Dimethylpropyl)phenyl)-2-methylpropyl)-2,6-dimethylmorpholine;Morpholine, 4-3-4-(1,1-dimethylpropyl)phenyl-2-methylpropyl-2,6-dimethyl-, (2R,6S)-rel-;Loceryl;Morpholine, 4-[3-[4-(1,1-dimethylpropyl)phenyl]-2-methylpropyl]-2,6-dimethyl-, cis-;Ro 14-4767;Ro 14-4767/000
• CAS NO: 78613-35-1
• Molecular Formula: C₂₁H₃₅NO
• Molecular Weight: 317.51
• Mol File: 78613-35-1.mol
• Article Data: 6

Chemical Properties

• Boiling Point: bp0.1 120°
• Flash Point: 119.612 °C
• Appearance: /
• Density: 0.925 g/cm³
• PKA: 7.33±0.10(Predicted)
• CAS DataBase Reference: Amorolfine(CAS DataBase Reference)
• NIST Chemistry Reference: Amorolfine(78613-35-1)
• EPA Substance Registry System: Amorolfine(78613-35-1)

Safety Data

• Hazard Codes: Xn
• Statements: 20/21/22-36/37/38
• Safety Statements: 26-36
• Hazardous Substances Data: 78613-35-1(Hazardous Substances Data)

Usage

Definition

ChEBI: A member of the class of morpholines that is cis-2,6-dimethylmorpholine in which the hydrogen attached to the nitrogen is replaced by a racemic 2-methyl-3-[p-(2-methylbutan-2-yl)phenyl]propyl group. An inhibitor of the action f squalene monooxygenase, Delta14 reductase and D7-D8 isomerase and an antifungal agent, it is used (generally as its hydrochloride salt) for the topical treatment of fungal nail and skin infections.

Clinical Use

Amorolfine is the only drug in this class that is employed clinically in the treatment of human fungal infections. Amorolfine is not currently available in the United States, but it is marketed in Europe and Asia for the topical treatment of dermatophytic infections.

InChI:InChI=1/C21H35NO/c1-7-21(5,6)20-10-8-19(9-11-20)12-16(2)13-22-14-17(3)23-18(4)15-22/h8-11,16-18H,7,12-15H2,1-6H3/t16?,17-,18+

Synthetic route

C21H33NO2 → amorolfine (78613-35-1)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 30℃; Reagent/catalyst; Inert atmosphere;	93%

tert-Amyl alcohol (75-85-4) + (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride (922734-43-8) → amorolfine (78613-35-1)

Conditions	Yield
Stage #1: (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride With sulfuric acid In dichloromethane at -10℃; for 0.166667h; Stage #2: tert-Amyl alcohol In dichloromethane at -10 - 20℃;	91.64%
sulfuric acid In dichloromethane at -5℃; for 1h; Friedel Crafts Alkylation;

amorolfine hydrochloride → amorolfine (78613-35-1)

Conditions	Yield
With sodium hydroxide In dichloromethane; water pH=13; Product distribution / selectivity;	90%

C16H26O3S + cis-2,6-dimethylmorpholine (141-91-3, 6485-45-6, 6485-55-8) → amorolfine (78613-35-1)

Conditions	Yield
With triethylamine In toluene at 25℃; for 8h; Solvent; Reagent/catalyst;	87%

2-methyl-2-butylchloride (594-36-5) → amorolfine (78613-35-1)

Conditions	Yield
Stage #1: (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride With iron(III) chloride In dichloromethane Stage #2: 2-methyl-2-butylchloride In dichloromethane at -20 - 20℃; Stage #3: With sodium hydroxide; water Product distribution / selectivity; more than 3 stages;	8%
Multi-step reaction with 4 steps 1.1: iron(III) chloride / dichloromethane / 0 - 5 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dimethyl sulfoxide / 1 h / 25 - 30 °C 2.2: 25 - 30 °C 3.1: palladium on activated charcoal; hydrogen / ethanol / 35 - 40 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 30 °C / Inert atmosphere View Scheme

2-methyl-2-butylchloride (594-36-5) → amorolfine (78613-35-1) + cis-4-<3-(4-tert-butylphenyl)-2-methylpropyl>-2,6-dimethylmorpholine (67564-91-4)

Conditions	Yield
Stage #1: (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride With iron(III) chloride In dichloromethane Stage #2: 2-methyl-2-butylchloride In dichloromethane at -52 - -20℃; Stage #3: With sodium hydroxide; water Product distribution / selectivity; more than 3 stages;	A n/a B 0.14%

(2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride (922734-43-8) + 2-methyl-2-butylchloride (594-36-5) → amorolfine (78613-35-1)

Conditions	Yield
Stage #1: (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride; Friedel-Craft catalyst In dichloromethane at -20℃; Stage #2: 2-methyl-2-butylchloride In dichloromethane Reactivity (does not react); Friedel Crafts Alkylation;
Stage #1: (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride; Friedel-Craft catalyst In dichloromethane at 0 - 30℃; Stage #2: 2-methyl-2-butylchloride In dichloromethane Product distribution / selectivity; Friedel Crafts Alkylation;
Stage #1: (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride; Friedel-Craft catalyst In dichloromethane at 20 - 30℃; Stage #2: 2-methyl-2-butylchloride In dichloromethane at -50℃; for 2.5h; Friedel Crafts Alkylation; Stage #3: With hydrogenchloride; sodium hydroxide Product distribution / selectivity; more than 3 stages;
Stage #1: (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride; iron(III) chloride In dichloromethane at 33℃; for 0.166667h; Friedel Crafts Alkylation; Stage #2: 2-methyl-2-butylchloride In dichloromethane at -20℃; for 2.5h; Product distribution / selectivity;

(2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride (922734-43-8) + 2-methyl-2-butylchloride (594-36-5) → amorolfine (78613-35-1) + cis-4-<3-(4-tert-butylphenyl)-2-methylpropyl>-2,6-dimethylmorpholine (67564-91-4)

Conditions	Yield
Stage #1: (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride; Friedel-Craft catalyst In dichloromethane Stage #2: 2-methyl-2-butylchloride In dichloromethane at -52 - -20℃; Product distribution / selectivity; Friedel Crafts Alkylation;

2-methyl-3-phenylacrylic acid (1895-97-2) → amorolfine (78613-35-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 0.5 h / 25 °C 1.2: 25 °C 2.1: magnesium / methanol / 60 - 70 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 35 °C 3.2: pH 3 - 4 4.1: sulfuric acid / dichloromethane / 0.17 h / -10 °C 4.2: -10 - 20 °C View Scheme

cis-2,6-dimethylmorpholine (141-91-3, 6485-45-6, 6485-55-8) → amorolfine (78613-35-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 0.5 h / 25 °C 1.2: 25 °C 2.1: magnesium / methanol / 60 - 70 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 35 °C 3.2: pH 3 - 4 4.1: sulfuric acid / dichloromethane / 0.17 h / -10 °C 4.2: -10 - 20 °C View Scheme

C16H21NO2 → amorolfine (78613-35-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: magnesium / methanol / 60 - 70 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 35 °C 2.2: pH 3 - 4 3.1: sulfuric acid / dichloromethane / 0.17 h / -10 °C 3.2: -10 - 20 °C View Scheme

C16H23NO2 → amorolfine (78613-35-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 35 °C 1.2: pH 3 - 4 2.1: sulfuric acid / dichloromethane / 0.17 h / -10 °C 2.2: -10 - 20 °C View Scheme

α-methylcinnamic acid (1199-77-5) → amorolfine (78613-35-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: iron(III) chloride / dichloromethane / 0 - 5 °C 2.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dimethyl sulfoxide / 1 h / 25 - 30 °C 2.2: 25 - 30 °C 3.1: palladium on activated charcoal; hydrogen / ethanol / 35 - 40 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 30 °C / Inert atmosphere View Scheme

C15H20O2 → amorolfine (78613-35-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dimethyl sulfoxide / 1 h / 25 - 30 °C 1.2: 25 - 30 °C 2.1: palladium on activated charcoal; hydrogen / ethanol / 35 - 40 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 30 °C / Inert atmosphere View Scheme

C21H31NO2 → amorolfine (78613-35-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: palladium on activated charcoal; hydrogen / ethanol / 35 - 40 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 0 - 30 °C / Inert atmosphere View Scheme

2-methyl-3-(4-tert-amylphenyl)propanol → amorolfine (78613-35-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / toluene / 6 h / 0 - 25 °C / Large scale 2: triethylamine / toluene / 8 h / 25 °C View Scheme

amorolfine (78613-35-1) → amorolfine hydrochloride

Conditions	Yield
With hydrogenchloride In ethanol at 0 - 5℃; pH=3 - 4;	94%

amorolfine (78613-35-1) → amorolfine hydrochloride

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 20℃; for 0.5h; pH=3 - 4;	93.36%
With hydrogenchloride In Isopropyl acetate at 0℃; pH=3 - 4; Large scale;	80%
With hydrogenchloride In ethanol at 10 - 65℃; pH=1.5 - 3;	77%
With hydrogenchloride In ethanol at -20 - 65℃; for 0.5 - 2h;	77%
With hydrogenchloride In isopropyl alcohol

Upstream product

• 594-36-5 2-methyl-2-butylchloride 
• 1199-77-5 α-methylcinnamic acid 
• 141-91-3 cis-2,6-dimethylmorpholine 
• 1895-97-2 2-methyl-3-phenylacrylic acid 
• 75-85-4 tert-Amyl alcohol 
• 922734-43-8 (2R,6S)-2,6-dimethyl-4-(2-methyl-3-phenylpropyl)morpholine hydrochloride 
• 78613-38-4 amorolfine hydrochloride 

Downstream Products

• 78613-38-4 amorolfine hydrochloride 
• 78613-38-4 amorolfine hydrochloride 

Relevant articles and documents

Preparation method of amorolfine hydrochloride

The invention relates to the technical field of pharmaceutical preparations. The invention discloses a preparation method of amorolfine hydrochloride. The method comprises the following steps: with 3-(4-tert-amylphenyl)-2-methyl propanol as a raw material, under alkaline condition, performing a reaction on the raw material with methylsulfonyl chloride and performing nucleophilic substitution reaction with cis-2,6-dimethylmorpholine; and finally performing a reaction with hydrogen chloride gas to form the amorolfine hydrochloride, that is, the final product. According to the present invention,the method has advantages of cheap raw material source, easily-controlled process operation, high yield, stable quality, less impurity, significantly-reduced cost compared to other methods, suitability for industrial production, and the like.

Amorolfine hydrochloride preparation method

The invention provides an amorolfine hydrochloride preparation method which specifically comprises the following steps: putting a compound of formula IIa shown in the specification into an organic solvent, further putting an amidation catalyst, carrying out a stirring reaction, further adding cis-2,6-dimethyl morpholine, and carrying out a reaction so as to obtain a compound III; carrying out backflow stirring on the compound III in absolute methanol, adding magnesium chips in batches, and carrying out a reaction so as to obtain a compound IV; carrying out a reaction on the compound IV under the action of a reducing agent, thereby obtaining a compound V. The method is novel in process route, cheap and easy in raw material obtaining, low in cost, simple in process operation, short in production cycle, gentle in reaction condition, high in yield, good in product quality and applicable to industrial production.

Process of producing amorolfine

The present invention refers to an improved process of producing Amorolfine base, which is a compound of formula (I): said process comprising the steps of: (i) contacting a compound of formula (II): with a Friedel-Crafts catalyst; and (ii) adding one equivalent of 2-halogeno-2-methylbutane, characterised in that the reaction mixture obtained in step (i) is cooled to a temperature between -40 to -60 °C prior to step (ii) and the Friedel-Craft catalyst is chosen among the group consisting of boron trifluoride complex, titanium chloride complex, zinc chloride, gallium chloride, antimony pentafluoride, molybdenum pentachloride, indium chloride, antimony pentachloride, lanthanide bromide, scandium(III)triflate, lanthanide (III) triflate, yterbium (III) triflate and silica gel associated with ferric chloride.