97664-55-6

Basic information

• Product Name: 6-N-Benzylamino-1-(4'-phenylbutoxy)Hexane
• Synonyms: 6-N-Benzylamino-1-(4'-phenylbutoxy)Hexane;6-Benzylamino-1-(4'-phenylbutoxy)hexane;N-[6-(4-Phenylbutoxy)hexyl]benzenemethanamine;[6-(4-Phenylbutoxy)hexyl]benzylamine;Benzenemethanamine, N-[6-(4-phenylbutoxy)hexyl]- oxalate;Salmeterol Intermediates
• CAS NO: 97664-55-6
• Molecular Formula: C₂₃H₃₃NO
• Molecular Weight: 339.51422
• EINECS: 1308068-626-2
• Mol File: 97664-55-6.mol
• Article Data: 7

Chemical Properties

• Boiling Point: 467.238 °C at 760 mmHg
• Flash Point: 207.26 °C
• Appearance: /
• Density: 0.979 g/cm³
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Sparingly), Ethyl Acetate (Slightly)
• PKA: 9.76±0.19(Predicted)
• CAS DataBase Reference: 6-N-Benzylamino-1-(4'-phenylbutoxy)Hexane(CAS DataBase Reference)
• NIST Chemistry Reference: 6-N-Benzylamino-1-(4'-phenylbutoxy)Hexane(97664-55-6)
• EPA Substance Registry System: 6-N-Benzylamino-1-(4'-phenylbutoxy)Hexane(97664-55-6)

Safety Data

• Hazardous Substances Data: 97664-55-6(Hazardous Substances Data)

Usage

Chemical Properties

Yellow Oil

Synthetic route

6-bromohexyl 4-phenylbutyl ether (94749-73-2) + benzylamine (100-46-9) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
Stage #1: benzylamine With triethylamine; potassium iodide In acetonitrile at 45℃; Stage #2: 6-bromohexyl 4-phenylbutyl ether In acetonitrile	76%
With triethylamine; sodium iodide	75%
With triethylamine; sodium iodide In dimethyl sulfoxide for 17h; Ambient temperature;	70%
With caesium carbonate In N,N-dimethyl-formamide at 60 - 80℃; for 5h;	38%

benzaldehyde (100-52-7) + D 2543 (97664-58-9) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
With sodium tetrahydroborate; molecular sieve 2.) ethanol; Yield given. Multistep reaction;

1 ,6-dibromohexane (629-03-8) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 51 percent / NaOH; tetra-n-butylammonium hydrogen sulphate; benzyltrimethylammonium chloride / CH2Cl2; H2O / 192 h / 20 °C 2: 38 percent / Cs2CO3 / dimethylformamide / 5 h / 60 - 80 °C View Scheme
Multi-step reaction with 4 steps 1: 60 percent 2: NaN3 / dimethylformamide 3: lithium aluminum hydride 4: 1.) mol. sieves; 2.) NaBH4 / 2.) ethanol View Scheme
Multi-step reaction with 2 steps 1: potassium hydroxide; tetrabutylammomium bromide / toluene / 10 h / 20 °C 2: triethylamine; potassium iodide / acetonitrile / 45 °C View Scheme

4-phenyl-butan-1-ol (3360-41-6) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 51 percent / NaOH; tetra-n-butylammonium hydrogen sulphate; benzyltrimethylammonium chloride / CH2Cl2; H2O / 192 h / 20 °C 2: 38 percent / Cs2CO3 / dimethylformamide / 5 h / 60 - 80 °C View Scheme
Multi-step reaction with 2 steps 1: 81 percent / NaH / tetrahydrofuran / 7 h / Ambient temperature 2: 70 percent / Et3N, NaI / dimethylsulfoxide / 17 h / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1: 60 percent 2: NaN3 / dimethylformamide 3: lithium aluminum hydride 4: 1.) mol. sieves; 2.) NaBH4 / 2.) ethanol View Scheme
Multi-step reaction with 2 steps 1: potassium hydroxide; tetrabutylammomium bromide / toluene / 10 h / 20 °C 2: triethylamine; potassium iodide / acetonitrile / 45 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydroxide / 2 h / 60 °C 1.2: 4 h / 110 °C 2.1: triethylamine / toluene / 5 h / 5 - 10 °C 3.1: sodium hydroxide / toluene / 12 h / 110 °C View Scheme

1 ,6-dibromohexane (629-03-8) + sodium-compound of (+-)-cyclopenten-(2)-yl-malonic acid diethyl ester → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 81 percent / NaH / tetrahydrofuran / 7 h / Ambient temperature 2: 70 percent / Et3N, NaI / dimethylsulfoxide / 17 h / Ambient temperature View Scheme

6-bromohexyl 4-phenylbutyl ether (94749-73-2) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaN3 / dimethylformamide 2: lithium aluminum hydride 3: 1.) mol. sieves; 2.) NaBH4 / 2.) ethanol View Scheme

1-azido-6-(4-phenylbutoxy)hexane (168412-89-3) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: lithium aluminum hydride 2: 1.) mol. sieves; 2.) NaBH4 / 2.) ethanol View Scheme

N-[6-(4-phenylbutoxy)hexyl] benzenemethanamine hydrochloride → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
With sodium carbonate In dichloromethane; water at 25 - 30℃; for 0.5h; pH=~ 8;

6-(4-phenylbutyloxy)hexyl methanesulfonate (135235-81-3) + benzylamine (100-46-9) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
With sodium hydroxide In toluene at 110℃; for 12h;

1,6-hexanediol (629-11-8) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / 2 h / 60 °C 1.2: 4 h / 110 °C 2.1: triethylamine / toluene / 5 h / 5 - 10 °C 3.1: sodium hydroxide / toluene / 12 h / 110 °C View Scheme

6-(4-phenyl-butoxy)-hexan-1-ol (97664-53-4) → N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / toluene / 5 h / 5 - 10 °C 2: sodium hydroxide / toluene / 12 h / 110 °C View Scheme

3-carbomethoxy-4-hydroxy-α-bromoacetophenone (36256-45-8) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → 5-(2-{Benzyl-[6-(4-phenyl-butoxy)-hexyl]-amino}-acetyl)-2-hydroxy-benzoic acid methyl ester (497063-91-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60℃;	100%
With triethylamine In acetonitrile at 20℃; for 0.666667h; Inert atmosphere;

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → D 2543 (97664-58-9)

Conditions	Yield
With hydrogen; 5%-palladium/activated carbon In ethanol at 20℃; under 760.051 Torr;	97.9%

3'-acetoxymethyl-4'-acetoxy-2-bromoacetophenone (24085-07-2) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → C36H45NO6

Conditions	Yield
With potassium carbonate In dichloromethane at 25℃; for 5h; Reagent/catalyst; Solvent;	95%
With potassium carbonate at 20℃; for 4h;

(R)-2,2-dimethyl-6-(oxiran-2-yl)-4H-benzo[d][1,3]dioxine (1067185-91-4) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → (R)-2-(benzyl(6-(4-phenylbutoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethanol (1067185-92-5)

Conditions	Yield
With triethylamine at 120℃; for 12h;	83%

5-(2-bromoacetyl)-2-hydroxybenzaldehyde (115787-50-3) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → 2-hydroxy-5-<<<6,6-(4-phenylbutoxy)hexylbenzyl>amino>acetyl>benzaldehyde (163923-19-1)

Conditions	Yield
In acetonitrile for 1h; Heating; other solvent;	71%
With N-ethyl-N,N-diisopropylamine In butanone at 0 - 10℃; for 11.5h;
With N-ethyl-N,N-diisopropylamine In butanone at 0 - 10℃;

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) + 2-benzyloxy-5-(R)-oxiranylbenzoic acid methyl ester (94749-70-9) → 2-Benzyloxy-5-((R)-2-{benzyl-[6-(4-phenyl-butoxy)-hexyl]-amino}-1-hydroxy-ethyl)-benzoic acid methyl ester (160889-19-0)

Conditions	Yield
In tetrahydrofuran Heating;	60%

Bromoacetaldehyde diethyl acetal (2032-35-1) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → N-benzyl-N-diethyloxyethyl-6-(4-phenylbutoxy)hexylamine

Conditions	Yield
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 80℃; for 22h;	51%

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) + 2-Benzyloxy-5-(S)-oxiranyl-benzoic acid methyl ester → 2-Benzyloxy-5-((S)-2-{benzyl-[6-(4-phenyl-butoxy)-hexyl]-amino}-1-hydroxy-ethyl)-benzoic acid methyl ester

Conditions	Yield
In tetrahydrofuran Heating;

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) + methyl 4-([1-13C]-α-bromoacetyl)salicylate (261381-22-0) → C32(13)CH41NO5 (261381-23-1)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 5h; Alkylation; Heating;
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60℃;

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → C24(13)CH34(2)H3NO4

Conditions	Yield
Multi-step reaction with 3 steps 1: i-Pr2EtN / tetrahydrofuran / 60 °C 2: LiAlD4 / tetrahydrofuran / 19 h / 0 - 20 °C 3: H2 / 10 percent Pd/C / ethanol / 4 h / 760 Torr View Scheme
Multi-step reaction with 3 steps 1: diisopropylethylamine / tetrahydrofuran / 5 h / Heating 2: 146 mg / LiAlD4 / diethyl ether / 2.5 h / Heating 3: 71 percent / H2 / Pd/C / ethanol / 3 h / 20 °C / 760 Torr View Scheme

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → C31(13)CH40(2)H3NO4 (1025930-27-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: i-Pr2EtN / tetrahydrofuran / 60 °C 2: LiAlD4 / tetrahydrofuran / 19 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: diisopropylethylamine / tetrahydrofuran / 5 h / Heating 2: 146 mg / LiAlD4 / diethyl ether / 2.5 h / Heating View Scheme

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → C25H34(2)H3NO4

Conditions	Yield
Multi-step reaction with 3 steps 1: 100 percent / i-Pr2EtN / tetrahydrofuran / 60 °C 2: 87 percent / LiAlD4 / tetrahydrofuran / 19 h / 0 - 20 °C 3: 77 percent / H2 / 10 percent Pd/C / ethanol / 4 h / 760 Torr View Scheme

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → C32H40(2)H3NO4 (497063-93-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 100 percent / i-Pr2EtN / tetrahydrofuran / 60 °C 2: 87 percent / LiAlD4 / tetrahydrofuran / 19 h / 0 - 20 °C View Scheme

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → salmeterol (89365-50-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 71 percent / acetonitrile / 1 h / Heating; other solvent 2: NaBH4 / methanol / 36 h / Ambient temperature 3: 0.21 g / H2 / Pd/C / methanol / 10 h View Scheme
Multi-step reaction with 3 steps 1: hydrogenchloride / 10 h / Cooling with ice 2: sodium tetrahydroborate / 8 h / 20 °C 3: palladium 10% on activated carbon / ethanol / 36 h / 45 °C View Scheme
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / butanone / 0 - 10 °C 2: methanol; sodium tetrahydroborate / 8 h / -5 - 30 °C / Inert atmosphere 3: palladium on carbon; hydrogen / methanol / 1.17 h / 25 °C / 413.73 - 517.16 Torr View Scheme
Multi-step reaction with 4 steps 1: triethylamine / acetonitrile / 0.67 h / 20 °C / Inert atmosphere 2: sodium tetrahydroborate / methanol / 1 h / 20 °C / Inert atmosphere 3: palladium 10% on activated carbon / methanol / 2 h / Inert atmosphere 4: lithium aluminium tetrahydride / diethyl ether / 1 h / 20 °C / Inert atmosphere View Scheme

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → 4-hydroxy-1-[[[6-(4-phenylbutoxy)hexyl](phenylmethyl)amino]methyl]-1,3-benzenedimethanol (934842-69-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 71 percent / acetonitrile / 1 h / Heating; other solvent 2: NaBH4 / methanol / 36 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / 10 h / Cooling with ice 2: sodium tetrahydroborate / 8 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / butanone / 0 - 10 °C 2: methanol; sodium tetrahydroborate / 8 h / -5 - 30 °C / Inert atmosphere View Scheme

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → (S)-Salmeterol

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran / Heating 2: 1.) LiAlH4; 2.) H2 / 2.) Pd-C / 1.) THF View Scheme

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → (R)-(-)-salmeterol

Conditions	Yield
Multi-step reaction with 2 steps 1: 60 percent / tetrahydrofuran / Heating 2: 1.) LiAlH4; 2.) H2 / 2.) Pd-C / 1.) THF View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / dichloromethane / 5 h / 25 °C 2: sulfuric acid / ethanol / 25 °C 3: (R)-diphenylprolinol; borane-THF / toluene / Inert atmosphere 4: palladium 10% on activated carbon; hydrogen / ethanol / 16 h / 45 °C View Scheme

8-(benzyloxy)-5-[(1R)-2-bromo-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one (662111-14-0) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → 8-(benzyloxy)-5-[(1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine at 120℃; for 4h;

5-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one (662111-25-3) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → 5-(benzyloxy)-8-(2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-hydroxyethyl)-2H-1,4-benzoxazin-3(4H)-one + 5-(benzyloxy)-8-({benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-2H-1,4-benzoxazin-3 (4H)-one (662111-26-4)

Conditions	Yield
Stage #1: 5-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one; N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine With acetic acid In dichloromethane for 4h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 72h; Stage #3: With sodium tetrahydroborate In methanol; dichloromethane for 2h;

4-(benzyloxy)-7-{(1R)-2-bromo-1-[tetrahydro-2H-pyran-2-yloxy]ethyl}-1,3-benzothiazol-2(3H)-one (662111-37-7) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → 4-(benzyloxy)-7-{(1R)-2-{benzyl[6-(4-phenylbutoxy)hexyl]amino}-1-[tetrahydro-2H-pyran-2-yloxy]ethyl}-1.3-benzothiazol-2(3H)-one

Conditions	Yield
With N-ethyl-N,N-diisopropylamine at 120℃; for 18h;

benzyl 7-(bromoacetyl)-2-oxo-2,3-dihydro-1,3-benzothiazol-4-yl carbonate (662111-43-5) + N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → 7-({benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one (662111-44-6)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 40℃; for 2h; Acidic aqueous solution;

N-[6-(4-phenylbutoxy)hexyl]benzenemethanamine (97664-55-6) → 4-hydroxy-α'-[[[6-(4-phenylbutoxy)hexyl]benzylamino]methyl]-1,3-benzenedirmethanol

Conditions	Yield
With hydrogenchloride for 10h; Cooling with ice;
Multi-step reaction with 2 steps 1: potassium carbonate / dichloromethane / 5 h / 25 °C 2: sulfuric acid / ethanol / 25 °C View Scheme

Upstream product

• 94749-73-2 6-bromohexyl 4-phenylbutyl ether 
• 100-46-9 benzylamine 
• 135235-81-3 6-(4-phenylbutyloxy)hexyl methanesulfonate 
• 629-11-8 1,6-hexanediol 
• 97664-53-4 6-(4-phenyl-butoxy)-hexan-1-ol 
• 163923-18-0 N-[6-(4-phenylbutoxy)hexyl] benzenemethanamine hydrochloride 
• 168412-89-3 1-azido-6-(4-phenylbutoxy)hexane 
• 629-03-8 1 ,6-dibromohexane 
• 3360-41-6 4-phenyl-butan-1-ol 
• 100-52-7 benzaldehyde 
• 97664-58-9 D 2543 

Downstream Products

• 261381-23-1 C₃₂⁽¹³⁾CH₄₁NO₅ 
• 662111-26-4 5-(benzyloxy)-8-({benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-2H-1,4-benzoxazin-3 (4H)-one 
• 662111-44-6 7-({benzyl[6-(4-phenylbutoxy)hexyl]amino}acetyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one 
• 135271-49-7 salmeterol xinafoate 
• 97664-58-9 D 2543 
• 135271-47-5 (R)-(-)-salmeterol 
• 135271-47-5 (S)-Salmeterol 
• 934842-69-0 4-hydroxy-1-[[[6-(4-phenylbutoxy)hexyl](phenylmethyl)amino]methyl]-1,3-benzenedimethanol 
• 89365-50-4 salmeterol 
• 497063-93-1 C₃₂H₄₀⁽²⁾H₃NO₄ 
• 1025930-27-1 C₃₁⁽¹³⁾CH₄₀⁽²⁾H₃NO₄ 
• 497063-91-9 5-(2-{Benzyl-[6-(4-phenyl-butoxy)-hexyl]-amino}-acetyl)-2-hydroxy-benzoic acid methyl ester 

Relevant articles and documents

Crystal of fumarate of salmeterol intermediate and preparation process thereof

The invention discloses a crystal of fumarate of a salmeterol intermediate and a preparation process thereof. The preparation process comprises the following steps: dissolving 6-benzylamino-1-(4'-phenylbutoxy)hexane in alcohol; adding fumaric acid; carrying out heating to 50 to 60 DEG C and carrying out stirring to allow the above substance to be thoroughly dissolved; carrying out cooling to 37 to 40 DEG C within 2 to 4 h so as to allow a crystal to be precipitated, and maintaining the temperature for 2 to 3 h; then allowing the temperature to drop to 12 to 15 DEG C within 6 to 8 h; and successively carrying out ageing for 8 to 12 h, filtering and drying so as to obtain a white solid so as to obtain the fumarate of the salmeterol intermediate 6-benzylamino-1-(4'-phenylbutoxy)hexane. The crystal obtained in the invention has good stability and can be stored for a long time; the preparation process is convenient to operate and easy for industrialization; the alcohol used in the invention is a low-toxicity solvent selected from an organic solvent; and the crystal form of the fumarate of the salmeterol intermediate can be stably obtained.

A convenient synthesis of (R)-salmeterol via Rh-catalyzed asymmetric transfer hydrogenation

(R)-Salmeterol was synthesized in eight steps with salicaldehyde as the starting material. The key chiral intermediate, alcohol 5, was prepared via Rh-catalyzed asymmetric transfer hydrogenation with (S,S)-PEG-BsDPEN or (S,S)-TsDPEN ligand and sodium formate as the hydrogen donor under mild conditions.

Improved synthesis of 13C,2H3- and 2H3-salmeterol by Cs2CO3-mediated monoalkylation of a primary amine

An abbreviated synthesis of isotopically labelled salmeterol has been achieved. The key improvement utilizes a highly selective Cs2CO3-mediated one-pot alkylation of benzylamine by 6-bromo-1-(4′-phenylbutoxy)hexane to prepare the limiting reagent, 6-N-benzylamino-1-(4′-phenylbutoxy)hexane without overalkylation. The method was applied to synthesis of the title compounds in >97 at% isotopic purity. Copyright