1378888-43-7

Basic information

• Product Name: Siponimod
• Synonyms: 1-(3-Ethyl-4-(hydroxymethyl)phenyl)ethanone;Ethanone, 1-[3-ethyl-4-(hydroxymethyl)phenyl]-;1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one
• CAS NO: 1378888-43-7
• Molecular Formula: C₁₁H₁₄O₂
• Molecular Weight: 178.22766
• Mol File: 1378888-43-7.mol
• Article Data: 5

Chemical Properties

• Boiling Point: 331.9±37.0 °C(Predicted)
• Appearance: /
• Density: 1.063±0.06 g/cm3(Predicted)
• Storage Temp.: Inert atmosphere,Room Temperature
• PKA: 14.26±0.10(Predicted)
• CAS DataBase Reference: Siponimod(CAS DataBase Reference)
• NIST Chemistry Reference: Siponimod(1378888-43-7)
• EPA Substance Registry System: Siponimod(1378888-43-7)

Safety Data

• Hazardous Substances Data: 1378888-43-7(Hazardous Substances Data)

Usage

Physical Form

Solid

Uses

1-3-Ethyl-4-(hydroxymethyl)-phenyl)ethanone is a reagent used in the prepration of Siponimod, it''s salts ans solid forms of the compound.

Synthetic route

3-ethynyl-4-hydroxymethylacetophenone → 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; under 3750.38 Torr; Reagent/catalyst; Autoclave;	95%

1-[3-ethenyl-4-(hydroxymethyl)phenyl]ethan-1-one (1418144-63-4) → 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7)

Conditions	Yield
With palladium on activated charcoal; hydrogen In ethanol at 20℃; for 3h;	89%
With palladium on activated charcoal; hydrogen at 20℃; under 760.051 Torr; for 3h;	3.93 g
With 5%-palladium/activated carbon; hydrogen In methanol at 28 - 29℃; under 775.743 Torr; for 4h;

3-bromo-4-methylacetophenone (40180-80-1) → 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 12 h / Reflux 1.2: 16 h / Reflux 2.1: sodium carbonate; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran; water / 5 h / 80 °C 3.1: palladium on activated charcoal; hydrogen / 3 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 4 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 12 h / 80 °C 2: calcium carbonate; water / 1,4-dioxane / 16 h / 100 °C 3: palladium dichloride; triphenylphosphine; caesium carbonate / tetrahydrofuran; water / 24 h / 85 °C 4: palladium on activated charcoal; hydrogen / ethanol / 3 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / 1,2-dichloro-ethane / 16 h / 28 - 80 °C 2.1: calcium carbonate; water / 1,4-dioxane / 16 h / 100 °C 3.1: sodium carbonate / tetrahydrofuran; water / 0.5 h / 28 °C / Inert atmosphere 3.2: 10 h / 29 - 80 °C 4.1: hydrogen; 5%-palladium/activated carbon / methanol / 4 h / 28 - 29 °C / 775.74 Torr View Scheme
Multi-step reaction with 6 steps 1.1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / 1,2-dichloro-ethane / 16 h / 28 - 80 °C 2.1: calcium carbonate; water / 1,4-dioxane / 16 h / 100 °C 3.1: 1H-imidazole / dichloromethane / 2 h / 7 - 28 °C / Inert atmosphere 4.1: sodium carbonate / tetrahydrofuran; water / 0.5 h / 28 °C / Inert atmosphere 4.2: 9 h / 29 - 80 °C 5.1: hydrogen; 5%-palladium/activated carbon / methanol / 3 h / 28 - 29 °C / 1034.32 Torr 6.1: hydrogenchloride / methanol; water / 0.33 h / 28 °C View Scheme

1-(3-bromo-4-(hydroxymethyl)phenyl)ethan-1-one (1418144-62-3) → 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate; bis-triphenylphosphine-palladium(II) chloride / tetrahydrofuran; water / 5 h / 80 °C 2: palladium on activated charcoal; hydrogen / 3 h / 20 °C / 760.05 Torr View Scheme
Multi-step reaction with 2 steps 1: palladium dichloride; triphenylphosphine; caesium carbonate / tetrahydrofuran; water / 24 h / 85 °C 2: palladium on activated charcoal; hydrogen / ethanol / 3 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; copper(I) bromide / tetrahydrofuran / 16 h / 80 °C / Inert atmosphere 2: water; potassium carbonate / methanol / 20 °C 3: palladium 10% on activated carbon; hydrogen / methanol / 20 °C / 3750.38 Torr / Autoclave View Scheme
Multi-step reaction with 2 steps 1.1: sodium carbonate / tetrahydrofuran; water / 0.5 h / 28 °C / Inert atmosphere 1.2: 10 h / 29 - 80 °C 2.1: hydrogen; 5%-palladium/activated carbon / methanol / 4 h / 28 - 29 °C / 775.74 Torr View Scheme
Multi-step reaction with 4 steps 1.1: 1H-imidazole / dichloromethane / 2 h / 7 - 28 °C / Inert atmosphere 2.1: sodium carbonate / tetrahydrofuran; water / 0.5 h / 28 °C / Inert atmosphere 2.2: 9 h / 29 - 80 °C 3.1: hydrogen; 5%-palladium/activated carbon / methanol / 3 h / 28 - 29 °C / 1034.32 Torr 4.1: hydrogenchloride / methanol; water / 0.33 h / 28 °C View Scheme

1-[3-bromo-4-(bromomethyl)phenyl]ethan-1-one (909190-70-1) → 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: calcium carbonate; water / 1,4-dioxane / 16 h / 100 °C 2: palladium dichloride; triphenylphosphine; caesium carbonate / tetrahydrofuran; water / 24 h / 85 °C 3: palladium on activated charcoal; hydrogen / ethanol / 3 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: calcium carbonate; water / 1,4-dioxane / 16 h / 100 °C 2.1: sodium carbonate / tetrahydrofuran; water / 0.5 h / 28 °C / Inert atmosphere 2.2: 10 h / 29 - 80 °C 3.1: hydrogen; 5%-palladium/activated carbon / methanol / 4 h / 28 - 29 °C / 775.74 Torr View Scheme
Multi-step reaction with 5 steps 1.1: calcium carbonate; water / 1,4-dioxane / 16 h / 100 °C 2.1: 1H-imidazole / dichloromethane / 2 h / 7 - 28 °C / Inert atmosphere 3.1: sodium carbonate / tetrahydrofuran; water / 0.5 h / 28 °C / Inert atmosphere 3.2: 9 h / 29 - 80 °C 4.1: hydrogen; 5%-palladium/activated carbon / methanol / 3 h / 28 - 29 °C / 1034.32 Torr 5.1: hydrogenchloride / methanol; water / 0.33 h / 28 °C View Scheme

1-(3-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)ethan-1-one → 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium carbonate / tetrahydrofuran; water / 0.5 h / 28 °C / Inert atmosphere 1.2: 9 h / 29 - 80 °C 2.1: hydrogen; 5%-palladium/activated carbon / methanol / 3 h / 28 - 29 °C / 1034.32 Torr 3.1: hydrogenchloride / methanol; water / 0.33 h / 28 °C View Scheme

1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-vinylphenyl)ethan-1-one → 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; 5%-palladium/activated carbon / methanol / 3 h / 28 - 29 °C / 1034.32 Torr 2: hydrogenchloride / methanol; water / 0.33 h / 28 °C View Scheme

C17H28O2Si → 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7)

Conditions	Yield
With hydrogenchloride In methanol; water at 28℃; for 0.333333h;

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) + C18H24F3NO2 → (E)-1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one-O-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-oxime (1418144-66-7)

Conditions	Yield
Stage #1: C18H24F3NO2 With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 0.5h; Stage #2: 1-[3-ethyl-4-(hydroxymethyl)phenyl]ethan-1-one With triethylamine In 1,4-dioxane; methanol at 20℃; pH=4 - 6;	95%

O-(4-cyclohexyl-3-trifluoromethyl-benzyl)-hydroxylamine + 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) → 1-(3-ethyl-4-hydroxymethylphenyl)ethanone O-(4-cyclohexyl-3-trifluoromethylbenzyl)oxime

Conditions	Yield
With sodium acetate at 20℃; for 2h; pH=4 - 6; Reagent/catalyst;	95%

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) + (E)-ethyl N-(4-cyclohexyl-3-iodobenzyl)oxyacetimidate → (E)-1-(3-ethyl-4-(hydroxymethyl)phenyl)ethanone O-(4-cyclohexyl-3-iodobenzyl) oxime

Conditions	Yield
Stage #1: (E)-ethyl N-(4-cyclohexyl-3-iodobenzyl)oxyacetimidate With hydrogenchloride In methanol; water at 20℃; for 0.5h; Stage #2: 1-[3-ethyl-4-(hydroxymethyl)phenyl]ethan-1-one With triethylamine In methanol; water at 20℃; for 16h; pH=Ca. 5;	92%

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) → 1-[3-ethyl-4-(hydroxymethyl)phenyl](2H3)ethan-1-one

Conditions	Yield
With water-d2; potassium carbonate at 100℃; for 15h;	90%

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) → (E)-1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one oxime

Conditions	Yield
With hydroxylamine hydrochloride; sodium acetate In methanol at 20 - 25℃; for 1h; Temperature;	86%

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) + N-(4-cyclohexyl-3-trifluoromethylbenzyloxy)acetimidic acid ethyl ester (1418144-65-6) → (E)-1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one-O-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-oxime (1418144-66-7)

Conditions	Yield
Stage #1: N-(4-cyclohexyl-3-trifluoromethylbenzyloxy)acetimidic acid ethyl ester With hydrogenchloride In methanol; diethyl ether at 20℃; for 0.5h; Stage #2: 1-[3-ethyl-4-(hydroxymethyl)phenyl]ethan-1-one With triethylamine at 20℃; for 16h; pH=4 - 6;	85%
Stage #1: N-(4-cyclohexyl-3-trifluoromethylbenzyloxy)acetimidic acid ethyl ester With hydrogenchloride In methanol at 20 - 25℃; Stage #2: 1-[3-ethyl-4-(hydroxymethyl)phenyl]ethan-1-one With triethylamine In methanol at 20 - 25℃; pH=0 - 4.5;

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) + (Z)-(ethyl-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl](2H2)methoxy]ethenecarboximidate) → [4-[(1E)-1-([[4-cyclohexyl-3-(trifluoromethyl)phenyl](2H2)methoxy]imino)ethyl]-2-ethylphenyl]methanol

Conditions	Yield
With hydrogenchloride; triethylamine In 1,4-dioxane; methanol at 20℃; pH=4 - 6;	79%

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) → 1-[3-ethyl-4-[hydroxy(2H3)methyl]phenyl]ethan-1-one

Conditions	Yield
With (carbonyl)(chloro)(hydrido)tris(triphenylphosphine)ruthenium(II); water-d2 In 1,4-dioxane at 100℃; for 4h;	74%

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) → 4-acetyl-2-ethylbenzaldehyde

Conditions	Yield
With manganese(IV) oxide In n-heptane at 50℃; for 2h;	73%

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) + N-(4-cyclohexyl-3-trifluoromethylbenzyloxy)acetimidic acid ethyl ester (1418144-65-6) → Siponimod (1230487-00-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / methanol; diethyl ether / 0.5 h / 20 °C 1.2: 16 h / 20 °C / pH 4 - 6 2.1: manganese(IV) oxide / 1,4-dioxane / 0.5 h / Reflux 2.2: 0.33 h / 20 °C 2.3: 1 h / 20 °C View Scheme

1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (1378888-43-7) → Siponimod (1230487-00-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / 1,4-dioxane; methanol / 0.5 h / 20 °C 1.2: 20 °C / pH 4 - 6 2.1: 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione / acetonitrile / 4 h / 81 °C 3.1: acetic acid / methanol / 0.33 h / 20 °C 3.2: 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: methanol / 16 h / 28 °C 2.1: manganese(IV) oxide / n-heptane / 3 h / 60 °C / Inert atmosphere 3.1: acetic acid / methanol / 0.5 h / 29 °C / Inert atmosphere 3.2: 1 h / 25 - 28 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium acetate; hydroxylamine hydrochloride / methanol / 1 h / 20 - 25 °C 2.1: potassium tert-butylate / N,N-dimethyl-formamide / 0.17 h / 0 - 20 °C 2.2: 0.42 h / 0 - 10 °C 3.1: manganese(IV) oxide / n-heptane / 1 h / 80 °C 4.1: methanol / 0.5 h / 20 - 25 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium acetate; hydroxylamine hydrochloride / methanol / 1 h / 20 - 25 °C 2.1: sodium tert-pentoxide / N,N-dimethyl-formamide; iso-butanol / 0.5 h 2.2: 1.17 h 3.1: manganese(IV) oxide / n-heptane / 1 h / 80 °C 4.1: methanol / 0.5 h / 20 - 25 °C View Scheme

Upstream product

• 103029-24-9 4-Amino-3-aethyl-acetophenon 
• 578-54-1 ortho-ethylaniline 
• 909190-70-1 1-[3-bromo-4-(bromomethyl)phenyl]ethan-1-one 
• 1418144-63-4 1-[3-ethenyl-4-(hydroxymethyl)phenyl]ethan-1-one 
• 1418144-62-3 1-[3-bromo-4-(hydroxymethyl)phenyl]ethan-1-one 
• 40180-80-1 3-bromo-4-methylacetophenone 

Downstream Products

• 1230487-00-9 Siponimod 
• 1418144-66-7 (E)-1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one-O-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-oxime 
• 1230487-01-0 4-[(1E)-1-([[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino)ethyl]-2-ethylbenzaldehyde 

Relevant articles and documents

Siponimod intermediate and preparation method thereof

The invention relates to a siponimod intermediate and a preparation method thereof, and belongs to the field of medicinal chemistry. According to the preparation method, by taking 2-ethylaniline as a starting material, 1-(3-ethyl-4-hydroxymethyl) acetophenone is obtained through multi-step reaction. The method has the advantages of high yield, simple and easily available raw materials, low cost and controllable reaction conditions and temperature, and is suitable for industrial large-scale production.

Method for preparing 3-ethyl-4-methylol acetophenone

The invention discloses a method for preparing 3-ethyl-4-methylol acetophenone. The method includes steps of S1, carrying out coupling reaction on 4-methylol-3-bromoacetophenone and trimethylsilylacetylene or ethynyltriisopropylsilane to generate 3-trimethyl silicon acetenyl-4-methylol acetophenone; S2, hydrolyzing the 3-trimethyl silicon acetenyl-4-methylol acetophenone under alkaline conditionsto generate 3-acetenyl-4-methylol acetophenone; S3, carrying out reduction on the 3-acetenyl-4-methylol acetophenone under the conditions of hydrogen, palladium and carbon to obtain the 3-ethyl-4-methylol acetophenone. The method has the advantages that the yield of the 3-ethyl-4-methylol acetophenone can be greatly increased, the highest yield of the 3-ethyl-4-methylol acetophenone can reach 55%at least, the method includes simple reaction steps and is easy to control, and reaction procedures are mild.

Discovery of BAF312 (Siponimod), a potent and selective S1P receptor modulator

A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 as the chemical starting point. Extensive structure-activity relationship studies led to the discovery of (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl) -2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.