112111-45-2

Usage

Uses

Used in Pharmaceutical Industry:
(R)-(-)-Modafinil acid is used as an active pharmaceutical ingredient for the treatment of human or animal oligospermia and ovum-deficient diseases. It helps improve sperm count and quality in males and promotes the development and maturation of ova in females, addressing fertility issues in both sexes.
Additionally, due to its stimulant properties, (R)-(-)-Modafinil acid may also be used as a potential treatment for various sleep disorders, such as narcolepsy, sleep apnea, and shift work sleep disorder, as well as for cognitive enhancement in conditions like ADHD and other neurodegenerative diseases. However, further research and clinical trials are necessary to establish its efficacy and safety in these applications.

InChI:InChI=1/C15H14O3S/c16-14(17)11-19(18)15(12-7-3-1-4-8-12)13-9-5-2-6-10-13/h1-10,15H,11H2,(H,16,17)/t19-/m1/s1

Synthetic route

(benzhydrylthio)acetic acid (63547-22-8) → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
With NADP; sodium hydroxide In isopropyl alcohol at 35℃; pH=8.54; Catalytic behavior; Concentration; Solvent; Reagent/catalyst; Temperature; pH-value; Alkaline conditions; enantioselective reaction;	100%
Multi-step reaction with 4 steps 1.1: 99 percent / H2SO4 / Heating 2.1: H2SO4; 2-propanol; aq. H2O2 / methanol / 20 °C 3.1: 62.1 g / NaOH; H2O / ethanol / 1 h / 20 °C 4.1: (R)-(+)-α-methylbenzylamine / H2O / Heating 4.2: aq. HCl / pH 2 View Scheme

2-((R)-Diphenyl-methanesulfinyl)-1-((R)-4-phenyl-2-thioxo-thiazolidin-3-yl)-ethanone (827603-84-9) → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
With lithium hydroxide In tetrahydrofuran; water at 0 - 20℃;	96%

Λ-[Ru(2,2-bipyridine)2((diphenylmethanesulfinyl)acetic acid-H)](PF6) → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
With trifluoroacetic acid In acetonitrile at 60℃; for 3h; Inert atmosphere; enantioselective reaction;	84%

modafinil acid (63547-24-0) → (R)-Modafinil acid (112111-45-2) + (+)-(S)-(diphenylmethanesulfinyl)acetic acid (112111-44-1)

Conditions	Yield
Stage #1: modafinil acid With (S)-1-phenyl-ethylamine In water Heating; Stage #2: With hydrogenchloride pH=2;	A 12.6 g B n/a
Stage #1: modafinil acid With (R)-1-phenyl-ethyl-amine In water Heating; Stage #2: With hydrogenchloride pH=2;	A n/a B 17.0 g

modafinil acid (63547-24-0) → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 44.5 percent / 4-(dimethylamino)pyridine; 1,3-dicyclohexylcarbodiimide / CH2Cl2 2: 96 percent / lithium hydroxide / tetrahydrofuran; H2O / 0 - 20 °C View Scheme

1,1-Diphenylmethanol (91-01-0) + BF3(C2H5)2O → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 99 percent / trifluoroacetic acid / 3 h / 20 °C 2.1: 99 percent / H2SO4 / Heating 3.1: H2SO4; 2-propanol; aq. H2O2 / methanol / 20 °C 4.1: 62.1 g / NaOH; H2O / ethanol / 1 h / 20 °C 5.1: (R)-(+)-α-methylbenzylamine / H2O / Heating 5.2: aq. HCl / pH 2 View Scheme

(diphenylmethyl)(ethyl acetate)sulfide (63547-23-9) → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: H2SO4; 2-propanol; aq. H2O2 / methanol / 20 °C 2.1: 62.1 g / NaOH; H2O / ethanol / 1 h / 20 °C 3.1: (R)-(+)-α-methylbenzylamine / H2O / Heating 3.2: aq. HCl / pH 2 View Scheme

(diphenylmethyl)(ethyl acetate)sulfoxide (118286-19-4) → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 62.1 g / NaOH; H2O / ethanol / 1 h / 20 °C 2.1: (R)-(+)-α-methylbenzylamine / H2O / Heating 2.2: aq. HCl / pH 2 View Scheme

(-)-α-methylbenzylamine (2627-86-3) + modafinil acid (63547-24-0) → (S)-modafinic acid*(S)-α-methylbenzylamine (949092-13-1) + (R)-Modafinil acid (112111-45-2)

Conditions	Yield
In isopropyl alcohol at 20℃; Product distribution / selectivity; Heating / reflux;
In ethyl acetate at 20℃; Product distribution / selectivity; Heating / reflux;
In N,N-dimethyl-formamide; acetone at 20℃; Product distribution / selectivity; Heating / reflux;

(benzhydrylthio)acetic acid (63547-22-8) → (R)-Modafinil acid (112111-45-2) + (+)-(S)-(diphenylmethanesulfinyl)acetic acid (112111-44-1)

Conditions	Yield
With 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate In tetrachloromethane at 20℃; for 48h; Title compound not separated from byproducts.;
Stage #1: (benzhydrylthio)acetic acid With 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 0 - 5℃; for 0.5h; Stage #2: With (1S)-(+)-(10-camphorsulfonyl)-oxaziridine In toluene at 25 - 30℃;

(+)-(S)-(diphenylmethanesulfinyl)acetic acid (112111-44-1) → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
In dimethyl sulfoxide at 90℃; for 17h; Product distribution / selectivity;
In N,N-dimethyl-formamide at 90℃; for 17h; Product distribution / selectivity;

2-(benzhydrylsulfinyl)acetic acid (-)-α-methylbenzylamine (112245-25-7) → (R)-Modafinil acid (112111-45-2)

Conditions	Yield
With hydrogenchloride In water at 20℃;

methyl iodide (74-88-4) + (R)-Modafinil acid (112111-45-2) → (R)-(-)-methyl (diphenylmethanesulfinyl)-acetate (713134-72-6)

Conditions	Yield
With potassium carbonate In acetone Reflux;	70%
With potassium carbonate In acetone Heating;	68%
With potassium carbonate In acetone for 4h; Reflux;

(R)-Modafinil acid (112111-45-2) → Nuvigil (112111-43-0)

Conditions	Yield
With Bacillus subtilis var. niger IFO-3180 In N,N-dimethyl-formamide at 28℃; for 168h;	60%
Multi-step reaction with 2 steps 1: 68 percent / K2CO3 / acetone / Heating 2: 55 percent / aq. NH4OH; NH4Cl / methanol / 20 °C View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / acetone / Reflux 2: ammonium hydroxide; ammonium chloride / methanol / 20 °C View Scheme
Stage #1: (R)-Modafinil acid With methanol; thionyl chloride at 0 - 20℃; for 3h; Stage #2: With ammonium hydroxide In methanol; water at 0℃; Reagent/catalyst; Temperature; Time;

methanol (67-56-1) + (R)-Modafinil acid (112111-45-2) → (R)-(-)-methyl (diphenylmethanesulfinyl)-acetate (713134-72-6)

Conditions	Yield
With hydrogenchloride In water at 20℃; for 1 - 24h; Product distribution / selectivity; Heating / reflux;
With thionyl chloride at 0 - 20℃; for 3 - 20h; Product distribution / selectivity;

(R)-Modafinil acid (112111-45-2) → (+)-(S)-(diphenylmethanesulfinyl)acetic acid (112111-44-1)

Conditions	Yield
Stage #1: (R)-Modafinil acid With indium; pivaloyl chloride In isopropyl alcohol at 15 - 30℃; for 3h; Stage #2: With hydrogenchloride In water; isopropyl alcohol at 20℃; for 0.5h; Product distribution / selectivity;
With perchloric acid; sodium bromide In water; ethyl acetate at 20℃; for 20h; Product distribution / selectivity;
With perchloric acid; sodium bromide In water; acetonitrile at 20℃; for 20h; Product distribution / selectivity;

isobutyl chloroformate (543-27-1) + (R)-Modafinil acid (112111-45-2) → C20H22O5S

Conditions	Yield
Stage #1: (R)-Modafinil acid With triethylamine In dichloromethane at 5 - 30℃; for 0.5h; Stage #2: isobutyl chloroformate In dichloromethane at 0 - 25℃; for 3.25h;

Upstream product

• 827603-84-9 2-((R)-Diphenyl-methanesulfinyl)-1-((R)-4-phenyl-2-thioxo-thiazolidin-3-yl)-ethanone 
• 91-01-0 1,1-Diphenylmethanol 
• 63547-23-9 (diphenylmethyl)(ethyl acetate)sulfide 
• 2627-86-3 (-)-α-methylbenzylamine 
• 63547-24-0 modafinil acid 
• 63547-22-8 (benzhydrylthio)acetic acid 
• 112111-44-1 (S)-(+)-(diphenylmethanesulfinyl)acetic acid 
• 112245-25-7 2-(benzhydrylsulfinyl)acetic acid (-)-α-methylbenzylamine 
• 118286-19-4 (diphenylmethyl)(ethyl acetate)sulfoxide 

Downstream Products

• 112111-43-0 Nuvigil 
• 112111-44-1 (S)-(+)-(diphenylmethanesulfinyl)acetic acid 
• 713134-72-6 (R)-(-)-methyl (diphenylmethanesulfinyl)-acetate 

Relevant academic research and scientific papers

Biocatalysts and methods for the synthesis of armodafinil

The present invention relates to non-naturally occurring polypeptides useful for preparing armodafinil, polynucleotides encoding the polypeptides, and methods of using the polypeptides. The non-naturally occurring polypeptides of the present invention are effective in carrying out biocatalytic conversion of the (i) 2-(benzhydrylsulfinyl)acetamide to (?)-2-[(R)-(diphenyl-methyl)sulfinyl]acetamide (armodafinil), or (ii) benzhydryl-thioacetic acid to (R)-2-(benzhydrylsulfinyl)acetic acid, which is a pivotal intermediate in the synthesis of armodafinil, in enantiomeric excess.

Asymmetric Oxidation Synthesis of Modafinil Acid by Use of a Recyclable Chiral-at-Metal Complex

The enantioselective oxidation synthesis of chiral modafinil acid and its analogues with high enantiomeric excess has been developed by means of a chiral-at-metal strategy. Treatment of ruthenium complexes cis-[Ru(bpy)2Cl2] or Δ/Λ-[Ru(bpy)2(MeCN)2](PF6)2 (bpy is 2,2′-bipyridine) with the appropriate prochiral thioether ligands afforded thioether complexes rac-1, Δ/Λ-1, rac-2, Δ/Λ-2, rac-3, and Δ/Λ-3. Diastereoselective oxidation of the thioether complexes in situ produced the corresponding sulfoxide complexes rac-1a, Δ/Λ-1a, rac-2a, Δ/Λ-2a, rac-3a, and Δ/Λ-3a. The configuration at the metal center in each case is stable during the coordination and oxidation reactions, and dictates the chirality of the sulfoxide ligand in the oxidation process. The chiral modafinil acids were obtained with ee values greater than 98% upon their removal from the corresponding sulfoxide complexes in the presence of TFA/MeCN. Moreover, the chiral ruthenium precursors Δ/Λ-[Ru(bpy)2(MeCN)2](PF6)2 are recyclable and reusable with complete retention of the configurations. Chiral modafinil acid and its analogues have been synthesized with high ee values by means of asymmetric coordination oxidation of a thioether complex in situ with a chiral-at-metal strategy.

NOVEL CRYSTALLINE POLYMORPH OF ARMODAFINIL AND AN IMPROVED PROCESS FOR PREPARATION THEREOF

The present invention relates to a novel crystalline polymorph of armodafinil. In another aspect the invention relates to an improved process for preparation of the novel polymorph of armodafinil.

PROCESSES FOR PREPARING ARMODAFINIL INTERMEDIATE

The present invention encompasses processes (1) for preparing racemic 2-(benzhydrylsulfinyl)acetic acid by combining the (S)- or the (R)-enantiomer with at least one organic solvent and at least one acid promoter, such as perchloric acid or an acyl halide; (2) for preparing racemic 2-(benzhydrylsulfinyl)acetamide or racemic 2-(benzhydrylsulfinyl)acetic acid by combining the (S)- or the (R)-enantiomer with at least one organic solvent having a boiling point above 60°C, heating to a temperature above 60°C and cooling. The present invention also encompasses the conversion of the racemic intermediates to armodfinil.

A PROCESS OF SULFOXIDATION OF BIOLOGICALLY ACTIVE COMPOUNDS

The present invention relates to a new process for the preparation of sulfoxides, preferably stereoselective preparation of substituted or unsubstituted chiral sulfinyl derivatives 2-(2- pyridylmethyl) sulfinyl-l H-benzimidazole by oxidation with oxaziridine in presence of suitable solvent and base.

Asymmetric synthesis of modafinil and its derivatives by enantioselective oxidation of thioethers: comparison of various methods including synthesis in ionic liquids

The oxidation of 2-(benzhydrylthio)acetic acid and its derivatives was performed with various catalytic and stoichiometric enantioselective reagents, the best results being obtained with stoichiometric chiral oxaziridine 5. The use of [bmim][PF6] as a solvent with 5 gave slightly higher yields and, in the case of the model compound thioanisole, a reversal of the enantioselectivity.

AN IMPROVED PROCESS FOR THE PREPARATION OF ARMODAFINIL

The invention encompasses processes for preparing intermediates, such as R-modafinic acid or (R)-C1-2 alkyl ester, of modafinic acid, and the conversion of the intermediates to armodafinil.

Synthesis and determination of the absolute configuration of the enantiomers of modafinil

The asymmetric synthesis of both enantiomers of modafinil, a unique CNS stimulant with a reduced abuse liability, is described. This approach effectively prepares modafinil on a multigram scale in several steps from benzhydrol. The described synthetic route has also been used to produce the more water soluble analogue, adrafinil. X-ray crystallographic analysis on (-)-(diphenylmethanesulfinyl)acetic acid has determined the absolute configuration to be R.

Synthesis and determination of the absolute stereochemistry of the enantiomers of adrafinil and modafinil

Both enantiomers of modafinil, adrafinil, modafinic acid and ethyl modafinate were prepared from the diastereomers formed by reacting racemic β-sulfinyl carboxylic acid with (4R)-phenyl-thiazolidinethione. The absolute stereochemistry of the sulfoxide group was confirmed via X-ray analysis of one of the thiazolidinethione diastereomers.