186204-35-3

Basic information

• Product Name: (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane
• Synonyms: (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane;(1R,2R)-1,2-CyclohexanediMethanol 1,2-DiMethanesulfonate;(1R,2R)-1,2-Bis(methanesulfonyloxymethyl)cyclohexane;(1R-trans)-1,2-Cyclohexanedimethanol dimethanesulfonate;(-)-(1R,2R)-bis(Methanesulfonyloxy-Methyl) cyclohexane;(1R,2R)-1,2-Bis(MethanesulfonyloxyMethyl)cyclohexan;(R,R)-1,2-Bis(MethanesulphonyloxyMethyl)cyclohexane;[(1R,2R)-2-(methylsulfonyloxymethyl)cyclohexyl]methyl methanesulfonate
• CAS NO: 186204-35-3
• Molecular Formula: C₁₀H₂₀O₆S₂
• Molecular Weight: 300.394
• EINECS: 1308068-626-2
• Product Categories: Sulfur & Selenium Compounds
• Mol File: 186204-35-3.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 495.284 °C at 760 mmHg
• Flash Point: 253.339 °C
• Appearance: off-white solid
• Density: 1.270
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly)
• CAS DataBase Reference: (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane(CAS DataBase Reference)
• NIST Chemistry Reference: (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane(186204-35-3)
• EPA Substance Registry System: (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane(186204-35-3)

Safety Data

• Hazardous Substances Data: 186204-35-3(Hazardous Substances Data)

Usage

Chemical Properties

Off-white Solid

Uses

(1R,2R)-1,2-Cyclohexanedimethanol 1,2-Dimethanesulfonate (cas# 186204-35-3) is a compound useful in organic synthesis.

Synthetic route

(+)-(1R,2R)-trans-1,2-bis(hydroxymethyl)cyclohexane (65376-05-8) + methanesulfonyl chloride (124-63-0) → (1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3)

Conditions	Yield
With triethylamine at 0 - 5℃; Industrial scale;	92.6%
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	92%
With triethylamine In chloroform at 0 - 20℃; for 5h;	90.8%

phthalic acid dimethyl ester (131-11-3) → (1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: Raney nickel; methanol / 50 - 60 °C / 73550.8 Torr / Hydrogenation.Behandeln des Reaktionsprodukts mit methanol. Natriummethylat 2: LiAlH4; diethyl ether 3: (1R)-menthyl isocyanate 4: pyridine View Scheme

(+/-)-trans-2-(hydroxymethyl)cyclohexylmethanol (76155-27-6) → (1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: (1R)-menthyl isocyanate 2: pyridine View Scheme

dimethyl cyclohexane-trans-1,2-dicarboxylate (3205-35-4) → (1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: LiAlH4; diethyl ether 2: (1R)-menthyl isocyanate 3: pyridine View Scheme

(1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid (46022-05-3) → (1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sulfuric acid / 18 h / 40 °C 2.1: diisobutylaluminium hydride / toluene / 6 h / -5 - 20 °C / Inert atmosphere 2.2: 13 h / -5 - 40 °C 3.1: triethylamine / chloroform / 5 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 65 °C 2.1: triethylamine / dichloromethane / 0.42 h / 25 - 35 °C / Inert atmosphere 2.2: 3 h / -5 - 35 °C View Scheme
Multi-step reaction with 4 steps 1: tetrahydrofuran / 1 h / 25 - 30 °C 2: tetrahydrofuran / 45 - 50 °C 3: sodium tetrahydroborate; water / tetrahydrofuran / 1 h 4: triethylamine / dichloromethane View Scheme
Multi-step reaction with 3 steps 1: sulfuric acid / 4 h / Reflux 2: sodium tetrahydroborate; methanol / tetrahydrofuran / 3 h / 40 °C / Reflux 3: triethylamine / dichloromethane / 1.5 h / 20 °C View Scheme

(1R,2R)-1,2-cyclohexanedicarboxylic acid dimethyl ester (140459-96-7) → (1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: diisobutylaluminium hydride / toluene / 6 h / -5 - 20 °C / Inert atmosphere 1.2: 13 h / -5 - 40 °C 2.1: triethylamine / chloroform / 5 h / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanol / tetrahydrofuran / 3 h / 40 °C / Reflux 2: triethylamine / dichloromethane / 1.5 h / 20 °C View Scheme

(1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) + (3aR,4S,7R,7aS)‑4,7‑methylene‑1H‑isoindole‑1,3(2H)-dione (14805-29-9) → ((1R,2R)-2-(((3aR,4S,7R,7aS)-1,3-dioxohexahydro-1H-4,7-methanoisoindol-2(3H)-yl)methyl)cyclohexyl)methylmethanesulfonate

Conditions	Yield
With potassium carbonate In isopropyl alcohol for 4h;	99%

(1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) + 2,2'-iminobis[ethanol] (111-42-2) → (3aR,7aR)-2,2-bis(2-hydroxyethyl)octahydro-1H-isoindolium mesylate (1421374-96-0)

Conditions	Yield
With sodium carbonate In chlorobenzene Reflux;	99%

(1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) + 3-(1-piperazinyl)-1,2-benzisothiazole (87691-87-0) → (3aR,7aR)-4’-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1’-piperazin]-2-ium methanesulfonate (186204-37-5)

Conditions	Yield
With calcium hydroxide In isopropyl alcohol for 20h; Reflux; Industrial scale;	97.3%
With potassium carbonate In water; acetonitrile at 82℃; for 3h; Temperature; Concentration; Solvent;	91%
With sodium carbonate In acetonitrile at 80 - 85℃; for 24h;	89.5%

3-(1-piperazinyl)-1,2-benzoisothiazole hydrochloride + (1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) → (3aR,7aR)-4’-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1’-piperazin]-2-ium methanesulfonate (186204-37-5)

Conditions	Yield
With potassium carbonate In acetonitrile at 80℃; Temperature;	92.4%

(1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) + 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride (87691-88-1) → (3aR,7aR)-4’-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1’-piperazin]-2-ium methanesulfonate (186204-37-5)

Conditions	Yield
With potassium carbonate In acetonitrile Reflux;	88%

(1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) → (3aR)-trans-octahydro-isobenzofuran (4743-54-8, 10479-79-5, 13149-01-4)

Conditions	Yield
With potassium hydroxide

(1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) + 3-(1-piperazinyl)-1,2-benzisothiazole (87691-87-0) → C19H26N3S(1+)*CH3O3S(1-)

Conditions	Yield
With potassium carbonate In toluene for 6h; Reflux;

(1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) + 3-(1-piperazinyl)-1,2-benzisothiazole (87691-87-0) + (3aR,4S,7R,7aS)‑4,7‑methylene‑1H‑isoindole‑1,3(2H)-dione (14805-29-9) → lurasidone

Conditions	Yield
With tetra(n-butyl)ammonium hydrogensulfate; potassium carbonate In water; N,N-dimethyl-formamide for 5h; Time; Reflux;

(1R,2R)-(-)-trans-cyclohexane-1,2-diylbis(methylene)dimethanesulfonate (186204-35-3) + 3-(1-piperazinyl)-1,2-benzisothiazole (87691-87-0) → (3aR,7aR)-4’-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1’-piperazin]-2-ium methanesulfonate (186204-37-5)

Conditions	Yield
With sodium carbonate In acetonitrile at 30℃; for 20h; Reflux;

Upstream product

• 65376-05-8 (+)-(1R,2R)-trans-1,2-bis(hydroxymethyl)cyclohexane 
• 124-63-0 methanesulfonyl chloride 
• 1687-29-2 dimethyl cis-1,2-cyclohexanedicarboxylate 
• 88-98-2 trans-cyclohex-4-ene-1,2-dicarboxylic acid 
• 2305-32-0 trans-1,2-cyclohexanedicarboxylic acid 
• 140459-96-7 (1R,2R)-1,2-cyclohexanedicarboxylic acid dimethyl ester 
• 46022-05-3 (1R,2R)-(-)-trans-cyclohexane-1,2-dicarboxylic acid 
• 3205-35-4 trans dimethyl cyclohexane-1,2-dicarboxylate 
• 76155-27-6 (+/-)-trans-2-(hydroxymethyl)cyclohexylmethanol 
• 131-11-3 phthalic acid dimethyl ester 

Downstream Products

• 186204-37-5 (3aR,7aR)-4’-(benzo[d]isothiazol-3-yl)octahydrospiro[isoindole-2,1’-piperazin]-2-ium methanesulfonate 
• 194861-74-0 lurasidone 

Relevant articles and documents

Preparation method for lurasidone hydrochloride

The invention discloses a preparation method for lurasidone hydrochloride. According to the preparation method, trans-1,2-cyclohexanedicarboxylic acid (SM-1) is used as a raw material and subjected to resolution, methyl esterification, reduction, methylsulfonylation, condensation, recrystallization and salt formation so as to eventually obtain lurasidone hydrochloride. The preparation method provided by the invention greatly reduces production cost and has the characteristics of high product yield, easy operation, low toxicity and suitability for industrial large-scale production.

AN IMPROVED PROCESS FOR THE PREPARATION OF LURASIDONE HYDROCHLORIDE

Disclosed herein is an improved process for the preparation of Lurasidone and its pharmaceutically acceptable salts via novel intermediate and use thereof for the preparation of an antipsychotic agent useful for the treatment of schizophrenia and bipolar disorder. Further, present invention provides a cost effective and eco-friendly process for producing Lurasidone hydrochloride of formula (I) substantially free of residual solvent(s) at industrial scale.

PROCESS FOR THE INDUSTRIAL SYNTHESIS OF LURASIDONE

Disclosed is a process for the industrial synthesis of Lurasidone from (1R,2R)-cyclohexane-1,2-diyldimethanol (1), 3-(piperazin-1- yl)benzo[d]isothiazole (3) and (3aR,4R,7R,7aS)-3a,4,7,7a-tetrahydro-4,7- methanoisobenzofuran-1,3-dione (6).). Said process is optimised to obtain Lurasidone with high yields and high purities by preparing highly pure synthesis intermediates, using critical raw materials and reagents in amounts close to the stoichiometric amounts, increasing productivity and reducing the costs and environmental impact of the process.