WO2022234528A1 - A novel process for the preparation of 3-thietanol - Google Patents

A novel process for the preparation of 3-thietanol Download PDF

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Publication number
WO2022234528A1
WO2022234528A1 PCT/IB2022/054195 IB2022054195W WO2022234528A1 WO 2022234528 A1 WO2022234528 A1 WO 2022234528A1 IB 2022054195 W IB2022054195 W IB 2022054195W WO 2022234528 A1 WO2022234528 A1 WO 2022234528A1
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Prior art keywords
formula
compound
thietanol
process according
scheme
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PCT/IB2022/054195
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French (fr)
Inventor
Suresh Kumar SYTHANA
Kantilal Balu SHENDE
Vijay Kumar SALVI
Anup Manikrao JAWALEKAR
Alexander G.M. KLAUSENER
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Pi Industries Ltd.
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Publication of WO2022234528A1 publication Critical patent/WO2022234528A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D331/00—Heterocyclic compounds containing rings of less than five members, having one sulfur atom as the only ring hetero atom
    • C07D331/04—Four-membered rings

Definitions

  • the present invention relates to a process for the preparation of 3-thietanol. More particularly, the present invention relates to a simple, efficient and cost effective process for the synthesis of 3- thietanol.
  • 3-Thietanol is known to be an important reagent used for the synthesis of chemical intermediates for various purposes, e.g. for the synthesis of active ingredients which can be used in the pharmaceutical and agrochemical industry.
  • Several methods have been disclosed in the literature, by which 3-thietanol can be obtained.
  • WO2019150220 describes a method for producing 3-thietanol by reacting epichlorohydrin with hydrogen sulfide using aqueous potassium hydroxide as a reaction medium.
  • 3-thietanol can be produced from oxiran-2-yl methanol (glycidol).
  • Srinivasan et ah, J. Org. Chem, 67(26), 9417-9420 (2002) also describe a method for producing 3-thietanol from oxiran-2-yl methanol using benzyltriethylammonium tetrathiomolybdate as a reagent.
  • 3-Thietanol can also be produced from epithiochlorohydrin.
  • An article by Allakhverdiev, M. A. et al. describes a process for producing 3-thietanol from 3-isothiocyanatothietane which can be prepared by reaction of epithiochlorohydrin and ammonium isothiocyanate.
  • These processes described in the prior art have shortcomings such as poor yields or purity of the desired intermediates or products, or synthetic procedures being not amenable to commercial scale, or of involving extreme reaction conditions making them uneconomical or posing safety risks if conducted on a technical scale.
  • Another objective is to provide a novel process for the preparation of 3-thietanol with high yield and high purity.
  • the present invention provides a solution to these objectives by offering a novel high yielding and economically attractive process that allows the preparation of 3-thietanol, overcoming at least one of the shortcomings of the processes described in the prior art.
  • the present invention provides a process for preparing 3-thietanol of formula (I) from a compound of formula (IV),
  • R 1 and R 2 are independently selected from halogen (X), hydroxyl and mercapto group; R 3 is selected from hydroxyl, alkoxy and halogen (X); R 4 is selected from hydrogen and alkoxy; or R 3 and R 4 taken together represent carbonyl or l,3-dioxolane-2-yl or l,3-dioxane-2-yl.
  • One embodiment provides a process for preparing 3-thietanol of formula (I), wherein the process steps can be carried out in a batch process.
  • compositions comprising, “comprising”, “includes”, “including”, “has”, “having”, “contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated.
  • a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.
  • alkyl includes straight-chain or branched Ci to G, alkyl.
  • alkyl include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1- dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1- ethylpropyl, hexyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,
  • hydroxy means -OH
  • sulfonyloxy means 0-S(0)2.
  • alkylsulfonyloxy include methylsulphonyloxy, ethylsulphonyloxy, propylsulphonyloxy, 1-methylethylsulphonyloxy, butylsulphonyloxy, 1- methylpropylsulphonyloxy, 2-methylpropylsulphonyloxy , 1 , 1 -dimethylethylsulphonyloxy , pentylsulphonyloxy, 1 -methylbutylsulphonyloxy, 2-methylbutylsulphonyloxy, 3- methylbutylsulphonyloxy, 2,2-dimethylpropylsulphonyloxy, 1 -ethylpropylsulphonyloxy, hexylsulphonyloxy, 1,1-dimethylpropylsulphonyloxy, 1 ,2-dimethylpropylsulphonyloxy
  • halogen either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different.
  • haloalkyl include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1 -bromoethyl, 1-fluoroethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2- difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1,1-dichloro- 2,2,2-trifluoroethyl, and l,l,l-trifluoroprop-2-yl.
  • alkoxy includes Ci to Ce alkoxy.
  • alkoxy include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1- ethylpropoxy, hexoxy, 1,1-dimethylpropoxy, 1 ,2-dimethylpropoxy, 1-methylpentoxy, 2- methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1 ,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1- ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1 -ethyl- 1- methylpropoxy and l-ethylbut
  • the present invention provides a process for the preparation of 3-thietanol of formula (I) from compounds of formula (IV) wherein, R 1 and R 2 are independently selected from halogen (X), hydroxyl and the mercapto group, R 3 is selected from hydroxyl, alkoxy, halogen (X), R 4 is selected from hydrogen, alkoxy; or R 3 and R 4 taken together represents carbonyl or l,3-dioxolane-2-yl or l,3-dioxane-2-yl.
  • a sulfur source in the presence of a suitable solvent to obtain 3-thietanol of formula (I).
  • One embodiment provides a process for preparing 3-thietanol of formula (I) from 1,3- dihalopropan-2-ol (IVa), as disclosed in reaction Scheme-I, wherein the process step can be carried out in a batch, semicontinuous or continuous reaction mode, specifically also under semi- continuous flow or continuous flow reaction conditions.
  • a process for preparing 3-thietanol of formula (I) from 1,3-dihalopropan- 2-ol (IVa) can be carried out as disclosed in Scheme-la, in which the process steps can be carried out, partly or as a whole, in a batch, semi-continuous or continuous mode, specifically also in a semi-continuous flow or continuous flow reaction mode, with or without isolation of the intermediate compound of formula (Ilia).
  • This process is depicted in Scheme-II.
  • Yet another embodiment provides a process for preparing 3-thietanol of formula (I) from 1,3- dihalo-2,2-dialoxyxypropane (IVb) as disclosed in Scheme-II, which can be realized in a way that the distinct process steps are carried out, partly or as a whole, in a batch, semi-continuous or continuous reaction mode, specifically in a semi-continuous flow or continuous flow mode, with or without isolation of the intermediate compounds of formula (IIIb) or (II).
  • the compounds of formula (IVd) can be converted to thietan-3-one of formula (II) in the presence of a suitable solvent and using a suitable base, followed by the conversion of thietan-3-one of formula (II) to afford 3-thietanol of formula (I) using a suitable reducing reagent. This process is depicted in Scheme-IV.
  • a process for preparing 3-thietanol of formula (I) from l-halo-3- mercaptopropan-2-one (IVd), as disclosed in reaction Scheme-IV can be carried out, partly or as a whole, in a batch, semi-continuous or continuous reaction mode, specifically in a semi- continuous flow or continuous flow mode, with or without isolation of the intermediate compound of formula (II).
  • the compounds of formula (IVe) can be reacted with a sulfur source in the presence of a suitable solvent to afford 2-halo-3-mercaptopropan-l-ol (Ille), followed by the conversion of this compound of formula (Ille) using a suitable base to afford a mixture of oxiran-2-ylmethanethiol (Ila) and thiiran -2-methanol (lib); and converting this mixture of oxiran- 2-ylmethanethiol (Ila) and thiiran-2-methanol (lib) to 3-thietanol of formula (I).
  • the process is depicted in Scheme-V. (Hb)
  • the process for preparing 3-thietanol (I) from 2,3-haloropropan-l-ol (IVe), as disclosed in reaction Scheme-V can be carried out, partly or as a whole, in a batch, semi- continuous or continuous reaction mode, specifically in a semi-continuous flow or continuous flow mode, with or without isolation of the intermediate compounds of formula (Hie), (Ila) and (lib).
  • a sulfur source in the presence of a suitable solvent
  • thietanol-3-one of formula (II) which can be converted to 3-thietanol of formula (I) using a suitable reducing reagent.
  • Scheme -VI The process is depicted in Scheme -VI.
  • a process for preparing 3-thietanol (I) from 1 ,3-dihalopropan-l-one (IVf), as disclosed in reaction Scheme-VI wherein, the process steps can be carried out, partly or as a whole, in a batch, semi-continuous or continuous reaction mode, specifically in a semi-continuous flow or continuous flow mode, with or without isolation of the intermediate compound of formula
  • 3-thietanol of formula (I) can be prepared from epihalohydrin wherein the halogen is selected from bromine or chlorine, by reacting with a suitable sulfur source in the presence of a suitable solvent, without isolating compound of formula (IVaa); as depicted in Scheme-VII.
  • l,3-dihalopropran-2-ol of formula (IVa) can be prepared from epihalohydrines under acidic conditions, for instance in the presence of 30% aqueous HC1, at carefully controlled temperatures, for instance at a temperature within the range of 0 °C to 5 °C for 10 to 12 hours. This process is depicted in Scheme-2.
  • l,3-dichloropropran-2-ol of formula (IVa-1) can be prepared from a solution of glycerol and acetic acid using trimethylsilyl chloride at elevated temperatures, preferably at a temperature of 100 °C to 110 °C and a reaction time of 5 to 25 hours. This process is depicted in Scheme-3.
  • 1,3 -Dihalo-2, 3 -dialkoxypropane of formula (IVb) can be prepared by brominating propan-2-one in a mixture of acetone and methanol at a temperature within the range of 20 °C to 25 °C under stirring for 2 hours, followed by cooling the mixture to - 18 °C overnight. This process is depicted in Scheme-4.
  • 1 -Halo-3 -mercaptopropan-2-one of formula (IVd) can be prepared from l,3-dihalopropan-3-one. The process is depicted in Scheme-6. 1 ,3 -Dihalopropan-2-one 1 -Halo-3 -mercaptopropan-2-one (IVd)
  • the sulfur source used in the above schemes can include but is not limited to sulfur, hydrogen sulfide, sodium sulfide, sodium hydrogen sulfide, thiourea and thioacetic acid.
  • the suitable solvents used in the above schemes can include but are not limited to hydrocarbons such as n-heptane, n-hexane, cyclohexane, n-pentane, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, and diisopropyl ether; halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichlorome thane, 1,2-dichloroethane, tetrachloroethane, and chlorobenzene; acid amides such as N, N-d i met h y I fo rmam i de, l,3-dimethyl-2-imidazolidinone, and N-methylpyrrolidone; esters
  • the suitable halogenating agents used in the above schemes can include but are not limited to a chlorinating agent, a brominating agent, or an iodinating agent, for example, chlorine, bromine, iodine, sulfuryl chloride, N-chlorosuccinimide, N-bromosuccinimide, l,3-dibromo-5,5- dimethylhydantoin, N-chloro-saccharin, N-bromo-saccharin, iodosuccinimide, tert-butyl hypochlorite, N-chloroglutarimide, N-bromoglutarimide, N-chloro-N-cyclohexyl- benzenesulfonimide, N-bromophthalimide, and the like.
  • a chlorinating agent for example, chlorine, bromine, iodine, sulfuryl chloride, N-chlorosuccinimide, N-bromosuccinimide
  • the suitable halogenating agents used in the above schemes can include but are not limited to bromine, chlorine, sulfuryl chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, phosphoms tribromide, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphoms oxybromide, phosphoms pentabromide, phosphoms triiodide, oxalyl dichloride, oxalyl dibromide, acetyl chloride, carbon tetrabromide, N- bromosuccinimide, N-bromo-saccharin, lithium chloride, sodium iodide, acetyl bromide, and the like
  • the suitable halogenating agents used in the above schemes can include but are not limited to phosphoms oxychloride, phosphoms trichloride, phosphorus pentachloride, thionyl chloride, phosphoms oxybromide, phosphoms tribromide, phosphoms pentabromide, oxalyl dichloride, oxalyl dibromide, triphosgene, diphosgene, phosgene, and sulfuryl chloride.
  • Oxidative halogenation would include for instance HCI/H2O2 or HBr/H 2 0 2 type systems, where the active halogen is generated by oxidation of HX.
  • the suitable base used in the above schemes can include but are not limited to organic bases such as triethylamine, pyridine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine, diisoprop ylethylamine, lutidine, collidine, diazabicycloundecene, and diazabicyclononene; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal halides such as sodium fluoride, potassium fluoride, and cesium fluoride; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; and alkali metal alkoxides such as sodium ter
  • the suitable acid used in the above schemes can include but are not limited to organic acid such as acids are, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and, alkylsulfonic acids such as methanesulfonic acid; inorganic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide and sulfuric acid.
  • organic acid such as acids are, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and, alkylsulfonic acids such as methanesulfonic acid
  • inorganic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide and sulfuric acid.
  • reaction time is not critical and depends on the batch size, temperature, reagent and solvent employed. Typically, the reaction time may vary from a few minutes to several hours. Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product, and optionally washing with solvent, further optionally drying of the product if required.
  • the isolation of the reaction product can be carried out by a technique which includes but is not limited to decantation, centrifugation, evaporation, liquid-liquid extraction, distillation, recrystallization, chromatography and the like or a combination thereof.
  • process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to work under reduced pressure or under pressure.

Abstract

The present invention discloses a simple, efficient and cost effective process for the synthesis of 3-thietanol.

Description

Title of the Invention: A NOVEL PROCESS FOR THE PREPARATION OF 3- THIETANOL
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 3-thietanol. More particularly, the present invention relates to a simple, efficient and cost effective process for the synthesis of 3- thietanol.
BACKGROUND OF THE INVENTION AND PROBLEM TO BE SOLVED
3-Thietanol is known to be an important reagent used for the synthesis of chemical intermediates for various purposes, e.g. for the synthesis of active ingredients which can be used in the pharmaceutical and agrochemical industry. Several methods have been disclosed in the literature, by which 3-thietanol can be obtained.
Several methods are reported for the preparation of 3-thietanol starting from epichlorohydrin. An article by Donald Dittmer and Marcia Christy, J. Org. Chem. 26, 1324 (1961) describes a method for producing 3-thietanol by exposing epichlorohydrin to a saturated solution of hydrogen sulfide (H2S) in the presence of Ba(OH)2.
WO2019150220 describes a method for producing 3-thietanol by reacting epichlorohydrin with hydrogen sulfide using aqueous potassium hydroxide as a reaction medium.
An article by Srinivasan et al., J. Org. Chem, 67(26), 9417-9420 (2002) describes a method for producing 3-thietanol from epichlorohydrin using benzyl triethylammonium tetrathiomolybdate as a reagent.
Alternatively, 3-thietanol can be produced from oxiran-2-yl methanol (glycidol). Srinivasan et ah, J. Org. Chem, 67(26), 9417-9420 (2002) also describe a method for producing 3-thietanol from oxiran-2-yl methanol using benzyltriethylammonium tetrathiomolybdate as a reagent.
3-Thietanol can also be produced from epithiochlorohydrin. An article by Allakhverdiev, M. A. et al. describes a process for producing 3-thietanol from 3-isothiocyanatothietane which can be prepared by reaction of epithiochlorohydrin and ammonium isothiocyanate. These processes described in the prior art have shortcomings such as poor yields or purity of the desired intermediates or products, or synthetic procedures being not amenable to commercial scale, or of involving extreme reaction conditions making them uneconomical or posing safety risks if conducted on a technical scale. Therefore, there is a need for a simple, cost-effective process which allows the preparation of 3- thietanol from cheap starting materials and under easily controllable reaction conditions, solving the aforesaid problems associated with processes described in the prior art, and being suitable for large-scale preparations in term of simplicity, yield, safety and purity of the product. OBJECTIVE OF THE INVENTION
It is therefore an objective to provide a novel and economically viable process for the preparation of 3-thietanol.
Another objective is to provide a novel process for the preparation of 3-thietanol with high yield and high purity. Surprisingly, the present invention provides a solution to these objectives by offering a novel high yielding and economically attractive process that allows the preparation of 3-thietanol, overcoming at least one of the shortcomings of the processes described in the prior art.
Other objectives and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY OF INVENTION
Accordingly, the present invention provides a process for preparing 3-thietanol of formula (I) from a compound of formula (IV),
Figure imgf000004_0001
3-Thietanol
(IV) (I) wherein, R1 and R2 are independently selected from halogen (X), hydroxyl and mercapto group; R3 is selected from hydroxyl, alkoxy and halogen (X); R4 is selected from hydrogen and alkoxy; or R3 and R4 taken together represent carbonyl or l,3-dioxolane-2-yl or l,3-dioxane-2-yl. In one embodiment, the present invention provides a process for preparing 3-thietanol of formula (I) from a compound of formula (IVa), wherein, R1 and R2 = halogen (X), R3 = OH and R4 is hydrogen; comprising reacting the compound of formula (IVa) with a sulfur source in the presence of a suitable solvent to obtain 3-thietanol (I).
In another embodiment, the present invention provides a process for preparing 3-thietanol of formula (I) from a compound of formula (IVa), wherein, R1 and R2 = halogen (X), R3 = OH and R4 is hydrogen; comprising the steps of: a) reacting the compound of formula (IVa) with a sulfur source in the presence of a suitable solvent to obtain l-halo-3-mercaptopropan-2-ol (Ilia); and b) converting the compound of formula (Ilia) of step (a) to 3-thietanol of formula (I).
In yet another embodiment, the present invention provides a process for preparing 3-thietanol of formula (I) from a compound of formula (IVb), wherein, R1 and R2 = halogen (X), R3 and R4 = alkoxy (OAk), in which Ak = Ci-6-alkyl or from a compound of formula (IVc), wherein, R1 and R2 = halogen (X), and R3 and R4 taken together represent l,3-dioxolane-2-yl or l,3-dioxane-2-yl; comprising the steps of: a) reacting a compound of formula (IVb or IVc) with a sulfur source in the presence of a suitable solvent to afford 3,3-dialkoxythietane (Illb) when R3 and R4 = alkoxy (OAk), or to afford 5,8-dioxa-2-thiaspiro[3,4]octane (IIIc) when R3 and R4 taken together represent l,3-dioxolane-2-yl; or to afford 5,9-dioxa-2-thiaspiro[3,5]nonane when R3 and R4 taken together represent l,3-dioxane-2-yl; b) converting the compound of formula (Illb or IIIc) to thietan-3-one (II) using a suitable acid; and c) converting the compound of formula (II) to 3-thietanol of formula (I) using a suitable reducing reagent.
Still another embodiment of the present invention provides a process for preparing 3-thietanol of formula (I) from a compound of formula (IVd), wherein R1 = halogen (X), R2 = SH, and R3 and R4 taken together represent carbonyl; comprising the steps of: a) converting a compound of formula (IVd) to thietan-3-one (II) in the presence of a suitable solvent; and b) converting the thietane-3-on (II) of step (a) to 3-thietanol of formula (I) using a suitable reducing reagent. Still another embodiment of the present invention provides a process for preparing 3-thietanol of formula (I) from a compound of formula (IVe), wherein, R1 and R3 = halogen (X), R2 = OH and R4 = hydrogen; comprising the steps of: a) reacting a compound of formula (IVe) with a sulfur source in the presence of a suitable solvent to afford 2-halo-3-mercaptopropan-l-ol (Ille); b) converting the compound of formula (Ille) of step (a) to a mixture of oxiran-2-yl methanethiol (Ila) and thiiran-2-yl methanol (lib) using a suitable base; and c) converting the mixture of oxiran-2-yl methanethiol (Ila) and thiiran-2-yl methanol (lib) of step (b) to 3-thietanol of formula (I). Yet another embodiment of the present invention provides a process for preparing 3-thietanol of formula (I) from a compound of formula (IVf), wherein R1 and R2 = halogen (X), and R3 and R4 taken together represent carbonyl; comprising the steps of: a) converting a compound of formula (IVf) in the presence of a suitable solvent to afford 3- thietan-3-one (II); and b) converting the compound of formula (II) of step (a) to 3-thietanol of formula (I). One embodiment provides a process for preparing 3-thietanol of formula (I), wherein the process steps can be carried out in a batch process.
Another embodiment provides a process for preparing 3-thietanol of formula (I), wherein the process steps can be carried out, partly or as a whole, in a semi -continuous process, e.g. in a semicontinuous flow process. Still another embodiment provides a process for preparing 3-thietanol of formula (I), wherein the process steps can be carried out, partly or as a whole, in a continuous process, e.g. in a continuous flow process.
DETAILED DESCRIPTION OF THE INVENTION GENERAL DEFINITIONS The definitions provided herein for the terminologies used in the present disclosure are for illustrative purpose only and in no manner limit the scope of the present invention disclosed in the present disclosure.
As used herein, the terms “comprises”, “comprising”, “includes”, “including”, “has”, “having”, “contains”, “containing”, “characterized by” or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process or method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process or method.
The term “alkyl” includes straight-chain or branched Ci to G, alkyl. Non-limiting examples of alkyl include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1- dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1- ethylpropyl, hexyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2- dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2- trimethylpropyl, 1,2,2-trimethylpropyl, 1 -ethyl- 1-methylpropyl and l-ethyl-2-methylpropyl.
The term “hydroxy” means -OH, “sulfonyloxy” means 0-S(0)2.
The term “carbonyl” means C(=0) Non-limiting examples of “alkylsulfonyloxy” include methylsulphonyloxy, ethylsulphonyloxy, propylsulphonyloxy, 1-methylethylsulphonyloxy, butylsulphonyloxy, 1- methylpropylsulphonyloxy, 2-methylpropylsulphonyloxy , 1 , 1 -dimethylethylsulphonyloxy , pentylsulphonyloxy, 1 -methylbutylsulphonyloxy, 2-methylbutylsulphonyloxy, 3- methylbutylsulphonyloxy, 2,2-dimethylpropylsulphonyloxy, 1 -ethylpropylsulphonyloxy, hexylsulphonyloxy, 1,1-dimethylpropylsulphonyloxy, 1 ,2-dimethylpropylsulphonyloxy, 1- methylpentylsulphonyloxy, 2-methylpentylsulphonyloxy, 3-methylpentylsulphonyloxy, 4- methylpentylsulphonyloxy, 1,1-dimethylbutylsulphonyloxy, 1,2-dimethylbutylsulphonyloxy, 1,3- dimethylbutylsulphonyloxy, 2,2-dimethylbutylsulphonyloxy, 2,3-dimethylbutylsulphonyloxy, 3 ,3 -dimethylbutylsulphonyloxy . The term “halogen”, either alone or in compound words such as “haloalkyl”, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Non limiting examples of “haloalkyl” include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1 -bromoethyl, 1-fluoroethyl, 2- fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2- difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 1,1-dichloro- 2,2,2-trifluoroethyl, and l,l,l-trifluoroprop-2-yl.
The term “alkoxy” includes Ci to Ce alkoxy. Examples of alkoxy include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 2,2-dimethylpropoxy, 1- ethylpropoxy, hexoxy, 1,1-dimethylpropoxy, 1 ,2-dimethylpropoxy, 1-methylpentoxy, 2- methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1,1-dimethylbutoxy, 1 ,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1- ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1 -ethyl- 1- methylpropoxy and l-ethyl-2-methylpropoxy.
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof could be fully understood and appreciated. In line with the above defined objectives, the present invention provides a process for the preparation of 3-thietanol of formula (I) from compounds of formula (IV)
Figure imgf000008_0001
wherein, R1 and R2 are independently selected from halogen (X), hydroxyl and the mercapto group, R3 is selected from hydroxyl, alkoxy, halogen (X), R4 is selected from hydrogen, alkoxy; or R3 and R4 taken together represents carbonyl or l,3-dioxolane-2-yl or l,3-dioxane-2-yl.
In one embodiment, compounds of formula (IV), wherein R1 and R2 = halogen (X), R3 = OH and R4 is hydrogen, which is represented by the compound of formula (IVa), can be reacted with a sulfur source in the presence of a suitable solvent to obtain 3-thietanol of formula (I). The process is depicted in Scheme-L
Figure imgf000008_0002
1 ,3-Dihalopropan-2-ol 3-Thietanol
(IVa) (I)
Scheme-I
One embodiment provides a process for preparing 3-thietanol of formula (I) from 1,3- dihalopropan-2-ol (IVa), as disclosed in reaction Scheme-I, wherein the process step can be carried out in a batch, semicontinuous or continuous reaction mode, specifically also under semi- continuous flow or continuous flow reaction conditions. In another embodiment, the compound of formula (IV), wherein R1 and R2 = halogen (X), R3 = OH and R4 is hydrogen, which is represented by the compound of formula (IVa), can be reacted with a sulfur source in the presence of a suitable solvent to obtain l-halo-3-mercaptopropan-2-ol (Ilia) in a first step. l-Halo-3-mercaptopropan-2-ol (Ilia), after isolation or without intermediate isolation, can be converted to afford 3-thietanol of formula (I) using a suitable base. The process is depicted in Scheme-la.
Figure imgf000009_0001
Figure imgf000009_0002
1 -Halo-3 -mercaptopropan-2-ol 3-Thietanol
(IVa) (Ilia) (T)
Scheme-la
In another embodiment, a process for preparing 3-thietanol of formula (I) from 1,3-dihalopropan- 2-ol (IVa) can be carried out as disclosed in Scheme-la, in which the process steps can be carried out, partly or as a whole, in a batch, semi-continuous or continuous mode, specifically also in a semi-continuous flow or continuous flow reaction mode, with or without isolation of the intermediate compound of formula (Ilia).
In a further embodiment, 3-thietanol of formula (I) can be prepared from an acetal of formula (IV), wherein R1 and R2 = halogen (X), R3 and R4 = OAk, which is represented by the compound of formula (IVb), can be reacted with a sulfur source in the presence of a suitable solvent to obtain 3,3-dialkoxythietane of formula (Illb), which in a subsequent step is converted into thietan-3-one of formula (II) using a suitable acid, which finally is the converted into 3-thietanol of formula (I) using suitable reducing reagent. This process is depicted in Scheme-II.
Figure imgf000010_0001
1,3 -Dihalo-2, 2-dialkoxypropane 3,3-Dialkoxythietane Thietan-3-one 3-Thietanol
(IVb) (IIIb) (p) (I)
Scheme-P
Yet another embodiment provides a process for preparing 3-thietanol of formula (I) from 1,3- dihalo-2,2-dialoxyxypropane (IVb) as disclosed in Scheme-II, which can be realized in a way that the distinct process steps are carried out, partly or as a whole, in a batch, semi-continuous or continuous reaction mode, specifically in a semi-continuous flow or continuous flow mode, with or without isolation of the intermediate compounds of formula (IIIb) or (II).
In yet another embodiment, 3-thietanol of formula (I) can be prepared from a compound of formula (IV), wherein, R1 and R2 = halogen (X), preferably X is Br or Cl, R3 and R4 taken together represent l,3-dioxolane-2-yl (m = 1) or l,3-dioxane-2-yl (m = 2) which is represented by the compound of formula (IVc), This compound of formula (IVc) can be reacted with a sulfur source in the presence of a suitable solvent to obtain 5,8-dioxa-2-thiaspiro[3,4]octane (IIIc, m = 1) or 5,9-dioxa-2- thiaspiro[3.5]nonane (IIIc, m = 2) followed by conversion of the compound of formula (IIIc) to thietan-3-one of formula (II) using a suitable acid which can be converted to 3-thietanol of formula (I) using a suitable reducing reagent. The process is depicted in Scheme-Ill.
Figure imgf000010_0002
Scheme-Ill
In one embodiment, a process for preparing 3-thietanol of formula (I) from 2,3-bis(halomethyl)- 1,3-dioxolane (IVc, m = 1) or 2,3-bis(halomethyl)-l,3-dioxane (IVc, m = 2) as disclosed in reaction Scheme-Ill, can be carried out, partly or as a whole, in a batch, semi-continuous or continuous reaction mode, specifically in a semi-continuous flow or continuous flow mode, with or without isolation of the intermediate compounds of formula (IIIc), or (II).
In yet another embodiment, 3-thietanol of formula (I) can be prepared from a compound of formula (IV), wherein R1 = halogen (X), R2 = SH, R3 and R4 taken together represent carbonyl, which is represented by a compound of formula (IVd). The compounds of formula (IVd) can be converted to thietan-3-one of formula (II) in the presence of a suitable solvent and using a suitable base, followed by the conversion of thietan-3-one of formula (II) to afford 3-thietanol of formula (I) using a suitable reducing reagent. This process is depicted in Scheme-IV.
Figure imgf000011_0001
1 -Halo-3 -mercaptopropan-2-one Thietan-3 -one OH
3-Thietanol
(IVd) (II) (I)
Scheme-IV
In another embodiment, a process for preparing 3-thietanol of formula (I) from l-halo-3- mercaptopropan-2-one (IVd), as disclosed in reaction Scheme-IV, can be carried out, partly or as a whole, in a batch, semi-continuous or continuous reaction mode, specifically in a semi- continuous flow or continuous flow mode, with or without isolation of the intermediate compound of formula (II).
In yet another embodiment, 3-thietanol of formula (I) can also be prepared from a compound of formula (IV), wherein R1 and R3 = halogen (X), R2 = OH and R4 = hydrogen, which is represented by a compound of formula (IVe). The compounds of formula (IVe) can be reacted with a sulfur source in the presence of a suitable solvent to afford 2-halo-3-mercaptopropan-l-ol (Ille), followed by the conversion of this compound of formula (Ille) using a suitable base to afford a mixture of oxiran-2-ylmethanethiol (Ila) and thiiran -2-methanol (lib); and converting this mixture of oxiran- 2-ylmethanethiol (Ila) and thiiran-2-methanol (lib) to 3-thietanol of formula (I). The process is depicted in Scheme-V.
Figure imgf000012_0002
(Hb)
Scheme-V
In one embodiment, the process for preparing 3-thietanol (I) from 2,3-haloropropan-l-ol (IVe), as disclosed in reaction Scheme-V, can be carried out, partly or as a whole, in a batch, semi- continuous or continuous reaction mode, specifically in a semi-continuous flow or continuous flow mode, with or without isolation of the intermediate compounds of formula (Hie), (Ila) and (lib).
In another embodiment, compound of formula (IV), wherein, R1, R2 = halogen (X), R3 and R4 taken together represent carbonyl, which is represented by a compound of formula (IVf), can be reacted with a sulfur source in the presence of a suitable solvent to obtain thietanol-3-one of formula (II), which can be converted to 3-thietanol of formula (I) using a suitable reducing reagent. The process is depicted in Scheme -VI.
Figure imgf000012_0001
1 ,3-Dihalopropan-2-one Thietan-3-one 3-Thietanol (IVf) (P)
(I)
Scheme-VI
In another embodiment, a process for preparing 3-thietanol (I) from 1 ,3-dihalopropan-l-one (IVf), as disclosed in reaction Scheme-VI, wherein, the process steps can be carried out, partly or as a whole, in a batch, semi-continuous or continuous reaction mode, specifically in a semi-continuous flow or continuous flow mode, with or without isolation of the intermediate compound of formula
(II).
In yet another embodiment, 3-thietanol of formula (I) can be prepared from epihalohydrin wherein the halogen is selected from bromine or chlorine, by reacting with a suitable sulfur source in the presence of a suitable solvent, without isolating compound of formula (IVaa); as depicted in Scheme-VII.
1 -Halo-3-merca to ro an-2-ol
Figure imgf000013_0002
Scheme- VII
Compounds of formula (IVa to IVd) can be prepared as per following Schemes 1-6: In that, l,3-Dihalopropran-2-ol of formula (IVa) can be prepared from (2, 2-dimethyl- 1,3- dioxolan-4-yl)methanol.
The according process is depicted in Scheme- 1.
Figure imgf000013_0001
(2, 2 -Dimethyl-1, 3-dioxolan-4-yl)methanol (IVa)
Scheme- 1
In a further embodiment, l,3-dihalopropran-2-ol of formula (IVa) can be prepared from epihalohydrines under acidic conditions, for instance in the presence of 30% aqueous HC1, at carefully controlled temperatures, for instance at a temperature within the range of 0 °C to 5 °C for 10 to 12 hours. This process is depicted in Scheme-2.
Figure imgf000014_0001
Epihalohydrine 1 ,3-Dihalopropan-2-ol (IVa)
Scheme-2
In another embodiment, l,3-dichloropropran-2-ol of formula (IVa-1) can be prepared from a solution of glycerol and acetic acid using trimethylsilyl chloride at elevated temperatures, preferably at a temperature of 100 °C to 110 °C and a reaction time of 5 to 25 hours. This process is depicted in Scheme-3.
Figure imgf000014_0002
Propane- 1 ,2,3-triol 1 ,3 -Dichloropropan-2-ol (IVa-1)
Scheme-3
1,3 -Dihalo-2, 3 -dialkoxypropane of formula (IVb) can be prepared by brominating propan-2-one in a mixture of acetone and methanol at a temperature within the range of 20 °C to 25 °C under stirring for 2 hours, followed by cooling the mixture to - 18 °C overnight. This process is depicted in Scheme-4.
Figure imgf000014_0003
1 ,3-Dihalo-2,2-dialkoxypropane
(IVb)
Scheme-4
2,3-Bis(halomethyl)-l,3-dioxalane of formula (IVc, m = 1) and 2,3-bis(halomethyl)-l,3-dioxane (IVc, m = 2) can be prepared from 1 ,3-dihaloropropan-2-ones. This process is depicted in Scheme-
5.
Figure imgf000015_0001
1 ,3-Dihalopropan-2-one 2,3-Bis(halomethyl)-l,3-dioxalane
(IVc)
Scheme-5
1 -Halo-3 -mercaptopropan-2-one of formula (IVd) can be prepared from l,3-dihalopropan-3-one. The process is depicted in Scheme-6.
Figure imgf000015_0002
1 ,3 -Dihalopropan-2-one 1 -Halo-3 -mercaptopropan-2-one (IVd)
Scheme-6
The sulfur source used in the above schemes can include but is not limited to sulfur, hydrogen sulfide, sodium sulfide, sodium hydrogen sulfide, thiourea and thioacetic acid.
The suitable solvents used in the above schemes can include but are not limited to hydrocarbons such as n-heptane, n-hexane, cyclohexane, n-pentane, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, and diisopropyl ether; halogenated hydrocarbons such as carbon tetrachloride, chloroform, dichlorome thane, 1,2-dichloroethane, tetrachloroethane, and chlorobenzene; acid amides such as N, N-d i met h y I fo rmam i de, l,3-dimethyl-2-imidazolidinone, and N-methylpyrrolidone; esters such as ethyl acetate and methyl acetate; sulfoxides such as dimethyl sulfoxide; sulfolane; ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; nitriles such as acetonitrile and propionitrile; water; and mixtures thereof. The suitable halogenating agents used in the above schemes can include but are not limited to a chlorinating agent, a brominating agent, or an iodinating agent, for example, chlorine, bromine, iodine, sulfuryl chloride, N-chlorosuccinimide, N-bromosuccinimide, l,3-dibromo-5,5- dimethylhydantoin, N-chloro-saccharin, N-bromo-saccharin, iodosuccinimide, tert-butyl hypochlorite, N-chloroglutarimide, N-bromoglutarimide, N-chloro-N-cyclohexyl- benzenesulfonimide, N-bromophthalimide, and the like.
The suitable halogenating agents used in the above schemes can include but are not limited to bromine, chlorine, sulfuryl chloride, hydrochloric acid, hydrobromic acid, hydroiodic acid, boron tribromide, phosphoms tribromide, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosphoms oxybromide, phosphoms pentabromide, phosphoms triiodide, oxalyl dichloride, oxalyl dibromide, acetyl chloride, carbon tetrabromide, N- bromosuccinimide, N-bromo-saccharin, lithium chloride, sodium iodide, acetyl bromide, and the like. The suitable halogenating agents used in the above schemes can include but are not limited to phosphoms oxychloride, phosphoms trichloride, phosphorus pentachloride, thionyl chloride, phosphoms oxybromide, phosphoms tribromide, phosphoms pentabromide, oxalyl dichloride, oxalyl dibromide, triphosgene, diphosgene, phosgene, and sulfuryl chloride.
Oxidative halogenation would include for instance HCI/H2O2 or HBr/H202 type systems, where the active halogen is generated by oxidation of HX.
The suitable base used in the above schemes can include but are not limited to organic bases such as triethylamine, pyridine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine, diisoprop ylethylamine, lutidine, collidine, diazabicycloundecene, and diazabicyclononene; alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal halides such as sodium fluoride, potassium fluoride, and cesium fluoride; alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride; and alkali metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide.
The suitable acid used in the above schemes can include but are not limited to organic acid such as acids are, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and, alkylsulfonic acids such as methanesulfonic acid; inorganic acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide and sulfuric acid.
The reaction time is not critical and depends on the batch size, temperature, reagent and solvent employed. Typically, the reaction time may vary from a few minutes to several hours. Any person skilled in the art knows the best work-up of the reaction mixtures after the end of the respective reactions. In one embodiment, the work-up is usually carried out by isolation of the product, and optionally washing with solvent, further optionally drying of the product if required.
The isolation of the reaction product can be carried out by a technique which includes but is not limited to decantation, centrifugation, evaporation, liquid-liquid extraction, distillation, recrystallization, chromatography and the like or a combination thereof.
The process steps according to the invention are generally carried out under atmospheric pressure. Alternatively, however, it is also possible to work under reduced pressure or under pressure.
Without further elaboration, it is believed that any person skilled in the art who is using the preceding description can utilize the present invention to its fullest extent.
EXAMPLES
The invention is further illustrated with reference to the following examples. It is apparent to those skilled in the art that many modifications, both to materials, methods and various reaction parameters, may be practiced without departing from the scope of the invention. The starting materials according to the present invention are known compounds that are commercially available or can be prepared in a known manner. Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.
Example- 1
Synthesis of l,3-dichloropropan-2-ol To a cooled solution of epichlorohydrin (500 kg, 540 mmol), 30% aq. HC1 (1200 kg, 987 mmol) was added slowly and under stirring at 0 °C over 10 h. After completion of the reaction, the undesired aq. HC1 layer was separated from the desired l,3-dichloropropan-2-ol product layer to obtain l,3-dichloropropan-2-ol (Yield 480 kg, 69%).
Synthesis of l,3-dibromo-2,2-dimethoxypropane Bromine (64 g, 0.4 mol) was added drop wise to a stirred solution of acetone (11.6 g, 0.2 mol) in methanol (200 mL) at 20-25 °C, and stirring was continued further for 2 hours at the same temperature. The reaction mixture was cooled to 0 °C and kept overnight at -18 °C to obtain 1,3- dibromo-2,2-dimethoxypropane (39 g, 0.15 mol).
Synthesis of 3,3-dimethoxythietane To a stirred solution of l,3-dibromo-2,2-dimethoxy-propane (102 g, 389 mmol) in N,N- dimethylformamide (1200 mL), sodium sulfide (66.8 g, 506 mmol) was added and the mixture was refluxed for 3 days. The mixture was cooled to room temperature, diluted with diethyl ether (1200 mL), washed with water (1200 mL), brine (1200 mL), dried over sodium sulphate and concentrated under reduced pressure to afford 3,3-dimethoxythietane as a yellowish oil (yield 40 g, 77%).
Synthesis of thietan-3-one
To a stirred solution of 3,3-dimethoxythietane (40 g, 600 mmol) in dichloromethane (2500 mL), dioxosilane (160 g) was added. The reaction mixture was refluxed for 2 days. Upon completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford the desired product.
Synthesis of l,3-dichloropropan-2-ol To a stirred solution of glycerol (2.78 g, 30 mmol) in acetic acid (0.054 g, 0.9 mmol), trimethylsilyl chloride (8.75 g, 10.5 ml, 75 mmol) was added, and the mixture was heated for 12 hours at 100 °C. The reaction mixture was distilled, and the distillate containing the product was collected at a temperature between 40 and 77 ° C under reduced pressure (18 mmHg). Example-2
Synthesis of l,3-dibromo-2,2-dimethoxypropane:
To a stirred solution of acetone (5.80 g, 100.00 mmol) in methanol (100 mL), bromine (32.00 g, 200.00 mmol) was added drop wise at 10 °C, and stirring was continued for 16 h at the same temperature. After completion of the reaction, the reaction mixture was concentrated (-50%) under reduced pressure and cooled to 0 °C. The resulting precipitate was filtered and dried to afford 1,3- dibromo-2,2-dimethoxypropane (2) as a white crystalline solid (21.00 g, 80%). lU NMR (400 MHz, DMSO) d 3.61 (s, 4H), 3.17 (s, 6H).
13C NMR (100.5 MHz, DMSO) d 99.4, 49.2, 31.2.
GCMS m/z = 230.94 [M] Synthesis of 3,3-dimethoxythietane:
To a stirred solution of l,3-dibromo-2,2-dimethoxypropane (2.50 g, 9.54 mmol) in dimethylsulfoxide (20 mL), sodium sulfide (1.35 g, 9.54 mmol) was added, and the reaction mixture was stirred at 120 °C for 12 h. After completion of the reaction, the reaction mixture was cooled to 25-30 °C, diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 3,3-dimethoxythietane as a brownish oil (0.90 g, 70%).
¾ NMR (400 MHz, DMSO) d 3.06 (s, 10H).
13C NMR (100.5 MHz, DMSO) d 101.9, 47.2, 36.6.
GCMS: m/z = 134 [M] Synthesis of 2,2-bis(chloromethyl)-l,3-dioxane: To a stirred solution of l,3-dichloropropan-2-one (5.00 g, 39.40 mmol) in toluene (5 mL), propane- 1, 3-diol (3.15 g, 41.40 mmol) and p-toluenesulfonic acid (0.16 g, 0.94 mmol) were added and the reaction mixture was stirred at 120 °C for further 6 h. The water generated in the reaction was removed via a Dean-Stark apparatus. After completion of the reaction, the reaction mixture was cooled to 25-30 °C, diluted with saturated sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 2,2-bis(chloromethyl)-l,3-dioxane as a colorless oil (5.30 g, 73%). lU NMR (400 MHz, DMSO) d 3.89 (t, 4H), 3.85 (s, 4H), 1.64 (m, 2H).
GCMS: m/z = 135 [M]
Synthesis of 5,9-dioxa-2-thiaspiro[3.5]nonane:
To a stirred solution of 2,2-bis(chloromethyl)-l,3-dioxane (2.50 g, 13.51 mmol) in dimethylsulfoxide (20 mL), sodium sulfide (1.91 g, 13.51 mmol) was added and the reaction mixture was stirred at 120 °C for further 12 h. After completion of the reaction, the reaction mixture was cooled to 25-30 °C, diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 5,9-dioxa-2-thiaspiro[3.5]nonane as a brown oil (1.40 g, 74%).
¾ NMR (400 MHz, DMSO) d 3.79 (t, 4H), 3.33 (s, 4H), 1.7 (m, 2H).
GCMS: m/z = 135.3 [M]
Synthesis of thietan-3-one:
Process-1:
To a stirred solution of 3,3-dimethoxythietane (1.00 g, 7.45 mmol) in dichloromethane (10 mL), trifluoroacetic acid (0.85 g, 7.45 mmol) was added, and the resulting mixture was stirred at 25-30 °C for further 5 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL). The dichloromethane layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford thietan-3-one as a yellowish oil (0.57 g, 87%). lU NMR (400 MHz, CDCh) d 4.37 (s, 4H) 13C NMR (100.5 MHz, DMSO) d 196.1, 55.1 GCMS: m/z = 88 [M]
Process-2:
To a stirred solution of 5,9-dioxa-2-thiaspiro[3.5]nonane (1.00 g, 6.84 mmol) in methanol (10 mL), hydrochloric acid (35%, 0.78 g, 7.52 mmol) was added, and stirring was continued at 25-30 °C for 5 h. After completion of the reaction, the reaction mixture was quenched with water (10 mL). The dichloromethane layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford thietan-3-one as a yellowish oil (0.52 g, 85%).
Synthesis of thietan-3-ol:
To a stirred solution of thietan-3-one (1.00 g, 11.35 mmol) in dichloromethane (8 mL) and methanol (2 mL), sodium borohydride (1.28 g, 34.00 mmol) was added in portions at 0-5 °C. The reaction mixture was stirred at 25-30 °C for further 5 h. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain thietan-3-ol as a colorless oil (0.90 g, 88%).
¾ NMR (400 MHz, DMSO) d 5.78 (d, 1H), 4.62 (m, 1H), 3.21 (dd, 2H), 3.09 (dd, 2H).
GCMS: m/z = 90 [M]
Example-3
Synthesis of l,3-dichloropropan-2-ol:
Into a round bottom flask containing 2-(chloromethyl)oxirane (100.00 g, 1081.00 mmol), hydrochloric acid (35%, 239.00 g, 1967.00 mmol) was added dropwise under stirring at 0-5 °C over a period of 1 h. The resulting reaction mixture was stirred at 25-30°C for further 10 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (500 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford l,3-dichloropropan-2-ol as a colorless oil (125.00 g, 90%). lU NMR (400 MHz, CDCb) d 4.05 (m, 1H), 3.68 (d, 4H). GCMS: mJz = 129 [M]
Synthesis of thietan-3-ol (7):
Condition 1: From l,3-dichloropropan-2-ol to thietan-3-ol:
To a cooled (10-15 °C) solution of potassium hydroxide (5.22 g, 93.00 mmol) in water (10 mL), hydrogen sulphide gas (3.20 g, 93.00 mmol) was purged for 1 h under stirring, followed by the addition of l,3-dichloropropan-2-ol (5.00 g, 38.80 mmol). The resulting reaction mixture was stirred at 50 °C for further 16 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (45 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford thietan-3-ol as a yellowish oil (2.00 g, 57%).
¾ NMR (400 MHz, DMSO) d 5.78 (d, 1H), 4.62 (m, 1H), 3.21 (dd, 2H), 3.09 (dd, 2H).
GCMS: m/z = 90 [M]
Condition 2: From 2-(chloromethyl)oxirane to thietan-3-ol:
To a stirred solution of potassium hydroxide (43.70 g, 778.00 mmol) in water (200 mL), hydrogen sulphide gas (44.19 g, 1296.00 mmol) was purged at 10-15°C for 1 h, followed by the addition of 2-(chloromethyl)oxirane (30.00 g, 324.00 mmol). The resulting reaction mixture was stirred at 60 °C for further 16 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (250 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford thietan-3-ol as a yellowish oil (14.89 g, 51%). Condition 3: From 2-(chloromethyl)oxirane (15) to thietan-3-ol:
To a 1 L pressure reactor, aqueous solution of potassium hydroxide (193.00 g, 2918.00 mmol in water 540 mL) was added. The reactor was cooled to 15-20°C and charged with hydrogen sulphide gas (66.30 g, 1945.00 mmol) at 2 bar. The resulting solution was heated to 55 °C, followed by the controlled dosing of 2-(chloromethyl)oxirane (90.00 g, 973.00 mmol) in 3 h. The reaction mixture was stirred further at 60 °C for 7 h. After completion of the reaction, the reaction mixture was extracted with tert-butyl methyl ether (750 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford thietan-3-ol as a yellowish oil (57.18 g, 65%).
Example-4
Synthesis of l-chloro-3-mercaptopropan-2-one: To a cooled (10-15°C) stirred solution of potassium hydroxide (2.60 g, 38.80 mmol) in water (15 mL), hydrogen sulphide gas (1.32 g, 38.80 mmol) was purged for 1 h, followed by the addition of l,3-dichloropropan-2-ol (5 g, 38.8 mmol). The resulting reaction mass was stirred at 25-30 °C for further 2 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (45 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford l-chloro-3-mercaptopropan-2-one as a yellowish oil (3.40 g, 70%).
GCMS: m/z = 126 [M]
Synthesis of thietan-3-ol:
To a stirred solution of l-chloro-3-mercaptopropan-2-one (2.00 g, 15.80 mmol) in dichloroethane (10 mL), l,8-diazabicyclo[5.4.0]undec-7-ene (1.20 g, 7.90 mmol) was added and stirring was continued at 25-30 °C for further 12 h. After completion of the reaction, the reaction mixture was extracted with dichloroethane (10 mL) and washed with water (10 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford thietan-3-ol as a yellowish oil (0.80 g, 56%). ¾ NMR (400 MHz, DMSO) d 5.78 (d, 1H), 4.62 (m, 1H), 3.21 (dd, 2H), 3.09 (dd, 2H).
GCMS: m/z = 90 [M]

Claims

CLAIMS:
1. A process for preparing 3-thietanol of formula (I),
Figure imgf000024_0001
3-Thietanol
(I) characterized in that reacting a compound of formula (IV),
Figure imgf000024_0002
wherein,
R1 and R2 are independently selected from halogen (X), hydroxyl or mercapto group, R3 is selected from hydroxyl, alkoxy or halogen (X),
R4 is selected from hydrogen and alkoxy, or
R3 and R4 taken together represent carbonyl or l,3-dioxolane-2-yl or l,3-dioxane-2-yl; with a suitable sulphur source in the presence of a suitable solvent to obtain 3-thietanol of formula (I);
2. The process according to claim 1 wherein the compound of formula (IV) is selected from, formula (IVa), (IVb), (IVc), (IVe) or (IVf);
Figure imgf000024_0003
( (IVc) (IVe) (ivf)
(IVa) IVb) wherein, X represents halogen; Ak represents C1-C2 alkyl; and m represents an integer of 1 or 2.
3. The process according to claim 1 or 2, wherein, compound of formula (IV) is a compound of formula (IVa); which comprises reacting a compound of formula (IVa) with a suitable sulfur source in the presence of a suitable solvent to obtain 3-thietanol of formula (I).
4. The process according to claim 1 or 2, wherein, the compound of formula (IV) is a compound of formula (IVa); comprising the steps of: a) reacting a compound of formula (IVa) with a sulfur source in the presence of a suitable solvent to obtain l-halo-3-mercaptopropan-2-ol of formula (Ilia); and b) converting the compound of formula (Ilia) obtained in step-a to 3-thietanol of formula (I); as shown in below scheme la:
OH x^Ax
Figure imgf000025_0001
(IVa) (IIIa) 3-Thietanol
Scheme-la
5. The process according to claim 1 or 2, wherein, the compound of formula (IV) is a compound of formula (IVb) or a compound of formula (IVc); comprising the steps of: a) reacting a compound of formula (IVb or IVc) with a sulfur source in the presence of a suitable solvent to afford 3,3-dialkoxythietane (Illb) or (IIIc) ; b) converting the compound of formula (Illb or IIIc) obtained in step-a to thietan-3-one of formula (II) using a suitable acid; and c) converting the compound of formula (II) obtained in step-b to 3-thietanol of formula (I) using a suitable reducing agent as shown in below scheme II and III.
Figure imgf000025_0002
(Illb) (II) (IVb) Thietan-3-one 3-Thietanol
Scheme-ll O ri O)m Sulfur source
X — ' X ' — X - -
Figure imgf000026_0001
(IVc) (lllc) (ID
Thietan-3-one 3-Thietanol
Scheme-Ill
6. The process according to claim 1 or 2, wherein, the compound of formula (IV) is a compound of formula (IVd); comprising the steps of: a) converting a compound of formula (IVd) to thietan-3-one of formula (II) in the presence of a suitable solvent; and b) converting the thietane-3-on of formula (II) obtained in step-a to 3-thietanol of formula (I) using a suitable reducing agent as shown in below scheme IV :
Figure imgf000026_0002
(IVd) (II)
Scheme-IV
7. The process according to claim 1 or 2, wherein, the compound of formula (IV) is a compound of formula (IVe); comprising the steps of: a) reacting a compound of formula (IVe) with a sulfur source in the presence of a suitable solvent to afford 2-halo-3-mercaptopropan-l-ol of formula (Ille); b) converting the compound of formula (Ille) obtained in step-a to a mixture of oxiran-2-yl methanethiol of formula (Ila) and thiiran-2-yl methanol (lib) using a suitable base; and c) converting the mixture of oxiran-2-yl methanethiol of formula (Ila) and thiiran-2-yl methanol of formula (lib) obtained in step-b to 3-thietanol of formula (I), as shown in below scheme V :
Figure imgf000027_0001
3-Thietanol
Scheme-V (lib)
8. The process according to claim 1 or 2, wherein, the compound of formula (IV) is a compound of formula (IVf); comprising the steps of: a) converting a compound of formula (IVf) in the presence of a suitable solvent to afford 3- thietan-3-one of formula (II); and b) converting a compound of formula (II) obtained in step-a to 3-thietanol of formula (I) by using a suitable reducing agent as shown in below scheme VI:
Figure imgf000027_0002
9. The process according to claim 1 wherein R1 and R2 represent halogen (X).
10. The process according to claims 3, 4, 5, 7 or 8, wherein said sulfur source used in the reaction selected from sulfur, hydrogen sulfide, sodium sulfide, sodium hydrogen sulfide, thiourea and thioacetic acid.
11. The process according to claims 3, 4, 5, 7 or 8, wherein said sulfur source used in the reaction is sodium sulfide or sodium hydrogen sulfide.
12. The process according to claim 9, wherein said halogen is chlorine atom.
13. The process according to claim 1 , wherein suitable solvent is selected from n-heptane, n- hexane, cyclohexane, n-pentane, toluene, xylene, diethyl ether, tetrahydrofuran, 2-methyl- tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, anisole, methyl tert-butyl ether, diisopropyl ether, carbon tetrachloride, chloroform, dichloromethane, 1,2- dichloroethane, tetrachloroethane, chlorobenzene, V.V-dimethylformamide, 1,3-dimethyl- 2-imidazolidinone, V-methylpyrrolidone, ethyl acetate and methyl acetate, as dimethyl sulfoxide, sulfolane, acetone, methyl ethyl ketone, methyl isobutyl keton, acetonitrile, propionitrile, water; and mixtures thereof.
14. The process according to claim 1, wherein suitable base is selected from triethylamine, pyridine, V-methylmorpholine, /V-methylpiperidine, 4-dimethylaminopyridine, diisopropylethylamine, lutidine, collidine, diazabicycloundecene, diazabicyclononene, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate; lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide; alkali metal halides such as sodium fluoride, potassium fluoride, cesium fluoride; lithium hydride, sodium hydride, potassium hydride; sodium tert-butoxide and potassium tert-butoxide.
15. The process according to claim 1, wherein suitable base is selected from formic acid, carbonic acid acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, methanesulfonic acid; hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide and sulfuric acid.
16. The process according to claim 1, wherein 3-thietanol of formula (I) is prepared from epihalohydrin by reacting with a suitable sulfur source in the presence of a suitable solvent without isolating compound of formula (IVaa) as shown in below scheme VII;
Figure imgf000028_0001
Scheme-VII wherein R1 is as defined in claiml .
PCT/IB2022/054195 2021-05-06 2022-05-06 A novel process for the preparation of 3-thietanol WO2022234528A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117105752A (en) * 2023-10-20 2023-11-24 昊维联众生物医药技术(天津)有限公司 Preparation method of 1, 3-dibromo-2, 2-dimethoxypropane

Citations (1)

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Publication number Priority date Publication date Assignee Title
GB1351736A (en) * 1970-04-14 1974-05-01 Robinson Bros Ltd Polymers based on 3-thietanol

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Publication number Priority date Publication date Assignee Title
GB1351736A (en) * 1970-04-14 1974-05-01 Robinson Bros Ltd Polymers based on 3-thietanol

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Title
KOTIN SANDRA MIGDALOF: "SYNTHESIS AND REACTIONS OF THIET ANE AND ITS DERIVATIVES", UNIVERSITY OF PENNSYLVANIA, PH.D., 1 January 1962 (1962-01-01), pages 3 - 4, XP093005257, [retrieved on 20221206] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117105752A (en) * 2023-10-20 2023-11-24 昊维联众生物医药技术(天津)有限公司 Preparation method of 1, 3-dibromo-2, 2-dimethoxypropane

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