WO2021038586A1 - Improved process for the preparation of tezacaftor intermediate - Google Patents

Improved process for the preparation of tezacaftor intermediate Download PDF

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Publication number
WO2021038586A1
WO2021038586A1 PCT/IN2020/050737 IN2020050737W WO2021038586A1 WO 2021038586 A1 WO2021038586 A1 WO 2021038586A1 IN 2020050737 W IN2020050737 W IN 2020050737W WO 2021038586 A1 WO2021038586 A1 WO 2021038586A1
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compound
formula
sodium
benzene
methyl
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PCT/IN2020/050737
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French (fr)
Inventor
Srinivas KOLUPULA
Sreenivas PEDDOLLA
Madhusudhan Reddy Ganta
Srinivas Benda
Venkatesham KUNNURU
Gollapelli KISHORE
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Keminntek Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/24—Preparation of ethers by reactions not forming ether-oxygen bonds by elimination of halogens, e.g. elimination of HCl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
    • C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups

Definitions

  • the present invention relates to an improved process for the preparation of tezacaftor intermediate. More particularly the present invention relates to industrial feasible and economically viable process for the preparation of tezacaftor intermediate
  • Tezacaftor is approved in combination with ivacaftor for the treatment of cystic fibrosis in US and Europe. Tezacaftor in combination with Ivacaftor is available in the market under the brand name Symdeko® as tablets containing lOOmg of tezacaftor and 150mg of ivacaftor.
  • Tezacaftor is chemically described as l-(2,2-difluoro-2H-l,3- benzodioxol-5-yl)-N- ⁇ l-[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lHindol-5- yl) cyclopropane- 1 -carboxamide (herein after referred as tezacaftor) and represented by the structural formula I as shown below:
  • U.S. Patent No. 7,776,905 describes tezacaftor and its related compounds, a pharmaceutical composition and a method of treatment.
  • U.S. Patent No. 9,840,513B2 discloses a process for the preparation of precursor of tezacaftor intermediate II by additionally using phase transfer catalyst to give compound of formula V which is subjected to oxidation by using pyridine-S0 3 complex in the presence of DMF and triethylamine to give the compound of formula IV which were isolated by column chromatography using ethyl acetate and heptane mixture.
  • Kozo shishido et al. Journal of organic chemistry volume 77, page 9240-9249, 2012 discloses the process for the preparation of compound of formula IV, III and II in similar process to the process of present invention but the reagents being used therein are very much lesser in molar equivalents than actually required thus effecting the yields and the purity of the desired compounds IV, III and II.
  • the present invention relates to an improved process for the preparation of tezacaftor intermediate (((2,2-dimethylbut-3-yn-l-yl)oxy)methyl)benzene compound of formula II
  • the present invention relates to an improved, commercially viable process for the preparation of tezacaftor intermediate compound of formula II comprising the steps of: a) Reacting the compound of formula (VI) with a compound of formula (VII) in the presence of a base to obtain the compound of formula (V), and
  • an improved process for the preparation of tezacaftor intermediate compound of formula II comprising the steps of: a) Reacting a compound bromomethyl)benzene of formula VII with a compound 2,2- dimethylpropane-l,3-diol of formula VI in the presence of a suitable base and an organic solvent to obtain the compound 3-(benzyloxy)-2,2-dimethylpropan-l-ol of formula (V), and
  • Inorganic bases include one or more of alkali metal hydrides such as sodium hydride and the like; alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide and the like; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; alkali metal carbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate and the like; or mixtures thereof or their aqueous or alcohol phases.
  • alkali metal hydrides such as sodium hydride and the like
  • alkali metal hydroxides such as sodium hydroxide or potassium hydroxide and the like
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like
  • alkali metal hydroxide potassium hydroxide in aqueous phase.
  • the reaction step (a) can be optionally performed in the absence of organic solvent i.e., neat conditions.
  • the reaction step (a) is preferably carried out using organic solvent or a mixture thereof selected from hydrocarbon solvents such as toluene, xylene, n- hexane, n-heptane, cyclohexane and the like; ethers such as to tetrahydrofuran (THF), 1,4- dioxane and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; or mixture thereof in various proportions without limitation.
  • hydrocarbon solvent toluene and ether solvent tetrahydrofuran (THF) independently.
  • the reaction step a) is performed by optionally employing phase transfer catalyst selected from the group consisting of tetra butyl ammonium bromide (TBAB), tetrabutylammonium iodide (TBAI) and the like or mixture thereof.
  • phase transfer catalyst selected from the group consisting of tetra butyl ammonium bromide (TBAB), tetrabutylammonium iodide (TBAI) and the like or mixture thereof.
  • TBAB tetra butyl ammonium bromide
  • TBAI tetrabutylammonium iodide
  • TBAI tetrabutylammonium iodide
  • phase transfer catalyst makes the conversion faster and enhances the yield of the desired product significantly over the prior art processes.
  • the reaction step (a) can be performed at any suitable temperature that can afford provide the desired compound with no or less side products and impurities, the reaction temperature can be in the range from about 25 °C to about 100°C or the boiling point of the solvent(s) used. Preferably the suitable reaction temperature can be about 25 °C -30°C.
  • the reaction time for the completion of the reaction generally depends on various factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction step (a) is effected under the preferred conditions discussed above, a period of from about 5 hours to about 25hours. Preferably, a reaction time of about 20-22 hrs is suffice.
  • the reaction step (b) is performed by employing any suitable oxidizing reagent or a complex thereof commonly used for such purpose.
  • TEMPO ((2,2,6,6-Tetramethylpiperidin-l- yl)oxyl), Dess Martin periodinane, Swern oxidation reagent and the like; Preferably TEMPO ((2,2,6,6-Tetramethylpiperidin-l-yl)oxyl) is being used.
  • the oxidizing agent TEMPO is being used in the presence of a catalyst not limited to sodium hypochlorite (NaOCl) in combination with a mild base such as sodium bicarbonate and additionally a base not limited to potassium bromide (KBr) particularly in aqueous phase.
  • a catalyst not limited to sodium hypochlorite (NaOCl) in combination with a mild base such as sodium bicarbonate and additionally a base not limited to potassium bromide (KBr) particularly in aqueous phase.
  • oxidizing agent TEMPO makes the process simple, efficient, ecofriendly and enhances the yield and purity of the desired compound of formula (IV) significantly which is advantageous over the prior art processes.
  • the reaction step (b) can be optionally performed in the absence of organic solvent i.e., neat conditions.
  • the reaction step (b) is preferably carried out using organic solvent or a mixture thereof selected from halogenated solvents such as dichlorome thane, ethylene dichloride and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; ethers such as to tetrahydrofuran (THF), 1,4-dioxane and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; or mixture thereof in various proportions without limitation.
  • halogenated solvent dichloromethane DCM
  • DCM halogenated solvent dichloromethane
  • the reaction step (b) can be performed at any suitable temperature that can afford the desired compound with no or less side products and impurities, the reaction temperature can be in the range from about 25°C to about 100°C or the boiling point of the solvent(s) used. Preferably the suitable reaction temperature can be about 25 °C -30°C.
  • reaction time for the completion of the reaction generally depends on various factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction step (b) is effected under the preferred conditions discussed above, a period of from about 2 hours to about 10 hours. Preferably, a reaction time of about 3-4 hrs is suffice.
  • the reaction step (c) is a reaction of compound of formula (IV) with a suitable agent include but are not limited to carbon tetrabromide (CBrz t ) in the presence of triphenyl phosphine (TPP) and the like to obtain the desired compound of formula (III) ; additionally the reaction of compound of formula (IV) with carbon tetrachloride (CCU) in the presence of triphenyl phosphine (TPP) to obtain the desired compound of formula (IIIA).
  • a suitable agent include but are not limited to carbon tetrabromide (CBrz t ) in the presence of triphenyl phosphine (TPP) and the like to obtain the desired compound of formula (III) ; additionally the reaction of compound of formula (IV) with carbon tetrachloride (CCU) in the presence of triphenyl phosphine (TPP) to obtain the desired compound of formula (IIIA).
  • the reagent carbon tetrabromide or carbon tetrachloride can be added to the reaction mixture at a temperature range from about -5°C to about 5°C to avoid the formation of side products and process related impurities which will affect the yield and purity of the desired compounds of formulae (III) and (IIIA).
  • the process of going through the step (c) is a major breakthrough for obtaining the final compound of formula II in better yield and purity over the prior art processes.
  • step (c) is simple, economical involving cheaper, commercially available reagents and viable on commercial scale.
  • the reaction step (c) can be optionally performed in the absence of organic solvent i.e., neat conditions.
  • the reaction step (c) is preferably carried out using organic solvent or a mixture thereof selected from halogenated solvents such as dichloromethane (DCM), ethylene dichloride and the like; esters such as ethyl acetate, isopropyl acetate and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; or mixture thereof in various proportions without limitation.
  • halogenated solvent dichloromethane (DCM) is being used.
  • the reaction step (c) can be performed at any suitable temperature that can afford the desired compound with no or less side products and impurities, the reaction temperature can be in the range from about 15°C to about 75°C or the boiling point of the solvent(s) used. Preferably the suitable reaction temperature can be about 25 °C -30°C.
  • reaction time for the completion of the reaction generally depends on various factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction step (c) is effected under the preferred conditions discussed above, a period of from about 2 hours to about 10 hours. Preferably, a reaction time of about 3-4 hrs is suffice.
  • the reaction step (d) is reaction of compound of formula (III) or (IIIA) with a suitable agent include but are not limited to n-butyl lithium (n-BuLi), Methyl Lithium, sodium sulfide or its hydrates thereof, alkaline earth metal carbonates such as cesium carbonate (CS2CO3) and the like.
  • a suitable agent include but are not limited to n-butyl lithium (n-BuLi), Methyl Lithium, sodium sulfide or its hydrates thereof, alkaline earth metal carbonates such as cesium carbonate (CS2CO3) and the like.
  • CS2CO3 cesium carbonate
  • step (d) employing methyl lithium in step (d) is a major breakthrough for obtaining the final compound of formula II in better yield and purity over the prior art processes.
  • the said agent is simple to handle on commercial scale, nonhazardous, cheaper, commercially available thus makes the process economical, ecofriendly over the prior art processes which involves expensive and hazardous reagents.
  • the reaction step (d) is preferably carried out using organic solvent or a mixture thereof selected from ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; or mixture thereof in various proportions without limitation.
  • ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like
  • aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like
  • aprotic polar solvent dimethylsulfoxide (DMSO) is being used when the reagent sodium sulfide employed and ether solvent tetrahydrofuran (THF) when methyl lithium or n-butyl lithium is employed.
  • the reaction step (d) can be performed at any suitable temperature that can afford the desired compound with no or less side products and impurities, the reaction temperature can be in the range from about 25 °C to about 75°C or the boiling point of the solvent(s) used. Preferably the suitable reaction temperature can be about 25 °C -30°C.
  • reaction time for the completion of the reaction generally depends on various factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction step (d) is effected under the preferred conditions discussed above, a period of from about 2 hours to about 10 hours. Preferably, a reaction time of about 2-3 hrs is suffice.
  • the intermediate compounds in the above described process steps are obtained with high purity by employing high vacuum distillation (HVD) under reduced pressure extremely below the atmospheric pressure and at temperatures from about 50°C to about 100°C. which is a novel method of obtaining pure compound which is not reported in the prior art.
  • HVD high vacuum distillation
  • the process steps are carried out in insitu i.e., one pot synthesis.
  • the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
  • reaction mixtures especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
  • the intermediate compounds obtained herein are optionally purified by recrystallisation, using a solvent or mixture of solvents or their combination with water in any proportion without limitation by conventional techniques well known for a person skilled in the art.
  • the intermediates obtained herein by the process of the present invention may exist in either crystalline or amorphous or mixture thereof.
  • Tezacaftor intermediate (II) results in the formation of impurities and bye products in significant amount due to usage of strong reagents and in lower molar equivalents and thus leading to poor yields and purities of the desired products. Thus essentially required to have purification process intermittently leading to non ecofriendly and expensive processes.
  • the process of present invention provides the intermediate compound of formula II in higher yield and purity compared to the prior art processes.
  • the yield of the intermediates is atleast about 60%, or more, more preferably, the yield is about 70% to about 80% by weight. Whereas the prior art processes results the compound of formula II in not more than 50%.
  • the process of present invention provides the compound of formula II has purity greater than about 99 area % by HPLC and total impurities less than about 1 area % with the compounds of formulae VII,VI,V,IV,III,IIIA each lesser than about 0.1 area % by HPLC. Whereas the prior art processes results in the compound of formula II not more than 80% by HPLC.
  • the compound of formula II obtained by the process of present invention is used as intermediate in the synthesis of benzodioxol compounds such as Tezacaftor and its related compounds.
  • the present invention provides simple, ecofriendly, economical, reproducible, robust and commercially viable process for preparation of tezacaftor intermediate (II) with enhanced yield and purity.
  • reaction progress was monitored by TLC and after completion of the reaction, the reaction mass was quenched by adding to the precooled water at 25-30°C.
  • the reaction mass was extracted with 2x2 lit. of ethyl acetate and the organic layer was washed with 2x4 lit. of brine solution and the organic layer was separated and distilled completely at below 50°C under vacuum to give residue which is further subjected to high vacuum distillation (HVD) to afford the title compound.
  • HVD high vacuum distillation
  • reaction progress was monitored by TLC and after completion of the reaction, the reaction mass was quenched with saturated aqueous sodium thiosulfate (Na 2 S 2 0 3 ) and extracted with 3x150 ml of ethyl acetate. The organic and aqueous layers were separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate and filtered on celite. The filtrate was distilled under vacuum to give the title compound. %Yield: 80%. (Purity by GC: 92%).

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Abstract

The present invention relates to an improved process for the preparation of tezacaftor intermediate compound of formula II. More particularly, the present invention relates to an improved, commercially viable process for the preparation of tezacaftor intermediate (((2,2-dimethylbut-3-yn-1- yl)oxy)methyl)benzene compound of formula II.

Description

PRIORITY
This application claims the benefit of priority from Indian provisional application. 201941034908 filed on 29th August 2019, entitled “IMPROVED PROCESS FOR THE PREPARATION OF TEZACAFTOR INTERMEDIATE”, the contents of which are incorporated herein by reference in its entirety. FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of tezacaftor intermediate. More particularly the present invention relates to industrial feasible and economically viable process for the preparation of tezacaftor intermediate
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
Tezacaftor is approved in combination with ivacaftor for the treatment of cystic fibrosis in US and Europe. Tezacaftor in combination with Ivacaftor is available in the market under the brand name Symdeko® as tablets containing lOOmg of tezacaftor and 150mg of ivacaftor. Tezacaftor is chemically described as l-(2,2-difluoro-2H-l,3- benzodioxol-5-yl)-N-{ l-[(2R)- 2,3-dihydroxypropyl]-6-fluoro-2-(l-hydroxy-2-methylpropan-2-yl)-lHindol-5- yl) cyclopropane- 1 -carboxamide (herein after referred as tezacaftor) and represented by the structural formula I as shown below:
Figure imgf000002_0002
U.S. Patent No. 7,776,905 describes tezacaftor and its related compounds, a pharmaceutical composition and a method of treatment.
U.S. Patent No. 9,840,513B2 (US20170101397A1) discloses a process for the preparation of precursor of tezacaftor intermediate II by additionally using phase transfer catalyst to give compound of formula V which is subjected to oxidation by using pyridine-S03 complex in the presence of DMF and triethylamine to give the compound of formula IV which were isolated by column chromatography using ethyl acetate and heptane mixture.
T.Chalopin et al., Tetrahedron vol.72 (2), page 318-327, 2016 the process disclosed in the publication illustrated by below scheme uses reagents in lesser molar equivalents than required which effects the yields and the purity of the desired compounds.
Figure imgf000003_0001
(bromomethyl)benzene
2 H .2C -dimethylproH pane-
Figure imgf000003_0002
1.3-diol (VI) NaH 3-(benzyloxy)-2,2- dimethylpropan-1 -ol
(V)
Dess-Martin periodinane
Figure imgf000003_0003
(or) 3-(benzyloxy)-2,2-
Swern Oxidation dimethylpropanal
(IV)
Kozo shishido et al., Journal of organic chemistry volume 77, page 9240-9249, 2012 discloses the process for the preparation of compound of formula IV, III and II in similar process to the process of present invention but the reagents being used therein are very much lesser in molar equivalents than actually required thus effecting the yields and the purity of the desired compounds IV, III and II.
Figure imgf000003_0004
3-(benzyloxy)-2,2- (((4,4-dibromo-2,2-dimethylbut-3- (((2,2-dimethylbut-3-yn- dimethylpropanal en-1-yl) 1 -yl)oxy)methyl)benzene oxy)methyl)benzene
(IV) (II)
(III) The above processes reported in the prior art are not viable on industrial scale and moreover the processes results in poor yields due to formation of impurities and side products which renders the processes inefficient and expensive by multiple purification steps to yield pure compounds. Hence there is need in the art to provided improved processes that are simple, ecofriendly, cost effective and feasible on commercial scale with the desired compounds in higher the yield and purity.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of tezacaftor intermediate (((2,2-dimethylbut-3-yn-l-yl)oxy)methyl)benzene compound of formula II
Figure imgf000004_0001
In one aspect, the present invention relates to an improved, commercially viable process for the preparation of tezacaftor intermediate compound of formula II comprising the steps of: a) Reacting the compound of formula (VI) with a compound of formula (VII) in the presence of a base to obtain the compound of formula (V), and
Figure imgf000004_0002
(VI) (V) b) Reacting the compound of formula (V) with a suitable agent to afford the compound of formula (IV), and
Figure imgf000004_0003
c) Reacting the compound of formula (IV) with a suitable agent to afford the compound of formula (III) alternatively compound of formula (IIIA)
Figure imgf000005_0001
d) Reacting the compound of formula (III) or (IIIA) with a suitable agent to afford the compound desired compound of formula (II)
Figure imgf000005_0002
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the present invention there is provided an improved process for the preparation of tezacaftor intermediate compound of formula II comprising the steps of: a) Reacting a compound bromomethyl)benzene of formula VII with a compound 2,2- dimethylpropane-l,3-diol of formula VI in the presence of a suitable base and an organic solvent to obtain the compound 3-(benzyloxy)-2,2-dimethylpropan-l-ol of formula (V), and
Figure imgf000005_0003
(VI) (V) b) Reacting the compound 3-(benzyloxy)-2,2-dimethylpropan-l-ol of formula (V) with a suitable agent in the presence of suitable organic solvent to obtain the compound 3- (benzyloxy)-2,2-dimethylpropanal of formula (IV), and
Figure imgf000006_0001
c) Reacting the compound 3-(benzyloxy)-2,2-dimethylpropanal of formula (IV) with a suitable agent in the presence of suitable organic solvent to obtain the compound (((4,4-dibromo-2,2-dimethylbut-3-en-l-yl) oxy)methyl)benzene of formula (III) or alternatively the compound (((4,4-dichloro-2,2-dimethylbut-3-en-l-yl) oxy)methyl)benzene of formula (IIIA), and
Figure imgf000006_0002
d) Reacting the compound (((4,4-dibromo-2,2-dimethylbut-3-en-l-yl) oxy)methyl)benzene of formula (III) or the compound (((4,4-dichloro-2,2-dimethylbut- 3-en-l-yl) oxy)methyl)benzene of formula (IIIA) with a suitable agent in the presence of suitable organic solvent to obtain the compound (((2,2-dimethylbut-3-yn-l- yl)oxy)methyl)benzene of formula (II)
Figure imgf000006_0003
In Step a) the suitable base that can be used include inorganic or inorganic base. Inorganic bases include one or more of alkali metal hydrides such as sodium hydride and the like; alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide and the like; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; alkali metal carbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate and the like; or mixtures thereof or their aqueous or alcohol phases.
Preferably alkali metal hydroxide potassium hydroxide in aqueous phase.
The reaction step (a) can be optionally performed in the absence of organic solvent i.e., neat conditions. The reaction step (a) is preferably carried out using organic solvent or a mixture thereof selected from hydrocarbon solvents such as toluene, xylene, n- hexane, n-heptane, cyclohexane and the like; ethers such as to tetrahydrofuran (THF), 1,4- dioxane and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; or mixture thereof in various proportions without limitation. Preferably hydrocarbon solvent toluene and ether solvent tetrahydrofuran (THF) independently.
In one embodiment of present invention, the reaction step a) is performed by optionally employing phase transfer catalyst selected from the group consisting of tetra butyl ammonium bromide (TBAB), tetrabutylammonium iodide (TBAI) and the like or mixture thereof. Preferably tetrabutylammonium iodide (TBAI) is being used.
Advantageously employing of phase transfer catalyst makes the conversion faster and enhances the yield of the desired product significantly over the prior art processes.
The reaction step (a) can be performed at any suitable temperature that can afford provide the desired compound with no or less side products and impurities, the reaction temperature can be in the range from about 25 °C to about 100°C or the boiling point of the solvent(s) used. Preferably the suitable reaction temperature can be about 25 °C -30°C.
The reaction time for the completion of the reaction generally depends on various factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction step (a) is effected under the preferred conditions discussed above, a period of from about 5 hours to about 25hours. Preferably, a reaction time of about 20-22 hrs is suffice. The reaction step (b) is performed by employing any suitable oxidizing reagent or a complex thereof commonly used for such purpose. The suitable oxidizing agent or complex that can be employed include but are not limited to TEMPO ((2,2,6,6-Tetramethylpiperidin-l- yl)oxyl), Dess Martin periodinane, Swern oxidation reagent and the like; Preferably TEMPO ((2,2,6,6-Tetramethylpiperidin-l-yl)oxyl) is being used.
In one embodiment of the present invention, the oxidizing agent TEMPO is being used in the presence of a catalyst not limited to sodium hypochlorite (NaOCl) in combination with a mild base such as sodium bicarbonate and additionally a base not limited to potassium bromide (KBr) particularly in aqueous phase.
Advantageously, employing the oxidizing agent TEMPO makes the process simple, efficient, ecofriendly and enhances the yield and purity of the desired compound of formula (IV) significantly which is advantageous over the prior art processes.
Moreover it is cheaper and commercially available reagent which makes the process most economical over the reported processes which employs highly corrosive, hazardous, expensive reagents.
The reaction step (b) can be optionally performed in the absence of organic solvent i.e., neat conditions. The reaction step (b) is preferably carried out using organic solvent or a mixture thereof selected from halogenated solvents such as dichlorome thane, ethylene dichloride and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; ethers such as to tetrahydrofuran (THF), 1,4-dioxane and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; or mixture thereof in various proportions without limitation. Preferably halogenated solvent dichloromethane (DCM) is being used.
The reaction step (b) can be performed at any suitable temperature that can afford the desired compound with no or less side products and impurities, the reaction temperature can be in the range from about 25°C to about 100°C or the boiling point of the solvent(s) used. Preferably the suitable reaction temperature can be about 25 °C -30°C.
The reaction time for the completion of the reaction generally depends on various factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction step (b) is effected under the preferred conditions discussed above, a period of from about 2 hours to about 10 hours. Preferably, a reaction time of about 3-4 hrs is suffice.
The reaction step (c) is a reaction of compound of formula (IV) with a suitable agent include but are not limited to carbon tetrabromide (CBrzt) in the presence of triphenyl phosphine (TPP) and the like to obtain the desired compound of formula (III) ; additionally the reaction of compound of formula (IV) with carbon tetrachloride (CCU) in the presence of triphenyl phosphine (TPP) to obtain the desired compound of formula (IIIA).
In one embodiment of the present invention the reagent carbon tetrabromide or carbon tetrachloride can be added to the reaction mixture at a temperature range from about -5°C to about 5°C to avoid the formation of side products and process related impurities which will affect the yield and purity of the desired compounds of formulae (III) and (IIIA).
Advantageously, the process of going through the step (c) is a major breakthrough for obtaining the final compound of formula II in better yield and purity over the prior art processes.
Moreover the process step (c) is simple, economical involving cheaper, commercially available reagents and viable on commercial scale.
The reaction step (c) can be optionally performed in the absence of organic solvent i.e., neat conditions. The reaction step (c) is preferably carried out using organic solvent or a mixture thereof selected from halogenated solvents such as dichloromethane (DCM), ethylene dichloride and the like; esters such as ethyl acetate, isopropyl acetate and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; or mixture thereof in various proportions without limitation. Preferably halogenated solvent dichloromethane (DCM) is being used.
The reaction step (c) can be performed at any suitable temperature that can afford the desired compound with no or less side products and impurities, the reaction temperature can be in the range from about 15°C to about 75°C or the boiling point of the solvent(s) used. Preferably the suitable reaction temperature can be about 25 °C -30°C.
The reaction time for the completion of the reaction generally depends on various factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction step (c) is effected under the preferred conditions discussed above, a period of from about 2 hours to about 10 hours. Preferably, a reaction time of about 3-4 hrs is suffice.
The reaction step (d) is reaction of compound of formula (III) or (IIIA) with a suitable agent include but are not limited to n-butyl lithium (n-BuLi), Methyl Lithium, sodium sulfide or its hydrates thereof, alkaline earth metal carbonates such as cesium carbonate (CS2CO3) and the like. Preferably methyl lithium is used.
Advantageously, employing methyl lithium in step (d) is a major breakthrough for obtaining the final compound of formula II in better yield and purity over the prior art processes.
Moreover the said agent is simple to handle on commercial scale, nonhazardous, cheaper, commercially available thus makes the process economical, ecofriendly over the prior art processes which involves expensive and hazardous reagents.
The reaction step (d) is preferably carried out using organic solvent or a mixture thereof selected from ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; or mixture thereof in various proportions without limitation. Preferably aprotic polar solvent dimethylsulfoxide (DMSO) is being used when the reagent sodium sulfide employed and ether solvent tetrahydrofuran (THF) when methyl lithium or n-butyl lithium is employed.
The reaction step (d) can be performed at any suitable temperature that can afford the desired compound with no or less side products and impurities, the reaction temperature can be in the range from about 25 °C to about 75°C or the boiling point of the solvent(s) used. Preferably the suitable reaction temperature can be about 25 °C -30°C.
The reaction time for the completion of the reaction generally depends on various factors, notably the reaction temperature and the nature of the reagents and solvents employed. However, provided that the reaction step (d) is effected under the preferred conditions discussed above, a period of from about 2 hours to about 10 hours. Preferably, a reaction time of about 2-3 hrs is suffice.
In one embodiment of the present invention, the intermediate compounds in the above described process steps are obtained with high purity by employing high vacuum distillation (HVD) under reduced pressure extremely below the atmospheric pressure and at temperatures from about 50°C to about 100°C. which is a novel method of obtaining pure compound which is not reported in the prior art.
In one embodiment, optionally the process steps are carried out in insitu i.e., one pot synthesis.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
In one embodiment, the intermediate compounds obtained herein are optionally purified by recrystallisation, using a solvent or mixture of solvents or their combination with water in any proportion without limitation by conventional techniques well known for a person skilled in the art.
Advantageously the intermediates obtained herein by the process of the present invention may exist in either crystalline or amorphous or mixture thereof.
The processes reported in the prior art for the preparation of Tezacaftor intermediate (II) results in the formation of impurities and bye products in significant amount due to usage of strong reagents and in lower molar equivalents and thus leading to poor yields and purities of the desired products. Thus essentially required to have purification process intermittently leading to non ecofriendly and expensive processes.
Advantageously, the process of present invention provides the intermediate compound of formula II in higher yield and purity compared to the prior art processes.
Preferably, the yield of the intermediates is atleast about 60%, or more, more preferably, the yield is about 70% to about 80% by weight. Whereas the prior art processes results the compound of formula II in not more than 50%.
Advantageous, the process of present invention provides the compound of formula II has purity greater than about 99 area % by HPLC and total impurities less than about 1 area % with the compounds of formulae VII,VI,V,IV,III,IIIA each lesser than about 0.1 area % by HPLC. Whereas the prior art processes results in the compound of formula II not more than 80% by HPLC.
In one embodiment, the compound of formula II obtained by the process of present invention is used as intermediate in the synthesis of benzodioxol compounds such as Tezacaftor and its related compounds.
The starting intermediate compounds of formulae (VII) and (VI) are known per se to the person skilled in the art or can be prepared by customary methods reported in the related art.
The present invention provides simple, ecofriendly, economical, reproducible, robust and commercially viable process for preparation of tezacaftor intermediate (II) with enhanced yield and purity.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1: Preparation of 3-(benzyloxy)-2,2-dimethylpropan-l-ol (V)
In a clean and dry RBF, sodium hydride (NaH) (50-63% dispersion in mineral oil) was charged and cooled to 0-5°C then tetrahydrofuran (THF) was charged and 2,2 dimethyl propane- 1,3 diol, in tetrahydrofuran (THF) was added slowly at 0-5°C. To the resultant reaction mixture, tetrabutylammonium iodide (n-BiuNI) was charged at 0-5°C and the reaction mass was stirred for 20-30 min. at 0-5°C. To the resultant reaction mixture benzyl bromide was added slowly at 0-5°C over a period of 20-30 min. and the reaction mass was maintained at 25-35°C for 12-14 hrs. After completion of the reaction, the reaction mass was quenched with ice cubes and saturated ammonium chloride (NH4CI) solution. The compound was extracted with ethyl acetate and the solvent was distilled completely to give residue which is further subjected to high vacuum distillation (HVD) to afford the title compound. % Yield: 63%. (Purity by GC: 93%). Example 2: Alternate preparation of 3-(benzyloxy)-2,2-dimethylpropan-l-ol (V)
In a clean and dry RBF, 1 Lit. of aqueous potassium hydroxide (KOH), 1 lit. of toluene and 200 gms of 2,3-dimethylpropane-l,3-diol (VI) were charged at 25-30°C and Then 36 gms of tetrabutyl ammonium iodide (TBAI) was charged to the reaction mixture and 328 gms of benzyl bromide (VII) was added slowly at about 25-30°C over about 1 hr. The resultant reaction mixture was stirred at 25-30°C for about 20-22 hrs. The reaction progress was monitored by TLC and after completion of the reaction, the reaction mass was quenched by adding to the precooled water at 25-30°C. The reaction mass was extracted with 2x2 lit. of ethyl acetate and the organic layer was washed with 2x4 lit. of brine solution and the organic layer was separated and distilled completely at below 50°C under vacuum to give residue which is further subjected to high vacuum distillation (HVD) to afford the title compound. %Yield: 75%. (Purity by GC: 92%).
Example 3: Preparation of 3-(benzyloxy)-2,2-dimethylpropanal of formula (IV)
In a clean and dry RBF, dichloromethane (DCM) and dimethylsulfoxide (DMSO) were charged and cooled to -70 to -75°C then oxalyl chloride was added slowly at -70 to -75°C and maintained for 2-3 hrs, after completion of the reaction tri ethylamine was added slowly to the reaction mass at -70 to -75 °C and maintained for 30-45 min at -50 to -75°C. The reaction mass temperature was raised to 25-30 °C and quenched by adding water. The compound was extracted with ethyl acetate and the solvent was distilled under vaccum to give residue which is subjected to high vacuum distillation (HVD) to afford the title compound. % Yield: 75%. (Purity by GC: 93%).
Example 4: Alternate preparation of 3-(benzyloxy)-2,2-dimethylpropanal of formula (IV)
In a clean and dry RBF, 23 gms of compound of formula V obtained from the above example, 150ml dichloromethane (DCM) were charged, 1 gm of potassium bromide (KBr) in 40ml of water, 143mg of TEMPO ((2,2,6,6-Tetramethylpiperidin-l-yl)oxyl ) were charged and a mixture of 76 ml of aqueous sodium hypochlorite (NaOCl) and 36 ml of saturated aqueous sodium bicarbonate (NaHCCh) was added drop wise at about -10°C over about 30 mins. The resultant reaction mixture was stirred at 25-30°C for about 3 hrs. The reaction progress was monitored by TLC and after completion of the reaction, the reaction mass was quenched with saturated aqueous sodium thiosulfate (Na2S203) and extracted with 3x150 ml of ethyl acetate. The organic and aqueous layers were separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate and filtered on celite. The filtrate was distilled under vacuum to give the title compound. %Yield: 80%. (Purity by GC: 92%).
Example 5: Preparation of (((4,4-dibromo-2,2-dimethylbut-3-en-l-yl) oxy)methyl)benzene (III)
In a clean and dry RBF, dichloromethane and tetrabromomethane (CBr4) and then tri phenyl phosphine (TPP) was charged to the reaction mass and cooled to 0-5°C. Compound IV obtained in example 2 was mixed with dichloromethane (DCM) then added to reaction mass and the reaction mass temperature was raised to 25-30°C and maintained for 3-4 hrs. The compound was isolated from n-hexane to give crude compound and subjected to solidification with silica and then slurried with methyl tertiary butyl ether (MTBE), filtered, distilled the filtrate to give residue which is subjected to high vacuum distillation (HVD) to afford the title compound. %Yield 65%. (Purity by GC: 93%).
Example 6: Preparation of (((4,4-dichloro-2,2-dimethylbut-3-en-l-yl) oxy)methyl)benzene (IIIA)
In a clean and dry RBF, dichloromethane and tetra chloromethane (CCU) were charged and then tri phenyl phosphine (TPP) was charged to the reaction mass and cooled to 0-5 °C. Compound IV obtained in example 4 was mixed with dichloromethane (DCM) then added to reaction mass and the reaction mass temperature was raised to 25-30 °C and maintained for 3- 4 hrs. The compound was isolated from n-hexane to give crude compound and subjected to solidification with silica and then slurried with methyl tertiary butyl ether (MTBE), filtered, distilled the filtrate to give residue which is subjected to high vacuum distillation (HVD) to afford the title compound. %Yield: 70%. (Purity by GC: 92%).
Example 7: Preparation of (((2,2-dimethylbut-3-yn-l-yl)oxy)methyl)benzene (II)
In a clean and dry RBF compound (III) and tetrahydrofuran (THF) were charged and cooled to -70 to -75 °C, then n-butyl lithium (n-BuLi) was added slowly at -70 to -75 °C to and maintained at -70 to -75°C for 5 - 6 hrs. After completion of the reaction, the reaction was quenched with ammonium chloride at -70 to -75°C and then compound was isolated with ethyl acetate and the concentrate was purified with column chromatography to afford title compound in pure form. %Yield: 65%. (Purity by HPLC: 96%). Example 8: Alternate preparation of (((2,2-dimethylbut-3-yn-l-yl)oxy)methyl)benzene
(II)
In a clean and dry RBF, compound (III), dimethyl sulfoxide (DMSO) (5.0 vol) and sodium sulfide nonahydrate (Na2S.9H20) (2.0 Eq) were charged at 25-30°C and maintained for 2-3 hrs at 25-30°C, checked TLC and the reaction was quenched by slowly adding 0.5 vol. of acetic acid, extracted the product with ethyl acetate and finally concentrated and purified with column chromatography to afford pure title compound. % Yield: 65 %. (Purity by HPLC: 98%).
Example 9: Alternate preparation of (((2,2-dimethylbut-3-yn-l-yl)oxy)methyl)benzene
(II)
In a clean and dry RBF, compound (III), dimethylsulfoxide (DMSO) (5.0 vol) and cesium carbonate (CS2CO3) (2.5 Eq) at 25-30 °C and the temperature of the reaction mixture was raised to 110-115 °C and maintained for 12-15 hrs at 110-115 °C, checked TLC and the reaction mass was cooled to 25-30 °C. The reaction mass was quenched with water at 25-30 °C and the extracted the product with ethyl acetate, concentrated and purified with column chromatography to afford pure title compound. % Yield: 65 %. (Purity by HPLC: 98 %). Example 10: Alternate preparation of (((2,2-dimethylbut-3-yn-l-yl)oxy)methyl)benzene
(II)
In a clean and dry RBF compound (IIIA), dimethylsulfoxide (DMSO) (5.0 vol) and sodium disulfide nonahydrate (Na2S.9H20) (6.0 Eq) were charged and stirred at 80-85 °C for 10-12 hrs. checked TLC and quenched the reaction mass with 0.5 vol. of acetic acid and extracted the product with ethyl acetate, concentrated and purified by high vacuum distillation (HVD) to afford pure title compound. % Yield: 65 %.( Purity by HPLC: 99 %).
Example 11: Alternate preparation of (((2,2-dimethylbut-3-yn-l-yl)oxy)methyl)benzene
(II)
In a clean and dry RBF compound (IIIA) and tetrahydrofuran (THF) were charged and cooled to -70 to -75 °C, then Methyl lithium (2.0Eq) was added slowly at -70 to -75 °C and maintained at -70 to -75 °C for 5 - 6 hrs. After completion of the reaction, the reaction was quenched with ammonium chloride at -70 to -75 °C and then compound was isolated with ethyl acetate and the concentrate was purified with column chromatography to afford title compound in pure form. %Yield: 65%. (Purity by HPLC: 99%)

Claims

CLAIMS:
1) An improved and commercially viable process for the preparation of compound (((2,2- dimethylbut-3-yn-l-yl)oxy)methyl)benzene of formula (II),
Figure imgf000016_0001
comprising: a) reacting the compound 2,2-dimethylpropane-l,3-diol of formula (VI) with a compound (bromomethyl)benzene of formula (VII) to afford the compound 3- (benzyloxy)-2,2-dimethylpropan-l-ol of formula (V), and
Figure imgf000016_0002
b) reacting the compound 3-(benzyloxy)-2,2-dimethylpropan-l-ol of formula (V) with a suitable agent to afford the compound 3-(benzyloxy)-2,2-dimethylpropanal of formula (IV), and
Figure imgf000016_0003
c) reacting the compound 3-(benzyloxy)-2,2-dimethylpropanal of formula (IV) with a suitable agent to afford the compound (((4,4-dibromo-2,2-dimethylbut-3-en-l- yl)oxy)methyl)benzene of formula (III) or a alternatively compound (((4,4- dichloro-2,2-dimethylbut-3-en-l-yl)oxy)methyl)benzene of formula (IIIA)
Figure imgf000017_0001
d) reacting the compound (((4,4-dibromo-2,2-dimethylbut-3-en-l- yl)oxy)methyl)benzene of formula (III) or the compound (((4,4-dichloro-2,2- dimethylbut-3-en-l-yl)oxy)methyl)benzene of formula (IIIA) with a suitable agent to afford the compound desired compound of formula (II)
Figure imgf000017_0002
2) The process of claim 1, wherein the step (a) is carried out in the presence of a base include inorganic bases selected from alkali metal hydrides such as sodium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate; or mixtures thereof or their aqueous or alcohol phases; wherein the reaction step (b) is performed by employing oxidizing agent or a complex thereof selected from TEMPO ((2,2,6,6-Tetramethylpiperidin-l-yl)oxyl), Dess Martin periodinane, Swern oxidation reagent; wherein the suitable agent employed in reaction step (c) is selected from carbon tetrabromide (CBrzt) or carbon tetrachloride (CCU) in the presence of triphenyl phosphine (TPP); wherein the suitable agent employed in step (d) is selected from sodium sulfide or its hydrates thereof, methyl lithium, n-butyl lithium, alkaline earth metal carbonate such as cesium carbonate (CS2CO3).
3) The process of claim 1, wherein the suitable organic solvent employed in step (a) is selected from hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane; ethers such as to tetrahydrofuran (THF), 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) or mixture thereof; wherein the suitable organic solvent employed in step (b) is selected from halogenated solvents such as dichlorome thane, ethylene dichloride; hydrocarbon solvents such as toluene, xylene, n-hexane, n- heptane, cyclohexane; ethers such as to tetrahydrofuran (THF), 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) or mixture thereof; wherein the suitable organic solvent employed in step (c) is selected from halogenated solvents such as dichloromethane (DCM), ethylene dichloride; esters such as ethyl acetate, isopropyl acetate; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) or mixture thereof; wherein the suitable organic solvent employed in step (d) is selected from ethers such as tetrahydrofuran (THF), 1,4- dioxane; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) or mixture thereof.
4) The process of claim 1, wherein the compounds of formulae (V), (IV), (III) and (II) are obtained in pure form by employing high vacuum distillation.
5) An improved process for the preparing compound 3-(benzyloxy)-2,2-dimethylpropan- l-ol of formula (V) by reacting the compound 2,2-dimethylpropane-l,3-diol of formula (VI) with a compound (bromomethyl)benzene of formula (VII) in the presence of inorganic base alkali metal hydroxide potassium hydroxide
Figure imgf000019_0001
(VI) (V)
6) An improved process for preparing compound of formula IV by reacting the compound of formula (V) with a suitable oxidant like TEMPO ((2,2,6,6-Tetramethylpiperidin-l- yl)oxyl)
Figure imgf000019_0002
7) An improved process for preparing compound of formula II by reacting the compound of formula (III) or (IIIA) with a suitable agent selected from sodium disulfide or hydrate thereof, cesium carbonate or hydrate thereof, n-butyl lithium or Methyl lithium to afford the desired compound of formula II.
Figure imgf000019_0003
8) The process of claim 1, wherein the reaction steps can be optionally carried out separately or can be performed in one pot and optionally carried out insitu.
9) The use of the compound of formula II in the synthesis of Tezacaftor and its related compounds. 10) The compound of formula II obtained by process of preceding claims, has purity greater than about 99 area % by HPLC and total impurities less than about 1 area % with the compounds of formulae VII,VI,V,IV,III,IIIA each lesser than about 0.1 area % by HPLC.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170101397A1 (en) * 2015-10-08 2017-04-13 Grünenthal GmbH Pyrazolyl substituted tetrahydropyranylsulfones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170101397A1 (en) * 2015-10-08 2017-04-13 Grünenthal GmbH Pyrazolyl substituted tetrahydropyranylsulfones

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Title
K. SHISHIDO ET AL.: "Total Synthesis of Debromoflustramines B and E Based on the Intramolecular Carbamoylketene−Alkene [2 + 2] Cycloaddition", JOURNAL OF ORGANIC CHEMISTRY, vol. 77, no. 20, 9 October 2012 (2012-10-09), pages 9240 - 9249, XP055794818 *
T. CHALOPIN ET AL.: "Regioselective dihydropyran formation from 4-iodo-2,6-disubstituted tetrahydropyran derivatives using In(OAc)3/LiI system as the promoter", TETRAHEDRON, vol. 72, no. 2, 2016, pages 318 - 327, XP029364741 *

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