WO2022097115A1 - Procédé amélioré de préparation de prohéxadione et de son sel de calcium - Google Patents

Procédé amélioré de préparation de prohéxadione et de son sel de calcium Download PDF

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Publication number
WO2022097115A1
WO2022097115A1 PCT/IB2021/060339 IB2021060339W WO2022097115A1 WO 2022097115 A1 WO2022097115 A1 WO 2022097115A1 IB 2021060339 W IB2021060339 W IB 2021060339W WO 2022097115 A1 WO2022097115 A1 WO 2022097115A1
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WIPO (PCT)
Prior art keywords
acid
propionyl
preparation
chloride
formula
Prior art date
Application number
PCT/IB2021/060339
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English (en)
Inventor
Sudhir Nambiar
Santosh Ghosh
Lakonda NAGAPRASADA RAO
Pramod Dodha SAWANT
Vinayak Shirishkumar LAMBATE
Dnyaneshwar Sambhajirao Nipunge
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Hikal Limited
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Publication of WO2022097115A1 publication Critical patent/WO2022097115A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups

Definitions

  • the present invention relates to an improved and efficient process for the preparation of Prohexadione and its calcium salt of formula (I).
  • the present invention further relates to one step process for preparation of ethyl 3,5-dioxo-4-propionyl-cyclohexanecarboxylate a key intermediate of 3, 5 -dioxo-4 -propionylcyclohexanecarboxy lie acid by avoiding an O- alkylation reaction.
  • Prohexadione, 3, 5 -dioxo-4 -propionyl-cyclohexanecarboxylic acid is a plant growth regulator, it is used (commonly as the corresponding calcium salt, known as Prohexadione-calcium) as an anti-lodging agent in small-grain cereals. It has a role as an agrochemical, a plant growth regulator and a gibberellin biosynthesis inhibitor.
  • Prohexadione was first disclosed in US patent 4,678,496 (hereinafter US‘496) and corresponding patent publications, as a cyclohexane derivative.
  • the references predominantly disclose the synthesis of ethyl 3,5-dioxo-4-propionyl cyclohexane carboxylate a key intermediate of Prohexadione in multiple operational steps: (i) reacting ethyl 3,5- dioxocyclohexane carboxylate with propionyl chloride; (ii) obtaining O -alkylated intermediate by treating with sodium bicarbonate, separating organic layer, drying and concentrating; (iii) Fries rearrangement to obtain C-alkylated compound; (iv) isolation by column chromatography with low yield 46.5%.
  • the reaction scheme is as shown in Scheme-1.
  • the patent application CN 101774906 disclose the process for the preparation of Prohexadione calcium which comprises steps; (i) hydrogenation; (ii) O-alkylation; (iii) rearrangement of O-alkylation to C-alkylation; (iv) hydrolysis; and (v) salt preparation.
  • the patent CN 107162907B disclose the preparation of Prohexadione calcium by using multiple reaction sequence: (i) Michael addition reaction; (ii) condensation; (iii) esterification and O -alkylation; (iv) rearrangement of O-alkylation to C-alkylation; (v) hydrolysis; and (vii) salt preparation.
  • the existing processes are suffered with one or more disadvantages for example: (i) O- alkylation step; (ii) more number of steps; (iii) use of multiple solvents; (iv) tedious column chromatography for purification; (v) long cycle time; (vi) more effluent generation.
  • the process further requires multiple operations for reduction or removal of impurities, which reduces overall yield, increase production cost and generate more hazardous waste for disposal.
  • the invention provides an improved process of 3,5-Dioxo-4-propionyl- cyclohexanecarboxylic acid calcium salt of formula (I)in high yield.
  • the invention provides a direct C-alkylation of ethyl 3 -hydroxy-5 - oxocyclohex-3-ene-l -carboxylate for a preparation of ethyl 3,5-dioxo-4-propionyl- cyclohexanecarboxylate by avoiding O -alkylation.
  • the present invention provides a cost-effective process by avoiding multiple operations(s) with an environment friendly and commercially viable manner.
  • the present invention relates to a process for the preparation of 3,5-dioxo-4- propionyl-cyclohexanecarboxylic acid calcium salt of formula (I) which comprises the steps of: a) reacting the compound of formula (II) where R is Ci-Cioalkyl, with propionyl chloride in presence of a base(s) and a solvent to obtain compound of formula (III);
  • the instant invention provides the preparation of Prohexadione calcium salt which involve only two steps starting from ethyl 3 -hydroxy-5 -oxocyclohex-3 -ene-1- carboxylate, thus the process is economically viable.
  • the process for preparation of Prohexadione calcium salt does not involve purification step and generates less effluent, thus process is environment friendly and thereby commercially viable.
  • solvent used herein refers to the single solvent or mixture of solvents.
  • the present invention provides a process for the preparation of 3,5-Dioxo- 4-propionyl-cyclohexanecarboxylic acid calcium salt of formula (I) is illustrated in the following synthetic scheme.
  • the present invention provides a process for the preparation of 3,5- dioxo-4-propionyl-cyclohexanecarboxylic acid calcium salt of formula (I) with purity greater than 90%, preferably greater than 96%.
  • the present invention provides a process for the preparation of 3,5- dioxo-4-propionyl-cyclohexanecarboxylic acid calcium salt of formula (I) with overall yield greater than 65%.
  • the present invention provides a C-alkylation process in one step for the preparation of ethyl 3,5-dioxo-4-propionyl-cyclohexanecarboxylate by avoiding O- alkylation.
  • the base(s) in step (a) is base selected from triethyl amine (TEA), ammonia, diisopropylethylamine, diethylamine, dipropylamine, diisopropylamine, pyridine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, histidine and guanidine, 4 -dimethylaminopyridine (DMAP), and 4- aminopyridines.
  • TAA triethyl amine
  • DBU diisopropylethylamine
  • DBU dipropylamine
  • DMAP diisopropylamine
  • 4- aminopyridines 4- aminopyridines.
  • step (a) wherein the base(s) in step (a) is used simultaneously and in any combination of TEA and DMAP.
  • solvent in step (a) is selected from dichloromethane (DCM), ethylene dichloride (EDC), chloroform (CHCE), carbon tetrachloride (CCU), toluene, cyclohexane, monohalobenzenes such as monochlorobenzene, dihalobenzenes such as dichlorobenzene, dialkyl (CfCn) ethers, and the like.
  • DCM dichloromethane
  • EDC ethylene dichloride
  • CHCE chloroform
  • CCU carbon tetrachloride
  • toluene cyclohexane
  • monohalobenzenes such as monochlorobenzene
  • dihalobenzenes such as dichlorobenzene
  • dialkyl (CfCn) ethers dialkyl
  • step (a) is carried out at a temperature between 20°C to 120°C, preferably 20°C to 45°C.
  • the base in step (b) is selected from lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (CS2CO3), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), ammonia (NH3), ammonium hydroxide (NH4OH), magnesium tertiary butoxide [(/-BuOhMgJ, potassium tertiary butoxide (Z-BuOK), and sodium tertiary butoxide (/-BuONa).
  • phase transfer catalyst in step (b) is selected from tetra alkyl ammonium halide such as tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetrabutylammonium chloride (TBAC1), tetrabutylammonium fluoride (TBAF), benzyltriethylammonium chloride; methyl tri alkyl ammonium halides such as methyltricaprylammonium chloride, methyl tributylammonium chloride, methyl trioctylammonium chloride, tetra butyl ammonium hydrogen sulphate (TBAHS), Aliquat 336; and potassium iodide (KI).
  • TBAB tetrabutylammonium bromide
  • TBAI tetrabutylammonium iodide
  • TBAC1 tetrabutylammonium chloride
  • the solvent in step (b) is selected from water, tetrahydrofuran (THF), toluene, inert organic solvents such as aliphatic, alicyclic and aromatic hydrocarbons solvent selected from cyclohexane, methylcyclohexane, xylene, benzene, 2 -methyltetrahydro furan, methyl tert-butyl ether, isopropyl ether, dimethoxyethane, dimethoxyme thane, 1,3 -dioxane, 1,4 -dioxane, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, polyethylene glycol dimethyl ether, cyclic, acyclic ethers, alcoholic solvent such as methanol, ethanol, isopropanol, n-butenol and the like.
  • solvent in step (b) is
  • an acid in step (b) is selected from hydrochloric acid (HC1), hydrobromic acid (HBr), sulfuric acid, trifluoroacetic acid (TFA), formic acid (HCOOH), phosphoric acid (H3PO4), sodium hydrogen sulfate (NaHSCU), p-toluenesulfonic acid (p-TSA), and acetic acid (AcOH).
  • step (b) is carried out at a temperature between 20°C to 90 °C, preferably 80 °C to 90°C.
  • step (b) is carried out by using base in presence or absence of phase transfer catalyst.
  • Step-1 To a solution of 3 -cyclohexene- 1 -carboxylic acid, 3 -hydroxy-5 -oxo-, ethyl ester 1 (17.0 g) in MDC (85 ml) triethylamine (14.01 g, 0.1385 mole, 1.5 eq.) was added at 20-30 °C. The c reaction mixture was cooled to 0°C to 5 °C. Propionyl chloride (0.1015 mole) was added to the reaction mixture over 30 min and allowed to stir the resulting mixture for 10-12 h.
  • Step-2 A mixture of 3 -Cyclohexene- 1 -carboxylic acid, 5 -oxo-3-(l -oxopropoxy)-, ethyl ester Ila (7.5 g) and 4 -dimethylamino pyridine (0.76 g) in toluene (110 ml) was heated to 80°C to 85 °C for 4-5 h. After completion of reaction, reaction mass was cooled to room temperature and washed with water and layer separated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé amélioré et efficace pour la préparation de prohéxadione et de son sel de calcium de formule (I). La présente invention concerne en outre un procédé en une étape pour la préparation de 3,5-dioxo-4-propionyl-cyclohexanecarboxylate d'éthyle, intermédiaire clé de l'acide 3,5-dioxo-4-propionyl-cyclohexanecarboxylique en évitant une O-alkylation.
PCT/IB2021/060339 2020-11-09 2021-11-09 Procédé amélioré de préparation de prohéxadione et de son sel de calcium WO2022097115A1 (fr)

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IN202021048837 2020-11-09
IN202021048837 2020-11-09

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114805067A (zh) * 2022-05-19 2022-07-29 浙江科技学院 一种调环酸钙中间体的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101774906A (zh) * 2010-02-10 2010-07-14 江苏康恒化工有限公司 3,5-二氧代-4-丙酞基环己烷按酸钙的制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101774906A (zh) * 2010-02-10 2010-07-14 江苏康恒化工有限公司 3,5-二氧代-4-丙酞基环己烷按酸钙的制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"New Trends in Green Chemistry", January 2004, SPRINGER, article V.K.AHLUWALIA ET AL.: "Phase-Transfer Catalysis in Green Synthesis", pages: 39 - 58, DOI: 10.1007/978-1-4020-3175-5_8 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114805067A (zh) * 2022-05-19 2022-07-29 浙江科技学院 一种调环酸钙中间体的制备方法

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