Radical addition initiator and method of use thereof

Abstract

The present invention relates to an initiator of a radical addition reaction, which comprises or consists of a persulfate and one or more transition metals, the transition metals being in elemental or oxide form. The present invention also relates to a method for preparing a compound of formula (I), where X is selected from S, Se, and O, which is used in a radical addition reaction in the presence of this reagent. [Formula I] TIFF2022518201000010.tif27170

Description

[Technical field]

[0001] The present invention relates to radical addition initiators and their use in the preparation of compounds of formula (I).

[0002] [ka]

[0003] where X is selected from S, Se and O; R1 is selected from H, an alkyl group, an aryl group, and an alkylaryl group; R2 is selected from H; OH; NR4R5; NHCOR4; OCOR4, where R4 and R5 may be the same or different and are selected from H, an alkyl group, an aryl group, an alkylaryl group; and a protecting group; R3 is selected from OH, CH2OH, COOH, COOR6, where R6 is selected from alkyl, CN, CONR4R5 and COZ, where R4 and R5 are defined as above and Z is a halogen, and a radical addition reaction is carried out in the presence of this reagent. [Background technology]

[0004] WO 98 / 32735 A1 describes a process for the preparation of methionine and hydroxymethylthiobutyric acid (HMTBA) and their derivatives in the addition reaction of methylthiol to the following compound:

[0005] [ka]

[0006] where R is COOH and the corresponding ester, amide, nitrile and trichloro functional groups, and R' is OH, NH2, oxycarbonyl and aminocarbonyl functional groups and protective groups. The reaction is initiated by UV irradiation in the presence of an initiator consisting of azobisisobutyronitrile (AIBN) at 50°C to 60°C under a pressure of 3.5 to 4.8 bar. The yield is at least 80%. The examples in this document are limited to the preparation of HMTBA, especially with regard to the aforementioned conditions. The reaction times are long and thermal activation is required at temperatures generally above 50°C. Furthermore, the regioselectivity in the addition is low and purification by distillation of the fractions is often necessary. Such initiators are therefore expensive, unstable and difficult to handle, leading to safety problems in transportation, storage and handling as well as cost.

[0007] Document WO2017 / 191196A1 describes a method for the preparation of methionine by the same radical addition reaction as document WO98 / 32735A1, which describes the reaction of methylthiol with vinylglycine in the presence of an initiator selected from AIBN, N-bromosuccinimide (NBS), benzoyl peroxide (DBPO) and 2,2'-azobis[2-(2-imidazolin-2-yl)propane] hydrochloride, or by selective UV irradiation in the presence of a photoinitiator. The yields vary greatly depending on the reaction conditions. The authors describe the reaction in the presence of ammonium persulfate, which also corresponds to a conversion rate of 23% of vinylglycine to methionine, indicating that the reagent is not effective.

[0008] Thus, there is a need for alternative solutions for the efficient synthesis of compounds via selective radical addition under energy-free and easily industrializable conditions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present invention provides initiators for radical addition reactions that overcome the problems associated with existing processes.

[0010] The reagent comprises or consists of a persulfate salt and one or more transition metals, the transition metals being in elemental or oxide form.

[0011] Unexpectedly, the transition metals behave as effective coinitiators of persulfates in radical addition reactions at temperatures close to room temperature. This discovery overcomes the problems associated with the use of persulfates in reactions at elevated temperatures, conditions that result in unavoidable energy losses.

[0012] According to the present invention, persulfates can be replaced in the same reaction by organic peroxides, depending on the objectives and regulations for the quality of the reaction products and process effluents.

[0013] The initiator and its advantages are described in detail in the section on the radical addition reaction of thiols, disulfides, selenols, diselenides or alcohols to vinyl compounds such as compound (III) below. The present invention is not limited to the reagents used in the radical addition reaction of thiols, disulfides, selenols, diselenides or alcohols to compounds having non-conjugated double bonds. This reagent is particularly effective when high selectivity is required.

[0014] Sodium persulfate is known to be used for soil remediation due to its strong oxidizing power and stability. Persulfate breaks down harmful substances into harmless small molecules such as CO2, water, and sulfates. In this application, it is used in the form of an aqueous solution with a concentration of about 5%, and rapidly produces active radicals with strong oxidizing power. Several types of pollutants, mainly hydrocarbons, are broken down to produce various small substances.

[0015] The present invention relates to the use of a combination of transition metals and persulfates as initiators for selective radical reactions. The effects and applications of the present invention are described in detail below, and the features of the present invention can be applied independently or in combination.

[0016] The terms used in the present invention are defined below.

[0017] Persulfate is an oxyanion S2O8 2- or a salt thereof formed with a counter ion.

[0018] An "organic peroxide" is an organic compound represented by the formula R7-OO-R8, where R7 and R8 may be the same or different and are selected from H, an alkyl group, an aryl group, an alkylaryl group and COR1, where R1 is described below.

[0019] Radical addition reactions correspond to chain reactions having an initial step initiated by an initiator, a propagation step which sees the radical formed during the initial reaction with a compound, and a termination step.

[0020] "Metal in elemental form" means a metal in its oxidized state or in its reduced form.

[0021] "Metal in oxidized form" means a metal in any oxidation state in combination with an anion or oxygen. This definition includes oxides, sulfates, phosphates, chlorides (e.g. FeCl3), carbides, hydroxides, nitrites, nitrates, acetates, alcoholates, hydrogen phosphates, and hydrogen sulfates.

[0022] In the formulas defining the compounds produced or used, «alkyl» is a linear or branched monovalent hydrocarbon radical of 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl or n-hexyl, or a cyclic monovalent hydrocarbon radical of 3 to 20 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl or cyclohexyl.

[0023] "Allyl group" is understood to mean an aromatic monovalent hydrocarbon radical containing 6 to 22 carbon atoms.

[0024] "Alkylaryl group" means an aryl group containing 6 to 22 carbon atoms, which is substituted by at least one alkyl group according to the above definition.

[0025] Thus, the present invention relates to a reagent, initiator or primer reagent for the initial step in a radical addition reaction, which comprises or consists of a persulfate salt and one or more transition metal elements or oxides thereof.

[0026] The persulfates are in the form of cationic salts, the cations being preferably selected from sodium, potassium, calcium, lithium, and ammonium ions, and the counter ions being appropriately selected.

[0027] As previously mentioned, in the present invention, in certain cases the persulfate is preferably an organic peroxide.

[0028] The persulfate is combined with one or more transition metals. When multiple transition metals are used, the mixture may consist of the same metal in the elemental state and / or different oxidation states, the same metal in the elemental state and / or the same or different oxidation states, or even an alloy, such as brass, in its oxidized state.

[0029] The transition metal is preferably selected from Cu, Zn and Fe, which may be in elemental or oxide form as previously described.

[0030] The molar ratio of the persulfate to the transition metal is preferably 0.5 to 10,000. If the metal is in excess, the selectivity of the reaction may decrease, but if the content is too low, the reaction rate, which is important for industrialization, decreases. Preferably, this molar ratio is 1 to 1,000.

[0031] In the present invention, the combination of one or more transition metals and persulfates described above is used in the initial step of a radical addition reaction using an organic species that reacts with a double bond to form a radical, which may not be conjugated and the reaction may terminate.

[0032] In the present specification, the initiator is used in a very small ratio to the organics used in the reaction. Here, the molar ratio of the organics to the initiator that functions directly on the reagent is 2 to 1000. Within this range, a person skilled in the art can select an appropriate ratio. The persulfate is preferably used in solution using an inert solvent. This consists of an aqueous mixture including a water-soluble organic solvent such as an alcohol, and water. In a preferred embodiment of the initiator, compound (III) is mixed with the metal, then compound (II) is added, and finally the persulfate solution is slowly poured into the mixture.

[0033] The present invention also relates to the use of the initiators, in particular to obtain compounds of formula (I).

[0034] [ka]

[0035] where X is selected from S, Se and O; R1 is selected from H, an alkyl group, an aryl group, and an alkylaryl group; R2 is selected from H; OH; NR4R5; NHCOR4; OCOR4, where R4 and R5 may be the same or different and are selected from H, an alkyl group, an aryl group, an alkylaryl group; and a protecting group; R3 is selected from OH, CH2OH, COOH, COOR6, where R6 is selected from alkyl, CN, CONR4R5, and COZ, where R4 and R5 are as defined above, and Z is a halogen.

[0036] The process comprises reacting a compound of formula (II) with a compound of formula (III).

[0037] [ka]

[0038] where X is selected from S, Se and O; R' is selected from H, alkyl groups, aryl groups, alkylaryl groups, thiol groups, thioalkyl groups, thioaryl groups, thioalkylaryl groups, selenol groups, selenoalkyl groups, selenoaryl groups, and selenoalkylaryl groups; R2' is selected from H, an alkyl group, an aryl group, and an alkylaryl group.

[0039] [ka]

[0040] Here, R2 and R3 are defined as described for compound (I).

[0041] The initiators described above are suitable for this reaction due to their aforementioned properties.

[0042] However, depending on the work carried out in this reaction, the preferred variants shown below are possible, either alone or in combination, which are the most efficient and most selective according to the method of the invention.

[0043] Thus, the persulfate is preferably potassium persulfate or sodium persulfate.

[0044] The molar ratio of compound (II) or compound (III) to the initiator is preferably 2-1,000, more preferably 10-500.

[0045] The molar ratio of compound (II) to compound (III) is 0.9-20, preferably 1.1-3.

[0046] As described above, the reaction temperature can be lowered by using the initiator of the present invention. The reaction can be carried out at -20°C to 60°C, preferably -20°C to 40°C, further 0°C to 40°C, and further 10°C to 40°C. This reaction condition is preferable because it has high selectivity without affecting the yield.

[0047] The initiator of the present invention is used in the radical addition reaction of the compound (II) selected from methylthiol or methylselenol with the aforementioned compound (III).The initiator of the present invention is also used in the radical addition reaction of the aforementioned compound (II) with methylvinylglycolic acid as the compound (III).

[0048] According to another aspect of the invention, the process is the preparation of HMTBA as compound (I) or its selenium analogue, hydroxymethylselenobutyric acid (HMSeBA). HMTBA and HMSeBA are obtained by radical addition reaction of methylthiol or methylselenol as compound (II) to methylvinylglycolic acid as compound (III), obtained after hydrolysis of the ester.

[0049] The invention and its advantages are further illustrated in the following examples.

[0050] Example 1: Preparation of methyl 2-hydroxy-4-(methylthio)butanoate by radical addition reaction using initiators of the present invention 26.0 g (0.22 mol) of methyl 2-hydroxybut-3-enoate and 0.17 g (0.00027 mol) of metallic copper were placed in a stirred reactor and cooled to −10° C. Then 12.1 g (0.25 mol) of methanethiol was added, followed by slow addition of an aqueous solution of sodium persulfate (0.023 mol).

[0051] The temperature was raised to 0° C. and the mixture was stirred for 1 h.

[0052] HPLC analysis of the reaction mixture showed that the yield of methyl 2-hydroxy-4-(methylthio)butanoate was 81% (selectivity of 81%).

[0053] Comparative Example 1: Preparation of methyl 2-hydroxy-4-(methylthio)butanoate by radical addition reaction using only persulfate compounds at high temperature 40.1 g (0.34 mol) of methyl 2-hydroxybut-3-enoate was placed in a stirred reactor and cooled to −15° C. Then 18.0 g (0.37 mol) of methanethiol was added, followed by slow addition of an aqueous solution of sodium persulfate (0.034 mol).

[0054] The temperature was raised to 60° C. and the mixture was stirred for 2 hours.

[0055] HPLC analysis of the reaction mixture indicated that the yield of methyl 2-hydroxy-4-(methylthio)butanoate was 7.6% (selectivity of 15%).

[0056] Example 2: Preparation of methyl 4-(butylsulfanyl)-2-hydroxybutanoate by radical addition reaction using the initiator of the present invention 20.4 g (0.18 mol) of methyl 2-hydroxybut-3-enoate and 0.025 g (0.00040 mol) of metallic copper were placed in a stirred reactor and cooled to −10° C. Then 17.7 g (0.20 mol) of butanethiol was added, followed by slow addition of an aqueous solution of sodium persulfate (0.054 mol).

[0057] The temperature was raised to 25° C. and the mixture was stirred for 1 hour.

[0058] HPLC analysis of the reaction mixture showed that the yield of methyl 4-(butylsulfanyl)-2-hydroxybutanoate was 16%.

[0059] Example 3: Preparation of 3-(methylsulfanyl)propan-1-ol by radical addition reaction using initiators of the present invention 14.8 g (0.25 mol) of propen-1-ol and 0.015 g (0.00023 mol) of metallic copper were placed in a stirred reactor and cooled to −10° C. Then 13.5 g (0.28 mol) of methanethiol was added, followed by slow addition of an aqueous solution of sodium persulfate (0.0077 mol).

[0060] The temperature was raised to 0° C. and the mixture was stirred for 1 h.

[0061] HPLC analysis of the reaction mixture showed that 3-(methylsulfanyl)propan-1-ol was obtained in quantitative yield.

[0062] Example 4: Preparation of methyl 2-hydroxy-4-(methylthio)butanoate by radical addition reaction using initiators of the present invention 26.3 g (0.23 mol) of methyl 2-hydroxybut-3-enoate, 0.020 g of iron(II) and 0.00013 mol of iron(III) oxide were placed in a stirred reactor and cooled to -10° C. 13.2 g (0.27 mol) of methanethiol was added, followed by slow addition of an aqueous solution of sodium persulfate (0.023 mol).

[0063] The temperature was raised to 0° C. and the mixture was stirred for 1 h.

[0064] HPLC analysis of the reaction mixture showed that the yield of methyl 2-hydroxy-4-(methylthio)butanoate was 79%.

[0065] Example 5: Preparation of methyl 2-hydroxy-4-(methylthio)butanoate by radical addition reaction using initiators of the present invention 26.1 g (0.22 mol) of methyl 2-hydroxybut-3-enoate and 0.089 g (0.00022 mol) of iron sulfide were placed in a stirred reactor and cooled to −10° C. 12.0 g (0.25 mol) of methanethiol was added, followed by slow addition of an aqueous solution of sodium persulfate (0.023 mol).

[0066] The temperature was raised to 0° C. and the mixture was stirred for 1 h.

[0067] HPLC analysis of the reaction mixture indicated that the yield of methyl 2-hydroxy-4-(methylthio)butanoate was 70% (selectivity 84%).

[0068] These examples demonstrate the effectiveness of the initiators of the present invention and methods of using the same.

Claims

1. A process for preparing a compound of formula (I), comprising the steps of: 【Chemistry 1】 X is S or Se; R 1 is H or CH ３ and R 2 is H or OH, R 3 OH, CH 2 OH, COOH, COOR 6 and COZ, where R 6 is an alkyl group and Z is a halogen; reacting a compound of formula (II) with a compound of formula (III) in the presence of at least one radical addition initiator comprising or consisting of a persulfate salt and one or more transition metal elements or oxides thereof, wherein the transition metal elements are selected from Cu, Zn and Fe in elemental form or in the form of an oxide selected from sulfates, phosphates, chlorides, carbonates, hydroxides, nitrites, nitrates, acetates, alcoholates, hydrogen phosphates and hydrogen sulfates; 【Chemistry 2】 where X is S or Se; R 1 ' is H or CH ３ and R 2 ' is H or an alkyl group, 【Chemistry 3】 Here, R 2 and R 3 is defined as in compound (I), the molar ratio of the persulfate to the transition metal is 1 to 1000; Methods for producing compounds.

2. 2. The method of claim 1, wherein the persulfate is a salt of a cation selected from salts of sodium, potassium, calcium, lithium and ammonium ions.

3. 3. The method according to claim 1 or 2, wherein the persulfate is potassium persulfate or sodium persulfate.

4. 4. The process according to claim 1, wherein the molar ratio of compound (II) or compound (III) to said initiator is from 2 to 1000.

5. 5. The process according to claim 1, wherein the molar ratio of compound (II) to compound (III) is from 0.9 to 20.

6. 6. The method according to claim 5, wherein the molar ratio of compound (II) to compound (III) is from 1.1 to 3.

7. 7. The method according to any one of claims 1 to 6, wherein compound (II) is methylthiol or methylselenol.

8. 8. The method according to claim 1, wherein the compound (III) is methyl vinyl glycolic acid.

9. The process according to any one of claims 1 to 8, wherein the reaction is carried out at a temperature of from -20°C to 40°C.

Images