Reagent for initiating free radical addition reaction and use method thereof

Abstract

The present invention relates to an agent for initiating a free radical addition reaction, comprising or consisting of a persulfate and one or more transition metals in elemental or oxidized form, and to a process for the preparation of a compound of formula (I) by a free radical addition reaction in the presence of such an agent; wherein X is selected from S, Se and O. # imgabs0 #

Description

[0001] This application is a divisional application of the invention patent application with application number 202080009035.5, application date January 16, 2020, and invention name “Reagents for initiating free radical addition reactions and methods of use thereof”. Technical Field

[0002] The present invention relates to a reagent for initiating a free radical addition reaction and its use in a method for preparing a compound of the formula

[0003] [Formula I]

[0004]

[0005] in

[0006] X is selected from S, Se and O;

[0007] R1 is selected from H, alkyl, aryl and alkylaryl;

[0008] R2 is selected from H; OH; NR4R5; NHCOR4; OCOR4; wherein R4 and R5 are the same or different and are selected from H, alkyl, aryl, alkylaryl; and protecting groups;

[0009] R3 is selected from OH; CH2OH; COOH; COOR6, wherein R6 is selected from alkyl; CN; CONR4R5, wherein R4 and R5 are as defined above; and COZ, wherein Z represents halogen.

[0010] According to WO98 / 32735A1, a method for preparing methionine and hydroxymethylthiobutyric acid (HMTBA) and derivatives thereof by adding methyl mercaptan free radical to a compound of the formula

[0011] [Formula I]

[0012]

[0013] Wherein R is selected from COOH and corresponding ester, amide, nitrile and trichloro functional groups, and R' is selected from OH, NH2, oxycarbonyl and aminocarbonyl functional groups and protecting groups. The reaction is initiated in the presence of an initiator consisting of azobisisobutyronitrile (AIBN) at a temperature in the range of 50°C to 60°C and a pressure in the range of 3.5 bar to 4.8 bar, or by UV irradiation. This gives a yield of at least 80%. The lessons learned from the literature, in particular with regard to the above conditions, are limited to obtaining HMTBA. The use of AIBN or its derivatives in this reaction has several disadvantages: the reaction time is long and thermal activation is required, the temperature is generally above 50°C. In addition, the regioselectivity of the addition is low and purification by distillation of fractions is more often required. Finally, such initiators are expensive, unstable and difficult to handle, which leads to safety issues and costs during their transportation, storage and handling. Background Art

[0014] Document WO2017 / 191196A1 describes a method for preparing methionine by the same free radical addition reaction as WO98 / 32735A1, by reacting methyl mercaptan with vinyl glycine 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 optionally in the presence of a photoinitiator by UV irradiation. The yield varies greatly depending on the operating conditions. The authors also illustrate this reaction in the presence of ammonium persulfate, but it only leads to a conversion of vinyl glycine to methionine of 23%, which proves the ineffectiveness of such a reagent in this indication.

[0015] Therefore, we are still searching for alternative solutions for the efficient synthesis of compounds via selective radical addition using energy-free and industrially amenable conditions. Summary of the invention

[0016] According to the present invention, a reagent for initiating free-radical addition reactions has been found which makes it possible to solve the problems of the known processes, in particular in the process of the invention as defined above.

[0017] The reagent comprises or consists of a persulfate and one or more transition metals, the one or more transition metals being present in elemental or oxidized form.

[0018] Unexpectedly, the transition metals behave as strong co-initiators for persulfates in free radical addition reactions in the temperature range close to room temperature. This discovery solves the selectivity problems associated with the use of persulfates, which, to be active, must be present in a heated reaction medium, a condition that results in an inevitable loss of selectivity.

[0019] According to the present invention, organic peroxides may be used in some cases instead of persulfates, depending on the objectives and restrictions on the quality of the reaction products and process effluents.

[0020] This initiator and its advantages are described in the remainder of this article, more specifically in the context of free radical addition reactions of thiols, disulfides, selenols, diselenides or alcohols on vinyl compounds (e.g., compounds of formula (III) shown below). Of course, it is not limited thereto, and the present invention relates to such a reagent, which can be used for any free radical addition reaction of thiols, disulfides, selenols, diselenides or alcohols on compounds with double bonds, which are non-conjugated and terminal or non-terminal. This reagent is particularly advantageous when high selectivity is desired.

[0021] Sodium persulfate is known to be used for soil remediation due to its strong oxidizing power and stability. In this mechanism, persulfate breaks down pollutants into harmless small molecules such as CO2, water and sulfate. In this application, it is used in the form of an aqueous solution with a concentration of about 5% and quickly produces free radicals after activation, some of which have strong oxidizing power. It acts on several types of polluting compounds, mainly hydrocarbons, and its degradation produces various small-sized products.

[0022] Therefore, the discovery of using persulfate in combination with transition metal as initiator for selective free radical reaction according to the present invention is surprising. In view of the fact that these features can be considered independently of each other or in combination, no matter what the combination is, the features, applications and advantages of the present invention will be explained in more detail below. DETAILED DESCRIPTION

[0023] Prior to this description, certain terms used are defined below.

[0024] The term "persulfate" refers to the oxygen-containing anion S2O8 2- , or a salt thereof with any counter ion.

[0025] The term "organic peroxide" refers to any organic substance of the formula R7-OO-R8, wherein R7 and R8 are the same or different and are selected from H, alkyl, aryl, alkylaryl and CO-R1 groups, wherein R1 is as defined below.

[0026] Free radical addition reactions follow a chain reaction mechanism that includes initiation from an initiator, propagation of free radicals formed during initiation that react with compounds, and then termination.

[0027] The term "elemental form of a metal" refers to a metal in oxidation state 0, or a metal in a reduced form.

[0028] The term "oxidized form of the metal" includes any combination of the metal with an anion or oxygen at any degree of oxidation of the metal. This definition includes oxides, sulfates, phosphates, chlorides (e.g., FeCl), carbonates, hydroxides, nitrites, nitrates, acetates, alkoxides, hydrogen phosphates, and hydrogen sulfates.

[0029] In the formulae defining the compounds obtained or used, the term "alkyl" represents a linear or branched monovalent hydrocarbon radical having 1 to 20 carbon atoms, advantageously 1 to 6 carbon atoms, such as methyl or ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, n-hexyl, or a cyclic monovalent hydrocarbon radical having 3 to 20 carbon atoms, advantageously 3 to 6 carbon atoms, such as cyclopropyl, cyclohexyl.

[0030] The term "aryl" is understood to mean an aromatic monovalent hydrocarbon radical containing from 6 to 22 carbon atoms.

[0031] The term "alkylaryl" refers to an aryl group containing 6 to 22 carbon atoms, which is substituted with at least one alkyl group corresponding to the above definition.

[0032] The present invention therefore relates to the use of an agent for initiation or an initiator agent or a primeragent in a free radical addition reaction, said agent comprising or consisting of a persulfate and one or more transition metals in elemental or oxidized form.

[0033] The persulfate may be in the form of a cationic salt, the relevant cation preferably being selected from sodium, potassium, calcium, lithium and ammonium ions, although any counterion may be suitable.

[0034] As mentioned above, according to the invention, persulfates can in certain cases advantageously be replaced by organic peroxides.

[0035] The persulfate may be combined with one or more transition metals. When several metals are used, the mixture may consist of: the same metal in the elemental state and / or in different oxidation states; different metals in the elemental state and / or in the same or different oxidation states, but also in the form of alloys, such as brass, possibly in oxidized form.

[0036] The transition metal or metals are advantageously chosen from Cu, Zn and Fe as defined above, in elemental or oxidized form.

[0037] Advantageously, the molar ratio of persulfate to one or more transition metals is in the range of 0.5 to 10,000. Excessive amounts of metals can result in decreased selectivity of the reaction, but too low a content can slow down the reaction, affecting its industrializable benefits. Preferably, the molar ratio is in the range of 1 to 1000.

[0038] According to the present invention, the combination of the above-mentioned persulfate and one or more transition metals is used to initiate a free radical addition reaction involving an organism capable of forming a free radical that reacts on a double bond. The double bond is non-conjugated. It may or may not be terminal.

[0039] In the context of the present invention, initiators are used in a very small ratio relative to the organic substances involved in the reaction. Therefore, the molar ratio of the organic substance on which the initiator directly acts to the reagent is in the range of 2 to 1000. It is within the capabilities of those skilled in the art to adjust the value of this ratio as much as possible. Persulfate is preferably used in a solution of an inert solvent. This can be composed of water and any aqueous mixture containing a water-soluble organic solvent (e.g., alcohol). According to a preferred variation of the embodiment of the initiator, compound (III) is mixed with a metal, compound (II) is then added, and finally a persulfate solution is slowly poured into the mixture.

[0040] The present invention also relates to an application of the initiator, in particular to its use in obtaining the compound of formula (I), namely,

[0041] [Formula I]

[0042]

[0043] in

[0044] X is selected from S, Se and O;

[0045] R1 is selected from H, alkyl, aryl and alkylaryl;

[0046] R2 is selected from H; OH; NR4R5; NHCOR4; OCOR4; wherein R4 and R5 are the same or different and are selected from H, alkyl, aryl, alkylaryl; and protecting groups;

[0047] R3 is selected from OH; CH2OH; COOH; COOR6, wherein R6 is selected from alkyl; CN; CONR4R5, wherein R4 and R5 are as defined above; and COZ, wherein Z represents a halogen;

[0048] The method comprises reacting a compound of formula (II) with a compound of formula (III)

[0049] [Formula II]

[0050]

[0051] in

[0052] X is selected from S, Se and O;

[0053] R1' is selected from the group consisting of H, alkyl, aryl, alkylaryl, thiol, thioalkyl, thioaryl, thioalkylaryl, selenol, selenoalkyl, selenoaryl and selenoalkylaryl, and

[0054] R2' is selected from H, alkyl, aryl and alkylaryl;

[0055] [Formula III]

[0056]

[0057] wherein R2 and R3 are as defined above for the compound of formula (I).

[0058] The initiators as described above, that is to say corresponding to any one or several of the mentioned characteristics, are suitable for this reaction.

[0059] However, work carried out on this reaction has made it possible to identify the preferred variants indicated below, which may be considered alone or in combination, according to which the process is most efficient and in particular most selective.

[0060] Therefore, the persulfate is preferably potassium persulfate or sodium persulfate.

[0061] The molar ratio of compound (II) or compound (III) to the initiator is advantageously in the range of 2 to 1000, more preferably 10 to 500.

[0062] The molar ratio of compound (II) to compound (III) is in the range of 0.9 to 20, preferably 1.1 to 3.

[0063] As mentioned above, the use of the initiator of the present invention allows the reaction temperature to be lowered; the reaction can be carried out at a temperature of -20°C to 60°C, preferably -20°C to 40°C, even 0°C to 40°C, even 10°C to 40°C. Such conditions are favorable for high selectivity without affecting the reaction yield.

[0064] The initiator of the present invention can be used for the free radical addition of a compound (II) selected from methyl mercaptan and methyl selenol with a compound (III) as defined above. It can also be used for the free radical addition of a compound of formula (II) as generally defined above with methyl vinyl glycolate as compound (III).

[0065] According to one variant of the invention, the method is intended to prepare HMTBA or its selenium analogue hydroxymethylselenobutyric acid (HMSeBA) as compound (I). HMTBA and HMSeBA can be obtained by adding methyl mercaptan or methyl selenol free radicals as compound (II) to methyl vinyl glycolate as compound (III) and then hydrolyzing the corresponding esters formed.

[0066] The invention and its advantages are illustrated in the following examples.

[0067] Example 1: Preparation of 2-hydroxy-4-(methylthio)- Methyl butyrate

[0068] 26.0 g (0.22 mol) of methyl 2-hydroxybut-3-enoate and 0.17 g of metallic copper (0.00027 mol) were placed in a stirred reactor and cooled to -10° C. Then 12.1 g of methyl mercaptan (0.25 mol) were injected, followed by the slow addition of an aqueous solution of sodium persulfate (0.023 mol).

[0069] The temperature was raised to 0°C, and the mixture was stirred for one hour.

[0070] HPLC analysis of the mixture at the end of the reaction indicated a yield of 81% (81% selectivity) of methyl 2-hydroxy-4-(methylthio)butanoate.

[0071] Comparative Example 1: Free Radical Addition Reaction with a Single Persulfate Compound at Elevated Temperature Preparation of methyl 2-hydroxy-4-(methylthio)butyrate

[0072] 40.1 g (0.34 mol) of methyl 2-hydroxybut-3-enoate were placed in a stirred reactor and cooled to -15° C. Then 18.0 g of methyl mercaptan (0.37 mol) were injected, followed by the slow addition of an aqueous solution of sodium persulfate (0.034 mol).

[0073] The temperature was raised to 60°C, and the mixture was stirred for two hours.

[0074] HPLC analysis of the mixture at the end of the reaction indicated a yield of 7.6% (15% selectivity) of methyl 2-hydroxy-4-(methylthio)butanoate.

[0075] Example 2: Preparation of 4-(butylthio)-2-hydroxy by free radical addition reaction using an initiator according to the invention Methyl butyrate

[0076] 20.4 g (0.18 mol) of methyl 2-hydroxybut-3-enoate and 0.025 g of metallic copper (0.00040 mol) were placed in a stirred reactor and cooled to -10° C. Then 17.7 g of butanethiol (0.20 mol) was injected, followed by the slow addition of an aqueous solution of sodium persulfate (0.0054 mol).

[0077] The temperature was raised to 25°C, and the mixture was stirred for one hour.

[0078] HPLC analysis of the mixture at the end of the reaction indicated a 16% yield of methyl 4-(butylthio)-2-hydroxybutyrate.

[0079] Example 3: Preparation of 3-(methylthio)propan-1-ol by free radical addition reaction with an initiator according to the invention

[0080] 14.8 g (0.25 mol) of propen-3-ol and 0.015 g of metallic copper (0.00023 mol) were placed in a stirred reactor and cooled to -10° C. Then 13.5 g of methyl mercaptan (0.28 mol) was injected, and then an aqueous solution of sodium persulfate (0.0077 mol) was slowly added.

[0081] The temperature was raised to 0°C, and the mixture was stirred for one hour.

[0082] HPLC analysis of the mixture at the end of the reaction indicated a quantitative yield of 3-(methylthio)propan-1-ol.

[0083] Example 4: Preparation of 2-hydroxy-4-(methylthio)- Methyl butyrate

[0084] 26.3 g (0.23 mol) of methyl 2-hydroxybut-3-enoate and 0.020 g of iron (II) oxide and iron (III) oxide (0.00013 mol) were placed in a stirred reactor and cooled to -10° C. 13.2 g of methyl mercaptan (0.27 mol) were then injected, followed by the slow addition of an aqueous solution of sodium persulfate (0.023 mol).

[0085] The temperature was raised to 0°C, and the mixture was stirred for one hour.

[0086] HPLC analysis of the mixture at the end of the reaction indicated a 79% yield of methyl 2-hydroxy-4-(methylthio)butanoate.

[0087] Example 5: Preparation of 2-hydroxy-4-(methylthio)- Methyl butyrate

[0088] 26.1 g (0.22 mol) of methyl 2-hydroxybut-3-enoate and 0.089 g of iron sulfate (0.00022 mol) were placed in a stirred reactor and cooled to -10° C. Then 12.0 g of methyl mercaptan (0.25 mol) were injected, followed by the slow addition of an aqueous solution of sodium persulfate (0.023 mol).

[0089] The temperature was raised to 0°C, and the mixture was stirred for one hour.

[0090] HPLC analysis of the mixture at the end of the reaction indicated a 70% yield (84% selectivity) of methyl 2-hydroxy-4-(methylthio)butanoate.

[0091] These examples demonstrate the performance of initiators and methods of implementing the same according to the present invention.

Claims

1. A method for preparing a compound of formula (I) [Formula I] in X is selected from S, Se and O; R1 is selected from H, alkyl, aryl and alkylaryl; R2 is selected from H; OH; NR4R5; NHCOR4; OCOR4; wherein R4 and R5 are the same or different and are selected from H, alkyl, aryl, alkylaryl; and protecting groups; R3 is selected from OH; CH2OH; COOH; COOR6, wherein R6 is selected from alkyl; CN; CONR4R5, wherein R4 and R5 are as defined above; and COZ, wherein Z represents a halogen; The method comprises reacting a compound of formula (II) with a compound of formula (III) [Formula II] in X is selected from S, Se and O; R1' is selected from the group consisting of H, alkyl, aryl, alkylaryl, thiol, thioalkyl, thioaryl, thioalkylaryl, selenol, selenoalkyl, selenoaryl and selenoalkylaryl, and R2' is selected from H, alkyl, aryl and alkylaryl; [Formula III] wherein R2 and R3 are as defined above for compounds of formula (I), The reaction is carried out in the presence of at least one reagent that initiates a free radical addition reaction, the reagent comprising or consisting of: persulfate and one or more transition metals in elemental or oxidized form.

2. The method according to claim 1, characterized in that The persulfate is in the form of a salt of a cation, preferably selected from the group consisting of sodium, potassium, calcium, lithium and ammonium ions.

3. The method according to claim 1 or 2, characterized in that The one or more transition metals are selected from Cu, Zn and Fe in elemental form or in oxidized form, the oxidized form being selected from sulfates, phosphates, chlorides, carbonates, hydroxides, nitrites, nitrates, acetates, alkoxides, hydrogen phosphates and hydrogen sulfates, and alloys thereof such as brass.

4. The method according to any one of claims 1 to 3, characterized in that The molar ratio of the persulfate to the one or more transition metals is in the range of 1 to 1000.

5. The method according to any one of claims 1 to 4, characterized in that The persulfate is potassium persulfate or sodium persulfate.

6. The method according to any one of claims 1 to 5, characterized in that The molar ratio of compound (II) or compound (III) to the initiator is in the range of 2 to 1,000.

7. The method according to any one of claims 1 to 6, characterized in that The molar ratio of compound (II) to compound (III) is in the range of 0.9 to 20, preferably 1.1 to 3.

8. The method according to any one of claims 1 to 7, characterized in that Compound (II) is methyl mercaptan or methyl selenol.

9. The method according to any one of claims 1 to 8, characterized in that Compound (III) is methyl vinyl glycolate.

10. The method according to any one of claims 1 to 9, characterized in that The reaction is carried out at a temperature of -20°C to 40°C.

11. Use of a reagent for initiating a free radical addition reaction to obtain a compound of formula (I) as defined in claim 1, the reagent comprising or consisting of: persulfate and one or more transition metals in elemental or oxidized form.

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