Process for the preparation of 2-(2-hydroxyphenoxy)acetates

Abstract

The present invention relates to 2-(2-hydroxyphenoxy)acetates of formula (I) as well as to processes for the synthesis of such compounds and their use as important intermediates in the synthesis of agrochemical and pharmaceutical active ingredients.

Description

[0001] BYC250028-FC STR

[0002] 1

[0003] Bayer AG

[0004] Process for the preparation of 2-(2-hydroxyphenoxy)acetates

[0005] The present invention relates to 2-(2-hydroxyphenoxy)acetates of formula (I) as well as to processes for the synthesis of such compounds and their use as important intermediates in the synthesis of agrochemical and pharmaceutical active ingredients.

[0006] Compounds of formula (I) are not known so far but can present important intermediates in the agrochemical and pharmaceutical production industry. The synthesis of compounds of formula (I) has not been described so far.

[0007] Catechol derived acids, such as catechol acetic acid, are known in the art, see for example H. Ludewig, Zur Kenntniss der Brenzcatechinessigsaure, Journal fuer Praktische Chemie, 1900.

[0008] It is known in the art that catechol acetic acid can be prepared by reacting catechol with chloroacetic acid in alkaline conditions (see DE87336).

[0009] It is also known in the art that catechol acetic acid can be purified by heating it to temperatures above 120 °C to transform it into its inner anhydride (lactone), which can be transferred to the acid by boiling in water see DE89593).

[0010] It is furthermore known that esters of catechol acetic acid can be prepared by reacting catechol acetic acid with the respective alkyl alcohol in concentrated sulfuric acid (see H. Ludewig, Journal fuer Praktische Chemie 1900). For such reaction, the alcohol compound is usually applied in clearly over-stoichiometric amounts to obtain an adequate yield. For inexpensive alcohols, such as methanol or ethanol, this does not reflect a high burden for large scale syntheses. However, for costly alcohol compounds it is desirable to reduce the amount of this reactant, while generating the product in a high yield. Thereby, important intermediates to produce active ingredients could be prepared in high yield, purity and at reasonable costs in large quantities, while reducing the environmental impact, e.g. in terms of waste products.

[0011] At least parts of these problems have been solved by the present invention.

[0012] The present invention relates to a process for the preparation of compounds of formula (I)BYC250028-FC STR

[0013]

[0014] with Ri being (C3-Cio)-alkyl, (Ci-Cio)-alkyl-0-(Ci-Cio)-alkyl, (Ci-Cio)-alkyl-(C3-C6)-cycloalkyl, wherein compounds of formula (II) are reacted with compounds of formula (III)

[0015]

[0016] in the presence of a Brpnsted acid.

[0017] The definition of Ri applies to compounds (I) and (III).

[0018] Preferably, Ri is selected to be (C3-Ce)-alkyl, (Ci-C6)-alkyl-O-(Ci-Ce)-alkyl, (Ci-C6)-alkyl-(C3-Ce)-cycloalkyl.

[0019] Further preferably, Ri is selected to be (Ci-C3)-alkyl-O-(Ci-C3)-alkyl, (Ci-C3)-alkyl-(C3-C6)-cycloalkyl. Even further preferably, Ri is selected to be methyl-cyclopropyl.

[0020] Brpnsted acids are known in the art, and can be selected from organic acids, such as carbonic acids, or mineral acids, and salts thereof. The Brpnsted acid may be in particular selected from chloroacetic acid, phenoxy acetic acid, which may be substituted, e.g. with one to three hydroxy groups, methanesulfonic acid, H2SO4, HNO3, H3PO4and HC1.

[0021] Preferably, the Brpnsted acid is HC1.

[0022] The Brpnsted acid, in particular HC1, may be pre-dissolved in an organic solvent, preferably cyclopentylmethylether or dioxan, further preferably cyclopentylmethylether.

[0023] The reaction may be performed in an organic solvent, preferably a nonpolar organic solvent.BYC250028-FC STR

[0024] 3

[0025] The solvent is preferably selected from methylcyclohexane, 1,4-dioxan, diethylether, diisopropylether, tert-butylmethylether, tetrahydrofurane, 2-methyltetrahydrofuran, toluene, cyclopentylmethylether, and n-heptane, or mixtures thereof.

[0026] Further preferred solvents are methylcyclohexane, 1,4-dioxan, toluene and cyclopentylmethylether, or mixtures thereof.

[0027] Even further preferred is cyclopentylmethylether or methylcyclohexane.

[0028] Most preferred is methylcyclohexane.

[0029] In a further preferred embodiment, the reaction is performed in methylcyclohexane, but the Brpnsted acid, in particular HC1, is provided pre-dissolved in cyclopentylmethylether to the reaction.

[0030] The molar ratio of the compound of formula (II) to the compound of formula (III) may be chosen to be within 1:3 to 3:1, preferably 1:2 to 1:1, further preferably 1:1.5 to 1:1, even further preferably 1:1.2 to 1:1, most preferably 1 : 1.02 to 1:1.

[0031] The reaction may be performed at a temperature of between 0 °C and 50 °C.

[0032] Preferably, the reaction is performed at a temperature gradient, starting at a temperature of between 35 °C and 45 °C, gradually reducing the temperature to between 0 °C and 10 °C.

[0033] By reducing the temperature, compound (I) is crystallized, and may be collected by filtration.

[0034] The compound of formula (II) may be prepared by reacting 1 ,2-dihydroxybenzene with chloroacetyl chloride in the presence of an organic base, preferably triethylamine. The reaction may be carried out at temperatures of between 60 and 90 °C, preferably at temperatures of between 70 and 85 °C. The reaction may be carried out in a nonpolar organic solvent, preferably selected from methylcyclohexane, 1,4-dioxan, diethylether, diisopropylether, tert-butylmethylether, tetrahydrofurane, 2-methyltetrahydrofuran, toluene and cyclopentylmethylether, further preferably toluene.

[0035] The compound of formula (II) does not need to be isolated from such reaction but can be directly used for the reaction with compound of formula (III) to obtain a compound of formula (I).

[0036] A further aspect of the present invention are compounds of formula (I)BYC250028-FC STR

[0037] 4

[0038]

[0039] with Ri being (C3-Cio)-alkyl, (Ci-Cio)-alkyl-0-(Ci-Cio)-alkyl, (Ci-Cio)-alkyl-(C3-C6)-cycloalkyl.

[0040] Preferably, Ri is selected to be (C3-Ce)-alkyl, (Ci-C6)-alkyl-0-(Ci-Ce)-alkyl, (Ci-C6)-alkyl-(C3-Ce)-cycloalkyl.

[0041] Further preferably, Ri is selected to be (Ci-C3)-alkyl-O-(Ci-C3)-alkyl, (Ci-C3)-alkyl-(C3-C6)-cycloalkyl. Even further preferably, Ri is selected to be methyl-cyclopropyl (compound Al = cyclopropylmethyl 2-(2-hydroxyphenoxy)acetate) .

[0042] Ring-opening transesterification reactions of lactones are known in the art. Critical for such reactions is the equilibrium ratio, and shift towards the ring-opened ester compound. It has now surprisingly been found that a specific combination of a catalytic Brpnsted acid and non-polar organic solvents can provide for a high chemical conversion towards the ring-opened ester compound for very specific alcohol reactants. The advantage of the present invention is that no high excess of the alcohol compound is needed, thereby rendering the reaction efficient in terms of cost and resource.

[0043] General definitions

[0044] Unless otherwise indicated, the expression “alkyl”, in isolation or in combination with other terms, refers to linear or branched saturated hydrocarbon chains, e.g. with up to 10 carbon atoms, i.e. Ci-Cio-alkyl. Examples of such alkyls are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.

[0045] Unless otherwise indicated, the expression „cycloalkyl“, in isolation or in combination with other terms, refers to a carbocyclic saturated ring system, e.g. with 3 to 8 ring C atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0046] Unless otherwise indicated, the expression “alkyl ... - cycloalkyl” refers to alkyl which is substituted by a cycloalkyl group.BYC250028-FC STR

[0047] 5

[0048] Explanation of the processes and intermediate products

[0049] Examples

[0050] The present invention is explained in more detail using the following examples, without restricting the invention to these.

[0051] The products were characterized using 1H-NMR.

[0052] Example 1: Preparation of l,4-benzodioxin-3-one

[0053]

[0054] Scheme 1

[0055] The lactone l,4-benzodioxin-3-one was prepared by reacting catechol with chloroacetyl chloride in the presence of the organic base triethylamine at a temperature of 80 °C. The solvent used is toluene. After reaction, the crude reaction products were used for preparing the compounds of formula (I) as shown in the following examples.

[0056] 'H NMR (600 MHz, DMSO) 5 = 7.19 (ddd, 7=7.9, 1.4, 0.5, 1H), 7.16 - 7.09 (m, 2H), 7.07 (ddd, 7=7.9, 6.4, 2.5, 1H), 4.90 (s, 2H).

[0057] Example 2: Cyclopropylmethyl 2-(2-hydroxyphenoxy)acetate (compound Al)

[0058]

[0059] Scheme 2

[0060] 300 g l,4-benzodioxin-3-one was provided as described in example 1 and solved in 400 ml methylcyclohexane (MCH) and heated to 40 °C. 163 ml cyclopropylcarbinol (purity 98 %) was added (1.1 eq. relative to l,4-benzodioxin-3-one). All compounds dissolved.

[0061] 9 ml HC1 in dioxan (4 mol%) was added, and the reaction incubated while stirring at 40 °C for 1.5 h, then cooled in a gradient to 0 °C.

[0062] Cyclopropylmethyl 2-(2-hydroxyphenoxy)acetate spontaneously crystallized at 20-25 °C.BYC250028-FC STR

[0063] 6

[0064] The crystallized product can be filtered and washed with cold methylcyclohexane.

[0065] Yield: 71.01 %.

[0066] >H NMR (600 MHz, DMSO) 5 = 9.08 (s, 1H), 6.85 - 6.77 (m, 3H), 6.70 (ddd, 7=8.0, 6.3, 2.8, 1H), 4.74 (s, 2H), 3.97 (d, 7=7.3, 2H), 1.10 (pt, 7=7.7, 4.8, 1H), 0.55 - 0.49 (m, 2H), 0.30 - 0.25 (m, 2H).

[0067] Example 3: Cyclopropylmethyl 2-(2-hydroxyphenoxy)acetate preparation under different conditions Cyclopropylmethyl 2-(2-hydroxyphenoxy)acetate was prepared as described in example 2, however with variation of the ratio of cyclopropylcarbinol to l,4-benzodioxin-3-one and the Brpnsted acid as indicated in the following table.

[0068]

[0069] BYC250028-FC STR

[0070] 7

[0071] Highest yield could be achieved with reaction conditions no. 8, with HC1 in CPME (Cyclopentylmethylether). At the same time, for these conditions, only a low eq. of cyclopropylcarbinol was required.

[0072] Example 4: Propyl 2-(2-hydroxyphenoxy)acetate

[0073]

[0074] Scheme 3

[0075] 15 g l,4-benzodioxin-3-one was provided as described in example 1 and solved in 34.9 ml 1-propanol at 20 °C. A catalytic amount of HC1 (0.1 eq to l,4-benzodioxin-3-one) and 2.3 ml dioxan were added; and the reaction was heated to 40 °C. The reaction was incubated for 2 h and concentrated in a rotation evaporator to dryness.

[0076] Yield: 73,01 %.

[0077] >H NMR (600 MHz, DMSO) 5 = 9.07 (s, 1H), 6.84 - 6.76 (m, 3H), 6.72 - 6.66 (m, 1H), 4.74 (s, 2H), 4.07 (t, 7=6.6, 2H), 1.59 (h, 7=7.1, 2H), 0.86 (t, 7=7.4, 3H).

[0078] Example 5: (2-methoxy-l-methyl-ethyl) 2-(2-hydroxyphenoxy)acetate

[0079]

[0080] 1 g l,4-benzodioxin-3-one was provided as described in example 1 and solved in 5 ml 1-methoxypropan-2-ol. A catalytic amount of HC1 (0.1 eq to l,4-benzodioxin-3-one) in 0.5 ml dioxan was then added, and the reaction heated to 80 °C. The reaction was incubated for 4 h and concentrated in a rotation evaporator to dryness.

[0081] Yield: 92,09 %.

[0082] 'H NMR (600 MHz, DMSO) 5 = 9.08 (s, 1H), 6.84 - 6.76 (m, 3H), 6.69 (ddd, 7=7.8, 6.3, 3.0, 1H), 5.06 (pd, 7=6.5, 3.9, 1H), 4.72 (d, 7=16.5, 1H), 4.69 (d, 7=16.5, 1H), 3.40 (dd, 7=10.8, 6.3, 1H), 3.37 (dd, 7=10.8, 4.0, 1H), 3.25 (s, 3H), 1.16 (d, 7=6.5, 3H).

Claims

BYC250028-FC STRClaims1. Process for the preparation of compounds of formula (I)with Ri being (C3-Cio)-alkyl, (Ci-Cio)-alkyl-0-(Ci-Cio)-alkyl, (Ci-Cio)-alkyl-(C3-C6)-cycloalkyl, wherein compounds of formula (II) are reacted with compounds of formula (III)in the presence of a Brpnsted acid.

2. Process according to claim 1, wherein Ri is (C3-Ce)-alkyl, (Ci-C6)-alkyl-O-(Ci-Ce)-alkyl, or (Ci-C6)-alkyl-(C3-Ce)-cycloalkyl.

3. Process according to claim 1, wherein Ri is selected to be (Ci-C3)-alkyl-O-(Ci-C3)-alkyl, or (Ci-C3)-alkyl-(C3-C6)-cycloalkyl.

4. Process according to claim 1, wherein Ri is selected to be methyl-cyclopropyl.

5. Process according to any one of the preceding claims, wherein the Brpnsted acid is selected from organic acids, such as carbonic acids, or mineral acids, and salts thereof, preferably wherein the Brpnsted acid is selected from chloroacetic acid, phenoxy acetic acid, which may be substituted, e.g. with one to three hydroxy groups, methanesulfonic acid, H2SO4, HNO3, HiPChand HC1. methanesulfonic acid, H2SO4, HNO3, H3PO4 and HC1.

6. Process according to any one of the preceding claims, wherein the Brpnsted acid is HC1.

7. Process according to any one of the preceding claims, wherein the reaction is performed in an organic solvent, preferably a nonpolar organic solvent.BYC250028-FC STR8. Process according to claim 7, wherein the solvent is selected from methylcyclohexane, 1,4-dioxan, diethylether, diisopropylether, tert-butylmethylether, tetrahydrofurane, 2-methyltetrahydrofuran, toluene, cyclopentylmethylether, and n-heptane, or mixtures thereof.

9. Process according to claim 7, wherein the solvent is selected from methylcyclohexane, 1,4-dioxan, toluene and cyclopentylmethylether, or mixtures thereof, preferably wherein the solvent is methylcyclohexane .

10. Process according to claim 7, wherein the solvent is methylcyclohexane.

11. Process according to any one of the preceding claims, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is within 1:3 to 3:1, preferably 1:2 to 1:1, further preferably 1 : 1.5 to 1 : 1 , even further preferably 1 : 1.2 to 1:1, most preferably 1 : 1.02 to 1:1.

12. Process according to any one of the preceding claims, wherein the reaction is performed at a temperature of between 0 °C and 50 °C; preferably wherein the reaction is performed at a temperature gradient, starting at a temperature of between 35 °C and 45 °C, gradually reducing the temperature to between 0 °C and 10 °C.

13. Compounds of formula (I)wherein Ri is (C3-Cio)-alkyI, (Ci-Cio)-alky!-0-(Ci-Cio)-alkyI, or (Ci-Cio)-alkyI-(C3-C6)-cycIoalkyI.

14. Compounds according to claim 13, wherein Ri is (C3-Ce)-alkyI, (Ci-C6)-alkyl-O-(Ci-Ce)-alkyl, or (Ci-C6)-alkyI-(C3-C6)-cycIoalkyI.

15. Compounds according to claim 13, wherein Ri is (Ci-C3)-alkyl-O-(Ci-C3)-alkyl, or (C1-C3)-alkyl-(C3-Ce)-cycloalkyl; preferably wherein Ri is methyl-cyclopropyl.

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