Method for producing ω-iodocarboxylic acid ester derivatives

Abstract

To provide a method for producing ω-iodine carboxylate derivatives at high yield.SOLUTION: The present invention discloses a method for producing a ω-iodine carboxylate derivative of the following formula (II), including mixing a lactone compound and iodine trialkylsilane to obtain a first mixture, and mixing the first mixture, alkyl alcohol, and sulfuric acid.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing an ω-iodocarboxylic acid ester derivative. [Background technology]

[0002] Ethyl 5-iodovalerate (ethyl 5-iodopentanoate) represented by the following formula (II') can be used as a material for synthesizing compounds that can be used for pharmaceuticals and the like.

[0003] [ka]

[0004] For example, Non-Patent Document 1 describes that the above-mentioned ethyl 5-iodovalerate can be used as a raw material for a zinc reagent for the synthesis of biotin. Biotin is considered to be a type of vitamin important for the health of humans and animals.

[0005] Non-Patent Document 1 describes a method of reacting the following thiolactone compound (DTL) with a zinc reagent synthesized from ethyl 5-iodovalerate to obtain the following compound (DVE), hydrogenating this compound (DVE) to obtain a compound (HVC), and debenzylating this compound (HVC) to obtain biotin (BIOF).

[0006] [ka]

[0007] Non-Patent Document 1 describes a method in which sodium iodide (NaI) and chlorotrimethylsilane (TMS-Cl) are added to a solution of δ-valerolactone, the solution is stirred, and then ethanol is added thereto to obtain ethyl 5-iodovalerate. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Toshiaki Shimizu, Masahiko Seki, “Facile synthesis of (+)-biotin via Fukuyama coupling reaction” Tetrahedron Letters, 41, 2000, 5099-5101. Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a method for producing an ω-iodocarboxylate derivative in high yield. [Means for solving the problem]

[0010] According to one embodiment, there is provided a method for producing an ω-iodocarboxylic acid ester derivative, which includes mixing a lactone compound represented by the following formula (I) with an iodotrialkylsilane to obtain a first mixture, and mixing the first mixture with an alcohol represented by the following formula (1) and sulfuric acid to obtain an ω-iodocarboxylic acid ester derivative represented by the following formula (II).

[0011] [ka]

[0012] In formula (I), R 1 , R 2 , and R 3 are each a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, an alkoxy group which may have a substituent, an aralkyl group which may have a substituent, or a heterocyclic group which may have a substituent. n is 0 or more and 4 or less.

[0013] R 4 -OH (1) In formula (1), R 4 is an alkyl group.

[0014] [ka]

[0015] In formula (II), R 1 , R 2 , R 3 and n have the same meaning as in formula (I). 4 has the same meaning as in formula (1). Effect of the Invention

[0016] According to an embodiment, a method for producing an ω-iodocarboxylic acid ester derivative in high yield is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The method for producing an ω-iodocarboxylate derivative according to the embodiment includes mixing a lactone compound represented by the above formula (I) (hereinafter also simply referred to as a lactone compound) with an iodotrialkylsilane to obtain a first mixture, and mixing an alcohol represented by the above formula (1) (hereinafter also simply referred to as an alcohol) and sulfuric acid into the first mixture. This can increase the yield of the ω-iodocarboxylate derivative represented by the above formula (II) (hereinafter also simply referred to as an ω-iodocarboxylate derivative). The present inventors believe that the reason for this is as follows.

[0018] First, in the method using a lactone compound and iodotrialkylsilane (TASI), it is believed that an ω-iodocarboxylate derivative is synthesized via the following two steps.

[0019] [ka]

[0020] In step 1, the lactone compound represented by formula (I) is contacted with TASI. This causes ring-opening of the lactone compound, and the ω-position is modified with an iodine group and the α-position is modified with a TAS (trialkylsilyl) group to obtain a first mixture containing the intermediate represented by formula (Ii). TASI can be obtained, for example, by contacting chlorotrialkylsilane (TASCl) with an iodinating agent (I agent).

[0021] Next, in step 2, an alcohol (R 4 -OH) is brought into contact with TASI. 4 The reaction of -OH with hydrogen iodide (HI) produces hydrogen iodide (HI). This HI promotes the removal of the TAS group from intermediate (Ii). After the removal of the TAS group, intermediate (Ii) and R 4 By reacting with -OH, the α-position of intermediate (Ii) is alkylated to produce an ω-iodocarboxylate derivative represented by formula (II). HI also promotes this alkylation.

[0022] In the method according to the embodiment, in step 2, R 4 Sulfuric acid (H2SO4) is mixed together with -OH. Sulfuric acid can promote alkyl esterification at the α-position. Therefore, according to the method of the embodiment, the yield of the ω-iodocarboxylic acid ester derivative can be increased compared to a method not using sulfuric acid. In addition, according to this method, the alkyl esterification at the α-position is sufficiently promoted, so that the amount of HI used can be reduced. Therefore, the amount of iodotrialkylsilane required for the production of HI, i.e., the amount of chlorotrialkylsilane and iodinating agent, can be reduced. Therefore, according to this method, the ω-iodocarboxylic acid ester derivative can be produced at a low cost and in a high yield.

[0023] The first mixture may be mixed with sulfuric acid simultaneously with the alcohol or after the alcohol is mixed. That is, in step 2, the first mixture is contacted with sulfuric acid together with the alcohol, thereby producing the ω-iodocarboxylate derivative at a lower cost. Alternatively, in step 3, the second mixture obtained by mixing the first mixture with the alcohol is contacted with sulfuric acid, thereby further increasing the yield of the ω-iodocarboxylate derivative.

[0024] The present invention will be described in detail below. (Lactone compounds) The lactone compound is represented by the following formula (I).

[0025] [ka]

[0026] In formula (I), R 1 , R 2 , and R 3 R each represents a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent, an alkoxy group which may have a substituent, an aralkyl group which may have a substituent, or a heterocyclic group which may have a substituent. 1 , R 2 , and R 3 is preferably a hydrogen atom.

[0027] The number of carbon atoms in the alkyl group which may have a substituent and the alkoxy group which may have a substituent is preferably from 1 to 20. The number of carbon atoms in the aryl group which may have a substituent, the aralkyl group which may have a substituent, and the heterocyclic group which may have a substituent is preferably from 5 to 30. Examples of heteroatoms contained in the heterocyclic group include a sulfur atom, a nitrogen atom, and an oxygen atom.

[0028] Examples of the substituent that the alkyl group, aryl group, alkoxy group, aralkyl group, or heterocyclic group has include an alkoxy group having 1 to 20 carbon atoms, an amino group, or a halogeno group. The halogeno group is a bromo group, a chloro group, an iodo group, or a fluoro group.

[0029] n is 0 or more and 4 or less. That is, the lactone compound is a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, or an 8-membered ring. n is preferably 1 or more and 2 or less.

[0030] A preferred specific example of the lactone compound is δ-valerolactone represented by the following formula (I′).

[0031] [ka]

[0032] (Iodotrialkylsilane) Iodotrialkylsilane (TASI) reacts with a lactone compound to produce the intermediate (Ii) and serves as a source of HI required for alkyl esterification at the α-position of intermediate (Ii).

[0033] The iodotrialkylsilane includes at least one selected from the group consisting of iodotrimethylsilane, iodotriethylsilane, iodotripropylsilane, and iodotributylsilane. The iodotrialkylsilane preferably includes iodotrimethylsilane.

[0034] The amount of TASI relative to 1 mole of lactone compound is, for example, 0.5 moles or more and 5 moles or less, preferably 1.0 moles or more and 3 moles or less. If the amount of TASI is excessively small, the yield of the ω-iodocarboxylic acid ester derivative may decrease. On the other hand, if the amount of TASI is excessively large, the cost increases. According to the method of the embodiment, the alkyl esterification at the α-position of the intermediate (Ii) can be promoted using sulfuric acid. Therefore, the amount of TASI relative to 1 mole of lactone compound can be reduced to 1.50 moles or less, 1.20 moles or less, or 1.10 moles or less.

[0035] The iodotrialkylsilane is preferably synthesized by contacting an iodinating agent with a trialkylchlorosilane (TASCl).

[0036] As the iodinating agent, an inorganic iodine compound or an organic iodine compound may be used. Examples of inorganic iodine compounds include sodium iodide (NaI), potassium iodide (KI), and ammonia iodide (NH4I). Examples of organic iodine compounds include Me4NI (tetramethylammonium iodide) and n-Bu4NI (tetrabutylammonium iodide). As the iodinating agent, one type may be used, or multiple types may be used. As the iodinating agent, NaI is preferably used.

[0037] The amount of the iodinating agent per mole of the lactone compound is, for example, 0.5 to 5 moles, preferably 1.0 to 3 moles. The amount of the iodinating agent per mole of the lactone compound can be reduced to 1.50 moles or less, 1.20 moles or less, or 1.10 moles or less.

[0038] The amount of the iodinating agent per mole of TASCl is preferably 0.5 moles or more and 2 moles or less. The molar ratio of TASCl to the iodinating agent is preferably 1.

[0039] The trialkylchlorosilane includes at least one selected from the group consisting of, for example, trimethylchlorosilane, triethylchlorosilane, tripropylchlorosilane, and tributylchlorosilane. The trialkylchlorosilane preferably includes trimethylchlorosilane.

[0040] The amount of trialkylchlorosilane per mole of lactone compound is, for example, 0.5 to 5 moles, preferably 1.0 to 3 moles. The amount of iodinating agent per mole of lactone compound can be reduced to 1.50 moles or less, 1.20 moles or less, or 1.10 moles or less.

[0041] (alcohol) The alcohol is represented by the following formula (1): 4 is an alkyl group. The number of carbon atoms in the alkyl group is preferably 1 or more and 20 or less, and more preferably 1 or more and 10 or less.

[0042] R 4 -OH (1) The alcohol preferably includes at least one selected from the group consisting of methanol, ethanol, 2-propanol, 1-butanol, 2-methyl-1-propanol, 2-butanol, and 2-methyl-2-propanol.The alcohol more preferably includes ethanol.

[0043] The amount of alcohol per 1 g of the lactone compound is, for example, 1 mL or more and 10 mL or less, and preferably 2 mL or more and 5 mL or less.

[0044] (sulfuric acid) Concentrated sulfuric acid is preferably used as the sulfuric acid. The concentration of sulfuric acid is preferably 95% by mass or more, and more preferably 98% by mass or more. There is no particular upper limit to the concentration of sulfuric acid, but according to one example, it is 100% by mass.

[0045] The amount of sulfuric acid per mole of lactone compound is preferably 0.001 mole or more and 1.0 mole or less. When the amount of sulfuric acid is within this range, the yield of the ω-iodocarboxylate derivative is further increased. The amount of sulfuric acid per mole of lactone compound is more preferably 0.01 mole or more and 0.5 mole or less, and further preferably 0.1 mole or more and 0.5 mole or less.

[0046] The amount of sulfuric acid per mole of TASI is preferably 0.01 mole or more and 1.0 mole or less, and more preferably 0.1 mole or more and 0.5 mole or less.

[0047] The amount of sulfuric acid per 1 mL of alcohol is, for example, 0.01 g or more and 1 g or less, and preferably 0.03 g or more and 0.10 g or less.

[0048] (ω-iodocarboxylate derivatives) The ω-iodocarboxylic acid ester derivative is represented by the following formula (II): This ω-iodocarboxylic acid ester derivative can be used, for example, as an intermediate for biotin synthesis.

[0049] [ka]

[0050] In formula (II), R 1 , R 2 , R 3 and n have the same meaning as in formula (I). 4 has the same meaning as in formula (1).

[0051] A specific example of the ω-iodocarboxylate derivative is ethyl 5-iodovalerate represented by the above formula (II′).

[0052] A compound represented by the following formula (III) can be obtained by contacting an ω-iodocarboxylate derivative with an organozinc compound. The compound represented by the formula (III) can be used, for example, as an intermediate for biotin synthesis or an organozinc reagent for Fukuyama coupling.

[0053] [ka]

[0054] In formula (III), R 1 , R 2 , R 3 and n have the same meaning as in formula (I). 4 has the same meaning as in formula (1).

[0055] (Method of producing ω-iodocarboxylic acid ester derivatives) The method for producing an ω-iodocarboxylic acid ester derivative according to the embodiment includes mixing a lactone compound and an iodotrialkylsilane to obtain a first mixture, and mixing the first mixture, an alcohol, and sulfuric acid to obtain the ω-iodocarboxylic acid ester derivative.

[0056] The mixing temperature of the lactone compound and the iodotrialkylsilane is, for example, from -10°C to 70°C, preferably from 0°C to 50°C, and more preferably from 10°C to 40°C. The mixing time of the lactone compound and the iodotrialkylsilane is, for example, from 2 hours to 48 hours, and preferably from 10 hours to 30 hours. It is preferable that the lactone compound and the iodotrialkylsilane are stirred during the mixing time.

[0057] The lactone compound and the iodotrialkylsilane are preferably mixed in a reaction solvent. As the reaction solvent, for example, at least one selected from the group consisting of ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, acetonitrile, propionitrile, tetrahydrofuran (THF), 2-methyl THF, 1,4-dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, xylene, hexane, and heptane is used. As the reaction solvent, acetonitrile is preferably used.

[0058] When a reaction solvent is used, the first mixture is preferably obtained by the following method. First, a lactone compound, an iodinating agent, and a reaction solvent are mixed to prepare a suspension. This suspension is mixed with a trialkylchlorosilane. As a result, an iodotrialkylsilane is generated in the reaction liquid, and this is reacted with the lactone compound to obtain the first mixture. The contact temperature between the suspension and the trialkylchlorosilane is preferably 0° C. or higher and 40° C. or lower, and the mixing time is preferably 10 hours or higher and 30 hours or lower.

[0059] Next, the first mixture thus obtained is mixed with alcohol and sulfuric acid to obtain a mixture containing an ω-iodocarboxylate derivative. The mixing temperature of the first mixture, alcohol and sulfuric acid is, for example, from −10° C. to 70° C., preferably from 0° C. to 50° C., and more preferably from 10° C. to 40° C. The first mixture, alcohol and sulfuric acid are preferably stirred for, for example, from 1 hour to 20 hours, preferably from 2 hours to 10 hours.

[0060] Sulfuric acid may be added to the second mixture obtained by mixing the first mixture with the alcohol. When sulfuric acid is added after mixing the first mixture with the alcohol, the yield of the ω-iodocarboxylic acid ester derivative tends to be higher. In this case, the mixing conditions of the first mixture with the alcohol may be the same as the mixing conditions of the first mixture with the alcohol and sulfuric acid. The mixing temperature of the second mixture with sulfuric acid is, for example, from -10°C to 70°C, preferably from 0°C to 50°C, more preferably from 10°C to 40°C. It is preferable that the second mixture and sulfuric acid are stirred for, for example, from 10 minutes to 10 hours, preferably from 1 hour to 5 hours.

[0061] The ω-iodocarboxylate derivative obtained by the above method is preferably extracted by the following method. First, the reaction solution is concentrated under reduced pressure to obtain a residue. Water is added to this residue, and then an organic solvent such as hexane is added to separate it into an organic layer and an aqueous layer. After the organic layer is extracted, an organic solvent is added to the aqueous layer to separate it again into an organic layer and an aqueous layer. The organic layer is extracted and combined with the organic layer extracted previously to obtain a total organic layer. The total organic layer is washed with an aqueous sodium sulfite solution, saturated saline, water, etc. The total organic layer after washing is concentrated under reduced pressure to obtain the product of the ω-iodocarboxylate derivative.

[0062] The structure of the ω-iodocarboxylate derivative can be confirmed, for example, by subjecting the product to nuclear magnetic resonance (NMR) spectroscopy. The purity of the ω-iodocarboxylate derivative in the product can be measured, for example, by gas chromatography. According to the method of the embodiment, a high-purity ω-iodocarboxylate derivative having a purity of 99.0% or more by area percentage of gas chromatography can be obtained. EXAMPLES

[0063] The present invention will be described in detail below with reference to examples. However, these are merely specific examples and the present invention is not limited to these.

[0064] <Example 1> The ethyl 5-iodovalerate represented by the formula (II’) was obtained from the δ-valerolactone represented by the above formula (I’) by the following method. 25 g (0.25 mol) of δ-valerolactone, 41.17 g (0.275 mol) of sodium iodide (NaI), and 125 mL of acetonitrile were mixed to obtain a suspension. To this suspension, 29.84 g (0.275 mol) of chlorotrimethylsilane (TMSCl) was added, and the mixture was stirred at a temperature of 30 °C for 24 hours to obtain a first mixture. The first mixture was developed on a thin layer chromatography to confirm the disappearance of δ-valerolactone. 62.5 mL of ethanol was added to the first mixture, and the mixture was stirred at a temperature of 30 °C for 5 hours to obtain a second mixture. 4.90 g (0.055 mol) of concentrated sulfuric acid was added to the second mixture, and the mixture was stirred at a temperature of 30 °C for 2 hours to obtain a reaction solution.

[0065] The reaction solution was concentrated under reduced pressure to obtain a residue. After adding 200 mL of water to this residue, 50 mL of hexane was added to separate the organic layer and the aqueous layer. After extracting the organic layer, 50 mL of hexane was added to the aqueous layer to separate the organic layer and the aqueous layer again. The organic layer was extracted and combined with the previously extracted organic layer to obtain a total organic layer. The total organic layer was washed in the order of 25 mL of 5 mass% aqueous sodium sulfite solution, 25 mL of saturated brine, and 25 mL of water. The washed total organic layer was concentrated under reduced pressure to obtain a product of ethyl 5-iodovalerate. The amount of the product of ethyl 5-iodovalerate was 57.2 g, and the yield was 89.48%.

[0066] <Comparative Examples 1, 2, and Reference Example 1> A product of ethyl 5-iodovalerate was obtained in the same manner as in Example 1 except that the amounts of sodium iodide and chlorotrimethylsilane were changed as shown in Table 1 below and sulfuric acid was omitted. The yields of ethyl 5-iodovalerate are shown in Table 1.

[0067] <NMR Spectral Analysis> It was confirmed that ethyl 5-iodovalerate was synthesized by NMR spectroscopic analysis of the products obtained in Example 1, Comparative Examples 1 and 2, and Reference Example 1. The analytical results were as follows. 1 H-NMR(CDCl3)δ: 4.132(q, J=7.6Hz, 2H), 3.166-3.211(m, 2H), 2.301-2.349(m, 2H), 1.564-1.894(m, 4H), 1.258(t, J=7.6Hz, 3H).

[0068] <Purity measurement> The purity of the products obtained in Example 1, Comparative Examples 1 and 2, and Reference Example 1 was measured by gas chromatography (GC). The results are shown in Table 1 below. The GC conditions were as follows.

[0069] Equipment name: Shimadzu Nexis GC-2030, A0C-20i PLUS, FID Detector Column: OV-5 (30m x 0.53mm, 3.0μm Detector: FID Carrier gas: Nitrogen Pressure: 2.8psi Split ratio: 1:10 Temperature: 100℃~280℃(10℃ / min.) Injector temperature: 300°C Injection Volume: 0.2 μL Retention time of ethyl iodovalerate: 13.075 min.

[0070] [Table 1]

[0071] In the above Table 1, the columns labeled NaI, TMSCl, and H2SO4 list the amounts of NaI, TMSCl, and H2SO4 per mole of 1 mole of δ-valerolactone, respectively.

[0072] As shown in Table 1 above, in Example 1, in which sulfuric acid was used, the amounts of NaI and TMSCl were small, but the yield and purity were equivalent to those of Reference Example 1, in which the amounts of NaI and TMSCl were large. In contrast, in Comparative Examples 1 and 2, in which sulfuric acid was not used, a high yield could not be achieved.

Claims

1. A method for producing a first mixture by mixing a lactone compound represented by the following formula (I) with an iodotrialkylsilane: mixing the first mixture, an alcohol represented by the following formula (1), and sulfuric acid to obtain an ω-iodocarboxylate derivative represented by the following formula (II); Including, The amount of the sulfuric acid relative to 1 mole of the lactone compound represented by formula (I) is 0.001 mole or more and 1 mole or less. 【Chemistry 1】 In the formula (I), R １ , R ２ , and R ３ each represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted alkoxy group, an optionally substituted aralkyl group, or an optionally substituted heterocyclic group, n is 0 to 4, R ４ -OH (1) In the formula (1), R ４ is an alkyl group, 【Chemistry 2】 In the formula (II), R １ , R ２ , R ３ and n are as defined in formula (I) above; R ４ has the same meaning as in the above formula (1).

2. The method for producing an ω-iodocarboxylate derivative according to claim 1, wherein the iodotrialkylsilane is obtained by contacting an iodinating agent with a trialkylchlorosilane.

3. The method for producing an ω-iodocarboxylate derivative according to claim 2, wherein the amount of the iodinating agent per mole of the lactone compound represented by formula (I) is 1.2 moles or less.

4. The method for producing an ω-iodocarboxylate derivative according to claim 2 or 3, wherein the amount of the trialkylchlorosilane per mole of the lactone compound represented by formula (I) is 1.2 moles or less.

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