Alcohol compound production method and alcohol compound derivative production method

Abstract

To provide an alcohol compound production method that enables formation of an alcohol compound from a raw material compound having both a THP ether group and an acetonide ether group, the alcohol compound retaining the acetonide group sufficiently and having the THP group of the THP ether group deprotected at a high ratio.SOLUTION: An alcohol compound production method includes a deprotection step of reacting a raw material compound having a tetrahydropyranyl ether group and an acetonide ether group with an acid catalyst in a mixed solvent containing an alcohol solvent and a ketone solvent, thereby deprotecting a tetrahydropyranyl group from the tetrahydropyranyl ether group.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing an alcohol compound and a method for producing an alcohol compound derivative. [Background technology]

[0002] In organic synthesis reactions, a method is often used in which an alcoholic hydroxyl group in a compound is converted to an inactive group, and after performing the necessary reaction, the inactive group is returned to the original alcoholic hydroxyl group. In this method, converting an alcoholic hydroxyl group to an inactive group is called "protection," and returning the inactive group to the original alcoholic hydroxyl group is called "deprotection." More specifically, "protection" is a process in which a substituent, collectively referred to as a protecting group, is directly bonded to the alcoholic hydroxyl group of a compound to be inactivated by an appropriate chemical reaction. Furthermore, "deprotection" is a process in which a compound having a group bonded to a protecting group is subjected to an appropriate chemical reaction to remove the protecting group from the group to which the protecting group is bonded, liberating the hydroxyl group and returning it to the original alcoholic hydroxyl group.

[0003] Conventionally, the tetrahydropyranyl group (THP group) has been known as a protecting group that can protect and deprotect the alcoholic hydroxyl group of an alcohol compound under relatively mild conditions. The acetonide group is known as a protecting group that can protect and deprotect the alcoholic hydroxyl groups forming the 1,2-diol structure (HO-CH2-CH(OH)-) of 1,2-diol compounds and the alcoholic hydroxyl groups forming the 1,3-diol structure (HO-(CH2)2-CH(OH)-) of 1,3-diol compounds under relatively mild conditions. The acetonide group can selectively protect the alcoholic hydroxyl groups forming the 1,2-diol structure or the 1,3-diol structure among the alcoholic hydroxyl groups in alcoholic compounds that have both the alcoholic hydroxyl groups forming the 1,2-diol structure or the 1,3-diol structure and other simple alcoholic hydroxyl groups.

[0004] For this reason, for example, an alcohol compound having an alcoholic hydroxyl group forming a 1,2-diol structure or a 1,3-diol structure and another simple alcoholic hydroxyl group can be reacted with a reactant that forms an acetonide group to selectively convert the alcoholic hydroxyl group forming the 1,2-diol structure or the 1,3-diol structure into an acetonide ether group, and then reacted with a THP group, thereby selectively converting the simple alcoholic hydroxyl group into a THP ether group.

[0005] In compounds having such protected alcoholic hydroxyl groups, the THP ether group is a group (-O(THP)) consisting of an alcoholic hydroxyl group protected by a tetrahydropyranyl group (THP group), and the acetonide ether group is a group (-OC(CH3)2-O-) that forms part of a ring structure in which two alcoholic hydroxyl groups are protected by an acetonide group (-C(CH3)2-).

[0006] The THP ether group and acetonide ether group are stable under basic conditions and inert to reactions with strong bases such as alkoxides, sodium hydride, lithium aluminum hydride, organolithium reagents, and Grignard reagents. For this reason, the THP group and acetonide group are widely used as protecting groups for alcoholic hydroxyl groups in various compounds in a variety of reactions.

[0007] Methods for deprotecting a THP group from a compound having a THP ether group and methods for deprotecting an acetonide group from a compound having an acetonide ether group include, for example, the methods described in Non-Patent Documents 1 to 6.

[0008] Non-Patent Document 1 describes a method for deprotecting a THP group and an acetonide group. Non-Patent Document 1 describes a method for deprotecting a THP group and an acetonide group, which is a general method for deprotecting a THP group and an acetonide group, in which a Brønsted acid is reacted in an alcohol solvent or in water. Non-Patent Document 1 also describes other deprotection methods, such as a method using a Lewis acid and a method using an oxidizing agent.

[0009] Non-Patent Documents 2 to 4 report a method of selectively deprotecting only the THP group by reacting a compound having a THP group and an acetonide group with a Lewis acid such as cerium chloride, bismuth triflate, or aluminum triflate. Furthermore, Non-Patent Documents 5 and 6 report a method for selectively deprotecting only the THP group by treating a substrate having a THP group and an acetonide group with relatively high steric hindrance with a Brønsted acid in an alcohol solvent. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] PROTECTIVE GROUPS in ORGANIC SYNTHESIS(5th ed.) [Non-patent document 2] Synth.Commun.2000, Vol.30, page 4107 [Non-patent document 3] Eur.J.Org.Chem.2003, 3827 pages [Non-patent document 4] Tetrahedron.2010, Vol.66, 4573 pages [Non-Patent Document 5] Tetrahedron.2008, Vol.64, 2090 pages [Non-patent document 6] Chem Bio Chem.2009, Vol.10, 2780 pages Summary of the Invention [Problem to be solved by the invention]

[0011] In conventional techniques, there has been a demand for a method for deprotecting a THP group that can remove the THP groups of THP ether groups at a higher rate while leaving a sufficient amount of acetonide groups from a starting compound having both a THP ether group, which is an alcoholic hydroxyl group protected by a THP group, and an acetonide ether group, which forms part of a ring structure in which two alcoholic hydroxyl groups are protected by acetonide groups.

[0012] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method for producing an alcohol compound, which can produce an alcohol compound from a raw material compound having both a THP ether group and an acetonide ether group, in which the acetonide groups remain sufficiently and the THP groups of the THP ether groups are deprotected in a high proportion. Another object of the present invention is to provide a method for producing an alcohol compound derivative using an alcohol compound produced by the above-mentioned production method, in which a sufficient amount of acetonide groups derived from the starting compound remain and the THP groups of the THP ether groups are selectively deprotected at a high rate. [Means for solving the problem]

[0013] In order to solve the above problems, the present inventors have conducted extensive studies, focusing on the deprotection reaction of the THP group and the acetonide group when deprotecting the THP group from a raw material compound having both a THP ether group and an acetonide ether group, and the reaction solvent used in the deprotection reaction of the THP group.

[0014] As a result, the present inventors have found that by reacting the above-mentioned starting compound with an acid catalyst in a mixed solvent containing an alcohol solvent and a ketone solvent, the THP group of the THP ether group can be selectively deprotected at a high rate while retaining the acetonide group of the starting compound, and have arrived at the present invention. That is, the present invention relates to the following items.

[0015] [1] A method for producing an alcohol compound, comprising a deprotection step of reacting a raw material compound having a tetrahydropyranyl ether group and an acetonide ether group with an acid catalyst in a mixed solvent containing an alcohol solvent and a ketone solvent to remove the tetrahydropyranyl group from the tetrahydropyranyl ether group.

[0016] [2] The method for producing an alcohol compound according to [1], wherein the alcohol solvent is an alcohol having 1 to 12 carbon atoms. [3] The method for producing an alcohol compound according to [2], wherein the alcohol solvent is at least one selected from the group consisting of methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 2-propanol, 2-butanol, 2-pentanol, 3-pentanol, 2-hexanol, t-butyl alcohol, 2-methyl-2-butanol, cyclopentanol, and cyclohexanol. [4] The method for producing an alcohol compound according to [3], wherein the alcohol solvent is 2-propanol.

[0017] [5] The method for producing an alcohol compound according to any one of [1] to [4], wherein the ketone solvent is a ketone having 3 to 12 carbon atoms. [6] The method for producing an alcohol compound according to [5], wherein the ketone solvent is at least one selected from the group consisting of acetone, ethyl methyl ketone, 2-pentanone, 3-pentanone, 2-hexanone, cyclopentanone, and cyclohexanone. [7] The method for producing an alcohol compound according to [6], wherein the ketone solvent is acetone.

[0018] [8] The method for producing an alcohol compound according to any one of [1] to [7], wherein the mass ratio of the alcohol solvent to the ketone solvent is alcohol solvent:ketone solvent=10:90 to 90:10.

[0019] [9] The method for producing an alcohol compound according to any one of [1] to [8], wherein the acid catalyst has an acid dissociation constant pKa value of −3.0 to 13.0.

[10] The method for producing an alcohol compound according to any one of [1] to [9], wherein the acid catalyst is at least one selected from the group consisting of pyridinium p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, acetic acid, ammonium acetate, pyridinium acetate, formic acid, ammonium formate, propionic acid, butanoic acid, isobutanoic acid, pivalic acid, hydrogen chloride, ammonium chloride, and pyridinium chloride.

[11] The method for producing an alcohol compound according to

[10] , wherein the acid catalyst is pyridinium p-toluenesulfonate.

[0020]

[12] The method for producing an alcohol compound according to any one of [1] to

[11] , wherein the amount of the acid catalyst used is 0.001 to 10 equivalents relative to 1 equivalent of the raw material compound.

[13] The method for producing an alcohol compound according to any one of [1] to

[12] , wherein the mass ratio of the raw material compound to the mixed solvent is raw material compound / mixed solvent=0.001 to 10.

[14] The method for producing an alcohol compound according to any one of [1] to

[13] , wherein the reaction temperature in the deprotection step is 0°C to 100°C.

[0021]

[15] The method for producing an alcohol compound according to any one of [1] to

[14] , wherein the starting compound is a compound represented by the following formula (1):

[0022] [ka] In formula (1), m represents an integer of 1 to 4, and n represents an integer of 1 to 50. Each of the n Xs independently represents -CY 1 Y 2 -, -CY 3 (OZ)- or -O-. Y 1 , Y 2 , Y 3and Z are each independently a hydrocarbon group having 1 to 8 carbon atoms which may have an ether oxygen atom other than at the bond terminal, or a hydrogen atom. However, in formula (1), -O- groups are not directly bonded to each other. One -CY 1 Y 2 -Y in 1 and Y 2 may be bonded to each other to form a ring structure. 3 (OZ)-Y in 3 and Z may be bonded to each other to form a ring structure. When n is 2 or more, -CY as one X may be 1 Y 2 -Y in 1 and Y 2 or -CY 3 (OZ)-Y in 3 and one of Z and the other X, -CY 1 Y 2 -Y in 1 and Y 2 or -CY 3 (OZ)-Y in 3 and one of Z may be bonded to each other to form a ring structure.

[0023]

[16] The method for producing an alcohol compound according to

[15] , wherein in the formula (1), X directly bonded to the ring structure containing the acetonide group is —CH 2 —.

[17] The method for producing an alcohol compound according to

[15] or

[16] , wherein, in the formula (1), n ​​is 2 or more and X directly bonded to -O(THP) is -CH2-.

[18] The method for producing an alcohol compound according to any one of

[15] to

[17] , wherein m is 1 or 2 in the formula (1).

[0024]

[19] A step of producing an alcohol compound having an alcoholic hydroxyl group by deprotecting a tetrahydropyranyl group using the method for producing an alcohol compound according to any one of [1] to

[18] ; and a conversion step of converting the alcoholic hydroxyl group of the alcohol compound into another group. [Effects of the Invention]

[0025] In the method for producing an alcohol compound of the present invention, a starting compound having a THP ether group and an acetonide ether group is reacted with an acid catalyst in a mixed solvent containing an alcohol solvent and a ketone solvent to deprotect the tetrahydropyranyl group from the THP ether group. Therefore, the method for producing an alcohol compound of the present invention can produce an alcohol compound from the starting compound in which a sufficient amount of acetonide groups remain and in which a high proportion of the THP groups in the THP ether groups have been deprotected.

[0026] Furthermore, in the method for producing an alcohol compound derivative of the present invention, an alcohol compound having an alcoholic hydroxyl group generated by deprotecting a THP group is produced using the method for producing an alcohol compound of the present invention. This alcohol compound has a sufficient amount of acetonide groups derived from the raw material compound remaining, and a high proportion of THP groups have been deprotected, resulting in a sufficient amount of alcoholic hydroxyl groups. Therefore, by performing the conversion step, an alcohol compound derivative can be produced that has a sufficient amount of acetonide groups remaining and a sufficient amount of other groups generated by converting the alcoholic hydroxyl groups. DETAILED DESCRIPTION OF THE INVENTION

[0027] The method for producing an alcohol compound and the method for producing an alcohol compound derivative of the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

[0028] [Method of producing alcohol compounds] The method for producing an alcohol compound of the present embodiment includes a deprotection step of reacting a raw material compound with an acid catalyst in a mixed solvent containing an alcohol solvent and a ketone solvent to remove the tetrahydropyranyl group from the tetrahydropyranyl ether group.

[0029] [Raw material compound] The raw material compound used in the method for producing an alcohol compound of this embodiment is a compound having a tetrahydropyranyl ether group (THP ether group (-O(THP))) and an acetonide ether group (-OC(CH3)2-O-). The THP ether group is a group in which an alcoholic hydroxyl group is protected with a tetrahydropyranyl group (THP group). The acetonide ether group is a group that forms part of a ring structure in which two alcoholic hydroxyl groups (-OH) are protected with acetonide groups (-C(CH3)2-).

[0030] In the THP ether group of the raw material compound, the alcoholic hydroxyl group protected by the THP group may be any of a primary hydroxyl group, a secondary hydroxyl group, and a tertiary hydroxyl group. The alcoholic hydroxyl group protected by the THP group is preferably a primary hydroxyl group, since this facilitates the synthesis of the raw material compound.

[0031] The number of THP ether groups in the raw material compound is not particularly limited and may be one or two or more, and is appropriately determined depending on the application of the target alcohol compound. When the number of THP ether groups is two or more, the structures of the alcoholic hydroxyl groups protected by the THP groups may be different from each other, or some or all of them may be the same.

[0032] In the acetonide ether group of the raw material compound, the two alcoholic hydroxyl groups protected by one acetonide group are preferably derived from a 1,2-diol structure or a 1,3-diol structure, and more preferably derived from a 1,2-diol structure, because this facilitates the synthesis of the raw material compound. The type of protected hydroxyl group is determined appropriately depending on the application of the target alcohol compound.

[0033] The number of acetonide ether groups in the raw material compound is not particularly limited and may be one or two or more, and is appropriately determined depending on the application of the alcohol compound. When the number of acetonide ether groups is two or more, the structures of the two alcoholic hydroxyl groups protected by the acetonide groups may be different from each other, or may be partially or entirely the same.

[0034] The starting compound may have not only a THP ether group and an acetonide ether group, but also an alcoholic hydroxyl group (-O-CHOCH, -O-CH(OCHCH)CH, -O-CHOCHCHOCH) protected with a methoxymethyl group (-CHOCH, MOM), an ethoxyethyl group (-CH(OCHCH)CH, EE), or a methoxyethoxymethyl group (-CHOCHCHOCH, MEM). The MOM, EE, and MEM groups protecting the alcoholic hydroxyl groups in the starting compound are retained without being deprotected even when the deprotection reaction of the present disclosure, which selectively deprotects the THP group of the THP ether group, is carried out.

[0035] The alcoholic hydroxyl group protected by the MOM group, EE group, or MEM group may be a primary hydroxyl group, a secondary hydroxyl group, or a tertiary hydroxyl group.

[0036] The number of alcoholic hydroxyl groups protected by MOM groups, EE groups, and MEM groups in the raw material compound is not particularly limited and may be one or two or more, and is appropriately determined depending on the application of the alcoholic compound. When the number of alcoholic hydroxyl groups protected by MOM groups, EE groups, and MEM groups is two or more, the structures of the alcoholic hydroxyl groups protected by MOM groups, EE groups, and MEM groups may be different from each other, or some or all of them may be the same.

[0037] Examples of the raw material compound include, but are not limited to, compounds represented by formula (1).

[0038] [ka] In formula (1), m represents an integer of 1 to 4, and n represents an integer of 1 to 50. Each of the n Xs independently represents -CY 1 Y 2 -, -CY 3 (OZ)- or -O-. Y 1 , Y 2 , Y 3 and Z are each independently a hydrocarbon group having 1 to 8 carbon atoms which may have an ether oxygen atom other than at the bond terminal, or a hydrogen atom. However, in formula (1), -O- groups are not directly bonded to each other. One -CY 1 Y 2 -Y in 1 and Y 2 may be bonded to each other to form a ring structure. 3 (OZ)-Y in 3 and Z may be bonded to each other to form a ring structure. When n is 2 or more, -CY as one X may be 1 Y 2 -Y in 1 and Y 2 or -CY 3 (OZ)-Y in 3 and one of Z and the other X, -CY 1 Y 2 -Y in 1 and Y 2 or -CY 3 (OZ)-Y in 3 and one of Z may be bonded to each other to form a ring structure.

[0039] In formula (1), m represents an integer of 1 to 4. In order to facilitate the synthesis of a compound having an acetonide ether group, the ring structure in which two alcoholic hydroxyl groups are protected by acetonide groups is preferably a 5- or 6-membered ring, and more preferably a 5-membered ring. That is, m in formula (1) is preferably 1 or 2, and more preferably 1.

[0040] In formula (1), n ​​represents an integer of 1 to 50. Because n is 50 or less, the viscosity of the mixture obtained by mixing the raw material compound and the mixed solvent can be prevented from increasing due to the large size of the molecules of the raw material compound. Therefore, when deprotecting the THP group from the THP ether group of the raw material compound, the raw material compound can be easily stirred with the acid catalyst and the mixed solvent. Furthermore, because n is 1 or more, the raw material compound can be easily obtained and synthesized. n is preferably 2 to 20, and more preferably 4 to 10.

[0041] In formula (1), n ​​Xs each independently represent -CY 1 Y 2 -, -CY 3 (OZ) represents either - or -O-. Y 1 , Y 2 and Y 3 are each independently a hydrocarbon group having 1 to 8 carbon atoms which may have an ether oxygen atom other than at the bond terminal, or a hydrogen atom. 1 and / or Y 2 is the hydrocarbon group, -CY 1 Y 2 The bond end that is bonded to C in - is a carbon atom. 3 is the hydrocarbon group, -CY 3 The bond terminal bonded to C in (OZ)- is a carbon atom. The hydrocarbon group is preferably a hydrocarbon group having 1 to 6 carbon atoms.

[0042] Because raw materials are easily available and synthesized, Y 1 , Y 2 and Y 3 are each independently preferably a hydrogen atom, a methyl group, an ethyl group, a vinyl group, an allyl group, or a phenyl group, more preferably a hydrogen atom or a methyl group, and most preferably a hydrogen atom. 1 Y 2 Specifically, - is preferably any one selected from -CH2-, -CH(CH3)-, and -C(CH3)2-.

[0043] In formula (1), Z is a hydrocarbon group having 1 to 8 carbon atoms which may have an ether oxygen atom other than at the bond terminal, or a hydrogen atom. When Z is the hydrocarbon group, -CY 3 The bond terminal bonded to O in (OZ)- is a carbon atom. The hydrocarbon group is preferably a hydrocarbon group having 1 to 6 carbon atoms. Z is preferably any one selected from a hydrogen atom, a methyl group, an allyl group, a methoxymethyl group (-CHOCH), an ethoxyethyl group (-CH(OCHCH)CH), and a methoxyethoxymethyl group (-CHOCHCHOCH), more preferably any one selected from a hydrogen atom, a methyl group, and a methoxymethyl group, and most preferably a methoxymethyl group. This is because the raw material compound has a flexible structure, which improves the solubility of the raw material compound in the mixed solvent. -CY 3 Specifically, (OZ)- is preferably any one selected from -CH(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -CH(OCH2OCH3)-, and -C(CH3)(OCH2OCH3)-.

[0044] One -CY 1 Y 2 -Y in 1 and Y 2 When Y are bonded to each other to form a ring structure, Y 1 is considered to be a single bond. 1 -Y 2 The number of carbon atoms contained in Y is 1 to 8. 1 -Y 2 The ring structure formed may contain an ether oxygen atom. The ring structure formed is preferably a 4- to 6-membered ring. One -CY 3 (OZ)-Y in 3 When Y and Z are bonded to each other to form a ring structure, Y 3 is considered to be a single bond. 3 -Z contains 1 to 8 carbon atoms, and Y 3An ether oxygen atom may be contained in -Z. The ring structure formed is preferably a 4- to 6-membered ring. n is 2 or more, and one X is -CY 1 Y 2 -Y in 1 and Y 2 or -CY 3 (OZ)-Y in 3 and one of Z and the other X, -CY 1 Y 2 -Y in 1 and Y 2 or -CY 3 (OZ)-Y in 3 When one of X and Z is bonded to each other to form a ring structure, Y forming a ring structure in the other X is not included, regardless of the above definition. 1 , Y 2 , Y 3 , or Z is considered a single bond. That is, Y as one X 1 , Y 2 , Y 3 , or Z and Y as other X 1 , Y 2 , Y 3 or the moiety formed by bonding with Z has 1 to 8 carbon atoms and may contain an ether oxygen atom. The ring structure formed is preferably a 5-membered ring or a 6-membered ring.

[0045] In formula (1), -O- groups are not directly bonded to each other. That is, X directly bonded to -O(THP) is not -O-, and when n is 2 or more, -(X) n -O- cannot be adjacent as an X in -. In formula (1), X directly bonded to the ring structure containing the acetonide group (when n is 2 or more, the leftmost X in formula (1)) is preferably -CH-, because this facilitates the synthesis of the starting compound. In formula (1), X directly bonded to -O(THP) (when n is 2 or more, the rightmost X in formula (1)) is preferably -CH2-, because this facilitates the synthesis of the raw material compound.

[0046] Specific examples of the compound represented by formula (1) used as a starting compound in this embodiment include, but are not limited to, the compounds represented by the following formulae (1-1) to (1-29): The compounds represented by formulae (1-1) to (1-29) can be produced by known production methods.

[0047] In the compounds represented by formulas (1-1) to (1-22) and (1-27) to (1-29), m in formula (1) is 1; in the compounds represented by formulas (1-23) and (1-24), m in formula (1) is 2; in the compound represented by formula (1-25), m in formula (1) is 3; and in the compound represented by formula (1-26), m in formula (1) is 4. The compounds represented by formulae (1-1) to (1-8) and (1-23) have a secondary hydroxyl group bonded to a chain-like skeleton protected by a MOM group.

[0048] The compounds represented by formula (1-27) and (1-28) are compounds in which n in formula (1) is 2 or more and one X is -CY 1 Y 2 -Y in 1 and Y 2 One of them and the other X as -CY 1 Y 2 -Y in 1 and Y 2 are bonded together to form a ring structure. The compound represented by formula (1-29) can be prepared by reacting one -CY in formula (1). 1 Y 2 -Y in 1 and Y 2 are bonded to each other to form a ring structure.

[0049] [ka]

[0050] [ka]

[0051] [ka]

[0052] [Acid catalyst] In the method for producing an alcohol compound of this embodiment, an acid or an acid salt is used as an acid catalyst in the deprotection step. The acid as the acid catalyst may be an organic acid or an inorganic acid. The acid salt as the acid catalyst may also be an acid salt of an organic acid or an acid salt of an inorganic acid.

[0053] The acid catalyst preferably has a pKa (acid dissociation constant) in water of -3.0 to 13.0. pKa is a commonly used index indicating the acid strength of a target substance. In this specification, pKa is a value at a temperature of 25°C. The pKa value can be determined by measurement using known methods. Alternatively, a calculated value using known software such as "ACD / Labs" (trade name, manufactured by Advanced Chemistry Development) can also be used. When the pKa of the acid catalyst is 13.0 or less, the deprotection reaction of the THP group from the THP ether group proceeds more efficiently, resulting in an alcohol compound in which a higher proportion of the THP group is deprotected. To more rapidly carry out the deprotection reaction of the THP group, the pKa of the acid catalyst is more preferably 11.0 or less, even more preferably 9.0 or less, and particularly preferably 7.0 or less. Furthermore, when the pKa of the acid catalyst is -3.0 or more, the acetonide group is less likely to be deprotected by the deprotection reaction of the THP group, allowing for more selective deprotection of the THP group, resulting in an alcohol compound in which a larger proportion of the acetonide group remains. To prevent side reactions such as decomposition of the raw material compound, the pKa of the acid catalyst is more preferably 1.0 or more, even more preferably 3.0 or more, and particularly preferably 5.0 or more.

[0054] The acid catalyst is preferably one that is easily available and easy to handle. Specific examples of such an acid catalyst include at least one selected from the group consisting of pyridinium p-toluenesulfonate (pKa: 5.2), p-toluenesulfonic acid (pKa: -2.8), methanesulfonic acid (pKa: -2.6), sulfuric acid (pKa: -3.0), acetic acid (pKa: 4.8), ammonium acetate (pKa: 9.9), pyridinium acetate, formic acid (pKa: 3.8), ammonium formate, propionic acid (pKa: 4.9), butanoic acid (pKa: 4.8), isobutanoic acid (pKa: 4.9), pivalic acid (pKa: 5.0), hydrogen chloride (pKa: -8.0), ammonium chloride (pKa: 9.2), and pyridinium chloride (pKa: 5.2).

[0055] Among these acid catalysts, it is more preferable to use at least one selected from the group consisting of pyridinium p-toluenesulfonate, acetic acid, ammonium acetate, pyridinium acetate, formic acid, ammonium formate, and ammonium chloride, because it can rapidly proceed with the deprotection reaction of the THP group while preventing side reactions such as decomposition of the raw material compounds.Furthermore, it is most preferable to use pyridinium p-toluenesulfonate as the acid catalyst, because it has sufficient solubility in the mixed solvent and has little odor.

[0056] In the method for producing an alcohol compound according to the present embodiment, the acid catalyst functions as a catalyst for the deprotection reaction of the THP group, and therefore, theoretically, there is no limit to the amount of the acid catalyst used. In practice, the greater the amount of acid catalyst used relative to the raw material compound, the more rapidly the deprotection reaction of the THP group tends to proceed. However, from the viewpoints of suppressing side reactions of the raw material compound and reducing raw material costs, the smaller the amount of acid catalyst used, the more preferable. For these reasons, the amount of acid catalyst used is preferably 0.001 to 10 equivalents relative to 1 equivalent of the raw material compound, more preferably 0.01 to 1 equivalent, and even more preferably 0.1 to 0.5 equivalents.

[0057] [Mixed solvent] In the method for producing an alcohol compound of the present embodiment, a mixed solvent containing an alcohol solvent and a ketone solvent is used as the reaction solvent in the deprotection step. In this embodiment, the deprotection reaction of the THP group proceeds by transferring the THP group from the starting compound having the THP group to the alcohol solvent through chemical equilibrium. Therefore, it is essential to use an alcohol solvent as the reaction solvent. On the other hand, if the reaction solvent used in the deprotection step is an alcohol solvent alone, not only the THP group in the starting compound but also the acetonide group will be easily deprotected, resulting in the generation of acetone as a by-product.

[0058] In this embodiment, a mixed solvent containing an alcohol solvent and a ketone solvent is used as the reaction solvent. This inhibits the elimination of acetone in the reaction in which the acetonide group is deprotected from the raw material compound, thereby hindering the progress of the deprotection reaction of the acetonide group. On the other hand, the ketone solvent is not involved in the deprotection reaction of the THP group. Therefore, even if the reaction solvent contains a ketone solvent, the progress of the deprotection reaction of the THP group is not hindered. For these reasons, by carrying out the deprotection reaction of the THP group in the raw material compound in a mixed solvent containing an alcohol solvent and a ketone solvent, the deprotection reaction of the acetonide group in the raw material compound is suppressed, and the THP group can be selectively deprotected while retaining the acetonide group in the raw material compound.

[0059] The alcohol solvent contained in the mixed solvent is preferably an alcohol having 1 to 12 carbon atoms. Since this allows the deprotection reaction of the THP group to proceed more quickly, the alcohol solvent is more preferably an alcohol having 6 or less carbon atoms, and even more preferably an alcohol having 4 or less carbon atoms.

[0060] Specifically, the alcohol solvent contained in the mixed solvent is preferably at least one selected from the group consisting of methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 2-propanol, 2-butanol, 2-pentanol, 3-pentanol, 2-hexanol, t-butyl alcohol, 2-methyl-2-butanol, cyclopentanol, and cyclohexanol, because they are easily available and can be handled.

[0061] Among these alcohol solvents, any one selected from methanol, ethanol, 1-propanol, 2-propanol, and t-butyl alcohol is more preferred because it facilitates removal of the mixed solvent after the deprotection reaction of the THP group, and 2-propanol is most preferred for the reasons described below. This is because, when 2-propanol is used as the alcohol solvent, the deprotection reaction of the THP group proceeds more rapidly. Furthermore, when 2-propanol is used as the alcohol solvent, the reaction between acetone liberated by deprotection of the acetonide group and / or acetone contained in the mixed solvent as a ketone solvent and the alcohol solvent 2-propanol is strongly inhibited by the steric hindrance of 2-propanol. As a result, the deprotection reaction of the acetonide group proceeds more slowly.

[0062] The mixed solvent may contain only one type of alcohol solvent, or two or more types. When the mixed solvent contains two or more types of alcohol solvents, the total mass of the alcohol solvents is used as the mass of the alcohol solvents in calculating the ratio (mass ratio) of the alcohol solvent to the ketone solvent.

[0063] The ketone solvent contained in the mixed solvent is preferably a ketone having 3 to 12 carbon atoms. This is because it effectively inhibits the deprotection reaction of the acetonide group. The ketone solvent is more preferably a ketone having 6 or less carbon atoms, and even more preferably a ketone having 4 or less carbon atoms.

[0064] Specifically, the ketone solvent contained in the mixed solvent is preferably at least one selected from the group consisting of acetone, ethyl methyl ketone, 2-pentanone, 3-pentanone, 2-hexanone, cyclopentanone, and cyclohexanone, because it is easily available and easy to handle. Among these, it is most preferable to use acetone as the ketone solvent. This is because, even if the deprotection reaction of the THP group goes out of control, the acetonide group is deprotected, and two alcoholic hydroxyl groups are generated together with acetone, when acetone is used as the ketone solvent, the generated two alcoholic hydroxyl groups can be reprotected by the acetonide group.

[0065] The mixed solvent may contain only one type of ketone solvent, or two or more types. When the mixed solvent contains two or more types of ketone solvents, the total mass of the ketone solvents is used as the mass of the ketone solvent in calculating the ratio (mass ratio) of the alcohol solvent to the ketone solvent.

[0066] The mixed solvent is an alcohol (R 1 -OH;R 1 represents an organic group.) and ketones (R 2 -(C=O)-R 3 ;R 2 , R 3 and each independently represent an organic group.) In the present specification, a compound that satisfies both of the above conditions is treated as an alcohol solvent.

[0067] The combination of the alcohol solvent and the ketone solvent contained in the mixed solvent is preferably any one of a combination of 2-propanol and acetone, a combination of methanol and acetone, a combination of ethanol and acetone, and a combination of t-butyl alcohol and acetone, and more preferably a combination of 2-propanol and acetone or a combination of methanol and acetone. The alcohol solvent and the ketone solvent contained in the mixed solvent may be completely miscible or may be partially separated, but are preferably completely miscible.

[0068] If the ratio of the alcohol solvent to the total amount of the alcohol solvent and the ketone solvent in the mixed solvent is too low, the deprotection reaction of the THP group will be difficult to proceed. Also, if the ratio of the ketone solvent to the total amount of the alcohol solvent and the ketone solvent is too low, the deprotection reaction of the acetonide group will be more likely to occur. Therefore, the mass ratio of the alcohol solvent to the ketone solvent contained in the mixed solvent is preferably alcohol solvent:ketone solvent = 10:90 to 90:10, more preferably 25:75 to 75:25, and even more preferably 33:67 to 67:33.

[0069] The mixed solvent may contain one or more solvents other than the alcohol solvent and the ketone solvent (hereinafter, sometimes referred to as "other solvents"). In this case, the total mass of the alcohol solvent and the ketone solvent relative to the mass of the mixed solvent (100 mass%) is preferably 50 mass% or more, more preferably 80 mass% or more, and even more preferably 95 mass% or more.

[0070] Examples of other solvents include methylene chloride, chloroform, dichloroethane, diethyl ether, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, benzene, toluene, xylene, chlorobenzene, etc. When the solubility of the raw material compound in a mixed solvent of an alcohol solvent and a ketone solvent is low, adding another solvent to the mixed solvent may increase the solubility of the raw material compound in the mixed solvent, thereby accelerating the deprotection reaction of the THP group.

[0071] [Concentration of raw material compounds] Considering the ease of isolation and purification of the alcohol compound produced by the deprotection reaction of the THP group, the concentration of the raw material compound in the mixed solvent is preferably high. On the other hand, if the amount of raw material compound contained in the mixed solvent is too large, the deprotection reaction of the THP group is likely to cause side reactions such as decomposition of the raw material compound and / or the reaction product. For this reason, the mass ratio of the raw material compound contained in the mixed solvent to the mixed solvent is preferably (raw material compound) / (mixed solvent) = 0.001 to 10, more preferably 0.01 to 1, and even more preferably 0.05 to 0.25.

[0072] In this embodiment, the mass of the mixed solvent is the total mass of the alcohol solvent and the ketone solvent when the mixed solvent consists only of an alcohol solvent and a ketone solvent, and is the total mass of the alcohol solvent, the ketone solvent, and the other solvent when the mixed solvent consists of an alcohol solvent, a ketone solvent, and the other solvent.

[0073] In this embodiment, the order in which the raw material compound, the mixed solvent, and the acid catalyst are mixed is not particularly limited. To avoid side reactions caused by contact of the raw material compound and the acid catalyst at high concentrations, it is preferable to add the raw material compound or the acid catalyst last. That is, it is preferable to add the acid catalyst to a mixture obtained by mixing the raw material compound and the mixed solvent, or to add the raw material compound to a mixture obtained by mixing the acid catalyst and the mixed solvent. In particular, when it takes time for the raw material compound and the mixed solvent to be sufficiently mixed, it is preferable to add the acid catalyst last.

[0074] [Reaction temperature] The reaction temperature in the deprotection step of this embodiment is not particularly limited as long as it is within a range in which the mixed solvent does not solidify or boil. The reaction temperature in the deprotection step is preferably 0°C to 100°C, more preferably 10°C to 80°C, and even more preferably 20°C to 60°C. When the reaction temperature in the deprotection step is 0°C or higher, the desired deprotection reaction of the THP group can proceed quickly. Furthermore, when the reaction temperature is 100°C or lower, undesired side reactions can be suppressed.

[0075] [Reaction time] The reaction time in the deprotection step of this embodiment can be appropriately set depending on the reaction temperature, but is preferably 0.1 to 200 hours, more preferably 0.5 to 100 hours, and even more preferably 1 to 50 hours. When the reaction time in the deprotection step is 0.1 hours or longer, the deprotection reaction of the THP groups in the raw material compound proceeds sufficiently, making it easier to obtain an alcohol compound in which a higher proportion of the THP groups have been deprotected. Furthermore, when the reaction time is 200 hours or shorter, the productivity of the alcohol compound is improved and undesired side reactions can be suppressed.

[0076] [Reaction atmosphere, pressure] The reaction atmosphere in the deprotection step of this embodiment is not particularly limited. The deprotection reaction of the THP group in this embodiment proceeds efficiently in air or in an inert gas such as nitrogen gas or argon gas. In general, the reaction is preferably carried out in air because the operation can be easily carried out. When using a raw material compound that is unstable to oxygen and / or water, the reaction can also be carried out in an appropriate inert gas atmosphere.

[0077] The pressure of the reaction system in the deprotection step of this embodiment is not particularly limited as long as it is within a range in which the mixed solvent does not solidify or boil. The pressure of the reaction system in the deprotection step is preferably normal pressure in terms of ease of operation.

[0078] Post-processing By carrying out the deprotection step of this embodiment, a reaction solution containing an alcohol compound in which the acetonide groups of the raw material compound remain sufficiently and a high proportion of the THP groups of the THP ether groups have been deprotected is produced. The alcohol compound in the resulting reaction solution can be isolated and purified using a method commonly used for isolating and purifying organic compounds. Specifically, the following method can be used as a method for isolating and purifying the alcohol compound.

[0079] The reaction mixture is treated with aqueous sodium bicarbonate, saline, or water, and extracted with an organic solvent such as ethyl acetate, diethyl ether, methylene chloride, or chloroform. The mixed solvent used in the deprotection reaction may be removed from the reaction mixture using an evaporator before extraction. The extract is then dried and concentrated using anhydrous magnesium sulfate, anhydrous sodium sulfate, or the like, to obtain a crude product. The resulting crude product is then purified, if necessary, by distillation, chromatography, recrystallization, or other methods.

[0080] The alcohol compound obtained by carrying out the deprotection step of this embodiment may be used as a material as it is, or may be converted into another compound by a subsequent chemical reaction. The alcohol compound produced by the deprotection step of this embodiment can be converted into an alcohol compound derivative, for example, by the method for producing an alcohol compound derivative described below.

[0081] [Method of producing alcohol compound derivatives] The method for producing an alcohol compound derivative of the present embodiment includes a step of producing an alcohol compound having an alcoholic hydroxyl group generated by deprotecting the THP group using the method for producing an alcohol compound of the present embodiment, and a conversion step of converting the alcoholic hydroxyl group of the alcohol compound into another group.

[0082] Examples of the other group include an alkoxy group, a group bonded via an ester bond, a group bonded via a urethane bond, and a leaving group for the subsequent reaction. Examples of the leaving group include a p-toluenesulfonyloxy group, a methanesulfonyloxy group, chlorine, bromine, and iodine. The alcoholic hydroxyl group of the alcohol compound may be oxidized and converted into an aldehyde, ketone, or carboxylic acid. In this embodiment, a known method can be used to convert the alcoholic hydroxyl group of the alcohol compound into another group, and the method can be determined depending on the type of the other group.

[0083] The following compounds can be used as reactants for converting an alcoholic hydroxyl group into a leaving group. For example, when the leaving group is a p-toluenesulfonyloxy group, p-toluenesulfonyl chloride can be used. When the leaving group is a methanesulfonyloxy group, methanesulfonyl chloride can be used. When the leaving group is chlorine, thionyl chloride can be used. When the leaving group is bromine, phosphorus tribromide can be used. Furthermore, a hydroxyl group can be converted to bromine by a reaction using carbon tetrabromide, triphenylphosphine, and a base. When the leaving group is iodine, a hydroxyl group can be converted to iodine by a reaction using iodine, triphenylphosphine, and a base.

[0084] The alcohol compound derivative obtained by the production method of this embodiment is obtained by converting the alcoholic hydroxyl groups of the alcohol compound produced by the production method of this embodiment to other groups. Therefore, it is a compound in which a sufficient amount of acetonide groups remain and a sufficient amount of other groups are obtained by converting the alcoholic hydroxyl groups generated by deprotection of a high proportion of THP groups. Furthermore, the alcohol compound derivative having a leaving group obtained by the production method of the present embodiment can be reacted with a hydroxyl group of another compound to eliminate the leaving group, thereby synthesizing an ether compound in which a group derived from the structure of the other compound is ether-bonded. [Example]

[0085] The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[0086] [Example 1] The compound represented by the above formula (1-1) was synthesized as a starting compound by the following method. The hydroxyl group of 3-buten-1-ol was protected using dihydropyran, and then the alkenyl group was oxidized with m-chloroperbenzoic acid. The resulting compound was then reacted with solketal, and the secondary hydroxyl group of the resulting compound was protected using chloromethyl methyl ether.

[0087] To a mixture of 3.60 g (10.3 mmol) of the compound represented by the above formula (1-1), which is the raw material compound, and a mixed solvent (reaction solvent) prepared by mixing 16 g of 2-propanol and 16 g of acetone, 0.52 g (2.07 mmol) of pyridinium p-toluenesulfonate, which is an acid catalyst, was added, and the mixture was stirred in an air atmosphere at a reaction temperature of 55°C for 7 hours to cause a deprotection reaction, thereby obtaining a reaction solution containing an alcohol compound.

[0088] The reaction solution obtained by the deprotection reaction 1 The compound was analyzed by H-NMR. From the results, the ratio of THP groups not contained in the reaction product after the deprotection reaction (THP group conversion rate) to the total THP groups contained in the raw material compound was calculated using the following formula. As a result, the THP group conversion rate was 97%. THP group conversion rate (%) = {(THP groups in the total amount of raw materials - THP groups in the reaction product) / THP groups in the total amount of raw materials} × 100

[0089] In addition, the reaction solution obtained by the deprotection reaction 1 From the results of H-NMR analysis, the percentage of acetonide groups remaining in the reaction product after the deprotection reaction (acetonide group residual rate) relative to the total acetonide groups contained in the raw material compound was calculated using the following formula: The acetonide group residual rate was found to be 95%. Acetonide group remaining rate (%) = (acetonide groups in reaction product / acetonide groups in total amount of raw material compounds) × 100

[0090] To the reaction solution obtained by the deprotection reaction, 0.52 g (5.17 mmol) of triethylamine was added to quench the acid catalyst. Then, the mixed solvent used in the deprotection reaction contained in the reaction solution was removed using an evaporator, and the reaction solution was purified by silica gel column chromatography. This procedure yielded 1.61 g of the compound represented by the following formula (2-1), which is the alcohol compound of Example 1. Thereafter, the compound represented by formula (2-1) was reacted with p-toluenesulfonyl chloride to obtain 2.15 g of a compound represented by the following formula (3-1), which is a derivative of the alcohol compound of Example 1.

[0091] [ka]

[0092] The obtained compounds (2-1) and (3-1) 1 H-NMR measurement was carried out, and the structure was identified from the following results. (2-1) 1 H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 1.80-2.00(2H), 3.30-3.40(3H), 3.40-3.80(8H), 3.80-4.20(3H), 4.60-4.80(2H) (3-1) 1 H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 1.80-2.00(2H), 2.40-2.50(3H), 3 .30-3.40(3H), 3.40-3.80(6H), 3.80-4.20(4H), 4.60-4.80(2H), 6.90-7.80(4H)

[0093] [Example 2] The compound represented by the above formula (1-2) was synthesized as a starting compound by the following method. The hydroxyl group of 5-hexen-1-ol was protected using dihydropyran, and then the alkenyl group was oxidized with m-chloroperbenzoic acid. The resulting compound was then reacted with solketal, and the secondary hydroxyl group of the resulting compound was protected using chloromethyl methyl ether.

[0094] The same operations as in Example 1 were performed except that the compound represented by the above formula (1-2) was used as the raw material compound instead of the compound represented by the above formula (1-1), thereby obtaining 4.40 g of a compound represented by the following formula (2-2), which is an alcohol compound of Example 2, and 6.12 g of a compound represented by the following formula (3-2), which is a derivative of the alcohol compound of Example 2.

[0095] In addition, in the same manner as in Example 1, the reaction solution obtained by the deprotection reaction in Example 2 was 1 The THP group conversion rate and the acetonide group remaining rate were determined by H-NMR analysis. As a result, the THP group conversion rate in Example 2 was 98%, and the acetonide group remaining rate was 94%.

[0096] [ka]

[0097] The obtained compounds (2-2) and (3-2) 1 H-NMR measurement was carried out, and the structure was identified from the following results. (2-2) 1 H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 1.80-2.00(6H), 3.30-3.40(3H), 3.40-3.80(7H), 3.80-4.20(4H), 4.60-4.80(2H) (3-2) 1 H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 1.80-2.00(6H), 2.40-2.50(3H), 3 .30-3.40(3H), 3.40-3.80(6H), 3.80-4.20(4H), 4.60-4.80(2H), 6.90-7.80(4H)

[0098] [Example 3] The compound represented by the above formula (1-3) was synthesized as a starting compound by the following method. The hydroxyl group of ethylene glycol monoallyl ether was protected using dihydropyran, and then the alkenyl group was oxidized with m-chloroperbenzoic acid. The resulting compound was then reacted with solketal, and the secondary hydroxyl group of the resulting compound was protected using chloromethyl methyl ether.

[0099] The same operations as in Example 1 were performed except that the compound represented by the above formula (1-3) was used as the raw material compound instead of the compound represented by the above formula (1-1), thereby obtaining 2.73 g of a compound represented by the following formula (2-3), which is the alcohol compound of Example 3, and 3.81 g of a compound represented by the following formula (3-3), which is a derivative of the alcohol compound of Example 3.

[0100] In addition, in the same manner as in Example 1, the reaction solution obtained by the deprotection reaction of Example 3 was 1 The THP group conversion rate and the acetonide group remaining rate were determined by H-NMR analysis. As a result, the THP group conversion rate in Example 3 was 96%, and the acetonide group remaining rate was 97%.

[0101] [ka]

[0102] The obtained compounds (2-3) and (3-3) 1 H-NMR measurement was carried out, and the structure was identified from the following results. (2-3) 1 H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 3.30-3.40(3H), 3.40-3.80(11H), 3.80-4.20(4H), 4.60-4.80(2H) (3-3) 1H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 2.40-2.50(3H), 3.30-3.40(3H), 3.40-3.80(10H), 3.80-4.20(4H), 4.60-4.80(2H), 6.90-7.80(4H)

[0103] [Example 4] The compound represented by the above formula (1-4) was synthesized as a starting compound by the following method. One of the hydroxyl groups of 1,3-propanediol was reacted with allyl bromide. Next, the other hydroxyl group of 1,3-propanediol was protected with dihydropyran, and the alkenyl group was oxidized with m-chloroperbenzoic acid. The resulting compound was then reacted with solketal, and the secondary hydroxyl group of the resulting compound was protected with chloromethyl methyl ether.

[0104] The same operations as in Example 1 were performed except that the compound represented by the above formula (1-4) was used as the raw material compound instead of the compound represented by the above formula (1-1), thereby obtaining 3.81 g of a compound represented by the following formula (2-4), which is the alcohol compound of Example 4, and 4.47 g of a compound represented by the following formula (3-4), which is a derivative of the alcohol compound of Example 4.

[0105] In addition, in the same manner as in Example 1, the reaction solution obtained by the deprotection reaction of Example 4 was 1 The THP group conversion rate and the acetonide group remaining rate were determined by H-NMR analysis. As a result, the THP group conversion rate in Example 4 was 94%, and the acetonide group remaining rate was 97%.

[0106] [ka]

[0107] The obtained compounds (2-4) and (3-4) 1 H-NMR measurement was carried out, and the structure was identified from the following results. (2-4) 1H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 1.80-2.00(2H), 3.30-3.40(3H), 3.40-3.80(11H), 3.80-4.20(4H), 4.60-4.80(2H) (3-4) 1 H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 1.80-2.00(2H), 2.40-2.50(3H), 3 .30-3.40(3H), 3.40-3.80(10H), 3.80-4.20(4H), 4.60-4.80(2H), 6.90-7.80(4H)

[0108] [Example 5] The compound represented by the above formula (1-14) was synthesized as a starting compound by the following method. The primary hydroxyl group of solketal was reacted with paratoluenesulfonyl chloride. Then, an equimolar amount of ethylene glycol was reacted with the resulting compound, and the hydroxyl group of the resulting compound was protected with dihydropyran.

[0109] The same operations as in Example 1 were performed except that the compound represented by the above formula (1-14) was used as the raw material compound instead of the compound represented by the above formula (1-1). As a result, 6.21 g of a compound represented by the following formula (2-14), which is the alcohol compound of Example 14, and 8.61 g of a compound represented by the following formula (3-14), which is a derivative of the alcohol compound of Example 14, were obtained.

[0110] In addition, in the same manner as in Example 1, the reaction solution obtained by the deprotection reaction of Example 5 was 1 The THP group conversion rate and the acetonide group remaining rate were determined by H-NMR analysis, and the results showed that the THP group conversion rate in Example 5 was 99%, and the acetonide group remaining rate was 92%.

[0111] [ka]

[0112] (2-14) 1H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 3.40-3.80(6H), 3.80-4.20(4H) (3-14) 1 H-NMR (acetone-D6): δ[ppm]=1.25-1.35(6H), 2.40-2.50(3H), 3.40-3.80(5H), 3.80-4.20(4H), 6.90-7.80(4H)

[0113] [Example 6] To a mixture obtained by mixing 0.50 g (1.43 mmol) of the compound represented by the above formula (1-1), which is the raw material compound, and a mixed solvent (reaction solvent) prepared by mixing 2.3 g of 2-propanol and 2.3 g of acetone, 0.072 g (0.29 mmol) of pyridinium p-toluenesulfonate, which is an acid catalyst, was added, and the mixture was stirred in an air atmosphere at a reaction temperature of 25°C for 48 hours to carry out a deprotection reaction, thereby obtaining a reaction solution containing an alcohol compound.

[0114] In the same manner as in Example 1, the reaction solution obtained by the deprotection reaction of Example 6 was 1 The THP group conversion rate and the acetonide group remaining rate were determined by H-NMR analysis, and the results showed that the THP group conversion rate in Example 6 was 93%, and the acetonide group remaining rate was 98%.

[0115] [Example 7] The same operation as in Example 6 was carried out, except that 2.3 g of methanol was used instead of 2-propanol and the deprotection reaction was carried out by stirring in an air atmosphere at a reaction temperature of 25°C for 2 hours, to obtain a reaction solution containing an alcohol compound. In the same manner as in Example 1, the reaction solution obtained by the deprotection reaction of Example 7 was 1 The THP group conversion rate and the acetonide group remaining rate were determined by H-NMR analysis. As a result, the THP group conversion rate in Example 7 was 97%, and the acetonide group remaining rate was 46%.

[0116] [Comparative Example 1] The same procedure as in Example 7 was carried out except that 4.6 g of methanol was used instead of the mixed solvent, to obtain a reaction liquid containing an alcohol compound. In the same manner as in Example 1, the reaction solution obtained by the deprotection reaction of Comparative Example 1 was 1 The THP group conversion rate and the acetonide group residual rate were determined by H-NMR analysis. As a result, the THP group conversion rate in Comparative Example 1 was 99%, and the acetonide group residual rate was less than 1%.

[0117] Comparative Example 2 The same procedure as in Example 6 was carried out except that 4.6 g of 2-propanol was used instead of the mixed solvent, to obtain a reaction liquid containing an alcohol compound. In the same manner as in Example 1, the reaction solution obtained by the deprotection reaction of Comparative Example 2 was 1 The THP group conversion rate and the acetonide group residual rate were determined by H-NMR analysis. As a result, the THP group conversion rate in Comparative Example 2 was 95%, and the acetonide group residual rate was 4%.

[0118] Comparative Example 3 The same procedure as in Example 6 was carried out except that 4.6 g of acetone was used instead of the mixed solvent, to obtain a reaction liquid containing an alcohol compound. In the same manner as in Example 1, the reaction solution obtained by the deprotection reaction of Comparative Example 3 was 1 The THP group conversion rate and the acetonide group residual rate were determined by H-NMR analysis. As a result, the THP group conversion rate in Comparative Example 3 was 3%, and the acetonide group residual rate was 99%.

[0119] The raw material compounds and reaction conditions for Examples 1 to 7 and Comparative Examples 1 to 3 carried out in this manner are shown in Table 1. The numerical values ​​for the proportions of reaction solvents in Table 1 are the mass ratios of the alcohol solvent to the ketone solvent. The THP group conversion rates and acetonide group residual rates for Examples 1 to 7 and Comparative Examples 1 to 3 are shown in Table 2, along with the raw material compounds.

[0120] [Table 1]

[0121] [Table 2]

[0122] As shown in Examples 1 to 5 of Tables 1 and 2, five raw material compounds (1-1) to (1-4) and (1-14) were reacted with pyridinium p-toluenesulfonate as an acid catalyst in a mixed solvent (reaction solvent) containing 2-propanol as an alcohol solvent and acetone as a ketone solvent in an air atmosphere at a reaction temperature of 55°C for 7 hours, thereby producing an alcohol compound in which 90% or more of the acetonide group remained and 90% or more of the THP group was deprotected at a high rate.

[0123] Furthermore, in Example 6, in which the reaction was carried out in an air atmosphere at a reaction temperature of 25°C for 48 hours, it was confirmed that an alcohol compound could be produced in which 90% or more of the acetonide groups remained and 90% or more of the THP groups were deprotected, as in Example 1, in which the reaction was carried out in an air atmosphere at a reaction temperature of 55°C for 7 hours.

[0124] Furthermore, in Example 7, in which a mixed solvent (reaction solvent) containing methanol, an alcohol solvent, and acetone, a ketone solvent, was used and the reaction was carried out in an air atmosphere at a reaction temperature of 25°C for 2 hours, it was confirmed that an alcohol compound could be produced in which the acetonide groups remained at a sufficiently high rate of 46% and the THP groups were deprotected at a high rate of 90% or more.

[0125] In contrast, as shown in Tables 1 and 2, in Comparative Example 1, in which only methanol was used instead of the mixed solvent without containing a ketone solvent, and in Comparative Example 2, in which only 2-propanol was used, the acetonide group residual rate was 5% or less in both cases. This is thought to be because the absence of a ketone solvent in the reaction solvent accelerated the elimination of acetone in the reaction in which the acetonide group is deprotected from the raw material compound, thereby promoting the progress of the deprotection reaction of the acetonide group.

[0126] In Comparative Example 3, in which only acetone was used instead of the mixed solvent without containing any alcohol solvent, the THP group conversion rate was only 3%, and the acetonide group residual rate was 99%. This is thought to be because the THP group could not be transferred from the raw material compound having the THP group to the alcohol solvent because the alcohol solvent was not present in the reaction solvent.

Claims

1. A method for producing an alcohol compound, comprising a deprotection step of reacting a raw material compound having a tetrahydropyranyl ether group and an acetonide ether group with an acid catalyst in a mixed solvent containing an alcohol solvent and a ketone solvent to remove the tetrahydropyranyl group from the tetrahydropyranyl ether group.

2. The method for producing an alcohol compound according to claim 1, wherein the alcohol solvent is an alcohol having 1 to 12 carbon atoms.

3. The method for producing an alcohol compound according to claim 2, wherein the alcohol solvent is at least one selected from the group consisting of methanol, ethanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 2-propanol, 2-butanol, 2-pentanol, 3-pentanol, 2-hexanol, t-butyl alcohol, 2-methyl-2-butanol, cyclopentanol, and cyclohexanol.

4. The method for producing an alcohol compound according to claim 3, wherein the alcohol solvent is 2-propanol.

5. The method for producing an alcohol compound according to claim 1, wherein the ketone solvent is a ketone having 3 to 12 carbon atoms.

6. The method for producing an alcohol compound according to claim 5, wherein the ketone solvent is at least one selected from the group consisting of acetone, ethyl methyl ketone, 2-pentanone, 3-pentanone, 2-hexanone, cyclopentanone, and cyclohexanone.

7. The method for producing an alcohol compound according to claim 6, wherein the ketone solvent is acetone.

8. 2. The method for producing an alcohol compound according to claim 1, wherein a mass ratio of the alcohol solvent to the ketone solvent is alcohol solvent:ketone solvent=10:90 to 90:

10.

9. 2. The method for producing an alcohol compound according to claim 1, wherein the acid catalyst has an acid dissociation constant pKa value of −3.0 to 13.

0.

10. 2. The method for producing an alcohol compound according to claim 1, wherein the acid catalyst is at least one selected from the group consisting of pyridinium p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, acetic acid, ammonium acetate, pyridinium acetate, formic acid, ammonium formate, propionic acid, butanoic acid, isobutanoic acid, pivalic acid, hydrogen chloride, ammonium chloride, and pyridinium chloride.

11. The method for producing an alcohol compound according to claim 10, wherein the acid catalyst is pyridinium p-toluenesulfonate.

12. 2. The method for producing an alcohol compound according to claim 1, wherein the amount of the acid catalyst used is 0.001 to 10 equivalents relative to 1 equivalent of the raw material compound.

13. 2. The method for producing an alcohol compound according to claim 1, wherein a mass ratio of the raw material compound to the mixed solvent is raw material compound / mixed solvent=0.001 to 10.

14. The method for producing an alcohol compound according to claim 1, wherein the reaction temperature in the deprotection step is 0°C to 100°C.

15. The method for producing an alcohol compound according to claim 1, wherein the raw material compound is a compound represented by the following formula (1): 【Chemistry 1】 (In formula (1), m represents an integer of 1 to 4, and n represents an integer of 1 to 50. Each of the n Xs independently represents -CY １ Y ２ -, -CY ３ (OZ)- or -O-. １ , Y ２ , Y ３ and Z each independently represent a hydrocarbon group having 1 to 8 carbon atoms which may have an ether oxygen atom other than at the bond terminal, or a hydrogen atom. However, in formula (1), -O- groups are not directly bonded to each other. １ Y ２ -Y in １ and Y ２ may be bonded to each other to form a ring structure. ３ (OZ)-in Y ３ and Z may be bonded to each other to form a ring structure. When n is 2 or more, -CY １ Y ２ -Y in １ and Y ２ or -CY ３ (OZ)-in Y ３ and one of Z and the other X is -CY １ Y ２ -Y in １ and Y ２ or -CY ３ (OZ)-in Y ３ and Z may be bonded to each other to form a ring structure.

16. In the formula (1), X directly bonded to the ring structure containing the acetonide group is —CH ２ The method for producing an alcohol compound according to claim 15, wherein

17. In the formula (1), n ​​is 2 or more, and X directly bonded to —O(THP) is —CH ２ The method for producing an alcohol compound according to claim 15, wherein

18. The method for producing an alcohol compound according to claim 15, wherein m is 1 or 2 in the formula (1).

19. a step of producing an alcohol compound having an alcoholic hydroxyl group generated by deprotecting a tetrahydropyranyl group using the method for producing an alcohol compound according to any one of claims 1 to 18; and a conversion step of converting the alcoholic hydroxyl group of the alcohol compound into another group.

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