JP2017190323A - Method for producing tetrahydro-2H-pyran derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing tetrahydro-2H-pyran derivatives suitable for industrial production, and intermediates that enable efficient synthesis of the derivatives.SOLUTION: A method for the synthesis of a tetrahydro-2H-pyran-derivative represented by formula (1) uses a compound represented by formula (A), (B) or (C) as an intermediate [Ris alkyl, alkenyl or alkoxy; Ris H or alkoxy; X is a hydroxy group or a leaving group; ring A-ring Aindependently represent 1,4-cyclohexylene, 1,4 phenylene or the like; Zis -CH-, -CH- or the like; Zand Zindependently represent -CH--CH-, -C- and the like, n and m independently represent 0 or 1].SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a tetrahydro-2H-pyran derivative, an intermediate, and a derivative thereof.

  Patent Document 3 discloses a liquid crystal compound that is a tetrahydro-2H-pyran derivative. 5-((4-Ethoxy-2,3-difluorophenoxy) methyl) -2-propyltetrahydro-2H-pyran and the like disclosed in Patent Document 1 are useful as liquid crystal compounds having a negative dielectric anisotropy It is. A method for synthesizing this compound is described in Patent Document 2 and the like, but has a drawback that a relatively expensive starting material is required, the number of steps is large, and the yield is low. A production method suitable for industrial production is desired.

International Publication No. 2008-114821 International Publication No. 2009-136534 International Publication No. 2011-021534

Chemische Berichte (1955), 88, 1676-84 Chemische Berichte (1959), 92, 877-883 Chemische Berichte (1959), 92, 884-894

  The first object of the present invention is to solve the above-mentioned problems of the prior art, provide a method for producing a tetrahydro-2H-pyran derivative suitable for industrial production, and enable efficient synthesis of the derivative. To provide an intermediate. The second problem is to provide a liquid crystal compound, a liquid crystal composition, and a liquid crystal display element at a lower price.

The present inventor found that a tetrahydro-2H-pyran-derivative can be efficiently obtained by using the compound (A), the compound (B), or the compound (C), and completed the present invention.

In the compound (A), the compound (B), and the compound (C), R ¹ is alkyl, alkenyl, or alkoxy, R ² is hydrogen or alkoxy, and X is a leaving group.

  The first advantage of the present invention is that it can provide a method for producing a tetrahydro-2H-pyran derivative suitable for industrial production, and can provide an intermediate that enables efficient synthesis of the derivative. A second advantage is that a liquid crystal compound, a liquid crystal composition, and a liquid crystal display element can be provided more inexpensively.

  An example of a method for synthesizing the compound (A), the compound (B), and the compound (C) will be described. The synthesis method up to compound (12) or compound (13) is described in Non-Patent Documents 1 to 3. The synthetic procedure is described in the Examples section. In addition to the methods described in the examples, the formation reaction of carbon-carbon bonds and the functional group conversion reaction are not limited to “Organic Syntheses, John Wiley & Sons, Inc.”, “Organic Reactions” (Organic Reactions). Reactions, John Wiley & Sons, Inc.), “Comprehensive Organic Synthesis, Pergamon Press”, “New Experimental Chemistry Course” (Maruzen), etc. I can do it. As the solvent used for the synthesis, an appropriate solvent that does not inhibit the reaction can be used in addition to the solvents described in the examples.

  The present invention includes the following items.

化合物（Ａ）、化合物（Ｂ）、および化合物（Ｃ）において、Ｒ^１はアルキル、アルケニル、またはアルコキシであり、Ｒ^２は水素またはアルコキシであり、Ｘは脱離基である。 Item 1. A method for producing a tetrahydro-2H-pyran derivative using compound (A), compound (B), or compound (C) as an intermediate.

In the compound (A), the compound (B), and the compound (C), R ¹ is alkyl, alkenyl, or alkoxy, R ² is hydrogen or alkoxy, and X is a leaving group.

Item 2. In Compound (A), Compound (B), or Compound (C), R ¹ is alkyl, X is nonafluorosulfonate, trifluoromethanesulfonate, fluorosulfonate, tosylate, mesylate, iodine, bromine, or chlorine, tetrahydro -2H- pyran method according to claim 1 R ² is hydrogen.

Item 3. Item 3. The method for producing a tetrahydro-2H-pyran derivative according to Item 1 or 2, wherein the compound (A), compound (B), or compound (C) derived from optionally substituted δ-valerolactone is used as an intermediate.

式（１）において、
Ｒ^１は炭素数１から１０のアルキルであり；
Ｒ^４は、水素、炭素数３から８のシクロアルカン、または炭素数１から１０のアルキルであり、このアルキルにおいて、少なくとも１つの−ＣＨ_２−は−Ｏ−で置き換えられてもよく、少なくとも１つの−ＣＨ_２ＣＨ_２−は−ＣＨ＝ＣＨ−で置き換えられてもよく；
環Ａ^１、環Ａ^２、および環Ａ^３は独立して、１，４−シクロへキシレン、１，４−シクロヘキセニレン、１，４−フェニレン、少なくとも１つの水素がハロゲンで置き換えられた１，４−フェニレン、ナフタレン−２，５−ジイル、少なくとも１つの水素がハロゲンで置き換えられたナフタレン−２，５−ジイル、テトラヒドロ−２Ｈ−ピラン−２，５−ジイル、ピリミジン−２，５−ジイル、ピリジン−２，５−ジイル、または１，３−ジオキサン−２，５−ジイルであり；
Ｚ^１は、−ＣＨ_２ＣＨ_２−、−ＣＨ＝ＣＨ−、−ＣＨ_２Ｏ−、または−ＣＯＯ−であり；
Ｚ^２およびＺ^３は独立して、単結合、−ＣＨ_２ＣＨ_２−、−Ｃ≡Ｃ−、−ＣＨ＝ＣＨ−、−ＣＦ_２Ｏ−、−ＯＣＦ_２−、−ＯＣＨ_２−、−ＣＨ_２Ｏ−、−ＯＣＯ−、−ＣＯＯ−、−ＣＨ_２ＣＨ_２ＣＨ_２Ｏ−、または−ＯＣＨ_２ＣＨ_２ＣＨ_２−であり；
ｎおよびｍは独立して、０または１である。 Item 4. Item 4. The method for producing a tetrahydro-2H-pyran derivative according to any one of Items 1 to 3, wherein the compound represented by the formula (1) is a target product.

In equation (1),
R ¹ is alkyl having 1 to 10 carbons;
R ⁴ is hydrogen, a cycloalkane having 3 to 8 carbon atoms, or alkyl having 1 to 10 carbon atoms, in which at least one —CH ₂ — may be replaced by —O—, and at least 1 Two —CH ₂ CH ₂ — may be replaced by —CH═CH—;
Ring A ¹ , Ring A ² , and Ring A ³ are independently 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-phenylene, 1 in which at least one hydrogen is replaced with a halogen , 4-phenylene, naphthalene-2,5-diyl, naphthalene-2,5-diyl, tetrahydro-2H-pyran-2,5-diyl, pyrimidine-2,5-diyl wherein at least one hydrogen is replaced by halogen , Pyridine-2,5-diyl, or 1,3-dioxane-2,5-diyl;
Z ¹ is —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ O—, or —COO—;
Z ² and Z ³ are each independently a single bond, —CH ₂ CH ₂ —, —C≡C—, —CH═CH—, —CF ₂ O—, —OCF ₂ —, —OCH ₂ —, —CH ₂ O—, —OCO—, —COO—, —CH ₂ CH ₂ CH ₂ O—, or —OCH ₂ CH ₂ CH ₂ —;
n and m are independently 0 or 1.

Item 5. Item 5. The method for producing a tetrahydro-2H-pyran derivative according to any one of Items 1 to 4, comprising a step of etherification reaction.

式（２）において、Ｒ^１はアルキル、アルケニル、またはアルコキシであり、Ｒ^２は水素またはアルコキシであり；
Ｑは、下記構造のいずれかである。

Item 6. Compound represented by formula (2)

In formula (2), R ¹ is alkyl, alkenyl, or alkoxy, R ² is hydrogen or alkoxy;
Q is one of the following structures.

Item 7. Use of the compound represented by the formula (1) produced by the production method of Item 4 or 5 as a component of a liquid crystal medium.

When the δ-valerolactone substitution product (10) is reacted with sodium hydride and ethyl formate, compound (11) is obtained. When compound (11) is reacted with hydrochloric acid in an alcohol solvent, a mixture of compound (12) and compound (13) is obtained. Compound (12) and compound (13) can be separated by silica gel chromatography or the like.

Preferred examples of R ¹ are alkyl having 1 to 10 carbons, alkenyl having 1 to 10 carbons, and alkoxy having 1 to 9 carbons. A more preferred example is alkyl having 1 to 10 carbons. Further preferred examples are alkyl having 1 to 5 carbon atoms.

R ³ is alkyl. Preferred examples of R ³ are methyl, ethyl, propyl, isopropyl, butyl, and t-butyl. More preferred examples are methyl and ethyl. A further preferred example is methyl.

Compound (13) is obtained by removing R ³ OH from compound (12) in the presence of an acid catalyst.

  Preferred examples of the acid catalyst are hydrochloric acid, sulfuric acid, p-toluenesulfonic acid monohydrate, heteropolyacid, and sulfonic acid modified silica gel.

Compound (14) is obtained by hydride reduction of compound (12).

  Examples of preferred reducing agents are lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, and sodium bis (2-methoxyethoxy) aluminum hydride. More preferred examples are lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride.

When compound (13) is hydrogenated, compound (15) is obtained.

  Examples of preferred reduction methods are catalytic hydrogenation and silane reduction. Silane reduction is more preferable from the viewpoint of stereoselectivity.

  In the catalytic hydrogenation, examples of preferable catalysts are palladium carbon, supported catalysts such as platinum carbon, palladium black, and Raney nickel. In addition to carbon, the support may be alumina, silica, zeolite, hydroxyapatite, or the like.

  In the silane reduction, examples of preferable silane reducing agents are triethylsilane, diphenylsilane, phenylsilane, and 1,1,3,3-tetramethyldisiloxane. More preferred examples are triethylsilane and 1,1,3,3-tetramethyldisiloxane.

  Examples of preferred acids for silane reduction are methanesulfonic acid, trifluoroacetic acid, aluminum chloride, zinc chloride, and boron trifluoride-diethyl ether complex. A more preferred example is methanesulfonic acid.

  In the silane reduction, a preferable reaction temperature is 50 ° C. or lower. A more preferred temperature is in the range of 0 ° C to 40 ° C.

When compound (15) is hydrolyzed, compound (B) is obtained.

  Hydrolysis is preferably under basic conditions. Examples of preferred bases are potassium hydroxide, sodium hydroxide, lithium hydroxide, and calcium hydroxide.

When compound (15) is hydride reduced, compound (16) is obtained.

  Examples of preferred reducing agents are lithium aluminum hydride, sodium borohydride, diisobutylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and triethylsilane. More preferred examples are lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride.

When a hydrogenation catalyst or a silane reducing agent capable of reducing both olefin and ester is used, compound (16) is obtained from compound (13).

  In the catalytic hydrogenation, examples of preferred hydrogenation catalysts are platinum oxide and rhodium oxide.

  In the silane reduction, examples of preferred silane reducing agents are triethylsilane, diphenylsilane, and 1,1,3,3-tetramethyldisiloxane. More preferred examples are triethylsilane and 1,1,3,3-tetramethyldisiloxane.

  Examples of preferred acids for silane reduction are methanesulfonic acid, trifluoroacetic acid, aluminum chloride, zinc chloride, and boron trifluoride-diethyl ether complex.

  In the silane reduction, a preferable reaction temperature is 120 ° C. or lower. A more preferred temperature is in the range of 40 ° C to 100 ° C.

化合物（１７）はジヒドロピラン誘導体であり、酸性条件下では水酸基の保護基としてはたらく。化合物（１７）の安定性を考慮すると、化合物（１３）から化合物（１５）を合成した後に、化合物（１６）へ誘導するほうが好ましい。 Compound (16) is obtained by hydride reduction of compound (13) and then hydrogenation reduction.

Compound (17) is a dihydropyran derivative, which acts as a hydroxyl-protecting group under acidic conditions. Considering the stability of the compound (17), it is preferable to synthesize the compound (15) from the compound (13) and then induce the compound (16).

好ましい還元剤は、ボラン錯体である。 When compound (B) is reduced, compound (16) is obtained.

A preferred reducing agent is a borane complex.

The hydroxyl group of compound (14) or compound (16) can be converted to a leaving group by a generally known method.

In the compound (14) and the compound (18), R ³ is alkyl. Since R ³ is alkyl, OR ³ is alkoxy.
In compound (18) or compound (19), preferred examples of X which is a leaving group are nonafluorosulfonate, trifluoromethanesulfonate, fluorosulfonate, tosylate, mesylate, iodine, bromine, and chlorine. More preferred examples are tosylate, mesylate, iodine, bromine and chlorine.

Compound (14) and compound (16) correspond to compound (C). Compound (18) and compound (19) correspond to compound (A). Compound (A) can be synthesized in a high yield without requiring an expensive reagent. From the compound (A), the phosphonium salt (20) used in the wittig reaction, the sulfone compound (21), the compound (22), or the compound (23) used in the Julia-Kocienski reaction can be synthesized.

  Using compound (A), compound (B), compound (C), compound (20), compound (21), compound (22), or compound (23), etherification, esterification, carbon-carbon forming reaction, etc. By performing this, a tetrahydro-2H-pyran derivative can be synthesized.

式（３）において、ＯＧは有機基である。

In the formula (3), OG is an organic group.

Tetrahydro-2H-pyran has a cis form and a trans form. The transformer body is preferred because it is thermodynamically stable. The liquid crystal compound used in the liquid crystal display element is preferably a trans form from the viewpoint of liquid crystallinity.

  The ratio of the trans form of compound (15), compound (16), or compound (19) is determined by the olefin reduction method of compound (13). When silane reduction is performed under preferable conditions, the ratio of the trans isomer of compound (19) is approximately 75 to 90%. A trans-tetrahydro-2H-pyran derivative can be synthesized more easily than in the prior art.

  In the etherification reaction, the elimination reaction takes precedence for the cis form of compound (19), and the etherification reaction takes precedence for the trans form. As a result, the ratio of the trans isomer of the product is improved. Furthermore, the amount of alcohol or phenol can be reduced to an amount corresponding to the trans form of compound (19).

式（４）において、ＯＧは有機基である。

In the formula (4), OG is an organic group.

式（１）において、
Ｒ^１は炭素数１〜１０のアルキルであり；
Ｒ^４は、水素、炭素数３〜８のシクロアルカン、または炭素数１〜１０のアルキルであり、このアルキルにおいて、少なくとも１つの−ＣＨ_２−は−Ｏ−で置き換えられてもよく、少なくとも１つの−ＣＨ_２ＣＨ_２−は−ＣＨ＝ＣＨ−で置き換えられてもよく；
環Ａ^１、環Ａ^２、および環Ａ^３は独立して、１，４−シクロへキシレン、１，４−シクロヘキセニレン、１，４−フェニレン、少なくとも１つの水素がハロゲンで置き換えられた１，４−フェニレン、ナフタレン−２，５−ジイル、少なくとも１つの水素がハロゲンで置き換えられたナフタレン−２，５−ジイル、テトラヒドロ−２Ｈ−ピラン−２，５−ジイル、ピリミジン−２，５−ジイル、ピリジン−２，５−ジイル、または１，３−ジオキサン−２，５−ジイルであり；
Ｚ^１は、−ＣＨ_２ＣＨ_２−、−ＣＨ＝ＣＨ−、−ＣＨ_２Ｏ−、または−ＣＯＯ−であり；
Ｚ^２およびＺ^３は独立して、単結合、−ＣＨ_２ＣＨ_２−、−Ｃ≡Ｃ−、−ＣＨ＝ＣＨ−、−ＣＦ_２Ｏ−、−ＯＣＦ_２−、−ＯＣＨ_２−、−ＣＨ_２Ｏ−、−ＯＣＯ−、−ＣＯＯ−、−ＣＨ_２ＣＨ_２ＣＨ_２Ｏ−、または−ＯＣＨ_２ＣＨ_２ＣＨ_２−であり；
ｎおよびｍは独立して、０または１である。 Formula (1) suitable for liquid crystal compounds using compound (A), compound (B), compound (C), compound (20), compound (21), compound (22), or compound (23) of the present invention. Can be synthesized.

In equation (1),
R ¹ is alkyl having 1 to 10 carbons;
R ⁴ is hydrogen, a cycloalkane having 3 to 8 carbon atoms, or an alkyl having 1 to 10 carbon atoms, in which at least one —CH ₂ — may be replaced by —O—, and at least 1 Two —CH ₂ CH ₂ — may be replaced by —CH═CH—;
Ring A ¹ , Ring A ² , and Ring A ³ are independently 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-phenylene, 1 in which at least one hydrogen is replaced with a halogen , 4-phenylene, naphthalene-2,5-diyl, naphthalene-2,5-diyl, tetrahydro-2H-pyran-2,5-diyl, pyrimidine-2,5-diyl wherein at least one hydrogen is replaced by halogen , Pyridine-2,5-diyl, or 1,3-dioxane-2,5-diyl;
Z ¹ is —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ O—, or —COO—;
Z ² and Z ³ are each independently a single bond, —CH ₂ CH ₂ —, —C≡C—, —CH═CH—, —CF ₂ O—, —OCF ₂ —, —OCH ₂ —, —CH ₂ O—, —OCO—, —COO—, —CH ₂ CH ₂ CH ₂ O—, or —OCH ₂ CH ₂ CH ₂ —;
n and m are independently 0 or 1.

Preferred examples of R ¹ are —CH ₃ , —C ₂ H ₅ , —C ₃ H ₇ , —C ₄ H ₉ , and —C ₅ H ₁₁ .

Preferred examples of R ⁴ include —CH ₃ , —C ₂ H ₅ , —C ₃ H ₇ , —C ₄ H ₉ , —C ₅ H ₁₁ , —CH═CH ₂ , —CH═CHCH ₃ , —CH═. _{CHC 2 H 5, -CH = CHC} 3 H 7, - (CH 2) 2 CH = CH 2, - (CH 2) 2 CH = CHCH 3, -CH = CH (CH 2) 2 CH = CH 2, ( _{CH 2) 2 CH = CH (} CH 2) 2 CH = CH 2, -OCH 3, -OC 2 H 5, -OC 3 H 7, and a -OC ₄ H _9.

Preferred examples of ring A ¹ , ring A ² , or ring A ³ include 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-phenylene, 2-fluoro-1,4-phenylene, and 2,3-difluoro-1,4-phenylene.

Preferred examples of Z ¹ are —CH ₂ CH ₂ —, —CH═CH—, and —CH ₂ O—.

Preferred examples of Z ² or Z ³ are a single bond, —CH ₂ CH ₂ —, —CH═CH—, —OCH ₂ —, and —CH ₂ O—.

2-Fluoro-1,4-phenylene means the following two divalent groups. In the chemical formula, fluorine may be leftward (L) or rightward (R). This rule also applies to divalent groups derived from left-right asymmetric rings such as tetrahydro-2H-pyran-2,5-diyl.

  The invention is explained in more detail by means of examples. The invention is not limited by these examples.

1. Example of Compound (A), Compound (B), and Derivative Compound (A), Compound (B), and derivative were synthesized by the following procedure. The synthesized compound was identified by a method such as NMR analysis.

NMR analysis: For measurement, DRX-500 manufactured by Bruker BioSpin Corporation was used. ^In the measurement of ¹ H-NMR, the sample was dissolved in a deuterated solvent such as CDCl ₃ and measured under conditions of room temperature, 500 MHz, and 16 integrations. Tetramethylsilane was used as an internal standard. ^{For 19} F-NMR measurement, CFCl ₃ was used as an internal standard, and the number of integrations was 24. In the description of the nuclear magnetic resonance spectrum, s is a singlet, d is a doublet, t is a triplet, q is a quartet, quint is a quintet, sex is a sextet, m is a multiplet, and br is broad.

  Gas chromatographic analysis: A GC-2010 gas chromatograph manufactured by Shimadzu Corporation was used for measurement. As the column, capillary column DB-1 (length 30 m, inner diameter 0.25 mm, film thickness 0.25 μm) manufactured by Agilent Technologies Inc. was used. Helium (1 ml / min) was used as the carrier gas. The temperature of the sample vaporizing chamber was set to 300 ° C., and the temperature of the detector (FID) portion was set to 300 ° C. The sample was dissolved in acetone to prepare a 1% by weight solution, and 1 μl of the obtained solution was injected into the sample vaporization chamber. For the recorder, a GCsolution system manufactured by Shimadzu Corporation was used.

  Gas chromatograph mass spectrometry: A QP-2010 Ultra gas chromatograph mass spectrometer manufactured by Shimadzu Corporation was used for measurement. As the column, capillary column DB-1 (length 60 m, inner diameter 0.25 mm, film thickness 0.25 μm) manufactured by Agilent Technologies Inc. was used. Helium (1 ml / min) was used as the carrier gas. The temperature of the sample vaporization chamber was set to 300 ° C., the temperature of the ion source was set to 200 ° C., the ionization voltage was set to 70 eV, and the emission current was set to 150 uA. The sample was dissolved in acetone to prepare a 1% by weight solution, and 1 μl of the obtained solution was injected into the sample vaporization chamber. A GCMSsolution system manufactured by Shimadzu Corporation was used for the recorder.

  HPLC analysis: Prominence (LC-20AD; SPD-20A) manufactured by Shimadzu Corporation was used for measurement. As the column, YMC-Pack ODS-A (length 150 mm, inner diameter 4.6 mm, particle diameter 5 μm) manufactured by YMC was used. As an eluent, acetonitrile and water were appropriately mixed and used. As a detector, a UV detector, an RI detector, a CORONA detector, or the like was appropriately used. When a UV detector was used, the detection wavelength was 254 nm. A sample was dissolved in acetonitrile to prepare a 0.1 wt% solution, and 1 μL of this solution was introduced into the sample chamber. As a recorder, C-R7 Plus manufactured by Shimadzu Corporation was used.

Example 1 Synthesis of methyl 2-propyl-3,4-dihydro-2H-pyran-5-carboxylate

First step:
To an ether suspension of sodium hydride (26.14 g, 599.16 mmol) was added 6-propyltetrahydro-2H-pyran-2-one (71.00 g, 499.30 mmol) and ethyl formate (44.39 g, 599. 16 mmol) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 2 hours and then heated to reflux for 5 hours. The reaction mixture was poured into 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3- (hydroxymethylene) -6-propyltetrahydro-2H-pyran-2-one (84.99 g, yield 99.0%).

Second step:
To a methanol solution of 3- (hydroxymethylene) -6-propyltetrahydro-2H-pyran-2-one (74.99 g, 440.58 mmol) obtained in the first step, concentrated hydrochloric acid (36.7 ml, 440.58 mmol). ) And stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel chromatography, methyl 2-methoxy-6-propyl-tetrahydro-2H-pyran-3-carboxylate and 2-propyl-3,4-dihydro-2H-pyran-5. -A mixture of methyl carboxylates (78.86 g) was obtained.

Third step:
Methyl 2-methoxy-6-propyl-tetrahydro-2H-pyran-3-carboxylate, methyl 2-propyl-3,4-dihydro-2H-pyran-5-carboxylate obtained in the second step (78.86 g) ) And 12 tungsto (VI) phosphate n-hydrate (0.394 g, 0.14 mmol) were refluxed for 3 hours under a Dean-stark condenser in toluene. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain methyl 2-propyl-3,4-dihydro-2H-pyran-5-carboxylate (65.71 g, yield 80.5% (2 steps)).

Example 2 Synthesis of (2-propyl-3,4-dihydro-2H-pyran-5-yl) methanol

  To a toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride (3.6 M toluene solution, 16.6 ml, 59.71 mmol), 2-propyl-3,4-dihydro-2H- obtained in Example 1 was added. A toluene solution of methyl pyran-5-carboxylate (10.00 g, 54.28 mmol) was added dropwise under ice cooling. The reaction mixture was stirred at 40 ° C. for 1 hour, poured into an aqueous potassium sodium tartrate solution, and extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain (2-propyl-3,4-dihydro-2H-pyran-5-yl) methanol (7.26 g, 46.47 mmol).

Example 3 Synthesis of trans-5-((4-ethoxy-2,3-difluorophenoxy) methyl) -2-propyltetrahydro-2H-pyran

First step:
Acetic acid solution of methyl 2-propyl-3,4-dihydro-2H-pyran-5-carboxylate (44.29 g, 240.40 mmol) and triethylsilane (83.86 g, 721.20 mmol) obtained in Example 1 To the mixture, methanesulfonic acid (69.31 g, 721.20 mmol) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain methyl 6-propyl-tetrahydro-2H-pyran-3-carboxylate (39.00 g, yield 86.7%). The isomer ratio of the obtained product was cis: trans = 17.4: 82.6.

Second step:
To a toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride (3.6M toluene solution, 23.8 ml, 86.56 mmol), 2-propyl-3,4-dihydro-2H- obtained in Example 1 was added. A toluene solution of methyl pyran-5-carboxylate (14.66 g, 77.80 mmol) was added dropwise under ice cooling. The reaction mixture was stirred at 40 ° C. for 1 hour, poured into a 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain (6-propyltetrahydro-2H-pyran-3-yl) methanol (10.00 g, yield 80.2%). The isomer ratio of the obtained product was cis: trans = 16.7: 83.3.

Third step:
To a dichloromethane solution of (6-propyltetrahydro-2H-pyran-3-yl) methanol (10.00 g, 63.19 mmol) and carbon tetrabromide (22.00 g, 66.35 mmol) obtained in the second step, Triphenylphosphine (17.40 g, 66.35 mmol) was added under ice cooling. The reaction mixture was stirred at room temperature for 1 hour and then concentrated with an evaporator. The residue was purified by silica gel chromatography to obtain 5- (bromomethyl) -2-propyltetrahydro-2H-pyran (11.00 g, yield 78.7%). The isomer ratio of the obtained product was cis: trans = 8.8: 91.2.

Fourth step:
5- (Bromomethyl) -2-propyltetrahydro-2H-pyran (11.00 g, 49.74 mmol), potassium carbonate (6.87 g, 49.74 mmol) and 4-ethoxy-2,3 obtained in the third step A mixture of difluorophenol (8.66 g, 49.74 mmol) was stirred in DMF at 70 ° C. for 5 hours. The reaction mixture was poured into water and extracted with toluene. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography and recrystallization to give trans-5-((4-ethoxy-2,3-difluorophenoxy) methyl) -2-propyltetrahydro-2H-pyran (9.32 g, yield). 59.6%). The isomer ratio of the crude product was cis: trans = 1.9: 98.1.

¹ H-NMR (CDCl ₃ ; δ ppm): 6.63-6.57 (2H, m), 4.15 (1H, ddd, J = 11.2, 4.1, 2.2 Hz), 4.05 (2H, q, J = 7.0 Hz), 3.82, 3.75 (2H, ABqd, J = 9.5, 5.3, 7.1 Hz), 3.26 (1H, dd, J = 11 .2, 11.2 Hz), 3.25-3.21 (1H, m), 2.15-2.06 (1H, m), 1.95-1.91 (1H, m), 1.71 -1.67 (1H, m), 1.57-1.31 (6H, m), 1.41 (3H, t, J = 7.0 Hz), 0.92 (3H, t, J = 7. 1 Hz).

Example 4 Synthesis of methyl 6-pentyl-tetrahydro-2H-pyran-3-carboxylate

  Methyl 2-pentyl-3,4-dihydro-2H-pyran-5-carboxylate (2.00 g, 9.42 mmol) synthesized by the method described in Example 1 and 1,1,3,3-tetramethyldi Methanesulfonic acid (2.72 g, mmol) was added dropwise to an acetic acid solution of siloxane (1.89 g, 28.26 mmol) under ice cooling. The reaction mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain methyl 6-pentyl-tetrahydro-2H-pyran-3-carboxylate (1.94 g, yield 96.0%). The steric ratio of the obtained product was cis: trans = 18.4: 81.6.

Example 5 Synthesis of 5-((4-ethoxy-2,3-difluorophenoxy) methyl) -2-pentyltetrahydro-2H-pyran

First step:
(6-Pentyltetrahydro-2H-pyran-3-yl) methanol (cis: trans = 11.1: 88.9) (8.00 g, 42.94 mmol) synthesized with the same method as in Example 2 and pyridine ( Paratoluenesulfonyl chloride (8.60 g, 45.09 mmol) was added to a dichloromethane solution of 3.74 g, 47.24 mmol) under ice cooling. The reaction mixture was stirred overnight and then poured into 1N hydrochloric acid. The dichloromethane layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was used in the next step without purification. The formation of (6-pentyltetrahydro-2H-pyran-3-yl) methyl 4-methylbenzenesulfonate was confirmed by gas chromatography mass spectrometry.

Second step:
(6-pentyltetrahydro-2H-pyran-3-yl) methyl 4-methylbenzenesulfonate (14.62 g, 42.94 mmol), potassium carbonate (5.93 g, 42.94 mmol) obtained in the first step and A mixture of 4-ethoxy-2,3-difluorophenol (7.47 g, 42.94 mmol) was stirred in DMF at 70 ° C. for 5 hours. The reaction mixture was poured into water and extracted with toluene. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The formation of 5-((4-ethoxy-2,3-difluorophenoxy) methyl) -2-propyltetrahydro-2H-pyran was confirmed by gas chromatography mass spectrometry. The isomer ratio of the crude product was cis: trans = 5.8: 94.2.

¹ H-NMR (CDCl ₃ ; δ ppm): 6.65-6.59 (2H, m), 4, 18 (1H, ddd, J = 11.2, 4.1, 2.2 Hz), 4.07 (2H, q, J = 7.0 Hz), 3.84, 3.78 (2H, ABqd, J = 9.5 Hz, 5.5, 7.1 Hz), 3.28 (1H, dd, J = 11 .1, 11.1 Hz), 3.27-3.22 (1H, m), 2.17-2.09 (1H, m), 1.97-1.93 (1H, m), 1.74. -1.70 (1H, m), 1.58-1.51 (1H, m), 1.49-1.26 (9H, m), 1.44 (3H, t, J = 7.0 Hz) , 0.91 (3H, t, J = 7.3 Hz).

Example 6 Synthesis of trans-5-((4-ethoxy-2,3-difluorophenoxy) methyl) -2-pentyltetrahydro-2H-pyran

  5- (Bromomethyl) -2-propyltetrahydro-2H-pyran (cis: trans = 17.8: 82.2) (5.00 g, 18.54 mmol), potassium carbonate (5.12 g, 37.08 mmol) and 4 A mixture of '-ethoxy-2', 3,3'-trifluoro- [1,1'-biphenyl] -4-ol (5.22 g, 19.47 mmol) was stirred in DMF at 70 ° C. for 5 hours. The reaction mixture was poured into water and extracted with toluene. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography and recrystallization, trans-5-(((4′-ethoxy-2 ′, 3,3′-trifluoro- [1,1′-biphenyl] -4-yl) oxy) Methyl-2-propyltetrahydro-2H-pyran was obtained (4.55 g, yield 60.0%) The isomer ratio of the crude product was cis: trans = 6.4: 93.6.

¹ H-NMR (CDCl ₃ ; δ ppm): 7.23 (1H, dt, J = 12.3, 1.4 Hz), 7.19 (1H, d, J = 8.7 Hz), 7.03 (1H , Td, J = 8.6, 2.2 Hz), 6.97 (1H, t, J = 8.7 Hz), 6.77 (1H, dd, J = 8.3, 1.8 Hz), 4. 18 (1H, ddd, J = 11.2, 4.2, 2.2 Hz,), 4.15 (2H, q, J = 7.1 Hz), 3.90, 3.84 (2H, ABqd, J = 9.5, 5.4, 7.0 Hz), 3.28 (1H, dd, J = 11.5, 11.1 Hz), 3.28-3.23 (1H, m), 2.20- 2.12 (1H, m), 1.99-1.96 (1H, m), 1.72-1.68 (1H, m), 1.55-1.30 (6H, m), 1. 47 (3H, t, J = .0Hz), 0.92 (3H, t, J = 7.3Hz).

Example 7 Synthesis of (E) -5- (2- (4- (2,3-difluoro-4-propylphenyl) cyclohexyl) vinyl) -2-propyltetrahydro-2H-pyran

First step:
5- (Bromomethyl) -2-propyltetrahydro-2H-pyran (cis: trans = 17.8: 82.2) (10.33 g, 46.71 mmol), 1-phenyl-1H-tetrazole-5-thiol (7 .57 g, 42.47 mmol), tetrabutylammonium hydrogen sulfate (1.44 g, 4.25 mmol) and potassium hydroxide (2.62 g, 46.71 mmol) in a toluene-water mixed solvent at room temperature. Stir for 3 hours. The toluene layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain 1-phenyl-5-(((6-propyltetrahydro-2H-pyran-3-yl) methyl) thio) -1H-tetrazole (9.64 g, yield 71). .3%).

Second step:
(1-Phenyl-5-(((6-propyltetrahydro-2H-pyran-3-yl) methyl) thio) -1H-tetrazole (9.64 g, 30.27 mmol), tetrabutyl obtained in the first step To an ethanol solution of ammonium hydrogensulfate (1.03 g, 3.03 mmol) and ammonium molybdate (1.00 g, 1.51 mmol) was added dropwise 30% aqueous hydrogen peroxide at 30 ° C. The reaction mixture was stirred overnight. After being poured into water and extracted with toluene, the combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. 5-(((6-Propyltetrahydro-2H-pyran-3-yl) methyl) sulfonyl) -1H-tetrazole was obtained (9.08 g, yield 85. %).

Third step:
1-phenyl-5-(((6-propyltetrahydro-2H-pyran-3-yl) methyl) sulfonyl) -1H-tetrazole (7.59 g, 21.66 mmol) and 4- ( To a solution of 4-ethoxy-2,3-difluorophenyl) cyclohexane-1-carbaldehyde (7.57 g, 42.47 mmol) in dimethoxyethane was added potassium t-butoxide at −65 ° C. The reaction mixture was returned to room temperature and then stirred at 60 ° C. for 2 hours. The reaction mixture was poured into water and extracted with toluene. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain (E) -5- (2- (4- (2,3-difluoro-4-propylphenyl) cyclohexyl) vinyl) -2-propyltetrahydro-2H-pyran ( 1.40 g, yield 19.7%)

¹ H-NMR (CDCl ₃ ; δ ppm): 6.83 (1H, td, J = 8.9, 2.2 Hz), 6.66 (1H, ddd, J = 16.5, 8.1, 1) .8 Hz), 5.44, 5.19 (2H, AXqd, J = 15.8, 6.9 Hz), 4.09 (2H, q, J = 7.0 Hz), 3.86 (1H, ddd, J = 11.2, 4.4, 2.1 Hz,), 3.21-3.16 (1H, m), 3.10 (1H, dd, J = 14.1, 11.2 Hz), 2. 73 (1H, tt, J = 12.2, 3.2 Hz), 2.21-2.15 (1H, m), 1.98-1.90 (1H, m), 1.88-1.81 (5H, m), 1.65-1.1.63 (1H, m), 1.53-1.1.20 (10H, m), 1.43 (3H, t, J = 7.0 Hz) , 0.91 (3 , T, J = 7.3Hz).

  By using the production method of the present invention, it is possible to provide a tetrahydro-2H-pyran derivative and an intermediate more easily and cheaply than the prior art. In particular, a trans-tetrahydro-2H-pyran-2,5-diyl derivative suitable for a liquid crystal compound can be provided.

Claims (7)

A method for producing a tetrahydro-2H-pyran derivative using compound (A), compound (B), or compound (C) as an intermediate.

In the compound (A), the compound (B), and the compound (C), R ¹ is alkyl, alkenyl, or alkoxy, R ² is hydrogen or alkoxy, and X is a leaving group. In Compound (A), Compound (B), or Compound (C), R ¹ is alkyl, X is nonafluorosulfonate, trifluoromethanesulfonate, fluorosulfonate, tosylate, mesylate, iodine, bromine, or chlorine, tetrahydro -2H- pyran method according to claim 1 R ² is hydrogen.   The method for producing a tetrahydro-2H-pyran derivative according to claim 1 or 2, wherein the compound (A), compound (B), or compound (C) derived from optionally substituted δ-valerolactone is used as an intermediate. . The method for producing a tetrahydro-2H-pyran derivative according to any one of claims 1 to 3, wherein the compound represented by the formula (1) is a target product.

In equation (1),
R ¹ is alkyl having 1 to 10 carbons;
R ⁴ is hydrogen, a cycloalkane having 3 to 8 carbon atoms, or alkyl having 1 to 10 carbon atoms, in which at least one —CH ₂ — may be replaced by —O—, and at least 1 Two —CH ₂ CH ₂ — may be replaced by —CH═CH—;
Ring A ¹ , Ring A ² , and Ring A ³ are independently 1,4-cyclohexylene, 1,4-cyclohexenylene, 1,4-phenylene, 1 in which at least one hydrogen is replaced with a halogen , 4-phenylene, naphthalene-2,5-diyl, naphthalene-2,5-diyl, tetrahydro-2H-pyran-2,5-diyl, pyrimidine-2,5-diyl wherein at least one hydrogen is replaced by halogen , Pyridine-2,5-diyl, or 1,3-dioxane-2,5-diyl;
Z ¹ is —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ O—, or —COO—;
Z ² and Z ³ are each independently a single bond, —CH ₂ CH ₂ —, —C≡C—, —CH═CH—, —CF ₂ O—, —OCF ₂ —, —OCH ₂ —, —CH ₂ O—, —OCO—, —COO—, —CH ₂ CH ₂ CH ₂ O—, or —OCH ₂ CH ₂ CH ₂ —;
n and m are independently 0 or 1.   The manufacturing method of the tetrahydro-2H-pyran derivative of any one of Claim 1 to 4 including the process of etherification reaction. Compound represented by formula (2)

In formula (2), R ¹ is alkyl, alkenyl, or alkoxy, R ² is hydrogen or alkoxy;
Q is one of the following structures.

  Use of the compound represented by the formula (1) produced by the production method of claim 4 or 5 as a component of a liquid crystal medium.