JP5484724B2 - Tetrahydropyran derivatives containing a plurality of oxygen-containing rings and method for preparing the same - Google Patents

Description

  The present invention relates to a process for the preparation of tetrahydropyran derivatives comprising a ring containing at least one further oxygen. In particular, compounds are prepared that contain two tetrahydropyran rings or at least one tetrahydropyran ring and at least one dioxane ring. Here, condensation with aldehydes and / or ring closure reactions are used. This preparation method produces a novel tetrahydropyran compound containing at least two O-heterocycles.

  Compounds having a tetrahydropyran ring as the central component of the molecule can be used, for example, as components of natural and synthetic fragrances, in drugs or mesogenic or liquid crystal compounds, or as precursors for the synthesis of these substances. It plays an important role in organic chemistry.

  Liquid crystal materials often have 1,4-substituted cyclohexane rings with a generally rod-like structure. When these cyclohexane rings are replaced in any desired direction by 2,5-substituted tetrahydropyran units, the overall physical properties of the molecule can be satisfactorily improved depending on the direction of the electronegative oxygen atom. In particular, an increase in dielectric anisotropy (Δε) can be achieved in both positive (Δε> 0) and negative (Δε <0) dielectric compounds.

  An example of a positive value of Δε is described in EP148201919A1 (Patent Document 1). Similarly, in a compound as described in EP0967261A1 (Patent Document 2), the value of negative Δε may increase. Has been found. Similarly, it is considered that the absolute value of Δε decreases specifically through tetrahydropyran units in opposite directions.

  An increase in positive Δε is advantageous for use in, for example, an IPS (In Plane Switching) type liquid crystal display, and an increase in negative Δε is advantageous in a VA (Vertical Alignment) type liquid crystal display.

  DE3306960A1 (Patent Literature 3), DE10353658A1 (Patent Literature 4), DE10353656A1 (Patent Literature 5), DE10359469A1 (Patent Literature 6), DE10318420A1 (Patent Literature 7) and EP1482021A1 (Patent Literature 8) and the above literature include 2,5. A substituted tetrahydropyran ring is disclosed as a component of the liquid crystal molecular structure. Although structurally interesting, heterocyclic structures such as the tetrahydropyran ring present the challenge of being asymmetric. Thus, not all of the benefits of these compounds are well known and to date the potential for structural diversity is not exhausted.

In particular, the combination of a tetrahydropyran ring with a further dioxane ring has so far only been described in document DE102004025808A1 (Patent Document 9) regarding its mesogenic properties. Compounds containing two or more dioxane and tetrahydropyran rings are not known as liquid crystals. At least two O- heterocycle (i.e., dioxane or tetrahydropyran) known liquid crystal or mesogenic material containing the to _{date, -CF 2 O -, - OCF} 2 -, - CF 2 CF 2 -, - Any chain linking element comprising a fluorinated group such as CH═CH—, —CF═CF—, —CH ₂ CH ₂ CF ₂ O— or —CF ₂ OCH ₂ CH ₂ — (below Z ¹ ~Z ⁶ referred to as) also does not include. In DE102004025808A1 (Patent Document 9), the pyran ring and the dioxane ring are all directly connected to each other.
EP1482019A1 EP0967261A1 DE3306960A1 DE10353658A1 DE10353656A1 DE10359469A1 DE10318420A1 EP1482021A1 DE102004025808A1

  Thus, methods for obtaining known mesogenic or liquid crystalline materials containing tetrahydropyran rings and further tetrahydropyran rings or dioxane rings and having favorable physical and chemical properties, and for using them in liquid crystal mixtures, The object is to prepare a novel liquid crystal substance of this structural type.

  This object is achieved according to the invention by the compounds of general formula I and the process for preparing them.

ただし、式Ｉ中、

However, in Formula I,

ａ、ｂ、ｃ、ｄ、ｅ、ｆは、互いに独立に、０または１を表し、ただし、ａ＋ｂ＋ｃ＋ｄ＋ｅ＋ｆは、１、２、３、４、５または６に等しく、およびｃ＋ｄは０に等しくなく、
Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ａ^５、Ａ^６は、互いに独立に、同一または異なって、回転されたものまたは鏡像のものでもよく、以下を表し、

a, b, c, d, e, f, independently of one another, represent 0 or 1, where a + b + c + d + e + f is equal to 1, 2, 3, 4, 5 or 6 and c + d is not equal to 0;
A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , independently of one another, may be the same or different, may be rotated or mirror images, and represent the following:

ただし、Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ａ^５、Ａ^６からの少なくとも１つの環は、ＣまたはＢを表すことを条件とし、
ただし、

Provided that at least one ring from A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ represents C or B;
However,

Ｙ^１、Ｙ^２およびＹ^３は、互いに独立に、水素、ハロゲン、ＣＮ、Ｃ_１〜６−アルカニル、Ｃ_２〜６−アルケニル、Ｃ_２〜６−アルキニル、−ＯＣ_１〜６−アルカニル、−ＯＣ_２〜６−アルケニルまたは−ＯＣ_２〜６−アルキニルを表し、ただし、脂肪族基は無置換であるか、ハロゲンにより１置換または多置換されており、
Ｚ^３、Ｚ^４は、単結合、−ＣＨ＝ＣＨ−または−ＣＨ_２ＣＨ_２−を表し、
Ｚ^１、Ｚ^２、Ｚ^５、Ｚ^６は、単結合、１〜６個の炭素原子を有し無置換かＦおよび／またはＣｌで１置換または多置換されているアルキレン架橋、または−ＣＨ＝ＣＨ−、−Ｃ≡Ｃ−、−ＣＦ＝ＣＦ−、−ＣＨ＝ＣＦ−、−ＣＨ_２Ｏ−、−ＯＣＨ_２−、−ＣＯ−Ｏ−、−Ｏ−ＣＯ−、−ＣＦ_２Ｏ−、−ＯＣＦ_２−、−ＣＨ_２ＣＨ_２ＣＦ_２Ｏ−または−ＣＦ_２ＯＣＨ_２ＣＨ_２−を表し、
ｎ１は、０、１、２、３または４であり、
ｎ２およびｎ３は、互いに独立に、０、１、２または３であり、
ｎ４は、０、１または２であり、
Ｗ^１は、−ＣＨ_２−、−ＣＦ_２−または−Ｏ−を表し、
Ｒ^１は、Ｈ、１〜１５個のＣ原子を有するアルキル基で、該基は無置換であるか、−ＣＮにより１置換されているか、ハロゲンにより１置換または多置換されており、ただし加えて、これらの基中の１個以上のＣＨ_２基は、鎖中のヘテロ原子が互いに直接結合しないようにして、−Ｃ≡Ｃ−、−ＣＨ＝ＣＨ−、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−、−ＣＯ−Ｏ−または−Ｏ−ＣＯ−で置き換えられていてもよく、
Ｒ^２は、Ｈ、ハロゲン、ＣＮ、ＮＣＳ、ＳＦ_５、ＣＦ_３、ＯＣＦ_３、ＮＨ_２、１〜１５個のＣ原子を有するアルキル基で、該基は無置換であるか、−ＣＮにより１置換されているか、ハロゲンにより１置換または多置換されており、ただし加えて、これらの基中の１個以上のＣＨ_２基は、鎖中のヘテロ原子が互いに直接結合しないようにして、−Ｃ≡Ｃ−、−ＣＨ＝ＣＨ−、−Ｏ−、−Ｓ−、−ＳＯ−、−ＳＯ_２−、−ＣＯ−Ｏ−または−Ｏ−ＣＯ−で置き換えられていてもよい。

Y ¹ , Y ² and Y ³ each independently represent hydrogen, halogen, CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, -OC _1-6 -alkanyl,- Represents OC _2-6 -alkenyl or —OC _2-6 -alkynyl, provided that the aliphatic group is unsubstituted or mono- or polysubstituted by halogen;
Z ³ and Z ^{4 each} represents a single bond, —CH═CH— or —CH ₂ CH ₂ —,
Z ¹ , Z ² , Z ⁵ , Z ⁶ are a single bond, an alkylene bridge having 1 to 6 carbon atoms, unsubstituted or mono- or polysubstituted with F and / or Cl, or —CH═ CH—, —C≡C—, —CF═CF—, —CH═CF—, —CH ₂ O—, —OCH ₂ —, —CO—O—, —O—CO—, —CF ₂ O—, _{-OCF 2 -, - CH 2 CH} 2 CF 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
R ¹ is H, an alkyl group having 1 to 15 C atoms, which is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen, provided that One or more CH ₂ groups in these groups are such that the heteroatoms in the chain are not directly bonded to each other so that —C≡C—, —CH═CH—, —O—, —S—, _{-SO -, - SO 2 -,} - CO-O- or may be replaced by -O-CO-,
R ² is H, halogen, CN, NCS, SF ₅ , CF ₃ , OCF ₃ , NH ₂ , an alkyl group having 1 to 15 C atoms, which group is unsubstituted or 1 by —CN Substituted or monosubstituted or polysubstituted by halogen, but in addition, one or more of the CH ₂ groups in these groups is such that the heteroatoms in the chain are not directly bonded to each other, ≡C -, - CH = CH - , - O -, - S -, - SO -, - SO 2 -, - CO-O- or may be replaced by -O-CO-.

The main features of the present invention include a simple process for preparing the compounds of formula I of the present invention. The method of the present invention is summarized in Scheme 1 and described in detail below. Here, MES and MES ′ represent mesogenic components. For example, the formula MES = R ¹ − (A ¹ −Z ¹ ) _a − (A ² −Z ² ) _b − (A ³ −Z ³ ) _c - or ^{MES '= R 2 - (a} 6 -Z 6) f - (a 5 -Z 5) e - (a 4 -Z 4) d - reproduced in the partial ^structure, Z ^{1~6, a 1~ 6} , af, R ¹ and R ² are as defined in Formula I. Similarly, MES and MES ′ can also represent components that can be derived in a small number of reaction steps to give the completed structure and thus correspond to the synthetic precursors of the desired final compound. For example, MES can contain a 1,3-diol group as a precursor for building a 1,3-dioxane ring. At least one of the partial structures MES and MES ′ comprises a further O-heterocycle (1,3-dioxane-2,5-diyl, tetrahydropyran-2,5-diyl), and as a whole at least one pyran ring Means present in the molecule. The reaction in Scheme 1 leads the product of Formula I from the starting material either directly or through an intermediate. Usually, following ring closure metathesis, for example, the double bond formed in the formation of the dihydropyran ring is catalytically hydrogenated.

式Ｉの化合物を調製するための本発明の方法は、以下で特徴付けられる。

The process of the invention for preparing compounds of formula I is characterized below.

  a) a diol and an aldehyde are condensed with each other to obtain the following dioxane compound,

または
ｂ）ジエン化合物をオレフィンメタセシスで環化して下記ピラン類を得て、および引き続き水素化して式Ｉの化合物を得るか、

Or b) cyclizing the diene compound with olefin metathesis to obtain the following pyrans and subsequent hydrogenation to obtain a compound of formula I,

または
ｃ）エニンエーテルを該エニンのオレフィン閉環メタセシスにより環化して下記ピラン化合物類を得て、および引き続き水素化により式Ｉの化合物類に転化するか、

Or c) cyclization of the enine ether by olefin ring-closing metathesis of the enine to give the following pyran compounds and subsequent conversion to compounds of formula I by hydrogenation,

または
ｄ）２−置換３−ブテニルアルコール（ホモアリルアルコール）および下式のアルデヒドを反応させて下式のピラン誘導体類を得て、およびそして（還元的）脱離および／または水素化による１つ以上の工程を経て式Ｉの化合物に転化するか、

Or d) reacting 2-substituted 3-butenyl alcohol (homoallyl alcohol) with an aldehyde of the following formula to give pyran derivatives of the following formula, and (reductive) 1 by elimination and / or hydrogenation: Conversion to a compound of formula I via one or more steps,

または
ｅ）２−置換３−ブテニルアルコール（ホモアリルアルコール）および少なくとも最初に水酸基が保護されている下式の２−ホルミル−１，３−ジオールを反応させて下式のピラン中間体の１つを得て、

Or e) reacting 2-substituted 3-butenyl alcohol (homoallyl alcohol) and 2-formyl-1,3-diol of the following formula, wherein the hydroxyl group is first protected, to give 1 of the pyran intermediate of the formula Get one

この中間体より、還元的脱離または還元、ジオールの脱保護、およびアルデヒドＯＨＣ−ＭＥＳ’と反応により化合物：

From this intermediate, the compound is obtained by reductive elimination or reduction, diol deprotection, and reaction with aldehyde OHC-MES ′:

を得る。
ただし、式中
Ｘ^１は、塩素、臭素またはヨウ素を表し、
Ｒ^３およびＲ^４は、アルコールのための保護基であり、および
ＭＥＳ、ＭＥＳ’は、メソゲン性、特にカラミティックメソゲン性または棒形状の基を表す。

Get.
Where X ¹ represents chlorine, bromine or iodine,
R ³ and R ⁴ are protecting groups for the alcohol, and MES, MES ′ represent mesogenic, in particular calamitic mesogenic or rod-shaped groups.

  The properties common to the variants a) to e) of the invention for the first time open the way to simple and variable and replaceable access to tetrahydropyran compounds containing multiple O-heterocycles.

  The process according to the invention for preparing compounds of the formula I is in particular characterized by:

  a) condensing a diol of formula II and an aldehyde of formula III with each other to obtain a dioxane compound of formula Ia,

または
ｂ）式ＩＶの化合物をオレフィンメタセシスで環化して式Ｖの化合物を得て、引き続き水素化して式Ｉの化合物を得るか、

Or b) cyclizing the compound of formula IV with olefin metathesis to give a compound of formula V followed by hydrogenation to give a compound of formula I,

または
ｃ）式Ｑａのエニンエーテルを該エニンのオレフィン閉環メタセシスにより環化して式Ｑｂの化合物を得て、引き続き水素化により式Ｉの化合物に転化するか、

Or c) cyclizing the enine ether of formula Qa by olefin ring-closing metathesis of the enine to obtain a compound of formula Qb, followed by conversion to a compound of formula I by hydrogenation,

または
ｄ）式ＶＩの２−置換３−ブテニルアルコール（ホモアリルアルコール）および式ＶＩＩのアルデヒドを反応させて式ＶＩＩＩまたはＩＸのピラン誘導体を得て、そして（還元的）脱離および／または水素化を含む１つ以上の工程を経て式Ｉの化合物に転化するか、

Or d) reacting a 2-substituted 3-butenyl alcohol of formula VI (homoallyl alcohol) and an aldehyde of formula VII to give a pyran derivative of formula VIII or IX and (reductive) elimination and / or hydrogen Conversion to a compound of formula I via one or more steps including

または
ｅ）式ＶＩの２−置換３−ブテニルアルコール（ホモアリルアルコール）および式Ｘのアルデヒドを反応させて式ＸＩまたはＸＩＩの中間体を得て、そして、式Ｉｅの化合物を中間体ＸＩまたはＸＩＩより、還元的脱離または還元し、ジオールを脱保護し、および式ＯＨＣ−［Ｚ^５−Ａ^５］_ｅ−［Ｚ^６−Ａ^６］_ｆ−Ｒ^２のアルデヒドと反応させて得る。

Or e) reacting a 2-substituted 3-butenyl alcohol of formula VI (homoallyl alcohol) and an aldehyde of formula X to give an intermediate of formula XI or XII and the compound of formula Ie to intermediate XI or Obtained from XII by reductive elimination or reduction, deprotection of the diol and reaction with an aldehyde of the formula OHC- [Z ⁵ -A ⁵ ] _e- [Z ⁶ -A ⁶ ] _f -R ² .

ただし、式中、
Ｘ^１は、塩素、臭素またはヨウ素を表し、
Ｒ^３およびＲ^４は、アルコールのための保護基であり、および
Ｒ^１、Ｒ^２、Ｂ、Ａ^１〜Ａ^６、ａ〜ｆおよびＺ^１〜Ｚ^６は、式Ｉで示される意味を有する。

However, in the formula:
X ¹ represents chlorine, bromine or iodine,
R ³ and R ⁴ are protecting groups for the alcohol, and R ¹ , R ² , B, A ^{1 to} A ⁶ , a to f and Z ^{1 to} Z ⁶ have the meanings shown in Formula I .

  In a preferred embodiment of process item a), B in the aldehyde compound of formula III represents the group of formula

酸素含有環およびＯ−複素環との用語は、特にピランおよびジオキサン環、特には２，５−置換ピラン誘導体（Ｂ）および２，５−置換１，３−ジオキサン誘導体（Ｃ）を表す。飽和している変体、即ちテトラヒドロピラン類および１，３−ジオキサン類、および１不飽和ジヒドロピラン類が好ましい。複素環は、好ましくは、無置換であるか、２，５−位で離れているか、１〜２個のハロゲン置換を有している。

The terms oxygen-containing ring and O-heterocycle represent in particular pyran and dioxane rings, in particular 2,5-substituted pyran derivatives (B) and 2,5-substituted 1,3-dioxane derivatives (C). Saturated variants are preferred, ie tetrahydropyrans and 1,3-dioxanes, and monounsaturated dihydropyrans. The heterocycle is preferably unsubstituted, separated at the 2,5-position, or has 1-2 halogen substitutions.

The compounds of formula I obtained from the method of the invention contain at least one pyran ring. In addition, the compounds of the formula I comprise at least one further O-heterocycle in the defined ring positions A ^{1 to} A ⁶ . Process variant a) results in compounds containing dioxane in addition to the pyran rings in the direction previously specified with respect to each other. According to other variants b) to e), further chain elements Z and A may also be located between the O-heterocycles. Preferably, the bond, ethylene bridge, vinylene bridge, cyclohexane-1,4-diyl ring, 1,3-cyclobutane-1,3-diyl ring or spiro [3.3] heptane-2,6-diyl ring is 2 Located between two O-heterocycles. Bonds or ethylene bridges, very particularly preferably single bonds, are particularly preferably located between the rings.

  The preparation of the starting material is described below.

In the first embodiment of the preparation method of the present invention, as shown in Scheme 2, the compound of formula I is prepared via a condensation reaction between an aldehyde group and a 1,3-propanediol compound substituted at the 2-position. Is done. Here, the aldehyde functional group is linked to the tetrahydropyran ring B, either directly or via a linking element Z ³ . At the same time, the position of the oxygen atom in the tetrahydropyran ring can be changed through the selection of an appropriate aldehyde compound.

スキーム２の好ましい実施形態において、式Ｉａのジオキサンジオキサン化合物は式ＩＩのジオールおよび式ＩＩＩのアルデヒドよりトルエン中で酸触媒により形成される。添加される酸は、好ましくはスルホン酸、特に好ましくはｐ−トルエンスルホン酸またはトリフルオロメタンスルホン酸である。好ましい方法において、形成される水は反応混合物より共沸蒸留によって示される反応条件下で除去される。同様に、ジオキサンを形成する好ましい方法は、ルイス酸を触媒とするアセタールを形成する変法である。ルテニウムハロゲン化物またはインジウムハロゲン化物、特にＲｕＣｌ_３およびＩｎＣｌ_３の触媒量の酸による特に穏和な方法も特に好ましい（文献Ｂ．Ｃ．Ｊａｎｕら、Ａｄｖ．Ｓｙｎｔｈ．Ｃａｔａｌ．（２００４）、３４６、４４６〜５０；Ｊ．−Ｙ．Ｑｉら、Ｔｅｔｒ．Ｌｅｔｔ．（２００４）、４５、７７１９〜２１；Ｓ．Ｋ．Ｄｅ、Ｒ．Ａ．Ｇｉｂｂｓ、Ｔｅｔｒ．Ｌｅｔｔ．（２００４）、４５、８１４１〜４参照）。穏和な反応条件は、特にエーテル型の成分を有する化合物および酸に敏感な基に特に適する。

In a preferred embodiment of Scheme 2, the dioxane dioxane compound of formula Ia is formed with an acid catalyst in toluene from a diol of formula II and an aldehyde of formula III. The acid added is preferably a sulfonic acid, particularly preferably p-toluenesulfonic acid or trifluoromethanesulfonic acid. In a preferred process, the water formed is removed from the reaction mixture under the reaction conditions indicated by azeotropic distillation. Similarly, a preferred method of forming dioxane is a modified method of forming acetals catalyzed by Lewis acids. A particularly mild method with ruthenium halides or indium halides, in particular RuCl ₃ and InCl _{3 with} a catalytic amount of acid, is also particularly preferred (ref. BC Janu et al., Adv. Synth. Catal. (2004), 346, 446- 50; see J.-Y.Qi et al., Tetr.Lett. (2004), 45, 7719-21; SK De, RA Gibbs, Tetr.Lett. (2004), 45, 8141-4. ). Mild reaction conditions are particularly suitable for compounds with ether type components and acid sensitive groups.

In a second embodiment of the preparation method of the invention, the compound of formula I is obtained by ring-closing metathesis on a diene compound, and a new pyran ring is formed as ring B as illustrated in Scheme 3. Through the proper selection of dienes, pyran rings with various oxygen atoms in the ring can generally be formed. Unsaturated dihydropyran formed after ring closure is converted to saturated tetrahydropyran, for example by catalytic hydrogenation. Hydrogenation is achieved on suitable homogeneous or heterogeneous metal catalysts, in particular on transition metal catalysts, by methods known from the literature. The diene required as starting material for ring-closing metathesis is preferably prepared by the method shown in Scheme 3a. At least one further tetrahydropyran or dioxane ring is located at the location of rings A ^{1 to} A ⁶ in the formula in scheme 3a, preferably at the location of A ³ and / or A ⁴ . As a result, compound Ib prepared in this embodiment contains at least two tetrahydropyran rings.

ここで、それぞれ式ＸＩＶおよびＸＶのアリルハロゲン化物およびホモアリルは、エーテル結合で連結される。エーテル化は、ジアルキルエーテルを形成するための文献から既知の方法により、原理的に行われる。アリルハロゲン化物ＸＩＶの調製およびエーテル化の可能性は、特にＥＰ１４８２０１８Ａ１に原理的に記載されており、よって、ここでは、代表的な方法で記載する。ホモアリルアルコールＸＶの調製を以下に記載する。

Here, allyl halides and homoallyls of formulas XIV and XV, respectively, are linked by an ether bond. Etherification is carried out in principle by methods known from the literature for forming dialkyl ethers. The preparation of allyl halide XIV and the possibility of etherification are described in particular in principle in EP 1482018 A1, and are therefore described here in a representative manner. The preparation of homoallylic alcohol XV is described below.

When A ³ represents a tetrahydropyran ring and X ² is a halogen or a substituent —OSO ₂ CF ₃ (Scheme 3b), the following synthesis of an allyl halide of formula XIV is preferred.

アルデヒドはＣｏｒｅｙ法（Ｅ．Ｊ．Ｃｏｒｅｙ、Ｐ．Ｌ．Ｆｕｃｈｓ、Ｔｅｔｒ．Ｌｅｔｔ．（１９７２）、３７６９）によりアセチレンに転化され、シリルホルミル化（Ｏｊｉｍａら、Ｔｅｔｒａｈｅｄｒｏｎ（１９９３）、４９、５４３１〜４４）、還元（Ｏｊｉｍａら）および通常の方法によるハロゲン化後、式ＸＩＶの化合物を得る。

Aldehydes are converted to acetylene by the Corey method (EJ Corey, PL Fuchs, Tetr. Lett. (1972), 3769), and silylformylation (Ojima et al., Tetrahedron (1993), 49, 5431-44). ), Reduction (Ojima et al.) And halogenation by conventional methods to give compounds of formula XIV.

  In a third embodiment of the preparation process of the invention, compounds of formula I containing at least two tetrahydropyran rings are prepared from the corresponding substituted enyne ethers by enyne metathesis, as is apparent from Scheme 4.

エニン前駆体の閉環メタセシスを、ＥＰ１４８２０２０Ａ１中のコメントに類似して行う。少なくとも１つの更なるテトラヒドロピランまたはジオキサンがスキーム４の式中の環Ａ^１〜Ａ^６の場所に位置しており、好ましくはＡ^３および／またはＡ^４の場所である。

Ring closure metathesis of the enine precursor is performed analogous to the comments in EP1482020A1. At least one additional tetrahydropyran or dioxane is located at the location of rings A ^{1 to} A ^{6 in} the scheme 4 scheme, preferably at the location of A ³ and / or A ⁴ .

The starting materials necessary for the preparation of Scheme 4 are generated from the preferred variant a) for A ³ equal to 2,5-tetrahydropyrandiyl or b) for A ⁴ equal to 2,5-tetrahydropyrandiyl. Starting materials that do not contain a tetrahydropyran ring are prepared as in EP1482020A1. In variant a), the synthesis of allylated tetrahydropyran is carried out analogously incorporating known methods for preparing tetrahydropyran compounds. In the case of b), formyltetrahydropyran which can be prepared by various methods (DE3306960A1) is required. Possible methods for the preparation of formyltetrapyran are, for example, the oxidation of the corresponding carboxylic acids, which are generally more readily available, the corresponding carbinol reduction or the corresponding dihydropyran formylation with a transition metal catalyst. It is.

In a fourth embodiment of the preparation process of the invention, the compound of formula I is prepared by forming a pyran ring from homoallylic alcohol and an aldehyde. At least one further tetrahydropyran or dioxane ring is located at the location A ^{1 to} A ^{6 in} the formula of Scheme 5, preferably at the location A ³ and / or A ⁴ . In this embodiment of the method, at least one reactive group is preferably linked to a partial structure that functions for the construction of a further tetrahydropyran ring B, dioxane ring or O-heterocycle. This type of group includes in particular those groups which can have a protecting group on the 1,3-diol for building dioxane, homoallyl alcohol for building (hydro) pyran ring or OH function. Derivatives of Preferred protecting groups are benzyl ethers, acetals, acyl derivatives or silyl groups. In a particularly preferred embodiment, the reactants are formyltetrahydropyran and substituted homoallyl alcohol. Said first product of ring formation is a tetrahydropyran of formula VIII substituted with halogen (X ¹ is Cl, Br, I) or a corresponding second product of formula IX with HX ¹ removed from VIII It is a thing. The reaction of the aldehyde with homoallyl alcohol is carried out with the aid of a halogen-containing acid, preferably a halogen-containing Lewis acid, for example in an organic solvent such as dichloromethane. Similar reactions of aldehydes with alkenols are described in J. Am. O. It is described in Metzger et al. And references cited therein (Bull. Soc. Chem. Belg. (1994), 103, 393-7).

The method can be carried out in the presence of a Lewis acid of formula M (X ¹ ) _n or R ⁵ M (X ¹ ) _n-1 , provided that
M represents B, Al, In, Sn, Ti, Fe, Zn, Zr, Au or Bi,
X ¹ represents Cl, Br or I;
R ⁵ represents a linear or branched alkyl group having 1 to 10 carbon atoms,
n is an integer of 2, 3 or 4 and is selected equal to the oxidation number on the M form.

Examples of particularly suitable Lewis acids for the reaction of the present invention are boron, aluminum, iron, zinc or bismuth element halides. For example, AlCl ₃ and BiBr ₃ are very suitable. On the other hand, a Bronsted acid such as hydrogen bromide (HBr) can also be used in place of the Lewis acid. The intermediate of formula VIII is converted (in situ or isolated) to the dihydropyran of formula IX by elimination or directly to the final product of formula I (and here Id) by reductive elimination. The elimination of the halide substituent X ¹ can be performed by the action of a base. Particularly preferably, for example, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1,1, The use of a strong nonionic nitrogen base such as a commercial base, such as 3,3-tetramethylguanidine, is preferred and warmed with bromotetrahydropyran in the solid state or in a solvent for 2-6 hours. Preferred solvents for this purpose are, for example, toluene and dioxane. Hydrogenation of the intermediate of formula IX gives the product of formula I by methods known from the literature, preferably in the form of transition metal complexes of rhodium, ruthenium or iridium with at least one phosphorus-containing ligand. A catalyst is used, particularly preferably a rhodium / phosphine complex such as [Rh (PPh ₃ ) ₃ Cl] or a corresponding mixture of commercial rhodium complex precursors together with a phosphine ligand.

Reductive elimination can be performed by various modifications. In a preferred variant, the reductive elimination of VIII to obtain the Id is carried out by free-radical chain reaction, in the course of the reaction - Given formally - halogen atoms for X ¹ in tetrahydropyran derivative of formula VIII is removed hydrogen Replaced with atoms. Here, X ^{1 in} the compound of the formula VIII to be reacted is particularly preferably bromine or chlorine, in particular bromine.

This variant of reductive elimination is preferably carried out in the presence of organotin hydride or organosilicon hydride. Preferred organotin hydrides here are trialkyl hydrides and monoaralkyldialkyltins, particularly preferably trialkyltin hydrides, in particular tri-n-butyltin hydride (Bu ₃ SnH). Typically 1 to 10 equivalents and preferably 2 to 4 equivalents of tin hydride are used based on the compound of formula VIII to be reduced. Furthermore, the use of organotin hydride bound to a solid, preferably a solid organic support is preferred, and the organotin hydride bound to a very particularly preferred solid support is Bu ₂ SnHLi (Bu is n-butyl). (Formed in situ) with α-haloalkylpolystyrene (eg, U. Gerigk et al., Synthesis (1990), 448-452 and G. Dumartin et al., Synlett. (1994)). 952-954). Organotin hydride bound to a solid carrier is usually used in 2 to 4 equivalents based on the compound of formula VIII.

Preferred organosilicon hydrides are substituted silanes, particularly preferably tris (trialkylsilyl) silanes, in particular tris (trimethylsilyl) silane (TTMSS) (eg M. Ballestri et al., J. Org. Chem. 1991, 56, 678). ~ 683)). The organosilicon hydride is usually used in an amount of 1 to 3 equivalents, preferably 1.1 to 1.5 equivalents, based on the compound of formula VIII to be reduced. TTMSS is used in combination with a further reducing agent such as, for example, a metal hydride complex of sodium borohydride NaBH ₄ (see, eg, M. Lesage et al., Tetrahedron Lett. (1989), 30, 2733-2734). It is very particularly preferred. In this variant, a substoichiometric amount of the actual reducing agent TTMSS can be used, which is reformed during the course of the reaction cycle with sodium borohydride and thus by using the cheaper NaBH ₄ , A considerable amount of relatively expensive TTMSS can be saved. Typical mixing ratios are 2 to 10 times, preferably about 5 times, NaBH ₄ and 5 to 20 mol%, preferably about 10 mol% TTMSS based on the compound of formula VIII.

  A preferred variant of reductive elimination using organotin hydride or organosilicon hydride is for example suitable azo or peroxy of AIBN (2,2′-azobisisobutyronitrile) or tert-butyl hydroperoxide. Usually in the presence of UV light in the presence of at least one free radical chain initiator (“free radical initiator”) such as a compound. Free radical initiators are used in conventional amounts for this type of reaction, preferably in amounts of 1 to 20 mol%. Instead of or in addition to the free radical initiator, the reaction can also be initiated by the action of UV irradiation.

  Suitable solvents for the preferred embodiment of the present invention are hydrocarbons such as heptane, benzene, xylene and ethers such as dimethoxyethane or methoxyethanol. The reaction is usually carried out at 20 to 140 ° C. The reaction time is generally 2 to 24 hours.

In a further preferred variant of reductive elimination, X ¹ in formula VIII is bromine and the reaction with hydrogen is carried out in the presence of a hydrogenation catalyst and an amine. The hydrogenation catalyst is a homogeneous catalyst (eg Pd (0) or Pd (II) or Ni (0) or Ni (II) complex of an alkyl- and / or aryl-substituted phosphine or phosphite ligand) or preferably Is a heterogeneous transition metal catalyst. The hydrogenation catalyst is particularly preferably a heterogeneous palladium or nickel catalyst, in particular palladium on carbon or palladium on aluminum oxide.

  The amine is preferably a trialkylamine, particularly preferably diisopropylethylamine or triethylamine, in particular triethylamine.

式Ｉの化合物の調製方法の第５の実施形態は、スキーム６に従い式ＶＩの２−置換ホモアリルアルコールおよび置換として１，３−ジオールシントンを含む式Ｘのアルデヒドから行われる。Ｒ^３およびＲ^４はジオールの保護基を表す。適当な保護基は、選択的開裂可能なエーテルまたはエステル型の文献より既知の保護基で、ここでは好ましくはベンジルエーテルおよびトリアルキルシリルエーテル（例えば、トリメチルシリルエーテル）である。脱保護後、２つのＯＨ基は、更なるアルデヒドＯＨＣ−（Ｚ^５−Ａ^５）_ｅ−（Ｚ^６−Ａ^６）_ｆ−Ｒ^２との縮合によりジオキサン環を構築するために機能する。ピラン環の形成は、スキーム５の反応と類似して進行する。この目的のために示される反応条件は、この実施形態に適用できる。

A fifth embodiment of the process for preparing the compound of formula I is performed according to scheme 6 from a 2-substituted homoallyl alcohol of formula VI and an aldehyde of formula X containing 1,3-diol synthon as a substitution. R ³ and R ⁴ represent a diol protecting group. Suitable protecting groups are those known from the selectively cleavable ether or ester type literature, here preferably benzyl ethers and trialkylsilyl ethers (eg trimethylsilyl ether). After deprotection, the two OH groups function to build a dioxane ring by condensation with further aldehydes OHC- (Z ⁵ -A ⁵ ) _e- (Z ⁶ -A ⁶ ) _f -R ² . Formation of the pyran ring proceeds analogously to the reaction of Scheme 5. The reaction conditions indicated for this purpose are applicable to this embodiment.

  Thus, according to two embodiments for the condensation of homoallylic alcohol with an aldehyde, the compound of formula VI is converted to an aldehyde of formula VII or X and at least one halide from the series of I, Br and Cl. Preference is given to a process for the preparation of compounds of the formula I, characterized by reacting in the presence of at least one (Lewis) acid comprising.

A particularly preferred fifth embodiment is the reaction under the action of a Lewis acid such as BiBr ₃ . Halogenated tetrahydropyran derivatives can be further reacted via various routes as described above with compounds of formula VIII. A preferred variant is the elimination of hydrogen halide under the action of a base. A preferred method is to treat a 4-bromotetrahydropyran derivative with DBN to obtain a compound of formula XI. Hydrogenate the double bond in the ring of Compound XI, leading to the corresponding tetrahydropyran derivative. Hydrogenation is carried out by catalytic hydrogenation methods known from the literature, for example hydrogenation on rhodium (I) complexes such as rhodium (I) tristriphenylphosphine chloride. A further preferred method is the reductive elimination of the group X ¹ by hydrogenation in the presence of a base such as triethylamine over a transition metal catalyst. X ¹ is preferably bromine.

In the case of the benzyl protecting group, the deprotection of the OH group is carried out by hydrogenation again after or after the hydrogenation of the double bond carried out in advance. Hydrogenation of double bonds with rhodium catalysts is preferred, very preferably rhodium phosphine catalysts. For the deprotection of benzyl ethers, support-fixed noble metal catalysts are preferred, in particular palladium or platinum catalysts on carbon or inert metal oxides, very particularly preferably palladium on carbon. Further guidance to the final product of formula Ie compounds of formula XI are partial structures remain the diol _{^{- [Z 5 -A 5] e}} - [Z 6 -A 6] aldehyde compound having f -R ² And at least once more in a manner analogous to the condensation of a compound of formula II with a compound of formula III. The order of the described reaction steps can also be varied in principle in order to obtain the product Ie.

式Ｉ（またはＩａ、Ｉｂ、Ｉｃ、ＩｄおよびＩｅ）の化合物を調製する先の実施形態も、負または減少されたΔεの特に適当な化合物の調製のために使用でき、複素ピラン成分は誘電異方性に対して（負の）寄与する。スキーム３ａ、４、５および６中の記載に関すれば、特に適当な化合物は左手側に向いているテロラヒドロピラン環によって区別される。形式上、負または減少されたΔεの特に適当な化合物は、基Ｒ^１およびＲ^２を交換し、構造要素Ｚ^１およびＡ^１の１〜６の番号を反転させる、即ち、指数６を１に代え、指数５を２に代え、指数４を３に代え、および反対に、指数１を６に代え、指数２を５に代え、指数３を４に代えることで達成できる。その式の部分的に鏡像反転された構造を形成するための示された方法は、概略図のスキーム１の右手側の部分に対応する。必須のアリルアルコールの調製も定式化でき、スキーム７、８および９を同様に修正することで行える。

The previous embodiments of preparing compounds of formula I (or Ia, Ib, Ic, Id and Ie) can also be used for the preparation of particularly suitable compounds with negative or reduced Δε, where the complex pyran component is Contributes (negative) to directionality. With regard to the description in schemes 3a, 4, 5 and 6, particularly suitable compounds are distinguished by the terahydropyran ring pointing to the left hand side. Formally, particularly suitable compounds with negative or reduced Δε exchange the groups R ¹ and R ² and invert the numbers ¹ to 6 of the structural elements Z ¹ and A ¹ , ie the index 6 to 1. Instead, it can be achieved by replacing index 5 with 2, index 4 with 3, and conversely, index 1 with 6, index 2 with 5, and index 3 with 4. The illustrated method for forming a partially mirrored structure of the formula corresponds to the right-hand part of Scheme 1 in the schematic. The preparation of the essential allyl alcohol can also be formulated and can be made by modifying Schemes 7, 8 and 9 as well.

  Preferred embodiments of said preparation process in variants a) to e) include a process for preparing a compound of formula I characterized by:

前記調製方法の特に好ましい実施形態は、式Ｉ中、中央の部分構造−［Ａ^３−Ｚ^３］_ｃ−Ｂ−［Ｚ^４−Ａ^４］_ｄ−が以下の式の１つであることを特徴とする式Ｉの化合物の調製方法を含む。

Particularly preferred embodiments of the method of preparation, in formula I, the central partial structures _{^{- [A 3 -Z 3] c}} -B- [Z 4 -A 4] d - that is one of the following formulas A process for the preparation of a compound of formula I characterized.

ただし、構造成分が全エカトリアルトランス配置である立体異性体が、非常に特に好ましい。式Ｉ中、中央部分構造−［Ａ^３−Ｚ^３］_ｃ−Ｂ−［Ｚ^４−Ａ^４］_ｄ−が以下の式の１つであることを特徴とする式Ｉの化合物の調製方法が、非常に特に好ましい。

However, stereoisomers whose structural components are all equatorial trans configurations are very particularly preferred. In formula I, the central partial structure ^- there is a process for the preparation of a compound of formula I which is characterized in that one of the following formulas _{^{- [A 3 -Z 3] c}} -B- [Z 4 -A 4] d Very particularly preferred.

同時に、特に好ましい方法は、式ＸＸＩＩＩ、ＸＸＩＶまたはＸＸＶの化合物を調製することを特徴とする。

At the same time, a particularly preferred method is characterized by preparing a compound of formula XXIII, XXIV or XXV.

ただし、
Ｘ^１は、Ｈ、Ｆ、ＣＮ、ＳＦ_５、ＯＣＦ_３、ＣＦ_３またはフッ素を含む電子吸引基を表し、
Ｑは、単結合、−ＣＦ_２Ｏ−または−ＯＣＦ_２−を表し、
Ｌ^１、Ｌ^２、Ｌ^３、Ｌ^４は、それぞれ独立に、同一または異なって、ＨまたはＦを表し、
ａ、ｍ、ｎは、０または１に等しく、
Ｂ^１、Ｂ^２は、独立に、同一または異なって、少なくともＢ^１またはＢ^２はＢに等しいように、Ｂまたは１，３−ジオキサン−２，５−ジイルを表し、および
Ｚ^３は、単結合、−ＣＨ_２ＣＨ_２−または−ＣＨ＝ＣＨ−を表す。

However,
X ¹ represents an electron withdrawing group containing H, F, CN, SF ₅ , OCF ₃ , CF ₃ or fluorine;
Q represents a single bond, —CF ₂ O— or —OCF ₂ —,
L ¹ , L ² , L ³ and L ⁴ are each independently the same or different and each represents H or F;
a, m, n are equal to 0 or 1,
B ^{1, B 2} are independently the same or different, such that at least ^{B 1} or ^{B 2} is equal to B, it represents B or 1,3-dioxane-2,5-diyl, and Z ³ are a single Represents a bond, —CH ₂ CH ₂ — or —CH═CH—.

Very particular preference is given to a process characterized in that in XXIII a compound of formula XXIII is prepared, in which the partial structure —B ¹ —Z ³ —B ² — represents:

同様に、ＸＸＩＶ中、部分構造−Ｂ^１−Ｚ^３−Ｂ^２−が以下を表す式ＸＸＩＶの化合物を調製することを特徴とする方法が、非常に特に好ましい。

Similarly, the process characterized in that in XXIV is characterized by preparing a compound of the formula XXIV in which the partial structure -B ¹ -Z ³ -B ^2- represents

前記調製方法の非常に特に好ましい実施形態は、以下の式Ａ〜Ｆの化合物の調製方法を含む。

A very particularly preferred embodiment of said preparation method comprises the following preparation method of compounds of formula AF.

ただし、ａｌｋｙｌ（アルキル）は下で定義される通りである。式Ａ〜Ｆのａｌｋｙｌ（アルキル）は、好ましくは直鎖状で８個までの炭素原子を有するアルコキシ、アルカニルまたはアルケニル基を表す。

Where alkyl (alkyl) is as defined below. Alkyl (alkyl) of the formulas A to F is preferably straight-chain and represents an alkoxy, alkanyl or alkenyl group having up to 8 carbon atoms.

In the context of the present invention, the term "alkyl"-unless otherwise defined in the description or claims--in its most general sense, is linear or branched, saturated or unsaturated. Carbon atoms of 1-15 (ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) carbon atoms that are saturated An aliphatic hydrocarbon group, which is unsubstituted or mono- or polysubstituted with fluorine, chlorine, bromine, iodine, carboxyl, nitro, NH ₂ , N (alkanyl) ₂ and / or cyano, provided that , They may be polysubstituted by the same or different substituents. The alkyl group in the aliphatic hydrocarbon chain may itself be functionalized.

When the alkyl group is saturated, it is also called “alkanyl”. Furthermore, the term “alkyl” also includes hydrocarbon groups which are unsubstituted or correspondingly the same or different, in particular mono- or polysubstituted by F, Cl, Br, I and / or CN, one or more CH ₂ groups, as hetero atoms in the chain (O or S) are not linked directly to one another, -O- ( "alkoxy", "oxaalkyl"), - S- ( "thioalkyl"), —SO ₂ —, —CH═CH — (“alkenyl”), —C≡C — (“alkynyl”), — (CO) O— or —O (CO) — may be substituted. Preferably, alkyl is a straight or branched, unsubstituted or substituted alkanyl, alkenyl or alkoxy group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Where alkyl represents an alkanyl group, this is preferably methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, neopentyl, n-hexyl, n- heptyl, n- _{octyl, CF 3, CHF 2, CH} 2 F, CF 2 CF 3. The alkanyl group is particularly preferably straight-chain, unsubstituted or substituted with F.

The term “alkyl” also includes “alkoxy” or “oxaalkyl” groups, as one or more CH ₂ groups in an alkyl group may be replaced by —O—. Alkoxy means an O-alkyl group in which the oxygen atom is substituted by an alkoxy group or directly attached to a substituted ring, where alkyl is as defined above; alkyl is preferably alkanyl Or alkenyl. Preferred alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy and octyloxy, although each of these groups is preferably substituted by one or more fluorine atoms. Particularly preferably, _{alkoxy, OCH 3, OC 2 H 5} , O-n-C 3 H 7, O-n-C 4 H 9, O-t-C 4 H 9, OCF 3, OCHF 2, OCHF , or it is a OCHFCHF _2. In the context of the present invention, the term “oxaalkyl” refers to an alkyl in which at least one non-terminal CH ₂ group is replaced by —O— so that there are no adjacent heteroatoms (O or S). Means a group. Preferably, the oxaalkyl comprises a linear group of formula C _a H _{2a + 1} —O— (CH ₂ ) _b —, wherein a and b are each independently 1, 2, 3, 4, 5, 6, Represents 7, 8, 9 or 10, and particularly preferably, a is an integer of 1 to 6 and b is 1 or 2.

  The starting materials in the indicated synthesis, in particular the diols of the formula II and the aldehydes of the formulas III and VII, are known from the prior art, are commercially available or prepared in principle by synthetic methods known from the literature it can.

  The homoallylic alcohols of the formulas VI and XV are also known from the prior art, are commercially available or can themselves be easily prepared by synthetic methods known from the literature.

  Scheme 7 shows the synthesis of 1-substituted homoallyl alcohols from aldehydes. In this synthesis, for example, an allyl-Grignard reagent is reacted with an aldehyde. In this case, aldehydes are known compounds, can be prepared by standard methods, or can be obtained by methods based on examples.

スキーム８は、式ＸＶＩＩＩのハロゲン化アリル誘導体より出発してホモアリルアルコールの２−置換改変体の合成経路の概要を示す。

Scheme 8 outlines a synthetic route for 2-substituted variants of homoallyl alcohol starting from an allyl halide derivative of formula XVIII.

式ＶＩＩＩの化合物（これは例えばアルデヒドＲ^１−［Ａ^１−Ｚ^１］_ａ−［Ａ^２−Ｚ^２］_ｂ−ＣＨＯより出発して、例えばＲｅｆｏｒｍａｔｓｋｙ合成により不飽和エステルＲ^１−［Ａ^１−Ｚ^１］_ａ−［Ａ^２−Ｚ^２］_ｂ−ＣＨ＝ＣＨ−ＣＯ_２−アルカニルを得て、引き続きＤＩＢＡＬ−Ｈを使用して対応するアリルアルコールＲ^１−［Ａ^１−Ｚ^１］_ａ−［Ａ^２−Ｚ^２］_ｂ−ＣＨ＝ＣＨ−ＣＨ_２ＯＨ還元し、最後にＰＢｒ_３（Ｈａｌ＝Ｂｒ）、ＰＣｌ_５またはＳＯ_２Ｃｌ_２（Ｈａｌ＝Ｃｌ）またはＨＩ（Ｈａｌ＝Ｉ）を使用して合成される）から出発して適当な金属または有機金属試薬との反応により化合物ＸＩＸを得る。ここで「Ｍｅｔ」はＣｕ、Ｂｉ（ｒａｄｉｃａｌ）_２、Ｉｎ（ｒａｄｉｃａｌ）_２、Ｓｎ（ｒａｄｉｃａｌ）_３、Ｓｎ（ｒａｄｉｃａｌ）、Ｚｎ（ｒａｄｉｃａｌ）、Ｇｅ（ｒａｄｉｃａｌ）を表し、使用される金属または有機金属試薬に依存して、「ｒａｄｉｃａｌ」は１種類以上の有機基、配位子または該金属上の対イオンを表す。中間体として形成されたＸＩＸを先立って単離することなく行うこともできるが、式ＸＩＸの化合物とホルムアルデヒド（または合成上同等のもの）の反応により、対応する処理の後に式ＩＩＩの所望のホモアリルアルコールを得る。

Compounds of the formula VIII (which are, for example, starting from the aldehydes R ^1- [A ¹ -Z ¹ ] _a- [A ² -Z ² ] _b -CHO, eg unsaturated esters R ^1- [A ^1- Z ¹ ] _a- [A ² -Z ² ] _b —CH═CH—CO ₂ -alkanyl is obtained, followed by the corresponding allyl alcohol R ^1- [A ¹ -Z ¹ ] _a − using DIBAL-H. [A ² -Z ² ] _b —CH═CH—CH ₂ OH reduced, finally using PBr ₃ (Hal = Br), PCl ₅ or SO ₂ Cl ₂ (Hal = Cl) or HI (Hal = I) Compound XIX is obtained by reaction with a suitable metal or organometallic reagent. Here, “Met” represents Cu, Bi (radical) ₂ , In (radical) ₂ , Sn (radical) ₃ , Sn (radical), Zn (radical), Ge (radical), and the metal or organometallic used Depending on the reagent, “radical” refers to one or more organic groups, ligands or counterions on the metal. XIX formed as an intermediate can also be carried out without prior isolation, but the reaction of the compound of formula XIX with formaldehyde (or a synthetic equivalent) can result in the desired homology of formula III after the corresponding treatment. Obtain allyl alcohol.

  Further acquisition of the homoallylic alcohol of formula III is performed as shown in Scheme 9. “Hal” has the same meaning as above in Scheme 8, “Met” is preferably Cu (see A. Carpita, R. Rossi, Synthesis (1982), 469).

ハロゲン化物ＸＸは、−スキーム８中の方法に対応するやり方で−適当な試薬を使用して有機金属誘導体ＸＸＩに転化され、引き続きＸＸＩＩと反応させて酢酸ホモアリルＸＸＩＩＩを得る。そして、式ＩＩＩの所望のホモアリルアルコールは、ＸＸＩＩＩから鹸化によって入手可能である。

The halide XX is converted to the organometallic derivative XXI using a suitable reagent in a manner corresponding to the method in Scheme 8 and subsequently reacted with XXII to give homoallyl acetate XXIII acetate. The desired homoallylic alcohol of formula III is then available from XXIII by saponification.

Furthermore, the homoallyl alcohol of the formula III in which R ^1- [A ¹ -Z ¹ ] _a- [A ² -Z ² ] _b- represents an alkyl group is also an alkyl chloride R ^1- [A ¹ of the dianion of crotonic acid. -Z ^1] _a - ^[available by subsequent reduction using the a ² -Z _2] alkyl or and LiAlH ₄ corresponding to use b -Hal. This dianion is obtained, for example, from crotonic acid by reaction with 2 equivalents of lithium diisopropylamide (LDA) (PE Pfeffer, LS Silbert, J. Org. Chem. (1971), 36, 3290; R. H. van der Veen, H. C. Fountain, J. Org. Chem. (1985), 50, 342).

  A further main feature of the present invention includes the compounds obtained by the method of the present invention. Thus, the compound contains at least one O-heterocycle in addition to the tetrahydropyran ring. Combining correctly with multiple O-heterocycles allows the preparation of compounds with improved properties, while maintaining important values such as viscosity, solubility in liquid crystal mixtures and optical anisotropy. In particular, it has an absolute value with high dielectric anisotropy. The materials can be prepared on an industrial scale, simply and by the indicated synthetic route, increasing their practical value as well as excellent physical properties. General synthesis methods do not necessarily have to be used in only one type of liquid crystal display. In contrast to this, the compounds according to the invention depend on the characteristics of their dipole properties (for example the value of Δε), which are completely different types of liquid crystal display devices (IPS, VA, TN, STN). Etc.). The physical and chemical properties of these novel compounds make them particularly suitable for alternative liquid crystal mixtures for these display devices.

  The compounds of the invention include in particular compounds of the formulas XXVI, XXVII and XXVIII.

ただし、式中、
Ｒ^１、Ａ^１、Ａ^４、Ａ^５、Ｚ^１、Ｚ^４、ａ、ｅは、式Ｉで定義される通りであり、
Ｚ^６は、−ＣＦ_２Ｏ−、−ＯＣＦ_２−、−ＣＦ_２ＣＦ_２−、−ＣＨ_２ＣＨ_２ＣＦ_２Ｏ−を表し、
Ｘ^１は、Ｆ、ＣＮ、ＳＦ_５、ＮＣＳ、ＯＣＦ_３、ＣＦ_３を表し、
Ｌ^１、Ｌ^２は、Ｈ、ＣｌまたはＦを表し、および
ｐは、０または１を表す。

However, in the formula:
R ¹ , A ¹ , A ⁴ , A ⁵ , Z ¹ , Z ⁴ , a, e are as defined in Formula I;
Z ⁶ _{are, -CF 2 O -, - OCF} 2 -, - CF 2 CF 2 -, - CH 2 CH 2 CF 2 O- to represent,
X ¹ represents F, CN, SF ₅ , NCS, OCF ₃ , CF ₃ ,
L ¹ and L ² represent H, Cl or F, and p represents 0 or 1.

Preferred compounds of the formulas XXVI, XXVII and XXVIII are characterized in that L ¹ represents F, L ² represents H or F, particularly preferably L ¹ and L ² represent F.

  Particularly preferred compounds of the invention are the following compounds of formulas C and D:

ただしａｌｋｙｌ（アルキル）は上で定義される通りである。

Where alkyl (alkyl) is as defined above.

  All formulas expressed, especially substituted ring systems, are projectional formulas and include all stereoisomers unless a specific and particularly emphasized form of attachment is indicated. Also for 1,4-, 2,5- or 3,6-2 substituted 6-membered rings, the formula generally represents all stereoisomers, as any desired mixture or pure substance. Of these, stereoisomers all in the trans configuration in the formula are particularly preferred, making the molecule the most linear shape in the chain. In the case of chiral compounds, both enantiomers are basically covered as any desired mixed or pure material.

  The following examples illustrate the present invention without limiting it.

Above and below, the percent data represents weight percent. All temperatures are given in degrees Celsius. Tg is the glass transition temperature, cl. p. Is the clearing point. Further, C is a crystalline state, N is a nematic phase, Sm is a smectic phase, and I is an isotropic phase. The data between these symbols represents the phase transition temperature. Δn represents optical anisotropy (589 nm, 20 ° C.), Δε represents dielectric anisotropy (1 kHz, 20 ° C.), and γ ₁ represents rotational viscosity (mPa · s) at 20 ° C.

  The Δn and Δε values of the compounds of the invention are determined from a liquid crystal mixture consisting of 10% of each compound of the invention and 90% of commercially available liquid crystal ZLI-4792 (Merck, Darmstadt). Obtained by extrapolation.

  The following abbreviations are used above and below.

RT room temperature MTB ether methyl tert-butyl ether THF tetrahydrofuran DBN 1,5-diazabicyclo [4.3.0] non-5-ene DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

Of the following examples, Examples of the present invention are Examples 1, 3, 5, 6, 7, and 10 (including the variations in the table), and other reference examples.
<Example 1>

３０ｍｇ（０．０３５ｍｍｏｌ）の塩化トリシクロヘキシルホスフィン（１，３−ビス（２，４，６−トリメチルフェニル）−４，５−ジヒドロイミダゾール−２−イリデンベンジリデンルテニウム（ＩＶ）を、メタセシス触媒（Ｇｒｕｂｂｓ２触媒）として、０．３５ｍｏｌ（８４．８ｇ）の固体状態のジオレフィン（１）に、４０℃において窒素雰囲気下で数回に分けて加え、最初は２０ｍｇ、２回目は１時間後に１０ｍｇである。２時間後、エチレンの発生が事実上完了する。トルエン／ヘプタン（１：４）によりシリカゲルを通して濾過後、反応混合物より６１．３ｇ（理論の８１．７％）の（２）を得て、ヒドロホルミル化に直接使用し、（３）を得る。

30 mg (0.035 mmol) of tricyclohexylphosphine chloride (1,3-bis (2,4,6-trimethylphenyl) -4,5-dihydroimidazol-2-ylidenebenzylidene ruthenium (IV) was added to the metathesis catalyst (Grubbs 2 Catalyst) to 0.35 mol (84.8 g) of the solid diolefin (1) in several portions at 40 ° C. under a nitrogen atmosphere, initially 20 mg, the second being 10 mg after 1 hour. After 2 hours, the evolution of ethylene is virtually complete, after filtration through silica gel with toluene / heptane (1: 4), 61.3 g (81.7% of theory) of (2) is obtained from the reaction mixture, Use directly in hydroformylation to obtain (3).

For this purpose, 0.25 mol (53.55 g) of (2) in 200 ml of toluene was used at 60 bar and 150 ° C. with 3 g of tris (triphenylphosphine) carbonylrhodium (I) hydride and the synthesis gas Hydroformylation takes place over the course of 24 hours until the uptake of (H ₂ / CO = 1: 1) is complete. The reaction product is liberated from the solvent by evaporation in vacuo and the residue is filtered through silica gel with toluene / ethyl acetate (9: 1). In order to concentrate the trans component of the configuration of substituents in the formyltetrahydropyran component, the residue from which the filtrate has been evaporated (37.2 g = 69.5% of theory) is isomerized with a base.

  For this purpose, 1.8 ml of 20% aqueous sodium hydroxide solution are added to 37.2 g of a mixture of 190 ml of methanol and 48 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 1 hour. The mixture is then neutralized using hydrochloric acid and the solution is evaporated to dryness. 1 l of MTB is added to the evaporation residue and the mixture is washed twice with 300 ml of water each time. After drying, the organic extract is evaporated, yielding 33 g of an 88% aldehyde mixture, which contains a little 4-formyltetrahydropyran in addition to trans-5-formyltetrahydropyran (3).

  To synthesize (4a), 33 g (0.135 mol) of (3) was refluxed for 2 hours, 27.1 g (0.135 mol) of 2- (4-trans-propylcyclohexyl)-in 250 ml of toluene. Warm on a water separator with 1,3-propanediol with 500 mg of toluene-4-sulfonic acid monohydrate until dehydration is complete.

  After cooling, 10 g of potassium carbonate is added with stirring, the mixture is filtered and the filtrate is evaporated to dryness. The evaporation residue is first filtered through silica gel with heptane / toluene (1: 1) and pure toluene.

  Two product fractions are obtained. From one side, 12.4 g of the desired linear all-trans isomer (4a) (21.4% of theory) was obtained by recrystallization, and from the other, a dioxane derivative derived from 4-formyltetrahydropyran To give 5 g of the wrong isomer.

  (4a): C106N206.91I, Δε = 21.7, Δn = 0.0871.

<Example 2>
In a manner similar to Example 1, (4b) is obtained from 2-propyl-1,3-propanediol and pyranaldehyde of formula (3).

（４ｂ）：Ｃ８７Ｉ、Δε＝２３．７、Δｎ＝０．０５５０。

(4b): C87I, Δε = 23.7, Δn = 0.0550.

<Example 3>
In a manner similar to Example 1, (4c) is obtained from -propyl-1,3-propanediol and the corresponding pyranaldehyde.

（４ｃ）：Ｃ８８Ｎ（８７．９）Ｉ、Δε＝３５．８、Δｎ＝０．０８８０。

(4c): C88N (87.9) I, Δε = 35.8, Δn = 0.0880.

  The required pyranaldehyde is prepared as follows.

窒素下、８００ｍｌのジエチルエーテル中の臭化アリルマグネシウムの１Ｍ溶液を２５℃より低い室温で、５００ｍｌＴＨＦ中の２７２ｇ（８００ｍｍｏｌ）のアルデヒド溶液に加える。反応物を一晩、室温で攪拌し、氷水に加え、引き続きメチルｔｅｒｔ−ブチルエーテルで抽出する。有機相を飽和ＮａＣｌ溶液で洗浄し、硫酸ナトリウム上で乾燥し、蒸発させる。得られた残渣を、シリカゲルに通す。

Under nitrogen, a 1M solution of allylmagnesium bromide in 800 ml diethyl ether is added to a solution of 272 g (800 mmol) of aldehyde in 500 ml THF at room temperature below 25 ° C. The reaction is stirred overnight at room temperature, added to ice water and subsequently extracted with methyl tert-butyl ether. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and evaporated. The resulting residue is passed through silica gel.

１０３ｇ（８１％、２２０ｍｍｏｌ）のアルコールおよび２１ｇ（８０ｍｍｏｌ）のトリフェニルホスフィンを５００ｍｌの酢酸エチルに溶解し、５００ｍｇの酢酸ロジウム二量体を加える。ヒドロホルミル化を２５ｂａｒの合成ガスおよび１００℃で行う。反応溶液を蒸発させ、シリカゲルを通す。

103 g (81%, 220 mmol) alcohol and 21 g (80 mmol) triphenylphosphine are dissolved in 500 ml ethyl acetate and 500 mg rhodium acetate dimer is added. The hydroformylation is carried out at 25 bar synthesis gas and 100 ° C. The reaction solution is evaporated and passed through silica gel.

窒素下、２４．５ｍｌ（３２０ｍｍｏｌ）の塩化メタンスルホニルを０〜５℃で、５００ｍｌのジクロロメタン中の１００ｇ（２４０ｍｍｏｌ）のラクトンおよび１０１ｍｌ（２９９ｍｍｏｌ）のトリエチルアミンの溶液に加える。反応物を一晩、室温で攪拌する。反応物を水に加え、ＭＴＢエーテルで抽出する。有機相を飽和ＮａＣｌ溶液で洗浄し、硫酸ナトリウム上で乾燥し、蒸発させる。残渣をシリカゲルに通す。

Under nitrogen, 24.5 ml (320 mmol) methanesulfonyl chloride is added at 0-5 ° C. to a solution of 100 g (240 mmol) lactone and 101 ml (299 mmol) triethylamine in 500 ml dichloromethane. The reaction is stirred overnight at room temperature. The reaction is added to water and extracted with MTB ether. The organic phase is washed with saturated NaCl solution, dried over sodium sulfate and evaporated. The residue is passed through silica gel.

６０ｇ（１４８ｍｍｏｌ）のエノールエーテルを３００ｍｌのトルエンに溶解し、９．８ｇ（１５ｍｍｏｌ）のトリス（２，４−ジ−ｔｅｒｔ−ブチルフェニル）ホスフィンおよび３９０ｍｇ（１．５ｍｍｏｌ）のジカルボニルアセチルアセトナートロジウム（Ｉ）を加える。ヒドロホルミル化を１００ｂａｒの合成ガスおよび１００℃で行う。溶液を引き続き蒸発させ、残渣をシリカゲルに通して、アルデヒドのシス／トランス混合物を得る。

60 g (148 mmol) of enol ether is dissolved in 300 ml of toluene, 9.8 g (15 mmol) of tris (2,4-di-tert-butylphenyl) phosphine and 390 mg (1.5 mmol) of dicarbonylacetylacetonatodium. Add (I). The hydroformylation is carried out at 100 bar synthesis gas and 100 ° C. The solution is subsequently evaporated and the residue is passed through silica gel to give a cis / trans mixture of aldehydes.

  The aldehyde proton signals are δ = 9.69 ppm and δ = 9.88 ppm.

    <Example 4>

２００ｍｌのテトラヒドロフラン中に溶解された０．２ｍｏｌ（４８．８ｇ）の（３）と、１００ｍｌのテトラヒドロ中の２モル濃度の塩化アリルマグネシウム溶液とを、滴下により３０分かけて１５および２５℃の間で加える。添加が完了すれば、混合物を室温で更に２時間攪拌し、そして２００ｍｌの０．５Ｎ塩酸に投入し、有機相を分離して、水相をメチルｔｅｒｔ−ブチルエーテルで２回抽出する。混合された有機抽出物を水で洗浄し、乾燥し蒸発させる。蒸発残渣をトルエン／酢酸エチル（９８：２から９：１）でシリカゲルを通して濾過する。濾液より、３８．７ｇ（理論の６７．６％）のホモアリルアルコール（５）の異性体混合物を得る。

0.2 mol (48.8 g) of (3) dissolved in 200 ml of tetrahydrofuran and a 2 molar solution of allylic magnesium chloride in 100 ml of tetrahydro were added dropwise between 15 and 25 ° C. over 30 minutes. Add in. When the addition is complete, the mixture is stirred at room temperature for a further 2 hours and poured into 200 ml of 0.5N hydrochloric acid, the organic phase is separated and the aqueous phase is extracted twice with methyl tert-butyl ether. The combined organic extracts are washed with water, dried and evaporated. The evaporation residue is filtered through silica gel with toluene / ethyl acetate (98: 2 to 9: 1). From the filtrate, 38.7 g (67.6% of theory) of the homoallylic alcohol (5) isomer mixture is obtained.

  0.135 mol (38.7 g) of (5) and 0.135 mol (16.1 g) of propargyl bromide were dissolved in 80 ml of tetrahydrofuran, sodium hydroxide pellets (0.27 mol; 10.8 g),. Add to a vigorously stirred emulsion containing 5 ml water, 40 ml tetrahydrofuran and 6.75 mmol (2.46 g) N-cetyl-N, N, N-trimethylammonium bromide and warm to 45 ° C. at this temperature. For 16 hours. The mixture is then added to 1.5 l of ice water, the organic phase is separated and the aqueous phase is extracted three times with MTB ether. After drying and evaporating in advance, the combined organic phase residue is filtered through silica gel with toluene / heptane 2: 8. The filtrate is evaporated to give 34.3 g (78.4% of theory) of (6), which is used directly as a crude mixture in enyne metathesis to give (7).

  For this, 115 mg (0.14 mmol) of bis (tricyclohexylphosphine) benzylideneruthenium (IV) chloride (Grubbs1 catalyst) are added to 0.028 mol (9.4 g) of (6) in 20 ml of dichloromethane and the mixture is added. After stirring for 4 hours at room temperature and adding 115 mg of the same amount of catalyst, the mixture is stirred for a further 16 hours at room temperature. Evaporate, filter through silica gel with toluene / heptane (3: 7), dry the filtrate and recrystallize the resulting residue (1.0 g) first from ethanol and from heptane, identified as structure (7). 0.6 g of isomer is obtained.

  (7): C97I, Δε = 14.2, Δn = 0.0800.

  0.2 g of (7) for 6 hours at 10 bar hydrogen pressure at 90 ° C. in 5 ml of methanol and 1 ml of toluene using 0.1 g of tris (triphenylphosphine) rhodium chloride (I) Hydrogenate. After cooling, the reaction mixture is evaporated in vacuo and filtered through silica gel with toluene / heptane (3: 7). After drying, 0.15 g of (8) is obtained as an oil.

    <Example 5>

化合物（９）を、対応するホモアリルアルコール前駆体から２−（ブロモメチル）アクリレートを使用して、Ｏ−アルキル化により調製する。このために、８０ｍｌのテトラヒドロフラン中の０．２ｍｏｌ（７６．１ｇ）のホモアリルアルコールを、温度を２０℃に保ちながら窒素の保護ガス雰囲気下で８０ｍｌのテトラヒドロフラン中の６０％の懸濁液としての０．２ｍｏｌ（８．０ｇ）の水素化ナトリウムに、滴下により攪拌および氷水を使用して外部より冷却しながら加える。約２時間後、水素の発生が完了する。そして、４０ｍｌのテトラヒドロフラン中の０．２ｍｏｌ（３８．６ｇ）の酢酸ブロモメチルを、温度が２５℃を超えない速度で滴下により加える。引き続き、攪拌を室温で更に１６時間継続する。そして、反応混合物を６００ｍｌの氷水に投入し、１ＮのＨＣｌを使用して中和し、有機相を分離する。水相をメチルｔｅｒｔ−ブチルエーテルで２回抽出後に、混合された有機相を蒸発させて乾燥し、トルエン／メチルｔｅｒｔ−ブチルエーテル（３：１）でシリカゲルを通して濾過する。濾液を蒸発させた残渣は、６５．９ｇ（理論の７１％）のアルキル化生成物（９）を含む。

Compound (9) is prepared by O-alkylation using 2- (bromomethyl) acrylate from the corresponding homoallylic alcohol precursor. For this purpose, 0.2 mol (76.1 g) of homoallyl alcohol in 80 ml of tetrahydrofuran as a 60% suspension in 80 ml of tetrahydrofuran under a protective atmosphere of nitrogen while keeping the temperature at 20 ° C. To 0.2 mol (8.0 g) of sodium hydride, it is added dropwise with stirring and cooling from outside using ice water. After about 2 hours, hydrogen evolution is complete. Then 0.2 mol (38.6 g) of bromomethyl acetate in 40 ml of tetrahydrofuran is added dropwise at a rate such that the temperature does not exceed 25 ° C. Subsequently, stirring is continued for an additional 16 hours at room temperature. The reaction mixture is then poured into 600 ml of ice water, neutralized using 1N HCl and the organic phase separated. After extracting the aqueous phase twice with methyl tert-butyl ether, the combined organic phases are evaporated to dryness and filtered through silica gel with toluene / methyl tert-butyl ether (3: 1). The residue from evaporation of the filtrate contains 65.9 g (71% of theory) of the alkylated product (9).

  0.1 mol (49.2 g) of (9) is warmed to 60 ° C. with 25 ml of toluene, and 212 mg of Grubbs 2 catalyst each is divided into 4 portions (1 mol% total) and added every hour. When the evolution of ethylene is complete, the mixture is filtered through silica gel with toluene / methyl tert-butyl ether. The filtrate is evaporated leaving 28.8 g (62% of theory) of the dihydropyran ester (10).

  0.05 mol (23.2 g) of dihydropyran ester (10) was dissolved in 2 g of tris (triphenylphosphine) rhodium chloride (I) in 10 ml of hydrogen pressure at 12 hours and 300 ml of methanol and 60 ml of toluene at 100 ° C. ) To hydrogenate. The solvent is evaporated and the residue is filtered through silica gel with toluene / methyl tert-butyl ether to give the hydrogenated ester (11) (18.4 g = 79% of theory).

  For the synthesis of aldehyde (12), 0.039 mol (18.4 g) of ester (11) in 80 ml of toluene was cooled to −70 ° C. and 32.5 ml of hydrogenated 1,2-N in toluene. -Add diisobutylaluminum (DIBAL-H) at -70 ° C with stirring, complete the addition after 4 hours, and continue stirring, then add the mixture to 100 ml of cold 1N HCl while it is still cold. The organic phase is washed with aqueous sodium hydrogen carbonate solution and water, dried and evaporated. The evaporation residue of aldehyde (12) can be used directly in the synthesis of (4c) as described in Example 1.

アルデヒド（１２）を引き続き２−エチル−１，３−プロパンジオールと反応させて、ジオキサン（４ｃ）を得る。このために、４４．５ｇ（１１０ｍｍｏｌ）のアルデヒド（１２）および１２．０ｇ（１１５ｍｍｏｌ）のジオール２−エチル−１，３−プロパンジオールを２５０ｍｌのトルエンに溶解し、４００ｍｇのｐ−トルエンスルホン酸一水和物を加え、アルデヒドの転化が完了するまで（ＴＬＣ）、混合物を水分離器上で還流下により加熱する。冷却された反応物を飽和炭酸水素ナトリウム溶液で３回洗浄し、乾燥し、シリカゲル（トルエン／ヘプタン７：３；トルエン；トルエン／酢酸エチル９５：５）を通す。生成物を含む画分を蒸発させ、残渣をエタノールより−２０℃で再結晶する。

The aldehyde (12) is subsequently reacted with 2-ethyl-1,3-propanediol to give dioxane (4c). For this purpose, 44.5 g (110 mmol) of aldehyde (12) and 12.0 g (115 mmol) of diol 2-ethyl-1,3-propanediol were dissolved in 250 ml of toluene and 400 mg of p-toluenesulfonic acid mono Hydrate is added and the mixture is heated under reflux on a water separator until aldehyde conversion is complete (TLC). The cooled reaction is washed 3 times with saturated sodium bicarbonate solution, dried and passed through silica gel (toluene / heptane 7: 3; toluene; toluene / ethyl acetate 95: 5). The fractions containing the product are evaporated and the residue is recrystallized from ethanol at -20 ° C.

  (4c): C88N (87.9) I; Δε = 35.8; Δn = 0.0880.

<Example 6>
The synthesis of (13) is also carried out analogously to Example 5 using diols of the following formula from aldehyde (12).

＜例７＞
（１４）の合成も例５および６に類似して行うが、この場合、アルデヒド（３）を使用する。

<Example 7>
The synthesis of (14) is also carried out analogously to Examples 5 and 6, but in this case aldehyde (3) is used.

（１４）：Ｃ９１ＳｍＨ（６３）Ｎ２０３．４Ｉ、Δε＝２１．３、Δｎ＝０．０８８０。

(14): C91SmH (63) N203.4I, Δε = 21.3, Δn = 0.0880.

    <Example 8>

メタセシスにより形成されたジヒドロピラン（３２）を、例１に類似のヒドロホルミル化によりアルデヒド（３３）に転化し、エン−カルボニル反応中でホモアリルアルコール（３４）と反応させ、最初にブロモテトラヒドロピラン（３５）を得る。

Dihydropyran (32) formed by metathesis was converted to aldehyde (33) by hydroformylation similar to Example 1 and reacted with homoallyl alcohol (34) in an ene-carbonyl reaction, first bromotetrahydropyran ( 35).

The synthesis of homo-allylic alcohol, carried out via the acetate of zinc alcohol (38) which can be prepared by classical methods by reaction with gaseous formaldehyde in the ₂ presence of zinc powder and CoBr.

このために、１ｍｌのトリフルオロ酢酸を使用して亜鉛を活性化したあと、分離可能なフラスコ中で１．０ｍｏｌ（３０ｇ）のパラホルムアルデヒドを２２０℃まで加熱して形成されるガス状ホルムアルデヒドを、４００ｍｌのアセトニトリル中の２６ｇの亜鉛粉（０．４ｍｏｌ）、１３．２ｇ（０．０６ｍｏｌ）のＣｏＢｒ_２および０．２ｍｏｌ（５１．２ｇ）の（３８）の溶液中を通過させる。導入が終了すれば、混合物を室温で更に１２時間攪拌する。そして、混合物を１００ｍｌの２ＮＨＣｌに投入し、有機相を分離し、水相をメチルｔｅｒｔ−ブチルで２回抽出する。混合された有機相を蒸発させ、残る残渣をトルエン／酢酸エチル（７：３）でシリカゲルを通して濾過し、より極性の画分を蒸発させ、ホモアリルアルコール（３４）を粗材料として理論の４８％の収率（２１．９ｇ）で得る。

For this purpose, gaseous formaldehyde formed by activating zinc using 1 ml of trifluoroacetic acid and then heating 1.0 mol (30 g) of paraformaldehyde to 220 ° C. in a separable flask, Pass through a solution of 26 g zinc powder (0.4 mol), 13.2 g (0.06 mol) CoBr ₂ and 0.2 mol (51.2 g) (38) in 400 ml acetonitrile. When the introduction is complete, the mixture is stirred for another 12 hours at room temperature. The mixture is then poured into 100 ml of 2N HCl, the organic phase is separated and the aqueous phase is extracted twice with methyl tert-butyl. The combined organic phases are evaporated, the remaining residue is filtered through silica gel with toluene / ethyl acetate (7: 3), the more polar fraction is evaporated and homoallylic alcohol (34) is used as crude material, 48% of theory. In a yield of 21.9 g.

Initially 0.09 mol (20.5 g) of homoallylic alcohol (34) is introduced at 0 ° C. with 0.69 mol (14.0 g) of aldehyde (33) and 5 mol% BiBr ₃ (2 g). And until HBr is generated from the washing bottle in front of the reaction vessel (about 10 minutes) as much as is generated from the bubble counter behind the reaction vessel, the temperature of HBr as a gas is between 5 and 20 ° C. Pass through while cooling from outside. The mixture is then poured quickly into ice-cold saturated sodium bicarbonate solution, the organic phase is washed with water, dried and evaporated. The isomeric mixture of isomers bromotetrahydropyran (35) is used in the next reaction step in the formation of crude purification to eliminate HBr to give dihydro (36).

0.057 mol of the isomer mixture (36) from the previous step (23.3 g, 63.3% of theory) was refluxed for 6 hours with 0.086 mol (10.2 ml) of 1,1 in 40 ml of toluene. Warm with 5-diazabicyclo [4.3.0] non-5-ene. After cooling, the pH is adjusted to 3 using water and dilute sulfuric acid and then the mixture is mixed vigorously. After separation, the organic phase is washed with saturated NaHCO ₃ solution and water and filtered through silica gel. Evaporation yields an isomer mixture of 15.7 g (84% of theory) of dihydropyran (36).

  The hydrogenation of the isomer mixture (36) (15.7 g) was dissolved in 300 ml methanol and 75 ml toluene and 0.48 mmol (448 mg) tris (triphenylphosphine) rhodium chloride at 10 bar, 90 ° C. for 20 hours. Hydrogenation is carried out using (I) as a catalyst. After evaporation of the solvent, the residue is filtered through silica gel with toluene. Repeat fractional crystallization from ethanol and heptane to obtain 0.5 g of (37).

    <Example 9>

３７５ｍｌ（１．８７ｍｏｌ）のマロン酸エステル（３９）を２．１ｌのキシレン中に、１４２ｍｌ（２．５５ｍｏｌ）のエチレングリコールおよび９．７５ｇ（５０ｍｍｏｌ）のｐ−パラトルエンスルホン酸一水和物と共に溶解し、沸騰するまで加熱する。１ｌのキシレンを最高温度１４０℃までで留去する。反応容器中に残った混合物を炭酸水素ナトリウムで洗浄し、蒸発させる。（４０）よりなる得られる残渣を真空で分留する。収率：２８０ｇの無色液体（６４％）。

375 ml (1.87 mol) malonic ester (39) in 2.1 l xylene with 142 ml (2.55 mol) ethylene glycol and 9.75 g (50 mmol) p-paratoluenesulfonic acid monohydrate Dissolve and heat until boiling. 1 l of xylene is distilled off at a maximum temperature of 140 ° C. The mixture remaining in the reaction vessel is washed with sodium hydrogen carbonate and evaporated. The resulting residue consisting of (40) is fractionated in vacuo. Yield: 280 g of colorless liquid (64%).

窒素下、ＴＨＦ中の１８７．２ｇ（７９０ｍｍｏｌ）のマロン酸エステル（４０）の溶液を、１ｌのＴＨＦ中の４５．５ｇ（１．０３ｍｏｌ）の水素化リチウムアルミニウムの懸濁液に沸点で加え、混合物を沸騰させながら１時間加熱する。冷却された反応物をＴＨＦ／水混合物（４：１）を使用して加水分解し、１２３ｍｌの水中の炭酸ナトリウム十水和物の溶液を８０℃で加える。２３０分後、形成された固体（４１）を分離し、ＭＴＢエーテルで洗浄する。有機相を蒸発させ、特に精製することなく引き続く工程で使用する。

Under nitrogen, a solution of 187.2 g (790 mmol) of malonic ester (40) in THF was added at a boiling point to a suspension of 45.5 g (1.03 mol) of lithium aluminum hydride in 1 l of THF, The mixture is heated for 1 hour while boiling. The cooled reaction is hydrolyzed using a THF / water mixture (4: 1) and a solution of sodium carbonate decahydrate in 123 ml of water is added at 80 ° C. After 230 minutes, the solid (41) formed is separated and washed with MTB ether. The organic phase is evaporated and used in subsequent steps without special purification.

窒素下、８６．３ｇ（５８０ｍｍｏｌ）のジオール（４１）を１１００ｍｌのＤＭＦに溶解し、１４ｇ（３８ｍｍｏｌ）のヨウ化テトラ−ｎ−ブチルアンモニウムを加える。８７．２ｇ（２．１８ｍｏｌ）のミネラルオイル中の６０％水素化ナトリウム懸濁液を何回かに分けて導入する。室温で３０分後、２６４ｍｌ（２．１８ｍｏｌ）のベンジルブロマイドを冷却しながら注意深く加える。室温で４８時間後、反応物を３ｌの水に加え、ＭＴＢエーテルで抽出する。有機相を水で洗浄し、蒸発させる。残渣をシリカゲル（トルエン）に通す。（４２）の３つの画分を単離する。

Under nitrogen, 86.3 g (580 mmol) of diol (41) is dissolved in 1100 ml of DMF and 14 g (38 mmol) of tetra-n-butylammonium iodide is added. A 60% sodium hydride suspension in 87.2 g (2.18 mol) of mineral oil is introduced in several portions. After 30 minutes at room temperature, 264 ml (2.18 mol) of benzyl bromide are carefully added with cooling. After 48 hours at room temperature, the reaction is added to 3 l of water and extracted with MTB ether. The organic phase is washed with water and evaporated. The residue is passed through silica gel (toluene). The three fractions of (42) are isolated.

69.6 g; content 62.9%
194.1g; Content 92.1%
23.0 g; content 64.8%

２９０ｍｌのギ酸を８３０ｍｌのトルエン中の１４９ｇ（９２．１％；５４０ｍｍｏｌ）のアセタール（４２）の溶液に加え、混合物を激しく攪拌しながら６０℃で６時間保持する。１ｌのヘプタンおよび１ｌの水を、冷却された反応物に加える。有機相を水および炭酸水素ナトリウム溶液で洗浄し、蒸発させる。残渣をシリカゲル（トルエン／ヘプタン）に通す。１６３．７ｇのアルデヒド（４３）を単離する（含有量：６３％；収率：６７％）。

290 ml of formic acid is added to a solution of 149 g (92.1%; 540 mmol) of acetal (42) in 830 ml of toluene and the mixture is kept at 60 ° C. with vigorous stirring for 6 hours. 1 l heptane and 1 l water are added to the cooled reaction. The organic phase is washed with water and sodium hydrogen carbonate solution and evaporated. The residue is passed through silica gel (toluene / heptane). 163.7 g of aldehyde (43) are isolated (content: 63%; yield: 67%).

２２．５ｇ（６３％；５０ｍｍｏｌ）のアルデヒド（４３）および５．９５ｇ（９６％；５０ｍｍｏｌ）の２−ビニルプロパノールを１４０ｍｌのジクロロメタンに溶解し、１１．４ｇ（２５ｍｍｏｌ）のビスマス（ＩＩＩ）ブロミドを加える。反応物を一晩、室温で攪拌する。反応物を引き続きシリカゲルを通して濾過し、蒸発させる。２６．１ｇの臭化化合物（４４）を単離する（含有量：６０％；収率：６８％）。

22.5 g (63%; 50 mmol) of aldehyde (43) and 5.95 g (96%; 50 mmol) of 2-vinylpropanol were dissolved in 140 ml of dichloromethane, and 11.4 g (25 mmol) of bismuth (III) bromide was dissolved. Add. The reaction is stirred overnight at room temperature. The reaction is subsequently filtered through silica gel and evaporated. 26.1 g of brominated compound (44) are isolated (content: 60%; yield: 68%).

窒素下、１００ｇ（２１９ｍｍｏｌ）の臭素化化合物（４４）を１６５ｍｌのトルエンに溶解し、３８．５ｍｌのＤＢＮを加え、混合物を沸騰させながら５時間加熱する。２００ｍｌの水を引き続き冷却された反応物に加え、そして希硫酸を使用して酸性とする。有機相を３００ｍｌのヘプタンで希釈し、分離して除去し、炭酸水素ナトリウム溶液で洗浄し、蒸発させる。得られる残渣をシリカゲル（トルエン）に通す。５７．１ｇの化合物（４５）を単離する（含有量：６０％；収率：４１％）。

Under nitrogen, 100 g (219 mmol) of brominated compound (44) is dissolved in 165 ml of toluene, 38.5 ml of DBN is added and the mixture is heated to boiling for 5 hours. 200 ml of water is subsequently added to the cooled reaction and acidified using dilute sulfuric acid. The organic phase is diluted with 300 ml of heptane, separated off, washed with sodium hydrogen carbonate solution and evaporated. The resulting residue is passed through silica gel (toluene). 57.1 g of compound (45) are isolated (content: 60%; yield: 41%).

５７ｇ（１５０ｍｍｏｌ）の不飽和ピラン（４５）を３６０ｍｌのメタノールおよび９０ｍｌのトルエンに溶解し、８ｂａｒ／８０℃で、（ＰＰｈ_３）_３ＲｈＣｌ触媒上で水素化する。水素化溶液を蒸発させ、残渣をシリカゲル（トルエン／ＭＴＢエーテル）に通し、ピラン（４６）の２つの画分を得る：３２．１ｇ（７７％含有量；４３％）および２１．６ｇ（含有量：６９％；収率：２６％）。

57 g (150 mmol) of unsaturated pyran (45) is dissolved in 360 ml of methanol and 90 ml of toluene and hydrogenated at 8 bar / 80 ° C. over (PPh ₃ ) ₃ RhCl catalyst. The hydrogenation solution is evaporated and the residue is passed through silica gel (toluene / MTB ether) to give two fractions of pyran (46): 32.1 g (77% content; 43%) and 21.6 g (content) : 69%; Yield: 26%).

３２．１ｇ（７７％）の保護されたジオール（４６）を３２１ｍｌのＴＨＦに溶解し、パラジウム触媒上で水素化する。触媒を引く続き分離し除去して、溶液を蒸発させる。（４７）の残渣を、更に精製することなく引き続く工程で使用する。

32.1 g (77%) of the protected diol (46) is dissolved in 321 ml of THF and hydrogenated over a palladium catalyst. The catalyst is subsequently separated and removed to evaporate the solution. The residue of (47) is used in subsequent steps without further purification.

１１ｇ（５４ｍｍｏｌ）のジオール（４７）を７０ｍｌのトルエンに８．８ｇ（５５ｍｍｏｌ）の３，４，５−トリフルオロベンズアルデヒドと共に加え、３５０ｍｇのｐ−トルエンスルホン酸一水和物を加え、混合物を水分離器上で沸騰するまで加熱する。反応物を引き続き、シリカゲルに通し、溶出液を蒸発させる。（４８）の得られる残渣を、アセトニトリル、アセトンおよびヘプタンから結晶化して精製する。

11 g (54 mmol) of diol (47) is added to 70 ml of toluene along with 8.8 g (55 mmol) of 3,4,5-trifluorobenzaldehyde, 350 mg of p-toluenesulfonic acid monohydrate is added, and the mixture is washed with water. Heat until boiling on separator. The reaction is subsequently passed through silica gel and the eluate is evaporated. The resulting residue of (48) is purified by crystallization from acetonitrile, acetone and heptane.

  (48): C61I; Δε = 21.6; Δn = 0.067.

    <Example 10>

１５．８ｇ（７８ｍｍｏｌ）のジオール（４７）を１００ｍｌのトルエンに２７．４ｇ（７８ｍｍｏｌ）のアルデヒド（４９）と共に加え、５００ｍｇのｐ−トルエンスルホン酸一水和物を加え、混合物を水分離器上で沸騰するまで加熱する。反応物を引き続き、シリカゲルに通し、溶出液を蒸発させる。（５０）の得られる残渣を、アセトニトリル、アセトンおよびヘプタンから結晶化して精製する。

15.8 g (78 mmol) of diol (47) is added to 100 ml of toluene along with 27.4 g (78 mmol) of aldehyde (49), 500 mg of p-toluenesulfonic acid monohydrate is added and the mixture is placed on a water separator. Heat until boiling. The reaction is subsequently passed through silica gel and the eluate is evaporated. The resulting residue of (50) is purified by crystallization from acetonitrile, acetone and heptane.

  (50): C92N113I; Δε = 35; Δn = 0.099.

  The following compounds are prepared in each case from a diol similar to compound (47) and a suitable aldehyde similar to formula (49).

ただし、Ｒ^１１、Ａ^１１、Ａ^１２、Ａ^２１、Ｚ^２１、Ａ^２２およびＸ^１１は、特に表１で示される意味を有する。

However, R ¹¹ , A ¹¹ , A ¹² , A ²¹ , Z ²¹ , A ²² and X ¹¹ have the meanings shown in Table 1 in particular.

以下を例１０に類似してアルデヒド（４９）および対応するジオールより調製する。

The following is prepared analogously to Example 10 from aldehyde (49) and the corresponding diol.

Claims (9)

Tetrahydropyran compounds of formula I:

{However, in Formula I,

a, d and e each independently represent 0 or 1, provided that a + d + e is equal to 1, 2 or 3;
b is 0,
c is 1,
A ¹ , A ² , A ⁴ , A ⁵ may be independently or mutually the same or different, rotated or mirror image,

A ³ represents C,
However,

Y ¹ , Y ² and Y ³ each independently represent hydrogen, halogen, CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, -OC _1-6 -alkanyl,- Represents OC _2-6 -alkenyl and —OC _2-6 -alkynyl, provided that the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ³ and Z ⁴ are a single bond Represents
Z ¹ , Z ² , Z ⁵ are a single bond, an alkylene bridge having 1 to 6 carbon atoms that is unsubstituted or mono- or polysubstituted with F and / or Cl, or —CH═CH—, —C≡C—, —CF═CF—, —CH═CF—, —CH ₂ O—, —OCH ₂ —, —CO—O—, —O—CO—, —CF ₂ O—, —OCF _{2 -, - CH 2 CH 2 CF} 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
R ¹ is H, an alkyl group having 1 to 15 C atoms, which is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen, provided that One or more CH ₂ groups in these groups are such that the heteroatoms in the chain are not directly bonded to each other so that —C≡C—, —CH═CH—, —O—, —S—, _{-SO -, - SO 2 -,} - CO-O- or may be replaced by -O-CO-,
R ² represents F, CN, SF ₅ , NCS, OCF ₃ , CF ₃ ,

Z ⁷ _{is, -CF 2 O -, - OCF} 2 -, - CF 2 CF 2 -, - CH 2 CH 2 CF 2 O- to represent,
L ¹ and L ² represent H, Cl or F.
}
A process for preparing a dioxane compound of formula Ia by condensing a diol of formula II and an aldehyde of formula III with each other.

(Where
R ¹ , R ² , B, A ¹ , A ² , A ⁴ , A ⁵ , a, b, d, e, Z ^{1 to} Z ⁵ and- [Z ⁶ -A ⁶ ] _f − are represented by Formula I Has the meaning. ) Tetrahydropyran compounds of formula I:

{However, in Formula I,

a, c, d, e, independently of one another, represent 0 or 1, where a + c + d + e is equal to 2, 3 or 4 and c + d is not equal to 0;
b is 0,
A ¹ , A ² , A ³ , A ⁴ , A ⁵ may be independently or mutually the same or different, rotated or mirror image,

Represents
Provided that at least one ring of A ³ and A ⁴ represents C;
However,

Y ¹ , Y ² and Y ³ each independently represent hydrogen, halogen, CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, -OC _1-6 -alkanyl,- Represents OC _2-6 -alkenyl and —OC _2-6 -alkynyl, provided that the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ³ and Z ⁴ are a single bond Represents
Z ¹ , Z ² , Z ⁵ are a single bond, an alkylene bridge having 1 to 6 carbon atoms that is unsubstituted or mono- or polysubstituted with F and / or Cl, or —CH═CH—, —C≡C—, —CF═CF—, —CH═CF—, —CH ₂ O—, —OCH ₂ —, —CO—O—, —O—CO—, —CF ₂ O—, —OCF _{2 -, - CH 2 CH 2 CF} 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
R ¹ is H, an alkyl group having 1 to 15 C atoms, which is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen, provided that One or more CH ₂ groups in these groups are such that the heteroatoms in the chain are not directly bonded to each other so that —C≡C—, —CH═CH—, —O—, —S—, _{-SO -, - SO 2 -,} - CO-O- or may be replaced by -O-CO-,
R ² represents F, CN, SF ₅ , NCS, OCF ₃ , CF ₃ ,

Z ⁷ _{is, -CF 2 O -, - OCF} 2 -, - CF 2 CF 2 -, - CH 2 CH 2 CF 2 O- to represent,
L ¹ and L ² represent H, Cl or F.
}
A process for preparing a compound of formula IV, wherein the compound of formula IV is cyclized with olefin metathesis to obtain a compound of formula V and subsequently hydrogenated to obtain a compound of formula I.

(Where
R ¹ , R ² , A ^{1 to} A ⁵ , a to e, Z ^{1 to} Z ⁵ and- [Z ⁶ -A ⁶ ] _f- have the meanings indicated by formula I. ) Tetrahydropyran compounds of formula I:

{However, in Formula I,

a, c, d, e, independently of one another, represent 0 or 1, where a + c + d + e is equal to 2, 3 or 4 and c + d is not equal to 0;
b is 0,
A ¹ , A ² , A ³ , A ⁴ , A ⁵ may be independently or mutually the same or different, rotated or mirror image,

Represents
Provided that at least one ring of A ³ and A ⁴ represents C;
However,

Y ¹ , Y ² and Y ³ each independently represent hydrogen, halogen, CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, -OC _1-6 -alkanyl,- Represents OC _2-6 -alkenyl and —OC _2-6 -alkynyl, provided that the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ³ and Z ⁴ are a single bond Represents
Z ¹ , Z ² , Z ⁵ are a single bond, an alkylene bridge having 1 to 6 carbon atoms that is unsubstituted or mono- or polysubstituted with F and / or Cl, or —CH═CH—, —C≡C—, —CF═CF—, —CH═CF—, —CH ₂ O—, —OCH ₂ —, —CO—O—, —O—CO—, —CF ₂ O—, —OCF _{2 -, - CH 2 CH 2 CF} 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
R ¹ is H, an alkyl group having 1 to 15 C atoms, which is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen, provided that One or more CH ₂ groups in these groups are such that the heteroatoms in the chain are not directly bonded to each other so that —C≡C—, —CH═CH—, —O—, —S—, _{-SO -, - SO 2 -,} - CO-O- or may be replaced by -O-CO-,
R ² represents F, CN, SF ₅ , NCS, OCF ₃ , CF ₃ ,

Z ⁷ _{is, -CF 2 O -, - OCF} 2 -, - CF 2 CF 2 -, - CH 2 CH 2 CF 2 O- to represent,
L ¹ and L ² represent H, Cl or F.
}
A reaction of a 2-substituted 3-butenyl alcohol of formula VI (homoallylic alcohol) and an aldehyde of formula VII to give a pyran derivative of formula VIII or IX, and
A method of preparation, characterized in that it is converted to a compound of formula I via one or more steps including reductive elimination for the pyran derivative of formula VIII and / or hydrogenation for the pyran derivative of formula IX.

(Where
R ¹ , R ² , A ^{1 to} A ⁵ , a to e, Z ^{1 to} Z ⁵ and- [Z ⁶ -A ⁶ ] _f- have the meanings shown in Formula I;
X ¹ represents chlorine, bromine or iodine . ) The method of claim 3, wherein the conversion of compounds of formula VIII, the compound of Formula I by pulling reductively substituents X ¹ from VIII.   4. The method of claim 3, wherein the compound of formula IX is converted to a compound of formula I by hydrogenating IX.   A compound of formula VI is reacted with an aldehyde of formula VII or X in the presence of at least one acid comprising at least one halide from the series I, Br and Cl. The method described. The reaction is carried out in the presence of a Lewis acid of formula M (X ¹ ) _n or R ⁵ M (X ¹ ) _n-1 , where M is boron, Al, In, Sn, Ti, Fe, Zn, Zr, Au or Represents Bi,
X ¹ represents Cl, Br or I;
R ⁵ represents a linear or branched alkyl group containing 1 to 10 carbon atoms, and n is an integer of 2, 3 or 4 and is selected to be equal to the formal oxidation number of M The method of claim 6 wherein: Tetrahydropyran compounds of formula I:

{However, in Formula I,

a, c and e each independently represent 0 or 1, provided that a + c + e is equal to 1, 2 or 3;
b is 0,
d is 1,
A ^{1 to} A ³ and A ⁵ may be the same or different, independently of each other, rotated or mirror image,

A ⁴ represents C,
However,

Y ¹ , Y ² and Y ³ each independently represent hydrogen, halogen, CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl, -OC _1-6 -alkanyl,- Represents OC _2-6 -alkenyl and —OC _2-6 -alkynyl, provided that the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, and Z ³ and Z ⁴ are a single bond Represents
Z ¹ , Z ² , Z ⁵ are a single bond, an alkylene bridge having 1 to 6 carbon atoms that is unsubstituted or mono- or polysubstituted with F and / or Cl, or —CH═CH—, —C≡C—, —CF═CF—, —CH═CF—, —CH ₂ O—, —OCH ₂ —, —CO—O—, —O—CO—, —CF ₂ O—, —OCF _{2 -, - CH 2 CH 2 CF} 2 O- or _{-CF 2 OCH} 2 CH 2 - represents,
n1 is 0, 1, 2, 3 or 4;
n2 and n3 are independently of each other 0, 1, 2 or 3,
n4 is 0, 1 or 2,
W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
R ¹ is H, an alkyl group having 1 to 15 C atoms, which is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen, provided that One or more CH ₂ groups in these groups are such that the heteroatoms in the chain are not directly bonded to each other so that —C≡C—, —CH═CH—, —O—, —S—, _{-SO -, - SO 2 -,} - CO-O- or may be replaced by -O-CO-,
R ² represents F, CN, SF ₅ , NCS, OCF ₃ , CF ₃ ,

Z ⁷ _{is, -CF 2 O -, - OCF} 2 -, - CF 2 CF 2 -, - CH 2 CH 2 CF 2 O- to represent,
L ¹ and L ² represent H, Cl or F.
}
A method of preparing a compound of formula VI reacting a 2-substituted 3-butenyl alcohol of formula VI (homoallyl alcohol) and an aldehyde of formula X to obtain an intermediate of formula XI or XII and the compound of formula Ie as an intermediate From XI or XII i) reductively eliminate intermediate XI or reduce intermediate XII
ii) A method of preparation characterized in that it is prepared by deprotecting the diol and iii) reacting with an aldehyde of the formula OHC- [Z ⁵ -A ⁵ ] _e- [Z ⁶ -A ⁶ ] _f -R ² .

(Where
R ¹ , R ² , A ^{1 to} A ³ , A ⁵ , a to c, e, Z ^{1 to} Z ³ , Z ⁵ and- [Z ⁶ -A ⁶ ] _f -have the meanings shown in Formula I. Where X ¹ represents chlorine, bromine or iodine;
R ³ and ^{R 4,} Ru protecting groups der for alcohol. ) A compound of formula XXVI.

(However,
R ¹ , A ¹ , A ⁴ , A ⁵ , Z ¹ , Z ⁴ , Z ⁷ , L ¹ and L ² are as defined by formula I in claim 1,
a and e each independently represent 0 or 1,
X ¹ _{is, F, CN, SF 5,} NCS, a OCF ₃ or CF ₃ to Table. )