JP5260279B2 - Process for the preparation of 2,5-2 substituted tetrahydropyran derivatives by reductive elimination of the corresponding 4-halogen derivatives - Google Patents

Description

  The present invention relates to a method for preparing tetrahydropyran derivatives from halogenated tetrahydropyran derivatives and precursors thereof.

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

  Of particular interest here are mesogenic or liquid-crystalline tetrahydropyran derivatives having suitable (mesogenic) substituents, rings and / or ring systems in the 2- and / or 5-position, which are It has several advantageous electro-optical and further physical properties for use. Therefore, there is basically a need for a very simple and effective synthetic method that opens up the way to obtain various 2,5-2 substituted tetrahydropyran derivatives with great structural diversity. In addition, the tetrahydropyran derivative must already have the desired stereochemistry completely or partially during preparation.

Two known methods of this type of synthesis are based on the use of olefin metathesis reactions with metal alkylidene complex catalysts. With the aid of these methods, 2,5-2 substituted dihydropyran derivatives can be obtained by ring-closing cross-metathesis (DE102004021338A1; patent document 1) or enyne metathesis and further cross-metathesis (DE102004022891A1; patent document 2). In each case, a suitable metal carbene complex (metal alkylidene complex) (for example Grubbs first generation or Grubbs second generation or related catalysts, in particular WO 96/04289 (Patent Document 3); WO 97/06185 (Patent Document 4) TM Trnka et al., Acc. Chem. Res. 2001, 34, 18 (Non-patent Document 1); SK Armstrong, J. Chem. Soc., Perkin Trans. I, 1998, 371 (Non-Patent Document 1); Patent Document 2 J. Renaud et al., Angew. Chem. 2000, 112, 3231 (Non-patent Document 3)). An overview of the two methods is shown in Scheme 1a and Scheme 1b, respectively, where “radical ¹ ” and “radical ² ” represent appropriate (mesogenic) substituents, rings and ring systems, respectively. Thus, the desired 2,5-2 substituted tetrahydropyran derivatives can also be prepared by (catalytic) hydrogenation from available dihydropyrans.

しかしながら、使用される金属アルキリデン触媒が高額であるため、これらの２つの合成方法はいつでも価値がある訳ではなく、結果として、より安価な方法が望ましいこととなる。

However, because the metal alkylidene catalysts used are expensive, these two synthetic methods are not always valuable, and as a result, cheaper methods are desirable.

J. et al. O. Metzger and U.S. Biermann, Bull. Soc. Belg. , 103, 1994, 393-397 (Non-Patent Document 4) describes an addition reaction of formaldehyde introduced with aluminum chloride onto a substituted alkene accompanied by formation of a 4-chlorine-substituted tetrahydropyran derivative. It can then be converted to the corresponding halogen-free tetrahydropyran derivative by the free radical method using Bu ₃ SnH. They describe one synthesis example of one kind of 4-chlorotetrahydropyran derivative having two substituents at the 2-position and 5-position, and a homoallyl alcohol having both of these substituents as a starting compound. is necessary. However, this synthesis method has a low conversion rate and divertability, and uses disubstituted homoallyl alcohol. Therefore, preparation of a precursor of a 2,5-2 substituted tetrahydropyran derivative having only a very limited structural range is required It can only be done. No mention is made of the stereochemistry of halogen-free tetrahydropyrans.

E. Hanschke, Chem. Ber. 88, 1955, 1053-1061 (Non-patent Document 5) shows that unsubstituted homoallyl alcohol is high in the presence of hydrochloric acid together with unsubstituted C _1-4 -alkanylaldehyde and crotylaldehyde in the presence of formaldehyde and hydrogen halide. The reaction at atmospheric pressure is described and the desired 4-halogen-substituted tetrahydropyran derivatives for further reactions are only obtained in low yields with no additional selectivity with further products. 2-Methyl-4-chlorotetrahydropyran using KOH is dehydrogenated to give 2-methyldihydropyran.
DE102004021338A1 DE102004022891A1 WO96 / 04289 WO97 / 06185 T. T. et al. M.M. Trnka et al., Acc. Chem. Res. 2001, 34, 18 S. K. Armstrong, J.M. Chem. Soc. Perkin Trans. I, 1998, 371 J. et al. Renaud et al., Angew. Chem. 2000, 112, 3231 J. et al. O. Metzger and U.S. Biermann, Bull. Soc. Belg. 103, 1994, 393-397 E. Hanschke, Chem. Ber. 88, 1955, 1053-1061

  Therefore, the aim is to show a simple and effective preparation method of tetrahydropyran derivatives, which itself is a starting compound for the synthesis of (further) mesogenic or liquid crystalline 2,5-2 substituted tetrahydropyran derivatives. Function. In addition, the tetrahydropyran derivative should have the desired trans-stereochemistry already fully or partially in the synthesis.

This object is achieved according to the invention by the reductive elimination of the substituent X ¹ from a tetrahydropyran derivative of formula II to obtain tetrahydropyran derivatives of formula I or precursors thereof, characterized in that This is achieved by a method of preparing derivatives.

ただし、式ＩおよびＩＩ中、
ａ、ｂ、ｃ、ｄ、ｅ、ｆは、それぞれ互いに独立に、０または１を表し、ただし、ａ＋ｂ＋ｃ＋ｄ＋ｅ＋ｆは、１、２、３または４に等しく、
Ｒ^１は、それぞれの場合で独立に、Ｈ、ハロゲン、−ＣＮ、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、鎖中の酸素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、それぞれの場合で独立に、Ｈ、ハロゲン、−ＣＮ、−ＮＣＳ、−ＮＯ_２、−ＯＨ、−ＳＦ_５、−Ｏ−アラルキル、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、ＯＨまたは−Ｏ−アラルキルにより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、鎖中の酸素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−、−ＣＯ−Ｏ−または−Ｏ−ＣＯ−で置き換えられていてもよく、
Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ａ^５、Ａ^６は、それぞれ互いに独立に、回転されたものまたは鏡像のものでもよく、以下を表し、

Where in formulas I and II:
a, b, c, d, e, f each independently represents 0 or 1, provided that a + b + c + d + e + f is equal to 1, 2, 3 or 4;
R ¹ is independently in each case H, halogen, —CN, an alkyl group having 1 to 15 C atoms, which group is unsubstituted, 1-substituted by —CN, halogen In addition to one or more of the CH ₂ groups in these groups in such a way that the oxygen atoms in the chain are not directly bonded to one another so that —C≡C—, —CH ═CH—, —O—, —S—, —SO—, —SO ₂ —, —CO—O— or —O—CO— may be substituted,
R ² is independently in each case H, halogen, —CN, —NCS, —NO ₂ , —OH, —SF ₅ , —O-aralkyl, an alkyl group having 1 to 15 C atoms, The group is unsubstituted, monosubstituted by —CN, or monosubstituted or polysubstituted by halogen, OH or —O-aralkyl, in addition to one or more CH in these groups _{The two} groups are formed so that oxygen atoms in the chain are not directly bonded to each other, so that —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, —CO— , -CO-O- or -O-CO-
A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , independently of each other, may be rotated or mirror images, and represent the following:

Ｚ^１は、それぞれの場合で独立に、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_２Ｏ−、−ＯＣＨ_２−、およびＡ^２がシクロヘキシレンおよびシクロヘキセニレン環ではない場合、−ＣＦ_２Ｏ−も表してよく、
Ｚ^２は、それぞれの場合で独立に、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を表し、
Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、それぞれ互いに独立に、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を表すか、または−ＣＨ_２Ｏ−、−ＯＣＨ_２−、−ＣＦ_２Ｏ−を表し、ただし、−ＣＦ_２Ｏ−架橋はシクロヘキシレンまたはシクロヘキセニレン環にそのＯ原子を介して直接結合しておらず、
ｎ１、ｎ２およびｎ３は、それぞれ互いに独立に、０、１、２、３または４であり、
Ｙ^１、Ｙ^２、Ｙ^３、Ｙ^４、Ｙ^５およびＹ^６は、それぞれ互いに独立に、Ｈ、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−アルケニルおよび−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、好ましくはＨまたはＦであり、および
Ｗ^１は、それぞれの場合で独立に、−ＣＨ_２−、−ＣＦ_２−または−Ｏ−を表し、
および式ＩＩ中では、
Ｘ^１は、塩素、臭素またはヨウ素を表し、
ただし、式ＩＩの化合物は、４−クロロ−２−ヘキシル−５−（７−メトキシカルボニルヘプチル）テトラヒドロピランではない。

Z ¹ is independently in each case a single bond, an alkylene bridge having 1 to 6 carbon atoms, unsubstituted or mono- or polysubstituted with F and / or Cl, or —CH ₂ O— , —OCH ₂ —, and A ² are not cyclohexylene and cyclohexenylene rings, may also represent —CF ₂ O—,
Z ² independently in each case represents a single bond, an alkylene bridge having 1 to 6 carbon atoms, unsubstituted or mono- or polysubstituted with F and / or Cl;
Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are each independently a single bond, an alkylene bridge having 1 to 6 carbon atoms, unsubstituted or mono- or polysubstituted with F and / or Cl. or represents, or _{-CH 2 O -, - OCH 2} -, - CF 2 O- to represent, however, _-CF 2 O-bridge directly linked via its O atoms in cyclohexylene or cyclohexylene ring Not
n1, n2 and n3 are each independently 0, 1, 2, 3 or 4;
Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are each independently H, halogen, —CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 — Represents alkynyl, —OC _1-6 -alkanyl, —OC _2-6 -alkenyl and —OC _2-6 -alkynyl, provided that the aliphatic group is unsubstituted or mono- or polysubstituted by halogen , Preferably H or F, and W ¹ in each case independently represents —CH ₂ —, —CF ₂ — or —O—,
And in Formula II:
X ¹ represents chlorine, bromine or iodine,
However, the compound of formula II is not 4-chloro-2-hexyl-5- (7-methoxycarbonylheptyl) tetrahydropyran.

In particular, the method involves directly preparing a derivative of formula I from a derivative of formula II, ie reductive elimination of a derivative of formula II to give a derivative of formula I. However, in a broader sense, it also includes the preparation of mesogenic components for liquid crystal compounds and liquid crystal mixtures of the formula I, which are obtained in a known manner from direct reductive elimination. The process according to the invention for the preparation of derivatives of formula I thus comprises at least one or two steps, characterized in that the substituent X ¹ is reductively eliminated from the compound of formula II. The other substituents of the tetrahydropyran ring have different meanings by derivatization in principle by known reactions. The two groups R ¹ , R ² , A ^1-6 , Z ^1-6 , af in the formulas I and II thus have the same or different meanings. The reductive elimination can be carried out in one step per se or in two steps: elimination of the substituent X ¹ and subsequent reduction of the double bond of the formed dihydropyran.

  For simplicity, the numbers of the positions of the tetrahydropyran ring in formulas I and II are as follows in this description-unless explicitly indicated otherwise.

発明による方法では、式ＩＩのハロゲン化されたテトラヒドロピラン誘導体から出発する容易に入手でき安価な試薬の助けによって、式Ｉのテトラヒドロピラン誘導体を単純なやり方で、良好な収率および高い化学的および立体的選択性で入手可能となる。式Ｉのテトラヒドロピラン誘導体はそれ自身さらにメソゲン性または液晶テトラヒドロピラン誘導体を調製するために使用することができる。他の場合では、式Ｉの誘導体は、既に例えば液晶性成分などの用途用の所望の化合物である。取り除くことが難しい副産物が形成されないため、生成物の精製が容易である方法はここで有利である。

In the process according to the invention, with the aid of readily available and inexpensive reagents starting from halogenated tetrahydropyran derivatives of formula II, the tetrahydropyran derivatives of formula I are obtained in a simple manner with good yields and high chemical and Available with stereoselectivity. The tetrahydropyran derivatives of formula I can themselves be used to further prepare mesogenic or liquid crystalline tetrahydropyran derivatives. In other cases, the derivatives of formula I are already the desired compounds for applications such as liquid crystalline components. Advantages here are methods in which the purification of the product is easy since no by-products that are difficult to remove are formed.

  In addition to the central tetrahydropyran ring, compounds of formula I that can be prepared by the process of the present invention may have no further rings, one, two, three or four additional rings (or ring systems). ), That is, the sum of the indices a, b, c, d, e and f is equal to 0, 1, 2, 3 or 4. (A + b + c + d + e + f) is preferably greater than 1, in particular 1, 2 or 3, and very particularly 1 or 2. It is preferred here that the halogenated tetrahydropyran derivative of the formula II and also the tetrahydropyran derivative of the formula I have no ring or one ring at the 5-position, ie a + b is preferred Is 0 or 1. Furthermore, it is preferred that the tetrahydropyran derivative of the formula II and further the tetrahydropyran derivative of the formula I have no further rings or have one, two or three additional rings in the 2-position, That is, c + d + e + f is equal to 0, 1, 2, or 3, and in particular 1 or 2.

R ¹ is preferably H, alkanyl, alkenyl, alkoxy or alkenyloxy, each having from 1 to 10 carbon atoms, unsubstituted or by one or more fluorine and / or chlorine atoms It is also preferred if it is substituted and a and / or b is 1, it represents chlorine, fluorine or bromine. R ¹ particularly preferably represents H, alkanyl or alkoxy, each having from 1 to 8 carbon atoms, unsubstituted or substituted each by one or more fluorine and / or chlorine atoms. Particularly preferably straight-chain alkanyl having 1, 2, 3, 4, 5 or 6 carbon atoms, unsubstituted or substituted by one or more fluorine atoms. Yes.

R ² is preferably H, Cl, F, Br, —OH, —CO ₂ —C _1-6 -alkanyl, —O-aralkyl, CH (CH ₂ O— “protecting group”) ₂ or alkanyl, alkenyl, Alkoxy or alkenyloxy, each having 1 to 8 carbon atoms, unsubstituted or substituted by one or more fluorine, chlorine or OH groups, particularly preferably F, Cl , —OH, —CO ₂ —C _1-6 -alkanyl, —OCH ₂ -phenyl, —CH (CH ₂ OCH ₂ -allyl) ₂ , CH (CH ₂ OH) _2, alkanyl or alkoxy, 1 to 8 respectively. Having 1 carbon atom, unsubstituted or substituted by one or more fluorine and / or chlorine atoms, and in particular F, Cl, —CO ₂ -methyl, -ethyl ,-N-propyl,-i-propyl,-n-butyl,-t-butyl or-n-hexyl, -OCH ₂ - phenyl, -CH _(CH 2 OCH ₂ - _{phenyl) 2,} in either substituted, Or linear alkanyl or alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, each unsubstituted or substituted by one or more fluorine atoms .

R ¹ and R ² further include groups resulting from multiple substitutions with CH ₂ groups by the above elements, where they are usually, for example, for R ² , arylsulfuric acid ester —O (SO ₂ ) —Ar or — O (SO ₂ ) —CH ₃ is also included and serves as a protecting or leaving group in subsequent synthesis. It is also possible to substitute all CH ₂ groups of the alkyl group with the indicated groups. For this purpose, the S—S direct bond and the —S—O— chain are generally unusual and preferably not part of R ¹ or R ² .

When (a + b) = 0, R ¹ preferably does not represent hydrogen, halogen and CN. When (c + d + e + f) = 0, R ² preferably does not represent hydrogen, —CN, —NCS, —NO ₂ , —OH, —SF ₅ , —O-aralkyl or alkoxy.
Rings A ¹ and A ² preferably represent, independently of one another, 1,4-cyclohexylene or 1,4-phenylene, which may be substituted by 1 to 4 fluorine atoms, and particularly preferably

である。
環Ａ^３、Ａ^４、Ａ^５およびＡ^６、好ましくは、互いに独立に、１，４−シクロヘキシルエンまたは１，４−フェニレンを表し、０〜４個のフッ素原子によって置換されており、および特に好ましくは

It is.
The rings A ³ , A ⁴ , A ⁵ and A ⁶ , preferably independently of one another, represent 1,4-cyclohexylene or 1,4-phenylene and are substituted by 0 to 4 fluorine atoms, and in particular Preferably

である。

It is.

Z ¹ and Z ² preferably, independently of one another, represent a single bond or an alkylene bridge having 2, 4 or 6 carbon atoms and may be substituted by one or more fluorine atoms. Z ¹ and Z ² are particularly preferably both single bonds.

Z ³ , Z ⁴ , Z ⁵ and Z ⁶ preferably independently of one another represent a single bond, —CH ₂ O— or —CF ₂ O—, wherein the —CF ₂ O— bridge is preferably cyclohexylene Or it is not directly linked to the cyclohexenylene via its O atom. Particularly preferably, independently of one another, is a single bond, —CF ₂ O— or —CH ₂ O—, very particularly preferably in each case of Z ³ , Z ⁴ , Z ⁵ and Z ⁶ . One is not a single bond. If the bridging element Z ³ , Z ⁴ , Z ⁵ or Z ⁶ contains an oxygen atom, it is preferably not directly joined to the tetrahydropyran ring in formula I or II. The corresponding situation also applies to the starting materials for preparing the compounds of formula II.

The reductive elimination process according to the invention is carried out starting from a halogenated tetrahydropyran derivative of the formula II. X ¹ here represents chlorine, bromine or iodine, preferably chlorine or bromine and in particular bromine.

  Particularly preferred compounds of formula II are selected from formulas II-1 to II-5.

本発明の方法の好ましい実施形態において、Ｉを得るＩＩの還元的脱離はフリーラジカル連鎖反応により行われ、反応の過程において−形式的に考えれば−式Ｉのテトラヒドロピラン誘導体中のハロゲン原子Ｘ^１が取り除かれ水素原子で置き換えられる。ここで、反応される式ＩＩの化合物中のＸ^１は臭素または塩素であることが特に好ましく、特に臭素である。

In a preferred embodiment of the process according to the invention, the reductive elimination of II to obtain I is carried out by a free radical chain reaction, and in the course of the reaction-formally considered-the halogen atom X in the tetrahydropyran derivative of formula I ¹ is removed and replaced with a hydrogen atom. Here, X ^{1 in} the compound of formula II to be reacted is particularly preferably bromine or chlorine, in particular bromine.

This embodiment of the reductive elimination of the present invention is preferably performed in the presence of organotin hydride or organosilicon hydride. Preferred organotin hydrides here are trialkyl hydrides and aralkyl dialkyl tins, particularly preferably trialkyl tin 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 I 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 support is usually used in 2 to 4 equivalents based on the compound of formula II.

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 II 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 variation, a substoichiometric amount of the actual reducing agent TTMSS can be used, which is reformed during the course of the reaction cycle by sodium borohydride, and thus compared by using the cheaper NaBH ₄ A considerable amount of 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 II.

  Preferred embodiments of the present invention using organotin hydride or organosilicon hydride are suitable for example of suitable azo or peroxy compounds of AIBN (2,2′-azobisisobutyronitrile) or tert-butyl hydroperoxide. In the presence of UV light in the presence of at least one free radical chain initiator ("free radical initiator"). 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 embodiment of the invention, X ¹ in formula II is bromine and the reductive elimination is carried out in the presence of hydrogen and a hydrogenation catalyst and a base, preferably 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, platinum or nickel catalyst, in particular palladium. Particular preference is given to palladium on carbon or palladium on aluminum oxide. The base is preferably a nitrogenous base or an amine, in particular a tertiary amine.

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

  The reaction is carried out in 3 to 20 times the amount of THF, at a hydrogen pressure between 1 and 50 bar and at a temperature of about 20 to about 120 ° C. over a period of 1 to 24 hours.

In this preferred embodiment, if the groups and substituents are appropriately selected, the reductive elimination performance of the present invention results in the halogenated tetrahydropyran to the corresponding dehalogenated tetrahydropyran ring. In addition to ring conversion, certain protecting groups can be reductively removed. In particular, this applies to compounds of the formula I in which R ² represents an O-aralkyl group, in particular an optionally substituted O-benzyl group.

  The two preferred embodiments of the present invention described above show that, inter alia, the reductive elimination of the tetrahydropyran derivative of formula I to give the tetrahydropyran derivative of formula I is the placement of substituents in the 2 and 5 positions of the tetrahydropyran ring. Specifically identified by the fact that it happens to keep. Thus, the halogenated compound of formula I in which all three substituents at positions 2, 4 and 5 are equatorial sequences such that the substituent at position 2 is oriented trans to the substituent at position 5 Tetrahydropyran gives the corresponding hydropyran derivative of formula I with trans 2,5-2 substitution while retaining stereochemistry.

In a further preferred embodiment of the invention, the reductive elimination of formula I giving the tetrahydropyran derivative of formula I is carried out in two steps, provided that in step 1 (A) the tetrahydropyran derivative of formula II is dihydropyran. Converted to a derivative, in particular of formula IIIa and / or IIIb,
And in the second step (B), the dihydropyran derivative or mixture of dihydropyran derivatives formed in this way is converted into a tetrahydropyran derivative of formula I.

ただし、ａ、ｂ、ｃ、ｄ、ｅ、ｆ、Ｒ^１、Ｒ^２、Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ａ^５、Ａ^６、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５、Ｚ^６は、式ＩおよびＩＩで上に定義される通りである。

However, a, b, c, d, e, f, R ¹ , R ² , A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ are as defined above in formulas I and II.

The elimination of HX ¹ (dehydrohalogenation) from the tetrahydropyran derivative of formula I is carried out using a strong base. In particular, suitable bases are found to be alkoxides, such as alkali metal alkoxides such as sodium ethoxide or potassium tert-butoxide, and strong nonionic nitrogen bases, especially those having a pKa value greater than 20. is there. Examples of these strong nonionic nitrogen bases are described in J. Am. G. Verkade, Topics in Current Chemistry 220, 3-44, among others 1,5-diazabicyclo [4.3.0] non-5-ene (DBN); 1,8-diazabicyclo [5 4.0] undec-7-ene (DBU); and 1,1,3,3-tetramethylguanidine (TMG); 7-methyl-1,5,7-triazabicyclo [4.4.0] Deca-5-ene (MTBD) and 2,8,9-triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3] undecane (TTPU) (S. Arumugam) , JG Verkade, J. Org. Chem. 1997, 62, 4827).

  The elimination is carried out in a suitable inert solvent or solvent mixture, for example aromatic hydrocarbons such as toluene or ethers such as 1,4-dioxane, dimethoxyethane and tetrahydrofuran. The use of nonpolar solvents is particularly preferred. In general, the reaction is carried out at a temperature between room temperature and boiling point, preferably at a high temperature from about 60 ° C. to the boiling point, particularly preferably from about 80 ° C. to the boiling point. The reaction time for the first step (A) is generally about 1 hour to about 48 hours, preferably about 4 hours to about 16 hours.

  When carrying out step (A) of this preferred embodiment of the present invention, a mixture of two dihydropyran derivatives of formula IIIa and IIIb is usually formed, most often with an isomer ratio of about 2: 1. Isomers are generally produced in secondary quantities—if any. Prior to further step (B), it is possible in principle to separate the isomers using conventional fractionation methods such as chromatography, but this is generally not performed. The compound of formula IIIb available according to this embodiment according to the invention has the same configuration as the starting compound of formula II with respect to the configuration of the substituents at the 2 and 5 positions of the tetrahydropyran ring. Thus, a tetrahydropyran derivative of formula II having a full equatorial configuration readily provides the corresponding trans-2,5-2 substituted tetrahydropyran derivative of formula IIIb.

Step (B) for the formation of the tetrahydropyran derivative of formula I is carried out by catalytic hydrogenation. Here, the hydrogenation can be carried out with homogeneous or heterogeneous catalysts. For the dihydropyran derivatives of formula IIIb, the hydrogenation itself and the choice of conditions under which the hydrogenation is carried out do not affect the stereochemical orientation of the substituents at the 2- and 5-positions of the heterocycle. Thus, normally and preferably present trans-2,5-2 substituted compounds of formula IIIb retain the stereochemistry to give the corresponding trans-2,5-2 substituted tetrahydropyrans of formula I. However, with respect to dihydropyran derivatives of formula IIIa, further reaction means for the formation of tetrahydropyran derivatives of formula I generally affect the configuration of the substituents at the 2- and 5-positions of the heterocyclic oxygen relative to each other. Effect. Thus, heterogeneous catalyzed hydrogenation produces, for example, predominantly or exclusively tetrahydropyrans of formula I in cis-2,5-configuration over heterogeneous palladium, platinum or nickel catalysts. To do. The isomerization uses, for example, a strong base such as potassium tert-butoxide, an acid, or a fluorine-containing compound such as CsF or tetrabutylammonium fluoride and the desired 2,5-trans An isomer of formula I in the configuration can be obtained. If as opposed to performing the hydrogenation in the homogeneous catalysts, for example, a Wilkinson catalyst chlorotris (triphenylphosphine) in the presence of a rhodium _{(I) (Cl-Rh [} P (C 6 H 5) 3] 3) In a suitable solvent (eg toluene) (see German patent application DE102004036068A1) over a hydrogen pressure of 10 to 100 bar, a temperature of about 80 ° C. to about 120 ° C., a reaction time of about 6 to about 48 hours, The desired 2,5-trans isomer of compound I is obtained in excess—usually the ratio of trans isomer to cis isomer is 3: 1. The desired trans-2,5-2 substituted tetrahydropyran derivatives of formula I are available in good yield.

  In connection with a process for the synthesis of a halogenated tetrahydropyran derivative of formula II which is subsequently converted to the desired tetrahydropyran derivative of formula I, in a further preferred embodiment of the invention, the compound of formula II is a homoallyl of formula IV Alcohol in the presence of an aldehyde of formula V or an acetal or hydrate thereof and at least one Lewis acid containing at least one chlorine, bromine or iodine atom and / or at least one chlorine, bromine or iodine; It is obtained in the presence of Bronsted acid containing ions.

ただし、式ＩＶおよびＶ中のａ、ｂ、ｃ、ｄ、ｅ、ｆ、Ｒ^１、Ｒ^２、Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ａ^５、Ａ^６、Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５、Ｚ^６は、式Ｉで上に定義される通りである。特定の酸を選択し、それぞれのハロゲン原子またはそれのハロゲン化物イオンが式ＩＩ中のＸ^１の意味を決定し、例えば、使用されるルイス酸はＡｌＣｌ_３のように塩素原子を含む場合、Ｘ^１は塩素であり、一方、使用されるブレンステッド酸がＨＢｒの場合、Ｘ^１は臭素である。

Provided that a, b, c, d, e, f, R ¹ , R ² , A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , Z ¹ , Z ² in formulas IV and V, Z ³ , Z ⁴ , Z ⁵ , Z ⁶ are as defined above in Formula I. If a particular acid is selected and each halogen atom or its halide ion determines the meaning of X ^{1 in} Formula II, for example, if the Lewis acid used contains a chlorine atom, such as AlCl ₃ , then X ¹ is chlorine, while X ¹ is bromine when the Bronsted acid used is HBr.

  This embodiment of the invention is in the presence of at least one Lewis acid containing at least one chlorine, bromine or iodine atom, or at least one containing at least one chloride, bromide or iodide anion. In the presence of a Bronsted acid (protic acid) or a mixture of at least one Lewis acid as defined above and at least one Bronsted acid as defined above. Embodiments according to the present invention can be carried out using one or more different Lewis and / or Bronsted acids, preferably using up to three different acids. In the process according to the invention, the use of only one Lewis acid or Bronsted acid or a mixture of Lewis and Bronsted acids is particularly preferred. Reference to “acid” above and below—when not otherwise indicated—means both a single acid and a plurality of different acids. In the use of more than one acid, the choice of multiple acids is not particularly limited as long as they are chemically compatible with each other and do not cause undesirable side reactions.

In a first preferred variant of this embodiment of the invention, the reaction of the homoallylic alcohol of formula IV with the aldehyde of formula V comprises at least one Lewis acid containing at least one chlorine, bromine or iodine atom. It is done in a state. In each case, the Lewis acid may contain only one type of these halogen atoms, i.e. in addition to the presence of any non-halogen groups or ligands, only chlorine atoms or only bromine atoms or only iodine atoms. desirable. The halogen substituent X ¹ of the tetrahydropyran derivative of formula I corresponds to this halogen atom of at least one Lewis acid. The Lewis acid very particularly preferably contains a bromine atom.

The at least one Lewis acid is preferably selected from the group comprising compounds of formula M (X ¹ ) _n and R ³ M (X ¹ ) _n-1 , where M is B, Al, In, Ga, In , Sn, Ti, Fe, Zn, Nb, Zr, Au and Bi,
X ¹ represents Cl, Br or I;
R ³ represents a linear or branched alkyl group having 1 to 10 carbon atoms, and n is an integer of 2, 3, 4 or 5, which represents an oxidation number in the form of M Selected to be equal.

Examples of these Lewis acids are diisobutylaluminum chloride and B ^III (X ¹ ) ₃ , Al ^III (X ¹ ) ₃ , Ga ^III (X ¹ ) ₃ , In ^III (X ¹ ) ₃ , Sn ^IV (X ¹ ) ₄ , Ti ^IV (X ¹ ) ₄ , Fe ^III (X ¹ ) ₃ , Zn ^II (X ¹ ) ₂ , Zr ^IV (X ¹ ) ₄ , Nb ^V (X ¹ ) ₅ , Au ^III (X ¹ ) ₃ and Bi ^III (X ¹ ) ₃ provided that X ¹ is chlorine, bromine or iodine, preferably chlorine or bromine, in particular bromine. Bromine can be easily removed from chlorine.

The exact amount of Lewis acid used can vary over a wide range, - in particular with respect to the minimum amount to be used - among other things, it depends on the number of halogen atoms X ¹ per one molecule of the Lewis acid. Thus, a Lewis acid with a formal oxidation number of atom M of 4 (IV), in as little as 25 mol% based on the homoallylic alcohol of formula IV to be reacted, guarantees complete conversion of the reactants. It is enough. Generally, the Lewis acid is used in an amount of about 20 mol% to about 300 mol%, preferably in an amount of about 34 mol% to about 250 mol%, and particularly preferably in an amount of about 50 mol% to about 200 mol%, provided that the amount is In each case based on the homoallylic alcohol of the formula IV.

  The reaction temperature is generally between about −80 ° C. and + 40 ° C., but the exact choice of the reaction temperature depends on the nature of the respective Lewis acid selected. Accordingly, preferred temperature ranges are -70 to -40 ° C for boron halides, -50 ° C to 0 ° C for Al, In, Sn and Ti halides, and 0 ° C to + 40 ° C for Zn and Bi halides. The reaction time is generally between 1 and 72 hours, preferably between 2 and 36 hours and particularly preferably between 4 and 24 hours. The reaction according to the invention can add a Lewis acid, in solid or solution, to a mixture dissolved or suspended in a suitable solvent of homoallylic alcohol of formula IV and aldehyde of formula V. Alternatively, the Lewis acid may be introduced first, for example followed by the addition of aldehyde and homoallylic alcohol, and vice versa.

The at least one Lewis acid is particularly preferably a compound of the formula M (X ¹ ) _n , where M is B, Al, Fe, Zn or Bi, and X ¹ in particular represents Br. The Lewis acid is in particular AlBr ₃ , ZnBr ₂ or BiBr ₃ .

  Furthermore, in a preferred variant of this embodiment of the invention, the process is carried out in the presence of a Bronsted acid containing at least one chlorine, bromine or iodine anion. Examples of Bronsted acids are hydrogen chloride, hydrogen bromide and hydrogen iodide. The Bronsted acid can be used, for example, as a gas, can be passed through, for example, a mixture in a suitable solvent containing other reactants of the process according to the invention, or a solution containing Bronsted acid can be used. For example, HBr in glacial acetic acid. The Bronsted acid used in the process of the present invention is particularly preferably hydrogen bromide. Bronsted acid is used, especially in the case of hydrohalic acid, in stoichiometric or over stoichiometric amounts (based on homoallylic alcohol of formula IV), preferably from about 100 mol% to about 350 mol%. In an amount of about 100 mol% to about 225 mol%, in particular an amount of about 150 mol% or less.

  The reaction temperature in this embodiment is generally between about 0 ° C. and about + 70 ° C., preferably between about 10 ° C. and about 40 ° C., particularly preferably around room temperature (18-25 ° C.). The reaction time is generally between 1 and 72 hours, preferably between 2 and 36 hours and particularly preferably between 4 and 24 hours, also influenced by the chosen solvent, for example the reaction In general, it proceeds faster in glacial acetic acid than water. The reaction according to the present invention involves adding Bronsted acid as a solution or passing the Bronsted acid as a gas to a homoallylic alcohol of formula IV and an aldehyde compound of formula V dissolved or suspended in a suitable solvent. Can be done.

Furthermore, in a preferred variant of this embodiment of the invention, the reaction of the homoallylic alcohol of the formula IV with the aldehyde of the formula V is carried out in the presence of a mixture of at least one Lewis acid and at least one Bronsted acid. Is done. These acids are selected so that they are chemically compatible with each other and do not lead to undesirable side reactions. It is advantageous for the Lewis acid to have the same halogen atom as the Bronsted acid, i.e. for example, M (Br) _n Lewis acid bromide is used in addition to hydrobromic acid. Preferred combinations are HBr and BiBr ₃ or AuBr ₃ . When the reaction is carried out in a corresponding manner (ie a reaction temperature between about 0 ° C. and about 50 ° C. and a molar ratio of Bronsted acid to Lewis acid of about 100: about 0.5: about 2), the Lewis acid is It can easily contain halogen atoms that are different from Bronsted acids. For example, this is the case of a combination of FeCl ₃ and HBr. And the compound of formula II prepared by this variant contains the Brönsted acid halogen as X ¹ , so in the example with FeCl ₃ and HBr, X ¹ is Br.

  In principle, Lewis acid and Bronsted acid can be used in any desired mixing ratio with each other. However, the Lewis acid relative to the Bronsted acid is preferably in an amount of about 0.1 mol% to about 20 mol%, particularly preferably in an amount of about 0.3 mol% to about 10 mol%, in particular about 0.5 mol% to about Used in an amount of 2 mol%. Here, the Bronsted acid is preferably used in an amount of at least stoichiometric (about 100 mol%) to more than stoichiometric (about 350 mol%) relative to the homoallylic alcohol of formula IV. The reaction temperature during this variant of the invention is generally between about -10 ° C and about + 70 ° C. Preferably, the aldehyde of formula V and the homoallylic alcohol of formula IV are first introduced into a suitable solvent, the Lewis acid is added at about -10 ° C to about + 35 ° C and the Bronsted acid is used as a gas at about 0 ° C. At about + 50 ° C.-preferably cooled externally-followed by passage until the reaction medium is saturated. A suitable solution of Bronsted acid can also be used. The reaction time is generally between a few minutes and 24 h, preferably between 10 minutes and 6 hours and particularly preferably between 15 minutes and 3 hours.

  The reaction of the homoallylic alcohol of the formula IV with the aldehyde of the formula V can be carried out in principle in a solvent-free manner and preferably in a solvent or solvent mixture. Suitable solvents here are those which themselves do not act as acids or to some extent are inert to the acid used. The exact choice of medium depends in particular on the dissolution behavior of the reactants and on the acid. Suitable solvents, which can be used as reaction medium alone or in a mixture of two or three solvents are, for example, water; hydrocarbons such as hexane, petroleum ether, benzene, toluene, xylene; Chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, chloroform and especially dichloromethane; alcohols such as methanol, ethanol, 2-propanol, n-propanol, n-butanol; diethyl ether, diisopropyl ether, tetrahydrofuran (THF) ) Or ethers such as 1,4-dioxane; ethylene glycol monomethyl or monoethyl ether (methyl glycol, ethyl glycol or polyethylene glycol), ethylene glycol dimethyl ether (digly Glycol ethers such as); carbon disulfide; nitro compounds such as nitromethane or nitrobenzene, but in the use of Lewis acids (alone or together with Bronsted acids) as acids used in the present invention, Water and alcohol are not used as solvents or solvent components. Aliphatic and chlorinated hydrocarbons, particularly preferably chlorinated hydrocarbons, especially dichloromethane.

Surprisingly, when this embodiment of the method according to the invention is carried out, the stereoisomers in which the substituents at positions 2 and 5 of the tetrahydropyran derivative of formula I are in trans configuration with respect to each other are predominantly or exclusively It was found to be formed. This situation is very advantageous for further use of these compounds to prepare tetrahydropyran derivatives of formula I by reductive elimination according to the present invention. This is important for mesogenic properties because the trans configuration of substituents at the 2 and 5 positions allows for bis-equatorial conformation with elongated molecular shapes. Even more surprising, the halogen substituent X ^{1 at} the 4-position of the compound of formula II prepared by this embodiment of the method according to the invention also has a trans configuration mainly or exclusively with respect to the substituent at the 5-position. I understood that I would take it. Thus, in this method step according to the present invention, tetrahydropyran derivatives in which the three substituents at the 2-position, 4-position and 5-position are oriented in all equatorial configurations are formed with high selectivity. The high selectivity of the reaction according to the invention is particularly evident when at least one Lewis acid, alone or in combination with at least one Bronsted acid, is involved in the reaction.

  In addition to the high stereochemical selectivity, the preparation according to the invention of halogenated tetrahydropyran derivatives of the formula II is distinguished by further advantages. Tetrahydropyran derivatives of formula II are available in good to very good yields. In addition, the reaction of the homoallylic alcohol of the formula IV with the aldehyde of the formula V takes place with high chemical selectivity, ie no unwanted by-products are produced or only very small amounts are produced, It does not affect further use of the tetrahydropyran derivative of formula II. The acid reagent used in the method according to the invention is usually readily available commercially and inexpensively and does not require any special or unusual prevention to handle it. The method has been shown to be particularly advantageous to open up intensive synthetic strategies to prepare further tetrahydropyran derivatives of formula I, especially with high structural diversity, in particular formula IV Starting from the homoallylic alcohols of the formula, changing the group of the aldehyde of the formula V allows for the extensive preparation of variously substituted tetrahydropyran derivatives of the formula II and subsequently the corresponding tetrahydropyran derivatives of the formula I. . The same applies to the complementary approach, i.e. starting from the aldehyde of formula V, especially by changing the group of the homoallylic alcohol of formula IV, with high structural diversity, the tetrahydro of formulas II and I. A pyran derivative can be prepared.

A, b, c, d, e, f, R ¹ , R ² , A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ , Z ¹ , in compounds of formula II, III, IV and V; Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ and X ¹ have the same preferred meaning as the compounds of formula I.

  The tetrahydropyran derivatives of the formula I obtainable by the process according to the invention are generally known per se from the prior art and have mesogenic or liquid crystalline properties and are used as elements of liquid-crystalline media, for example electro-optical displays As a starting compound for the preparation of further mesogenic or liquid crystalline compounds comprising devices and / or tetrahydropyran structural elements.

  The reagents and solvents used in the process steps according to the invention are known from the literature and are usually commercially available. It is also described in the literature (for example, standard works of synthetic organic chemistry such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). And can be accurately carried out under reaction conditions known and appropriate for the above reaction. However, it is also possible to carry out variants which are known per se and are not described in detail.

Aldehydes of formula V are commercially available or are available from other aldehydes by reactions known in the prior art. Thus, an aldehyde of formula V to which a formyl group is conjugated to a cyclohexyl ring (for example when c is equal to 1 in formula V, Z ³ represents a single bond and A ³ represents a cyclohexylene group) is shown in DE19612814A1 Can be prepared by Whether the formyl group is linked to an optionally substituted phenylene group, for example via a single bond (eg c in formula V is equal to 1, Z ³ represents a single bond and A ³ represents a phenylene group) To the cyclic group via an alkylene bridge, —CH ₂ O—, —OCH ₂ — or —CF ₂ O— (eg, c in formula V is equal to 1 and Z ³ is an alkylene bridge) , —CH ₂ O—, —OCH ₂ — or —CF ₂ O— and when A ³ has one of the meanings indicated in claim 1 and above, further aldehydes of the formula V Can be prepared from carboxylic acid esters or carboxylic acid derivatives which are known from the literature and / or commercially using suitable reducing agents such as diisobutylaluminum hydride (DIBAL-H). Available (see inter alia German patent application DE102004021334A1).

An aldehyde of the formula V in which the formyl group is bonded to the 5-position of the tetrahydropyranyl group via a single bond and the 2-position is substituted is likewise available. Here, the starting materials are, for example, the corresponding carboxylic acid esters or nitrile precursors, for example the metathesis method shown in Scheme 1a (for example where radical ¹ is —CO ₂ -alkyl or —CN) and subsequent catalytic hydrogenation, for example It can be obtained using a homogeneous catalyst such as a Wilkinson catalyst, which is reacted with diisobutylaluminum hydride (DIBAL-H) to give a formyl derivative.

  Similarly, homoallylic alcohols of the formula IV are known from the prior art, are commercially available or can be readily prepared by synthetic methods known per se from the literature. Scheme 2 outlines a synthetic route starting from an allyl halide derivative of formula A.

Ａより出発して、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を使用して還元し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を得て、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、適当な金属または有機金属試薬との反応により化合物Ｂを得るが、ここで「Ｍｅｔ」は、使用される金属または有機金属試薬に依存して、Ｃｕ、Ｂｉ（ｒａｄｉｃａｌ）_２、Ｉｎ（ｒａｄｉｃａｌ）_２、Ｓｎ（ｒａｄｉｃａｌ）_３、Ｓｎ（ｒａｄｉｃａｌ）、Ｚｎ（ｒａｄｉｃａｌ）、Ｇｅ（ｒａｄｉｃａｌ）を表し、「ｒａｄｉｃａｌ」は１種類以上の適当な基または該金属上の配位子を表す。形成されたＢは中間体として先立って単離することなく行うこともできるが、更なるＢとホルムアルデヒド（または合成上同等のもの）との反応により、対応する処理の後に、式ＩＶの所望のホモアリルアルコールを得る。

Starting from A, for example starting from aldehyde R ^1- [A ¹ -Z ¹ ] _a- [A ² -Z ² ] _b -CHO, for example unsaturated ester R ^1- [A ¹ -Z by Reformatsky synthesis. _{^{1] a - [a 2 -Z}} 2] b -CH = CH-CO 2 - Newsletter alkanyl, subsequently allyl alcohol ^R 1 and reduced using DIBAL-H corresponding ^- _[a 1 ^-Z _{1] a} - to obtain _{^{[a 2 -Z 2] b -CH}} = CH-CH 2 OH, finally _{PBr 3 (Hal = Br),} PCl 5 or _{SO 2 Cl 2 (Hal = Cl} ) or HI (Hal = I) To obtain compound B by reaction with a suitable metal or organometallic reagent, where “Met” is Cu, Bi (radical) ₂ , depending on the metal or organometallic reagent used, In (Radical) ₂ , Sn (radical) ₃ , Sn (radical), Zn (radical), Ge (radical), where “radical” represents one or more suitable groups or a ligand on the metal. The formed B can also be carried out as an intermediate without prior isolation, but by further reaction of B with formaldehyde (or a synthetic equivalent), after the corresponding treatment, the desired formula IV Homoallylic alcohol is obtained.

  Further acquisition of the homoallylic alcohol of formula IV is carried out as shown in Scheme 3, where “Hal” has the same meaning as above in Scheme 2 and “Met” is preferably Cu (A. Carpita, R. Rossi, Synthesis (1982), 469).

ハロゲン化物Ｃは、−スキーム２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Ｄに転化され、引き続きＥと反応させて酢酸ホモアリルＦを得る。そして、式ＩＶの所望のホモアリルアルコールを、Ｆから鹸化によって入手する。

Halide C—in a manner corresponding to the method in Scheme 2—is converted to organometallic derivative D using a suitable reagent and subsequently reacted with E to give homoallyl acetate F. The desired homoallylic alcohol of formula IV is then obtained from F by saponification.

Furthermore, the homoallylic alcohol of the formula IV 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] alkylation 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).

In the context of the present invention, the term “alkyl” —unless otherwise defined in the description or in the claims—is in its most general sense linear or branched, saturated or unsaturated. An aliphatic hydrocarbon group having 1 to 15 (ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) carbon atoms. This group is unsubstituted or mono- or polysubstituted by fluorine, chlorine, bromine, iodine, carboxyl, nitro, NH ₂ , N (alkanyl) ₂ and / or cyano, provided that the same or different substituents It may be polysubstituted. 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 is —OCH ₃ , —OC ₂ H ₅ , —O—N—C ₃ H ₇ , —O—N—C ₄ H ₉ , —Ot—C ₄ H ₉ , —OCF _3. , -OCHF _2, is a -OCHF or -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 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.

A “thioalkyl” group is present when one or more CH ₂ groups in an alkyl group as defined above are replaced by sulfur. “Thioalkyl” preferably comprises a straight chain group of the formula C _a H _{2a + 1} —S— (CH ₂ ) _b —, where a is 1, 2, 3, 4, 5, 6, 7, 8, 9 Or 10 and b is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and particularly preferably, a is an integer of 1 to 6 and b is 1 or 2. Similarly, a thioalkyl group may be substituted with F, Cl, Br, I and / or —CN, and is preferably unsubstituted.

In the context of the present invention, the term “alkenyl” means an alkyl group as defined above in which one or more —CH═CH— groups are present. If there are two —CH═CH— groups in this group, they can also be referred to as “alkadienyl”. An alkenyl group can contain 2 to 15 (ie 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15) carbon atoms and can be branched Or it is preferably a straight chain. This group is unsubstituted or identically or differently mono- or polysubstituted, in particular F, Cl, Br, I and / or CN, ie hydrogen of one or both of the —CH═CH— units and A further CH ₂ or CH ₃ group hydrogen of the alkenyl group may be replaced by a corresponding substituent. Furthermore, —O— (“alkenyloxy”), —S—, —C≡C—, so that one or more CH ₂ groups are independent of each other and heteroatoms (O or S) are not directly bonded to each other. -CO-,-(CO) O-, and -O (CO)-may be substituted. When there are other than hydrogen on both carbon atoms of the CH═CH group, for example, when it is not a terminal group, there are two configurations of CH═CH: the E isomer and the Z isomer. The corresponding state applies to C═C double bonds substituted with halogen and / or —CN. In general, the E isomer (trans) is preferred. Preferably, the alkenyl group contains 2, 3, 4, 5, 6 or 7 carbon atoms and is vinyl, allyl, 1E-propenyl, 2-propenyl, 1E-butenyl, 1E-pentenyl, 1E-hexenyl, 1E- Heptenyl, 2-propenyl, 2E-butenyl, 2E-pentenyl, 2E-hexenyl, 2E-heptenyl, 3-butenyl, 3E-pentenyl, 3E-hexenyl, 3E-heptenyl, 4-pentenyl, 4Z-hexenyl, 4E-hexenyl, Mean 4Z-heptenyl, 5-hexenyl or 6-heptenyl. Particularly preferred alkenyl groups are vinyl, allyl, 1E-propenyl, 2-propenyl and 3E-butenyl.

An alkynyl group is present when one or more CH ₂ groups in an alkyl group are replaced with —C≡C—. It is also possible to replace one or more CH ₂ groups with — (CO) O— or —O (CO) —. Preferred groups here are: acetoxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pentanoyloxymethyl, 2-acetoxyethyl 2-propionyloxyethyl, 2-butyryloxyethyl, 2-acetoxypropyl, 3-propionyloxypropyl, 4-acetoxybutyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, methoxycarbonylmethyl, Ethoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, 2- (methoxycarbonyl) ethyl, 2- (ethoxycarbonyl) ethyl, 2- (propyl Po alkoxycarbonyl) ethyl, 3- (methoxycarbonyl) propyl, 3- (ethoxycarbonyl) propyl and 4- (methoxycarbonyl) butyl.

When the CH ₂ group of the alkyl group is replaced with unsubstituted or substituted —CH═CH—, and the adjacent CH ₂ group is replaced with CO, —CO—O— or —O—CO—, This group may be linear or branched. Preferably it is straight-chain and has 4 to 12 C atoms. Therefore, particularly preferred are acryloyloxymethyl, 2-acryloyloxyethyl, 3-acryloyloxypropyl, 4-acryloyloxybutyl, 5-acryloyloxypentyl, 6-acryloyloxyhexyl, 7-acryloyloxyheptyl, 8-acryloyloxy. Octyl, 9-acryloyloxynonyl, methacryloyloxymethyl, 2-methacryloyloxyethyl, 3-methacryloyloxypropyl, 4-methacryloyloxybutyl, 5-methacryloyloxypentyl, 6-methacryloyloxyhexyl, 7- Means methacryloyloxyheptyl or 8-methacryloyloxyoctyl.

  When an alkyl group, alkanyl group, alkenyl group or alkoxy group is replaced by at least one halogen, preferably this group is straight-chain. Halogen is preferably F or Cl. In the case of polysubstitution, preferably the halogen is F. The resulting groups also include perfluorinated groups. In the case of monosubstitution, fluorine or chlorine substitution may be at any desired position, but is preferably at the ω position.

In the context of the present invention, “alkylene” or “alkylene bridge” —unless otherwise defined in the specification or in the claims—is in the chain 1, 2, 3, 4, 5, 6, 7, Represents a divalent aliphatic hydrocarbon group having 8 carbon atoms, and may be mono- or polysubstituted by halogen, CN, carboxyl, nitro, alkanyl, alkoxy, —NH ₂ or —N (alkanyl) ₂ However, it may be polysubstituted by the same or different substituents. “Alkylene” or “alkylene bridge” preferably means a straight chain saturated aliphatic group having 1, 2, 3, 4, 5, 6 carbon atoms, unsubstituted or monosubstituted by fluorine Or a polysubstituted group, in particular, —CH ₂ CH ₂ —, —CH ₂ CH ₂ CH ₂ —, — (CH ₂ ) ₄ —, —CF ₂ CF ₂ — or — (CF ₂ ) ₄ —. .

In the context of the present invention, the term “aralkyl” refers to an arylalkyl group, ie a group in which an aryl substituent is connected to an atom, chain, other group or functional group via an alkyl bridge. The alkyl bridge is preferably a saturated divalent hydrocarbon group (“alkylene”), in particular methylene (—CH ₂ —) or ethylene (—CH ₂ —CH ₂ —). Preferred examples of aralkyl groups are benzyl and phenethyl. For the purposes of the present invention, an “aralkyl-O-radical” is an aralkyl group that is linked to an additional atom, chain, other group or functional group through an oxygen atom bonded to the alkyl bridge. is there. Preferred examples of aralkyl-O-radicals are O-benzyl and O—CH ₂ —CH ₂ -phenyl. The methylene group in the aralkyl group may in turn be replaced with a heterobridge such as —O—, —SO ₂ —, — (CO) —, etc., to provide conventional leaving and protecting groups.

  In the context of the present invention, the term “aryl” represents an aromatic or partially aromatic ring system, in a narrow sense represents a benzene ring, to modify or electronically screen its electronic properties ( For example, tert-butyl) may be mono-, di- or tri-substituted with simple groups such as 1-5C alkyl, halogen, nitro, cyano and the like. The aryl group is preferably a phenyl group or a p-tolyl group.

  In the context of the present invention, “halogen” represents fluorine, chlorine, bromine or iodine.

  When the group or substituent of the compound used in the present invention or the compound itself used in the present invention can exist as a group, substituent or compound which may be optically active or stereoisomeric, for example, since it has an asymmetric center, these It is included in the present invention. These compounds are in isomerically pure state, e.g. pure enantiomers, diastereomers, E or Z isomers, trans or cis isomers, or mixtures of isomers in any desired ratio, e.g. Needless to say, it can exist in racemic, E / Z isomer mixtures or cis / trans isomer mixtures.

  In order to protect any reactive functional groups or substituents present in the compounds used in the methods of the invention from the reactions of the invention and / or from previous or subsequent reactions and / or undesired reactions in a series of operations. , Protecting groups that can be cleaved off again when the reaction is complete can be used. Methods of using suitable protecting groups are known to those skilled in the art and are described, for example, in T.W. W. Green, P.M. G. M.M. Wuts: Protective group s in Organic Synthesis, 3rd edition, John Wiley & Sons (1999).

  The following examples illustrate the present invention without limiting it.

In the formulas, the group —C _n H _{2n + 1} represents an n-alkyl group, where n is greater than 2.

  In addition to the common and well-known abbreviations, the following abbreviations are used.

  C is a crystalline state, N is a nematic phase, Sm is a smectic phase, and I is an isotropic phase. Data between these symbols indicates the phase transition temperature of a particular material. Temperature data is in degrees Celsius unless otherwise indicated.

  The physical, physicochemical or electro-optical parameters are generally determined by known methods, among others, the booklet “Merck Liquid Crystals-Licristal®-Physical Properties of Liquid Crystals-Descriptor of the Mess. , “Darmstadt”.

  Above and below, Δn represents optical anisotropy (589 nm, 20 ° C.) and Δε represents dielectric anisotropy (1 kHz, 20 ° C.). The dielectric anisotropy Δε is determined at 20 ° C. and 1 kHz. The optical anisotropy Δn is determined at 20 ° C. and a wavelength of 589.3 nm.

  The Δn and Δε values and clearing points (cl.p.) of the individual compounds are determined by 5-10% of a particular compound of the invention and 90-95% of the commercially available liquid crystal mixture ZLI-4792 ( Obtained by linear extrapolation from a liquid crystal mixture consisting of Merck, Darmstadt City).

<Example 1: GWP1-reductive elimination in the presence of a heterogeneous catalyst and a trialkylamine>
The brominated material of formula II is dissolved in an appropriate amount of tetrahydrofuran (between about 4 and 12 times the volume or weight of the compound of formula II) and 10% of 5% palladium on carbon (55% water). ˜30% by weight, preferably 20% by weight (corresponding to about 0.5-6 mol% based on II), 2.5 molar equivalents of triethylamine and twice the amount (based on the substance) of water, pressure autoclave In, hydrogen at a pressure of 4-6 bar is used and the mixture is hydrogenated until a theoretical amount of hydrogen is taken up. After cooling, the reaction mixture is filtered, the filtrate is poured onto ice and the pH is adjusted to 1 using concentrated hydrochloric acid. The mixture is extracted once with each heptane and heptane / toluene mixture. The combined organic phases are washed 4 times with water, dried and evaporated. Further purification is performed-depending on the nature of the product-by crystallization, chromatography and / or distillation.

  Detailed data and yields on the reaction conditions of the tetrahydropyran derivatives of formula I obtained by GWP1 are shown in Table 1.

    <Example 2—Reductive elimination using tributyltin hydride>

１８．５ｇ（０．０５ｍｏｌ）の４−クロロテトラヒドロピランＩＩ−ａを、５００ｍｌのベンゼン中の３２ｇ（０．１１ｍｏｌ）の水素化トリブチルスズおよび０．８１ｇ（５ｍｍｏｌ）のアゾジイソブチロニトリルと一緒に２４時間、還流で加熱する。溶媒を引き続き蒸発させて除去し、残渣を２００ｍｌのメチルｔｅｒｔ−ブチルエーテル（ＭＴＢＥ）中で回収する。２３２ｍｌの１０％ＫＦ水溶液（０．４ｍｏｌのＫＦ）および１．０８ｇ（２．５ｍｍｏｌ）の１８−クラウン−６を加え、混合物を激しく攪拌する。有機相を乾燥し、蒸発させ、ヘプタン／トルエン（９：１）でシリカゲルを通して濾過し、再蒸発後得られる残渣をヘプタンから再結晶する。Ｉの収率（最適化せず）：８．７ｇ（５２％、１００％の全エカトリアル異性体）。Ｃ５５Ｉ。

18.5 g (0.05 mol) of 4-chlorotetrahydropyran II-a together with 32 g (0.11 mol) of tributyltin hydride and 0.81 g (5 mmol) of azodiisobutyronitrile in 500 ml of benzene Heat at reflux for hours. The solvent is subsequently removed by evaporation and the residue is recovered in 200 ml of methyl tert-butyl ether (MTBE). 232 ml of 10% aqueous KF (0.4 mol KF) and 1.08 g (2.5 mmol) 18-crown-6 are added and the mixture is stirred vigorously. The organic phase is dried, evaporated, filtered through silica gel with heptane / toluene (9: 1) and the residue obtained after re-evaporation is recrystallized from heptane. Y yield (not optimized): 8.7 g (52%, 100% total equatorial isomers). C55I.

    Example 3: Reductive elimination using tris (trimethylsilyl) silane (TTMSS)

６００ｍｌの１，２−ジメトキシエタン中の２０．７５ｇ（０．０５ｍｏｌ）の４−ブロモテトラヒドロピランＩＩ−ｂを、６０ｍｇ（２ｍｍｏｌ）のｐ−メトキシベンゾイルペルオキシドの添加後、１．２４ｇ（５ｍｍｏｌ）のＴＴＭＳＳおよび９．５ｇ（０．２５ｍｏｌ）のＮａＢＨ_４と共に、１２時間、石英器具中で攪拌しながら、波長２５４ｎｍの光を照射する。その後、引き続き溶媒を真空で蒸発させて取り除き、残渣をヘプタン／シリカゲルでシリカゲルを通して濾過する。蒸発させ、ヘプタンから再結晶し、Ｉ−ｂを得る。収率（最適化せず）：８．１ｇ（４８％、１００％の全エカトリアル異性体）。Ｃ５８Ｉ。

20.75 g (0.05 mol) of 4-bromotetrahydropyran II-b in 600 ml of 1,2-dimethoxyethane was added after addition of 60 mg (2 mmol) of p-methoxybenzoyl peroxide to 1.24 g (5 mmol) of Irradiate light with a wavelength of 254 nm with TTMSS and 9.5 g (0.25 mol) NaBH ₄ while stirring in a quartz instrument for 12 hours. The solvent is subsequently removed by evaporation in vacuo and the residue is filtered through silica gel with heptane / silica gel. Evaporate and recrystallize from heptane to give Ib. Yield (not optimized): 8.1 g (48%, 100% total equatorial isomers). C58I.

Example 4 Dehydrohalogenation of a Compound of Formula I to give a Compound of Formula IIIa and / or IIIb
<Example 4.1>

１５６ｇ（０．４８７ｍｏｌ）の４−ブロモ−２−（４−ブロモフェニル）テトラヒドロピラン４−１（異性体化合物、２，４−シス：２，４−トランス＝８４：１６）を、３３０ｍｌのトルエン中の８７．２ｍｌ（０．７３ｍｏｌ）の１，５−ジアザビシクロ［４．３．０］ノナ−５−エン（ＤＢＮ）と共に還流下、攪拌しながら３時間攪拌し、その間に懸濁が生じる。）の下で暖められる。冷却後、４００ｍｌの水および希硫酸を使用して混合物のｐＨを３に調整し激しく混合する。有機相を分離および除去し、水およびＮａＨＣＯ_３溶液で洗浄し、シリカゲルを通して濾過し、蒸発させ、１０５ｇ（９０％）の４−２ａおよび４−２ｂを６５：３５の比で含む生成混合物を得る。

156 g (0.487 mol) of 4-bromo-2- (4-bromophenyl) tetrahydropyran 4-1 (isomer compound, 2,4-cis: 2,4-trans = 84: 16) was added to 330 ml of toluene. The mixture is stirred for 3 hours under stirring with 87.2 ml (0.73 mol) of 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), during which suspension occurs. ) Warmed under. After cooling, adjust the pH of the mixture to 3 using 400 ml water and dilute sulfuric acid and mix vigorously. The organic phase is separated and removed, washed with water and NaHCO ₃ solution, filtered through silica gel and evaporated to give a product mixture containing 105 g (90%) of 4-2a and 4-2b in a ratio of 65:35. .

    <Example 4.2>

１０ｇ（０．０２７３ｍｏｌ）のシス−４−ブロモ−２−（４−ベンジルオキシ）フェニルテトラヒドロピランを、２０ｍｌの１，４−ジオキサン中の５．０８ｇ（０．０４０１ｍｏｌ）のＤＢＮと共に、還流下、４時間、攪拌しながら温める。そして溶媒を真空で蒸発することで取り除き、残渣を１００ｍｌのトルエンおよび１００ｍｌの希硫酸で回収し、激しく攪拌する。トルエン相を重炭酸ナトリウム溶液および水で洗浄し、乾燥し、シリカゲルを通して濾過する。濾液を蒸発して、６．８８ｇ（９５％）の４−４ａおよび４−４ｂを６７：３２の比で含む生成混合物を得る。

10 g (0.0273 mol) of cis-4-bromo-2- (4-benzyloxy) phenyltetrahydropyran together with 5.08 g (0.0401 mol) of DBN in 20 ml of 1,4-dioxane under reflux. Warm with stirring for 4 hours. The solvent is then removed by evaporation in vacuo and the residue is recovered with 100 ml toluene and 100 ml dilute sulfuric acid and stirred vigorously. The toluene phase is washed with sodium bicarbonate solution and water, dried and filtered through silica gel. The filtrate is evaporated to give a product mixture containing 6.88 g (95%) of 4-4a and 4-4b in a 67:32 ratio.

  Alternatively, HBr desorption can be performed at 130 ° C. for 3 hours without solvent.

    <Example 4.3>

４９．７ｇ（０．１５ｍｏｌ）の異性体的に純粋な全エカトリアル配置の４−ブロモ−２−（４−ブロモフェニル）−５−メチルテトラヒドロピラン４−５を、２０ｍｌのトルエン中の２７．８ｇ（０．２２５ｍｏｌ）のＤＢＮと共に、還流下、４時間、攪拌する。そして、混合物を０℃に冷却し、塩の沈殿を濾過して取り除き、濾液を濃縮し、トルエン／ヘプタン（１：１）でシリカゲルを通して濾過する。濾液を蒸発させ、残渣をエタノールより結晶化する。得られた唯一の異性体は４，５−ジヒドロ−５−メチルテトラヒドロピラン４−６ａ；収率（最適化していない）：１５．６ｇ（７３％）。

49.7 g (0.15 mol) of isomerically pure all equatorial configuration of 4-bromo-2- (4-bromophenyl) -5-methyltetrahydropyran 4-5 was dissolved in 27.8 g of 20 ml of toluene. Stir with refluxing (0.225 mol) DBN for 4 hours. The mixture is then cooled to 0 ° C., the salt precipitate is filtered off, the filtrate is concentrated and filtered through silica gel with toluene / heptane (1: 1). The filtrate is evaporated and the residue is crystallized from ethanol. The only isomer obtained was 4,5-dihydro-5-methyltetrahydropyran 4-6a; yield (not optimized): 15.6 g (73%).

    <Example 4.4>

例４．３に類似して、４−７（異性体混合物２，４−シス：２，４−トランス＝８５：１５；３２．９ｇ、０．１０７ｍｏｌ）より４−８ａを得る；収率（最適化していない）：８９％。

Analogously to Example 4.3, 4-8 is obtained from 4-7 (isomer mixture 2,4-cis: 2,4-trans = 85: 15; 32.9 g, 0.107 mol); yield ( Not optimized): 89%.

    <Example 4.5>

例４．３に類似して、４−９（異性体的に純粋２，４−シス）より４−１０ａを得る；収率（最適化していない）：９３％。

Analogous to Example 4.3, 4-10a is obtained from 4-9 (isomerically pure 2,4-cis); yield (not optimized): 93%.

    <Example 4.6>

２３．０ｇ（０．０５５６ｍｏｌ）の４−ブロモテトラヒドロピラン４−１１（異性体混合物）を、６０ｍｌのトルエン中の１０．３６ｇ（０．０８３４ｍｏｌ）のＤＢＮと共に、還流下、３時間、攪拌する。そして、混合物を室温まで冷却し、４００ｍｌの水を加え、そして希硫酸を使用して攪拌しながら混合物を酸性とする。乾燥およびトルエン／ヘプタン混合物（１：１）でシリカゲルを通して濾過後、分離された有機相を濾液より、４−１２ａ、４−１２ｂおよび４−１２ａが主な異性体である更なるジヒドロピラン誘導体を含む異性体混合物１７．８ｇ（９６％）を与える。

23.0 g (0.0556 mol) of 4-bromotetrahydropyran 4-11 (mixture of isomers) is stirred under reflux with 10.36 g (0.0834 mol) of DBN in 60 ml of toluene for 3 hours. The mixture is then cooled to room temperature, 400 ml of water is added, and the mixture is acidified with stirring using dilute sulfuric acid. After drying and filtration through silica gel with a toluene / heptane mixture (1: 1), the separated organic phase is separated from the filtrate by further dihydropyran derivatives with the main isomers 4-12a, 4-12b and 4-12a. 17.8 g (96%) of the isomer mixture containing are obtained.

    <Example 4.7>

４７．３２ｇ（０．１ｍｏｌ）のブロモテトラヒドロピラン４−１３（異性体混合物２，４−シス：２，４−トランス＝８６：１４）を、１５０ｍｌのトルエン中の１４．９ｇ（０．１２ｍｏｌ）のＤＢＮと共に、還流下、２．５時間、攪拌しながら加熱する。冷却後、混合物を水／希硫酸およびトルエンに溶解し、有機相をＮａＨＣＯ_３溶液および水で洗浄し、乾燥し、蒸発させる。残渣は主な生成物（８９％）として４−１４ａを含み、トルエン／ヘプタン（３：７）でシリカゲルを通して濾過する。溶出液の２番目の画分より、蒸発およびヘプタンからの再結晶後、２０．７ｇ（５３％）のジヒドロピラン４−１４ａを得る。

47.32 g (0.1 mol) of bromotetrahydropyran 4-13 (isomer mixture 2,4-cis: 2,4-trans = 86: 14) were added to 14.9 g (0.12 mol) in 150 ml of toluene. The mixture is heated with stirring under reflux for 2.5 hours. After cooling, the mixture is dissolved in water / dilute sulfuric acid and toluene, the organic phase is washed with NaHCO ₃ solution and water, dried and evaporated. The residue contains 4-14a as the main product (89%) and is filtered through silica gel with toluene / heptane (3: 7). The second fraction of the eluate gives 20.7 g (53%) of dihydropyran 4-14a after evaporation and recrystallization from heptane.

    <Example 4.8>

８１．３ｇ（０．２５ｍｏｌ）のエステル４−１５を、４００ｍｌのトルエン中の３７．３ｇ（０．３ｍｏｌ）のＤＢＮと共に、還流下、２．５時間、攪拌しながら加熱する。冷却後、希硫酸を加え、および有機相を引き続き乾燥し、蒸発し、トルエン／ヘプタン（３：７）でシリカゲルを通して濾過する。主な画分は、３９．６ｇ（６５％）のジヒドロピラン４−１６ａを含む。

81.3 g (0.25 mol) of ester 4-15 is heated with stirring for 3 hours under reflux with 37.3 g (0.3 mol) of DBN in 400 ml of toluene. After cooling, dilute sulfuric acid is added and the organic phase is subsequently dried, evaporated and filtered through silica gel with toluene / heptane (3: 7). The main fraction contains 39.6 g (65%) of dihydropyran 4-16a.

    <Example 4.9>

２２．３ｇ（０．０５ｍｏｌ）の４−１７（異性体混合物２，５−シス：２，５−トランス＝４２：５８）を、７５ｍｌのトルエン中の９．３１ｇ（０．０７５ｍｏｌ）のＤＢＮと共に、還流下、３時間、加熱する。希硫酸およびトルエンで水系の作業後、有機相をＮａＨＣＯ_３溶液および水で洗浄し、乾燥し、蒸発させる。残渣をトルエンでシリカゲルを通して濾過し、１０．４３ｇ（５７％）のジヒドロピラン４−１８ａを得る。

22.3 g (0.05 mol) 4-17 (isomer mixture 2,5-cis: 2,5-trans = 42: 58) together with 9.31 g (0.075 mol) DBN in 75 ml toluene. Heat at reflux for 3 hours. After working aqueous with dilute sulfuric acid and toluene, the organic phase is washed with NaHCO ₃ solution and water, dried and evaporated. The residue is filtered through silica gel with toluene to give 10.43 g (57%) of dihydropyran 4-18a.

    <Example 4.10>

２２．５ｇ（０．０４ｍｏｌ）の４−１９（異性体混合物２，５−シス：２，５−トランス＝２５：７５）を、１００ｍｌのトルエン中の７．５ｇ（０．０６ｍｏｌ）のＤＢＮと共に、還流下、４時間、攪拌する。希硫酸およびトルエンで水系の作業後に乾燥し、シリカゲルを通して有機相を濾過し、蒸発させる。残渣をエタノールより再結晶する。４−２０ａの収率（最適化していない）：１０．７ｇ（５５％）。

22.5 g (0.04 mol) of 4-19 (isomer mixture 2,5-cis: 2,5-trans = 25: 75) together with 7.5 g (0.06 mol) of DBN in 100 ml of toluene Stir at reflux for 4 hours. Dry after working with dilute sulfuric acid and toluene and filter the organic phase through silica gel and evaporate. The residue is recrystallized from ethanol. Yield of 4-20a (not optimized): 10.7 g (55%).

    <Example 4.11>

窒素下で、１００ｇ（２１９ｍｍｏｌ）のブロモテトラヒドロピラン４−２１を１６５ｍｌのトルエンに溶解し、３８．５ｍｌのＤＢＮを加え、混合物を５時間、煮沸で加熱する。２００ｍｌの水を冷却された反応物に引き続き加え、希硫酸を使用して酸性化する。有機相を３００ｍｌのヘプタンで希釈し、分離し、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）を通し、５７．１ｇの化合物４−２２（含有量：６０％；収率：４１％）を得る。

Under nitrogen, 100 g (219 mmol) of bromotetrahydropyran 4-21 are dissolved in 165 ml of toluene, 38.5 ml of DBN are added and the mixture is heated at 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 heptane, separated, washed with sodium hydrogen carbonate solution and evaporated. The obtained residue is passed through silica gel (toluene) to obtain 57.1 g of compound 4-22 (content: 60%; yield: 41%).

Example 5-GWP2: Hydrogenation of dihydropyran of formula III from Examples 4.1 to 4.10
6 mmol of dihydropyran IIIa (and / or IIIb) (from Examples 4.1 to 4.11), 0.6 mmol of tris (triphenylphosphine) rhodium (I) chloride (Wilkinson's catalyst) and toluene, ethanol or methanol Into a pressure autoclave together with a mixture of After introducing 10 bar of nitrogen and replacing the gas, and degassing three times, 60 bar of hydrogen gas is injected, and the mixture is heated to 80 ° C. After about 20 hours, the mixture is allowed to cool and tetrahydropyran I is obtained in quantitative yield. The isomer ratio of trans-2,5-isomer to cis-2,5-isomer of formula I is about 3: 1 in each case.

  Detailed data and yields on the reaction conditions of the tetrahydropyran derivative of formula II obtained by GWP2 are shown in Table 6.

Example 6 GWP3: Preparation of Halogenated Dihydropyran of Formula II
First, 0.1 mol of an aldehyde of formula V and 0.1 mol of homoallylic alcohol of formula IV are introduced into 100 ml of dichloromethane. 0.05 mol to 0.06 mol of solid form Lewis acid is added to the mixture. When the reaction is complete (TLC check), the reaction mixture is filtered through silica gel or an aqueous work is performed. In this case, 100 ml water is added dropwise to the mixture and 30 ml concentrated hydrochloric acid is added. The mixture is stirred until phase separation is complete. Water, hydrochloric acid and heptane are added to the organic phase and, after stirring, the aqueous phase is separated and removed. The aqueous phase is extracted with dichloromethane, the organic phases are combined and evaporated. The residue is further purified by chromatography on silica gel, crystallization or distillation.

  Detailed data and yields on the reaction conditions of the tetrahydropyran derivative of formula II obtained by GWP3 are shown in Table 2.

Example 7-GWP4: Preparation of halogenated tetrahydropyran of formula II
First, 0.05 mol to 0.055 mol of Lewis acid is introduced into 100 ml of dichloromethane and the suspension is stirred. The aldehyde of formula V (0.1 mol) is then introduced in several portions. Subsequently, homoallylic alcohol of formula IV (0.1 to 0.11 mol) is added. When the reaction is complete (TLC check), the reaction mixture is filtered through silica gel or an aqueous work-up as described above in GEP3.

  Detailed data and yields on the reaction conditions of the tetrahydropyran derivative of formula I obtained by GWP4 are shown in Table 3.

Example 8-GWP5: Preparation of halogenated tetrahydropyran of formula II
First, 0.1 mol of an aldehyde of formula V, 0.1 mol of homoallylic alcohol of formula IV and 0.5-5 mol% of a Lewis acid are introduced into 100 ml of dichloromethane at a temperature between 0 ° C. and room temperature. Then, gaseous hydrohalic acid is passed through while being cooled from outside until it is saturated. The reaction mixture is then added to a saturated aqueous sodium bicarbonate solution with stirring. The organic phase is separated and removed, dried and evaporated. The residue is purified by chromatography on silica gel, crystallization or distillation.

  Detailed data and yields on the reaction conditions of the tetrahydropyran derivative of formula II obtained by GWP5 are shown in Table 4.

Example 9-GWP6: Preparation of halogenated tetrahydropyran of formula II
1.5 molar equivalents of saturated hydrohalic acid in water or glacial acetic acid are added with stirring to a 0.1 M solution of aldehyde of formula V and homoallylic alcohol of formula IV in dichloromethane, 5 mol% of Lewis acid may be added. When the reaction is complete (TLC check), the reaction mixture is processed as described in GEP3.

  Detailed data on the reaction conditions and yield of the tetrahydropyran derivative of formula II obtained by GWP6 are shown in Table 5.

核磁気共鳴スペクトル（ＮＭＲ）または質量スペクトルによる表１〜５に示すテトラヒドロピラン誘導体ＩおよびＩＩの同定を以下に行う。同定されたサンプル（その全ては主要異性体２−、２，５−および２，４，５−置換２Ｈ−３，４，５，６−テトラヒドロピラン誘導体の全エカトリアル配向イス型コンホメーションである）の^１Ｈ−ＮＭＲスペクトルのプロトンの帰属は、以下の式を参照して行われる。

The tetrahydropyran derivatives I and II shown in Tables 1 to 5 are identified below by nuclear magnetic resonance spectrum (NMR) or mass spectrum. Identified samples, all of which are all equatorially oriented chair conformations of the major isomers 2-, 2,5- and 2,4,5-substituted 2H-3,4,5,6-tetrahydropyran derivatives The ¹ H-NMR spectrum of ¹ ) is assigned with reference to the following formula.

＜表１からのテトラヒドロピラン誘導体＞
信号の位置はテトラメチルシラン（＝０）に関するｐｐｍで引用され、結合定数Ｊの大きさはヘルツ（Ｈｚ）で示される。信号の略称は、ｓが一重項、ｄが二重項、ｔが三重項、ｑが四重項およびｍが多重項を表わす。これらのデータは、さらに他の表に列記されたＮＭＲスペクトルにも当てはまる。他に示されないかぎり、使用された溶媒はＣＤＣｌ_３である。

<Tetrahydropyran derivatives from Table 1>
The signal position is quoted in ppm with respect to tetramethylsilane (= 0) and the magnitude of the coupling constant J is given in hertz (Hz). Signal abbreviations are s for singlet, d for doublet, t for triplet, q for quartet and m for multiplet. These data also apply to NMR spectra listed in other tables. Unless otherwise indicated, the solvent used is CDCl ₃ .

1a / b) 250 MHz ¹ H-NMR spectrum 4 aromatic H: AB-q, center 6.89, 2o-H for tetrahydropyranyl substitution: d7.10 J = 8; 2o-H for phenol group: d6.52 J = 8;
_{H 2a: dd4.28 J = 12,2;} H 6e: dm3.97 J = 12,4; H 6a: t3.15 J = 12; H 3e, H 4e, H 5a and _H 3a: _m1.57- 1.94; H _4a : dq1.22 J = 12, 4; CH ₃ : d0.75 J = 7.
Melting point: 91 ° C.

2a / b) 300 MHz ¹ H-NMR spectrum 4 Aromatic H: AB-q, center 6.88, 2o-H for tetrahydropyranyl substitution: d7.15 J = 8; 2o-H for phenol OH group: dd6. 60 J = 8;
_{H 2a: dd4.20 J = 12,2;} H 6e: dm4.07 J = 12,4; H 6a: t3.20 J = 12 ,? H _3e : dm 1.99J = 12,? _{; H 4e dm1.80J = 12; H} 3a, H 5a: m1.50-1.75; side chain CH ₂ and _{H 4a: m1.1-1.3; CH 3:} t0.92J = 7.
Melting point: 92 ° C.

3) 250 MHz ¹ H-NMR spectrum 4 Aromatic H: AB-q, center 6.95, 2o-H for tetrahydropyranyl substitution: d7.20 J = 8; 2o-H for phenol OH group: d6.70 J = 8; H _2a : dd 4.20 J = 12, 2; H _6e : dm 4.07 J = 12, 4; H _2a dd 4.20; H _6a : t 3.20 J = 12; H _3e : dm 1.99 J _{= 12; H 4e: dm1.80 J} = 12,3; H 3a and _H 5a _m1.50-1.75; 2 side chains 4H, CH ₂ and _H 4a: _m1.10-1.30; CH ₃ : T0.92 J = 7.
Melting point: 94 ° C.

4a / b) 250 MHz ¹ H-NMR spectrum 4 Aromatic H: AB-q, center 6.95, 2o-H for tetrahydropyranyl substitution: d7.20 J = 8; 2o-H for phenol OH group: d6. 70 J = 8; H _2a dd4.20 J = 12, 2; H _6e : dm4.06 J = 12, 4; H _6a : t3.18 J = 12; H _3e : dm1.97 J = 12; H _4e : dm1.82 J = _{12; H 5a} and _H 3a: _m1.53-1.74; 3CH ₂ group of 6 side chains Hs and _{H 4a: m1.05-1.45; CH 3:} t0.90 J = 7.
Melting point: 87 ° C.

6) 400 MHz ¹ H-NMR spectrum

ｔ７．３２ Ｊ＝８（ｏ−Ｈおよびｍ−Ｆカップリング）、その他の４芳香族Ｈ：ｍ７．１８；Ｈ_２ａ：ｄｄ４．２８ Ｊ＝１２，２；Ｈ_６ｅ：ｄｍ４．０４ Ｊ＝１２，？；Ｈ_６ａ：ｔ３．１８ Ｊ＝１２；Ｈ_３ｅおよびＨ_４ｅ：ｍ１．８６−２．０；Ｈ_５ａ：ｍ１．７８；Ｈ_３ａ：ｄｑ１．６０ Ｊ＝１２，４；Ｈ_４ａ：ｄｑ１．３２ Ｊ＝１２，４；ＣＨ_３：ｄ０．８６ Ｊ＝７。

t7.32 J = 8 (o-H and m-F couplings), the other four aromatic _{H: m7.18; H 2a: dd4.28} J = 12,2; H 6e: dm4.04 J = 12 ,? _{; H 6a: t3.18 J = 12} ; H 3e and _{H 4e: m1.86-2.0; H 5a:} m1.78; H 3a: dq1.60 J = 12,4; H 4a: dq1.32 _{J = 12,4; CH 3: d0.86} J = 7.

7) 250 MHz ¹ H-NMR spectrum

ｔ７．３２ Ｊ＝８（ｏ−Ｈおよびｍ−Ｆカップリング）、その他の４芳香族Ｈ：ｍ７．１８；Ｈ_２ａ：ｄｄ４．２８ Ｊ＝１２，２；Ｈ_６ｅ：ｄｍ４．０９ Ｊ＝１２，４；Ｈ_６ａ：ｔ３．２０ Ｊ＝１２；Ｈ_３ｅおよびＨ_４ｅ：ｍ１．８３−２．１２；Ｈ_３ａおよびＨ_５ａ：ｍ１．４７−１．８０；３側鎖ＣＨ_２基の６ＨｓおよびＨ_４ａ：ｍ１．０５−１．４０；ＣＨ_３：ｔ０．８７ Ｊ＝７。

t7.32 J = 8 (o-H and m-F couplings), the other four aromatic _{H: m7.18; H 2a: dd4.28} J = 12,2; H 6e: dm4.09 J = 12 _{, 4; H 6a: t3.20 J} = 12; H 3e and _H 4e: _{m1.83-2.12; H 3a} and _H 5a: _m1.47-1.80; 3 sidechain CH ₂ groups 6Hs and _{H 4a: m1.05-1.40; CH 3:} t0.87 J = 7.

<Tetrahydropyran derivative II from Table 2>
1a / b) 250 MHz ¹ H-NMR spectrum 4 Aromatic H: AB-q, center 7.33; 2o-H for bromine substitution: d7.46 J = 8; 2o-H for tetrahydropyranyl substitution: d7.19 _{J = 8; H 2a, H} 4a, H 6e: m4.08-4.33; H 6a: dt3.57 J = 12,2; H 3e: ddd2.44 J = 12,4,2; H 5e, _{H 5a: m2.08-2.28; H 3a:} q1.98 J = 12.

2) 500 MHz ¹ H-NMR spectrum 4 Aromatic H: AB-q; Center 7.09; 2o-H for tetrahydropyranyl substitution: d7.15 J = 8; 2o-H for phenol OH group: d6.75 J = 8; H _2a : dd 4.25 J = 12, 2; H _6e : dd 4.18 J = 12, 4; H _4a : dt 4.02 J = 12, 4; H _6a : t 3.27 J = 12; H _{3e: ddd2.47 J = 12,4,2; H} 3a: q2.22 J = 12; H 5a and CH ₂ of sidechain 1H: m1.93; of one another 1 side chain H: m1.23; CH ₃ : t0.93 J = 7.

3) 250 MHz ¹ H-NMR spectrum 4 Aromatic H: AB-q; Center 6.95; 2o-H for tetrahydropyranyl substitution: d7.15 J = 8; 2o-H for phenol OH group: d6.75 J = 8; H _2a : dd 4.27 J = 12, 2; H _4a : dt 4.15 J = 12, 4; H _6e : dd 4.08 J = 12, 2; H _6a : t 3.26 J = 12; H _3e : ddd 2.45 J = 12, 4, 2; H _3a : q2.10 (J = 12); CH ₂ side chain H _5a and 1H: m1.68-1.98; 2 side chain CH ₂ group further _{3Hs: m1.10-1.53; CH 3: t0.90} J = 7.
Melting point: 104 ° C.

4) 250 MHz ¹ H-NMR spectrum 4 aromatic H: AB-q; center 6.99; 2o-H for tetrahydropyranyl substitution: d7.20 J = 8; 2o-H for phenol OH group: d6.78 J = 8; H _2a : dd 4.30 J = 12, 2; H _6e and H _4a : m 4.10-4.25; H _6a : t 3.28 J = 12; H _3e : ddd 2.48 J = 1,4 _{, 2; H 3a: q2.17 J} = 12; H 5a and CH ₂ sidechain 1H: m1.72-2.00; 3 additional side chain CH ₂ groups 5Hs: m1.15-1.50; CH _3: t0.95 J = 7.

6) 250 MHz ¹ H-NMR spectrum 5 aromatic H of phenylbenzyl group: m 7.28-7.45, 4 aromatic H of second phenyl ring: AB-q; center 7.10; tetrahydro in it 2o-H for pyranyl substituted: d7.26 J = 8; O- benzyl against group 2o-H: d6.94 J = 8 ; 2CH 2 groups _{benzyl: s5.06; H 2a: dd4.28 J} = 12 H _6e : dd 4.07 J = 12,4; H _4a : dt 3.98 J = 1,4; H _6a : t 3.22 J = 12; H _3e : ddd 2.48 J = 12,4,2 _{; H 3a: q2.18 J = 12} ; H 5a: m2.07; CH 3: d1.03 J = 7.

7) 250 MHz ¹ H-NMR spectrum 5 aromatic H of phenylbenzyl group: m 7.30-7.47, 4 aromatic H of second phenyl ring: AB-q; center 7.09; tetrahydro in it 2o-H for pyranyl substituted: d7.25 J = 8; O- benzyl against group 2o-H: d6.93 J = 8 ; 2CH 2 groups _{benzyl: s5.05; H 2a: dd4.27 J} = 12 H _6e : dd 4.19 J = 12, 4; H _4a : dt 4.03 J = 12, 4; H _6a : t 3.26 J = 12; H _3e : ddd 2.50 J = 12, 4, 2 _{; H 3a: q2.18 J = 12} ; the CH ₂ sidechain _{H 5a} and 1H: m1.83-2.0; second H of CH ₂ sidechain: m1.12-1.38; _CH 3: t0.93 J = 7.

8) 250 MHz ¹ H-NMR spectrum 5 aromatic H of phenyl benzyl group: m 7.29-7.44, 4 aromatic H of second phenyl ring: AB-q; center 7.09; tetrahydro in it 2o-H for pyranyl substituted: d7.25 J = 8; O- benzyl against group 2o-H: d6.93 J = 8 ; 2CH 2 groups _{benzyl: s5.05; H 2a: dd4.26 J} = 12 H _6e : dd 4.17 J = 12, 4; H _4a : dt 4.02 J = 1, 4; H _6a : t 3.25 J = 12; H _3e : ddd 2.48 J = 12, 4, 2 _{; H 3a: q2.20 J = 12} ; the CH ₂ sidechain _{H 5a} and 1H: m1.78-2.05; 3 sidechain CH ₂ groups 5Hs: _m1.10-1.45; CH 3: t0 .90 J = 7.

9) 400 MHz ¹ H-NMR spectrum

ｔ７．３５ Ｊ＝８（カップリングおよびｍ−Ｆカップリング）、その他の４芳香族Ｈ：ｍ７．０９−７．２６；Ｈ_２ａ：ｄｄ４．４０ Ｊ＝１２，２；Ｈ_６ｅ：ｄｄ４．１０ Ｊ＝１２，４；Ｈ_４ａ：ｄｔ３．７８ Ｊ＝１２，４；Ｈ_６ａ：ｔ３．２５ Ｊ＝１２；Ｈ_３ｅ：ｄｄｄ２．４３ Ｊ＝１２，４，２；Ｈ_３ａおよびＨ_５ａ：ｍ１．８３−２．２０；ＣＨ_３：ｄ１．０７ Ｊ＝７。

t7.35 J = 8 (coupling and m-F couplings), the other four aromatic _{H: m7.09-7.26; H 2a: dd4.40} J = 12,2; H 6e: dd4.10 _{J = 12,4; H 4a: dt3.78} J = 12,4; H 6a: t3.25 J = 12; H 3e: ddd2.43 J = 12,4,2; H 3a and _H 5a: m1. _{83-2.20; CH 3: d1.07 J =} 7.

11) 400 MHz ¹ H-NMR spectrum

ｔ７．３８ Ｊ＝８（カップリングおよびｍ−Ｆカップリング）、その他の４芳香族Ｈ：ｍ７．１０−７．２３；Ｈ_２ａ：ｄｄ４．３７ Ｊ＝１２，２；Ｈ_６ｅ：ｄｄ４．１２ Ｊ＝１２，４；Ｈ_４ａ：ｄｔ３．９３ Ｊ＝１２，４；Ｈ_６ａ：ｔ３．２５ Ｊ＝１２；Ｈ_３ｅ：ｄｄｄ２．５５ Ｊ＝１２，４，２；Ｈ_３ａ：ｑ２．１４ Ｊ＝１２；Ｈ_５ａ：ｍ２．０８；ＣＨ_３：ｄ１．０７ Ｊ＝７。

t7.38 J = 8 (coupling and m-F coupling), other 4 aromatics H: m 7.10-7.23; H _2a : dd 4.37 J = 12, 2; H _6e : dd 4.12. _{J = 12,4; H 4a: dt3.93} J = 12,4; H 6a: t3.25 J = 12; H 3e: ddd2.55 J = 12,4,2; H 3a: q2.14 J = _{12; H 5a: m2.08; CH} 3: d1.07 J = 7.

12) Mass spectrum molecular peaks M (+) 60, 462: unclear; 369, 371: (M-91) (+)-benzyl; 290: 369, 371-Br; 289: 369, 371-HBr; 91: _Ph-CH 2 (+) (base peak).

<Tetrahydropyran derivative II from Table 3>
1) ¹ H-NMR spectrum is No. 9 / according to Table 2.

2) The ¹ H-NMR spectrum is No. 4 / according to Table 2.

<Tetrahydropyran derivative II from Table 4>
1a) The ¹ H-NMR spectrum is no. 1a / according to Table 2.

1b) The ¹ H-NMR spectrum is no. 1a / according to Table 4.

3) 250 MHz ¹ H-NMR spectrum

ｔ７．３６ Ｊ＝８（カップリングおよびｍ−Ｆカップリング）、その他の２芳香族Ｈ：ｍ７．１０−７．２５；Ｈ_２ａ：ｄｄ４．３０ Ｊ＝１２，２；Ｈ_６ｅ：ｄｄ４．０８ Ｊ＝１２，４；Ｈ_４ａ：ｄｔ３．８８ Ｊ＝１２，４；Ｈ_６ａ：ｔ３．２０ Ｊ＝１２；Ｈ_３ｅ：ｄｄｄ２．４８ Ｊ＝１２，４，２；Ｈ_３ａおよびＨ_５ａ：ｍ１．９５−２．１７；ＣＨ_３：ｄ１．０４× Ｊ＝７。

t7.36 J = 8 (coupling and m-F coupling), other 2 aromatic H: m 7.10-7.25; H _2a : dd 4.30 J = 12, 2; H _6e : dd 4.08 _{J = 12,4; H 4a: dt3.88} J = 12,4; H 6a: t3.20 J = 12; H 3e: ddd2.48 J = 12,4,2; H 3a and _H 5a: m1. 95-2.17; CH ₃ : d1.04 × J = 7.

5) Mass spectrum 414, 412: Molecular peak; 333: M (+)-Br; 332: M (+)-HBr

＜表５からのテトラヒドロピラン誘導体ＩＩ＞
表５からの１ａ、１ｂ、１ｃの^１Ｈ−ＮＭＲスペクトルは、表２のＮｏ．１ａものと一致。

<Tetrahydropyran derivative II from Table 5>
The ¹ H-NMR spectra of 1a, 1b and 1c from Table 5 are shown in No. 2 of Table 2. Match with 1a.

<Tetrahydropyran derivative I from Table 6>
Examples 14-23 from Table 6 are prepared analogously to compounds 1-13 in this table. Since they have 3 or 4 rings in the molecular structure, they can be crystallized and can therefore have a content higher than 99.5% by purification by crystallization. Here, attention was directed to purity rather than crystal yield. Thus, a clearer identification than the melting and phase behavior of these compounds is possible without interpretation of complex NMR spectra. NMR for these compounds is available and is consistent with the structure shown.

Claims (9)

A process for preparing tetrahydropyran derivatives of the formula I, characterized in that the substituent X ¹ is reacted from the tetrahydropyran derivative of the formula II with a catalyst in the presence of a base with hydrogen in the presence of a base and reductively eliminated.

(However, in Formulas I and II,
a, b, c, d, e, f each independently represents 0 or 1, provided that a + b + c + d + e + f is equal to 1, 2, 3 or 4;
R ¹ is independently in each case halogen, —CN, an alkyl group having 1 to 15 C atoms, which group is unsubstituted, 1-substituted by —CN, or 1 by halogen. Substituted or polysubstituted, but in addition one or more of the CH ₂ groups in these groups is such that the oxygen atoms 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 independently in each case halogen, —CN, —NCS, —NO ₂ , —OH, —SF ₅ , —O-aralkyl, an alkyl group having 1 to 15 C atoms, Is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen, OH or —O-aralkyl, but in addition, one or more CH ₂ groups in these groups In such a manner that the oxygen atoms in the chain are not directly bonded to each other, and —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, —CO—, — CO—O— or —O—CO— may be substituted,
A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ may each be independently of each other rotated or mirror image,

Represents
Z ¹ is independently in each case a single bond, an alkylene bridge having 1 to 6 carbon atoms, unsubstituted or mono- or polysubstituted with F and / or Cl, or —CH ₂ O— , —OCH ₂ —, and A ² are not cyclohexylene and cyclohexenylene rings, may also represent —CF ₂ O—,
Z ² independently in each case represents a single bond, an alkylene bridge having 1 to 6 carbon atoms, unsubstituted or mono- or polysubstituted with F and / or Cl;
Z ³ , Z ⁴ , Z ⁵ and Z ⁶ are each independently a single bond, an alkylene bridge having 1 to 6 carbon atoms, unsubstituted or mono- or polysubstituted with F and / or Cl. or represents, or _{-CH 2 O -, - OCH 2} -, - CF 2 O- to represent, however, _-CF 2 O-bridge directly linked via its O atoms in cyclohexylene or cyclohexylene ring Not
n1, n2 and n3 are each independently 0, 1, 2, 3 or 4;
Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are each independently H, halogen, —CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 — Represents alkynyl, —OC _1-6 -alkanyl, —OC _2-6 -alkenyl and —OC _2-6 -alkynyl, provided that the aliphatic group is unsubstituted or mono- or polysubstituted by halogen , And W ¹ each independently represents —CH ₂ —, —CF ₂ — or —O—,
And in Formula II:
X ¹ is to table a bromine,
However,
when a and b are simultaneously 0, R ¹ does not represent halogen or CN; and
When all of c, d, e and f are simultaneously 0, R ² does not represent halogen, —CN, —NCS, —NO ₂ , —OH, —SF ₅ , —O-aralkyl or alkoxy . ) A ¹ and A ² are independently of each other

And A ³ , A ⁴ , A ⁵ and A ⁶ are independently of each other,

The method of claim 1 wherein: Z ¹ and Z ² are each a single bond, and Z ³ , Z ⁴ , Z ⁵ and Z ⁶ each independently represent a single bond, —CF ₂ O— or —OCH ₂ —. The method according to claim 1 or 2.   4. The compound of formula II has substituents other than hydrogen at the 2-position and 5-position of the tetrahydropyran ring, and these substituents are in the trans configuration with respect to each other. 2. The method according to item 1.   The method according to claim 1, wherein (a + b + c + d + e + f) is 1, 2 or 3.   The method according to claim 1, wherein the catalyst is a heterogeneous transition metal catalyst.   The method according to claim 1, wherein the base is a tertiary amine.   The method according to claim 1, wherein the base is triethylamine. The compound of formula II is a homoallylic alcohol of formula IV, an aldehyde of formula V or an acetal or hydrate thereof and the presence of at least one Lewis acid containing at least one bromine atom and / or at least 1 The method according to claim 1, which is obtained by reacting in the presence of a Bronsted acid containing one bromine ion.

^{(However, a, b, c, d} , e, f, R 1, R 2, A 1, A 2, A 3, A 4, A 5, A 6, Z 1, Z 2, Z 3, Z 4 , ^Z 5, ^{Z 6} is Ri as der as defined in claim 1,
However,
a + b is equal to 0, 1 or 2;
c + d + e + f is equal to 0, 1, 2, 3 or 4 . )