JP5259391B2 - Process for the preparation of tetrahydropyran derivatives - Google Patents

Description

  The present invention relates to a process for the preparation of tetrahydropyran derivatives, the use of these tetrahydropyran derivatives for preparing these tetrahydropyran derivatives and further tetrahydropyran derivatives. In particular, the present invention relates to the preparation of halogenated tetrahydropyran derivatives.

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

  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.

Two synthetic methods of this type 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.

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.

J. et al. S. Yadav et al., Synth. Comm. (2002), 32, 1803-1808 (Non-patent Document 6) describes cyclization of a benzaldehyde derivative together with (1-aryl) allyl alcohol. The resulting 4-chlorotetrahydropyran is insufficient for the desired process. The product is unsubstituted at the 3 and 5 positions. The proposed reagent is bismuth (III) chloride with microwaves without solvent, but not bromide and iodide.
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 J. et al. S. Yadav et al., Synth. Comm. (2002), 32, 1803-1808.

  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 in accordance with the invention the presence of a homoallylic alcohol of formula II, an aldehyde of formula III or an acetal or hydrate thereof and at least one Lewis acid containing at least one chlorine, bromine or iodine atom. It is achieved by a process for the preparation of halogenated tetrahydropyran derivatives of the formula I characterized in that they are reacted under and / or in the presence of a Bronsted acid containing at least one chlorine, bromine or iodine ion.

ただし、式Ｉ、ＩＩおよびＩＩＩ中、
ａ、ｂ、ｃ、ｄ、ｅおよび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または４に等しく、
Ｘ^１は、塩素、臭素またはヨウ素を表し、
Ｒ^１は、Ｈ、ハロゲン、−ＣＮ、１〜１５個のＣ原子を有するアルキル基を表し、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、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を表し、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およびＡ^６は、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、

Provided that in formulas I, II and III:
a, b, c, d, e and f, independently of one another, represent 0 or 1, provided that a + b + c + d + e + f is equal to 1, 2, 3 or 4;
X ¹ represents chlorine, bromine or iodine,
R ¹ represents H, halogen, —CN, an alkyl group having 1 to 15 C atoms, and the group is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen In addition, however, one or more of the CH ₂ groups in these groups may be such that —C≡C—, —CH═CH—, —O, such that the oxygen atoms in the chain are not directly bonded to each other. -, - S -, - SO -, - SO 2 -, - CO-O- or may be replaced by -O-CO-,
R ² represents H, halogen, —CN, —NCS, —NO ₂ , —OH, —SF ₅ , —O-aralkyl, an alkyl group having 1 to 15 C atoms, and the group is unsubstituted. Is, is monosubstituted by —CN, or monosubstituted or polysubstituted by halogen or —O-aralkyl, but in addition one or more of the CH ₂ groups in these groups is an oxygen in the chain The atoms are not directly bonded to each other so that —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, —CO—, —CO—O— or — May be replaced by O-CO-,
A ¹ , A ² , A ³ , A ⁴ , A ⁵ and A ⁶ , independently of one another, may be rotated or mirror images and represent the following:

Ｚ^１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を表すか、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−を表し、
Ｚ^２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を表し、
Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、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、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、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、−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、−ＣＨ_２−、−ＣＦ_２−または−Ｏ−を表し、
ただし、
ａおよびｂが同時に０の場合、Ｒ^１は水素を表さず、および
ａ、ｂ、ｃ、ｄ、ｅおよびｆの全てが同時に０の場合、Ｒ^１およびＲ^２はＨまたは無置換のアルカニルではない。

Z ¹ represents 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 if ^{a 2} is not a cyclohexylene and cyclohexenylene ring, it represents _-CF 2 O-,
Z ² 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 bonded to via its O atoms in cyclohexylene or cyclohexylene ring Not
n1, n2 and n3 are independently of each other 0, 1, 2, 3 or 4;
Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are independently of each other H, halogen, —CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl. , -OC _1-6 -alkanyl, -OC _2-6 -alkenyl, -OC _2-6 -alkynyl, wherein the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, Preferably it is H or F, and W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
However,
when a and b are simultaneously 0, R ¹ does not represent hydrogen, and when all of a, b, c, d, e and f are simultaneously 0, R ¹ and R ² are H or unsubstituted alkanyl is not.

When (a + b) = 0, R ¹ is preferably not hydrogen, halogen or CN. When (c + d + e + f) = 0, R ² is preferably not H, halogen, —CN, —NCS, —NO ₂ , —OH, —SF ₅ , —O-aralkyl and an alkoxy group.

  For simplicity, the numbers of the positions of the tetrahydropyran ring in formula I are as follows in this description unless otherwise indicated.

発明による方法では、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。

In the process according to the invention, with the aid of readily available and inexpensive reagents, tetrahydropyran derivatives of the formula I can be obtained in a simple manner with good yields and high chemical and stereoselectivity. The tetrahydropyran derivatives of formula I can themselves be used to further prepare mesogenic or liquid crystalline tetrahydropyran derivatives.

  The process according to the invention comprises at least one Bronsted containing at least one chloride, bromide or iodide anion in the presence of at least one Lewis acid containing at least one chlorine, bromine or iodine atom. It can be carried out in the presence of an acid (protic acid) or in the presence of a mixture of at least one Lewis acid as defined above and at least one Bronsted acid as defined above. The process according to the 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 embodiment of the invention, the reaction of the homoallylic alcohol of formula II with the aldehyde of formula III is in the presence of at least one Lewis acid containing at least one chlorine, bromine or iodine atom. Done. In each case, the Lewis acid contains only one type of these halogen atoms, ie in addition to the presence of any non-halogen groups or ligands, only chlorine atoms or only bromine atoms or only iodine atoms. It is desirable to include. 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 bromine atoms.

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, Ga, In, Sn , Ti, Fe, Zn, Nb, Zr, Au or 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.

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 an atomic M formal oxidation number of 4 (IV), as little as 25 mol% based on the homoallylic alcohol of formula II to be reacted, ensures 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 II.

  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 II and aldehyde of formula III. 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 .

  In a further preferred embodiment of the invention, the process according to the invention is carried out in the presence of a Bronsted acid comprising 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. The Bronsted acid is used-especially in the case of hydrohalic acid-in stoichiometric or over stoichiometric amounts (based on the homoallylic alcohol of formula II), 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 invention involves adding Bronsted acid as a solution or passing Bronsted acid as a gas to a compound of formula II homoallylic alcohol and formula III aldehyde dissolved or suspended in a suitable solvent. Can be done.

In a further preferred embodiment of the invention, the reaction of the homoallylic alcohol of the formula II with the aldehyde of the formula III is carried out in the presence of a mixture of at least one Lewis acid and at least one Bronsted acid. 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 I 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.

  According to this embodiment of the present invention, only a very small amount of Lewis acid may be used as compared to embodiments using only one or more Lewis acids and no Bronsted acid. This modification results in lower costs because the Bronsted acid used is generally less expensive than the Lewis acid. At the same time, the use of a Lewis acid allows the process of the present invention to be carried out under milder conditions (especially lower reaction temperatures) than those when using only Bronsted acids.

  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 II.

  The reaction temperature in this embodiment of the invention is generally between about −10 ° C. and about + 70 ° C. Preferably, the aldehyde of formula III and the homoallylic alcohol of formula II are first initially 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 according to the invention can in principle be carried out in a solvent-free manner and preferably in a solvent or solvent mixture in each embodiment. 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 the process according to the invention is carried out, stereoisomers of tetrahydropyran derivatives of the formula I, in which the substituents at the 2- and 5-positions are in trans configuration with each other, are mainly or exclusively formed. I understood that. This situation is a major advantage for using these compounds in liquid crystal media or for preparing further mesogenic or liquid crystal tetrahydropyran derivatives. This is important for mesogenic properties, because the trans configuration of substituents at the 2- and 5-positions allows for a bis-equatorial conformation with an extended molecular shape. The tetrahydropyran derivatives of formula I prepared by the process according to the invention generally have a ratio of trans-2,5-isomer to cis-2,5-isomer of about 75:25 or 80:20 to 100: 0. Have Other preparation methods of mesogenic or liquid crystalline tetrahydropyran derivatives usually give isomer mixtures with a very high content of cis-2,5-isomer.

  If the product is produced in crystalline form, a particularly high selectivity is obtained after work, which is measured with the isolated product. Crystal formation favors the high purity of the product from the process.

Even more surprisingly, it has been found that the halogen substituent X ^{1 at} the 4-position of the compounds of formula I prepared by the process of the invention also takes the trans configuration mainly or exclusively with respect to the substituent at the 5-position. It was. Thus, by this method according to the invention, a tetrahydropyran derivative in which the three substituents at the 2-position, 4-position and 5-position are oriented in the full equatorial configuration is 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 method according to the invention 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 II with the aldehyde of the formula III takes place with high chemical selectivity, ie no unwanted by-products are produced or only very small quantities are produced, It does not affect further use of the tetrahydropyran derivative of formula I. 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 of the present invention has been shown to be particularly advantageous to open up intensive synthetic strategies for the preparation of further tetrahydropyran derivatives with high structural diversity, in particular homoallyl of formula II Starting from an alcohol, changing the group of the aldehyde of formula III allows a wide range of preparation of variously substituted tetrahydropyran derivatives of formula I. The same applies to the complementary approach, i.e. starting from the aldehyde of the formula III, by changing the group of the homoallylic alcohol of the formula II, with high structural diversity, the tetrahydropyran derivatives of the formula I Can be prepared.

  In addition to the central halogenated tetrahydropyran ring, the compounds of formula I which can be prepared by the process of the invention may have no further rings, one, two, three or four additional rings. (Or ring system), ie 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 homoallylic alcohol 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 preferably 0 or 1 It is. Furthermore, it is preferred that the aldehyde of formula III and also the tetrahydropyran derivative of formula I have no further rings or have 1, 2 or 3 further rings in the 2-position, ie c + d + e + f is equal to 0, 1, 2 or 3, in particular 1 or 2.

X ¹ is determined by the choice of Lewis acid and / or Bronsted acid, preferably bromine or chlorine, in particular bromine. Bromine can be reductively eliminated more easily than chlorine.

R ¹ is preferably alkanyl, alkenyl, alkoxy or alkenyloxy, each having from 1 to 10 carbon atoms, unsubstituted or substituted by one or more fluorine and / or chlorine atoms And when a and / or b is 1, it preferably represents chlorine, fluorine or bromine. R ¹ particularly preferably represents alkanyl or alkoxy, each having from 1 to 8 carbon atoms, unsubstituted or substituted by one or more fluorine and / or chlorine atoms, Particularly preferably, it is a linear alkanyl having 1, 2, 3, 4, 5 or 6 carbon atoms, unsubstituted or substituted with one or more fluorine atoms.

R ² is preferably 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 or alkanyl or alkoxy, each having 1 to 8 carbon atoms. cage, either unsubstituted or is substituted by one or more fluorine and / or chlorine atoms, and especially 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} or is substituted, or 1, 2, 3, Linear alkanyl or alkoxy having 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, halogen, —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 aldehyde group in formula III. The bridging elements Z ³ , Z ⁴ , Z ⁵ or Z ⁶ are particularly preferably selected so that they do not contain oxygen atoms when they are directly bound to the tetrahydro ring or aldehyde group of formula I.

  Particularly preferred homoallylic alcohols of the formula II are selected from the formulas II-1 to II-9.

式中、Ｒ^１は上で定義されるとおりであり、好ましくは１〜７Ｃアルキル基を表す。

In which R ¹ is as defined above and preferably represents a 1-7C alkyl group.

In a further preferred embodiment of the process according to the invention, the compound of formula I obtainable by reacting the homoallylic alcohol of formula II with an aldehyde of formula III in the presence of a Lewis acid and / or Bronsted acid is Reductive elimination of X ¹ gives a tetrahydropyran derivative of formula IV.

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、独立に式Ｉで上に定義される通りであり、即ち、置換基は、一般に、式Ｉ、ＩＩ、ＩＩＩおよびＩＶ中で、異なる定義を有してよい。

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 independently as defined above in formula I, ie the substituents may generally have different definitions in formulas I, II, III and IV.

  The present invention further includes a process for preparing a compound of formula IV comprising at least one step of reacting a homoallylic alcohol of formula II with an aldehyde of formula III or an acetal or hydrate thereof as described above.

本発明の方法は、好ましくは、式Ｉの化合物上の置換基Ｘ^１を還元的に脱離することを特徴とする工程を更に有し、ただし、テトラヒドロピラン環の他の置換基は、誘導体化のために異なる意味を有することもできる。この更なる工程は、好ましくは、ＩＩのＩＩＩとの反応の後に還元的脱離によって行われ、特に好ましくは、環形成後に更なる中間工程なしで行われる。

The method of the invention preferably further comprises the step characterized by reductive elimination of the substituent X ¹ on the compound of formula I, provided that the other substituent of the tetrahydropyran ring is a derivative It can also have different meanings for the sake of simplicity. This further step is preferably carried out by reductive elimination after the reaction of II with III, particularly preferably after the ring formation without further intermediate steps.

A preferred embodiment of the reductive elimination of I to give IV comprises a free radical chain reaction, and in the course of the reaction—when considered formally—the halogen atom X ¹ in the tetrahydropyran derivative of formula I is removed and a hydrogen atom Is replaced by Here, X ^{1 in} the compound of formula I to be reacted is particularly preferably bromine or chlorine, in particular bromine.

A preferred embodiment of the reductive elimination of the present invention is preferably carried out 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 I.

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. 30, 2733-2734, 1989). 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 I.

  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% based on the compound of formula I. 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 this embodiment of the 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 I 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.

  Two preferred embodiments of the above reductive elimination include inter alia, the reductive elimination of the tetrahydropyran derivative of formula I giving the tetrahydropyran derivative of formula IV is a substituent in the 2- and 5-positions of the tetrahydropyran ring. Especially identified by the fact that it happens to keep its position. Thus, the halogenated compound of formula I in which all three substituents at the 2, 4 and 5 positions are in the equatorial configuration such that the substituent at the 2 position is oriented trans to the substituent at the 5 position. 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 the formula I giving the tetrahydropyran derivative of the formula IV is carried out in two steps, provided that in the first step (A) the tetrahydropyran derivative of the formula I is dihydropyran. Converted to a derivative, in particular the formula Va and / or Vb;
And in the second step (B), the dihydropyran derivative formula Va and / or Vb formed in this way is converted into a tetrahydropyran derivative of formula IV.

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 and Z ⁶ are as defined above in Formula I.

The elimination of HX ¹ 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 sodium ethoxide or potassium tert-butoxide, for example alkali metal alkoxides, and strong nonionic nitrogen bases, especially those having a pKa value greater than 20. It was. 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 the boiling point, preferably at an elevated 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 invention, a mixture of two dihydropyran derivatives of the formulas Va and Vb is usually formed, in most cases with an isomer ratio of about 2: 1. Isomers are generally produced in secondary quantities—if any. (In some cases, additional isomeric dihydropyran compounds are also obtained in which the intracyclic double bonds are not in the 4,5- and 3,4-positions. According to the invention, these double bond isomers are also of the formula IV In principle, it is possible to separate the isomers using conventional fractionation methods such as chromatography, before further step (B). This is generally not performed. The compounds of formula Vb obtainable according to this embodiment according to the invention have the same configuration as the starting compounds of formula I with respect to the configuration of the substituents at the 2 and 5 positions of the tetrahydropyran ring. Thus, tetrahydropyran derivatives of formula I having a full equatorial configuration readily give the corresponding trans-2,5-2 substituted tetrahydropyran derivatives of formula Vb.

Step (B) for the formation of the tetrahydropyran derivative of formula IV is carried out by catalytic hydrogenation. Here, the hydrogenation can be carried out with homogeneous or heterogeneous catalysts. For the dihydropyran derivative of formula Vb, 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 Vb retain the stereochemistry to give the corresponding trans-2,5-2 substituted tetrahydropyrans of formula IV. However, for dihydropyran derivatives of formula Va, further reaction means for the formation of tetrahydropyran derivatives of formula IV generally affect the configuration of substituents at the 2- and 5-positions of the heterocyclic oxygen relative to each other. Effect. Thus, heterogeneously catalyzed hydrogenation produces, for example, predominantly or exclusively tetrahydropyrans of formula IV 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 IV of the configuration can be obtained. In contrast, if hydrogenation is carried out with a homogeneous catalyst, for example, in the presence of chlorotris (triphenylphosphine) rhodium (I) (Cl-Rh [P (C ₆ H ₅ ) ₃ ] ₃ ) as a Wilkinson catalyst. 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 the compound of IV 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 IV are available in good yield.

  The invention further relates to compounds of formula I.

ただし、
ａ、ｂ、ｃ、ｄ、ｅおよび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または４に等しく、
Ｘ^１は、塩素、臭素またはヨウ素を表し、
Ｒ^１は、Ｈ、ハロゲン、−ＣＮ、１〜１５個のＣ原子を有するアルキル基を表し、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、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を表し、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およびＡ^６は、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、

However,
a, b, c, d, e and f, independently of one another, represent 0 or 1, provided that a + b + c + d + e + f is equal to 1, 2, 3 or 4;
X ¹ represents chlorine, bromine or iodine,
R ¹ represents H, halogen, —CN, an alkyl group having 1 to 15 C atoms, and the group is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen In addition, however, one or more of the CH ₂ groups in these groups may be such that —C≡C—, —CH═CH—, —O, such that the oxygen atoms in the chain are not directly bonded to each other. -, - S -, - SO -, - SO 2 -, - CO-O- or may be replaced by -O-CO-,
R ² represents H, halogen, —CN, —NCS, —NO ₂ , —OH, —SF ₅ , —O-aralkyl, an alkyl group having 1 to 15 C atoms, and the group is unsubstituted. Is, is monosubstituted by —CN, or monosubstituted or polysubstituted by halogen or —O-aralkyl, but in addition one or more of the CH ₂ groups in these groups is an oxygen in the chain The atoms are not directly bonded to each other so that —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, —CO—, —CO—O— or — May be replaced by O-CO-,
A ¹ , A ² , A ³ , A ⁴ , A ⁵ and A ⁶ , independently of one another, may be rotated or mirror images and represent the following:

Ｚ^１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を表すか、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−を表してもよく、
Ｚ^２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を表し、
Ｚ^３、Ｚ^４、Ｚ^５およびＺ^６は、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、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、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、−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、および
Ｗ^１は、−ＣＨ_２−、−ＣＦ_２−または−Ｏ−を表し、
ただし、
ａおよびｂが同時に０の場合、Ｒ^１は水素を表さず、および
ａ、ｂ、ｃ、ｄ、ｅおよびｆの全てが同時に０の場合、Ｒ^１およびＲ^２はＨまたは無置換のアルカニルではない。

Z ¹ represents 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 if ^{a 2} is not a cyclohexylene and cyclohexenylene ring, it may represent a _-CF 2 O-,
Z ² 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 bonded to via its O atoms in cyclohexylene or cyclohexylene ring Not
n1, n2 and n3 are independently of each other 0, 1, 2, 3 or 4;
Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are independently of each other H, halogen, —CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl. , -OC _1-6 -alkanyl, -OC _2-6 -alkenyl, -OC _2-6 -alkynyl, wherein the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, And W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
However,
when a and b are simultaneously 0, R ¹ does not represent hydrogen, and when all of a, b, c, d, e and f are simultaneously 0, R ¹ and R ² are H or unsubstituted alkanyl is not.

When c, d, e and f are all 0 at the same time, R ² preferably represents an alkyl group having 1 to 15 C atoms, which group is unsubstituted or monosubstituted by —CN. Or are mono- or polysubstituted by halogen or —O-aralkyl, but in addition one or more of the CH ₂ groups in these groups are such that the oxygen atoms in the chain are not directly bonded to one another. -C≡C -, - CH = CH - , - O -, - S -, - SO -, - SO 2 -, - CO -, - CO-O- or be replaced by -O-CO- Good.

These compounds are suitable as starting compounds or intermediate compounds for preparing further 2,5-2 substituted tetrahydropyran derivatives. As indicated, substituent X ¹ can be replaced with hydrogen. X ¹ may be substituted with other groups by known nucleophilic substitution reactions, giving interesting structures.

Groups, substituents and indices a, b, c, d, e, f, X ¹ , R ¹ , R ² , A ¹ , A ² , A ³ , A ⁴ , A ⁵ , of the compound of formula I of the present invention A ⁶ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ are preferably the same meanings as preferred meanings given in formula I above, particularly preferred meanings in connection with the preparation method of the present invention. Have

  The substituents in the 2,5-position are preferably in trans configuration with respect to one another. In the chair conformation, in this case, both of these substituents are in an equatorial configuration.

  Particular preference is given to tetrahydropyran derivatives of the formula I according to the invention in which the three substituents at the 2-position, 4-position and 5-position of the central tetrahydropyran ring are in the equatorial configuration.

  The starting compounds of the formulas II and III used in the process according to the invention can be found in the literature (for example Houben-Weyl, Methoden der organicis Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, In a manner known per se, and is carried out exactly under the reaction conditions known and appropriate for the reaction. However, it is also possible to carry out variants which are known per se and are not described in detail.

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

An aldehyde of the formula III in which the formyl group is bonded via a single bond to the 5-position of the tetrahydropyranyl group 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 formula II 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ＩＩ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 without prior isolation as an intermediate, but by further reaction of B with formaldehyde (or a synthetic equivalent), after the corresponding treatment, the desired formula II Homoallylic alcohol is obtained.

  Further acquisition of the homoallylic alcohol of formula II is carried out as shown in Scheme 3, where “Hal” has the same meaning as above in Scheme 2 and “Met” is preferably Cu (I) (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ＩＩ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 II is then obtained from F by saponification.

Furthermore, the homoallyl alcohol of the formula II 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 dianio 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.

  In the context of the present invention, an “acetal” is an aldehyde on one equivalent of an aldehyde (also referred to as “hemiacetal”) of an alcohol (eg, ethanol) or two equivalents (or two alcohols) of an alcohol. Is the product of a (formal) addition reaction onto the carbonyl functionality. In the context of the present invention, an “aldehyde” of an aldehyde is the equivalent of one equivalent of water on the carbonyl function of an aldehyde (also called “hemi” or “semihydrate”) or the second equivalent of water. It means the product of the (formal) addition reaction of an amount of aldehyde onto the carbonyl function. It has to be noted here that aldehydes may also exist in equilibrium with the corresponding acetals (and hemiacetals) or their hydrates (and hemihydrates).

  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.

<GWP1 (General operation method 1)
First, 0.1 mol of an aldehyde of formula III and 0.1 mol of homoallylic alcohol of formula II 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 treatment 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 derivatives of formula I obtained by GWP1 are shown in Table 1.

<GWP2>
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 III (0.1 mol) is then introduced in several portions. Subsequently, homoallylic alcohol of formula II (0.1 to 0.11 mol) is added. When the reaction is complete (TLC check), the reaction mixture is filtered through silica gel or treated with water as described above in GEP1.

  Detailed data and yields on the reaction conditions of tetrahydropyran derivatives of formula I obtained by GWP2 are shown in Table 2.

<GWP3>
First, 0.1 mol of an aldehyde of formula III, 0.1 mol of homoallylic alcohol of formula II and 0.5-5 mol% of 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 I obtained by GWP3 are shown in Table 3.

<GWP4>
A 1.5 molar equivalent of a saturated hydrohalic acid solution in water or glacial acetic acid is added with stirring to a 0.1 M solution of aldehyde of formula III and homoallylic alcohol of formula II in dichloromethane, optionally 0 0.5-5 mol% of Lewis acid may be added. When the reaction is complete (TLC check), the reaction mixture is treated as described for GWP1.

  Detailed data and yields on the reaction conditions of the tetrahydropyran derivative of formula I obtained by GWP4 are shown in Table 4.

Preparation of compounds of formula IV from halogenated tetrahydrofuran derivatives of formula I
<GWP5-reductive elimination in the presence of heterogeneous catalyst and trialkylamine>
The brominated material of formula I is dissolved in a suitable amount of tetrahydrofuran (between about 4 and 12 times the volume or weight of the compound of formula I) and 10% to 30% (based on I) of 5% Palladium on carbon (containing 54.7% water), 2.5 molar equivalents of triethylamine and 2 volumes (based on material) of water are added and hydrogen at a pressure of 4-6 bar is added in a pressure autoclave. Use and hydrogenate the mixture until the 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 twice with heptane or 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 derivative of formula IV obtained by GWP5 are shown in Table 5.

    <Reductive elimination using tributyltin hydride>

１８．５ｇ（０．０５ｍｏｌ）の４−クロロテトラヒドロピランである表２からのＮｏ．９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。ＩＶ−ａの収率（最適化せず）：８．７ｇ（５２％）。

No. 1 from Table 2 which is 18.5 g (0.05 mol) 4-chlorotetrahydropyran. 9 is heated at reflux with 32 g (0.11 mol) tributyltin hydride and 0.81 g (5 mmol) azodiisobutyronitrile in 500 ml benzene for 24 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. Yield of IV-a (not optimized): 8.7 g (52%).

    <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（表１からのＮｏ．１６）を、６０ｍｇ（２ｍｍｏｌ）のｐ−メトキシベンゾイルペルオキシドを添加後、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、ＩＶ−ｂを得る。収率（最適化せず）：８．１ｇ（４８％）。

20.75 g (0.05 mol) of 4-bromotetrahydropyran (No. 16 from Table 1) in 600 ml of 1,2-dimethoxyethane was added after adding 60 mg (2 mmol) of p-methoxybenzoyl peroxide. Irradiate light with a wavelength of 254 nm with .24 g (5 mmol) of TTMSS and 9.5 g (0.25 mol) of NaBH ₄ while stirring in a quartz apparatus 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 IV-b. Yield (not optimized): 8.1 g (48%).

Dehydrohalogenation of compounds of formula I to give compounds of formula Va and / or Vb
<Example A>

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（表１からのＮｏ．３ａ、ｂ）（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時間温め、その間に懸濁が生じる。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のＡ１およびＡ２を含む生成混合物を６５：３５の比で得る。

156 g (0.487 mol) of 4-bromo-2- (4-bromophenyl) tetrahydropyran (No. 3a, b from Table 1) (isomer compound, 2,4-cis: 2,4-trans = 84 16) was warmed under reflux with stirring with 87.2 ml (0.73 mol) 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) in 330 ml toluene for 3 hours, During that time suspension occurs. 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 of A1 and A2 in a ratio of 65:35.

    <Example B>

４９．７ｇ（０．１５ｍｏｌ）の異性体的に純粋な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（表３からのＮｏ．２）を、２００ｍｌ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、析出する塩を濾別し、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。濾液を蒸発し、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Ｂ１である。収率（最適化せず）：１５．６ｇ（７３％）。

49.7 g (0.15 mol) of isomerically pure 4-bromo-2- (4-bromophenyl) -5-methyltetrahydropyran (No. 2 from Table 3) was dissolved in 200 ml of toluene. Stir for 4 hours under reflux with 0.8 g (0.225 mol) of DBN. The mixture is then cooled to 0 ° C., the precipitated salt 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 is 4,5-dihydro-5-methyltetrahydropyran B1. Yield (not optimized): 15.6 g (73%).

    <Example C>

例Ｂに類似して、テトラヒドロピラン誘導体（表３からのＮｏ．３）（異性体混合物２，４−シス：２，４−トランス＝８５：１５；３２．９ｇ、０．１０７ｍｏｌ）よりＣ１を得る；収率（最適化していない）：８９％。

Analogously to Example B, C1 was obtained from a tetrahydropyran derivative (No. 3 from Table 3) (isomer mixture 2,4-cis: 2,4-trans = 85: 15; 32.9 g, 0.107 mol). Yield; yield (not optimized): 89%.

    <Example D>

例Ｂに類似して、テトラヒドロピラン誘導体（表３からのＮｏ．４）（異性体的に純粋２，４−シス）よりＤ１を得る；収率（最適化していない）：９３％。

Similar to Example B, D1 is obtained from a tetrahydropyran derivative (No. 4 from Table 3) (isomerically pure 2,4-cis); yield (not optimized): 93%.

    <Example E>

２３．０ｇ（０．０５５６ｍｏｌ）の４−ブロモテトラヒドロピラン（表３からのＮｏ．６）（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、Ｅ１およびＥ２を含みＥ１が主な異性体である異性体混合物１７．８ｇ（９６％）を与える。

23.0 g (0.0556 mol) 4-bromotetrahydropyran (No. 6 from Table 3) (isomer mixture) together with 10.36 g (0.0834 mol) DBN in 60 ml toluene under reflux. Stir 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 filtering through silica gel with a toluene / heptane mixture (1: 1), the separated organic phase is separated from the filtrate by 17.8 g (96%) of an isomer mixture containing E1 and E2 with E1 being the major isomer. give.

    <Example F>

窒素下で、１００ｇ（２１９ｍｍｏｌ）のブロモテトラヒドロピラン（表１からのＮｏ．１８）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Ｆ１（含有量：６０％；収率：４１％）を得る。

Under nitrogen, 100 g (219 mmol) of bromotetrahydropyran (No. 18 from Table 1) 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 F1 (content: 60%; yield: 41%).

  Hydrogenation of a compound of formula V to give a tetrahydropyran of formula IV

１ｍｏｌ％の塩化トリス（トリフェニルホスフィン）ロジウム（Ｉ）を、６００ｍｌのエタノールおよび２００ｍｌのトルエンの混合物中の０．２ｍｏｌ（６６．４ｇ）の例Ｅからの異性体混合物Ｅ１およびＥ２に加える。密封されたオートクレーブ中の混合物を５０ｂａｒまで窒素を注入してガス抜きを３回行い、それぞれの場合で引き続いて圧抜きをする。１０ｂａｒの水素を注入後、混合物を１００℃で２４時間温める。冷却および減圧後、反応混合物を蒸発させ、ヘプタン／トルエン（８：２）でシリカゲルを通して濾過する。そして、エタノールおよびヘプタンから再結晶して、２４．８ｇ（理論の３７％）の９９．５％の水素化生成物ＩＶ−ｃを全てがトランス配座で得る（融点６２℃、Ｃ６２ＳｍＢ２１８Ｉ、１０％のネマチック混合物ＺＬＩ−４７９２から外挿された透明点２３１℃）。

1 mol% of tris (triphenylphosphine) rhodium (I) chloride is added to 0.2 mol (66.4 g) of the isomer mixtures E1 and E2 from Example E in a mixture of 600 ml of ethanol and 200 ml of toluene. The mixture in the sealed autoclave is degassed three times by injecting nitrogen up to 50 bar, followed by depressurization in each case. After injecting 10 bar of hydrogen, the mixture is warmed at 100 ° C. for 24 hours. After cooling and reduced pressure, the reaction mixture is evaporated and filtered through silica gel with heptane / toluene (8: 2). Recrystallization from ethanol and heptane then gives 24.8 g (37% of theory) of 99.5% of the hydrogenated product IV-c all in the trans conformation (melting point 62 ° C., C62SmB218I, 10% Clearing point 231 ° C. extrapolated from the nematic mixture ZLI-4792).

＜物質の特性解析＞
核磁気共鳴スペクトル（ＮＭＲ）または質量スペクトルまたは相データによる表１〜５に示す物質の特性解析を以下に行う。既述のサンプル（全エカトリアル配置の主要異性体２Ｈ−３，４，５，６−テトラヒドロピラン誘導体で、イス型コンフォメーションである）の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。

<Characteristic analysis of substances>
Characteristic analysis of the substances shown in Tables 1 to 5 by nuclear magnetic resonance spectrum (NMR), mass spectrum, or phase data is performed below. The assignment of protons in the NMR spectrum of the above-described sample (major isomer 2H-3,4,5,6-tetrahydropyran derivative with chair-type conformation in all equatorial configurations) is shown in the following formula. Done.

＜表１からのテトラヒドロピラン誘導体Ｉ＞
１ａ）ＣＤＣｌ_３中の２５０ＭＨｚ^１Ｈ−ＮＭＲスペクトル
信号の位置はテトラメチルシランに対する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。略号ｍは多重項、ｓは一重項、ｄは二重項、ｔは三重項、ｑは四重項を表わす。これらの詳細は、列記される全ての他のＮＭＲスペクトルにも当てはまる。
Ｈ_４ａ：ｍ４．１３；Ｈ_６ｅ：ｄｄｄ３．９６ Ｊ＝１２，４，２；Ｈ_６ａ：ｄｔ３．３７ Ｊ＝１２，２；Ｈ_２ａ：ｍ３．２５；Ｈ_３ｅおよびＨ_５ｅ：ｍ２．０８〜２．３；Ｈ_５ａ：ｄｑ２．０５ Ｊ＝１２，４；Ｈ_３ａ：ｑ１．７３ Ｊ＝１２；側鎖の２つのメチレン基４つのＨ：ｍ１．２５〜１．６；ＣＨ_３基：ｔ０．９ Ｊ＝７。

<Tetrahydropyran derivative I from Table 1>
1a) 250 MHz ¹ H-NMR spectrum in CDCl ₃ The position of the signal is quoted in ppm relative to tetramethylsilane and the magnitude of the coupling constant J is given in hertz (Hz). The abbreviation m is a multiplet, s is a singlet, d is a doublet, t is a triplet, and q is a quartet. These details also apply to all other NMR spectra listed.
_{H 4a: m4.13; H 6e:} ddd3.96 J = 12,4,2; H 6a: dt3.37 J = 12,2; H 2a: m3.25; H 3e and _H 5e: _{m2.08~ 2.3; H 5a: dq2.05 J =} 12,4; H 3a: q1.73 J = 12; four two methylene groups in the side chain of H: m1.25~1.6; CH ₃ group: t0 .9 J = 7.

  1b) NMR spectrum is identical to 1a.

2) CDCl ₃ in 250 MHz ¹ H spectrum _{H 4a: m4.1; H 6e:} ddd3.95 J = 12,4,2; H 6a: dt3.35 J = 12,2; H 2a: m3.0; 16H: m0.9~2.3, remaining tetrahydropyran, protons cyclohexylene and side chain _{methylene; CH 3: t0.85 J = 7} .

3a) 500 MHz ¹ H spectrum in CDCl ₃ 4 aromatic H: AB-q, center 7.33, 2 oH for bromine substitution: d7.46 J = 8; 2 o- for tetrahydropyranyl substitution _{H: 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:} m2.05~2.28; H 3a: q1.98 (J = 12).

  3b) NMR identical to 3a.

4) 250 MHz ¹ H spectrum in CDCl ₃ 2 aromatic H: m 6.95; H _4a , H _6e , H _2a : m 4.08-4.32; H _6a : dt3.56 J = 12, 2; H _{3e: ddd2.44 J = 12,4,2; H} 5a, H 5e: m2.06~2.32; H 3a: q1.93 J = 12.

5) Five aromatic H of 500 MHz ¹ H spectrum phenylbenzyl group in CDCl ₃ : m 7.27-7.45; four aromatic H of second phenyl ring: AB-q, center 7.09 two o-H for tetrahydropyranyl substituted in this: d7.27 J = 8; two for benzyl-substituted o-H: d6.94 J = 8 ; 2 one H of benzene soluble CH ₂ groups: s5 _{.06; H 2a, H 4a:} m4.27; H 6e: d, d, d4.13 J = 12,4,2; H 6a: dt3.56 J = 12,2; H 3e: ddd2.44 J _{= 12,4,2; H 5e, H 5a} : m2.0~2.5; H 3a: q2.10 J = 12.

6) 500 MHz ¹ H spectrum in CDCl ₃ 4 aromatic H: AB-q, center 7.09; 2 oH for ester group: d8.02 J = 8; 2 oH for tetrahydropyran substitution _{: d7.40 J = 8; H 2a} : dd440 J = 12,2; H 6e: dd4.21 J = 12,4; H 4a: m3.92; OCH 3: s3.92; H 6a: t3.25 _{J = 12; H 3e: ddd2.53} J = 12,4,2; H 3a: q2.13 J = 12; H 5a: m2.1; CH 3: d1.05 J = 7.

7) 500 MHz ¹ H spectrum in CDCl ₃ 4 aromatic H: AB-q, center 7.09; 2 oH for tetrahydropyran substitution: d7.15 J = 8; 2 o for phenolic OH groups _{-H: d6.75 J = 8; H} 2a: dd4.25 J = 12,2; H 6e: dd4.18 J = 12,4; H 4a: dt4.02 J = 12.4; H 6a: t3 .27 J = 12; H _3e : ddd2.47 J = 12,4,2; H _3a : q2.22 J = 12; one of H _5a and CH ₂ side chains H: m1.93; additional _{H: 1.23; CH 3: t0.93} J = 7.
8) 250 MHz ¹ H spectrum in CDCl ₃ 4 aromatic H: AB-q, center 6.95; 2 oH for tetrahydropyran substitution: d7.15 J = 8; 2 o for phenolic OH groups _{-H: d6.75 J = 8; H} 2a: dd4.27 J = 12,2; H 4a: dt4.15 J = 12.4; H 6e: dd4.08 J = 12.2; H 6a: t3 .26 J = 12; H _3e : ddd2.45 J = 12,4,2; H _3a : q2.10 J = 12; one H of H _5a and CH ₂ side chains: m 1.68 to 1.98; its side chain further two CH ₂ three _{H: m1.10~1.53; CH 3; t0.90} J = 7.
Melting point: 104 ° C
9) 250 MHz ¹ H spectrum in CDCl ₃ in CDCl ₃
4 aromatic H: AB-q, center 6.99; 2 o-H for tetrahydropyran substitution: d7.20 J = 8; 2 o-H for phenolic OH groups: 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 = 12,4,2; H _3a : q2.17 J = 12; one H of H _5a and CH ₂ side chains: m 1.72-2.00; three additional CH ₂ of that side chain: H 1.15-15 _{.5; CH 3: t0.95 J =} 7.

11) Five aromatic Hs of 250 MHz ¹ H spectrum phenylbenzyl group in CDCl ₃ : m 7.28-7.45; four aromatic Hs of second phenyl ring: AB-q, center 7.10 ; two for tetrahydropyran substituted therein o-H: d7.26 J = 8 ; O- 2 two o-H for benzyl group: d6.94 J = 8; 2 single H benzylic CH ₂ groups: s5 _{.06; H 2a: dd4.28 J =} 12,2; H 6e: dd4.07 J = 12,4; H 4a: dt3.98 J = 12,4; H 6a: t3.22 J = 12; H _{3e: ddd2.48 J = 12,4,2; H} 3a: q2.18 J = 12; H 5a: m2.07; CH 3: d1.03 J = 7.

12) 250 MHz ¹ H spectrum in CDCl ₃ Further H5 aromatic H in its side chain: m 7.30-7.47; 4 aromatic H in the second phenyl ring: AB-q, center 7. 09; two for tetrahydropyran substituted therein o-H: d7.25 J = 8 ; O- 2 two o-H for benzyl group: d6.93 J = 8; 2 single H benzylic CH ₂ groups: _{s5.05; H 2a dd4.27 J = 12,2} ; H 6e: dd4.19 J = 12,4; H 4a: dt4.03 J = 12,4; H 6a: t3.26 J = 12; H _{3e: ddd2.50 J = 12,4,2; H} 3a: q2.18 J = 12; H 5a and CH ₂ of one of the side-chain H: m1.83~2.0; two CH ₂ side chains eye _{H: m1.12~1.38; CH 3: t0.93} J = .

13) 250 MHz ¹ H spectrum in CDCl ₃ Further H5 aromatics in its side chain: m 7.29-7.44; 4 aromatics H in the second phenyl ring: AB-q, center 7. 09; two o-H for tetrahydropyran substituted: d7.25 J = 8; O- 2 two o-H for benzyl group: d6.93 J = 8; 2 single H benzylic CH ₂ groups: S5.05 _{; H 2a: dd4.26 J = 12,2} ; H 6e: dd4.17 J = 12; H 4a: dt4.02 J = 12,4; H 6a: t3.25 J = 12; H 3e: ddd2. 48 J = 12, 4, 2; H _3a : q2.20 J = 12; one H in H _5a and CH ₂ side chains: 5 in 3 CH ₂ groups in m 1.78 to 2.05 side chains _{H: m1.10~1.45CH 3: t0.90 J =} 7.

14) 250 MHz ¹ H spectrum in CDCl ₃

ｔ７．３５ Ｊ＝８（ｏ−Ｈカップリングおよびｍ−Ｆカップリング）；残りの４つの芳香族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 (o-H coupling and m-F coupling); the remaining four aromatic _{H: m7.09~7.26; H 2a: dd4.40} J = 12,2; H 6e : Dd 4.10 J = 12, 4; H _4a : dt 3.78 J = 1, 4; H _6a : t 3.25 J = 12; H _3e : ddd 2.43 J = 12, 4, 2; H _3a and H _{5a: m1.83~2.20; CH 3: d1.07} J = 7.

15) 400 MHz ¹ H spectrum in CDCl ₃

ｔ７．３８ Ｊ＝８（ｏ−Ｈカップリングおよびｍ−Ｆカップリング）；残りの４つの芳香族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 (o-H coupling and m-F coupling); remaining 4 aromatics H: m 7.10-7.23; H _2a : dd 4.37 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.

16) 500 MHz- ¹ H spectrum in CDCl ₃ 4 aromatic H: m 6.95; H _2a : dd 4.35 J = 12, 2H _6e : dd 4.12 J = 12, 4; H _4a : m 3.91; _{H 6a: t3.23 J = 12;} H 3a and _{H 5a: m = 2.05; CH} 3 d1.06 J = 7.

17) 500 MHz- ¹ H spectrum in D ₆ -dimethylsulfoxide Two aromatic H: m 7.26; H _4a : dt 4.10 J = 12.4, H _6e : dd3.87 J = 12.4, H _{2a : m3.10; H 6a: t3.03 J} = 12; H 3e: ddd2.25 J = 12,4,2; H 5a: m2.10; H 3a and 10 one-cyclohexylene H: m1.00~2 .04; CH ₃ d0.93 J = 7.

20) Mass spectrum molecular peak M (+) 460, 462: not detected; 369, 371: (M-91) (+) benzyl; 290: 369, 371-Br; 289: 369, 371-HBr; 91: PhCH ₂ (+) (base peak).

21) 250 MHz- ¹ H spectrum in CDCl ₃ 2 aromatic H: m 2.95; 5 H in OCH ₂ , H _4a , H _2a , H _6e : m 4.2-4.5; H _6a : t3. 59 J = 12; H _5a : dt 3.04 J = 12, 4; H _3e : ddd2.54 J12, 4, 2; H _3a : q1.99 J = 12; CH ₃ : t1.30 J = 7.

Mass spectrum:
Molecular peak M (+) 366,368; 287: 366,368-Br; 286: 366,368-HBr; 241: 286-45 (OC 2 H 5) =

２８６のレトロジエン分解物；

１２６＝

286 retrodiene degradation products;

126 =

９８：１２６−エチレン−ＭｃＬａｆｆｅｒｔｙ、基底ピーク。

98: 126-ethylene-McLufferty, basal peak.

<Tetrahydropyran derivatives from Table 2>
1) NMR identical to 3a from Table 1.

  2) Table 1, no. Same as 7 NMR.

  3) No. 1 from Table 1 NMR identical to 8.

      Melting point: 104 ° C.

  4) No. 1 from Table 1 NMR identical to 9.

  9) No. 1 from Table 1 NMR identical to 14.

<Tetrahydropyran derivatives from Table 3>
1a), 1b) No. 1 from Table 1. NMR identical to 3a.

2) 250 MHz- ¹ H-NMR spectrum in CDCl ₃ 4 aromatic H: AB-q, center 7.34; 2 o-H for bromine substitution: d7.48 J = 8; 2 for tetrahydropyran substitution _{o-H: d7.19 J = 8} ; H 6e: ddd4.04 J = 12,2,1; H 4a: dt3.96 J = 12,4; H 2a: d3.89 J = 12; H 6e: dt3.55 J = _{12,2; H 3a} and _{H 5e: m2.77~2.38; H 5a:} m1.98; CH 3: d0.86 J = 7.

Aromatic ortho H to 3) CDCl ₃ solution of 250MHz- ¹ H-NMR spectrum Cl: t7.36 J = 8 (o -H coupling and m-F coupling); the remaining two aromatic 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 and _{H 5a: m1.95~2.17; CH 3:} d1.04 J = 7.

5) Mass spectrum 338,336: molecular peak; 319,317: M-19 (F ); 257: M (+) - Br; 97: C 7 H 13? , 55: C ₄ H ₇ ? -Basal peak.

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

５５：基底ピーク。

９）質量スペクトル
５９８、５９６：分子ピーク；５７９、５７７：Ｍ−１９（Ｆ）；

55: Basal peak.

9) Mass spectrum 598, 596: molecular peak; 579, 579: M-19 (F);

５１７：５９８、５９６−Ｂｒ；５１６：５９８、５９６−ＨＢｒ；
４５１、４４９：分子ピーク−

517: 598, 596-Br; 516: 598, 596-HBr;
451, 449: molecular peak-

（Ｃ_２１Ｈ_２６ＢｒＦ_４Ｏ）、基底ピーク。

(C ₂₁ H ₂₆ BrF ₄ O), base peak.

<Tetrahydropyran derivative I from Table 4>
Compound No. The NMR spectra of 1a, 1b and 1e are obtained from compound No. Same as 3a.

<Tetrahydropyran derivative IV from Table 5>
1a / b) 250 MHz- ¹ H spectrum in CDCl ₃ 4 aromatic H: AB-q, center 6.89, 2 o-H for tetrahydropyran substitution: d 7.10 J = 8; for phenolic OH group two _{o-H: 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 spectrum in CDCl ₃ 4 aromatic H: AB-q, center 6.88, 2 o-H for tetrahydropyran substitution: d7.15 J = 8; for phenolic OH group 2 o-H: d 6.60 J = 8; H _2a : dd 4.20 J = 12, 2; H _6e : dm 4.07 J = 12, 4; H _6a : t3.20 J = 12; H _3e : dm1.99 J = 12,? _{; H 4e: dm1.80 J = 12} ; H 3a, H 5a: m1.50~1.75; side chain -CH ₂ and _{H 4a: m1.1~1.3; CH 3:} t0.92 J = 7.
Melting point: 92 ° C.

3) 250 MHz- ¹ H spectrum in CDCl ₃ 4 aromatic H: AB-q, center 6.95, 2 o-H for tetrahydropyran substitution: d 7.20 J = 8; 2 for phenolic OH groups _{o-H: d6.70 J = 8} ; H 2a: dd4.20 J = 12,2; H 6e: dm4.07 J = 12,4; H 6a: t3.20 J = 12; H 3e: dm1. 99 J = 12 ,? _{; H 4e: dm1.80 J = 12} ,? H _3a , H _5a : m1.50 to 1.75; 2 side chains CH ₂ and ₄ H of H _4a : m1.10 to 1.30; CH ₃ : t0.92 J = 7.
Melting point: 94 ° C.

4a / b) 250 MHz- ¹ H spectrum in CDCl ₃ 4 aromatic H: AB-q, center 6.95, 2 o-H for tetrahydropyran substitution: d7.20 J = 8; for phenolic OH group two _{o-H: 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 5a: _m1.53~1.74; three side chains the CH ₂ groups of six H and _H 4a: _{m1.05~ 1.45; CH 3: t0.90 J =} 7.
Melting point: 87 ° C.

6) 250 MHz ¹ H-NMR spectrum in CDCl ₃

ｔ７．３２ Ｊ＝８（ｏ−Ｈカップリングおよびｍ−Ｆカップリング）；残りの４つの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つの側鎖ＣＨ_２基の６つのＨおよびＨ_４ａ：ｍ１．０５〜１．４０；ＣＨ_３：ｔ０．８７ Ｊ＝７。
融点：５８℃（Ｃ５８Ｉ）。

t7.32 J = 8 (o-H coupling and m-F coupling); the remaining four 4 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 one side chain CH six H and _H 4a of _{2 groups: m1.05~1.40; CH 3: t0.87 J} = 7.
Melting point: 58 ° C. (C58I).

7) 400 MHz-H ₁ -NMR spectrum in CDCl ₃

ｔ７．３２ Ｊ＝８（ｏ−Ｈカップリングおよびｍ−Ｆカップリング）；残りの４つの芳香族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。
融点：５５℃（Ｃ５５Ｉ）。

t7.32 J = 8 (o-H coupling and m-F coupling); the remaining 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.
Melting point: 55 ° C (C55I).

Claims (16)

In one reaction step, the homoallylic alcohol of formula II is reacted in the presence of an aldehyde of formula III or an acetal or hydrate thereof and at least one Lewis acid containing at least one chlorine, bromine or iodine atom and A process for the preparation of halogenated tetrahydropyran derivatives of the formula I, characterized by reacting in the presence of a Bronsted acid containing at least one chlorine, bromine or iodine ion.

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

Represents
Z ¹ represents 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 if ^{a 2} is not a cyclohexylene and cyclohexenylene ring, it may represent a _-CF 2 O-,
Z ² 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 bonded to via its O atoms in cyclohexylene or cyclohexylene ring Not
n1, n2 and n3 are independently of each other 0, 1, 2, 3 or 4;
Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are independently of each other H, halogen, —CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl. , -OC _1-6 -alkanyl, -OC _2-6 -alkenyl, -OC _2-6 -alkynyl, wherein the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, And W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
However,
when a and b are simultaneously 0, R ¹ does not represent hydrogen, halogen or CN, and when all of c, d, e and f are simultaneously 0, R ² is hydrogen, halogen, —CN, —NCS , _-NO 2, _-OH, -SF 5, do not represent -O- aralkyl or alkoxy,
In the above formula I, 3 substituents tetrahydropyran ring Ri whole equatorial arrangement der,
However,
For Formula II, a + b is equal to 0, 1 or 2;
For formula III, c + d + e + f is equal to 0, 1, 2, 3 or 4 . )   2. The process according to claim 1, wherein at least one Lewis acid is used. Said Lewis acid is selected from the group comprising compounds of formula M (X ¹ ) _n and R ³ M (X ¹ ) _n-1 , provided that
M represents B, Al, In, Sn, Ti, Fe, Zn, Nb, Zr, Au, or 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 3. Method according to claim 1 or 2, characterized in that they are chosen to be equal.   The Lewis acid is used in an amount of 25 mol% to 300 mol%, based on the homoallylic alcohol of the formula II used in each case. Method.   The method according to claim 1, wherein the Bronsted acid is hydrobromic acid.   4. The process according to claim 1, wherein a mixture of at least one Lewis acid and at least one Bronsted acid is used.   7. Process according to claim 6, characterized in that the Lewis acid is used in the mixture in an amount of 0.1-20 mol%, based on the homoallylic alcohol of the formula II used in each case. . The method according to claim 1, wherein X ¹ is bromine.   9. The compound of formula I has one substituent other than hydrogen at the 2- and 5-positions of the tetrahydropyran ring, these substituents being in the trans configuration with respect to each other. The method according to any one of the above.   The method according to claim 1, wherein (a + b + c + d + e + f) is 1, 2 or 3. A compound of formula I.

(However,
a, b, c, d, e and f, independently of one another, represent 0 or 1, provided that a + b + c + d + e + f is equal to 1, 2, 3 or 4;
X ¹ represents chlorine, bromine or iodine,
R ¹ represents H, halogen, —CN, an alkyl group having 1 to 15 C atoms, and the group is unsubstituted, monosubstituted by —CN, monosubstituted or polysubstituted by halogen In addition, however, one or more of the CH ₂ groups in these groups may be such that —C≡C—, —CH═CH—, —O, such that the oxygen atoms in the chain are not directly bonded to each other. -, - S -, - SO -, - SO 2 -, - CO-O- or may be replaced by -O-CO-,
R ² represents H, halogen, —CN, —NCS, —NO ₂ , —OH, —SF ₅ , —O-aralkyl, an alkyl group having 1 to 15 C atoms, and the group is unsubstituted. Is, is monosubstituted by —CN, or monosubstituted or polysubstituted by halogen or —O-aralkyl, but in addition one or more of the CH ₂ groups in these groups is an oxygen in the chain The atoms are not directly bonded to each other so that —C≡C—, —CH═CH—, —O—, —S—, —SO—, —SO ₂ —, —CO—, —CO—O— or — May be replaced by O-CO-,
A ¹ , A ² , A ³ , A ⁴ , A ⁵ and A ⁶ , independently of one another, may be rotated or mirror images,

Represents
Z ¹ represents 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 if ^{a 2} is not a cyclohexylene and cyclohexenylene ring, it may represent a _-CF 2 O-,
Z ² 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 bonded to via its O atoms in cyclohexylene or cyclohexylene ring Not
n1, n2 and n3 are independently of each other 0, 1, 2, 3 or 4;
Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ and Y ⁶ are independently of each other H, halogen, —CN, C _1-6 -alkanyl, C _2-6 -alkenyl, C _2-6 -alkynyl. , -OC _1-6 -alkanyl, -OC _2-6 -alkenyl, -OC _2-6 -alkynyl, wherein the aliphatic group is unsubstituted or mono- or polysubstituted by halogen, And W ¹ represents —CH ₂ —, —CF ₂ — or —O—,
However,
when a and b are simultaneously 0, R ¹ does not represent hydrogen, halogen or CN, and when all of c, d, e and f are simultaneously 0, R ² is hydrogen, halogen, —CN, —NCS , _-NO 2, _-OH, -SF 5, do not represent -O- aralkyl or alkoxy,
In the above formula I, the three substituents at the 2-position, 4-position and 5-position of the tetrahydropyran ring are all equatorial. )   12. The compound according to claim 11, wherein (a + b + c + d + e + f) is 1, 2 or 3. A tetrahydropyran derivative of formula I is prepared by the method according to any one of claims 1 to 10, and then the tetrahydropyran derivative of formula IV is prepared from the tetrahydropyran derivative of formula I by a reductive elimination reaction. how you and obtaining.

^{(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 and Z ⁶ are as defined in claim 1 independently.)   14. The method of claim 13, wherein the reductive elimination is performed using an organotin hydride or organosilicon reagent. X ¹ is bromine, and method of claim 13, wherein the reductive elimination is hydrogenated in the debromination in the presence of a catalyst and a base. A tetrahydropyran derivative of the formula I is prepared by the method according to any one of claims 1 to 10, and then from the tetrahydropyran derivative of the formula I by dehydrohalogenation reaction of the formula Va and / or Vb A method characterized in that after obtaining a dihydropyran derivative, the dihydropyran derivative of formula Va and / or Vb is hydrogenated to obtain a tetrahydropyran derivative of formula IV .

^{(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 and Z ⁶ are as defined in claim 1 independently.)

^{(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 and Z ⁶ are as defined in claim 1 independently.)