JP5148482B2 - Method for preparing tetrahydropyrans from tetrahydropyran-3-ones - Google Patents

Description

  The present invention relates to a process for preparing 2,5-2 substituted tetrahydropyrans from tetrahydropyran-3-ones and novel intermediates from their synthesis.

  As a component of the chemical structure, the tetrahydropyran ring is an important principal in a whole series of compounds. For example, as described in EP967261A1 (Yamada et al., Chisso Corporation, 1999; Patent Document 1), tetrahydropyrans have already played an important role in substances classified as liquid crystals. Of particular interest in this field are 2,5-substituted derivatives of tetrahydropyrans that are structurally similar to conventional 1,4-substituted cyclohexane derivatives.

  Obtaining such compounds is described, for example, in DE 3306960 A1 (Patent Document 2). The method described therein is based on hydrogenating 5-substituted 3,4-dihydro-2H-pyrans in order to obtain the target compound. Starting from 3,4-dihydro-2H-pyran, only the synthesis of 2-unsubstituted compounds is described. Here, unfortunately, the 2-substituted 3,4-dihydropyrans necessary for the synthesis of the compounds according to the invention can only be obtained by difficult methods.

For the synthesis of 2-methyl-5-phenyltetrahydropyran, toxic mercury compounds are described in S. H. Kang et al. (Tetr. Lett., 1998, 39, 59-62; Non-Patent Document 1).
EP967261A1 DE3306960A1 S. H. Kang et al., Tetr. Lett. 1998, 39, 59-62

  Thus, the aim is to develop a general method for obtaining 2- and 5-substituted tetrahydropyrans.

  This object is achieved according to the invention by a process for the preparation of tetrahydropyran derivatives of the formula I.

その方法は、式ＩＩの化合物をケト官能基で求核性炭素原子を有する試薬類（「Ｃ求核試薬類」）と反応させることで特徴付けられる。

The method is characterized by reacting a compound of formula II with reagents having a nucleophilic carbon atom at the keto functionality ("C nucleophiles").

ただし、式ＩおよびＩＩ中、互いに独立に、同一または異なって、
Ｒ^１およびＲ^２は、Ｈ、ハロゲン、ＣＮ、ＮＣＳ、ＳＦ_５、１〜１５個の炭素原子を有するアラルキル、−Ｏ−アラルキルまたはアルキル基を表し、該基は無置換であるか、同一か異なってハロゲンまたはＣＮにより１置換または多置換されており、ただし加えて、この基中の１個以上のＣＨ_２基は、ヘテロ原子（Ｏ、Ｓ）が互いに直接結合しないように、−Ｃ≡Ｃ−、−ＣＨ＝ＣＨ−、−Ｏ−、−Ｓ−、−Ｃ（Ｏ）−Ｏ−および／または−Ｏ−Ｃ（Ｏ）−で置き換えられていてもよく、
Ａ^１、Ａ^２、Ａ^３、Ａ^４、Ａ^５、Ａ^６は、１，４−フェニレン（該１，４−フェニレンは、互いに独立に、ハロゲン、ＣＨ_３、ＣＦ_３、ＣＨＦ_２、ＣＨ_２Ｆ、ＯＣＨ_３、ＯＣＨＦ_２、ＯＣＦ_３で、０〜４回置換されていてもよく、ただし、環のＣＨはＮで０〜２回置換されていてもよく）、シクロヘキサン−１，４−ジイル（ＣＨ_２は、互いに独立に、ＯまたはＳで０〜２回、および／またはＦで０〜１０回置換されていてもよく）、シクロブタン−１，４−ジイル、ビシクロ［１．１．１］ペンタン−１，３−ジイル、ビシクロ［２．２．２］オクタン−１，４−ジイル、スピロ［３．３］ヘプタン−２，６−ジイルを表し
Ｚ^１、Ｚ^２、Ｚ^３、Ｚ^４、Ｚ^５、Ｚ^６は、互いに独立に、同一か異なって、単結合、−ＣＨ_２ＣＨ_２−、−ＣＦ_２ＣＨ_２−、−ＣＨ_２ＣＦ_２−、−ＣＦ_２ＣＦ_２−、−ＣＨ_２Ｏ−、−ＯＣＨ_２−、−ＣＦ_２Ｏ−または−ＯＣＦ_２−を表し、および
ａ、ｂ、ｃ、ｄ、ｅ、ｆは、０または１を表す。

Provided that in formulas I and II, independently of one another, the same or different,
R ¹ and R ² represent H, halogen, CN, NCS, SF ₅ , an aralkyl, —O-aralkyl or alkyl group having 1 to 15 carbon atoms, the groups being unsubstituted or identical. Differently mono- or polysubstituted by halogen or CN, but in addition one or more CH ₂ groups in this group may be —C≡ so that the heteroatoms (O, S) are not directly bonded to one another. C—, —CH═CH—, —O—, —S—, —C (O) —O— and / or —O—C (O) — may be substituted,
A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ are 1,4-phenylene (the 1,4-phenylene is independently of each other halogen, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , OCHF ₂ , OCF ₃ may be substituted 0 to 4 times, provided that CH in the ring may be substituted 0 to 2 times with N), cyclohexane-1,4-diyl (CH ₂ may be independently substituted 0-2 times with O or S and / or 0-10 times with F), cyclobutane-1,4-diyl, bicyclo [1.1.1 ] Represents pentane-1,3-diyl, bicyclo [2.2.2] octane-1,4-diyl, spiro [3.3] heptane-2,6-diyl, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , and Z ⁶ are independently the same or different and are each a single bond, —C H ₂ CH ₂ —, —CF ₂ CH ₂ —, —CH ₂ CF ₂ —, —CF ₂ CF ₂ —, —CH ₂ O—, —OCH ₂ —, —CF ₂ O— or —OCF ₂ — is represented. , And a, b, c, d, e, f represent 0 or 1.

  The process of the present invention is based on the preparation and use of dihydropyran-3-one intermediates of formula II.

式ＩＩの化合物の調製は文献に僅かに例が記載されているのみで、高度な合成上の複雑さを伴う。Ｍ．Ｍ．ＣｏｏｋおよびＣ．Ｄｊｅｒａｓｓｉ（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ．（１９７３年）、第１１巻、第３６７８〜８６頁）に記載される５−メチルテトラヒドロフルフリルアルコールの環拡張による合成の場合、６−メチルテトラヒドロピラン−３−の収率は必ず低いものとなる。Ｓ．Ｚｈａｎｇらは、有毒な水銀化合物類を使用するビニル化により単に式ＩＩの類似体の入手を達成している（Ｂｉｏｏｒｇ．Ｍｅｄ．Ｃｈｅｍ．Ｌｅｔｔ．（２００３年）、第１３巻、第１５９１〜５頁）。式ＩＩのケトン類に対応するアルコール化合物である２−ｔｅｒｔ−ブチルテトラヒドロピラン−５−オールがＣ．Ａｎｓｅｌｍｉにより複雑な方法で調製されており、限定された生成物の範囲でのみ使用できる（Ｔｅｔｒａｈｅｄｒｏｎ（１９７７年）、第３３巻、第２２７１〜５頁）。対照的に、本発明方法の実施形態によれば出発材料としてラクトン類を使用でき（スキーム３参照）、ラクトン類はしばしば商業的に入手可能であるか、文献より公知の方法を経て複雑ではない方法により入手できる。よって、有利な方法で、材料としてこれまで知られていなかった式ＩＩの新規なジヒドロピラノン類の形で、多様な興味ある中間体類の入手手段が開かれる。

The preparation of compounds of formula II is only described in the literature with few examples and involves a high degree of synthetic complexity. M.M. M.M. Cook and C.I. In the case of synthesis by ring expansion of 5-methyltetrahydrofurfuryl alcohol described in Djerassi (J. Am. Chem. Soc. (1973), 11, pp. 3678-86), 6-methyltetrahydropyran- The yield of 3- will always be low. S. Zhang et al. Have achieved access to analogs of formula II simply by vinylation using toxic mercury compounds (Bioorg. Med. Chem. Lett. (2003), 13, 1591-5). page). 2-tert-Butyltetrahydropyran-5-ol, an alcohol compound corresponding to the ketones of formula II, is C.I. It has been prepared in a complex way by Anselmi and can only be used in a limited range of products (Tetrahedron (1977), 33, 2271-5). In contrast, lactones can be used as starting materials according to embodiments of the process of the present invention (see Scheme 3), which are often commercially available or not complicated via methods known from the literature. It can be obtained by the method. Thus, in an advantageous manner, access to a variety of interesting intermediates is opened up in the form of novel dihydropyranones of the formula II, which have not previously been known as materials.

  In an embodiment of the invention, the compound of formula I is prepared by a method comprising a reaction step according to scheme 1.

本発明の方法の式Ｉの特に好ましい生成物は、以下のように特徴付けられる。

Particularly preferred products of formula I of the process of the invention are characterized as follows:

a + b + c is 0, 1 or 2;
d + e + f is 0, 1 or 2;
a + b + c + d + e + f is 0, 1 or 2;
A ¹ , A ² and A ³ , if present, are independently of each other cyclohexane-1,4-diyl or tetrahydropyran-2,5-diyl, or A ⁴ , A ⁵ and A ⁶ are If present, independently of one another, may be fluorinated 1,4-phenylene, 1,3-dioxane-2,5-diyl or 1,4-cyclohexanediyl.

  The process for preparing a compound of formula I comprises a step characterized in that a keto compound of formula II and a metal-containing compound of formula III are reacted to obtain a compound of formula IV.

ただし、式ＩＩＩおよびＩＶ中、互いに独立に、同一または異なって、
ｎは、１または２であり、
Ｍは、金属、ハロゲン化金属、更なる有機基を有する金属または陰イオンとしての^（-）［（Ｚ^４−Ａ^４）_ｄ−（Ｚ^５−Ａ^５）_ｅ−（Ｚ^６−Ａ^６）_ｆ−Ｒ^２］とのイオン対の任意の所望の陽イオンを表し、および
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、ａ、ｂ、ｃ、ｄ、ｅおよびｆは、それぞれの場合で独立に、式Ｉの上の意味を有する。

Provided that in formulas III and IV, independently of one another, the same or different,
n is 1 or 2,
M is a metal, a metal halide, a metal having a further organic group, or ⁽⁻⁾ [(Z ⁴ -A ⁴ ) _d- (Z ⁵ -A ⁵ ) _e- (Z ⁶ -A ⁶ ) as an anion. _f— R ² ] represents any desired cation of the ion pair, and 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 , a, b, c, d, e and f each independently have the above meaning of formula I.

  The metal-containing compounds of the formula III preferably represent Grignard compounds, alkyllithium compounds or metallated compounds of the carbanion type with any desired counterion, usually the counterion of the base used.

  The reaction is carried out in a conventional manner for the addition reaction of metal alkyls or carbanions onto the carbonyl group. If the metallated or deprotonated compound is not commercially available, the metallization is carried out by exchanging protons or halogens with the metal species “in situ”. Conventional variants (eg Grignard reaction, metallization using butyllithium, exchange of halides with alkyl MgBr / LiCl by the method of P. Knochel et al, reaction with strong non-nucleophilic bases) are known from the literature And is very suitable for the preparation of multiple reaction partners.

  Furthermore, the process for the preparation of the compound of formula I comprises a reaction step characterized by converting the reaction product of formula IV into a compound of formula Va and / or Vb by dehydration.

ただし、式ＶａおよびＶｂ中の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、ａ、ｂ、ｃ、ｄ、ｅ、ｆは、式Ｉの上の意味を有する。

Provided that 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 , in the formulas Va and Vb, a, b, c, d, e, f have the above meanings of Formula I.

  The process is further characterized in that in one reaction step, the compound of formula Va or Vb is converted to the compound of formula I by hydrogenation.

  The described reaction steps from formula II to formula I are carried out in the order shown or simultaneously. The intermediate can be isolated or used or reacted immediately by subsequent reactions. Furthermore, intermediate steps such as purification, epimerization, racemic conversion or concentration of the desired isomer can also be performed between the reactions.

  A preferred process for the preparation of a compound of formula I uses an organometallic compound of formula III, and when n is equal to 1, M represents Li, Na or HalMg, where Hal represents I, Br or Cl. , N is equal to 2, M represents Mg.

  In a second embodiment of the invention, the tetrahydropyranone of formula II is essentially reacted with an α-alkoxyphosphoryl ylide (α-alkoxyphosphorane) to give formyltetrahydropyran by a Wittig reaction followed by hydrolysis. (Scheme 2) The compound of formula I is prepared in the step.

使用されるウィッティッヒ試薬はハロゲン化（アルコキシメチル）トリフェニルホスホニウムのようなエノールエーテルシントン、特に、例えば臭化または塩化（メトキシメチル）トリフェニルホスホニウムのような商業的に入手できる試薬である。反応条件は、ウィッティッヒ反応のための従来工程と類似している。

The Wittig reagent used is an enol ether synthon such as a halogenated (alkoxymethyl) triphenylphosphonium, in particular a commercially available reagent such as, for example, brominated or (methoxymethyl) triphenylphosphonium chloride. The reaction conditions are similar to the conventional process for Wittig reaction.

  Thus, the process for preparing the compound of formula I involves reacting the keto compound of formula II and the phosphorus ylide compound of formula VI to give the enol ether compound VII, which is hydrolyzed to give the aldehyde of formula VIII. The aldehyde is subsequently reacted with a 1,3-diol compound of formula IX to obtain a compound of formula I.

R ³ ₃ P = CHOR ⁴ VI
However, R ³ denotes an aryl group, R ⁴ is an organic group.

ただし、式Ｉ中の−［Ｚ^４−Ａ^４］_ｄ−は、以下の式のジオキサン基を意味し、

However, in the formula _{^{I - [Z 4 -A 4]}} d - means dioxane group of the formula,

および、式ＩＸ中のＲ^２、Ａ^５、Ａ^６、Ｚ^５、Ｚ^６、ｅおよびｆは、式Ｉで定義される通りである。

And R ² , A ⁵ , A ⁶ , Z ⁵ , Z ⁶ , e and f in Formula IX are as defined in Formula I.

R ⁴ is preferably a single bond, linear or branched and an alkyl group having 1 to 10 carbon atoms, in particular a methyl or ethyl group.

  The aldehyde intermediate of formula VIII is very suitable for the preparation of further products that can ultimately be converted to tetrahydropyran derivatives of formula I. The reaction of the aldehyde derivative may be, for example, a simple method of the form of condensing 1,3-propanediol to obtain a dioxane ring, or halogenation to obtain a precursor of a further tetrahydropyran ring as described in EP1482020A1. Performed by reaction with allylmagnesium. It is possible to further use aldehydes for the synthesis of tetrahydropyran for liquid crystals by condensing with acrylates according to WO 2004/048357 A1. In addition, the aldehyde functionality can be converted to an alkenyl chain by a simple method via a Wittig reaction, and then hydrogenated to a terminal alkyl chain. This makes it possible to simply obtain tetrahydropyran derivatives that are alkyl substituted on the ring (at the 5 position). Due to the direction of the oxygen atom, the dipole moment in the longitudinal direction of the molecule is increased in a clever combination with further polar groups in the molecule, which makes these compounds for polar compounds with a dielectric anisotropy greater than zero. Especially interesting. Because of these diverse reaction possibilities, the synthesis of tetrahydropyranaldehyde is particularly beneficial for the synthesis of various variants of the tetrahydropyran compound of formula I.

  Accordingly, a process for preparing a compound of formula I characterized by reacting a compound of formula II with a Wittig reagent in a first step to obtain a compound of formula VII and subsequent hydrolysis to obtain an aldehyde compound of formula VIII Is preferred.

ただし、
Ｒ^５は、任意の所望の方法、特にはメチル基で置換されたアルキル基を表し、
式ＶＩＩおよびＶＩＩＩ中のａ、ｂ、ｃ、Ｒ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ａ^１、Ａ^２およびＡ^３は、式Ｉと同じ意味を有する。

However,
R ⁵ represents any desired method, in particular an alkyl group substituted with a methyl group,
A, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in formulas VII and VIII have the same meaning as in formula I.

  Aldehydes of formula VIII are also suitable for the formation of alkenyl chains by reaction with simple Wittig reagents such as phosphorus ylides. Using an appropriate Wittig reagent, an optionally substituted alkenyl group can also be attached to the tetrahydropyran ring. Alkenyl groups are suitable as chain-type end groups or as linking components between ring systems in mesogenic molecules. Double bonds generated in the vicinity of the tetrahydropyran ring can also be subsequently hydrogenated to give 1,2-ethylene bridges, which now have a wide range of mesogenic substances available. The formed ethylene group can be used as a linking component between rings of mesogenic molecules or as part of a terminal alkyl group. Thus, the aldehyde VIII is used to construct an alkenyl group (which may be substituted) via a Wittig reaction with phosphorus ylide or to subsequently hydrogenate the alkenyl group (which may be substituted) to construct an alkyl group Preference is also given to a process for the preparation of compounds of the formula I in which the aldehydes of the formula VIII or the aldehyde precursors of the formula VII are used as intermediates.

The aldehyde of formula VIII is a very useful intermediate. Thus, similarly, part of an embodiment of the present invention is a reaction of tetrahydropyran-3-one with a Wittig reagent of formula R ³ ₃ P═CHOR ⁴ to obtain a compound of formula VII as described above, followed by hydrolysis. To prepare a tetrahydropyran containing an aldehyde group characterized by obtaining a compound of formula VIII. Preferred is a process for preparing an aldehyde of formula VIII from a keto compound of formula II.

  The present invention further relates to novel 3-ketotetrahydropyrans having at least one substitution at the 6-position, which is para to the keto group, which serves as an intermediate. The derivatives known to date are only 6-methyl and 6-tert-butyl derivatives to represent simple alkyl derivatives, with a few specific derivatives that are not worth using as mesogens or as liquid crystal compounds. is there.

  New compounds suitable as intermediates are compounds of formula II.

ただし、Ｒ^１がメチルに等しい場合ａ＋ｂ＋ｃは０に等しくなく、他の場合、ａ、ｂ、ｃ、Ｒ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ａ^１、Ａ^２およびＡ^３は、式ＩＩに関して上で示される意味を有する。

However, when R ¹ is equal to methyl, a + b + c is not equal to 0; otherwise, a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ are of formula II Has the meaning indicated above.

a + b + c has a value of 0 or 1, and R ¹ is an alkyl group having ¹ to 15 carbon atoms, in particular 2 to 8 carbon atoms, which is unsubstituted or the same or different, halogen or CN is mono- or polysubstituted, but in addition, one or more CH ₂ groups in this group are —C≡C—, —, such that heteroatoms (O, S) are not directly bonded to each other. Preference is given to compounds of the formula II characterized in that they may be replaced by CH═CH—, —O—, —S—, —C (O) —O— and / or —O—C (O) —. . When a is equal to 1, ring A ¹ here preferably represents 1,4-phenylene, cyclohexane-1,4-diyl or tetrahydropyran-2,5-diyl, each monosubstituted or polysubstituted by F May be.

Similarly, a + b + c has a value of 1 to 3, and R ¹ is F, Cl, Br, CN, CF ₃ , OCF ₃ or an alkyl group having 1 to 15 carbon atoms, which is unsubstituted , Identically or differently, mono- or polysubstituted by halogen or CN, but in addition one or more CH ₂ groups in this group are such that heteroatoms (O, S) are not directly bonded to one another, Characterized by optionally substituted by -C≡C-, -CH = CH-, -O-, -S-, -C (O) -O- and / or -O-C (O)-. The compound of formula II is preferred. From this relationship, compounds of formula II in which A ¹ , A ² , A ³ represent 1,4-phenylene and are mono- or polysubstituted by F are particularly preferred. In this connection, compounds of the formula II in which Z ¹ or Z ² each represents a single bond or —OCF ₂ — are also particularly preferred. In addition, particularly preferred are compounds of the formula II, characterized in that A ¹ , A ² and A ³ , independently of one another, represent one of the following structural elements:

本発明によれば、式ＩＩの化合物は、２，５−置換ピラン誘導体を調製するための中間体として使用される。

According to the invention, the compound of formula II is used as an intermediate for preparing 2,5-substituted pyran derivatives.

  For the preparation of an aldehyde compound characterized by reacting a compound of formula II with a Wittig reagent to give a compound of formula VII and subsequent hydrolysis to give an aldehyde compound of formula VIII, the compound of formula II is It is preferable to use it.

ただし、式ＶＩＩおよびＶＩＩＩ中のａ、ｂ、ｃ、Ｒ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ａ^１、Ａ^２およびＡ^３は、式Ｉに関するものと同じ意味を有する。

However, a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in formulas VII and VIII have the same meaning as for formula I.

A further aspect of the invention is to prepare tetrahydropyran-3-ones of formula II as starting materials for further preparation methods. The synthesis is accomplished as generally shown in Scheme 3. Here and below, MES represents an organic partial structure, in particular also a mesogenic partial structure and its parts, ie for example a simple alkyl chain, and analogously to formula II, the group R ^1- [A ^{1- _{Z 1] a - [A 2}} -Z 2] b - [A 3 -Z 3] c - also represents. In certain situations, multiple steps in a reaction sequence can be combined as reactions in a single reaction vessel.

ラクトンから出発して、例えば水素化ジイソブチルアルミニウム（ＤＩＢＡＬ−Ｈ）を使用して還元することによりラクトンを得て、これより、脱水および引き続くヒドロホウ素化によりヒドロキシル化合物を調製できる。更に酸化すれば、所望のケト化合物を得る。

Starting from the lactone, the lactone can be obtained by reduction using, for example, diisobutylaluminum hydride (DIBAL-H), from which the hydroxyl compound can be prepared by dehydration and subsequent hydroboration. Further oxidation results in the desired keto compound.

  The starting lactones are commercially available, for example lactones and dihydropyrans can be prepared from aldehydes as shown in Scheme 4. Aldehyde (MES-CHO) is reacted with a Grignard compound to obtain an alcohol, from which hemiacetal is obtained, and an aldehyde is obtained after hydrolysis of the acetal group.

式ＩＩのテトラヒドロピラノンの調製の好ましい実施形態において、示される式中の成分ＭＥＳは、式Ｘで下に定義されるように式−［Ｚ^３−Ａ^３］_ｃ−［Ｚ^２−Ａ^２］_ｂ−［Ｚ^１−Ａ^１］_ａ−Ｒ^１の基を表す。従って、式ＩＩのテトラヒドロピラノン類の好ましい調製方法は、式Ｘの化合物を酸化することで特徴付けられる。

In a preferred embodiment of the preparation of the tetrahydropyranone of formula II, the component MES in the formula shown is of the formula-[Z ³ -A ³ ] _c- [Z ² -A ² as defined below in formula X. It represents the _{^{[Z 1 -A 1] a -R}} 1 group -] _b. Accordingly, a preferred method of preparing tetrahydropyranones of formula II is characterized by oxidizing the compound of formula X.

ただし、式Ｘ中のａ、ｂ、ｃ、Ｒ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ａ^１、Ａ^２およびＡ^３は、式Ｉと同じ意味を有する。

However, a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in formula X have the same meaning as in formula I.

  Likewise preferred is a process for preparing a compound of formula II, characterized in that the 2-substituted 3,4-dihydro-2H-pyran of formula XI is converted to X by hydroboration.

ただし、式ＸＩ中のａ、ｂ、ｃ、Ｒ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ａ^１、Ａ^２およびＡ^３は、式Ｉと同じ意味を有する。

However, a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in formula XI have the same meaning as in formula I.

  Finally, in the first step, a compound of formula II is prepared from a lactone of formula XII, characterized in that the lactone XII is converted to an intermediate of formula XI by reducing and eliminating the keto group A method is additionally preferred.

ただし、式ＸＩＩ中のａ、ｂ、ｃ、Ｒ^１、Ｚ^１、Ｚ^２、Ｚ^３、Ａ^１、Ａ^２およびＡ^３は、式Ｉと同じ意味を有する。

However, a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in formula XII have the same meaning as in formula I.

  The advantage of the method described in the variant results from the fact that it can be performed simply and does not use significant amounts of heavy metal reagents. The synthetic strategy allows the use of a large number of readily available starting materials, yields a wider range of products, and broadens the range of known and industrially available compounds.

  The following abbreviations are used above and below.

RT room temperature THF tetrahydrofuran MTB ether methyl tert-butyl ether i. v. Under vacuum DCM Dichloromethane PCC Pyridinium chlorochromate

  The invention is further illustrated by the following examples without the purpose of limiting the invention.

Example 1 6-Pentyldihydropyran-3-one 1.1.6-pentyltetrahydropyran-2-ol

１１９ｇ（０．７ｍｏｌ）のδ−デカノラクトンを１．２ｌのジクロロメタンに溶解し、８００ｍｌのトルエン中の水素化ジイソブチルアルミニウムの１Ｍ溶液を−７８℃で滴下により加える。４時間後、１ｌの飽和炭酸水素ナトリウム溶液を加え、冷却を止め、反応物を濾過する。水相を分離し、ジクロロメタンで３回抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥する。溶媒を真空下で除去し、１２０ｇの６−ペンチルテトラヒドロピラン−２−オールを無色の液体として得て、更に精製することなく反応させる。

119 g (0.7 mol) of δ-decanolactone is dissolved in 1.2 l of dichloromethane and a 1 M solution of diisobutylaluminum hydride in 800 ml of toluene is added dropwise at −78 ° C. After 4 hours, 1 l of saturated sodium bicarbonate solution is added, cooling is stopped and the reaction is filtered. The aqueous phase is separated and extracted three times with dichloromethane. The combined organic phase is washed with water and dried over sodium sulfate. The solvent is removed under vacuum to give 120 g of 6-pentyltetrahydropyran-2-ol as a colorless liquid and reacted without further purification.

  1.2.2-Pentyl-3,4-dihydro-2H-pyran

１２０ｇの１．１からの粗生成物を１ｌのジクロロメタンに溶解し、２２５ｍｌ（１．６ｍｏｌ）のトリエチルアミンおよび１．６５ｇ（１３．５ｍｍｏｌ）のＮ，Ｎ−ジメチルアミノピリジンを加え、６２．０ｍｌ（０．８００ｍｏｌ）の塩化メシルを１０℃で滴下により加える。反応物を４時間還流させ、水で３回洗浄し、蒸発させる。残渣をペンタン／ジクロロメタン（８：１）でシリカゲルを通して濾過し、４９．８ｇ（４６％、２段階）の２−ペンチル−３，４−ジヒドロ−２Ｈ−ピランを無色の液体として得る。

120 g of the crude product from 1.1 was dissolved in 1 l of dichloromethane, 225 ml (1.6 mol) of triethylamine and 1.65 g (13.5 mmol) of N, N-dimethylaminopyridine were added and 62.0 ml ( 0.800 mol) of mesyl chloride is added dropwise at 10 ° C. The reaction is refluxed for 4 hours, washed 3 times with water and evaporated. The residue is filtered through silica gel with pentane / dichloromethane (8: 1) to give 49.8 g (46%, 2 steps) of 2-pentyl-3,4-dihydro-2H-pyran as a colorless liquid.

  1.3.6-Pentyltetrahydropyran-3-ol

８．４１ｇ（５４．５ｍｍｏｌ）の２−ペンチル−３，４−ジヒドロ−２Ｈ−ピランを１００ｍｌのＴＨＦ中に溶解し、７０ｍｌ（７０ｍｍｏｌ）のＴＨＦ中の１Ｍボラン溶液を−１７℃で滴下により加える。１時間後、冷却を止め、反応物を室温で１時間攪拌する。１６ｍｌのエタノール、２３ｍｌのペルヒドロールおよび１００ｍｌの１Ｍ水酸化ナトリウム溶液を引き続き連続して加え、混合物を２時間還流する。反応混合物を水に加え、エーテルで３回抽出する。混合された有機相を飽和食塩溶液で洗浄し、硫酸ナトリウム上で乾燥し、蒸発させる。粗生成物をジクロロメタン／ＭＴＢエーテル（９：１）でシリカゲルを通して濾過し、４．７０ｇ（４９％）の６−ペンチルテトラヒドロピラン−３−オールを無色の液体として得る。

8.41 g (54.5 mmol) of 2-pentyl-3,4-dihydro-2H-pyran is dissolved in 100 ml of THF, and a solution of 1M borane in 70 ml (70 mmol) of THF is added dropwise at -17 ° C. . After 1 hour, cooling is stopped and the reaction is stirred at room temperature for 1 hour. 16 ml of ethanol, 23 ml of perhydrol and 100 ml of 1M sodium hydroxide solution are subsequently added successively and the mixture is refluxed for 2 hours. The reaction mixture is added to water and extracted three times with ether. The combined organic phases are washed with saturated saline solution, dried over sodium sulfate and evaporated. The crude product is filtered through silica gel with dichloromethane / MTB ether (9: 1) to give 4.70 g (49%) of 6-pentyltetrahydropyran-3-ol as a colorless liquid.

  1.4.6-Pentyldihydropyran-3-one

４ｍｌのジメチルスルホキシドおよび８０ｍｌのジクロロメタンを最初に窒素下で導入し、−７０℃まで冷却し、５．６ｍｌ（４０．１ｍｍｏｌ）のトリフルオロ酢酸無水物を滴下により加える。１０分後、８ｍｌのジメチルスルホキシド中の４．５６ｇ（２６．７ｍｍｏｌ）の６−ペンチルテトラヒドロピラン−３−オールの溶液および２０ｍｌのジクロロメタンを加え、混合物を−７０℃で１時間攪拌する。１３ｍｌ（９３．５ｍｍｏｌ）のトリエチルアミンを反応物に引き続き加え、３０分攪拌し、温め、２０ｍｌの２Ｎ塩酸を使用して加水分解し、エーテルで３回抽出する。混合された有機相を水で３回洗浄し、硫酸ナトリウム上で乾燥し、真空下で蒸発させる。粗生成物をジクロロメタンでシリカゲルを通して濾過し、４．３ｇの６−ペンチルジヒドロピラン−３−オンを黄色の液体として得る。

4 ml of dimethyl sulfoxide and 80 ml of dichloromethane are initially introduced under nitrogen, cooled to −70 ° C. and 5.6 ml (40.1 mmol) of trifluoroacetic anhydride are added dropwise. After 10 minutes, a solution of 4.56 g (26.7 mmol) 6-pentyltetrahydropyran-3-ol in 8 ml dimethyl sulfoxide and 20 ml dichloromethane are added and the mixture is stirred at −70 ° C. for 1 hour. 13 ml (93.5 mmol) of triethylamine are subsequently added to the reaction, stirred for 30 minutes, warmed, hydrolyzed using 20 ml of 2N hydrochloric acid and extracted three times with ether. The combined organic phases are washed 3 times with water, dried over sodium sulphate and evaporated under vacuum. The crude product is filtered through silica gel with dichloromethane to give 4.3 g of 6-pentyldihydropyran-3-one as a yellow liquid.

<Example 2> 5- (4-Ethoxy-2,3-difluorophenyl) -2-pentyltetrahydropyran-2.1.3- (4-Ethoxy-2,3-difluorophenyl) -6-pentyltetrahydropyran-3 -All

２４．０ｇ（１５２ｍｍｏｌ）の２，３−ジフルオロエトキシベンゼンを２５０ｍｌのＴＨＦに溶解し、９２ｍｌ（１５２ｍｍｏｌ）のヘキサン中１５パーセントのｎ−ブチルリチウム溶液を−７０℃で滴下により加える。１時間後、２５０ｍｌのＴＨＦ中の２５．９ｇ（１５２ｍｍｏｌ）の６−ペンチルジヒドロピラン−３−オンを滴下により加え、混合物を更に２時間攪拌する。反応物を温め、１００ｍｌの水を使用して加水分解し、２Ｍの塩酸を使用して酸性とする。水相を分離し、ＭＴＢエーテルで３回抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥する。溶媒を真空下で除去し、ヘプタン／ＭＴＢエーテル（７：３）によりシリカゲル上で残渣のクロマトグラフィーを行い、１７．１ｇ（３２％）の３−（４−エトキシ−２，３−ジフルオロフェニル）−６−ペンチルテトラヒドロピラン−３−オールを無色の個体として得る。

24.0 g (152 mmol) 2,3-difluoroethoxybenzene is dissolved in 250 ml THF and 92 ml (152 mmol) 15 percent n-butyllithium solution in hexane is added dropwise at -70 ° C. After 1 hour, 25.9 g (152 mmol) of 6-pentyldihydropyran-3-one in 250 ml of THF is added dropwise and the mixture is stirred for a further 2 hours. The reaction is warmed, hydrolyzed using 100 ml of water and acidified using 2M hydrochloric acid. The aqueous phase is separated and extracted 3 times with MTB ether. The combined organic phase is washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel with heptane / MTB ether (7: 3) to give 17.1 g (32%) of 3- (4-ethoxy-2,3-difluorophenyl) -6-pentyltetrahydropyran-3-ol is obtained as a colorless solid.

  2.2.5- (4-Ethoxy-2,3-difluorophenyl) -2-pentyl-3,4-dihydro-2H-pyran and 5- (4-Ethoxy-2,3-difluorophenyl) -2 -Pentyl-3,6-dihydro-2H-pyran

９．３０ｇ（２８．３ｍｍｏｌ）の３−（４−エトキシ−２，３−ジフルオロフェニル）−６−ペンチルテトラヒドロピラン−３−オールを５０ｍｌのピリジンに溶解し、４．２ｍｌ（５７．９ｍｍｏｌ）の塩化チオニルを氷冷しながら滴下により加える。反応物を引き続き放置して室温で一晩攪拌し、溶液を氷水に加える。水相を分離し、ＭＴＢエーテルに３回抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥し、溶媒を真空下で除去する。ヘプタン／ＭＴＢエーテル（１７：３）によりシリカゲル上で残渣のクロマトグラフィーを行い、５．８ｇ（５４％）の２種類の異性体ジヒドロピランを無色の個体として得る。

9.30 g (28.3 mmol) of 3- (4-ethoxy-2,3-difluorophenyl) -6-pentyltetrahydropyran-3-ol was dissolved in 50 ml of pyridine and 4.2 ml (57.9 mmol) of Thionyl chloride is added dropwise with ice cooling. The reaction is subsequently left to stir overnight at room temperature and the solution is added to ice water. The aqueous phase is separated and extracted three times with MTB ether. The combined organic phases are washed with water, dried over sodium sulfate and the solvent is removed under vacuum. Chromatography of the residue on silica gel with heptane / MTB ether (17: 3) gives 5.8 g (54%) of the two isomeric dihydropyrans as colorless solids.

  2.3.5- (4-Ethoxy-2,3-difluorophenyl) -2-transpentyltetrahydropyran

５．８ｇの５−（４−エトキシ−２，３−ジフルオロフェニル）−２−ペンチルジヒドロ−２Ｈ−ピラン異性体をＴＨＦに溶解し、５ｂａｒおよび５０℃でパラジウム／活性炭素触媒（５％）存在下で水素化を完了する。触媒を除去し、シスおよびトランス生成物の混合物をクロマトグラフィーで分離し、２．０ｇ（３４％）の５−（４−エトキシ−２，３−ジフルオロフェニル）−２−トランスペンチルテトラヒドロピランを融点５２℃の無色の個体として得る。

5.8 g of 5- (4-Ethoxy-2,3-difluorophenyl) -2-pentyldihydro-2H-pyran isomer dissolved in THF and present in palladium / activated carbon catalyst (5%) at 5 bar and 50 ° C. Complete the hydrogenation under. The catalyst was removed and the mixture of cis and trans products was chromatographed to separate 2.0 g (34%) of 5- (4-ethoxy-2,3-difluorophenyl) -2-transpentyltetrahydropyran Obtained as a colorless solid at 52 ° C.

Example 3 5- (4-Ethoxy-2,3-difluorophenyl) -2- (6-pentyltetrahydropyran-3-yl) -1,3-dioxane 3.1.5-methoxymethylene-2-pentyl Tetrahydropyran

４７．２ｇ（１３８ｍｍｏｌ）の臭化メトキシメチルトリフェニルホスホニウムを１５０ｍｌのＴＨＦ中に最初に導入し、１３．８ｇ（１２０ｍｍｏｌ）のカリウムｔｅｒｔ−ブトキシドを氷冷しながら加える。１時間後、１８．８ｇ（１１０ｍｍｏｌ）の７５ｍｌのＴＨＦ中の６−ペンチルジヒドロピラン−３−オンを加える。冷却を止め、反応物を室温で一晩攪拌する。水を加えたのち、水相を除去し、ＭＴＢエーテルで３回抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥する。溶媒を真空下で除去し、ヘプタン／ＭＴＢエーテル（２０：１）によりシリカゲル上で残渣のクロマトグラフィーを行い、１９．９ｇ（９１％）の５−メトキシメチレン−２−ペンチルテトラヒドロピランを無色の油分として得る。

47.2 g (138 mmol) of methoxymethyltriphenylphosphonium bromide are initially introduced into 150 ml of THF and 13.8 g (120 mmol) of potassium tert-butoxide are added with ice cooling. After 1 hour, 18.8 g (110 mmol) of 6-pentyldihydropyran-3-one in 75 ml of THF is added. Cooling is stopped and the reaction is stirred at room temperature overnight. After adding water, the aqueous phase is removed and extracted three times with MTB ether. The combined organic phase is washed with water and dried over sodium sulfate. The solvent was removed in vacuo and the residue was chromatographed on silica gel with heptane / MTB ether (20: 1) to give 19.9 g (91%) of 5-methoxymethylene-2-pentyltetrahydropyran as a colorless oil. Get as.

  3.2. Trans-6-pentyltetrahydropyran-3-carbaldehyde

１９．９ｇ（１００ｍｍｏｌ）の５−メトキシメチレン−２−ペンチルテトラヒドロピランを１００ｍｌのＴＨＦに溶解し、６ｍｌの濃塩酸を加えた後、出発物質が薄層クロマトグラフィー上で見出せなくなるまで室温で攪拌する。１００ｍｌの飽和食塩溶液を加えた後、反応物をＭＴＢエーテルで３回抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥し、蒸発させる。粗生成物を２５０ｍｌのメタノールに溶解し、５ｍｌの１５パーセント水酸化ナトリウム溶液を加え、混合物を室温で３．５時間激しく攪拌する。反応物を２Ｍ塩酸を使用して中和し、ＭＴＢエーテルで抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥し、蒸発させる。ヘキサン／ＭＴＢエーテル（５：１）で粗生成物のクロマトグラフィーを行い、１３．０ｇ（７１％）の６−ペンチルテトラヒドロピラン−３−カルバルデヒドを無色の油分として得る（トランス／シス＝２：１）。

Dissolve 19.9 g (100 mmol) of 5-methoxymethylene-2-pentyltetrahydropyran in 100 ml of THF, add 6 ml of concentrated hydrochloric acid and stir at room temperature until no starting material can be found on thin layer chromatography . After adding 100 ml of saturated saline solution, the reaction is extracted 3 times with MTB ether. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. The crude product is dissolved in 250 ml of methanol, 5 ml of 15 percent sodium hydroxide solution is added and the mixture is stirred vigorously at room temperature for 3.5 hours. The reaction is neutralized using 2M hydrochloric acid and extracted with MTB ether. The combined organic phases are washed with water, dried over sodium sulfate and evaporated. Chromatography of the crude product with hexane / MTB ether (5: 1) yields 13.0 g (71%) of 6-pentyltetrahydropyran-3-carbaldehyde as a colorless oil (trans / cis = 2: 1).

  3.3.2- (4-Ethoxy-2,3-difluorophenyl) propane-1,3-diol

６．１ｇ（１９．３ｍｍｏｌ）のマロン酸ジエチル２−（４−エトキシ−２，３−ジフルオロフェニル）（Ｅ．Ｊ．Ｈｅｎｎｅｓｓｙら、Ｏｒｇ．Ｌｅｔｔ．（２００２年）、第４巻、第２６９〜７２頁の方法により２，３−ジフルオロ−４−エトキシヨードベンゼンより調製される）を１００ｍｌのＴＨＦに溶解し、５０ｍｌのＴＨＦ中の２．３０ｇ（６０．６ｍｍｏｌ）の水素化アルミニウムリチウムの懸濁液に氷冷しながら滴下により加える。冷却を止め、反応物を室温で一晩攪拌する。２０ｍｌの水を冷却しながら加えた後、反応混合物を２Ｎの硫酸を使用して酸性とし、ＭＴＢエーテルにより３回抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥する。溶媒を真空下で除去し、ＭＴＢエーテルによりシリカゲル上で残渣のクロマトグラフィーを行い、２−（４−エトキシ−２，３−ジフルオロフェニル）プロパン−１，３−ジオールを無色の油分として得る
３．４．１−エトキシ−２，３−ジフルオロ−４−（２−トリメチルシラニルオキシ−１−トリメチルシラニルオキシメチルエチル）ベンゼン

6.1 g (19.3 mmol) of diethyl malonate 2- (4-ethoxy-2,3-difluorophenyl) (EJ Hennessy et al., Org. Lett. (2002), Volume 4, 269- (Prepared from 2,3-difluoro-4-ethoxyiodobenzene by the method on page 72) in 100 ml THF and suspension of 2.30 g (60.6 mmol) lithium aluminum hydride in 50 ml THF Add dropwise to the solution with ice cooling. Cooling is stopped and the reaction is stirred at room temperature overnight. After adding 20 ml of water with cooling, the reaction mixture is acidified using 2N sulfuric acid and extracted three times with MTB ether. The combined organic phase is washed with water and dried over sodium sulfate. 2. Remove the solvent under vacuum and chromatograph the residue on silica gel with MTB ether to give 2- (4-ethoxy-2,3-difluorophenyl) propane-1,3-diol as a colorless oil. 4. 1-Ethoxy-2,3-difluoro-4- (2-trimethylsilanyloxy-1-trimethylsilanyloxymethylethyl) benzene

５．７０ｇ（２４．１ｍｍｏｌ）の２−（４−エトキシ−２，３−ジフルオロフェニル）プロパン−１，３−ジオールおよび１７．３ｍｌ（１２４ｍｍｏｌ）のトリエチルアミンを１４０ｍｌのＤＭＦ中に溶解し、７．７ｍｌ（６１ｍｍｏｌ）のクロロトリメチルシランを加え、混合物を８０℃で２時間温める。反応物を放冷し、１００ｍｌのペンタンを加え、混合物を氷水中に投入する。水相を分離し、ペンタンで３回抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥する。溶媒を真空下で除去し、８．７ｇの１−エトキシ−２，３−ジフルオロ−４−（２−トリメチルシラニルオキシ−１−トリメチルシラニルオキシメチルエチル）ベンゼンを黄色の油分として得て、更に精製することなく反応させる。

5.70 g (24.1 mmol) of 2- (4-ethoxy-2,3-difluorophenyl) propane-1,3-diol and 17.3 ml (124 mmol) of triethylamine are dissolved in 140 ml of DMF. 7 ml (61 mmol) of chlorotrimethylsilane are added and the mixture is warmed at 80 ° C. for 2 hours. The reaction is allowed to cool, 100 ml of pentane is added and the mixture is poured into ice water. The aqueous phase is separated and extracted three times with pentane. The combined organic phase is washed with water and dried over sodium sulfate. The solvent was removed under vacuum to obtain 8.7 g of 1-ethoxy-2,3-difluoro-4- (2-trimethylsilanyloxy-1-trimethylsilanyloxymethylethyl) benzene as a yellow oil, The reaction is carried out without further purification.

  3.5.5- (4-Ethoxy-2,3-difluorophenyl) -2- (6-pentyltetrahydropyran-3-yl) -1,3-dioxane

７．７０ｇ（２０．４ｍｍｏｌ）の１−エトキシ−２，３−ジフルオロ−４−（２−トリメチルシラニルオキシ−１−トリメチルシラニルオキシメチルエチル）ベンゼンおよび０．４６ｍｌ（２．３ｍｍｏｌ）のトリフルオロメタンスルホン酸トリメチルシリルを９０ｍｌのジクロロメタン中に−７８℃で最初に導入し、２０ｍｌのジクロロメタン中の１３．９ｇ（１７％）の６−ペンチルテトラヒドロピラン−３−カルバルデヒドを滴下により加える。２時間後、２．４ｍｌ（２９．４ｍｍｏｌ）のピリジンを加え、反応物を温める。１００ｍｌの飽和炭酸水素ナトリウム溶液を加えた後、水相を分離し、ジクロロメタンで抽出する。混合された有機相を水で洗浄し、硫酸ナトリウム上で乾燥し、真空下で蒸発させる。エタノールから結晶化し、６．０ｇ（７４％）の５−（４−エトキシ−２，３−ジフルオロフェニル）−２−（６−ペンチルテトラヒドロピラン−３−イル）−１，３−ジオキサンを、融点５８℃の無色の個体として得る。

7.70 g (20.4 mmol) 1-ethoxy-2,3-difluoro-4- (2-trimethylsilanyloxy-1-trimethylsilanyloxymethylethyl) benzene and 0.46 ml (2.3 mmol) trifluoro Trimethylsilyl lomethanesulfonate is initially introduced into 90 ml of dichloromethane at −78 ° C. and 13.9 g (17%) of 6-pentyltetrahydropyran-3-carbaldehyde in 20 ml of dichloromethane is added dropwise. After 2 hours, 2.4 ml (29.4 mmol) of pyridine is added and the reaction is warmed. After adding 100 ml of saturated sodium hydrogen carbonate solution, the aqueous phase is separated and extracted with dichloromethane. The combined organic phases are washed with water, dried over sodium sulphate and evaporated under vacuum. Crystallized from ethanol, 6.0 g (74%) of 5- (4-ethoxy-2,3-difluorophenyl) -2- (6-pentyltetrahydropyran-3-yl) -1,3-dioxane was melted at the melting point. Obtained as a colorless solid at 58 ° C.

Example 4 2- (4-Propylcyclohexyl) -5-vinyltetrahydropyran 4.1.6- (4-Propylcyclohexyl) tetrahydropyran-3-carbaldehyde

例１および例３に記載される合成に類似の方法により、６−（４−プロピルシクロヘキシル）テトラヒドロピラン−２−オンより出発して、６−（４−プロピルシクロヘキシル）テトラヒドロピラン−３−カルバルデヒドを得る。

By a method analogous to the synthesis described in Examples 1 and 3, starting from 6- (4-propylcyclohexyl) tetrahydropyran-2-one, 6- (4-propylcyclohexyl) tetrahydropyran-3-carbaldehyde Get.

  4.2.2- (4-Propylcyclohexyl) -5-vinyltetrahydropyran

１９．６ｇ（０．０５５ｍｏｌ）の臭化メチルトリフェニルホスホニウムを１００ｍｌのＴＨＦに最初に導入し、６．１７ｇ（０．０５５ｍｏｌ）のカリウムｔｅｒｔ−ブトキシドを氷冷しながら加える。１時間後、５０ｍｌのＴＨＦ中の１１．９ｇ（０．０５５ｍｏｌ）の６−（４−プロピルシクロヘキシル）テトラヒドロピラン−３−カルバルデヒドを加える。冷却を止め、反応物を室温で一晩攪拌する。３．１のように操作を行い、２−（４−プロピルシクロヘキシル）−５−ビニルテトラヒドロピランを得る。

19.6 g (0.055 mol) of methyltriphenylphosphonium bromide are initially introduced into 100 ml of THF and 6.17 g (0.055 mol) of potassium tert-butoxide are added with ice cooling. After 1 hour, 11.9 g (0.055 mol) of 6- (4-propylcyclohexyl) tetrahydropyran-3-carbaldehyde in 50 ml of THF is added. Cooling is stopped and the reaction is stirred at room temperature overnight. The procedure is as in 3.1 to give 2- (4-propylcyclohexyl) -5-vinyltetrahydropyran.

<Example 5>
5.1

窒素下で、８１ｍｌ（８０ｍｍｏｌ）のＴＨＦ中のボラン／ＴＨＦ錯体の１０％溶液を、９０ｍｌのＴＨＦ中の２２．９ｇ（６０ｍｍｏｌ）のエノールエーテル１の溶液に、−２５℃〜−１５℃で加える。−２０℃および室温でそれぞれ１時間攪拌後、１８．５ｍｌのエタノールおよび引き続いて２５ｍｌの水中に溶解している４．４ｇ（１１０ｍｍｏｌ）の水酸化ナトリウムを反応物に加える。そして、反応温度が４５℃を超えない速度で、２１．５ｍｌ（２５０ｍｏｌ）の２５％過酸化水素水溶液を反応混合物に加える。反応物を４５℃で２時間、引き続いて室温で一晩攪拌する。沸騰するまで短時間加熱した後、反応物を冷却し、水に加える。水相をＭＴＢエーテルで抽出し、有機相を飽和食塩溶液で洗浄し、乾燥し、蒸発させる。残渣をシリカゲル上で精製する（ＭＴＢ／ＤＣＭ、１：６）。

Under nitrogen, a 10% solution of borane / THF complex in 81 ml (80 mmol) of THF is added to a solution of 22.9 g (60 mmol) of enol ether 1 in 90 ml of THF at −25 ° C. to −15 ° C. . After stirring for 1 hour at −20 ° C. and room temperature, respectively, 18.5 ml of ethanol and subsequently 4.4 g (110 mmol) of sodium hydroxide dissolved in 25 ml of water are added to the reaction. Then 21.5 ml (250 mol) of 25% aqueous hydrogen peroxide is added to the reaction mixture at a rate such that the reaction temperature does not exceed 45 ° C. The reaction is stirred at 45 ° C. for 2 hours followed by overnight at room temperature. After heating briefly to boiling, the reaction is cooled and added to water. The aqueous phase is extracted with MTB ether and the organic phase is washed with saturated brine solution, dried and evaporated. The residue is purified on silica gel (MTB / DCM, 1: 6).

  5.2

窒素下で、５０ｍｌのジクロロメタン中の１２．６ｇ（３１ｍｍｏｌ）のアルコール２の溶液を、１５０ｍｌのジクロロメタン中の１５ｇのセライト（登録商標）および７．３ｇ（３４ｍｍｏｌ）のＰＣＣの懸濁液に加え、混合物を一晩攪拌する。個体を引く続き分離し、ジクロロメタンで洗浄する。濾液を蒸発させ、残渣をシリカゲル（トルエン／ＭＴＢエーテル、９：１；１：１）で精製する。

Under nitrogen, a solution of 12.6 g (31 mmol) of alcohol 2 in 50 ml of dichloromethane was added to a suspension of 15 g of Celite® and 7.3 g (34 mmol) of PCC in 150 ml of dichloromethane, Stir the mixture overnight. The solid is subsequently separated and washed with dichloromethane. The filtrate is evaporated and the residue is purified on silica gel (toluene / MTB ether, 9: 1; 1: 1).

  5.3

窒素下で、３．５ｍｌ（３．５ｍｍｏｌ）のＴＨＦ中のビス(トリメチルシリル)リチウムアミドの１Ｍ溶液を、５ｍｌのＴＨＦ中の１．４ｇ（４ｍｍｏｌ）の塩化メトキシメチルトリフェニルホスホニウムの懸濁液に−２０℃で加える。３０分後、反応物を室温まで温め、５ｍｌのＴＨＦ中の１．５ｇ（３．６ｍｍｏｌ）のケトン３の溶液を加え、混合物を一晩攪拌する。反応混合物を引き続き氷水に加え、１６％硫酸を使用して酸性（ｐＨ５）とする。ＭＴＢエーテルで抽出後、有機相を飽和炭酸水素ナトリウム溶液で洗浄し、引き続き乾燥および蒸発させる。残渣をシリカゲル上（トルエン／ｎ−ヘプタン、４：１）で精製する。

Under nitrogen, a 1M solution of bis (trimethylsilyl) lithium amide in 3.5 ml (3.5 mmol) of THF was added to a suspension of 1.4 g (4 mmol) of methoxymethyltriphenylphosphonium chloride in 5 ml of THF. Add at -20 ° C. After 30 minutes, the reaction is warmed to room temperature and a solution of 1.5 g (3.6 mmol) of ketone 3 in 5 ml of THF is added and the mixture is stirred overnight. The reaction mixture is subsequently added to ice water and acidified (pH 5) using 16% sulfuric acid. After extraction with MTB ether, the organic phase is washed with saturated sodium hydrogen carbonate solution and subsequently dried and evaporated. The residue is purified on silica gel (toluene / n-heptane, 4: 1).

  5.4

窒素下で、０．３ｍｌの１６％硫酸を１０ｍｌのＴＨＦ中の２００ｍｇ（０．５ｍｍｏｌ）のエノールエーテル４を加え、混合物を最初に室温で攪拌し、そして転化を完結するために沸騰させながら１時間加熱する。反応物を引き続き水およびＭＴＢエーテルで希釈する。有機相を乾燥し、蒸発させる。残渣をシリカゲル（トルエン；トルエン／ＭＴＢエーテル９：１）上で精製し、アルデヒド５のシス／トランス混合物を得る。^１Ｈ−ＮＭＲ中のアルデヒドプロトンのシグナルは、δ＝９．９ｐｐｍおよびδ＝９．７ｐｐｍである。

Under nitrogen, 0.3 ml of 16% sulfuric acid, 200 mg (0.5 mmol) of enol ether 4 in 10 ml of THF are added, the mixture is first stirred at room temperature and boiled to complete the conversion. Heat for hours. The reaction is subsequently diluted with water and MTB ether. The organic phase is dried and evaporated. The residue is purified on silica gel (toluene; toluene / MTB ether 9: 1) to give a cis / trans mixture of aldehyde 5. The signals of aldehyde protons in ¹ H-NMR are δ = 9.9 ppm and δ = 9.7 ppm.

  To obtain the various compounds of formula I, aldehydes can be derived.

  For example, an aldehyde can be subsequently converted to an alkenyl chain by a Wittig reaction and further hydrogenated to obtain an alkyl chain.

  On the other hand, condensation by cyclization is performed with 1,3-propanediol to obtain a compound containing a dioxane ring.

    <Example 6>

アルデヒド５を引き続き２−エチル−１，３−プロパンジオールと反応させ、ジオキサン６を得る。このために、４４．５ｇ（１１０ｍｍｏｌ）のアルデヒド５および１２．０ｇ（１１５ｍｍｏｌ）のジオール６を２５０ｍｌのトルエンに溶解し、４００ｍｇのｐ−トルエンスルホン酸一水和物を加え、アルデヒドの転化が完了するまで（ＴＬＣ）、混合物を水分離器上で還流する。反応物を冷却し、飽和炭酸水素ナトリウム溶液で３回洗浄し、蒸発させ、シリカゲル（トルエン／ヘプタン７：３；トルエン；トルエン／酢酸エチル９５：５）を通す。生成物を含む画分を蒸発させ、残渣をエタノールより−２０℃で再結晶する。融点：８８℃。

Aldehyde 5 is subsequently reacted with 2-ethyl-1,3-propanediol to give dioxane 6. For this purpose, 44.5 g (110 mmol) of aldehyde 5 and 12.0 g (115 mmol) of diol 6 are dissolved in 250 ml of toluene and 400 mg of p-toluenesulfonic acid monohydrate are added to complete the conversion of the aldehyde. The mixture is refluxed on a water separator until (TLC). The reaction is cooled, washed three times with saturated sodium bicarbonate solution, evaporated and passed through silica gel (toluene / heptane 7: 3; toluene; toluene / ethyl acetate 95: 5). The fractions containing the product are evaporated and the residue is recrystallized from ethanol at -20 ° C. Melting point: 88 ° C.

Claims (13)

In one reaction step, the lactone XII is converted to the dihydropyran intermediate of formula XI by reducing and leaving the keto group to an OH group,
In one reaction step, a 2-substituted 3,4-dihydro-2H-pyran of formula XI is converted to a compound of formula X by hydroboration,
In one reaction step, the compound of formula X is oxidized to prepare tetrahydropyranones of formula II;
In one reaction step, a compound of formula II having a keto functional group and a nucleophilic carbon atom (“C nucleophiles”) (provided that the C nucleophiles are Grignard compounds, alkyllithium compounds) Or a counter ion thereof, a metallized compound of the carbanion type with a counter ion of the base, and a Wittig reagent) . A process for the preparation of tetrahydropyran derivatives of the formula I, characterized in that

(In formulas I, II, X, XI and XII , independently of one another, identical or different,
R ¹ and R ² represent H, halogen, CN, NCS, SF ₅ , an aralkyl, —O-aralkyl or alkyl group having 1 to 15 carbon atoms, the groups being unsubstituted or identical. Differently mono- or polysubstituted by halogen or CN, but in addition one or more CH ₂ groups in this group may be —C≡ so that the heteroatoms (O, S) are not directly bonded to one another. C—, —CH═CH—, —O—, —S—, —C (O) —O— and / or —O—C (O) — may be substituted,
A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ are 1,4-phenylene (the 1,4-phenylene is independently of each other halogen, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , OCHF ₂ , OCF ₃ may be substituted 0 to 4 times, provided that CH in the ring may be substituted 0 to 2 times with N), cyclohexane-1,4-diyl (CH ₂ may be independently substituted 0-2 times with O or S and / or 0-10 times with F), cyclobutane-1,4-diyl, bicyclo [1.1.1 ] Represents pentane-1,3-diyl, bicyclo [2.2.2] octane-1,4-diyl or spiro [3.3] heptane-2,6-diyl Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , and Z ⁶ are independently the same or different, _{-CH 2 CH 2 -, - CF} 2 CH 2 -, - CH 2 CF 2 -, - CF 2 CF 2 -, - CH 2 O -, - OCH 2 -, - CF 2 O- or -OCF ₂ - and And a, b, c, d, e, f represent 0 or 1,
However, a + b + c has a value of 1 to 3,
^{However, R 1, R 2, A} 1~6 in formula I and ^{II, Z 1 to 6} and a~c are in each case to adopt identical or different meanings. ) The method of claim 1, wherein in one reaction step, the keto compound of formula II and the metal-containing compound of formula III are reacted to give a compound of formula IV.

(Wherein in formulas III and IV, independently of one another, the same or different,
M is a metal, a metal halide, a metal having a further organic group, or ⁽⁻⁾ [(Z ⁴ -A ⁴ ) _d- (Z ⁵ -A ⁵ ) _e- (Z ⁶ -A ⁶ ) as an anion. _f −R ² ] is any desired cation of the ion pair, and n is equal to 1 or 2,
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 , a, b, c, d, e and f are as defined in claim 1 independently in each case. ) 3. A process according to claim 1 or 2, characterized in that the reaction product of formula IV is converted to a compound of formula Va or Vb by dehydration.

(However, a, b, c, d, e, f, R ¹ , R ² , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , A ¹ , A ^{2 in} the formulas Va and Vb. , A ³ , A ⁴ , A ⁵ and A ⁶ are independently as defined in claim 1 for Formula I.) For at least one hydrogenation process according to any one of 請 Motomeko 1-3 you characterized by converting a compound of formula Va and / or Vb to a compound of formula I. The compound of formula III represents an organometallic compound, wherein when n is equal to 1, M represents Li, Na or HalMg, where Hal means I, Br or Cl, and when n is equal to 2, M is the method according to any one of 請 Motomeko 1-4 you characterized by representing a mg. A keto compound of formula II and a phosphorus ylide compound of formula VI are reacted to obtain an enol ether compound, which is hydrolyzed to obtain an aldehyde, which is subsequently reacted with a 1,3-diol compound of formula IX. the method according to any one of 請 Motomeko 1-5 you and obtaining a compound of formula I.
R ³ ₃ P = CHOR ⁴ VI
(However, R ³ means an aryl group, and R ⁴ means an organic group.)

(However, in the formula _{^{I - [Z 4 -A 4]}} d - means dioxane group of the formula,

And R ² , A ⁵ , A ⁶ , Z ⁵ , Z ⁶ , e and f in formula IX are as defined in claim 1 in formula I. ) A compound of formula VIII according to claim 1, characterized in that the compound of formula II according to claim 1 is reacted with a suitable Wittig reagent to give a compound of formula VII and subsequently hydrolyzed to give an aldehyde compound of formula VIII. Preparation method.

(However, a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in formulas VII and VIII have the same meaning as in formula 1 in claim 1). Using an aldehyde VIII to construct an alkenyl group (optionally substituted) via a Wittig reaction with a phosphorus ylide or to subsequently hydrogenate the alkenyl group (optionally substituted) to construct an alkyl group wherein the method according aldehyde precursors of aldehydes or formula VII of formula VIII to any one of 請 Motomeko 1-7 to use as an intermediate compound. In one reaction step, process for the preparation of tetrahydropyranone such type you characterized by oxidizing a compound of the formula X II.

(In formulas II and X, independently of one another, identical or different,
R ¹ represents H, halogen, CN, NCS, SF ₅ , an aralkyl, —O-aralkyl or alkyl group having 1 to 15 carbon atoms, which group is unsubstituted or the same or different Or CN is mono- or poly-substituted, but in addition, one or more CH ₂ groups in this group may be —C≡C—, such that heteroatoms (O, S) are not directly bonded to each other. -CH = CH-, -O-, -S-, -C (O) -O- and / or -O-C (O)-may be substituted,
A ¹ , A ² , A ³ are 1,4-phenylene (the 1,4-phenylene is independently of each other halogen, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , OCHF ₂ , OCF ₃ may be substituted 0 to 4 times, provided that CH of the ring may be substituted 0 to 2 times with N, cyclohexane-1,4-diyl (CH ₂ is independently of each other, Optionally substituted 0 or 2 times with O or S and / or 0 to 10 times with F), cyclobutane-1,4-diyl, bicyclo [1.1.1] pentane-1,3-diyl, Represents bicyclo [2.2.2] octane-1,4-diyl or spiro [3.3] heptane-2,6-diyl
Z ¹ , Z ² and Z ³ are independently the same or different and are each a single bond, —CH ₂ CH ₂ —, —CF ₂ CH ₂ —, —CH ₂ CF ₂ —, —CF ₂ CF ₂ —, Represents —CH ₂ O—, —OCH ₂ —, —CF ₂ O— or —OCF ₂ —, and
a, b and c each represents 0 or 1;
However, a + b + c has a value of 1-3. ) In one reaction step, the 2-substituted 3,4-dihydro -2H- pyran of the formula XI, in 請 Motomeko 9 you characterized by converting a compound of formula X according to claim 9, wherein the hydroboration The method described.

(Where a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in formula XI are as defined in claim 9 ). Lactones of formula XII, characterized in that in one reaction step, the lactone XII is converted to the dihydropyran intermediate of formula XI according to claim 10 by reducing and leaving the keto group to an OH group. A process for the preparation of a compound of formula II according to claim 9 .

(Where a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in Formula XII are as defined in claim 9 ). Compounds of formula II.

(However,
When R ¹ is equal to methyl, a + b + c is equal to 1, 2 or 3;
A, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in Formula II are as defined in claim 9 . )   Use of a compound of formula II according to claim 12 for the preparation of 2,5-2 substituted pyran derivatives.