WO2006125550A1 - Method for producing tetrahydropyranes from tetrahydropyran-3-ones - Google Patents

Abstract

The invention relates to methods for producing 2,5-disubstituted tetrahydropyranes from tetrahydropyran-3-ones, and to novel intermediates from these syntheses.

Description

 Process for the preparation of tetrahydropyrans from tetrahydropyran-3-ones

The present invention relates to processes for the preparation of 2,5-disubstituted tetrahydropyrans from tetrahydropyran-3-ones as well as novel intermediates from these syntheses.

Tetrahydropyran rings as a component of chemical structures are an important feature of a wide range of classes of compounds. The tetrahydropyrans already play an important role in the

Substance class of liquid crystals, such. In EP 967261A1 (Yamada, et al., Chisso Corp., 1999). Of particular interest in this field are 2,5-substituted derivatives of tetrahydropyrans in structural analogy to the usual 1,4-substituted cyclohexane derivatives.

An access to such compounds is z. B. in DE 3306960 A1 discloses. The process described there is based on the hydrogenation of 5-substituted-3,4-dihydro-2H-pyrans to the target compounds. Starting from 3,4-dihydro-2-H-pyran, only the synthesis of compounds which are unsubstituted in the 2-position is described. The disadvantage here is that the required for the synthesis of the compounds of the invention, substituted in 2-position 3,4-dihydropyrans are difficult to access.

Toxic mercury compounds are found in S.H. Kang et al. to synthesize a 2-methyl-5-phenyl-tetrahydropyran (Tetr. Lett., 1998, 39, 59-62).

It is therefore the object to develop a general access to 2-position 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,

which is characterized in that compounds of the formula II

reacting at the keto function with reagents with a nucleophilic carbon atom ("C-nucleophiles"), wherein in formulas I and II independently of one another, same or different, R ¹ and R ^{2 are} H, halogen, CN, NCS ₁ SF ₅ , aralkyl, -O-aralkyl or an unsubstituted or mono- or polysubstituted by identical or different halogen or CN substituted alkyl radical having 1 to 15 carbon atoms, wherein in this radical also one or more CH ₂ groups by -C≡C-, -CH = CH -, -O-, -S-, -C (O) -O- and / or -O-C (O) - may be replaced so that

Heteroatoms (O, S) are not directly linked, A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ 1, 4-phenylene (which 0-4 times independently of each other by halogen, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F ₁ OCH ₃ , OCHF ₂ , OCF ₃ may be substituted and wherein a ring CH may be substituted 0-2 times by N), cyclohexane-1, 4-diyl (CH ₂ may be 0-2 independently of one another by O or S and / or 0-10 times by F), cyclobutane-1, 4-diyl, bicyclo [1.1.1] 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 , Z ^6, independently of one another, the same or different, a single bond, -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 a, b, c, d, e, f denote 0 or 1.

The process according to the invention is based on the preparation and use of dihydropyran-3-one intermediate compounds of the formula II.

O-

" ^■ + ^AL z4lf ^A - ^Z2 -kKz ³ -K> °

The preparation of compounds of formula II is described in the literature only for a few examples and associated with high synthetic effort. Low yields of 6-methyltetrahydropyran-3-one promise a synthesis according to M. M. Cook and C. Djerassi via a ring expansion of 5-methyltetrahydrofurfuryl alcohol (J. Am. Chem. Soc. (1973), 11, 3678-86). Only vinylation with toxic mercury compounds succeeds S. Zhang et al. access to analogs of Formula II (Bioorg Med Med Chem., Lett., (2003) 13, 1591-5). A corresponding alcohol compound to give the ketones of formula II, 2-tert-butyltetrahydropyran-5-ol, manufacture C. Anselmi in a complex manner, which is applicable only to a limited range of products (Tetrahedron (1977), 33, 2271-5). On the other hand, one embodiment of the process according to the invention makes it possible to use lactones as starting materials (cf., Scheme 3), many of which are commercially available or are accessible in a straightforward manner by methods known from the literature. This opens up access to a variety of interesting intermediates in the form of new dihydropyranones of the formula II, which are hitherto unknown as substances.

In one embodiment of the invention, the preparation of compounds of the formula I is carried out in a process which comprises the reaction steps according to Scheme 1. - A -

R '+ A ^ 4 _I f 2 = -A'iR IV

+

^« + ^AL z4 + ^A2 - ^Z ^ ^A» - ^z H ^j {> f ^Z4 - ^Ai ^ ^Z5 - ^A5 - ^ ^Zβ - ^Aβ + ^{R2 Vb}

Scheme 1. Preparation of compounds of formula I from II via coupling with metal-containing compounds.

Particularly preferred products of formula I of the invention

Method 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 θ, 1 or 2,

A ¹ , A ² and A ³ are, if present, independent 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 each other, optionally fluorinated 1, 4-phenylene, 1, 3-dioxane-2,5-diyl or 1, 4-cyclohexanediyl. The process for the preparation of compounds of the formula I comprises a process step which is characterized in that a keto compound II and a metal-containing compound IM

to a compound of formula IV

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 with another organic radical or any cation of an ion pair with

⁽⁾ [(Z ⁴ -A ⁴ ) _d - (Z ⁵ -A ⁵ ) _e - (Z ⁶ -A ⁶ ) _f -R ² ] as anion, 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, f have the meaning as above for formula I.

Preferably, the metal-containing compound of the formula III is a metallated

A compound of the type of Grignard compounds, lithium alkyls or carbanions with any counterion, usually the counterion of the base used.

The reaction takes place in one for additions of metal alkyls or of

Carbanions in Carbonylgruppen usual way. Preference is given to the metalation, as far as the metalated or deprotonated compound not is commercially available, generated "in situ" by replacement of a proton or halogen with a metal species, and common variants (eg, Grignardization, metallation with butyllithium, exchange of halides with alkylMgBr-LiCl according to P. Knöchel et al., reaction with strong , non-nucleophilic bases) are known from the literature and well suited to provide a variety of reactants.

Furthermore, the process for the preparation of compounds of the formula I comprises a reaction step, which is characterized in that a compound of the formula IV by elimination of water to give compounds of the formula Va and / or Vb

^ ¹ + A ^ Z ^ A ² -Z ^ A ³ -zH ^ y ^ Z ⁴ -A ^ Z ⁵ -A ⁵ -j _i fz ⁶ -A ⁶ iR ² Va

wherein 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, in the formulas Va and Vb have the same meaning as above for formula I.

The process is further characterized in that, in a reaction step, compounds of the formulas Va or Vb are converted by hydrogenation into compounds of the formula I.

The described reaction steps of formula II according to formula I are carried out in the order shown or simultaneously. Intermediates can be isolated or be used directly in the subsequent reaction or implemented. Between the reactions, additional intermediate steps can be switched, such. For cleaning, Epimerization, racemate resolution or for the enrichment of a desired isomer.

Preferred processes for the preparation of compounds of the formula I make use of organometallic compounds of the formula III which are characterized in that M is Li, Na, HaImg, when n is 1, where Hal is I, Br or Cl, or M equal to Mg when n equals 2.

In a second embodiment of the invention, the compounds of the formula I are prepared in a process which essentially converts the tetrahydropyranones of the formula II via a Wittig reaction with an α-alkoxyphosphorylide (α-alkoxyphosphorane) and subsequent hydrolysis to formyltetrahydropyrans ( Scheme 2).

R ^L fA A AkHiQ-CHO

I

Scheme 2. Preparation of compounds of formula I from II via aldehyde intermediates.

The Wittig reagent used is an enol ether synthon, such as the (alkoxymethyl) triphenylphosphonium halides, in particular commercially available Reagents, such. B. (methoxymethyl) triphenylphosphonium bromide or chloride. The reaction conditions are analogous to those customary for Wittig reactions.

The process for the preparation of compounds of the formula I is accordingly characterized in that a keto compound II and a phosphorylide compound of the formula VI,

R ³ ₃ P = CHOR ⁴ VI

wherein R ^{3 is} an aryl radical and R ^{4 is} an organic radical, to give an enol ether compound VII, hydrolyzed this to an aldehyde of formula VIII and then the aldehyde with a 1, 3-diol compound of the formula IX

to a compound of formula I, in which case - [Z ⁴ -A ⁴ ] _d - in

Formula I is a group of the formula and where in

Formula IX R ² , A ⁵ , A ⁶ , Z ⁵ , Z ⁶ , e and f are as defined for formula I. R ⁴ is preferably a simple, straight-chain or branched alkyl radical having 1-10 carbon atoms, in particular a methyl or ethyl radical.

The aldehyde intermediates of the formula VIII are excellently suitable for the preparation of further products which can ultimately be converted into tetrahydropyran derivatives of the formula I. The implementation of aldehyde derivatives z. B. in a simple manner in the form of

Condensation with 1, 3-propanediols to dioxane rings, or, as described in EP 1482020 A1, via reaction with allyl magnesium halide to precursors of another Tetrahydropyranringes. A further use of aldehydes for the tetrahydropyransynthesis for liquid crystals is possible according to WO 2004/048357 A1 by condensation with acrylic esters. In addition, the aldehyde function can be converted in a simple manner via a Wittig reaction in alkenyl chains, and therefrom via hydrogenation into terminal alkyl chains. This gives easy access to right-sided (5-position) alkyl-substituted tetrahydropyran derivatives. Owing to the orientation of the oxygen atom, these compounds are of particular interest for polar compounds having a dielectric anisotropy Δε> 0, since, when skillfully combined with other polar groups in the molecule, an enhanced dipole moment results in the direction of the longitudinal axis of the molecule. From these various reaction possibilities, the particular value of tetrahydropyranaldehydes results for the synthesis of different variants of the tetrahydropyran compounds according to formula I.

Preference is therefore also given to processes for the preparation of compounds of the formula I which are characterized in that, in a first step, a compound of the formula II is reacted with a Wittig reagent to give compounds of the formula VII

is reacted and then to an aldehyde compound of formula VIII

hydrolysiert wird, wobei

is hydrolyzed, wherein

R ^{5 is} an arbitrarily substituted alkyl radical, in particular a methyl group, a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in the formulas VII and VIII have the same meaning as for formula I have.

The aldehydes of the formula VIII are also suitable for the preparation of alkenyl chains by reaction with simple Wittig reagents such as phosphorylidene. Optionally substituted alkenyl groups can also be attached to the tetrahydropyran ring using suitable Wittig reagents. Alkenyl radicals are useful as chain end groups or as linkers between ring systems in mesogenic molecules. The generated double bond in the vicinity of the tetrahydropyran ring can also be subsequently hydrogenated to a 1, 2-ethylene bridge, which in turn makes a wide range of mesogenic substances accessible. The ethylene group formed can be used as a link between rings of the mesogenic molecule or as part of a terminal alkyl group. Preference is therefore also given to processes for the preparation of compounds of the formula I using aldehydes of the formula VIII or of aldehyde precursors of the formula VII

Intermediates, characterized in that the aldehyde VIII is used via a Wittig reaction with a phosphorylide for the construction of (optionally substituted) alkenyl groups or, by subsequent hydrogenation of the alkenyl group, for the construction of (optionally substituted) alkyl groups.

The aldehydes of formula VIII are extremely useful intermediates. One aspect of the present invention is therefore also a process for preparing tetrahydropyrans having an aldehyde group, which is characterized in that a one tetrahydropyran-one 3-, as described above, with a Wittig reagent of the formula R ³ ₃ P = CHOR ⁴ to give a compound of formula VII and then to compounds of Hydrolyzed Formula VIII. Preference is given to a process for the preparation of aldehydes of the formula VIII from keto compounds of the formula II.

Another object of the invention are serving as an intermediate new 3-keto-tetrahydropyrans having at least one

Substituents in position 6, para to the keto group. So far, only the 6-methyl and the 6-tert-butyl derivative are known as representatives of simple alkyl derivatives and a few special derivatives without value for use as mesogen or as a liquid crystalline compound.

Novel compounds which are useful as intermediates are compounds of formula II

where a + b + c is other than 0 when R ¹ is methyl, and otherwise a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ^{3 are} the same as described above Formula II given meaning.

Preference is given to compounds of the formula II which are characterized in that a + b + c has a value of 0 or 1 and R ^{1 is} an unsubstituted or mono- or polysubstituted by identical or different, halogen or CN substituted alkyl radical having 1 to 15 carbon atoms, in particular having 2 to 8 carbon atoms, means in this

Also, one or more CH ₂ groups are represented by -C≡C-, -CH = CH-, -O-, -S-, -C (O) -O- and / or -O-C (O) - so may be replaced that heteroatoms (O, S) are not directly linked. Here, for a equal to 1, the ring A ^{1 is} preferably an optionally mono- or polysubstituted with F 1, 4-phenylene, cyclohexane-1, 4-diyl or a tetrahydropyran-2,5-diyl. Also preferred are compounds of formula II, which are characterized in that a + b + c has a value of 1 to 3 and R ^{1 is} F, Cl, Br, CN, CF ₃ , OCF ₃ , or a single or multiple, the same or different, with halogen or CN substituted alkyl radical having 1 to 15 carbon atoms, wherein in this radical also one or more CH ₂ groups by -C≡C-, -CH = CH-, -O-, -S-, - C (O) -O- and / or -O-C (O) - may be substituted so that heteroatoms (O, S) are not directly linked together. Particularly preferred in this context are compounds of the formula II, for which A ¹ , A ² , A ^{3 is} a mono- or polysubstituted with F 1, 4-phenylene. In this context, compounds of the formula II in which Z ¹ or Z ^{2 are} each a single bond or -OCF ₂ - are particularly preferred. Preference is furthermore given to compounds of the formula II which are characterized in that A ¹ , A ² or A ³ independently of one another are one of the following structural elements

mean.

Compounds of the formula II are used according to the invention as intermediates for the preparation of 2,5-substituted pyran derivatives.

Preference is given to the use of compounds of the formula II for the preparation of aldehyde compounds, which is characterized in that a compound of the formula II is reacted with a Wittig reagent to give compounds of the formula VII

is reacted and then to an aldehyde compound of formula VIII

is hydrolyzed, wherein a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in the formulas VII and VIII have the same meaning as in relation to formula I.

A further aspect of the invention is the preparation of tetrahydropyran-3-ones of the formula II as starting material for the others

Production method. The synthesis is achieved as outlined in Scheme 3. Here and below, MES stands for an organic molecule radical, in particular for mesogenic molecule radicals and parts thereof, ie for example also for a simple alkyl chain or analogously to formula II for the radical R ¹ - [A ¹ -Z ¹ ] _a - [A ² -Z ² ] _b - [A ³ -Z ³ ] _c -. Also in the reaction sequence may be several steps in one

One-pot reaction can be summarized.

hydroboration /

Scheme 3. Process for the preparation of 3-keto-tetrahydropyrans. Starting from the lactones is obtained by reduction with z. For example, diisobutylaluminum hydride (DIBAL-H), the lactols from which the hydroxy compounds can be prepared by dehydration and subsequent hydroboration. Further oxidation provides the desired keto compounds.

The lactones as starting material are commercially available, or it may be the lactols and dihydropyrans z. B. be prepared from aldehydes according to Scheme 4. The aldehydes (MES-CHO) are reacted with Grignard compounds to give the alcohols from which the hemiacetals are obtained after hydrolysis of the acetal group to the aldehyde.

Scheme 4. Process for the preparation of dihydropyrans as an intermediate for the preparation of 3-keto-tetrahydropyrans.

In a preferred embodiment of the preparation of tetrahydropyranones of the formula II, the molecular radical MES in the formulas given is a radical of the formula - [Z ³ -A ³ ] _c - [Z ² -A ² ] _b - [Z ¹ -A ¹ ] _a -R ¹ as defined below for the formula X. A preferred process for the preparation of tetrahydropyranones of the formula II is therefore characterized in that a compound of the formula X is oxidized,

where a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in the formula X are the same

Meaning as for formula I have.

Also preferred is a process for the preparation of compounds of the formula II, which is characterized in that a 2-substituted 3,4-dihydro-2H-pyran of the formula XI

" ¹ + * ^Lz Hf * ^Lz Hϊh ^s -H xi

converted by a hydroboration in X, wherein a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in the formula Xl have the same meaning as for formula I.

In addition, a process for the production of

Compounds of the formula II from lactones of the formula XI,

which is characterized in that, in a first step, the lactone XII by reduction of the keto group and elimination in

Intermediates of formula Xl converted, wherein a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in the formula XII have the same meaning as for formula I.

The advantages of the method set forth in its variants result from the simple feasibility, which incidentally manages without the use of considerable amounts of heavy metal reagents. The synthesis strategy allows a variety of easily accessible Starting materials and it leads to a wide range of products that extends the range of known and industrially produced compounds.

The following abbreviations are used above and below:

RT room temperature

THF tetrahydrofuran

MTB ether methyl tert-butyl ether i. Vak. in a vacuum

DCM dichloromethane

PCC pyridinium chlorochromate

The present invention will be further illustrated by the following examples without being limited to them.

Examples

example 1

6-pentyl-dihydropyran-3-one

1.1. 6-pentyl-tetrahydropyran-2-ol

119 g (0.7 mol) of δ-decanolactone are dissolved in 1.2 l of dichloromethane and, at -78 ° C., 800 ml of a 1 M solution of diisobutylaluminum hydride in toluene are added dropwise. After 4 h, 1 l sat. Nariumhydrogencarbonatlösung added, the cooling removed and the approach filtered. The aqueous phase is separated and extracted three times with dichloromethane. The united org. Phases are washed with water and dried over sodium sulfate. After removal of the solvent i. Vak. 120 g of 6-pentyl-tetrahydropyran-2-ol are obtained as a colorless liquid which is reacted without further purification.

1.2. 2-pentyl-3,4-dihydro-2H-pyran

120 g of the crude product from 1.1. are dissolved in 1 l of dichloromethane, 225 ml (1, 6 mol) of triethylamine and 1, 65 g (13.5 mmol) of N, N-dimethylaminopyridine added and added dropwise at 10 ° C 62.0 ml (0.800 mol) of mesyl chloride , The mixture is heated under reflux for 4 h, washed three times with water and concentrated. The residue is filtered through silica gel with pentane / dichloromethane (8: 1). This gives 49.8 g (46%, 2 stages) of 2-pentyl-3,4-dihydro-2H-pyran as a colorless liquid.

1.3. 6-pentyl-tetrahydropyran-3-ol

8.41 g (54.5 mmol) of 2-pentyl-3,4-dihydro-2H-pyran are dissolved in 100 ml of THF and added dropwise at -17 ⁰ C 70 ml (70 mmol) of a 1 M solution of borane in THF , After 1 h, the cooling is removed and the mixture is stirred for 1 h at RT. Subsequently, 16 ml of ethanol, 23 ml of perhydrol and 100 ml of 1 M sodium hydroxide solution are added successively and heated under reflux for 2 h. The reaction mixture is added to water and washed three times Ether extracted. The united org. Phases are filled with sat. Sodium chloride solution, dried over sodium sulfate and concentrated. Filtration of the crude product over silica gel with dichloromethane / MTB ether (9: 1) gives 4.70 g (49%) of 6-pentyl-tetrahydropyran-3-ol as a colorless liquid.

1.4. 6-pentyl-dihydropyran-3-one

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 acid are added.

- _j c anhydride was added dropwise. After 10 minutes, a solution of 4.56 g (26.7 mmol) of 6-pentyl-tetrahydropyran-3-ol in 8 ml of dimethyl sulfoxide and 20 ml of dichloromethane is added and stirred at -70 ° C for 1 hour. Subsequently, the batch is treated with 13 ml (93.5 mmol) of triethylamine, stirred for 30 min, thawed, hydrolyzed with 20 ml of 2 N hydrochloric acid and washed three times

Extracted 2Q ether. The combined organic phases are washed with water, dried over sodium sulfate and i. Vak. concentrated. After filtration of the crude product with dichloromethane over silica gel gives 4.3 g of 6-pentyl-dihydropyran-3-one as a yellow liquid.

25

Example 2

5- (4-ethoxy-2,3-difluorophenyl) -2-pentyl-tetrahydropyran

2.1. 3- (4-Ethoxy-2,3-difluoro-phenyl) -6-pentyl-tetrahydropyran-3-ol 30

24.0 g (152 mmol) of 2,3-difluoroethoxybenzene are dissolved in 250 ml of THF and at -70 ° C 92 ml (152 mmol) of a 15proz. Added solution of n-butyllithium in hexane. After 1 h, 25.9 g (152 mmol) of 6-pentyl-dihydropyran-3-one are added dropwise in 250 ml of THF and stirred for a further 2 h. The mixture is thawed, hydrolyzed with 100 ml of water and acidified with 2 M hydrochloric acid. The aqueous phase is separated and extracted three times with MTB ether. The united org. Phases are washed with water and dried over sodium sulfate. The solvent is i. Vak. removed and the residue with heptane / MTB ether (7: 3) on silica gel chromatographies. This gives 17.1 g (32%) of 3- (4-ethoxy-2,3-difluorophenyl) -6-pentyl-tetrahydropyran-3-ol as a colorless solid.

2.2. 5- (4-Ethoxy-2,3-difluoro-phenyl) -2-pentyl-3,4-dihydro-2H-pyran, and 5- (4-ethoxy-2,3-difluoro-phenyl) -2-pentyl -3,6-dihydro-2H-pyran

9.30 g (28.3 mmol) of 3- (4-ethoxy-2,3-difluorophenyl) -6-pentyl-tetrahydropyran-3-ol are dissolved in 50 ml of pyridine and 4.2 ml under ice-cooling (57.9 mmol) of thionyl chloride was added dropwise. The mixture is then allowed to stir overnight at RT and the solution is added to ice-water. The aqueous phase is separated and extracted three times with MTB ether. The united org. Phases are washed with water, over sodium sulfate dried and the solvent i. Vak. away. The residue is chromatographed on silica gel using heptane / MTB ether (17: 3). 5.8 g (54%) of the two isomeric dihydropyrans are obtained as a colorless solid.

2.3. 5- (4-ethoxy-2,3-difluoro-phenyl) -2-trans-pentyl-tetrahydropyran

5.8 g of the isomers of 5- (4-ethoxy-2,3-difluoro-phenyl) -2-pentyldihydro-2H-pyran are dissolved in THF and in the presence of palladium activated carbon catalyst (5%) at 5 bar and 50 ^0th C hydrogenated to a standstill. The catalyst is separated off and the mixture of cis and trans product is separated by chromatography. This gives 2.0 g (34%) of 5- (4-ethoxy-2,3-difluoro-phenyl) -2-trans-pentyl-tetrahydropyran as a colorless solid of mp. 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

47.2 g (138 mmol) of methoxymethyltriphenylphosphonium bromide are initially charged in 150 ml of THF and, under ice-cooling, 13.8 g (120 mmol) of potassium tert-butoxide are added. After 1 h, 18.8 g (110 mmol) of 6-pentyl dihydropyran-3-one in 75 ml of THF. The cooling is removed and the batch is stirred overnight at RT. After addition of water, the aqueous phase is separated and extracted three times with MTB ether. The united org. Phases are washed with water and dried over sodium sulfate. The solvent is i. Vak removed and the

The residue with heptane / MTB ether (20: 1) filtered through silica gel. This gives 19.9 g (91%) of 5-methoxymethylene-2-pentyl-tetrahydropyran as a colorless oil.

3.2. trans-6-pentyl-tetrahydropyran-3-carbaldehyde

19.9 g (100 mmol) of 5-methoxymethylene-2-pentyl-tetrahydropyran be in

Dissolved 100 ml of THF and after addition of 6 ml of conc. Hydrochloric acid stirred at RT until no starting material is found by thin layer chromatography. After addition of 100 ml of sat. Sodium chloride solution, the batch is extracted three times with MTB ether. The united org. Phases are washed with water, dried over sodium sulfate and concentrated. The crude product is dissolved in 250 ml of methanol, 5 ml 15proz. Sodium hydroxide added and stirred vigorously for 3.5 h at RT. The mixture is neutralized with 2 M hydrochloric acid and extracted with MTB ether. The united org. Phases are washed with water, dried over sodium sulfate and concentrated. Chromatography of the crude product with hexane / MTB ether (5: 1) yields 13.0 g (71%) of 6-pentyl-tetrahydropyran-3-carbaldehyde as a colorless oil (trans / cis = 2: 1). 3.3. 2- (4-Ethoxy-2,3-difluoro-phenyl) -propane-1,3-diol

6.1 g (19.3 mmol) of diethyl 2- (4-ethoxy-2,3-difluorophenyl) malonate (prepared from 2,3-difluoro-4-ethoxyiodobenzene according to E. J. Hennessy et al., Org. Lett ), 4, 269-72) are dissolved in 100 ml of THF and added dropwise, with ice cooling, to a suspension of 2.30 g (60.6 mmol) of lithium aluminum hydride in 50 ml of THF. The cooling is removed and the batch is stirred overnight at RT. After adding 20 ml of water with cooling, the reaction mixture is acidified with 2 N sulfuric acid and extracted three times with MTB ether. The united org. Phases are washed with water and dried over sodium sulfate. The solvent is i. Vak. removed and the residue with MTB ether over silica gel chromatographies. 2- (4-Ethoxy-2,3-difluoro-phenyl) propane-1,3-diol is obtained as a colorless oil.

3.4. 1-ethoxy-2,3-difluoro-4- (2-trimethylsilanyloxy-1-trimethylsilanyloxymethyl-ethyl) -benzene

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, Added 7 ml (61 mmol) of chlorotrimethylsilane and heated to 80 ⁰ C for 2 h. The mixture is allowed to cool, 100 ml of pentane are added and the mixture is poured into ice-water. The aqueous phase is separated and extracted three times with pentane. The combined organic phases are mixed with water washed and dried over sodium sulfate. After removal of the solvent i. Vak. there are obtained 8.7 g of 1-ethoxy-2,3-difluoro-4- (2-trimethylsilanyloxy-1-trimethylsilanyloxymethyl-ethyl) benzene as a yellow oil which is reacted without further purification.

3.5. 5- (4-Ethoxy-2,3-difluorophenyl) -2- (6-pentyltetrahydropyran-3-yl) - [1,3] dioxane

7.70 g (20.4 mmol) of 1-ethoxy-2,3-difluoro-4- (2-trimethylsilanyloxy-1-trimethylsilanyloxy-methyl-ethyl) -benzene and 0.46 ml (2.3 mmol) of trimethylsilyltrifluoro - Methanesulfonate are introduced into 90 ml of dichloromethane at -78 ⁰ C and a solution of 13.9 g (71%) of 6-pentyl-tetrahydropyran-3-carbaldehyde in 20 ml of dichloromethane was added dropwise. After 2 h, 2.4 ml (29.4 mmol) of pyridine are added and the batch is thawed. After addition of 100 ml of sat. Sodium bicarbonate solution. the aqueous phase is separated and extracted with dichloromethane. The united org. Phases are washed with water, dried over sodium sulfate and i. Vak. concentrated. Crystallization from ethanol provides 6.0 g (74%) of 5- (4-ethoxy-2,3-difluorophenyl) -2- (6-pentyl-tetrahydropyran-3-yl) - [1,3] dioxane as a colorless solid from M.p. 58 ° C. Example 4

2- (4-propyl-cyclohexyl) -5-vinyl-tetrahydro-pyran

4.1. 6- (4-propyl-cyclohexyl) -tetrahydropyran-3-carbaldehyde

In analogy to the syntheses described in Example 1 and Example 3, 6- (4-propylcyclohexyl) tetrahydropyran-2-one gives 6- (4-propylcyclohexyl) tetrahydropyran-3-carbaldehyde.

4.2. 2- (4-propyl-cyclohexyl) -5-vinyltetrahydropyran

19.6 g (0.055 mol) of methyltriphenylphosphonium bromide are initially charged in 100 ml of THF and 6.17 g (0.055 mmol) of potassium tert-butoxide are added with ice-cooling. After 1 h, 11, 9 g (0.05 mol) of 6- (4-propylcyclohexyl) tetrahydropyran-3-carbaldehyde in 50 ml of THF are added. The cooling is removed and the batch is stirred overnight at RT. Work-up as in 3.1. provides 2- (4-propylcyclohexyl) -5-vinyltetrahydropyran.

1 2

Under nitrogen, a solution of 22.9 g (60 mmol) of the enol ether 1 in 90 ml of THF at -25 ° C to -15 ° C with 81 ml (80 mmol) of a 10% Solution of borane-THF complex in THF added. After stirring for 1 h at -2O ⁰ C and at RT 18.5 ml of ethanol and then 4.4 g (110 mmol) of sodium hydroxide dissolved in 25 ml of water in the mixture. The reaction mixture is then mixed with 21, 5 ml (250 mol) of a 25% aqueous hydrogen peroxide solution, so that the reaction temperature does not exceed 45 ° C. The mixture is stirred for 2 h at 45 ° C and then at RT overnight. After boiling for a short time, the cooled mixture is added to water. The aqueous phase is extracted with MTB ether, the organic phase is washed with sat. Washed with sodium chloride solution, dried and concentrated. The residue is purified on silica gel (MTB / DCM 1: 6).

5.2

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

5.3

Unter Stickstoff wird eine Suspension von 1 ,4 g (4 mmol) Methoxymethyl- triphenylphosphoniumchlorid in 5 ml THF bei -20 ⁰C mit 3,5 ml (3,5 mmol) einer 1 M Lösung von Bis-(trimethylsilyl)-lithiumamid in THF versetzt. Nach 30 min wird der Ansatz auf RT erwärmt und mit einer Lösung von 1 ,5 g (3,6 mmol) des Ketons 3 in 5 ml THF versetzt und über Nacht gerührt. Anschließend wird das Reaktionsgemisch auf Eiswasser gegeben und mit 16 %iger Schwefelsäure angesäuert (pH 5). Nach Extraktion mit MTB-Ether wird die organische Phase mit ges. Natriumhydrogencarbonatlsg. gewaschen, anschließend getrocknet und eingeengt. Der Rückstand wird an Kieselgel (Toluol/n-Heptan 4:1) gereinigt.

Under nitrogen, a suspension of 1, 4 g (4 mmol) of methoxymethyl triphenylphosphonium chloride in 5 ml of THF at -20 ⁰ C with 3.5 ml (3.5 mmol) of a 1 M solution of bis (trimethylsilyl) -lithiumamid in THF added. After 30 min, the batch is warmed to RT and treated with a solution of 1, 5 g (3.6 mmol) of the ketone 3 in 5 ml of THF and stirred overnight. Subsequently, the reaction mixture is added to ice-water and acidified with 16% sulfuric acid (pH 5). After extraction with MTB ether, the organic phase is washed with sat. Sodium bicarbonate solution. washed, then dried and concentrated. The residue is purified on silica gel (toluene / n-heptane 4: 1).

5.4

Under nitrogen, a solution of 200 mg (0.5 mmol) of the enol ether 4 in 10 ml of THF with 0.3 ml of 16% sulfuric acid and stirred first at RT, then heated to complete the conversion for 1 h to boiling. The mixture is then diluted with water and MTB ether. The organic phase is dried and concentrated. The residue is purified on silica gel (toluene, toluene / MTB ether 9: 1). A cis / trans mixture of aldehyde 5 is obtained. The signals of the aldehyde protons in ¹ H-NMR are δ = 9.9 ppm and δ = 9.7 ppm.

The aldehyde can be derivatized to various compounds of formula I. The aldehyde, for example, is subsequently converted by a Wittig reaction into an alkenyl chain, which can optionally be further hydrogenated to the alkyl chain.

Alternatively, condensation takes place with ring formation with a 1,3-propanediol to form compounds with a dioxane ring: Example 6

The aldehyde 5 is then reacted with 2-ethyl-1, 3-propanediol to dioxane 6. For this purpose, 44.5 g (110 mmol) of the aldehyde 5 and 12.0 g (115 mmol) of the diol 6 are dissolved in 250 ml of toluene, treated with 400 mg of p-Toluolsulfonsäuremonohydrat and until complete conversion of the aldehyde (DC) on a water heated to reflux. The cooled batch is washed three times with sat. Washed sodium bicarbonate solution, concentrated and passed through silica gel (toluene / heptane 7: 3, toluene, toluene / ethyl acetate 95: 5). The product-containing fractions are concentrated and the residue recrystallized at -20 ⁰ C from ethanol. Mp .: 88 ⁰ C.

Claims

claims 1. Process for the preparation of tetrahydropyran derivatives of the formula I.

characterized in that in a reaction step Compounds of the formula II

reacting at the keto function with reagents having a nucleophilic carbon atom ("C-nucleophiles"), wherein in formulas I and II independently of one another, same or different, R ¹ and R ^{2 are} H, halogen, CN, NCS, SF ₅ , aralkyl, -O-aralkyl or an unsubstituted or mono- or polysubstituted by identical or different halogen or CN substituted alkyl radical having 1 to 15 carbon atoms, wherein in this Rest and one or more CH ₂ groups by -C≡C-, -CH = CH-, -O-, -S-, -C (O) O- and / or -OC (O) - may be replaced so such that heteroatoms (O, S) are not directly linked to one another, A ¹ , A ² , A ³ , A ⁴ , A ⁵ , A ⁶ 1, 4-phenylene (which is 0-4 times independently of one another by halogen, CH ₃ , CF ₃ , CHF ₂ , CH ₂ F, OCH ₃ , OCHF ₂ , OCF ₃ may be substituted and wherein a ring CH may be substituted 0-2 times by N), cyclohexane-1, 4-diyl (CH ₂ can be 0-2 times independently by O or S and / or 0-10 times be substituted by F), cyclobutane 1, 4-diyl, bicyclo [1.1.1] 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 , Z ^{6 are} independently, same or different, a single bond, -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 a, b, c, d, e, f is O or 1, where R ¹ , R ² , A ^{1 "6} , Z ^1'6 and ac in the formulas I and II can each assume the same or different meaning. 2. The method according to claim 1, characterized in that in a reaction step, a keto compound of the formula II and a metal-containing compound of the formula III

to a compound of formula IV R ¹ 4-A ¹ -Z ^ A ² -Z ^ A ³ -zH _F {34 ^ ^z4 - ^Ai ^ fz ⁵ -A ⁵ -fefz ⁶ -A ⁶ -tR ² IV in formulas III and IV, independently of one another, the same or different, M is a metal, a metal halide, a metal with another organic radical or any cation of an ion pair with ⁽⁾ [(Z ⁴ -A ⁴ ) _d - (Z ⁵ -A ⁵ ) _e - (Z ⁶ -A ⁶ ) _f -R ² ] as an anion, and n is 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 each independently defined in claim 1. 3. The method according to claim 1 or 2, characterized in that the reaction product of formula IV by dehydration Compounds of formula Va or Vb ^ + A ^ 4 ^ A ² -Z ^ A ³ -zHr (> ^^ A ^ Z ⁵ -A ⁵ -tz ⁶ -A ⁶ iR ² Va R ^ A ^^ A ^ Z ^ A ^ ZZ ^^ Z ^ A ^ Z ^ R ² Vb wherein 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 , A ³ , A ⁴ , A ⁵ and A ⁶ are independently defined in formulas Va and Vb as in claim 1 for formula I. 4. The method according to one or more of the preceding claims, characterized in that the compounds of formulas Va and / or Vb are converted by at least one hydrogenation to compounds of formula I. 5. The method according to one or more of the preceding claims, characterized in that a compound of formula III is an organometallic compound with M is Li, Na or HaIMg when n is 1, wherein Hal is I, Br or Cl, or with M equal to Mg, when n is equal to 2. 6. The method according to one or more of the preceding claims, characterized in that a keto compound of the formula II and a phosphoryl compound of the formula VI, R ³ ₃ P = CHOR ⁴ VI where R ^{3 is} an aryl radical and R ^{4 is} an organic radical, converted into an enol ether compound, hydrolyzed to an aldehyde and then the aldehyde with a 1, 3-diol compound of the formula IX

to form a compound of formula I, wherein - [Z -A] _d - in formula I O ^ is a dioxane group of the formula - () - and where in O- ⁷ Formula IX R ² , A ⁵ , A ⁶ , Z ⁵ , Z ⁶ , e and f are as defined in claim 1 for formula I. 7. Process for the preparation of aldehydes of the formula VIII,

characterized in that a compound of the formula according to claim 1

with a suitable Wittig reagent to compounds of formula VII

and then hydrolyzed to an aldehyde compound of the formula VIII, where a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in the Formulas VII and VIII have the same meaning as in claim 1 for formula I. 8. The method according to one or more of the preceding ^ claims using aldehydes of the formula VIII or of Aldehyde precursors of the formula VII as intermediates, characterized in that the aldehyde VIII via a Wittig reaction with a phosphorus ylide to build (optionally substituted) alkenyl groups or for the construction of subsequent hydrogenation of ⁵ alkenyl group (optionally substituted) alkyl groups is used. 9. A process for the preparation of Tetrahydropyranonen of the formula II as defined in claim 1, characterized in that oxidizing a compound of formula X in a reaction step ^0,

⁵ wherein a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in the formula X as in Claim 1 are defined. 10. The method according to one or more of the preceding Claims, characterized in that in a 0 Reaction step, a 2-substituted 3,4-dihydro-2H-pyran of the formula xl

by hydroboration into a compound of formula X according to Claim 9, wherein a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ^{3 are defined} in the formula Xl as in claim 1. 11. A process for the preparation of compounds of the formula I or II according to one or more of the preceding claims Lactones of the formula XII, O " ¹ + A ^L z4rh ^a -z4ϊKz ³ -k {> XII characterized in that one converts the lactone XII in a reaction step by reduction of the keto group to the OH group and elimination in dihydropyran intermediates of formula Xl, wherein a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ^{3 are defined} in the formula XII as in claim 1. 12. Compounds of the formula II ^K '+ ^AA ' - ^Z ^ ^A ^ -i ^O when R ¹ is methyl, a + b + c is 1, 2 or 3, and wherein a, b, c, R ¹ , Z ¹ , Z ² , Z ³ , A ¹ , A ² and A ³ in of formula II as defined in claim 1. 13. Use of compounds of the formula II according to claim 12 for the preparation of 2,5-disubstituted pyran derivatives.