CN101180285B - Formyltetrahydropyrans, method for the production thereof and use thereof in the production of liquid crystal compounds - Google Patents

Formyltetrahydropyrans, method for the production thereof and use thereof in the production of liquid crystal compounds Download PDF

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CN101180285B
CN101180285B CN2006800180648A CN200680018064A CN101180285B CN 101180285 B CN101180285 B CN 101180285B CN 2006800180648 A CN2006800180648 A CN 2006800180648A CN 200680018064 A CN200680018064 A CN 200680018064A CN 101180285 B CN101180285 B CN 101180285B
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E·珀奇
V·迈尔
W·宾德尔
L·利曹
K·耶尔林
K·布雷克
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Merck Patent GmbH
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Abstract

The invention relates to formyltetrahydropyrans comprising mesogenic substituents, to a method for the production thereof and to the use thereof for producing substituted tetrahydropyran derivatives.

Description

Formyl radical tetrahydropyrans, Its Preparation Method And Use
Technical field
The present invention relates to have mesomorphic (mesogenic) substituent formyl radical tetrahydropyrans, relate to its preparation method, and relate to it for the preparation of the purposes of the tetrahydropyran derivatives that replaces.
Background technology
Have amylene oxide ring and play an important role in organic chemistry as the compound of the center integral part of molecule, for example as the composition of natural or synthetic fragrance matter, medicine or mesomorphic or liquid crystalline cpd, or as the precursor for the synthesis of these materials.
Liquid crystal material has the cyclohexane ring in the Isosorbide-5-Nitrae of bar-shaped one-piece construction inside-replacement usually.If these cyclohexane rings are had 2 of any required orientation, the tetrahydropyrans unit that 5-replaces substitutes, and then depends on the orientation of electronegativity Sauerstoffatom and decides, and can cause the promising change for the overall physical properties of described molecule.Especially, for positive dielectricity (Δ ε＞0) and for the compound of bearing dielectricity (Δ ε＜0), all can obtain the increase of the anisotropy (Δ ε) of electric constant.The example of positive value delta ε is open in EP 1482019 A1, finds comparably the increase of negative Δ ε value in the compound in being disclosed in BP 0967261A1.The reduction of the absolute value of Δ ε is tetrahydropyrans unit by having opposite orientation but can expect equally.
The increase of positive Δ ε, for example, for the IPS type (
Figure S2006800180648D00011
) liquid-crystal display in use be favourable, the VA type that is increased in of negative Δ ε (
Figure S2006800180648D00012
) liquid-crystal display in be favourable.
Linear 4-replacement (the calimitic shape is shaft-like or bar-shaped) formyl radical hexanaphthene is valuable intermediate for the preparation of the liquid crystal product that comprises cyclohexane ring.The salient point of formyl radical is its general reactivity, particularly for the chain extension that is used for making up carbon skeleton and is used to form ethylidene ether structure.Therefore; the liquid crystal of high value-added or the preparation of mesomorphic end product can be by the formyl radical hexanaphthenes; utilize Wittig reaction (for example EP 0122389 A2, DE 3509170 A1, WO 95/30723A1) or by with 1; the condensation reaction of 3-dihydroxy compound (for example EP 0433836 A2, DE 3306960 A1) is carried out.
Have been found that now the formyl radical derivative also is valuable intermediate for the derivatize of amylene oxide ring.DE 3306960 A1 have described the separation structure of formula Ia
Figure S2006800180648D00021
Yet disclosed implementation method (embodiment 14) has a lot of steps and relates to unsettled (partly) acetal intermediates, and it causes poor and unrepeatable yield.In addition, be not disclosed in therein and have formyl radical on 2 and have other substituent material at 5.In addition, document up to now only the people such as P.Kocienski (Synthesis (1991), 11, comprise the compound of a kind of formula Ib in 1029-38).
Figure S2006800180648D00022
DE 3306960 A1 disclose aldehyde can be by being carried out oxidation or reduce the idea for preparing by carboxylic acid by alcohol, but do not disclose any embodiment.
Have been found that some dihydropyrane compound is suitable as the raw material of preparation formyl radical tetrahydropyrans, only having seldom in the described formyl radical tetrahydropyrans, number is known.In order to mention the known typical material with linear structure, (2S)-2-(4-fluorophenoxy methyl)-3,4-dihydro-2H-pyrans is by the people such as M.K.Gurjar (Synthesis (2000), 4,557-60) preparation, 3-(2-benzyloxy ethyl)-3,4-dihydro-2H-pyrans is by the people such as A.P.Kozikowski (J.Chem.Soc.Chem.Commun. (1980), 11,477-9) preparation.Also describe simple 2-alkyl or the 3-alkyl derivative of 3,4-dihydro-2H-pyrans, do not related to liquid crystal.Up to now, the dihydropyrane that alkyl (alkylidene group) replaces is known, and is such as from people such as C.Fehr, known among Helv.Chim.Acta (1981) 65, the 1247-56.
Other purpose is the preparation method that increases the formyl radical tetrahydropyrans of the linearity replacement with variable pyranoid ring orientation, and its synthetic method is provided.Formed aldehyde is inserted into existing and novel for the preparation of in 2,5-, two substituted-tetrahydro pyrylium compounds synthetic, and described synthetic end product can be used as for example mesomorphic or liquid crystalline cpd.
Summary of the invention
Described purpose is the preparation method of the formyl radical tetrahydropyrans of through type II and reaching according to the present invention,
Wherein, in formula II,
A 4Expression
Figure DEST_PATH_GSB00000828898200012
A, b, c represent 0 or 1 independently of one another, and wherein a+b+c equals 0,1,2 or 3;
A 1, A 2, A 3Independently of one another, identical or different ground is also through rotation or one-tenth mirror image ground, expression
Figure DEST_PATH_GSB00000828898200013
Figure DEST_PATH_GSB00000828898200014
One of them is substituted by N to two C atoms are optional,
Figure DEST_PATH_GSB00000828898200015
Figure S2006800180648D00036
Substitute; With
Y 1, Y 2And Y 3Represent independently of one another hydrogen, halogen, CN, NCS, SF 5, C 1-6Alkyl (alkanyl), C 2-6Thiazolinyl, C 2-6Alkynyl, OC 1-6Alkyl, OC 2-6Thiazolinyl or OC 2-6Alkynyl, wherein aliphatic group is unsubstituted or by halogen list or polysubstituted; With
Z 1, Z 2, Z 3Represent singly-bound, have the alkylidene bridge of 1 to 6 carbon atom, this alkylidene bridge is unsubstituted or single or polysubstituted by F and/or Cl, or-CH 2O-,-OCH 2-,-(CO) O-,-O (CO)-,-CF 2O-,-OCF 2-,-CH 2CH 2CF 2O-or-OCF 2CH 2CH 2-,
N1 is 0,1,2,3 or 4;
N2 and n3 are 0,1,2 or 3 independently of one another;
N4 is 0,1 or 2;
W 1Expression-CH 2-,-CF 2-or-O-;
R 1Expression H, halogen, CN, NCS, SF 5, CF 3, OCF 3, NH 2, boric acid ester, have the alkyl of 1 to 15 C atom, it is unsubstituted or is replaced or by halogen list or polysubstituted by CN is single, wherein, in addition, the one or more CH in these groups 2Group can be separately independently of one another by-C ≡ C-,-CH=CH-,-O-,-S-,-SO-,-SO 2-,-O (CO)-or-(CO) O-with the heteroatoms in described chain each other not direct-connected mode substitute,
And it is characterized in that
A) with the compound hydroformylation of formula III a, IIIb and/or IIIc,
Figure S2006800180648D00041
Or
B) with the compound of formula IV
R 1
Figure 2006800180648_24
A 1-Z 1
Figure 2006800180648_25
a A 2-Z 2
Figure 2006800180648_27
b
Figure 2006800180648_28
A 3-Z 3
Figure 2006800180648_29
cA 4-R 3 IV
Comprise that by IV one or more the reaction of at least one reduction step reacts,
Wherein
R 3Expression CN, COOH, CONHR 4, COOR 4, and R 4Expression alkyl, aralkyl or (optional replacement) aryl,
Perhaps
C) with the aldehyde of the pure oxidation accepted way of doing sth II of formula V
R 1
Figure 2006800180648_30
A 1-Z 1
Figure 2006800180648_31
a
Figure 2006800180648_32
A 2-Z 2
Figure 2006800180648_33
b A 3-Z 3
Figure 2006800180648_35
cA 4-CH 2OH V
Wherein, in formula III a-c, IV and V,
A 1, A 2, A 3, A 4, Z 1, Z 2, Z 3, a, b, c and R 1Has the implication of pointing out for formula II.
Method of the present invention is so that the tetrahydropyrans aldehyde of formula II can be from the intermediate of formula III a-c, IV or V, by means of that be easy to obtain and reagent cheapness, obtains with simple mode, good yield and high chemistry and stereoselectivity.Described aldehyde be synthetic many kinds different separately or in mixture, be used as the useful intermediate of the compound of liquid crystal material.Described aldehyde can also as hydrate forms, as with the adducts of sulfite or with their acetal form prepare, separate, purifying or use.
Therefore the present invention also comprises the aldehyde of formula II, does not wherein comprise the compound of following formula
With
Figure S2006800180648D00052
Preferred compound is mentioned hereinafter or the preferred form relevant with one or more preparation methods of the compound of formula II or one or more purposes is consistent.
Preferred preparation formula II compound is characterized in that, independently of one another,
A 4Expression
Figure S2006800180648D00053
R 1Expression F, OCF 3, CF 3, OCF 2H, SF 5,
A 1And A 2Represent independently of one another Isosorbide-5-Nitrae-phenylene, 2,5-two fluoro-Isosorbide-5-Nitrae-phenylenes or 2-fluoro-Isosorbide-5-Nitrae-phenylene,
A, b equal 1,
C equals 0, and/or
Z 1Be singly-bound ,-CF 2O-,-OCF 2-,-(CF 2) 2-,-CH 2CF 2-,-CF 2CH 2-,-CH 2CH 2CF 2O-or-OCF 2CH 2CH 2-.
The compound of same preferred preparation formula II is characterized in that
R 1Expression F, Cl, Br, boric acid ester or have the alkyl of 1 to 15 C atom, this alkyl be unsubstituted or replaced or by halogen list or polysubstituted by CN is single, wherein additionally, and the one or more CH in these groups 2Group can be separately independently of one another by-C ≡ C-,-CH=CH-,-O-,-S-,-SO-,-SO 2-,-(CO) O-or-O (CO)-with the heteroatoms in described chain each other not direct-connected mode substitute, and
A 1, A 2And A 3Expression Isosorbide-5-Nitrae-phenylene, 2,3-two fluoro-Isosorbide-5-Nitrae-phenylenes, 2-fluoro-Isosorbide-5-Nitrae-phenylene or 3-fluoro-Isosorbide-5-Nitrae-phenylene, and
A, b and c are 0 or 1 independently of one another.
The compound of preparation formula A-G very particularly preferably
Figure S2006800180648D00061
Wherein, X 2Expression F or OCF 3, and
G represents 0,1 or 2, and alkyl is such as hereinafter definition.
Corresponding to the preferred preparation method of institute, suitable raw material with variant a), b) and c) use.
In the first embodiment of the present invention (a), tetrahydropyrans aldehyde II is formed by the dihydropyrane of formula III a-c.In the preferred embodiment of (a), in hydroformylation reaction, preferably utilize in the catalytic hydroformylation of the gaseous mixture that comprises hydrogen and carbon monoxide, carry out the conversion to described aldehyde.In the embodiment of alternative, use silane containing hydrogen (hydrosilane) to substitute hydrogen, wherein formed silene alcohol ether can easily be converted to corresponding aldehyde.In preferred embodiments, adopt those of transition-metal catalyst, particularly transition metal rhodium (Rh), ruthenium (Ru) or the cobalt (Co) be applicable to hydroformylation.The metal core of described catalyzer can have multiple ligands at the central atom of described transition metal, for example has CO (Brennstoffchemie (1966), 47,207), phosphine (J.Organomet.Chem. (1977), 124,85), phosphine oxide (J.Chem.Soc.Chem.Commun. (1994), 115; J.Organomet.Chem. (1995), 488, C20-C22) and phosphorous acid ester (J.Organomet.Chem. (1991), 421,121; The same (1993), 451, C15-C17).Particularly preferred catalyzer is the rhodium compound that has the cobalt compound of carbonyl ligands or have phosphorus-containing ligand.Described catalyzer can also be by processing suitable commercially available (precursor) salt with respective ligand, for example Rh (I) salt is (referring to, Strem catalogue No.20, StremChemicals Inc., Kehl, Germany), Rh (I) acac (CO) for example 2(acac=acetylacetonate), Rh (I) acac (COD) (COD=1,5-cyclooctadiene), [RhCl (COD)] 2Or [RhCl (CO) 2] 2And form at the reaction mixture situ, in the situation that these salt for example, adopt triphenylphosphine or three (o-tert-butyl phenyl) phosphorous acid ester of 2 to 10 times of molar weights.(specific embodiments of the water of load=SAP) also can be used for described hydroformylation reaction in (Angew.Chemie (1993), 105,1588) known two-phase or multiphase catalysis from document.Therefore, has hydrophilic substituent, for example OH, NH 2, COOH, SO 3The dihydropyrane of the formula III a-c of H can be in water-based/organic two-phase system, at HRh (CO) (tppts) 3Under the existence of (three sulfonate sodiums of tppts=triphenylphosphine) by hydroformylation.The hydroformylation of the lipophilic raw material of formula III a-c can for example advantageously utilize so-called SAP catalyzer to carry out; described SAP catalyzer is comprised of the particulate porous support material with large internal surface area, and catalyst complexes is distributed by absorption or distributes as form of film on described internal surface area.The fixing catalyst system of such carrier can preferably utilize HRh (CO) (tppts) 3Or Co 2(CO) 6(tppts) 2Preparation also is used for described hydroformylation.
The feature of the method for the hydroformylation of substrate II especially is, described catalysis utilizes the transition metal complex of metal rhodium or cobalt to carry out, and described title complex is comprised of the cobalt compound with carbonyl or rhodium compound with phosphorus-containing ligand.If with cobalt octacarbonyl; or has a P part; for example the Rh title complex of three (o-tert-butyl phenyl) phosphorous acid esters or triphenylphosphine then can become compound III a the aldehyde of corresponding formula II as catalyzer with IIIc hydroformylation under high regioselectivity.Yet it is not satisfied that the hydroformylation of compound III b becomes the regioselectivity of corresponding aldehyde II.Even when using relatively low temperature (40 to 60 ℃) and on the Rh catalyzer during low mole part ratio (be 2 to 4 times about phosphorous acid ester or phosphine), acquisition is roughly the regional isomer (people such as A.Polo of 1: 1 ratio, J.Chem.Soc., Chem.Commun.1990,600).The hydroformylation of therefore preferred derivative III a or IIIc, particularly IIIa.
In second embodiment of the present invention (b), tetrahydropyrans aldehyde II prepares from carboxylic acid derivative IV, particularly free carboxy acid, carboxylicesters, acid amides or nitrile of operable raw material wherein, what perhaps other had a carbon atom is in identical oxidation state (+III) compound in this position.Particularly preferably use in this embodiment the method for the raw material of nitrile and alkyl ester type, described raw material is the compound of formula III very particularly, wherein R 3The expression CN or-C (O) O-alkyl, wherein alkyl represents again methyl, ethyl, sec.-propyl, the tertiary butyl or benzyl especially.In the preferred embodiment of (b), by means of reducing metal, metal hydride, alkyl metal cpd or low price boron compound, formula IV compound is reduced, this has been avoided described aldehyde further to be reduced to alcohol, particularly preferably metal hydride and/or hydroborons, it can be with other alkyl, amino, halogen or alkoxyl group.In particularly preferred embodiments, in being reduced to the method for described aldehyde, use diisobutyl alanate (DIBAL-H), for example by E.Winterfeldt in Synthesis (1975), 9, described in 617-630 and the document quoted in this article like that, the perhaps lithium aluminum hydride that replaces of other dialkyl aluminum hydride or amino or alkoxyl group, for example LiAlH (NH 2) 2And LiAIH (O-t-Bu) 3Be known on the described methodological principle and be found in the classic, J.March for example, Advanced Organic Chemistry, the 4th edition, Wiley, among the New York (1992) as embodiment and reference.
In the 3rd embodiment (c), by means of the aldehyde of oxidising agent with the alkylol cpd oxidation accepted way of doing sth IV of formula V.In the preferred variants of the method, described oxidation is carried out by means of the method for oxidation that can avoid over oxidation to become carboxylic acid or to be oxidized to carboxylicesters, particularly by means of using CrO 3Or chromic salt (VI) (chromic acid pyridine particularly
Figure 2006800180648_36
), periodinane (cross iodine alkane) type organic iodine reagent (Dess-Martin oxidation), DMSO/DCC (Pfitzner-Moffatt oxidation), DMSO/ oxalyl chloride (Swern oxidation), acetone/Al (O-alkyl) 3The method of (Oppenauer oxidation) or NaOCl (by 2,2,6,6-tetramethyl piperidine N-oxide compound (TEMPO) or by transition-metal catalyst catalysis).Following reference conduct provides about the representative of the known technical literature of mentioned reaction type:
CrO 3Oxidation: (a) J.C.Sauer in " Organic Synthesis ", John WileySons, New York (1963), Coll.Vol.4,813; B) people such as G.R.Rasmusson, the same (1973), Coll.Vol.5,324; C) R.W.Ratcliffe; The same (1988), Coll.Vol.6,373; D) J.C.Collins, W.W.Hess, the same (1988), Coll.Vol.6,644; E) people such as B.Khadilkar, Synth.Commun. (1996), 26,205.
Dess-Martin oxidation: a) D.B.Dess, J.C.Martin, J.Org.Chem. (1983), 48,4155; J.Amer.Chem.Soc. (1991), 113,7277; B) people such as A.Speicher, J.Pract.Chem. (1996), 338,588.
Pfitzner-Moffatt oxidation: J.G.Moffat in " Oxidation (oxidation) ", the 2nd volume, R.L.Augustine and D.J.Trecker-editor are Marcel Dekker, NewYork, 1971,1-64 (use DMSO/DCC).
Swern oxidation: a) A.K.Sharma, D.Swern, Tetrahedron Lett. (1974), 1503; B) people such as D.Swern, J.Org.Chem (1976) 41, and 3329; C) P.
Figure S2006800180648D00091
R.Whitby, Synthesis (1991), 1029.
Oppenauer oxidation: C.Djerassi in " Organic Reactions (organic reaction) ", John Wiley Sons, New York (1951), the 6th volume, 207.
The NaOCl oxidation, Ru or TEMPO-catalysis: a) R.J.Crawford, J.Org.Chem. (1983) 48, and 1367; B) people such as P.L.Anelli, Org.Synth. (1990), 69,212.
Figure S2006800180648D00092
Mention 2-formyl radical tetrahydropyrans Deng the Swern oxidation of the corresponding methyl alcohol of describing among the people.
Alkylol cpd V is usually by standard method, prepares by reduction from nitrile and the carboxylic acid derivative of formula IV.Strong reductant, for example LiAlH 4, can be used for this purpose.
The invention still further relates to the preparation of 2-or the dihydropyrane compound that 3-replaces of formula III a-c, particularly IIIb and IIIc, described compound astoundingly simple mode prepares (scheme 1-3) from corresponding homoallylic alcohol through intermediate.
The novel cpd of formula III b and IIIc is a part of the present invention.Known 2-substituted-dihydro pyrans is to derive from the people such as C.Fehr up to now, Helv.Chim.Acta (1981) 65, the dihydropyrane that the alkyl of 1247-56 (alkylidene group) replaces, with derive from the people such as M.K.Gurjar, Synthesis (2000), the compound of the following formula among 4, the 557-60
They are produced and do not relate to liquid crystalline cpd.The dihydropyrane of known 3-replacement is to derive from such as people such as P.Kocienski up to now, J.Chem.Soc.Perkin Trans. (1985), the dihydropyrane that the alkyl of 1879-84 replaces.
The compound of formula III b of the present invention and IIIc:
Figure S2006800180648D00102
Be characterised in that:
If a, b, c are 0 simultaneously,
R then 1Halogen, CN, NCS, SF 5, CF 3, OCF 3, NH 2, have an alkyl of 1 to 15 C atom, this alkyl is replaced or by halogen list or polysubstituted by CN is single, wherein additionally, the one or more CH in these groups 2Group can be separately independently of one another by-C ≡ C-,-CH=CH-,-O-,-S-,-SO-,-SO 2-,-COO-or-OCO-with the heteroatoms in described chain each other not direct-connected mode substitute, and if, for IIIb, a=1 and b+c=0 and A 1Equal Isosorbide-5-Nitrae-phenylene, then Z 1Be not equal to-OCH 2-or-CH 2CH 2-.
A preferably 1,2 or 3.A is in 0 the situation therein, R 1Preferred expression has the alkyl of 1 to 15 carbon atom, and this alkyl is by fluorine list or polysubstituted, wherein additionally, and the one or more CH in these groups 2Group can be separately independently of one another by-C ≡ C-,-CH=CH-,-O-,-S-,-SO-,-SO 2-,-COO-or-OCO-with the heteroatoms in described chain each other not direct-connected mode substitute.
In the first kind of way of the dihydropyrane compound of preparation formula IIIa-c, the homoallylic alcohol that 1-replaces is located by allylation in free OH group, and the diolefin of open chain changes into 3 of 2-replacement, 6-dihydro-2H-pyrans by means of the closed loop olefin metathesis reactions of following ethylene molecule to eliminate.In the preferred embodiment shown in scheme 1, the dihydropyrane IIIa that 2-replaces is that intermediate VII obtains by the O-allylation the synthetic method that the homoallylic alcohol from formula VI begins.In the second reactions steps, VII changes into VIII by the closed loop metathesis reaction.The closed loop transposition of described alkene preferably by means of the ruthenium with Cabbeen or phosphine part-methylene radical catalyzer (such as by means of as various " the Grubbs catalyzer " described by people such as Grubbs), or the variant of novel improved and carrying out.
The allylation of VI for example utilizes to be adopted the nicellar catalysis of allyl halide and carries out (B. in the presence of the hexadecyl trimethylammonium bromide in tetrahydrofuran (THF) and a small amount of water
Figure S2006800180648D00111
Deng the people, Tetrahedron (1988) 44, and 6677).
Figure S2006800180648D00112
Scheme 1. prepares 3 of 2-replacement, 6-dihydro-2H-pyrans through metathesis reaction
In the second way of described operation process, the homoallylic alcohol that 1-replaces usually experiences hydroformylation and then or simultaneously carries out closed loop, forms hemiacetal.From the tetrahydropyrans that formed OH-replaces, eliminate the OH group with adjacent proton and advantageously obtain 3 of required 2-replacement, 6-dihydro-2H-pyran derivate.In preferred embodiments, use the homoallylic alcohol of formula VI, its as shown in the scheme 2 like that, hydroformylation, hemiacetal form and the elimination of formed OH group after obtain the variant of the 2-replacement of dihydropyrane IIIb.Described OH group is eliminated or is eliminated after changing into leavings group as the form of water, particularly preferably is eliminated after p-toluenesulfonic esters changes into leavings group by changing into methanesulfonates or changing into.
Figure S2006800180648D00121
Scheme 2. is passed through 3 of the standby 2-replacement of Wuts legal system, 4-dihydro-2H-pyrans
Two reactions steps describing in scheme 2 can in succession be carried out or be carried out in the reaction sequence that merges.Described hydroformylation is followed in principle from the known in the literature method, particularly based on the people such as Wuts (Tetrahedron Lett. (1984), 25, laboratory 4051-4) is synthetic.Used rhodium catalyst, the rhodium acetate dimer obtains good selectivity and easy handling.In principle, from other commercially available rhodium catalyst of described known in the literature or organo-metallic cobalt catalyst, particularly cobalt-carbonyl, also can be used for substituting the rhodium acetate that is easy to obtain.
In the third mode of preparation dihydropyrane, homoallylic alcohol experience hydroformylation and closed loop that the 2-of formula XII replaces are to obtain the compound of formula XIII.The subsequently elimination of the OH group on XIII obtain that the 3-of formula III c replaces 3,4-dihydro-2H-pyrans (scheme 3).
Figure S2006800180648D00131
3 of scheme 3. preparation 3-replacements, 4-dihydro-2H-pyrans
The commentary identical with the substrate VI that replaces for the 2-according to scheme 2 is applicable to adopt the simultaneously hydroformylation of closed loop.
The process that OH group in compounds X and XIII is eliminated be eliminated respectively product IIIb and IIIc is to be undertaken by the elimination that is similar to people's (J.Am.Chem.Soc. (1991), 113,5337-53, scheme 3) such as Boeckman.For this purpose, for example, use methylsulfonyl chloride and triethylamine to carry out methylsulfonyl described OH group, and eliminate by the heating of gentleness immediately afterwards.Tosyl chloride is equally applicable to the formation of leavings group.
Particularly preferably from the method for the compound of the compound preparation formula II of formula III b or IIIc.They are characterised in that, the compound of formula III b or IIIc can be respectively from the compound as shown in the formula X or XIII, by direct elimination hydroxyl or after changing into leavings group, eliminate and prepare,
Figure S2006800180648D00132
A wherein 1, A 2, A 3, Z 1, Z 2, Z 3, a, b, c and R 1Have as for formula II to implication.
In preferred operating process, the compound of formula X and XIII from the compound of formula VI and XII, prepares by hydroformylation step and closed loop respectively,
Figure S2006800180648D00141
A wherein 1, A 2, A 3, Z 1, Z 2, Z 3, a, b, c and R 1Have as for formula II to implication.
The homoallylic alcohol of formula VI and XII is well known in the prior art, and is commercially available, perhaps can be easily by self preparing from the known in the literature synthetic method.
Scheme 4 shows the homoallylic alcohol that replaces from the synthetic 1-of aldehyde.In this is synthetic, for example, with allyl group-Grignard reagent and aldehyde reaction.Described aldehyde is again known compound or can for example obtains by the method based on the inventive method.
Figure S2006800180648D00142
The homoallylic alcohol that scheme 4. preparation 1-replace
Scheme 5 has been summarized the route of synthesis that begins to prepare the variant that the 2-of homoallylic alcohol replaces from the allyl halide derivative of formula XVI:
Figure S2006800180648D00151
The homoallylic alcohol that scheme 5. preparation 2-replace
The preparation example of XVI is as can be from aldehyde R 1-[A 1-Z 1] a-[A 2-Z 2] b-[A 3-Z 3] c-CHO begins, and is for example synthetic to obtain unsaturated ester by Reformatsky
R 1-[A 1-Z 1] a-[A 2-Z 2] b-[A 3-Z 3] c-CH=CH-CO 2-alkyl uses subsequently DIBAL-H to reduce and obtains corresponding vinyl carbinol R 1-[A 1-Z 1] a-[A 2-Z 2] b-[A 3-Z 3] c-CH=CH-CH 2OH, and use at last PBr 3(Hal=Br), PCl 5Or SO 2Cl 2(Hal=Cl) or HI (Hal=I) carry out halogenation, from XVI, obtain compounds X VII with suitable metal or organometallic reagent reaction; Wherein " Met " depends on used metal or organometallic reagent and decides, expression Cu, Bi (group) 2, In (group) 2, Sn (group) 3, Sn (group), Zn (group), Ge (group), wherein " group " is illustrated in one or more organic groups, part or the gegenion on the described metal.The further reaction that XVII and formaldehyde (perhaps synthetic equivalent) carry out, also can carry out not adopting in the situation of isolating in advance the XVII that forms as intermediate forms, this reaction obtains the homoallylic alcohol of needed formula XII after accordingly aftertreatment.
Other method of the homoallylic alcohol of acquisition formula XII realizes as shown in the scheme 6; " Hal " has as above implication identical in scheme 5 here; " Met " be Cu (referring to A.Carpita, R.Rossi, Synthesis (1982), 469) preferably:
Figure S2006800180648D00161
Scheme 6.2-replaces the alternative preparation method of homoallylic alcohol
With halogenide XVIII-changing into Organometallic derivatives XIX corresponding to the mode of the operation steps in scheme 4-suitable reagent of employing, its subsequently with the XX reaction, obtain the high allyl ester XXI of acetic acid.Then the homoallylic alcohol of needed formula XII can be obtained by XXI by means of saponification.
In addition, the homoallylic alcohol of formula XII, wherein R 1-[A 1-Z 1] a-[A 2-Z 2] b-[A 3-Z 3] cThe expression alkyl, the alkylogen R of two negatively charged ion that also can be by utilizing accordingly β-crotonic acid 1-[A 1-Z 1] a-[A 2-Z 2] b-[A 3-Z 3] cThe alkylation of-Hal and subsequently utilize LiAlH 4Reduction and obtain.This two negatively charged ion is by β-crotonic acid, for example by diisopropylaminoethyl lithium (LDA) reaction with 2 equivalents obtain (referring to, P.E.Pfeffer, L.S.Silbert, J.Org.Chem. (1971), 36,3290; R.H.van der Veen, H.Cerfountain, J.Org.Chem. (1985) 50 342).
Synthetic as the reference of carboxylic acid derivative that is used for being reduced into the formula IV of aldehyde is carried out summarizing in the common example of scheme 7 and 8.MES here represents such as the mesomorphic group R in formula IV 1-[A 1-Z 1] a-[A 2-Z 2] b-[A 3-Z 3] c-.Described ester group can also be by for R among the formula IV 3The substituting group of pointing out substitutes.In two examples, formula IV compound (being described by exemplary compounds X XIV and XXVII) obtains by the hydrogenation of closed loop metathesis reaction from the precursor of the corresponding replacement of formula XXII or XXV and described metathesis product subsequently.For these or similar diolefin, as obtaining the precursor of formula XXII and XXV described in the EP1482019 A1.Perhaps, the vinyl carbinol HO-CH (MES) of the compound of formula XXII by utilizing corresponding acrylic compound and carry out-CH 2CH=CH 2Alkylation obtain.
Figure S2006800180648D00171
The preparation method of scheme 7. formula XXIV compounds is as the preparation method's of general formula I V compound variant
Figure S2006800180648D00172
The preparation method of scheme 8. formula XXVII compounds is as the preparation method's of general formula I V compound variant
Typical material (the R that the cyano group of formula IV replaces 3=CN) for example can indirectly obtain by dihydropyrane IIIc.These can be similar to and utilize gaseous hydrogen chloric acid to unsubstituted 5, and the chlorination of 6-dihydro-4H-pyrans is carried out like that chlorination and then utilized AgCN (people such as B.A.Nelson, J.Org.Chem. (1956), 21,798) or at SnCl 2Existence under transform the cyano compound of accepted way of doing sth IV by means of trimethylsilyl cyanide people such as (, Tetrahedron (1983), 33,961) M.Reetz.
Therefore the method for the tetrahydropyrans aldehyde of especially preferred preparation formula II is characterised in that, hydrogenation by dihydropyran derivatives prepares the formula IV compound that is intended to for reduction accepted way of doing sth II compound, and described dihydropyran derivatives is again from the diene preparation of suitable replacement by the catalysis closed loop transposition of following the ethene elimination.
The tetrahydropyrans aldehyde of formula II can be used for preparing other mesomorphic or liquid crystal tetrahydropyran derivatives.Aldehyde cpd II is preferred for synthetic addition or the condensation product that is used for making up mesomorphic structure aldehyde group partly.Described aldehyde group is particularly preferred for making up 5 to 6 yuan of ring systems, very especially for the ring that makes up other amylene oxide ring or 1,3-dioxane.
Therefore, the preferred purposes of the aldehyde of formula II is characterised in that, adopts 1,3-glycol to react and obtains dioxane.This is undertaken by self known method, as as described in the literature (for example, in the classic of synthetic organic chemistry, Houben-Weyl for example, Methodender organischen Chemie (organic chemistry method), Georg-Thieme-Verlag, Stuttgart).Described 1, the 3-glycol preferably on position 2 by simple substituting group R for example 1(such as in formula II definition) replace, or replaced by mesomorphic group.Particularly preferably by group R for example 1Or group-A-R 1Replace A representative ring hexane-Isosorbide-5-Nitrae-two base wherein, tetrahydropyrans-2,5-two base or 1,3-dioxane-2,5-two bases.
The in addition preferred purposes of the aldehyde of formula II is characterised in that, described reaction adopts the allyl group metallic compound to carry out obtaining homoallylic alcohol as the precursor of tetrahydropyrans.Formed high allyl compound is as the raw material by the other adjacent pyranoid ring of method (the scheme 1 and 2) preparation of as above having described.
Aldehyde group in the aldehyde cpd of formula II is preferred for the chain extension by the Wittig reaction equally, and this causes forming the vinylene bridge at tetrahydropyrans.Therefore, the feature of the purposes of the aldehyde cpd of formula II particularly in, by the Wittig reaction compound from aldehyde II preparation formula IX
Figure S2006800180648D00181
Wherein,
R 1, R 2, A 1, A 2, A 3, A 4, Z 1, Z 2, Z 3, a, b, c have the pointed implication for formula II, and in each case independently of one another,
A 5And A 6As for A 1Define,
Z 5And Z 6As for Z 1Define, and
E and f are as defining for a.
In the further preferred form of the purposes of the compound of formula II, the dihydropyrane ring of the vinyl substituted that is optionally substituted is by carbonyl functional group's allylation, utilizes proyl to the etherificate of alcohol and eneyne metathesis reaction subsequently and from described aldehyde preparation (referring to EP 1482020 A1).Here described optional substituting group depends on the optional replacement of allyl group for described allylation-Grignard compound and decides.Therefore, the purposes of the aldehyde cpd of formula II feature in this case especially is the compound of preparation formula Qa,
The synthetic precursor with formula Qb or Qc of the hydrogenated products that (part) of formula Qa compound is saturated or Qa
Figure S2006800180648D00192
Wherein in Qa, Qb and Qc,
R 1, R 2, A 1, A 2, A 3, A 4, Z 1, Z 2, Z 3, a, b, c have the pointed implication for formula II, and in each case independently of one another,
A 5And A 6As for A 1Define,
Z 5And Z 6As for Z 1Define, and
E and f are as defining for a among the formula II.
A in Qa, Qb and Qc 4The ring of following formula preferably
Figure S2006800180648D00193
In this case, preferably use the compound of formula II, wherein, in relevant structural formula, independently of one another,
A 4Expression
Figure S2006800180648D00194
R 1Expression F, OCF 3, CF 3, OCF 2H, CN, SF 5,
A 1And A 2Represent independently of one another Isosorbide-5-Nitrae-phenylene, 2,5-two fluoro-Isosorbide-5-Nitrae-phenylenes or 2-fluoro-Isosorbide-5-Nitrae-phenylene,
A, b equal 1,
C equals 0, and
Z 1Be singly-bound ,-CF 2O-,-OCF 2-,-(CF 2) 2-,-CH 2CF 2-,-CF 2CH 2-,-CH 2CH 2CF 2O-or-OCF 2CH 2CH 2-.
The compound of same preferred use formula II is characterized in that,
R 1Expression F, Cl, Br, boric acid ester or have the alkyl of 1 to 15 C atom, this alkyl be unsubstituted or replaced or by halogen list or polysubstituted by CN is single, wherein additionally, and the one or more CH in these groups 2Group can be separately independently of one another by-C ≡ C-,-CH=CH-,-O-,-S-,-SO-,-SO 2-,-(CO) O-or-O (CO)-with the heteroatoms in described chain each other not direct-connected mode substitute, and
A 1, A 2And A 3Expression Isosorbide-5-Nitrae-phenylene, 2,3-two fluoro-Isosorbide-5-Nitrae-phenylenes, 2-fluoro-Isosorbide-5-Nitrae-phenylene or 3-fluoro-Isosorbide-5-Nitrae-phenylene, and
A, b and c are 0 or 1 independently of one another.
Particularly preferably use the tetrahydropyrans aldehyde of following formula A-G:
Figure S2006800180648D00201
Figure S2006800180648D00211
Wherein, X 2Expression F or OCF 3, and general following definition of alkyl.Especially, the alkyl in formula A-G represents to have straight chain, the saturated or unsaturated carbochain of 1-8 C atom.
Obtain generally preparing the method for 2,5-, two substituted-tetrahydro pyran derivates for the preparation of method according to the present invention of the aldehyde of formula II and uses thereof, particularly have the method for the derivative of following formula,
R 1
Figure 2006800180648_37
A 1-Z 1
Figure 2006800180648_38
a A 2-Z 2
Figure 2006800180648_40
b A 3-Z 3
Figure 2006800180648_42
cA 4
Figure 2006800180648_43
Z 5-A 5
Figure 2006800180648_44
e
Figure 2006800180648_45
Z 6-A 6 fR 2，
The method comprises
A) by one or more preparation formyl radical tetrahydropyranss in the aforesaid method, and
B) use described formyl radical tetrahydropyrans by one or more preparations 2,5-two substituted-tetrahydro pyran derivates in the above-mentioned embodiment of the present invention,
Wherein
R 1, R 2, A 1, A 2, A 3, A 4, Z 1, Z 2, Z 3, a, b, c have the pointed implication for formula II, and in each case independently of one another,
A 5And A 6As for A 1Define,
Z 5And Z 6As for Z 1Define, and
F is 0,1 or 2, and
E is as defining for a among the formula II.The implication of variable depends on described method and approach and decides, the restriction of being stipulated therein or directly from wherein obviously as can be known.
For purifying or as the purpose of the protection of described aldehyde in purifying, chemical reaction or storage process, the other purposes of the aldehyde of formula II is as the derivatize of hydrate or sulfite adducts form or forms acetal.
Another aspect of the present invention comprises the as defined above novel formyl radical tetrahydropyrans of formula II, and it preferably is characterised in that, independently of one another,
Z in described molecule 1, Z 2, Z 3In at least one corresponding to-CF 2CF 2-,-CF 2CH 2-,-CH 2CF 2-,-CH 2CH 2CF 2O-,-OCF 2CH 2CH 2-,-CF 2O-or-OCF 2-group, perhaps wherein
R 1Corresponding to NCS, SF 5, CF 3, OCF 3Or OCHF 2,
Perhaps wherein
A 1, A 2, A 3In at least one expression
Figure S2006800180648D00221
Or
Figure S2006800180648D00222
The aldehyde of formula IIa, IIb and IIc particularly preferably
Figure S2006800180648D00223
Wherein
R 11And R 12Expression F, CF 3, OCF 3, CN, NCS, SF 5Or have 1 to 15 C atom by halogen list or polysubstituted alkyl, wherein additionally, the one or more CH in these groups 2Group can be separately independently of one another by-C ≡ C-,-CH=CH-,-O-,-S-,-SO-,-SO 2-,-(CO) O-or-O (CO)-with the heteroatoms in described chain each other not direct-connected mode substitute,
R 13As for the R among the formula II 1It is defined such,
L 1, L 2Be H, Cl or F independently of one another, and
A 1, A 2, Z 1, Z 2, a, b have such as the definition in formula II.
The formyl radical tetrahydropyrans of very particularly preferably above-mentioned formula A, B, C, D, E, F and G.
Ground related to the present invention, term " alkyl " unless-in this specification sheets or in addition definition in claims-with straight or branched, the saturated or undersaturated aliphatic alkyl of its most general implication (namely 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15) carbon atom that represents to have 1 to 15; This group is unsubstituted or by fluorine, chlorine, bromine, iodine, carboxyl, nitro, NH 2, N (alkyl) 2And/or cyano group list or polysubstituted, wherein saidly polysubstitutedly can adopt identical or different substituting group to carry out.Alkyl self in described aliphatics hydrocarbon chain also can be through functionalized.
If this alkyl is saturated group, it is also referred to as " alkyl ".In addition, term " alkyl " also comprises following alkyl, and it is unsubstituted or is particularly correspondingly singly replaced by F, Cl, Br, I and/or CN or identical or different polysubstituted, and wherein one or more CH 2Group can by-O-(" alkoxyl group ", " oxa alkyl ") ,-S-(" alkylthio ") ,-SO 2-,-CH=CH-(" thiazolinyl ") ,-C ≡ C-(" alkynyl ") ,-(CO) O-or-O (CO)-with the heteroatoms in described chain (O, S) each other not direct-connected mode substitute.Alkyl preferably has alkyl, thiazolinyl or the alkoxyl group straight or branched, that do not replace or replace of 1,2,3,4,5,6,7 or 8 carbon atom.If alkyl represents alkyl, it is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, neo-pentyl, n-hexyl, n-heptyl, n-octyl, CF preferably 3, CHF 2, CH 2F, CF 2CF 3Described alkyl particularly preferably be straight chain with unsubstituted or replaced by F.
Because the one or more CH in alkyl 2Group can be substituted by-O-, and term " alkyl " also comprises " alkoxyl group " or " oxa alkyl ".Alkoxyl group refers to the O-alkyl, and wherein Sauerstoffatom directly is bonded on the group that is replaced by described alkoxyl group or is bonded on the substituted ring, and alkyl as defined above; So preferably alkyl or thiazolinyl of alkyl.Preferred alkoxyl group be methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy, heptan oxygen base and octyloxy, wherein each in these groups also can preferably be replaced by one or more fluorine atoms.Alkoxyl group particularly preferably is OCH 3, OC 2H 5, O-n-C 3H 7, O-n-C 4H 9, O-t-C 4H 9, OCF 3, OCHF 2, OCHF or OCHFCHF 2Ground related to the present invention, term " oxa alkyl " is expressed as follows alkyl, wherein at least one non-terminal CH 2Group is substituted in the mode that does not have adjacent heteroatoms (O, S) by-O-.Oxa alkyl preferably includes formula C aH 2a+1-O-(CH 2) b-straight chain group, wherein a and b represent 1,2,3,4,5,6,7,8,9 or 10 separately independently of one another; A particularly preferably is that 1 to 6 integer and b are 1 or 2.
If the one or more CH in alkyl as defined above 2Group is substituted by sulphur, then has " alkylthio "." alkylthio " preferably includes formula C aH 2a+1-S-(CH 2) b-straight chain group, wherein a be 1,2,3,4,5,6,7,8,9 or 10 and b be 0,1,2,3,4,5,6,7,8,9 or 10; A particularly preferably is that 1 to 6 integer and b are 0,1 or 2.Described alkylthio can be replaced by F, Cl, Br, I and/or CN equally and be preferably unsubstituted.
Ground related to the present invention, wherein there is the as defined above alkyl of one or more-CH=CH-group in term " thiazolinyl " expression.If there is two-CH=CH-group in described group, it can also be called " alkane dialkylene ".Alkenyl group can comprise 2 to 15 (namely 2,3,4,5,6,7,8,9,10,11,12,13,14 or 15) individual carbon atom, and be side chain or straight chain preferably.Described group is unsubstituted or replaced or identical or different polysubstituted by particularly F, Cl, Br, I and/or CN are single, i.e. other CH of one or two hydrogen of described-CH=CH-unit and/or described thiazolinyl 2Or CH 3One or more hydrogen of group can be substituted by corresponding one or more substituting groups.In addition, one or more CH 2Group can be separately independently of one another by-O-(" alkene oxygen base ") ,-S-,-C ≡ C-,-CO-,-(CO) O-,-mode of O (CO)-be not connected to each other directly with heteroatoms (O, S) substitutes.If all with the group of non-hydrogen, if for example it is non-end group, then described CH=CH group can exist by two kinds of configurations described CH=CH group, namely as E isomer with as the Z isomer form on two carbon atoms.Corresponding situation be applicable to by halogen and/or-two key groups of C=C that CN replaces.Normally, preferred E isomer (trans).Described thiazolinyl preferably comprises 2,3,4,5,6 or 7 carbon atoms and represents vinyl, allyl group, 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, 4Z-heptenyl, 5-hexenyl or 6-heptenyl.Particularly preferred thiazolinyl is vinyl, allyl group, 1E-propenyl, 2-propenyl and 3E-butenyl.
If the one or more CH in alkyl 2Group is substituted by-C ≡ C-, and what then exist is alkynyl.One or more CH 2Group by-(CO) O-or-O (CO)-substitute also is possible.Be preferably as follows these groups at this: acetoxyl group, propionyloxy, butyryl acyloxy, penta acyloxy, hexylyloxy, acetoxy-methyl, the propionyloxy methyl, the butyryl acyloxy methyl, valeryl oxygen ylmethyl, 2-acetoxyl group ethyl, 2-propionyloxy ethyl, 2-butyryl acyloxy ethyl, 2-acetoxyl group propyl group, 3-propionyloxy propyl group, 4-acetoxyl group butyl, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, butoxy carbonyl, pentyloxy carbonyl, the methoxycarbonyl methyl, the ethoxy carbonyl methyl, the propoxycarbonyl methyl, butoxy carbonyl methyl, 2-(methoxycarbonyl) ethyl, 2-(ethoxy carbonyl) ethyl, 2-(propoxycarbonyl) ethyl, 3-(methoxycarbonyl) propyl group, 3-(ethoxy carbonyl)-propyl group and 4-(methoxycarbonyl) butyl.
If the CH in alkyl 2Group is substituted and adjacent CH by unsubstituted or replacement-CH=CH- 2Group by CO ,-(CO) O-or-O (CO)-substitute, then this group can be straight or branched.Preferably straight chain and have 4 to 12 C atoms.Therefore, it particularly preferably represents the acryloyl-oxy ylmethyl, 2-acryloxy ethyl, 3-acryloxy propyl group, 4-acryloxy butyl, 5-acryloxy amyl group, 6-acryloxy hexyl, 7-acryloxy heptyl, 8-acryloxy octyl group, 9-acryloxy nonyl, the methacryloxy methyl, the 2-methacryloxyethyl, the 3-methacryloxypropyl, 4-methacryloxy butyl, 5-methacryloxy amyl group, 6-methacryloxy hexyl, 7-methacryloxy heptyl or 8-methacryloxy octyl group.
If described alkyl, alkyl, thiazolinyl or alkoxyl group are replaced by at least one halogen, this group straight chain preferably then.Halogen is F or Cl preferably.In polysubstituted situation, halogen is F preferably.Formed group also comprises the perfluoro group.In mono-substituted situation, described fluorine or chlorine substituting group can be on the position of any hope, but preferably in ω-position.
Ground related to the present invention, " alkylidene group " or " alkylidene bridge " unless-this term is at other place of this specification sheets or define in addition-be illustrated in the divalence aliphatic alkyl that has 1,2,3,4,5,6,7 or 8 carbon atom in the described chain in claims, its can also choose wantonly by halogen, CN, carboxyl, nitro, alkyl, alkoxyl group ,-NH 2Or quilt-N (alkyl) 2Single or polysubstituted, wherein said polysubstituted can being undertaken by identical or different substituting group." alkylidene group " or " alkylidene bridge " preferred expression has the saturated aliphatic groups of the straight chain of 1,2,3,4,5,6 carbon atom, and it is unsubstituted or by fluorine list or dibasic, particularly expression-CH 2CH 2-,-CH 2CH 2CH 2-,-(CH 2) 4-,-CF 2CF 2-and-(CF 2) 4-.
Ground related to the present invention, term " aralkyl " expression arylalkyl represents that namely aryl substituent wherein is connected to group in atom, chain, another group or the functional group by the alkyl bridging.Described alkyl bridge is saturated bivalent hydrocarbon radical (" alkylidene group "), particularly methylene radical (CH preferably 2-) or ethylidene (CH 2-CH 2-).The preferred example of aralkyl is benzyl and styroyl.For the purposes of the present invention, " aralkyl-O-group " is to be connected in aralkyl in other atom, chain, another group or the functional group by being bonded in Sauerstoffatom on the described alkyl bridge.The preferred example of aralkyl-O-group is O-benzyl and O-CH 2-CH 2-phenyl.
Ground related to the present invention, " halogen " expression fluorine, chlorine, bromine or iodine.
The product of the product (being also referred to as " hemiacetal ") of the alcohol (for example ethanol) that ground related to the present invention, " acetal " refer to monovalent (form) addition reaction on the carbonyl functional group of aldehyde or the alcohol (perhaps two kinds of alcohol) of two equivalents (form) addition reaction on the carbonyl functional group of aldehyde.Ground related to the present invention, " hydrate " of aldehyde refer to product (being also referred to as " semihydrate ") or two products when water gaging (form) addition reaction on the carbonyl functional group of aldehyde of monovalent water (form) addition reaction on the carbonyl functional group of aldehyde.Should be noted that at this aldehyde can also become with corresponding acetal (with hemiacetal) or with its hydrate (with semihydrate) balance to exist.
According to the present invention, boric acid ester is formula-B (O-alkyl) 2Group, wherein these two alkyl also can be substituted by alkylidene bridge or another bivalent hydrocarbon radical.
If the group of compound used according to the invention or substituting group or compound self used according to the invention can be used as optical activity or stereomeric group, substituting group or compound form exist, then because they have for example center of asymmetry, so these also can comprise in the present invention.Here the self-evident form that is these compounds can isomer-pure exists, for example as pure enantiomer, diastereomer, E or Z isomer, trans or cis-isomeride form existence, or as wishing that with any the form of mixtures of the multiple isomer of ratio exists, for example as racemic modification, E/Z isomer mixture or as cis/trans isomer mixture form.
In order to protect in the methods of the invention functional group that exist in the compound that uses any may responding property or substituting group in reaction of the present invention and/or in advance or undesirable reaction do not occur in reaction subsequently and/or the post-processing step; can use blocking group, it can be removed by fracture when described reacting completely again.The method of using suitable blocking group is known to those skilled in the art and is described in for example T.W.Green, P.G.M.Wuts:Protective Groups in Organic Synthesis (blocking group in the organic synthesis), the 3rd edition, John Wiley ﹠amp; Among the Sons (1999).
Embodiment
The present invention further illustrates by following embodiment, is not limited to these embodiment and be not meant to.
In context, per-cent data representation weight percent.All temperature are degree centigrade to provide.Tg is second-order transition temperature, and c1.p. is clearing point.In addition, C=crystalline state, N=nematic phase, Sm=smectic phase and I=isotropic phase.Data representation transition temperature between these symbols.Δ n represents optical anisotropy (589nm, 20 ℃), and Δ ε represents dielectric anisotropy (1kHz, 20 ℃), and γ 1Be illustrated in the rotary viscosity [mPas] under 20 ℃.
The Δ n of the compounds of this invention and Δ ε value obtain by extrapotation from the liquid crystal compound that is comprised of 10% each compound of the present invention and 90% commercially available liquid crystal ZLI 4792 (Merck, Darmstadt).
In context, use following abbreviation:
The RT room temperature
The DMSO methyl-sulphoxide
The DCC dicyclohexylcarbodiimide
TEMPO 2,2,6,6-tetramethyl piperidine N-oxide compound
DIBAL-H diisobutyl alanate
Embodiment
Embodiment 1
Figure S2006800180648D00281
Tricyclohexyl phosphine (1 with 30mg (0.035mmol), 3-two (2,4, the 6-trimethylphenyl)-4, under nitrogen atmosphere, under 40 ℃, portioning joins in the diolefine (1) of solid-state 0.35mol (84.8g) 5-glyoxalidine-2-subunit benzylidene ruthenium chloride (IV) as metathesis catalyst (Grubbs2 catalyzer), wherein first part is 20mg, and adds second part of 10mg after one hour.After 2 hours, separating out of ethene is basically complete.Adopting toluene/heptane (1: 4) by after the filtered through silica gel, this reaction mixture obtains (2) of 61.3g (theoretical value 81.7%), and it is directly used in described hydroformylation reaction to obtain (3).
For this purpose, under 60 bar and 150 ℃, utilize 3g three (triphenylphosphine) rhodium carbonyl (I) hydride to carry out hydroformylation with the 0.25mol (53.55g) in 200ml toluene (2), continue 24 hours until synthetic gas (H 2/ CO=1: absorption 1) is complete.This reaction product is removed solvent by evaporating in a vacuum, and adopts toluene/ethyl acetate (9: 1) to pass through filtered through silica gel resistates.The resistates of filtrate evaporation (37.2g=theoretical amount 69.5%) is carried out the trans component that alkali isomerization is arranged with enrichment substituting group in described formyl radical tetrahydropyrans component.
For this purpose, 20% aqueous sodium hydroxide solution of 1.8ml is joined in the described mixture of 37.2g in 190ml methyl alcohol and 48ml tetrahydrofuran (THF), and this mixture was at room temperature stirred one hour.Then this mixture is used the hydrochloric acid neutralization, and solution evaporation is extremely done.One liter of methyl tertiary butyl ether is joined in the resistates of described evaporation, and this mixture is used twice of 300ml water washing at every turn.After the drying, with the organic extract evaporation, obtain 88% aldehyde mixture of 33g, it also comprises a small amount of 4-formyl radical tetrahydropyrans except trans-5-formyl radical tetrahydropyrans (3).
For synthetic (4a), with (3) of 33g (0.135mol) and the 2-of 27.1g (0.135mol) (4-trans-propyl group cyclohexyl)-1, the 3-propane diol together, in the 250ml toluene that contains 500mg toluene-4-sulfonic acid monohydrate, on water separator, under refluxing warm 2 hours, until water is eliminated fully.
After the cooling, under agitation add 10g salt of wormwood, this mixture is filtered, and filtrate is evaporated to dried.Evaporation residue is at first adopted heptane/toluene (1: 1), then adopt pure toluene, pass through filtered through silica gel.
Two product fractions have been obtained.Fraction obtains the straight chain alltrans isomer (4a) that 12.4g needs (theoretical amount 21.4%) by recrystallization, and another fraction obtains 5g derived from the incorrect isomer of the 3-dioxane derivatives of 4-formyl radical tetrahydropyrans.
(4a)：C 106 N 206.9 I；Δε＝21.7；Δn＝0.0871
Embodiment 2
The operating process that is similar to embodiment 1 obtains (4b):
Figure S2006800180648D00291
(4b)：C 87 I；Δε＝23.7；Δn＝0.0550
Embodiment 2
The operating process that is similar to embodiment 1 obtains (4c):
(4c)
(4c)：C 88 N(87.9)I；Δε＝35.8；Δn＝0.0880
Embodiment 4
Figure S2006800180648D00301
0.2mol (48.8g) (3) are dissolved in the 200ml tetrahydrofuran (THF), and under 15 to 25 ℃, in 30min, drip the tetrahydrofuran solution of 2 moles of allylmgcl of 100ml.When interpolation is finished, this mixture was at room temperature stirred 2 hours in addition, then pour in the 0.5N hydrochloric acid of 200ml, and isolate organic phase, and with water methyl tertiary butyl ether extracting twice.The organic extract that merges is washed with water dry and evaporation.This evaporation residue is filtered by silica gel with toluene/ethyl acetate (98: 2 to 9: 1).Filtrate obtains the isomer mixture of the homoallylic alcohol (5) of 38.7g (theoretical amount 67.6%).
Be dissolved in the propargyl bromide of 0.135mol (38.7g) (5) and 0.135mol (16.1g) in the 80ml tetrahydrofuran (THF) and join vigorous stirring contain sodium hydroxide pellets (0.27mol; 10.8g), N-hexadecyl-N of 0.5ml water, 40ml tetrahydrofuran (THF) and 6.75mmol (2.46g), N in the emulsion of N-trimethylammonium bromide, is warmed to 45 ℃, and stirs 16 hours under this temperature.Then this mixture is poured in 1.5 liters the frozen water, isolates organic phase, and with water with MTB ether extraction 3 times.After predrying and evaporation, the resistates of the organic phase that merges is filtered by silica gel with toluene/heptane 2: 8.Filtrate evaporation is obtained 34.3g (theoretical amount 78.4%) (6), it is directly used in the eneyne transposition as the crude mixture form, obtains (7).
For this purpose, two (tricyclohexyl phosphine) benzylidene ruthenium chlorides (IV) (Grubbs 1 catalyzer) of 115mg (0.14mmol) are joined in (6) of the 0.028mol (9.4g) in the 20ml methylene dichloride, and this mixture at room temperature stirred 4 hours, the catalyzer that adds afterwards identical part 115mg, and this mixture at room temperature continued to stir 16 hours.Evaporation is also filtered by silica gel with toluene/heptane (3: 7), and at first from ethanol, then recrystallization obtains the specified isomer of 0.6g structure (7) by the resistates (1.0g) with described filtrate evaporation acquisition from heptane.
(7)：C 97 I；Δε＝14.2；Δn＝0.0800
Be 10 bar and under 90 ℃ with 0.2g (7) at hydrogen pressure, in 5ml methyl alcohol and 1ml toluene, adopt 0.1g three (triphenylphosphine) rhodium chloride (I) to carry out hydrogenation 6 hours.After the cooling, reaction mixture is evaporated in a vacuum and it is filtered by silica gel with toluene/heptane (3: 7).Evaporation obtains (8) as oil form of 0.15g.
Embodiment 5
Figure S2006800180648D00311
From corresponding homoallylic alcohol precursor, utilize 2-(brooethyl) ethyl propenoate, prepare compound (9) by the O-alkylation.For this purpose; 0.2mol (76.1g) homoallylic alcohol in the 80ml tetrahydrofuran (THF) is being stirred and carrying out with frozen water under the condition of exterior cooling; be added drop-wise in the sodium hydride of the 0.2mol (8.0g) of 60% form of suspension of conduct in the 80ml tetrahydrofuran (THF) under the nitrogen protection gas atmosphere; during this period, temperature remains on 20 ℃.Approximately after 2 hours, the separating out fully of hydrogen.Then so that temperature is no more than 0.2mol (38.6g) the vinylformic acid bromo methyl esters that drips under 25 ℃ the speed in the 40ml tetrahydrofuran (THF).At room temperature continue subsequently to stir other 16 hours.Then this reaction mixture is poured in the 600ml frozen water and neutralize with the HCl of 1 N, and isolate organic phase.After water is used the methyl tertiary butyl ether extracting twice, the organic phase that merges is evaporated to dry doubling adopts toluene/methyl tertiary butyl ether (3: 1) to filter by silica gel.Described filtrate evaporation residue comprises the alkylate (9) of 65.9g (theoretical amount 71%).
0.1mol (49.2g) (9) are warmed to 60 ℃ with 25ml toluene, and Grubbs 2 catalyzer (altogether 1mol%) of 4 parts of each 212mg are added under one hour interval.When separating out of ethene is complete, adopt toluene/methyl tertiary butyl ether to filter by silica gel this reaction mixture.The evaporation of described filtrate is stayed the dihydropyrane ester (10) of 28.8g (theoretical amount 62%).
Be 10 bar and under 100 ℃ with the dihydropyrane ester (10) of 0.05mol (23.2g) at hydrogen pressure, in 300ml methyl alcohol and 60ml toluene, carried out hydrogenation 12 hours with 2g three (triphenylphosphine) rhodium chloride (I).After filtering by silica gel with toluene/methyl tertiary butyl ether with solvent evaporation and with resistates, obtain the ester (11) (18.4g=theoretical amount 79%) of hydrogenation.
For synthetic aldehyde (12), the ester (11) of 0.039mol (18.4g) in 80ml toluene is cooled to-70 ℃, under agitation-70 ℃ lower add 32.5ml in toluene 1,2-N-diisobutyl alanate (DIBAL-H), and adding fully and stirring rear 4 hours continuing, this mixture is being poured among the cold 1N HCl of 100ml in still cold.With organic phase sodium bicarbonate aqueous solution and water washing, dry and evaporation.The evaporation residue of aldehyde (12) can be directly used in synthetic (4c), as described in embodiment 1 part.
Embodiment 6
(13) synthetic also is similar to embodiment 5 and carries out.
Figure S2006800180648D00321
Embodiment 7
(14) synthetic also is similar to embodiment 5 and carries out, and uses specifically aldehyde (3).
(14)：C 91 SmH(63) N 203.4 I；Δε＝21.3；Δn＝0.0880
Embodiment 8
Figure S2006800180648D00331
With the sodium salt by methylallyl alcohol adopt the Na salt of bromoacetic acid carry out alkylation (under 60 ℃ in tetrahydrofuran (THF) 16 hours) acid (15) for preparing is in the presence of as the dicyclohexylcarbodiimide (DCCI) of dewatering agent and 4-dimethylaminopyridine (DAP), in methylene dichloride, obtain ester (16) with vinyl carbinol reaction (16 hours, room temperature).By means of the diisopropylaminoethyl lithium, in the presence of trimethysilyl chloride, by the Claisen-Ireland method its rearrangement is obtained (17) (in-75 ℃ of lower addings, then at room temperature 16 hours, solvents tetrahydrofurane).With 3,4, the 5-trifluoromethyl phenol carries out esterification and obtains (18) in the presence of DCCI and DAP with (17).For the closed loop that acquisition dihydropyrane ester (19) carries out is passed through at N 2Lower be warmed to 80 ℃ and add Grubbs 2 catalyzer of 0.5mol% and carry out solid-state under the protection gas, during this period, since separate out after ethene bubbled 15 minutes this mixture remained on 80 ℃ under other 5 minutes.After passing through filtered through silica gel with toluene, to isolate (with theoretical amount 65%) dihydropyrane ester (19) (11g) under 100 ℃ and 11 bar, with Wilkinson catalyzer (2mol%), three (triphenylphosphine) rhodium chloride (I) carries out hydrogenation 17 hours to obtain tetrahydropyrans ester (20) in 60ml ethyl methyl ketone and 60ml toluene.
With (20) of 0.05mol (13.7g), as among the embodiment 3 for ester (11) is reduced into aldehyde (12) described, reduce with DIBAL-H and to obtain aldehyde (21).
Embodiment 9
Be similar to embodiment 8, from ester (22) preparation aldehyde (23)
Embodiment 10
Figure S2006800180648D00342
The dihydro pyranyl ester (27) that allylation by homoallylic alcohol and the closed loop transposition of (26) are carried out synthetic is similar to dihydro pyranyl ester (10) synthetic of embodiment 3.Be 10 bar and under 23 ℃ with 51g ester (27) at hydrogen pressure, in the 600ml normal heptane, in 9 hours, utilize the Pd/C (5%) of 12g to carry out hydrogenation, obtain the isomer mixture of tetrahydropyrans ester (28).
With the isomer ester (28) of 0.074mol (21g) and 0.081mol (4.55g) KOH in 200ml methyl alcohol refluxed under nitrogen 6 hours, and at room temperature stirred other 12 hours.Then with solvent basically stripping remove, the HCl of resistates with the 1N of 90ml processed, filter out and wash with water.Toluene is joined in the described resistates, it is evaporated again with azeotropic drying.In the process of alkaline saponification, cis ester or the cis acid of vast scale are isomerizated into antiderivative, obtain the tetrahydropyrans acid (29) of 17g (theoretical amount 90%).
The acid (29) of 0.067mol (17g) in the 90ml tetrahydrofuran (THF) is added drop-wise to the LiAlH of 0.05mol (1.91g) under the speed that slight backflow only occurs 4In the mixture in the 10ml tetrahydrofuran (THF).When adding when complete, with this mixture under refluxing warm other 6 hours.Allow this mixture cool off, and the 2N HCl that 75ml cooled off is under agitation added.Two be separated after, water is extracted other twice with each 100ml methyl tertiary butyl ether.With the organic phase saturated NaHCO of 50ml that merges 3Solution and water washing be until neutrality, and dry and evaporation obtains the alcohol (30) of 12.3g (theoretical amount 76.4%).
Alcohol (30) is oxidized to aldehyde (31) by the Swern method.For this purpose, with the trifluoroacetic anhydride of the 0.0525mol (12.5g) in the 15ml methylene dichloride under-60 ℃, under agitation, in 5 minutes, join in 0.0635mol (4.95g) methyl-sulphoxide in the 60ml methylene dichloride, wherein temperature is remained under-60 ℃.When adding is complete and after stirring other 10 minutes under-60 ℃, under agitation drip the alcohol (30) of the 0.05mol (12.0g) in the 40ml methylene dichloride, wherein temperature is remained under-60 ℃ in 10 minutes after 5 minutes dropping process neutralization.Then allow this mixture be warmed to room temperature, and in 10 minutes, drip the 18.5ml triethylamine under the speed that is higher than 30 ℃ temperature is not risen.When adding is complete, this mixture was kept at room temperature other 30 minutes, and then with the 100ml water washing of this reaction mixture.With water 50ml dichloromethane extraction.After dry and evaporation, the organic phase of merging obtains the aldehyde (31) of 6.4g (theoretical amount 54%).
Embodiment 11
Figure S2006800180648D00361
To change into aldehyde (33) by the hydrocarbonylation that is similar to embodiment 1 by the dihydropyrane (32) that metathesis forms; and in alkene-carbonyl reaction, react with homoallylic alcohol (34), at first obtain bromo tetrahydropyrans (35).
The synthetic acetic ester (38) by zinc alcohol of described homoallylic alcohol carries out, and described zinc alcohol can pass through classical way, by at zinc powder and CoBr 2Existence under with the reaction of gaseous formaldehyde preparation.
Figure S2006800180648D00362
For this purpose, the gaseous formaldehyde by the paraformaldehyde of 1.0mol (30g) being heated to 220 ℃ of formation in independent flask is being passed into 26g zinc powder (0.4mol), 13.2g (0.06mol) CoBr with zinc after with the activation of 1ml trifluoroacetic acid 2And in (38) solution in the 400ml acetonitrile of 0.2mol (51.2g).When introducing is complete, this mixture was at room temperature continued to stir 12 hours.Then be poured among the 2N HCl of 100ml, isolate organic phase, and water is extracted 2 times with methyl tertiary butyl ether.With the organic phase evaporation that merges, the resistates that stays is filtered by silica gel with toluene/ethyl acetate (7: 3), and will be more the fraction evaporation of polarity, obtain homoallylic alcohol (34) as the roughage form with 48% yield (21.9g) of theoretical amount.
Initially with the homoallylic alcohol (34) of 0.09mol (20.5g) and the aldehyde (33) of 0.69mol (14.0g) and the BiBr of 5mol% 3(2g) together 0 ℃ of lower introducing.Then will under 5-20 ℃ exterior cooling, pass into as the HBr of gas form, until the number of bubbles out of the bubble counter after being arranged in reaction vessel with from being arranged in the wash bottle number of bubbles out identical (approximately 10 minutes) before the described reaction vessel.Then this mixture is poured in the ice-cooled saturated sodium bicarbonate solution rapidly, washed with water organic phase, dry and evaporation.The isomer mixture of the bromo tetrahydropyrans (35) of isomery is used in next reactions steps with the crude product form, and the elimination of HBr obtains dihydropyrane (36).
The isomer mixture that derives from previous step (36) (23.3g with 0.057mol; Theoretical amount 63.3%) with 1 of 0.086mol (10.2ml), 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene together in 40ml toluene under refluxing warm 6h.After the cooling, water and dilute sulphuric acid be pH regulator to 3, and this mixture is acutely mixed.After separation, with the saturated NaHCO of organic phase 3Solution and water washing, and filter by silica gel.Evaporation obtains the isomer mixture of the dihydropyrane (36) of 15.7g (theoretical amount 84%).
20 hour carry out isomer mixture (36) (15.7g) hydrogenation as catalyzer at 10 bar and 90 ℃ of lower hydrogenations by means of three (triphenylphosphine) rhodium chloride (I) of 0.48mmol (448mg) by being dissolved in the neutralization of 300ml methyl alcohol and 75ml toluene.After the evaporation of solvent, resistates is filtered by silica gel with toluene.The fractional crystallization that repeats from ethanol and heptane obtains 0.5g (37).
Embodiment 12
Figure S2006800180648D00371
Under nitrogen, the diethyl ether solution of the 1M allyl group bromination magnesium of 800ml is joined under being lower than 25 ℃ temperature in the solution among the 500ml THF of aldehyde of 272g (800mmol).This batch of material at room temperature stirred spend the night, join in the frozen water and extract with methyl tertiary butyl ether subsequently.Organic phase is with saturated NaCl solution washing, through dried over sodium sulfate and evaporation.The resistates that obtains is passed through silica gel.
Figure S2006800180648D00381
With 103g (81%; The triphenylphosphine dissolved of pure and mild 21g (80mmol) 220mmol) is in the 500ml ethyl acetate, and adding 500mg rhodium acetate dimer.At 25 bar synthetic gas with under 100 ℃, carry out hydroformylation.With the evaporation of this reaction soln and pass through silica gel.
Figure S2006800180648D00382
Under nitrogen, the methylsulfonyl chloride of 24.5ml (320mmol) is joined under 0-5 ℃ in the solution of triethylamine in the 500ml methylene dichloride of the lactol of 100g (240mmol) and 101ml (299mmol).This batch of material at room temperature stirred spend the night.This batch of material is added to the water and extracts with methyl tertiary butyl ether.Organic phase is with saturated NaCl solution washing, through dried over sodium sulfate and evaporation.The resistates that obtains is passed through silica gel.
Figure S2006800180648D00383
The enol ether of 60g (148mmol) is dissolved in the 300ml toluene, and adds three (2, the 4-di-tert-butyl-phenyl) phosphorous acid esters of 9.8g (15mmol) and the dicarbonyl rhodium acetylacetonate (I) of 390mg (1.5mmol).At 100 bar synthetic gas with under 100 ℃, carry out hydroformylation.By silica gel, obtain the cis/trans mixture of described aldehyde subsequently with solution evaporation, and with resistates.
The signal of described aldehyde proton is at δ=9.69ppm and δ=9.88ppm place.
With aldehyde (43) and 2-ethyl-1,3-PD reaction, obtain dioxane (4c) (referring to embodiment 3) subsequently.For this purpose, with the aldehyde (43) of 44.5g (110mmol) and the glycol 2-ethyl-1 of 12.0g (115mmol), ammediol is dissolved in the 250ml toluene, add 400mg tosic acid monohydrate, and this mixture is heated until the conversion of described aldehyde complete (TLC) under refluxing on the water separator.The batch of material of cooling is washed 3 times with saturated sodium bicarbonate solution, and evaporation is also by silica gel (toluene/heptane 7: 3; Toluene; Toluene/ethyl acetate 95: 5).To contain the fraction evaporation of product, and with resistates from ethanol at-20 ℃ of lower recrystallizations.
(4c)：C 88N(87.9)I；Δε＝35.8；Δn＝0.0880
Embodiment 13
Figure S2006800180648D00392
With the 3-(4 '-amyl group cyclohexyl) of the 9.0g (0.038mmol) in 100ml toluene-2H-3, the cobalt octacarbonyl of 4-dihydropyrane (44) and 0.4g is under 140 ℃/300 bar, at 1.7 liters of synthetic gas (H 2/ CO=1: 1) lower reaction is 2 hours.After the cooling, reaction soln is evaporated, and resistates is filtered by silica gel with heptane/toluene (1: 1).After evaporation, filtrate obtains 9.1g light brown oily resistates, and wherein alcohol (46) is 4: 1 with the ratio of aldehyde (45).This mixture is directly used in and is oxidized to aldehyde (45) (also referring to the Swern oxidation step in embodiment 10).

Claims (20)

1. the formyl radical tetrahydropyran derivatives of formula II,
Figure FSB00000828898100011
Wherein in formula II,
A 4Expression
Figure FSB00000828898100012
A, b, c represent 0 or 1 independently of one another, and wherein a+b+c equals 1,2 or 3;
A 1, A 2, A 3Independently of one another, identical or different ground is also through rotation or one-tenth mirror image ground, expression
Figure FSB00000828898100013
Figure FSB00000828898100014
One of them is substituted by N to two C atoms are optional,
Figure FSB00000828898100015
Y 1, Y 2And Y 3Represent independently of one another hydrogen, halogen, CN, NCS, SF 5, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl, OC 1-6Alkyl, OC 2-6Thiazolinyl or OC 2-6Alkynyl, wherein aliphatic group is unsubstituted or by halogen list or polysubstituted; With
Z 1, Z 2, Z 3Represent singly-bound, have the alkylidene bridge of 1 to 6 carbon atom, this alkylidene bridge is unsubstituted or single or polysubstituted by F and/or Cl, or-CH 2O-,-OCH 2-,-(CO) O-,-O (CO)-,-CF 2O-,-OCF 2-,-CH 2CH 2CF 2O-or-OCF 2CH 2CH 2-,
N1 is 0,1,2,3 or 4;
N2 and n3 are 0,1,2 or 3 independently of one another;
N4 is 0,1 or 2;
W 1Expression-CH 2-,-CF 2-or-O-;
R 1Expression H, halogen, CN, NCS, SF 5, CF 3, OCF 3, NH 2, boric acid ester, have the alkyl of 1 to 15 C atom, this alkyl is unsubstituted or replaced or by halogen list or polysubstituted by CN is single, wherein additionally, the one or more CH in these groups 2Group can be separately independently of one another by-C ≡ C-,-CH=CH-,-O-,-S-,-SO-,-SO 2-,-(CO) O-or-O (CO)-with the heteroatoms in described chain each other not direct-connected mode substitute,
The compound that does not wherein comprise following formula
Figure FSB00000828898100021
2. according to claim 1 the formyl radical tetrahydropyran derivatives of formula II is characterized in that the A among the formula II 4Expression
Figure FSB00000828898100022
3. according to claim 1 the formyl radical tetrahydropyran derivatives of formula II is characterized in that R 1Expression F, OCF 3, CF 3, OCF 2H, SF 5
4. according to claim 1 the formyl radical tetrahydropyran derivatives of formula II is characterized in that they are selected from formula IIa, IIb and IIc
Figure FSB00000828898100023
Wherein
R 11And R 12Expression F, CF 3, OCF 3, CN, NCS, SF 5Or have 1 to 15 C atom by halogen list or polysubstituted alkyl, wherein, in addition, the one or more CH in these groups 2Group can be separately independently of one another by-C ≡ C-,-CH=CH-,-O-,-S-,-SO-,-SO 2-,-(CO) O-or-O (CO)-with the heteroatoms in described chain each other not direct-connected mode substitute,
R 13As in claim 1 to R 1It is defined such,
L 1, L 2Be H, Cl or F independently of one another, and
A 1, A 2, Z 1, Z 2, a, b have the definition of pointing out for formula II as in claim 1.
5. the method for the formyl radical tetrahydropyran derivatives of preparation formula II
Figure FSB00000828898100031
Among its Chinese style II such as the claim 1-4 defined in each,
It is characterized in that,
A) with the compound hydroformylation of formula III a, IIIb and/or IIIc,
Or
B) with the compound of formula IV
Figure FSB00000828898100033
Comprise that by IV one or more the reaction of at least one reduction step reacts, wherein
R 3Expression CN, COOH, CONHR 4, COOR 4, and R 4Expression alkyl, aralkyl or the optional aryl that replaces, perhaps
C) with the pure oxidation of formula V
Figure FSB00000828898100034
Wherein, in formula III a, IIIb, IIIc, IV and V,
A 1, A 2, A 3, A 4, Z 1, Z 2, Z 3, a, b, c and R 1Has the pointed implication for formula II.
6. according to claim 5 method is characterized in that, the compound of formula III b and/or IIIc respectively by the compound of following formula X and/or XIII by direct elimination hydroxyl or after changing into leavings group, eliminate and prepare
A wherein 1, A 2, A 3, Z 1, Z 2, Z 3, a, b, c and R 1Independently as defining for formula II in the claim 5.
7. according to claim 6 method is characterized in that, the compound of formula X and XIII is prepared by hydroformylation step and closed loop by the compound of formula VI and XII respectively,
Figure FSB00000828898100042
A wherein 1, A 2, A 3, Z 1, Z 2, Z 3, a, b, c and R 1Have as in the claim 5 for the pointed implication of formula II.
8. according to claim 5 method, it is characterized in that, the new tetrahydropyran compound of formula IV prepares by the hydrogenation of corresponding dihydropyran derivatives, and described dihydropyran derivatives is prepared by the catalysis closed loop transposition that is attended by the ethene elimination by the diene of suitable replacement again.
9. according to claim 5 or 8 method, it is characterized in that, with the process of the aldehyde of formula IV compound reduction accepted way of doing sth II by means of reducing metal, metal hydride, alkyl metal cpd or boron compound and carrying out at a low price.
10. according to claim 5 or 8 method, it is characterized in that, the reduction of formula IV compound utilizes the lithium aluminum hydride that diisobutyl alanate, dialkyl aluminum hydride or amino or alkoxyl group replace and carries out.
11. according to claim 5 or 6 method; it is characterized in that, the hydroformylation of formula III a, IIIb or IIIc compound uses carbon monoxide and hydrogen at the same time, perhaps replaces hydrogen ground; use silane containing hydrogen or manthanoate, subsequently with the intermediate hydrolysis and catalysis is carried out.
12. according to claim 5 or 6 method, it is characterized in that, the hydroformylation of formula III a, IIIb or IIIc compound utilizes transition metal and catalysis is carried out.
13. according to claim 5 or 6 method, it is characterized in that, described catalysis utilizes the transition metal complex of metal rhodium or cobalt and carries out, and described transition metal complex is comprised of cobalt compound and carbonyl ligands or rhodium compound and phosphorus-containing ligand.
14. method according to claim 5 is characterized in that, the oxidation of formula V compound is carried out by means of following method, and described method is used CrO 3, by the iodine reagent of Dess-Martin method, use DMSO/DCC by the Pfitzner-Moffatt oxidation, use the DMSO/ oxalyl chloride by the Swern oxidation, use acetone/Al (O-alkyl) 3By the Oppenauer oxidation, or use NaOCl, carry out catalysis by 2,2,6,6-tetramethyl piperidine N-oxide compound or transition-metal catalyst.
15. such as the aldehyde cpd of the formula II defined in each among the claim 1-4 for the synthesis of the addition of aldehyde group or the purposes of condensation product.
16. purposes according to claim 15 is characterized in that, described aldehyde group is used for making up optional 5 to 6 yuan of rings that replace.
17. according to claim 15 or 16 purposes, it is characterized in that, described reaction and glycol carry out obtaining dioxane, perhaps carry out obtaining homoallylic alcohol and further obtain thus second amylene oxide ring with the allyl group metallic compound.
18. purposes according to claim 15 is characterized in that, by the compound of Wittig reaction from aldehyde II preparation formula IX
Figure FSB00000828898100051
Wherein
R 1, R 2, A 1, A 2, A 3, A 4, Z 1, Z 2, Z 3, a, b, c have the implication of pointing out for formula II in each as among the claim 1-4, and in each case independently of one another
A 5, A 6As for A 1Define,
Z 5, Z 6As for Z 1Define, and
E, f are as defining for a among the formula II.
19. it is characterized in that according to claim 15 or 16 purposes, the compound of preparation formula Qa
Figure FSB00000828898100052
The synthetic precursor of the hydrogenated products that (part) of formula Qa compound is saturated or the Qa of formula Qb or Qc
Figure FSB00000828898100061
Wherein, in Qa, Qb and Qc,
R 1, R 2, A 1, A 2, A 3, A 4, Z 1, Z 2, Z 3, a, b, c have as among the claim 1-4 in each for the pointed implication of formula II, and in each case independently of one another,
A 5, A 6As for A 1Define,
Z 5, Z 6As for Z 1Define, and
E, f are as defining for a among the formula II.
20. prepare the method for 2,5-, two substituted-tetrahydro pyran derivates, it comprises
A) according to claim 5 the formyl radical tetrahydropyran derivatives of each method preparation formula II-14, and
B) the formyl radical tetrahydropyran derivatives of the formula II of preparation prepares 2,5-, two substituted-tetrahydro pyran derivates in using a).
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