CN101180286A - Method for producing tetrahydropyran derivatives - Google Patents

Method for producing tetrahydropyran derivatives Download PDF

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CN101180286A
CN101180286A CNA2006800179265A CN200680017926A CN101180286A CN 101180286 A CN101180286 A CN 101180286A CN A2006800179265 A CNA2006800179265 A CN A2006800179265A CN 200680017926 A CN200680017926 A CN 200680017926A CN 101180286 A CN101180286 A CN 101180286A
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CN101180286B (en
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E·珀奇
W·宾德尔
M·基施鲍姆
R·舍费尔
D·本辛格
G·诺特纳格尔
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Merck Patent GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

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Abstract

The invention relates to a method for producing tetrahydropyran derivatives, to said tetrahydropyran derivatives and to the use of said tetrahydropyran derivative for producing other tetrahydropyran derivatives. The invention in particular relates to producing halogenated tetrahydropyran derivatives.

Description

The method for preparing tetrahydropyran derivatives
Technical field
The present invention relates to prepare the method for tetrahydropyran derivatives, relate to these tetrahydropyran derivatives, and relate to the purposes that these tetrahydropyran derivatives are used to prepare other tetrahydropyran derivatives.The invention particularly relates to the halogenated tetrahydropyran derivatives of preparation.
Background technology
Having amylene oxide ring plays an important role in organic chemistry as the compound of the centre portions of molecule, for example as the composition of natural or synthetic fragrance matter, medicine or mesomorphic (mesogenic) or liquid crystalline cpd, perhaps conduct is used for the precursor of synthetic these useful matteies.
Here interested especially is mesomorphic or the liquid crystal tetrahydropyran derivatives, it has suitable (mesomorphic) substituting group, ring and/or ring system on 2-and/or 5-position are because they have some favourable electrooptics performances that are used for liquid crystal media and other physicals.Therefore, need extremely simple and efficient synthetic method basically, described synthetic method make in addition can obtain on the structure very various multiple 2, the dibasic tetrahydropyran derivatives of 5-.
Such two kinds of synthetic methods are based on uses so-called olefin metathesis reactions, and it adopts metal-alkylidene group coordination catalysis effect.By these methods, can pass through closed loop cross metathesis (DE102004021338 A1) or obtain 2 by eneyne transposition and optional further cross metathesis (DE 102004022891 A1), 5-two substituted-dihydro pyran derivates are in each case all at suitable metal carbene title complex (metal-alkylidene complex) (for example Grubbs I or Grubbs II catalyzer or relevant catalyzer; Referring to, especially WO 96/04289; WO97/06185; People such as T.M.Trnka, Acc.Chem.Res.2001,34,18; S.K.Armstrong, J.Chem.Soc., Perkin Trans.I (1998), 371; People such as J.Renaud, Angew.Chem. (2000), 112,3231) existence under carry out.These two kinds of methods are summarized in scheme 1a and scheme 1b respectively, wherein " group 1" and " group 2" represent suitable (mesomorphic) substituting group, ring or ring system separately.Also can prepare from obtainable dihydropyrane then by means of (catalysis) hydrogenation needed 2, the dibasic tetrahydropyran derivatives of 5-.
Figure S2006800179265D00021
Scheme 1a.Cy=cyclohexyl.
Figure S2006800179265D00022
Scheme 1b.
Yet these two kinds of synthetic methods are the cost height owing to the price height of the metal-alkylidene complex that is adopted, and therefore needs lower-cost method.
J.O.Metzger and U.Biermann, Bull.Soc.Belg. (1994), 103,393-397 has described the addition reaction of aluminum chloride inductive formaldehyde on the alkene that replaces, formed the tetrahydropyran derivatives that 4-chlorine replaces, it can be subsequently converted to corresponding halogen tetrahydropyran derivatives.They disclose and have synthesized the single example that has two substituent 4-chlorine tetrahydropyran derivatives on 2-and 5-position, and they need be as this two substituent homoallylic alcohols that have of initial compounds.Yet this is synthetic to have low convergency and divergency, and uses dibasic homoallylic alcohol only can prepare only to have 2 of very limited range of structures, the precursor of 5-two substituted-tetrahydro pyran derivates.
E.Hanschke, Chem.Ber. (1955) 88,1053-61 have retouched unsubstituted homoallylic alcohol and formaldehyde reacts in the presence of hydrogen halide, with and with unsubstituted C 1-4Alkyl (alkanyl) aldehyde and react being higher than under the atmospheric pressure in the presence of the hydrogenchloride with crotonic aldehyde, the tetrahydropyran derivatives that wherein needs to be used for further 4-halogen-replacements of reaction only non-selectively is accompanied by other product acquisition with low yield.
People such as J.S.Yadav, Synth.Comm. (2002), 32,1803-1808 has described benzaldehyde derivative employing (1-aryl) vinyl carbinol and has carried out cyclisation.The 4-chlorine tetrahydropyrans of gained is not substituted in the way you want.Product is not substituted on 3-and 5-position.The reagent that is proposed is the muriate at the bismuth (III) that does not have to be associated with microwave under the situation of solvent, rather than bromide or iodide.
Summary of the invention
Therefore, the objective of the invention is to point out a kind of simple and efficient method for preparing tetrahydropyran derivatives, described tetrahydropyran derivatives self can be used as and is used to synthesize (other) mesomorphic or liquid crystal type 2, the initial compounds of 5-two substituted-tetrahydro pyran derivates.In addition, in described preparation process, described tetrahydropyran derivatives should completely or partially have required trans stereochemistry.
The method of the halogenated tetrahydropyran derivatives according to the present invention by preparation formula I has reached this purpose
Figure S2006800179265D00031
It is characterized in that,
Homoallylic alcohol with formula II
At least a Lewis acid that comprises at least one chlorine, bromine or iodine atom and/or comprise at least one chlorine, the anionic Br  of bromine or iodine nsted acid in the presence of, with aldehyde or its acetal or the hydrate reaction of formula III
Figure S2006800179265D00042
Wherein, in formula I, II and III,
A, b, c, d, e and f represent 0 or 1 independently of one another, and wherein a+b+c+d+e+f equals 0,1,2,3 or 4;
X 1Be chlorine, bromine or iodine;
R 1Expression H, halogen ,-CN, having the alkyl of 1 to 15 C atom, this alkyl is unsubstituted or the single replacement of quilt-CN or by halogen list or polysubstituted, 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-substitutes in the mode that the Sauerstoffatom in described chain does not directly link to each other each other;
R 2Expression H, halogen ,-CN ,-NCS ,-NO 2,-OH ,-SF 5,-O-aralkyl, have the alkyl of 1 to 15 C atom, this alkyl be unsubstituted or quilt-CN single replace or by halogen or-O-aralkyl list or polysubstituted, 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-,-CO-O-or-O-CO-substitutes in the mode that the Sauerstoffatom in described chain does not directly link to each other each other;
A 1, A 2, A 3, A 4, A 5And A 6Independently of one another, also through rotation or one-tenth mirror image ground, expression
Figure S2006800179265D00043
Z 1The expression 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, perhaps expression-CH 2O-,-OCH 2-, and, if A 2Not cyclohexylidene or phenylidene ring, then Z 1Also can represent-CF 2O-;
Z 2The expression 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;
Z 3, Z 4, Z 5And Z 6Represent singly-bound independently of one another, have the alkylidene bridge of 1 to 6 carbon atom, this alkylidene bridge is unsubstituted or single or polysubstituted by F and/or Cl, perhaps expression-CH 2O-,-OCH 2-,-CF 2O-, wherein-CF 2The O-bridge is not connected directly to cyclohexylidene or phenylidene ring by its O atom;
N1, n2 and n3 are 0,1,2,3 or 4 independently of one another;
Y 1, Y 2, Y 3, Y 4, Y 5And Y 6Represent independently of one another H, halogen ,-CN, 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; Preferred H or F; With
W 1Expression-CH 2-,-CF 2-or-O-;
Wherein
Be under 0 the situation simultaneously at a and b, R then 1Be not hydrogen and
All be simultaneously under 0 the situation at a, b, c, d, e and f, R then 1And R 2Not H or unsubstituted alkyl.
If (a+b)=0, R then 1Preferably not hydrogen, halogen or CN.If (c+d+e+f)=0, R then 2Preferably be not hydrogen, halogen ,-CN ,-NCS ,-NO 2,-OH ,-SF 5,-O-aralkyl or alkoxyl group.
In order to simplify, unless the numbering of the tetrahydropyrans ring position in formula I-clearly indicate in addition-as follows in this manual:
Figure S2006800179265D00052
Method of the present invention makes can be by that be easy to obtain and reagent cheapness, the halogenated tetrahydropyran derivatives that obtains formula I with simple mode, good yield and high chemistry and stereoselectivity.These tetrahydropyran derivatives of formula I self can be used for preparing other mesomorphic or liquid crystal type tetrahydropyran derivatives.
Method of the present invention can be in the presence of at least a Lewis acid that comprises at least one chlorine, bromine or iodine atom, or at least a comprise at least one chlorine, the anionic Br  of bromine or iodine nsted acid (protonic acid) in the presence of, or in the presence of the mixture of at least a Lewis as defined above acid and at least a  of Br as defined above nsted acid, carry out.Method of the present invention can utilize one or more different Lewis and/or Br  nsted acid to carry out, and preferably adopts no more than three kinds of different acid.Preferred especially, in the method for the invention, only use the mixture of a kind of Lewis acid or Br  nsted acid or Lewis acid and Br  nsted acid." acid " mentioned in the context therefore-except as otherwise noted-both refers to use single acid, also refers to use multiple different acid.Under situation about using more than a kind of acid, the selection of multiple acid is not particularly limited, as long as they are chemical each other compatible and can not cause any undesirable side reaction.
In first embodiment preferred of the present invention, at least a Lewis that comprises at least one chlorine, bromine or iodine atom that is reflected at of the homoallylic alcohol of formula II and the aldehyde of formula III carried out under sour the existence.Preferred described Lewis acid except any non-halogen group or part that exist, only comprises a type in these halogen atoms in each case,, perhaps has only the chlorine atom that is, perhaps has only bromine atoms, perhaps has only the iodine atom.The halogenic substituent X of the tetrahydropyran derivatives of formula I 1This halogen atom corresponding to described at least a Lewis acid.Described Lewis acid very particularly preferably comprises bromine atoms.
Described at least a Lewis acid is preferably selected from formula M (X 1) nAnd R 3M (X 1) N-1Compound, wherein
M represents B, Al, Ga, In, Sn, Ti, Fe, Zn, Nb, Zr, Au or Bi;
X 1Expression Cl, Br or I;
R 3Expression has the straight or branched alkyl of 1 to 10 carbon atom; With
N is integer 2,3,4 or 5 and select in its mode that equals the form Oxidation Number of M.
The example of these Lewis acid is diisobutyl aluminum chloride and B III(X 1) 3, A LIII(X 1) 3, Ga III(X 1) 3, In III(X 1) 3, Sn IV(X 1) 4, Ti IV(X 1) 4, Fe III(X 1) 3, Zn II(X 1) 2, Zr IV(X 1) 4, Nb V(X 1) 5, Au III(X 1) 3And Bi III(X 1) 3, X wherein 1Be chlorine, bromine or iodine, preferred chlorine or bromine, and bromine particularly.
The accurate consumption of used Lewis acid can change in wide region and especially depend on-halogen atom X particularly about existing in minimum amount-each Lewis acid molecule 1Number.Therefore, be under the situation of Lewis acid of 4 (IV) at the form Oxidation Number of atom M, few to 25mol% based on the homoallylic alcohol meter of the formula II of question response, possible sufficient to guarantee reactant transforms complete.Usually, the consumption of described Lewis acid for about 20mol% to about 300mol%, preferably about 34mol% is about 250mol% and especially preferably about 50mol% about 200mol% extremely extremely, wherein described in each case usage data is based on the homoallylic alcohol meter of formula II.
Temperature of reaction is generally-80 ℃ to+40 ℃ approximately approximately, and wherein the character of selected each Lewis acid is also depended in the accurate selection of temperature of reaction.Therefore, preferred temperature range is-70 ℃ to-40 ℃ for halogenation boron, is-50 ℃ to 0 ℃ and is 0 ℃ to+40 ℃ for the halogenide of Zn and Bi for the halogenide of Al, In, Sn and Ti.Reaction times is generally 1 to 72 hour, and preferred 2 to 36 hours, and preferred especially 4 to 24 hours.According to reaction of the present invention can by to dissolving or be suspended in the homoallylic alcohol of the formula II in the suitable solvent and the mixture of the aldehyde of formula III in add as solid or the acid of the Lewis in solution and carry out; Perhaps, also initial then for example the introducing also of described Lewis acid in succession, add described aldehyde and described homoallylic alcohol, or can vice versa.
Described at least a Lewis acid is formula M (X especially preferably 1) nCompound, wherein M is B, Al, Fe, Zn or Bi, particularly Bi.Especially, X 1Expression Br.Especially, described Lewis acid is AlBr 3, ZnBr 2Or BiBr 3
In the other embodiment preferred of the present invention, method of the present invention comprise at least one chlorine, the anionic Br  of bromine or iodine nsted acid in the presence of carry out.The example of this Br  nsted acid is hydrogenchloride, hydrogen bromide and hydrogen iodide.Described Br  nsted acid can be for example used as gas form, and it is passed in the mixture of other reactant that comprises method of the present invention in suitable solvent for example; Perhaps, also can use the solution that comprises described Br  nsted acid, for example the HBr in Glacial acetic acid.The preferred especially hydrogen bromide of Br  nsted acid that is used for the inventive method.If it is haloid acid-use (based on the homoallylic alcohol of formula II) with stoichiometry or superstoichiometric amount for described Br  nsted acid-particularly, preferable amount is the amount of about 100mol% to about 350mol%, especially preferably about 100mol% is to about 225mol% and particularly no more than about 150mol%.
Temperature of reaction in this embodiment is generally about 0 ℃ to+70 ℃ approximately, preferred about 10 ℃ to about 40 ℃ and especially preferably about room temperature (18-25 ℃).Reaction times is generally 1h to 72h, preferred 2h to 36h and preferred especially 4h to 24h, and be subjected to selected solvent effect: for example, described being reflected in the Glacial acetic acid than in water, carrying out sooner usually.Reaction of the present invention can by to dissolving or be suspended in the homoallylic alcohol of the formula II in the suitable solvent and the mixture of the aldehyde of formula III in add as the Br  nsted acid of solution form and carry out; Perhaps, described Br  nsted acid also can be used as the gas form feeding.
In other embodiment preferred of the present invention, under existing, the mixture that is reflected at least a Lewis acid and at least a Br  nsted acid of the homoallylic alcohol of formula II and the aldehyde of formula III carries out.These acid are chemical each other compatible and do not cause the mode of undesirable side reaction to be selected with them.Advantageously, described Lewis acid comprises and the identical halogen atom of described Br  nsted acid,, for example, except Hydrogen bromide, also adopts formula M (Br) that is nLewis acid bromide.Preferred combination is HBr and BiBr 3Or AuBr 3If described reaction is carried out (promptly in the corresponding way, temperature of reaction is about 0 ℃ to about 50 ℃, with the mol ratio of Br  nsted acid and Lewis acid be about 100: about 0.5: about 2), described Lewis acid can easily comprise the halogen atom that is different from described Br  nsted acid, as for example at FeCl 3With under the situation of the combination of HBr like that.The formula I compound of variant preparation so just comprises the halogen of described Br  nsted acid as X by this method according to the present invention 1, so X 1Adopting FeCl 3Be Br in the described example of HBr.
This embodiment of the present invention does not have the embodiment of Br  nsted acid to compare with wherein only using one or more Lewis acid, allows to use Lewis acid significantly more in a small amount.Because used Br  nsted acid is more not expensive than described Lewis acid usually, so this method variant causes lower cost.Simultaneously, the application of described Lewis acid allows method of the present invention to carry out (particularly under lower temperature of reaction) under the condition of comparing milder with the condition that must keep under the situation of using Br  nsted acid uniquely.
In principle, described Lewis acid and Br  nsted acid can be with any required blending ratio uses each other.Yet, preferred described Lewis acid with respect to the consumption of described Br  nsted acid for about 0.1mol% to about 20mol%, especially preferably about 0.3mol% is about 10mol% and particularly about 0.5mol% about 2mol% extremely extremely.Described Br  nsted acid this preferably in respect to the homoallylic alcohol of formula II at least stoichiometry (about 100mol%) to the amount of hyperstoichiometry (about 350mol%) use.
Temperature of reaction in this embodiment of the present invention is usually at-10 ℃ to+70 ℃ approximately approximately.At first preferably initially be introduced in the aldehyde of the formula III in the suitable solvent and the homoallylic alcohol of formula II, and add described Lewis acid down at about-10 ℃ to about+35 ℃; Subsequently with described Br  nsted acid under about 0 ℃ to approximately+50 ℃-preferably adopt exterior cooling-feed as gas form, saturated until reaction medium.Can also use the solution of suitable Br  nsted acid.Reaction times is generally several minutes to 24 hour, preferred 10min to 6h and preferred especially 15min to 3h.
In principle, in each embodiment, reaction of the present invention can not have the mode of solvent to carry out, and preferably carries out in solvent or in the solvent mixture.At this suitable solvent is those effects of self not playing acid, perhaps only plays the solvent of effect of acid on slight extent, and is inert to used acid.The accurate selection of medium is depended on the dissolution characteristics of described reactant especially and is depended on described acid.Suitable solvent, its can be separately or with the form of mixtures of 2 kinds or 3 kinds solvents as reaction medium, for example, water; Hydrocarbon, for example hexane, sherwood oil, benzene,toluene,xylene; Hydrochloric ether, trieline, 1 for example, 2-ethylene dichloride, chloroform and particularly methylene dichloride; Alcohol, for example methyl alcohol, ethanol, 2-propyl alcohol, n-propyl alcohol, propyl carbinol; Ether, for example ether, Di Iso Propyl Ether, tetrahydrofuran (THF) (THF) or 1,4-dioxane; Glycol ethers, for example ethylene glycol monomethyl ether or single ether (methyl glycol, ethyl glycol or polyoxyethylene glycol), glycol dimethyl ether (diglyme); Dithiocarbonic anhydride; Nitro-compound, for example Nitromethane 99Min. or oil of mirbane wherein, when using Lewis acid (separately or with Br  nsted acid) as acid used according to the invention, do not make water and alcohol as solvent or solvent composition.Preferred aliphat, aromatic series and hydrochloric ether, preferred especially hydrochloric ether, particularly methylene dichloride.
Astoundingly, have been found that when implementing method of the present invention that mainly form or unique those steric isomers that form the tetrahydropyran derivatives of formula I, wherein the substituting group on 2-and 5-position is each other in trans arrangement.This situation significantly helps the application of these compounds in liquid crystal media, perhaps help preparing other mesomorphic or liquid crystal type tetrahydropyran derivatives, because the substituent trans arrangement in 2-and 5-position makes it possible to achieve two equatorial conformations, the shape of molecule of the elongation that having formed overstates for mesomorphic performance wants.It is trans-2 that the tetrahydropyran derivatives of formula I by method of the present invention preparation generally has, and 5-and cis-2, the ratio of 5-isomer are about 75: 25 or 80: 20 to 100: 0.The common isomer mixture that obtains of other method for preparing mesomorphic or liquid crystal type tetrahydropyran derivatives has significantly bigger cis-2,5-content of isomer.
If described product generates with crystallized form, then after aftertreatment, obtain the extra high selectivity that institute's separated products is measured.The high purity that derives from the product of described method helps forming crystal.
In addition, it has surprisingly been found that halogenic substituent X on the 4-position of the formula I compound by method of the present invention preparation 1Also main or unique being orientated with substituting group in the 5-position becomes trans.By means of method of the present invention, therefore three substituting groups on 2-, 4-and 5-position form with highly selective with the tetrahydropyran derivatives of full equatorial position orientation.
If with at least a Lewis acid-make up-participate in the described reaction separately or with at least a Br  nsted acid, then the highly selective of the present invention's reaction is significant especially.
Except described high stereochemistry selectivity, the salient point of method of the present invention is that also the tetrahydropyran derivatives of additional advantage: formula I can be well to extraordinary yield acquisition.In addition, the reaction of the homoallylic alcohol of formula II and the aldehyde of formula III is carried out with high chemo-selective, that is, unwanted by product does not form or forms with the minimum of the tetrahydropyran derivatives that do not disturb further use formula I.The sour reagent of Shi Yonging is easy to obtain also commercially available usually and can obtains at an easy rate in the method for the invention, and its operation is without any need for special or uncommon preventive measures.
Verifiedly particularly advantageous be, method of the present invention has been opened up the convergency synthetic schemes that is used to prepare other tetrahydropyran derivatives with high structure diversity: from the homoallylic alcohol of specific formula II, and the tetrahydropyran derivatives of formula I that the variation of the group of the aldehyde of formula III makes the various replacements can prepare wide region.It is applicable to the complement operation process, that is, from the aldehyde of specific formula III, the also feasible tetrahydropyran derivatives that can prepare formula I of the variation of the group of the homoallylic alcohol of formula II with big structure diversity.
Except the halogenated amylene oxide ring at center, can can not have other ring by the formula I compound of method of the present invention preparation or have other ring (or ring system) of, two, three or four, that is, the summation of index a, b, c, d, e and f equals 0,1,2,3 or 4.(a+b+c+d+e+f) preferred 〉=1, particularly 1,2 or 3 and very particularly 1 or 2.For the homoallylic alcohol of formula II and therefore preferred not ring or have a ring on the 5-position for the tetrahydropyran derivatives of formula I, that is, a+b is preferably 0 or 1 at this.In addition, for the aldehyde of formula III with therefore preferably do not have other ring for the tetrahydropyran derivatives of formula I or have one, ring that two or three are other on the 2-position, that is, c+d+e+f equals 0,1,2 or 3, and particularly 1 or 2.
X 1Determine also preferably bromine or chlorine, particularly bromine by selecting Lewis acid and/or Br  nsted acid.The comparable chlorine of bromine is easier to reductibility and eliminates.
R 1Preferably alkyl, thiazolinyl, alkoxyl group or alkene oxygen base, wherein each has 1 to 10 carbon atom and is unsubstituted or is replaced by one or more fluorine and/or chlorine atom, and if-a and/or b are that 1-can also be chlorine, fluorine or bromine.R 1Especially preferably represent alkyl or alkoxyl group, wherein each has 1 to 8 carbon atom and is unsubstituted or is replaced by one or more fluorine and/or chlorine atom, especially, be the straight chained alkyl with 1,2,3,4,5 or 6 carbon atom, it is unsubstituted or is replaced by one or more fluorine atoms.
R 2Preferably Cl, F, Br ,-OH ,-CO 2-C 1-6-alkyl ,-the O-aralkyl ,-CH (CH 2O-" blocking group ") 2Or alkyl, thiazolinyl, alkoxyl group or alkene oxygen base, wherein each has 1 to 8 carbon atom and is unsubstituted or is replaced by one or more fluorine and/or chlorine atom, preferred especially F, Cl ,-OH ,-CO 2-C 1-6-alkyl ,-OCH 2-phenyl ,-CH (CH 2OCH 2-aryl) 2Or alkyl or alkoxyl group, wherein each has 1 to 8 carbon atom and is unsubstituted or is replaced and F particularly Cl ,-CO by one or more fluorine and/or chlorine atom 2-methyl ,-ethyl ,-n-propyl ,-sec.-propyl ,-normal-butyl ,-tertiary butyl or-n-hexyl ,-OCH 2-phenyl ,-CH (CH 2OCH 2-phenyl) 2, or have the straight-chain paraffin base or the alkoxyl group of 1,2,3,4,5 or 6 carbon atom, wherein each is unsubstituted or is replaced by one or more fluorine atoms.
R 1And R 2Also comprise by by described element to CH 2The group that the multiple replacement of group forms, if they are conventional, for example, for R 2Also comprise aromatic yl sulphonate-O (SO 2)-Ar or-O (SO 2)-CH 3, it is used as blocking group or as leavings group in subsequently synthetic.All CH of alkyl 2Group also can be replaced by pointed group.For this purpose, directly the S-S key and-the S-O-chain is normally more not conventional, and preferably is not R 1Or R 2The part of group.
Therein under the situation of (a+b)=0, R 1Preferably do not represent hydrogen, halogen or CN.Therein under the situation of (c+d+e+f)=0, R 2Preferably do not represent hydrogen, halogen ,-CN ,-NCS ,-NO 2,-OH ,-SF 5,-O-aralkyl or alkoxyl group.
Ring A 1And A 2Preferably represent 1 independently of one another, 4-cyclohexylidene or represent 1,4-phenylene, its optional replacement by 1 to 4 fluorine atom and especially preferably expression
Or
Ring A 3, A 4, A 5And A 6Preferably represent 1 independently of one another, 4-cyclohexylidene or represent 1,4-phenylene, its optional replacement by 0 to 4 fluorine atom and especially preferably expression
Figure S2006800179265D00123
Or
Figure S2006800179265D00124
Z 1And Z 2The preferred alkylidene bridge of representing singly-bound independently of one another or having 2,4 or 6 carbon atoms, it also can be replaced by one or more fluorine atoms.Z 1And Z 2It especially preferably all is singly-bound.
Z 3, Z 4, Z 5And Z 6Preferably represent independently of one another singly-bound ,-CH 2O-or-CF 2O-, wherein-CF 2The O-bridge is not connected directly to cyclohexylidene or phenylidene ring by its O atom.They especially preferably be independently of one another singly-bound ,-CF 2O-or-CH 2O-, very particularly preferably in each case, Z 3, Z 4, Z 5And Z 6In only have one not to be singly-bound.Z therein 3, Z 4, Z 5Or Z 6Comprise under the situation of Sauerstoffatom, it preferably directly is not bonded to the aldehyde group in the formula III.Described bridging part Z 3, Z 4, Z 5And Z 6Especially preferably select as follows: if they directly are bonded to the amylene oxide ring in formula I or are bonded to described aldehyde group, then they do not comprise Sauerstoffatom.
The homoallylic alcohol of preferred formula II is selected from the compound of formula II-1 to II-9:
Wherein, R 1The also preferred as defined above alkyl of representing 1-7 C.
In the other embodiments of the inventive method, but the aldehyde of the homoallylic alcohol of through type II and formula III reacted in the presence of Lewis acid and/or Br  nsted acid and the formula I compound that obtains carries out substituent X 1Reduction eliminate to obtain the tetrahydropyran derivatives of formula IV:
Wherein a, b, c, d, e, f, R 1, R 2, A 1, A 2, A 3, A 4, A 5, A 6, Z 1, Z 2, Z 3, Z 4, Z 5, Z 6As above formula I is defined independently, that is, described substituting group can have and definition different in formula I, II, III and IV usually.
Therefore the present invention also comprises the method for preparation formula IV compound, and it comprises at least one following method steps, wherein with the aldehyde of the homoallylic alcohol of formula II and formula III or its acetal or hydrate reacting like that as described:
Figure S2006800179265D00141
Method of the present invention preferably has other method steps, it is characterized in that the substituent X of formula I compound 1Reduction eliminate, other substituting group of wherein said amylene oxide ring is because derivatize and can have different implications.This other method steps preferably carries out after the reaction of II and III, and wherein said reduction elimination does not have other intermediate steps particularly preferably in carrying out after the ring formation.
The reduction of I is eliminated the embodiment preferred that obtains IV and is comprised free chain reaction, in this process-consider in form-and halogen atom X in the tetrahydropyran derivatives of formula I 1Be drawn out of and substituted by hydrogen atom.At this, the X in the formula I compound of question response 1Especially preferably bromine or chlorine, particularly bromine.
This embodiment preferred that reduction of the present invention is eliminated is preferably carried out in the presence of organotin hydride or organosilicon hydride.At this preferred organotin hydride is trialkyltin hydride and single aralkyl dialkyl tin hydride, preferred especially trialkyltin hydride, particularly tri-n-butyl tin hydride (Bu 3SnH).Typically, use is based on 1 to 10 equivalent and preferred 2 to the 4 normal described tin hydrides of formula I compound meter to be restored.Further preferred the use is incorporated into solid carrier, the organotin hydride on the preferred SOLID ORGANIC carrier; The organotin hydride that is incorporated on the solid carrier very particularly preferably is to pass through Bu 2The reaction of SnHLi (Bu=normal-butyl) (original position forms) and alpha-halogen alkyl polystyrene obtain those (referring to for example, people such as U.Gerigk, Synthesis 1990, people such as 448-452 and G.Dumartin, Synlett 1994,952-954).The common consumption of organotin hydride that is incorporated on the solid carrier is 2 to 4 equivalents based on formula I compound meter.
Preferred organosilicon hydride is the silane that replaces, especially preferably three (trialkylsilkl) silane, particularly three (trimethyl silyl) silane (TTMSS) (referring to for example, people such as M.Ballestri, J.Org.Chem.1991,56,678-683).The common consumption of described organosilicon hydride is 1 to 3 equivalent based on formula I compound meter to be restored, preferred 1.1 to 1.5 equivalents.Very particularly preferably be used in combination TTMSS with other reductive agent, described other reductive agent for example is a composite metal hydride, sodium borohydride for example, NaBH 4(referring to for example, people such as M.Lesage, Tetrahedron Lett. the 30th volume, 2733-2734,1989).This method variant allows to use the actual reductive agent TTMSS that is lower than stoichiometric amount, and it forms in the reaction cycle process by sodium borohydride again; Therefore can be by using more not expensive NaBH 4Save a large amount of relatively costly TTMSS.Typical blending ratio is 2 to 10 times of amounts, the NaBH of preferred about 5 times of amounts 4, and 5-20mol%, the TTMSS of preferred 10mol% is in each case based on the compound of formula I.
This embodiment preferred of the present invention of using organotin hydride or organosilicon hydride is usually at least a free chain reaction initiator (" radical initiator "), for example suitable azo or peralcohol, for example AIBN (2,2 '-azobis isobutyronitrile) or under the existence to the methoxybenzoyl superoxide, in the presence of UV light, carries out.Described radical initiator to be to be used for the usual amounts of such reaction, preferably uses in 1 to 20mol% amount based on formula I compound.Alternatively or except radical initiator, described reaction can also cause by the effect of UV radiating.
The suitable solvent that is used for this preferred embodiment of the present invention is a hydrocarbon, for example heptane, benzene, dimethylbenzene and ether, for example glycol dimethyl ether or methyl cellosolve.Described reaction is carried out under 20 to 140 ℃ usually.Duration of the reaction is generally 2 to 24 hours.
In the further preferred embodiment that reduction of the present invention is eliminated, the X in formula I 1Be bromine, and described reduction is eliminated by carrying out with hydrogen reaction in the presence of hydrogenation catalyst and alkali.Described hydrogenation catalyst is homogeneous catalyst (for example title complex of Pd (0) or Pd (II) or Ni (0) or Ni (II) phosphine that replace with alkyl and/or that aryl replaces or phosphite ester ligand formation) or preferably heterogeneous transition-metal catalyst.The especially preferably heterogeneous palladium of described hydrogenation catalyst, platinum or nickel catalyzator, particularly palladium.Particularly preferably in palladium on the carbon or the palladium on aluminum oxide, the particularly palladium on carbon.Described alkali is nitrogen base or amine, particularly tertiary amine preferably.
Described amine is trialkylamine preferably, especially preferably diisopropylethylamine or triethylamine, particularly triethylamine.Described reaction at the THF of 3 to 20 times of amounts, is under 1 to 50 crust at hydrogen pressure preferably, in 1 to 24 hour, carries out to about 120 ℃ temperature about 20.
Under the situation of this embodiment preferred, the carrying out that reduction is eliminated under given group and substituent suitable selection, not only causes the halogenation amylene oxide ring to change into corresponding dehalogenation amylene oxide ring, and causes reduction to remove some blocking group.This is particularly useful for wherein R 2The formula I compound of expression O-aralkyl, the particularly optional O-benzyl group that replaces of described O-aralkyl.
The salient point of two preferred embodiments of the above-mentioned reduction elimination effect of mentioning is especially that the reduction of the tetrahydropyran derivatives of the formula I that carries out for the tetrahydropyran derivatives that obtains formula IV is eliminated under the situation of 2-that keeps described amylene oxide ring and the substituent configuration on the 5-position to carry out.Therefore, all be that calm alignment is arranged and made the halogenated tetrahydropyrans that becomes the formula I of trans arrangement at the substituting group on the 2-position with the substituting group on the 5-position wherein at 2-, 4-and all three substituting groups on the 5-position, keeping under the stereochemical situation, had accordingly trans-2, the tetrahydropyran derivatives of the dibasic formula IV of 5-.
In further preferred embodiment of the present invention, the reduction of the formula I compound that carries out for the tetrahydropyran derivatives that obtains formula IV is eliminated and is carried out in two steps, wherein, in the first step (A), the tetrahydropyran derivatives of formula I is changed into dihydropyran derivatives, particularly the dihydropyran derivatives of formula Va and/or Vb:
Figure S2006800179265D00161
Wherein a, b, c, d, e, f, R 1, R 2, A 1, A 2, A 3, A 4, A 5, A 6, Z 1, Z 2, Z 3, Z 4, Z 5, Z 6Define for formula I as above-mentioned;
With, in second step (B), the dihydropyran derivatives of formula Va and/or Vb is transformed the tetrahydropyran derivatives of accepted way of doing sth IV.
Utilize highly basic to carry out HX 1Elimination from the tetrahydropyran derivatives of formula I.The verified especially alkoxide of suitable alkali, alkali metal alcoholates for example, for example sodium ethylate or potassium tert.-butoxide and strong non-ionic type nitrogen base, it has pKa value＞20.The example of the non-ionic type nitrogen base that these are strong is by J.G.Ve rkade, Topicsin Current Chemistry 220, those that 3-44 mentions, especially 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN); 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU); And 1,1,3,3-tetramethyl guanidine (TMG), 7-methyl isophthalic acid, 5,7-three azabicyclos [4.4.0] last of the ten Heavenly stems-5-alkene (MTBD) and 2,8,9-triisopropyl-2,5,8,9-four azepines-1-phospha dicyclo [3.3.3] undecane (TTPU) is (equally referring to S.Arumugam, J.G.Verkade, J.Org.Chem.1997,62,4827).
Described elimination is preferably carried out in suitable inert solvent or in solvent mixture, for example at aromatic hydrocarbon, and toluene for example, perhaps ether, for example 1, the 4-dioxane is in glycol dimethyl ether and the tetrahydrofuran (THF).Especially preferably use non-polar solvent.Described reaction is carried out to the temperature between the boiling point in room temperature usually, preferably carries out to the temperature of the rising of boiling point at about 60 ℃, preferred especially about 80 ℃ to boiling point.The duration of the reaction of the described the first step (A) is generally about 1h to about 48h, is preferably about 4h to about 16h.
When the step of carrying out this preferred embodiment of the present invention (A), form the mixture of two kinds of dihydropyran derivatives of formula Va and Vb usually, be to form in about 2: 1 with isomer proportion as a rule.(in some cases, also obtain wherein endocyclic double bond not 4,5-or 3, other isomer dihydropyrane compound of 4-position.These double bond isomers can also easily change into the tetrahydropyran derivatives of the formula IV of needs according to the present invention.) although these two kinds of isomer can utilize conventional separation method basically, for example chromatography is separated, however before the further reaction in step (B), it does not carry out usually.According to the compound of the obtainable formula Vb of this embodiment of the present invention,, have the configuration identical with the initial compounds of formula I about the 2-of described amylene oxide ring and the substituent configuration aspect on the 5-position.Therefore, the tetrahydropyran derivatives with formula I of complete calm arrangement obtains the trans 2 of corresponding formula Vb, 5-two substituted-tetrahydro pyran derivates easily.
The step (B) that is used to form the tetrahydropyran derivatives of formula IV adopts catalytic hydrogenation to carry out.Can adopt homogeneous catalysis or adopt heterogeneous catalysis to carry out in this hydrogenation.About the dihydropyran derivatives of formula Vb, described hydrogenation self and to the selection of carrying out the condition that described hydrogenation adopts for the directed not influence of the substituent stereochemistry on described heterocyclic 2-and 5-position.Therefore, usually and the preferred formula Vb that exists trans-2,5-two substitution compounds are keeping under the stereochemical situation, obtain the trans-2 of corresponding formula IV, 5-two substituted-tetrahydro pyrans.Yet about the dihydropyran derivatives of formula Va, the other operation process that is used to form the tetrahydropyran derivatives of formula IV has influence to the substituent arrangement on oxygen heterocyclic 2-that is relative to each other and 5-position usually.Therefore, for example, the hydrogenation of the heterogeneous catalysis of on heterogeneous palladium, platinum or nickel catalyzator, carrying out, the common cis of production IV-2 mainly or uniquely, the tetrahydropyrans of 5-configuration.Highly basic is for example used in its isomerization, and potassium tert.-butoxide for example uses acid or uses fluorine-containing compound, and for example CsF or tetrabutyl ammonium fluoride make 2 of the formula IV that can obtain to wish, the isomer of 5-transconfiguration.If, on the contrary, adopt homogeneous catalysis to carry out described hydrogenation, for example at the Wilkinson catalyzer, chloro three (triphenylphosphine) rhodium (I) (Cl-Rh[P (C 6H 5) 3] 3) existence under, at hydrogen pressure is under 10 to 100 crust, in temperature is under about 80 ℃ to about 120 ℃, duration of the reaction is about 6 to about 48 hours, in suitable solvent, carry out (referring to German patent application DE 102004036068A1) in (for example toluene), 2 of needed formula IV compound, the 5-trans-isomer(ide) is so that excessive acquisition-ratio with trans-isomer(ide) and cis-isomeride is acquisition in about 3: 1 usually.Therefore can good yield obtain the trans-2 of needed formula IV, the dibasic tetrahydropyran derivatives of 5-.
The invention further relates to the compound of formula I
Figure S2006800179265D00181
Wherein,
A, b, c, d, e and f represent 0 or 1 independently of one another, and wherein a+b+c+d+e+f equals 0,1,2,3 or 4;
X 1Be chlorine, bromine or iodine;
R 1Expression H, halogen ,-CN, having the alkyl of 1 to 15 C atom, this alkyl is unsubstituted or the single replacement of quilt-CN or by halogen list or polysubstituted, 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-substitutes in the mode that the heteroatoms in described chain does not directly link to each other each other;
R 2Expression H, halogen ,-CN ,-NCS ,-NO 2,-OH ,-SF 5,-O-aralkyl, have the alkyl of 1 to 15 C atom, this alkyl be unsubstituted or quilt-CN single replace or by halogen or-O-aralkyl list or polysubstituted, 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-,-CO-O-or-O-CO-substitutes in the mode that the Sauerstoffatom in described chain does not directly link to each other each other;
A 1, A 2, A 3, A 4, A 5And A 6, independently of one another, also through rotation or one-tenth mirror image ground, expression
Figure S2006800179265D00191
Z 1The expression 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, perhaps expression-CH 2O-,-OCH 2-, and, if A 2Not cyclohexylidene or phenylidene ring, then Z 1Can also represent-CF 2O-;
Z 2The expression 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;
Z 3, Z 4, Z 5And Z 6Represent singly-bound independently of one another, have the alkylidene bridge of 1 to 6 carbon atom, this alkylidene bridge is unsubstituted or single or polysubstituted by F and/or Cl, perhaps expression-CH 2O-,-OCH 2-,-CF 2O-, wherein-CF 2The O-bridge is not connected directly to cyclohexylidene or phenylidene ring by its O atom;
N1, n2 and n3 are 0,1,2,3 or 4 independently of one another;
Y 1, Y 2, Y 3, Y 4, Y 5And Y 6Represent independently of one another H, halogen ,-CN, 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
W 1Expression-CH 2-,-CF 2-or-O-;
Wherein
Be under 0 the situation at a and b, R then 1Not hydrogen; With
All be simultaneously under 0 the situation at a, b, c, d, e and f, R then 1And R 2Not H or unsubstituted alkyl.
C, d, e and f are simultaneously under 0 the situation therein, then R 2Preferred expression has the alkyl of 1 to 15 C atom, this alkyl be unsubstituted or the single replacement of quilt-CN or by halogen or-O-aralkyl list or polysubstituted, 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-,-CO-O-or-O-CO-substitutes in the mode that the Sauerstoffatom in described chain does not directly link to each other each other.
These compounds be suitable as be used to prepare other 2, the initial compounds or the midbody compound of 5-two substituted-tetrahydro pyran derivates.Described substituent X 1Can as pointing out, be substituted by hydrogen.X 1Also can be replaced by other group, produce object construction by known nucleophilic substitution reaction.
The group of formula I compound of the present invention, substituting group and index a, b, c, d, e, f, X 1, 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 6Preferably has identical preferred and particularly preferred as implication that above-mentioned and of the present invention preparation method points out for formula I relatively.
2, the substituting group of 5-position is preferably each other in trans arrangement.In chair conformation, they are in this case all at equatorial position.
The tetrahydropyran derivatives of preferred especially formula I of the present invention is wherein all arranged in calm mode at 2-, the 4-of center amylene oxide ring and three substituting groups on the 5-position.
The initial compounds of formula II of Cai Yonging and III can be by self known method preparation in the method for the invention, as as described in the literature (for example, in the classic of synthetic organic chemistry, Houben-Weyl for example, Methoden der organischen Chemie (vitochemical method), Georg-Thieme-Verlag, Stuttgart), accurately known and be suitable under the reaction conditions of described reaction.Yet can also use self does not knownly have the more detailed version of mentioning at this.
The aldehyde of formula III is commercially available or can be for example obtained by other aldehyde by reaction well known in the prior art.Therefore, wherein said formyl radical is bonded in the aldehyde of the formula III of cyclohexyl ring (if for example, the c in formula III equals 1, then Z 3Expression singly-bound and A 3The expression cyclohexylidene) can be by being disclosed in the method preparation among DE 19612814 A1.The aldehyde of other formula III, wherein said formyl radical for example are connected in the optional phenylene that replaces (if for example, the c in formula III equals 1, then Z by singly-bound 3Expression singly-bound and A 3The expression phenylene), perhaps by alkylidene bridge ,-CH 2O-,-OCH 2-or-CF 2O-is bonded in cyclic group (if for example, the c in formula III equals 1, then Z 3Be alkylidene bridge ,-CH 2O-,-OCH 2-or-CF 2O-and A 3Have in claim 1 and one of above implication of in specification sheets, pointing out), can use appropriate reductant, diisobutyl aluminium hydride (DIBAL-H) for example, by obtaining and/or commercially available corresponding carboxylic acid ester or carboxylic acid derivative preparation (especially referring to, German patent application DE 102004021334 A1) by known method from document.
Wherein said formyl radical is bonded in the formula III on the 5-position of THP trtrahydropyranyl by singly-bound aldehyde also simply mode obtain, this THP trtrahydropyranyl also is substituted on the 2-position.The parent material here for example is corresponding carboxylic acid ester or nitrile precursor, its can be for example by the transposition method shown in the scheme 1a (wherein, for example, group 1=-CO 2-alkyl or-CN) with subsequently, for example use homogeneous catalyst, for example obtain after the catalytic hydrogenation that the Wilkinson catalyzer carries out, and, obtain described formyl radical derivative itself and diisobutyl aluminium hydride (DIBAL-H) reaction.
The homoallylic alcohol of formula II is from well known in the prior art equally, and is commercially available, perhaps can easily prepare by self known synthetic method from document.Scheme 2 has been summarized the route of synthesis that begins from the allyl halide derivative of formula A:
Figure S2006800179265D00211
Scheme 2
A for example can be from aldehyde R 1-[A 1-Z 1] a-[A 2-Z 2] b-CHO begins, for example by the synthetic unsaturated ester R that obtains of Reformatsky 1-[A 1-Z 1] a-[A 2-Z 2] b-CH=CH-CO 2-alkyl uses DIBAL-H to reduce subsequently and obtains corresponding vinyl carbinol R 1-[A 1-Z 1] a-[A 2-Z 2] b-CH=CH-CH 2OH and use PBr at last 3(Hal=Br), PCl 5Or SO 2Cl 2(Hal=Cl), or HI (Hal=I) carries out halogenation and prepares, and begins to obtain compd B with the reaction of suitable metal or organometallic reagent from A; 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 suitable group or the part on the described metal.B and formaldehyde (perhaps synthetic equivalent) carry out further is reflected at the homoallylic alcohol that obtains needed formula II after the corresponding aftertreatment, and this reaction also can be carried out under situation about need not isolate in advance as the B of intermediate formation.
Realize other preparation method of the homoallylic alcohol of formula II according to scheme 3; " Hal " here has and identical implication in scheme 2 above; " Met " be Cu (I) (referring to A.Carpita, R.Rossi, Synthesis 1982,469) preferably:
Figure S2006800179265D00221
Scheme 3
---according to the operation steps in scheme 2---use suitable reagent to change into Organometallic derivatives D halogenide C, it reacts with E subsequently, obtains the high allyl ester F of acetate.The homoallylic alcohol of needed formula II can be obtained by F by means of saponification then.
In addition, the homoallylic alcohol of formula II, wherein R 1-[A 1-Z 1] a-[A 2-Z 2] b-expression alkyl also can be by utilizing two anionic alkyl halide R of Ba Dousuan accordingly 1-[A 1-Z 1] a-[A 2-Z 2] bThe alkylation of-Hal and subsequently utilize LiAlH 4Reduction and obtain.This two negatively charged ion is by Ba Dousuan, and for example (referring to, P.E.Pfeffer, L.S.Silbert, J.Org.Chem.36 (1971) 3290 by obtaining with the reaction of 2 normal lithium diisopropylamines (LDA); R.H.van der Veen, H.Cerfountain, J.Org.Chem.50 (1985) 342).
Ground related to the present invention, term " alkyl " is unless---other place or definition in addition in claims in this manual---represents to have straight or branched, the saturated or undersaturated aliphatic alkyl of 1 to 15 (that is, 1,2,3,4,5,6,7,8,9,10,11,12,13,14 or 15) carbon atom with its most general implication; This group be unsubstituted or by fluorine, chlorine, bromine, iodine, carboxyl, nitro ,-NH 2,-N (alkyl) 2And/or cyano group list or polysubstituted, wherein said polysubstituted can carrying out with identical or different substituting group.Alkyl self in described aliphatics hydrocarbon chain also can be 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 correspondingly particularly replaced or polysubstituted and wherein one or more CH in identical or different ground by F, Cl, Br, I and/or CN list 2Group can by-O-(" alkoxyl group ", " oxa alkyl ") ,-S-(" alkylthio ") ,-SO 2-,-CH=CH-(" thiazolinyl ") ,-C ≡ C-(" alkynyl ") ,-CO-O-or-O-CO-substitutes in the not direct-connected each other mode of the heteroatoms in described chain (O, S), wherein-O-SO 2-keyed jointing is again possible.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 is represented 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 preferably; CF 3, CHF 2, CH 2F, CF 2CF 3Described alkyl special preferably straight chain and unsubstituted or replaced by F.
Because the one or more CH in alkyl 2Group can be substituted by-O-, so term " alkyl " also comprises " alkoxyl group " or " oxa alkyl ".Alkoxyl group is meant 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; Preferably alkyl or thiazolinyl of alkyl like this.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 especially preferably-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 is special, and preferably 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 is special, and preferably 1 to 6 integer and b are 0,1 or 2.Described alkylthio equally can by F, Cl, Br, I and/or-CN replaces and preferably unsubstituted.
Ground related to the present invention, wherein there is the alkyl as defined above 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 as " alkane dialkylene ".Thiazolinyl can comprise 2 to 15 (promptly 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 identical or differently by particularly F, Cl, Br, I and/or CN are single or polysubstituted, other CH of unitary one or two hydrogen of promptly described-CH=CH-and/or described thiazolinyl group 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-(" thiazolinyl oxygen base ") ,-S-,-C ≡ C-,-CO-,-CO-O-,-OC-O-with heteroatoms (O, S) each other directly the mode of keyed jointing substitute.If described CH=CH group all has non-hydrogen group on two carbon atoms, if for example it is non-end group, then described CH=CH group can exist by two kinds of configurations, promptly as E isomer with as the Z isomer form.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 quilt-CO-O-or-it also is possible that O-CO-substitutes.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-substitutes, then this group can be a straight or branched.Preferably straight chain and have 4 to 12 C atoms.Therefore, it especially 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 is straight chain preferably.Halogen is F or Cl preferably.Under polysubstituted situation, halogen is F preferably.Formed group also comprises the perfluoro group.Under 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 other place or definition in addition in claims in this manual---is illustrated in the divalence aliphatic alkyl that has 1,2,3,4,5,6,7 or 8 carbon atom in the described chain, its optional also can 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 or 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-or-(CF 2) 4-.
Ground related to the present invention, term " aralkyl " expression arylalkyl represents that promptly aryl substituent wherein is connected to group in atom, chain, another group or the functional group by the alkyl bridging.The bivalent hydrocarbon radical that described alkyl bridge is preferably saturated (" alkylidene group "), particularly methylene radical (CH 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 the Sauerstoffatom that is bonded in described alkyl bridge.The preferred example of aralkyl-O-group is O-benzyl and O-CH 2CH 2-phenyl.Methylene radical in this aralkyl again can be by heteroatom bridges, for example-O-,-SO 2-,-(CO)-and wait alternatively, obtain conventional leaving away and blocking group.
Ground related to the present invention, term " aryl " expression aromatic series or part aromaticity ring system, representing phenyl ring more narrowly, it can be by simple group, for example the alkyl of 1-5 C, halogen, nitro, cyano group etc. are single, two or three replacements, to change its electronic property or solid space shielding (for example tertiary butyl) is provided.Described aryl is phenyl or p-methylphenyl preferably.
Ground related to the present invention, " halogen " expression fluorine, chlorine, bromine or iodine.
The product of product (being also referred to as " hemiacetal ") of the alcohol (for example ethanol) that ground related to the present invention, " acetal " are meant monovalent (form) addition reaction to the carbonyl functional group of aldehyde or two normal alcohol (perhaps two kinds of alcohol) (form) addition reaction to the carbonyl functional group of aldehyde.Ground related to the present invention, " hydrate " of aldehyde are meant the product (being also referred to as " semihydrate ") or two products when water gaging (form) addition reaction to the carbonyl functional group of aldehyde of monovalent water (form) addition reaction to the carbonyl functional group of aldehyde.Should be noted that at this aldehyde can also become balance to exist with corresponding acetal (with hemiacetal) or with its hydrate (with semihydrate).
If the group of compound of the present invention or substituting group and compound used according to the invention or compound of the present invention and compound self used according to the invention can be used as optical activity or steric isomer group, substituting group or compound form exist, because they for example have the center of asymmetry, these are also included by the present invention so.Here self-evidently be, compound of the present invention can the pure form of isomer exist, for example as pure enantiomer, diastereomer, E or Z isomer, trans or cis-isomeride form, or as wishing that with any the multiple mixture of isomers form 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 exist in the compound that uses any to have reactive functional group or substituting group in reaction of the present invention and/or formerly or undesirable reaction do not take place in the subsequent reaction and/or in the post-processing step; can use blocking group, it can be removed by fracture when described reaction is finished once more.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, the 3rd edition, John Wiley﹠amp; Among the Sons (1999).
Embodiment
The present invention further illustrates by following embodiment, and be not meant to it is limited to these embodiment.
GWP1 (general operation step 1)
Initially the homoallylic alcohol with the formula II of the aldehyde of the formula III of 0.1mol and 0.1mol is incorporated in the 100ml methylene dichloride.The Lewis acid of the solid form of 0.05mol to 0.06mol is joined in this mixture.When reacting completely (TLC inspection), this reaction mixture filtered by silica gel or carry out moisture aftertreatment.In this case, the 100ml water droplet is added in this mixture, and adds the 30ml concentrated hydrochloric acid then.This mixture is stirred until being separated fully.Water, hydrochloric acid and heptane are joined in the organic phase, and water is isolated after sedimentation.With the water dichloromethane extraction, and with organic phase merging and evaporation.With resistates further by separating in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, crystallization or distillation and purifying.
Be shown in Table 1 about the reaction conditions of the tetrahydropyran derivatives of the formula I that obtains by GWP1 and the detailed data of yield.
GWP2
Initial Lewis acid with 0.05mol to 0.055mol is incorporated in the 100ml methylene dichloride and by stirring and suspends.Then aldehyde (0.1mol) portioning of formula III is introduced.The homoallylic alcohol (0.1-0.11mol) that adds formula II subsequently.When this reacts completely (TLC inspection), this reaction mixture filtered by silica gel or carry out moisture aftertreatment-as described in the above-mentioned GWP1 part.
Be shown in Table 2 about the reaction conditions of the tetrahydropyran derivatives of the formula I that obtains by GWP2 and the detailed data of yield.
GWP3
Initially the homoallylic alcohol of the formula II of the aldehyde of the formula III of 0.1mol and 0.1mol and 0.5 to 5mol% Lewis acid are incorporated in the 100ml methylene dichloride to the temperature between the room temperature at 0 ℃.Under the condition that adopts exterior cooling, feed the gaseous hydrogen hydracid then to saturated.Then this reaction mixture is under agitation joined in the saturated sodium bicarbonate aqueous solution.Organic phase is isolated dry and evaporation.With resistates by separating in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, crystallization or distillation and purifying.
Be shown in Table 3 about the reaction conditions of the tetrahydropyran derivatives of the formula I that obtains by GWP3 and the detailed data of yield.
GWP4
The saturated halogen acid solution in water or in the Glacial acetic acid of 1.5 molar equivalents is under agitation joined in the dichloromethane solution of homoallylic alcohol of the aldehyde of formula III of 0.1M and formula II, wherein optionally add 0.5 to 5mol% Lewis acid.When this reacts completely (TLC inspection), with this reaction mixture as described in the GWP1, carrying out aftertreatment.
Be shown in Table 4 about the reaction conditions of the tetrahydropyran derivatives of the formula I that obtains by GWP4 and the detailed data of yield.
Compound from the halogenation tetrahydropyran derivatives preparation formula IV of formula I
The reduction of GWP5-in the presence of heterogeneous catalyst and trialkylamine eliminated
The substrate of the bromination of formula I is dissolved in the tetrahydrofuran (THF) of capacity (volume or weights of about 4 to 12 times of formula II compounds), 5% palladium/the carbon that adds 10 to 30 weight % (based on I), it comprises 54.7% water, 2.5 the triethylamine of molar equivalent and the water of doubling dose (based on described substrate) use hydrogen under 4 to 6 bar pressures to be hydrogenated to the theoretical absorbed dose of hydrogen in the pressurization autoclave in this mixture.After the cooling, filter this reaction mixture, and filtrate be poured on ice, and with concentrated hydrochloric acid with pH regulator to 1.With this mixture with heptane or heptane/toluene mixture extracting twice.The organic phase that merges is washed 4 times with water dry and evaporation.Character according to product is decided, and is further purified by means of crystallization, chromatographic separation and/or distillation.
Be shown in Table 5 about the reaction conditions of the tetrahydropyran derivatives of the formula IV that obtains by GWP5 and the detailed data of yield.
The reduction that utilizes tri-n-butyltin hydride to carry out is eliminated
Figure S2006800179265D00291
Numbering 9-table 2 IV-a
18.5g (0.05mol) numbered 9 4-chlorine tetrahydropyrans with the heating 24 hours under refluxing in 500ml benzene of the Diisopropyl azodicarboxylate of 32g (0.11mol) tri-n-butyltin hydride and 0.81g (5mmol) in table 2.Subsequently solvent evaporation is removed, and resistates is absorbed in the 200ml methyl tertiary butyl ether (MTBE).Add the 10%KF aqueous solution (0.4mol KF) of 232ml and the 18-hat-6 of 1.08g (2.5mmol), and this mixture is acutely mixed.With the organic phase drying, evaporation is adopted heptane/toluene (9: 1) to filter by silica gel, and will be evaporated resistates recrystallization from heptane that the back obtains once more.The yield of IV-a (not having optimization): 8.7g (5 2%).
The reduction that utilizes three (trimethyl silyl) silane (TTMSS) to carry out is eliminated
Numbering 16-table 1 IV-b
Will be at 1 of 600ml, the 20.75g in the 2-glycol dimethyl ether (0.05mol) in table 1, number 16 4-bromine tetrahydropyrans under agitation in quartz devices with the TTMSS of 1.24g (5mmol) and the NaBH of 9.5g (0.25mol) 4Be the rayed 12 hours of 254nm adding 60mg (2mmol) peroxidation after to methoxybenzoyl together with wavelength.Then solvent basic evaporation under vacuum is removed, and adopt heptane/silica gel to filter resistates by silica gel.The evaporation and from heptane recrystallization obtain IV-b; Yield (not having optimization): 8.1g (48%).
The dehydrohalogenation of formula I compound obtains the compound of formula Va and/or Vb
Embodiment A
Figure S2006800179265D00301
Numbering 3a, b-table 1 A1 A2
With the numbering 3a of 156g (0.487mol) in table 1,4-bromo-2-(4-bromophenyl) tetrahydropyrans (isomer mixture 2 of b, 4-cis: 2,4-is trans=84: 16) with 1 of 87.2ml (0.73mol), 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN) under agitation refluxed in 330ml toluene warm 3 hours, formed suspension during this period.After cooling, this mixture is adjusted to pH3 and violent the mixing with 400ml water and dilute sulphuric acid.Organic phase is isolated and water and NaHCO 3Solution washing, by filtered through silica gel and evaporation, obtaining 105g, to comprise ratio be 65: 35 A1 and the product mixtures of A2.
Embodiment B
Numbering 2-table 3 B1
4-bromo-2-(4-the bromophenyl)-5-methyl tetrahydropyrans that the isomer of numbering 2 is pure in table 3 of 49.7g (0.15mol) and the DBN of 27.8g (0.225mol) are stirred 4h under refluxing in 200ml toluene.Then this mixture is cooled to 0 ℃, and the salt throw out is removed by filter, and concentrate and adopt toluene/heptane (1: 1) to pass through filtered through silica gel filtrate.With this filtrate evaporation and with resistates crystallization from ethanol.The unique isomer that obtains is 4,5-dihydro-5-methyl tetrahydropyrans B1; Yield (not having optimization): 15.6g (73%)
Embodiment C
Numbering 3-table 3 C1
Be similar to Embodiment B, and numbering 3 tetrahydropyran derivatives in table 3 (isomer mixture 2, the 4-cis: 2,4-is trans=and 85: 15; 32.9g, 0.107mol) obtain C1, yield (not having optimization): 89%.
Embodiment D
Figure S2006800179265D00312
Numbering 4-table 3 D1
Be similar to Embodiment B, numbering 4 tetrahydropyran derivatives in table 3 (isomer pure 2,4-cis) obtains D1, yield (not having optimization): 93%.
Embodiment E
Figure S2006800179265D00313
The 4-bromine tetrahydropyrans (isomer mixture) of numbering 6 in table 3 of 23.0g (0.0556mol) and the DBN of 10.36g (0.0834mol) are stirred 3h under refluxing in 60ml toluene.Then this mixture is cooled to room temperature, adds 400ml water, and with this mixture with dilute sulphuric acid acidifying under agitation.In evaporation with adopt toluene/heptane mixture (1: 1) by after the filtered through silica gel, isolated organic phase obtain the isomer mixture that comprises E1 and E2 of 17.8g (96%), wherein E1 is main isomer.
Embodiment F
Figure S2006800179265D00321
Numbering 18-table 1 F1
The bromo tetrahydropyrans of numbering 18 in table 1 of 100g (219mmol) is dissolved under nitrogen in the 165ml toluene, adds the DBN of 38.5ml, and this mixture was heated 5 hours under boiling.In the refrigerative batch of material, add 200ml water subsequently, with the dilute sulphuric acid acidifying of this batch of material.Organic phase is isolated with the dilution of 300ml heptane, with sodium hydrogen carbonate solution washing and evaporation.The resistates that obtains is passed through silica gel (toluene), obtain the compound F 17-hydroxy-corticosterone 1 (content: 60% of 57.1g; Yield: 41%).
Formula V hydrogenation of compounds obtains the tetrahydropyrans of formula IV
Figure S2006800179265D00322
Three (triphenylphosphine) rhodium (I) muriate of 1mol% is joined in the isomer mixture of the E1 that derives from embodiment E of the 0.2mol (66.4g) in the mixture of 600ml ethanol and 200ml toluene and E2.To outgas for 3 times by nitrogen injection to 50 crust at this mixture in the autoclave of sealing, all carry out release in each case subsequently.After injecting 10 crust hydrogen, this mixture was descended warm 24 hours at 100 ℃.After cooling and release, filtered through silica gel is passed through in this reaction mixture evaporation and employing heptane/toluene (8: 2).Recrystallization obtains the 99.5% hydrogenated products IV-c of 24.8g (theoretical amount 37%) from ethanol and heptane then, and it is alltrans configuration (62 ℃ of fusing points; C 62 SmB 218I are from the extrapolation of 10% concentration among nematic mixture ZLI-4792 clearing point: 231 ℃).
Table 1
* isomer proportion: ratio with isomer (I) Yu all other steric isomers of complete calm arrangement
Table 2
Figure S2006800179265D00361
Figure S2006800179265D00371
* isomer proportion: ratio with isomer (I) Yu all other steric isomers of complete calm arrangement
Table 3
Figure S2006800179265D00381
Figure S2006800179265D00391
* isomer proportion: ratio with isomer (I) Yu all other steric isomers of complete calm arrangement
Table 4
Figure S2006800179265D00401
* isomer proportion: ratio with isomer and all other steric isomers of complete calm arrangement
Table 5
Figure S2006800179265D00411
* based on the substituting group on 2-and 5-position
Material characterizes
The material of pointing out in table 1-5 is by following the carrying out of sign of NMR (Nuclear Magnetic Resonance) spectrum (NMR) or mass spectrum or phase data.For mentioned complete calm main isomer, be in the 2H-3 of chair conformation, 4,5, the 6-tetrahydropyrans spreads out, and the designated reference following formula of proton carries out in the NMR spectrum of example of thing.
Figure S2006800179265D00421
H=H 4eOr halogen
R=H 5eOr substituting group
R '=substituting group
The tetrahydropyran derivatives I of table 1
1a) at CDCl 3In 250MHz 1H-NMR
Described signal location is in the ppm citation with respect to tetramethylsilane, and the size of coupling constant J is represented with hertz (Hz).Abbreviation m represents multiplet, and s represents unimodal, and d represents bimodal, and t represents triplet, and q represents quartet.These details also are applicable to all other cited NMR spectrum.
H 4a：m?4.13；H 6e：ddd?3.96·J＝12，4，2；H 6a：dt?3.37·J＝12.2；
H 2a: m 3.25; H 3eAnd H 5e: m 2.08-2.3; H 5a: dq 2.05J=12.4;
H 3a：q?1.73·J＝12；
The 4H:m 1.25-1.6 of two methylene radical in side chain; CH 3Group: t 0.9J=7.
1b) NMR spectrum is identical with 1a.
2) at CDCl 3In 250MHz 1H spectrum
H 4a：m?4.1；H 6e：ddd?3.95·J＝12，4，2；H 6a：dt?3.35·J＝12，2；H 2a：m?3.0；
16 H m 0.9-2.3 are made up of remaining tetrahydropyrans, cyclohexylidene and side chain methene proton; CH 3: t 0.85J=7.
3a) at CDCl 3In 500MHz 1H spectrum
4 fragrant H:AB-q, center 7.33 is for two ortho position H:d 7.46J=8 of bromine replacement; 2 ortho position H:d 719J=8 for the THP trtrahydropyranyl replacement;
H 2a，H 4a，H 6e：m?4.08-4.33；H 6a：dt?3.57·J＝12，2；
H 3e：ddd?2.44·J＝12，4，2；H 5e，H 5a：m?2.05-2.28；
H 3a：q?1.98(J＝12)
3b) NMR is identical with 3a
4) at CDCl 3In 250MHz 1H spectrum
2 fragrant H:m 6.95; H 4a, H 6e, H 2a: m 4.08-4.32; H 6a: dt 3.56J=12,2; H 3e: ddd 2.44J=12,4,2; H 5a, H 5e: m 2.06-2.32; H 3a: q 1.93J=12
5) at CDCl 3In 500MHz 1H spectrum
5 fragrant H:m 7.27-7.45 of the benzyl of phenyl; 4 fragrant H:AB-q of second phenyl ring, center 7.09, wherein 2 ortho position H:d 7.27J=8 that replace for THP trtrahydropyranyl; 2 ortho position H:d 6.94J=8 for the benzyloxy replacement; The CH of benzyl 22 H:s 5.06 of group; H 2a, H 4a: m 4.27; H 6e: d, d, d 4.13J=12,4,2;
H 6a：dt?3.56·J＝12，2；H 3e：ddd?2.44·J＝12，4，2；H 5e，
H 5a：m?2.0-2.5；H 3a：q?2.10·J＝12
6) at CDCl 3In 500MHz 1H spectrum
4 fragrant H:AB-q, center 7.09; 2 ortho position H:d 8.02J=8 for ester group; 2 ortho position H:d 7.40J=8 for the tetrahydropyrans replacement;
H 2a：dd?440·J＝12，2；H 6e：dd?4.21·J＝12，4；H 4a：m?3.92；
OCH 3：s?3.92；H 6a：t?3.25·J＝12；H 3e：ddd?2.53·J＝12，4，2；
H 3a：qq?2.13·J＝12；H 5a：m?2.1；CH 3：d?1.05·J＝7
7) at CDCl 3In 500MHz 1H spectrum
4 fragrant H:AB-q, center 7.09; 2 ortho position H:d 7.15J=8 for the tetrahydropyrans replacement; 2 ortho position H for phenol OH base:
d?6.75·J＝8；H 2a：dd?4.25·J＝12，2；H 6e：dd?4.18·J＝12，4；
H 4a：dt?4.02·J＝12.4；H 6a：t?3.27·J＝12；H 3e：ddd?2.47·J＝12，4，2；
H 3a: q 2.22J=12; CH 2The H of side chain 5aWith 1H:m 1.93; The other H m 1.23 of described side chain; CH 3: t 0.93J=7
8) at CDCl 3In 250 MHz 1H spectrum
4 fragrant H:AB-q, center 6.95 is for 2 ortho position H:d 7.15J=8 of tetrahydropyrans replacement; 2 ortho position H:d 6.75J=8 for phenol OH base;
H 2a：dd?4.27·J＝12，2；H 4a：dt?4.15·J＝12.4；H 6e：dd?4.08·J＝12.2；H 6a：t?3.26·J＝12；H 3e：ddd?2.45·J＝12，4，2；H 3a：q?2.10·J＝12；
CH 2The H of side chain 5aWith 1H:m 1.68-1.98; Two CH of described side chain 23 other H:m 1.10-1.53; CH 3T 0.90J=7
Fusing point: 104 ℃
9) at CDCl 3In 250MHz 1H spectrum
4 fragrant H:AB-q, center 6.99; 2 ortho position H:d 7.20J=8 for the tetrahydropyrans replacement; 2 ortho position H:d 6.78J=8 for phenol OH base;
H 2a：dd?4.30·J＝12，2；H 6e?H 4a；m?4.10-4.25；
H 6a：t?3.28·J＝12；H 3e：ddd?2.48·J＝12，4，2；H 3a：q?2.17·J＝12；
CH 2The H of side chain 5aWith 1H:m 1.72-2.00; Three CH of described side chain 2Other 5 H:m 1.15-1.5; CH 3: t 0.95J=7.
11) at CDCl 3In 250MHz 1H spectrum
5 fragrant H:m 7.28-7.45 of the benzyl of phenyl; 4 fragrant H:AB-q of second phenyl ring, center 7.10, wherein 2 ortho position H:d 7.26J=8 that replace for THP trtrahydropyranyl; 2 ortho position H:d 6.94J=8 for the O-benzyl group; The CH of benzyl 22 H of group:
s?5.06；H 2a：dd?4.28·J＝12，2；H 6e：dd?4.07·J＝12，4；H 4a：dt?3.98·J＝12，4；H 6a：t?3.22·J＝12；H 3e：ddd?2.48·J＝12，4，2；H 3a：q?2.18·J＝12；H 5a：m?2.07；CH 3：d?1.03·J＝7
12) at CDCl 3In 250MHz 1H spectrum
5 fragrant H:m 7.30-7.47 of the benzyl of phenyl; 4 fragrant H:AB-q of second phenyl ring, center 7.09, wherein 2 ortho position H:d 7.25J=8 that replace for tetrahydropyrans; 2 ortho position H:d 6.93J=8 for the o-benzyl group; The CH of benzyl 22 H of group:
s?5.05；H 2a?dd?4.27·J＝12，2；H 6e：dd?4.19·J＝12，4；H 4a：dt?4.03·J＝12，4；H 6a：t?3.26·J＝12；H 3e：ddd?2.50·J＝12，4，2；H 3a：q?2.18·J＝12；
Described CH 2The H of side chain 5aWith 1 H:m 1.83-2.0; Described CH 2Second H:m 1.12-1.38 of side chain; CH 3: t 0.93J=7
13) at CDCl 3In 250MHz 1H spectrum
5 fragrant H:m 7.29-7.44 of the benzyl of phenyl; 4 fragrant H:AB-q of second phenyl ring, center 7.09, wherein 2 ortho position H:d 7.25J=8 that replace for tetrahydropyrans; 2 ortho position H:d 6.93J=8 for the o-benzyl group; The CH of benzyl 22 H:s 5.05 of group;
H 2a：dd?4.26·J＝12，2；H 6e：dd?4.17·J＝12；H 4a：dt?4.02·J＝12，4；
H 6a：t?3.25·J＝12；H 3e：ddd?2.48·J＝12，4，2；H 3a：q?2.20·J＝12；
Described CH 2The H of side chain 5aWith 1 H:m 1.78-2.05; 3 CH in described side chain 25 H:m 1.10-1.45 CH of group 3: t 0.90J=7
14) at CDCl 3In 250MHz 1H spectrum
Fragrance H 2 : t 7.35J=8 (an ortho position H coupling and a position F coupling); All the other 4 fragrant H:m 7.09-7.26; H 2a: dd 4.40J=12,2; H 6e: dd 4.10J=12,4; H 4a: dt 3.78J=12,4; H 6a: t 3.25J=12; H 3e: ddd 2.43J=12,4,2; H 3aH 5a: m 1.83-2.20; CH 3: d 1.07J=7
15) at CDCl 3In 400MHz 1H spectrum
Fragrance H 2
Figure S2006800179265D00461
: t 7.38J=8 (an ortho position H coupling and a position F coupling); All the other 4 fragrant H:m 7.10-7.23; H 2a:
dd?4.37·J＝12，2；H 6e：dd?4.12·J＝12，4；H 4a：dt?3.93·J＝12，4；
H 6a：t?3.25·J＝12；H 3e：ddd?2.55·J＝12，4，2；H 3a：q?2.14·J＝12；
H 5a：m?2.08；CH 3：d?1.07·J＝7
16) at CDCl 3In 500MHz- 1H spectrum
4 fragrant H:m 6.95; H 2a: dd 4.35J=12,2 H 6e: dd 4.12J=12,4;
H 4a: m 3.91; H 6a: t 3.23J=12; H 3aAnd H 5a: m=2.05; CH 3D 1.06J=7
17) at D 6500MHz-in the-methyl-sulphoxide 1H spectrum
2 fragrant H:m 7.26; H 4a: dt 4.10J=12,4; H 6e: dd 3.87J=12,4;
H 2a：m?3.10；H 6a：t?3.03·J＝12；H 3e：ddd?2.25·J＝12，4，2；H 5a：m?2.10；
H 3aWith 10 cyclohexylidene H:m 1.00-2.04; CH 3D 0.93J=7.
20) mass spectrum
Molecule peak M 460,462: can not discern; 369,371:(M-91) -benzyl; 290:369,371-Br; 289:369,371-HBr; 91:PhCH 2 (base peak)
21) at CDCl 3In 250MHz- 1H spectrum
2 fragrant H:m 2.95; 5 OCH 2H, H 4a, H 2a, H 6e: m 4.2-4.5; H 6a: t3.59J=12; H 5a: dt 3.04J=12,4; H 3e: ddd 2.54J 12,4.2;
H 3a：q?1.99·J＝12；CH 3：t?1.30·J＝7
Mass spectrum:
Molecule peak M 366,368; 287:366,368-Br; 286:366,368-H Br; 241:
Figure S2006800179265D00462
Derive from 286 contrary diene decomposition:
Figure S2006800179265D00471
126-ethene-McLafferty, base peak.
Derive from the tetrahydropyran derivatives I of table 2
1) with the identical NMR of 3a in the table 1
2) identical with the NMR of numbering 7 in the table 1
3) with the identical NMR of numbering 8 in the table 1
Fusing point: 104 ℃
4) with the identical NMR of numbering 9 in the table 1
9) with the identical NMR of numbering 14 in the table 1
Derive from the tetrahydropyran derivatives I of table 3
1a), 1b) with the identical NMR of numbering 3a in the table 1
2) at CDCl 3In 250MHz- 1H-NMR spectrum
4 fragrant H:AB-q, center 7.34; 2 ortho position H:d 7.48J=8 for the bromine replacement; 2 ortho position H:d 7.19J=8 for the THP trtrahydropyranyl replacement;
H 6e：ddd?4.04·J＝12，2，1；H 4a：dt?3.96·J＝12，4；H 2a：d?3.89·J＝12；H 6e：dt?3.55·J＝12，2；H 3a?H 5e：m?2.77-2.38；H 5a：m?1.98；
CH 3：d?0.86·J＝7
3) at CDCl 3In 250MHz- 1H-NMR spectrum
For Cl adjacent fragrance H:t 7.36J=8 (an ortho position H coupling and a position F coupling); All the other two fragrant H:m 7.10-7.25;
H 2a：dd?4.30·J＝12，2；H 6e：dd?4.08·J＝12，4；H 4a：dt?3.88·J＝12，4；
H 6a: t 3.20J=12; H 3e: ddd 2.48J=12,4,2; H 3aWith
H 5a：m?1.95-2,17；CH 3：d?1.04·J＝7
5) mass spectrum
338,336: the molecule peak; 319,317:M-19 (F) 257:M -Br; 97:C 7H 13,
55:C 4H 7-base peak.
7) mass spectrum
414,412: the molecule peak; 333:M-Br; 332:M-HBr
289，287：
Figure S2006800179265D00481
207:
Figure S2006800179265D00482
55: base peak
9) mass spectrum
598,596: the molecule peak; 579,577:M-19 (F);
Figure S2006800179265D00483
517：598，596-Br；516：598，596-HBr；
451,449: the molecule peak
Figure S2006800179265D00484
(C 21H 26BrF 4O), base peak
The tetrahydropyran derivatives I of table 4
Numbering 1a, the NMR spectrum of 1b and 1e compound is identical with the numbering 3a compound of table 1.
The tetrahydropyran derivatives IV of table 5
1a/b) at CDCl 3In 250MHz- 1H spectrum
4 fragrant H:AB-q, center 6.89; 2 ortho position H:d 7.10J=8 for the THP trtrahydropyranyl replacement; 2 ortho position H for phenol OH base:
D 6.52J=8; H 2a: dd 4.28J=12,2; H 6e: dm 3.97J=12,4; H 6a: t 3.15J=12; H 3e, H 4e, H 5aAnd H 3a: m 1.57-1.94; H 4a: dq 1.22J=12,4; CH 3: d 0.75J=7
Fusing point: 91 ℃
2a/b) at CDCl 3In 300MHz- 1H spectrum
4 fragrant H:AB-q, center 6.88; 2 ortho position H:d 7.15J=8 for the THP trtrahydropyranyl replacement; 2 ortho position H for phenol OH base:
D 6.60J=8; H 2a: dd 4.20J=12,2; H 6e: dm 4.07J=12,4; H 6a: t 3.20J=12; H 3e: dm 1.99J=12,? H 4e: dm 1.80J=12; H 3a, H 5a: m 1.50-1.75; Side chain-CH 2And H 4a: m 1.1-1.3; CH 3: t 0.92J=7
Fusing point: 92 ℃
3) at CDCl 3In 250MHz- 1H spectrum
4 fragrant H:AB-q, center 6.95; 2 ortho position H:d 7.20J=8 for the THP trtrahydropyranyl replacement; 2 ortho position H for phenol OH base:
D 6.70J=8; H 2a: dd 4.20J=12,2; H 6e: dm 4.07J=12,4; H 6a: t 3.20J=12; H 3e: dm 1.99J=12,? H 4e: dm 1.80J=12,? H 3a, H 5a: m 1.50-1.75; 2 side-CH 24 H and H 4a: m 1.10-1.30; CH 3: t 0.92J=7
Fusing point: 94 ℃
4a/b) at CDCl 3In 250MHz- 1H spectrum
4 fragrant H:AB-q, center 6.95; 2 ortho position H:d 7.20J=8 for the THP trtrahydropyranyl replacement; 2 ortho position H for phenol OH base:
D 6.70J=8; H 2a: dd 4.20J=12,2; H 6e: dm 4.06J=12,4; H 6a: t 3.18J=12; H 3e: dm 1.97J=12; H 4e: dm 1.82J=12; H 5aAnd H 5a: m 1.53-1.74; 3 CH 26 side chain H of group and H 4a: m 1.05-1.45; CH 3: t 0.90J=7
Fusing point: 87 ℃
6) at CDCl 3In 250MHz 1H-NMR spectrum
Fragrance H 2
Figure S2006800179265D00491
: t 7.32J=8 (an ortho position H coupling and a position F coupling); All the other 4 fragrant H:m 7.18; H 2a: dd 4.28J=12,2; H 6e: dm 4.09J=12,4; H 6a: t 3.20J=12; H 3eAnd H 4e: m 1.83-2.12; H 3aAnd H 5a: m 1.47-1.80;
Described three side chain-CH 26 H of group and H 4a: m 1.05-1.40; CH 3: t 0.87J=7 fusing point: 58 ℃ (C 58 I)
7) at CDCl 3In 400MHz- 1H-NMR spectrum
Fragrance H 2 : t 7.32J=8 (an ortho position H coupling and a position F coupling); All the other 4 fragrant H:m 7.18; H 2a: dd 4.28J=12,2; H 6eDm 4.04J=12,? H 6a: t 3.18J=12; H 3eAnd H 4e: m 1.86-2.0; H 5a: m 1.78; H 3a: dq 1.60J=12,4; H 4a: dq 1.32J=12,4; CH 3: d 0.86J=7
Fusing point: 55 ℃ (C 55 I)

Claims (19)

1. the method for the halogenation tetrahydropyran derivatives of preparation formula I,
Figure S2006800179265C00011
It is characterized in that, in a reactions steps,
Homoallylic alcohol with formula II
Figure S2006800179265C00012
At least a Lewis acid that comprises at least one chlorine, bromine or iodine atom and/or comprise at least one chlorine, the anionic Br  of bromine or iodine nsted acid in the presence of, with aldehyde or its acetal or the hydrate reaction of formula III
Wherein, in formula I, II and III, in each case independently,
A, b, c, d, e and f represent 0 or 1 independently of one another, and wherein a+b+c+d+e+f equals 0,1,2,3 or 4;
X 1Be chlorine, bromine or iodine;
R 1Expression H, halogen ,-CN, having the alkyl of 1 to 15 C atom, this alkyl is unsubstituted or the single replacement of quilt-CN or by halogen list or polysubstituted, 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-substitutes in the mode that the Sauerstoffatom in described chain does not directly link to each other each other;
R 2Expression H, halogen ,-CN ,-NCS ,-NO 2,-OH ,-SF 5,-O-aralkyl, have the alkyl of 1 to 15 C atom, this alkyl be unsubstituted or quilt-CN single replace or by halogen or-O-aralkyl list or polysubstituted, 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-,-CO-O-or-O-CO-substitutes in the mode that the Sauerstoffatom in described chain does not directly link to each other each other;
A 1, A 2, A 3, A 4, A 5And A 6Independently of one another, also through rotation or one-tenth mirror image ground, expression
Figure S2006800179265C00021
Z 1The expression 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, perhaps expression-CH 2O-,-OCH 2-, and, if A 2Not cyclohexylidene or phenylidene ring, then Z 1Can also represent-CF 2O-;
Z 2The expression 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;
Z 3, Z 4, Z 5And Z 6Represent singly-bound independently of one another, have the alkylidene bridge of 1 to 6 carbon atom, this alkylidene bridge is unsubstituted or single or polysubstituted by F and/or Cl, perhaps expression-CH 2O-,-OCH 2-,-CF 2O-, wherein-CF 2The O-bridge is not connected directly to cyclohexylidene or phenylidene ring by its O atom;
N1, n2 and n3 are 0,1,2,3 or 4 independently of one another;
Y 1, Y 2, Y 3, Y 4, Y 5And Y 6Represent independently of one another H, halogen ,-CN, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl ,-OC 1-6Alkyl ,-OC 2-6Thiazolinyl ,-OC 2-6Alkynyl, wherein aliphatic group is unsubstituted or by halogen list or polysubstituted; With
W 1Expression-CH 2-,-CF 2-or-O-;
Wherein
Be under 0 the situation simultaneously at a and b, R then 1Be not hydrogen and
All be simultaneously under 0 the situation at a, b, c, d, e and f, R then 1And R 2Not H or unsubstituted alkyl.
2. according to the method for claim 1, it is characterized in that, use at least a Lewis acid.
3. according to the method for claim 1 or 2, it is characterized in that described Lewis acid is selected from formula M (X 1) nAnd R 3M (X 1) N-1Compound, wherein
M represents B, Al, In, Sn, Ti, Fe, Zn, Nb, Zr, Au or Bi;
X 1Expression Cl, Br or I;
R 3Expression has the straight or branched alkyl of 1 to 10 carbon atom; With
N is 2,3,4 or 5 integer and selects in its mode that equals the form Oxidation Number of M.
4. according to one or multinomial method in the aforementioned claim, it is characterized in that, the consumption of described Lewis acid for about 25mol% to about 300mol% and preferable amount be extremely about 200mol% of about 50mol%, in each case based on the homoallylic alcohol meter of used formula II.
5. according to one or multinomial method in the aforementioned claim, it is characterized in that described Br  nsted acid is Hydrogen bromide.
6. according to one or multinomial method in the aforementioned claim, it is characterized in that, use the mixture of at least a Lewis acid and at least a Br  nsted acid.
7. according to one or multinomial method in the aforementioned claim, it is characterized in that, is 0.1 to 20mol% at the consumption of Lewis acid described in the described mixture, and preferred 0.25 to 10mol%, in each case based on the homoallylic alcohol meter of used formula II.
8. according to one or multinomial method in the aforementioned claim, it is characterized in that X 1It is bromine.
9. according to one or multinomial method in the aforementioned claim, it is characterized in that described formula I compound respectively has a non-hydrogen substituting group on 2-and 5-position, and these substituting groups have each other and to be trans configuration.
10. according to one or multinomial method in the aforementioned claim, it is characterized in that, (a+b+c+d+e+f) 〉=1, particularly 1,2 or 3.
11. the compound of formula I
Wherein,
A, b, c, d, e and f represent 0 or 1 independently of one another, and wherein a+b+c+d+e+f equals 0,1,2,3 or 4;
X 1Be chlorine, bromine or iodine;
R 1Expression H, halogen ,-CN, having the alkyl of 1 to 15 C atom, this alkyl is unsubstituted or the single replacement of quilt-CN or by halogen list or polysubstituted, 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-substitutes in the mode that the heteroatoms in described chain does not directly link to each other each other;
R 2Expression H, halogen ,-CN ,-NCS ,-NO 2,-OH ,-SF 5,-O-aralkyl, have the alkyl of 1 to 15 C atom, this alkyl be unsubstituted or quilt-CN single replace or by halogen or-O-aralkyl list or polysubstituted, 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-,-CO-O-or-O-CO-substitutes in the mode that the heteroatoms in described chain does not directly link to each other each other;
A 1, A 2, A 3, A 4, A 5And A 6Independently of one another, also through rotation or one-tenth mirror image ground, expression
Figure S2006800179265C00041
Z 1The expression 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, perhaps expression-CH 2O-,-OCH 2-, and, if A 2Not cyclohexylidene or phenylidene ring, then Z 1Can also represent-CF 2O-;
Z 2The expression 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;
Z 3, Z 4, Z 5And Z 6Represent singly-bound independently of one another, have the alkylidene bridge of 1 to 6 carbon atom, this alkylidene bridge is unsubstituted or single or polysubstituted by F and/or Cl, perhaps expression-CH 2O-,-OCH 2-,-CF 2O-, wherein-CF 2The O-bridge is not connected directly to cyclohexylidene or phenylidene ring by its O atom;
N1, n2 and n3 are 0,1,2,3 or 4 independently of one another;
Y 1, Y 2, Y 3, Y 4, Y 5And Y 6Represent independently of one another H, halogen ,-CN, C 1-6Alkyl, C 2-6Thiazolinyl, C 2-6Alkynyl ,-OC 1-6Alkyl ,-OC 2-6Thiazolinyl ,-OC 2-6Alkynyl, wherein aliphatic group is unsubstituted or by halogen list or polysubstituted; With
W 1Expression-CH 2-,-CF 2-or-O-;
Wherein
Be under 0 the situation simultaneously at a and b, R then 1Be not hydrogen and
All be simultaneously under 0 the situation at a, b, c, d, e and f, R then 1And R 2Not H or unsubstituted alkyl.
12. the compound according to claim 11 is characterized in that, three substituting groups of the tetrahydropyran derivatives of formula I are all arranged in calm mode.
13. according to one or multinomial compound in the aforementioned claim, it is characterized in that, (a+b+c+d+e+f) 〉=1, particularly 1,2 or 3.
14. according to one or multinomial method in the aforementioned claim, it is characterized in that, make the tetrahydropyran derivatives of formula I reduce elimination to obtain the tetrahydropyran derivatives of formula IV
Figure S2006800179265C00051
Wherein a, b, c, d, e, f, R 1, R 2, A 1, A 2, A 3, A 4, A 5, A 6, Z 1, Z 2, Z 3, Z 4, Z 5, Z 6Independently as defined in claim 1.
15. according to one or multinomial method in the aforementioned claim, it is characterized in that, utilize organotin hydride or organosilicon reagent to carry out described reduction and eliminate.
16., it is characterized in that X according to one or multinomial method in the aforementioned claim 1Be bromine, and described reduction elimination is the debrominate hydrogenation process in the presence of catalyzer and alkali.
17., it is characterized in that according to one or multinomial method in the aforementioned claim, make the tetrahydropyran derivatives of described formula I carry out dehydrohalogenation, obtain dihydropyran derivatives, particularly the dihydropyran derivatives of formula Va and/or Vb:
Figure S2006800179265C00061
Wherein a, b, c, d, e, f, R 1, R 2, A 1, A 2, A 3, A 4, A 5, A 6, Z 1, Z 2, Z 3, Z 4, Z 5, Z 6Independently as defined in claim 1.
18., it is characterized in that the dihydropyran derivatives hydrogenation that will form according to claim 17 is to obtain formula IV compound according to one or multinomial method in the aforementioned claim, it as defined in claim 14.
19. preparation is characterized in that according to the method for the formula IV compound of claim 14 it comprises at least one method steps according to claim 1, the wherein a in formula I, II, III and IV, b, c, d, e, f, R 1, R 2, A 1, A 2, A 3, A 4, A 5, A 6, Z 1, Z 2, Z 3, Z 4, Z 5, Z 6Definition independently of one another.
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