The way epoxidation of olefins prehiring

 

(57) Abstract:

The invention relates to a method for epoxidation prehiring of olefin, which includes the interaction prehiring of the olefin with oxygen source in the presence of salt catalyst. Epoxidation is carried out in the presence of isoquinoline-N-oxide, which is a donor ligand. As the catalyst is used as a compound of the formula (IB) or (II) described in paragraph 2 of the claims. In addition, a variant of the method, according to which the interaction prehiring of the olefin with the source of oxygen is carried out in the presence of a salt of the catalyst compounds of the formula (II) and the source of the ligand, giving up an electron. 2 s and 5 C.p. f-crystals.

The invention relates to a new process for the preparation of epoxides from olefins, in particular hereinabove epoxides, to certain new catalysts used in such a way, and to the connections associated with this method.

In the application WO 91/14694 describes some of the catalysts having the following formula:

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in which M is a transition metal ion, a is an anion and n is 0 or 1, or 2. At least one of X1or X2choose UB> or X4selected from the same group. Y1, Y2, Y3, Y4, Y5and Y6independently selected from the group consisting of hydrogen, halides, Akilov, aryl groups, silyl groups, and alkyl groups having heteroatoms, such as alkoxy and halide. In addition, at least one of R1, R2, R3and R4selected from a first group consisting of N, CH3C2H5and primary Akilov. In addition, if R1choose from the first group, then R2and R3selected from a second group consisting of aryl groups having a heteroatom aromatic groups, secondary Akilov and tertiary Akilov. If R2choose from the mentioned first group, then R1and R4choose from the mentioned second group. If R3choose from the mentioned first group, then R1and R4choose from the mentioned second group. If R4choose from the mentioned first group, then R2and R3choose from the mentioned second group. Such catalysts are described as suitable for enatioselective epoxydecane properally olefins.

In addition, in the application WO 91/14694 describes some of the catalysts having negatived the camping anion; n is 3, 4, 5 or 6; at least one of X1or X2selected from the group consisting of arrow, primary Akilov, secondary Akilov, tertiary Akilov and heteroatoms, at least one of X3or X4selected from the group consisting of arrow, primary Akilov, secondary Akilov, tertiary Akilov and heteroatoms, at least one of Y1or Y2selected from the group consisting of arrow, primary Akilov, secondary Akilov, tertiary Akilov and heteroatoms, at least one of Y4or Y5selected from the group consisting of arrow, primary Akilov, secondary Akilov, tertiary Akilov and heteroatoms; Y3and Y6independently selected from the group consisting of hydrogen and primary alkyl groups; R1and R4are in the TRANS position in relation to each other, and at least one of R1and R4selected from the group consisting of primary Akilov and hydrogen; and carbon (C)nparts have substituents selected from the group consisting of hydrogen, alkyl, aryl and heteroatoms.

Such catalysts are described as suitable for the enantioselective epoxydecane properally olefins. These catalysts, DVD, the joint consideration of international patent application PCT/GB 93/01666 (currently, international patent application publication number WO 94/03271) also presents a number of salt catalysts the structure is different from the catalysts of formula (I) and having the General formula (II)

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in which M represents a transition metal ion;

And, if necessary, is protivoiona;

r, s and t are independently 0 to 3, the sum r+s+t must be in the range from 1 to 3;

Ra, Rb, Rcindependently are hydrogen or CH2OR', where R' is hydrogen or an organic group;

B and E are independently oxygen, CH2, NRdwhere Rdis alkyl, hydrogen, alkylcarboxylic or arylcarboxylic or SOnwhere n is 0 or an integer 1 or 2, provided that b and E are not simultaneously CH2and that, when b is oxygen, NRdor SOnthen r cannot be 0, and when E is oxygen, NRdor SOnthen t cannot be zero;

R1, R2, R3, R4, R5, R6, R7, R8, R9and R10independently are hydrogen, alkyl or alkoxy.

The compounds of formula (II) also catalyze the enantioselective epoxidation of certain properally olefins.

In this area it was assumed that the use of compounds such as the mi catalysts, improves chemical yield of such reactions (Syn. Lett. , April, 1991, 265-266), although the effect on the enantioselectivity catalyzed reactions is currently unclear (Tetrahedron. Vol. 50, N15, R. 4323-4334, 1994). In this context, pyridinone and 2-Mei is referred to as "donor ligands", because they believe that they are related donor communication with the ion of the metal salt catalyst.

One important problem associated with the use of such donor ligands, is the complete removal of the donor ligand of the final epoxy product, especially in large-scale reactions and, mainly, when using two-phase reaction system.

It was found that one particular compound, isoquinoline-N-oxide, which has not previously been reported as the donor ligand is particularly effective as a donor ligand, as it increases the turnover of the catalyst and, in addition, he has a very good solubility for use as a donor ligand, which gives the opportunity to use it in epoxidation reactions catalyzed complex metal, and subsequently easily removed from the epoxy reaction products. It was also discovered that a specific group of salt catageory ligands consistently gives not only increase the reaction rate, but also increase enantioselective specificity of epoxidation reactions.

In addition, there was obtained another set of salt catalysts that structure different from the catalysts of formulas (I), (IA) and (II) and which, surprisingly, also have the ability to catalyze the enantioselective epoxidation of certain properally olefins.

Respectively according to the first aspect of the invention provides a method for enantioselective epoxidation properally olefins, including interaction prehiring of the olefin with oxygen source in the presence of salt catalyst and source of the ligand, giving the electron, characterized in that the donor ligand is isoquinoline-N-oxide or a compound having activity donor ligand and having essentially the same properties of solubility, as isoquinoline-N-oxide.

Suitable salt catalyst is a compound of formula (I), (IA), (II) or the compound of formula (III). The compound of formula (III) will be determined in the future.

The invention also provides as a donor ligand isoquinoline-N-oxide or a compound having activity donor ligand, and having essentially the same sweet way enantioselective epoxidation prehiring of olefin, including interaction prehiring of the olefin with oxygen source in the presence of salt catalyst is a source of ligand radiating electron, characterized in that the salt catalyst is a compound of formula (II).

The source of the ligand, giving the electron adequately provide through connections, which are capable of forming donor bond with the transition metal M mentioned salt catalyst, in order when using the increased speed of reaction of epoxidation and could also increase enantioselective specificity of the obtained product.

The source of the ligand, giving the electron adequately provide through connections, which are capable of forming donor bond with the transition metal M salt catalyst, in order when using increased enantioselective specificity of the compounds of formula (I).

A suitable source of ligand, giving the electron, can be selected from the list consisting of pyridine-N-oxide, 2-methylpyridine-N-oxide, 4-methylpyridine-N-oxide, 4-phenylpyridine-N-oxide or isoquinoline-N-oxide, is particularly suitable isoquinoline-N-oxide.

In the compounds of formulas (I) and (IA) p is Y5, Y6, R1, R2, R3, R4defined in WO 91/14694.

Suitable catalysts are catalysts of the formula (IA), which is defined above.

A preferred group of catalysts are catalysts of the formula (IB), which is defined below

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in which Y1and Y2are the same and are selected from the group consisting of methyl, tert-butyl or methoxy, and R2and R3both are phenyl or together with the carbon atoms to which they are attached, form hexylene ring.

In the catalysts of the formula (IB) are most preferably both Y1and Y4are tert-bootrom and R2and R3together with the carbon atoms to which they are attached, form hexylene ring.

In the compounds of formula (II) suitable, benefits and preferred values of the variables a, b, E, Ra, Rc, Rd, R', Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, n, r, s and t are as described in WO 94/03271, if it is not specified otherwise.

Suitable organic groups R' include alkyl, alkylcarboxylic the group.

One example of R' is triphenylethylene group.

Preferred values of s and t is zero, r is 1 and Rais hydrogen, A is oxygen and E represents CH2or r, s, t equal to 1, Ra, Rband Rcare hydrogen and both b and E is oxygen or s is 0, both r and t is 1, Rais hydrogen or triphenyltetrazolium and Rcis hydrogen, A is oxygen and E predstavlyaet-CH2-; or both r and t is 1, s is Oh, Raand Rcare hydrogen, A is NRdwhere Rdis phenylcarbinol and E is CH2.

Each of R2, R4, R5and R7suitably independently represents hydrogen.

Each of R1, R3, R6and R8suitably independently represents C1-6alkyl.

R1and R8preferred are branched alkyl groups, for example tertiary alkyl groups.

R3and R6also advantageous are branched alkyl groups.

One preferred example of any one of R1and R8is tertiary butyl.

Specific examples of R3 is astavliaut hydrogen.

Examples of compounds of the formula (II) include such as those shown as examples in WO 94/03271, and in particular such compounds, referred to herein.

As mentioned above, one aspect of the invention is the detection of a new range of salt catalysts.

Accordingly in one aspect the present invention provides a compound of formula (III)

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in which M is a transition metal ion;

And, if necessary, represents a counterion;

B, b', E and E' independently are selected from the group consisting of hydrogen, aryl, C1-6of alkyl, Srila or aryl-C1-6of alkyl, which aryl or alkyl optional component is replaced, or' and or E' and E together form a C2-6polymethene communication, provided that only one of the carbons marked with an asterisk represents a chiral center;

R1, R2, R3, R4, R5, R6, R7, R8, R9and R10independently are hydrogen, alkyl or alkoxy.

In the compounds of the formula (III)

Each of R2, R4, R5and R7suitably independently represents hydrogen.

Each of R1, R3, R

R3and R6also advantageous are branched alkyl groups.

One preferred example of any one of R1and R8is tertiary butyl.

Specific examples of R3and R6are tertiary butyl and methyl.

Examples R2, R4, R5and R7is hydrogen.

One of the examples b and E is phenyl, methyl or isopropyl, and the other is hydrogen. One of the most preferred examples of b and E is phenyl and the other is hydrogen.

The compounds of formula (III) are also suitable salt catalysts for use in the method of the invention.

In the compounds of formula (I), (IA), (IB), (II) and (III)

The relationship between M and has a varying degree of ionic character, dependent anion.

Suitable ions of the transition metal M include MP, CR, Fe, Ni, Co, Ti, V, Ru and 0s in the appropriate oxidation state.

Preferred ion of the transition metal M is MP in oxidation States (II) or (III).

Note that in some cases, for example, when M is MP (II), the counterion is not necessary.

In the method of the invention

Suitable probiralsya olefins include compounds that contain as part of its structure the following connections: cyclohexen, 5,6-dihydro-2H-Piran, 1,2,5,6-tetrahydropyridine, 1,2,3,4-tetrahydropyridine, and 5,6-dihydro-2H-thiopyran.

Using preference probiralsya olefins include compounds that contain as part of its structural forms of the following groups: 1,2-dihydronaphthalene 2N-chromen, 1,2-dihydroisoquinoline and 2H-thiochroman. Such compounds are well known in the field of potassium channel activators.

Preferred probiralsya olefins include those that are mentioned in EP-A-0376254, for example the compounds of formula (XIV), in particular 2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran.

Suitable sources of oxygen include oxidants such as sodium hypochlorite.

To ensure the required epoxide reaction of epoxidation can be carried out using appropriate methods, which interact properly olefin, a source of oxygen, a compound of formula (I) and the source of the ligand, giving an electron.

The reaction is suitably carried out in a biphasic system, especially kagoda is sodium hypochlorite.

Suitable two-phase systems are those systems that are usually used in this field, while taking into account the nature of the specific reactants, for example a two-phase system is methylene chloride and water.

Salt catalysts, for example the compound of formula (I), (IA), (II) or (III), properly olefin and the source of the ligand, giving an electron, in an inert, vodosmeshivayuschego solvent, for example dichloromethane, can interact with the source of oxygen in the water.

Usually the reaction is carried out at a pH in the range between 10 and 13, preferably between 10.5 and 12, most preferably between 11 and 11.5, pH conveniently regulate through the presence of a buffer, such as monopotassium phosphate.

The reaction may be carried out at a suitable temperature providing a suitable rate of formation of the required product. Due to the increase in reaction rate caused by the presence of the source of the ligand, giving the electron, the reaction can be performed at a temperature lower than the temperature at which the reaction is carried out without ligand, for example in the range between 0 and 40oC. Generally carried out at ambient or slightly elevated so is E. the compounds of formula (I) to ProfileName the olefin is in the range from 0.01 to 10, preferably in the range of from 0.1 to 0.05, 0.5 to 5, from 1 to 5, 1 to 3, 0.5 to 2, most preferably in the range of from 0.2 to 2.

A suitable molar ratio of the source of the ligand, giving an electron to ProfileName the olefin is in the range from 0.05 to 3, for example from 0.1 to 2.0, or from 1 to 2, the preferred range is from 0.1 to 2. A suitable molar ratio for N-pyridinoline is, for example, in the range from 0.5 to 2. A suitable molar ratio for isoquinoline-N-oxide is, for example, in the range from 0.1 to 0.5.

The present invention also extends to obtaining all of epoxides, which are precursors of compounds of formula (I) and EP-A-0376524, in particular the specific examples of this application.

The present invention also extends to obtaining all of epoxides, which are precursors of compounds of formula (I) in WO 92/22293, in particular the specific examples of this application.

The present invention also applies to the subsequent conversion of any of the above-mentioned epoxides to the corresponding compounds of formula (I) of EP-A-0376524, particularly on the transformation of the relevant previous epoxides to the corresponding specific example with the-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-6-pentafluoroethyl-2H-1-benzopyran-3-ol or (+)-TRANS-isomer.

The present invention also applies to the subsequent conversion of any of the above-mentioned epoxides to the corresponding compounds of formula (I) WO 92/22293, in particular on the transformation of the relevant previous epoxides to the corresponding specific example of the compounds of WO 92/22293, particularly on the conversion of (3R, 4R)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran in TRANS-6-acetyl-4S-(4-perbenzoate)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol or 3S, 4R-isomer.

The present invention also applies to the product formed between salt catalyst, for example a compound of formula (I), (IA), (IB), (II) or (III), and the ligand, giving an electron.

The term "chiral salt catalyst" refers to salt catalysts dominated by one specific enantiomer and which in use provide the predominance of one specific enantiomer of the epoxide derived from prehiring olefins.

The term "alkyl", when used only when he or alkyl forms a part of other groups (for example, alkoxygroup or alkylcarboxylic group) includes an alkyl group with straight or branched chain, containing from 1 to 12 carbon atoms, the approach is to inuu, isobutylene or tert-boutelou group.

When I use the term "aryl", he includes phenyl and naphthyl, optionally substituted by groups of up to five, preferably up to three, selected from halogen, alkyl, phenyl, alkoxy, halogenoalkane, alkylcarboxylic and phenylcarbinol.

The preferred aryl group is a substituted or unsubstituted phenyl group.

Transition metals M include such metals, which have a degree of oxidation equal to (II) or more.

Suitable aryl substituents include alkyl, halogen and alkoxy.

Optional substituents of the aryl include those that are mentioned here for the aryl groups, a particular example is phenyl.

Note that the carbon atoms marked with an asterisk represent chiral centers and that the present invention extends to each individual enantiomer and any mixture.

Compounds of formula (I), (IA) and (IB) can be obtained in accordance with the methods described in WO 91/14694, or by similar methods.

The compounds of formula (II) can be obtained in accordance with the methodologies presented in the international sekretnye descriptions and examples listed here for reference.

With regard to compounds of formula (III), the present invention also provides a method of obtaining compounds of formula (III), which includes the formation of the complex of the transition metal of the following compounds of formula (IV):

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in which the variables R1, R2, R3, R4, R5, R6, R7, R8, R9and R10B, B', E and E' are as defined in relation to formula, in which only one of the carbons marked with an asterisk, is a chiral center, and further, if necessary, separation of enantiomers.

Complex ion of the transition metal may be suitably formed by adding the appropriate salt of the transition metal, such as manganese acetate (II) or (III), preferably the acetate of manganese (III) to the compound of formula (IV) in an appropriate solvent, for example ethanol or methylenechloride, at elevated temperature. Optional substitution or vzaimoprevrascheny the counterion can be done by adding a suitable source of the desired counterion, such as a salt of an alkali metal, such as LiCI.

The separation of enantiomers can be accomplished obiaztelno enantiomers preferably carried out before the formation of the complex of the transition metal.

The invention also provides a method for producing compounds of the formula (IV), which includes the sequential condensation, in any order, the compounds of formula (V)

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in which b, b', E and E' are as defined in formula (III), and R11and R12independently represent hydrogen or a protective group for the amine, provided that at least one of R11and R12is hydrogen, with

(i) a compound of formula (VI)

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in which R1, R2, R3, R4and R9are as defined in relation to formula (III), and

(ii) a compound of formula (VII)

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in which R5, R6, R7, R8and R10are as defined in relation to formula (III), and further, when necessary, removing the protective group R11and R12the selection of the desired compounds, including, if it is necessary, separation of enantiomers.

Preferably, the compound of formula (IV) were obtained from optically pure compounds of the formula (V), which are preferably derived from optically pure starting materials. Alternative racemate or a mixture of enantiomers of formula (VI) or (VII) can dissolve is adopted.

When are the required compounds of formula (IV), in which one or more of R1, R2, R3, R4and R9unequal, respectively, when are unequal, one or more of R8, R7, R6, R5and R10then the compounds of formula (V) can be sequentially condensing compounds of the formula (VI) and formula (VII) in any order, by heating suitably protected compounds of formula (V) with the compound of the formula (VI) or (VII) (at a molar ratio of 1:1) in an inert solvent, for example ethanol, if necessary, purification formed intermediate compounds of formula (VIII) or (IX)

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in which the variables R1to R12E , E', and b' are as defined in relation to formula (V), (VI) or (VII) using conventional separation techniques such as chromatography; the removal of the protective group R11or R12and then, when necessary, repeat the reaction using compounds of formula (VI) or (VII).

Suitable protective groups R11or R12include a conventional protective group for the amine, the introduction and removal are compatible with the nature of the molecules to be protected, e.g. Yelnya group.

Remove R11or R12when they represent a protective group can be carried out using methods which are generally accepted in this field, depending on the nature of the protective group.

Note that when each of R1, R2, R3, R4and R9is the same, and each of R8, R7, R6, R5and R10accordingly, the compounds of formulas (VI) and (VII) are the same, so it is preferable to use the compounds of formula (V) in which R11and R12are hydrogen and two molecules of compounds of formula (VI) or (VII).

The reaction is suitably carried out in an inert solvent, for example ethanol, at elevated temperature, for example at the distillation temperature of the selected solvent.

The compounds of formula (V) are either known compounds or can be obtained in accordance with known methods, or according to methods similar to the known, or in accordance with methods similar to those described here.

The compounds of formula (VI) and (VII) are known commercially available compounds or can be obtained in accordance with known methods or in aghi et al. J. Chem. Soc. Perkin Transactions I, 1980, p. 1862-1865.

The new compounds of the formula (IV), (VI), (VII), (VIII) and (IX) form an aspect of the present invention.

As indicated here above, the compounds of formula (II) can be obtained using the methods presented in the joint review of international patent application PCT/GB 93/01666 (now the international patent application WO 94/03271). For the avoidance of doubt these methods include the following.

The compounds of formula (II) can be obtained by forming a complex of the transition metal of the following compounds of formula (X):

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in which the variables R1to R10, B, E, r, s, t, Ra, Rb, Rcare as defined in relation to formula (II), and then, if necessary, separation of enantiomers.

The complex of the transition metal may be suitably formed by adding the appropriate salt of the transition metal, such as manganese acetate (II) or (III), preferably the acetate of manganese (III) to the compound of formula (II) in an appropriate solvent, for example ethanol or methylenechloride, at elevated temperature. Optional substitution or vzaimoprevrascheny the counterion may be osushestvlenie Lil.

The separation of enantiomers can be carried out by standard methods, for example the derivative crystallization or chromatography. Note, however, that the division enatiomers preferably carried out before the formation of the complex of the transition metal.

The compounds of formula (X) can be obtained by successive condensation, in any order of the compounds of formula (XI)

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in which r, s, t, Ra, Rband RcE, are as defined in formula (II), and R11and R12independently represent hydrogen or a protective group for the amine, provided that at least one of R11and R12is hydrogen, with a compound videopreteen formulas (VI) and (VII). Reaction conditions similar to the conditions described above with respect to the reaction between the compound of formula (V) and compounds of formula (VI) and (VII).

Preferably, the compound of formula (X) obtained from optically pure compounds of the formula (XI), which are preferably derived from optically pure starting materials. Alternative racemate or a mixture of enantiomers of formula (X) or (XI) can dissolve when using conventional methods in this area is, the one or more of R1, R2, R3, R4and R9unequal, respectively, when are unequal, one or more of R8, R7, R6, R5and R10then the compounds of formula (XI) can be sequentially condensing compounds of the formula (VI) and formula (VII), in any order, by heating suitably protected compounds of formula (XI) with the compound of the formula (VI) or (VII) (at a molar ratio of 1:1) in an inert solvent, for example ethanol, if necessary, purification formed intermediate compounds of formula (XII) or (XIII)

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< / BR>
in which the variables R1to R12, r, s, t, Ra, Rband Rc, E and b are as defined in formula (XI), (VI) and (VII), using conventional methods, such as chromatography, removal of the protective groups R11or R12and then, when necessary, repeat the reaction using compounds of formula (VI) or (VII).

Suitable protective groups R11and R12and removal of such groups are as described above.

Note that when each of R1, R2, R3, R4and R9Yaya formulas (VI) and (VII) are the same, therefore, it is preferable to use the compounds of formula (XI) in which R11and R12are hydrogen, and apply two molecules of compounds of formula (VI) or (VII) in an inert solvent, for example ethanol, at elevated temperature, for example at a temperature of distillation.

The compounds of formula (XI) are known compounds or can be obtained in accordance with known methods or according to methods similar to the known, or according to methods similar to the methods described here, for example, when the compound of the formula (XI) is 3,4-diaminetetraacetate, this connection can be obtained in accordance with the following scheme, for example, as described in descriptions 1 and 2.

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Alternative (S,S)-TRANS - 3,4-diaminetetraacetate can be obtained in accordance with the following scheme, for example, as described in the descriptions 4-6.

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5R, 6R-Diamino-1,3-dioxan can be obtained in accordance with the methods described in the descriptions 8-13.

3R, 4S-Diaminetetraacetate can be obtained in accordance with the methods described in the descriptions 15-17.

3R,4S-Diamino-(2S)(triphenylmethyl)tetrahydrofuran may be hypericin can be obtained in accordance with methods, which are described in the descriptions 25-27.

Catalysts of the formula (III) receive, preferably in chiral form by use of the dissolved compounds of formula (XI), which can be dissolved using conventional methods. The connection of the formula (XI) can be obtained from the respective preceding compounds, such as those outlined above in General terms and which can be dissolved using conventional methods or can be purchased in dissolved form. Alternative a bound compound of formula (X) can be dissolved using conventional methods.

The present invention also provides a method of obtaining compounds of formula (A), which is defined in WO 93/17026, or when it is appropriate, their pharmaceutically acceptable salts or their pharmaceutically acceptable MES, which includes the interaction of the compounds of formula (I), source of oxygen, the compounds of formula (C) and the source of the ligand, giving the electron, and then the conversion of the compounds of formula (I) in the compound of formula (A) or, when this is appropriate, its pharmaceutically acceptable salt or its pharmaceutically acceptable MES.

The compounds of formula (C) are commercially available or can be obtained in accordance with methods that are referenced by or that are outlined in EP-A-0376524.

The present invention explain the following description and examples.

(A) Examples of using the catalysts presented in WO 91/14694.

Example 1. Obtain (2R,4R)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran using pyridine-N-oxide as a ligand, giving an electron.

With 8N NaOH established pH of sodium hypochlorite solution (54 ml, 13.7% of the weight./vol.), 0.05 M Na2HPO4(50 ml) and water (70 ml), equal to 11.3.

Mixed together 6-acetyl-2,2-DIMETHYLPROPANE (10 g, 0,049 mol) and R,R-[1,2-bis(3,5-di-tert-butylaniline)cyclohexane] manganese(III)chloride catalyst (320 mg, 1 mol.%), pyridine-N-oxide (9.5 g, 2 EQ) and dichloromethane (50 ml) and the mixture was stirred for 1 hour.

The solution was diluted D (dichloromethane) (200 ml) and filtered through celite, the layers were separated. The aqueous layer was extragonadal DCM (200 ml), then the organic layers combined. The organic phase was washed with water (I ml) and boiled away the dryness to obtain coric is from RE (2 1/2 volume), hunted by epoxide to obtain a named connection in the form of not-quite-white/brown solid (6,45 g, 60%), E. E. 99%.

For carrying out the same reaction without added ligand, giving an electron, for example, pyridine-N-oxide, usually 1 mol. % of catalyst to achieve full transformation at room temperature for about 4 hours (crude epoxide, E. E. 92%).

Example 2. Obtain (3R,4R)-2,2-dimethyl-3,4-epoxy-6-pentafluoroethyl-2H-1-benzopyran using isoquinoline N-oxide as a ligand, giving an electron.

Using diluted phosphoric acid has set the pH of the sodium hypochlorite solution (44 ml, 17% wt./vol.), water (70 ml) and 0.05 M NaH2PO4(50 ml), equal to 11.3. Added 2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran (13,6 g, 50 mmol), dichloromethane (100 ml), isoquinoline-N-oxide (0,725 g, 10 mol.%) and R,R-[1,2-bis(3,5-di-tert-butylaniline)cyclohexane]manganese(III)chloride (64 mg, 0.2 mol.%) and the mixture was quickly mixed at room temperature. After 2 hours the analysis of HPLC (high performance liquid chromatography) showed 95% conversion of chromene in epoxide. The reaction mixture was stirred for a further 3 hours at room temperature, but additional preferencei HPLC of 92.5%. The mixture was diluted with dichloromethane (200 ml), filtered through celite and the layers were separated. The organic phase was washed with water (I ml), then boiled away dokuja to obtain the crude titled compound (15.0 g) as a yellow solid. The crude product was recrystallize from hexane (3 volume) to obtain pure titled compound (8.0 g, 54%) as colorless needle-like crystals (E. E. > 99%).

For carrying out the same reaction without the ligand, giving an electron, for example isoquinoline-N-oxide, usually requires 2 mol.% catalyst for a complete transformation.

Example 3. Obtain (3R,4R)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran using isoquinoline-N-oxide as a ligand, giving an electron.

Repeating the procedure of example 1 using 10 mol.% isoquinoline-N-oxide instead of pyridine-N-oxide. The amount of catalyst is also reduced to 0.1 mol. %. Complete conversion into the desired epoxide (E. E. 96%) was reached within less than 15 minutes.

Example 4. Obtain (2R,4R)-6-acetyl-2,2-dimethyl-3,4-epoxy-8-iodo-2H-1-benzopyran using isoquinoline-N-oxide as a ligand, giving an electron.

Repeating the procedure of example 1 using 0.2 equivalent is whether a complete transformation into the epoxide (E. E. 98%). The crude product was recrystallize from RE (3 volume) to obtain enantiomerically pure titled compound, melting point 123,6-125,4oC, yield 72%.

(C) Examples of using the catalysts presented in WO 94/03271.

Example 5. Obtain (3R,4R)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran using pyridine-N-oxide as a ligand, giving an electron.

Using 8N Paon established pH of sodium hypochlorite (21,5 ml, 17.3% of the weight. /about. ), water (34 ml) and 0.05 M PA2NRA4(25 ml), equal to 13. To dichlormethane (50 ml) was added 6-acetyl-2,2-dimethyl-2H-1-benzopyran (5.0 g, 25 mmol), pyridine-N-oxide (5.0 g, 52 mmole) and S,S-Mn-salt catalyst - (3S, 4S)-bis(3,5-di-tert-butylaniline)tetrahydrofuran manganese(II)chloride (D34, 152 mg, 1 mol.%), and the mixture was mixed at room temperature. After 2 hours in accordance with the HPLC analysis, the reaction has ended. The mixture was diluted with dichloromethane and filtered through celite. The two phases were separated and the organic phase was washed with water (200 ml), then boiled away to dryness under reduced pressure to obtain the crude titled compound as a brown oil (5.0 g). As shown by chiral HPLC, E. E. was 94%.

The named compound was obtained enantiomerically pure (that is, 4%.

Example 6. Obtain (3S,4S)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran without the use of a ligand, giving an electron.

With 8N NaOH established pH of sodium hypochlorite solution (8.0 ml, 17.3% of the weight. /about. ), water (14 ml) and 0.05 M Na2HPO4(10 ml), equal to 13. To dichlormethane (20 ml) was added 6-acetyl-2,2-dimethyl-2H-1-benzopyran (2.0 g, 10.0 mmol), (R, R-Mn-salt catalyst - R,R-[5,6-bis(3,5-di-tert-butylaniline)-1,3-dioxan] manganese(III)chloride (D31, 63 mg, 1 mol.%) and the mixture was stirred at room temperature overnight. The HPLC analysis showed that about 13% of chromene still remained.

The mixture was diluted with dichloromethane (50 ml) and filtered through celite. The organic phase was separated, then washed with water (100 ml) and boiled away the dryness to obtain the crude titled compound as an oil (2.1 g, yield 96 wt.%). The analysis of this sample chiral HPLC showed E. E. 86%.

Example 7. Obtain (3S,4S)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran using pyridine-N-oxide as a ligand, giving an electron.

Repeating the procedure of example 6, but with the addition of pyridine-N-oxide (1.9 g, 20 mmol). The HPLC analysis showed that after stirring for overnight at room temperature the reaction was completed. The same is Chile enantiomerically pure (E. E. > 98%) by recrystallization of the crude product from diisopropyl ether, the degree of extraction was 50%.

Example 8. Obtain (3R,4R)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran using isoquinoline-N-oxide as a ligand, giving an electron.

Repeating the procedure of example 5, but with the addition instead of pyridine-N-oxide, isoquinoline-N-oxide (1,74 g, 12 mmol). The HPLC analysis showed that after stirring for 30 minutes at room temperature the reaction was completed. The same way has provided the crude product, having named the crude compound as a brown oil (5.1 g). Chiral HPLC showed that E. E. was 94%. The named compound was obtained enantiomerically pure (E. E. > 99,8%) by recrystallization from diisopropyl ether, the extraction rate was 48%.

Example 9. Obtain (3S,4S)-6-acetyl-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran.

Using 8N Paon set the pH of the sodium hypochlorite solution (31 ml, 12.1% by weight. /about. , 50 mmol), water (34 ml) and 0.05 M PA2NRA4(25 ml), equal to 13. To dichlormethane (50 ml) was added 6-acetyl-2,2-dimethyl-2H-1-benzopyran (5.0 g, 25 mmol), isoquinoline-N-oxide (0,362 g, 5 mmol, 0.2 EQ) and (3R, 4S)-bis(3,5-di-tert-butylaniline)hydroporinae HPLC, the reaction was completed.

The mixture was diluted with dichloromethane and filtered through celite. Divided in two phases and the organic phase was washed with water (I ml), then boiled away to dryness under reduced pressure to obtain the crude titled compound as pale brown oil (5.3g). Chiral chromatography showed that E. E. amounted to 92%.

The named compound was obtained enantiomerically pure (E. E. > 99,8%), melting point 51oWith, by recrystallization of the crude product from diisopropyl ether, the extraction rate was 41%.

Example 10. Obtain (3S,4S)-6-cyano-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran.

Repeated the procedure described in example 9, using as romanovas basics 6-cyano-2,2-dimethyl-2H-1-benzopyran (4,63 g, 25 mmol). Educated crude epoxide (3S,4S) had E. E. 93%. It was recrystallize from 2-propanol to obtain the titled compound (E. E.> 99%), melting point 144-145oC, the extraction rate was 75%.

Example 11. Obtain (3S,4S)-6-bromo-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran.

Repeated the procedure described in example 9, using 6-bromo-2,2-dimethyl-2H-1-benzopyran (5,98 g, 25 mmol) as romanovas basis. Educated crude epoxide (3S,4S) had E. E. 95%.101-102oC, the extraction rate of 65%.

(C) Examples of using as the catalyst compounds of the formula (III).

Example 12. (R)-1-Phenyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)ethane manganese(III)chloride (E12).

In ethanol (50 ml) was dissolved (R)-1-phenyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)ethane (D 37, 2,42 g, 5.0 mmol) and added solid acetate tetrahydrate manganese(II) (2,45 g, 10.0 mmol). The solution was heated in a flask under reflux for 2 hours, then added lithium chloride (anhydrous) (0.64 g, 15.0 mmol) and the solution was heated in a flask under reflux for a further 30 minutes. Then to mix the solution was added with cooling water (1 ml). The precipitate was removed by filtration, washed with 90% aqueous solution of ethanol (10 ml), then dried in vacuum over P2ABOUT5to obtain the titled compound as a brown solid, 2,73 g, yield 95%.

Example 13. Chiral epoxidation of 2,2-dimethyl-6-pentafluorotoluene using (E12) to obtain 2,2-dimethyl-6-pentafluoroethyl-1-N-benzopyran-(3R, 4R)-epoxide.

Aqueous sodium hypochlorite solution (8.5 wt./about., of 17.5 ml, 20.0 mmol) was diluted to 25 ml with water, then added 0.05 M Pan2RHO4(aqueous solution) (10 ml). the Romaine (2,78 g, 10.0 mmol) and (E12) (0,115 g, 0.20 mmol) in methylene chloride (10 ml) at 0oC. the Reaction mixture was stirred for 1 hour at 0oC, then at room temperature throughout the night.

Added hexane (100 ml) and water (50 ml) and separated the organic layer. The aqueous layer was extracted with an additional portion of hexane (100 ml), combined organic layer was dried over gSO4was removed in vacuum, the solvent having a named connection in the form of a brown oil, 2.7 g (yield 94%).

The oil was purified thin (flash) chromatography (silica gel 60, MERCK 9385, 230-400 mesh mesh) (30 g) with elution with 0.5% diethyl ether in hexane to obtain the titled compound in the form of a pale yellow, semi-crystalline solids, 2,11 g, yield 72%, with the same reliable breakdown (1H NMR, TLC (thin layer chromatography), HPLC)), as shown by chiral HPLC, E. E. 63%.

Example 14. (R)-1-Phenyl-1,2-bis(3,5-di-tert-butylaniline)atanarjuat(III)chloride (E14).

(R)-1-Phenyl-1,2-bis(3,5-di-tert-butylaniline)ethane (D38, 1.70 g, 3.0 mmole) was dissolved in ethanol (30 ml) and added acetate tetrahydrate manganese(II) (1.47 g, 6.0 mmol). The solution was heated in a flask under reflux for 16 hours, then domovino, then cooled to room temperature.

To mix the solution was added water (1 ml) and the precipitate was removed by filtration, receiving the product as a brown solid, which was dried in vacuum over P2ABOUT5until receipt of 2.56 g of the named compound, yield 78%.

Example 15. Chiral epoxidation of 2,2-dimethyl-6-pentafluorotoluene using (E14) to obtain 2,2-dimethyl-6-pentafluoroethyl-1H-benzopyran-(3R, 4R)-epoxide.

An aqueous solution of sodium hypochlorite (8.5% of the weight./about., of 17.5 ml, 20.0 mmol) was diluted to 25 ml with water, then added 0.05 M NaH2PO4(aqueous solution) (10 ml). Set pH equal to 11.3 and the solution was cooled to 0oC, then added to a solution of 2,2-dimethyl-6-pentafluorotoluene (2,78 g, 10.0 mmol) and (R)-1-phenyl-1,2-bis(3,5-di-tert-butylaniline)atanarjuat(III)chloride (E14) (0,131 g, 0.20 mmol) in methylene chloride (10 ml) at 0oC. the Reaction mixture was stirred for 2 hours at 0oC, then overnight at room temperature.

Added hexane (100 ml) and water (50 ml) and separated the organic layer. The aqueous layer was extracted with an additional portion of hexane (100 ml), mixed organic layers were dried over MgSO4Oud is slo cleared thin (flash) chromatography (silica gel 60, MERCK 230 400 mesh) (40 g) with elution with 0.5% diethyl ether in hexane to obtain the titled compound as a pale yellow crystalline solid, is 1.81 g, yield 62%, with the same reliable breakdown (1H NMR, TLC, HPLC), as shown by chiral HPLC, E. E. 68%.

Example 16. (S)-1-Methyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)atanarjuat(III)chloride (e).

(S)-1-Methyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)ethane (D39) (338 mg, 0.8 mmol) was dissolved in EtOH (8 ml) and added acetate tetrahydrate manganese(II) (392 mg, 1.6 mmole). The mixture was heated in a flask under reflux for 2 hours, then added lithium chloride (102 mg, 2.4 mmole) and after additional heating in a flask under reflux for one hour the mixture was cooled to ambient temperature. Added a few drops of water, the precipitate was filtered and dried in vacuum over P2ABOUT5to obtain the titled compound as a brown powder, 270 mg (yield 66%).

Example 17. Chiral epoxidation of 2,2-dimethyl-5-pentafluorotoluene using (e) to obtain 2,2-dimethyl-6-panafcortelone-(3S, 4S)-epoxide.

An aqueous solution of sodium hypochlorite (x 16.75% wt./about., the 8.9 ml, 20 mmol) was diluted to or was cooled to 0oC, then added to a solution of 2,2-dimethyl-6-pentafluorotoluene (2,78 g, 10.0 mmol) and (S)-1-methyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)atanarjuat(III)chloride (e, 102 mg, 0.20 mmol) in methylene chloride (10 ml) at 0oC. Reaktsionnuyu the mixture was stirred for one hour at 0oC, then overnight at room temperature.

Added hexane (100 ml) and water (50 ml) and separated the organic layer. The aqueous layer was extracted with an additional portion of hexane, the combined organic layers were dried over gS4and the solvent was removed in vacuum, obtaining the crude titled compound as a brown oil, 2,78 g (yield 95%). Quantitative analysis (HPLC) showed that it contains, and 2.27 g (yield 77%) of these compounds with the same reliable breakdown (TLC, HPLC), as shown by chiral HPLC, E. E. 32%.

Example 18. (S)-1-Isopropyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)atanarjuat(III)chloride (E18).

In ethanol (10 ml) was dissolved (S)-1-isopropyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)ethane (D40, 240 mg, of 0.53 mmole) and added acetate dihydrate manganese(III) (0.14 g, of 0.53 mmole). The mixture was heated in a flask under reflux for 2 hours, then added lithium chloride (34 mg, 0.8 mmole). After additional oritel and the residue was subjected to chromatography on silica (MERCK 9385, 20 grams, with elution with 0.6% methanol in chloroform) to obtain the titled compound as a brown powder 60 mg (yield 21%).

Example 19. Chiral epoxidation of 2,2-dimethyl-6-pentafluorotoluene using (E18) to obtain 2,2-dimethyl-6-panafcortelone-(3S, 4S)-epoxide.

An aqueous solution of sodium hypochlorite (15,24%, wt./about., 2 ml, 4 mmole) was diluted to 5 ml with water. Added 0.05 M Pan2RHO4(aqueous solution) (2 ml) and established a pH equal to 11.3. The solution was cooled to 0oC, then added to the solution (0.56 g, 2 mmole) and the catalyst (S)-1-isopropyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)atanarjuat(III)chloride (E18, 21,5 mg, 0.04 mmole) in methylene chloride (6 ml). The mixture was stirred at 0oC for 1 hour, then at room temperature overnight.

Added hexane (20 ml) and water (10 ml) and separated the organic layer. The aqueous phase was extracted with an additional portion of hexane (20 ml), mixed organic phase was dried (MgSO4) and the solvent was removed in vacuum, obtaining the named compound as a yellow oil (0.51 g). Quantitative analysis (L) showed that it contained 0,42 g (71% yield) of the named compound, identical with authentic breakdown (TLC, HPLC), as shown IEM (E14) to obtain 6-acetyl-2,2-DIMETHYLPROPANE-(3R, 4R)-epoxide.

Using 8N Paon set the pH of the sodium hypochlorite solution (8.6 ml, 17.3% of the weight./vol.), water (14 ml) and Na2HPO4(0.05 M, 10 ml) is equal to 11.3. Added 6-acetyl-2,2-DIMETHYLPROPANE (2 g), (E14) (65,6 MMG, 1 mol.%) and dichloromethane (20 ml) and the mixture was rapidly stirred at room temperature overnight.

The mixture was diluted with dichloromethane (50 ml) and filtered through celite. Two layers were separated and the organic phase was washed with water (100 ml), dried to dryness, obtaining the titled compound (2.0 g, 92%), E. E. 67%, as shown by chiral L.

Example 21. Chiral epoxidation of 6-acetyl-2,2-DIMETHYLPROPANE using E14 to obtain 6-acetyl-2,2-DIMETHYLPROPANE-(3R,4R)epoxide using pyridine-N-oxide as a catalyst, giving the electron.

Repeating the reaction of example 20 adding pyridine-N-oxide (1.9 g, 2 EQ). When using chiral L was found that E. E. this product is 79%.

Description intermediates for producing compounds of the formula (II) (described in WO 94/03271)

Description 1.

(+)-2,5-Dihydro-3-nitrofuran (D1).

A mixture of ()-TRANS-3-chloromercuri-4-nitro-2,5-dihydrofuran1(38,54 g, 109.6 mmol) and Et3N (11,07 g, 1 is Onna acid (1.1 l) and stirring continued for a further 5 minutes. The mixture was filtered through celite, the separated organic phase, which was washed with 5% aqueous citric acid solution (220 ml), dried over PA2SO4and concentrated in vacuum. After chromatography of the residue on silica (MERCK 9385 g, 300 g) with elution CHCl3-hexane (1:1-->1:0) received (D1) as a pale yellow oil, which crystallized in the cold setting, the 5.45 g (43.2 per cent).

(CDCl3): of 4.95 (4H, s) and 7.10 (1H, s).

1. P. Bitha and Y.-I. Lin. J. Heterocyclic Chem., 1988, 25, 1035-1036.

Description 2.

(A) 3,4-Diaminetetraacetate (D2).

Solution (a) 4-amino-3-microtitration obtained from (D1) using the method Bitsa and Lina1, (of 4.66 g, 35,3 mmole) in t (100 ml) containing 10% palladium on carbon (2.5 g), was first made in swinging the Parr flask at a pressure of 35 si (2,4609 kg/cm2) for 65 hours at 20oC. the Suspension was filtered, the solid washed EtOH (100 ml) and the combined filtrate is boiled away in vacuum, receiving ()-(D2) as a colourless oil, 3,26 g (81,5%).

(CDCl3): of 1.40 (4H, bs), 3,20 (2H, m), 3,50 (2H, dd) and 4,08(2H, dd).

Description 3.

()-3,4-bis(3-tert-butyl-5-methylsulfonylamino)tetrahydrofuran (D3).

A solution of racemic diamine (D2) (8,55 mg, 8.38 mmole) and 3-Tr is a period of 1.5 hours. The solvent was removed in vacuo and the residue was subjected to chromatography on silica (MERCK 9385, 300 g) using as eluent CHCl3, receiving (a) through(D3) as pale yellow needle crystals, 1.35 g (35.8 per cent).

(CDCl3): of 1.42 (18H, s in), 2.25 (6H, s) 3,95-4,10 (2H, m), 4,43 (2H, q), of 6.90 (2H, d), to 7.15 (2H, d), 8,30 (2H, s) and 13,10 (2H, bs).

Description 4.

(S,S)-TRANS-3,4-bis(Methanesulfonate)tetrahydrofuran (D4).

A solution of 1,4-anhydrous-L-trait (2,45 g, 23.5 mmole), for example, ldrich hemical Company (Aldrich chemical company) in a mixture F (75 ml) and Et2O (75 ml) at 0oWith sequentially treated with triethylamine (7.2 ml, 51,7 mmole, 2.2 EQ) and methanesulfonamide (3,82 ml, 49,35 mmole, 2.1 EQ). The mixture was stirred for 4 hours, then kept at 0oWith the evening and overnight (~ 16 hours).

The reaction mixture was filtered and the solid washed THF (20 ml). Mixed filtrate is boiled away in vacuum and divided between 10% aqueous citric acid solution (60 ml) and t (150 ml). The organic phase was dried (MgSO4and boiled away to obtain (D4) as a colorless oil, of 5.82 g (95%).

(CDCl3): of 3.12 (6H, bs), of 4.00 (2H, dd), 4,18 (2H, dd) and 5.25 (2H, dd).

Description 5.

(S,S)-TRANS-3,4-Dezideratelor (D5).

The mixture dimethyl After cooling to ambient temperature the reaction mixture was diluted with water (1 l) and was extracted with t (1 l, 2x0,75 l). The combined organic phase was washed with water (0.5 l) and brine (0.5 l), dried over gSO4and boiled away in a vacuum to obtain the titled compound as a pale yellow oil, 2,18 g (61,5%).

(CDCl3): of 3.75 (2H, dd) and 3,90-of 4.05 (4H, m).

Description 6.

(S,S)-TRANS-3,4-Diaminetetraacetate.

To lithium aluminum hydride (2,05 g, 54 mmole) in dry F (tetrahydrofuran) (150 ml) at 0oWith dropwise within 10 minutes added diazed (D5) (2,08 g, 13.5 mmol) in F (50 ml). After 15 minutes the solution was heated to ambient temperature, then was stirred for 16 hours.

The reaction mixture was re-cooled to 0oWith, and then sharply sequentially cooled H2About (2 ml), 15% aqueous solution Paon (2 ml) and additional water (6 ml) and warmed to ambient temperature. After stirring for 1 hour the mixture was filtered through celite, washed THF (I ml) and the combined filtrate is boiled away in vacuum, receiving (D6) as a pale yellow oil, 1.28 g (93%).

(CDCl3): of 1.30 (4H, bs), 3,30 (2H, dd), 3,50 (2H, dd) and 4,08 (2H, dd).

Description 7.

(S, S)-TRANS-3,4-bis(3-tert-Butyl-5-methylsulfonylamino)tetrahydrofuran (D7).

A solution of (S, S)-diamine (D6) (1.26 g, 12,35 mmol) and 3-tert-butyl-5-wt. The solution was cooled and the solvent was removed in vacuum, obtaining the crude compound (5) as a yellow oil, 5.50 g (99%).

A sample of raw material (4,55 g) was subjected to chromatography on silica (MERCK 9385, gradient CHCl3in hexane), receiving (D7) as a yellow foam, 4,39 g (yield 95.5 percent).

(CDCl3): 1,42 (N, s), 2,25 (6N, s), 3.95 to 4,10 (4H, m) to 4.33 (2H, q), of 6.90 (2H, d), to 7.15 (2H, d), 8,30 (2H, s), 13,15 (2H, bs).

Description 8.

(2R,3R)-1,4-Dimensions-2,3-dimethanesulfonate.

To a solution of (2R, 3R)-(+)-1,4-dimensions-2,3-butanediol (25,3 g 83,7 mmole, for example, Aldrich chemical company) in dichloromethane (165 ml), cooled in a salt ice bath, was added methanesulfonamide (13,0 ml, 167,4 mmole). Then slowly added triethylamine (23,3 ml, 167,4 mmole) so that the temperature did not exceed 5oC. After complete addition, the reaction mixture was stirred in the ice bath for 3 hours. Then added water (600 ml) and the separated organic phase. The aqueous phase was extragonadal dichloromethane (200 ml) and the combined organic phases are washed with water (400 ml) and brine (400 ml), dried (gSO4) and the solvent is boiled away, receiving a pale yellow solid. When crushed into a powder with diethyl EPE is>/P>1H NMR (CDCl3): 3,03 (s, 6H, 2xCH3), 3,76 (m, 4H, 2xCH2O), 4,48 (d, 2H, CH2Ph), of 4.57 (d, 2H, CH2Ph) to 5.00 (m, 2H, 2xCH), 7,27-7,39 (m,10H, 2xPh).

13C NMR (DCl3): 38,8 (2xCH3), 68,7 (2xCH2), 73,7 (2xCH2), to 78.7 (2xCH), 128,1, 128,2, 137,0 (2xPh).

EI-MS: m/e 459 (MH+), 367 (M+-CH2Ph).

C20H26O8S2. Calculated,%: 52,39; N 5,72.

Found,%: C 52,36; N 5,59.

Description 9.

(2R, 3R)-1,4-Dimethanesulfonate-1,4-diol.

In acetone (500 ml) was dissolved (2R,3R)-1,4-dimensions-2,3-dimethanesulfonate (27,6 g, 60,3 mmole) (D8) was added a suspension of 10% PD/C (of 29.9 g) in acetone (300 ml) and the mixture was first made at a pressure of 1 atmosphere for two hours at ambient temperature. The mixture is then three times filtered through a pad of silica and celite and the solvent is boiled away, getting a named connection in the form of oil color straw (14,7 g, 87%) which solidified upon standing.

1H NMR (DMSO-d6): 3,24 (s, 6H, 2xCH3), of 3.69 (m, 4H, HSN2), was 4.76 (m, 2H, HSN), 5,33 (t, 2H, hon).

13With NMR (DS-d6): 38,1 (2xCH3), 59,7 (2xCH2), 80,3(HSN).

EI-MS: m/e 279 (MH+), 261 (MH+-H2O), 183 (M+-OMs), 165 (M+-OMSH2O).

sebutan-1,4-diol (14,7 g, 52,9 mmole) (D9) was dissolved in dimethoxymethane (89,5 ml) and dichloromethane (30 ml) at 40oC. was Added lithium bromide (0,91 g) and the monohydrate of n-toluensulfonate (1.01 g, from 5.29 mmole) and the mixture was heated in a flask under reflux for 3 hours. The reaction mixture was cooled to ambient temperature and then poured into saturated sodium bicarbonate solution (200 ml), extracted with ethyl acetate (CH ml), dried (gS4and boiled away, receiving a colorless oil (8.2 g, 42%). It was purified column chromatography on silica with elution with 0.1% methanol in dichloromethane, receiving the named compound as a colourless oil (8.2 g, 42%).

1H NMR (CDCl3): 3,13 (s, 6H, 2xCH3), 3,39 (s, 6H, 2xOCH3), a 3.87 (m, 4H, 2xCH2), of 4.66 (m, 4H, 2xOCH2O) 5,02 (m, 2H, 2xCH).

13C NMR (Dl3): 38,8 (2xSCH3) and 55.8 (2xOCH3), 66,1 (2xCH2), 78,4 (2xCH), 96,8 (2xOCH2O).

CI-MS: m/e 384 (MNH4+).

C10H22O10S2. Calculated,%: C 32,78; N 6,05.

Found,%: C 32,22; N 5,62.

Description 11.

(5R,6R)-Dimethanesulfonate-1,3-dioxan.

A solution of (6R,7R)-dimethanesulfonate-2,4,9,11-tetraxetan (8,2 g, 22.4 mmole) (D10) and monohydrate p-tawassul Ariel and the brown residue was ground into powder with diethyl ether, receiving a named connection in the form of not-quite-white solid (5.9 g, 91%), melting point 133-134oC.

1H NMR (CDCl3): 3,13 (s, 6H, 2xCH3), a-3.84 (m, 2H, 2CH2), 4,06 (m, 2H, CH2), of 4.77 (s, 2H, och2About), to 4.81 (m, 2H, HSN).

13With NMR (DCl3): 38,8 (2xSCH3), 64,1 (HSN2), 78,3 (HSN), 94,6 (och2O).

EI-MS: m/e 291(MNH4+), 195(M+-s).

WITH7H14O8S2. Calculated,%: C Of 28.96; N 4,86.

Found,%: C 29,22; N Br4.61.

Description 12.

(5R,6R)-Diazido-1,3-dioxan.

A mixture of (5R, 6R)-Dimethanesulfonate-1,3-dioxetane (5.0 g, 17.2 mmole) (D11) and lithium azide (4,2 g, 86 mmol) in dimethyl sulfoxide (60 ml) was stirred and heated to 110-120oWith all night. Then the reaction mixture was cooled, poured into water (200 ml) and was extracted with ethyl acetate (CH ml). The combined organic phases are washed with water (I ml) and brine (150 ml), dried (gSO4and boiled away, getting a named compound as a brown oil (2.7 g, 85%).

1H NMR (CDCl3): to 3.49 (m, 2H, HSN), 3,74 (m, 2H, HSN2), 3,93 (m, 2H, CH2), to 4.73 (s, 2H, och2O).

13With NMR (CD Cl3): 64,3 (2xCH), 64,6 (HSN2), 94,3 (OCH2O).

Found,%: 32,33; N. Of 4.67; N 45,38.

Description 13.

(5R,6R)-Diamino-1,3-dioxan.

To a suspension of lithium aluminum hydride (2.1 g, 55,3 mmole) in dry tetrahydrofuran (70 ml) at 0oC in an atmosphere of argon dropwise added a solution of (5R, 6R)-diazido-1,3-dioxetane (2.6 g, a 14.1 mmole) (D12) in dry tetrahydrofuran (50 ml). During the addition the reaction temperature was maintained below 10oUsing salt baths with ice. After the reaction mixture was heated to ambient temperature and was stirred for another 1.5 hours. Then the reaction mixture was re-cooled, and then abruptly cooled by adding water (2 ml), 2 M Paon (2 ml) and water (4 ml), the temperature is again maintained below 0oUsing salt baths with ice. Abruptly cooled reaction mixture was heated to ambient temperature, stirred for a further 2 hours, then filtered through celite and filtered gasket was well washed with tetrahydrofuran. The combined filtrate was boiled away, getting a named connection in the form of a pale yellow oil (1.3 g, 70%).

1H NMR (CDCl3): 1,56 (brs, 4H, 2xNH3), 2,62 (m, 2H, HSN), to 3.58 (m, 2H, CH2), of 3.77 (m, 2H, HSN2), 4,72 (s, 2H, och2N2O2. Calculated,%: 45,44; N 9,15; N 21,20.

Found,%: C 45,13; N 8,76; N 19,58.

EI-MS: m/e 133(MH+), 116(M+-NH2)+.

Description 14.

(5R,6R)-Di-(3,5-di-tert-butyl)salicylidene-1,3-dioxetane.

(5R, 6R)-Diamino-1,3-dioxan (1.0 g, 7.6 mmole) (D13) and 3,5-di-tert-butylsilane aldehyde (3.6 g, 15.4 mmole, 2 EQ) was dissolved in ethanol (100 ml) and the solution was stirred under heating in a flask under reflux for 3 hours. Then the reaction mixture is cooled, boiled away the solvent and the residue was purified column chromatography on silica with elution 4% diethyl ether in hexane. Got the named compound as a light yellow foam (3.5 g, 82%).

1H NMR (CDCI3): of 1.23 (s, 18H, 6xCH3), of 1.41 (s,18H, 6xCH3), 3,85 (m, 2H, CH2), 4,07 (m, 2H, CH2), to 4.87 (s, 2H, och2O), of 6.99 (d, 2H, Ar), 7,33 (d, 2H, Ar), with 8.33 (s, 2H, 2xCH=N), 13,20 (brs, 2H, hon).

13WITH NMR (DCI3): 29,4 (6xCH3), 31,4 (6xCH3), 34,1

35,0 , 67,7 (2xCH), 73,8 (HSN2), 94,2 (OCH2About), 117,6, 126,4, 127,4, 136,6, 140,3, 157,9 (AG), 168,4 (HS=N).

C35H52N2O4. Calculated,%: C 74,43; H 9.28 Are; N 4,96.

Found,%: C 74,56; N 9,15; N 4,92.

CI-MS: m/e 566 (MN+).

Description 15.

2(400 mg), was first made at atmospheric pressure for 3.5 hours at 25oC. the Suspension was filtered through celite, washed with 50% aqueous ethanol (50 ml) and water (50 ml) and the combined filtrate is boiled away in vacuum, obtaining the titled compound as a colourless oil, 9.6 g (85%).

(CDCl3): 1,30-1,50 (1H, m), 2,10 (6N, s), 2,10-of 2.20 (1H, m), 3,35-of 3.60 (2H, m), of 3.80-4.00 points (2H, m) and 4.80 to 5,00 (2H, m).

2. Dictionary of Organic Compounds, 5th Edition, 1982, Chapman & Hall, London, 579 and references therein.

Description 16.

(3R,4R)-Diabetesmeridiarecentresearch (D16).

Sodium (~50 mg) was dissolved in methanol (100 ml) at ambient temperature. To the resulting solution was added a solution of the ester of dibasic acid (D15) (9,56 g, 47,3 mmole) in methanol (100 ml) and the mixture was stirred for 72 hours. Added resin Amberlite IR 12 OH+(20 g) and the mixture was filtered. After concentration of the filtrate in vacuo got diol as a colourless oil. It was dissolved in a mixture of tetrahydrofuran (220 ml) and diethyl ether (220 ml). Added triethylamine (10,86 g, 107,5 mmole), the solution was cooled to 0oC. At 0oWith dropwise added methanesulfonamide (11,76 g 102,7 mmole), the solution was stirred for another hour, then HRH ml) and diethyl ether (CH ml). The combined filtrate is boiled away in vacuum and the residue is divided between ethyl acetate (200 ml) and 10% aqueous citric acid solution (200 ml). The organic phase was dried (gSO4), was filtered in vacuo to obtain the titled compound as a colourless foam, 12,07 g (93%).

(CDCl3): 3,10 (6N, s), 2.00 in to 2.40 (2H, m), 3,40-4,20 (4H, m), 4,55 with 4.65 (1H, m) and 4,70-is 4.85 (1H, m).

Description 17.

(3R,4S)-Diaminetetraacetate (D17).

In dimethyl sulfoxide (88 ml) was dissolved dimesylate (D16) (12,07 g, 44 mmole) and treated with lithium azide (10.8 g, 220 mmol). The mixture was heated at 100oC for 40 hours, then cooled to ambient temperature, poured into water (1,03 l) and was extracted with ethyl acetate (1,03 l, 2x0,59 l). The combined organic phase was washed with water (300 ml) and brine (300 ml), dried over MgSO4and concentrated in vacuum, receiving raw DIACID in the form of a brown oil 3,7, It was dissolved in tetrahydrofuran (45 ml) and dropwise added to a cold (0o(C) suspension of lithium aluminum hydride (3,34 g, 88 mmol) in tetrahydrofuran (220 ml), keeping the temperature below 10oC. After complete addition the suspension was stirred for 0.5 hours at 0oC, then warmed to ambient temperature and was stirred tip) in tetrahydrofuran (5 ml), 15% aqueous sodium hydroxide solution (3,34 ml) and additional water (10 ml). The mixture was heated to ambient temperature, stirred for 1 hour, then filtered through celite, washed with tetrahydrofuran (g ml). Combined filtrate was concentrated in vacuum, obtaining the titled diamine as a colourless oil, 2,62 g (51%).

(CDCl3): 1,20-1,90 (6H, m), 2.40 a-2,50 (2H, m), 2,90 is 3.40 (2H, m) and of 3.80-4.00 points (2H, m).

Description 18.

(3R,4S)-bis(3,5-Di-tert-butylaniline)tetrahydropyran (D18).

To the diamine (D17) (2.55 g, 22 mmole) in ethanol (220 ml) was added 3,5-di-tert-butylsilane aldehyde (10.3 g, 44 mol). The mixture was heated in a flask under reflux for 2 hours, cooled to ambient temperature, filtered and the crystalline product was dried in vacuum to obtain the titled compound as yellow crystals, to 4.81 g (40%).

(CDCl3): 1,29 (N, s), 1,40 (N, s), 1,50-2,20 (2H, m), of 3.50-3.70 (4H, m), 4,00-to 4.15 (2H, m), 7,00 (2H, bs), 7,35 (2H, bs), with 8.33 (1H, s), of 8.37 (1H, s) and 13,20 (2H, bs).

Description 19.

(3R,4S)-bis(3-tert-Butyl-5-methylsulfonylamino)tetrahydropyran (D19).

A solution of diamine (D17) (0,62 g to 5.35 mmole) and 3-tert-butyl-5-methylsalicylate aldehyde (2,05 g, 10.7 mmole) in ethanol (40 ml) was heated in a flask with a return hole the CSO sludge. It was filtered, washed with cold 95% aqueous ethanol (5 ml) and dried in vacuum to obtain these compounds, 1.22 g (49%).

(CDCl3): 1,40 (N, s), 1,80-2,20 (2H, m), of 2.20 (6H, s), 3,40-3,70 (4H, m), 4,00-4,20 (2H, m), to 6.80 (2H, bs), 7,05 (2H, bs), of 8.27 (1H, s), 8,30 (1H, s) and 13,30 (2H, bs).

Description 20.

(3S,4S)-bis(3,5-Di-tert-butylaniline)tetrahydrofuran (D20).

A solution of (S, S)-diamine (D6) (0.96 g, 9.4 mmole) and 3,5-tert-butylsilane aldehyde (4.4 g, 18,8 mmole) in ethanol (90 ml) was heated in a flask under reflux for 2 hours. The mixture was cooled to 0oC, then filtered, the solid washed with cold ethanol and dried, obtaining the titled compound as yellow crystals, of 3.07 g (61%).

(CDCl3): of 1.27 (18H, s), 1,45 (N, s), 3.95 to 4,10 (4H, m), 4,30-and 4.40 (2H, m), 7,05 (2H, d), 7,40 (2H, d), 8,35 (2H, s) and 13,20 (2H, s).

Description 21.

(3S,4R)-Dihydroxy-(2R)-(hydroxymethyl)tetrahydrofuran (D21).

A solution of D-glucola3(16.0 g, of 0.11 mol) in 50% aqueous ethanol (500 ml) was treated with platinum oxide (0.75 g) and was first made at ambient temperature and atmospheric pressure for 5 hours. The suspension was treated with charcoal (50 g), filtered through celite (200 g) and the solid was washed with 50% aqueous ethanol (300 ml). United Figo oil, 16.0 g (99%).

(CD3OD): 1,50-1,70 (1H, m), 1,80-2,20 (1H, m) 3,00-3,20 (2H, m), 3,30-3,70 (3H, m), of 3.80-4.00 points (2H, m) and the 4.90 (3H, bs).

3. Dictionary of Organic Compounds, 5thEdition, 1982, Chapman and Hall, London, 2754 and references therein.

Description 22.

(3S,4R)-Dihydroxy-(2R)-(triphenylmethyl)tetrahydropyran (D22).

The solution of the triol (D21) (1,76 g, 11.9 mmol) in pyridine (20 ml) was treated with Fritillaria (of 3.31 g, 11.9 mmol) and 4-(dimethylamino)pyridine (50 mg). Added diisopropylethylamine (1.92 g, of 14.8 mmole, 1.25 EQ) and the solution was stirred for 4 hours at ambient temperature.

The mixture was poured into water (200 ml) and was extracted with diethyl ether (CH ml). The combined organic phase was washed with 10% aqueous citric acid solution (100 ml) and brine (100 ml), dried over MgSO4and concentrated in vacuum to obtain oil. The residue was subjected to chromatography on silica (eluent: gradient of methanol in chloroform) to obtain the titled compound as a colourless foam, 3,70 g (79.7 per cent).

(CDCl3): 1,60-1,80 (1H, m), 1,90-2,00 (1H, m), 2,70 (2H, bs, D2O exchange rate. ), 3,25-3,50 (5H, m), 3,60-3,70 (1H, m), 3,90-4,00 (1H, m) and (7,20-7,50 (15 NM, m).

Description 23.

(3R, 4R)-Dimethanesulfonate-(2R)-triphenylmethyl)tetrahydropyran (D23).

To dio is). The mixture was cooled to 0oWith and added methanesulfonamide (1,91 g, 16.7 mmole). After 2 hours the suspension was filtered and the filtrate was concentrated in vacuo and re-dissolved in ethyl acetate (200 ml). The solution was washed with 10% aqueous citric acid solution (100 ml) and brine (50 ml), then dried over gS4. The solvent was removed in vacuum and the residue was dried to obtain (12) in the form of a colorless solid, 4.26 deaths / g (95%).

(CDCl3): 2,20-of 2.50 (2H, m), of 2.50 (3H, s), 3,10 (3H, s), 3,20-3,30 (1H, m), 3,40-of 3.60 (3H, m), 3.95 to-4,10 (1H, m), 4,70-4,80 (2H, m) and (7,20-7,50 (15 NM, m).

Description 24.

(3R, 4S)-bis(3,5-Di-tert-butylaniline)-(2S)-triphenylmethyl)tetrahydropyran (D24).

A mixture of dimesilate (D23) (2.85 g, with 5.22 mmole) and lithium azide (1.28 g, 26,1 mmole) in dimethyl sulfoxide (20 ml) was heated at 100-110oC for 24 hours. The solution was cooled, poured into water (200 ml) and was extracted with ethyl acetate (CH ml). The combined organic phase was washed with water (I ml) and brine (300 ml) and dried over gS4. After removal of solvent received intermediate connection DIACID as a yellow foam (1.52 g).

To a suspension of lithium aluminum hydride (470 mg, 12.4 mmole) in tetrahydrofuran (30 ml) at 0oWith added 1.40 g dyazide in tetrahydrofuran (30 ml). Phanie 16 hours. The suspension was again cooled to 0oAnd then sharply sequentially cooled by water (0.5 ml), 15% aqueous sodium hydroxide solution (0.5 ml) and then water (1.5 ml). After warming to ambient temperature and stirring for 1 hour the mixture was filtered, the solid was washed with tetrahydrofuran (2x20 ml) and the combined filtrate is boiled away, receiving crude diamine in the form of foam (1.28 g).

Part of the diamine (1.18 g) and 3,5-di-tert-butylsilane aldehyde (1.42 g, between 6.08 mmol) in ethanol (30 ml) was heated in a flask under reflux for 4 hours, then cooled to ambient temperature. The solvent was removed in vacuo and the residue was subjected to chromatography on silica (eluent: gradient of chloroform in hexane) to obtain the titled compound as a yellow powder, 210 mg, total yield of (D23) of 8.4%.

(CDCl3): 1,25 (N, m), 1,30-1,60 (2H, m), 1,32 (9H, s), 1,40 (N, s), 1,50 (N, s), 2.40 a is 2.55 (1H, s), 2.70 height is 2.80 (1H, s), 3,30-of 3.60 (2H, m), 3,90-4,39 (3H, m), 6,85 (1H, bs), 7,00-7,35 (N, m), 7,38 (1H, bs), 8,30 (1H, s), and 8.50 (1H, s), 13,25 (1H, s) and 13.50 (1H, s).

Description 25.

()-TRANS-1-Benzoyl-3,4-bis(methanesulfonate)piperidine (D25).

()-TRANS-1-Benzylpiperidine-3,4-diol4(3 g, 13.6 mmol) suspended in dichloromethane (70 ml) and was added triethylamine (5,74 ml, 43 mmole). Was poured into a mixture of ice and water (50 ml) and the organic layer washed with 5% aqueous citric acid solution (30 ml). The solution was dried over gS4and concentrated in vacuo to obtain a foam of 5.3 g (100%).

H(CDCl3): 1,95 (2H, m), is 2.30 (2H, m), 3.15 in (6N, s), 4,70 (2H, m), is 4.85 (2H, m) and was 7.45 (5H, m).

V. Petrow and O. Stephenson, J. Pharm. Pharmacol., 1962, 14, 306-314.

Description 26.

()-TRANS-1-Benzoyl-3,4-disadaptation (D26).

A mixture of dimesilate (D25) (5,3 g, 14 mmol) and lithium azide (3.4 g, 69 mmol) in dimethyl sulfoxide (36 ml) was heated at 100oC for 18 hours. After cooling, the reaction mixture was separated between dichloromethane (200 ml) and water (50 ml). The aqueous phase is separated and then was extracted with dichloromethane (100 ml, 50 ml) and combined organic extracts were washed with water (I ml), dried (Na2SO4) and concentrated in vacuum. The residue was subjected to chromatography on silica (eluent: gradient of methanol in dichloromethane), receiving the named compound as a colourless solid, 90 mg (24%).

H(CDCl3): to 1.60 (2H, m), 2,10 (2H, m), 3,05, 2H, s), 3,20 (2H, m) and yield of 7.40 (5H, m).

Description 27.

()-TRANS-1-Benzoyl-3,4-diaminopyridine (D27).

The solution diazide (D26) (450 mg, 1.7 mmole) in ethanol (30 ml) was treated with Lindlar catalyst (5% Pd/CaCO3, 250 mg) and stirred under hydrogen (1 ATM) for La, 350 mg (94%).

H(DMSO): 1,20 (1H, m), of 1.65 and 1.80 (2H, m), of 2.20 (2H, m), 2,70 (1H, m) of 3.00 (1H, m), 3,30 (1H, m), and 4.40 (1H, m) and yield of 7.40 (5H, m).

Description 28.

(-)-TRANS-1-Benzoyl-3,4-bis(3,5-di-tert-butylaniline)piperidine (D28).

A solution of amine (D27) (350 mg, 1.6 mmole) and 3,5-di-tert-butylsilane aldehyde (960 mg, 4.1 mmole) in ethanol (40 ml) was heated in a flask under reflux for 3 hours. The mixture was cooled and filtered to obtain racemic bis-imine, 6,52 mg (63%).

Separated of 100 mg sample of chiral HPLC (CHIRALPAK AD, eluent 2% ethanol in hexane), receiving a named connection in the form of a single enantiomer, []25D= -228o(C=0,13, CHCl3).

H(CDCl3): of 1.20 (18H, s), a 1.45 (18H, s), from 2.00 (2H, m), of 3.25 (2H, m), of 3.45 (1H, m), 3,55 (1H, m), 4,35 (2H, m), 6,95 (2H, s), 7,40 (7H, m), 8,30 (2H, s), 13,15 (2H, bs).

Description 29.

()-3,4-bis(3-tert-Butyl-5-methylsulfonylamino)tetrahydrofuranyl(III)chloride (D29).

A suspension of racemic ligand (D3) (690 mg, 1,53 mmole) in t (25 ml) was heated with MP(SLA)24H2About (750 mg, a 3.06 mmol) in a flask under reflux for 18 hours. Added Lil (195 mg, 4,49 mmole) and heated in a flask under reflux continued for a further 0.5 hour. The solvent was removed in UB>3
to obtain the titled compound as a brown powder (90 mg, 11%) along with unreacted (D3), 420 mg, the degree of recovery of 61%.

Description 30.

(S,S)-TRANS-3,4-bis(3-tert-Butyl-5-methylsulfonylamino)tetrahydrofuranyl(III)chloride (D30).

Solution (D7) (0.95 g, 2,11 mmole) and MP(SLA)24H2On (1,03 g, 4,22 mmole) in EtOH (40 ml) was heated in a flask under reflux for 17 hours. Added lithium chloride (268 mg, 6,33 mmole) and heated in a flask under reflux continued for a further 0.5 hour. After cooling to ambient temperature the solvent was removed in vacuo and the residue was subjected to chromatography on silica (MERCK 9385, gradient Meon in CHCl3) to obtain (E3) as a brown powder, 26 mg (2,3%) along with unreacted (D7), 683 mg (72%).

Method using acetate of manganese(III) 5.

Solution (D7) (1,53 g, 3.4 mmole) in a mixture of CH2Cl2(17 ml) and Meon (17 ml) was treated with Mn(OAc)32H2O (0.01 g, 3.4 mmole). The mixture was heated in a flask under reflux for 3 hours, cooled to ambient temperature and treated with lithium chloride (0.21 g, 5.1 mmole). After stirring for 16 hours the solvent content was reduced in the solid washed Et2On (3h20 ml) and dried in vacuum, obtaining the (E3) as a brown powder, of 1.57 g (86%).

5. T. Matsushita and T. Shono, Bull. Chem. Soc. Japan., 1981, 54, 3743-3748.

Description 31.

Receive (R,R)-[5,6-bis(3,5-di-tert-butylaniline)-1,3-dioxan] manganese(III)chloride (D31).

(5R, 6R)-Di-(3,5-di-tert-butyl)salicylidene-1,3-dioxan (1.0 g, or 1.77 mmole) (D14) and acetate tetrahydrate manganese(II) (2.17 g, 8,87 mmole) suspended in 95% aqueous ethanol (50 ml) and the mixture was heated in a flask under reflux with stirring overnight. Then added lithium chloride (0,38 g, 8,96 mmole) and heating continued for a further 30 minutes. Then the reaction mixture is cooled, added water (60 ml) and filtered through celite. The dark precipitate was washed with water, then dissolved in dichloromethane (80 ml), dried (gSO4) and the solvent is boiled away to obtain the titled compound in the form of a dark brown solid (0.9 g, 78%).

WITH35H50N2ABOUT4Mnl. Calculated,%: 64,36; N 7,72; N 4,29.

Found,%: C 64,57; N EUR 7.57; H 4.09 To.

CI-MS: m/e 565 (MN-MP,CL)+, 235 (3,5-di-tert-butylsilane aldehyde N)+< / BR>
Description 32.

(3R,4S)-bis(3,5-di-tert-Butylaniline)tetrahydropyrimidines(III)chloride (acetate (2.35 g, 8.8 mmole) and the mixture was heated in a flask under reflux for 4 hours. Added lithium chloride (0.56 g, 13.2 mmole) and heated in a flask under reflux continued for a further 1 hour. The mixture was cooled, concentrated in vacuo and the residue was ground into powder with diethyl ether (220 ml). The solid product was filtered, washed with diethyl ether (CH ml) and dried to obtain (5) in the form of a brown powder of 5.3 g (94%).

Description 33.

(3R,4S)-bis(3-tert-Butyl-5-methylsulfonylamino)tetrahydropyrimidines(III)chloride (D33).

A solution of ligand (D19) (9.28 are g, 2 mmole) in dichloromethane-methanol (1:1, 20 ml) was treated with dihydrate manganese triacetate (536 mg, 2 mmole) and the mixture was heated in a flask under reflux for 3 hours. The mixture was cooled to ambient temperature, was added lithium chloride (128 mg, 3 mmole) and the solution was stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was ground into powder with diethyl ether (40 ml). The solid product was filtered, washed with diethyl ether (CH ml) and dried in vacuo to obtain the titled compound as a brown powder, of 1.09 g (98%).

Description 34.

(3S,4S)-bis(3,5-Di-tert-butylaniline)tetrahydropyrrole) in a mixture of dichloromethane and methanol (1:1, 20 ml) was heated in a flask under reflux for 6.5 hours. The solution was cooled to ambient temperature, was added lithium chloride (128 mg, 3 mmole) and the mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue was ground into powder with diethyl ether (50 ml). The solid product was filtered, washed with diethyl ether (CH ml) and dried in vacuo to obtain the titled compound as a brown powder, 1.12 g (89%).

Description 35.

(3R,4S)-bis(3,5-di-tert-Butylaniline)-(2R)-(triphenylmethyl)tetrahydropyrimidines(III)chloride (D35).

The ligand (D24) (160 mg, 195 mmol) in dichloromethane-methanol (3:2, 5 ml) was added Paon (0,93 ml 0,417 M in methanol, 390 mmol) and the dihydrate manganese triacetate (52,5 mg, 195 mmol). The solution was heated in a flask under reflux for 3 hours, was added lithium chloride (12.5 mg, 300 mmol) and the mixture was stirred for 15 hours. The solution was removed in vacuo and the residue was ground into powder with diethyl ether (10 ml). The solid product was filtered, washed with diethyl ether (2 × 2 ml) and dried in vacuo to obtain the titled compound as a brown powder, 136 mg (77%).

Description 36.

(-)-TRANS-1-Benzoyl-3,4-bis(3,5-di-trdata of manganese triacetate (10 mg, 0,037 mmole) in dichloromethane-methanol (3:2, 5 ml) was heated in a flask under reflux for 4 hours. Added lithium chloride (1.6 mg, of 0.038 mmole) and heated in a flask under reflux continued for a further 1 hour.

The solvent was removed in vacuo and the residue was subjected to chromatography on silica (eluent: 10% methanol in dichloromethane) to obtain the titled compound as a brown powder, 22 mg (97%).

Description intermediates for producing compounds of the formula (III).

Description 37. (R)-1-Phenyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)ethane (D37).

(R)-1,2-Diamino-1-Penilaian obtained from (R)-2-aminophenylacetamido 6by restoring to the diamine by the method of brown and Game 7(of 1.36 g, 10.0 mmol) was dissolved in ethanol (50 ml) and added solid 2-hydroxy-3-tert-butyl - 5-methylbenzaldehyde obtained from 2-tert-butyl-4-METHYLPHENOL through the method of Casiraghi and other8(of 3.84 g, 20.0 mmol). After 90 minutes of heating in a flask with reflux condenser, the reaction mixture was cooled and added water (1 ml). Formed yellow solid product was removed by filtration, washed with 95% aqueous ethanol (10 ml) and dried in vacuum over P2O5to Polus (N, s), 2,22 (3H, s), of 2.23 (3H, s), 3,93 (1H, dd), of 4.12 (1H, dd), and 4.68 (1H, dd), at 6.84 (2H, s), to 7.09 (2H, s), 7,30 is 7.50 (5H, m), of 8.25 (1H, s), of 8.37 (1H, s) and 13.50 (2H, bs).

6. C. G. Nielson and D. F. Ewing, J. Chem. Soc., (C) 1966, pp.393-397.

7. H. C. Brown and P. Heim, J.Org. Chem., 1973, 38, pp.912-916.

Description 38. (R)-1-Phenyl-1,2-bis(3,5-di-tert-butylaniline)ethane (D38).

(R)-1,2-Diamino-1-Penilaian (0.68 g, 5.0 mmol) was dissolved in ethanol (50 ml) and added 2-hydroxy-3,5-di-tert-butylbenzaldehyde obtained from 2,4-di-tert-butylphenol method Casiraghi and other8(of 2.34 g, 10.0 mmol). The reaction mixture was heated in a flask under reflux for 2 hours, cooled to room temperature and stir the solution was added water (1 ml). The product was isolated by filtration, washed with 95% aqueous ethanol (5 ml) and dried in vacuum over P2ABOUT5to obtain the titled compound in the form of a yellow solid, 2,11 g, yield 74%.

(CDCl3): of 1.24 (9H, s), 1.27mm (N, s) of 1.41 (9H, s), 1,45 (N, s), of 3.95 (1H, dd), is 4.15 (1H, dd), 4,70 (1H, dd), 7,05 (2H, bs), 7,30 is 7.50 (7H, m), a 8.34 (1H, s), 8,42 (1H, s) and 13,60 (2H, bs).

8. G. Casiraghi, G. Casnati, G. Puglia, G. Sartori and G. Terenghi, J. Chem. Soc. Perkin l, 1980, pp. 1862-1865.

Description 39. (S)-1-Methyl-1,2-bis(3-tert-butylaniline)ethane (D39).

A suspension of (S)-1,2-diaminopropionic (290 mg, 2 mmole) in t (5 ml) was treated with 1M the N under reflux for 1.5 hours. The suspension was filtered, partially boiled away and the draught of these compounds in the form of a yellow solid was added a small amount of water. It was filtered, washed with 95% aqueous solution t and dried in vacuum over P2ABOUT5to obtain these compounds, 730 mg (yield 86%).

(CDCl3): of 1.33 (3H, s), of 1.36 (18H, d), of 2.25 (6H, s), 3,32 (2H, m), 3,76 (1H, m), to 6.80 (2H, s), 7,03 (2H, s), to 8.20 (1H, s), of 8.25 (1H, s), 13,50 (2H, bs).

Description 40. (S)-1-Isopropyl-1,2-bis(3-tert-butyl-5-methylsulfonylamino)ethane (D40).

To borgetto sodium (1.13 g, 30 mmol) in glyme (30 ml) under nitrogen with stirring was added (S)-validatedirectory (1,53 g, 10 mmol), suspended in glyme (35 ml). The solution was cooled to 10oAnd dropwise within 20 minutes added ether compound of boron TRIFLUORIDE with 4.9 ml, 40 mmol) in glyme (10 ml), then the mixture was heated in a flask under reflux for 16 hours. After cooling to ambient temperature, added water (7.5 ml), then 3M Paon (15 ml) and the resulting clear solution was heated in a flask under reflux for 2 hours. The solution was removed in a vacuum, getting a white solid product, which was extracted with chloroform (3x10 ml) and the combined extract was boiled away, having diamine (0.34 g). It is heated in a flask under reflux for 2 hours, cooled, concentrated in vacuo and the residue was subjected to chromatography on silica (R 9385, while elution with 0.6% Meon in chloroform), getting a named connection, 0.73 g (yield 16%).

(CDCl3): 1,04 (6N, m), 1.39 in (N, 2s), 2,10 (1H, m), 2,24 (6H,s), 3,3-4,0 (3H, bm), 6,85 (2H, m), to 7.09 (2H, m), 8,24 (2H, s), 13,60 (2H, bs).

1. The way enantioselective epoxidation prehiring olefins, including interaction prehiring of the olefin with oxygen source in the presence of salt catalyst and donor ligand, wherein the donor ligand is isoquinoline-N-oxide.

2. The method according to p. 1, characterized in that the salt catalyst is: (i) the compound of formula (IB)

< / BR>
in which YIand Y4are the same and are selected from the group consisting of methyl, tert-butyl or methoxy;

R2and R3both are phenyl or together with the carbon atoms to which they are attached, form hexylene ring;

(ii) a compound of the formula (II)

< / BR>
in which M represents a transition metal ion;

And, if necessary, is a counterion;

r, s and t are independently 0 to 3 and the sum r+s+t must be in the range from 1 to 3;

Ra, R
B and E are independently kislota, CH2, NRdwhere Rdis alkyl, hydrogen, alkylcarboxylic or arylcarboxylic or SOnwhere n is 0 or an integer 1 or 2, provided that b and E are not simultaneously CH2and that, when b is oxygen, NRdor SOnthen there can be 0 and when E is oxygen, NRdor SOnthen t cannot be zero;

R1, R2, R3, R4, R5, R6, R7, R8, R9and R10independently are hydrogen, alkyl, alkoxy;

3. The method according to p. 1 or 2, characterized in that the salt catalyst selected from the group consisting of:

R, R-[1,2-bis(3,5-di-tert-butylaniline)cyclohexane] manganese (III)-chloride;

(3S, 4S)-bis-(3,5-di-tert-butylaniline)tetrahydrofuranyl (III) chloride;

(R, R)-5,6-bis(3,5-di-tert-butylaniline)-1,3-dioxan] -manganese (III)-chloride;

(R)-1-phenyl-1,2-bis-(3-tert-butyl-5-methylsulfonylamino) atanarjuat (III) chloride;

(R)-1-phenyl-1,2-bis-(3,5-di-tert-butylaniline) atanarjuat (III) chloride;

(S)-1-methyl-1,2-bis-(3-tert-butyl-5-methylsulfonylamino) atanarjuat(III) chloride;

(S)-1-isopropyl-1,2-bis-(3-tert-butyl-5-metals what olefin is 2,2-dimethyl-6-pentafluoroethyl-2H-1-benzopyran or 6-acetyl-2,2-dimethyl-2H-1-benzopyran.

5. The method according to any one of paragraphs. 1-4, characterized in that the oxygen source is sodium hypochlorite.

6. The way enantioselective epoxidation prehiring olefins, including interaction prehiring of the olefin with oxygen source in the presence of salt catalyst and source of the ligand, giving the electron, characterized in that the salt catalyst is a compound of formula (II) under item 2.

7. The method according to p. 6, in which the source of the ligand, giving the electron is isoquinoline-N-oxide.

Priority points and features:

04.02. , 1994 p. 2, where the catalyst has the formula (II), PP. 5 and 6;

15.06.1994 under item 1 and 2, where the catalyst has the formula (IB), PP. 4 and 7.

 

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