JPH04503521A - Asymmetric chemical synthesis and intermediates for producing antifungal compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Asymmetric chemical synthesis and intermediate steric Q background for producing antifungal compounds In European Patent Application No. 178533 and European Patent Application No. 61835, the formula (In the formula, ph is a phenyl group, or substituted with la or two halogen atoms. It is a C8 cycloalkylalkyl group or a 03-C6 cycloalkyl group: (n is 0.1 or 2) Certain antifungal compounds with a 2@ chiral center and their acid additions Salt is disclosed. Some of these isomers are racemic mixtures from which they are derived. It has been found that it provides more favorable properties than glue. However, published Does the application disclose any asymmetric chemical synthesis for producing the individual isomers? It is not possible to produce individual pure isomers economically and in sufficient yields. It would be highly advantageous to provide methods and intermediates for the following.

U.S. Patent No. 4,526.983 describes the formula (where n is an integer of 3 or 4). Certain optically active antifungal compounds and their acid addition salts have optically active The production method involves separation of diastereomers using polycarboxylic acid esters. Disclosed. This is unsuitable for large scale commercial synthesis. it takes effort However, the yield is low and it is uneconomical.

The present invention provides a method for producing chemically pure enantiomeric compounds with antifungal activity. 6 One aspect of the present invention relates to a series of important new intermediates useful for formula II. IV (where Ar is phenyl, substituted phenyl, 3-chenyl device lA3-chenyl , 3-furanyl or substituted 3-furanyl; R is alkyl, substituted alkyl R1 represents H or alkyl; R1 represents H or alkyl; X represents wax, bromo or iodo; Xl represents OH, chloro, bromo, represents iodine or Pl, where Pl is alkoxy phenyloxy , benzyloxy, substituted benzyloxy, acyloxy, alkylthio, phenyloxy ruthio, substituted phenylthio or -NHP'', where R2 is an amino group. Protecting groups such as phenyl, substituted phenyl, benzyl, substituted benzyl, alkanoyl , γ-alkoxycarbonyl, phenoxycarbonyl or substituted phenoxycarbonyl and P represents H or a hydroxy protecting group) compounds, said compounds are indicated by a single asterisk (ne) and a double asterisk (**). The compounds have one or more asymmetric centers and have the same chemical structure. Substantially free of one or more compounds with carbons marked with an asterisk with other absolute stereochemical configurations at the center (e.g. double asterisk (Kimoto) in formula XIT) both represent the absolutely steric configuration yIR, and such a compound RR has its SS (substantially free of type, RR type and SR type), said intermediate compound or pharmaceutical and their salts which are acceptable to the public.

Preferred intermediates of the invention are those in which Ar, R, R' and P are as defined above. It has the formula XIT. Preferably, in the compound having the formula Both carbon atoms marked with a double star (**) are in their absolute stereochemical configuration R. In other words, it is an RR type compound. However, the SS type with formula XII It is noted that also is within the scope of the present invention.

Another preferred intermediate of the invention is one in which Ar, P and R are as defined above. In a preferred form of the compound having formula XI, which is one having formula XI , - The carbon atom marked with a double star (**) is its absolute stereoconfiguration TIR.

Asymmetric centers indicated by a single asterisk in compounds having formula II and formula III are preferably in their absolute stereochemical configuration S, while formula IV and formula VlI Asymmetric centers marked with a double asterisk (**) in compounds with I are Preference is given to the allelic chemical configuration R.

In the above formula, preferably Ar is substituted phenyl, more preferably Ar is mono-substituted, di-substituted or tri-N-substituted halophenyl, e.g. 2,4-difluoro b, 2,6-difluoro, 4-fluoro, 2-fluoro, 2,4-dichloro, 2 ．． 6-dichloro, 4-chloro or 2-chloro substituted phenyl. Especially preferred The group Ar is 2,4-difluorophenyl. Preferably R is alkyl, In particular, methyl. P is preferably Alkyloxyalkyl, alkylthioalkyl or R'R"R'"silyl Yes, but R', R'' and FL- may be the same or different and each selected from alkyl, cycloalkyl or phenyl. Change Preferably, P is 2-tetrahydropyranyl; al is preferably It is H. X is preferably chloro or bromo. Xl is preferably , chloro1-1, bromo, alkoxy-substituted phenyloxy, benzyloxy or Substituted benzyloxy.

Said new intermediate has the formula XVT (wherein, Ar is phenyl, substituted phenyl, 2- or 3-chenyl, substituted 2 - or 3-chenyl, 2- or 3-furanyl, substituted 2- or 3-phenyl ranyl, 2-14- or 5-imidazolyl, 3- or 5-(1,2,4 -triazolyl), 5-tetrazolyl, 2-14- or 5-thiazolyl, 2 -04- or 5-oxasilyl, 3-14- or 5-inxazolyl, 2-13- or 4-pyridinyl, 2- or 3-pyrrolyl, 3- or 4-pyrazolyl, 2-benzimidazolyl, 2-benzthiazolyl or 2-1 represents 4- or 6-gelinyl, provided that the above-mentioned imidazolyl group, triazolyl group, tetrazolyl group, benzimidazolyl group, benzthiazolyl group and The saturated nitrogen atom of the nyl group is H, alkyl, substituted alkyl, cycloalkyl, substituted May be substituted with substituted cycloalkyl, phenyl or substituted phenyl; Ar1 is 1-(1,2,4-triazolyl), 1-(1,3,4-triazolyl) or 1-imidazolyl; R2 is alkyl, cycloalkyl or cycloalkyl; chloroalkylalkyl: and n is 1 or 2) has an asymmetric carbon center indicated by an asterisk (*), and has an asymmetric carbon center indicated by an asterisk (*). Both carbon centers have the same absolute stereochemical configuration, and the compound described above has the same absolute stereochemical configuration. substantially free of compounds having other absolute stereochemical configurations at the carbon center, such as Provides a highly convenient starting material for producing the desired antifungal end product .

In the method described below, Ar, R, R', X, x1 and P are particularly As defined above, unless otherwise specified. The wavy line is (as also indicated by R/S) ) indicates a mixture of possible isomers; an asterisk (*) indicates a mixture of possible isomers (here and throughout the specification); ) indicates the asymmetric carbon center in its absolute stereochemistry R or S form, and double asterisk in the method described below. (**) is the absolute stereochemistry opposite to the leather-asterisk (book) carbon in the reaction scheme. 0 representing an asymmetric carbon center with the configuration, for example, an asterisk (ne) or an absolute stereochemistry R type. Where indicated, a double asterisk (**) indicates absolute stereochemistry of the S form and vice versa. Ru.

Accordingly, one implementation of the present invention provides compounds having the formula ArH and their pairs. Formula I is substantially free of the #i image isomer, in which the asterisk (ne) represents (preferably , the asymmetric center of its absolute standing chemical configuration S, and L is a suitable leaving group, e.g. B, a compound having C representing an acid anhydride, etc., and a Lewis acid such as AlCl3, By reacting in the presence of S n Cl 4 etc., formula II producing a compound having; Reacting a compound having formula II with a non-basic reducing agent to form a compound having formula ITT generates: and Reacting a compound having formula ITT with a base to produce a compound having formula IV The asymmetric center indicated with a double asterisk (**) is Reversed (preferably to the R configuration) about the indicated asymmetric center. This method is However, usually a commercially available or easily available compound having the formula It is convenient in that you can leave the airport without leaving the airport. Surprisingly, the smell of reaction with ArH 2 Racemization does not occur; furthermore, enantiomeric integrity can be improved using various reducing agents. , is retained when reducing a compound of formula TI to a compound of formula III. Furthermore, that In the process, the inversion at a carbon atom of the group X of a compound of formula I (formula IV) with respect to the same carbon atom of the compound) with a specificity of approximately 100%. therefore, If the carbon atom marked with an asterisk (ne) in the formula r is in its absolute steric configuration IS, then In the above method of combination, the same carbon atom of formula IV marked with a double asterisk (**) , its absolute stereochemical configuration R, and the asterisk (*) in formula I is the absolute stereochemical configuration When R is represented, the carbon atom marked with a double asterisk (*) in formula IV is its absolute steric character. Distribution IFS. Similarly, in the subsequent reactions shown below, the asterisk (ne) and the stereochemistry represented by a double asterisk (ne*) have the same relationship.

In another embodiment, formula IV [In the formula, the double asterisk (*) represents the asymmetric center (preferably of absolute stereochemical configuration R) is reacted with an epoxide ring-opening agent to form a compound having A compound is formed, and the absolute stereochemical configuration at the double asterisk (*) asymmetric center is substantially maintained. Next, a compound having the formula compounds can be produced.

The compound with formula VrlI is then reacted with an oxidizing agent in one step or in two FANs. , Formula XI A compound having the following can be produced.

Xl is a halo, OH or hydroxy-derived leaving group, e.g. mesylate. A compound having a VTrI of formula IX is reacted with a reducing agent to form formula IX A compound having the following can be produced.

In another embodiment of the invention, the formula IV [wherein the double asterisk is (preferably) In other words, a compound having an asymmetric center (of absolute stereochemical configuration R) is treated with an oxidizing agent ( and a hydrolyzing agent, e.g. water) for a compound having the formula VT to Vl and/or a compound having the formula VTI, double asterisk (*) asymmetric medium The absolute stereochemical configuration at the heart is substantially preserved.0 order, then the formula Vl or the formula Vll is are reacted with a hydroxy protecting agent to form formula X or formula XI, respectively. It is possible to produce a compound having

A compound of formula X may be oxidized to a compound of formula XI. A compound having I is reacted with an epoxidizing agent, such as a dialkyl sulfoxide anion. 5, formula XII A compound having the following can be produced.

For example, R1 is H when dimethyl sulfoxide is used. Surprisingly, Ar The stereochemical configuration at the newly formed asymmetric center bound to R substantially the same as the central location.

Next, following reaction with the claimed nuclear Ar” anion using a compound having formula XII and remove any protecting group P to obtain the formula XITI (wherein Ar1 is 1-<1.2 ．． 4-triazolyl), 1-<1.3.4-triazolyl) or 1-imidazo by producing a compound having the formula The antifungal end product can be produced by H.

This intermediate compound having the formula 0178533 It is disclosed in the specification in the racemic form.

Compounds having formula XHT can then be prepared by formula By using methods known per se for compounds having the formula XVT i.e., for example, converting XIII to a compound having methanesulfonate chloride reaction with a methanesulfonating agent such as , which is then reacted with a mercaptan anion having formula SR2 to form formula XV (wherein R2 is alkyl, cycloalkyl or cycloalkylalkyl) ) which is then reacted with an oxidizing agent to form a compound of formula where n is 1 or 2). Ar' is preferred Ar is preferably 1-(1,2,4-triazolyl), and Ar is preferably 2° 4-difluorophenyl, R and R2 are preferably methyl, R1 is preferably H, n is preferably 2 and double asterisk Both carbon atoms indicated by (book*) have the absolute stereochemical configuration R. similar chemistry and a single asterisk (*) carbon in the absolute stereochemical configuration R Starting from , compound XVT has absolute It can be obtained with the stereochemical configuration S.

The present invention provides substantially pure enantiomers and such substantially pure enantiomers. Relating to a method of manufacturing a body. Substantially pure means that such a compound For example, one mirror@isomer is substantially free of any other fi enantiomer of , more preferably in an amount greater than about 95 mole % with respect to any other enantiomer, said to be present in greater than about 97 mol%, most preferably in excess of about 99 mol%. It means that.

As used herein, the following terms have the meanings described below, unless otherwise specified. Has taste.

Acyl includes alkanoyl, halo-substituted alkylcarbonyl, benzoyl and substituted Representing benzoyl: Alkyl (alkylthio, alkoxy, alkyloxyalkyl, alkylthio Alkyl, alkanoyl, alkoxycarbonyl, hydroxyalkyl, etc. including the kill moiety) having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. H or branched hydrocarbon chain; substituted alkyl is a substituted alkyl in which 1 to 3 hydrogen atoms are b. Protected hydroxy, phenyl, substituted phenyl that is not reactive with Lewis acids, etc. represents an alkyl group as defined above, substituted with; Cycloalkyl (including the cycloalkyl part of cycloalkylalkyl) is 3 represents a saturated carbocyclic ring having ~8, preferably 3 to 6 carbon atoms; ro represents fluoro, chloro, bromo or iodo; the amine protecting group is represents a group that protects an amino group during a desired chemical reaction, such as the reaction described in For example, suitable amine protecting groups include benzyl, substituted benzyl, and alkoxy-substituted groups. phenyl, acyl, alkoxycarbonyl, halo-substituted alkoxycarbonyl, unsubstituted substituted or substituted allyloxycarbonyl, etc.: Hydroxy protecting groups are as described above. Represents a group that protects a hydroxyl group during a desired chemical reaction, such as the reactions described, e.g. For example, suitable hydroxy protecting groups include benzyl, substituted benzyl, alkoxy Substituted phenyl, acyl, alkoxycarbonyl, halo substituted alkoxycarbonyl aryl, non-monosubstituted or substituted allyloxycarbonyl, alkyl, alkyloxycarbonyl, alkyl, alkylthioalkyl or R'R''R'''silyl (however, R' + R'' and R'' may be the same or different and each selected from phenyl, cycloalkyl or phenyl; and Substituted allyloxycarbonyl is an allyl group in which the allyl group is halo, phenyl, substituted phenyl, etc. Represents a substituted allyloxycarbonyl group; substituted phenyl, substituted benzyl substituted benzoyl, substituted 3-chenyl and substituted 3-furanyl phenyl ring, chenyl ring or furanyl ring is 71-unit, alkyl, hydroxyalkyl Kyl, hydroxy, alkoxy, alkydthio, phenoxy, alkanoyl, benzoyl, alkanoyloxy, benzoyloxy, amine alkyl amine di substituted with one or two substituents each independently selected from alkylamino, etc. Represents a group that has been replaced.

The novel process and intermediates of the invention are illustrated in the reaction sequence according to the scheme below, where Ar, Ar', R, R', R2, p, x and Xl are as defined above It is.

The asymmetric carbon center indicated by a single asterisk (*) in formula ■ is preferably The stereochemistry is S-type and therefore both carbon centers marked with a double asterisk (**) The final product of formula XvI with absolute stereochemical configuration R, i.e. having formula XVI Compounds with formula I, in which the RR form of the compound occurs, are marked with a single asterisk (*). double asterisk (* *) both of the carbon atoms indicated are in their absolute stereochemical configuration S, i.e. In other words, it is the SS type of the compound having the formula x■■.

In step A, L is any suitable leaving group, such as halo, anhydride or OH 5 Preferably, the reaction mixture can be halo, e.g. chloro. Solvents such as non-reactive, non-polar solvents such as ArH itself, CH2Cl2, It can include tadichlorobenzene, C82, and the like. use any suitable temperature be able to. Preferably, the reaction mixture is cooled to, for example, about 0°C and heated to a suitable temperature. Add Lewis acid 0 Typical Lewis acids include AlCl3, SnCl4 , F e C13, etc. The Lewis acid contains about 1 equivalent to about 3 equivalents, preferably The 6-reactant, which can be present in approximately equivalent amounts, contains water, preferably ice water. The product can be quenched by extracting it with a suitable solvent. Ru.

In step B, a ketohalide having formula II is treated with a suitable non-basic reducing agent. , for example, NaBH3CN, borane, alkylborane, etc. Preferably , the reaction is carried out in a suitable solvent, e.g. methanol, tetrahydrofuran, diethyl ether. The reducing agent is used in excess, for example, about 0.5 to about 1.0 molar excess. The reaction can be carried out at any suitable temperature, such as room temperature.

In step C, a halohydrin having formula III is treated with a suitable base scavenger or The reaction with an acid scavenger, such as a 2CO3,0H-5 organic base, is a suitable method. polar solvents such as methanol, ethanol, dimethyl sulfoxide < DMSO ) One reaction which is preferably carried out at a constant temperature is at any suitable temperature, e.g. from about 0 to about 80°C. You can proceed with The base is preferably in an amount of about 1 to about 1.5 molar amounts. Preferably used in approximately equimolar amounts, typically the solvent is removed and the residue is diluted with water. Wash and extract in CHCl. At this point, a compound having the formula ITI The stereochemistry at the single asterisked carbon (ne) is the double asterisk of the compound having formula IV. It should be noted that the carbons marked (ne*) are inverted.

In the process, the epoxide having formula IV is treated with any suitable epoxide ring-opening reagent. Drugs such as halotrialkyranes, phenoxytos, substituted phenoxytos, anilines , monovalent aniline, benzyl alcohol, substituted benzyl alcohol, acyl amine , alkoxycarbonylamino, alkyl or aryl mercaptan, etc. 0 reaction that can selectively open the ring at an aryl-substituted carbon by eg halotrialkylsilane, dry UK solution, in a suitable or suitable solvent. alkoxy-substituted sodium phenol in a medium such as CH2Cl2 or methanol. This can be done using a oxysalt or the like. Any suitable temperature can be used; Preferably, low temperatures below about -20<0>C to about 80<0>C. The ring opening agent typically is It is added gradually in an amount of about 1.0 equivalents to about 5.0 equivalents relative to the epoxide solution.

The reaction is neutralized and the product is extracted into a suitable solvent such as methylene chloride.

In step F, the compound having formula ether, dihydropyranyl ether, alkoxyalkyl or alkyl Unsaturated or halo derivatives of thioalkyl ethers (e.g. vinyl alkyl ethers) ether or chloroalkylalkyl ether), halotrisubstituted silyl ether, etc. react with. A preferred protecting agent is, for example, dihydropyranyl ether.

Typically, a compound with 2 is reacted with an excess of 11i protectant. Lewis A catalyst such as an acid may be used, the preferred catalyst is POCl3. The reaction is optional. The process can be carried out at a suitable temperature, for example from 0° C. to room temperature. Typically, then: The reaction mixture is washed with a base such as aqueous sodium carbonate and extracted with a suitable solvent. Ru.

In step G, the protected compound having formula VIII is converted to If so, it is reacted with a suitable oxidizing agent such as DMSO. In other cases, the group X1 is first For example, if Xl is converted into an oxide and then converted into a keto group, e.g. If phenoxy or dialkylaminophenoxy, ceric ammonium nitrate Monium can be used, and the resulting droxy group can be replaced with a normal oxidizing agent, e.g. For example, it can be oxidized by manganese dioxide, Jones reagent, chromium trioxide, etc. can. When Xl is an alkylmercapto group or an arylmercapto group, Oxidizing agents such as chlorine or sulfuryl chloride can be used and subsequent hydrolysis The solution results in a ketone having formula XI. When Xl is an acyloxy group, Hydrolysis can be carried out with a suitable hydrolyzing agent, e.g. aqueous sodium hydroxide. and the resulting hydroxy groups are oxidized using the conventional oxidizing agents described above. can be converted into a keto group.

Ketone XI can also be prepared from compound IV by the following process steps.

Here, epoxide ■■ and dialkyl sulfoxide, such as dimethyl sulfoxide, are used. oxide and Lewis acid, such as boron trifluoride, trimethylsilyl triflate. (triflate), Zn", T14+, z, 4+, sn4+, Mg2 One reaction in which the reaction is carried out in the presence of a metal Lewis acid such as from about -20°C to about 60°C, preferably in a non-participating solvent such as or CH2Cl□. , can proceed at temperatures ranging from about 0<0>C to about 30<0>C. hydroxyketone The ratio of VII to diol will vary depending on the reaction conditions and Lewis acid. The desired product VII and the hydroxy protecting agent (Step L) are then combined as mentioned above. The reaction is carried out in the presence of a non-enolizing acid catalyst as described above. Chirality towards keto groups It has been noted that alpha remains intact during the hydroxyl protection process. sea bream.

When a hydrolyzing agent such as water is present, the by-product vI produced in reaction step E is First select the hydroxy group using a suitable hydroxy protecting agent as mentioned in to the ketone XI (step U), where R has a group OP Ar is of order 0, which can also give rise to compounds with the formula The remaining unprotected hydroxyl groups attached are removed using conventional reagents such as MnO2, C Oxidized to keto in step K with rO3, Jones reagent, KMnO4, etc. Using reagents such as air in the presence of 2Cr207, base (02+OH), etc. in a solvent, such as acetone, methylene chloride (biphasic) acetonitrile, DMF, etc. Preferably, by oxidizing in acetone at a temperature of about 30°C to about 30°C. Compound IX can also be prepared from compound IX (step J), where the group X1 is halo , OH or hydroxy-derived leaving groups, such as acyloxy or methy from compound VIII in step H, as appropriate as known in the art. R2, trialkyltin or hydride, zinc, tin, sodium in a suitable solvent. Alternatively, it can be reduced to a methylene group using a reagent such as magnesium metal. It can be manufactured by

In step M, the keto compound Make it react. Typically, the reaction is carried out in a non-participating polar solvent, such as dimethylforma 9 reactions that can be carried out in DMF, dimethyl sulfoxide, etc. at 0°C. It can proceed at any suitable temperature of -50<0>C, preferably 0<0>C to 10<0>C.

The sulfoxide anion is a strong base such as sodium hydride, lithium or is sodium hexaalkyldisilazane, sodium or potassium amide, etc. is prepared by using it appropriately or in the same eluent as keto compound XI. Once a reaction is complete, it can be neutralized, e.g. to pH 7, and then epoxide XII in a suitable solvent such as methylene dichloride or ethyl acetate. Isolate by extraction. At this point, bond to the epoxy ring and form the fS carbon. The new chiral center created has the same relative stereochemistry as the carbon attached to the group OP. It is noteworthy that, for example, the stereochemistry of the ketone with formula XI is double If R is indicated with an asterisk (rate), the carbon bonded to the epoxy group is The newly formed center also has R stereochemistry, with ketone XI marked with a double asterisk (**) If it is S where indicated by It has S stereochemistry at the center of the digit. Therefore, a suitable R of a compound having formula I By starting with the S form, formula XII, formula XI I I, formula X The stereochemistry of the compounds having IV, formula X and formula XVI can be determined in advance as desired. can be determined.

In step N, the 6 reaction in which epoxide XII is reacted with Ar' anion is R1 regioselectivity at the center that connects the It's convenient. Ar” is 1-(1,2,4-triazolyl), 1-(1,3゜ 4-triazolyl) or imidazolyl, the anion is , strong bases such as sodium hydride, sodium amide, potassium amide, hydroxy acid Produced by reaction with cesium chloride, etc. Solvent Selection Class 17III is polar Non-participating solvents such as dimethylformamide, N-methylpyrrolidinone, hexa Methylphosphoramide (catalytic amount), dimethyl sulfoxide, etc., to approx. 0°C, preferably 70°C to 80°C in dimethylformamide. It is ℃.

Once the reaction is complete, it is treated with a strong acid such as aqueous HCI, H2SO in step N. 4. Acidify using phosphoric acid or trifluoroacetic acid. This method provides oxygen protection Allowing cleavage of the group to yield a free hydroxyl group. Compound XIII is The pH of the reaction is adjusted to, for example, a pH of about 8-9 and the product is extracted in a suitable solvent. isolated by Alternatively, product XIII may be prepared at a pH of 8-9. It can be precipitated from the medium during preparation.

Steps P, Q and W are described in European Patent Application No. 0178533. For example, a compound having formula XIIT and methane chloride methanesulfonating agents such as sulfonyl in an inert solvent (e.g., benzene, chloromethane, etc.) in the presence of a base at about 30°C to about 30°C to convert formula yields methanesulfonate with Typically, the sulfonating agent is in excess (1-2 equivalent) used. The base can be, for example, an organic amine, such as pyridine. Wear.

Next, a methanesulfonate having the formula XIV and a methanesulfonate having the formula R25-, where R2 mercaptans in which is alkyl, cycloalkyl or cycloalkylalkyl React with anions. Preferably the counterion is an alkali metal salt and The solvent is preferably inert (e.g. DMSOlDMF etc.), thiol The salt can be used in excess (2 to 10 equivalents) and the temperature typically ranges from 0 to 8 It is 0°C.

The sulfide having formula XV is then treated in step W with an oxidizing agent such as a peracid, e.g. using metachloroperbenzoic acid in an inert solvent, e.g. chloroform, at about -30°C. Oxidize at ~reflux temperature.

The following examples are intended to illustrate but not limit the invention. do not have.

Obstruction doctor 1 1 g of S-(-)-2-chloroglopionic acid, 1.5 g of m-difluorobenzene, Pour 0.35ml of dimethylformamide (DMP) into a flask and cool to 0°C. do. Gradually add 1.28 g of oxalyl chloride and stir for about 16 hours. obtained The reaction mixture was mixed with 31.25 g of AlCl in 1.05 g of m-difluorobenzene. Add to. Stir at 0°C for about 6 hours, add 50 ml of methylene chloride, and cool in ice water. Add to. Leave for 1 hour. Separate the CH2Cl2 layer and brine with H20. Wash. Dry over N a 2 S O4. Rotary evaporation of solvent Removed by evaporation in a generate g.

Group X Legend 1.5 g of the product A from Example 1 above and 15 ml of THF. 1.5ml of vinegar a Add 1.83g of N a B H3CN to it, and - late stirring do.

The solvent was removed on a rotary evaporator and 25 ml of methylene chloride and 75% Add 10 ml of saturated aqueous brine solution and stir for about 25 minutes. methylene chloride Separate and wash twice with 75% saturated brine. methylene chloride solution with Na2SO 4. Dry on top. The solvent was removed on a rotary evaporator to obtain the above 2B. 1.53 g of the desired product are obtained.

Ying Chong District Dan 15.1 g of the product with NiB from Example 2 above, (distilled over Ca H2) ) Add IO, Ig of 2C03 to 150ml of methyl alcohol and the powder, and Stir at room temperature until disappearance of starting material as shown by thin layer chromatography. Stir. Remove KHCO3 and remove methyl alcohol using a rotary evaporator. Remove under vacuum at about 40°C. Add methylene chloride to the residue, followed by two portions with water. Wash with brine and dry over Na2SO4. methylene chloride - Distilled with a tally evaporator to obtain 11.28 g of the product having the above 2〇 Obtained as an oil.

Last month - 1st birthday Add 2 g of the above compound with 2〇 from Example 3, 100 iM methylene ion , cool the mixture using an ice/acetone bath. Bromotrimethylsilane1. Gradually add 7ml over 10 minutes, then heat to 0℃ for about 45 minutes. Stir. The resulting reaction mixture was stirred with 50% saturated brine solution and separated. Remove, wash with saturated brine and dry over Na2SO4. Low solvent Removal in a tally evaporator gives 2.79 g of a group of products having the above formula. is obtained.

ml 0.5 g of the compound satisfying the above formula from Example 4, dry CH2Cl. 1゜m 1, dihydropiraf 1.81 ml and POCl3 were placed in a 15 mg flask, Stir at room temperature for 4 hours. Add saturated sodium bicarbonate solution, stir for 5 minutes and 1 min. , washed with water, and dried over N a 2 S O 4 . the product obtained was run through a series of silica columns and 2.5% CH2Cl2/hexane AE 30% CH It was prepared by making it mM using a gradient of 2Cl2/hexane and 498 mg of the desired product with an E of 2 are obtained.

X 1 g of the compound with 2E from Example 5 above, 5 ml of dimethyl sulfoxide and 1. Add 752 mg of silver and benzoate a to a flask.The reaction mixture was heated at 60°C for 2 hours. Heat and cool to room temperature. Add 50 ml of ether and 275 ml of sodium bicarbonate. mg of water, washed with water and then brine, and dried over Na2SO4. let Removal of the solvent on a rotary evaporator yielded a pale yellow oil; The product was run through a series of silica gel columns, containing 10% AE, 50% CH2Cl2/Hex. Using a gradient of is obtained.

large 1 mark 11 Put 836 mg of 50% Na in oil into a vial and wash twice with 0.5 ml of hexane. Purify. Decant the hexane and dry with a stream of N2. 0.5ml dry DMSO Add and stir for 5 minutes. (CH3) Add 163 mg of 3S (0) I, approx. 2 Stir for an hour. Compound with 2F from Example 6 above! iJI1100mg and 0.5 ml of dry THF and stirred for about 3 hours. Pour into 5ml of ice water0 The reaction mixture is extracted with diethyl ether. Wash ether with water and brine and dry over Na2SO4. Filter and rotary evaporate the solvent. to yield 88 mg of the product with the above-mentioned 2G.

Class X Ward Dan Add 85mg of sodium triazole and 0.5+nl of dry DMF to the flask. and stir for 30 minutes. 88 mg of the compound with 2G from Example 7 above was Add in 5 ml of MFo and stir at 90 °C for 4 h. Cool the reaction mixture to room temperature. Add toluene, wash with water then brine, and dry over Na25o4. Drying yields 82 mg of the compound with formula H above.

Ino Ward Dan 82 mg of the compound having formula H from Example 8 above was dissolved in 0.2 m of 4N-MCI. 1 under a violet blanket and stirred at room temperature for about 4 hours. 25% aqueous hydroxide Sodium is activated by increasing the pH to 9 and forms a precipitate.

Add approximately 5 ml of methylene chloride. Methylene chloride solution is anhydrous [using sodium chloride] After drying to remove water, the methylene chloride solution is decanted and the residue is chlorinated. Extract twice with methylene. Dry the methylene chloride solution over magnesium sulfate, Concentrate to dryness on a rotary evaporator to yield 81 mg of crude product. Living The composition was first diluted with methylene chloride to 1% to 2% methanol/methylene chloride and then , on a silica gel column using a gradient of 3% methanol/methylene chloride. Purification by chromatography yielded 22.9 mg of the compound having formula J above. Ikuinujiku Kamidan A compound having the above formula J! 259 mg of Ig, 2.5 rnl of dry methylene chloride and and 0.4 ml of triethylamine. The resulting solution was cooled to 5°C and salted. I requested 1 ml of Mesyl O. Remove cooling bath and thin layer chromatography 1. Stir the reaction mixture at room temperature until the reaction is complete as indicated by Dilute with methylene chloride, wash twice with water, and dry over sodium tEa. . The solvent was removed on a rotary evaporator and the mesylation with K yielding 372 mg of compound.

Sushi Ward Kamigami 372 mg of the mesylate having formula K above were added to 1.3 ml of dimethyl sulfoxide. Add to. Add 1.4 ml of 15% aqueous sodium methyl sulfide at room temperature. Warm stirring Stir. The product precipitates out of solution. indicated by thin layer chromatography When the reaction is complete, add 3.3 ml of ice water to the reaction mixture at - 0°C. Stir for 15 minutes. The product is filtered and washed once with ice water and then with hexane.

The product was dried at 40° C. in open vacuum to give compound 232 with the above formula. Produce mg.

Inuse Ward 1λ The solution was cooled to 5°C and 299 mg of meta-chloroperbenzoic acid (85%) was added. Add little by little. Remove bath E and stir the reaction mixture at room temperature for 2 hours. thin layer When chromatography shows that the reaction is complete, remove the insoluble material from P leave Wash the precipitate once with methylene chloride. P solution with 10% sodium bicarbonate solution Wash with solution, followed by brine. Dry the solution over sodium sulfate and Evaporate to dryness using a tally evaporator. Triturate the residue with ethyl ether to give a white A colored crystalline solid is produced which is filtered to yield 223 mg of crude product. @product was crystallized in acetonitrile to produce 117 mg of the compound with 2M as described above. do.

Although the invention has been described in terms of the foregoing examples, many modifications and variations are possible. . It is intended that all such modifications and variations be within the scope of the following claims. Ru.

Claims (10)

[Claims] 1. Formula II▲There are mathematical formulas, chemical formulas, tables, etc.▼II, Formula III▲Mathematical formulas, chemical formulas, There are tables, etc.▼III, Formula IV▲There are mathematical formulas, chemical formulas, tables, etc.▼IV, Formula V III▲There are mathematical formulas, chemical formulas, tables, etc.▼VIII, Formula XI▲Mathematical formulas, chemical formulas, tables, etc. etc.▼XI or Formula XII▲There are mathematical formulas, chemical formulas, tables, etc.▼XII ( In the formula, Ar is phenyl, substituted phenyl, 3-thienyl, substituted 3-thienyl, 3 -furanyl or substituted 3-furanyl; R is alkyl or cycloalkyl; represents kyl; R1 represents H or alkyl; X represents chloro, bromo or iodo; X1 represents OH, chloro, bromo, represents iodine or P1, where P1 is alkoxy-substituted phenyloxy, benzyloxy, substituted benzyloxy, acyloxy, alkylthio, phenylthio represents a substituted phenylthio or -NHP2, where P2 is an amino protecting group and P represents H or a hydroxy protecting group). Thus, the compounds mentioned above are indicated by a single asterisk (*) and a double asterisk (**). have one or more asymmetric centers and the compounds have the same chemical structure. The carbons marked with an asterisk are substantially free of one or more compounds that Compounds as described above or pharmaceutically acceptable thereof having other absolute stereochemical configurations in the heart salt. 2. Carbon atoms marked with a single asterisk (*) are in their absolute stereochemical configuration S; Claims that the carbon atoms indicated with a double asterisk (**) are in their absolute stereochemical configuration R A compound according to item 1. 3. Formula XII ▲There are mathematical formulas, chemical formulas, tables, etc.▼XII (In the formula, Ar, P, R and R1 are 2. A compound according to claim 1, having the formula (as defined in claim 1). 4. Ar is 2,4-difluorophenyl, R is methyl, and P is 2-difluorophenyl. trahydrobilanyl, R1 is H, and X is chloro or bromo; 4. A compound according to certain claims 1, 2 or 3. 5. has the formula ArH, where Ar is phenyl, substituted phenyl, 3-chenyl, a compound representing substituted 3-chenyl, 3-furanyl or substituted 3-furanyl and a compound of formula I ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, the asterisk (*) indicates an asymmetric center, and R represents alkyl or cycloalkyl. represents a leaving group, and X represents chloro, bromo or iodo. Was) in the presence of a Lewis acid, Formula II▲There are mathematical formulas, chemical formulas, tables, etc.▼Produce a compound with II; A compound having formula II is reacted with a non-basic selection agent to form formula III▲mathematical formula, chemical formula , there are tables etc.▼Produce a compound having III; and A compound having formula III is reacted with a base to form formula IV▲ which has a mathematical formula, chemical formula, table etc. ▼Involves producing compounds with IV; indicated with double asterisk (**) The asymmetric center in the compound having formula IV is Formula IV according to claim 1, inverted about the asymmetric center indicated by a single asterisk (*) A method for producing a compound having 6. Formula IV, ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV (In the formula, the double asterisk (**) indicates the asymmetric center. represents phenyl, substituted phenyl, 3-thienyl, substituted 3-thienyl , 3-furanyl or substituted 3-furanyl, and R is alkyl or cycloalkyl) with an epoxide ring-opening agent, Formula V▲There are mathematical formulas, chemical formulas, tables, etc.▼V (wherein, X1 represents OH, chloro, bromo, iodo or P1, provided that p 1 is alkoxy, phenyloxy, substituted phenyloxy, benzyloxy, substituted substituted benzyloxy, acyloxy, alkylthio, phenylthio, substituted phenyl thio or -NHP2, where P2 is an amino protecting group) including the formation of compounds and extinctions at asymmetric centers marked with a double asterisk (**). of a compound having formula V according to claim 1, wherein the allelic chemistry is substantially conserved. Production method. 7. (a) Reacting a compound of formula V with a hydroxy protecting agent to form a compound of formula VIII 3▲There are mathematical formulas, chemical formulas, tables, etc.▼VIII (in the formula, P is H or hydroxy a protecting group in which Ar, X1 and R are as defined in claim 6) (b) (1) reacting the compound of formula VIII with an oxidizing agent; to produce a compound having the formula Taha (b) (2) Reacting a compound having formula VIII with a selection agent to obtain formula IX▲ There are chemical formulas, tables, etc. ▼ Generate a compound with IX; and then generate the formula IX By reacting the compound with an oxidizing agent, formula XI▲There are mathematical formulas, chemical formulas, tables, etc.▼ producing a compound having XI; or (b) (3) Reacting a compound having formula VIII with an oxidizing agent to There are academic formulas, tables, etc. ▼X and then reacting the compound having formula X with an oxidizing agent. Therefore, there are formulas, chemical formulas, tables, etc. to produce a compound having formula XI. and; A claim for the preparation of a compound of formula XI from a compound of formula V, comprising: The method described in 6. 8. Formula IV▲There are mathematical formulas, chemical formulas, tables, etc.▼IV (In the formula, double asterisks (**) are , represents an asymmetric center, and Ar represents phenyl, substituted phenyl, 3-thienyl, substituted 3- represents thienyl, 3-furanyl or substituted 3-furanyl, and R is alkyl or cycloalkyl) with an oxidizing agent to form a compound of formula V I and/or Formula VII▲ Contains mathematical formulas, chemical formulas, tables, etc.▼ producing a compound having; Double asterisk (**) asymmetric medium for compounds having formula VI and/or formula VII The absolute stereochemical configuration at heart is substantially the same with respect to that configuration of a compound having formula IV. held; (b) (1) Reacting a compound having formula VI with a hydroxy protecting agent to obtain formula There are formulas, chemical formulas, tables, etc.▼X or (b) (2) Reacting a compound having formula VII with a hydroxy protecting agent to obtain formula XI , ▲There are mathematical formulas, chemical formulas, tables, etc.▼Produce a compound with XI; (c) reacting a compound having formula XI with an epoxidizing agent to form a compound having formula XII▲, There are scientific formulas, tables, etc.▼XII (in the formula, R1 is H or alkyl) and (d) converting the compound of formula XII to a nucleophilic Ar1 anion. Formula XIII, ▲There are mathematical formulas, chemical formulas, tables, etc.▼XIII (In the formula, Ar1 is 1-(1, 2, 4-triazolyl), 1-(1,3,4-triazolyl) or 1-imidazolyl to produce a compound having A method for producing a compound having formula XIII, comprising: 9. Formula XVI ▲There are mathematical formulas, chemical formulas, tables, etc.▼A method for producing a compound having XVI, Formula XIII ▲ Numerical formulas, chemical formulas, tables, etc. ▼ substituted phenyl, 2- or 3-thienyl, substituted 2- or 3-thienyl , 2- or 3-furanyl, substituted 2- or 3-furanyl, 2-, 4- or or 5-imidazolyl, 3- or 5-(1,2,4-triazolyl), 5- Tetrazolyl, 2-, 4- or 5-thiazolyl, 2-, 4- or 5-o xazolyl, 3-, 4- or 5-isoxazolyl, 2-, 3- or 4- represents pyridinyl or 2-,4- or 6-purinyl, provided that the saturated nitrogen source and the above-mentioned imidasilyl group, triazolyl group, tetrazolyl group, benzimide Dazolyl group, benzthiazolyl group and purinyl group are H, alkyl, substituted alkyl substituted with phenyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl Ar1 may be substituted with 1-(1,2,4-triazolyl), 1-(1 , 3,4-triazolyl) or 1-imidazolyl; R is alkyl, represents substituted alkyl or cycloalkyl; R1 represents H or alkyl; death; R2 is alkyl, cycloalkyl or cycloalkylalkyl; and hand n is 1 or 2) using methods known per se for compounds having: an asymmetric carbon center is indicated by a double asterisk (**), where both asterisk carbon centers (**) are identical absolute have an allelic chemical configuration, and the said compound has such a carbon center that the other absolute The above method is substantially free of compounds having a stereochemical configuration. 10. A method known per se according to claim 9, comprising: (a) a compound having formula XIII; reacting with a methanesulfonating agent to form formula XIV ▲There are mathematical formulas, chemical formulas, tables, etc.▼Produce a compound with XIV; (b) reacting a compound having formula XIV with a mercaptan anion having formula R2S; Correspondingly, formula XV ▲There are mathematical formulas, chemical formulas, tables, etc.▼Produce a compound with XV; and (c) reacting a compound having formula XV with an oxidizing agent to obtain formula XVI▲mathematical formula, chemical formula, There are tables etc. ▼Including producing a compound having XVI, R, R1, R2 , Ar, Ar1 and n are as described in claim 9. Law.