JP2002544276A - Method for producing fused ring imidazo-containing compound - Google Patents

Abstract

(57) Abstract: The present invention relates to a method for producing a compound having the structural formula (2) and cyclizing to produce a condensed ring compound containing an imidazo having the structural formula (1), wherein , n, R, R1, Q1 and Q2 are as defined herein, -X1 is selected -Cl, -Br, -I, from -OH and -COOH,-SEM is -CH ₂ OCH ₂ CH ₂ —Si (CH ₃ ) ₃ .

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to a method for producing certain substituted fused ring imidazo compounds.

BACKGROUND [0002] Some fused-ring imidazo compounds are drugs that are known to be involved in the control of one or more cardiovascular activities, inflammatory mechanisms, oncology, and protein transport from cells. Has physical activity. The method of the present invention is useful for producing such compounds.

SUMMARY OF THE INVENTION The present invention includes a method for producing a compound having the structure of

[0004]

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[Wherein (a) m is an integer from 0 to about 6, (b) n is an integer from 0 to about 6, (c) -Q1- is not present, or -CR = CR-, -O-, -S-, -NR-
, -C (O)-, -NR-C (O)-, -OC (O)-, and (d) -Q2- is absent or -C (O)-; -R is each independently selected from hydrogen, alkyl, aryl, and heterocycle; (f) -R1 is each independently selected from hydrogen, alkyl, aryl, heterocycle, or two R1 are Attaching to form a cycloalkenyl, aryl or heterocyclic ring] The production method comprises the following steps: (A) treating a compound having a structure of the following formula,

[0006]

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[Wherein m, n, -Q1- and -R1 are the same as in the compound (1), and -X1 is -C
l, -Br, -I, if chosen from -OH and -COOH] (i) -X1 is -OH, by treatment with MsOCl or TsOCl and Et ₃ N in compound (2) in a solvent - X1 is converted to -X2, -X2 is -OMs or -OTs, respectively, or -X1 is converted to -X2 by treating compound (2) with a halogenated reactant in a solvent, and -X2 is converted to -X2. -Cl or -Br or -I, and (ii) when -X1 is -COOH, -X1 is converted to -X2 by treating compound (2) with phosgene or oxalyl chloride in a solvent;
2 is -C (O) Cl, whereby some or all of the intermediate formed in this step (A) reacts more spontaneously to form compound (1); and (B)- X1 is -Cl or -Br or -I, or the step (A)
When the conversion to the compound (1) is insufficient, the conversion to the compound (1) is performed by treating each of the compound (2) or the reaction product of the step (A) with nBu ₄ NF in a solvent. Causing.

[0008] The invention also includes a method having an additional step before and / or after step (A) and / or (B). The invention also includes a combinatorial library of compounds produced by this method.

DETAILED DESCRIPTION OF THE INVENTION Glossary As used herein, unless otherwise specified, "alkyl" refers to a branched, straight or cyclic, saturated or unsaturated (but not aromatic), A substituted or unsubstituted hydrocarbon chain is meant. The term “alkyl” can be used alone or as part of another term that can be shortened to “alk” (eg, in alkoxy, alkylacyl). Preferred straight chain alkyls are from 1 to about 20
Carbon atoms, more preferably 1 to about 10 carbon atoms, even more preferably 1 to about 6 carbon atoms, even more preferably 1 to about 4 carbon atoms, and most preferably methyl Or ethyl. Preferred cyclic and branched alkyls have 3 to about 20 carbon atoms, more preferably 3 to about 10 carbon atoms, even more preferably 3 to 7 carbon atoms, even more preferably 3 to about 5 carbon atoms. Has a carbon atom. Preferred cyclic alkyls have one hydrocarbon ring, but can have two, three or more fused or spirocyclic hydrocarbon rings. Preferred alkyls are unsaturated from one to about three double or triple bonds, preferably double bonds, and more preferably are mono-unsaturated with one double bond. Even more preferred alkyls are saturated. Saturated alkyl is
It is referred to herein as "alkanyl". Alkyls unsaturated with only one or more double bonds (no triple bonds) are referred to herein as "alkenyl". Preferred alkyl substituents include halo, alkyl, aryl, heterocyclic, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl , Arylacyl, carboxy and its alkyl and aryl esters and amides, sulfo, alkylsulfo, arylsulfo, sulfino, alkylsulfino, arylsulfino, phospho, alkylphospho, arylphospho, phosphino, alkylphosphino, arylphosphino, Includes nitro and cyano. Cycloalkyl substituents also include cycloalkyl, aryl and heterocycles that are fused or spiro rings with the first cycloalkyl. Also, unsubstituted alkyl is preferred.

[0010] As used herein, "heteroatom" means a nitrogen, oxygen, or sulfur atom.

As used herein, “alkylene” refers to an alkyl linked to two other moieties, and “heteroalkylene” refers to an alkylene having one or more heteroatoms in the bond. I do.

In the present specification, unless otherwise specified, “aryl” means a substituted or unsubstituted aromatic hydrocarbon ring (or fused ring). The term “aryl”
It can be used alone or as part of another term (eg, aryloxy, arylacyl). Preferred aryls have from 6 to about 1 in the aromatic ring.
It has 4, preferably up to about 10 carbon atoms, for a total of from about 6 to about 20, preferably up to about 12 carbon atoms. Preferred aryls are phenyl or naphthyl, most preferred is phenyl (Ph). Preferred aryl substituents include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,
Arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, sulfo, alkylsulfo, arylsulfo, sulfino, alkylsulfino, arylsulfino, phospho, alkyl Includes phospho, aryl phospho, phosphino, alkyl phosphino, aryl phosphino, nitro, and cyano. Aryl substituents also include cycloalkyl and heterocycles fused to an aryl ring or rings. Also, unsubstituted aryl is preferred.

As used herein, unless otherwise specified, “heterocycle” or “heterocyclic” refers to a saturated, unsaturated, or aromatic having one or more heteroatoms in the hydrocarbon ring (s). It means a cyclic hydrocarbon ring (or fused ring). Preferred heterocycles are ring (s)
Has from 1 to about 6 heteroatoms, more preferably 1 or 2 or 3 heteroatoms in the ring (s). Preferred heterocycles have from 3 to about 14, preferably up to about 10 carbon and heteroatoms in the ring (s), more preferably 3 to about 7 in the ring (s), even more preferably 5 or 6 Carbon and heteroatoms,
It has a total of from 3 to about 20 carbons and heteroatoms, more preferably 3 to about 10, even more preferably 5 or 6 carbons and heteroatoms. Preferred heterocycles are one ring, but can be two, three, or more fused rings. More preferred heterocycles include one ring having 5 or 6 carbon and heteroatoms in the ring, having up to 3 ring heteroatoms, of which up to 2 are O and S. Even more preferably, one or two ring atoms are O or S and the other is C, or one, two or three ring atoms are N and the other is C It is a heterocycle of 5 or 6 ring atoms. Such preferred 5 or 6 ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic. Such preferred heterocycles of 5 or 6 ring atoms are monocyclic, saturated,
Is unsaturated with three double bonds or is fused to a hydrocarbon ring of three to six ring atoms that is aromatic (phenyl), or another such five or six ring atoms Is preferably condensed with a heterocyclic ring. Heterocycles are unsubstituted or substituted. Preferred heterocyclic substituents are the same as those for alkyl.

Methods of the Invention Scheme I The methods of the invention include those depicted in Scheme I.

[0015]

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In Scheme I and other schemes herein, m is an integer from 0 to about 6, preferably 0 to about 2, more preferably 0 or 1, and n is 0 to about 6, preferably 0 to about 6. An integer of about 2, more preferably 0 or 1, and m + n is 0 to 12, preferably 0 to about 4, more preferably 1 to about 3, more preferably 2 or 3.

In Scheme I and other schemes herein, each -R is independently selected from hydrogen, alkyl, aryl, and heterocycle. The non-hydrogen -R is selected from phenyl, a heterocycle having 5 or 6 ring atoms containing 1 or 2 heteroatoms, and an alkyl having 1 to about 6 carbon atoms, such R Is unsubstituted or substituted, preferably unsubstituted. Preferably, no more than two, more preferably no more than one of all -R are other than hydrogen, and even more preferably, all of -R are hydrogen.

As used herein, in Scheme I and other schemes, -R1 is each independently selected from hydrogen, alkyl, aryl, and heterocycle, wherein both R1 are attached to form a cycloalkenyl, aryl, or heterocycle. I do. Two R1s are attached,
Preferably they form a cycloalkenyl, aryl or heterocycle, more preferably a cycloalkenyl or aryl ring, even more preferably an aryl ring, especially phenyl. When two R1s are attached to form a phenyl ring, one or preferably both of the para positions of the phenyl ring are attached to them relative to the R1 attached position shown in Scheme I by a non-hydrogen substitution. Having a group. Such substituents are preferably attached to the phenyl ring by a heteroatom, wherein the heteroatom is preferably oxygen and such a substituent is preferably alkoxy, especially methoxy.

As used herein, in Scheme I and other schemes, -Q1- is absent or -CR = CR-, -O-, -S-, -NR-, -C (O)-,- NR-C
(O)-, and -OC (C)-, preferably not present or -O (C)-.
-, -S-, -NR- and -C (O)-. More preferably -Q
1- does not exist. When -Q1- is absent, m + n is preferably from 1 to about 4, more preferably from 1 to about 3.

As used herein, in Scheme I and other schemes, -X1 is -Cl,-
Selected from Br, -I, -OH and -COOH. When -X1 is -OH,
-X2 can be -OMs or OTs, and -Q2- is absent. Alternatively, when -X1 is -OH, -X2 is -Cl or -Br or -I and -Q2- is absent. When -X1 is -COOH, -X2 is -C (
O) Cl and -Q2- is -C (O)-. -X1 is -Cl or -Br
Or in the case of -I, step (A) is omitted and -X2 is the same as -X1 (compound (2) and compound (3) are the same).

As used herein, in Scheme I and other schemes, -SEM has the structure CH ₂ OCH ₂ CH ₂ —Si (CH ₃ ) ₃ .

Step (A) In step (A) of Scheme I, the reactant corresponds to -X1.

When -X1 is -OH, compound (2) is preferably prepared in the presence of a base (eg, triethylamine (Et ₃ N)) in a solvent, preferably dichloromethane, with methylsulfonyl chloride (MsOCl) or p -Can be treated with any of toluenesulfonyl chloride (TsOCl). This reaction is preferably performed under an inert atmosphere, more preferably under an argon atmosphere. The MsOCl or TsOCl is preferably added slowly, preferably over a period of about 2 hours, more preferably over a period of about 1/4 hour to about 1 hour. Even more preferably, about 1 /
Take 2 hours. During the addition of MsOCl or TsOCl, the temperature of the reaction mixture is preferably from about -20C to about 25C, more preferably about 0C. After the addition of MsOCl or TsOCl is complete, the reaction mixture is preferably brought to about 0 ° C to about 4 ° C.
Warm up to a temperature of 0 ° C., more preferably to about room temperature, at which temperature the reaction mixture is stirred, preferably for about 1/2 hour to about 6 hours, more preferably for about 1 hour.

Alternatively, when -X1 is -OH, -OH is -Cl, -Br or -I (-X
Compound (2) is reacted with a halogenated reactant to convert to (2) to form compound (3). Known halogenation reaction conditions suitable for compounds of structures (2), (3) and (1) are suitable. Preferred halogenation reactions are selected from:

(A) reacting compound (2) with thionyl chloride (SOCl ₂ ), preferably in the presence of a base (eg, triethylamine) in a solvent, preferably dichloromethane, to obtain a compound (-X2 being Cl) 3) can be generated. This reaction is preferably performed under an inert atmosphere, more preferably under an argon atmosphere.
Thionyl chloride is preferably added slowly, preferably over a period of about 2 hours, more preferably over a period of about 1/4 hour to about 1 hour. Even more preferably about 1
/ 2 hours. During the addition of thionyl chloride, the temperature of the reaction mixture is preferably about -2.
0 ° C to about 25 ° C, more preferably about 0 ° C. After the addition of thionyl chloride is complete, the reaction mixture is preferably warmed to a temperature of about 0 ° C. to about 40 ° C., more preferably to about room temperature, at which temperature the reaction mixture is preferably heated to about 1/2 hour to about 40 ° C. Stir for 6 hours, more preferably about 1 hour.

(B) Compound (2) is treated with NBS in a solvent, preferably in dimethylformamide (DMF), preferably in the presence of triphenylphosphine (Ph ₃ P), or a base (eg, Treatment with tribromophosphine (PBr ₃ ) in the presence of pyridine) in a solvent, preferably dichloromethane, gives -X2 to -B
Compound (3), which is r, can be produced. This reaction is preferably performed under an inert atmosphere, more preferably under a nitrogen atmosphere. The temperature of the reaction mixture is preferably from about 0 ° C to about 40 ° C, more preferably about 20 ° C. The reaction mixture is preferably stirred for about 1/2 hour to about 12 hours, more preferably about 2 hours.

(C) Compound (2) is reacted with a solvent in the presence of a strong acid (eg, phosphoric acid, sulfuric acid),
Treatment with sodium iodide (NaI) or potassium iodide (KI), preferably in a solvent of DMF, can produce compound (3) where -X2 is -I. The temperature of the reaction mixture is preferably from about 0 ° C to about 90 ° C, more preferably about 20 ° C. The reaction mixture is preferably stirred for about 1 hour to about 12 hours, more preferably for about 2 hours.

When -X1 is -COOH, compound (2) is treated with phosgene (Cl ₂ CO) or oxalyl dichloride ((ClCO) ₂ ) in a solvent, preferably dichloromethane. This reaction is preferably performed under an inert atmosphere, more preferably under an argon atmosphere. The phosgene or oxalyl dichloride is preferably added slowly, preferably over a period of about 2 hours, more preferably over a period of about 1/4 hour to about 1 hour. Even more preferably, it takes about 1/2 hour. During the addition of phosgene or oxalyl dichloride, the temperature of the reaction mixture is preferably from about -20C to about 25C, more preferably about 0C. After the addition of phosgene or oxalyl dichloride is complete, the reaction mixture is preferably warmed to a temperature of about 0 ° C. to about 40 ° C., more preferably to about room temperature, at which point the reaction mixture is preferably cooled to about 1/2 Stir for about 6 to about 6 hours, more preferably about 1 hour.

In the step (A), -X1 is converted to -X2. When -X1 is -OH,-
X2 is selected from -OMs, -OTs, -Cl, -Br and -I. -X1
Is -COOH, -X2 is -C (O) Cl.

When -X1 is -Cl or -Br or -I, the step (A) is unnecessary,
-X2 is the same as -X1, that is, compound (2) is also compound (3). In this case, only step (B) is required to produce compound (1).

Depending on the reaction conditions of step (A), it is possible to separate the -SEM protecting group on the imidazo nitrogen, allowing the reactive -X2 moiety to react spontaneously at the ring-closed position, thereby giving the compound ( 1) can be formed. If this ring closure is sufficient in step (A), step (B) is not required. In other cases, sufficient ring closure is performed using step (B).

Step (B) If the solvent for step (B) is different from that used in step (A), the solvent of step (A) is evaporated, preferably under vacuum at room temperature, to give step (A) From the final reaction mixture.

The compound (3) or the reaction product of step (A) is treated with tetrabutylammonium fluoride (nBu ₄ NF) in a solvent, preferably tetrahydrofuran (THF). This treatment is performed at a temperature of about 0 ° C. to about 60 ° C., more preferably at about room temperature, preferably for a time of about 1/2 hour to about 12 hours, more preferably about 4 hours.

The compound (1) is preferably obtained by evaporating an organic solvent from the reaction mixture of the step (A) and / or the step (B), washing the product with water and / or an aqueous solution, and converting the aqueous layer to an organic layer. And the organic layer is dried by evaporation and isolated and purified by purification by chromatography.

Scheme II The method of the invention disclosed in Scheme I above optionally includes an additional step (C) shown in Scheme II.

[0036]

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In Scheme II, m, n, —R, —Q 1-, and —R 1 are the same as defined in Scheme I above. -X3 is a subgroup of -X1 and represents -OH or -CO
OH.

As used herein, in Scheme II and other schemes, -Z is -Br
, -I or -OTf, preferably -Br.

As used herein, in Scheme II and other schemes, -J is alkanyl having 1 to about 4 carbon atoms, preferably J is methyl or n-butyl.

Step (C) In the step (C), the compound (4) and the compound (5) are reacted in a solvent, preferably in dioxane, preferably in the presence of a Pd (PPh ₃ ) ₄ catalyst to give a compound (2) is generated. A small amount of a radical scavenger, preferably 2,6-di-tert
-Butyl-4-methylphenol (DTBMP) is included in the reaction mixture of step (C). When -Z is trifluoromethanesulfonate (-OTf), preferably lithium chloride (LiCl) is also included in the reaction mixture. The components of the reaction mixture are preferably combined at about room temperature, and then the reaction mixture is heated to about reflux. The reaction mixture is maintained at about reflux temperature for about 2 hours to about 24 hours, preferably for about 5 hours. The reaction mixture is maintained during step (C) under an inert atmosphere, preferably under an argon atmosphere. Preferably, the reaction mixture is cooled to about room temperature. The cooled reaction mixture is preferably treated with a mixture of ether and saturated aqueous potassium fluoride, preferably about a 1: 1 mixture, preferably for about 1 hour to about 24 hours, more preferably for about 15 hours.

The purified compound (2) is obtained from the reaction mixture, preferably by filtration, washing with ether, washing with water and water, drying, and purification by chromatography.

Scheme III In the method of the present invention, the steps shown in Scheme III are optional additions to the steps in Scheme I, instead of those in Scheme II. Scheme III below is used to generate compound (2a), which is a subpopulation of compound (2).

[0043]

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In Scheme III, m, n, —R, —J, and —X1 correspond to Schemes I and I
Same as I. Ring T represents all of the ring moieties that can be formed when two R1s of compound (2) are attached. -Q3- is a subset of -Q1-, wherein -Q3- is -O-, -S-, -NR-, -NR-C (O)-, and -O-.
C (O)-, preferably selected from -O-, -S- and -NR-.

In Scheme III, -Y is -NHR, -OH or -SH, preferably -N
HR or -OH, more preferably -OH.

In Scheme III, -W is -I, -Br or -C (O) V, preferably-
Br or —C (O) V, more preferably —Br. -V is -OH, -Cl
Or -Br, preferably Cl.

Step (D) In Step (D) of Scheme III, compound (6) and compound (5) are
The reaction is preferably carried out in dioxane in the presence of a Pd (PPh ₃ ) ₄ catalyst to produce compound (7). Preferred conditions for step (D) in Scheme III are Scheme I
It is the same as that of step (C) of I.

Step (E) In step (E), compound (7) and compound (8) are reacted in a solvent, preferably dichloromethane, preferably in the presence of a base, to produce compound (2a) . Preferred bases useful in this step include sodium carbonate and triethylamine, more preferably triethylamine. This step is preferably performed at about 0 ° C. to about 45 ° C., more preferably at about room temperature, preferably for about 2 hours to about 14 hours, more preferably for about 6 hours.

Scheme IV In the method of the present invention, compound (1) or compound (11) shown in scheme IV
From compound (9).

[0050]

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In Scheme IV, m, n, -R, -Q1-, -Q2-, -J and -R1 are the same as in Schemes I and II above.

In Scheme IV, —R2 can be hydrogen, in which case steps (G) and (H) are not used. -R2 is hydrogen, halo, alkyl, aryl, heterocyclic,
Selected from carboxy and its alkyl esters and amides. Preferred -R2 is selected from hydrogen, halo, C ₁ -C ₄ alkyl, and phenyl. More preferred -R2 is selected from hydrogen and unsubstituted and substituted phenyl, and the substituents on such phenyl are preferably selected from hydroxy, alkoxy, thio and alkylthio. Most preferred -R2 is hydrogen.

In Scheme IV, —R 3 is selected from hydrogen, alkyl, aryl and heterocycle. Preferred -R3 is alkyl, aryl, and heterocycle. More preferred -R3 is unsubstituted and substituted phenyl and benzyl. Preferred substituents of such phenyl and benzyl, halo, C ₁ -C ₄ alkyl, aryl, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, formyl, alkyl acyl, aryl It is selected from acyl, carboxy and its alkyl and aryl esters, amides, thioesters and thioamides. More preferred -R3 is benzyl, alpha-carbon of the benzyl is unsubstituted or substituted, preferred substituents are alkyl (preferably C ₁ -C _4), is selected from aryl and heterocycle.

Step (F) In the step (F), the compound (1) or the compound (11) is combined with the compound (12) and n-butyllithium (nBuLi) in a solvent, preferably tetrahydrofuran, to give the compound (9). Generate Preferably, compound (12) is first dissolved in a solvent and the resulting solution is cooled from about -30C to about 5C, preferably to about 0C. This solution is preferably placed under an inert atmosphere, more preferably under an argon atmosphere. nBuLi is preferably added to the solution slowly over a period of about 0.2 hours to about 1 hour, more preferably over a period of about 0.5 hours. The resulting mixture is stirred for about 1/2 hour to about 1 hour, preferably about 3/4 hour. Next, compound (1) or compound (11) dissolved in a solvent, preferably THF, is added. The reaction mixture is preferably warmed to room temperature and then preferably heated to about reflux for a period of about 2 hours to about 24 hours, more preferably about 12 hours. When the reaction is completed, the reaction mixture is preferably quenched with methanol.

Compound (9) is purified from the reaction mixture by evaporating the solvent, redissolving with a solvent, preferably dichloromethane, washing with water and aqueous solutions, drying and purifying by chromatography. Is preferred.

Steps (G) and (H) Non-hydrogen, -R2, is optionally obtained on compound (9) by performing optional steps (G) and (H) of Scheme IV.

In step (G), compound (1) and N-bromosuccinimide (NBS) are combined in a solvent, preferably carbon tetrachloride. It is preferred to add a radical initiator, preferably benzoyl peroxide. The reaction mixture is heated, preferably to a temperature from about 0 ° C to about 100 ° C, more preferably to a temperature of about 90 ° C. The reaction mixture is maintained at the elevated temperature for about 5 minutes to about 120 minutes, more preferably for about 10 minutes.

The purified compound (10) is preferably obtained by filtration, evaporation and purification by chromatography.

In the step (H), the compound (10) is treated with a solvent in the presence of a Pd (PPh ₃ ) ₄ catalyst,
Compound (11) is produced preferably by compounding with compound (13) or compound (14) in toluene. A small amount of a radical scavenger, preferably DTBMP, is added to the process (
It is preferably added to the reaction mixture of H). The reaction mixture is heated, preferably to reflux, under an inert atmosphere, preferably under a nitrogen atmosphere, preferably for about 3 hours to about 24 hours, more preferably for about 6 hours. After completion of the reaction, the reaction mixture is preferably cooled to about room temperature.

The purified compound (11) is preferably obtained from the reaction mixture by extraction, treatment with aqueous KF, filtration, washing with water and aqueous solutions, extraction, drying and purification by chromatography.

Scheme V The method of the present invention optionally includes one or more additional steps to purify compound (5), as shown in Scheme V.

[0062]

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In Scheme V, -J and -SEM are the same as specified in Schemes II and III above.

The additional steps of Scheme V required for the process of the invention depend on any of the compounds (15), (16), (17) and (18) used as starting materials.

Compound (15), imidazole, preferably in the presence of sodium hydride,
In a solvent, preferably dimethylformamide (DMF), preferably under an inert atmosphere, preferably at about −20 ° C. to about 60 ° C., more preferably at about room temperature, preferably about 1/2 hour to about 12 hours, More preferably, the SEM in about 2 hours
React with —Cl to produce compound (16).

Compound (16) is initiated in a solvent, preferably THF, in the presence of phenyl disulfide and n-butyllithium, preferably at about -80 ° C to about 25 ° C, more preferably at about -80 ° C. And then terminate at about room temperature, preferably from about 1/2 hour to about 6 hours, more preferably about -80 ° C for about 1/2 hour after adding n-butyllithium, at about 0 ° C. About 1 hour after adding phenyl disulfide,
And about 1 hour at about room temperature to produce compound (17).

Compound (17) is reacted with an oxidizing reagent, preferably MCPBA, in a solvent, preferably dichloromethane, preferably under an inert atmosphere, preferably from about 0 ° C. to about 40 ° C.
At about room temperature, preferably about 2 hours to about 24 hours, more preferably about 15 hours to produce compound (18).

Compound (18) can be prepared by trialkyltin chloride, preferably tributyltin chloride, in a solvent, preferably THF, preferably in the presence of n-butyllithium, preferably under an inert atmosphere, preferably about -80 ° C to about 40 ° C, more preferably at about room temperature, preferably about 1/2 hour to about 6 hours, more preferably about -8 hours.
Compound (5) was reacted at 0 ° C. for about 1/2 hour after addition of n-butyllithium, at about 0 ° C. for about 1 hour after addition of tributyltin chloride, and at room temperature for about 4 hours to give compound (5). Generate.

EXAMPLES The following examples further provide information regarding the methods of the present invention. These are merely examples and do not limit the scope of the invention.

[0070]

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NaH (6.5 g, 0.162 mol, dissolved in anhydrous DMF (300 ml)
The suspension (washed twice with hexane) is cooled in an ice / acetone bath (bath temperature -15 ° C). A small portion of solid imidazole (10 g, 0.145 mol) is added and the mixture is stirred at room temperature (rt) for 0.5 h, turning the solution clear. SEM-Cl (2
5 g, 0.150 mol) with a syringe pump. t. , And NaCl precipitates during the addition. This mixture was r. t. And stir for about 1 hour.
Monitor the progress of the reaction by TLC (CH ₂ Cl ₂ / MeOH, 9: 1). H ₂ O (1
(0 ml) is carefully added to stop the reaction. Evaporate the solvent in vacuo. Residue is E
Dissolve in t ₂ O (200 ml), wash with H ₂ O (4 × 50 ml), brine (50 ml), dry (MgSO ₄ ), filter and evaporate in vacuo to give compound A as an orange liquid obtain.

[0072]

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SEM-protected imidazole A (1.48 g, dissolved in dry THF (75 ml)
7.50 mmol) in n-BuLi (1
. 6M hexane solution) (6 ml, 9.60 mmol) was added dropwise, and the mixture was added to -78.
Stir at 30 ° C. for 30 minutes. Then phenyl disulfide (2.1 g, 9.60 mmol) dissolved in THF (2 ml) is added dropwise. After the addition, replace the dry ice / acetone bath with an ice bath. The mixture is allowed to stand at 0 ° C. for 1 hour, then at r. t. And stir for 1 hour. Monitor progress by TLC (CH ₂ Cl ₂ / MeOH, 9: 1). H ₂ O (
(5 ml) is added to stop the reaction. The solvent was evaporated in vacuo and the residue Et ₂ O
And washed with 5% NaHCO ₃ (3 × 20 ml), brine (20 ml),
Dry (MgSO ₄ ), evaporate in vacuo and purify by chromatography (silica gel, hexane / EtOAc 3: 1) to give B as a yellow oil.

[0074]

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3-Chloroperoxybenzoic acid (MCPBA, 80-85%) (17.03 g)
, SEM protection was dissolved 78.9Mol) in anhydrous CH ₂ Cl ₂ (160mL) 2-
Add to a solution of phenylsulfide imidazole B (9.71 g, 31.6 mmol) and stir the reaction at room temperature under argon for 15 hours. TL progress
Monitor with C (Hexane / EtOAc, 3: 1). Sodium thiosulfate (3.9
g) is added to remove excess MCPBA. The mixture is filtered. 5 filtrates
% Na ₂ CO ₃ ( ₃ × 150 mL), wash with brine (150 mL), dry (MgSO ₄ ), filter, evaporate in vacuo and purify by chromatography (silica gel, hexane / EtOAc 3: 1). To give C as a pale yellow oil.

[0076]

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A solution of SEM-protected 2-phenylsulfonimidazole C (8.61 g, 25.4 mmol) dissolved in anhydrous THF (250 mL) under argon under −7
At 8 ° C., n-BuLi (1.6 M hexane solution) (19.0 mL, 30.0 mmol)
l) is added dropwise with a syringe pump and the solution is stirred at -78 ° C for 30 minutes. Tributyltin chloride (6.9 mL, 25.4 mmol) is added dropwise with a syringe pump. The mixture is stirred at room temperature for 1 hour. Progress through TLC (Hexane / EtOAc,
9: 1). The reaction is stopped by adding H ₂ O (30 mL). The solution is evaporated in vacuum. The residue was dissolved in ether (550 mL) and saturated NH ₄ C
1 (3 × 150 mL), brine (150 mL), dried (MgSO ₄
), Filter, evaporate in vacuo and chromatograph (silica gel, gradient: hexane (500 mL), hexane / EtOAc 50: 1; hexane / EtOAc 1)
Purify 2: 1) to give D as a clear oil.

[0078]

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Pd (PPh ₃ ) ₄ (0.0177 g, 0.015 mmol) dissolved in anhydrous dioxane (4.0 mL) is a stannylimidaz
ol) D (0.51 g, 0.80 mmol), 4,5-dimethoxy-2- (2-
Hydroxyethyl) phenyl bromide E (0.33 g, 1.1 mmol) and LiCl (0.087 g, 2.1 mmol) are added at room temperature. A small amount of crystals of the radical scavenger, 2,6-di-tert-butyl-4-methylphenol (about 2 m
g) Add and heat the reaction to reflux under argon for 5 hours. The reaction was cooled to room temperature and extracted with a 1: 1 mixture of ether and saturated aqueous KF (10 mL) for 15 minutes.
Time processing. Monitor progress by TLC (Hexane / EtOAc, 3: 1). The mixture is filtered through a pad of celite and rinsed with ether. The filtrate was washed with water (3 × 12 m
L), washed with brine (3x12mL), dried (MgSO _4), filtered,
Evaporate in vacuo and chromatograph (silica gel, hexane / EtOAc, 2
: 3) to give F as an orange oil.

[0080]

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F (2.2 g, 4.24 mmol) dissolved in dichloromethane (200 mL)
And Et ₃ N (886 mL) at 0 ° C. under argon with methylsulfonyl chloride (MsCl, 492 mL) over 0.5 h. The reaction is then warmed to room temperature and stirred for 1 h. TLC (EtOAc:
Using hexane, 1: 1), shows that ring closure occurs in one vessel following MsO-ester formation and SEM cleavage. This mixture was added to CH ₂ Cl ₂ (25 m
Diluted with L), cold aqueous HCl (0.5 N), NaHCO ₃ solution, H ₂ O, washed with brine, dried over MgSO _4. Filtration and evaporation of the solvent gives a yellow solid. Preparative HPLC (EtOAc: hexane, gradient 1: 1 to 1: 0
) To give the product G (1.3 g).

[0082]

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In a 25 mL one neck round bottom flask equipped with a magnetic stir bar, an argon inlet, and a rubber septum, 1-methyl-1-phenyl-ethylamine (H) (164 mg, 1 .2 mmol) is cooled to 0 ° C. under an argon atmosphere. NBuLi dissolved in hexane (0.5 mL, 2.4 M
) Is slowly added to this solution. The reaction turns pale yellow. After stirring for 45 minutes,
Compound G (150 mg, 0.405 mmol) dissolved in THF (1 mL) is added. The solution is warmed to room temperature and further heated at reflux for 12 hours. TLC (
CH ₂ Cl ₂ : CH ₃ OH, 99: 1) indicates the completion of the reaction. The solution was quenched with MeOH and evaporated to give a residue, redissolved in CH ₂ Cl ₂ ,
Wash with aqueous NaHCO ₃ (5%), H ₂ O, brine and dry over Na ₂ SO ₄ .
The crude product was filtered off and evaporated under strong vacuum to remove excess amine H, then purified by chromatography (CH ₂ Cl ₂ : CH ₃ OH, 99: 1) to give compound J of the invention. obtain.

[0084]

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In a 25 mL one neck round bottom flask, Compound J dissolved in anhydrous THF (10 mL)
(181 mg, 0.5 mmol) was cooled to 0 ° C. under an argon atmosphere, then
NaH (18 mg) pre-washed with hexane was added to the solution as a suspension in hexane.
Add. After stirring for 15 minutes, methyl iodide (71 mL) dissolved in THF (0.5 mL) was used.
mg, 0.5 mmol). Allow the solution to warm to room temperature and complete the reaction
Heat to reflux for an additional 2 hours. The solution was quenched with MeOH and evaporated.
To give a residue, CH_TwoCl_TwoRedissolved in NaHCO_ThreeAqueous solution (5%), H_TwoO
, Washed with saline and Na_TwoSO_FourDry with. The crude product is chromatographed (CH _Two Cl_Two: CH_ThreeOH, 99: 1 to 95: 5) to give compound P of the present invention.
You.

[0086]

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N-bromosuccinimide (NBS) solid (98 mg, 0.26 mmol)
Is added to a solution of compound G (0.5 mmol) dissolved in 15 mL of CCl ₄ .
The radical initiator benzoyl peroxide (2 mol%) is then added. Place the flask in a 90 ° C. oil bath. After stirring for 10 minutes, the reaction is complete. The mixture is filtered through a pad of celite and the filtrate is evaporated to give a residue. Chromatography (Et
Purification by OAc: hexane, 1: 3 to 1: 1) gives compound K.

[0088]

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K (0.22 mmol) and Pd (PPh ₃ ) dissolved in 7 mL of anhydrous toluene
) ₄ (13 mg, 0.056 mmol) in a solution of phenyltributyltin (0
. 26 mmol) and some (about 2 mg) crystals of 2,6-di-tert-butyl-4-methylphenol. The reaction mixture is brought to 110 ° C. under nitrogen
At reflux for 6 hours to complete the reaction. The reaction mixture is cooled and then diluted with 1-2 mL of ethyl acetate (EtOAc). The resulting mixture was washed with water, then brine, and extracted with CH ₂ Cl _2, dried over Na ₂ SO _4, and filtered. The filtrate is treated with 3 mL of a 30% aqueous KF solution at room temperature for 2 hours. Filter the solid. Filtrate to C
Dilute with H ₂ Cl ₂ , wash with water, 30% aqueous NH ₄ OH (3 ×), brine, extract with EtOAc, dry (Na ₂ SO ₄ ) and concentrate in vacuo to give crude Obtain the product. Chromatography (silica gel, EtOAc: hexane, 1: 1 to 1:
Compound L is obtained by purification according to 0).

[0090]

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In a 25 ml one neck round bottom flask equipped with a magnetic stir bar, an argon inlet, and a rubber septum, (1-methyl-1-phenyl-ethylamine) (M) (1) dissolved in anhydrous THF. 2 mmol) is cooled to 0 ° C. under an argon atmosphere. NBuLi in hexane (0.5 mL, 2.4 M) is slowly added to the solution. The reaction turns pale yellow. After stirring for 45 minutes, THF (1
Compound L (180 mg, 0.405 mmol) dissolved in (mL). The solution is warmed to room temperature and heated at reflux for 12 hours to complete the reaction. The solution was quenched with MeOH and evaporated to give a residue, redissolved in CH ₂ Cl ₂ , washed with aqueous NaHCO ₃ (5%), H ₂ O, brine, and Na ₂ SO ₄ dry. The crude product is filtered off and evaporated under strong vacuum to remove excess amine M, then purified by chromatography to give compound N of the invention.

[0092]

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Stannylimidazole D (0.51 g, 0.80 mm) in which Pd (PPh ₃ ) ₄ (0.0177 g, 0.015 mmol) was dissolved in anhydrous dioxane (4.0 mL)
ol), 2-nitro-4-methoxyphenol triflate O (0.33 g, 1
. 1 mmol) and a solution of LiCl (0.087 g, 2.1 mmol) at room temperature. Spoon tip amount of radical scavenger, 2,6-di-tert-butyl-4
Add methylphenol and heat at reflux for 5 hours under argon. The reaction is then cooled to room temperature and treated with a 1: 1 mixture of ether and saturated aqueous KF (10 mL) for 15 hours (TLC, monitored by hexane / EtOAc 3: 1). The mixture was filtered through a pad of celite, rinsed with ether, and the filtrate was washed with water (3 × 12 mL), brine (3 × 12 mL), dried (MgSO ₄ )
, Filtered, evaporated in vacuo and chromatographed (silica gel, hexane / E
Purification by tOAc 3: 1) gives compound P as an orange oil.

[0094]

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Pd (0.20 g, 0.19 mmol, 10% on activated carbon) was added to ethyl acetate (
(37 mL) in a solution of compound P (0.91 g, 1.85 mmol). After hydrogenating the reaction mixture under H ₂ at 40 psi for 2 hours, methanol (1
0 mL) is added to the mixture and the hydrogenation is continued for a further 3 hours. The mixture is filtered over silica and the filtrate is evaporated under vacuum to give compound Q as an orange oil.

[0096]

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Anhydrous CH_TwoCl_Two(3 mL) dissolved in 4-dimethylaminopyridine (0.18
g, 1.5 mmol) in anhydrous CH._TwoCl_Two(15.7mL)
To a solution of product Q (0.69 g, 1.5 mmol) and the solution was added under argon.
And stir at room temperature. After 10 minutes, chloroacetyl chloride (ClC (O) CH _Two Cl) (0.12 mL, 1.5 mmol) is added dropwise. This solution is allowed to
Stir for hours (TLC, monitored with hexane / EtOAc 3: 1). This solution is CH _Two Cl_TwoDiluted with H_TwoWash with O (2 × 20 mL) and brine (25 mL)
And dried (MgSO_Four), Filter, evaporate in vacuo and chromatograph
(Silica gel, gradient, hexane / EtOAc 10: 1, 5: 1, 1: 1)
To give compound S as a white solid (53.3 mg).

[0098]

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1-methyl-1-phenyl-ethylamine (68 mg, dissolved in anhydrous THF)
0.5 mmol) is cooled to 0 ° C. under an argon atmosphere. NBuLi in hexane (0.2 mL, 2.4 M) is slowly added to the solution. The reaction mixture becomes pale yellow. After stirring for 45 minutes, the compound S (3) dissolved in THF (1 mL) was added.
9 mg, 0.1 mmol) are added. The solution is warmed to room temperature and further heated at reflux for 12 hours. The solution was quenched with MeOH and evaporated to give a residue, redissolved in CH ₂ Cl _2, NaHCO ₃ solution _{(5%), H 2 O} , washed with brine, dried over Na ₂ SO ₄ I do. The crude product was filtered off and evaporated under strong vacuum to remove excess amine H, followed by chromatography (CH ₂ Cl ₂ : CH ₃ OH, 99
1) to give compound T.

While particular embodiments of the present invention have been described, it will be apparent to those skilled in the art that various changes and modifications can be made to the present invention without departing from the spirit and scope of the invention. It is intended that the appended claims cover all such modifications as fall within the scope of the invention.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72 ) Inventor Min Li United States 45069 West Chester, LA Lacota Springs Drive 7563 F-term (reference) 4C050 AA01 AA07 BB05 CC11 EE02 FF01 GG04 GG05 HH01

Claims (10)

[Claims] 1. A method for producing a compound having a structure represented by the following formula: [Wherein (a) m is an integer from 0 to about 6, (b) n is an integer from 0 to about 6, (c) -Q1- is not present, or -CR = CR-, -O-, -S-, -NR-
, -C (O)-, -NR-C (O)-and -OC (O)-, wherein (d) -Q2- is absent or -C (O)-; (E) -R is each independently selected from the group consisting of hydrogen, alkyl, aryl, and heterocyclic; and (f) -R1 is each independently selected from the group consisting of hydrogen, alkyl, aryl, and heterocyclic. Or two R1s are attached to form a cycloalkenyl, aryl or heterocycle.] (A) a step of treating a compound having the structure of the following formula: Wherein m, n, -Q1- and -R1 are the same as in the compound (1), and -X1 is -C
l, -Br, -I, if selected from the group consisting of -OH and -COOH] (i) -X1 is -OH, treated with MsOCl or TsOCl and Et ₃ N in compound (2) in a solvent -X1 is then converted to -X2, where -X2 is -OMs or -OTs, respectively, or -X1 is converted to -X2 by treating compound (2) with a halogenated reactant in a solvent. , -X2 is -Cl or -Br or -I. (Ii) When -X1 is -COOH, -X1 is converted to -X2 by treating compound (2) with phosgene or oxalyl chloride in a solvent. And -X
2 is -C (O) Cl, whereby part or all of the intermediate formed in this step (A) reacts more spontaneously to form compound (1); and (B)- X1 is -Cl or -Br or -I, or the step (A)
If the conversion to the compound (1) is not sufficient, by treating each of the compound (2) or the reaction product of the step (A) with nBu ₄ NF in a solvent,
Comprising the step of causing conversion to compound (1), preferably wherein m and n are each independently an integer from 0 to about 2, and no more than 2 -R are other than hydrogen, preferably 2 R1 are Attach to form a ring and preferably compound (2) has the structure of [Wherein m, n, -R, and -X1 are the same as compound (2), and -Q3- is -O
-, -S-, -NR-, -NR-C (O)-, -OC (O)-, and -SC (
O)-, wherein ring T is cycloalkenyl or aryl or heterocycle]. 2. The method according to claim 1, wherein -X1 is -COOH, -Cl or -Br or -I. Wherein -X1 is -OH, the compound in step (A) (2) with SOCl ₂ and Et ₃ N or NBS and Ph ₃ P,,, or PBr ₃ and pyridine or NaI or KI, and the method of claim 1, wherein the treatment with strong acid or MsOCl or TsOCl and Et ₃ N,. 4. -Q1- is absent or selected from the group consisting of -O-, -S-, -NR-, and -C (O)-, -Q2- is absent, and m + n is 1 The method of claim 1, wherein 5. The method of claim 1, wherein the two -R1s are attached to form an unsubstituted or substituted phenyl ring. 6. -Q2- is absent, -Q1- is absent, and m + n is from 1 to 4, or -Q1- is -CR = CR- and m + n is from 0 to 2. The method of claim 5, wherein: 7. A compound (2) comprising the following steps: (C) a compound having a structure of the following formula: A compound having a structure of the following formula: [Wherein, m, n, -R-, -Q1- and -R1 are the same as those in the compound (2);
X3 is -OH or -COOH, and -Z is -Br or -I or -OTf.
And -J is an alkanyl having 1 to about 4 carbon atoms.] The method of claim 1 or 5, wherein 8. A compound (2a) comprising the following step: (E) a compound having a structure of the following formula: A compound having the structure of the following formula and W- (CR ₂ ) _n -X 1 (8) wherein m, n, -R, -X 1 and T are the same as compound (2a), and -Y is -NHR Or -OH or -SH, and -W is -I or -Br or -C
(O) V, wherein -V is -OH or -Cl or -Br.] Reacting. 9. A compound (7) having the following steps: (D) a compound having the structure of the following formula: A compound having a structure of the following formula: Wherein m, -R, -Y and T are the same as in the compound (7), Z is -Br or -I or -OTf, and -J is alkanyl having 1 to about 4 carbon atoms. And preferably -Q3- is -O- or -S- or -NR-, and -W-
Is -Br or -I, Q2- is absent, and m + n is from 1 to 3.] The reaction is performed by the following method. 10. Compound (1) has already or optionally been converted to a compound having the structure of the following formula: Wherein m, n, -R, -Q1-, -Q2- and -R1 are the same as those in the compound (1), and -R2 is hydrogen, halo, alkali, aryl, heterocycle, carboxy and its alkyl ester, Selected from the group consisting of amides, and a compound having the structure: The following steps, namely compound _{R3-NH 2 (12) (} F) Compound (11) having a structure of the following formula [wherein -R3 is selected from hydrogen, alkyl, from the group consisting of aryl and heterocycle] The method according to claim 1, 7 or 9, which is prepared by reacting.