KR100228327B1 - Process for preparing 3-alkylindole - Google Patents

Abstract

The present invention relates to a process for the preparation of (2R) -methyl-4,4,4-trifluoro butylamine or acid addition salts thereof comprising the following steps.

a) acylating the optically active amine with 2-methyl-4,4,4-trifluorobutanoic acid or a reaction derivative thereof to produce butyramide.

b) separating the (R) -diastereomeric butyramid from the (S) -diastereomeric butyramide; And

c) converting the (R) -diastereomeric butyrylamide to the desired (2R) -methyl-4,4,4-trifluorobutyl amine or acid addition salts thereof.

The product is acylated with a carboxylic acid represented by the following general formula (III) or a reaction derivative thereof to give (R) -4- [5- (N- [4,4,4, -trifluoro-2- Methylbutyl] carbamoyl) -1-methylindol-3-ylmethyl] -3-methoxy-NO-tolylsulfonylbenzamide can also be produced. The indole may be usefully used as a leukotriene antagonist, for example, in the treatment of asthma or allergic rhinitis.

Wherein U represents carboxy.

Description

[Name of invention]

Process for preparing 3-alkylated indole

Detailed description of the invention

The present invention relates to a novel process for preparing indole substituted at the 3-position and intermediates useful in this process.

Indole substituted at position 3 is useful as a chemical intermediate, for example, in the manufacture of pharmaceutical preparations. Examples of such medicaments include the compounds described in European patent applications EP-A2-0199543 and EP-A2-0220066. Other agents include compounds based on 3-substituted indoltryptophan, serotonin and melatonin.

It is known that indole can be alkylated at the 3-position, for example by reaction with alkyl halides. However, this reaction proceeds somewhat difficult and may involve alkylation reactions in the 1-position and / or 2-position.

U.S. Patent No. 3,976,639 describes a process for preparing 3-unsubstituted indole comprising reacting a reducing agent capable of selectively reducing nitro groups with N- (2-nitrostyryl) enamine. Columns 6, 49-52 of this document describe that 3-unsubstituted indole can be used as an intermediate to prepare tryptophan and serotonin which are indole substituted at the 3-position.

The present invention provides a process for preparing 3-alkylated indole, the process comprising the following steps.

a) reacting N- (2-nitrostyryl) enamine with an alkylating agent to obtain an imine salt, b) optionally reacting the imine salt with water to obtain (2-nitrophenyl) acetaldehyde, And c) reacting the imine salt or (2-nitrophenyl) acetaldehyde with a reducing agent capable of selectively reducing the nitro group to obtain the desired 3-alkylated indole.

It has been found that by the process of the invention it is possible to obtain 3-alkylated indole in an improved yield without being contaminated by 1-alkylated indole and / or 2-alkylated indole.

In this method, it is preferred that the imine salt is reacted with water to give (2-nitrophenyl) acetaldehyde. The aldehyde is a stable intermediate, unlike the imine salt, it may be easy to handle on an industrial scale.

The N- (2-nitrostyryl) enamine used in the process of the present invention is a tertiary amine having a (2-nitrostyryl) group as one of the substituents of the nitrogen atom of the tertiary amino group. Thus, it is 2-nitro-β- (disubstituted amino) styrene. The remaining two substituents of the nitrogen atom are preferably alkyl groups such as (1-4C) alkyl groups such as methyl or ethyl, or two ends of 4- or 5-membered alkylene or heteroalkylene chains, thereby avoiding To form a 5- or 6-membered ring such as a lollidine or a morpholine ring. Thus, the N- (2-nitrostyryl) enamine is, for example, 2-nitro-β (di-nitro-β- (dimethylamino) styrene or 2-nitro-β- (diethylamino) styrene, for example. (1-4C) alkylamino) styrene, 2-nitro-β- (1-pyrrolidinyl) styrene, 2-nitro-β- (1-piperidinyl) styrene or 2-nitro-β- (4-mor Polyyl) -styrene.

The (2-nitrostyryl) group in the N- (2-nitrostyryl) enamine may have one or more substituents on the benzene ring, provided none of these interfere with the steps of the process of the invention. Thus, for example, the 2-nitrostyryl group is halogen, alkyl, alcoholic, haloalkyl, haloalkoxy, cycloalkyl, aryl, heteroaryl, aryloxy, aralkoxy, alkoxycarbonyl, carboxy, aralkyloxycar On the benzene ring by one or more substituents selected from carbonyl, acyl, acyloxy, nitro, acylamino, cycloalkoxycarbonylamino, aralkylamino, cyano, alkenyl, cycloalkenyl, alkynyl and carbamoyl It may be substituted in.

Unless stated otherwise, when referring herein to halogen atoms themselves or halogen atoms of groups such as haloalkyl or haloalkoxy groups, they will be, for example, fluorine, chlorine or bromine atoms.

The alkyl group itself or for example an alkyl group in an alkoxy, halo alkoxy or alkoxycarbonyl group is C ₁ -C ₁₀ , such as C ₁ -C ₆ such as methyl, ethyl, propyl, butyl, 2-methylbutyl and pentyl.

The aryl group is, for example, a phenyl group.

Cycloalkyl or cycloalkenyl groups have, for example, 3 to 6 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl or cyclopentenyl.

Acyl groups are, for example, alkanoyl groups such as acetyl.

Heteroaryl groups are, for example, heterocyclic rings containing one or more 5- or 6-membered aromatic hydrocarbons, nitrogen, oxygen or sulfur atoms such as pyridyl, pyrimidyl, imidazolyl, tetrazolyl, pyri Dill, thiophenyl or furyl.

Aralkyl groups are, for example, benzyl groups.

Alkenyl or alkynyl groups may have, for example, from 2 to 10 carbon atoms, for example, from 2 to 6 carbon atoms, such as ethenyl, propenyl or propynyl.

Carbamoyl groups are, for example, aminocarbonyl groups, alkylaminocarbonyl groups or dialkylaminocarbonyl groups, where the alkyl groups may carry one or more halogen substituents, such as fluorine, for example 2-methyl-4,4,4-trifluoro Robutylamino-carbonyl.

The alkylating agent used in the process of the invention can be any organic compound having a leaving atom or a saturated carbon atom attached to the leaving group. More specifically, the alkylating agent is X-CH ₂ -CO ₂ R ^h , X-CH ₂ -CH = C (CH ₃ ) CH ₃ , X-CH ₂ -phenyl and a compound of formula V wherein X Is a leaving atom or leaving group, T is COOR ^h and R ^h is an acid protecting group that is easily removed. Preferred alkylating agents are halides (e.g. bromide or iodide), or optionally substituted hydrocarbylsulfonyloxyesters (e.g. p-toluenesulfonyloxy, p-bromophenylsulfonyloxy, methanesulfonyloxy or tri Fluoromethanesulfonyloxy ester). Most preferred alkylating agents are halides.

The organic moiety of the alkylating agent can be, for example, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group.

An optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group may have one or more substituents, provided none of these interfere with the steps of the process of the invention. For example, they may be substituted by one or more substituents selected from halogen atoms, alkyl groups, cycloalkyl groups, alkoxycarbonyl groups, aralkyloxycarbonyl groups, alkanoyl groups, alkanoylamino groups, aralkylamino groups, carbamoyl groups, or phenyl groups. The substituent may have one or more substituents selected from halogen atoms, alkyl groups, alkoxy groups, alkoxycarbonyl groups, N-arylsulfonylaminocarbonyl groups, carboxyl groups, aralkyloxycarbonyl groups, alkanoylamino groups, or aralkyl amino groups. have.

British Patent Application No. 8927981.4, filed Dec. 11, 1989, discloses 4- [5- (N- [4,4,4-trifluoro-2-methylbutyl] carbamoyl) -1-methylindole-3 -Ylmethyl] -3-methoxy-No-tolylsulfonylbenzamide compound is described. This compound is represented by the following general formula (I).

[Formula I]

The compound has been found to antagonize one or more arachidonic acid metabolites known as leukotrienes. Such compounds are useful where antagonism is required. Thus, it may be important in the treatment of diseases associated with leukotriene, such as in the treatment of allergic or inflammatory diseases, or in the treatment of toxic or traumatic shock symptoms.

It is preferred that the compound of formula (I) is in substantially pure (R) -form.

The compound of formula (I) may be a 2-methyl-4,4, -4-trifluorobutylamine of formula (II) or an acid addition salt thereof (e.g. hydrochloride) and a carboxylic acid of formula (III) It can be prepared by acylation. The acylation reaction is readily carried out in the presence of a dehydrating agent such as 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride, optionally with an organic base such as 4-dimethylaminopyridine.

[Formula II]

[Formula III]

Wherein U is carboxy or a reactive derivative thereof.

The compound of formula (III) may be prepared from a compound of formula (VI).

[Formula VI]

Wherein T is COOR ^h , U is COOR ^j , wherein R ^h and R ^j are each independently an acid protecting group, such as phenyl; benzyl; Or (1-6C) alkyl optionally with acetoxy, (1-4C) alkoxy or (1-4C) alkylthio substituents. In particular, R ^h and R ^j are, for example, methyl, ethyl, propyl, t-butyl, acetoxymethyl, methoxymethyl, 2-methoxyethyl, methylthiomethyl, phenyl or benzyl.

Thus, the compound of formula (VI) is converted to the corresponding compound of formula (VII) by reaction with a commonly used methylating agent (eg methyl iodide or dimethylsulfate).

[Formula VII]

Subsequently, the compound of formula (VII) is treated with an alkali metal hydroxide, such as sodium hydroxide or lithium hydroxide, and water to form another compound of formula (VII), wherein T represents a carboxyl group by selective conversion of the COOR ^h group. ) Can be converted to

Compounds of formula (VII), wherein T is a carboxyl group, are then converted to compounds of formula (VII), wherein T is COCl by reaction with a chlorinating agent (eg, thionylchloride).

The compound of formula (VII), wherein T is COCl, is then reacted with 2-methylbenzenesulfonamide to prepare a compound of formula (III), wherein U is COOR ^j or a salt thereof.

The compound of formula (III) wherein U is COOR ^j can then be converted to a compound of formula (III) wherein U is a carboxyl group by decomposing (eg, treating with sodium hydroxide and water) the ester group COOR ^j .

The compounds of formula (II) may be prepared in racemic or substantially pure enantiomeric forms (eg, (R) -enantiomers).

The racemic compound of formula (II) reacts 2-methyl-4,4,4-trifluorobutyric acid, or a reactive derivative thereof (e.g. hydrochloride) with ammonia, and then reduces the resulting amide (e.g., , Lithium aluminum hydrate).

Compounds of formula (II) of substantially pure (R) -enantiomer type can be prepared from 4,4,4-trifluorobutyric acid as described below.

4,4,4-trifluorobutyric acid can be converted to 4,4,4-trifluorobutyryl chloride by treatment with oxalyl chloride. The 4,4,4, -trifluorobutyryl chloride is then reacted with (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone in the presence of butyl lithium (4R , 5S) -4-methyl-3-3 (4,4,4-trifluorobutyryl) -5-phenyl-2-oxazolidinone. The reaction product is then methylated by treatment with sodium bis (trimethylsilylamide) and then with methyl iodide (4R, 5S) -4-methyl-4 (2R) -2-methyl-4,4,4 -Trifluorobutyryl) -5-phenyl-2-oxazolidinone can be obtained. The product can then be treated with lithium aluminum hydrate to afford (R) -2-methyl-4,4,4-trifluorobutan-1-ol. The alcohol was treated with phthalimide in the presence of triphenylphosphine and diethyl azodicarboxylate to give (R) -2- (2-methyl-4,4,4-trifluorobutyl) -1H-iso Indole-1,3 (2H) -dione is obtained.

The product is treated with hydrazine monohydrate followed by hydrochloric acid to give the desired (R) -2-methyl-4,4,4-trifluorobutylamine as hydrochloride.

As mentioned above, the compounds of formula (I) have the properties of leukotriene antagonists. Thus, it antagonizes at least one action of one or more arachidonic acid metabolites (C ₄ , D ₄ and / or E ₄ ) known as leukotriene (known as potent spasmogen (particularly in the lung)). Thereby increasing vascular permeability and correlating with the pathogenesis of asthma and inflammation as well as endogenous shock and traumatic shock. Thus, compounds of formula (I) are useful for treating diseases associated with leukotriene and requiring antagonistic action on these actions. Examples of such diseases are allergic pulmonary artery disorders (eg asthma, fever and allergic rhinitis) and certain inflammatory diseases (eg bronchitis, ecotopic eczema, irritable eczema and psoriasis), as well as vascular spasms of cardiovascular disease. , Toxic and traumatic shock diseases.

The compounds of formula (I) are potent leukotriene antagonists and are useful whenever such activity is desired. For example, the compounds of formula (I) are valuable as pharmacological standards for the development and standardization of new disease models and assays for use in developing new therapeutic agents for treating diseases associated with leukotriene.

When a compound of formula (I) is used to treat one or more of the diseases described above, it is generally administered as a suitable pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier in combination with the compound of formula (I), wherein the composition is It is suitable for the particular route of administration chosen. The compositions can be obtained using conventional methods, excipients and binders, and can be present in various dosage forms. For example, they may be in the form of tablets, capsules, services or suspensions for oral administration, in the form of suppositories for rectal administration, in the form of sterile solutions or suspensions for injection or administration intravenously or intramuscularly, aerosols for inhalation administration, spray solutions or In the form of a suspension, and together with a pharmaceutically acceptable inert solid diluent such as lactose for aeration. If a solid dosage form of the compound of formula (I) is required, it is preferred to use it in an amorphous form, wherein the amorphous forms an aqueous acid (e.g., arithmetic) in an alcohol, water mixture (methanol-water mixture). It can be prepared by precipitating the compound of formula (I) by adding it to a sodium salt solution of the compound.

Tablets or capsules containing up to 250 mg (usually 5 to 100 mg) of the compound of formula (I) may be readily used for oral administration. Likewise, sterile solutions or suspensions containing up to 10% w / w (typically 0.05 to 5% w / w) of a compound of formula (I) can be readily used for intravenous or intramuscular injection or infusion.

The dosage of the compound of formula (I) may be varied according to well-known principles in consideration of the route of administration, the severity of symptoms, the weight and age of the patient being treated. Generally, however, compounds of formula (I) are administered to warm-blooded animals (eg, humans) such that 0.01-25 mg / kg (typically 0.1-5 mg / kg) is accommodated.

The leukotriene antagonist properties of the compounds of formula (I) are demonstrated using standard experiments. Thus, for example, these are described by Krell in J. Pharmacol. Exp. Ther., 1979, 211, 436 and European Patent Application Publication Nos. 220,066 and US Pat. No. 4,859,692, using standard in vitro standard guinea pig organ strip preparation.

The selectivity of action of compounds such as leukotriene antagonists against nonspecific smooth muscle inhibitors is determined in vivo in the presence of indomethacin (5 × 10 ⁻⁶ M concentration), using nonspecific spasmogenated barium chloride with a concentration of 1.5 × 10 ⁻³ M. This can be seen by performing the other processing.

Alternatively, the antagonist properties of the compounds of formula (I) are described by Aharony in Fed. Proc. 1987,46,691, as demonstrated by in vitro receptor-ligand binding assays.

In general, the compounds of formula (I) tested showed statistically high activity as LTC ₄ , LTD ₄ and / or LTE ₄ antagonists in one of the experiments at a concentration of about 10 ⁻⁸ M. For example, the pKi value of the compound of formula (I), which is substantially (R) -enantiomer type, was determined to be 9.4.

Activity as a leukotriene antagonist can also be demonstrated in vivo in experimental animals, for example, in guinea pig aerosol experiments (Synder et al., J. Pharmacol. Methods., 1988, 19, 219). In particular, the above experiments demonstrated useful leukotriene antagonist properties of carbamoyl derivatives of formula (I). According to the experimental procedure, aerosol of leukotriene LTE ₄ was added to guinea pigs (30 µg / 2 in solution Prior to administration of the test compound as a solution in poly (ethyleneglycol) (generally 1 hour) and recording the effect of the test compound on the change in the mean time of the disclosed leukotriene in the breathing pattern (initiation of breathing) It is compared with the guinea pig control group not administered. The protection rate developed by the test compound is measured from the time at which the onset of dyspnea comparable to the animal control is delayed. Typically, 1.1 μmol / kg of ED ₅₀ was observed after oral administration of a compound of formula (I), which is substantially (R) -enantiomer type, with no undesirable side effects at three or four times the minimum effective dose. In contrast, an oral ED ₅₀ of 19.2 μmol / kg was measured for the compound of Example 10 of European Patent Application Publication No. 220,066.

According to a preferred embodiment, the present invention provides a process for preparing 3-alkylated indole of formula (VI), wherein U is COOR ^j , T is COOR ^h , and R ^h and R ^j are each independently easily removed. As the acid protecting group, for example, phenyl; benzyl; Or (1-6C) alkyl optionally with acetoxy, (1-4C) alkoxy or (1-4C) alkylthio substituents. Specific examples of R ^h and R ^j include methyl, ethyl, propyl, t-butyl, acetoxymethyl, methoxymethyl, 2-methoxyethyl, methylthiomethyl, phenyl or benzyl.

The 3-alkylated indole of formula (VI) is selected from compounds of formula (IV) as N- (2-nitrostyryl) enamine and compounds of formula (V) as alkylating agents in the process of the present invention. You can get along.

[Formula IV]

[Formula V]

In the above formulas, U is as defined above, each R independently represents a (1-4C) alkyl group or together represents a 4-membered or 5-membered-alkylene or heteroalkylene chain, T is as defined above, and X Is a leaving atom or leaving group.

The reaction of the N- (2-nitrostyryl) enamine and the alkylating agent is 0 to 120 , Preferably 15 to 80 Is easily performed in Suitable solvents for the reaction include nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, ethers such as tetrahydrofuran, hydrocarbons such as toluene, esters such as ethyl acetate, and amides such as dimethyl formamide or dimethylacetamide. Can be.

The product of the alkylation reaction is an imine salt. The salts do not separate and readily react with water directly. This reaction is from 0 to 100 , Preferably 15 to 35 Is easily performed in Suitable solvents for this reaction are the same solvents used in the alkylation reaction.

The imine salt is reacted with water to give (2-nitrophenyl) acetaldehyde.

In another embodiment, the present invention provides (2-nitrophenyl) acetaldehyde of formula (VIII).

[Formula VIII]

Wherein U and T are as defined above. (2-nitrophenyl) acetaldehyde of formula (VIII) is the aforementioned leukotriene antagonist, 4- [5- (N- [4,4,4-trifluoro-2-methylbutyl] carbamoyl) -1- Methylindol-3-ylmethyl] -3-methoxy-No-tolylsulfonylbenzamide is a useful intermediate.

The (2-nitrophenyl) acetaldehyde is converted into predetermined indole by reaction with a reducing agent capable of selectively reducing the nitro group. In other words, the reducing agent is a reagent that reduces the nitro group but does not reduce the aldehyde group. Other substituents of (2-nitrophenyl) acetaldehyde, such as substituents other than nitro groups, may also be reduced.

Examples of suitable reducing agents include iron in the presence of an acid (examples include inorganic acids such as hydrochloric acid, carboxylic acids such as acetic acid or propanoic acid); Tin chloride; Titanium trichloride; Sodium dithionite; Hydrazine with Raney nickel; And hydrogen in the presence of a transition metal hydrogenation catalyst (eg palladium or Raney nickel). Excellent results were obtained using iron in the presence of an acid (eg acetic acid).

The reduction is usually 0 to 120 , Preferably 15 to 100 Perform on Suitable solvents include aromatic hydrocarbons such as toluene, benzene and xylene; Ethers such as tetrahydrofuran; Alcohols such as entanol; Esters such as water and ethyl acetate. In the case of using iron in the presence of acetic acid, excess acetic acid can be readily used as a solvent.

Such N- (2-nitrostyryl) enamine initiators are described in US Pat. No. 3,979,410 or in Organic Synthesis, Vol. 63, 1985, pages 214-215, which may be prepared from 2-nitrotoluene. For example, it can be prepared by reacting 2-nitrotoluene with dimethylformamide dimethyl acetal. The reaction is preferably carried out in the presence of pyrrolidine, in which case the N- (2-nitrostyryl) enamine product is derived from (2-nitrostyryl) dimethylamine and (2-nitrostyryl) pyrrole. Mixture of lollidine.

As mentioned above, the process of the invention and the novel intermediates of formula (VIII) are particularly useful when preparing compounds of formula (I). Thus, according to another feature of the invention, the invention provides 4 [5- (N- [4,4,4-trifluoro-2-methylbutyl] -carbamoyl) -1-methylindole-3- Provided is a method of using (2-nitrophenyl) acetaldehyde of Formula (VIII) to prepare ylmethyl] -3-methoxy-No-tolylsulfonyl-benzamide.

In addition, the present invention provides 4- [5- (N- [4,4,4-trifluoro-2-methylbutyl] carbamoyl) -1-methylindol-3-yl-methyl] -3-methoxy Provided is a method for preparing -No-tolylsulfonylbenzamide, the method comprising the following steps.

(a) reacting a compound of formula (V) with a compound of formula (IV) to obtain an amine salt, wherein each R is independently a (1-4C) alkyl group or together a 4 or 5 member An alkylene or heteroalkylene chain, X is a leaving atom or leaving group, T is COOR ^h , U is COOR ^j , and R ^h and R ^j are each independently an acid protecting group.

(b) reacting the imine salt with water to obtain (2-nitrophenyl) acetaldehyde of formula (VIII),

(c) reacting (2-nitrophenyl) acetaldehyde of formula (VIII) with a reducing agent capable of selectively reducing nitro groups to obtain a compound of formula (VI),

(d) methylating the compound of formula (VI) to obtain a compound of formula (VII),

(e) converting the T group to a 2-methylbenzenesulfonamido carbonyl group by removing the R ^h protecting group and reacting the resulting carboxylic acid or a reactive derivative thereof with 2-methylbenzenesulfonamide or a salt thereof, and

(f) converting the U group to a 2-methyl-4,4,4-trifluorobutylaminocarbonyl group by removing the R ^j protecting group, and the resulting carboxylic acid or a reactive derivative thereof is converted to 2-methyl-4,4, Reacting with 4-trifluorobutylamine or acid addition salts thereof.

Steps (e) and (f) may be performed in sequence or in reverse order.

To illustrate the present invention according to the following examples, the present invention is not limited by these examples. NOTE NMR data are in the form of delta values and expressed in parts per million parts relative to tetramethylsilane as an internal standard. Kieselgel is a trademark of Darmstadt-E-Merck, Germany. Yields are described for illustrative purposes only and do not mean the maximum values obtained after being carried out by conventional methods. Unless otherwise noted, experiments were conducted at ambient temperature and atmospheric pressure.

Example 1

Methyl 4- (5-methoxycarbonylindol-3-ylmethyl) -3-methoxybenzoate

a) methyl 3-methyl-4-nitrobenzoate

Methanol (400 In a stirred suspension of 3-methyl-4-nitrobenzoic acid (100 g, 0.55 mole) was dissolved in thionyl chloride (36 g, 0.30 mole) for 1 hour (the temperature of the reaction mixture was about 35 to 40). Rises). The mixture was heated to reflux for 1.5 hours, then 50 to 55 Cooled to and maintained at that temperature for 30 minutes before cooling to ambient temperature. Water is added over 30 minutes, cooled to 20-25 Was maintained. After filtration, the solid was purified by water (2 ) And 40 under vacuum Drying in afforded 103 g (95%) of methyl 3-methyl-4-nitrobenzoate as a yellow solid. mp 83 ~ 85 ; NMR (250 MHz, CDCl ₃ ), 2.62 (s, 3H, ArCH ₃ ), 3.98 (s, 3H, CO ₂ CH ₃ ), 8.01 (m, 3H).

b) 5-methoxycarbonyl-2-nitro-β- (1-pyrrolidinyl) styrene and 5-methoxycarbonyl-2-nitro-β- (dimethylamino) styrene

N, N-dimethylformamide (3000 A mixture of the product of step (a) (1000 g, 5.13 mole), N, N-dimethylformamide dimethyl acetal (1219 g, 10.26 mole) and pyrrolidine (382 g, 5.38 mole) in It was refluxed and kept at reflux for 2.5 hours gently. After cooling the reaction mixture to ambient temperature, it was added to 10 liters of ice / water over 20 minutes. The resulting slurry is stirred for 30 minutes before filtration and the solid is cold water (3 × 1500). )). 50 under vacuum Of the 5-methoxycarbonyl-2-nitro-β- (1-pyrrolidinyl) styrene and 5-methoxycarbonyl-2-nitro-β- (1-dimethylamino) styrene as dark red solids 1208 g (83.3%) of a mixture (82:18) was obtained. mp 109-112 ; NMR (250MHz, CDCl ₃ ), 1.97 (m, 0.82 × 4H), 2.95 (s, 0.18 × 6H, N (CH ₃ ) ₂ ), 3.37 (m, 0.82 × 4H), 3.93 (s, 3H, CO2CH3 ), 5.77 (d, 0.82 × 1H), 5.78 (d, 0.18 × 1H), 7.08 (d, 0.18 × 1H), 7.39 (d, 0.82 × 1H), 7.49 (dd, 0.82 × 1H), 7.53 (dd , 0.18 × 1 H), 7.82 (d, 1 H), 8.13 (m, 1 H).

c) 2- (50methoxycarbonyl-2-nitro) phenyl-2- (2-methoxy-4-methoxycarbonyl) benzylacetaldehyde

Acetonitrile (2000) ) And the product of step (b) (800 g, 2.95 mole) and methyl 4-bromomethyl-3-methoxybenzoate (770 g, 2.97 mole) dissolved in the above were heated to reflux for 20 minutes, and the temperature was Hold for 50 minutes. Then further benzoate (35 g, 0.135 mole) was added and heating continued for a total of 4 hours. After cooling to ambient temperature, the mixture was washed with water (2000). ), Added over 5 minutes, during which time a dark brown solid precipitated out. The mixture was stirred for 30 minutes, filtered and the precipitate was washed with acetonitrile (500 ) Under vacuum Dried over. 914.5 g (77.3%) of 2- (5-methoxycarbonyl-2-nitro) phenyl-2- (2-methoxy-4-methoxycarbonyl) benzylacetaldehyde as a light brown solid were obtained. mp 117-120 ; NMR (250 MHz, CDCl ₃ ): 3.11 (dd, 1H), 3.50 (dd, 1H), 3.82, 3.90, 3.97 (s, 3H, OCH ₃ + 2 × CO ₂ CH ₃ ), 4.65 (dd, 1H, respectively) ), 7.00 (d, 1H), 7.46 (m, 2H), 7.88 (d, 1H), 7.93 (d, 1H), 8.04 (dd, 1H), 9.82 (s, 1H).

d) methyl 4- (5-methoxycarbonylindol-3-ylmethyl) -3-methoxybenzoate

A stirred suspension of the product of step (c) (600 g, 1.49 mole) and iron powder (600 g, 10.7 mole) dissolved in acetic acid (2.2 L) and toluene (3.8 L) was carefully heated to reflux. 95 Exotherm occurs at, so reflux occurs in the mixture without external heating. Then, if necessary, it was heated to reflux for a total of 2 hours. Cool the mixture to ambient temperature and allow to mix for 5 minutes before filtration. Cooled to toluene (2 × 200) )). The combined filtrates and washes were washed with 15% brine (3.8 L) and 5% sodium bicarbonate solution (3.8 L) and evaporated under reduced pressure. The resulting solid was recrystallized from methanol (2 L) to give methyl 4- (5-methoxycarbonylindol-3-ylmethyl) -3-methoxybenzoate (420 g, 79.9%). mp 136 ~ 138 ; NMR (250 MHz, CDCl ₃ ): 3.88, 3.90, 3.92 (s, 3H, OCH ₃ + 2 × CO ₂ CH ₃ ), 4.16 (s, 2H, ArCH ₂ Ar ′), 6.98 (d, 1H), 7.12 (d, 1H), 7.33 (d, 1H), 7.52 (m, 2H), 7.89 (dd, 1H), 8.30 (br, s, 1H), 8.36 (d, 1H).

Comparative Example

Process for preparing methyl 4- (5-benzyloxycarbonylindol-3-ylmethyl) -3-methoxybenzoate by alkylating benzyl indole-5-carboxylate

N, N-dimethylformamide (900 ) A solution of benzyl indole-5-carboxylate (86.8 g), methyl 4-bromomethyl-3-methoxybenzoate (89.5 g) and potassium iodide (57.4 g) Heated at for 10 h. The reaction mixture was evaporated and separated between diethylether and water. The organic layer was separated and washed with water. The aqueous washes were combined and extracted with diethyl ether. The combined organic extracts were dried (MgSO ₄ ) and evaporated. Flash chromatography eluting the residue sequentially with ethyl acetate: hexane: methylene chloride at 0: 1: 1, 2:48:50, 4:46:50, 5:45:50 and 10:40:50 Purification by chromatography gave methyl 4-iodomethyl-3-methoxybenzoate (27.8 g), and the benzyl indole-5-carboxylate (29.6 g) and the crude product of a tan solid (50.6 g). Recovered. N, N-dimethylformamide (250 Recovered benzyl indole-5-carboxylate (29.6 g) in methyl 4-iodomethyl-3-methoxybenzoate (29.8 g); After treatment for 12 h at evaporation, a dark residue was obtained, which was dissolved in diethyl ether and washed three times with water. The washes were combined and extracted with diethyl ether. The combined organic extracts were dried (MgSO ₄ ) and evaporated. The residue was purified by flash chromatography, eluting with ethyl acetate: hexane: methylene chloride at 0: 1: 1, 2:48:50, 5:45:50 and 10:40:50, again as a tan solid. Another crude raw material (31.9 g) was obtained. The combined crude product (82.5 g) was diluted with diethyl ether (400 ), Heated to reflux for 30 minutes, then cooled and filtered to give methyl 4- (5-benzyloxycarbonylindol-3-ylmethyl) -3-methoxybenzoate (46.1 g, 31%) was obtained. Partial NMR (250 MHz, CDCl ₃ ): 3.84 (s, 3H, CO ₃ CH ₃ ), 3.88 (s, 3H, OCH ₃ ), 4.14 (s, 2H, CH ₂ ), 5.35 (s, 2H, OCH ₂ ), 6.97 (d, 1H, indole H (2)), 8.15 (br, 1H, NH), 8.37 (s, 1H, indole-H (4)).

The comparative example demonstrates that the yield of the 3-alkylated product obtained by direct alkylation of indole is low compared to that obtained by the process of the present invention.

Example 2

Method for preparing methyl 3-benzylindole-5-carboxylate

a) 2- (5-methoxycarbonyl-2-nitro) phenyl-2-benzylacetaldehyde

Acetonitrile (15 Product of Example (1b) (5.42 g, 20 mmole) and benzyl bromide (2.39) , 20 mmole) was heated at reflux under a nitrogen atmosphere for 5 hours. Water (2 ) Was added and the solution was concentrated in vacuo. The residue was taken as dichloromethane (300) as eluent. ) Was passed through a silica column (50 g, Kiegelgel 60). Concentration in vacuo gave the intermediate aldehyde (5.8 g) as a black oil. NMR (250 MHz, CDCl ₃ ): 3.11 (dd, 1H), 3.57 (dd, 1H), 3.97 (s, 3H, OCH ₃ ), 4.56 (dd, 1H), 7.03-7.40 (m, 5H, Ph) , 7.95 (m, 2H), 8.10 (dd, 1H), 9.82 (s, 1H, CHO).

b) methyl 3-benzyindole-5-carboxylate

The product of step a) (5.8 g) was added to 95 (26.4) with iron powder (5.17 g, 92.7 mmole) under nitrogen atmosphere ) And toluene (40 ) For 3.5 hours. After cooling overnight the solids were removed by filtration and toluene (2 × 20 )). Combine the filtrate and washings with 15% brine and saturated aqueous sodium bicarbonate solution (40 ), Then concentrated in vacuo. The residue was used as eluent in dichloromethane (100 ) Was passed through a silica column (35 g Kiegel gel 60) and the eluate was concentrated in vacuo. Toluene (15 The residue was crystallized to give 2.65 g (50% total from enamine) of methyl-3-benzylindole-5-carboxylate. NMR (250 MHz, CDCl ₃ ) F: 3.91 (s, 3H, OCH ₃ ), 4.14 (2, 2H, ArCH 2 Ar ′), 6.92 (d, 1H), 7.15-7.36 (m, 6H), 7.90 (dd, 1H), 8.25 (br. S, 1H, NH), 8.32 (s, 1H); Microanalysis found: C, 76.8; H, 5.6; N, 5.1%; C ₁₇ H ₁₅ NO ₂ requires: C, 77.0; H, 5.7; N, 5.3%.

Example 3

Process for the preparation of methyl 3- (3-methylbut-2-enyl) indole-5-carboxylate

(a) 2- (5-methoxycarbonyl-2-nitro) phenyl-2- (3-methyl-but-2-enyl) acetaldehyde

Acetonitrile (15 Product of Example (1b) (5.42 g, 20 mmole) and 1-bromo-3-methylbut-2-ene (2.33) , 20 mmole) was stirred overnight at ambient temperature, then 50 Heated for 1 h. The solution was treated as in Example 2 to give 2- (5-methoxycarbonyl-2-nitro) phenyl-2- (3-methyl-but-2-enyl) acetaldehyde (5.46 g) as a dark red oil. ) Was obtained. NMR (250 MHz, CDCl ₃ ): 1.51 (s, 3H, CCH ₃ ), 1.63 (s, 3H, CCH ₃ ), 2.57 (m, 1H), 2.90 (m, 1H), 3.97 (s, 3H, OCH ₃ ), 4.24 (m, 1H), 5.04 (m, 1H, C = CH), 8.00 (m, 2H), 8.00 (d, 1H), 9.82 (s, 1H, CHO).

(b) Methyl 3- (3-methylbut-2-enyl) indole-5-carboxylate

The product of step (a) was reduced according to the method of Example (2b) to give a yellow oil which was left to crystallize. Cyclohexane (20 Recrystallization) gave 3.14 g of methyl 3- (3-methylbut-2-enyl) -indole-5-carboxylate (64.6% total from enamine). mp 88-91 ; NMR (250 MHz, CDCl ₃ ): 1.78 (s, 6H, CH ₃ ) ₂ ), 3.48 (d, 2H, ArCH ₂ ), 3.95 (S. 3H, OCH ₃ ), 5.43 (m, 1H, C = CH ), 7.00 (s, 1H), 7.33 (d, 1H), 7.90 (dd, 1H), 8.22 (br.s, 1H, NH), 8.38 (s, 1H); Microanalysis found: C, 74.1; H, 7.2; N, 5.8%, C ₁₅ H ₁₇ NO ₂ requires: C, 74.0; H, 7.0; N, 5.8%.

Example 4

Method for preparing methyl 3-methoxycarbonylmethylindole-5-carboxylate

(a) 2- (5-methoxycarbonyl-2-nitro) phenyl-2-methoxycarbonylmethyl-acetaldehyde

Acetonitrile (15 Product of Example (1b) (5.42 g, 20 mmole), methylbromoacetate (1.89) , 20 mmole) and sodium iodide (3.00 g, 20 mmole) Heated under nitrogen atmosphere for 24 h. The cooled mixture was washed with water (3 ), Concentrated in vacuo, and water (50). ) And ethyl acetate (50 )). The organic layer was washed with 10% aqueous sodium sulfate solution (50 ) And concentrated in vacuo. Dichloromethane 1000 Chromatography of silica (200 g, kiesel gel 60) eluting with red gum 2- (5-methoxycarbonyl-2-nitro) phenyl-2-methoxycarbonylmethyl-acetaldehyde (2.35) g) was obtained. NMR (250 MHz, CDCl ₃ ): 2.80 (dd, 1H), 3.30 (dd, 1H), 3.69 (s, 3H, OCH ₃ ), 3.97 (s, 3H, OCH ₃ ), 4.70 (t, 1H), 7.96 (d, 1H), 8.06 (d, 1H), 8.17 (dd, 1h), 9.78 (s, 1H, CHO)

(b) Methyl-3-methoxycarbonylmethylindole-5-carboxylate

The product of step (a) was reduced by the method of Example (2b) to give a dark solid. Dichloromethane-toluene (15 Recrystallization gave 1.24 g of methyl 3-methoxycarbonylmethylindole-5-carboxylate (25.6% total from enamine). mp 131-133 ; NMR (250 MHz, CDCl ₃ ): 3.73 (s, 3H, OCH ₃ ), 3.81 (s, 2H, ArCH ₂ ), 3.95 (s, 3H, OCH ₃ ), 7.20 (d, 1H), 7.32 (d, 1H), 7.90 (dd, 1H), 8.37 (s, 1H), 8.50 (br.s, 1H, NH); Microanalysis found: C, 63.0; H, 5.3; N, 5.6%, C ₁₃ H ₁₃ NO ₄ requires: C, 63.2; H, 5.3; N, 5.7%.

Example 5

(R) -4- [5- (N)-[4,4,4-trifluoro-2-methylbutyl] -carbamoyl) -1-methylindol-3-yl-methyl] -3-meth Process for the preparation of oxy-No-tolylsulfonyl-benzamide

(a) Methyl 4- (5-methoxycarbonyl-1-methylindol-3-ylmethyl) -3-methoxybenzoate

Tetrahydrofuran (333 Product of Example (1d) (50 g, 142 mmol) and methyl iodide (87.5) Concentrated sodium hydroxide solution (40) , 0.71 mole) was added. Water (200 7.5 hours after the addition of), the organic layer was separated and brine (150 ) And finally water (150 )). Distillate 300 under reduced pressure After removing, the precipitated solid was collected by filtration and hexane (50 )). 40 under vacuum The beige solid was dried at to give 48.0 g (91.3%) of methyl 4- (5-methoxycarbonyl-1-methylindol-3-ylmethyl) -3-methoxybenzoate. mp 137-140 ; NMR (250 MHz, DMSO-d ₆ ): 3.91 (s, 3H, N-CH ₃ ), 3.98 (s, 6H, 2 × CO ₂ CH ₃ ), 4.07 (s, 3H, OCH ₃ ), 4.22 (s , 2H, ArCH ₂ Ar '), 7.34 (m, 2H), 7.61 (m, 3H), 7.90 (dd, 1H), 8.33 (d, 1H).

(b) 4- (5-methoxycarbonyl-1-methylindol-3-ylmethyl) -3-methoxybenzoic acid

Tetrahydrofuran (335 ) And methanol (100 To a solution of the product of step (a) (33.50 g, 91.3 mmole) in ) And lithium hydroxide monohydrate (4,025 g, 95.8 mmole) were added. The reaction mixture was stirred at ambient temperature for about 20 hours, then heated to reflux and about 250 mL of distillate was collected. The residual solution was cooled to room temperature and water (210 ) And toluene (210 ), The organic layer is separated, and water (40 Extracted). The combined aqueous layers were extracted with acetic acid (4.18 , 73.0 mmole), and stirred for 30 minutes before collecting the precipitate by filtration. Water (2 × 67 ) And methanol (2 × 67 ), 28.07 g (84.1%) of 4- (5-methoxycarbonyl-1-methylindol-3-ylmethyl) -3-methoxybenzoic acid was obtained as a white solid. mp 228-230 ; NMR (250 MHz, DMSO-d ₆ ): 3.77, 3.83, 3.93 (each s, 3H, OCH ₃ + NCH ₃ + CO ₂ CH ₃ ), 4.08 (s, 2H, ArCH ₂ Ar '), 7.17 (d, 1H0) , 7.23 (s, 1 H), 7.49 (m, 3 H), 7.77 (dd, 1 H), 8.21 (d, 1 H).

(c) 4- (5-methoxycarbonyl-1-methylindol-3-ylmethyl) -3-methoxybenzoyl chloride

Dichloromethane (10 Thionyl chloride in (2.42) , 33 mmole) was dissolved in N, N-dimethylformamide (0.2 ) Dichloromethane (90) To the suspension of the product of step (b) (10.59 g, 30 mmole) dissolved in) over 5 minutes was added dropwise and stirred at reflux under a nitrogen atmosphere. After 2 hours, the solvent was removed from the resulting yellow solution by distillation, and the distillate was about 85 Was collected. Dilute the residue with methyl t-butyl ether for 15 minutes After stirring at, the solid was collected by filtration. Methyl t-butyl ether (2 × 20 After washing with), 10.10 g (90.6%) of 4- (5-methoxycarbonyl-1-methylindol-3-ylmethyl) -3-methoxybenzoyl chloride as an off-white solid was obtained. mp 147-149 ; NMR (250 MHz, DMSO-d ₆ ): 3.76, 3.92, 3.97 (s, 3H, NCH ₃ + OCH ₃ + CO ₂ CH ₃ ), 4.16 (s, 2H, ArCH ₂ Ar '), 6.87 (s, 1H, respectively) ), 7.20 (d, 1H), 7.29 (d, 1H), 7.54 (d, 1H), 7.66 (dd, 1H), 7.92 (dd, 1H), 8.32 (d, 1H).

(d) 4- (5-methoxycarbonyl-1-methylindol-3-ylmethyl) -3-methoxy-N- (2-methylphenylsulfonyl) benzamide

Dichloromethane (20 Solution of 4- (dimethylamino) pyridine (8.17 g, 66.9 mmole) in dichloromethane (30). To a stirred suspension of the product of step (c) (9.94 g, 26.8 mmole) and 2-methylbenzenesulfonamide (6.87 g, 40.1 mmole) in C) over 15 minutes. After 45 minutes, the solution was heated to reflux and distilled 20 Was collected. Acetone (150 ) And distillate (80 ) Was collected further. The mixture was cooled overnight and filtered before the solid was collected. 15 Stirred at. Then, methanol (3 x 30 ) And washing the slurry with 4- (5-methoxycarbonyl-1-methylindol-3-ylmethyl) -3-methoxy-N- (2-methylphenylsulfonyl) benzamide to give 4- (dimethyl 16.22 g (96.4%) were obtained as the amino) pyridine salt. mp 185-187 ; NMR (250 MHz, DMSO-d ₆ ): 2.53 (s, 3H, ArCH ₂ Ar '), 3.13 (s, 6H, N (CH ₃ ) ₂ ), 3.76, 3.83, 3.86 (s, 3H, OCH respectively) ₃ + NCH ₃ + CO ₂ CH ₃ ), 4.02 (s, 2H, ArCH ₂ Ar '), 6.92 (d, 2H), 7.02 (d, 1H), 7.11-7.32 (m, 4H), 7.39-7.53 (m, 3H), 7.75 (dd, 1H), 7.88 (d, 1H), 8.20 (m, 3H).

(e) 4- (5-carboxy-1-methylindol-3-ylmethyl) -3-methoxy-N- (2-methylphenylsulfonyl) benzamide

Product of step (d) (15 g, 23.8 mmole), concentrated sodium hydroxide solution (6.75 mL, 119 mmole), water (85 ) And tetrahydrofuran (18 A mixture of 65 By stirring for 3 hours in the homogeneous solution 50 ~ 55 Cooled to and maintained at this temperature during subsequent acidification and extraction steps. Concentrated hydrochloric acid is added until the pH is 7-8, and tetrahydrofuran (44 ) And n-butyl acetate (29 ) Was added to adjust the pH to 1-2. The reaction mixture was precipitated to separate the lower aqueous layer. The organic layer was washed with 5% saline solution (2 × 20 )). Distill the tetrahydrofuran (jacket temperature 95 Distillate collected by about 40 ) And remove the remaining mixture from 15 to 20 Cooled to. The product was collected by filtration to give butyl acetate (15 ) And 50 Dried over. 11.08 g (94%) of 4- (5-carboxy-1-methylindol-3-ylmethyl) -3-methoxy-N- (2-methylphenylsulfonyl) -benzamide was obtained. mp 264-267 ; NMR (250 MHz, DMSO-d ₆ ): 2.63 (s, 3H, ArCH ₂ Ar '), 3.78 (s, 3H, NCH ₃ ), 3.95 (s, 3H, OCH ₃ ), 4.08 (s, 2H , ArCH ₂ Ar '), 7.18 (d, 1H), 7.22 (s, 1H), 7.38-7.65 (m, 6H), 7.79 (d, 1H), 8.06 (d, 1H), 8.20 (s, 1H) .

(f) (R) -4- (5-N- [4,4,4-trifluoro-2-methylbutyl] carbamoyl) -1-methylindol-3-ylmethyl] -3-methoxy _No-tolylsulfonylbenzamide

4- (5-carboxy-1-methylindol-3-ylmethyl) -3-methoxy-N- (2-methylphenylsulfonyl) benz in tetrahydrofuran (distilled from sodium benzophenone ketyl) (2.0 L) A mixture of amide (103.5 g), 4-dimethylaminopyridine (112.4 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (51.8 g) was stirred for 2 hours, and there (R ) -2-methyl-4,4,4-trifluorobutylamine hydrochloride (42.6 g) was added. The reaction mixture was stirred overnight (about 18 hours, incomplete reaction) and heated to reflux for 2 hours (complete reaction). The cooled reaction was diluted with ethyl acetate (2 L) and washed with 1N hydrochloric acid (twice) and brine, dried (MgSO ₄ ) and evaporated. The residue (138.6 g) was combined with the impure product in a similar manner (28.0 g) and purified by flash chromatography eluting with methylene chloride: ethyl acetate (1: 0, 9: 1 and 3: 1 in sequence) to give a solid. Was triturated twice with ether to afford the crude title compound (135.2 g), which was recrystallized from ethanol (1.2 L) and acetone (0.3 L) (boiled to about 0.9 L, concentrated and cooled), Drying in vacuo gave the title compound as a white crystalline solid. mp 141.5 ~ 143.5 ; NMR (300MHz, DMSO-d ₆ ): 1.01 (d, 3H, CH ₃ ), 2.0-2.2 (m, 2H, CF ₃ CH ₂ ), 2.3-2.5 (jm, 1H, CHCH ₃ ), 2.61 (s , 3H, ArCH ₃ ), 3.23 (br t, 2H, CH ₂ N), 3.76 (s, 3H, NCH ₃ ), 3.92 (s, 3H, OCH ₃ ), 4.07 (s, ArCH ₂ Ar '), 7.13 (s, 1H), 7.17 (d, 2H), 7.38-7369 (m, 6H), 7.72 (d, 1H), 8.05 (d, 1H), 8.11 (s, 1H), 8.46 (br t, 1H, NHCO); Anal for C ₃₁ H ₃₂ F ₃ N ₃ O ₅ S: Theoretical C, 60.48; H, 5.24: N, 6.83%. Found C, 60.47; H, 5. 27; N, 6.67%.

Starting material amine hydrochloride was prepared as follows.

a. 4,4,4-trifluorobutyric acid

A solution of lithium hydroxide monohydrate (324 g) in water (1.8 L) was added to a stirred solution of ethyl 4,4,4-trifluorobutyrate (436 g) in methanol (2.0 L) and anhydrous tetrahydrofuran (2.0 L). Was added and the suspension was stirred overnight. After partially evaporating the suspension, the residue was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 6 M hydrochloric acid and extracted with diethyl ether. The combined extracts were washed (brine), dried (MgSO ₄ ) and filtered. The filtrate was evaporated and the residue was distilled off (bp 165 ~ 168 ), 4,4,4-trifluorobutyric acid (347 g, 95%) was obtained. mp 27-30 ; Partial NMR; (300 MHz, CDCl ₃ ): 2.33-2.57 (m, 2H, CF ₃ CH ₂ ), 2.66 (t, 2H, CH ₂ CO ₂ H).

b. 4,4,4-trifluorobutyryl chloride

Dimethyl Formamide (1.0 ) And oxaryl chloride (239 ) Anhydrous methylene chloride (230 0 of 4,4,4-trifluorobutyric acid in Add to solution and warm to room temperature overnight. The methylene chloride was distilled off and the residue was distilled off to give 4,4,4-trifluorobutyryl chloride (328 g, 85%). bp 103 ~ 106 Partial NMR (300 MHz, CDCl ₃ ): 2.47-2.64 (m, 2H, CF ₃ CH ₂ ), 3.19 (t, 2H, CH ₂ COCl).

c. (4R, 5S) -4-methyl-3- (4,4,4-trifluorobutyryl) 5-phenyl-2-oxazolidinone

-78 under inert atmosphere A solution of n-butyllithium (2.0 mole) in hexane in anhydrous tetrahydrofuran (2500 ) To a stirred solution of (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (353 g). The solution to -70 After stirring for 15 minutes at -60 4,4,4-trifluorobutyryl chloride (320 g) was added over 30 minutes at and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was evaporated to separate the residue from diethyl ether and water. The ether layer was washed [IN hydrochloric acid, brine (twice)], dried (MgSO ₄ ) and evaporated to afford crude product (604 g, about 100%). Silica gel 3000 using methylene chloride: hexane (1: 1) as eluent Filtration through gave a white solid. Methylene chloride: recrystallized from hexane to give (4R, 5S) -4-methyl-3- (4,4,4-trifluorobutyryl) -5-phenyl-2-oxazolidinone (519 g, 86%). Obtained. mp 93 ~ 95 ; Partial NMR (300 MHz, CDCl ₃ ): 0.91 (d, 3H, CH ₃ ), 2.45-2.65 (m, 2H, CF ₃ CH ₂ ), 3.18-3.40 (m, 2H, CH ₂ CO), 4.78 ( m, 1H, 4-H oxazolidinone), 5.70 (d, 1H, 5-H oxazolidinone), 7.30-7.44 (m, 5H, Ar).

d. (4R, 5S) -4-methyl-3-((2R) -2-methyl-4,4,4-trifluorobutyryl) -5-phenyl-2-oxazolidinone

-40 under inert atmosphere Tetrahydrofuran (1900) Anhydrous tetrahydrofuran (800) in a stirred solution of sodium bis (trimethylsilylamide) (1.9 mole) in A solution of (4R, 5S) -4-methyl-3- (4,4,4-trifluorobutyryl) -5-phenyl-2-oxazolidinone (517 g) in was added. The mixture was -40 for 1.5 hours -35 for an additional 1.5 hours Warmed to. -35 To 30 Iodomethane (142) was added to the mixture while maintaining the internal reaction temperature of ) Was added over about 15 minutes. -30 to the mixture The mixture was stirred for an additional 2 hours at, and the cold reaction mixture was poured into cooled aqueous ammonium chloride (700 g in 2 liters of water). The mixture was diluted with diethyl ether (1 L) and the layers separated. The organic layer was washed. (25% w / v aqueous sodium disulfide, brine). The aqueous portion was extracted with 1: 1 methylene chloride: diethyl ether and methylene chloride. The combined organic layers were dried (MgSO ₄ ) and evaporated to afford the crude product (595 g) of a reddish oil. Silica gel (3000) using a 1-5% ethyl acetate gradient in hexane Filtration through) followed by evaporation yielded a white solid (490 g) which was a mixture of the desired product, diastereomeric methylation byproducts and unmethylated starting material. Diethyl ether: crystallized from hexane to give a white solid of (4R, 5S) -4-methyl-3-((2R) -2-methyl-4,4,4-trifluorobutyryl) -5-phenyl-2 -Oxazolidinone (370 g, 68%) was obtained. mp 68-70 . HPLC [Zorbax silica gel, 4.6 mm × 25 cm, 1: 9 ethyl acetate: hexane, FR = 1.5 Per minute, UV detection at 254 nm], the purity of the sample was about 99% (retention volume = 2.6). The white solid was secondly recrystallized from diethyl ether: hexane to give a colorless transparent acicular (4R, 5S) -4-methyl-3-((2R) -2-methyl-4,4,4-trifluoro- An analytical sample of butyryl) -5-phenyl-2-oxazolidinone (300 g, 55%) was obtained (mp 74.5-75) ) Partial NMR (300 MHz, CDCl ₃ ): 0.89 (d, 3H, 4-CH _{3 of} oxazolidinone), 1.33 (d, 3H, CH (CH ₃ ) CO), 2.10-2.31 (m, 1H, CF ₃ CH ₂ ), 2.74-2.97 (m, 1H, CF ₃ CH ₂ ), 4.03-4.17 (m, 1H, CHCO), 4.79 (m, 1H, 4-H of oxazolidinone, 5.71 (d, 1H , 5-H) of oxazolidinone, 7.26-7.44 (m, 5H, phenyl) The HPLC analysis showed a purity of 99.9% C ₁₅ H ₁₆ F ₃ NO ₃ Assay: Theoretical value: C, 57.14; H, 5.11; N, 4.44%, Found: C, 57.17; H, 5.16; N, 4.59%

e. (R) -2-methyl-4,4,4-trifluorobutan-1-ol

Aluminum lithium hydrate (10.26 g) to -20 under inert atmosphere Anhydrous diethyl ether (200 Of (4R, 5S) -4-methyl-3-((2R) -2-methyl-4,4,4-trifluorobutyryl) -5-phenyl-2-oxazolidinone (28 g) in After addition to the stirred solution, the mixture was added to 0 After 2 hours in water (10.27 ) 10% w / v sodium hydroxide (10.27 ) And water (31 ) Was added and the mixture was stirred for 20 minutes. The salt was filtered off and washed with distilled diethyl ether. The diethyl ether solution was dried (K ₂ CO ₃ ) and diluted with pentane. As a result, the recovered (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone precipitated out, which was separated by filtration. The filtrate was concentrated by distillation to give some fractions. First fraction (bath temperature 60 ) Were pentane and ethyl ether. Second fraction (bath temperature 60-100 ) Is 12 g of oil which is a mixture of (R) -2-methyl-4,4,4-trifluorobutan-1-ol (measured by 4.8 g of alcohol) and diethyl ether (40:60) by NMR. It was. Targin residue under vacuum (13,330 Pa) (bath temperature 85 ) Was additionally obtained to obtain 7.2 g of (R) -2-methyl-4,4,4-trifluorobutan-1-ol. (Total yield, 12.0 g, 94%); Partially NMR (300 MHz, CDCl ₃ -D ₂ O shaking): 1.06 (d, 3H, CH ₃ ), 1.41 (br, t, 1H, 0H, 1.86-2.07 (m, 2H, CH (CH ₃ ) +) One CF ₃ CH ₂ ), 2.31-2.42 (m, 1H, one CF ₃ CH ₂ ), 3.49 (dd, 1H, one CH ₂ OH), 3.58 (dd, 1H, one CH ₂ OH).

f. (R) -2- (2-methyl-4,4,4-trifluorobutyl) -1H-isoindole-1,3 (2H) -dione

Diethyl azodicarboxylate (15.4 0 Diethyl ether (about 6.5 g) and anhydrous tetrahydrofuran (110 To a stirred slurry of (R) -2-methyl-4,4,4-trifluorobutan-1-ol (about 12.0 g), phthalimide (13.4 g) and triphenylphosphine (23.7 g) in Add, warm to rt overnight, and stir for 8 h more. The mixture was evaporated, methylene chloride was added to the residue and the slurry was filtered. The filtrate was purified by flash chromatography eluting with methylene chloride: hexane (1: 1) to give (R) -2- (2-methyl-4,4,4-trifluorobutyl) -1H-iso of a white solid. Indole-1,3 (2H) -dione (17.1 g, 75%) was obtained. mp 45 ~ 47 ); Partial NMR (400 MHz, CDCl ₃ ): 1.08 (d, 3H, CH ₃ ), 1.94-2.07 (m, 1H, CF ₃ CH ₂ ), 2.14-2.31 (m, 1H, CF ₃ CH ₂ ), 2.36 -2.50 (m, 1H, CHCH ₃ ), 3.58 (dd, 1H, CH ₂ N), 3.64 (dd, 1H, CH ₂ N).

g. (R) -2-methyl-4,4,4-trifluorobutylamine hydrochloride

Hydrazine monohydrate was added to (R) -2- (2-methyl-4,4,4-trifluorobutyl) -1H-isoindole-1,3 (2H) -dione (17.1 g) in anhydrous ethanol (85 mL). ) Was added to the stirred solution and heated to reflux. After refluxing for 3 hours, the solution was cooled and ethanol (40 mL) was added. Then the solution was acidified to pH 1 by addition of concentrated hydrochloric acid and filtered. The filtrate was evaporated and the residue sublimed (bath temperature 170 at 6.6 Pa) And purified to give (R) -2-methyl-4,4,4-trifluorobutylamine hydrochloride (9.89 g, 88%) as a white solid. mp 187-191 ; Partial NMR (300 MHz, DMSO-d ₆ -D ₂ O shaking): 1.05 (d, 3H, CH ₃ ), 2.06-2.36 (m, 2H, CF ₃ CH ₂ ), 2.36-2.54 (m, 1H, CHCH ₃ ), 2.73 (dd, 1H, CH ₂ N), 2.87 (dd, 1H, CH ₂ N), 8.20 (br s, 2H, NH ₂ ).

Example 6

Acetonitrile (66 A solution of the product of Example (1b) (26.0 g, 100 mmol) and methyl 4-bromomethyl-3-methoxybenzoate (26.7 g, 103 mmol) in) was heated to reflux for 3.3 hours, and The dark brown gum resulting from removal of the solvent under reduced pressure was stored under nitrogen atmosphere for 18 hours. The residue was acetic acid (284 ) And iron powder (16.6 g, 300 mmol) was added. 100 of the mixture Heated for 2.5 hours at room temperature, cooled to room temperature, maintained at this temperature for 0.5 hours, and then filtered to remove the residue with acetic acid (2x20). )). Water in combined filtrate (240 ) Was added over 20 minutes and the mixture was left at room temperature for 66 hours. The solid residue was triturated and filtered. The residue was recrystallized from methanol to give 18.6 g of methyl 4- (5-methoxycarbonyl-indol-3-ylmethyl) -3-methoxy benzoate as a white solid.

Claims (9)

N- (2-nitrostyryl) enamine is selected from the group consisting of X-CH ₂ -CO ₂ R ^h , X-CH ₂ -CH = C (CH ₃ ) CH ₃ , X-CH ₂ -phenyl and a compound of formula (V) Reacting with an alkylating agent selected from X wherein X is a leaving atom or leaving group, T is COOR ^h and R ^h is an acid protecting group that is easily removed, and b) the imine salt is obtained. Reaction of a 3-alkylated indole comprising reacting with a reducing agent selected from hydrogen in the presence of iron, stannous chloride, titanium trichloride, sodium dithionite, hydrazine with Raney nickel or a transition metal dehydration catalyst Method of solving. Formula (V) Wherein X and T are as defined above. a) N- (2-nitrostyryl) enamine, X-CH ₂ -CO ₂ R ^h , X-CH ₂ -CH = C (CH ₃ ) CH ₃ , X-CH ₂ -phenyl and Reacting with an alkylating agent selected from a compound of wherein X is a leaving atom or leaving group, T is COOR ^h and R ^h is an acid protecting group that is easily removed, to obtain an imine salt, b) the imine salt Reacting with water to obtain (2-nitrophenyl) acetaldehyde, and c) the (2-nitrophenyl) acetaldehyde, iron, tin chloride, titanium trichloride, sodium dithionite, Raney nickel in the presence of an acid A process for preparing 3-alkylated indole comprising reacting with a reducing agent selected from hydrogen in the presence of a hydrazine or transition metal hydrogenation catalyst having a hydrogen peroxide. Formula (V) Wherein X and T are as defined above. The method of claim 1 or 2, wherein the N- (2-nitrostyryl) enamine is 2-nitro-β- (di (1-4C) alkylamino) styrene, 2-nitro-β- (1- Process for producing 3-alkylated indole, which is pyrrolidinyl) styrene, 2-nitro-β- (1-piperidinyl) -styrene or 2-nitro-β- (4-morpholinyl) styrene. 3. The 3-alkylated indole of claim 1, wherein the N- (2-nitrostyryl) enamine is a compound of formula (IV) and the alkylating agent is a compound of formula (V). Way. Formula (IV) Formula (V) Wherein each R is independently a (1-4C) alkyl group or together is a 4- or 5-membered alkylene or heteroalkylene chain, X is a leaving atom or leaving group, T is COOR ^h , U Is COOR ^j , and R ^h and R ^j are each independently an acid protecting group which is easily removed. The process for producing 3-alkylated-indole according to claim 1 or 2, wherein the reducing agent is iron in the presence of acetic acid. The method according to claim 1 or 2, wherein the alkylation reaction and the reduction reaction is 0 to 120 Process for producing 3-alkylated indole that is carried out in the temperature range of. The method of claim 2, wherein the imine salt is 0 to 100 Process for producing 3-alkaline indole which is reacted with water at a temperature of. (2-nitrophenyl) acetaldehyde of formula (VIII) Formula (VIII) Wherein T is COOR ^h , U is COOR ^j , and R ^h and R ^j are each independently phenyl; benzyl; And (1-6C) alkyl which may have acetoxy, (1-4C) alkoxy or (1-4C) alkylthio substituents. (a) reacting a compound of formula (V) with a compound of formula (IV) to obtain an imine salt, (b) reacting the imine salt with water to form (2-nitrophenyl of formula (VIII) Obtaining acetaldehyde, (c) hydrazine or transition with (2-nitrophenyl) acetaldehyde of formula (VIII) in the presence of an acid with iron, tin chloride, titanium trichloride, sodium dithionite, Raney nickel Reacting with a reducing agent selected from hydrogen in the presence of a metal plasticization catalyst to obtain a compound of formula (VI), (d) methylating the compound of formula (VI) to obtain a compound of formula (VII) (e) converting the T group to a 2-methylbenzenesulfonamido carbonyl group by removing the R ^h protecting group and reacting the resulting carboxylic acid or its reactive derivative with 2-methylbenzenesulfonamide or a salt thereof, and ( f) R ^j beam By removing the group, the U group is converted to a 2-methyl-4,4,4-trifluoro butylaminocarbonyl group, and the resulting carboxylic acid or a reactive derivative thereof is converted into 2-methyl-4,4,4-trifluorobutylamine Or 4- [5- (N- [4,4,4-trifluoro-2-methylbutyl] carbamoyl) -1-methylindol-3-ylmethyl comprising reacting with an acid addition salt thereof ] -3-methoxy-No-tolylsulfonylbenzamide. Formula (IV) Formula (V) Formula (VI) Formula (VII) Formula (VIII) In which each R is independently (1-4C) alkyl or together is a 4- or 5-membered alkylene or heteroalkylene chain, X is a leaving atom or leaving group, T is COOR ^h , U is COOR ^j , and R ^h and R ^j are each independently an acid protecting group which is easily removed.