HK1066004B - Method for the preparation of aryl ethers - Google Patents

Description

Process for preparing aryl ethers

The application is a divisional application of the invention entitled aryl ether preparation method with application number 99815302.8, application date 1999, 12.23.23.

Technical Field

The present invention relates to an improved process for the preparation of certain aryl ethers useful as antidepressants. The invention also relates to intermediates used in the process and to processes for preparing these intermediates.

Background

1980.10.21 issued to USP4229449 discloses compounds of general formula (a) or pharmaceutically acceptable salts thereof,

wherein

n and n1 independently represent 1, 2 or 3;

each of the radicals R and R, which may be identical or different, being₁Is hydrogen; halogen; halogen substituted C₁～C₆An alkyl group; a hydroxyl group; c₁～C₆An alkoxy group; optionally substituted C₁～C₆An alkyl group; optionally substituted aryl-C₁～C₆An alkyl group; optionally substituted aryl-C₁～C₆Alkoxy radical；-NO₂；NR₅R₆Wherein R is₅And R₆Independently represent hydrogen or C₁～C₆Alkyl, or two adjacent R groups or two adjacent R₁The radicals together forming-O-CH₂-an O-group;

R₂is hydrogen; optionally substituted C₁～C₁₂Alkyl, or aryl-C₁～C₆An alkyl group; each radical R which may be identical or different₃And R₄Is hydrogen; optionally substituted C₁～C₆Alkyl radical, C₂～C₄Alkenyl radical, C₂～C₄Alkynyl, optionally substituted aryl-C₁～C₄Alkyl, optionally substituted C₃～C₇Cycloalkyl, or R₃And R₄And the nitrogen atom to which they are attached form a five-or six-membered saturated or unsaturated, optionally substituted, heteromonocyclic group, optionally containing a further heteroatom belonging to the group O, S and N;

or R₂And R₄Together form-CH₂-CH₂-a group.

These compounds are said to have antidepressant activity.

In particular, USP4229449 discloses the following compounds:

2- [ α - (2-ethoxyphenoxy) benzyl ] morpholine:

and pharmaceutically acceptable salts thereof, which have antidepressant properties. This compound is also known as Reboxetine.

As illustrated in figure 4, USP 5068433(1991.11.26 grant) and related USP 5391735(1995.2.21 grant) disclose methods for preparing single diastereomers of compounds of general formula VIb and suitable intermediates:

wherein R is C₁～C₆Alkoxy or trihalomethyl. These diastereomers are said to be useful intermediates for the preparation of compounds of formula a, including Reboxetine. However, the processes disclosed in these patents and USP4229449 are not efficient and the overall yield of the compound of formula a is low when carried out on an industrial scale. Furthermore, these methods require the use of expensive reagents and require long production times. It is therefore uneconomical to prepare the compounds of the formula A on an industrial scale by the processes disclosed in these patents.

There is therefore a need for an improved process for the preparation of compounds of formula (a), and for the preparation of intermediates useful in the preparation of compounds of formula (a). Ideally, the improved process should use less expensive reagents, proceed faster than existing processes, or provide improved intermediates or overall yields. These improvements will facilitate the industrial scale-up of the production of the compounds of formula (a).

Summary of The Invention

As illustrated in fig. 2, the present invention provides a process for the preparation of an amine compound of formula VIIa,

VIIa

the method comprises the following steps:

a) oxidizing the optionally substituted trans-cinnamyl alcohol to obtain an intermediate epoxide of formula Ia:

Ia

b) reacting the epoxide with an optionally substituted phenol to give a diol of the formula IIa:

IIa

c) reacting the diol with a silylating agent to provide an alcohol of formula IIIa:

IIIa

wherein P is a silyl-linked group;

d) reacting an alcohol of formula IIIa with a reactive derivative of a sulphonic acid to give a compound of formula IVa:

IVa

wherein Ra is the residue of a sulfonic acid;

e) removing P from the compound of formula IVa to give an alcohol of formula Va:

Va

f) displacement of the sulfonyloxy group gives an epoxide of the general formula VIa:

VIa

and

g) the epoxide is reacted with ammonia to give the compound of formula VIIa.

As illustrated in fig. 3, the present invention also provides a method further comprising the steps of:

h) reacting a compound of formula VIIa

VIIa

And general formula is HOOCCH₂(ii) a carboxylic acid or a reactive derivative thereof of L, wherein L is a leaving group, to give an amide of formula VIIIa:

VIIIa

i) reacting the compound of formula VIIIa to give a compound of formula IXa:

IXa

and

j) reducing a compound of formula IXa to give the corresponding compound of the formula:

the invention also provides novel intermediates (e.g., compounds of formulae III-V and IIIa-Va) as disclosed herein, and methods for their synthesis.

Detailed Description

Unless otherwise indicated, the following definitions are used: halogen is fluorine, chlorine, bromine or iodine. Alkyl, alkoxy, alkenyl, alkynyl and the like refer to straight and branched chain groups; however, reference to a single group such as "propyl" includes only straight chain groups and branched chain isomers such as "isopropyl" are specifically indicated. Aryl refers to phenyl or ortho-fused bicyclic carbocyclic groups having about 9 to 10 ring atoms, wherein at least one ring is aromatic. "Industrial-scale" means on the order of kilograms, e.g., at least about 10 kilograms, about 100 kilograms, or about 1000 kilograms, of material sufficient to be distributed to a large number of consumers.

It will be appreciated by those skilled in the art that compounds of formula (a) and intermediates disclosed herein having chiral centers may exist and may be isolated in the form of optically active and racemic mixtures. Some compounds will have polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, and that it is well known in the art how to prepare optically-active forms (e.g., by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

The process of the present invention allows the preparation of mixtures of individual diastereomers and intermediates of the compounds of general formula a disclosed herein. It will be appreciated that separation into the corresponding enantiomers may be carried out using techniques well known in the art. Accordingly, the present invention also provides a process for the preparation of the single enantiomers of the compounds of general formula (a) disclosed herein as well as the single enantiomers of any intermediate compounds. The stereochemistry of preferred compounds corresponds to that of Reboxetine.

The specific and preferred values for the groups, substituents and ranges set forth below are for illustrative purposes only; they do not exclude other defined values or other values within the limits defined for the groups and substituents.

Specifically, n is 1.

Specifically, n1 is 1.

Specifically, R is hydrogen, halogen, trifluoromethyl, hydroxyl, C₁～C₆Alkoxy radical, C₁～C₆Alkyl, aryl-C₁～C₆Alkyl, aryl-C₁～C₆Alkoxy, nitro, or NR₅R₆。

Specifically, n is 2 and two adjacent R groups form a methylene dioxy group.

Specifically, R₁Is hydrogen, halogen, trifluoromethyl, hydroxy, C₁～C₆Alkoxy radical, C₁～C₆Alkyl, aryl-C₁～C₆Alkyl, aryl-C₁～C₆Alkoxy, nitro, or NR₅R₆。

Specifically, n1 is 2 and two adjacent R₁The radicals form methylene dioxy groups.

Specifically, each R₅And R₆Is hydrogen.

Specifically, R₂Hydrogen, methyl, ethyl, phenyl, benzyl or phenethyl.

Specifically, each R₃And R₄Is hydrogen.

Specifically, at least one R₃And R₄Is optionally substituted C₁～C₆Alkyl radical, C₂～C₄Alkenyl radical, C₂～C₄Alkynyl, optionally substituted aryl-C₁～C₄Alkyl, optionally substituted C₃～C₇Cycloalkyl, or R₃And R₄And the nitrogen atom to which they are attached form a morpholino, piperidino, N-pyrrolidinyl, N-methyl-piperazinyl, or N-phenylpiperazinyl group.

Specifically, R₂And R₄Together form-CH₂-CH₂-a group; and R is₃Is hydrogen.

In particular, any event when a group can be substituted with "one or more" groups, that group can be substituted with at least 1, 2, or 3 groups.

Preferred compounds are those in which n is 1 and R is 2-methoxy or 2-ethoxy.

Another group of preferred compounds is that n1 is 1 and R₁Is hydrogen or halogen.

Examples of some specific and preferred values for the substituents and groups described herein are disclosed in USP4229449, 5068433 and 5391735. It is to be understood that these specific and preferred values are also specific and preferred values for the corresponding substituents and groups described herein. For example, USP4229449 includes descriptions of the following substituents and groups:

a) the alkyl, alkenyl, alkynyl and alkoxy groups may be straight or branched;

b) when one or more of R and R₁The radicals being substituted C₁～C₆When alkyl, C is preferred₁～C₆Alkyl is substituted by one or more groups selected from hydroxy, C₁～C₆Alkoxy, -NR₅R₆or-C (═ O) NR₅R₆Substituted with the substituent(s);

c) aryl is preferably phenyl;

d) when one or more R is₃And R₄The radicals being substituted C₁～C₆When alkyl, C is preferred₁～C₆Alkyl is substituted by one or more groups selected from halogen, hydroxy, C₁～C₆Alkoxy, -NR₅R₆or-C (═ O) NR₅R₆Substituted with the substituent(s); the same substituents may also be presentIn the substituted C₁～C₁₂On the alkyl group;

e) substituted aryl-C₁～C₆Alkyl, aryl-C₁～C₄Alkyl and aryl-C₁～C₆Alkoxy is preferably one in which the aryl group is substituted by one or more C₁～C₆Alkyl, halogen, halogeno C₁～C₆Alkyl, hydroxy, C₁～C₆Alkoxy and-NR₅R₆Substituted aryl-C₁～C₆Alkyl, aryl-C₁～C₄Alkyl and aryl-C₁～C₆An alkoxy group;

f) substituted C₃～C₇Cycloalkyl being substituted by one or more groups preferably selected from C₁～C₆Alkyl, halogen, halogeno C₁～C₆Alkyl, hydroxy, C₁～C₆Alkoxy and-NR₅R₆C substituted by a substituent of₃～C₇A cycloalkyl group;

g)C₁～C₆alkyl is preferably methyl, ethyl or isopropyl;

h)C₁～C₁₂alkyl is preferably methyl, ethyl, isopropyl or octyl;

i)C₂～C₄alkenyl is preferably vinyl or allyl; c₂～C₄The alkynyl group is preferably propargyl;

j) halo-C₁～C₆The alkyl group is preferably trihalo-C₁～C₆Alkyl, especially trifluoromethyl;

k)C₁～C₆alkoxy is preferably methoxy or ethoxy;

1) aryl-C₁～C₆Alkyl or aryl-C₁～C₄Alkyl is preferably benzyl or phenethyl;

m) aryl-C₁～C₆Alkoxy is preferably benzyloxy;

n) is at-NR₅R₆In the radical, R₅And R₆Preferably independently hydrogen or C₁～C₃An alkyl group; in particular methyl, ethyl or isopropyl;

o)C₃～C₇cycloalkyl is preferably cyclopropyl, cyclopentyl or cyclohexyl;

p) when R is₃And R₄And the nitrogen atom to which it is attached form a substituted heteromonocyclic group, the substituent is preferably C₁～C₆Alkyl or aryl, especially methyl or phenyl; preferred heteromonocyclic groups are morpholino, piperidino, N-pyrrolidinyl, N-methyl-piperazinyl and N-phenyl-piperazinyl; and

q) when two adjacent R groups or two adjacent R groups₁The radicals forming-O-CH₂-O-group, it is preferably 3, 4-methylenedioxy;

USP4229449 also discloses that compounds of formula (a) may be administered in the form of pharmaceutically acceptable salts, including salts with inorganic acids such as hydrochloric acid, hydrobromic acid and sulphuric acid; and salts with organic acids such as citric acid, tartaric acid, methanesulfonic acid, fumaric acid, malic acid, maleic acid, and mandelic acid. Preferred salts are disclosed as being-NR with an amine group₃R₄The acid salt formed (e.g. hydrochloric acid or methanesulphonate). Therefore, the method for producing the compound of the general formula (a) according to the present invention may optionally further comprise preparing a salt of the compound of the general formula (a). The pharmaceutically acceptable salts can be obtained using standard procedures well known in the art.

Epoxidation of optionally substituted trans-cinnamyl alcohols of the formula,

the reaction to give the epoxides of the formula Ia can be carried out conveniently by using suitable epoxidizing agents, for example vanadium pentoxide and hydrogen peroxide, vanadium diacetylacetonate and tert-butyl hydroperoxide, or peroxy acids such as perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, pertrifluoroacetic acid or mono-or di-peroxyphthalic acid. The reaction may be carried out in any suitable solvent or solvent mixture, for example in a hydrocarbon, halogenated hydrocarbon, straight or branched chain ether, carboxylic acid or ester solvent. Specific solvents include benzene, toluene, chloroform, dichloromethane, diethyl ether, dioxane, acetic acid and ethyl acetate. The reaction is preferably carried out in dichloromethane or ethyl acetate. More preferably in dichloromethane. The reaction may be carried out at any suitable temperature from the freezing point to the reflux temperature of the reaction mixture. Preferably, the reaction is carried out at a temperature of from about 0 to about 50 deg.C, more preferably from about 5 to about 25 deg.C.

USP 5068433 and related USP 5391735 teach the preparation of epoxides of formula Ib from trans-cinnamyl alcohol using suitable oxidizing agents such as vanadium pentoxide and hydrogen peroxide, or peroxy acids such as perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, mono-or di-peroxyphthalic acid, or peroxytrifluoroacetic acid. In example 1, these patents specifically describe the preparation of epoxides of the general formula Ib by oxidation of trans-cinnamyl alcohol with meta-chloroperbenzoic acid. Melloni et al, Tetrahedron, 1985, 41, No.7, 1393-.

The use of m-chloroperbenzoic acid on an industrial scale is expensive. Thus, for the industrial scale production of the compounds of formula (A), different epoxidizing agents will be preferred. Studies with mono-peroxyphthalic acid have shown that epoxide Ib can be prepared on an industrial scale using this reagent. However, the preparation of mono-peroxyphthalic acid from phthalic anhydride and hydrogen peroxide is very time consuming. In addition, epoxidation reactions with mono-peroxyphthalic acid produce large amounts of solid phthalic acid by-product, which must be filtered from the product mixture. This filtration step is time consuming and generates a large amount of aqueous solid waste. Therefore, m-chloroperbenzoic acid and mono-peroxyphthalic acid are not ideally suited for industrial scale epoxidation of trans-cinnamyl alcohol.

It has been found that the epoxidation of cinnamyl alcohol can be conveniently carried out on an industrial scale with peracetic acid. Peracetic acid is cheaper and liquid, and it is easier to handle on a large scale than m-chloroperbenzoic acid, which is a solid. Furthermore, the use of peracetic acid can reduce the time required to prepare epoxide Ib, since the preparation of mono-peroxyphthalic acid is not required; peracetic acid also greatly reduces the amount of aqueous solid waste generated by the epoxidation reaction compared to reactions with mono-peroxyphthalic acid.

Accordingly, the present invention provides a process for the preparation of epoxides of the general formula Ia,

ia the process comprises oxidizing the corresponding optionally substituted trans-cinnamic alcohol with peracetic acid. Epoxide Ia is very readily decomposed by strong acids. Commercial peracetic acid is stabilized with sulfuric acid. Thus, peracetic acid should be treated with a suitable base (e.g., sodium or potassium acetate) prior to use; alternatively the reaction may conveniently be carried out in the presence of a suitable solid base such as sodium or potassium carbonate. Preferably, the reaction is carried out on an industrial scale. The reaction is preferably carried out in dichloromethane and at a temperature of less than about 30 ℃.

The diols of the formula IIa can be prepared by reaction of the epoxides of the formula Ia with optionally substituted phenols, conveniently using suitable bases, for example aqueous sodium or potassium hydroxide, sodium or potassium hydride. The reaction may be carried out in any suitable solvent or solvent mixture, for example in a hydrocarbon, halogenated hydrocarbon or straight or branched chain ether solvent, for example benzene, toluene, tetrahydrofuran, dichloromethane, diethyl ether or dioxane. The reaction may be carried out at any suitable temperature from the freezing point to the reflux temperature of the reaction mixture. The reaction is preferably carried out at a temperature of from about 0 to about 100 deg.C, more preferably from about 20 to about 50 deg.C. Preferably, the reaction can be carried out under phase transfer conditions using a suitable phase transfer catalyst (e.g., tributylmethylammonium chloride), as described in example 2.

Melloni et al, Tetrahedron, 1985, 41, No.7, 1393-. It has been found that the compound of formula II can be conveniently isolated by recrystallization from methyl tert-butyl ether (MTBE). MTBE is relatively inexpensive and is less prone to form explosive peroxides than isobutyl ether. Thus, the compound of formula II can be isolated, preferably by recrystallization from MTBE.

Any suitable silylating agent (e.g., chlorot-butyldimethylsilyl, chlorotrimethylsilyl, chlorot-butyldiphenylsilyl, chlorotriethylsilyl, chlorotriisopropylsilyl, hexamethyldisilazane with or without the same chlorotrimethylsilyl, or chlorotriphenylsilyl) can be used to protect the primary hydroxyl group in the diol of formula IIa to form the mono-protected compound of formula IIIa, where P is a protecting group attached to the silyl group. The reaction may be carried out in any suitable solvent or solvent mixture, for example in a hydrocarbon, ester, halogenated hydrocarbon or straight or branched chain ether solvent, for example benzene, toluene, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, ethyl acetate or dioxane. The reaction may be carried out at any suitable temperature that selectively protects the primary alcohol but not the secondary alcohol, provided that the temperature is above the freezing point of the reaction mixture. The reaction is preferably carried out at a temperature below-5 ℃. More preferably, the reaction is carried out at a temperature below-10 ℃ or below-15 ℃. Most preferably, the reaction is carried out at a temperature of from about-15 to about-25 ℃. Other suitable silylating agents and reaction conditions are well known in the art, see, for example, Greene, t.w.; wutz, p.g.m. "Protecting Groups In organic synthesis" second edition, 1991, new york, John Wiley & sons, inc.

As illustrated in FIG. 4, USP 5068433 and 5391735 indicate that diols of formula IIb can be esterified to giveTo compounds of the formula IIIb, in which R₂Is the residue of a carboxylic acid. Unfortunately, under the conditions disclosed in these patents, the selectivity of protection for the primary alcohol of the diol is low; at the same time, up to 13% of esters of secondary alcohols are formed. The formation of mono-p-nitrobenzoate esters on secondary alcohols directly leads to a decrease in the yield of amines of formula VIb. Formation of mono-p-nitrobenzoate esters on secondary alcohols also produces the unwanted diastereomer of the amine of formula VIb, which is a contaminant in the amine product. In addition, the formation of di-p-nitrobenzoate leads to a decrease in the yield of amine of formula VIb and yields di-p-nitrobenzoate as a contaminant in the product amine. Due to the presence of these undesirable contaminants, further purification of the amine product is required, which is time consuming and results in additional reduction of the yield. Thus, the processes disclosed in USP 5068433 and 5391735 are not ideally suited for the industrial scale production of amines of formula VIa.

It has now been surprisingly found that primary alcohols in diols of formula IIb can be selectively protected in high yields using silyl protecting groups. In particular, it was found that primary alcohols can be selectively protected with trimethylsilyl groups. In the reaction with primary and secondary alcohols, the reaction with monochlorotrimethylsilane is almost completely selective and no bis (trimethylsilyl) ether is formed. As a result, the yield of amine VIIb obtained by the process of the present invention is significantly improved over that obtained using previously known processes. In addition, monochlorotrimethylsilane is less expensive, more readily available, and more amenable to large scale processing than p-nitrobenzoyl chloride, which is a liquid and a solid.

Little selectivity was seen in the reaction of IIb with chlorotrimethylsilane. Trimethylsilyl is used extensively in alcohol derivatization, primarily in analytical applications, where the desired result is complete silylation. Considerable selectivity has been found in the reaction of secondary alcohols under different circumstances (see, for example, h.j.schneider, r.horning, leitigsann.chem., 1974, 1864-. However, there is no information on the relative rates of reaction of primary and secondary alcohols, and there is no example in the literature of selective protection of primary alcohols with chlorotrimethylsilanes in the presence of secondary alcohols. Examples of reactions of primary alcohols in the presence of secondary alcohols by monochlorotrimethylsilane catalysed with hexamethyldisilazane (J.Cossy, P.Tile, Tet.Lett.1987, 6039-.

Selective protection of the primary alcohol can be achieved at low temperatures with a silyl protecting group, preferably monochlorotrimethylsilane. It has also been determined that the migration of silyl protecting groups can be prevented by: 1) maintaining the protected compound of formula IIIa at low temperature throughout the conversion from the compound of formula IIa to the compound of formula Va, and 2) performing the desired sequence of reactions in a short time (e.g., less than about 5 hours, preferably less than about 4 hours, about 3 hours, or about 2 hours). As illustrated in example 6, this is conveniently achieved by carrying out the conversion of the diol of the formula IIa to the compounds of the formulae IIIa, IVa and Va in one reactor without isolation of the intermediates of the formulae IIIa, IVa.

Accordingly, the present invention provides a process for the preparation of a compound of formula IIIa,

IIIa wherein P is a silyl-linked group; the process comprises reacting a diol of formula IIa with a suitable silylating agent.

IIa preferably, P is trimethylsilyl and the silylating agent is chlorotrimethylsilane. Preferred solvents include ethyl acetate and dichloromethane.

Reaction of an alcohol of formula IIIa with a reactive derivative of a sulphonic acid to give a compound of formula IVa, wherein Ra is the residue of the sulphonic acid, may be carried out using any suitable sulphonylating agent, for example a sulphonyl halide, particularly a sulphonyl chloride (e.g. p-toluenesulphonyl chloride, benzenesulphonyl chloride, (C)₁～C₆) Alkyl sulfonyl chloride, or trifluoromethyl sulfonyl chloride). A preferred reactive derivative of sulfonic acid is methanesulfonyl chloride. The reaction is conveniently carried out in the presence of a suitable base, such as triethylamine or pyridine. The reaction may be carried out in any suitable solvent or solvent mixture, for example in a hydrocarbon, halogenated hydrocarbon, organic ester, or straight or branched chain ether solvent, such as benzene, toluene, tetrahydrofuran, dichloromethane, ethyl acetate, diethyl ether or dioxane. The reaction is preferably carried out in ethyl acetate. The reaction may be carried out at any temperature above the freezing point of the reaction mixture. Preferably, the reaction is carried out at a temperature below-5 ℃. More preferably, the reaction is carried out at a temperature below-10 ℃ or below-15 ℃. Most preferably, the reaction is carried out at a temperature of from about-15 to about-25 ℃. Other suitable reactive derivatives of sulfonic acids and reaction conditions are well known in the art, see, for example, Jerry March, Advanced organic chemistry, fourth edition, 1992, New York, John Wiley& sons，Inc.，352-356。

The silyl group P may be removed from the compound of formula IVa using any suitable catalyst, for example an acid (e.g. hydrochloric acid) or a fluoride ion source (e.g. tetrabutylammonium fluoride) to give the alcohol of formula Va. The reaction may be carried out in any suitable solvent or solvent mixture, for example in a hydrocarbon, halogenated hydrocarbon, organic ester, or straight or branched chain ether solvent, such as benzene, toluene, chloroform, dichloromethane, ethyl acetate, diethyl ether, tetrahydrofuran or dioxane. The reaction is preferably carried out in ethyl acetate. The reaction may be carried out at any temperature above the freezing point of the reaction mixture. Preferably, the reaction is carried out at a temperature of from about-78 to about 100 ℃. More preferably, the reaction is carried out at a temperature of from about-50 to about 50 ℃. Most preferably, the reaction is carried out at about-25 to about 25 ℃.

The alcohol of formula Va may be reacted in the presence of any suitable base, for example an alkali or alkaline earth metal hydroxide such as sodium or potassium hydroxide, to give the epoxide of formula VIa. The reaction may be carried out in any suitable solvent or solvent mixture, for example in a hydrocarbon, halogenated hydrocarbon, or straight or branched chain ether solvent, such as benzene, toluene, chloroform, dichloromethane, diethyl ether, tetrahydrofuran or dioxane. Preferably, the reaction is carried out in a mixture of toluene and water in the presence of a suitable phase transfer catalyst (e.g., tributylmethylammonium chloride) under phase transfer conditions. The reaction may be carried out at any temperature above the freezing point of the reaction mixture and below the reflux temperature. Preferably, the reaction is carried out at a temperature of from about-78 to about 100 ℃. More preferably, the reaction is carried out at a temperature of from about-50 to about 50 ℃. Most preferably, the reaction is carried out at about 15 to about 30 ℃.

As illustrated in FIG. 4, USP 5068433 and 5391735 indicate that compounds of formula IVb can be converted to epoxides of formula Vb by treatment with a suitable base in an aqueous organic solvent such as dioxane or dimethylformamide (see column 4, lines 19-27 and example 5 therein). Melloni et al, Tetrahedron, 1985, 41, No.7, 1393-.

When carried out on a large scale (about 165 kg), the reaction is slow (18 hours), and removal of dioxane is difficult due to its high boiling point and high freezing point (mp 11.8 ℃). Distillation may therefore take 1 or 2 days, with the risk of the dioxane solidifying in the equipment during distillation, resulting in damage to the condenser. Furthermore, dioxane is carcinogenic and toxic.

As illustrated in figure 2, and as shown by example 6 below, it has now been found that compounds of formula Va can be converted to epoxides of formula VIa in a mixture of toluene and water under phase transfer conditions. The reaction can be carried out on a large scale in about 45 minutes and the toluene can be easily removed from the product mixture. Accordingly, the present invention provides a process for the preparation of compounds of the general formula VIa,

VIa

r, R therein₁N and n1 are as defined herein; the process comprises treating a corresponding compound of formula Va with a suitable base under phase transfer conditions,

Va

wherein Ra is the residue of a sulfonic acid. Preferably, the reaction is carried out at a temperature in the range of from about 0 ℃ to about the reflux temperature of the reaction mixture. More preferably, the reaction is carried out at a temperature of from about 15 to about 35 ℃.

The reaction of the epoxide of formula VIa with ammonia to give the amine of formula VIIa may be carried out in the presence of any suitable source of ammonia, such as aqueous ammonia or ammonium hydroxide. The reaction may be carried out in any suitable solvent or mixture of solvents, for example in a hydrocarbon, halogenated hydrocarbon, aliphatic alcohol or straight or branched chain ether solvent, such as benzene, toluene, chloroform, dichloromethane, diethyl ether, methanol, ethanol, isopropanol, dioxane, tetrahydrofuran or dimethylformamide. Preferably, the reaction is carried out in methanol using ammonium hydroxide as the ammonia source, as described in example 7. The reaction may be carried out at the reflux temperature of the reaction mixture or at any temperature below the reflux temperature. Preferably, the reaction is carried out at a temperature of from about-50 to about 100 ℃. More preferably, the reaction is carried out at a temperature of from about 0 to about 80 ℃. Most preferably, the reaction is carried out at about 20 to about 50 ℃.

Conveniently represented by the general formula HOOCCH₂Reactive derivatives of carboxylic acids of L, wherein L is a suitable leaving group, are reacted with amines of formula VIIa to give the corresponding amides of formula VIIIa. Suitable leaving groups are well known in the art and include halides (e.g., bromine, chlorine or iodide), sulfonyl esters (e.g., 4-toluenesulfonyloxy, methylsulfonyloxy, trifluoromethylsulfonyl-oxy, (C)₁～C₆) Alkyl sulfonyl oxygen, or phenyl sulfonyl oxygen, wherein the phenyl group may optionally be substituted with one or more substituents independently selected from halogen, (C)₁～C₆) Alkyl, nitro, (C)₁～C₆) Alkoxy, trifluoromethyl and cyano). The preferred carboxylic acid is chloroacetyl chloride.

The reaction is conveniently carried out in the presence of a suitable base, such as triethylamine or pyridine. The reaction may be carried out in any suitable solvent or solvent mixture, for example in a hydrocarbon, halogenated hydrocarbon, organic ester, or straight or branched chain ether solvent, for example benzene, toluene, chloroform, dichloromethane, ethyl acetate, dimethyl carbonate, diethyl ether, tetrahydrofuran or dioxane. Preferably, the reaction is carried out in dimethyl carbonate or dichloromethane. The reaction may be carried out at any temperature above the freezing point of the reaction mixture. Preferably, the reaction is carried out at less than 50 ℃. More preferably, the reaction is carried out at a temperature below 25 ℃ or below 15 ℃. Most preferably, the reaction is carried out at about 0 to about 10 ℃.

Compounds of formula VIIIa may be conveniently reacted to form morpholinones of formula IXa in the presence of a suitable base, such as sodium hydride, potassium hydride, or potassium tert-butoxide. The reaction may be carried out in any suitable solvent or solvent mixture, for example in a hydrocarbon, halogenated hydrocarbon, aliphatic alcohol or straight or branched chain ether solvent, such as benzene, toluene, dichloromethane, diethyl ether, isopropanol, tetrahydrofuran or dioxane. Preferably, the reaction is carried out in isopropanol using potassium tert-butoxide as a base, as described in example 9. The reaction may be carried out at any temperature above the freezing point of the reaction mixture, at its reflux temperature, or below the reflux temperature. Preferably, the reaction is carried out at a temperature of from about-78 to about 100 ℃. More preferably, the reaction is carried out at a temperature of from about-25 to about 50 ℃. Most preferably, the reaction is carried out at about 0 to about 30 ℃.

The morpholinones of formula IXa can be conveniently reduced in the presence of a suitable reducing agent (e.g., borane, lithium aluminum hydride, diisobutylaluminum hydride, diisopropylaluminum hydride, or sodium bis (2-methoxyethoxy) aluminum hydride) to form compounds of formula (A) wherein R is₂And R₄Is an ethylene group. The reaction may be carried out in any suitable solvent or mixture of solvents, for example in a hydrocarbon, or straight or branched chain ether solvent, for example benzene, toluene, diethyl ether or tetrahydrofuran. The reaction may be carried out at any temperature above the freezing point of the reaction mixture, at its reflux temperature, or below the reflux temperature. Preferably, the reaction is carried out at a temperature of from about-78 to about 100 ℃. More preferably, the reaction is carried out at a temperature below 50 ℃ or below 10 ℃. Most preferably, the reaction is carried out at about-20 to about 5 ℃.

Melloni et al, Tetrahedron, 1985, 41, No.7, 1393-.

When the reaction is carried out on a large scale (about 25 kg of morpholinone), the reaction product is typically contaminated with 0.6-1% of the following impurities:

in order for the final pharmaceutical product of formula (a) to meet regulatory requirements in some countries, the concentration of this impurity in the final product must be less than 0.1%. Removal of this impurity is difficult, but at a pH of about 5.2, controlled pH extraction can be used to achieve this. However, in the extraction process, 20-30% of the compound of formula (A) is usually lost and is not easily recovered.

It has now been determined that the amount of impurities resulting from reduction can be significantly reduced by adding a solution of morpholinone IXa to a solution containing an excess (e.g., about 5 equivalents) of sodium bis (2-methoxyethoxy) aluminum hydride. Using this method, it has been found that this reaction can directly produce Reboxine free base containing less than 0.1% impurities. This material can be used directly without controlled pH extraction. This reduces processing time and eliminates 20-30% product loss.

It was found that using less than 5 equivalents of reducing agent would reduce the yield of the reaction. Preferably, therefore, the reduction is carried out using at least about 4 equivalents of sodium bis (2-methoxyethoxy) aluminum hydride or other suitable reducing agent. More preferably, the reduction is carried out using at least about 5 equivalents of a suitable reducing agent, such as at least about 5 to about 10 equivalents of sodium bis (2-methoxyethoxy) aluminum hydride. The reducing agent is preferably not lithium aluminium hydride.

Accordingly, the present invention provides a process for the preparation of a compound of the general formula,

r, R therein₁N and n1 are as defined herein; the process comprises adding the corresponding compound of formula IXa to a solution containing at least 4 equivalents of a suitable reducing agent.

IXa

The present invention also provides compounds of formula IIIa:

IIIa

r, R therein₁N and n1 are as defined above for the corresponding groups in the compounds of general formula (A), specific values or preferred values, P is a suitable silyl protecting group (e.g.tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, triphenylsilyl). Preferably, the compound of formula IIIa is a compound of formula III.

The present invention also provides compounds of formula IVa:

IVa

r, R therein₁N and n1 are as defined above for the corresponding groups in the compound of formula (A), and P is a suitable silyl protecting group (e.g.tert-butyldimethylsilyl, trimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl, triisopropylsilyl, triphenylsilyl); ra is the residue of a sulfonic acid (e.g., p-toluenesulfonyl, benzenesulfonyl, methanesulfonyl, ethanesulfonyl, or trifluoromethanesulfonyl). Preferably, the compound of formula IVa is a compound of formula IV.

The invention also provides compounds of formula Va:

Va

r, R therein₁N and n1 are as defined above for the corresponding groups in the compound of formula (A), the values specified or preferred; ra is sulfonic acidA residue of (e.g., p-toluenesulfonyl, benzenesulfonyl, methanesulfonyl, ethanesulfonyl, or trifluoromethanesulfonyl). Preferably, the compound of formula Va is a compound of formula V.

As illustrated in fig. 1, the present invention also preferably provides a process for the preparation of a compound of formula VII,

the method comprises the following steps:

a) oxidizing the optionally substituted trans-cinnamyl alcohol to obtain an intermediate epoxide of formula I:

b) reacting the epoxide with an optionally substituted phenol to give a diol of the general formula II:

c) reacting the diol with a silylating agent to provide an alcohol of formula III:

d) reacting an alcohol of formula III with a reactive derivative of methanesulfonic acid to give a compound of formula IV:

e) removing the trimethylsilyl group from the compound of formula IV to give an alcohol of formula V:

f) displacing the sulfonyloxy group to give an epoxide of the formula VI:

VI

and

g) the epoxide is reacted with ammonia to give the compound of formula VII. The resulting compound of formula VII may be conveniently isolated by conversion to the mesylate salt, for example, as described in example 7.

The process for preparing the above compound of formula VII may optionally further comprise:

h) reacting a compound of formula VII with chloroacetyl chloride to give an amide of formula VIII:

i) reacting a compound of formula VIII to give a compound of formula IX:

and

j) reducing a compound of formula IX to give the corresponding morpholino compound of formula:

the invention is further illustrated by the following non-limiting examples in which, unless otherwise stated:

a) the melting point was determined in an open capillary with a Buchi melting point apparatus, uncorrected;

b) NMR spectral data were recorded on Bruker AMX400 and observed¹H time at 400.13MHz, observe¹³C is operated at 100.62 MHz; the sample was dissolved in CDCl₃And using it as an internal reference (¹Hδ＝7.26；¹³Cδ＝77.0)；

c) Mass spectral data were acquired on a Fisons Trio 2000 single quadrupole spectrometer, which operated in Electron Impact (EI) or Chemical Ionization (CI) mode; the scanning range is 110-600 amu for CI, and 45-600 amu for EI; the source temperature (sourcetemperature) is 150 ℃, the electron intensity is 400V, and the electron energy is-70 eV; chemical ionization with ammonia as a reagent gas and adjustment of the source pressure to 1.4X 10^-4mTorr；

d) The reaction was routinely monitored by Perkin Elmer HPLC (series 200 pump, 235C diode array detector) using a Nucleosil-100C-18 column, a mixture of water and acetonitrile as the eluent, with or without trifluoroacetic acid; the conversion of cinnamyl alcohol to epoxide was detected at 215nm, all others at 275 nm;

e) the reagent and the solvent are both commodities, and are not purified when in use;

f) the reaction was carried out under nitrogen; and

g) thin Layer Chromatography (TLC) was performed using Analtech single-sided silica gel plates (250 μ, cat No. 02521).

Examples

Example 1(2RS, 3RS) -2, 3-epoxy-3-phenylpropanol (I)

Sodium carbonate (224g) and trans-cinnamyl alcohol (200.0g) were mixed with 2L of dichloromethane. A slow nitrogen purge was maintained in the vaporous part of the flask and the mixture was cooled to 15-20 ℃ with a cold water bath. A peracetic acid solution (35%, 381.2ml) was added over 3 hours, maintaining the internal temperature below 25 ℃. After the peracetic acid solution is added, the mixture is stirred for 2 to 3 hours until HPLC analysis shows that the reaction is complete. The mixture was cooled to 10 ℃ with an ice bath and then a solution of sodium sulfite (160g) in 1200ml of water was added slowly over 90 minutes, maintaining the temperature below 30 ℃. The phases were separated and the aqueous phase was extracted with dichloromethane (200ml) to give a solution of the title compound.

Example 2(2RS, 3SR) -3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropanol (II)

Water (800ml), sodium hydroxide (50%, 83.1ml), tributylmethylammonium chloride (75%, 27.5ml) and 2-ethoxyphenol (306.72g) were mixed and stirred at 20-25 ℃. A solution of 2, 3-epoxy-3-phenylpropanol obtained in example 1 in dichloromethane was added and the biphasic mixture was stirred and heated to an internal temperature of 40 ℃. The methylene chloride is distilled at atmospheric pressure for 3 to 4 hours. When the dichloromethane had been removed, the internal temperature was raised to 60 ℃ for 2 hours. The mixture was cooled to below 30 ℃ and toluene (1200ml) was added and the mixture was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with toluene (800 ml). The toluene solution was mixed and washed with 1N NaOH (2X 400ml) and water (400ml) at about 25 ℃. Keeping the internal temperature at 40-50 ℃, and concentrating the toluene solution under partial vacuum. The residual oil was dissolved in methyl tert-butyl ether (760ml) and the water content determined by potassium fluoride analysis to be less than 0.1%. Seed crystals of the title compound were added to the solution at 20-25 ℃, stirred for 1 hour, then cooled to 0 ℃ and held for 2 hours. The resulting solid was filtered, washed with methyl tert-butyl ether (2X 200ml, cooled to-15 ℃) and dried under vacuum to give 256.1g of the title compound (60.5% conversion from cinnamyl alcohol).

Example 3(2RS, 3SR) -3- (2-ethoxyphenoxy) -2-hydroxy-3-phenyl-1- (trimethylsilyloxy) propane (III)

The 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropanol (1.44g, 5mmol) obtained in example 2 and triethylamine (0.77ml, 5.5mmol) were dissolved in ethyl acetate (15ml) and cooled to-17 ℃. Monochlorotrimethylsilane (0.64ml, 5.0mmol) dissolved in 5ml of ethyl acetate was added thereto over 10 minutes, the temperature being kept below-15 ℃ and a white precipitate formed during this addition. The mixture was stirred at a temperature below-15 ℃ for 15 minutes and 20ml pentane was added. The solid was removed by filtration and the filtrate was concentrated in vacuo to give a cloudy oil. The oil was chromatographed on silica (230-400 mesh) using 4: 1 heptane-ethyl acetate as eluent. The product-containing fractions were concentrated to give the title compound as a clear colorless oil 1.80g (88.5%);

¹H NMR(400.13MHZ，CDCl₃)

d0.09(s，9H)，1.47(t，J＝6.8Hz，3H)，2.82(d，J＝5.2，1H)，3.80(m，3H)，4.0-4.11(m，4H)，5.08(d，J＝6.0，1H)，6.76(m，2H)，6.85(m，2H)，7.2-7.45(m，5H)；¹³C NMR(100.62MHZ，CDCl₃)d 0.0，15.54，63.34，65.06，75.22，83.71，114.28，118.60，121.51，122.95，127.84，128.49，128.84，138.93，148.34，150.40；MS(ei)m/e 360；

example 4(2RS, 3SR) -3- (2-ethoxyphenoxy) -2-methanesulfonyloxy-3-phenyl-1- (trimethylsilyloxy) propane (IV)

The 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropanol (1.44g, 5mmol) obtained in example 2 and triethylamine (0.77ml, 5.5mmol) were dissolved in ethyl acetate (15ml) and cooled to-17 ℃. Monochlorotrimethylsilane (0.64ml, 5.0mmol) dissolved in 5ml of ethyl acetate was added thereto over 10 minutes, maintaining the temperature below-15 ℃. A white precipitate formed during this addition. The mixture was stirred at a temperature below-15 ℃ for 15 minutes. Triethylamine (0.8ml, 5.7mmol) was added followed by methanesulfonyl chloride (0.46ml, 6.0mmol) dissolved in 5ml ethyl acetate, maintaining the temperature below-15 ℃. The mixture was stirred at below-15 ℃ for 15 minutes. Adding pentaneAlkane (20ml) and the solids were removed by filtration. The filtrate was concentrated under vacuum to give a cloudy oil. The oil was chromatographed on silica (230-400 mesh) using 4: 1 heptane-ethyl acetate as eluent. The product-containing fractions were concentrated to give 2.00g (91.2%) of the title compound as an oil which solidified upon standing; the melting point is 80-82.5 ℃;¹H NMR(400.13MHZ，CDCl₃)d 0.17(s，9H)，1.50(t，J＝6：8Hz，3H)，3.06(s，3H)，3.77(dd，J＝11，6，1H)，4.00(dd，J＝11，6，1H)，4.10，(q，J＝6.8，2H)，5.07，(m，1H)，5.51(d，J＝4.4，1H)，6.75(m，2H)，6.91(m，2H)，7.2-7.49(m，5H)；¹³C NMR(100.62MHZ，CDCl₃)d 0.0，15.66，38.87，61.57，64.88，79.90，85.20，113.97，116.99，121.32，122.79，128.26，129.09，129.14，136.75，147.72，149.95；MS(ei)m/e 438。

example 5(2RS, 3SR) -3- (2-ethoxyphenoxy) -2-methanesulfonyloxy-3-phenyl-1-propanol (V)

The 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropanol (0.288g, 1mmol) obtained in example 2 and triethylamine (0.15ml, 1.1mmol) were dissolved in ethyl acetate (5ml) and cooled to-17 ℃. Monochlorotrimethylsilane (0.13ml, 1.0mmol) dissolved in 2ml of ethyl acetate was added thereto over 10 minutes, maintaining the temperature below-15 ℃. A white precipitate formed during this addition. The mixture was stirred at below-15 ℃ for 15 minutes. Triethylamine (0.15ml, 1.1mmol) was added followed by methanesulfonyl chloride (0.085ml, 1.1mmol) dissolved in 2ml ethyl acetate, maintaining the temperature below-15 ℃. The mixture was stirred at below-15 ℃ for 15 minutes. Hydrochloric acid (2N, 2ml) was added and the mixture was warmed to 20-25 ℃ and stirred for 30 minutes. The phases were separated, the organic phase was washed with saturated aqueous sodium chloride (5ml) and dried over sodium sulfate. The solution was evaporated to give 0.377g of oil. The oil was chromatographed on silica (230-400 mesh) using 1: 1 hexane ethyl acetate as eluent. The product-containing fractions were concentrated to give 0.33g (91) of the title compound as an oil%) the compound solidified upon standing; the melting point is 83-86 ℃;¹H NMR(400.13MHZ，CDCl₃)d 1.66(t，J＝8.2Hz，3H)，2.85(s，3H)，4.14-4.35(m，4H)，5.12(m，1H)，5.52(d，J＝6.1Hz)，6.8-7.15(m，4H)，7.5-7.7(m，5H)；¹³C NMR(100.62MHZ，CDCl₃)d 14.73，37.80，62.19，64.27，81.40，84.04，112.88，117.19，120.67，122.86，127.40，128.77，128.86，137.02，146.40，149.30；MS(ei)m/e 366.

example 6(2RS, 3RS) -1, 2-epoxy-3- (2-ethoxyphenoxy) -3-phenylpropane (VI)

The 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenyl-1-propanol (28.8g) obtained in example 2 and triethylamine (16.7ml) were dissolved in ethyl acetate (170ml), and cooled to-20 to-15 ℃. A solution of monochlorotrimethylsilane (13.2ml) dissolved in 20ml of ethyl acetate was added thereto, maintaining the reaction temperature at-20 to-15 ℃. After the addition was complete, the mixture was stirred at-20 to-15 ℃ for 5 minutes.

Methanesulfonyl chloride (9.3ml) was added to the solution, maintaining the temperature at-20 to-15 ℃. Triethylamine (16.7ml) was then added, again maintaining the temperature at-20 to-15 ℃. The mixture was stirred for 15 minutes after the addition of triethylamine.

To the reaction mixture was added a solution of concentrated hydrochloric acid (8.3ml) and water (92 ml). The mixture is warmed to 15-25 ℃ and stirred for 45 minutes. The reaction was monitored by TLC. The phases were separated and the organic phase was washed with a solution of sodium bicarbonate (5g) in 45ml of water and then with a solution of 12.5g of sodium chloride and 37.5ml of water. The organic phase was concentrated under vacuum to give an oil. Toluene (200ml) was added and the solution was concentrated to give an oil which was again dissolved in 200ml of toluene.

To the toluene solution were added sodium hydroxide solution (50%, 36g), water (60ml) and tributylmethylammonium chloride (70%, 2.5 g). The mixture was purged with nitrogen, stirred at 20-25 ℃ for 45 minutes at a high rate, and analyzed by HPLC. The phases were separated and an oily yellow interface was maintained in the organic phase. The aqueous phase was extracted with toluene (50ml) and the toluene solution was mixed. The toluene solution was washed with a saturated sodium chloride solution (50ml, 12.5g sodium chloride and 37.5ml water). The toluene solution was concentrated to 60ml under vacuum (bath temperature 40 ℃). Methanol (300ml) was added and the solution was concentrated to 60ml under vacuum. Methanol (300ml) was added and the mixture was concentrated again to 60ml to give a solution of the title compound.

Example 7(2RS, 3RS) -3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropylamine (VII)

To the methanol solution obtained in example 6 were added 270ml of methanol and 300ml of ammonium hydroxide. The mixture was stirred and heated to 40 ℃ in a closed vessel for 3 hours. After 3 hours the reaction was cooled and analyzed by HPLC. Dichloromethane (223ml) was added and the mixture was stirred and then allowed to stand. The phases were separated and the aqueous phase was extracted with dichloromethane (2X 100 ml). The organic layers were mixed and distilled under vacuum to a volume of 300 ml. Dichloromethane (180ml) was added back to the solution. The dichloromethane solution was washed with 250ml of water. The water was extracted with 100ml of dichloromethane and the dichloromethane solution was then mixed.

To the combined dichloromethane solution was added a solution of 250ml of water and 10ml of concentrated hydrochloric acid. The pH was adjusted to below 2 by adding more HCl. The mixture was stirred and then allowed to stand. The phases were separated and the organic phase was extracted with 250ml of water. The aqueous phases were mixed and washed with 46ml of dichloromethane.

Dichloromethane (144ml) was added to the aqueous phase and the pH was adjusted to greater than 12 with 50% aqueous NaOH (about 10 gr). The phases were separated and the aqueous phase was extracted with 72ml of dichloromethane. The organic phases were mixed and distilled to a volume of 200mL isopropanol (200mL) was added and the mixture was distilled to a volume of 200 mL. Isopropanol (200mL) was added and the solution was again distilled to a volume of 200mL methanesulfonic acid (7.9g) was added and the mixture was stirred at 20-25 ℃ for 2 hours. The resulting slurry was cooled to 0-5 ℃ and stirred for 60 minutes. The solid was filtered and washed with 100ml of isopropanol. The resulting solid was dried in a vacuum oven at 60 ℃ to give 24.5g of the title compound as a methanesulfonate salt (64% total conversion from 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenyl-1-propanol).

Example 8(2RS, 3SR) -N-chloroacetyl-3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropylamine (VIII)

(2RS, 3RS) -1, 2-epoxy-3- (2-ethoxyphenoxy) -3-phenylpropane (47.7g) and dimethyl carbonate (700ml) were stirred to form a white slurry. Triethylamine (52ml) was added and the mixture was cooled to 6-10 ℃ with an ice water bath. A solution of chloroacetyl chloride (13.8ml) in dimethyl carbonate (50ml) was added over 30 minutes, maintaining the temperature at 4-10 ℃. The mixture was stirred for 1 hour. The mixture was washed with 500ml of water and then with 500ml of 3% aqueous sodium chloride solution. The organic layer was concentrated in vacuo at 40 ℃ to give a dark oil. Isopropanol (500ml) was added and the mixture was again concentrated to remove any residual dimethyl carbonate to give the title compound.

Example 9(2RS, 3RS) -2- [ alpha- (2-ethoxyphenoxy) benzyl ] morpholin-5-one (IX)

The product obtained in example 8 was stirred with 200ml of isopropanol to form a slurry. A solution of isopropanol (305ml) and potassium tert-butoxide (30.6g) was prepared. The solution was added to an isopropanol slurry and the reaction temperature was maintained at 20-23 ℃ with an ice bath. The mixture is stirred at 20-25 ℃ for 1 hour. The pH of the mixture was adjusted to 6.4 by addition of 1N HCl (ca 210 ml). The mixture was evaporated under vacuum to an oil. To the residue were added water (170ml) and toluene (150ml), and the mixture was stirred for 5 minutes. The aqueous layer was extracted with 100ml of toluene. The toluene extracts were combined and washed with 100ml of 1N HCl and 100ml of 10% sodium chloride solution. The toluene solution was evaporated to an oil and the residue was redissolved in 240ml of toluene to give a solution of the title compound.

Example 10(2RS, 3RS) -2- [ alpha- (2-ethoxyphenoxy) benzyl ] morpholine (Reboxetine)

A toluene solution (65%, 187ml) of sodium dihydrogen aluminum (vitride) was diluted with 187ml of toluene and the solution was cooled to below 5 ℃. The toluene solution obtained in example 9 was added over 1 hour, maintaining the temperature below 5 ℃. After the addition of this material was complete, the mixture was stirred for 15 minutes. To 60g of 50% sodium hydroxide solution was added a sufficient amount of water to a volume of 350ml, and the solution was added to the mixture, maintaining the temperature below 55 ℃. After the addition was complete, the two-phase mixture was stirred at 55 ℃ for 15 minutes. The toluene phase was washed with 5% sodium carbonate solution (3X 170 ml). Water was added to the toluene solution, and 1N HCl was added to bring the pH to 3.11. The aqueous phase was extracted with 480ml of toluene. Toluene (480ml) was added to the aqueous solution and the pH was adjusted to above 12 with 50% sodium hydroxide. The aqueous phase was extracted with 240m1 toluene. The two toluene solutions were mixed and then washed with sodium carbonate solution (5%, 175ml) and water (175 ml). The toluene was evaporated to give 32g of the title compound as a free base.

Example 11(2RS, 3RS) -2- [ alpha- (2-ethoxyphenoxy) benzyl ] morpholine methanesulfonate

The oil obtained in example 10 was dissolved in 122ml of acetone and stirred with 2G of activated Carbon (e.g., Darco G-60, Calgon Carbon Corporation; or Norit, American Norit Corporation) and 2G of Celite (celite) at 20-25 ℃ for 1 hour. The mixture was filtered and the volume of the filtrate was adjusted to 320 ml. The solution was cooled to 0 ℃ and methanesulfonic acid (5.1ml) was added. The mixture was stirred at 0 ℃ for 70 minutes and then filtered. The solid was washed with 100ml of acetone and dried under nitrogen to give 30.08g of a white solid. The solid was slurried in 200ml acetone and stirred at 50 ℃ for 2 hours. The slurry was cooled to 0 ℃, held for 30 minutes and filtered. The solid was dried under nitrogen to give 27.72g of the title compound (54.3% total conversion from 3- (2-ethoxyphenoxy) -2-hydroxy-3-phenylpropylamine).

The entire disclosures of all publications, patents and patent documents referred to herein, and U.S. provisional application 60/114092, are incorporated herein by reference as if individually incorporated by reference. The invention has been described in detail with reference to various specific and preferred embodiments and techniques. It will be understood that various changes and modifications may be made within the spirit and scope of the invention.

Claims (1)

1. A process for the preparation of a compound of the general formula,

wherein

n and n1 are 1;

r is methoxy or ethoxy;

R₁is hydrogen or halogen;

the process comprises adding to a solution containing 5 to 10 equivalents of a reducing agent selected from borane, diisobutylaluminum hydride, diisopropylaluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride a corresponding compound of formula IXa:

wherein n, n1, R and R1 are as defined above.