Novel reduction compositions are prepared from an active hydride, an additive, and a Lewis base in a hydrocarbon solvent. Such compositions can provide a superior reducing system for organic substrates.

Description

23 parts

›CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of commonly owned U.S. application Ser. No. 08/817,003, filed Mar. 31, 1997, now abandoned, the entire disclosure of which is hereby incorporated by reference, and is related to commonly owned provisional application Ser. No. 60/001,857, filed Aug. 3, 1995 and claims the benefit of the earlier filing date of this application under 35 USC §119(e), and is also a continuation-in-part application of commonly owned U.S. application Ser. No. 09/051,813, filed Apr. 15, 1998, now abandoned, the entire disclosure of which is incorporated by reference, which is related to commonly owned provisional application Ser. No. 60/026,552, filed Sep. 23, 1996, and claims the benefit of the earlier filing date of this application under 35 U.S.C. §119(e).

›FIELD OF THE INVENTION

This invention relates to novel compositions for reduction of organic substrates, and processes for preparing and using the same.

›BACKGROUND OF THE INVENTION

There are a wide variety of reducing agents available for organic synthesis. For example, sodium borohydride, borane, lithium aluminum hydride and hydrogen are all employed to perform reductions industrially. Lithium aluminum hydride (LiAlH 4 ) is a powerful reducing agent, soluble in organic solvents, and has found wide utility in organic synthesis. A wide variety of functional groups are reduced with this reagent, including aldehydes, ketones, esters, amides, epoxides, nitrites and imides. However, the expense of lithium aluminum hydride prevents its wider industrial employment.

A variety of synthetic methods exist for the commercial preparation of lithium aluminum hydride. One method involves the metathesis of sodium aluminum hydride (NaAlH 4 )with lithium chloride to form lithium aluminum hydride and sodium chloride (equation 1). Another method is the hydrogenation of a mixture of lithium (or lithium hydride) and aluminum to generate lithium aluminum hydride (equations 2 and 3). There are several others variations of equations 1-3 as well as from aluminum chloride and alkali salts and hydrides (equations 4 and 5). It should be noted that preparations of lithium aluminum hydride are never targeted for the preparation of a mixed alkali aluminum hydride such as a mixture of lithium and sodium aluminum hydrides.

LiCl+NaAlH 4 →LiAlH 4 +NaCl 1.

Li+Al+2H 2 →LiAlH 4 2.

LiH+Al+3/2H 2 →LiAlH 4 3.

4 NaH+AlCl 3 +LiCl→LiAlH 4 +NaCl 4.

4 LiH+AlCl 3 →LiAlH 4 +3NaCl 5.

All of these preparations are typically conducted in an organic solvent, such as toluene, diethyl ether, or tetrahydrofuran. Also, at the conclusion of the reaction, the reaction mixture is laboriously filtered to remove the unreacted starting materials and/or by-product inorganic salts. These filtrations are time consuming, the equipment is capital intensive, and some of the lithium aluminum hydride product adheres to the solids, which reduces the yield. The solid by-products and starting materials are very hazardous and must be handled, recycled, and quenched very carefully.

›SUMMARY OF THE INVENTION

It has been discovered that a composition prepared from an active hydride, an additive, and a Lewis base, optionally in a hydrocarbon solvent, can provide a superior reducing system for organic substrates. For example, a composition prepared from 60 mole % tetrahydrofuran as the Lewis base, 10 mole % lithium chloride as the additive, 10 mole % sodium aluminum hydride as the active hydride, and 20 mole % toluene can afford excellent yields in standard organic reductions. In addition, the compositions of the invention are non-pyrophoric and are more thermally stable than pure THF solutions of sodium aluminum hydride (NaAlH 4 ) or lithium aluminum hydride (LiAlH 4 ).

The novel compositions of the invention can be prepared by initially adding the Lewis base to the additive. The hydride species can then be added, optionally in the hydrocarbon solvent. The mixture can then be optionally heated to the reflux temperature (or less), typically from about thirty minutes to about four hours.

The present invention also provides processes for the reduction of organic substrates using the compositions of the invention.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 3

Various active hydrides, including metal hydrides such as sodium aluminum hydride, trisodium aluminum hexahydride, and the like and mixtures thereof can be employed as the active hydride component. Examples of useful additives include, but are not limited to, lithium chloride, lithium bromide, aluminum trichloride, titanium tetrachloride, titanium tetrabromide, lithium alkoxides, lithium alkoxides of chiral alcohols (such as menthol), lithium dialkylamides, lithium dialkyl amides of chiral amines (such as (+) bis-[(R)-1-phenethyl]amine), and the like and mixtures thereof. Examples of useful hydrocarbon solvents include, but are not limited to, pentane, hexane, heptane, cyclohexane, decane, toluene, xylenes, ethylbenzene, cumene, cymene, and the like and mixtures thereof. Examples of useful Lewis bases include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dibutyl ether, methyl t-butyl ether (MTBE), 1,2-diethoxyethane, 1,2-dimethoxyethane, triethylamine, tributylamine, N, N, N′, N′-tetramethylethylenediamine (TMEDA), diisopropylethylamine, and the like and mixtures thereof.

Typical concentrations (mole %) of the components used to prepare the reducing composition of the invention are listed in the table below.

The novel compositions of the invention can be prepared by initially adding the Lewis base to the additive. The hydride species can then be added, optionally in the hydrocarbon solvent. The mixture can then be optionally heated to the reflux temperature (or less) for a few hours, typically from about thirty minutes to about four hours.

In one advantageous embodiment of the invention, the novel composition is prepared by adding a slurry of sodium aluminum hydride/toluene to a slurry of lithium chloride/tetrahydrofuran. Because the addition is very exothermic, care should be taken. When using the specific reagents sodium aluminum hydride and lithium chloride, the reagents must be combined in a precise manner to result in reduction product yields comparable to that of lithium aluminum hydride. Otherwise, reduction product yields comparable to that of sodium aluminum hydride result.

When using sodium aluminum hydride as a starting material, the composition of the invention is also unique as it is prepared from a slurry of sodium aluminum hydride in hydrocarbon solvent (i.e., about 80 weight percent (wt %) or less sodium aluminum hydride) and a minimal amount of tetrahydrofuran, in contrast to solid or damp cake forms of sodium aluminum hydride. For example, the slurry can be a commercially available slurry of 40 wt % sodium aluminum hydride in toluene. The use of a hydrocarbon solvent alone, such as toluene, without a Lewis base, such as tetrahydrofuran, can hinder the preparation of this effective, novel composition.

Although not wishing to be bound by any explanation of the invention, it is believed that the composition of the invention can include starting materials, counterion exchange products, complexes of starting materials and/or counterion exchange products, and mixtures thereof.

The novel reduction composition of this invention can also be characterized by its particle size distribution. For example, typical particle size distribution of a novel reduction composition in accordance with the invention prepared from 56.9 mole % tetrahydrofuran as the Lewis base, 15.7 mole % lithium chloride as the additive, 12.6 mole % sodium aluminum hydride as the active hydride, and 14.8 mole % toluene was determined on a Malvern MasterSizer. The mean diameter for the reduction composition is around 350 μm and the median is 400 μm. By comparison, the particle size distribution of sodium aluminum hydride exhibits a mean diameter at 216 μm and a median at 200 μm. The particle size distribution of lithium chloride exhibits a mean diameter at 424 ,μm and a median at 448 μm.

It has also been found that this same representative reduction composition slurry sample can be analyzed for sodium, lithium and aluminum by ICP (Inductively Coupled Plasma) and for chloride by wet titration. This data confirms the appropriate proportions of NaAlH 4 and LiCl combined during the preparation of this novel reduction composition. This is especially important when the sodium aluminum hydride charge cannot be accurately determined, for example, on large scale. Example ICP and chloride analyses are represented below. Chloride analysis is faster and combined with a hydride content analysis, should confirm the ratio of NaAIH 4 and LiCl.

The thermal behavior of the novel reduction composition was studied in an RSST (Reactive System Screening Tool) and found to be more thermally stable than 10 wt % LiAlH 4 /THF or 40 wt % NaAlH 4 . The LiAlH 4 /THF solution was found to produce a runaway reaction represented by a rapid rate acceleration when heated above 130° C. Likewise, a NaAlH 4 /THF solution was found to produce a runaway reaction represented by a rapid rate acceleration when heated above 220° C. Whereas a similar experiment with a novel reduction composition mixture prepared from 9.7 mole % NaAIH 4 , 16 mole % LiCl, 10.4 mole % toluene and 63.9 mole % THF showed a rate acceleration/runaway behavior only when heated above 300° C. These experiments demonstrate that the novel reduction composition formulation is safer and thus more stable than a 10 wt % LiAlH 4 /THF solution as well as a 40 wt % NaAIH 4 /THF solution.

In use, the organic compound to be reduced is added to the reduction composition of the invention under an inert atmosphere. Alternatively, the reduction composition can be added to the organic substrate, or the reduction composition and organic substrate added simultaneously. The reduction reaction proceeds under appropriate conditions at a temperature sufficient and for a time sufficient for the reduction reaction to proceed, generally at a temperature of about ambient to about the reflux temperature of the mixture for about one hour to about 24 hours. The reaction can be terminated by quenching the mixture, for example, by addition of water and aqueous NaOH and cooling. Work-up of the reduction reaction mixture and isolation of the reduced product can be accomplished using conventional procedures known in the art.

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 3

The compositions of the invention can be used for the reduction of a variety of organic compounds including without limitation aldehydes, ketones, esters, amides, epoxides, nitrites, and other imides. Exemplary compounds which can be reduced in accordance with the invention include (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (to (+1-) trans 4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine), N-methylsuccinimide, ethyl 1-methylnipecotate, and the like.

For example, typical reducing agents and yields are listed in the table below for the reduction of (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione to (+/−) trans 4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine.

It is reported in the literature that commercial sodium aluminum hydride (NaAlH 4 ) is capable of reducing selected organic functional groups including aldehydes, ketones, esters, carboxylic acids, epoxides, amides, imides, and sulfoxides. Many times, however, the yields are lower using sodium aluminum hydride instead of lithium aluminum hydride, as demonstrated by the above table. See also Example 4 below, which demonstrates that use of sodium aluminum hydride alone as the reducing agent resulted in reduction product yields from 45 to 55%, using toluene/THF solvent mixtures and THF alone. Use of LiCl in limiting amounts (0.1 equivalent) also gave low yields (50%).

The inventors have found that the reactivity of sodium aluminum hydride can be improved by the addition of various additives. Thus, in accordance with this invention, reductions can be accomplished with sodium aluminum hydride when its activity is modified with various additives as described above. For example, the additive lithium chloride could be mixed with sodium aluminum hydride in order to produce a resulting hydride composition that performs as well as lithium aluminum hydride alone.

It is also known that LiCl can be reacted with NaAlH 4 in stoichiometric amounts to form lithium aluminum hydride, which is then separated from the by-product, NaCl, prior to use. This metathesis reaction, however, requires the addition of a catalyst, such as a small amount of LiAlH 4, to initiate the reaction, or alternatively a NaAlH 4 solution forming prestep. In this invention LiCl can be added in less than stoichiometric amounts, and without requiring LiAlH 4 as a catalyst, or a NaAlH 4 solution forming prestep. As discussed above, when the starting compounds include sodium aluminum hydride and lithium chloride, the order of addition of the additive is important. However, it is not currently believed that the order of addition of the additives is critical when using other starting materials, in which case it is currently believed that the additives can be added at various times during the entire reduction.

Although reductions performed with LiAlH 4 provide better yields than when using NaAlH 4 (i.e., NaAlH 4 without additives may be less reactive in some cases), LiAlH 4 is much more expensive than NaAlH 4 . Reductions of functional groups, especially imides, employing NaAIH 4 in accordance with the invention, however, with the appropriate additives gave identical results as obtained when using the more costly commercial LiAlH 4 .

The present invention also describes less expensive alternatives for organic functional group reductions, using in situ generated alkali hydride reducing agents. This aspect of the present invention overcomes prior difficulties associated with the commercial preparation of lithium aluminum hydride. It has been discovered that unfiltered solutions of lithium aluminum hydride (equations 1 to 5) are capable of reduction of functional groups, especially imides. Unfiltered lithium aluminum hydride prepared from sodium aluminum hydride and lithium chloride, or unfiltered lithium or sodium aluminum hydride prepared from the elements can be used directly in subsequent reduction of the substrate. If required for yield improvement, other additives can be added to the sodium aluminum hydride. The resulting unfiltered, in situ-prepared hydride reducing agents are used directly for reduction of a substrate in an organic solvent. Overall this process saves in number of filtration steps, causes filtrations to be safer, and reduces the handling large amounts of ethereal solvents required for the preparation of the reducing agent. The yields with the in situ reduction protocol are essentially identical to the yields obtained when the reduction is performed with filtered lithium aluminum hydride solution. Further, all functional groups that are typically reduced with filtered lithium aluminum hydride are reduced with the unfiltered lithium aluminum hydride solutions. Work-up of the reduction reaction and isolation of the reduced product involves employment of the standard procedure used for commercial lithium aluminum hydride. The inorganic by-products are most often removed by filtration or become part of any aqueous phase that may be present.

For example, reduction of (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione or (+/−) trans 3-methoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione with unfiltered lithium aluminum hydride afforded (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yields and with similar impurity profiles as with commercial LiAlH 4 .

In another aspect of this invention, reductions can be accomplished with sodium aluminum hydride when its activity is modified with various additives. It is reported in the literature that commercial sodium aluminum hydride (NaAlH 4 ) is capable of reducing selected organic functional groups including aldehydes, ketones, esters, carboxylic acids, epoxides, amides, imides, and sulfoxides. Many times the yields are lower using sodium aluminum hydride instead of lithium aluminum hydride. It was found that the reactivity of sodium aluminum hydride can be improved by the addition of various additives. For example the additive, lithium chloride, could be mixed with sodium aluminum hydride in order to produce a resulting hydride that performed as well as sodium aluminum hydride with the additive, lithium aluminum hydride, or lithium aluminum hydride alone. It is known that LiCl can be reacted with NaAlH 4 in stoichiometric amounts to form lithium aluminum hydride (equation 1), which is then separated from the by-product, NaCl, prior to use. In this invention it was found that it is unnecessary to filter the NaCl prior to use of the in situ formed lithium aluminum hydride. Also, in this invention LiCl can be added in less than stoichiometric amounts and the NaCl is not separated from the resulting hydride. This invention shows that this filtration is unnecessary. The additives can be added at various times during the entire reduction. Although NaAlH 4 without additives may be less reactive in some cases, it is superior due to the high cost of LiAlH 4 . Reductions of functional groups, especially imides, employing NaAlH 4 with the appropriate additives gave identical results as obtained when using the more costly, commercial LiAlH 4 .

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 3

For example, reduction of (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione with in situ modified NaAIH4 afforded (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and with similar impurity profile as with commercial LiAlH 4 .

Optionally, inorganic or organic additives can be added to either reduction protocol to aid the reduction. These additives can be employed in 0.01 equivalents up to and including 5 equivalents. Examples of useful additives, which can be used in combination as well, include, but are not limited to LiCl, HCl, LiBr, AlCl 3 , TiCl 4 , AlBr 3 , TiBr 4 , LiAlH 4 , NaBH 4 , LiBH 4 , LiBH(R) 3 , NaBH 3 (anilide), THF-BH 3 , LiAlH(OMe) 3 , LiAlH(O-t-Bu) 3 , NaAlH 2 (OC 2 H4OCH 3 ), AlH 3 ; ethers such as methyl t-butyl ether, dimethoxyethane, glymes; alcohols such as methanol, ethanol, isopropanol, t-butanol, ethereal alcohols and/or their corresponding metal alkoxides; primary and/or secondary amines both aromatic and/or aliphatic and their corresponding metal amides; and tertiary amines such as tetramethylethylene diamine, triethylamine.

The following examples further illustrate the invention.

›Examples16

›EXAMPLE 1

Preparation of Novel Reduction

Composition at Room Temperature

A 500 ml., three-necked round-bottom flask was fitted with a mechanical stirrer, a Teflon® stopper, and a Claisen adapter fitted with a dry ice condenser, a Teflon® clad thermocouple, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 10.00 grams (0.237 mole) of anhydrous lithium chloride, and 70 ml. of tetrahydrofuran. The resultant slurry was stirred at 350 RPMs. A slight exotherm, 3° C., was observed. This slurry was stirred at room temperature for 30 minutes. A slurry of 12.80 grams (90% assay NaAlH 4 , 0.213 mole) in 24 ml. of toluene was added. An exotherm of 9° C. was observed within four minutes.

This slurry was prepared from 15.3 mole % lithium chloride, 56.1 mole % tetrahydrofuran, 13.9 mole % sodium aluminum hydride, and 14.7 mole % toluene.

The dark gray slurry was employed in a reduction after stirring at room temperature for one hour.

›EXAMPLE 2

Preparation of Novel Reduction

Composition at Low Temperature

A 500 ml., three-necked, jacketed, round-bottom flask was fitted with a mechanical stirrer, a Teflon® stopper, and a Claisen adapter fitted with a dry ice condenser, a Teflon® clad thermocouple, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 13.80 grams (0.327 mole) of anhydrous lithium chloride, and 97 ml. of tetrahydrofuran. The resultant slurry was stirred at 350 RPMs. A slight exotherm, 3° C., was observed. This slurry was stirred at room temperature for five hours. The slurry was cooled to 0° C. with a chiller. A slurry of 13.00 grams (95% assay NaAlH 4 , 0.229 mole) in 38 ml. of toluene was added. An exotherm of 9° C. was observed immediately.

This slurry was stirred at less than 10° C. for one hour, then allowed to gradually warm to ambient temperature overnight.

This slurry was prepared from 15.5 mole % lithium chloride, 56.8 mole % tetrahydrofuran, 10.9 mole % sodium aluminum hydride, and 16.9 mole % toluene.

The dark gray slurry was employed in a reduction after stirring at room temperature overnight.

›EXAMPLE 3

Preparation of Novel Reduction

Composition at High Temperature

This slurry was prepared from 15.3 mole % lithium chloride, 56.1 mole % tetrahydrofuran, 13.9 mole % sodium aluminum hydride, and 14.7 mole % toluene.

The dark gray slurry was employed in a reduction after stirring at 70° C. for two hours.

›EXAMPLE 4

Comparative Example

Reduction with Sodium Aluminum Hydride

A 500 ml., three-necked, jacketed flask was equipped with a mechanical stirrer, a 125 ml. pressure-equalizing addition funnel, and a Claisen adapter fitted with a Teflon® clad thermocouple, a dry ice condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with tetrahydrofuran, 70 ml. This solution was stirred at 350 RPMs and cooled to 0° C. with a circulating chiller. Sodium aluminum hydride, 12.11 grams of 95% assay (2.70 equivalents, 213 mmole) was added to the reactor. An immediate exotherm of 8° C. was noted, which quickly subsided. Toluene, 24 ml., was then added. This suspension was stirred at 0° C. for an additional thirty minutes. A dry, 250 ml., single-necked flask was fitted with a large, egg-shaped magnetic stir bar, and an argon inlet. This flask was purged with argon, then charged with 24.4 grams of 94.5% assay (+/−) trans 3-ethoxy or 3-methoxy carbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (1.00 equivalent, 79 mmole) and 65 ml. of toluene. This suspension was stirred at room temperature. After all the imide-ester dissolved, the solution was transferred to the addition funnel. The 250 ml. flask was rinsed with additional toluene, 8 ml, and this was added to the addition funnel. The imide-ester solution was added dropwise. This resulted in a very exothermic reaction. The feed rate was adjusted to maintain the reaction temperature at 10-15° C. Total imide-ester feed time was 62 minutes. After the end of the feed, the reaction mixture was heated to 65° C. for two hours, then recooled to 0° C. Additional toluene, 85 ml., was added. This was followed by slow addition of 9 ml. of water. The reaction mixture got very thick at the end of this addition. Aqueous sodium hydroxide, 15%, 9 ml., was then added dropwise. The solid started to break up at the end of this addition. Water, 9 ml., was then added dropwise. At the end of this feed, the reaction mixture was warmed to 65° C. The reaction mixture was stirred at 65° C. for thirty minutes, recooled to 27° C., then the solids were collected on a Büchner funnel. The solids were reslurried with toluene (2×30 ml.). The filtrate was two layers. It was concentrated on the rotary evaporator to 250 ml., and transferred to a separatory funnel. The mixture was diluted with water (100 ml.) and toluene (100 ml.). The aqueous layer was drawn off and discarded. The organic layer was washed with water (1×100 ml.), and dried with magnesium sulfate. The desired product was isolated by precipitation from the organic layer, washed, air dried, then dried in a vacuum desiccator overnight.

This afforded a white solid, yield=8.01 grams, 45.4%.

›EXAMPLE 5

Reduction with Novel Reduction Composition

A 500 ml., four-necked, round bottom flask was equipped with a mechanical stirrer, a 125 ml. pressure-equalizing addition funnel, a Teflon® stopper and a Claisen adapter fitted with a Teflon® clad thermocouple, a dry ice condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. Lithium chloride, 9.85 grams (2.64 equivalents, 232.36 mmole) was added. The flask was then charged with tetrahydroflran, 67 ml. This solution was stirred at 350 RPMs. Sodium aluminum hydride, 12.01 grams of 95% assay (2.40 equivalents, 211.24 mmole) slurried in toluene, 21 ml., was added to the reactor. The slurry composition was prepared from 15.8 mole % lithium chloride, 56.3 mole % tetrahydrofuran, 14.4 mole % sodium aluminum hydride, and 13.4 mole % toluene. Additional tetrahydrofuran, 39 ml., was added and this suspension was stirred at room temperature for fifty minutes. Toluene, 31 ml., was then added. This suspension was cooled to 10° C. and stirred for an additional five minutes. A dry, 250 ml., single-necked flask was fitted with a large, egg-shaped magnetic stir bar, and an argon inlet. This flask was purged with argon, then charged with 27.1 grams of 94.5% assay (+/−) trans 3-ethoxy or 3-methoxy carbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (1.00 equivalent, 88 mmole) and 69 ml. of toluene. This suspension was stirred at room temperature. After all of the imide ester had dissolved, the solution was transferred to the addition funnel. The imide-ester solution was added dropwise. This resulted in a very exothermic reaction. The feed rate was adjusted to maintain the reaction temperature at 10-15° C. After the end of the feed, the 250 ml. flask was rinsed with additional toluene, 7 ml, and this was added to the addition funnel. The reaction mixture was heated to 75° C. for three hours, then recooled to 10° C. Additional toluene, 50 ml., was added. The speed of the agitator was increased to 500 RPMs. This was followed by slow addition of 9 ml. of water. The reaction mixture got very thick at the end of this addition. Aqueous sodium hydroxide, 15%, 9 ml., was then added dropwise. The solid started to break up at the end of this addition. Water, 18 ml., was then added dropwise. At the end of this feed, the reaction mixture was warmed to 65° C. for twenty minutes and the stirrer was slowed to 350 RPMs. The reaction mixture was then cooled to 400° C., then the solids were collected on a Buchner funnel. The solids were reslurried with toluene (2×31 ml.). The desired product was isolated by precipitation from the combined filtrates, washed, air dried, then dried in a vacuum desiccator overnight.

This afforded a white solid, yield=16.85 grams, 85.9%.

›EXAMPLE 6

Reduction of N-Methyl Succinimide with NaAIH 4 /LiCl

To a cooled solution of lithium chloride (0.11 mol) in THF is added NaAlH 4 (0.22 mol) in toluene/THF under argon. N-methylsuccinimide (0.083 mol) in THF is added holding the temperature below 15° C. After addition is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H 2 O or aqueous NaOH is used as necessary. The insoluble inorganic salts are removed by filtration. These solids are washed with additional THF or toluene to obtain a solution which contained N-methyl pyrrole, as determined by GLC analysis. Similar results were obtain using 0.02 mole of lithium chloride, but a longer heating period is required.

›EXAMPLE 7

Reduction of N-methyl succinimide with

NaAlH 4 /Lithium t-butoxide

To a cooled solution of NaAlH 4 (0.22 mol) in toluene/THF under argon is added lithium tert-butoxide (0.11 mol) in THF. N-methylsuccinimide (0.083 mol) is added in THF (65 ml) holding the temperature below 15° C. After addition is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature, the reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (5 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H 2 O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene to obtain solution which contained N-methyl pyrrole, as determined by GLC analysis.

›EXAMPLE 8

Reduction of N-Methylsuccinimide

To a cooled solution of filtered or unfiltered LiAlH 4 (2 mole) under argon was added N-methylsuccinimide (1 mole) in THF. After addition was complete, reaction was heated to 40 to 50° C. for 2 hr and then stirred overnight at room temperature. The reaction was quenched by adding H 2 O, and aqueous NaOH using appropriate cooling. The solution was filtered and solids were washed with fresh THF. The yields were determined by GC analysis of crude filtered reaction solutions using nonane as an internal standard. Essentially no difference in yields was observed with filtered or unfiltered LiAlH 4 solutions.

›EXAMPLE 9

Reduction of Ethyl 1-methylnipecotate

To a cooled solution of filtered or unfiltered LiAlH 4 (2 mole) under argon was added ethyl 1-methylnipecotate (1 mole) in THF. After addition was complete, reaction was heated to 40 to 50° C. for 2 hr and then stirred overnight at room temperature. The reaction was quenched by adding H 2 O, and aqueous NaOH using cooling as required. The solution was then filtered and solids were washed with fresh THF. Yields were determined by GC analysis of crude filtered reaction solutions using nonane as an internal standard. Essentially no difference in yields was observed with filtered or unfiltered LiAlH 4 solutions.

›EXAMPLE 10

Reduction of (+/−) Trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione

To a cooled solution of filtered or unfiltered LiAlH 4 (2.7 mol) in THF under argon as added (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (1 mol) in THF. After addition was complete, reaction was heated to 40 to 50° C. for 2 hr and then stirred overnight at room temperature. The reaction was quenched by adding H 2 O, and aqueous NaOH using cooling as required. The solution was then filtered and solids were washed with fresh THF. The filtrate was analyzed by NMR and HPLC. The presence of unreduced product was not detectable by 1 H NMR for either filtered or unfiltered LiAlH 4 .

›EXAMPLE 11

Reduction of (±) Trans-3-Ethoxycarbonyl-4-(4′-Fluorophenyl)-N-Methylpiperidin-2.6-Dione with NaAlH 4

To a cooled solution of NaAlH 4 (0.22 mol) in toluene/THF under argon was added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition was complete, reaction was allowed to warm to room temperature. After 30 minutes at room temperature, the reaction was heated to >40° C. for 2 hr. The reaction was then cooled to <5° C. and toluene (50 ml) was added. Water (9 ml) was then added slowly holding the temperature below 15° C. Additional H 2 O or aqueous NaOH were used as necessary. The solid inorganic salts were removed by filtration. These solids were washed with additional THF or toluene. The filtered solution was then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in lower yield (but similar impurity profile as with LiAlH 4 ) as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.

›EXAMPLE 12

Comparative Example: Reduction of (A-Trans-3-Ethoxycarbonyl-4-(4′-Fluorophenyl)-N-Methylpiperidin-2,6-Dione with LiAlH 4

To a cooled solution of LiAlH 4 (0.22 mol) in toluene/THF under argon was added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition was complete, the reaction was allowed to warm to room temperature. After 30 minutes at room temperature reaction was heated to >40° C. for 2 hr. Reaction was then cooled to <5° C. and toluene (50 ml) was added. Water (9 ml) was then added slowly holding the temperature below 15° C. Additional H 2 O or aqueous NaOH was used as necessary. The solid inorganic salts were removed by filtration. These solids were washed with additional THF or toluene. The filtered solution was then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in higher yield (but similar impurity profile) as with NaAlH 4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvent.

›EXAMPLE 13

Reduction of (±)-Trans-3-Ethoxycarbonyl-4-(4′-Fluorophenyl)-N-Methylpiperidin-2,6-Dione with NaAlH 4 /LiAlH 4

To a cooled 50:50 mole mixture of NaAlH 4 /LiAlH 4 (0.22 mol) in toluene/THF under argon is added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. Reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H 2 O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene. The filtered solution is then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and similar impurity profile as with LiAlH 4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.

›EXAMPLE 14

Reduction of (±)-Trans-3-Ethoxycarbonyl-4-(4′-Fluorophenyl)-N-Methylpiperidin-2,6-Dione with NaAlH 4 /LiCl.

To a cooled mixture of NaAlH 4 (0.22 mol) in toluene is added LiCl (0.11 mol) in THF. Note: LiCl can be added to the reactor prior to the addition of NaAlH 4 or after the addition of the substrate, (+/−)trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione. Next, (+/−)trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) is added in THF (65 ml) holding the temperature below 15° C. After addition is completed, reaction is allowed to warm to room temperature. After 30 minutes at room temperature, the reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H 2 O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene. The filtered solution is then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and similar impurity profile as with LiAlH 4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.

›EXAMPLE 15

Reduction of N-Methyl Succinimide with NaAlH 4 /LiCl.

To a cooled solution of NaAlH 4 (0.22 mol) in toluene/THF under argon is added LiCl (0.11 mol) in THF. Note: LiCl can be added to the reactor prior to the addition of NaAlH 4 or after the addition of the substrate. N-methylsuccinimide (0.083 mol) in THF is added holding the temperature below 15° C. After addition is completed, reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H 2 O or aqueous NaOH is used as necessary. The insoluble inorganic salts are removed by filtration. These solids are washed with additional THF or toluene to obtain a solution which contained N-methyl pyrrole, as determined by GLC analysis. Similar results were obtained using 0.02 mole of lithium chloride, but a longer heating period is required.

›EXAMPLE 16

Reduction of N-methyl succinimide with NaAlH 4 /Lithium t-butoxide.

It is understood that upon reading the above description of the present invention, one skilled in the art could make changes and variations therefrom. These changes and variations are included in the spirit and scope of the following appended claims.

›Tables in the description — 3

COMPONENT	MINIMUM	MAXIMUM
Lewis Base	45	80
Solvent	0	30
Additive	5	20
Hydride	5	20

Theoretical	Lot# 10976	Lot# 11011
11.4% NaAlH 4	10.9% by Na	11.0% by Na
	11.5% by Al	11.7% by Al
9.8% LiCl	9.9% by Li	9.9% by Li
	9.3% by Cl	9.2% by Cl

Notes: 1 See Example 4 of the present application. 2 See Example 7 of U.S. Pat. No. 4,902,801, Process for Preparing Aryl-Piperidine Carbinols and Novel Intermediates Used in the Process, E. A. Faruk, R. T. Martin, Beecham Group, February 20, 1990. 3 See Example 5 of the present application.

REAGENT	YIELD
Sodium Aluminum Hydride	45% 1
Lithium Aluminum Hydride	65-75% 2
Composition of the Invention	85% 3

Claims as granted

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5 codes

IPC · International Patent Classification

Section C — Chemistry; metallurgy

C07D295/023
C07D211/22

USPC · US Patent Classification

423/644546/220546/240

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