GRANGER ERIC J (US)
SIMS PHILIP F (US)
SCHWINDEMAN JAMES A (US)
WEDINGER ROBERT S (US)
RATHMAN TERRY L (US)
ENGEL JOHN F (US)
GRANGER ERIC J (US)
SIMS PHILIP F (US)
SCHWINDEMAN JAMES A (US)
WEDINGER ROBERT S (US)
RATHMAN TERRY L (US)
| US4902801A | 1990-02-20 | |||
| US5258517A | 1993-11-02 |
CASREACT on STN, Chemical Abstracts Service, (Columbus, OH), 115:91342, GYOUNG, Y.S. et al., "A Convenient Procedure for the Conversion of Tertiary Amides to the Corresponding Alcohols with Lithium Aluminum Hydride", Reaction (1) of 2; & J. KOREAN CHEM. SOC., 35(3), 1991.
CASREACT on STN, Chemical Abstracts Service, (Columbus, OH), 123:286279, ARITSUKA, M. et al., "Preparation of Alkenysilanes from Alkenychlorosilanes", Reaction (1) of 1; & JP,A,07 173 173 (MITSUI TOATSU CHEMICALS) 11 July 1995.
J. MED. CHEM., 05 August 1994, Vol. 37, No. 16, MACOR, J.E. et al., "5-((3-Nitropyrid-2-yl)amino)indoles: Novel Serotonin Agonist with Selectivity for the 5-HT1D Receptor. Variation of the C3 Substituent on the Indole Template Leads to Increased 5-HT1D Receptor Selectivity", pages 2509-2512.
See also references of EP 0789573A4
| 1. | A process for the reduction of organic structures having functional groups with hydride reducing agents which process is selected from: a) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together elemental sodium and lithium with elemental aluminum and hydrogen. b) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together sodium hydride and lithium hydride with elemental aluminum and hydrogen . c) contacting an organic substrate to be reduced with a mixture of sodium aluminum hydride and lithium aluminum hydride in an organic solvent. d) contacting an organic substrate to be reduced with a mixture of sodium borohydride and alkali aluminum hydride in an organic solvent. e) contacting an organic substrate to be reduced with a mixture of sodium aluminum hydride and a metal halide selected from the group consisting of aluminum halides and titanium halides in an organic solvent. f) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together elemental lithium, aluminum and hydrogen. g) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together lithium hydride and elemental aluminum and hydrogen. h) contacting an organic substrate to be reduced with sodium aluminum hydride in an organic solvent, the sodium aluminum hydride being reacted with more than 0.01 equivalents of lithium halides before, during or after the contact between the sodium aluminum hydride and the organic substrate. i) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together elemental sodium, aluminum and hydrogen. j) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together sodium hydride with elemental aluminum and hydrogen. k) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together lithium chloride with elemental lithium, aluminum and hydrogen. I) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together lithium chloride with lithium hydride and elemental aluminum and hydrogen. m) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together lithium chloride with elemental sodium, aluminum and hydrogen. n) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together lithium chloride with sodium hydride and elemental aluminum and hydrogen. o) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together lithium hydride and aluminum halides. p) contacting an organic substrate to be reduced, in an organic solvent, with the hydride produced by reacting together lithium chloride, aluminum trichloride and sodium hydride. q) contacting an organic substrate to be reduced, in an organic solvent, with mixture of alkali aluminum hydride and lithium borohydride. |
| 2. | r) contacting an organic substrate to be reduced, in an organic solvent, with the mixture of alkali aluminum hydride and lithium amino borohydride. s) contacting an organic substrate to be reduced with sodium aluminum hydride in an organic solvent, the sodium aluminum hydride being reacted with a 0.01 to 5 equivalents of a lithium compound selected from the group consisting of lithium halides, lithium alkoxides and lithium organoamides. t) contacting an organic substrate to be reduced, in an organic solvent, with the mixture of alkali aluminum hydride and diisobutylaluminum hydride. u) contacting an organic substrate to be reduced, in an organic solvent, with the mixture of alkali aluminum hydride and NaAIH2(OC2H4OCH3). |
| 3. | Th_ process of claim 1 alkoxides, metal organoamides, and mixtures thereof.characterized in that hydride contains an additive selected from the group consisting of metal halides, metal alkoxides, metalorganoamides and mixtures thereof. |
| 4. | The process of claim 1 characterized in that the organic substrate is (+/) trans 3ethoxycarbonyl4(4'fiuorophenyl)Nmethylpiperidine2,6 dione. |
| 5. | The process of claim 1 characterized in that alkoxides, metal organoamides, and mixtures thereof, the organic substrate is (+/) trans 3 methoxycarbonyl4(4'fluorophenyl)Nmethylpiperidine2,6dione. |
| 6. | The process of claim 1 characterized in that the organic substrate is () trans 3ethoxycarbonyl4(4'fluorophenyl)Nmethylpiperidine2,6 dione. |
| 7. | The process of claim 1 characterized in that the organic substrate () trans 3methoxycarbonyl4(4'fluorophenyl)Nmethylpiperidine ,6dione. |
This process concerns the use of certain alkali aluminum hydrides in the reduction of organic functional groups. 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 (LiAIH 4 ) is a powerful reducing agent, soluble in organic solvents. This reagent has found wide utility in organic synthesis, due to its reducing power. A wide variety of functional groups are reduced with this reagent, including aldehydes, ketones, esters, amides, epoxides, nitriles and imides. However, the expense of lithium aluminum hydride prevents its wider industrial employment. The present invention describes less expensive alternatives for organic functional group reductions, using in situ generated alkali hydride reducing agents.
A variety of synthetic methods exist for the commercial preparation of lithium aluminum hydride. One method involves the metathesis of sodium aluminum hydride (NaAIH ) 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.
1. LiCl + NaAIH 4 > LiAIH 4 + NaCl
2. Li + Al + 2 H 2 > LiAIH 4
3. LiH + Al + 3/2 H 2 > LiAIH 4
4. 4 NaH + AICI 3 + LiCl > LiAIH 4 + 4 NaCl
5. 4 LiH + AICI3 > UAIH4 + 3 NaCl
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.
The present invention overcomes these difficulties. It has been discovered that unfiltered solutions of lithium aluminum hydride (equations 1 to 5) are capable of reduction. 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 (+/-) ?raπs-4-(4'-fluorophenyl)- 3-hydroxymethyl-N-methylpiperidine in essentially the same yields and with similar impurity profiles as with commercial LiAIH 4 .
In another aspect of this invention, reductions can be accomplished with sodium aluminum hydride when its activity is modified with vaπous additives. It is reported in the literature that commercial sodium aluminum hydride (NaAIH ) 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 NaAIH 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 NaAIH 4 without additives may be less reactive in some cases, it is superior due to the high cost of LiAIH 4 . Reductions of functional groups, especially imides, employing
NaAIH 4 with the appropriate additives gave identical results as obtained when using the more costly, commercial LiAIH .
For example, reduction of (+/-) trans 3-ethoxycarbonyl-4-(4'- fluorophenyl)-N-methyl-piperidine-2,6-dione with in situ modified NaAIH 4 afforded (+/-) frans-4-(4'-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and with similar impurity profile as with commercial LiAIH 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, AICI 3 , TiC-U, AIBr 3 , TiBr 4 , LiAIH 4 , NaBH 4 , LiBH 4 , LiBH(R) 3 , NaBH 3 (anilide), THF-BH 3) LiAIH(OMe) 3> LiAIH(O-t-Bu) 3 , NaAIH 2 (OC 2 H 4 OCH 3 ), AIH 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. Experimental:
Example 1 ) Reduction of N-Methylsuccinimide
+ LiAIH 4
To a cooled solution of filtered or unfiltered LiAIH 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 2hr 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 LiAIH 4 solutions.
Example 2) Reduction of Ethyl 1-methylnipecotate
To a cooled solution of filtered or unfiltered LiAIH (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 2hr and then stirred overnight at room temperature. The reaction was quenched by adding H 2 0, 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 LiAIH solutions.
Example 3) Reduction of (+/-) Trans 3-ethoxycarbonyl-4-(4'- fluorophenyl)-N-methyl-piperidine-2,6-dione
LIAIH 4
To a cooled solution of filtered or unfiltered LiAIH (2.7 mol) in THF under argon was 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 0, 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 LiAIH 4. .
Example 4) Reduction of (±)-Trans-3-Ethoxycarbonyl-4-(4'-Fluorophenyl)-N- Methylpiperidin-2,6-Dione with NaAIH 4
To a cooled solution of NaAIH 4 (0.22 mol) in toluene/ HF 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 0 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 LiAIH 4 ) as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.
Example 5) Comparative Example: Reduction of (±)-Tt-at7S-3-
Ethoxycarbonyl-4-(4'-Fluorophenyl)-N-Methylpiperidin-2,6- Dione with LiAIH 4
To a cooled solution of LiAIH 4 (0.22 mol) in toluene/THF under argon was added (-r/-) 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 0 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- methylpipehdine in higher yield (but similar impurity profile) as with NaAIH 4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvent.
Example 6) Reduction of (±)-Traπs-3-Ethoxycarbonyl-4-(4'-Fluorophenyl)-N- Methylpiperidin-2,6-Dione with NaAIH4/LiAIH 4
To a cooled 50:50 mole mixture of NaAIH4/LiAIH 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 0 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 (+/-) zrans-4-(4'-fluorophenyl)-3- hydroxymethyl-N-methylpiperidine in essentially the same yield and similar impurity profile as with LiAIH 4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents
Example 7) Reduction of (±)-Traπs-3-Ethoxycarbonyl-4-(4'-Fluorophenyl)-N- Methylpiperidin-2,6-Dione with NaAIH 4 /LiCl.
To a cooled mixture of NaAIH 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 NaAIH or after the addition of the substrate, (+/-) trans 3- ethoxycarbonyl- -(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 0 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 LiAIH 4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.
Example 8) Reduction of N-Methyl Succinimide with NaAIH /LiCl.
To a cooled solution of NaAIH 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 NaAIH 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 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 0 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 9) Reduction of N-methyl succinimide with NaAIH^Lithium t- butoxide.
To a cooled solution of NaAIH 4 (0.22 mol) in toluene/THF under argon is added lithium tert-butoxide (0.1 1 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 0 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.