Field of the Invention

The present invention relates to a process for the reduction of carbonyl compounds, in particular to the corresponding alcohols.

Background of the invention

Processes for the reduction of particular functional groups, including carbonyl groups, are known in the art. Among those, the reduction of carbonyl groups of aldehydes and ketones is a known and convenient route for the preparation of primary and secondary alcohols, and therefore has been given great attention. The most known method exploits metal hydrides, such as lithium aluminum hydride (LiAlH^ and sodium borohydride (NaBH ₄ ), as the reducing reagents. The reaction is carried out under anhydrous conditions, e.g., in an etheric solvent. According to another known method, diborane is used as the reducing compound.

However, the reagents employed in the prior art methods present severe drawbacks: they are normally quite expensive and inconvenient to use. For example, LiAlH ₄ is both hazardous and non- selective.

Other processes known in the art require the use of a catalyst. Typically, in the catalytic hydrogenation of aldehydes and ketones, they are reduced to alcohols by hydrogen gas in the presence of a metal catalyst. However, this technique also present substantial drawbacks, inasmuch as the catalysts used (Pd, Pt, Ru, Rh) are expensive, and the reaction is not selective, leading to the undesired

hydrogenation of other functional groups, such as C=C and C≡C, with the resulting formation of by-products.

When stereospecific reactions are needed, the carbonyl compound can be converted to the corresponding alcohol by enzymatic reduction, using alcohol dehydrogenase enzymes.

It is therefore clear that it would be highly desirable to provide a method for the reduction of carbonyl compounds, which does not require expensive reagents, which is easy to carry out, and which leads to good yields.

It is an object of the invention to provide a process for the reduction of carbonyl compounds, which overcomes the drawbacks of prior art processes.

It is another object of the invention to provide a process which can be carried out in a simple manner, without the need for complicated reaction steps and/or equipment.

It is a further object of the invention to provide a process by which the reduction of carbonyl compounds to alcohols can be carried out in a simple and economical manner, without the need for expensive reagents or catalysts.

It is a still further object of the invention to provide a process which permits to effect the complete reduction of at least part of the starting carbonyl compounds.

It is still further object of the invention to provide such a process which can be carried out either in batch or in a continuous manner.

It is a still further object of the invention to provide such a process which does not require the application of pressure.

Other objects of the invention will become apparent as the description proceeds.

Summary of the Invention

The process for the reduction of carbonyl compounds, according to the invention, comprises contacting a carbonyl compound with an alcoholic reagent at temperatures above 200°C.

The carbonyl compound and the alcoholic reagent may be mixed, e.g. by dissolving the carbonyl compound in the alcoholic reagent, and the mixture, e.g. the solution, be brought to said temperatures or they may be separately brought to said temperatures and then contacted.

According to an aspect of the invention, the process is carried out under autogenous pressure.

According to a preferred embodiment of the invention, the process comprises mixing a carbonyl compound of formula I:

o II c

/ \

R ⁱ R ² (I) wherein R ¹ and R ² are independently selected from among hydrogen, linear or branched alkyl, alkenyl, alkynyl, cycloalkyl, polycycloalkyl, heterocycloalkyl, aromatic moiety selected from the group consisting of aryl, heterocyclic ring of 5 or 6 members wherein the heteroatoms are nitrogen, oxygen or sulfur, aryl-

fused, heteroaryl-fused, wherein one or more rings of said aryl-fused and heteroaryl-fused systems are optionally non-aromatic or a 4-8 membered ring in which one or two of the carbon atoms are replaced by nitrogen, oxygen or sulfur, and wherein the above alkyl, alkenyl, alkynyl, cycloalkyl, polycycloalkyl, heterocycloalkyl and aromatic moiety are optionally substituted by halogen, hydroxy, alkoxy, phenoxy, cyano, nitro, NR R ⁴ wherein R ³ and R ⁴ may be hydrogen or alkyl, or one of R ¹ and R ² is R ⁵ -CH=CH-(CH ₂ )m- wherein R ⁵ is alkyl, phenyl or substituted phenyl and m is 0, 1 or 2; or R ¹ and R ² , together with the carbon to which they are attached, form a cyclic or polycyclic system selected from the group consisting of cycloalkyl, polycycloalkyl, heterocyclic ring wherein the heteroatoms are nitrogen, oxygen or sulfur, the said cyclic or polycyclic systems being optionally fused with optionally substituted aryl or heteroaryl, and said cyclic or polycyclic system may be substituted with halogen, alkyl, hydroxy, alkoxy, phenoxy, cyano, nitro, NR ³ R ⁴ wherein R ³ and R ⁴ may be hydrogen or alkyl;

with an alcoholic reagent, and bringing the mixture to a temperature higher than 200°C, to yield an alcohol of formula (II):

OH

I

CH

Rl R2

(ID

wherein Rl and R^ have the meanings listed above, and/or a fully reduced compound of formula (III): R ^] — CH2 — R ² .

The alcoholic reagent is oxidized in part to the corresponding carbonyl compound or derivative.

As stated, the mixing of a carbonyl derivative compound of formula (I) with an alcoholic reagent may be effected by dissolving said compound in said reagent. Typical, but non- limitative weight ratios of the compound of formula (I) to the reagent in said mixture or solution are between 7% and 50% by weight.

Preferably, the mixture is brought to a temperature above 300°C and more preferably comprised between 300°C and 400°C or higher. In an embodiment of the invention, the mixture is brought to a temperature above the critical temperature of the alcoholic reagent. In this case, or in other cases when the temperature is sufficiently high, the reaction occurs in the gas phase. Reaction times may preferably be between 0.25 and 3 hours. When the reaction had been completed, the reaction product is cooled, optionally to room temperature and it is condensed. Its components can be separated by any suitable separation methods, known in the art and which need not be described, preferably after condensation.

The invention therefore comprises a process for preparing a desired alcohol, or a completely reduced compound, from the corresponding carbonyl compound, which comprises the steps of mixing and vaporizing the carbonyl compound and an alcoholic reagent, keeping the resulting vapor mixture at the required reaction temperature, which is over 200°C and preferably above the critical temperature of the alcoholic reagent and more preferably above 300°C, for a time sufficient to produce therein the desired reduced compound, and subsequently condensing it. The desired alcohol and/or other reduced compound is thus obtained in solution in the alcoholic reagent and may be separated by known procedures.

In an embodiment thereof, the invention provides a continuous process which comprises continuously feeding the carbonyl compound and an alcoholic reagent to a reaction space, subjecting them in said space to a temperature above 200°C, and withdrawing the reaction product from said reaction space. The carbonyl compound and the alcoholic reagent may be fed separately to the reaction space, or the carbonyl compound may be dissolved in the alcoholic reagent and the solution be fed to the reaction space.

In particular, said continuous process comprises the steps of: a) continuously passing the carbonyl compound and an alcoholic reagent at a controlled rate through a reaction space at a temperature adequate to produce, in said carbonyl compound and said alcoholic reagent passed therethrough, the required reaction temperature, whereby they are transformed, at least partially but preferably entirely, into a mixture of vapors; b) passing said vapor mixture from the aforesaid heated reaction space into a post-reaction space and cooling the same therein to a temperature below the boiling point of the alcoholic reagent, whereby to condense the same to a solution of the desired reduction product in said alcoholic reagent; and c) collecting the resulting solution.

When operating continuously, a significant conversion of the carbonyl compound to the corresponding alcohol is detected already after a few minutes.

The reaction space and the post-reaction space are preferably elongated spaces and are defined by tubular members. The reaction space is generally defined by a pipe arrayed in spiral form, but this is not critical. The appropriate temperatures in said spaces are preferably produced by enclosing said tubular members in a space which is kept at such a temperature as to transmit heat to

or draw heat from said tubular members at such a rate as to produce therein said appropriate temperatures. In the case of the post-reaction space, this may be achieved even by exposing the post-reaction tubular member to an ambient at room temperature.

As has been said, the reaction mass, including the alcoholic reagent, which enters the reaction space as a liquid, vaporizes therein, and condenses upon and/or after reaching the post-reaction space. If the reaction temperature is higher than the critical temperatures of the reagents, as is preferred, said reagents become superheated vapors and react as such. It has been found that, when so operating, no significant superatmospheric pressure is detectable in the post-reaction space.

In an embodiment of the invention, particularly useful when the starting carbonyl compound has a boiling point above reaction temperature, e.g. above 300°C, the said compound is molten and the alcoholic reagent is passed as a superheated vapor through the molten mass. Such carbonyl compounds may be, for instance, fluorenone or 4-carboxybenzaldehyde. The alcoholic reagent may be, for instance, isopropanol, brought to a temperature of 350°C. The alcoholic reagent, which has passed through the molten mass, can be collected and recycled, after separating from it the carbonyl compounds into which part of it has been transformed (acetone, in the case of isopropanol). This manner of operating combines features of a continuous and of a batch process.

The invention also comprises an apparatus for preparing a desired alcohol and/or other reduced compound from the corresponding carbonyl compound, which comprises: a) means for defining a reaction space;

b) means for maintaining said reaction space at the reaction temperature; c) means for defining a post-reaction space; and c) means for continuously passing the carbonyl compound and an alcoholic reagent through said reaction space and said post-reaction space at a controlled flow rate.

Brief Description of the Drawing

The drawing is a schematic representation of an apparatus for carrying out a continuous process according to an embodiment of the invention.

Detailed Description of Preferred Embodiments

According to a preferred embodiment of the invention, the reagent is an alcohol of the formula ROH, wherein R is selected from linear Cχ-Cιo alkyl, branched Ci- Cio alkyl, and C ₃ -C ₁₀ cycloalkyl. According to another preferred embodiment of the invention, aromatic alcohols are also useful as alcoholic reagents. For example, suitable alcohols of formula ROH are those in which R is R ⁶ -CHXι, and Xi is hydrogen or Ci-Cio alkyl, and R ⁶ is aryl, or aryl substituted by C ₁ -C ₁₀ alkyl or branched C ₁ -C ₁₀ alkyl. The most convenient reagents are ethanol and isopropanol, due to cost considerations and ease of handling.

Further, according to a preferred embodiment of the invention, a basic catalyst may be added to the reaction mixture, in order to enhance the reaction rates. For instance, bases derived from alkali metals, such as NaOH, may serve for this purpose, if the process is carried out in batch. The base concentration may vary between 5 10 ³ M and 5 10' ² M, preferably 2.5 10 ² M, depending on the nature of the carbonyl compound.

As will be understood by the skilled person, ketones as well as aldehydes may be converted to alcohols by the process of the invention. Compounds of formula I of particular interest are ketones in which R ¹ is alkyl and R ² is phenyl or substituted phenyl, or wherein R ¹ and R ² together form a ring containing 4-9 carbon atoms, optionally fused with one or more aryl systems. Other examples of particularly interesting compounds are aldehydes in which R ¹ is hydrogen and R ² is selected from an aliphatic moiety (alkyl, alkenyl and alkynyl), phenyl, substituted phenyl, heteroaryl, R ⁵ -CH=CH-(CH ₂ )m- wherein R ⁵ is alkyl or phenyl and m is 0, 1 or 2, or naphthalene.

According to another preferred embodiment of the invention, the compound of formula I to be reduced is selected from among acetophenone, cyclohexanone, acetone, 2-butanone, p-nitroacetophenone, fluorenone, p-chloroacetophenone, benzaldehyde, m-anisaldehyde, m-phenoxybenzaldehyde, naphthaldehyde, cinnamaldehyde, 4-pyridinecarboxaldehyde, 3-pyridinecarboxaldehyde, and butyraldehyde.

Operating at sufficient temperature is a requirement of the process of the present invention. The solution is brought to, and kept at, a temperature above 200°C, preferably comprised from 300°C and 400°C or higher, e.g. above the critical temperature of the alcoholic reagent. Autogenous pressure is developed as a consequence. The desirable operating temperature is of course limited by the temperature stability of the compound involved. The skilled chemist will be easily be able to select the appropriate safe maximal operating temperature for a given compound. Higher temperatures will increase the reaction rate, and therefore will permit to obtain good yields in short periods of time, but on the other hand they may cause undesirable thermal decomposition. For practical

purposes, it has been found that a temperature of about 300-400°C is convenient for many reactions.

As will be appreciated by a person skilled in the art, the reaction time also affects the reaction yield. The reaction time is determined by the reaction temperature, by the presence or absence of a basic catalyst, and by other considerations, such as conversion of the starting material or the production of by products, as will be further illustrated by the examples to follow. All the above and other characteristics and advantages of the invention will be better understood from the following illustrative and non-limitative examples.

Embodiments of the invention in which the process is carried out in batch mode will be described firstly.

General Batch Procedure

In the following examples, unless otherwise indicated, the process was carried out as follows:

The substrate was dissolved in the appropriate alcoholic reagent (at a concentration of about 10% by weight). Whenever a base was used, its concentration was 0.025M. Usually the solution occupied about 60% of the total volume (a few milliliters) of the reaction vessel. The vessel was then introduced into an oven which had been preheated to the desired temperature and left at the same temperature for the indicated time. They represent the percentages of the product resulting from the conversion of the starting carbonyl compound. The alcoholic reagent is oxidized in part to the corresponding ketone, but this is not included in the by-products listed in the examples. The product was isolated

by methods known in the art, such as evaporation of the alcoholic reagent when high yields were obtained, or distillation and crystallization when low yields were obtained.

Example 1 Reduction of Acetophenone

Table I summarizes the results of the reduction of acetophenone, under different conditions ( reagent, base, time):

Table I

Alcoholic NaOH Temp. Time starting Alcohol By-Products Reagent (°C) (h) material(%) (yield, %) (%)

EtOH . 300 1.5 83 14 3 iPrOH . 300 1.5 7 93 _β

EtOH + 300 1.5 . 42 58 iPrOH + 300 1.5 7 78 15 iPrOH 300 0.5 3 85 12 iPrOH + 300 0.5 4 95 1

Example 2 Reduction of Cyclohexanone

Table II summarizes the results of the reduction of cyclohexanone under different conditions (reagent, base, time):

Table II

Alcoholic NaOH Temp. Time starting Alcohol By-Products Reagent (°C) (h) material(%) (yield, %) (%)

EtOH _ 300 1.5 64 36 . iPrOH . 300 1.5 41 41 18

EtOH + 300 1.5 4 50 46 iPrOH + 300 1.5 . 100 _

Example 3 Reduction of m-anisaldehvde

Table III summarizes the results of the reduction of m-anisaldehyde under different conditions (reagent, base, time):

Table III

Alcoholic NaOH Temp. Time starting Alcohol by-Product Reagent (°C) (h) material(%) (yield, %) (%)

EtOH _ 300 1.5 19 52 28 iPrOH . 300 1.5 4 85 11

EtOH + 300 1.5 . 58 42 iPrOH + 300 1.5 99 1 iPrOH . 300 0.5 52 21 27 iPrOH + 300 0.5 12 55 33

Example 4 Reduction of m-phenoxybenzaldehyde

Table IV summarizes the results of the reduction of m-phenoxybenzaldehyde under different conditions (reagent, base, time):

Table IV

Alcoholic NaOH Temp. Time starting Alcohol By-Products Reagent (°C) (h) material(%) (yield, %) (%)

EtOH 300 1.5 3 67 30 iPrOH . 300 1.5 _ >98 <2

EtOH + 300 1.5 4 50 46 iPrOH + 300 1.5 . 56 44

Example 5 Reduction of p-chloroacetophenone

The reaction was carried out in isopropanol at 300°C for 1.5 hours. No base was used. The yield of the corresponding alcohol obtained was 32%.

Example 6 Reduction of α-naphthaldehvde

The reaction was carried out in isopropanol at 300°C for 1.5 hours. No base was used. The yield of the corresponding alcohol obtained was 62%.

Example 7

Reduction of flurenone

The reaction was carried out in isopropanol at 300°C for 1.5 hours. No base was used. The yield of the corresponding alcohol obtained was 66%.

Example 8 Reduction of p-nitroacetophenone

The reaction was carried out in isopropanol at 300°C for 1.5 hours. No base was used. The yield of the corresponding alcohol obtained was 19%.

Example 9 Reduction of cinnamaldehvde (Ph-CH=CH-CHO)

The reaction was carried out in isopropanol at 300°C for 1.0 hour. No base was used. The yield of the cinnamyl alcohol obtained was 46%.

Example 10

Reduction of 4-Pyridinecarboxaldehyde

The reaction was carried out in isopropanol at 300°C for 3.0 hour. No base was used. The yield of the corresponding alcohol obtained was >95%.

Example 11 Reduction of 3-Pyridinecarboxaldehvde

The reaction was carried out in isopropanol at 300°C for 3.0 hour. No base was used. The yield of the corresponding alcohol obtained was >98%.

Example 12 Reduction of Butyraldehvde (CHaCH _g CH _£ CHO)

The reaction was carried out in isopropanol at 300°C for 3.0 hour. No base was used. The yield of the corresponding alcohol obtained was >98

Example 13 Reduction of m-methoxybenzaldehvde at various temperatures

Table V illustrates the temperature effect on the reaction yield, the time and the reagent being constant. The reduction was carried out in isopropanol for 1.5 hours, in the absence of a base.

Temperature (°C) 240 260 280 300

Yield (%) 32 61 89 99

Example 14 Reduction of m-phenoxybenzaldehvde at 200HC

The reaction was carried out in isopropanol for 3 hours, in the absence of a base, and the yield was 18%.

Example 15 Reduction of acetone in aromatic alcoholic solvent

The reaction was carried out in benzyl alcohol for 2 hours at 300°C, in the absence of a base, and the yield was 20%.

Example 16

Reduction of m-phenoxybenzaldehyde at an initial concentration of 46% (by weight)

The reaction was carried out in isopropanol at 300°C for 1.5 hours. No base was used. The yield of the corresponding alcohol obtained was 71%.

Continuous Procedure

Embodiments of the invention in which the process is carried out in continuous mode will now be described.

The drawing schematically illustrates an apparatus for carrying out such embodiments. Numeral 10 indicates a container for the alcoholic reagent. Numeral 11 indicates a like container for the carbonyl compound to be

transformed to the corresponding alcohol and/or other reduced compound. Through pipes 12, 13 and 14 the reagent and the carbonyl compound are fed to a container 15 in which the second one is dissolved into the first, if required under stirring and at an appropriate temperature. The resulting solution is impelled by a pump 16 through thin pipe 17 and the following parts of the apparatus. In an alternative embodiment of the apparatus, indicated in the drawing by broken lines, the alcoholic reagent and the carbonyl compound are fed thorough separate pipelines 12' and 13', at flow rates controlled by pumps 16' and 16", to said pipe 17 and/or to the following parts of the apparatus. Said following parts comprise a spiral tube 18, of a relatively large diameter, which defines the reaction space. Spiral tube 18 is enclosed in an oven 19, in which the temperature required to bring the reaction space to the reaction temperature is maintained. The alcoholic reagent and the carbonyl compound vaporize in tube

18, become superheated if the temperature therein is high enough, particularly if it is higher than the critical temperatures of the reagents, and the desired reaction occurs in the resulting gaseous reaction mixture. At the exit from oven

19, the reaction mixture enters a pipe 20 of narrow cross-section, which defines the post-reaction space. The gaseous reaction mixture condenses therein forming a solution of the desired alcohol and/or other reduced compound, which has formed as a result of the reaction, in the alcoholic reagent. Its discharge from the post-reaction space is controlled by a valve 21, through which it is discharged, in liquid form, into collecting vessel 22. In steady state condition, of course, the mass flow rate through said valve 21 corresponds to the mass flow rate through the feed pump or to the overall flow rate through the feed pumps. No significant superatmospheric pressure is measurable in said post-reaction space. The volume of the apparatus between the feed pump or pumps and valve 21 may be considered as a closed space and any pressure that may exist therein would be an autogenous pressure. In the following examples, isopropyl alcohol

was used as the alcoholic reagent. Four carbonyl compound were reduced. They were dissolved in the alcohol, the solution was pumped through the apparatus hereinbefore described and the reaction mixture was condensed. However, the same results would have been obtained had the alcohol and the carbonyl compound been fed separately, in corresponding relative amounts, to the reaction space. The acetone, resulting from the oxidation of the isopropanol, is not considered in the analysis of the reaction product.

Example 17 Reduction of benzaldehyde

Benzaldehyde was dissolved in isopropyl alcohol to a concentration of 13.9% by weight. The temperature in oven 19 was 350°C. The reaction product contained 18% of the starting material, 62% of benzyl alcohol (C ₆ H ₅ CH ₂ OH) and 19% of toluene, and 2% of unknown impurities. This result shows, as the results of examples 2 and 3 will show, that the reduction does not necessarily stop at the alcohol and fully reduced compounds can also be obtained.

Example 18 Reduction of acetophenone

Acetophenone was dissolved in isopropyl alcohol to a concentration of 14.1% by weight. The oven temperature was 350°C. The reaction product contained 59%) of the starting compound, 18% of 1-phenylethanol (C ₆ HδCH(OH)CH3), 16% of ethylbenzene (C6H5CH2CH3), 4% of styrene and 3% of unknown impurities.

Example 19 Complete reduction of acetophenone

Acetophenone was dissolved in isopropyl alcohol to a concentration of 10% by weight. The oven temperature was 400°C. The reaction product contained 80% of the starting material and 20% of ethylbenzene, but no 1-phenylethanol.

Example 20 Reduction of 3-pyridinecarboxaldehvde

3-pyridinecarboxaldehyde was dissolved in isopropyl alcohol to a concentration of 11.8% by weight. The oven temperature was 350°C. The reaction mixture contained 30% of the starting material, 15% of nicotinyl alcohol (3-pyridine carbinol), 34% of 3-picoline and 20% of undefined impurities.

Example 21 Reduction of 2-butanone

2-butanone (methyl ethyl ketone) was dissolved in isopropyl alcohol to a concentration of 10.4% by weight. The oven temperature was 400°C. The reaction mixture contained 76% of the starting material and 24% of 2-butanol (CH ₃ CH(OH)CH ₂ CH3).

Example 22 Reduction of 2-butanone

2-butanone was dissolved in isopropyl alcohol to a concentration of 13.4% by weight. The oven temperature was 300°C. The reaction product contained 88% of the starting material and 12% of 2-butanol.

Example 23 Reduction of 2-butanone

2-butanone was dissolved in isopropyl alcohol to a concentration of 15% by weight and reacted at an oven temperature of 350°C, but a first time at a flow rate of 2 ml/hr and a second time at a flow rate of 14 ml/hr. The reaction product contained in the first case 81% of the starting material and 19% of 2-butanol, and in the second case 98% of the starting material and 2% of 2-butanol, indicating that a longer exposure to reaction temperature tends to increase the yield of the desired alcohol. Such a longer exposure, of course, can be obtained not only by reducing the flow rate, as in this example, but also by increasing the volume of the reaction space, and particularly by increasing the length of the spiral tube 18, which defines the reaction space.

All the above description and examples have been provided for the purpose of illustration, and are not intended to limit the invention in any way. Many modifications can be carried out by the skilled chemist without departing from the spirit of the invention or exceeding its scope. For instance, different alcohols can be used as reagents, and different starting materials can be reacted, at

different temperatures and for different periods of time, with or without the presence of a basic catalyst, to yield different products.