Novel process for the production of 4,6-dimethyl-7-hydroxynonan-3-one

BACKGROUND OF THE INVENTION
This invention relates to an improved method for the production of 4,6-dimethyl-7-hydroxynonan-3-one.
The female cigarette beetle (Lasioderma Serricorne F.) has been shown to secrete a sex pheromone which attracts the male beetle. This pheromone has been identified in the literature as (4S,6S,7S)-4,6-dimethyl-7-hydroxynonan-3-one.
The sex pheromone may be applied to pest prevention by attracting male insects to a given place to catch and kill them or by disturbing the normal mating behavior of male cigarette beetles. Alternatively, a sex pheromone may be used to attract and collect insect pests in order to make a field survey on the hatching or growing of the insect pests. On the basis of the results of such periodic surveys, it is possible to judge whether insecticide spraying is needed or not and to select the effective amount of an insecticide, thereby reducing the quantity of the insecticide used as a whole.
Research has been made on pest prevention by attracting insects for catching and killing them, or disturbing the communication between male and female insects using an insect sex pheromone.
In general, the paring behavior of insects is controlled by an extremely small amount of an odorous substance secreted by the insect, usually the female insect. The female insect releases a volatile, odorous substance in the air. The male insect perceives this odor and moves on legs or wings toward the female insect who is the source of the odor. The male insect who finds the female insect, sexually excites and mates therewith.
One type of odorous substance secreted by female insects is generally called a sex pheromone or sex attractant and is a very important substance in the mating behavior of insects.
DESCRIPTION OF THE PRIOR ART
The use of 4,6 dimethyl-7-hydroxynonan-3-one as a sex attracting composition is known in the art and it is the subject matter of U.S. Pat. No. 4,317,836. The patentees disclose both a pure compound and the use of the same as a sex attractant in the prevention of the cigarette beetle (lasioderma serricornin F.) which is an insect pest feeding on cured tobacco leaves and which causes serious damage to the tobacco industry. The serricornin of U.S. Pat. No. 4,317,836 is isolated from a natural product.
The literature also discloses a wide variety of techniques for the actual synthesis of (.+-.)-serricornin (as opposed to its isolation) and a substantial number of the syntheses have as a key intermediate the production of 5-hydroxy-2,4-dimethylheptanenitrile (see for example Ono et al, Agriculture Biological Chemistry, volume 44 (number 9) pages 2259-2260 (1980) as well as Canadian patent 1,160,240. The production of (.+-.)-serricornin from said intermediate compound is a synthesis well known in the art and the disclosure of the Ono et al article and said Canadian patent being herein incorporated by reference.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
It is known in the art that 4,6-dimethyl-7-hydroxynonan-3-one is in reality a mixture of optical isomers. Thus, the natural pheromone is one of eight optical isomers which are possible for serricornin due to its three asymmetric carbon atoms (C-4, C-6 and C-7). More recently, it has been shown that each of these optical isomers can exist in two different forms--open or cyclic. Consequently there are 24 possible isomers of 4,6-dimethyl-7-hydroxy-nonan-3-one.
The isomers have been studied in great detail in the literature and it has been reported that the ratio of 6,7-threo to 6,7-erythro for (.+-.)-serricornin is of importance in determining the effectiveness of the compound for the attraction of male cigarette beetles. Thus, it has been reported in the literature that the 6,7-threo isomers were at least a thousand times more active than 6,7-erythro isomers. While obviously the 6,7 threo to 6,7-erythro isomer ratio is of extreme importance in producing an effective compound in producing an effective cigarette beetle attraction, it is not the sole determinant factor. Trace amounts of impurities, as well as synergistic/antagonistic effects of various isomers can have a disastrous effect on activity.
Literature articles discussing the importance of the ratios include: Chuman et al, Agriculture Biological Chemistry, Volume 46 (No. 2) pages 593-595 (1982), Chuman et al, Agriculture Biological Chemistry, Volume 46 (No. 12), pages 3109-3112 (1982), Mochizuki et al, Agriculture Biological Chemistry, Volume 48, (No. 11), pages 2833-2834 1984), Mori et al, Journal of Chemical Ecology, Volume 12, (No. 1), pages 83-89 (1986)and Levinson et al, Naturwissenschaften 73, S. 36 (1986), the disclosure of said articles being herein incorporated by reference.
The novel process of this invention is predicted on the discovery that the stereochemistry of the (.+-.)-serricornin is set at the production of 5-hydroxy-2,4-dimethylheptanitrile and once the stereochemistry of this intermediate compound is set the processing of this intermediate to the final product does not seriously affect the final 6,7-threo/erythro isomer ratio.
However, as will be demonstrated later, the setting of the ratio is but one factor in determining the activity of the final product. Very specific purification techniques are required and unless the purification techniques are carried out, optimum activity will not be obtained even though the isomer ratio has been set.

BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 represents in schematic form the synthesis of the 4,6-dimethyl-7-hydroxynonan-3-one in an unpurified form.
FIG. 2 represents, in schematic form, two separate purification techniques identified as A and B, either of which must be used in order to produce 4,6-dimethyl-7-hydroxynonan-3-one of enhanced activity.
FIG. 3 depicts the 8 optical isomers of serricornin.
FIGS. 4, 5 and 6, and 7 depict the fact that each optical isomer of FIG. 3 can exist in two additional forms, open and cyclic.
FIG. 8 depicts the 4 isomers of 2,4-dimethyl-5-oxoheptanitrile.
FIGS. 9 and 10 depict results of cigarette beetle trapping tests.

DETAILED DESCRIPTION OF THE INVENTION
The novel process of this invention involves a series of process steps which are mutually essential to produce the (.+-.)-serricornin having enhanced activity.
The manufacture of (.+-.)-serricornin (Compound IVd of FIG. 2) is carried out by reacting pyrrolidine and 3-pentanone in the presence of p-toluenesulfonic acid monohydrate in order to obtain N-(1-ethyl-1-propenyl)pyrrolidine. This compound is shown as I in FIG. 1 and its method of preparation is a standard procedure which is reported in the literature. No novelty is claimed for this step. In step 2, compound I is reacted with methacrylonitrile in absolute alcohol in order to produce 2-4-dimethyl-5-oxoheptanitrile which is identified as IIa in FIG. 1. This reaction is also old in the literature and no novelty is claimed for this step.
The novel approach of this invention really begins in the treatment of IIa in order to produce a product which is identified as IIb in FIG. 1. This is fundamentally a base equilibration of IIa to give IIb with a reproducible ratio of stereoisomers. The importance of the base equilibration step can be best explained by reference to certain of the figures. Compound IIa of FIG. 1 has two asymmetric carbon atoms namely C-2 and C-4. As such it can exist in four different isomeric forms. These four isomeric forms are set forth in FIG. 8. As prepared by the prior art, including the reaction scheme set forth in FIG. 1, this compound is a mixture of two racemic compounds, i.e., it is a mixture of all 4 isomers depicted in FIG. 8 with the amount of II.1 equaling II.2 and II.3 equaling II.4 because these are enantiomers. The ratio of II.1 to II.3 and consequently II.2 to II.4 can vary depending on the method of synthesis of IIa.
Investigation has shown that the ratio of diastereomers can change from reaction to reaction using the very same synthesis for IIa and during the purification of the product by conventional means such as vacuum distillation. The novel process of this invention consistently gave the same ratio of isomers regardless of the starting ratio. Thus, even when a base equilibration is run on IIa which is approximately 95 +% of one diastereomer or the other, the final product has the same diastereomer ratio. Thus, the base equilibration of IIa gives the thermodynamic product.
In order to ensure that it is the thermodynamic product which is reduced in step 4 of FIG. 1, the equilibrated product IIb of FIG. 1 is not isolated but is reduced by direct treatment of the product solution from step 3 with sodium borohydride.
As has heretofore been set forth, the consequences of this equilibration are that the stereochemistry at C-2 and C-4 of IIb are reproducibly fixed prior to the final reduction step. The stereochemistry of these carbon atoms affect the reduction carried out in step 4 of FIG. 1, i.e., a different isomer ratio for IIb would be reduced to give III with a different isomer ratio. Once the stereochemistry at C-4 and C-5 of III are set they stay unaltered throughout the remainder of the synthesis. Therefore, the setting of the IIb isomer ratio is the determining factor in setting the stereochemistry at C-4 and C-5 for III, and it defines the stereochemistry of C-6 and C-7 of (.+-.)-serricornin, i.e., the 6,7-threo/erythro isomer ratio (see FIG. 3).
The base equilibration can be carried out by treatment of IIa with a suitable base such as sodium hydroxide, lithium hydroxide, calcium hydroxide, etc. The reaction is carried out at temperatures ranging from -20.degree. C. to 40.degree. C., conveniently at atmospheric pressure, for a period of time ranging from 2 to 48 hours.
The reduction of the ketone to produce 2,4-dimethyl-5-hydroxyheptanenitrile is also a very critical step. It involves the reduction of the ketone with a conventional reducing agent such as sodium borohydride but in the presence of added base. It is to be understood that the sodium borohydride reduction of a ketone functional group is a standard, well established procedure and it is known in the art that sodium borohydride reduces IIA of FIG. 1 to III of FIG. 1. See the Levinson et al and the Ono et al publications previously mentioned. The reaction conditions of this invention are similar to those used by Ono et al with two critical differences. In the process of the instant invention, the reaction is run on the equilibrated material (IIb) and, equally important, the reaction is run in presence of a base. The full consequences of the added base in carrying out this reaction are not completely understood but without it inferior results are obtained with regard to the effectiveness of the desired final product.
The bases which are applicable to this step are the same as those applicable in the prior step. The reaction is usually carried out in a solvent such as aliphatic alcohols or water. It is preferred to use isopropanol.
The next step in the novel process of this invention involves the reaction of 2,4-dimethyl-5-hydroxyheptanenitrile (Compound III of FIG. 1) with a Grignard reagent such as ethyl magnesium bromide to obtain the crude (.+-.)-serricornin (IVa in FIG. 1). The reaction conditions employed are essentially identical to those reported in the literature, i.e., Levinson et al and Ono et al, previously referred to. The crude (.+-.)-serricornin, i.e., Compound IVa of FIG. 1, is then purified by either of two separate and distinct routes which are labeled as A and B in FIG. 2. Briefly put, procedure A involves converting the (.+-.)-serricornin, i.e., Compound IVA from FIG. 2, via dehydration to (.+-.) anhydroserricornin, i.e., Compound V in FIG. 2, followed by rehydration of (.+-.)-anhydroserricornin (V of FIG. 2) to (.+-.)-serricornin, (IVC of FIG. 2) from which trace impurities have been removed, i.e., but needs to be equilibrated at the 4 carbon atom to obtain a stable/optimum mixture of isomers.
The purification procedure identified as B in FIG. 2 can briefly be described as the acylation of (.+-.)-serricornin, i.e., Compound IVA, in order to obtain 4,6-dimethyl-7-acetoxynonan-3-one (Compound VI of FIG. 2), followed by conversion of the Compound VI of FIG. 2 to (.+-.)-serricornin (Compound IVB of FIG. 2) from which trace impurities have been removed, i.e., but needs to be equilibrated at the 4 carbon atom to obtain a stable/optimum mixture of isomers.
Although both procedure A and procedure B utilize different methods, nevertheless they both start with an impure (.+-.)-serricornin, i.e., IVA, and they involve the production of a purified (.+-.) serricornin, i.e., IVC of FIG. 2 for procedure A and IVB of FIG. 2 for procedure B.
In order to complete the purification process from either procedure A or procedure B, both products must be subject to a base equilibration step which involves contacting the material dissolved in a suitable solvent such as alcohol with an appropriate base. The nature of the base is not narrowly critical but it is preferred to use sodium hydroxide. This serves to optimize and equilibrate the compound at the 4 carbon.
As will be illustrated in the examples which follow, the novel process of this invention, including the purification procedures, involves a series of steps which interconnect in some way to produce a material having enhanced activity.
The following examples will now illustrate the novel process of this invention.
EXAMPLE 1
Synthesis of N-(1-ethyl-1-propenyl) pyrrolidine (Compound I, FIG. 1)
Pyrrolidine (1608 g, 22.6 moles), 3-pentanone (860 g, 9.98 moles), and p-toluenesulfonic acid monohydrate (470mg, 2.7 moles) were placed in dry benzene (5.4L) in a 12 liter 3-neck round bottom flask equipped with a soxlet extractor containing 4A molecular sieves (2Kg). The solution was refluxed for 20 hours under a nitrogen atmosphere. The reaction mixture was then cooled and the solvent removed under reduced pressure (30 mm). The resulting crude enamine was distilled at 38-40.degree. C. and 0.70 mm to give a 75.5% yield of I (1048 g, 7.54 moles). GC and NMR data confirmed the above structure.
The reaction was repeated on the same molar scale and a yield of 85% of I was obtained.
EXAMPLE 2
Synthesis of 2.4-Dimethyl-5-Oxoheptanenitrile (Compound IIa, FIG. 1)
The enamine (I, 1182 g, 8.50 moles) and methacrylonitrile (581 g, 8.67 moles) were combined in absolute ethanol (6.8L) in a 12 liter round bottom flask. The stirring mixture was then refluxed for 18 hours under nitrogen. The mixture was cooled and the ethanol removed under reduced pressure (30 mm). Diethyl ether (lL) and water (lL) were added to the residue. After shaking in a separatory funnel, the organic layer was removed and the aqueous layer again extracted with diethyl ether (lL). The combined organic layers were washed with 10% aqueous hydrochloric acid (2.times.500 ml) and with saturated aqueous sodium chloride solution (500 ml). After drying (MgSO.sub.4), the solvent was removed and the crude produced distilled at 61.degree.-64 .degree. C. and 0.20 mm to give a 60% yield of 2,4-dimethyl-5-oxoheptanenitrile (799 g, 5.22 moles). IR, NMR, and MS data confirmed the above structure.
EXAMPLE 3
Equilibration to 2,4-Dimethyl-5-Oxoheptanenitrile (Compound IIb)
To a stirred solution of 2,4-dimethyl-5-oxoheptanenitrile (IIa 957 g, 6.25 moles) in isopropyl alcohol (5L) under a nitrogen atmosphere was added a catalytic amount of 50% aqueous sodium hydroxide (20 drops, .about.400mg). This solution was stirred for 20 hours at room temperature. The alcoholic solution of IIb may be carried directly to the next step.
As has heretofore been pointed out, this is one of the most crucial steps in the novel process of this invention and the importance of this step can be best illustrated with reference to the following table which sets forth various diastereomer ratios for compounds IIa and IIb of FIG. 1. In the table which follows, seven separate runs were carried out and the diasteronic ratio for IIa and IIb were determined both in the crude form prior to purification i.e., see Example 2; the distilled form i.e., the product from Example 2 (after distillation); IIa which is purified by high performance liquid chromatography to obtain each diastereomer; and, finally, IIb from example III. The results are shown in Table 1.
TABLE 1______________________________________Diastereomer Ratios for IIa and IIbIsomer Ratios.sup.1,2Run Crude IIa.sup.3 Distilled IIa.sup.4 IIa Isomer.sup.5 IIb.sup.6______________________________________1 59.9/40.1 55/45 NA.sup.7 ND.sup.82 ND 52.6/47.4 NA ND3 NA NA 98/2 67.5/32.54 NA NA 5/95 67.7/32.35 ND 68/32 NA 65/356 ND 57.5/42.5 NA 63/377 62.3/37.7 61.5/38.5 NA ND______________________________________ .sup.1 Ratio is IIb.1/IIb.2:IIb.3/IIb.4 (FIG. 7) .sup.2 Determined by gas chromatography .sup.3 IIa from step 2 prior to purification .sup.4 Product (IIa) from step 2 .sup.5 IIa purified by high performance liquid chromatography to obtain each diastereomer .sup.6 Product (IIb) from step 3 .sup.7 Not applicable .sup.8 Not determined
As can be seen from Table 1, the base catalyzed equilibration, i.e., IIb, is always approximately the same irrespective of the ratio of isomers which existed before this step. Compare runs 3, 4, 5 and 6 and it can been seen the base equilibration step produced a product which had a fairly uniform ratio of isomers.
EXAMPLE 4
Synthesis of 2,4-Dimethyl-5-Hydroxyheptanenitrile (Compound III, FIG. 1)
To a stirred solution of 2,4-dimethyl-5-oxoheptanenitrile (IIb, 239 g, 1.56 moles) in isopropanol (2.5L) at 5.degree. C. under a nitrogen atmosphere, was added sodium borohydride (60 g, 1.59 moles) over a 15 minute period. The mixture was stirred for 40 hours at room temperature, after which GC analysis indicated complete reaction. The reaction mixture was cooled to -5.degree. C. and carefully quenched with water (1L) followed by saturated aqueous ammonium chloride (200 ml). After the gas evolution had subsided, the isopropanol was removed under reduced pressure (30 mm). The residue was extracted with diethyl ether (1.times.750 ml, 2.times.350 ml) and the combined organic layers washed with water (2.times.200 ml) and saturated aqueous sodium chloride (200 ml). After drying (MgSO.sub.4), the solvent was removed at reduced pressure (30 mm) and the crude product distilled at 75-80.degree. C. and 0.20-0.10 mm to give a 88% yield of 2,4-dimethyl-5-hydroxyheptanenitrile (212 g, 1.37 moles).
IR, NMR, and MS data confirmed the above structure.
EXAMPLE 5
Synthesis of 4,6-Dimethyl-7-hydroxynonan-3-one (.+-.)-Serricornin (Compound IVa, FIG. 1)
A solution of 2,4-dimethyl-5-hydroxyheptanenitrile (III, 25 g, 0.16 mole) in anhydrous diethyl ether (700ml) was set stirring with a mechanical stirrer under a nitrogen atmosphere. After cooling the solution to -10.degree. C., 2.8 molar ethylmagnesium bromide (127 ml in hexane, 0.36 mole) was added dropwise over 20 minutes. A thick white precipitate formed which was stirred for 18 hours at room temperature.
The reaction mixture was cooled to -0.degree. C. and carefully quenched with water (100 ml), followed by saturated aqueous ammonium chloride (75 ml). After stirring for 15 minutes, a buffer mixture of sodium acetate (41 g)/acetic acid (87 ml)/water (87 ml) was added over 20 minutes. The pH of the reaction mixture was then adjusted to pH 4.5 with careful addition of 6N hydrochloric acid and stirred for 1 hour at room temperature. The ethereal layer was removed and the aqueous layer extracted with diethyl ether (2.times.350 ml). The combined organic layers were washed successively with water (200 ml), saturated aqueous sodium bicarbonate (3.times.200 ml), water (200 ml) and a saturated aqueous solution of sodium chloride (200 ml). After drying (MgSO.sub.4), the solvent was removed to give a 83% yield of (.+-.)-serricornin (25 g, 0.13 mole).
It is to be understood that prior to use the above compound must be purified since at this stage its activity is obviously not as great as the purified product. Methods of purification of (.+-.)-serricornin are well known in the art and are mentioned in the articles previously referred to.
Examples 6, 7 and 8 illustrate the purification scheme identified as A in FIG. 2.
EXAMPLE 6
Synthesis of 4,6-diethyl-3,5-dimethyl-2H-pyran, anhydroserricorni (Compound V, FIG. 2)
Compound IVa (18 g, 0.097 mole) was dissolved in benzene (180 ml) containing a catalytic amount (0.01 mole equivalents) of p-toluenesulfonic acid monohydrate. The stirring solution was refluxed under nitrogen for 18 hours using a Dean-Stark trap system to collect the water. The reaction mixture was cooled and 75% of the benzene was removed under reduced pressure (30 mm). The mixture was quickly filtered under a nitrogen atmosphere to remove any residues. The crude product was distilled at 87.degree.-90.degree. C. and 30 mm to give a 80% yield of pure anhydroserricornin (13 g, 0.077 mole).
It is to be understood that this particular method of dehydration is not novel per se and is, in fact, disclosed by Chuman et al, Journal of Chemical Ecology, Vol. 11, No. 4 (1985), the entire disclosure of which is incorporated herein by reference.
EXAMPLE 7
Synthesis of 4,6-Dimethyl-7-hydroxynonan-3-one, (.+-.)-Serricornin (Compound IVc, FIG. 2)
Freshly distilled anhydroserricornin (V, 13 g, 0.077 mole) was set stirring in peroxide-free dioxane (690 ml passed through basic alumina, Activity 1) under a nitrogen atmosphere. Water (120 ml) and 0.01 N perchloric acid (120 mg in 120 ml water, 1.2 mmoles) were added and the resulting solution was stirred at room temperature for 18 hours. The solution was then neutralized with aqueous sodium bicarbonate to pH7 and most of the dioxane was removed under reduced pressure (30 mm). Water (100 ml) was added and the resulting mixture extracted with diethyl ether (1.times.400 ml, 2.times.200 ml). The combined organic layers were washed with water (100 ml) and then with saturated aqueous sodium chloride (100 ml). The ether solution was dried (MgSO.sub.4) and solvent removed to give a 90% yield of purified (.+-.)-serricornin (13 g, 0.070 mole).
The above rehydration of (.+-.)-anhydroserricornin is quite different than the one described in the Chuman et al reference mentioned in connection with Example 6. It has been found that if conditions other than those set forth in Example 7 are used to rehydrate Compound V, the resulting (.+-.)-serricornin will contain impurities which lower its pheromone activity.
A principal contaminant resulting from inappropriate rehydration conditions is (.+-.)-anhydroserricornin (V, FIG. 2). The procedure of Example 7 rehydrates V in dioxane and water using perchloric acid as the catalyst. The product (IVc) is obtained in an average yield of 90% and is free of all (.+-.)-anhydroserricornin and is essentially 100% pure.
EXAMPLE 8
Equilibration to 4,6-Dimethyl-7-hydroxynonan-3-one, (.+-.)-serricornin (Compound IVd, FIG. 2)
Compound IVc (3.08 g, 0.017 mole) was dissolved in methanol (140 ml) and sodium hydroxide (64 mg, 1.6 mmole) was added to this stirring solution under a nitrogen atmosphere. The solution was then stirred for 72 hours at room temperature. Approximately 75% of the methanol was removed under reduced pressure (30 mm) after which diethyl ether (70 ml) and water (40 ml) were added. The ethereal layer was removed and the aqueous phase extracted with diethyl ether (3.times.40 ml). The combined organic layers were washed with water (40 ml) and then with saturated aqueous sodium chloride (50 ml) and dried (MgSO.sub.4). The solvent was removed to give a 97% recovery of (.+-.)-serricornin (3.0 g, 0.016 mmol).
GLC, HPLC, TLC, IR, and MS confirmed the basic structure. NMR confirmed the cyclic and acyclic forms of equilibrated (.+-.)-serricornin as well as the ratios of the diastereomers.
The final step in the purification, as represented by Example 8, is believed to be novel (step 10 of FIG. 2).
A threo/erythro ratio of 73/27 was found (Table 2).
TABLE 2______________________________________(.+-.)-Serricornin Isomer Ratios.sup.1,2 -Purification Effects 6,7- Threo/ IV.1; IV.3; IV.5; IV.7; ErythroProduct Step IV.2 IV.4 IV.6 IV.8 Ratio______________________________________Example 1(.+-.)-Serricornin (IVa) 5 49.8 36.4 5.4 8.4 86.2/13.8(.+-.)-Serricornin (IVc) 7 35.4 42.3 7.3 14.9 77.7/23.3(.+-.)-Serricornin (IVd) 10 31.4 41.9 9.6 17.1 73.3/26.7Example 2(.+-.)-Serricornin (IVa) 5 53.5 31.1 6.2 9.2 84.6/15.4(.+-.)-Serricornin (IVc) 7 28.5 45.6 8.4 17.5 74.1/25.9(.+-.)-Serricornin (IVd) 10 33.7 42.8 9.0 15.5 76.5/23.5Example 3(.+-.)-Serricornin (IVb) 9 53.5 32.3 trace 14.2 85.8/14.2(.+-.)-Serricornin (IVd) 11 53.7 22.8 4.4 19.1 76.5/23.5Example 4(.+-.)-Serricornin (IVb) 9 52.3 20.5 9.4 17.8 72.8/27.2(.+-.)-Serricornin (IVd) 11 54.1 18.5 10.0 17.3 72.6/27.4______________________________________ .sup.1 Ratios determined by Nuclear Magnetic Resonance. .sup.2 Each of the isomers may exist partially or completely in its respective cyclic forms.
Examples 9-11 represent purification Scheme B set forth in FIG. 2.
EXAMPLE 9
Synthesis of 4,6-Dimethyl-7-acetoxynonan-3-one (Compound VI, FIG. 2)
A solution of 4,6-dimethyl-7-hydroxynonan-3-one (IVa, 10 g, 53.8 mmoles) in acetic anhydride (13.8 g, 135 mmoles) and pyridine (12.8 g, 162 mmoles) was set stirring under a nitrogen atmosphere. After stirring for 20 hours at room temperature, most of the acetic anhydride and pyridine were removed at reduced pressure to leave a clear oil (11 g crude weight). The crude product was then distilled at 60.degree. C. and 0.16 mm to give a 68% yield of 4,6-dimethyl-7-acetoxynonan-3-one (8.4 g, 36.8 mmoles).
EXAMPLE 10
Synthesis of 4,6-Dimethyl-7-hydroxynonan-3-one (Compound IVb, FIG. 2) from the acetate
A solution of 4,6-dimethyl-7-acetoxynonan-3-one (VI, 4.0 g, 17.5 mmoles) in degassed absolute ethanol was set stirring under a nitrogen atmosphere. After cooling the solution to 10.degree. C., potassium hydroxide (7.5 g, 116 mmoles) in water (7.5 ml) and absolute ethanol (40 ml) was added dropwise over 10 minutes. The yellow solution was then stirred for 18 hours at room temperature.
The procedures for the purification of the pheromone as described by Examples 9 and 10 has not been previously discussed in the literature. However, the methods used in both Examples 9 and 10 are individually well known.
Thus, for example, the acylation of (.+-.)-serricornin as well as serricornin and isomers has been carried out by many researchers in their pheromone studies. The acylation of an alcohol with acetic anhydride and pyridine is a well established procedure in the art. However, please note that the instant process purifies (.+-.)-serricornin acetate (VI, FIG. 2) by vacuum distillation. This has not been reported in the literature.
Similarly, the cleavage of an acetate with a base to the corresponding alcohol is a well known chemical reaction. Numerous workers have used this general method for the hydrolysis of (.+-.)-serricornin acetate and acetate of serricornin isomers to the corresponding alcohol.
It is important to reiterate that no one has reported the purification of (.+-.)-serricornin by its conversion to the acetate, distillation of the acetate and subsequent base hydrolysis, as well as the base equilibration thereof.
EXAMPLE 11
Equilibration of 4,6-Dimethyl-7-hydroxynonan-3-one, (.+-.)-serricornin (Compound IVb, FIG. 2)
The equilibration of (.+-.)-serricornin (IVb) was carried out on a 3.25 g (17.5 mmoles) scale as described in Example 8. A 97% recovery of equilibrated (.+-.)-serricornin (IVd, 3.15 g, 16.9 mmoles) was observed.
FIELD TRIALS
EXAMPLE 12
Extensive entymological field testing has been carried out to determine the effectiveness of the (.+-.)-serricornin, i.e., Compound IVd, FIG. 2, Scheme A as a monitoring tool for attracting the male cigarette beetle. This was accomplished by comparing said Compound IVd against a commercial trap sold under the Trademark.RTM., by the Fuji Flavor Co., Ltd., as well as against the standard electrical traps already in use in the Phillip Morris facilities. The results of these tests are given in Tables 3 and 4 and illustrated in FIGS. 9 and 10.
The Fuji Serrico.RTM. sex pheromone adhesive trap manufactured by the Fuji Flavor Co., Ltd., Tokyo, Japan, a commercially available product, was the trap system used to compare the instantly synthesized materials with the prior art.
The trap consists of a two-sided folding cardboard body (80 mm.times.150 mm.times.60 mm) that contains two adhesive strips on the inner surface and slits along the sides for the male beetle to enter. Once the adult male cigarette beetle is lured, the adhesive surface immobilizes the insect.
The Serrico.RTM. kit employs a 1.5 cm absorbent assay disk which contains the serricornin. The absorbent assay disk serves as the controlled release delivery device. Prior to use the assay disk is sealed with a blister package to maintain freshness. Once the disk is removed from the blister package, it is then activated and affixed directly to the adhesive surface of the trap.
In order to test the material of the instant invention, as well as making other comparative tests, a weighted amount usually 50 mg) brought to 100 .mu.L in pesticide grade hexane of the various pheromones was injected into a cigarette tow, manufactured by the Hoechst Celanese Corporation, which is encapsulated by an extruded plastic cover. The plastic tow measures 9 mm in diameter by 20 mm in length. Even though the target insect attractant is incorporated over and into the entire surface volume (1271.6 mm.sup.3) of the Hoechst Celanese tow, the surface area which releases the attractant is confined to the ends (2.times.63.5 square mm). Thus, this design restricts or controls the release rate. Following injection onto the plastic tow, it is affixed to the adhesive surface of the Serrico.RTM. trap.
In testing Compound IVd, made through Scheme A of FIG. 2, 50 mg was used for the majority of the test period. In approximately the last seven weeks of the test, the application rate was 25 mg per tow. A slight drop-off in trapping efficiency was noticed as compared to the 50 mg per tow.
The number of the traps used in the study were as follows:
1. 200 electric grid traps constructed on an aluminum steel frame and anodized aluminum exterior case, 135 cm .times.60 cm.times.43 cm with a nickel-chrome plated guard and 20 80 watt UV insect attractant lamps (Gilbert, Jonesboro, Arkansas).
2. 100 Serrico.RTM. traps containing the instant synthesized (.+-.)-serricornin.
3. 100 Serrico.RTM. traps containing the Japanese synthesized (.+-.)-serricornin.
The electric grid traps had been permanently placed within the manufacturing environment at an earlier time. The pheromone traps were strategically secured on vertical posts, walls, processing machinery, etc. and were alternated every 6 weeks within the monitoring area, thereby removing the possibility of the position to affect either the Fuji or the instantly synthesized pheromones. The number of cigarette beetles trapped was determined on a weekly basis, and fresh lures both for the instantly synthesized pheromones and the Japanese synthesized serricornin were applied every 6 weeks.
The testing results from April to December are shown in detail in Table 3 and are summarized in Table 4. Out of 9,057 cigarette beetles caught on the traps (greater than 99% male), 6,922 or 76% were caught on the traps containing (.+-.)-serricornin manufactured by the instant process.
TABLE 3______________________________________Entomological Field TrialApril 23-December 26______________________________________ 4/23 4/30 5/7 5/14 5/21 5/29 Total______________________________________PM.sup.1 23 46 108 116 107 132 532Fuji.sup.2 54 48 40 58 61 93 354Elec- -- -- -- -- -- -- 343tricGridTotal 77 94 148 174 168 225______________________________________ 6/4 6/11 6/18 6/25 7/1 7/8______________________________________PM 88 129 93 170 281 277 1038Fuji 88 57 22 17 69 115 368Elec- -- -- -- -- -- -- 789tricGridTotal 176 186 115 187 350 392______________________________________ 7/16 7/23 7/30 8/6 8/13 8/20______________________________________PM 228 145 220 396 432 521 1942Fuji 212 98 60 58 50 62 540Elec- -- -- -- -- -- -- 1035tricGridTotal 440 243 280 454 482 583______________________________________ 8/27 9/4 9/10 9/17 9/24 10/2______________________________________PM 134 328 267 397 399 401 1926Fuji 75 122 68 88 57 28 438Elec- -- -- -- -- -- -- 787tricGridTotal 209 450 335 485 456 429______________________________________ 10/8 10/15 10/22 10/29 11/5 11/12______________________________________PM 100 128 188 177 124 161 878Fuji 48 42 53 17 23 14 197Elec- -- -- -- -- -- -- 206tricic GridTotal 148 170 241 194 147 175______________________________________ 11/19 11/26 12/3 12/10 12/17 12/26______________________________________PM 88 49 95 114 95 165 606Fuji 80 31 33 37 14 43 238Elec- -- -- -- -- -- -- 241tricGridTotal 168 80 128 151 109 208______________________________________ .sup.1 (.+-.)-Serricornin IVd from IVc .sup.2 Fuji Flavor Co. Ltd. pheromone
TABLE 4______________________________________Summary of Trapping Efficiencies.sup.1 No. of No of Cigarette GenderTrap Type Traps Beetles Trapped Trapped______________________________________Electric Grid 200 3401 Male & FemalePM Pheromone-IVd 100 6922 MaleFuji Pheromone- 100 2135 Male"Serrico" .RTM.______________________________________ .sup.1 Summary of data from Table 3
EXAMPLE 13
Another field test was conducted at a tobacco warehouse for a period of 11 days. All the material synthesized in accordance with the process of this invention, either purified, partially purified, or fully purified, were loaded onto the standard traps previously described at 70 mg per tow. The commercially available Serrico.RTM. trapping system from Fuji Flavor Company was employed, excluding the food attractant disk. The control was the Serrico.RTM. trap minus the pheromone and food attractant disks, the traps were rotated, and the counts were taken every 2 to 3 days. The results are shown in Table 5.
TABLE 5______________________________________The Actual Number of Cigarette Beetles Trapped by EachTreatment in a Tobacco Warehouse Within 2 and 3 Day Intervals Treatment %September 3 6 9 12 14 Total Trapped______________________________________CONTROL 69 25 34 19 147 2.7(.+-.)-Anhydro- 16 13 10 9 48 .9serricornin (V)25:75.sup.a 70 62 89 50 271 5.050:50.sup.a 73 65 150 65 353 6.575:25.sup.a 86 95 122 64 367 6.8(.+-.)-Serricornin 86 68 189 93 436 8.1(IVa)(.+-.)-Serricornin 731 402 922 923 2978 55.1(IVd)"Serrico" .RTM. -- 203 356 247 806 14.9WAREHOUSE 1131 933 1872 1470 5406 100.0TOTAL______________________________________ .sup.a (.+-.)-Serricornin (IVa):(.+-.)Anhydroserricornin (V)
The above results clearly demonstrate the improved activity of the (.+-.)-serricornin made in accordance with the novel process of this invention. Thus, for example, Table 5 shows the results obtained with (.+-.)-anhydroserricornin (V) as well as mixtures of the unpurified (.+-.)-serricornin (IVa from FIG. 1) in admixture with various amounts of anhydroserricornin (V). Table 5 also clearly shows the results obtained with the unpurified serricornin, i.e., Compound IVa of FIG. 1, as well as the fully purified (.+-.)-serricornin of this invention, i.e., Compound IVd from FIG. 2, Scheme A. As can be seen, the fully purified material was vastly superior in its ability to trap cigarette beetles.
EXAMPLE 14
This Example will illustrate that (.+-.)-serricornin purified by scheme B of FIG. 2 is effective.
Equilibrated (.+-.)-serricornin (IVd) synthesized from the acetate intermediate (VI) was tested in a manufacturing facility at Philip Morris.
Twenty traps containing (.+-.)-serricornin (IVd from VI) were prepared as previously described at a load level of 70 mg per trap. An additional 20 traps at a load level of 70 mg per trap were prepared using equilibrated (.+-.)-serricornin (IVd) synthesized via the anhydroserricornin (V).
Table 6 summarizes the results over a four week testing period. From all indications, the equilibrated (.+-.)-serricornin prepared from the acetate intermediate appears to be as successful as equilibrated (.+-.)-serricornin prepared through the anhydroserricornin intermediate.
TABLE 6______________________________________ Procedure B Procedure A FIG. 2 FIG. 2Week No. 20 Traps of IVd from VI 20 Traps of IVd from V______________________________________1 10 102 3 43 19 104 20 5______________________________________
The following Examples 15 and 16 will demonstrate that the novel process of this invention is crucial in producing a (.+-.)-serricornin of enhanced activity. If conventionally available serricornins are purified by the exact same procedure, i.e., Scheme A of FIG. 2, equivalent results will not be obtained since the (.+-.)-serricornin has not gone through all steps of the process. Additionally, these experiments will demonstrate that if one were to purify the (.+-.)-serricornin produced by the instant process up to IVa of FIG. 1 by conventional distillation as opposed to carrying out the remaining steps shown in FIG. 2, inferior results will have been obtained.
EXAMPLE 15
This example will again demonstrate that the total process for the preparation of the (.+-.)-serricornin is necessary in order to obtain a material of enhanced activity. This experiment compares Compound IVd purified via method A of FIG. 2 with Compound IVa of FIG. 1 which purified by conventional distillation.
The experimental traps utilized have been previously described and the following Table 7 represents the data obtained over a 6-week monitoring period.
TABLE 7______________________________________Monitoring Sample PreparationsPeriod Experiment #1 Experiment #2 IVd IVa(Weeks) IVd IVa IVa IVa (total) (total)______________________________________1 159 7 40 3 199 102 160 3 118 6 278 93 99 1 143 4 242 54 117 6 150 18 267 245 66 1 41 0 107 16 11 1 26 0 37 1 612 19 518 31 1130 50______________________________________
As can be seen from the above table, this experiment was run in duplicate and consistently Compound IVd which was prepared according to FIG. 2, procedure A, was far superior in activity to Compound IVa which is the material of FIG. 1 purified by conventional distillation. The above table clearly demonstrates the fact that (.+-.)-serricornin cannot merely be distilled in order to obtain enhanced activity, i.e., see the results with Compound IVa, but the entire purification process, as well as the synthesis process, must be utilized in order to obtain superior results.
EXAMPLE 16
The following examples will again illustrate that merely carrying out the purification procedure, as set forth in FIG. 2, on any (.+-.)-serricornin does not result in the improved results of the instant process. In these examples which were run in duplicate, a sample of a commercial pheromone provided by the British American Tobacco Company for its Lasiotrap.RTM. cigarette beetle was tested in the manner previously described. As received, this material is labelled A. A sample of A was purified via route A of FIG. 2 and this material is labelled B.
Both of the materials were evaluated for cigarette beetle attraction over a 6-week monitoring period with the following results.
TABLE 8______________________________________Monitoring Sample PreparationsPeriod Experiment #3 Experiment #4 A B(Weeks) A B A B (total) (total)______________________________________1 349 97 121 3 470 1002 244 49 218 36 462 853 81 50 112 46 193 964 100 41 140 6 240 475 84 9 300 26 384 356 3 0 14 3 17 3 861 246 892 120 1766* 366*______________________________________ *Significantly different (at the 0.05 confidence level) based on statistical analysis of variance and covariance with repeated measures (J Tindall). British American Tobacco (BAT) Lasiotrap .RTM. pheromone unmodified British American Tobacco (BAT) Lasiotrap .RTM. pheromone purified via ste V as per the invention record Scheme I. (#) Alternate warehouse that traps were moved to for duration of the study (last 2 weeks) since original warehouse were being fumigated.
As can be seen from the two experiments above, the pheromone purified via procedure A of FIG. 2 actually gave poorer performance with regard to the number of adult cigarette beetles trapped than did the unmodified material. Thus, the mere application of the purification technique of FIG. 2 to any pheromone does not result in enhanced activity.
EXAMPLE 17
The following example will demonstrate how Compound IVa of FIG. 1 was distilled in the tests above reported in Example 15.
Compound IVa (10.0 g, 0.5 moles) was distilled on a short path distillation apparatus (short path distillation head) with attached Vigreaux distillation column (30 mm). The distillation at 50-72.degree. C. and 0.080 mm gave a 43.3% yield of distilled IVa (4.33 g, 0.023 mole).
TABLE 9______________________________________Temp (.degree.C.)Pot Head Vacuum (mm of Hg) Result______________________________________R.T. R.T. 0.20-0.080 Nothing collectedR.T.-100 R.T.-50 0.080 Start of distillation100-120 50-72 0.080 4.33 g distilled IVa120-150 72-45 0.080 Nothing collected______________________________________
__________________________________________________________________________GLOSSARY__________________________________________________________________________Serricornin: (4S, 6S, 7S)-4,6-Dimethyl-7-hydroxy-3-nonanone The terms Serricornin and (.+-.)-Serricornin have been used throughout this application to refer to both open and hemiacetal (closed) forms:(.+-.)-Serricornin: 4,6-Dimethyl-7-hydroxy-3-nonanone (NOTE: See above)Enantiomeric pair: Stereoisomers which are related as object and nonsuperimposable mirror image.Enantiomer: One of enantiomeric pairOptical isomer: An enantiomerDiasteriomer: Stereoisomer which is not an enantiomerIsomers: Chemical species which have the same molecular formula but differ in structure and are separated by energy barriers.Constitution of a molecule: The description of the sequential arrangement of atoms regardless of the direction in space.Chiral Carbon or Asymmetric Carbon Atom: A carbon to which four substituents are attached which differ in the sense that exchange of any two gives a new stereoisomerAnhydroserricornin: (5S,6S)-2,6-Diethyl-5,6-dihydro-3,5-dimethyl- 2H-pyran [NOTE: This term also used in the literature to refer to the racemic anhydroserricornin (See (.+-.)-anyhdroserricornin)]Racemic Compound: An equal mixture of enantiomers(.+-.)-Anhydroserricornin: 2,6-Diethyl-5,6-dihydro-3,5-dimethyl-2HpyranR* or S*: Designates racemic carbon and equivalent of mixture of 1:1 R and S.Stereoisomers: Molecules with the same constitution but differing, as isomers, in the spatial arrangement of these atoms.Threo Isomers: Stereoisomer with the substituents on the opposite sides of the Fischer projectionErythro Isomer: Stereoisomer with the substituents on the same side of the Fischer projection.Threo Isomers of Serricornin: The 6,7-threo diasteriomers which are compounds IV.1-IV.4.Erythro Isomers of Serricornin: The 6,7-erythro diastereomers which are compounds IV.5-IV.8.__________________________________________________________________________

Novel process for the production of 4,6-dimethyl-7-hydroxynonan-3-one

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