CA1127159A - Derivatives of 3-azabicyclo(3.1.0)hexane and processes for their preparation - Google Patents

Abstract

ABSTRACT
The compound 3-benzyl-3-azabicyclo[3,1,0]hexan-2,4-dione, and a process for its preparation, is described. This compound finds use as an intermediate in the preparation of 2-carboxy-3-azabicyclo[3,1,0]hexane, which has valuable biological properties.

Description

This application is divided out of copending Canadian application serial number 329,751, filed June 14, 1979.
This invention relates to derivatives of 3-azabicyclo[3.1.0]hexane and processes for their preparation.

2-Carboxy-3-azabicyclo[3.1.0]hexane and certain of its salts and esters have very valuable biological properties, being capable of sterilizing the male anthers of plants. The 3-azabicyclohexane ring structure is, however, extremely difficult to synthesize.
The applicants have described in application 329,751 that 3-benzyl-3-azabicyclo[3.1.0]hexane can be synthesized and used as an intermediate for the preparation of 2-carboxy-3-azabicyclo[3.1.0]hexane and derivatives thereof.
Application 329,751 also provides a process for the preparation of this compound, which comprises reacting the compound 3-benzyl-3-azabicyclo[3.1.0]-hexan-2,4-dione, which has the formula:

/ ~ N

with a complex aluminium hydride reducing agent, thereby selectively reducing the carbonyl groups.
Preferred reducing agents are lithium aluminium anhydride and, espe-cially~ sodium bis-(2-methoxyethoxy)-aluminium dihydride or sodium aluminium di-ethyl dihydride.

llZ7159 Suitably an excess of the aluminium hydride reducing agent is used.
Depending on the specific reducing agent, an excess of up to six-fold, preferably up to two-fold, may be used. Preferably from lO to 40%, for example 20 to 40%
excess is used. Any suitable solvent, for example an aromatic hydrocarbon, such as toluene, or an ether, may be used. The hydride reducing agents are often marketed as solutions or dispersions in liquid hydrocarbons. Such products can be used directly, the hydrocarbon not interfering with the desired reaction, or the hydrocarbon may be removed. The reduction is preferably effected by mixing the reactants and heating the stirred mixture to a moderately elevated tempera-ture, for example 50C to 120C. If preferred, the reactants can be mixed ini-tially at a low temperature, for example 0 to 15C, and then heated together.
; The resulting mixture is then suitably treated with water or an aqueous solution of an alkali metal base to destroy the excess reducing agent, and is filtered ~ to remove inorganic salts and stripped of solvent ~o yield the crude desired ; product, from which the pure product can be isolated by conventional techniques.
Alternatively, a phase separation step may be useful.
Thus this invention provides the compound 3-benzyl-3-azabicyclo[3.1.0]-hexan-2,4-dione.
The compound of the general formula II may be prepared by reacting cis 1,2-cyclopropane dicarboxylic acid or the anhydride thereof, with benzylamine, and the invention therefore also provides this novel process. Preferably the acid or anhydride is treated with a substantially equimolar amount of benzylamine~
at amoderatelyelevatedtemperature, for example at a temperature of from 150C
to 200C. If desired, the reaction may be carried out in the presence of a suitable solvent, for example water or in the absence of a solvent, water being distilled off from the reaction mixture during the course of the reaction. Pre-ferably the reaction is carried out in the presence of a solvent which is an ~ ~ , llZ~59 azeotroping agent, so that water may be removed during the reaction. Xylene is especially suitable. The product can, if desired, be recovered from the final reaction mixture by any suitable method, for example by removing any water which has not been distilled off during the course of the treatment, and pouring the crude product (ordinarily an oil) into a suitable liquid medium, for example isopropyl alcohol, in which the desired product is at most only sparingly soluble, but which is a solvent for any unreacted material and any by-products. Alter-natively, the product can be further reacted in situ.
If free cis 1,2-cyclopropane dicarboxylic acid, rather than its an-hydride, is used as starting material, it may be in admixture with the trans acid without any adverse effect on the course of the reaction, since the trans acid forms a polymer which can be removed at any convenient stage in the reaction.
A preferred procedure involves dehydrating the mixed cis and trans acids to form the cyclic eis anhydride and the polymeric trans anhydride, and then distilling off the cis anhydride to use in the subsequent reaction.
1,2-Cyclopropane dicarboxylic acid and its anhydride can be prepared by treatment of a diester of the acid, as described in Journal of the American Chemical Society, Vol. 80, pages 6568 - 6572 (1958).
The compound of the general formula I may be converted into 3-azabi-cyclo[3.1.0]hexane, which has the formula:
A
> ~III) N

by hydrogenolysis of the N-benzyl bond. This hydrogenolysis is suitably effected ., . ' ~ '~, ' .

by catalytic hydrogenation using a noble metal, preferably a palladium catalyst.
The ben~yl compound is hydrogenolyzed under mild conditions, preferably using a palladium-on-carbon catalyst. Room temperature, for example a temperature up to 50C, or somewhat above, is generally suitable. Suitable hydrogen pressures are in the range of from 1.5 to 30, for example 2.5 to 7 atmospheres gauge. Low pressures, for example 1.5 to 2 atmospheres gauge, may be very suitable. Suit-able solvents include the lower alkanols, for example ethanol or, especially, ; methanol.
Isolation of the 3-azabicyclo[3.1.0]hexane may be facilitated by con-verting it to its hydrochloride salt, which is non-volatile.

3-Azabicyclo[3.1.0]hexane may be converted into 2-carboxy-3-azabicyclo-[3.1.0]hexane as described in our co-pending Canadian application Serial No.
329,752.
The following Examples illustrate the invention. In these Examples, the identities of intermediate and final products were confirmed by appropriate chemi-cal and spectral analyses.
Example 1 - (A) Preparation of (cis,trans)-1,2-cyclopropanecarboxylic acid ~1) With exclusion of moisture, a stirred mixture of 43.3 g ~1.01 mol.) of 56% sodium hydride-mineral oil dispersion in 200 ml of toluene was treated with 10 - 20 ml of a blend of 100.1 g ~1 mol.) ethyl acrylate and 122.6 g ~1 mol,) ethyl chloroacetate followed by several drops of ethanol. After an induction period of about 1 hour, steady gas and heat evolution began. Then the remaining mixed ester reagent was carefully added dropwise with ice-bath cooling so as to maintain a reaction temperature of 30 - 38C. After addition was completed ~4 hours), the mixture was cooled, washed with water, and dried ~MgS04). Dis-tillation gave diethyl (cis,trans)-1,2-cyclopropanedicarboxylate, ~lA), as a colourless liquid, b.p.: 78 - 89C. ~0.7 Torr.). ~Literature value: 50 - 90C

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- . ~

~1 Torr.)).
Saponification of 190.1 g (1.02 mol.) of lA was achieved with 116.0 g (2.90 mol.) of sodium hydroxide in 780 ml water at reflux for 5 hours. After removal of ethanol with a rotary evaporator, the remaining solution was acidified with a slight excess of 12N hydrochloric acid (268 ml, 3.2 mol.). The resulting mixture was stripped to dryness. The solid residue was extracted with hot ethyl acetate (3 x 500 ml). Evaporation of solvent from the dried (MgS04) extracts gave 1, m.p.: 108 - 128C (with gas evolution).
; (B) 3-Benzyl-3-azabicyclo[3.1.0~hexane-2,4-dione (2) A mixture of 128.1 g (0.984 mol.) of 1, 100 ml of water, and 105.5 g ~0.984 mol.) of benzylamine was heated at 180C, for 2 hours, while water was allowed to distill out. The mixture then was cooled somewhat and the warm mix-ture was slowly poured into 1000 ml of isopropyl alcohol. The mixture was thoroughly chilled and filtered to give impure 2, m.p.: 90 - 150C. The major byproduct appears to be a non-cyclic material formed from the trans-isomer of the acid. It is not very readily separated from 2. It does not~ however, inter-fere in the subsequent reduction of 2, but forms a by-product from which 3 is readily separated (step C(i)).
(C) 3-Benzyl-3-azabicyclo[3.1.0~hexane (3) (i) 142.3 g (0.707 mol.) of the product of step B were added, in portions, to an ice-cooled and stirred suspension of 105.6 g ~1.59 mol.) of 57.2% lithium ~ aluminium hydride/mineral oil dispersion in 2000 ml of tetrahydrofuran, the tem-; perature of the mixture being maintained at or below 15C. The mixture was cautiously brought to reflux temperature and refluxed for 4 hours, and was then allowed to stand overnight at room temperature. Then, 200 ml of 50% sodium hydroxide solution, followed by 150 ml of water, were added over a 3 hour period.
Celite was added and the mixture was filtered to remove inorganic salts. The llZ7159 filtrate was dried ~MgS04), the solvent was evaporated, and the residue was distilled in the presence of several drops of Dow Corning Antifoam A, to give 3, b.p.: 73 - 74 (0.01 Torr.).
~ ii) 63.2 g ~0.486 mol.) of 1 were added in portions to 150 ml of thionyl chloride. The mixture was refluxed for 1 hour, then was stripped. The residue was distilled to give cis-1,2-cyclopropane-dicarboxylic acid anhydride (3~i)), b.p.: 134C (10 Torr.). 2.14 g ~0.02 mol.) of ben~ylamine were carefully added to 2.24 g ~0.02 mol.) of 3~i); the reaction was very exothermic. The mixture was heated to 180C for 2 hours. After cooling, the residue was recrystallized from isopropyl alcohol to give 3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione, as white needles, m.p.: 90 - 91C ~3~ii)). A cooled ~0) solution of 305 ml ~1.09 mol.) of 70% sodium bis~2-methoxyethoxy)-aluminium hydride in benzene diluted with 600 ml of ether was treated with 48.7 g ~0.25 mol.) of 3~ii). The mixture was stirred at 0 for ~ hour and refluxed for 3 hours. After standing at room temperature overnight, excess metal hydride was destroyed by cautiously adding cold water. The mixture was filtered after addition of diatomaceous silica ~Celite). The ether layer was removed and the aqueous layer was extracted with ether. The combined organic layers were dried ~MgS04). Ether and 2-methoxy-ethanol were evaporated under reduced pressure to give 3, as an Oil. Distilla-tion gave 3, b.p.: 79 - 80C ~0.01 Torr.).
(D) 3-Azabicyclo[3.1.0]hexane ~4) Catalytic hydrogenation ~2.05 g, 10% palladium-on-charcoal) of 40.5 g ~0.234 mol.) of undistilled 3, procedure ~ , in I50 ml ethanol was carried out with a Parr apparatus ~4~ atmospheres gauge initially, room temperature) over-night. After filtration of catalyst, ethanol was fractionally distilled through a 40 cm Vigreux column. The product contained detectable ~MMR~ amounts of ethanol. Two fractions were collected: b.p.: 104 - 110C, 7.78 g, purity 84%

.

~lZ7~59 and b.p.: 110 - 114C, 9.00 g, purity 94%. The relative amounts of 4 and im-purity ethanol in these fractions were determined by MMR analysis.
(E) 3-Azabicyclo[3.1.0]hexane hydrochloride (5) 82.6 g (0.476 mol.) of 3, procedure (i), in 100 ml of absolute alcohol, were catalytically hydrogenated (4 g, 10% palladium-on-charcoal) in a Parr appa-ratus for 5 days at room temperature, the pressure of the hydTogen being main-tained at 4~2 atmospheres gauge. The catalyst was removed, 39.7 ml (0.476 mol.) of concentrated hydrochloric acid were added and the solution was concentrated under reduced pressure. The last traces of water and ethanol were removed by azeotropic distillation with benzene to give 5, m.p.: 158 - 161C. An analyti-cal sample, m.p.: 161 - 163C (with gas evolution), was obtained by trituration of the above product with cold isopropyl alcohol.
Example 2 - (A) Cis- and trans-diethylcyclopropane 1,2-dicarboxylates A 50 litre glass reactor equipped with a stirrer, addition funnel, thermowell and condenser was blanketed with nitrogen. Sodium hydride (6360 g, of 50% in oil, 132.5 M) was charged and washed three times with dry toluene (5 litres, 2~2 litres, 3 litres), the solvent being successively removed with a filter stick. Addition of dry toluene (6 litres) was followed by a portion (1 litre) of a mixture of ethyl chloroacetate (16.2 kg, 132.5 M) ethyl acrylate (13.25 kg, 132.5-M, stabilized with 0.02% hydroquinone) and dry toluene (12 litres). The slurry was stirred and absolute ethanol (3 ml) added as initiator to minimize the induction period. Reaction commenced after about an hour. Cooling with isopropanol/solid carbon dioxide was applied lowering the internal temperature to 10C. The addition of mixed esters-toluene feedstock was then continued at such a rate as to maintain a pot temperature in the range 10 - 20C, with the cooling bath at -20 to 40C. The overall addition time was 11~2 hours and re-action was essentially complete after a further 2 hours.

.`'' ~ .

~715~

After stirring overnight the contents were cooled to 5C and a solu-tion of glacial acetic acid ~1.5 litre, 26M) in toluene ~3 litres) slowly added, bringing the pH to approximately 6. This mixture was then slowly added with vigorous agitation to a 100 litre vessel containing water ~12.5 litres) cracked ice ~10 kg) and concentrated hydrochloric acid ~4.5 litres).
High acidity was maintained throughout this operation. A further por-tion of water 25 1 was used for transfer purposes. Phases were separated and the organic layer washed with demineralized water ~10 litres). The combined aqueous solution was re-extracted with toluene ~5 litres). Toluene was removed on rotary evaporator at 60/25 mm to give crude product ~27.9 kg, c /trans ratio 75/25).
Claisen distillation afforded mixed cis-and trans-diethyl cyclopropane 1,2-dicarboxylates, b.p.: 75 - 90 at 0.5 - 1 mm Hg ~18.08 kg, c /trans =
72/28); yield = 73% based on starting esters.
~B) Cyclopropane 1,2-dicarboxylic anhydride (6) Mixed diethylcyclopropane 1,2-dicarboxylates ~28.3 kg, c /trans 72/28 152.2 M), formic acid ~70 litres of 98%, 1818 M) and concentrated sulphuric acid (610 ml of 98%, 11.2 M) were brought to reflux with stirring in a 100 litre ; glass reactor. Ethyl formate was distilled off. The reaction was shut down and allowed to cool overnight. Sodium formate ~1.7 kg, 25 M) was added to neutralize sulphuric acid catalyst and formic acid removed in vacuo by rotary evaporation; the crude mixed acids containing sodium sulphate weighed 22.7 kg at this stage. Crude acids were dissolved in acetic anhydride ~40 litres) at 40 - 50 and dehydrative cyclization effected by addition of this solution to stirred acetic anhydride ~10 litres) maintained at 135. This required 1~ hours and reaction was 'finished' for a further 1 hour at 125 - 140. After cooling to 20, insoluble material ~sodium sulphate) was removed by filtration through a . ~ . :

11~,7159 Celite pad. Acetic acid and excess acetic anhydride were removed by rotary evaporation in vacuo.
Claisen distillation, after removal of light ends afforded 6, b.p.
105 - 120 at 0.2 to 1.0 mm Hg ~10.4 kg, 92.9 M) which readily crystallized on cooling, m.p.: 55 - 60. The yield over the acidolysis and dehydration steps was 85% based on cls-content of the cyclopropane di-ester. Still bottoms weighed 5.19 kg and consist of polymeric trans-anhydride.
(C~ 3-Benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione (7) A 10 litre stirred reaction flask was charged with 6 (3.37 kg, 30.1 M) and the temperature raised to 75. Heating was discontinued and benzylamine (3.22 kg, 30.1 M) was added cautiously. The temperature rose over one hour to 160 at which point 2 kg had been fed. Heating was resumed to maintain 155 -165 whilst removing water in a gentle current of nitrogen via a Dean-Stark trap.
Benzylamine addition was complete after 2~ hours, and the reaction was 'finished' at 175 - 180 for a further 1~ hours. The reactor contents were allowed to cool to 110 and added with stirring to isopropanol ~12.5 litres).
After cooling to 10, product was recovered by filtration. Air drying gave 7, (5.44 kg, 27.1 M), m.p. 93 - 95, which represents a 90% yield on 6.
(D) 3-Benzyl-3-azabicyclo[3.1.0¦hexane (8) A 250 litre anchor stirred glass-lined reactor was purged and blanketed with nitrogen. Sodium bis-~2-methoxyethoxy)aluminium dihydride (63 kg, 61.5 litres of 70% w/v in toluene, 212.5 M) and dry (azeotropically) toluene (25 li-tres) were then charged and brought to 60. 7 (17.1 kg, 85 M) was dissolved in dry toluene at 60 (85 litres) and added over a period of 3~ hours to the reduc-ing agent with no external heating. The temperature rose from 60 to 110 duringthis time. Reaction was 'finished' for ~ hour at 110. After cooling to 10, a solution of sodium hydroxide (8.5 kg, 212.5 M) in water (80 litres) was run in : . :' .. .; ; :

1~7159 slowly. After the first 1.5 litre had been added, hydrogen evolution ceased and the temperature was easily controlled at 15 - 25 by water cooling: total caustic addition time was 1~ hours.
The organic layer was washed with demineralized water (30 litres) and the combined aqueous layers re-extracted with toluene (10 litres).
Removal of solvent in a rotary evaporator gave crude product (15.48 kg).
- Claisen distillation afforded 8, b.p., 95 - 100C at 0.2 - 0.5 mm Hg (13.57 kg, 78.4 M) in 92% yield.
(E) 3-Azabicyclo[3.1.0]hexane (9) 5% Palladium-on-carbon (250 g) was slurried with methanol (1.2 litre) which had been cooled to -70~. 8 (2.6 kg, 15.0 M), the catalyst slurry and an additional portion of methanol (4 litres) were loaded into a 10 litre anchor stirred stainless steel autoclave. The vessel was closed, purged three times with nitrogen, twice with hydrogen and finally to 18 atmospheres gauge with hydrogen. After 4 hours the pressure was boosted to 28 atmospheres gauge and maintained at this value overnight. After 21 hours the conversion of starting material was 95%. A further 4 hours reaction (25 hours total) resulted in com-plete disappearance of 8.
Catalyst was removed by filtration and washed with methanol. Toluene, methanol azeotrope was distilled off. 9 was obtained in 95% yield. A nitrogen blanket was maintained throughout.

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Claims (8)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. 3-Benzyl-3-azabicyclo[3.1.0]hexan-2,4-dione.

2. A process for the preparation of 3-benzyl-3-azabicyclo [3.1.0]hexan-2,4-dione characterized in that it comprises reaching cis-1,2-cyclopropane dicarboxylic acid or the anhydride thereof with benzylamine.

3. A process as claimed in claim 2 wherein the benzyl-amine and the cyclopropane derivative are heated together at a temperature of from 150 to 200°C, and water is distilled off during the reaction.

4. The process as claimed in claims 2 or 3 wherein the reaction is carried out in the presence of a solvent which is an azetroping agent for water.

5. The process as claimed in claims 2 or 3 wherein the reaction is carried out using xylene as a solvent.

6. A process as claimed in claim 2 wherein free cis 1,2-cyclopropane dicarboxylic acid is used as starting material.

7. A process as claimed in claims 2 or 6 wherein the cis 1,2-cyclopropane dicarboxylic acid reactant is present in admixture with its trans isomer.

8. A process as claimed in claim 2 wherein the cis 1,2-cyclopropane dicarboxylic acid reactant is obtained by dehydrating a mixture of cis and trans 1,2-cyclopropane di-carboxylic acids to form cyclic cis anhydride and polymeric trans anhydride followed by distillation to recover the cyclic cis anhydride from the polymeric trans anhydride.