CA1117128A

CA1117128A - 2-cyano-3-azabicyclo(3.1.0)hexane

Info

Publication number: CA1117128A
Application number: CA000335722A
Authority: CA
Inventors: Derek A. Wood; Ronald F. Mason
Original assignee: Shell Canada Ltd
Current assignee: Shell Canada Ltd
Priority date: 1978-10-27
Filing date: 1979-09-17
Publication date: 1982-01-26
Also published as: DK451379A; ZA795723B; JPS6232188B2; JPS5559166A

Abstract

ABSTRACT
"Process for the Preparation of Pyrrolidine derivatives"

2-cyano-3-azabicyclo ¦3.1.0] hexane, useful as an intermediate in the preparation of the corresponding acid, and certain derivatives thereof, may be prepared by reacting a compound of the general formula II and/or the trimer thereof:

Description

2~

~'Process for the preparation of pyrrolicllne derivatives"
Tllis invention reLates to a process for the preparation of 2-cyano-3-azabicyclo r3.1.0~ hexane and certain derivatives thereof.
2-carboxy-3-azabicyclo L3.1.0~ hexane and certain salts and esters thereof have useful biological properties, being capable of sterilising the male anthers in plants. Therefore there is considerable interest in methods for the preparation of these compounds. The available preparation methods, however, have proved to be relatively complex. One possible synthetic route involves the hydrolysis of the corresponding 2-cyano compound, but so far this cyano compound could not be easily synthesised.
Canadian Patent Application No. 321,300 discloses that 2-cyano-3-azabicyclo ~3.1.~ hexane and certain substituted derivatives thereof can be prepared by reaction of the corresponding 2-cyano-4-oxo compound with a trialkyl oxoniumfluoroborate and subsequently with a reducing agent. This reaction however is a two-step process which may require the use of expensive reagents.
Canadian Patent Application No. 329,752 discloses that 2-2Q cyano-3-azabicyclo [3.1.~ hexane can be prepared by reacting 3-azabicyclo [3.1.~ hex-2-ene with an alkali metal bisulphite, and subsequently wi~h an alkali metal cyanide. This process too is a two-stage process.
A process has now been found by which a cyano group can be introduced into the bicyclohexane ring system in a single step.
The invention provides a process for the preparation of a compound of the general formula ~".,~
.
~, ' , ~ -, ~ ~

7~2~

R ~ / \ ~ Rl (I) ~ N ~
I

H

i h f Rl R2 R3 R4 RS J R6 and R7 independently re-presents a hydrogen atom or an alkyl group of up to 4 carbon atoms, characterizecl in that a compound of the general iormula II and/or the trimer thereof:

R ~ R2 R7 ~ N ~
h ein Rl R2 R3 R4 R5 R6 and R7 have the meanings given for the general formula I, is reacted with hydrogen cyanide.
Preferably~ Rl represents a hydrogen atom or an alkyl group ~; 10 of up to 4 carbon atoms~ e.g. a methyl group; and R2, R3, R4, : R5, R6 and R7 each independently represents a hydrogen atom or an alkyl group of up to 4 carbon atoms, for example a methyl group.
Most preferably, each of R , R2, R3, R4, R, R6 and R7 ~ !
, ., ,~".
'

3 ~7J.28 represents a hydrogerl atorn, The process accordine to the invention is suitably carried out in the preserlce of an iner-t solven-t, for example an alcohol, an e-ther such as diethyl ether or a hydrocarbon or chlorinated 5 hydrocarbon such as dichloroMe-thane. A mixture Or solvents may be used. The reaction temperature may for example be in the range of from 0 to 60 C, preferably 10 to 30 C. For example, the reaction may be conducted at the reflux temperature o~ the solvent usea.
It is however most conveniently conducted at room -temperature.
The molar ratio of the reactants may vary over a wide range.
An excess of hydrogen cyanide, for example up to a 5-fold, preferably up to a 3-fold, especially up to a 1.5 fold, excess, may be used, or an approximately stoichiometric amount may be used.
The hydrogen cyanide may be generated in situ for example by 15 the action of a strong mineral acid on an alkali metal cyanide, or by the use of a cyanohydrin under alkaline conditions, but it is preferably added as such, in the form of a gas, a solution in the reaction solvent, or, preferably, a liquid, to the compound of the general formula II and/or the trimer thereof.
The compound of the general formula II and/or its trimer may for example be produced by direct oxidation of a compound of the general formula R R5 '~ ' R3 ~ __R2 R ~ ~ Rl (III) H

in which Rl-R7 ha~e the meanings given for the general formula I.
Manganese dioxide is a suitable reagent, and the oxidation can be 25 performed simply by stirring the compound of the generai formula III with manganese dioxide in the presence of a suitable solvent, for example a hydrocarbon such as benzene or light petroleum conveniently at room temperature.
Alternatively, the compound of the genera1 for~u1a II an~/or .

:~ ' 1~7~

its trimer n~ay be prodllced by dehydrohaloge~ation Or a compound of the general forrnl~a Rl~ R5 V

R3 A~ R2 >/\ X ( IV ) Hal i h f Rl R2 R3 Rl~, R5, R6 and R7 has the meaning given for the general formula I, and Hal represents a chlorine or 5 bromine atom.
The dehydrohalogenation may be carried out using any suitable dehydrohalogenating agent, for example a strong organic base such as triethylamine or pyridine in non-aqueous solution, or a strong inorganic base, for example sodium hydroxide, in aqueous or non-lO aqueous solution. Suitable polar solvents are f'or example ethers,alcohols, or water. The reaction is preferably carried out at a temperature of up to 150 C, preferably at a temperature in the range 20 to 80C. The process can conveniently be carried out at the reflux temperature of the solvent used.
It is believed that the dehydrohalogenation process leads to a solution consisting largely of the monomer of the general formula II. On removal of the solvent, a solid is produced which has a complex NMR spectrum and is believed to be the trimer:

n~

~; N- ~ N
. . Rl 1,~
:
~ illustrated here with substituents R to R7 not shown. When~
- 20 the solid trimer is re-dissolved, a solution is formed in which the trimer is in equilibrium with the monomer, the concentration of each species being dependent~on the dilution of the solution.

' ` - : ~.

,~ ~

~1~7~

Tile process uccording to the ;nven-t-ion may be carrled out irrespective of the rela-t:ive proportiorls Or monomer and trimer in the reac-tioln solu-tion.
T~ne compound of the general f`ormula IV may for example be 5 preparecl by the N-chlorination or N-bromination of a compound of the general ~orm~a III given above. Any suitable chlorinating or brominating agent may be used, for example an N-halo compound, for example N-bromo- or, especially, N chlorosuccinimide, or an inorganic hypohalite, for example sodium hypochlorite. Sodium lO hypochlorite may conveniently be used in the form of sodium hydroxide plus chlorine. This process is suitably carried out by admixing a slight excess o-f the halogenating agent with the compound of` the general formula IV. Any suitable solvent, for example an ether, may be used. The reaction may for example be 15 carried out at room temperature.
Thus the invention also provides a process for the preparation of a compound of the general formula I, which comprises converting a compound of the general formula III into a compound of the general formula II and/or the trimer thereo~, and reacting at 20 least part of` said compound with hydrogen cyanide.
The compounds of the general formula III wherein each of R1, R6 and R7 represents a hydrogen atom may be prepared by reacting a compound of the general formula R3 ~ R2 ~D ~ (v) wherein each of R2, R3, R and R5 have meanings given above, or 25 a mono- or di-acyl halide or a mono- or di-ester or the anhydride thereof, with ammonia and optionally water; e~fecting cyclisation by subjecting the resultant product to elevated temperature to produce a compound of the general formula ~1~7128 Rll R5 \/
R ~ ~ R2 / \ (VI) ~\ /
N
~1 wherein each of R2, R3 and R have the meanings given above; and reducing the carbonyl groups in -the 2 and 4 positions of the compound of the general formula VI, for example using lithium aluminium hydride. Compounds of the general formula IV wherein R , R
and/or R7 represent moieties other than hydrogen atoms, may be prepared by introducing these moieties by methods analogous to those known in the art.
A compound of the general formula I may be hydrolysed to form a compound of the general formula R3 ~ R
/ \ (VII) R6 / ~< Rl I

in which Rl - R7 have the meanings given above. Such compounds have interesting pollen-suppressing and plant growth regulating properties. The hydrolysis may for example be carried out by refluxing the compound of the general formula I in the presence~
of an aqueous acid. This hydrolysis may lead to an acid addition ~ ;

~L17~LZ~

salt o~ the compcund of the general rorMula VII. Refluxing of a compound of -the eenera:L f`orMula I in the presence of an alcohol and dry hydroeen chloride produces an ester of the compound of the general formula VII or the ~ICl salt -thereof.
Thus, -the invention also provides a process for the preparation of a compo~md o~ the general ~ormula VIII, or a salt and/or ester thereo~, which comprises hydrolysinK or alcoholising a compound o~ the general ~ormula I which has been prepared by the process according to the invention.
In the compounds o~ the general ~ormula I, the 2-cyano eroup may be cis or trans- to the ` ~R4R5 group, and in addition, for each of these geometric isomers, a pair o~ optical isomers exists due to the asymmetry of the 2-carbon atom. In addition, other geometric and/or optical isomers may exist depending on 15 the meanings of R4, R5, R6 and R7. In some applications of the process according -to the invention, certain isomers are formed exclusively; for example, when each of R , R , R3, R , R5, R and R represents a hydrogen atom, the process according to the invention generally leads exclusively to trans 2-cyano-3-azabicyclo 3.1.0 20 hexane As stated above, the compounds of the general formula I
may be converted, ~or example by treatment with strong acid, into -the corresponding 2-carboxylic acids. For example trans (D,~) 2-cyano-3-azabicyclo [3.1.03hexane may be hydrolysed to give trans 25 (D,L) 2-carboxy-3-azabicyclo r3.1.0~hexane. This preparation of a single geometric isomer may be extremely useful since, generally, a mixture of geometric isomers presents manufacturing and formulation problems as the two geometric isomers have different physical properties.
The process according to the invention is of particular interest for the preparation of trans 2-carboxy-3-azabicyclo ~3.1.0~hexane, or a salt and/or es-ter thereof, which may be prepared by hydrolysing or alcoholysing trans 2-cyano-3-azabicyclo ~3.1.0Jhexane ~rhich has been prepared by the reaction of a cornpound of the f`ormula I~ arld/or the triMer -thereof ~/ith hydroeen cyanide.
Thus, a preferred route for the preparation of trans 2-carboxy-3-a~abicyclo r3 ~ 1 . 0~ hexane comprises:
(i) converting 3-azabicyclo 3.1.0 hexane into 3-azabicyclo r3.1.~ hex-2-ene and/or the trimer thereof, for example by direct oxidation or by N-chlorination or N-bromination followed by dehydrohalogena-tion;
(ii) reacting the product from (i) with hydrogen cyanide to produce trans 2-cyano-3-azabicycloL3.1.0~hexane;
and (iii) hydrolysing or alcoholising the product from (ii) to produce 2-carboxy-3-azabicyloL3.1.0~hexane or a salt and/or ester thereof.
However, in some cases, the direct hydrolysis of a compound of the general formula I containing inorganic impurities, to a free acid of the general formula VII or an acid addition salt thereof, may be ~ather costly to perform on a large scale. The free acid is an amlno acid which is not distillable and is 20 soluble in both acidic and basic solutions. Thus, in order to obtain a product free from inorganic impurities, it is convenient to purify the product by passage over an ion exchange column using a series of aqueous eluants. This procedure is perfectly adequate in the laboratory, but may, on a larger scale, 25 become rather costly in view of the large volumes of demineralised water required for elution of the product.
The need for elution can be avoided by converting the compound of the general formula I obtained by the process according to the invention, into a lower alkyl ester of the acid of the general 30 formula VII, by alcoholysis using the corresponding a}kanol in the presence of a non-aqueous acid catalyst, suitably dry hydrogen chloride. Alkanols having 1 to 3 carbon atoms are suitable. The resulting ester is distillable, unlike the free acid, and can therefore be purified by distillation. Subsequently, the ester 35 can be hydrolysed, using water optionally containing a small quantity of a mineral acid, or aqueous ammonia, to produce 71~3 _ 9 _ ~he Pree acicl. Alkalirle hydrolysis s ~mdesirable, since this introduces inorganic ;ons in-to the reaction mixture, which need to be remo~ed on ~n ion exchange colu~n.
Ie it is required to produce relatively pure trans compounds, 5 the trans 2-cyano compound is preferab]y isolated or further reacted as soon as possible after its formation.
Thus the invention also provides a process for the preparation of an acid of -the general formula VII, which comprises alcoholising a compo~md of the general formula I which has been prepared by 10 -the process according to the inven-tion, using an alkanol having 1 to 3 carbon atoms; purifying the resulting ester by distillation;
and hydrolysing the purified ester using water optionally containing a catalytic amount of a mineral acid, or aqueous ammonia, to produce the desired acid. This process is especially advantageous 15 when the compound of the general formula I is trans 2-cyano-3-azabicyclo [3.1.0~hexane, since it provides a convenient method of preparing trans 2-carboxy-3-azabicyclo C3.1.0~hexane.
The following Examples illustrate the invention:
Example 1 20 Preparation of trans 2-cyano-3-azabicyclo r3.1.01hexane A slurry of N-chlorosuccinimide (23.6 g, 0.175 mol) in diethyl ether (500 ml) was stirred at room temperature under a nitrogen blanket while 3-azabicyclo~3.1. o3 hexane (8.4 g, 0.1 mol) was added. The mixture was stirred at room temperature for 22 25 hours under the nitrogen blanket, and was then filtered to remove succinimide. The filtrate was washed with two 100 ml portions of water and one 50 ml portion of a saturated aqueous solution of sodium chloride.
The combined filtrates were dried over Na2S04 and concentrated 3 to a volume of approximately 60 ml on a rotary evaporator at 20-25 C and approximately 60 mm Hg pressure. The remaining solution was added to 6.6 g of 85% potassium hydroxide in absolute ethanol (50 ml) at 5-10 C. An exothermic reaction occurred and the -temperature rose to 30C. The mixture was 35 stirred at room temperature o~ernight under nitrogen, and then filtered. Liquid hydrogen cyanide (5.4 g, 0.2 mol) was added to the filtrate and the temperature rose from 22C to 29C over .

~ . -' .

- L0 _ 5 mir~ute3. Tilc mixtllre was stirred for 1~ hours at room temperature and ~hen strippe~ on a rotary evaporator a-t 50 C -to give 11 g of an oily produc-t con-taining so~ne crystals.
Disti:LIation frorrl an oil bath yielded trans 2-cyano-3-aza-S bicyclo [3.1.03hexane, B.Pt. 56C a-t 0.1 mm Hg pressure. ~ield: 65%.
Example 2 Preparation of trans 2-carboxy-3-azabicyclor3.1.01hexane A slurry oP N-ch:Lorosuccinimide (l5g g, 1.2 mol) in diethyl ether (500 ml) was stirred at 20 C whilst 3-azabicyclo~3.1.03 hexane (83 g, 1.0 mol) was added over 30 minutes. The mixture was stirred for a fur-ther 1.5 hours, and then filtered to remove the succinimide. The filter pad was washed with two 50 ml portions of diethyl ether and the filtrates were combined.
A solution of sodium hydroxide (48 g, 1.2 rnol) in methanol (300 ml) was added to the diethyl ether solution of N-chloro-3-azabicyclol3.1.0¦hexane, and when the initial exothermic reac-tion had subsided, the mixture was stirred and refluxed overnight (16 hours)~ After cooling to 20 C, an excess of liquid hydrogen cyanide (40 g) was added to this solution o~ 3-azabicyclol3.1.0J
hex-2-ene, and the mixture was stirred for 1 hour.
6N hydrochloric acid (800 ml) was added to the resulting solution of trans 2-cyano-3-aæabicyclo L3.1.0~hexane, and the reaction mixture was heated at 100 C for 3 hours, during which period the diethyl ether and methanol distilled off, leaving an aqueous acidic solution which was then treated on the X+ form of an ion exchange resin using aqueous ammonia as eluent. Re-rystallisation from aqueous isopropyl alcohol gave 77.7 g of a white crystalline material, M.Pt. 248-250 C (with decomposition).
Analysis showed this product to be isomerically pure trans (D,L) 30 2-carboxy-3-azabicycloL3.1.0]hexane, with a chemical purity of 98.3%. Overall yield from 3-azabicyclo r3.1.0Jhexane: 61.2%.
Example 3 Preparation of trans 2-carboxy-3-azabicyclo¦3.1.01hexane under acid conditions 3-azabicyclo L3.1.0~ hexane (0.15 mol) was treated with N-c :orosucclnimlde and t~en with potassium h~droxi:e as in Ex~mp1e .

~79LZ~

1. 'L'he resultirlg solution was treated with 20 ml 10 M ~ICl in ethanol. The tempera-ture was held belo~ 10 C by cooling on an ice bath. The resulting mix-ture was then treated with liquid hydrogerI cyanide (7.7 ml, 0.2 mol) at 10-13 C. The reaction mixture was -then allowed to reach room temperature and stirred for 2 hours. The p~I was approximately 2.
The mixture was then strippe~ of solvent in a rotary evaporator to give a very viscous orange oil, which was purified by distillation. The resulting product was hydrolysed usin~ 6N
hydrochloric acid as in Example 2, to give 2-carboxy~3-azabic~clo C3.1.0~ hexane-2-carboxylic acid. 13C ~MR revealed no cis-isomer present.
Example 4 Preparation of trans_2-cyano-3-azabicycloL3.1.0Jhexane under alkaline conditions The procedure of ExarQple 3 was repeated except that the ~ICl was replaced by 1.5 ml of triethylamine. The pH of the reaction mixture after addition of hydrogen cyanide was 9-10.
3C NMR showed that the product was trans 2-cyano-3-aza-bicyclo¦3.1.0~hexane, with no cis-isomer present.
Example 5 - Preparation of trans 2-carboxy-3-azabicyclo r3.1.01hexane via the corresponding ethyl ester ~-chlorosuccinimide (4.01 kg, 30 mol) was suspended in 12.5 1 diethyl ether, and 3-azabicyclo~3.1.0~hexane (2.08 kg, 25 mol) was added over 80 minutes. The temperature was held within the range 11 to 22 C during the addition and then within the :
range 18 to 20 for a further 2 hours. The reaction mixture was then filtered, and added over 2 hours to a solution of sodium hydroxide (1.2 kg, 30 M) in ethanol (10 1) under a blan~et of nitrogen and at a temperature of 10 C. The temperature rose to 23C, and then over the next hour to 38C. The mixture was then refluxed for 6 hours, and cooled to 10C.
Liquid hydrogen cyanide (844 g~ 31.25 mol) was added over 30 minutes and stirring was continued at room temperature for a further hour. The~resulting mixture was filtered, and then ~dde~ ~ver 20 mlDutes to 22.~ 1 absol~te ethn~o c~ntaining 1.3 ~g :

, ' " - ' ' ~7~

(200 mol) anhydrouc; hy(lroeerl chLoride maini;airled at a-temperature bctween -10 and -~? C. ~t t'ni~ stage a ~ul-ther batch of trans 2-cyano-3-azabicyclo[3.1.0~hexane solu-tion, prepared from 50 mol 3-azabicycloL3.1.01hexane, was also added to the reaction mixture.
S Ether was then distllled off, fmd the mixture was re~luxed for

4 hours and then cooled to -5 C. Anhydrous ammonia was passed into the reaction mixture for 2 hours, un-til -the pH was 10Ø
The reaction mixture was filtered, and the solvent ~as stripped on a rotary evaporator.
There were obtained 5.42 kg of 2-ethoxycarbonyl-3-azabicyclo L3.1.0~hexane, which was shown by ~TMR to be chemical]y 99% pure and to contain 96% trans isomer. This represents an overall yield of 70% based on 3-azabicyclor3.1.0~hexane.
This preparation was repeated several times. 8.3 kg (53.3 mol) of the prepared trans 2-ethoxycarbonyl-3-azabicycloC3.1.~hexane were added over 1 hour to 217 mls of concentrated hydrochloric acid in 83 1 water, under reflux. Heating was continued for a further 2~ hours during which time ethanol was distilled off.
Water was then stripped from the reaction mixture in a rotary eYapOratOr until crystals formed. Isopropyl alcohol was added, and the resulting precipitate was filtered and -the solid residue was washed with isopropyl alcchol and then hexane and air dried.
The product was 5.o8 kg (40 mol) 2-carboxy-3-azabicycloi3.1.0 hexane, 98% of which was the trans isomer. This was a yield of 75% based on the corresponding ethyl ester.
A further crop of 1.20 kg of 2-carboxy-3-azabicycloL3.1.0J
hexane was obtained from the washings and flltrate. This crop had a trans:cis ratio of 33:65.

.~

Claims

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

1. A process for the preparation of a compound of the general formula (I) wherein each of R1, R2, R3, R4, R5, R6 and R7 independently represents a hydrogen atom or an alkyl group of up to 4 carbon atoms, characterized in that a compound of the general formula II and/or the trimer thereof:

(II) wherein R1, R2, R3, R4, R5, R6 and R7 have the meanings given for the general formula I, is reacted with hydrogen cyanide.

2. A process as claimed in claim 1, characterised in that a starting material is used in which each of R1 to R7 represents a hydrogen atom.

3. A process as claimed in either of claims 1 or 2, characterised in that liquid hydrogen cyanide is used as reactant.

4. A process as claimed in claim 1, characterised in that the reaction temperature is in the range of from 0 to 60°C.

5. A process as claimed in claim 4, characterised in that the reaction temperature is in the range of from 10 to 30°C.

6. A process as claimed in claim 1, characterised in that an excess of hydrogen cyanide of up to 5 fold is used.

7. A process as claimed in claim 1, characterised in that there is used as starting material a compound of the general formula II and/or the trimer thereof which has been prepared by oxidation of a compound of the general formula (III) in which R1 to R7 have the meanings given for the general formula I.

8. A process as claimed in claim 7, characterised in that the compound of the general formula III has 'been directly oxidised to the compound of the general formula II and/or the trimer thereof, or has been indirectly oxidized by N-chlorination or N-bromination and subsequent dehydro-halogenation to give the compound of the general formula II and/or the trimer thereof.

9. A process as claimed in any one of claims 1, 2 and 7, characterised in that it also comprises a further step in which the compound of the general formula I is hydrolysed and/or alcoholised to produce a compound of the general formula VII or a salt and/or an ester thereof:
(VII) in which R1 to R7 have the meanings given for the general formula I.

10. A process as claimed in claim 5, characterised in that hydrogen cyanide is added to 3-azabicyclo[3.1.0]hex-2-ene and/or the trimer thereof to produce trans 2-cyano-3-3azabicyclo[3.1.0] hexane, which compound is hydrolysed and/or alcoholised to produce trans 2-carboxy-3-azabicyclo[3.1.0]hexane or a salt and/or an ester thereof.

11. A process as claimed in claim 1, characterised in that it also comprises the further step in which the compound of the general formula I is alcoholised using an alkanol having 1 to 3 carbon atoms; the resulting ester is purified by distillation; and the purified ester is hydrolysed using a mineral acid or aqueous ammonia to produce an acid of the general formula VII given in claim 3.