Cyclopropane derivatives are well documented in the art and can be synthesised in a number of ways. To date though, many of these prior art methods rely on the use of hazardous reagents and/or reaction conditions. In particular, such methods often involve the use and/or isolation of diazoalkanes which may be hazardous when used in the laboratory, and are potentially explosive, particularly when used in large scale operations.

It is well known in the art that the cyclopropanation of a double bond can be achieved by reacting an a-carbonyl diazo compound in the presence of a rhodium, iron, ruthenium, osmium, platinum, copper or palladium catalyst. For example, cyclopropanation using a rhodium catalyst is disclosed in the following references: (a) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J.; Pieters, R. J.; Protopopova, M.

N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L. and Martin, S. F. J. Am. Chem. Soc.

1995,117,5763; (b) Davies, H. M. L.; Ahmed, G. ; Calvo, R. L.; Churchill, M. R. and Churchill, D. G. J Org. Chem. 1998,63,2641; (c) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V. and Ruppar, D. A. J. Am. Chem. Soc. 1995,117,11021; (d) Doyle, M. P. and Kalinin, A. V. J Org. Chem. 1996,61,2179. The use of iron catalysts is discussed in Seitz, W. J.; Saha, A. K. and Hossain, M. M. Organometallics 1993, 12, 2604, and ruthenium catalysts are disclosed in Demonceau, A.; Abreu Dias, E.; Lemoine, C. A.; Stumpf, A. W.; Noels, A. F. ; Pietrasuk, C.; Gulinski, J. and Marciniec, B. Tetrahedron Lett. 1995,36,3519. Osmium catalysts are disclosed in Demonceau, A.; Lemoine, C. A. and Noels, A. F. Tetrahedron Lett. 1996,37,1025, and platinum catalysts are discussed in Boverie, S.; Simal, F.; Demonceau, A.; Noels, A. F.; Eremenko, I. L.; Sidorov, A. A. and Nefedov, S. E. Tetrahedron Lett.

1997,38,7543. The use of copper catalysts is documented in Doyle, M. P.;

Peterson, C. S.; Zhou, Q.-L. and Nishiyama, H. J. Chem. Soc. Chem. Commun.

1997,211. Finally, palladium catalysts are disclosed in Anciaux, A. J.; Hubert, A. J.; Noels, A. F; Petiniot, N. and Teyssie, P. J. Org Chem. 1980,45,695.

Diazoalkanes are extremely useful intermediates in organic chemistry as they can be transformed into a wide range of different compounds [Doyle, M. P.; Chem. Rev.

1986,86,919]. However, their instability and the dangers associated with their preparation restrict their use and applicability on a large scale.

Diazoesters, in particular, are valuable intermediates for a wide range of pharmaceutical compounds. More specifically, diazoesters are useful precursors for a class of compounds known as pyrethroids. The synthesis of pyrethroids has received considerable attention as they are a class of compounds which display excellent insecticidal activity but which are non-persistent in the environment [Davies, J. H."The Pyrethroid Insecticides", Leahey, J. P.; Ed. Taylor and Francis Ltd., 1985, p5]. The general structure of a pyrethroid is shown in Figure 1 and features a cyclopropane bearing gem dimethyl groups, an acid (or ester) group and an olefin functionality.

Figure 1 Alternative methods for preparing cyclopropane derivatives which avoid the use of diazoalkanes are also known in the art. However, many of these routes use alternative yet still hazardous reagents such as zinc carbenoids (i. e. the Simmons- Smith reaction) and are time-consuming, multi-step processes which involve costly reagents.

For example, one such process involves the double alkylation of an enolate ester, followed by a cyclization step [Perkin Jr W. H. Ber. 1883,16,1787]. Cyclopropane derivatives may also be synthesised via a Simmons-Smith reaction in which an alkene is reacted with diethyl zinc and diiodomethane [Simmons, H. E.; Cairns, T.

L.; Vladucuick, S. A.; Hoiness, C. M., Org React. 1973,20,1]. However, this reaction still involves the use of potentially hazardous reagents. Alternatively, cyclopropane derivatives may prepared by reacting a dichlorocarbene with an alkene. The two chlorine atoms may then be removed in subsequent steps [Castro, J.

L.; Castedo, L.; Riguera, R. J Org. Chem. 1987,52,3579].

The present invention seeks to provide a process for preparing a cyclopropane that avoids some or a number of the problems associated with the prior art processes.

In this respect, and in contrast to the prior art, the present invention provides a one- pot process for producing a cyclopropane from an amine, or salt thereof, via a diazoalkane intermediate. In the process of the present invention the diazoalkane intermediate is not isolated or purified from the reaction mixture.

Aspects of the present invention are presented in the accompanying claims and in the following description.

More specifically, the present invention relates to a process for preparing a cyclopropane ; said process comprising the following steps: (i) generating a diazoalkane from an amine, or salt thereof, in a reaction mixture; and (ii) forming said cyclopropane from said diazoalkane and an alkene-containing moiety; wherein said diazoalkane is not isolated or purified from said reaction mixture.

The present process avoids many of the hazards associated with handling diazoalkanes. More particularly, the present invention utilizes a catalyst in the cyclopropanation step which can withstand the conditions required to generate the diazoalkane in situ.

In a preferred embodiment, step (ii) of the process of the present invention is a catalytic coupling reaction.

More preferably, the catalytic coupling reaction is catalysed by a transition metal catalyst. Suitable transition metals include palladium, copper, rhodium.

In a preferred aspect of the invention, the catalyst comprises a transition metal porphyrin complex. Suitable porphyrin complexes include transition metal complexes of formula 1, or derivatives thereof wherein R is phenyl, binaphthyl, naphthyl, 2,4-dimethoxyphenyl, 4-methylphenyl, p-Cl-C6H4, p-alkyl-C6H4, 3,5- (alkyl) 2-C6H3, wherein"alkyl"is a branched or straight chain alkyl group, and is preferably a Cl-lo alkyl group.

More preferably, R is phenyl.

The term"derivative"encompasses structures having one or more substituents that do not affect the catalytic action of the compound.

In a highly preferred embodiment of the invention, the catalyst is a rhodium (III) complex of 5,10,15,20-tetraphenylporphyrin. More preferably, the catalyst is the iodide salt of a rhodium (III) complex of 5, 10,15,20-tetraphenylporphyrin.

In another preferred aspect of the invention, the catalyst comprises a transition metal complex of phthalocyanine 2, or a derivative thereof.

The term"derivative"encompasses structures having one or more substituents that do not affect the catalytic action of the compound.

Other catalysts suitable for use in the present invention include Rh2 (OAc) 4, PdC12, Pd (OAc) 2, Cu (OAc) 2, PdCl2 (CH3CN) 2, Pd (N03) 2. xH20, Cu-bronze, and catalysts of formulae Rh2 (OCOAr) 4, Rh2 (OCORf) 4, wherein Rf is (CF2) nCF3, and n is 0,1,2, 3.... 15, Rh2 (OCOCnHn l) 4, wherein n is 1,2,3.... 15, or derivatives thereof.

Further suitable catalysts include salen complexes of formula 3, or derivatives thereof, wherein each of R16 and Rl7 is independently aryl, or alkyl, preferably Cl-lo alkyl, or R16 and Rl7 are joined to form a cycloalkyl group; Rl8 is alkyl, preferably Cl l0 alkyl, and more preferably t-butyl; M is Mn and X is Cl ; or M is Cu and X is either absent or a solvent ligand.

Again, the term"derivative"encompasses structures having one or more substituents that do not affect the catalytic action of the compound.

Preferably, the catalyst of the present process is not inhibited by the reactants and/or products of step (i). In this way, formation of the cyclopropane can be achieved without the need to isolate or purify the diazoalkane, thereby avoiding the hazards associated with handling such compounds.

In a preferred embodiment of the invention, the aminoalkane is an a-aminocarbonyl compound.

In a more preferred embodiment, the aminoalkane is an a-aminoester, or salt thereof.

Typical a-aminoester salts include hydrochloric acid salts or para-toluensulfonic acid salts.

Even more preferably, the a-aminoester is glycine ethyl ester hydrochloride. Other examples of a-aminoesters suitable for use in the present invention include benzyl, t- butyl and p-nitrobenzyl esters of glycine, and salts thereof.

The process of the present invention involves reacting an alkene-containing moiety with a diazoalkane. Preferably, the alkene-containing moiety is selected from a simple alkene, a subsituted alkene, a diene or a triene. Where the alkene-containing moiety is a substituted alkene, typical substituents include lower alkyl, alkoxy and alkoxycarbonyl groups. The alkyl component of such substituents may be linear or branched. Other suitable substituents include halogens.

In one preferred embodiment of the invention, the alkene-containing moiety is a terminal alkene of formula I, wherein Ri is selected from an aryl group, an alkyl group, an alkoxy group, or an alkoxy carbonyl group, preferably a Cl-i2 alkyl, a Cl-4 alkoxy, or a Cl-4 alkoxy carbonyl group.

In a second preferred embodiment, the alkene-containing moiety is styrene, or a substituted styrene wherein the arene substituent is selected from NO2, CN, CF3, CO2Ra, CORa (wherein Ra is an alkyl group, preferably a Cl-lo alkyl group), an alkyl group, an alkoxy group or a halogen, preferably a Cl 4 alkyl group, a CI-4 alkoxy group, chlorine, or fluorine.

In a third preferred embodiment, the alkene-containing moiety is a trans-substituted alkene of formula II

wherein each of R2 and R3 is independently an aryl group, an arylalkyl group, or an alkyl group, preferably a Cl l0 alkyl group.

More preferably, each of R2 and R3 is independently methyl, ethyl, pentyl or hexyl.

In a fourth preferred embodiment, the alkene-containing moiety is a cis-substituted alkene of formula III wherein each of R4 and Rs is independently an aryl group, an arylalkyl group, or an alkyl group, preferably a Cl-lo alkyl group. More preferably, each of R4 and Rs is independently methyl or heptyl.

In an alternative embodiment, the alkene-containing moiety is a cyclic alkene. Preferably, the cyclic alkene is selected from cyclopentene, cyclohexene and cyclooctene.

In a fifth preferred embodiment, the alkene-containing moiety is a diene.

Preferably, the diene is of formula IV,

wherein each of R6, R7, R8 and R9 is independently selected from an aryl group, an arylalkyl group, H or an alkyl group, preferably H or a CI-lo alkyl group.

In a sixth preferred embodiment, the alkene-containing moiety is a geminal substituted alkene.

Preferably, the geminal substituted alkene is of formula V and either wherein each of Rl° and R"is independently an aryl group, an arylalkyl group, or an alkyl group, preferably a C1-10 alkyl group, or wherein Rl° and Rll are joined to form a cycloalkyl ring.

More preferably, each of Rl° and Rll is independently methyl or phenyl, or Rl° and Rll are joined to form a cycloalkyl ring, more preferably a cyclohexyl ring.

In a seventh preferred embodiment, the alkene-containing moiety is a triene.

Preferably, the triene is of formula VI

wherein each of R12, R13, R14 and Ris is independently selected from an aryl group, an arylalkyl group, H or an alkyl group, preferably H or C1-10 alkyl group.

In a preferred embodiment, the alkene-containing moiety is selected from the following groups: In a preferred aspect, the process of the present invention involves generating a diazoalkane by the action of a nitrite on said aminoalkane in the presence of a suitable catalyst.

Preferably the nitrite is a metal nitrite, more preferably, sodium nitrite. The nitrite may also be an alkyl nitrite, for example, t-butyl nitrite or iso-amyl nitrite.

In the preferred embodiment, the catalyst for forming the diazoalkane is sulphuric acid. However, Lewis acids are also suitable for this purpose. Further examples of catalysts useful in the present invention include acetic acid, lanthanide catalysts, and combinations thereof. Suitable catalysts include LnR3, HfR4 and ZrRf4, wherein R is OTf, CTf3, NTf2, OS02 (CF2) nCF3, N [S02 (CF2) nCF3] 2 or C [SO2 (CF2) nCF3] 3, wherein Tf is-S02CF3 and n is 1 to 9. Other suitable catalysts include metal salts of formula MRy, for example, where M is Sc and y is 3, where M is Zr and y is 4, where M is Hf and y is 4, where M is Bi and y is 3. Preferred lanthanide catalysts include lanthanide triflates such as ytterbium triflate, or ytterbium triflimide.

The process of the present invention thus provides an efficient, one-pot route for producing cyclopropanes which avoids some of the problems associated with prior art methods. More specifically, the present process can be readily adapted by routine

modification of the substrates to produce a wide range of cyclopropane derivatives, which may then undergo subsequent modification, as necessary, to yield products suitable for use in the chemical and/or pharmaceutical industry. By way of example, the present process may be useful in the preparation of cyclopropane amines, which can be synthesised by modification of the appropriate cyclopropane carboxylic ester precursors prepared in accordance with the invention. The process of the present invention may thus have applications in the preparation of drugs containing cyclopropane and/or cyclopropylamino groups such as tranylcypromine, betaxolol, calcipotriol, cibenzoline, cilastatin, cinetropium bromide, ciprofibrate, flutoprazopram, nevirapine, prazepam, rilmenidine, spizofurone, buprenorfine, nalmefine, naltrexone, ciprofloxacin, grepafloxacin, and quinolone derivatives containing fluoro-substituted cyclopropane rings.

The present invention will now be described by way of examples.

EXAMPLES TPPRh (III) I, BocGlyOPNB and GlyOPNB were prepared by standard procedures using methodology well known in the art.

General procedure for the formation of cyclopropanes To a solution of glycine ethyl ester hydrochloride (84.0 mg, 0.60 mmol) in distilled water (1 ml) and dichloromethane (10 ml) was added an alkene (6.00 mmol) and TPPRh (III) I (2.50 mg, 30.0 pmol) in one portion. The biphasic reaction mixture was cooled to-10 °C and NaN02 (50 mg, 0.72 mmol) in distilled water (0.50 ml) and aqueous H2SO4 (57.0, ul of a 5% w/w solution) were added in one portion. The reaction mixture was allowed to warm up to room temperature and stirred for 4 days.

The reaction mixture was then diluted with dichloromethane (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on silica gel.

Ethyl-2-phenvlcyclopropane-1-carboxylate To a stirred two-phase solution of GlyOEt-HCl (83.8 mg, 0.60 mmol), styrene (0.69 ml, 6.0 mmol) and TPPRhI (III) (2.5 mg, 0.003 mmol) in CH2C12 (10 ml) and H20 (1 ml) was added aq. NaN02 solution (50 mg, 0.72 mmol in 0.5 ml water) was added at -5°C (internal). 5% (w/w) H2S04 was then added at the same temperature. The bath was removed, and the mixture was stirred at room temperature (18-19°C) for 88hr. In 24hr the diazoester was consumed on tlc. The reaction mixture was diluted with CH2C12 and dried over Na2S04. The solvent and styrene were evaporated in vacuo at 45°C, and the remaining styrene was co-evaporated in vacuo with n-hexane at the same temperature. The residual oil (0.20 g) was separated by preparative TLC (Merck Art. 5715, Et2O : n-hexane = 1: 10,1 sheet), which afforded 54.7mg (48%) of the product, ethyl-2-phenylcyclopropane-1-carboxylate. Alternatively, the residual oil may be purified by flash chromatography using Si02 (61%). NMR (270MHz, CDC13) cis-isomer 5 : 7.19-7.30 (m, 5H), 3.89 (ABq, 2H, J=7.1), 2.60 (ABq, 1H, J=8.5), 2.10 (ddd, 1H, 8,5.5,4.5), 1.73 (dt, 1H, J=7.5,5.5), 1. 34 (dt, 1H, J=8.5,5), 0.99 (t, 3H, J= 7.1) 1; trans-isomer 5 : 7.20-7. 33 (m, 3H), 7.12 (d, 2H, J=8.4), 4.20 (Abq, 2H, J=7.1), 2.54 (ddd, 1H, J=9,6.5,4), 1.92 (ddd, 1H, J=8.5,5, 4), 1.62 (ddd, lH, J=8.5,6.5,4), 1.34 (ddd, 1H, J=9,5,4), 1.30 (t, 3H, J=7.1).

The above general procedure was used to carry out a series of TPPRh (III) I catalysed cyclopropanations with glycine ethyl ester hydrochloride and a range of different olefin substrates. The results are shown below in Table 1. a Table 1 c Alkene Yield 5 (%) a Entry Alkene Yield 5 (%) a 1 61 11 5 55 5 2 72 12 45 \/ o-jr Cl 14 3 49 \ 5 z 20 15 < 59 6 9 59 16 C 57 7 54 17 60 8 < 53 18 0= 64 0 o 9 X 53 19 < OMe 40 10 O 50 20 o-t-gu 63 aIsolated yields after silica gel chromatography.

Formation of the"hidden"diazoalkane may be followed by solution infra red spectroscopy. Where the alkene-containing moiety is styrene, the characteristic diazoalkane signal (2114 cm-1) is detected shortly after the start of the reaction and remained in situ for 7.5 h. In general, cyclopropane formation is observed (1721 cm- 1) approximately 2 h after the beginning of the experiment.

Variation of the catalyst The above general procedure was used to carry out a series of cyclopropanation reactions with styrene, GlyOBn and a range of different catalysts. The results are shown below in Table 2. PhCH=CH BnOOC GlyOBn AcOH t-BuONO Ph catalyst CH2CI2

Table 2 Catalyst Temperature Yield of cyclopropane (%) TPPRh (III) I r. t. 50 (5. 5h) Cu (OAc) 2 r. t. 40 (14h) Rh2 (OAc) 4 r. t. 35 (14h) PdCl2 reflux 19 PdCl2 (CH3CN) 2 reflux 21 Pd (N03) 2. xH20 reflux 16 Pd (OAc) 2 reflux 16 Cu-bronze reflux 27 Various modifications and variations of the described methods of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, various modifications of the described modes for carrying out the invention which are obvious to those skilled in chemistry or related fields are intended to be within the scope of the following claims.