Methods for producing N-protected-azetidine-2-carboxylic acids

There is disclosed a method for producing an essentially enantiomerically pure N-protected-azetidine-2-carboxylic acid of formula (1): ##STR1## which method is characterized by: PA1 subjecting a crude enantiomerically excess N-protected-azetidine-2-carboxylic acid comprising said enantiomer represented by formula (1) in excess to the other enantiomer thereof to crystallization in an organic solvent selected from aromatic hydrocarbon, aliphatic ether, aliphatic alcohol, aliphatic ketone, aliphatic nitrile, aliphatic amide, aliphatic sulfoxide, aliphatic ester and a mixed solvent thereof, PA1 wherein R is: PA2 an optionally substituted alkyl, alicyclic or alicyclicalkyl group, PA2 an optionally substituted alkenyl group, PA2 an optionally substituted aryl group, PA2 an optionally substituted heteroaryl group, or PA2 a dialkylamino group, and PA2 absolute configuration of the asterisked asymmetric carbon atom is S or R.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 The present invention relates to a process for producing an optically
 active N-protected-azetidine-2-carboxylic acid, which is a useful starting
 material for producing pharmaceuticals as described, for example, in
 WO98/50420 or Brain Res., 801 (1-2), p. 158, 1998.
 2. Description of Related Art
 Enantiomerically pure N-protected-azetidine-2-carboxylic acid such as
 (S)-N-benzoylazetidine-2-carboxylic acid has been produced by
 recrystallizing (S)-N-benzoylazetidine-2-carboxylic acid(94% e.e.) as
 disclosed in WO98/02568. For further derivatization to enantiomerically
 pure azetidine-2-carboxylic acid or a peptide, however, said compound
 required cumbersome alkaline hydrolysis and neutralization steps or
 further step of introducing a suitable protective group.
 SUMMARY OF THE INVENTION
 An object of the invention is to provide a method for purifying
 azetidine-2-carboxylic acid, which method can conveniently produce an
 enantiomerically pure azetidine-2-carboxylic acid with a suitable
 N-protective group.
 The present invention provides:
 a method for producing an essentially enantiomerically pure
 N-protected-azetidine-2-carboxylic acid of formula (1):
 ##STR2##
 which method comprises:
 subjecting a crude enantiomerically excess
 N-protected-azetidine-2-carboxylic acid comprising said enantiomer
 represented by formula (1) in excess to the other enantiomer thereof to
 crystallization in an organic solvent selected from aromatic hydrocarbon,
 aliphatic ether, aliphatic alcohol, aliphatic ketone, aliphatic nitrile,
 aliphatic amide, aliphatic sulfoxide, aliphatic ester and a mixed solvent
 thereof,
 wherein R is:
 an optionally substituted alkyl, alicyclic or alicyclicalkyl group,
 an optionally substituted alkenyl group,
 an optionally substituted aryl group,
 an optionally substituted heteroaryl group, or
 a dialkylamino group, and
 absolute configuration of the asterisked asymmetric carbon atom is S or R.

DESCRIPTION OF THE PREFERRED EMBODIMENTS
 In the present invention, the term "essentially enatiomerically pure" means
 an enantiomeric excess (% e.e.) of approximately 98% e.e. or higher. Such
 compounds can be advantageously used for preparing pharmaceuticals or
 pesticides without further purification.
 The crude enantiomerically excess N-protected-azetidine-2-carboxylic acid
 to be purified by the present method comprises enantiomer of formula (1)
 in excess to the other enantiomer thereof
 The enantiomer of formula (1) will be explained below.
 The optionally substituted alkyl group for R in formula (1) include an
 alkyl, alicyclic or alicyclicalkyl group having 1 to 13 carbon atoms,
 which may be substituted.
 Said optionally substituted alkyl, alicyclic or alicyclicalkyl group may be
 substituted with
 at least one group selected from:
 a cyano group, a halogen atom, a tri(C1-C4)alkylsilyl group,
 a (C1-C4)alkylthio group,
 a (C1-C4)alkysulfinyl group,
 a (C1-C4)alkylsulfonyl group,
 a phosphonio group substituted with groups selected from a (C1-C4)alkyl and
 phenyl group,
 wherein the (C1-C4)alkyl groups may be bonded at their terminals to form a
 ring, and
 a (C6-C14)aryl, (C6-C14)arylsulfonyl, (C7-C15)arylcarbonyl,
 (C4-C13)heteroaryl group, wherein said aryl or heteroaryl group may be
 substituted with at least one group selected from:
 a (C1-C4)alkyl group, a halogen atom, an amino group,
 a nitro group, a (C1-C4)alkoxy group,
 a (C1-C4)alkylsulfinyl group and a sulfonic group.
 In the above-described definition, the halogen atom means a fluorine atom,
 a chlorine atom, a bromine atom or an iodine atom.
 Examples of the (C1-C4)alkyl groups described above include a methyl group,
 an ethyl group, an i-propyl group, a n-propyl group, a n-butyl group, an
 i-butyl group, sec-butyl group and t-butyl group.
 Examples of the (C1-C4)alkoxy groups include a methoxy group, an ethoxy
 group, an i-propoxy group, a n-propoy group, a n-butoxy group, an i-butoxy
 group, sec-butoxy group and t-butoxy group.
 Examples of the (C6-C14)aryl groups include a phenyl group, a naphthyl
 group, an anthranyl group and a biphenyl group.
 Examples of the (C4-C13)heteroaryl group include a 2,3-, and 4-pyridyl
 group, a 2,7-di-t-butyl-9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)
 group, a quinolyl group such as 8-quinolyl group.
 Examples of the alkyl, alicyclic or alicyclicalkyl group having 1 to 13
 carbon atoms include methyl, ethyl, isobutyl, t-butyl, 1-adamantyl,
 1-(1-adamantyl)-1-methylethyl and the like.
 Examples of the alkyl group which may be substituted with a (C6-C14)aryl
 group which may be substituted include benxyl, p-methoxybenzyl,
 p-nitrobenzyl, p-bromobenzyl, 4-methylsulfinylbenzyl, 2,4-dichlorobenzyl,
 2-phenylethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl,
 9-(2,7-dibromo)fluorenylmethyl, 1-methyl-1-(4-biphenylyl)ethyl,
 1-(3,5-di-t-butylphenyl)-1-methylethyl, 9-anthranylmethyl, diphenylmethyl
 and the like.
 Examples of the alkyl group substituted with a cyano group include
 1,1-dimethyl-2-cyanoethyl.
 Examples of the alkyl group substituted with a halogen atom include
 trichloroethyl, 1,1-dimethyl-2-chloroethyl, 1,1-dimethyl-2,2-dibromoethyl
 and 1,1-dimethyl-2,2,2,-trichloroethyl.
 Examples of the alkyl group substituted with arylcarbonyl group, which aryl
 group may be substituted, include a methoxyphenacyl group.
 Examples of the alkyl group substituted with said silyl group include a
 trimethylsilylethyl group.
 Examples of the alkyl group substituted with the alkylthio group include
 2-methylthioethyl and [2-(1,3-dithianyl)]methyl.
 Examples of the alkyl group substituted with the alkylsulfonyl or
 arylsulfonyl group include 2-methylsulfonylethyl and
 2-(p-toluenesulfonyl)ethyl.
 Examples of the alkyl group substituted with the phosphonio group include
 2-trimethylphosphonioethyl and 2-triphenylphosphonioisopropyl.
 Examples of the alkyl group substituted with the hetroaryl group include
 2-(2'-pyridyl)ethyl group,
 2,7-di-t-butyl-9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)methyl or
 the like.
 The optionally substituted alkenyl group for R include a (C2-C6)alkenyl
 group which may be substituted with a phenyl or nitrophenyl group such as
 vinyl, allyl, 1-isopropylallyl, cinnamyl and 4-nitrocinnamyl.
 The optionally substituted aryl group for R include a phenyl group which
 may be substituted with at least one methylthio group such as phenyl,
 4-methylthiophenyl or 2,4-dimethylthiophenyl.
 The optionally substituted heteroaryl group for R include a
 (C5-C9)heteroaryl group such as a pyridyl group or a quinolyl group (e.g.,
 8-quinolyl).
 The dialkylamino group for R include a di(C1-C6)alkylamino group, wherein
 said alkyl groups may be bonded each other at their terminals to form a
 ring such as piperidinyl and the like.
 Preferred R group includes the optionally substituted alkyl group, more
 preferred groups include t-butyl, 9fluorenylmethyl, benzyl and the like.
 Specific examples of the compound of formula (1) include following
 compounds in which the configuration of the asterisked asymmetric carbon
 atom is R or S:
 N-methyloxycarbonyl-azetidine-2-carboxylic acid,
 N-ethyloxycarbonyl-azetidine-2-carboxylic acid,
 N-isobutyloxycarbonyl-azetidine-2-carboxylic acid,
 N-t-butyloxycarbonyl-azetidine-2-carboxylic acid,
 N-(1-adamantyl)oxycarbonyl-azetidine-2-carboxylic acid,
 N-[1-(1-adamantyl)-1-methylethyl]oxycarbonyl-azetidine-2-carboxylic acid,
 N-benzyloxycarbonyl-azetidine-2-carboxylic acid,
 N-(p-methoxybenzyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(p-nitrobenzyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(p-bromobenzyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(4-methylsulfinylbenzyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(2,4-dichlorobenzyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(2-phenylethyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(9-fluorenylmethyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-[9-(2-sulfo)fluorenylmethyloxycarbonyl]-azetidine-2-carboxylic acid,
 N-[9-(2,7-dibromo)fluorenylmethyloxycarbonyl]-azetidine-2-carboxylic acid,
 N-[2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)-methyl
 oxycarbonyl]-azetidine-2-carboxylic acid,
 N-[1-methyl-1-(4-biphenylyl)ethyloxycarbonyl]-azetidine-2-carboxylic acid,
 N-[1-(3,5-di-t-butylphenyl)-1-methylethyloxycarbonyl]-azetidine-2-carboxyli
 c acid,
 N-(9-anthranylmethyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-diphenylmethyloxycarbonyl-azetidine-2-carboxylic acid,
 N-[(1,1-dimethyl-2-cyanoethyl)oxycarbonyl]-azetidine-2-carboxylic acid,
 N-trichloroethyloxycarbonyl-azetidine-2-carboxylic acid,
 N-(1,1-dimethyl-2-chloroethyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(1,1-dimethyl-2,2-dibromoethyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(1,1-dimethyl-2,2,2-trichloroethyloxycarbonyl)-azetidine-2-carboxylic
 acid,
 N-methoxyphenacyloxycarbonyl-azetidine-2-carboxylic acid,
 N-trimethylsilylethyloxycarbonyl-azetidine-2-carboxylic acid,
 N-(2-methylthioethyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(2-methylsulfonylethyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-[2-(1,3-dithianyl)]methyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-[2-(p-toluenensulfonyl)ethyloxycarbonyl]-azetidine-2-carboxylic acid,
 N-(2-trimethylphosphonioethyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(2-triphenylphosphonioisopropyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-[2-(2'-pyridyl)ethyloxycarbonyl]-azetidine-2-carboxylic acid,
 N-vinyloxycarbonyl-azetidine-2-carboxylic acid,
 N-allyloxycarbonyl-azetidine-2-carboxylic acid,
 N-(1-isopropylallyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-cinnamyloxycarbonyl-azetidine-2-carboxylic acid,
 N-(4-nitrocinnamyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-phenyloxycarbonyl-azetidine-2-carboxylic acid,
 N-(4-methylthiophenyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(2,4-dimethylthiophenyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-(8-quinolyloxycarbonyl)-azetidine-2-carboxylic acid,
 N-[(1-piperidinyl)oxycarbonyl]-azetidine-2-carboxylic acid and the like.
 Examples of the organic solvent include:
 an aromatic hydrocarbon(e.g., (C6-C8) aromatic hydrocarbon which may be
 substituted with a halogen atom) such as benzene, toluene, ethylbenzene,
 xylene or chlorobenzene,
 an aliphatic ether (e.g., (C4-C6) aliphatic ether) such as
 t-butylmethylether, isopropylether, tetrahydrofuran or dioxane,
 an aliphatic ester (e.g., (C4-C6) aliphatic ester) such as ethyl acetate,
 butyl acetate or isopropyl acetate
 an aliphatic alcohol (e.g., (C1-C4) aliphatic alcohol) such as methanol,
 ethanol, isopropanol, n-ethanol or t-butanol,
 an aliphatic ketone (e.g., (C3-C6) aliphatic ketone) such as acetone,
 2-butanone, methyl isopropyl ketone or methyl isobutyl ketone
 an aliphatic nitrile (e.g., (C2-C4) aliphatic nitrile) such as
 acetonitrile, propionitrile or butyronitrile
 an aliphatic amide (e.g., N,N-dimethyl(C1-C2)acylamide) such as
 N,N-dimethylformamide or N,N-dimethylacetamide,
 an aliphatic sulfoxide such as dimethylsulfoxide.
 The solvent may be employed alone or as a mixture of two or more thereof.
 The aromatic hydrocarbon is preferably employed, and toluene and a mixed
 solvent thereof with other solvents are more preferred.
 The amount of the solvent to be used is not particularly limited but may be
 set by taking account of the amount of the crude enantiomerically excess
 N-protected-azetidine-2-carboxylic acid comprising compound of formula (1)
 in excess to the other enantiomer thereof and the kind of the solvent and
 is, for example, about 0.1 to 100 parts by weight, preferably 0.5 to 50
 parts by weight per 1 part by weight of said crude
 N-protected-azetidine-2-carboxylic acid.
 The crude enantiomerically excess N-protected-azetidine-2-carboxylic acid
 may be obtained by a conventional chemical or enzymatic resolution and the
 like. The crude enantiomerically excess N-protected-azetidine-2-carboxylic
 acid with about 80% e.e. or higher is preferably used in the present
 method.
 The crude N-protected-azetidine-2-carboxylic acid is usually subjected to
 crystallization by decreasing the temperature of a solution of the crude
 compound in the organic solvent as described above. The crystallization
 may be conducted in the copresence of a bad solvent. Examples of the bad
 solvent includes an aliphatic or alicyclic hydrocarbon solvent (e.g.,
 (C6-C8) aliphatic or alicyclic hydrocarbon) such as n-hexane, heptane,
 cyclohexane or isooctane, which may be added to the solution of the crude
 compound before precipitation of the desired crystals, or may be dropwise
 added to the precipitating crystallization solution. A seed crystal may be
 also added to the solution in order to induce precipitation of the
 crystals.
 The crystallization is conducted usually at a temperature range of between
 -50.degree. C. to 200.degree. C., preferably -20.degree. C. to 150.degree.
 C., more preferably -20.degree. C. to 100.degree. C. The temperature is
 not particularly restricted and may be optionally set based on the amount
 and kind of the solvent to be used.
 After the crystallization, precipitated crystals may be collected by a
 conventional method such as a filtration. If necessary, the collected
 crystal may be washed with water, the organic solvent as described above
 for crystallization or bad solvent as described above.
 An essentially enatiomerically pure N-protected-azetidine-2-carboxylic acid
 (1) thus obtained may be subjected to a subsequent reaction as it is, or
 may be deprotected, if necessary, to give an essentially optically pure
 azetidine-2-carboxylate or its salt.
 Typically, the deprotection of the above-described N-protecting group can
 be conducted by reacting the crystallized compound under an acidic
 condition by using hydrochloric acid, sulfuric acid, trifluoroacetic acid
 or the like in water or an organic solvent, and heating if necessary.
 Alternatively, the deprotection reaction can be conducted by the following
 typical methods or may be conducted by those methods as disclosed in the
 reference below.
 When R is, for example, allyl, benzyl, p-nitrobenzyl, 2,4-dichlorobenzyl,
 cinnamyl, 9-anthranymethyl or diphenylmethyl group, removal of the
 protecting group is usually conducted by reacting such a compound in the
 presence of a catalyst, with a reducing agent to produce the
 enantiomerically pure azetidine-2-carboxylic acid.
 The catalyst may be, for example, noble metal catalysts usually employed in
 a catalytic hydrogenation reaction, more specifically palladium, palladium
 acetate, palladium chloride, palladium oxide, palladium hydroxide and the
 like, which may be supported on activated carbon, alumina and the like.
 The amount of the catalyst to be used is usually within a range of from
 0.0001 to 0.5 part by weight per 1 part by weight of the essentially
 enantiomerically pure N-protected azetidine-2-carboxylic acid.
 Examples of the reducing agent include hydrogen, hydrazine and a salt
 thereof such as a hydrochloride, a sulfate, an acetate and the like, and
 formic acid and an ammonium salt thereof.
 The reaction is usually carried out in a solvent. Examples of the solvent
 include: water, an alcohol solvent such as methanol, ethanol and
 2-propanol, an ester solvent such as ethyl acetate, methyl acetate and
 butyl acetate, a nitrile solvent such as acetonitrile, an aromatic
 hydrocarbon solvent such as toluene, xylene and benzene, an aliphatic
 hydrocarbon solvent such as hexane and heptane, a halogen-containing
 hydrocarbon solvent such as dichloromethane, dichloroethane, chloroform,
 chlorobenzene and orthodichlorobenzene, an ether solvent such as diethyl
 ether, isopropyl ether and t-butyl methyl ether, an amide solvent such as
 acetamide, N, N-dimethyl formamide and N, N-dimethylacetamide. These
 solvents may be used alone or in combination of two or more. The amount of
 the solvent to be used is usually within a range of from 2 to 100 parts by
 weight per part by weight of the essentially enantiomerically pure
 N-substituted azetidine-2-carboxylic acid compound represented by the
 formula (1).
 When hydrogen is employed as a reducing agent, for example, a catalyst and
 the crystallized essentially enantiomerically pure N-protected
 azetidine-2-carboxylic acid compound of formula (1) are usually added to a
 solvent, and a hydrogen gas is thereafter supplied into the reaction
 system. The supply of the hydrogen gas may be carried out by passing the
 gas through the reaction system or the reaction system may be stirred
 under a hydrogen gas atmosphere at normal pressure or compressed pressure.
 When a reducing agent other than hydrogen is employed, for example, the
 essentially enantiomerically pure N-protected azetidine-2-carboxylic acid
 compound of formula (1) and a catalyst may be added to a solvent and the
 reducing agent may thereafter be added to the mixture.
 The reaction temperature is usually within a range of from -50.degree. C.
 to 200.degree. C., preferably from 0.degree. C. to 150.degree. C.
 When R is an allyl group in the N-substituted azetidine-2-carboxylic acid
 compound of formula (1), the deprotected compound can be obtained, for
 example, by using tri-n-butyltin hydride, acetic acid and the like in the
 presence of a catalyst such as tetrakis(triphenylphosphine)palladium.
 The deprotection may also be performed according to a known method such as
 that described in "Protective Groups in Organic Synthesis" (T. W. Greene,
 P. G. M. Wuts, 1991, John Willey & Sons, Inc.), the whole disclosure of
 which is incorporated herein by reference.
 The crude enantiomerically excess N-protected-azetidine-2-carboxylic acid
 can be obtained by introducing a N-protecting group of formula: ROCO,
 wherein R has the same meaning as defined above, to a crude
 enantiomerically excess azetidine-2-carboxylic acid according to a method
 as described in "Protective Groups in Organic Synthesis" (T. W. Greene, P.
 G. M. Wuts, 1991, John Willey & Sons, Inc.) and the like.
 Said introduction of the protecting group may be carried out by reacting
 crude enatiomeric excess azetidine-2-carboxylic acid with a protective
 reagent of formula ROCO-L, wherein L represents a leaving group, in the
 presence of a base.
 Examples of the leaving group "L" include a halogen atom, ROCOO,
 succinimidyloxy group and the like.
 For example, t-butoxycarbonyl group can be introduced by using
 di-t-butyldicarbonate according to a known method.
 Alternatively, the crude enantiomerically excess azetidine-2-carboxylic
 acid which contains N-protected-azetidine-2-carboxylic acid of formula (1)
 in excess to the other enantiomer may be produced by a conventional
 chemical or enzymatic resolution.
 According to the invention, an essentially optically pure
 N-protected-azetidine-2-carboxylic acid can readily and efficiently be
 produced by crystallizing a crude enantiomerically excess
 N-protected-azetidine-2-carboxylic acid, which contains one of its isomers
 in excess, from an organic solvent.
 EXAMPLES
 The present invention is further described in the following examples, which
 are not to be construed to limit the invention thereto.
 Example 1
 161.4 g of an aqueous solution containing (S)-azetidine-2-carboxylic acid
 having 94.6% e.e. (azetidine-2-carboxylic acid content: 20.0 g, 198 mmol)
 was combined with a 64% by weight toluene solution of
 di-t-butyldicarbonate (di-t-butyldicarbonate: 56.1 g, 257 mmol) and then
 treated dropwise with 38.1 g of a 27% aqueous solution of sodium hydroxide
 (sodium hydroxide: 10.8 g, 257 mmol) and stirred at 40.degree. C. for 4
 hours. After the reaction, 80.0 g of toluene was added and the mixture was
 stirred for 30 minutes and then allowed to stand to separate the phases to
 obtain 230.0 g of an aqueous layer
 (N-t-butyloxycarbonyl-azetidine-2-carboxylic acid content: 38.9 g, 193
 mmol). 222.3 g of this aqueous layer
 (N-t-butyloxycarbonyl-azetidine-2-carboxylic acid content: 37.6 g, 187
 mmol) was combined with 35.0 g of sodium chloride, treated dropwise with
 26.9 g of a 36% hydrochloric acid, and then extracted twice with 75.0 g of
 toluene. The toluene layer was washed with a 20 (w/w)% aqueous sodium
 chloride solution, settled and separated to give 194.4 g of a toluene
 solution of N-t-butyloxycarbonyl-azetidine-2-carboxylic acid
 (N-t-butyloxycarbonyl-azetidine-2-carboxylic acid content: 37.2 g, 185
 mmol). The (S)-N-t-butyloxycarbonyl-azetidine-2-carboxylic acid thus
 obtained showed 94.6% e.e.
 Subsequently, a 177.9 g of this toluene solution
 (N-t-butyloxycarbonyl-azetidine-2-carboxylic acid content: 34.0 g, 169
 mmol) was evaporated under reduced pressure at 60.degree. C. to distill
 the solvent, and concentrated to 69.4 g
 (N-t-butyloxycarbonyl-azetidine-2-carboxylic acid concentration: 49.0% by
 weight). While keeping the concentration at 60.degree. C., 0.15 g of a
 seed crystal was added and the mixture was stirred for 1 hour and then
 cooled to 0.degree. C. at the cooling rate of 20.degree. C./h. The crystal
 which was precipitated was filtered, washed with 20.0 g of a cooled
 toluene and dried to give 30.3 g of
 (S)-N-t-butyloxycarbonyl-azetidine-2-carboxylic acid (crystallization
 yield: 86.6%), of which HPLC analysis on a chiral column showed 99.6% e.e.
 Example 2
 5.00 g of (S)-N-t-butyloxycarbonyl-azetidine-2-carboxylic acid (99.6% e.e.)
 obtained in a similar manner as in Example 1 was added to 53 g of a 17%
 solution of hydrogen chloride in ethyl acetate and stirred for 1 hour. The
 reaction mixture was concentrated under reduced pressure to give 3.45 g of
 (S)-azetidine-2-carboxylic acid hydrochloride. The yield was 100%, and an
 HPLC analysis of the salt on a chiral column showed 99.6% e.e.