The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

INTRODUCTION
Aspects of the invention relate to methods of producing compositions of trans-4-amino-2-cyclopentene-1-carboxylic acid derivatives.
The trans-4-amino-2-cyclopentene-1-carboxylic acid derivatives represented by structural formula 1  are important intermediates  used in the synthesis of several active pharmaceutical ingredients.

International Application Publication No. WO 00/58500 taught a method of making a composition diastereomerically enriched with the trans-4-amino-2-cyclopentene-1-carboxylic acid  1. As taught in that publication  the first step was epimerization  preferably of the N-protected cis- amino ester  2 

to form the complex mixture of reaction products 2  3  and 4.

The WO 00/58500 publication teaches that efficient separation of the complex product mixture to isolate substantially pure trans isomer was not possible by crystallization and that chromatographic separation methods were difficult to perform at any appreciable scale. Rather  the publication teaches that separation by selective hydrolysis of the trans- isomer using selective enzymes is possible. See also R. C. Lloyd et al.  “Use of hydrolases for the synthesis of cyclic amino acids ” Tetrahedron  Vol. 60 (3)  pp. 717-728  2004.
Consequently  there is a continuing need for the development of scalable and cost effective process for the preparation of trans-4-amino-2-cyclopentene-1-carboxylic acid derivatives.
SUMMARY
An aspect of the invention provides methods for producing trans-4-amino-2-cyclopentene-1-carboxylic acid derivatives comprising:
(a) providing a composition comprising a compound of formula A 

having components present in both cis- and trans- structures  wherein R1 is an alkyl or aryl group having  in embodiments  up to about 12  or up to about 6 carbon atoms  such as a t-butyl group  in a solvent;
(b) combining the composition with an amine to form salts  wherein the composition is characterized in that some salt precipitates but the salt of the trans structure of compound A remains in the solution in excess of the amount of the salt of the cis structure of compound A remaining in the solution;
(c) separating the precipitate from the solution;
(d) adding acid to the solution to reform carboxylic acids from the salts in the solution;
(e) isolating the compound which is the trans structure of compound A to yield the trans structure of compound A in a diastereomeric excess at least about 80%  or about 85%; and
(f) optionally purifying the trans-compound from step (e) to produce a diastereomeric excess of the trans structure of compound A of at least about 98%  by recrystallization.
In an aspect  the present application provides an amine salt of a compound having formula A 

having components present in both cis and trans structures  where R1 is an alkyl or aryl group having  in embodiments  up to about 12  or up to about 6 carbon atoms  such as a t-butyl group.

DETAILED DESCRIPTION
In an aspect  the invention provides methods for producing trans-4-amino-2-cyclopentene-1-carboxylic acid derivatives comprising:
(a) providing a composition comprising a compound having formula A 

having components present in both cis- and trans- structures  where R1 is an alkyl or aryl group having  in embodiments  up to about 12  or up to about 6 carbon atoms  such as a t-butyl group  in a solvent;
(b) combining the composition with an amine to form salts  wherein the composition is characterized in that some salt precipitates but the salt of the trans structure of compound A remains in the solution in excess of the amount of the salt of the cis structure of compound A remaining in the solution;
(c) separating the precipitate from the solution;
(d) adding acid to the solution to re-form carboxylic acids from the salts in the solution;
(e) isolating the compound which is the trans- structure of compound A to yield the trans- structure of compound A in a diastereomeric excess at least about 80%  or about 85%; and
(f) optionally  purifying the trans-compound from (e) to produce a diastereomeric excess of the trans- structure of compound A of at least about 98%  by recrystallization.
A trans- structure of a compound having formula A may either be the 1R 4R trans species as shown in structure 1 

or the 1S 4S trans structure.
For convenience  the discussion which follows will be directed to the structure of compound 1  but it should be understood that the 1S 4S trans- species could also be formed instead of the 1R 4R trans- species. The cis- species is shown as compound 5.

A composition comprising compounds 1 and 5 may also comprise other components  such as the conjugated 4-amino-2-cyclopentene-1-carboxylic acid  compound 6.

Typical solvents for compound A are organic solvents. Examples of useful solvents include  but are not limited to: lower alcohols having up to 6 carbon atoms  or up to 4 carbon atoms  or up to 3 carbon atoms  such as isopropanol  ethanol  and methanol; alkyl acetates  where the alkyl group comprises up to 6 carbon atoms  or up to 4 carbon atoms  such as ethyl acetate and butyl acetate; ethers having up to 10 carbon atoms  such as tert-butyl methyl ether (MTBE); and any mixtures thereof  wherein alkanes such as pentane  hexane or heptane may be present as co-solvents but not as the sole solvents.
A composition comprising compounds 1 and 5 may be formed using any known method. In embodiments  the composition is formed using (1S 4R)-2-aza-bicyclo[2.2.1]heptan-3-one  compound 7  as a starting material. Note that  to form compound 1S 4S trans species  one could begin with (1R 4S)-2-aza-bicyclo[2.2.1]heptan-3-one.

This compound may be made using known approaches. See  e.g.  International Application Publication No. WO 98/10075  or Hiroto Nakano et al.  “Lipase-catalyzed resolution of 2-azabicyclo[2.2.1]hept-5-en-3-ones ” Tetrahedron: Asymmetry  Vol. 7 (8)  pp. 2381-2386  1996.
According to one approach  compound 7 is esterified in an acidic solution of a lower alcohol as shown in Scheme 1.

Scheme 1
where R2 is any lower alkyl group having up to about four carbon atoms  such as methyl  and HX is any inorganic acid  such as hydrochloric acid.
Suitable alcohols for this transformation include  but are not limited to  methanol  ethanol  2-propanol  and 1-butanol. The acidic solution can be made by adding thionyl chloride  oxalyl chloride  acetyl  or another acyl chloride  or hydrogen chloride gas to a lower alcohol.
Typically  this addition is done at about 0-10°C  by adding from 0.1 equivalents to 2 equivalents  or about 1.1-1.2 equivalents  of acid  per mole of compound 7. Alternatively  other strong acids  such as sulfuric acid  may be used.
Typically  this reaction is done in 4-5 volumes of the alcohol solvent  although up to 20 volumes can be used. As used herein  “volumes” means the milliliters (mL) of solvent  per gram of reactant.
The nitrogen group is then protected as shown in Scheme 2. This reaction is carried out in about 0-10 volumes  or about 3-5 volumes  of solvent. Typical solvents for the reaction include tetrahydrofuran (THF)  dichloromethane  and tert-butyl methyl ether (MTBE).
The base used in this reaction can be any tertiary amine base  such as triethylamine. In a typical procedure  at least one  and up to about 2  or about 1.1-1.3 molar equivalents of base will be used.
Typically  at least 1 equivalent and up to 2 equivalents of the protecting reagent  such as di-tert-butyldicarbonate  are used. The protecting reagent can be  for example  any alkyl or aryl chloroformate  di tert-butyldicarbonate or N-(9H-fluoren-9-ylmethoxycarbonyl)succinimide.
The reaction can be carried out between about 0°C and 40°C  or about 5-20°C.
Alternatively  this reaction may be carried out in an aqueous system: 8 is dissolved in water (up to 10 volumes  or about 1.5-3 volumes) and the pH is adjusted to about 10-13  or about 11  by adding any metal hydroxide base (e.g.  sodium or potassium hydroxide).
The protecting reagent  which is described above (about 1-2 equivalents  or about 1.1 equivalents) is then added in a solvent such as THF (up to 5 volumes  or about 1-3 volumes  or about 2 volumes)  while maintaining the pH of the reaction mixture in the range of about 10-13  or about 11  by the addition of the metal hydroxide base.

Scheme 2
The resulting cis compound 2 is epimerized by any methods  such as is taught  for example  in WO 00/58500  to form alkyl esters of the following formulas 2  3  and 4:

This reaction is carried out in an alcohol solution  such as about 4 volumes  although a range of 1-20 volumes is useful. The choice of alcohol and alcoxide base is restricted by the ester functionaility of 2 (for example  for a methyl ester  use sodium methoxide in methanol). Typically  0.1 molar equivalents  or about 0.05–1 equivalents  of alkoxide base is used. Any metal alkoxide is useful  including sodium and potassium. The reaction temperature is typically about 0°C  or a range of about -10°C to 10°C may be used.
In another approach  compound 7 is protected by addition of a protecting group such as any of those mentioned above  including a tert-butoxycarbonyl group  on the nitrogen to give a compound such as 9.

This protection reaction can be carried out as described By S. M. Daluge et al.  “An Efficient  Scalable Synthesis of the HIV Reverse Transcriptase Inhibitor Ziagen® (1592U89)  Nucleosides  Nucleotides & Nucleic Acids  Vol. 19 (1 and 2)  pp. 297-327  2000. Compound 9 may be reacted directly to form the composition comprising the alkyl esters of formulas 2  3  and 4.
This reaction may be undertaken by treating an alcoholic solution of compound 9 with a catalytic amount of the corresponding alkoxide base. Alcohols include  but are not limited to  methanol  ethanol  2-propanol  and 1-butanol. Typically  this reaction is carried out in 10-15 volumes of alcohol solvent  although a much wider range of about 2-20 volumes may be used. Up to about 1 molar equivalent of alkoxide may be used  typically in the range of 0.05-0.2 equivalents. Typical temperatures for the reaction are about 0°C  although in practice a range of about -10°C to 10°C may be used.
These compounds 2  3  and 4 then are hydrolyzed to form the compositions comprising compounds 1 and 5. The hydrolysis may be performed by any hydrolysis method. For example  the hydrolysis can be performed using lithium hydroxide  although other metal hydroxides may be used.
In embodiments  the ether solution obtained from the previous reaction is added to the appropriate alcohol (determined by the ester group  using about 2 volumes  although a range of 1 to 5 volumes is useful)  prior to the addition of the metal hydroxide as an aqueous solution. The temperature is kept below about 5°C  to minimize formation of compound 6.
The composition comprising compounds 1 and 5 is reacted with an amine to produce an excess of the salt of compound 1 in the solution  relative to compound 5. In embodiments  the salt of compound 5 preferentially precipitates out of the solution.
The salt-forming amine can have the formula NR1R2R3  where: R1 is benzyl  or a non-cyclic alkyl or alkenyl group of 3 to 10  or about 3 to 8  carbon atoms; R2 is benzyl  an alkyl group of about 1 to 10  or about 3 to 8  carbon atoms  an alkenyl group of about 3 to 10  or about 3 to 8 carbon atoms  an alkylamino of up to three carbon atoms  or hydrogen; and R3 is benzyl  an alkyl group of about 1 to 10  or about 3 to 8  carbon atoms  an alkenyl of about 3 to 10  or about 3 to 8  carbon atoms  an alkylamino of up to three carbon atoms  or hydrogen; provided that R1 and R2 cannot both be alkyl groups of four or fewer carbon atoms when R3 is hydrogen.
In embodiments  the salt-forming amine is allylamine or 3-dimethylaminopropylamine. The amount of amine added is in a stoichiometric or an excess stoichiometric amount of amine  relative to the total moles of compounds 1 and 5. Generally  about 1 to 1.5 molar equivalents. based on moles of compounds 1 and 5 may be used.
This reaction can be carried out in the solvents described above  including ethyl acetate. The solvent is generally present in 5 to 10 volumes.
After formation of the salts  the precipitate is removed and the carboxylic acids are re-formed by addition of an acid to the solution. The acid added may be hydrochloric acid  although other inorganic acids  such as for example sulfuric  may be used  such that the pH of the final solution is about 2.5.
The compound of formula 1 is then isolated. Isolation may be by crystallization  such as by combination with a lower alkane (less than about 10  or less than about 8  carbon atoms  including at least 5  6  or 7 carbon atoms  or a heptane). Alternatively  isolation may include solvent removal.
Additional purification and isolation steps may be used  as desired. For example  recrystallization may be used to further increase the diastereomeric purity.
A method of this invention  when the optional step of purification by re-crystallization is used  can achieve compound 1 in a diastereomeric excess greater than about 98%.
In an aspect  the present application provides an amine salt of a compound having formula A 

having components present in both cis and trans structures  where R1 is an alkyl or aryl group having  in embodiments  up to about 12  or up to about 6 carbon atoms  such as a t-butyl group.
The salt-forming amine can have the formula NR1R2R3  where: R1 is benzyl  or a non-cyclic alkyl or alkenyl group of 3 to 10  or about 3 to 8  carbon atoms; R2 is benzyl  an alkyl group of about 1 to 10  or about 3 to 8  carbon atoms  an alkenyl group of about 3 to 10  or about 3 to 8 carbon atoms  an alkylamino of up to three carbon atoms  or hydrogen; and R3 is benzyl  an alkyl group of about 1 to 10  or about 3 to 8  carbon atoms  an alkenyl of about 3 to 10  or about 3 to 8  carbon atoms  an alkylamino of up to three carbon atoms  or hydrogen; provided that R1 and R2 cannot both be alkyl groups of four or fewer carbon atoms when R3 is hydrogen.
In embodiments  the amine is allylamine or 3-dimethylaminopropylamine.
The following examples will further describe certain specific aspects and embodiments of the invention. These examples are provided only for purposes of illustration  and should not be construed as limiting the scope of the invention in any manner.

EXAMPLE 1: Preparation of (1S 4R)-methyl 4-aminocyclopent-2-enecarboxylate  hydrochloride salt  10.

Methanol (11 L) is combined with 7 (2.50 kg  22.91 mol) under nitrogen. The solution is cooled to 0°C and thionyl chloride (1.88 L  25.78 mol) is added over 2.5 hours. The mixture is allowed to warm to 8°C  stirred for 16 hours  then concentrated to a volume of 7.5 L. MTBE (20 L) is added and the resulting precipitate is collected and dried to give 10 as an off-white solid (3.74 kg  92% yield).
1H NMR (400MHz  MeOH): δ 6.24-6.23 (1H  m)  6.06-6.0.3 (1H  m)  4.40 (1H  brs)  3.81-3.74 (4H  m)  2.77-2.69 (1H  m)  2.22-2.15 (1H  m).

EXAMPLE 2: Preparation of (1S 4R)-methyl 4-(tert-butoxycarbonyl)-aminocyclopent-2-enecarboxylate  11.

Triethylamine (2.43 L  17.43 mol) is added to a cooled suspension of 10 (2.55 kg  14.37 mol) in dichloromethane (10 L)  under N2 at 5°C. The mixture is cooled to 0°C  di tert-butyldicarbonate (3.14 kg  14.40 mol) is added at a rate that maintains the internal temperature of the reaction at 10°C or less  the addition time being 3.5 hours. The mixture is allowed to warm to room temperature and is then stirred for 16 hours. The mass is washed with water (3 L)  10% KHSO4 solution (3 L)  and brine (2×3 L)  then the mixture is concentrated. After 9 L of solvent is removed  methanol (2.5 L) is added and the mixture is further concentrated until 2.5 L of solvent is removed  and the mixture is diluted with further methanol (2.5 L) to give the crude product 11 as a methanolic solution.
A sample (2 mL) is removed from the bulk and concentrated to give a neat sample of 11 for analysis.
1H NMR (400MHz  MeOH): δ 5.91-5.89 (1H  m)  5.82-5.81 (1H  m)  4.64 (1H  brs)  3.57-3.53 (1H  m) 3.37  (3H  s)  3.33-3.33 (1H  m)  2.60-2.52 (1H  m)  1.84-1.78 (1H  m)  1.46 (9H  s).

EXAMPLE 3: Epimerisation of (1S 4R)-methyl 4-(tert-butoxycarbonyl)amino cyclopent-2-enecarboxylate  11.

A methanol solution of 11 (10 L  containing about 23.63 mol) is cooled to -2°C. A solution of sodium methoxide (127.6 g  2.36 mol) in methanol (700 mL) is added over 30 minutes  at a rate that maintains the reaction temperature at 0°C or less. After 50 minutes  gas chromatography (GC) analysis indicates a product distribution of 43% compound 12  54% compound 11  and 3% compound 13.
Acetic acid (140 mL) is added over 5 minutes  the mixture is allowed to warm to 10°C  then the mass is concentrated. After 7 L of solvent has been removed  the concentrated mixture is diluted with water (2 L) and MTBE (10 L). The aqueous layer is extracted with further MTBE (1 L). The combined organic layers are concentrated to give the products 11+12+13 in a MTBE solution  with a total volume of 7.5 L.
A sample (2 mL) is removed from the bulk and concentrated further  and this is found to contain 1.5 g of product and therefore 7.5 L should contain 5.625 kg  (99% mass recovery).
GC analysis shows the material to be 44% compound 12  52% compound 11  and 4% compound 13.
trans Diastereoismer 12; 1H NMR (400MHz  MeOH): δ 5.91-5.87 (1H  m)  5.85-5.81 (1H  m)  4.74 (1H  brs)  3.75-3.72 (1H  m) 3.66  (3H  s)  2.60-2.49 (1H  m)  1.89-1.78 (1H  m)  1.46 (9H  s).
cis Diastereoismer 11; 1H NMR (400MHz  MeOH): δ 5.91-5.87 (1H  m)  5.85-5.81 (1H  m)  4.65 (1H  brs)  3.72  (3H  s)  3.57-3.52 (1H  m)  2.60-2.49 (1H  m)  1.89-1.78 (1H  m)  1.46 (9H  s).

EXAMPLE 4: Ester hydrolysis.

A solution of a mixture of methyl esters 11+12+13 in MTBE (3.5 L  containing about 11.0 mol) is diluted with methanol (4 L) under N2  then cooled to -3.5°C (jacket temperature -5°C). A solution of lithium hydroxide monohydrate (508 g  12.08 mol) in water (2.5 L) is added over 5.5 hours with the reaction temperature being kept below 2°C at all times during the addition. Once the addition is complete  the mass is stirred for at 2°C for 30 minutes  then at 10°C for 16 hours.
The mass is neutralised with 6 M HCl and concentrated. After 4 L of solvent has been removed  the concentrated mixture is acidified to pH 3 by the addition of further 6M HCl. The acidic mixture is extracted with ethyl acetate (10 L  then 2.5 L)  and the combined organics are washed with brine (2×1.5 L)  then concentrated. Toluene (2×2.5 L) is added during the concentration to aid the removal of water. The products 14+15+16 are recovered as an off white solid (2.67 kg  94% yield).
trans Diastereoismer 15; 1H NMR (400MHz  MeOH): δ 5.93-5.90 (1H  m)  5.84-5.83 (1H  m)  4.75 (1H  brs)  3.72-3.67 (1H  m)  2.59-2.49 (1H  m)  1.90-1.78 (1H  m)  1.45 (9H  s).
cis Diastereoismer 14; 1H NMR (400MHz  MeOH): δ 5.93-5.90 (1H  m)  5.84-5.83 (1H  m)  4.67 (1H  brs)  3.52-3.48 (1H  m)  2.59-2.49 (1H  m)  1.90-1.78 (1H  m)  1.45 (9H  s).

EXAMPLE 5: Preparation of (1R 4R)-4-(tert-butoxycarbonyl)aminocyclopent-2-enecarboxylic acid  15.

A mixture of 14+15+16 (1.81 kg  7.99 mol) in ethyl acetate (15 L) is warmed to 50°C under N2. The resulting cloudy solution is cooled to 8°C (jacket temperature 5°C) and 3-dimethylaminopropylamine (1 L  7.99 mol) is added drop-wise over 1.5 hours  keeping the mixture temperature below 15°C. The mixture is stirred at 25°C for 16 hours. The precipitate is collected and washed with ethyl acetate (2 L).
The combined filtrates are partially concentrated and 8 L of solvent is removed. The concentrated solution is diluted with water (4 L) and acidified to pH 3 by the addition of 6 M HCl  then stirred for 30 minutes. The aqueous layer is washed with ethyl acetate (2.5 L). The combined organic layers are washed with brine (1.5 L) and concentrated to give 15 as an off white solid (550 g  30% yield).
Liquid chromatography (LC) analysis shows the material to be 88% compound 15  8% compound 14  and 4% compound 16.
A mixture of 15  14 and 16 in the ratio described above (1.74 kg  2.68 mol) is dissolved in MTBE (3.5 L) at 55°C  under N2. The solution is allowed to cool to 40°C and heptane (7 L) is added. The mixture is cooled to 20°C and further heptane (1 L) is added to aid stirring. The mass is stirred at 20°C for 16 hours. The solid material is collected  washed with a 1:3 mixture of MTBE and heptane (2 L) and dried to give 15 as a white solid (1.3 kg  75% yield).
LC analysis shows the material to be 96.4% compound 15  2.2% compound 14  and 0.6% compound 16.
This mixture (1.30 kg  5.73 mol) is dissolved in ethyl acetate (2.6 L) at 60°C  under N2. The solution is allowed to cool to 50°C and heptane (6 L) is added. The mixture is cooled to 20°C and stirred for 16 hours. The solid material is collected  washed with a 1:3 mixture of ethyl acetate and heptane (1.5 L) and dried to give 15 as a white solid (1.09 kg  84% yield).
LC analysis shows the material to be 99.4% compound 15  0.6% compound 16.
1H NMR (400MHz  MeOH): δ 5.92-5.90 (1H  m)  5.83-5.82 (1H  m)  4.75 (1H  br)  3.70-3.67 (1H  m)  3.33-3.32 (1H  m)  2.56-2.50 (1H  m)  1.88-1.81 (1H  m)  1.46 (9H  s).

EXAMPLE 6
The procedure of Example 5 is repeated  using the amines and solvents as shown in the table below. The weight ratios of compounds 14:15 in the precipitate and remaining in the solution are shown in the following table.
Amine Solvent Yield (%) Solid 14:15 Filtrate 14:15
Benzylamine i-PrOH 23 8:1 1:2.7
Cyclohexylamine EtOAc 83 1:1.2 1:1
Octylamine EtOAc 8 16:1 1:1.6
Isopropylamine i-PrOH 16 9:1 1:2
tert-Butylamine i-PrOH 22 6:1 1:2
tert-Octylamine i-PrOH 24 5:1 1:2
Ethanolamine No solid
Morpholine EtOAc 11 1:15 1.2:1
Methylamine (8M in EtOH) EtOAc 53 1:1.6 1.4:1
Dibenzylamine EtOAc 22 1.5:1 1:2
(S)-(-)--Methylbenzylamine i-PrOH 35 1:1.4
(R)-(+)--Methylbenzylamine i-PrOH 56 1:1
Pyrrolidine No solid
Piperidine No solid
Allylamine i-PrOH 28 7:1 1:2.8
Allylamine EtOAc 49 6.8:1 1:12
3-Dimethylaminopropylamine EtOAc 37 16:1 1:6
Dicyclohexylamine i-PrOH 45 1:2.4 1.8:1
Dibutylamine No solid

EXAMPLE 7: Opening (1R 4S)-tert-butyl 3-oxo-2-aza-bicyclo[2.2.1]hept-5-ene-2-carboxylate to give epimer mixture 11+12+13.

Compound 17 (7.5 g  35.89 mmol) is dissolved in methanol (100 mL) at 1.5°C. A solution of sodium methoxide (0.19 g  3.59 mmol) in methanol (5 mL) is added over 10 minutes  with the mixture temperature being kept below 2°C during the addition. After 100 minutes  GC analysis indicates a product distribution of 36% compound 12  62% compound 11   2% compound 13.
The reaction is quenched by the addition of acetic acid (0.2 mL) and the mixture is concentrated to remove methanol. The residue is partitioned between water (30 mL) and MTBE (80 mL) and the aqueous layer is extracted with MTBE (40 mL). The combined organic layers are dried over sodium sulfate and concentrated to give methyl esters 11+12+13 as a pale yellow oil (8.45 g  104% yield).
GC analysis indicates a product distribution of 37% compound 12  62% compound 11  and 1% compound 13.

EXAMPLE 8: Opening (1S 4R)-tert-butyl 3-oxo-2-aza-bicyclo[2.2.1]hept-5-ene-2-carboxylate 18 to give epimer mixture 19+20+21.

Compound 18 (75.3 g  360 mmol) is dissolved in methanol (1.2 L) at 1.5°C. A solution of sodium methoxide (3.9 g  72.1 mmol) in methanol (50 mL) is added over 10 minutes  and the mixture temperature is kept below 2°C during the addition. After 300 minutes  GC analysis indicates a product distribution of 43% compound 19 (trans diastereoisomer)  55% compound 20 (cis diastereoisomer)  and 2% compound 21.
The pH is adjusted to 6 with acetic acid  added over 5 minutes  and the mixture is allowed to warm to 10°C  then concentrated. After 1.2 L of solvent has been removed  the concentrated mixture is diluted with water (200 mL) and MTBE (750 mL). The aqueous layer is extracted with further MTBE (250 mL). The combined organic layers are concentrated to give methyl esters 19+20+21 (87 g).
GC analysis shows the material to be 44% compound 19 (trans diastereoisomer)  54% compound 20 (cis diastereoisomer) and 2% compound 21.
1H NMR: data as above for compounds 11 (cis diastereoisomer) and 12 (trans diastereoisomer).

EXAMPLE 9: Ester hydrolysis.

A mixture of methyl esters 19+20+21 (87 g) is dissolved methanol (800 mL) under N2  then cooled to -3.5°C (jacket temperature -5°C). A solution of lithium hydroxide monohydrate (18.2 g  432 mmol) in water (150 mL) is added over 30 minutes  with the mixture temperature being kept below 0°C at all times during the addition. After the addition is complete  the mixture is stirred at 2°C for 16 hours.
A sample (2 mL) is removed from the mass  quenched with acetic acid  and extracted into MTBE (5 mL). Solvent is removed to give a neat sample for analysis. NMR analysis shows the material to be 43% 19+20+21.
Additional LiOH (2.0 g  47.5 mmol) is added and the mixture is stirred at 0°C for 4 hours. NMR analysis shows the material to be 30% 19+20+21.
Additional LiOH (9.0 g  213 mmol) is added and the mixture is stirred at 0°C for 72 hours. The mass is cooled to -2°C before being neutralized with 6 M HCl and concentrated. After 1.2 L of solvent has been removed  the concentrated mixture is acidified to pH 5 by the addition of further 6M HCl. The acidic mixture is extracted with ethyl acetate (800 mL  then 400 mL)  and the combined organic layers are washed with brine (400 mL  then 200 mL)  then concentrated. The products 22+23+24 are recovered as an off-white solid (83 g).
1H NMR: data as above for compounds 14 (cis diastereoisomer) and 15 (trans diastereoisomer).

EXAMPLE 10: Preparation of (1S 4S)-4-(tert-butoxycarbonyl)aminocyclopent-2-enecarboxylic acid  22.

The mixture of 22+23+24 (83 g  365 mmol) in ethyl acetate (600 mL) is warmed to 50°C under N2. The resulting cloudy solution is cooled to -2°C and 3-dimethylaminopropylamine (52.5 mL  0.417 mol) is added drop-wise over 30 minutes  keeping the temperature below 2°C. The mixture is stirred at 25°C for 16 hours. The precipitate is collected and washed with ethyl acetate (75 mL).
The combined filtrates are diluted with water (600 mL) and acidified to pH 2.5 by the addition of 6 M HCl  then stirred for 30 miutes. The aqueous layer is washed with ethyl acetate (100 mL). The combined organic layers are washed with brine (2×300 mL) and concentrated to give 22 as an off-white solid (26 g  31% yield). LC analysis shows the material to be 92% compound 22  5% compound 23  and 1% compound 24.
A mixture of 22  23 and 24 in the ratio described above (26 g  114 mmol) is dissolved in ethyl acetate (52 mL) at 60°C  under N2. The solution is allowed to cool to 50°C and heptane (120 mL) is added. The mass is cooled to 20°C and stirred for 16 hours. The solid material is collected  washed with a 1:3 mixture of ethyl acetate and heptane (1.5 L) and dried to give 22 as a white solid (15 g  58% yield).
LC analysis shows the material to be 99.8% compound 22  0.2% compound 24.
1H NMR: data as above for compound 15.

We claim:
1. A process for preparing trans-4-amino-2-cyclopentene-1-carboxylic acid derivatives represented by formula 1  comprising:

1
a) providing a composition comprising a compound of formula A 

A
having components present in both cis- and trans- structures  wherein R1 is an alkyl or aryl group having up to about 12 carbon atoms  in a solvent;
b) combining with an amine to form salts  wherein some salt precipitates but the salt of a trans- structure of compound A remains in the solution in excess of the amount of the salt of the cis- structure of compound A remaining in the solution;
c) separating the precipitate from the solution;
d) adding acid to the solution to re-form carboxylic acids from the salts in the solution;
e) isolating the compound 1   which is the trans-structure of compound A; and
f) optionally  purifying the composition from e) to produce a diastereomeric excess of the trans- structure of compound A.
2. The process of claim 1  wherein a composition comprising compounds of formula A is obtained by hydrolysing a mixture including compounds 2  3 and 4

2 3 4
where R1 is an alkyl or aryl group having up to about 12 carbon atoms  and R2 is a lower alkyl group having up to about four carbon atoms.
3. The process of claim 1   wherein a solvent in a) is a lower alcohol  alkyl acetate  ether  or a mixture of two or more thereof.
4. The process of claim 3  wherein an alkyl acetate is ethyl acetate.
5. The process of claim 1  wherein a salt-forming amine has the formula NR1R2R3  where: R1 is benzyl  or a non-cyclic alkyl or alkenyl group of 3 to 10 carbon atoms; R2 is benzyl  an alkyl group of about 1 to 10 carbon atoms  an alkenyl group of about 3 to 10 carbon atoms  an alkylamino of up to three carbon atoms  or hydrogen; and R3 is benzyl  an alkyl group of about 1 to 10 carbon atoms  an alkenyl of about 3 to 10 carbon atoms  an alkylamino of up to three carbon atoms  or hydrogen; provided that R1 and R2 cannot both be alkyl groups of four or fewer carbon atoms when R3 is hydrogen.
6. The process of claim 1  wherein a salt-forming amine is allylamine or 3-dimethylaminopropylamine.
7. The process of claim 1   wherein the compound of formula 1 is isolated by crystallization  after combining a solution containing the compound of formula 1 with a lower alkane.
8. The process of claim 11  whereon a lower alkane has less than about 10 carbon atoms.
9. The process of claim 1  further comprising recrystallizing the compound of formula 1 from a suitable solvent.
10. The process of claim 1  wherein the compound of formula 1 is in a diastereomeric excess greater than about 98%.