NZ528663A - Method for preparing 4-hydroxymethylpyrrolidin-3-ol compounds - Google Patents
Method for preparing 4-hydroxymethylpyrrolidin-3-ol compoundsInfo
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- NZ528663A NZ528663A NZ52866303A NZ52866303A NZ528663A NZ 528663 A NZ528663 A NZ 528663A NZ 52866303 A NZ52866303 A NZ 52866303A NZ 52866303 A NZ52866303 A NZ 52866303A NZ 528663 A NZ528663 A NZ 528663A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
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Abstract
A method of preparing (3R,4R)-3-hydroxy-4-hydroxymethylpyrrolidine of formula (A) and its enantiomer (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine of formula (E) is disclosed, wherein the method includes a step of enzyme catalysed enantioselective esterification of a hydroxy group of a hydroxypyrroildine and separation of the diastereomers, wherein (3R,4R)-3-hydroxy-4-hydroxymethylpyrrolidine and (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine are key intermediate compounds for the synthesis of certain inhibitor compounds.
Description
New Zealand Paient Spedficaiion for Paient Number 528663
Patents Form No. 5
OurRef: HP220404
NEW ZEALAND PATENTS ACT 1953
Complete After Provisional No. 528663 Filed: 3 October 2003
COMPLETE SPECIFICATION
METHOD FOR PREPARING 3-HYDROXY-4-HYDROXYMETHYLPYRROLIDINE
COMPOUNDS
We, INDUSTRIAL RESEARCH LIMITED, a New Zealand company, of Brooke House, 24 Balfour Road, Parnell, Auckland, New Zealand hereby declare the invention, for which We pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:
IwftLLcCTUAl O/FICc" ]
Of ;iZ |
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METHOD FOR PREPARING 3-HYDROXY-4-HYDROXYMETHYLPYRROUDINE COMPOUNDS
TECHNICAL FIELD
This invention relates to a method for preparing 3-hydroxy-4-hydroxymethylpyrrolidine compounds. In particular, the invention relates to a method of preparing (3R4f?)-3-hydroxy-4-hydroxymethylpyrrolidine, including the steps of enzyme catalysed enantioselective esterification of an hydroxy group of an hydroxypyrrolidine, and separation of the diastereomers obtained. The invention further relates to a method for preparing (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine, which is the enantiomer of (3R,4f?)-3-hydroxy-4-hydroxymethyipyrrolidine.
BACKGROUND
The known compound of formula (A), (3f?,4R)-3-hydroxy-4-hydroxymethylpyrrolidine, is a key intermediate compound for the synthesis of certain of the applicant's inhibitor compounds, including potent purine nucleoside phosphorylase inhibitors (see for example WO 2004/018496).
H
(A)
Makino and Ichikawa (K. Makino and Y. Ichikawa, Tetrahedon Letters (1998) 39, 8245) have reported a synthesis of compound (A). The requisite chirality of compound (A) is introduced using a Sharpless asymmetric epoxidation.
Karlsson and Hogberg (S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymmetry (2001) 12, 1977) describe an alternative synthesis method. In this method, chirality is introduced using a chiral sultam auxiliary. -• ,
- 8 OCT 200} j pcrci\/rn I
3
However, synthetic methods that employ an achiral starting material suffer from the disadvantages associated with additional reaction steps necessary to introduce chirality. The disadvantages include a greater number of handling steps, lower product yields, 5 scale-up difficulties, and costly reagents.
Filichev et ai. (V. V. Filichev and E. B. Pedersen, Tetrahedron (2001) 57, 9163; V. V. Filichev, M. Brandt and E. B. Pedersen, Carbohydrate Research (2001) 333, 115) have used chiral starting materials to produce compound (A). For example, compound (A) can 10 be prepared from diacetone-D-glucose or from D-xylose. However, both synthetic procedures are complex and require many reaction steps.
An alternative method for introducing chirality involves the use of biological catalysts. For example, Hansen and Bols (S. U. Hansen and M. Bols, Acta Chemica Scandinavica 15 (1998) 52, 1214) attempted the enzymatic resolution of the N-Boc derivative of racemic frans-3-hydroxy-4-hydroxymethylpyrrolidine using immobilised lipases from Candida antarctica and Mucor mihei. This method focuses on attempting to resolve the diol by enzymatic means. However, poor enantiomeric excesses were obtained in this way, resulting in only small amounts of compound (A) being made available for use as an 20 intermediate in the preparation of other compounds. Low product yields mean considerable wastage and therefore high overall cost.
The published syntheses of compound (A) are therefore unsatisfactory as commercially viable routes to this valuable intermediate compound. There has been an ongoing need 25 to overcome this problem by developing an improved method which employs only a few reaction steps and with an acceptable overall product yield.
It is known that lipase catalysed resolution of carbocyclic cis- and frans-p-hydroxy esters by O-acylation can provide enantiopure compounds in high yields (L. M. Levy, J. R. Dehli 30 and V. Gotor, Tetrahedron: Asymmetry (2003) 14, 2053). However, it can be difficult to predict the reactivity of an enzyme to a potential substrate. Even when a particular compound is found to be an enzyme substrate there is often little certainty as to reaction yield and enantiomeric purity of the product.
However, in the search for new and improved methods for preparing compound (A), the applicant has surprisingly found that compound (A) can be pre^^ ^-^jab -yield and in
I'
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high enantiomeric excess, via lipase catalysed esterification of a racemic 1-A/-protected frans-4-hydroxypyrrolidine-3-carboxylic acid alkyl ester. The applicant's new method also advantageously allows the preparation of compound (E), the enantiomer of compound (A).
It is therefore an object of the invention to provide an improved method for preparing 3-hydroxy-4-hydroxymethylpyrrolidine compounds, or at least to provide a useful choice.
STATEMENTS OF INVENTION
In a first aspect, the invention provides process for preparing a compound of formula (A) or a compound of formula (E), or salts thereof including the steps of (a), (b) and (c):
where step (a) is enzyme-catalysed enantioselective esterification of the hydroxyl group of a racemic 3,4-frans-1-N-protected-4-hydroxypyrrolidine-3-carboxylic acid ester compound of formula (B)
h h
(A)
(E)
(B)
where R1 is a straight or branched chain alkyl group; and R2 is a protecting group;
to give either a mixture of a compound of formula (C) and a compound of formula (D)
(C) <D)
where R1 and R2 are as defined above; and R3 is acyl;
or a mixture of a compound of formula (C'), and a compound of formula (D')
(C') (D')
where R1 and R2 are as defined above; and R3 is acyl;
where the enzyme-catalysed enantioselective esterification is carried out using either
(1) an enzyme capable of producing an enantiomeric excess of compound (C); or
(2) an enzyme capable of producing an enantiomeric excess of compound
(□');
step (b) is separation of the compound of formula (C) from the compound of formula (D); or T" - •
- 8 OCT 2CC} i R ?= P. FI \/ P n
6
separation of the compound of formula (C') from the compound of formula (D');
and
step (c) is transformation of the compound of formula (c) or the compound of formula (D') to the compound of formula (A); or transformation of the compound of formula (C') or the compound of formula (D) to the compound of formula (E).
Preferably the enzyme-catalysed enantioselective esterification in step (a) gives a mixture of compounds of formulae (C) and (D), and the enantiomeric excess of compound (C) is at least about 80%, most preferably at least about 90%.
Alternatively it is preferred that the enzyme-catalysed enantioselective esterification in 15 step (a) gives a mixture of compounds of formulae (C') and (d'), and the enantiomeric excess of compound (d') is at least about 80%, most preferably at least about 90%.
It is preferred that the enzyme used in step (a) is an enzyme capable of catalysing the formation of an ester bond, preferably a lipase, most preferably lipase from Candida 20 antarctica.
It is preferred that the transformation of the compound of formula (C) or the compound of formula (D') to the compound of formula (A) includes the step of reduction of the ester group of the compound of formula (C), or reduction of both ester groups of the compound of formula (D').
Preferably the transformation further includes the step of replacement of the R2 group with hydrogen to give the compound of formula (A).
Alternatively, it is preferred that the transformation of the compound of formula (C') or the 30 compound of formula (D) to the compound of formula (E) includes the step of reduction of the ester group of the compound of formula (C'), or reduction of both ester groups of the compound of formula (D). In that case, the transformation preferably further includes the step of replacement of the R2 group with hydrogen to give the compound of formula (E).
It is preferred that the reduction is carried out using either LiAIH4 or LiBH4.
I
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II
It is further preferred that the replacement of the R2 group with hydrogen is carried out either in the presence of HCI or with HCOOH/CH3OH in the presence of Pd-C.
Preferably the separation of the compound of formula (C) from the compound of formula (D) or the separation of the compound of formula (C') from the compound of formula (D') is effected by chromatography or fractional crystallisation.
Preferably R1 is a straight or branched chain Ci-C6 alkyl group, most preferably ethyl.
It is also preferred that R3 is COR4, where R4 is a straight or branched chain Ci-C6 alkyl group, and that R1 is ethyl and R2 is benzyl or f-butoxycarbonyl.
In a preferred embodiment of the invention, R1 is ethyl, R2 is benzyl and R3 is acetyl.
In another preferred embodiment of the invention R1 is ethyl, R2 is f-butoxycarbonyl and R3 is acetyl.
Preferably the enantioselective esterification in step (a) is carried out using vinyl acetate as an acyl donor, to give a mixture of compounds of formulae (C) and (D) where R3 in the compound of formula (D) is acetyl; or a mixture of compounds of formulae (C') and (D1) where R3 in the compound of formula (D') is acetyl.
In another aspect, the invention provides process for preparing a compound of formula (A), or a salt thereof where step (a) is enzyme-catalysed enantioselectr roxyl h
(A)
including the steps of (a), (b) and (c):
8
group of a racemic 3,4-frans-1-N-protected-4-hydroxypyrrolidine-3-carboxylic acid ester compound of formula (B)
R2
(B)
where R1 is a straight or branched chain alkyl group; and R2 is a protecting group;
to give either a mixture of a compound of formula (C) and a compound of formula (D)
(C) (D)
where R1 and R2 are as defined above; and R3 is acyl;
or a mixture of a compound of formula (C), and a compound of formula (D1)
•- GrrlCE
- 8 OCT 2c;i
9
(C) (D1)
where R1 and R2 are as defined above; and R3 is acyl;
where the enzyme-catalysed enantioselective esterification is carried out using either
(1) an enzyme capable of producing an enantiomeric excess of compound (C);. or
(2) an enzyme capable of producing an enantiomeric excess of compound
(□');
step (b) is separation of the compound of formula (C) from the compound of formula (D); or separation of the compound of formula (C') from the compound of formula (D');
and step (c) is transformation of the compound of formula (C) or the compound of formula (D') to the compound of formula (A).
In still another aspect, the invention provides process for preparing a compound of formula (E), or a salt thereof
hoh2(f
(E)
including the steps of (a), (b) and (c):
where step (a) is enzyme-catalysed enantioselective esterification of the hydroxyl group of a racemic 3,4-<ra/7s-1-N-protected-4-hydroxypyrrolidine-3-carboxylic acid ester compound of formula (B)
r102c
(B)
where R1 is a straight or branched chain alkyl group; and R2 is a protecting group;
to give either a mixture of a compound of formula (C) and a compound of formula 15 (D)
DF i'w 7
- 8 OCT 2CC'i
PPPPl\/r- r
11
where R1 and R2 are as defined above; and R3 is acyl;
or a mixture of a compound of formula (C'), and a compound of formula (D')
R'02Cf OH
(C1)
where R1 and R2 are as defined above; and R3 is acyl;
r102c
(D')
wherein the enzyme-catalysed enantioselective esterification is carried out using either
(1) an enzyme capable of producing an enantiomeric excess of compound (C); or
(2) an enzyme capable of producing an enantiomeric excess of compound (□');
step (b) is separation of the compound of formula (C) from the compound of formula (D); or separation of the compound of formula (C') from the compound of formula (D');
and step (c) is transformation of the compound of formula (C') or the compound of formula (D) to the compound of formula (E).
The invention further provides a compound of formula (C)
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12
r1o2c
(C)
where R1 is a straight or branched chain alkyl group; and R2 is a protecting group.
In addition, the invention provides a compound of formula (D)
(D)
where R1 is a straight or branched chain alkyl group; 10 R2 is a protecting group; and
R3 is acyl.
The invention also provides a compound of formula (C')
r2
where R1 is a straight or branched chain alkyl group; and
INfELLECTUAL F!
OF
-8 OCT _R£C E! V <,
13
R2 is a protecting group.
The invention further provides a compound of formula (D')
R2
where R1 is a straight or branched chain alkyl group;
R2 is a protecting group; and R3 is acetyl.
Preferred intermediate compounds include a compound of formula (C) as defined above where R1 is ethyl and R2 is benzyl and a compound of formula (C) as defined above where R1 is ethyl and R2 is f-butoxycarbonyl.
Preferred intermediate compounds include a compound of formula (D) as defined above where R1 is ethyl, R2 is benzyl and R3 is acetyl and a compound of formula (D) as defined above where R1 is ethyl, R2 is f-butoxycarbonyl and R3 is acetyl.
In a further aspect, the invention provides a compound of formula (A) as defined in claim 1, when prepared by the above process.
In a final aspect, the invention provides a compound of formula (E) as defined in claim 1, when prepared by the above process.
DETAILED DESCRIPTION
This invention relates to the lipase or acylase catalysed resolution of a (±)-trans-4-hydroxypyrrolidine-3-carboxylic acid alkyl ester. This provides a convenient route to compound (A). As noted above, this compound is useful in the preparation of the
14
applicant's purine nucleoside phosphorylase inhibitor compounds, such as those described in WO 2004/018496.
The invention has the added advantage that the enantiomer of (A), a compound of 5 formula (E), can also be produced. Compound (E) may find use in other applications.
The invention therefore provides an improved route to a valuable starting material and its enantiomer.
Advantageously, compounds (C) and (D) (or compounds (C') and (D')) are produced in 10 high chemical yield with high enantioselectivity. Furthermore, these compounds are readily separated and converted to the diols (A) and (E).
According to one preferred embodiment of the invention (Scheme 1), enantioselective acylation of the 4-hydroxy group of (±)-frans-1-A/-benzyl-4-hydroxypyrrolidine-3-carboxylic 15 acid ethyl ester (1) is carried out using Novozyme® 435 lipase from Candida antarctica,
and vinyl acetate as the acyl donor molecule. The two products are then readily separated by chromatography on silica gel. Compound (A) is obtained from compound (2) by reduction of the ester group using LiAIH4 and removal of the benzyl protecting group using CH3OH/HCOOH and Pd/C. Advantageously, compound (E) may also be 20 obtained from compound (3).
li * ' wLLw'J ! UAL f'; *•; ."i j •
OF ?\Z.
- 8 OPT
received
Scheme 1
Novozyme435 Bu'OMe,
vinyl acetate
Et02C (±)-l *OH Et02C" 2
AcjO/pyridine
LiAlH,
/%
EtO,C (±)"5 *OAc
HOH2C
HOH2cf 6
LiAlHi
/ %
W ''
HOH,C (±)-7 'OH
HCOOH-MeOH Pd-C
HOH2C "OH
s~ (+)"(A)
HC1 (
(+HA), HC1
HCOOH-MeOH Pd-C
HOH2cf "OH
' (-ME)
HC1 '
f (-HE)
HQ
According to another preferred embodiment of the invention (Scheme 2) enantioselective acylation of the 4-hydroxy group of frans-(±)-4-hydroxypyrrolidine-1 -A/-3-dicarboxylic acid-1-fe/t-butyl ester-3-ethyl ester (10) is also carried out using Novozyme® 435 lipase from Candida antarctica, and vinyl acetate as the acyl donor molecule. As Scheme 2 shows, compound (10) can be prepared in high yield from (EH±)-1-A/-benzyl-4-benzyloxypyrrolidine-3-carboxylic acid ethyl ester (8) which may itself be prepared from commercially available A/-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine and frans-3-benzyloxyacrylic acid ethyl ester.
Compounds (12) and (13) are readily separated by chromatography. Compound (A) is obtained in two steps from compound (12) by reduction of the ester group using LiBH4 and removal of the f-butoxycarbonyl protecting group. Similarly, compound (E) may also be obtained from compound (13).
Scheme 2
16
M«3Si
EIO2C,
±V9 OCH2Ph
(±>1
EIO2C 12 'OH
(+)_4 HyPd-C (Boc^O
/ ^
BO2C (±)-ll OAc
(+HA),HC1
(->E, HC1
The compounds of formulae (A) and (E) may be converted to the salts thereof, using a suitable inorganic acid, such as HCI, or organic acid, such as p-toluenesulphonic acid.
It will be appreciated by a person skilled in the art that alternative acyl donor molecules may be employed in the method of the present invention. Suitable alternative donor 10 molecules include methyl acetate, ethyl acetate, isopropenyl acetate, vinyl benzoate, vinyl propanoate, vinyl butyrate, vinyl laurate, 2,2,2-trichloroethyl acetate, 2,2,2-trichloroethyl butyrate, 2,2,2-trichloroethyl laurate, 2,2,2-trifluoroethyl butyrate, 2,2,2-trifluoroethyl laurate, and methyl propanoate.
Similarly, it will be appreciated that any suitable reducing agent may be used to reduce the ester group, following the enantioselective esterification. Preferably the reducing agent used is LiAIH4 or lithium borohydride. However, other possible reducing agents include sodium borohydride with or without a Lewis acid catalyst such as AICI3 or BF3, L-Selectride, NaBH(OMe)3, LiAIH(0-tBu)3, LiAIH(OMe)3, and AIH3._
17
Although it is preferred that the compound of formula (B) incorporates a benzyl protecting group or a f-butoxycarbonyl protecting group, it will be clear to the skilled person that other N-protecting groups may be employed (see for example, "Protective Groups in Organic Synthesis" by Theodora W. Greene, Wiley-lnterscience, 3rd edition (May 15, 1999)). As 5 used herein, the term "protecting group" means "a group that selectively protects an organic functional group, temporarily masking the chemistry of that functional group and allowing other sites in the molecule to be manipulated without affecting the functional group". Other suitable protecting groups include 4-methoxybenzyl, 2-(trimethylsilyl)ethyl, and diphenylmethyl.
Methods of removing such N-protecting groups are known to those skilled in the art, and it is envisaged that any suitable reagent may be used in the deprotection step, including:
(a) in the case of a benzyl, 4-methoxybenzyl, or diphenylmethyl protecting group, catalytic hydrogenolysis using hydrogen (or a source of hydrogen such as
formic acid) and a metal catalyst such as Pd/C;
(b) in the case of a 2-(trimethylsilyl)ethyl group, a source of fluoride ion such as tetrabutylammonium fluoride; or
(c) in the case of a 4-methoxybenzyl protecting group, an acidic catalyst such as trifluoroacetic acid or an oxidant such as eerie ammonium nitrate.
(d) in the case of f-butoxycarbonyl, acidic cleavage using HCI.
It will be clear to the person skilled in the art that any suitable separation method may be used to separate the compound of formula (C) from the compound of formula (D) or to separate the compound of formula (C') from the compound of formula (D'). However, it is preferred that the separation is effected either by chromatography or by fractional 25 crystallisation.
The process of the invention contemplates the use, in the enzyme-catalysed enantioselective esterification step, of any enzyme capable of catalysing the formation of an ester bond. However, it is preferred that a lipase is used, most preferably lipase from 30 Candida antarctica.
While it is preferred that the compound of formula (B) is one where R1 is ethyl, it will be appreciated that R1 may be other straight or branched chain alkyl substituents.
Compounds of formula (B) may be produced via known methods (see for example A. C.
Pinto, R. V. Abdala, P. R. R. Costa, Tetrahedron Asymmetry (2000) 11, 4239; E. Jaeger
- 8 OCT
18
and J. H. Biel, J. Org. Chem., (1965) 30, 740; M. N. Deshmukh, K. K. Gangakhedkar and U. S. Kumar, Synthetic Communications (1996) 26, 1657).
As used herein, the structural formulae showing the "wedge" notation, e.g.:
are intended to represent racemic mixtures.
EXAMPLES
The invention is further described with reference to the following examples. It is to be appreciated that the invention is not limited by these examples.
General Chemical Methods: Melting points were measured on a Reichert hot stage microscope and are uncorrected. Optical rotations were determined with a Perkin Elmer 241 polarimeter and are in units of 10"1deg cm2 g"1 (conventionally °). TLC was performed on glass or aluminium backed silica gel 60 F254 (Merck) with detection by UV absorption and/or by heating after dipping in (NH4)6Mo7024-6H20 (5 g) and Ce(S04)2 (100 mg) in 5% aq. H2S04 (100 ml.) solution or in a solution of l2 (200 mg) and Kl (7 g) in 10% aq. H2S04 (100 mL). Chromatography (flash column) was performed on Scharlau or Merck silica gel 60 (40-60 pm). Chromatography solvents were distilled prior to use. Anhydrous solvents were those commercially available. Organic solutions were dried over MgS04 and evaporated under reduced pressure. All air sensitive reactions were performed under argon. NMR spectra were recorded on a Bruker AC300E spectrometer at 300 MHz (1H ) for solutions in CDCI3, CD3OD (internal Me4Si, 8 0) or D20 or at 75.5 MHz (13C) for solutions in CDCI3 (centre line 8 77.0), or CD3OD(centre line 8 49.0). Assignments of 1H and 13C resonances were based on 2D (1H-1H DQF-COSY, 1H-13C HSQC) and DEPT experiments. The 13C spectra gave unambiguous data on the numbers of protons bonded to each carbon atom; these are expressed as s, d, t and q being the multiplicities are intended to represent pure enantiomeric forms.
The structural formulae showing the "rectangular" notation e.g.:
-8
0 UU 1
19
expected in C,H undecoupied spectra. High-resolution MS determinations were performed on a VG-7070 high resolution mass spectrometer.
Example 1
Trans-(±)-1-N-benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester (1).
This compound was prepared by the method described by E. Jaeger and J.H. Biel, J. Org. Chem., 1964, 30, 740, but used ethyl A/-benzyl-A/-(2-carbethoxyethyl)glycinate as prepared by A.C. Pinto, R.V. Abdala and P.R.R. Costa, Tetrahedron: Asymm., 2000, 11, 10 4239 and also used the Dieckmann cyclization conditions described by M.N. Deshmukh,
K.K. Gangakhedkar and U.S. Kumar, Synth. Commun., 1996, 26, 1657. It was purified by chromatography (eluant ethyl acetate-hexanes 1:2 v/v ->1:1 v/v —methyl acetate) and crystallized at -20 °C to a colourless solid.
Mp 52-53 °C (colourless needles, 40-60 petrol, -20 °C).
1H NMR (CDCIa) 8 7.37-7.22 (m, 5 H), 4.53-4.49 (m, 1 H, H-4), 4.16 (q, 2 H, J 7.1 Hz,
CH2CH3), 3.64 (s, 2 H, PhChh), 3.12 (t, 1 H, J 9.0 Hz, H-2), 2.95 (dt, 1 H, J 7.5, 3.3 Hz, H-3), 2.76 (dd, 1 H, J 10.0, 2.8 Hz, H-5), 2.65 (dd, 1 H, J 10.0, 5.5 Hz, H-5'), 2.55 (dd, 1 H, J 9.4, 7.4 Hz, H-2'), 2.32 (br. s, 1 H, OH), 1.26 (t, 3 H, J 7.1 Hz, CH2CH3).
13C NMR (CDCI3) 8 173.3 (s), 138.2 (s), 128.8 (d), 128.3 (d), 127.1 (d), 74.1 (d), 61.9 (t), 20 60.8 (t), 59.7 (t), 55.3 (t), 53.1 (d), 14.2 (q).
Example 2
Trans-(±)-1-N-benzyl-4-acetoxypyrrolidine-3-carboxylic acid ethyl ester (5). 25 Trans-(±)-1-W-benzyl-4-hyroxypyrrolidine-3-carboxylic acid ethyl ester from example 1 (1,
100 mg, 0.4 mmol) was dissolved in a mixture of pyridine (4 mL) and acetic anhydride (2 mL) and left at ambient temperature overnight. The solvent was evaporated and the resulting oil dissolved in ethyl acetate and washed with sat. NaHC03, dried and evaporated. The residue was chromatographed (eluant ethyl acetate-hexanes 15:85 v/v) 30 to afford frans-(±)-1-A/-benzyl-4-acetoxypyrrolidine-3-carboxylic acid ethyl ester (5) as a colourless oil (111 mg, 95%). It was stored at -20 °C.
1H NMR (CDCI3) 8 7.38-7.22 (m, 5 H), 5.42-5.38 (m, 1 H, H-4), 4.16 (q, 2 H, J 7.1 Hz, CJiCHa), 3.65 (d, 1 H, J 12.9 Hz, PhCHH), 3.59 (d 1 H, J 12.9 Hz, PhCHH), 3.15 (t, 1 H, J 8.5 Hz, H-2), 3.06 (dt, 1 H, J 8.0, 3.9 Hz, H-3), 2.87-2.74 (m, 2 H, H-5, H-51), 2.50 (br. t, 1 35 H, J ~ 8.3 Hz, H-2'), 2.04 (s, 3 H, COCH3), 1.25 (t, 3 H, J 7.1 Hz, CH2CH3).
- 8 "if"-',
13C NMR (CDCI3) 8 172.3 (s), 170.5 (s), 138.0 (s), 128.7 (d), 128.3 (d), 127.2 (d), 76.0 (d, C-4), 61.0 (t, CH2CH3), 59.6 (t, PhCH2 or C-5), 59.5 (t, PhCH2 or C-5), 56.0 (t, C-2), 50.1 (d, C-3), 21.0 (q, COCH3), 14.1 (q, CHsCHa).
+ve FABMS: m/zCalcd. for Ci6H22N04 (M+H)+ 292.154883. Found: 292.156263.
Example 3
Trans-(±)-1-N-benzyi-3-hydroxy-4-hydroxymethyl pyrrolidine (7). 7ra/7s-(±)-1-A/-benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester from example 1 (1, 10 500 mg, 2.01 mmol) was dissolved in a mixture of dry Et20 (10 mL) and dry THF (5 mL)
and cooled in an ice bath. Lithium aluminium hydride (4.2 mL, 4.2 mmol, 1M) was added and the mixture warmed to ambient temperature and stirred for 1 hr. The reaction mixture was cooled in an ice bath, quenched by the dropwise addition of water and extracted with ethyl acetate. The organic extract was washed with sat NaHC03, dried and evaporated to 15 a residue that was chromatographed (eluant CH2CI2-MeOH-cNH3 95:5:0.5-^90:10:0.5 v/v)
to give frans-(±)-1-A/-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine (7) as a colourless gum (364 mg, 88%).
1H NMR (CD3OD) 6 7.42-7.20 (m, 5 H), 4.04-3.95 (m, 1 H, H-3), 3.68-3.47 (m, 4 H, PhCHa & CH2O), 2.89 (br. t, 1 H, J~8.8 Hz, H-5), 2.72 (dd, 1 H, J 10.0, 6.3 Hz, H-2), 2.55 (dd, 1 20 H, J 10.0, 4.1 Hz, H-2'), 2.34 (dd, 1 H, J 9.6, 6.6 Hz, H-5'), 2.23-2.12 (m, 1 H, H-4).
13C NMR (CD3OD) 5 139.4 (s), 130.2 (d), 129.3 (d), 128.3 (d), 74.1 (d, C-3), 64.2 (t, PhCH2 or CH20), 63.1 (t, C-2), 61.5 (t, PhCH2 or CH20), 57.3 (t, C-5), 51.2 (d, C-4). +ve FABMS: m/z Calcd. for Ci2H18N02 (M+H)+ 208.133754. Found: 208.134589.
Example 4
(3S,4R)-1-N-Benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester (2) and (3R,4S)-4-acetoxy-1-N-benzylpyrrolidine-3-carboxylic acid ethyl ester (3).
Vinyl acetate (0.22 mL, 2.4 mmol) and Novozyme® 435 lipase from Candida antarctica 30 (138 mg, product No L4777, 2002-2003 Sigma catalogue, batch 083K0739) were added sequentially to a solution of fra/7S-(±)-1-A/-benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester from example 1 (1, 200 mg, 0.8 mmol) in ferf-butyl methyl ether (9.5 mL). The mixture was stirred at 25-30 °C for 16 h then diluted with CHCI3 (10 mL) and filtered through Celite. After evaporating the solvent at reduced pressure, the residue was 35 dissolved in CHCI3, washed with sat. NaHC03, dried and evaporated. 1H NMR (CDCI3) analysis indicated a 1:0.99 ratio of (3f?,4S)-4-acetoxy-1-A/-benzylpyrrolidine-3-carboxylic
J - 8 OCT 2004 1
21
acid ethyl ester (3):(3S,4R)-1-/V-benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester (2). The residue was chromatographed (eluant EtOAc-hexanes 6:4 v/v) to give first (3R,4S)-4-acetoxy-1-A/-benzylpyrrolidine-3-carboxylic acid ethyl ester (3) as a colourless gum (115 mg, 99%) that was stored at -20 °C. The 1H NMR was identical to that for compound 5 in example 2.
wd -41° (c 0.36, CHCI3).
Further elution of the column with EtOAc gave (3S,4R)-1-A/-benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester (2) also as a colourless gum (93 mg, 93%). The 1H NMR was identical to that for compound 1 in example 1.
[a]" +17° (c 0.295, CHCI3).
Example 5
(3S,4R)-1-N-Benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester (2) and (3R,4S)-4-acetoxy-1-N-benzylpyrrolidine-3-carboxylic acid ethyl ester (3).
Vinyl acetate (6.66 mL, 72.21 mmol) and Novozyme® 435 lipase from Candida antarctica (4.2 g, Novozymes Australia Pty. Ltd, batch LC200207) were added sequentially to a solution of frans-(±)-1-A/-benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester from example 1 (1, 6.00g, 24.1 mmol) in fert-butyl methyl ether (200 mL). The mixture was stirred at 40 °C for 2.5 h then filtered through Celite. The solids were washed with a little ethyl acetate and the combined filtrates were washed with sat. NaHC03, dried and evaporated. 1H NMR (CDCI3) analysis indicated a 1:0.99 ratio of (3R,4S)-4-acetoxy-1 -N-benzylpyrrolidine-3-carboxylic acid ethyl ester (3):(3S,4R)-1-A/-benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester (2). The residue was chromatographed (eluant EtOAc-hexanes 6:4 v/v) to give first (3R,4S)-4-acetoxy-1-A/-benzylpyrrolidine-3-carboxylic acid ethyl ester (3) as a colourless gum (3.44 g, 98%) that was stored at -20 °C. The 1H NMR was identical to that for compound 5 in example 2.
[a]o -42° (c 0.74, CHCI3).
Further elution of the column with EtOAc gave (3S,4R)-1-A/-benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester (2) also as a colourless gum which crystallized at -20 °C (2.53 g, 84%). The 1H NMR was identical to that for compound 1 in example 1.
r 121 l4,0/.m< .
INTELLECTUAL Pr.GPdHTY^rRc";
OF Nil.
- 8 CCT 2»
IUJD ■II vu w ' 1 < *-»n\^i3;.
MP 51-52 °C.
Example 6
22
(3R,4R)- 1-N-Benzyl-3-hydroxy-4-hydroxymethylpyrrolidine (4). (3S,4R)-1-/S/-Benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester from example 5 (2, 2.53 g, 10.15 mmol) was dissolved in THF (20 mL) and Et20 (40 mL) and treated with lithium aluminium hydride (20.3 mL, 20.3 mmol, 1M in ether) as described in example 3 to afford (3R,4R)-1-A/-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine (4) as a colourless gum (1.54 g, 73%). The 1H NMR was identical to compound 7 from example 3.
[a]" +33° (c0.745, MeOH).
Example 7
(3R,4R)-3-Hydroxy-4-hydroxymethylpyrrolidine hydrochloride. [(+)-A, HCI]
(3S,4R)-1-/\/-Benzyl-4-hydroxypyrrolidine-3-carboxylic acid ethyl ester from example 4 (2, 93 mg, 0.37 mmol) was dissolved in Et20 (5 mL). A solution of lithium aluminium hydride in Et20 (0.78 mL, 0.78 mmol, 1M) was added and the mixture stirred at ambient temperature for 1 h. The excess hydride was quenched with H20 (0.1 mL). Magnesium sulfate was added, the mixture filtered through Celite and the solvent evaporated. The residue was chromatographed (eluant CHCI3-MeOH-Et3N, 95:5:0.5 —> 8:2:0.5 v/v) to give 52 mg of crude (3R,4R)-1-A/-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine (4) which was dissolved in MeOH-98% HCOOH (9:1 v/v, 8 mL) and 10% Pd-C (80 mg) added. The mixture was heated under reflux for 30 mins, filtered through Celite and the solvent evaporated. Chromatography (eluant CH2CI2-Me0H-cNH3-H20, 4:3:0.5:0.5 v/v) gave (3R,4R)-3-hydroxy-4-hydroxymethylpyrrolidine ((+)-A) as a colourless gum (16 mg, 37%) which began to darken on standing. The 1H NMR (CD3OD) was in agreement with the literature citing by V.V. Filichev, M. Brandt and E. Pedersen, Carbohydr. Res., 2001, 333, 115.
The latter product was dissolved in MeOH (2 mL), 5% HCI (1 mL) added and the solvent evaporated to give 21 mg of (3R,4R)-3-hydroxy-4-hydroxymethylpyrrolidine hydrochloride ((+)-A, HCI) as a colourless gum. The 1H NMR (D20) was in agreement with the data in S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymm., 2001,12, 1977.
[a]" +190 (c 1.05, MeOH). Lit. [a]* +19 00 (c 1.0, MeOH) (S. Karlsson and H.-E.
Hfigberg, Tetrahedron: Asymm., 2001,12, 1977).
23
Example 8
(3S,4S)-3-Hydroxy-4-hydroxymethylpyrrolidine hydrochloride [(-)-E, HCI]
(3ft,4S)-4-Acetoxy-1-A/-benzylpyrrolidine-3-carboxylic acid ethyl ester from example 4 (3, 113 mg, 0.39 mmol) was dissolved in Et20 (6 mL). A solution of lithium aluminium hydride in Et20 (1.6 mL, 1.6 mmol, 1M) was added and the mixture stirred at ambient temperature for 1 h. The excess hydride was quenched with H20 (0.18 mL). Magnesium sulfate was 10 added, the mixture filtered through Celite and the solvent evaporated to give 55 mg of
(3S,4S)-1-A/-benzyl-3-hydroxy-4-hydroxymethylpyrrolidine (6). Without further purification the latter was dissolved in MeOH-98% HCOOH (9:1 v/v, 8 mL). 10% Pd-C (80 mg) was added and the mixture was heated under reflux for 30 mins, filtered through Celite and evaporated. Chromatography (eluant CH2CI2-Me0H-cNH3-H20, 4:3:0.5:0.5 v/v) gave 15 (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine ((-)-E) as a colourless gum (18 mg, 39%)
which began to darken on standing. The 1H NMR was identical to that described in example 7 for (3R,4f?)-3-hydroxy-4-hydroxymethylpyrrolidine ((+)-A).
The latter ((-)-E) product was dissolved in 5% HCI (3 mL) and evaporated to give 21 mg of 20 (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine hydrochloride ((-)-E, HCI) as a colourless gum. The 1H NMR (D20) was in agreement with the literature data (S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymm., 2001,12, 1977).
[a]" -19 0 (c 1.05, MeOH). Lit.[a]o -18.7 0 (c 1.2, MeOH) (S. Karlsson and H.-E. 25 Hogberg, Tetrahedron: Asymm., 2001,12, 1977).
i- - 8 CCT 22:'}
i *
i p^CEiy-io j
24
Example 9
(3S,4S)-3-Hydroxy-4-hydroxymethylpyrrolidine hydrochloride [(-)-E, HCI], (3f?,4S)-4-Acetoxy-1-A/-benzylpyrrolidine-3-carboxylic acid ethyl ester from example 5 (3, 5 1.2 g, 4.12 mmol) was dissolved in Et20 (35 mL) and cooled in an ice bath. Lithium aluminium hydride (16.9 mL, 16.9 mmol, 1M) was added and the mixture stirred 1 h at ambient temperature. After cooling in an ice bath water (3 mL) was added then the mixture extracted with ethyl acetate. The organic extract was washed with sat. NaHC03, dried and the solvent evaporated to give crude (3S,4S)-1-A/-benzyl-3-hydroxy-4-10 hydroxymethylpyrrolidine (6) as a gum (880 mg). The gum was dissolved in a mixture of
MeOH-98% HC02H (4:1 v/v 50 mL), 10% Pd-C (500 mg) added and heated under reflux for 45 min. The mixture was cooled and filtered through Celite and the solvent evaporated. The residue was chromatographed (eluant CH2CI2-Me0H-H20-cNH3 4:3:0.5:0.5 v/v) to give (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine ((-)-E) as a colourless gum (345 mg). 15 The 1H NMR was identical to that described in example 7 for the (3R,4R)-enantiomer. The latter ((-)-E) was dissolved in H20 (10 mL) and MeOH (20 mL) and acidified with cHCI (0.2 mL) then evaporated to dryness, affording the hydrochloride as a colourless gum (449 mg). The 1H NMR (D20) was in agreement with data reported in S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymm., 2001, 12, 1977.
[a]p -18° (c 0.5, MeOH). Lit [a]^5 -18.7° (c 1.2, MeOH) (S. Karlsson and H.-E. Hogberg,
Tetrahedron: Asymm., 2001, 12, 1977).
Example 10
Trans-(±)-1-N-benzyl-4-benzyloxypyrrolidine-3-carboxylic acid ethyl ester (8).
/N/-(Methoxymethyl)-/V-(trimethylsilylmethyl)-benzylamine (commercially available from Aldrich) (10.24 mL, 40.0 mmol) was added dropwise over 40 mins to a solution of 3-benzyloxyacrylic acid ethyl ester [6.35 g, 30.8 mmol, prepared as an ~ 12:1 mixture of E:Z isomers in 90% yield using the method described for the methyl ester in R. Hirsenkorn 30 and R.R. Schmidt, Liebigs Ann. Chem., 1990, 883. For the major E-isomer 1H NMR
(CDCI3) 5 7.67 (d, 1 H, J 12.6 Hz), 7.41-7.32 (m, 5 H), 5.31 (d, 1 H, J 12.6 Hz), 4.90 (s, 2 H), 4.17 (q, 2 H, J 7.1 Hz), 1.27 (t, 3 H, J 7.1 Hz). The 13C NMR assignment for the major E-isomer was in agreement with data reported in S. Blaya, R. Chinchilla and C. N£jera, Tetrahedron, 1995, 51, 3617. Bp 110-115 °C/0.02 mmHg] in 5 mM TFA-CH2CI2 (150 mL) 35 and the mixture stirred at ambient temperature for 1.5 hr. The mixture was washed with sat. NaHC03 solution, dried and the solvent evaporated. The residue was
1 l.v/ei-LiJiL.AL P
OF
- 8 OCT 2C:;
chromatographed (eluant toluene-ethyl acetate 97:3->94:6 v/v) to give trans-(±)^-N-benzyl-4-benzyloxypyrrolidine-3-carboxylic acid ethyl ester (8) as a colourless oil (7.41 g, 70%) which darkened slightly on standing.
1H NMR (CDCU) 8 7.35-7.21 (m, 10 H), 4.57 (d, 1 H, J 12.0 Hz, OCHHPh), 4.50 (d, 1 H, J
12.0 Hz, OCHHPh), 4.38-4.35 (m, 1 H, H-4), 4.15 (q, 2 H, J 7.1 Hz, CH2CH3), 3.65 (d, 1 H, J 13.0 Hz, NCHHPh), 3.58 (d, 1 H, J 13.0 Hz, NCHHPh), 3.09-3.03 (m, 1 H, H-3), 2.98 (t, 1 H, J 8.6 Hz), 2.80-2.63 (m, 3 H), 1.25 (t, 3 H, J 7.1 Hz, CH2CH3).
13C NMR (CDCI3) 8 173.4 (s), 138.4 (s), 138.1 (s), 128.7 (d), 128.3 (d), 128.2 (d), 127.7 10 (d), 127.6 (d), 127.0 (d), 80.8 (d, C-4), 71.4 (t, OCH2Ph), 60.8 (t, CH2CH3), 59.8 (2t,
NCH2Ph & C-5 or C-2), 55.7 (t, C-5 or C-2), 50.6 (d, C-3), 14.2 (q, CH2CH3).
+ve FABMS: /77/zCalcd. forC21H26N03 (M+H)+ 340.191269. Found: 340.190784.
Example 11
Trans-(±)-4-benzyloxypyrrolidine-1-N'3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester (9) and trans-(±)'4-hydroxypyrrolidine-1-N-3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester (10).
To a solution of frans-(±)-1-A/-benzyl-4-benzyloxypyrrolidine-3-carboxylic acid ethyl ester 20 from example 10 (8, 4.90 g, 14.4 mmol) and di-fert-butyl dicarbonate (3.15 g, 14.4 mmol) in ethanol (100 mL) was added 10% Pd-C (500 mg) then hydrogen was added from a balloon. After stirring for 20 h the mixture was filtered through Celite. A small aliquot was removed (consisted mainly of fra/7s-(±)-4-benzyloxypyrrolidine-1-A/-3-dicarboxylic acid-1-fert-butyl ester-3-ethyl ester (9) by 1H NMR) and chromatographed (eluant ethyl acetate-25 hexanes 1:9 v/v) to give fra/7s-(±)-4-benzyloxypyrrolidine-1-/S/-3-dicarboxylic acid-1-tert-
butyl ester-3-ethyl ester (9) as a colourless gum.
1H NMR (CDCI3) 8 7.48-7.27 (m, 5 H), 4.56 (s, 2 H, PhCHa) 4.38-4.29 (br. m, 1 H, H-4), 4.17 (q, 2 H, J 7.1 Hz, ChbCHa), 3.77-3.53 (br.m, 3 H, H-5, H-2, H-2'), 3.53-3.32 (br.m, 1 H, H-5'), 3.18-3.07 (br.m, 1 H, H-3), 1.45 (s, 9 H, C(CH3)3, 1.26 (t, 3 H, J 7.1 Hz, CH2CH3). 30 13C NMR (CDCI3) 8 171.9 (s), 154.3 (s), 137.6 (s), 128.5 (d), 127.9 (d), 127.7 (d), 79.8 &
79.0 (d, C-4), 79.7 (s, C(CH3)3), 71.6 (t, PhCH2), 61.2 (t, CH2CH3), 50.9 & 50.1 (t, C-5), 49.4 & 48.4 (d, C-3), 46.7 (t, C-2), 28.4 (q, C(CH3)3), 14.1 (q, CHzCHa).
+ve EIMS: m/z Calcd. for C^HsyNOg (M)+ 349.18892. Found: 349.18865.
Fresh 10% Pd-C (500 mg) was added to the bulk of the ethanol solution from above and 35 the mixture treated with hydrogen for a further 16 h. After filtering through Celite, the solvent was evaporated and the residue chromatographed (eluant ethyl acetate-hexanes livid.!..:J : ,, ... ,
- 8 CCT 2C^
26
4:6 v/v) to afford fraA7s-(±)-4-hydroxypyrrolidine-1-A/-3-dicarboxylic acid-1-terf-butyl ester-3-ethyl ester (10) as a colourless oil (3.66 g, 98%).
1H NMR (CDCI3) 8 4.59-4.51 (m, 1 H, after D20 exchange became a q at 5 4.54, J 5.9 Hz), 4.19 (q, 2 H, J, 7.1 Hz), 3.83-3.65 (br.m, 2 H), 3.56 (dd, 1 H, J 11.0, 7.1 Hz), 3.33-5 3.22 (br.s, 1 H), 3.05-2.92 (br.s, 1 H), 2.35 (d, 1 H, J 3.9 Hz, exchanged to D20), 1.46 (s, 9 H), 1.28 (t, 3 H, J 7.1 Hz).
13C NMR (CDCI3) 8 171.9 (s), 154.4 (s), 79.8 (s), 72.5 & 71.9 (d), 61.2 (t), 52.5 & 52.1 (t), 51.1 & 50.5 (d), 46.3 & 46.0 (t), 28.4 (q), 14.1 (q).
+ve FABMS: m/zCalcd. for C12H22N05 (M+H)+ 260.149798. Found: 260.149259.
Example 12
Trans-(±)-4-hydroxypyrrolidine-1-N-3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester (10).
7rans-(±)-1-A/-benzyl-4-hyroxypyrrolidine-3-carboxylic acid ethyl ester from example 1 (1,
1.92 g, 7.70 mmol) and di-te/f-butyl dicarbonate (1.75 g, 8.00 mmol) were dissolved in EtOH (30 mL), 10% Pd-C was added and the mixture hydrogenolysed for 16 h with stirring. Purification as in example 11 gave trans-(±)-4-hydroxypyrrolidine-1-A/-3-dicarboxylic acid-1-terf-butyl ester-3-ethyl ester (10) as a colourless oil (1.92 g, 92%).
Example 13
Trans-(±)-4-acetoxypyrrolidine-1-N-3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester (11).
7ira/7s-(±)-4-hydroxypyrrolidine-1-A/-3-dicarboxylic acid-1-ferf-butyl ester-3-ethyl ester from examples 11 or 12 (10, 100 mg, 0.39 mmol) was dissolved in a mixture of pyridine (4 mL) and acetic anhydride (2 mL) and left to stand at ambient temperature overnight. The solvent was evaporated and the residue dissolved in ethyl acetate, washed with sat. NaHC03, brine, dried and evaporated. The residue was chromatographed (eluant ethyl 30 acetate-hexanes 2:8 v/v) to give frans-(±)-4-acetoxypyrrolidine-1 -A/-3-dicarboxyIic acid-1-
fert-butyl ester-3-ethyl ester (11) as a colourless gum (118 mg, 100%).
1H NMR (CDCI3) 8 5.45 (br.s, 1 H), 4.19 (q, 2 H, J 7.1 Hz), 3.84-3.61 (m, 3 H), 3.51-3.30 (m, 1 H), 3.14-3.04 (m, 1 H), 2.07 (s, 3 H), 1.46 (s, 9 H), 1.27 (t, 3 H, J 7.1 Hz).
13C NMR (CDCI3) 8 170.9 (s), 170.1 (s), 154.1 (s), 79.9 (s), 74.6 & 73.8 (d), 61.4 (t), 51.0 35 & 50.5 (t), 48.9 & 47.9 (d), 46.7 (t), 28.4 (q), 20.9 (q), 14.0 (q).
+ve CIMS: m/z Calcd. for C14H24N06 (M+H)+ 302.16036. Found: 302.16041.
- 8 OCT 2CG j
27
Example 14
(3S,4R)-4-Hydroxypyrrolidine-1-N-3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester 5 (12) and (3R,4S)-4-acetoxypyrrolidine-1-N-3-dicarboxylic acid-1-tert-butyl ester-3-ethyl ester (13).
Novozyme® 435 lipase from Candida antarctica (3 g, Novozymes Australia Pty. Ltd, batch LC200207) was added to a solution of frans-(±)-4-hydroxypyrrolidine-1-A/-3-dicarboxylic acid-1-ferf-butyl ester-3-ethyl ester from examples 11 and 12 (10, 4.3 g, 16.58 mmol) and 10 vinyl acetate (4.6 mL, 50.17 mmol) in ferf-butyl methyl ether (180 mL) and the mixture stirred at 30 °C for 20 h. The solids were removed by filtration through Celite and washed with a little ethyl acetate. The combined filtrates were washed with sat. NaHC03, dried and evaporated to a pale yellow oil (4.4 g). 1H NMR (CDCI3) analysis indicated a 1:0.96 ratio of (3R,4S)-4-acetoxypyrrolidine-1-A/-3-dicarboxylic acid-1-ferf-butyl ester-3-ethyl 15 ester (13):(3S,4R)-4-hydroxypyrrolidine-1-A/-3-dicarboxylic acid-1-ferf-butyl ester-3-ethyl ester (12). The residue was chromatographed (eluant ethyl acetate-hexanes 3:7 v/v) to afford (3R,4S)-4-acetoxypyrrolidine-1-A/-3-dicarboxylic acid-1-ferf-butyl ester-3-ethyl ester
(13) as a pale yellow oil (2.49 g, 99%). The 1H NMR was identical to that described for compound 11 in example 13.
[a]*1 -19° (c 0.63, CHCI3).
The column was further eluted with ethyl acetate-hexanes (6:4 v/v) to give (3S,4R)-4-hydroxypyrrolidine-1-A/-3-dicarboxylic acid-1-ferf-butyl ester-3-ethyl ester (12) as a colourless oil (1.83 g, 85%). The 1H NMR was identical to that described for compound 10 in example 11.
[a]o +19° (c 0.53, CHCI3).
The equal and opposite rotations for 12 and 13 appear to be coincidental.
Example 15
(3R,4R)-3-Hydroxy-4-hydroxymethylpyrrolidin-1-N-carboxylic acid tert-butyl ester
(14).
Lithium borohydride (228 mg, 10.47 mmol) was added to a solution of (3S,4R)-4-hydroxypyrrolidine-1-A/-3-dicarboxylic acid-1-ferf-butyl ester-3-ethyl ester from example 14 (12, 1.81 g, 6.98 mmol) in anhydrous Et20 (27 mL) and methanol (0.49 mL, 12.22 mmol) 35 and the mixture heated under reflux with stirring for 30 mins (using the general method of
- 8 OCT 2c:
28
K. Soai and A. Ookawa, J. Org. Chem., 1986, 51, 4000). After cooling, methanol (10 mL) was added and the solvent evaporated. The residue was dissolved in ethyl acetate and washed with sat NaHC03, dried and evaporated to a colourless gum (1.48 g). It was chromatographed (eluant ethyl acetate-methanol 19:1 v/v) to afford (3f?,4f?)-3-hydroxy-4-5 hydroxymethylpyrrolidin-1-A/-carboxylic acid tert-butyl ester (14) as a colourless gum (1.36
g, 90%). The 1H and 13C NMR were in agreement with that reported by G.B. Evans, R.H. Furneaux, A. Lewandocwicz, V.L. Schramm and P.C. Tyler, J. Med. Chem., 2003, 46, 5271.
[a]o +15.5° (c 1.09, MeOH). A sample prepared as in G.B. Evans, R.H. Furneaux, A. 10 Lewandocwicz, V.L. Schramm and P.C. Tyler, J. Med. Chem., 2003, 46, 5271, ultimately derived from D-xylose, had an [a]^1 +16° (c 0.795, MeOH).
Example 16
(3R,4R)-3-Hydroxy-4-hydroxymethylpyrrolidin-1-N-carboxylic acid tert-butyl ester
(14).
% Pd-C (300 mg) was added to a stirred solution of (SfM/^-l-N-benzyl-S-hydroxy^-hydroxymethylpyrrolidine from example 6 (4, 1.49 g, 7.19 mmol) and di-tert-butyl dicarbonate (1.63 g, 7.47 mmol) in MeOH (30 mL) and hydrogen added from a balloon for 20 24 h. The mixture was filtered through Celite, evaporated and the residue chromatographed (eluant ethyl acetate-methanol19:1, v/v) to afford (3R,4R)-3-hydroxy-4-hydroxymethylpyrrolidin-1-/V-carboxylic acid ferf-butyl ester (14) as a colourless gum (1.56 g, 100%).
[a]o +16° (c 1.09, MeOH). A sample prepared as in G.B. Evans, R.H. Furneaux, A. 25 Lewandocwicz, V.L. Schramm and P.C. Tyler, J. Med. Chem., 2003, 46, 5271, ultimately derived from D-xylose, had [a] ^ +16° (c 0.795, MeOH).
29
Example 17
(3R,4R)-3-Hydroxy-4-hydroxymethylpyrrolidine hydrochloride. [(+)-A, HCI]
A 25 mg portion of (3ft,4f?)-3-hydroxy-4-hydroxymethylpyrrolidin-1-A/-carboxylic acid ferf-butyl ester (14) from example 15 was dissolved in methanol (2 mL), 5% HCI (1 mL) added and the solution left to stand at ambient temperature overnight. Evaporation of the solvent left (Sft^/^-S-hydroxy^-hydroxymethylpyrrolidine hydrochloride [(+)-A, HCI] as a colourless gum. The 1H NMR (D20) was in agreement with that reported in S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymm., 2001,12,1977.
[alp1 +18° (c 0.81, MeOH). Lit [a]" +19.0° (c 1.0, MeOH) (S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymm., 2001,12, 1977).
Example 18
(3R,4R)-3-Hydroxy-4-hydroxymethylpyrrolidine hydrochloride. [(+)-A, HCI]
A 25 mg portion of (3R,4f?)-3-hydroxy-4-hydroxymethylpyrrolidin-1-A/-carboxylic acid ferf-butyl ester (14) from example 16 was dissolved in methanol (2 mL), 5% HCI (1 mL) added and the solution left to stand at ambient temperature overnight. Evaporation of the solvent left (3f?,4f?)-3-hydroxy-4-hydroxymethylpyrrolidine hydrochloride [(+)-A, HCI] as a colourless gum. The 1H NMR was in agreement with that reported in S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymm., 2001, 12, 1977.
[q]d +19° (c 0.795, MeOH). Lit [a]" +19.0° (c 1.0, MeOH) (S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymm., 2001,12, 1977).
Example 19
(3S,4S)-3-Hydroxy-4-hydroxymethylpyrrolidin-1-N-carboxylic acid tert-butyl ester
(15).
Lithium borohydride (87 mg, 3.99 mmol) was added to a solution of (3R,4S)-4-acetoxypyrrolidine-1-A/-3-dicarboxylic acid-1-ferf-butyl ester-3-ethyl ester from example 14 (13, 400 mg, 1.33 mmol) in anhydrous Et20 (6 mL) and methanol (0.19 mL, 4.66 mmol) and the mixture heated under reflux with stirring for 30 mins (using the general method of K. Soai and A. Ookawa, J. Org. Chem., 1986, 51, 4000). After cooling, methanol (3 mL) was added and the solvent evaporated. The residue was dissolved in ethyl acetate and washed with sat NaHC03, dried and evaporated to a colourless gurDL,(300 mg). it was li'< i cLLcC i UAL r. ,
OF ; ,7
- 8 OCT 2ZZ)
Claims (3)
- 30 chromatographed (eluant ethyl acetate-methanol 19:1 v/v) to afford (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidin-1-A/-carboxylic acid tert-butyl ester as a colourless gum (205 mg, 71%). The 1H and 13C NMR were in agreement with the data for the (3R,4R)-enantiomer in G.B. Evans, R.H. Furneaux, A. Lewandocwicz, V.L. Schramm and P.C. Tyler, J. Med. 5 Chem., 2003, 46, 5271. [a]o -14° (c 0.93, MeOH). A sample of the (3R,4R) enantiomer prepared as in G.B. Evans, R.H. Furneaux, A. Lewandocwicz, V.L. Schramm and P.C. Tyler, J. Med. Chem., 2003, 46, 5271, ultimately derived from D-xylose, had [a]^1 +16° (c 0.795, MeOH). 10 Example 20 (3S,4S)-3-Hydroxy-4-hydroxymethylpyrrolidine hydrochloride. [(-)-E, HCI] A portion of (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidin-1-/V-carboxylic acid ferf-butyl ester (15) from example 19 (25 mg) was dissolved in MeOH (2 mL), cHCI (1 mL) added 15 and the solvent evaporated to give (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine hydrochloride [(-)-E, HCI] as a colourless gum. The 1H NMR (D20) was in agreement with that reported by S. Karlsson and H.-E. H6gberg, Tetrahedron: Asymm., 2001,12, 1977. [q]d -15° (c , 0.855 MeOH). Lit [a]" -18.7° (c 1.2, MeOH) (S. Karlsson and H.-E. Hogberg, Tetrahedron: Asymm., 2001,12, 1977). 20 25 Although the invention has been described by way of example, it should be appreciated that variations or modifications may be made without departing from the scope of the invention. Furthermore, when known equivalents exist to specific features, such equivalents are incorporated as if specifically referred to in the specification. INDUSTRIAL APPLICABILITY This invention relates to a method for preparing 3-hydroxy-4-hydroxymethylpyrrolidine compounds. These compounds are key intermediates for the synthesis of certain potent 30 inhibitor compounds such as the purine nucleoside phosphorylase inhibitors disclosed in WO 2004/018496, for example. O y u v. } rbct iv 31 CLAIMS 1. A process for preparing a compound of formula (A) or a compound of formula (E), or salts thereof H H (A) (E) including the steps of (a), (b) and (c): where step (a) is enzyme-catalysed enantioselective esterification of the hydroxyl group of a racemic 3,4-£rans-1-N-protected-4-hydroxypyrroiidine-3-carboxylic acid ester compound of formula (B) R2 (B) where R1 is a straight or branched chain alkyl group; and R2 is a protecting group; to give either a mixture of a compound of formula (C) and a compound of formula (D) 32 r102c t>h r102c^ (C) (D) where R1 and R2 are as defined above; and R3 is acyl; or a mixture of a compound of formula (C), and a compound of formula (D') r102c (C1) (D1) 10 where R1 and R2 are as defined above; and R3 is acyl; where the enzyme-catalysed enantioselective esterification is carried out using either 15 (1) an enzyme capable of producing an enantiomeric excess of compound (C); or (2) an enzyme capable of producing an enantiomeric excess of compound (□'); 20 step (b) is separation of the compound of formula (C) from the compound of formula (D); or separation of the compound of formula (C') from the compound of formula (D'); - 8 OCT mh and 33 step (c) is transformation of the compound of formula (C) or the compound of formula (D') to the compound of formula (A); or 5 transformation of the compound of formula (C') or the compound of formula (D) to the compound of formula (E).
- 2. A process according to claim 1, where the enzyme-catalysed enantioselective esterification in step (a) gives a mixture of compounds of formulae (C) and (D), and 10 the enantiomeric excess of compound (C) is at least about 80%.
- 3. A process according to claim 2, where the enantiomeric excess is at least about 90%. 15 4. A process according to claim 1, where the enzyme-catalysed enantioselective esterification in step (a) gives a mixture of compounds of formulae (C') and (D'), and the enantiomeric excess of compound (D') is at least about 80%. 5. A process according to claim 4, where the enantiomeric excess is at least about 20 90%. 6. A process according to any one of claims 1 to 5, where the enzyme used in step (a) is an enzyme capable of catalysing the formation of an ester bond. 25 7. A process according to claim 6 where the enzyme used is a lipase. 8. A process according to claim 7 where the enzyme is lipase from Candida antarctica. 30 9. A process according to any one of claims 1 to 8 where the transformation of the compound of formula (C) or the compound of formula (D') to the compound of formula (A) includes the step of reduction of the ester group of the compound of formula (C); or reduction of both ester groups of the compound of formula (D'). 35 10. A process according to claim 9 which further includes the step of replacement of the R2 group with hydrogen to give the compound of formula (A). _ j li\i i £Lt-CU fLnL Hi '• 8r^T r-,' - , UU i CiJxjl 34 11. A process according to any one of claims 1 to 8 where the transformation of the compound of formula (C') or the compound of formula (D) to the compound of formula (E) includes the step of reduction of the ester group of the compound of 5 formula (C'); or reduction of both ester groups of the compound of formula (D). 12. A process according to claim 11 which further includes the step of replacement of the R2 group with hydrogen to give the compound of formula (E). 10 13. A process according to claim 9 or claim 11 where the reduction of the ester group or groups is carried out using either LiAIH4 or LiBH4. 14. A process according to claim 10 or claim 12 where the replacement of the R2 group with hydrogen is carried out either in the presence of HCI or with 15 HCOOH/CH3OH in the presence of Pd-C. 15. A process according to any one of claims 1 to 14 where the separation of the compound of formula (C) from the compound of formula (D) or the separation of the compound of formula (C') from the compound of formula (D') is effected by 20 chromatography or fractional crystallisation. 16. A process according to any one of claims 1 to 15 where R1 is a straight or branched chain C^Ce alkyl group. 25 17. A process according to claim 16 where R1 is ethyl. 18. A process according to any one of claims 1 to 17 where R3 is COR4, where R4 is a straight or branched chain Ci-Ce alkyl group. 30 19. A process according to any one of claims 1 to 18 where R1 is ethyl and R2 is benzyl or f-butoxycarbonyl. 20. A process according to claim 19 where R1 is ethyl, R2 is benzyl and R3 is acetyl. 35 21. A process according to claim 19 where R1 is ethyl, R2 is f-butoxycarbonyl and R3 is acetyl. | '^cLLcCTUAL P/.w-^iY GrfiCt", !j - 8 l-i-vr, J 0 Uo I tui/1 35 A process according to any one of claims 1 to 15 where the enantioselective esterification in step (a) is carried out in the presence of vinyl acetate to give a mixture of compounds of formulae (C) and (D) where R3 in the compound of formula (D) is acetyl; or a mixture of compounds of formulae (C') and (D') where R3 in the compound of formula (D') is acetyl. A process for preparing a compound of formula (A), or a salt thereof h (A) including the steps of (a), (b) and (c): where step (a) is enzyme-catalysed enantioselective esterification of the hydroxyl group of a racemic 3,4-frans-1-N-protected-4-hydroxypyrrolidine-3-carboxylic acid ester compound of formula (B) r2 (B) where R1 is a straight or branched chain alkyl group; and R2 is a protecting group; 36 to give either a mixture of a compound of formula (C) and a compound of formula (D) r1o2c (C) (D) where R1 and R2 are as defined above; and R3 is acyl; or a mixture of a compound of formula (C'), and a compound of formula (D') where R1 and R2 are as defined above; and R3 is acyl; where the enzyme-catalysed enantioselective esterification is carried out using either (1) an enzyme capable of producing an enantiomeric excess of compound (C); or (2) an enzyme capable of producing an enantiomeric excess of compound m step (b) is separation of the compound of formula (C) from the compound of formula (D); or _ 37 separation of the compound of formula (C') from the compound of formula (D1); and step (c) is transformation of the compound of formula (C) or the compound of formula (D') to the compound of formula (A). A process for preparing a compound of formula (E), or a salt thereof h (E) including the steps of (a), (b) and (c): where step (a) is enzyme-catalysed enantioselective esterification of the hydroxyl group of a racemic 3,4-fra/?s-1-N-protected-4-hydroxypyrrolidine-3-carboxylic acid ester compound of formula (B) r2 (B) where R1 is a straight or branched chain alkyl group; and R2 is a protecting group; 38 to give either a mixture of a compound of formula (C) and a compound of formula (D) r1o2c "oh f0o2& (C) (D) where R1 and R2 are as defined above; and R3 is acyl; or a mixture of a compound of formula (C'), and a compound of formula (D') r102c (C1) (D1) where R1 and R2 are as defined above; and R3 is acyl; wherein the enzyme-catalysed enantioselective esterification is carried out using either (1) an enzyme capable of producing an enantiomeric excess of compound (C); or (2) an enzyme capable of producing an enantiomeric excess of compound (□'); step (b) is separation of the compound of formula (C) from the compound of formula (D); or „, 39 separation of the compound of formula (C') from the compound of formula (D'); and 5 step (c) is transformation of the compound of formula (C') or the compound of formula (D) to the compound of formula (E). 25. A compound of formula (C) r2 where R1 is a straight or branched chain alkyl group; and R2 is a protecting group. 15 26. A compound of formula (D) (D) where R1 is a straight or branched chain alkyl group; R2 is a protecting group; and 20 R3 is acyl. 27. A compound of formula (C') j w&l.cu£l7. ■ w ^ -k — r r , ~ , 0 | ~0 ^ j 40 5 (C*) where R1 is a straight or branched chain alkyl group; and R2 is a protecting group. 28. A compound of formula (D1) r102c (D1) where R1 is a straight or branched chain alkyl group; 10 R2 is a protecting group; and R3 is acetyl. 29. A compound according to claim 25 where R1 is ethyl and R2 is benzyl. 15 30. A compound according to claim 26 where R1 is ethyl, R2 is benzyl and R3 is acetyl. 31. A compound according to claim 25 where R1 is ethyl and R2 is f-butoxycarbonyl. 32. A compound according to claim 26 where R1 is ethyl, R2 is f-butoxycarbonyl and R3 20 is acetyl. 33. A compound of formula (A) as defined in claim 1, when prepared by the process of claim 1 or claim 23. j bi/airj"rT - 8 OCT ? 10 15 20 41 34. A compound of formula (E) as defined in claim 1, when prepared by the process of claim 1 or claim 24. 35. A process as claimed in claim 1, substantially as herein described with reference to any one of the examples. 36. A process as claimed in claim 23 or claim 24, substantially as herein described with reference to any one of the examples. 37. A compound as claimed in claim 25, as specifically set forth herein. 38. A compound as claimed in claim 26, as specifically set forth herein. END OF CLAIMS INDUSTRIAL RESEARCH LIMITED By its Attorneys Baldwins . ' i . - 8 n.^r RECriv 42 ABSTRACT This invention relates to a method of preparing (3ft,4R)-3-hydroxy-4-hydroxymethylpyrrolidine, a key intermediate compound for the synthesis of certain inhibitor compounds, including the step of enzyme catalysed enantioselective esterification of an hydroxy group of an hydroxypyrrolidine. The invention further relates to a method for preparing (3S,4S)-3-hydroxy-4-hydroxymethylpyrrolidine, which is the enantiomer of (3f?,4R)-3-hydroxy-4-hydroxymethylpyrrolidine.
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| PCT/NZ2004/000239 WO2005033076A1 (en) | 2003-10-03 | 2004-10-01 | Method for preparing 3-hydroxy-4-hydroxymethyl-pyrrolidine compounds |
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