Preparation of allyl succinate derivatives and starting materials therefor

A process for the preparation of a compound of formula (I) wherein R.sub.2 is a (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, heteroaryl(C.sub.1 -C.sub.6)alkyl, cycloalkyl(C.sub.1 -C.sub.6)alkyl or cycloalkenyl(C.sub.1 -C.sub.6)alkyl group, any one of which may be optionally substituted by one or more substituents selected from (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl, --S(C.sub.1 -C.sub.6)alkyl, halo and cyano (--CN); and R.sub.7 is a carboxylic acid protecting group, which process comprises the internal molecular rearrangement of an allyl carboxylate compound of formula (II) wherein R.sub.2 and R.sub.7 are as defined in relation to formula (I) to form the desired compound of formula (I). Compounds (I) are intermediates for the preparation of Matrix metaloproteinase inhibitors. ##STR1##

This invention relates to the preparation of 4-carboxy-protected, 
optionally 3-substituted, 2-allyl-succinates. Such compounds are useful as 
intermediates in the preparation of known inhibitors of matrix 
metalloproteinases. 
BACKGROUND TO THE INVENTION 
Compounds which have the property of inhibiting the action of 
metalloproteinases involved in connective tissue breakdown such as the 
collagenases, stromelysins, gelatinases and matrilysin (known as "matrix 
metalloproteinases", and herein referred to as MMPs) are considered 
potentially useful for the treatment or prophylaxis of conditions 
involving such tissue breakdown, for example rheumatoid arthritis, 
osteoarthritis, osteopenias such as osteoporosis, periodontitis, 
gingivitis, corneal epidermal or gastric ulceration, and tumour 
metastasis, invasion and growth. It has been found that hydroxamic acid 
MMP inhibitors can also inhibit the production of the cytokine tumour 
necrosis factor ("TNF"). Compounds which inhibit the production or action 
of TNF are considered potentially useful for the treatment or prophylaxis 
of many inflammatory, infectious, immunological or malignant diseases. 
These include, but are not restricted to, septic shock, haemodynamic shock 
and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's 
disease, mycobacterial infection, meningitis, psoriasis, congestive heart 
failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune 
disease, rheumatoid arthritis, multiple sclerosis, radiation damage, 
toxicity following administration of immunosuppressive monoclonal 
antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury. 
Metalloproteinases are characterised by the presence in the structure of a 
zinc(II) ionic site. It is now known that there exists a range of 
metalloproteinase enzymes that includes fibroblast collagenase (Type 1), 
PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, 
stromelysin-2 and PUMP-1. Many known MMP inhibitors are peptide 
derivatives, based on naturally occuring amino acids, and are analogues of 
the cleavage site in the collagen molecule. Other known MMP inhibitors are 
less peptidic in structure, and may more properly be viewed as 
pseudopeptides or peptide mimetics. Such compounds usually have a 
functional group capable of binding to the zinc (II) site in the MMP, and 
known classes include those in which the zinc binding group is a 
hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus 
(eg phosphinic acid and phosphonamidate including aminophosphonic acid) 
groups. 
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a 
hydroxamic acid group and a carboxylic group respectively as their zinc 
binding groups. With a few exceptions, such known MMPs may be represented 
by the structural formula (A) 
##STR2## 
in which X is the zinc binding hydroxamic acid (--CONHOH) or carboxylic 
acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in 
accordance with the specific prior art disclosures of such compounds. 
A particular class of known MMP inhibitors is characterised by the presence 
of an allyl group in the R.sub.1 position. Such compounds are disclosed, 
for example in WO 94/21625. That publication states that the preferred 
stereochemical configuration at the carbon atom carrying the allyl group 
is S and at the carbon atom carrying the R.sub.2 group is R. It also 
states that the disclosed MMP inhibitors may be prepared by coupling an 
acid of formula (B) or an activated derivative thereof with an amine of 
formula (C): 
##STR3## 
wherein R.sub.2 -R.sub.5 are as defined in the publication, and R.sub.6 
represents an alkyl (eg t-butyl) or benzyl group, and if desired then 
converting the --COOR.sub.6 group to a hydroxamic acid group. 
BRIEF DESCRIPTION OF THE INVENTION 
It follows from the above that compounds of type B and carboxylate variants 
thereof, particularly those having the stereochemical configuration 
referred to above, are useful intermediates for the preparation of the MMP 
inhibitors. This invention relates to a novel process for the preparation 
of such compounds, and to novel starting materials useful in such process. 
The aliphatic Claisen rearrangement of allyl enol ethers has become one of 
the most powerful tools for stereocontrolled carbon-carbon bond formation 
(for recent reviews see P. Wipf in Comprehensive Organic Synthesis, Vol. 5 
(Eds.: B. M. Trost, I. Fleming, L. A. Paquette) Pergamon, N.Y., 1991, p 
827; S. Blechert, Synthesis, 1989, 71; F. E. Zeigler, Chem. Rev., 1988, 
88, 1423). Among the available methods for effecting this 3,3! 
sigmatropic rearrangement is the Ireland-Claisen procedure by which a 
silyl ketene acetal of an allyl ester can be converted to an .alpha.-allyl 
carboxylic acid. A particularly important aspect of the Ireland Claisen 
rearrangement is that, through efficient control of ketene acetal 
geometry, a highly reliable transfer of stereochemistry from starting 
material to product can be realised (R. E. Ireland, P. Wipf and J. D. 
Armstrong, J. Org. Chem. 1991, 56, 650; ibid 56, 3572). The process of the 
present invention is based on the application of the Ireland-Claisen 
rearrangement to the synthesis of 2,3-disubstituted succinates 
DETAILED DESCRIPTION OF THE INVENTION 
According to the present invention there is provided a process for the 
preparation of a compound of formula (I): 
##STR4## 
wherein R.sub.2 is a (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, 
(C.sub.2 -C.sub.6)alkynyl, phenyl(C.sub.1 -C.sub.6)alkyl, 
heteroaryl(C.sub.1 -C.sub.6)alkyl, cycloalkyl(C.sub.1 -C.sub.6)alkyl or 
cycloalkenyl(C.sub.1 -C.sub.6) alkyl group, any one of which may be 
optionally substituted by one or more substituents selected from (C.sub.1 
-C.sub.6)alkyl, --O(C.sub.1 -C.sub.6)alkyl, --S(C.sub.1 -C.sub.6)alkyl, 
halo and cyano (--CN); and R.sub.7 is a carboxylic acid protecting group, 
which process comprises the internal molecular rearrangement of an allyl 
carboxylate compound of formula (II): 
##STR5## 
wherein R.sub.2 and R.sub.7 are as defined in relation to formula (I) to 
form the desired compound of formula (I). 
It has been found that if the stereochemical configuration of the compound 
(II) is as shown in formula (IIA), then the resultant product of formula 
(I) contains the preferred diastereomer (IA) as a substantial and often 
preponderant proportion of the whole. Further enrichment or complete 
separation of the desired diastereomer may be effected by the usual 
methods of differential solubility or chromatography. 
##STR6## 
In one convenient aspect of the invention, the rearrangement may be 
effected in an aprotic solvent such as tetrahydrofuran, by first 
converting the allyl ester II/IIA to the enol form, for example by 
treatment with a strong organic base, such as lithium diisopropylamine, 
followed by silylation of the enol hydroxy group, using a silylating agent 
(eg trimethylsilyl chloride, triethylsilyl chloride, tripropylsilyl 
chloride, tert-butyldimethylsilyl chloride, or tert-butyldiphenylsilyl 
chloride). The resultant silyl ketene acetal then undergoes the desired 
rearrangement to produce the readily hydrolysable silyl ester of compound 
I/IA. In the foregoing procedure, enolisation and silylation are 
preferably effected at low temperature, eg -70.degree. C. or lower, and 
the rearrangement may be induced by raising the temperature, eg to about 
4.degree. C. to 55.degree. C. 
Carboxylic acid protecting groups R.sub.7 are of course well known, eg from 
the art of peptide synthesis, and are discussed in the widely used 
handbook by T. W. Greene and P. G. M. Wuts, Protective groups in Organic 
Synthesis, 2nd Edition, Wiley, N.Y. 1991, and elsewhere in the chemical 
literature. Clearly the protecting group will be chosen from amongst those 
which are non-labile under the conditions for the internal rearrangement 
of compound (II)/(IIA). Specific examples of carboxylic acid protecting 
groups which should be suitable under most such conditions include allyl, 
tert-butyl, and benzyl, optionally substituted in the phenyl ring by one 
or more nitro or methoxy substituents, for example 4-methoxybenzyl or 
2,4-dimethoxybenzyl. 
The intermediates of formula (II)/(IIA) as defined and discussed above are 
novel structures in there own right, and constitute a further aspect of 
the present invention. 
The group R.sub.2 in compounds (II)/(IIA) will generally be predetermined 
by the intended MMP inhibitor for which compound (I)/(IIA) is the 
intermediate. In the above definition of the group R.sub.7 : 
The term "(C.sub.1 -C.sub.6)alkyl" or "lower alkyl" means a straight or 
branched chain alkyl moiety having from 1 to 6 carbon atoms, including for 
example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 
t-butyl, pentyl and hexyl. 
The term "(C.sub.2 -C.sub.6)alkenyl" means a straight or branched chain 
alkenyl moiety having from 2 to 6 carbon atoms at least one double bond of 
either E or Z stereochemistry where applicable. This term would include, 
for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl. 
The term "cycloalkyl" means a saturated alicyclic moiety having from 3-8 
carbon atoms and includes, for example, cyclohexyl, cyclooctyl, 
cycloheptyl, cyclopentyl, cyclobutyl and cyclopropyl. 
The term "cycloalkenyl" means an unsaturated alicyclic moiety having from 
3-8 carbon atoms and includes, for example, cyclohexenyl, cyclooctenyl, 
cycloheptenyl, cyclopentenyl, cyclobutenyl and cyclopropenyl. In the case 
of cycloalkenyl rings of from 5-8 carbon atoms, the ring may contain more 
than one double bond. 
The unqualified term "heteroaryl" means a 5-7 membered substituted or 
unsubstituted aromatic heterocyclic ring, optionally fused to a benzene 
ring, including for example, pyridinyl, thienyl and furanyl. 
Specific examples of the group R.sub.2 include n-pentyl, n-hexyl, n-heptyl, 
n-octyl, n-nonyl, n-decyl, cyclohexylpropyl, phenylpropyl, 
4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 
phenylbutyl, propyloxymethyl, propylsulphanyl, and in particular isobutyl. 
Compounds of formula (II)/(IIA) may be prepared by esterification of a 
compound of formula (III)/(IIIA) with allyl alcohol, 
##STR7## 
R.sub.2 and R.sub.7 being as defined in relation to formula (I) above. 
Such esterification reaction may be assisted by the presence of a 
dehydrating agent such as a carbodiimide, eg 
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride in the 
presence of a catalytic amount of dimethylaminopyridine.

Compounds of formula (III)/(IIIA) are either known or are accessible by 
methods analagous to those used in the Examples herein. 
The following Example 1 illustrates an embodiment of the process of the 
invention, and Example 2 illustrates the use of the product of that 
process as an intermediate in the preparation of a known MMP inhibitor.: 
The following abbreviations have been used throughout: 
DCM Dichloromethane 
DMAP 4-Dimethyl-aminopyridine 
DMF N,N-Dimethylformamide 
EDC N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride 
HOBt 1-Hydroxybenzotriazole 
LIOH Lithium hydroxide monohydrate 
MeOH Methanol 
NMM N-methylmorpholine 
TESCI Chlorotriethylsilane 
TFA Trifluoroacetic acid 
THF Tetrahydrofuran 
TLC Thin layer chromatography 
.sup.1 H NMR spectra were recorded using a Bruker AC 250E spectrometer at 
250.1 MHz. 
EXAMPLE 1 
##STR8## 
2S-Allyl-3R-isobutyl-succinic acid-4-tert-butyl ester (10:1, SR:RR) Step 
A: 
2-Benzyloxycarbonyl-3R-isobutyl-succinic acid 4-tert-butyl ester 1-benzyl 
ester 
2-Benzyloxycarbonyl-3R-isobutyl-succinic acid benzyl ester (prepared by the 
method described in EP 0 446 267 ) (25.0 g, 62.8 mmol) was dissolved in 
diethyl ether (13 ml) and concentrated H.sub.2 SO.sub.4 (0.66 ml) was 
added with stirring. The resulting solution was cooled to -78.degree. C. 
and isobutylene gas was condensed into the reaction vessel until the 
volume had doubled. The reaction was allowed to warm slowly to room 
temperature and stirred overnight. The reaction mixture was poured into a 
mixture of sodium hydroxide (9 g, 0.225 mol), ice (32 g) and water (32 
ml). The layers were separated and the aqueous layer further extracted 
with diethyl ether. The organic extracts were combined, dried and 
concentrated under reduced pressure to give a clear oil. This was purified 
by column chromatography (silica gel, dichloromethane) to provide the 
title compound as an oil which crystallised on standing (14.6 g, 51%). 
.delta. (CDCl.sub.3), 7.32 (10H, s), 5.15 (4H, m), 3.79 (1H, d, J=10.2 
Hz), 3.11 (1H, ddd, J=10.3, 4.3, 4.3 Hz), 1.69-1.52 (2H, m),1.43 (9H, s), 
1.19-1.07 (1H, m), 0.89-0.84 (6H, m). 
Step B: 
2-Carboxy-3R-isobutyl-succinic acid 4-tert-butyl ester 
The product from step A (22.8 g, 50.0 mmol) was dissolved in ethanol (300 
ml) and the solution was placed under a blanket of argon. 10% Palladium on 
charcoal (3.2 g) was added and a fine stream of hydrogen gas was passed 
through the suspension for 15 min and then the solution was left under an 
atmosphere of hydrogen gas overnight with stirring. TLC showed that all 
the starting material had been consumed. The system was purged with argon 
and the catalyst was removed by filtration. Solvent was evaporated to give 
the desired product (13.7 g, 100%). .delta. (CDCl.sub.3), 9.96 (2H, bs), 
3.71-3.68 (1H, m), 3.11-3.02 (1H, m), 1.68-1.56 (2H, m), 1.43 (9H, s), 
1.35-1.21(1H, m), 0.95-0.88 (6H, m). 
Step C: 
3R-isobutyl-succinic acid-4-tert-butyl ester 
The product from step B (13.7 g 50.0 mmol) was dissolved in toluene (200 
ml) and resulting solution was heated at reflux for 4 h. The reaction was 
cooled to room temperature and the solvent removed under reduced pressure 
to give the desired product as a colourless oil (10.1 g, 88%). .delta. 
(CDCl.sub.3), 11.58 (1H, bs), 2.76-2.57 (2H, m), 2.39 (1H, dd, J=16.0, 4.4 
Hz), 1.63-1.51 (2H, m), 1.42 (9H, s), 1.28-1.21 (1H, m), 0.92(3H, d, J=6.4 
Hz), 0.88 (3H, d, J=6.4 Hz). 
Step D: 
2R-isobutyl-succinic acid 4-allyl ester 1-tert-butyl ester 
The product from Step C (10.0 g, 43.0 mmol) was dissolved in DMF (100 ml) 
and EDC (9.99 g, 52.0 mmol), DMAP (catalytic) and allyl alcohol (3 ml, 
45.0 mmol) were added with stirring. The reaction mixture was stirred at 
room temperature overnight. The solvent was removed under reduced pressure 
and the residue was taken up in ethyl acetate and washed successively with 
1M HCl, 1 M Na.sub.2 CO.sub.3, brine, dried and concentrated under reduced 
pressure to give the desired product as a colourless oil (9.3 g, 80%). 
.delta. (CDCl.sub.3), 5.92-5.79 (1H, m), 5.32-5.16 (2H, m), 4.55-4.52 (2H, 
m), 2.78-2.69 (1H, m), 2.62 (1H, dd, J=16.0, 9.3 Hz), 2.35 (1H, dd, 
J=16.0, 5.0 Hz), 1.61-1.46 (2H, m), 1.40 (9H, s), 1.26-1.14 (1H, m), 0.90 
(3H, d, J=6.5 Hz), 0.86 (3H, d, J=6.5 Hz). 
Step E: 
2S-Allyl-3R-isobutyl-succinic acid-4-tert-butyl ester (10:1, SR:RR) 
To a stirred solution of diisopropylamine (0.3 ml, 2.21 mmol) in dry THF 
(10 ml) under an argon atmosphere at -70.degree. C. was slowly added 
butyllithium (1.3 ml, 2.02 mmol, 1.6M solution in hexanes). The solution 
was warmed to -30.degree. C. and stirred for 10 min and then cooled back 
to -70.degree. C. A solution of 2R-isobutyl-succinic acid 4-allyl ester 
1-tert-butyl ester (500 mg, 1.84 mmol) in dry THF (5 ml) was added and the 
reaction stirred for 30 min at -70.degree. C. and TESCI (0.6 ml) added. 
After a further 5 min at -70.degree. C. the reaction was warmed to 
4.degree. C. and left at this temperature for 3 days. Methanol (7 ml) was 
added and solvent was removed under reduced pressure. The residue was 
taken up in ethyl acetate and washed successively with 1M citric acid and 
brine. The aqueous layer was further extracted with ethyl acetate and the 
combined organic extracts were dried and concentrated to give a pale 
yellow oil. This was purified by column chromatography (silica gel, 
gradient elution, 0-4% methanol in dichloromethane) to afford the title 
compound as a yellow oil (276 mg, 55%). .delta. (CDCl.sub.3), 5.83-5.67 
(1H, m), 5.09-4.99 (2H, m), 2.66-2.59 (2H, m), 2.41-2.22 (2H, m), 
1.71-1.47 (2H, m), 1.44 (8.2H, s), 1.41 (0.8H, s), 1.19-1.09 (1H, m), 0.89 
(3H, d, J=2.7 Hz), 0.87 (3H, d, J=2.7 Hz). 
The above intermediate can be used to prepare matrix metalloproteinase 
inhibitors, such as those described in WO 94/21625, by methods as 
described in example 2 using the appropriate starting materials. 
EXAMPLE 2 
##STR9## 
2S-Allyl-N 4-(2,2-dimethyl-1-methyl 
carbamoyl-propyl)-N-1-hydroxy-3R-isobutyl-succinamide 
Step A: 
2S-Allyl-3R-isobutyl-succinic acid-1-tert-butyl ester 4-methyl ester 
A solution of 2S-Allyl-3R-isobutyl-succinic acid-4-tert-butyl ester (10:1, 
SR:RR) (3.50 g, 13.0 mmol) in DCM was treated with diazomethane (generated 
by the procedure described in Chemistry & Industry, 708, 1990) to yield 
the desired product as a yellow oil (3.08 g, 83%). .delta. (CDCl.sub.3), 
5.78-5.61 (1H, m), 5.27-4.96 (2H, m), 3.64 (2.7H, s), 3.63 (0.3H, s), 
2.70-2.55(2H, m), 2.38-2.19 (2H, m), 1.68-1.46 (2H, m), 1.43 (8.2H,. s), 
1.40 (0.8H, s), 1.23-0.97 (1H, m), 0.87 (3H, d, J=3 Hz), 0.85 (3H, d, J=3 
Hz). 
Step B: 
2S-Allyl-3-R-isobutyl-succinic acid 4-methyl ester 
The product from step A (3.08 g, 10.8 mmol) was treated a solution of 
TFA/DCM (20 ml of each) at 4.degree. C. overnight. The solvents were 
removed under reduced pressure. Residual TFA was removed by toluene 
azeotrope (.times.3) and the resulting oil was triturated with ether to 
give the product as a pale yellow foam (2.37 g, 96%)..delta. (CDCl.sub.3), 
10.81 (1H, bs), 5.80-5.63 (1H, m), 5.13-5.00 (2H, m), 3.69 (3h, s), 
2.81-2.71 (2H, m), 2.47-2.24 (2H, m), 1.73-1.54 (2H, m), 1.18-1.09 (1H, 
m), 0.90 (6H, d, J=6.5 Hz). 
Step C: 
2S-1-(2,2-dimethyl-1-methyl carbamoyl-propyl 
carbamoyl)-3R-methyl-butyl!-pent-4-enoic acid methyl ester 
To a stirred solution of 2S-Allyl-3 R-isobutyl-succinic acid 4-methyl ester 
(2.37 g, 10.0 mmol) in EtOAc (50 ml) was added HOBt (1.40 g, 10.0 mmol), 
EDC (1.90 g, 10.0 mmol), tert-leucine N-methylamide(1.80 g, 12.0 mmol) and 
NMM (1.1 ml, 10.0 mmol). The resulting mixture was heated at reflux 
overnight. After cooling to room temperature the mixture was washed with 1 
M HCl, sat sodium bicarbonate solution and brine, dried and the solvent 
removed under reduced pressure yield the desired product as a yellow solid 
(2.90 g, 82%). .delta. (CDCl.sub.3), 7.26 (1 H, m), 6.88 (1 H, d, J=9.4 
Hz), 5.78-5.62 (1H, m), 5.06-4.97 (2H, m), 4.50 (0.9H, d, J=9.4 Hz), 4.42 
(0.1H, d, J=9.4Hz), 3.66 (2.7H, s), 3.65 (0.3, s), 2.76 (3H, d, J=4.7 Hz), 
2.73-2.55 (1H, m), 2.38-2.26 (1H, m), 1.63-1.54 (1H, m), 1.51-1.31 (1H, 
m), 1.12-1.03 (1H, m), 0.99 (7.8H, s), 0.97 (1.1H, s), 0.81 (3H, d, J=6.5 
Hz), 0.77 (3H, d, J=6.6 Hz). 
Step D: 
2S-Allyl-N 4-(2,2-dimethyl-1-methyl carbamoyl-propyl)-N 
1-hydroxy-3R-isobutyl-succinamide 
The product from Step C (2.90 g, 8.18 mmol) was dissolved with stirring in 
a solution of THF(30 ml) and water (30 ml). LIOH (514 mg, 12.27 mmol) was 
added and stirring was continued at room temperature for 3 days. The 
reaction was quenched with 1 M HCl and concentrated under reduced 
pressure. The solution was extracted with EtOAc (.times.3). The organic 
extracts were combined, dried and evaporated to dryness under reduced 
pressure. The resulting pale yellow solid was purified by column 
chromatography, eluting with 50% hexane in EtOAc then 100% EtOAc to give 
2S-l-(2,2dimethyl-1-methyl carbamoyl-propyl 
carbamoyl)-3R-methyl-butyl!-pent-4enoic acid as a yellow foam. This was 
converted directly into the hydroxamic acid as follows: 
2S-1-(2,2-dimethyl-1-methyl carbamoyl-propyl 
carbamoyl)-3R-methyl-butyl!-pent-4-enoic acid (1.86 g, 5.46 mmol) was 
taken up in DMF (25 ml) and HOBt (886 mg, 6.56 mmol) and EDC (1.30 g, 6.56 
mmol) added. The resulting mixture stirred at room temperature for 2 h. A 
solution of hydroxylamine hydrochloride (569 mg, 8.19 mmol) and NMM (0.9 
ml, 8.19 mmol) in DMF (5 ml) was added and the mixture stirred at room 
temperature overnight. The solvent was removed under reduced pressure. The 
resulting residue was purified by column chromatography on acid washed 
silica, eluting with 2% MeOH in DCM to yield the product as a white foam. 
The .sup.1 H nmr was in accordance with that quoted previously in WO 
94/21625.