WILSON IAN (GB)
WIFFEN JONATHAN (GB)
WILSON IAN (GB)
| WO1995018107A1 | 1995-07-06 |
| EP0480717A1 | 1992-04-15 | |||
| US5523477A | 1996-06-04 |
LABELLE M ET AL: "Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enxyme induction" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 5, no. 3, 2 February 1995 (1995-02-02), pages 283-288, XP004817884 ISSN: 0960-894X cited in the application
Claims
1. A method of preparing a leukotriene of formula (1);
[Formula 1] by condensation of an alcohol of formula (2)
[Formula 2]
With a thiol of formula (3)
HS- (CR 2 R 3 ) a (CR 4 R 5 ) b (CR 6 R 7 ) c Q
[Formula 3] wherein R 1 is selected from the group comprising: H, halogen, -CF3, and -CN;
each of R 2 to R 13 is independently selected from the group comprising: H, Ci -7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, -CF 3 , -CH 2 F, -CHF 2 , CH 2 CF 3 , CH 2 OC 1-7 alkyl, CH 2 SCi -7 alkyl, phenyl, benzyl, and 2-phenethyl, wherein each of phenyl, benzyl, or 2-phenethyl may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: Ci -7 alkyl, -SR 5 , -OR 6 , - NR 6 R 6 , -NO 2 , SCF 3 , halogen, -C(O)R 7 , -CN, and -CF 3 ; and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a ring of up to 6 members which contains from 0 to 2 heteroatoms chosen from O, S 1 and N the ring being optionally substituted with from 1 to 3 halo atoms. R 14 is selected from the group comprising: C i -7 alkyl, -C(O)R 17 , phenyl, and benzyl;
R 15 is selected from the group comprising: R 14 , H, or two R 15 groups joined to the same N form a ring of 5 or 6 members an optionally containing a second heteroatom selected from O, S and N;
R 16 is selected from the group comprising: H and C 1-4 alkyl,
R 17 is selected from the group comprising: H, Ci -7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, -CF 3 , -CH 2 F, -CHF 2 , CH 2 CF 3 , phenyl, benzyl, and 2-phenethyl, wherein each of phenyl, benzyl, or 2-phenethyl may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: Ci- alkyl, - SR 14 , -OR 15 , -NR 15 R 15 , -NO 2 , SCF 3 , halogen, -C(O)R 16 , -CN, and -CF 3 ;
het is selected from the group comprising: C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl,
Q is selected from the group comprising: C(O)OH, C(O)OCi -7 alkyl, C(O)OZ, 1H tetrazol-5-yl, 2H tetrazol-5-yl, -C(O)NHS(O) 2 R 2 , -NHS(O) 2 R 2 , and -C(O)N R 18 R 18 wherein each R 18 is independently selected from the group comprising: H, Ci- 7 alkyl, phenyl, benzyl, and 2-phenethyl, wherein each of phenyl, benzyl, or 2-phenethyl may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: Ci-alkyl, - SR 14 , -OR 15 , - NR 15 R 15 , -NO 2 , SCF 3 , halogen, -C(O)R 16 , -CN, and -CF 3 ;
X is halo;
Z is an alkali metal ion; a is from 0 to 5; b is from 0 to 5; c is from 0 to 5; provided always that a + b + c equals from 1 to 5; d is 2 or 3; and e is 0 or 1.
2. A method as claimed in claim 1 , wherein R 1 is selected from the group comprising: halogen, and -CF3; more preferably R 1 is chloro.
3. A method as claimed in claim 1 or 2, wherein R 2 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
4. A method as claimed in any preceding claim, wherein R 3 is independently selected from the group comprising: H, C 1-7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
5. A method as claimed in any preceding claim, wherein R 4 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F 1 -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
6. A method as claimed in any preceding claim, wherein R 5 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
7. A method as claimed in any preceding claim, wherein R 6 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
8. A method as claimed in any preceding claim, wherein R 7 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
9. A method as claimed in any preceding claim, wherein R 8 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
10. A method as claimed in any preceding claim, wherein R 9 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
11. A method as claimed in any preceding claim, wherein R 10 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
12. A method as claimed in any preceding claim, wherein R 11 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
13. A method as claimed in any preceding claim, wherein R 12 is selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
14. A method as claimed in any preceding claim, wherein R 13 is selected from the group comprising: H, C 1-7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of up to 6 members optionally substituted with from 1 to 3 halo atoms; more preferably, the carbocyclic ring has 3 members.
15. A method as claimed in any preceding claim, wherein each of R 2 ,R 3 and R 6 to R 13 , is independently selected from H and Ci -7 alkyl.
16. A method as claimed in any preceding claim, wherein R 4 and R 5 together with the carbon to which they are attached form a carbocyclic ring of up to 6 members.
17. A method as claimed in any preceding claim, wherein het is selected from the group comprising: quinolinyl, isoquinolinyl, and quinazolinyl.
18. A method as claimed in any preceding claim, wherein Q is selected from the group comprising: C(O)OH, C(O)OC 1-7 alkyl, and C(O)OZ.
19. A method as claimed in any preceding claim, wherein X is chloro or bromo.
20. A method as claimed in any preceding claim, wherein Z is sodium or potassium.
21. A method as claimed in any preceding claim, wherein a is 1.
22. A method as claimed in any preceding claim, wherein b is 1.
23. A method as claimed in any preceding claim, wherein c is 1.
24. A method as claimed in any preceding claim, wherein d is 2.
25. A method as claimed in any preceding claim, wherein e is 0.
26. A method of preparing an alcohol of Formula (2) by the Heck reaction of an alcohol compound of Formula (4)
with a heterocyclic compound of Formula (5).
[Formula 5]
in the presence of a palladium (II) compound, an alkyl or aryl phosphine and an aprotic solvent, wherein R 1 to R 13 are at each occurrence as previously defined above in relation to Formulae 1 to 3.
27. A method of preparing an alcohol of Formula (4)
[Formula 4]
by the Grignard reaction of an alcohol ester compound of Formula (6).
[Formula 6]
with an alkyl magnesium compound of Formula (7)
R 13 MgX [Formula 7]
in the presence of an aprotic solvent, wherein R 1 to R 13 are at each occurrence as previously defined above in relation to Formulae 1 to 3.
28. A method of preparing an alcohol ester compound of Formula (6)
[Formula 6]
by the chiral reduction of the ketone ester compound of Formula (8)
[Formula 8]
in the presence of a chiral catalyst, wherein R 1 to R 13 are at each occurrence as previously defined above in relation to Formulae 1 to 3.
29. A method of preparing an ketone ester compound of Formula (8)
[Formula 8]
by the esterification of the ketone carboxylic acid compound of Formula (9)
[Formula 9] in the presence of an acid and a Ci -7 alcohol, wherein R 1 to R 13 are at each occurrence as previously defined above in relation to Formulae 1 to 3.
30. A method of preparing an ketone carboxylic acid compound of Formula (9)
[Formula 9]
by the enone saturation reaction of the conjugated ketone compound of Formula (10)
[Formula 10]
in the presence of a metal catalyst and a polar protic solvent, wherein R 1 to R 13 are at each occurrence as previously defined above in relation to Formulae 1 to 3. |
Synthesis of Leukotriene Compounds
The present invention relates to the synthesis of leukotriene receptor agonist compounds and to novel intermediates employed in their preparation.
Leukotriene agonists and their use in the treatment of asthma, as well as other conditions mediated by leukotrienes such as inflammation and allergies, are known and are described in, for example, WO 95/18107.
A compound of particular interest is montelukast. The structure of montelukast is shown below:
Montelukast is a leukotriene receptor agonist (LTRA) administered in oral form for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies. LTRAs inhibit the effects of the cysteinyl leukotrienes, which represent 3 of a large number of chemical mediators of asthma. Leukotrienes are released by several types of cells and can cause bronchoconstriction and inflammation. The cysteinyl leukotrienes are particularly important mediators in patients with aspirin-sensitive asthma (characterized by chronic severe asthma symptoms, nasal polyps, and aspirin-induced bronchospasm). LTRAs competitively block leukotriene receptors on bronchial smooth muscle and elsewhere. Montelukast is rapidly absorbed after oral administration and is highly bound to plasma albumin; the half-life of montelukast is 3 to 6 hours.
The synthesis of montelukast is described in a number of patents and the literature. The following references are exemplary of the methods know for synthsising montelukast. The prior art effectively teaches that montelukast can be obtained by two related ways:
1. The method shown in Scheme 1 below and based on:
King, S.; Pipik, B.; Conlon, DA (Merck & Co., Inc.); Process for the preparation of 1-(thiomethyl)-cyclopropaneacetic acid. US 5523477 .
Bhupathy, M.; McNamara, J. M.; Sidler, D.R.; Volante, R.P.; Bergan, J.J. (Merck & Co., Inc.); Process for the preparation of leukotriene antagonists. WO 9518107 .
Belley, M. L.; Leger, S.; Roy, P.; Xiang, Y.B.; Labelle, M.; Guay, D. (Merck Frosst Canada Inc.); Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists. EP 0480717; JP 1993105665 .
Graul, A.; Martin, L.; Castaner, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103.
The Grignard reaction of 3-[2(E)-(7-chloroquinolin-2-yl)vinyl]benzaldehyde (I) with vinylmagnesium bromide (II) in toluene/THF gives the expected secondary alcohol (III), which is condensed with methyl 2-bromobenzoate (IV) by means of palladium acetate and lithium acetate in DMF to yield methyl 2- [3-[3-[2(E)-(7-chloroquinolin-2-yl)vinyl]phenyl]-3-oxopropyl ]benzoate (V). The enantioselective reduction of the keto group of (V) with (-)-B- chlorodiisopinocampheylborane in THF affords methyl 2-[3-[3-[2(E)-(7- chloroquinolin-2-yl)vinyl]phenyl]-3(S)-hydroxypropyl] benzoate (Vl), which is reacted with methylmagnesium bromide in tolueneπηF or methylmagnesium chloride/CeCI3 in THF to give the expected tertiary diol (VII). The selective esterification of (VII) with mesyl chloride and diisopropylethylamine in toluene/acetonitrile yields the expected secondary mesylate (VIII), which is condensed with 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (IX) by means of butyllithium in THF to afford the corresponding condensation product as free
acid that is separated by addition of dicyclohexylamine and precipitates the corresponding salt (X). Finally, this dicyclohexylamine salt (X) is treated with NaOH in toluene/water.
The 2-[1-(sulfanylmethyl)cyclopropyl]acetic acid (IX) has been obtained as follows: The reaction of 1,1-cyclopropanedimethanol (Xl) with SOCI2 or diisopropyl sulfite in dichloromethane gives 1 ,1-cyclopropanedimethanol cyclic sulfite (XII), which is treated with NaCN in dichloromethane yielding 2-[1- (hydroxymethyl)cyclopropyl]acetonitrile (XIII). The reaction of (XIII) with mesyl chloride and triethylamine affords the corresponding mesylate (XIV), which is treated with potassium thioacetate in isopropyl acetate giving 2-[1- (acetylsulfanyl)cyclopropyl]acetonitrile (XV). Finally, this compound is hydrolyzed with NaOH in toluene/water to afford (IX).
MeSOp
■ CπO
Scheme 1
2. The method shown in Schemes 2 and 3 below and based on:
Bhupathy, M.; McNamara, J.M.; Sidler, D.R.; Volante, R.P.; Bergan, JJ. (Merck & Co., Inc.); Process for the preparation of leukotriene antagonists. WO 9518107 .
Belley, M.L.; Leger, S.; Roy, P.; Xiang, Y.B.; Labelle, M.; Guay, D. (Merck Frosst Canada Inc.); Unsaturated hydroxyalkylquinoline acids as leukotriene antagonists. EP 0480717; JP 1993105665 .
Labelle, M.; Belley, M.; Gareau, Y.; et al.; Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enzyme induction. Bioorg Med Chem Lett 1995, 5, 3, 283-8.
Graul, A.; Martin, L.; Castaήer, J.; Montelukast Sodium. Drugs Fut 1997, 22, 10, 1103.
Compound (XIX) is condensed with 2-[1-
(acetylsulfanylmethyl)cyclopropyl]acetic acid methyl ester (XX) by means of Cs2CO3 in acetonitrile yielding the expected condensation product (XXI). Finally, this compound is treated successively with pyridine and p- toluenesulfonic acid to eliminate the tetrahydropyranyl protecting group, and with NaOH to hydrolyzed the acetate ester group of (XXI).
The 2-[1-(acetylsulfanylmethyl)cyclopropyl]acetic acid methyl ester (XX) has been obtained as follows: The reduction of diethyl cyclopropane-1 ,1- dicarboxylate (XXII) with LiAIH4 in THF gives 1 ,1-cyclopropanedimethanol (Xl), which is monobenzoylated with benzoyl chloride (XXIII) and pyridine in dichloromethane yielding benzoic acid 1-(hydroxymethyl)cyclopropylmethyl ester (XXIV). The mesylation of (XXIV) as usual affords the mesylate (XXV), which is treated with NaCN in DMSO to give 2-[1-
(benzoyloxymethyl)cyclopropyl]acetonitrile (XXVI). The hydrolysis of (XXVI) with KOH in refluxing ethanol, followed by methylation with diazomethane, yields methyl 2-[1-(hydroxymethyl)cyclopropyl]acetate (XXVII), which is mesylated as usual affording the mesylate (XXIII). Finally, this compound is treated with cesium thiocetate in dichloromethane to give (XX).
Scheme 2
The selective silylation of the diol (VII) with tert-butyldimethylsilyl chloride (TBDMS-CI)/dimethylaminopyridine (DMAP) and imidazole in dichloromethane gives the monosilylated compound (XVI), which is treated with dihydropyran and triphenylphosphonium bromide to yield (XVII) with the tertiary alcohol protected as its tetrahydropyranyl ether. The desilylation of (XVII) with tetrabutylammonium fluoride (TBAF) in THF affords the secondary alcohol (XVIII), which is mesylated as usual giving the mesylate (XIX).
DHP
(XIX)
Scheme 3
Known methods of producing intermediates, such as thiomethyl cyclopropane-acetic acid, for use in methods of producing such leukotriene antagonists include the reaction shown in Scheme 4 below:
HS ;^ ^-S-*-~~~< CO 2 H
Scheme 4
Such methods of forming these intermediates are complex, have a low yield and involve the handling of potentially toxic compounds which are difficult and costly to dispose of.
It can be seen from the above that the prior art describes various routes to leukotriene derivatives, such as montelukast. However, none of these processes involves the condensation of the two main parts of the molecule in a convergent synthesis with all the necessary sustituents formed previously. Each of the prior art processes suffers disadvantages.
In certain cases the starting materials are expensive to purchase or synthsise. In other cases there are handling concerns and there are issues of worker safety and concerning the environment. After use, spent reactants are difficult and expensive to dispose of because of the adverse effects the compounds may have on their surroundings. A further problem with the prior art processes is the fact that after convergence further synthetic steps are needed. Each synthetic step leads both to a reduction in yield and increasing
the possibility of competing side reactions. Thus the conventional reaction requires more effort to purify the final product and may not give an optimal yield.
It is an aim of the present invention to provide a synthetically efficient process for the production of leukotriene derivatives which avoids the problems of the prior art process. It is also an aim to provide a process in which the efficiency of convergency (ie the bringing together of synthetic fragments) is maximised. It is thus an aim to provide a route to leukotriene compounds of formula which offers an improved yield relative to the existing routes. It is a further aim of the present invention to provide a process which minimizes the number of synthetic steps required and which avoids the problem of competing reactions and/or the disposal of hazardous materials and/or the need for additional work-up procedures.
We have found an improved route to the leukotriene derivatives which satisfy some or all of the above problems.
According to the present invention, there is provided a method of preparing a leukotriene of formula (1);
[Formula 1] by condensation of an alcohol of formula (2)
[Formula 2]
With a thiol of formula (3)
HS- (CR 2 R 3 ) a (CR 4 R 5 ) b (CR 6 R 7 ) c Q
[Formula 3] wherein R 1 is selected from the group comprising: H, halogen, -CF3, and -CN;
each of R 2 to R 13 is independently selected from the group comprising: H, Ci -7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, -CF 3 , -CH 2 F, -CHF 2 , CH 2 CF 3 , CH 2 OC 1-7 alkyl, CH 2 SC 1-7 alkyl, phenyl, benzyl, and 2-phenethyl, wherein each of phenyl, benzyl, or 2-phenethyl may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: Ci -7 alkyl, -SR 5 , -OR 6 , - NR 6 R 6 , -NO 2 , SCF 3 , halogen, -C(O)R 7 , -CN, and -CF 3 ; and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a ring of up to 6 members which contains from 0 to 2 heteroatoms chosen from O, S, and N the ring being optionally substituted with from 1 to 3 halo atoms.
R 14 is selected from the group comprising: C i -7 alkyl, -C(O)R 17 , phenyl, and benzyl;
R 15 is selected from the group comprising: R 14 , H, or two R 15 groups joined to the same N form a ring of 5 or 6 members an optionally containing a second heteroatom selected from O, S and N;
R 16 is selected from the group comprising: H and C 1-4 alkyl,
R 17 is selected from the group comprising: H, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, -CF 3 , -CH 2 F, -CHF 2 , CH 2 CF 3 , phenyl, benzyl, and 2-phenethyl, wherein each of phenyl, benzyl, or 2-phenethyl may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C 1- alkyl, - SR 14 , -OR 15 , -NR 15 R 15 , -NO 2 , SCF 3 , halogen, -C(O)R 16 , -CN, and -CF 3 ;
het is selected from the group comprising: C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl,
Q is selected from the group comprising: C(O)OH, C(O)OCi -7 alkyl, C(O)OZ, 1H tetrazol-5-yl, 2H tetrazol-5-yl, -C(O)NHS(O) 2 R 2 , -NHS(O) 2 R 2 , and -C(O)N R 18 R 18 wherein each R 18 is independently selected from the group comprising: H, Ci -7 alkyl, phenyl, benzyl, and 2-phenethyl, wherein each of phenyl, benzyl, or 2-phenethyl may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: C^alkyl, - SR 14 , -OR 15 , - NR 15 R 15 , -NO 2 , SCF 3 , halogen, -C(O)R 16 , -CN, and -CF 3 ;
X is halo;
Z is an alkali metal ion;
a is from O to 5; b is from O to 5; c is from O to 5; provided always that a + b + c equals from 1 to 5; d is 2 or 3; and e is O or 1.
Halo means fluoro, chloro, bromo, or iodo.
Preferably, R 1 is selected from the group comprising: halogen, and -CF3. More preferably R 1 is chloro.
Preferably, each of R 2 to R 13 is independently selected from the group comprising: H, Ci -7 alkyl, and -CF 3 , -CH 2 F, -CHF 2 , and -CH 2 CF 3 , and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a carbocyclic ring of
up to 6 members optionally substituted with from 1 to 3 halo atoms. Most preferably, the carbocyclic ring has 3 members.
In each case above, and also below in respect of further preferred features, the limitation of any one particular substituent chosen from R 2 to R 13 to preferred groups is independent of any limitation to the other substituent definitions.
More preferably, each of R 2 ,R 3 and R 6 to R 13 , is independently selected from H and Ci -7 alkyl; and most preferably each is H or methyl. Most preferably, each of R 2 ,R 3 and R 6 to R 11 is H. Most preferably, R 12 is methyl. Most preferably, R 13 is methyl.
More preferably, R 4 and R 5 together with the carbon to which they are attached form a carbocyclic ring of up to 6 members. Most preferably, R 4 and R 5 together with the carbon to which they are attached form a cyclopropyl ring. This ring may be optionally substituted with from 1 to 3 halo atoms.
Preferably, het is selected from the group comprising: quinolinyl, isoquinolinyl, and quinazolinyl. More preferably, het is quinolinyl; most preferably het is quinolin-2-yl.
Preferably, Q is selected from the group comprising: C(O)OH, C(O)OCi -7 alkyl, and C(O)OZ. Most preferably, Q is C(O)OZ.
Preferably X is chloro or bromo.
Preferably Z is sodium or potassium. Most preferably Z is sodium.
Preferably a is 1.
Preferably b is 1.
Preferably c is 1.
Preferably d is 2.
Preferably e is 0.
The alcohol of Formula (2) can be obtained by a multi-step synthesis from 3- bromoacetophenone. Similarly, the thiol of Formula (3) can be prepared in a multi-step synthesis from 1-(methansulphonyl)cyclopropane-N- phenylacetamide. The synthesis of 1-(methansulphonyl)cyclopropane-N- phenylacetamide is described below.
The present invention also relates to novel features of the individual synthetic steps used to prepare the alcohol of Formula (2) and the thiol of Formula (3) and novel intermediates produced in those steps.
In the further aspects of the invention described below the same definitions are used for the various substituents as are used above in relation to the compounds of Formula (1). Similarly, the definitions of the preferred substituents discussed above in relation to the compounds of Formula (1) applies to the following aspects of the invention.
According to another aspect of the present invention, there is provided a method of preparing an alcohol of Formula (2) by the Heck reaction of an alcohol compound of Formula (4)
with a heterocyclic compound of Formula (5).
[Formula 5]
in the presence of a palladium (II) compound, an alkyl or aryl phosphine and an aprotic solvent, wherein R1 to R9 are as previously defined above. The alcohol of Formula (2) is then subjected to enantiomeric enrichment in a subsequent step using an enzyme-based process. Lipase is particularly suitable and gives good enrichment
According to another aspect of the present invention, there is provided a method of preparing an alcohol of Formula (4)
[Formula 4]
by the Grignard reaction of an alcohol ester compound of Formula (6).
[Formula 6]
with an alkyl magnesium compound of Formula (7)
R 13 MgX [Formula 7]
in the presence of an aprotic solvent. Suitable solvents include diethyl ether, THF, toluene and glyme-type solvents such as diglyme.
In an alternate embodiment, the compound of Formula (6) can be coupled with the compound of Formula (5) in a Heck reaction under the same conditions described previously. Subsequently, the resulting compound is then subjected to a Grignard reaction with a compound of Formula (7), under the same conditions as described previously, to produce the alcohol of Formula (2).
According to another aspect of the present invention, there is provided a method of preparing an alcohol ester compound of Formula (6)
[Formula 6]
by the chiral reduction of the ketone ester compound of Formula (8)
[Formula 8]
in the presence of a chiral catalyst. The catalyst can be any conventional chiral metal catalyst. The reaction may be carried out in a single phase or in a transfer hydrogenation catalyst using a transfer hydrogenation catalyst.
According to another aspect of the present invention, there is provided a method of preparing an ketone ester compound of Formula (8)
[Formula 8]
by the esterification of the ketone carboxylic acid compound of Formula (9)
[Formula 9]
in the presence of an acid and a Ci -7 alcohol.
According to another aspect of the present invention, there is provided a method of preparing an ketone carboxylic acid compound of Formula (9)
[Formula 9]
by the enone saturation reaction of the conjugated ketone compound of Formula (10)
[Formula 10]
in the presence of a metal catalyst and a polar protic solvent.
The conjugated ketone compound of Formula (10) is prepared according to a literature process by the reaction of a suitably substituted haloaromatic ketone and 2-carboxybenzaldehyde.
The skilled man will appreciate that the compounds of the invention could be made by methods other than those herein described, by adaptation of the methods herein described and/or adaptation of methods known in the art, for example the art described herein, or using standard textbooks such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley- VCH (1999 or later editions), "March's Advanced Organic Chemistry - Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later) "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions), "Organic Synthesis - The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.
It is to be understood that the synthetic transformation methods mentioned herein are exemplary only and they may be carried out in various different sequences in order that the desired compounds can be efficiently assembled. The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound. For
example, substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinafter in conjunction with a particular reaction. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis. The procedures may be adapted as appropriate to the reactants, reagents and other reaction parameters in a manner that will be evident to the skilled person by reference to standard textbooks and to the examples provided hereinafter.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TVV Greene and PGM Wuts, John Wiley & Sons lnc (1999), and references therein.
Schemes 5 and 6 below shows an example of the reaction scheme applied specifically to montelukast. Schemes 5 and 6 differ in the order of the last 2 steps and these steps can be conducted in either order. The conditions exemplified therein are generally applicable to the above generally described synthetic steps.
DMF Pd(OAc) 2
P(OtOIy) 3
Scheme 5
Scheme 6 STEP 1 Condensation
2-carboxybenzaldehyde (23.8 g) was dissolved in ethanol (315 g) followed by the addition of 3-bromoacetophenone (28.7 g) and chilled to 3°C. 6.67 N sodium hydroxide (10.32 g) was added drop-wise over 4 minutes to the stirring reaction. The reaction mixture was stirred for a further 4 minutes at 0 0 C. This procedure was repeated for 8.29 g, 6.68 g and 3.14 g of 6.67 N sodium hydroxide solution. The reaction mixture was then allowed to warm to 25 0 C and stirred for a further 12 hours. Brine (400 mL) was then added to the reaction mixture and the resultant white slurry filtered. The cake was further washed with brine (200 mL) and allowed to air dry for 30 minutes. The cake was vacuum oven dried at 25 0 C for 120 hours. Resulting in the desired product as a white solid (59.5 g).
Sodium-2-[3-(3-Bromo-phenyl)-3-oxo-propenyl]-benzoate, actual weight 47.2g [79.5 % w/w by HPLC (equals 59.5g).
Yield 93%
HPLC purity was 97 % area, largest single impurity was 2.7 % area.
Purity by 1 H nmr was excellent & reflects HPLC purity. Product appears to contain no major organic impurities, & therefore impurities are likely to be inorganic salts.
STEP 2 Enone Saturation
Sodium-2-[3-(3-Bromo-phenyl)-3-oxo-propenyl]-benzoate (5Og) was dissolved in ethanol (2.5 L, 50 volumes) followed by the addition of 5 M NaOH (25 mL) and the reaction stirred for 30 minutes. A solution of ammonium acetate (116g, 10 equivalents) in water (233 mL, 5 volumes) was then added to the reaction under nitrogen and continued to stir before the portion-wise addition of Zinc dust (10μm) over a 30 minute period (3x4. Og, 3x0.061 moles, 3x0.5
equivalents). The mixture was allowed to age for a further 30mins and TLC analysis indicated the disappearance of Sodium-2-[3-(3-Bromo-phenyl)-3-oxo- propenyl]-benzoate and the appearance of a new spot. The mixture was filtered through celite, concentrated (~1 L, 20 volumes) before the addition of water (500 ml_, 10 volumes). The mixture was acidified to pH 1-2 with concentrated HCI (~150ml, 4 volumes) and extracted with DCM (2x500ml, 10 volumes). The organic layers were dried using anhydrous sodium sulphate, filtered washed with DCM (80ml, 2 volumes) and concentrated to dryness. The isolated material solidifies to an off-white solid.
Yield: 70%
NMR purity was greater than 85%.
STEP 3 Esterification
2-[3-(3-Bromo-phenyl)-3-oxo-propyl]-benzoic acid (38g) was slurried in methanol (228 ml_) followed by the addition of sulphuric acid (3.2 g) and heated to 70 0 C overnight with the removal of 60 mL of solvent under atmospheric distillation conditions. The reaction mixture was allowed to cool to 40 0 C, followed by the addition of a seed resulting in the precipitation of an off-white solid. The reaction mixture was further cooled to room temperature. The solid was collected by filtration and air dried for 30mins.
2-[3-(3-Bromo-phenyl)-3-oxo-propyl]-benzoic acid methyl ester, actual weight 34g.
Yield 89%
NMR purity was greater than 95%.
STEP 4 Chiral Reduction
2-[3-(3-Bromo-phenyl)-3-oxo-propyl]-benzoic acid methyl ester (1g) was dissolved in ethyl acetate (4.5 mL) followed by the addition of TEAF (0.5 mL).
(1S,2S)-p-TsNCH(C 6 H 5 )CH-(C 6 H 5 )NH2](77 6 -p-mesitylene) (15 mg) was then added to the reaction mixture and heated at 40 0 C for 16hrs. TLC analysis (:50; ethyl acetate: Hexane, KMnO 4 stain) showed the consumption of 2-[3-(3- Bromo-phenyl)-3-oxo-propyl]-benzoic acid methyl ester and the appearance of the desired chiral alcohol. The reaction was cooled to room temperature followed by the addition of water (10 ml_) and extraction into ethyl acetate (2x10 ml_). The combined organic layers were then washed with sat. NaHCO 3 solution (10 mL) and brine (6 ml_), dried using anhydrous sodium sulphate, filtered and concentrated to dryness. The isolated material solidifies to a brown solid.
Yield 95%
NMR purity was greater than 90%.
STEP 5 Heck
2-[3-(3-Bromo-phenyl)-3-hydroxy-propyl]-benzoic acid methyl ester (16.8g) and vinyl quinoline (7.9g) was dissolved in anhydrous DMF (109 mL) followed by the addition of Pd(OAc) 2 (0.5g) and P(o-tolyl) 3 (2.6g) under a nitrogen atmosphere. Triethylamine (9.1 mL) was then added and the mixture was heated to 100°C for 3 hours. The reaction was cooled to 40 0 C, poured into ethyl acetate (600 mL) and washed with water (700 mL). The aqueous layer was then re-extracted with ethyl acetate (200 mL). The combined organic layers were washed with water (3x100 mL), sat. aqueous NaHCO 3 (100 mL) and finally with brine (100 mL). The organic layer was filtered through celite and evaporated to dryness. The residue was dissolved in isopropyl acetate (130 mL) followed by the addition of water (2.4 mL). The resulting precipitate was allowed to age for 20 mins before the addition of heptane (170 mL) and stirred for a further 20 mins. The precipitation was filtered, washed with isopropyl acetate/heptane (3:7, 40 mL) and heptane (60 mL). The solid was air dried for 20 mins and then vacuumed dried overnight, yielding 2-(3-{3-[2- (7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-hydroxy-propyl)-be nzoic acid methyl ester mono hydrate.
Yield 75%
NMR purity was greater than 95%, ee purity greater than 99%
STEP 6 Gripnard
2-(3-{3-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-hydroxy -propyl)-benzoic acid methyl ester mono hydrate (7.Og) was slurried in toluene (60 ml_) and heated to 150°C to remove the water. The mixture was azeotroped to a volume of 20 ml_ under atmospheric conditions. The reaction mixture was then added dropwise to a 1.5M MeMgCI tetrahydrofuran (50 ml_) solution at 5°C. After complete addition the mixture was continued to stir at 10 0 C for a further 45 mins. The reaction mixture was then quenched by the dropwise addition to a 2M aqueous acetic acid solution (57 mL) and toluene (15mL) at 20 0 C. The layers were separated, organic washed with 10% Na 2 CO 3 (50 mL) and distilled to 30 mL. The toluene solution was then added dropwise to 1.5M MeMgCI tetrahydrofuran (30 mL) solution at 5°C. After complete addition the mixture was continued to stir at 10 0 C for a further 45 mins. The reaction mixture was then quenched by the dropwise addition to a 2M acetic acid (38 mL) and toluene (15mL) at 20 0 C. The layers were separated, organic washed with 10% Na 2 Cθ 3 (40 mL). The organic layer was then concentrated, dissolved in MTBE and treated through a silica plug with solvent elution MTBE/Hexane. The solvent was then evaporated to dryness yielding a pale yellow solid - 1-{3-[2-(7-Chloro-quinolin-2-yl)-vinyl]-phenyl}-3-[2-(1-hydr oxy-1- methyl-ethyl)-phenyl]-propan-1-ol.
Yield 85%
NMR purity was greater than 98%, ee purity greater than 99%
According to another aspect of the present invention there is provided a method of producing intermediate compounds useful in the synthesis of leukotriene antagonists such as leukotriene intermediates having the structure:
The method comprises the steps of:
1a) reacting a compound of Formula 1 with a thioacetate, such as potassium thioacetate to form a compound according to Formula 2:
o Step la T - j o
Mso JOV I h — - -y O JOV ' Ph
Formula 1 Formula 2
1b) hydrolysing the compound according to Formula 2 to form a 1-
(mercaptomethyl) cyclopropaneacetic acid compound according to Formula 3:
Formula 3.
1-(mercaptomethyl)cyclopropaneacetic acid (compound of Formula 3) is a useful intermediate in the production of leukotriene antagonists. The method of the present invention provides a cost effective, reliable method of forming such intermediates having a high associated yield
In step 1a the compound of Formula 1 is typically converted to the compound of Formula 2 through contact with potassium thioacetate in the presence of a solvent, such as DMF or MeCN. Potassium thioacetate is generally added to the compound of Formula 1 in excess.
Step 1a suitably proceeds at room temperature. The reaction of step 1a is typically allowed to proceed for five hours or more, suitably ten hours or more, more suitably for fifteen hours or more, preferably 65 hours or more. The yield associated with step 1a is generally 75% or more, suitably 80% or more, typically 85% or more.
Step 1a may suitably include a separation step wherein the compound of Formula 2 is extracted. Any known method of extraction may be used. In one embodiment the extraction method may include distillation. The reaction mixture of step a may be combined with water, and extracted with a solvent such as, for example EtOAc. The compound of Formula 2 is typically in the form of an oil which may be purified using chromatography, suitably column chromatography.
The thioacetate for use in step 1a may be formed using any suitable method. Suitably the thioacetate is formed by reacting thioacetic acid with Cs 2 CO 3 in a solvent such as methanol.
The thioacetate so formed may then be reacted with potassium carbonate to form potassium thioacetate. This reaction suitably proceeds in the presence of a solvent such as MeCN. The reaction is suitably allowed to proceed for 30 mins or more, typically 1 hour.
In step 1b of the method described above the compound according to Formula 2 is contacted with water. Suitably KOH is dissolved in the water prior to contact with the compound according to Formula 2. The resulting solution may be degassed, for instance by bubbling through nitrogen.
Alternatively the compound according to Formula 2 may be dissolved in 50:50 mix of water and organic solvent, such as THF.
The hydrolysis reaction of step 1 b suitably takes place at temperatures above room temperature, suitably at temperatures of 80 0 C or higher, more suitably
100 0 C or higher, preferably at temperatures around 12O 0 C. The hydrolysis reaction of step 1b may be allowed to proceed for more than 5 hours, typically more than ten hours, suitably 14 hours or more.
Step 1b typically includes an extraction step to extract the compound of Formula 3. Any suitable extraction method may be used. The extraction step may include acidifying the mixture following contact with water, typically through the addition of HCI.
The compound according to Formula 3 may be extracted with organic solvents such as DCM or EtOAc. The extract containing compounds according to Formula 3 may be dried using any known method. Typically the compound according to Formula 3 is dried over MgSO 4 and concentrated. Formula 3 is suitably in the form of an orange wax. The yield associated with step 1b is generally 50% or more, preferably 80% or more.
In one embodiment the compound according to Formula 3 may be formed according to the reaction scheme below:
«J?λ.™ ^- v Jζ λ Ph
hydrolysis
yJ^λ HS
OH j α OH
According to a further aspect of the present invention there is provided a compound according to Formula 1. o
MsO >.JOv
Formula 1.
According to a further aspect of the present invention there is provided the use of a compound according to Formula 1 as an intermediate in the production of i-(mercaptomethyl) cyclopropaneacetic acid as shown in Formula 3 above.
According to a further aspect of the present invention there is provided the use of a compound according to Formula 1 as an intermediate in the production of a leukotriene antagonist, in particular in the production of a leukotriene antagonist having a structure as shown below:
According to a further aspect of the present invention there is provided a method of forming a leukotriene antagonist comprising steps a and b as described above. In particular the structure of the leukotriene antagonist is as shown above.
According to one embodiment, the compound according to Formula 1 may be formed according to the reaction scheme shown below:
Step 2
Step 3
MsO ■vXA-"- HO j UV Ph formula 1 formula c
The compound according to formula a may be formed by reacting itaconic anhydride with N-Methylaniline as shown in the reaction scheme below:
-W
Ph HO o^o^c O '
The itaconic anhydride may be dissolved in a solvent such as hexane or toluene, typically anhydrous toluene. The itaconic anhydride solution may be heated, for instance to over 6O 0 C, preferably to over 70 0 C before addition to the N-Methylaniline. However, the temperature of the itaconic anhydride solution should preferably not exceed 75 0 C. The solution of itaconic anhydride and N-methylaniline may be heated to, for example 8O 0 C and maintained at this temperature for around 15 minutes before being allowed to cool. Upon cooling to 4O 0 C, hexane may be added to the mixture. The mixture may then be cooled for example to O 0 C, and is suitably kept at this temperature for 30 minutes or more.
The compound of Formula a may be in the form of a white solid, and the compound of Formula a may be extracted using any suitable method, such as filtration.
Step i
The process of Step 1 may be formed according to a catalysed, or uncatalysed method and both of these methods are described below. Catalysed method
The compound of Formula a may be converted to the compound of Formula b through contact with a catalyst having the following structure:
The following novel compounds may be formed as byproducts of the step 1 catalysed reaction:
According to a further aspect of the present invention there is provided a compound according to the following structures:
Suitably the catalyst for use in step 1 as described above is formed according to the following reaction scheme:
The catalyst according to formula y may be formed through the addition of diazomethane to dibutylitaconate (compound of Formula x) in the presence of Pd(OAc) 2 . The reaction typically proceeds in the presence of a solvent such as THF. The reaction suitably proceeds at a temperature below room temperature, more suitably at a temperature of O 0 C or below. The reaction may proceed under a nitrogen atmosphere. Following mixing of the reactants the reaction mixture is typically allowed to warm slowly, suitably the reaction mixture is allowed to warm over one day or more, suitably two days or more, preferably 65 hours or more. The reaction may be quenched, for instance with acetic acid. The catalyst of Formula y may be extracted using any known method. Suitably extraction involves filtration, for instance through a silica plug. Any remaining dibutylitaconate (compound of formula x) may be selectively reacted with piperidine according to the Michael reaction. Reaction with piperidine is suitably repeated until analysis indicates the consumption of dibutylitaconate (compound of formula x) is substantially complete.
As noted above, the catalyst of formula y is suitably formed through the addition of diazomethane to dibutylitaconate (compound of formula x). Diazomethane is suitably formed through dissolving diazald in a solvent such as ether, and adding this mixture to a solution of alcohol (ie EtOH), water and KOH. The mixture is heated, typically to a temperature of 5O 0 C or more, suitably 60 to 65 0 C such that diazomethane is distilled. The reaction is suitably allowed to proceed for 1 hour or more, more suitably 1.5 hours.
The product may be purified through any suitable method, such as dilution with a solvent, typically ether, suitably followed by washing with acid such as HCI. If necessary, further purification may be undertaken through chromatography, in particular column chromatography.
Step 1
Step 1a: Uncatalysed method
Alternatively, the compound according to Formula b may be synthesised through an uncatalysed method.
Diazomethane is added to a compound of Formula a, suitably in the presence of a solvent such as THF. The reaction typically takes place at a temperature below room temperature, suitably a temperature of around O 0 C. A compound according to Formula j is formed:
Formula j
Step 1a may include an extraction step comprising extracting the compound of Formula j from the reaction mixture. Any suitable method may be used for extraction. Suitably the extraction method involves cooling and quenching of the reaction mixture. The reaction mixture is suitably cooled to 1O 0 C or less, more suitably O 0 C. Following quenching, the reaction mixture may be allowed to warm up, typically to room temperature, followed by repeated cooling and quenching procedures. The reaction product may be extracted using any suitable method.
The diazomethane may be formed according to the method as noted above.
According to a further aspect of the present invention there is provided a compound according to Formula j:
Formula j
According to a further aspect of the present invention there is provided the use of a compound according to Formula J as an intermediate in the production of i-(mercaptomethyl) cyclopropaneacetic acid as shown in Formula 3 above.
According to a further aspect of the present invention there is provided the use of a compound according to Formula j as an intermediate in a method of forming leukotriene antagonists.
Step 1b: Uncatalysed method
Formula j Formula b
The compound of Formula j may be converted to a compound of Formula b through contact with pyrazoline. The resulting solution may be heated or exposed to irradiation, such as UV light. Suitably the solution is heated, typically to above 100 0 C, more suitably to approximately 13O 0 C. Preferably a triplet sensitizer such as benzophenone may be added to the solution. It is thought that the use of a triplet sensitiser increases the yield of the reaction.
The heating may take place under a gentle flow of nitrogen. The heat of the reaction mixture is suitably maintained for 15 minutes or more.
Alternatively the solution may be irradiated using, for instance, an Hg lamp in a gas-inlet reactor. The irradiation may take place in the presence of a solvent, such as dioxane/acetone. The irradiation reaction typically takes place under a nitrogen atmosphere. The solution is typically irradiated for 50 minutes or more, suitably 3 hours or more.
The compound according to Formula b may be extracted using any suitable method. Typically the reaction mixture is concentrated and purified by chromatography, such as column chromatography. If a triplet sensitiser has been used, the product may be washed with solvents such as t- butylmethylether (TBME).
The following novel byproducts may be formed from the reaction of step 1b (uncatalysed method):
NMePh NMePh
According to a further aspect of the present invention there is provided a compound according to any one of the following structures:
According to a further aspect of the present invention there is provided a compound according to Formula c above
According to a further aspect of the present invention there is provided a compound according to Formula b as an intermediate in the production of 1- (mercaptomethyl) cyclopropaneacetic acid as shown in Formula 3 above.
According to a further aspect of the present invention there is provided the use of a compound according to Formula b as an intermediate in the production of a leukotriene antagonist.
Step 2
Ph
A compound of Formula b is suitably added to LiBH 4 . The solution formed is typically heated, for instance to 5O 0 C or more. The solution may be held at this temperature until the reaction has neared completion. This can be monitored through NMR analysis of the reaction mixture. The reaction may be cooled upon completion of the reaction, generally to below room temperature, more suitably to around O 0 C. A compound of Formula c may be extracted using any suitable method. Suitably the method of extraction involves extracting the product with a solvent such as ethyl acetate and washing the product, for instance with water.
The LiBH 4 added to the compound of Formula b may be formed through the addition of an alcohol such as tert butanol to lithium aluminium hydride.
According to a further aspect of the present invention there is provided a compound according to Formula c above
According to a further aspect of the present invention there is provided a compound according to Formula c as an intermediate in the production of 1- (mercaptomethyl) cyclopropaneacetic acid as shown in Formula 3 above.
According to a further aspect of the present invention there is provided the use of a compound according to Formula c as an intermediate in the production of a leukotriene antagonist.
Byproducts including compounds according to the Formula k below may be formed according to the reaction of step 1b (uncatalysed method):
H0 - — ^ OH
Formula k
According to a further aspect of the present invention there is provided a compound according to Formula k:
Formula k
0 Step 3 o
Hθ, Jζ X,' Ph Ms0 JKJV Ph
\ I formula c formula 1
The compound of Formula c is suitably converted to a compound of Formula 1 through contact with mesyl chloride. Mesyl chloride may be added to the compound of Formula c slowly, preferably dropwise over 15 minutes or more. The compound of Formula c may be dissolved in a solvent, such as DCM and Et 3 N. The solution may be cooled, typically to below room temperature, preferably to O 0 C. The reaction of step 3 may be allowed to proceed for more than one hour, preferably for three hours or more. The compound of Formula 1 may be separated from the reaction mixture using any suitable method.
The product containing a compound according to Formula 1 is typically in the form of a light orange oil.
According to a further aspect of the present invention there is provided a method according to the reaction schemes below:
The invention will now be described by way of example only.
Example 1
Preparation of 2-Methylene-succinic acid 4-methylanilide (Compound of
Formula a)
An hd ride
Reagents
Procedure
To a stirred suspension of ltaconic Anhydride (500 g, 4.46 mol) in Toluene (1500 mL) at 70 0 C was added over 1 hr λ/-Methylaniline (503 mL, 4.64 mol) such that the internal temperature did not exceed 75 0 C. The mixture was then heated to 80 0 C and stirred a further 15 mins before being allowed to cool. Having cooled to 40 0 C, the mixture was poured into Hexane (585 mL) and cooled, with stirring, to 0 0 C for 30 mins. The resulting white solid was collected by filtration and dried over night in a vacuum oven to afford the title compound 903 g (92.5 % yield). Preparation of Compound of Formula j (Uncatalysed)
Diazald (52.5 g) in 300 mL ether was added to a solution of 48 mL EtOH, 18 mL water and KOH (12 g) held at 60-65 0 C in a flask (with a still head fitted to a condenser) such that the ether/diazomethane distilled at a rate matching the diazald addition (~1.5hrs). The receiving flask contained a stirred solution of a compound according to Formula a (26 g, 112 mmol) in 100 mL THF cooled to O 0 C. After it had cooled, the distillation flask was quenched with AcOH and removed. The reaction was allowed to stir under nitrogen, gradually warming to it It was observed that the solution remained yellow - it was then re-cooled to 0 0 C and quenched with roughly 1 eq AcOH (7 mL). Gas evolution observed (very roughly for the first 4 mL). The mixture was allowed to warm
to rt and ether removed at reduced pressure. The residue was taken up in 250 ml_ EtOAc washed 2x100 ml_ NaHCO 3 then dried over MgSO 4 and concentrated. This gave 33.3g.
Pyrazoline: 1.55-1.61 (1H, m, CHH 1 CHH 1 N), 2.25 (1H, d, CHH 1 C=O), 2.46- 2.52 (1H, m, CHH 1 CHH 1 N), 3.26 (3H, s, CH 3 N), 3.51 (1 H, d, CHH 1 C=O), 3.76 (3H, s, OCH 3 ), 4.56-4.61 (1H, m, CHH 1 N), 4.69-4.75 (1 H, m, CHH 1 N), 7.22- 7.24 (2H, m, o-Ph), 7.35-7.38 (1 H, m, p-Ph), 7.42-7.45 (2H, m, m-Ph).
Preparation of Compound of Formula b (Thermal)
A syringe was charged with pyrazoline (980 mg, 3.6 mmol) and a few drops were added to a 5 mL round-bottomed flask which contained a compound of Formula j. The flask was then slowly heated to 130 0 C, under a gentle flow of nitrogen, whereupon gas evolution was observed. The remaining pyrazoline was slowly added (ca. 30 mins) and heating was maintained for a further 15 mins after which time the mixture was allowed to cool. Analysis by 1 H NMR spectroscopy indicated consumption of starting material and formation of product along with significant amounts of olefinic by-products, yield 20-30%.
Cyclopropane: 0.72-0.74 (2H, m, CHH 1 CHH 1 antHo CO 2 Me), 1.29-1.32 (2H, m, CHH 1 CHH 1 syn to CO 2 Me), 2.18 (2H, s, CH 2 C=O), 3.28 (3H, s, CH 3 N), 3.64 (3H, s, OCH 3 ), 7.23-7.25 (2H, m, o-Ph), 7.32-7.36 (1H, m, p-Ph), 7.41-7.45 (2H, m, m-Ph)
Alternate method of producing compound of Formula b (Photochemical)
A solution of crude pyrazoline (16 g, 58 mmol) in MeOH (250 mL) was added to a compound of Formula j and the mixture was irradiated with a medium- pressure Hg lamp in a gas-inlet reactor for 50 mins with a nitrogen purge
(lamp (model 3040) and reactor purchased from Photochemical Reactors Ltd. The mixture was concentrated in vacuo and purified by column chromatography (4:1-1 :1 petrol:EtOAc) to afford the product containing a compound of Formula b (9.7 g, 65%) contaminated with some olefinic byproducts.
Use of a triplet sensitier (eg 10% benzophenone) has been found to increase the reaction yield to 87%. This can be removed post reaction by washing the resultant solid with TBME.
Cyclopropane: 0.72-0.74 (2H, m, CHH 1 CHH' anti to CO 2 Me), 1.29-1.32 (2H, m, CHH 1 CHH 1 syn to CO 2 Me), 2.18 (2H, s, CH 2 C=O), 3.28 (3H, s, CH 3 N), 3.64 (3H, s, OCH 3 ), 7.23-7.25 (2H, m, o-Ph), 7.32-7.36 (1 H, m, p-Ph), 7.41-7.45 (2H, m, m-Ph)
Alternate method of forming a compound of Formula b (Catalysed)
THF
Method:
A solution of diazomethane was prepared as before then added slowly (via a dropping funnel over ca. 35 min) to a stirred solution of dibutyl itaconate 1
(17.2 ml_, 70 mmol) and Pd(OAc) 2 (39 mg, 1.75 mmol) in THF (100 ml_) at O 0 C under N 2 atmosphere. Little obvious gas evolution but notable darkening of the mixture is observed. The reaction is allowed to warm slowly and stirring continued over 65 hr whereupon the mixture is quenched with acetic acid (4 mL, 70 mmol) and concentrated in vacuo. To provide crude product in 23% yield.
Cyclopropane: 0.72-0.74 (2H, m, CHH 1 CHH 1 anti to CO 2 Me), 1.29-1.32 (2H, m, CHH 1 CHH 1 syn to CO 2 Me), 2.18 (2H, s, CH 2 C=O), 3.28 (3H, s, CH 3 N), 3.64 (3H, s, OCH 3 ), 7.23-7.25 (2H, m, o-Ph), 7.32-7.36 (1 H, m, p-Ph), 7.41-7.45 (2H, m, m-Ph)
Purification:
Purification could be effected by filtration through a silica plug and subsequent selective Michael reaction of 1 with piperidine.
Typical procedure: the residue was dissolved in hexane {ca. 1 g/ 10 mL) and stirred with piperidine (0.4 mL /1 g substrate) until TLC analysis indicated the consumption of dibutyl itaconate (ca. 40 hr). The mixture was then diluted with ether and washed with 2 M HCI. The organic layer was dried over MgSO 4 and concentrated in vacuo. If necessary, further purification was achieved by column chromatography.
The catalyst (2) is added to a compound of formula a to form a compound of Formula b.
Method of producing compound of Formula c
Tert butanol (21ml) was slowly added to Lithium aluminium hydride (2.78g) at 0 deg C in THF (200ml) and held for 30 mins at room temp. (5.66g). The compound of Formula b was added in portions and the solution heated to 5O 0 C and held until the reaction neared completion by NMR. The mass was cooled to O 0 C and was quenched with 2M HCI. The product was then
extracted with ethyl acetate, washed with water and reduced in vaccuo to afford and orange oil (4.6g,81% yield).
NMR: 0.23-0.25; 0.52-0.74; 2.25; 3.28; 3.42; 4.65; 7.15-7.43.
Method of forming compound of Formula 1
The compound of Formula c (0.4g) was dissolved in DCM (10ml) with Et 3 N (0.382ml) and cooled to O 0 C. Mesyl chloride (0.426g) was added dropwise over 15 min and the reaction stirred for 3 hrs at O 0 C. The mass was partitioned between water DCM, separated and reduced in vacuo to afford a light orange oil (540mg, 100% yield).
NMR: 0.45; 0.62-0.64; 2.18; 2.99; 3.27; 4.23; 7.17-7.44.
Method of forming compound of Formula 2
Thioacetic acid (28ul) was added to Cs 2 CO 3 (117mg) in Methanol (5ml) and the solvent was exchanged from DMF (2ml) and was added to a solution of a compound according to Formula 1 (100mg) in DMF at room temperature. The mass was held overnight and was extracted from an ether water mixture. The solvent was reduced in vaccuo to afford an oil containing the compound of Formula 2 which was purified by chromatography (75mg, 80%).
NMR: 0.40; 0.54; 2.09; 2.29; 3.05; 3.27; 7.17-7.42.
Method of forming compound of Formula 3
The compound of Formula 2 (150mg) was dissolved in 50% THF in water (4ml) and led at 8O 0 C until the reaction neared completion. The mixture was
acidified and extracted with DCM, redcued in vaccuo to afford an orange wax (40mg, 50% yield)
NMR: 0.53-0.63; 1.34-1.38; 2.53; 2.63-2.65.
Alternative method of forming compound of Formula 3
KOH (4.34 g, 77 mmol, 15 eq) was dissolved in water (39 ml_) and de-gassed by bubbling through N 2 for 5 mins. This solution was added to thioacetate (1.43 g, 5.2 mmol) and the resulting suspension heated under reflux (bath temperature 120 0 C) for 14 hr. Having cooled, the mixture was extracted with ether (50 mL) then acidified with 2M HCI (50 ml_) and extracted with EtOAc (2 x 75 mL). The EtOAc extracts were dried over MgSO4 and concentrated in vacuo to afford the compound of Formula 3 (604 mg, 80%).
All documents referred to in this specification are hereby incorporated by reference. Various modifications and variations to the described embodiments of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the art are intended to be covered by the present invention.
Further Routes
Further aspects of the present invention include performing the various steps in the synthesis of the leukotriene compounds in different orders. The alcohol fragment used to form the leukotriene compounds by coupling with a thiol fragment can be considered in general terms as itself being formed from a heterocyclic fragment and an aromatic fragment. The aromatic fragment carries the alcohol group or a suitably protected form of the alcohol group.
The thiol and / or carboxylate functionality on the thiol fragment may be protected as necessary.
Thus in accordance with the invention it is possible in general terms to couple the various fragments in different ways. These are exemplified in relation to montelukast in the Synthetic Routes indicated below but are generally applicable to leukotriene derivatives of formula (1).
In Synthetic Route 1, the alcohol fragment (bearing a protected alcohol group) and the thiol fragment (bearing a protected carboxylate group) are first coupled, and the resulting molecule is then reacted with the heterocyclic fragment.
Route 1
In Synthetic Route 2 the alcohol fragment and the heterocyclic fragment (bearing a protected carboxylate group) are first coupled, and the resulting molecule is then reacted with the thiol fragment.
Route 2
In Synthetic Route 3 the alcohol fragment (bearing a protected alcohol group) and the thiol fragment are first coupled, and the resulting molecule is then reacted with the heterocyclic fragment.
Route 3
In Synthetic Route 4 the alcohol fragment (bearing a protected alcohol group) and the thiol fragment are first coupled, and the resulting molecule is then reacted with the heterocyclic fragment.
Route 4
MeMgBr
In Synthetic Route 5 the alcohol fragment (bearing a protected alcohol group) and the thiol fragment are first coupled, and the resulting molecule is then reacted with the heterocyclic fragment.
Route 5
MsCI/Et3N
Next Patent: SYSTEM AND METHOD FOR COUNT BY WEIGHT CORRECTION