WO2008035379A2 - Process for and intermediates of leukotriene antagonists - Google Patents
Process for and intermediates of leukotriene antagonists Download PDFInfo
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- WO2008035379A2 WO2008035379A2 PCT/IN2007/000414 IN2007000414W WO2008035379A2 WO 2008035379 A2 WO2008035379 A2 WO 2008035379A2 IN 2007000414 W IN2007000414 W IN 2007000414W WO 2008035379 A2 WO2008035379 A2 WO 2008035379A2
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- 0 BCc1cccc(C(*=*)=O)c1 Chemical compound BCc1cccc(C(*=*)=O)c1 0.000 description 2
- XZQALEJBXGGWAC-UHFFFAOYSA-N CC1=CCCC(C(OC)=O)=C1 Chemical compound CC1=CCCC(C(OC)=O)=C1 XZQALEJBXGGWAC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/18—Halogen atoms or nitro radicals
Definitions
- the present invention provides a novel method of producing Montelukast sodium and novel intermediates therefore.
- Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. It has been found that antagonists to leukotrienes can perform valuable functions in the treatment or amelioration of certain disease states, particularly those associated with inflammation.
- Montelukast sodium is an important leukotriene antagonist and useful in the treatment of asthma and other related disorders.
- the compound synthesized by this method has the following structural formula (VII') and the method comprises:
- the malonate comprises one or more of potassium alkyl malonate or diethylmalonate. Such a reaction may occur in the presence of a base to produce a ⁇ -Keto ester.
- methylbenzoate to form alkyl 3-bromomethylbenzoate.
- 3-methylbenzoic acid reacts with an alcohol in the presence of a strong acid
- alkyl 3-methylbenzoate for example sulphuric acid
- Any suitable alcohol may be used, but preferably it is selected from one or more of methyl, ethyl, propyl, butyl or benzyl alcohol.
- Bromination according to this aspect of the invention may be carried out in any suitable fashion. However, it has been found advantageous to carry it out with one or more of N- bromosuccinimide or l,3-Dibromo-5,5-dimethyl hydantoin and a suitable organic solvent.
- the organic solvent is preferably selected from one or more of dichioromethane, chloroform, acetonitrile or carbon tetrachloride.
- Conversion into a formyl group may occur by any suitable means. According to one preferred embodiment, conversion is in the presence of one or more of hexamine or manganese dioxide and a suitable solvent.
- the solvent may be any suitable solvent, and preferably selected from one or more of acetic acid, aqueous acetic acid or water..
- the condensation may be carried out in any suitable fashion. According to one preferred embodiment, it is carried out in the presence of a mixture selected from one or more of: (a) acetic anhydride, (b) acetic anhydride and toluene, (c) acetic anhydride and pyridine, (d) acetic anhydride and triethylamine or (e) acetic anhydride, pyridine and toluene.
- the condensation temperature may be any suitable temperature required for the reaction. Preferably it is maintained between 80- 15O 0 C and more particularly between 100-130 0 C.
- VI comprising hydrolysing alkyl 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoate to give 3- [((7- Chloro-2-quinolinyl)ethenyl)]benzoic acid.
- hydrolysis of the ester is carried out in the presence of one or more of aqueous sodium hydroxide, methanolic sodium hydroxide, sodium ethoxide, sodium methoxide or sodium tertiary amyloxide.
- the acid is treated with one or more of the thionyl chloride, thionyl chloride and triethylarnine. oxalyl chloride or DMF and POCI 3 to form the corresponding acid chloride.
- the compound synthesized by this method has the following structural formula (VII') and the method comprises;
- VU' converting 3-methylbenzoic acid into alkyl 3-methylbenzoate; reacting 3-methylbenzoate to form alkyl 3-bromomethylbenzoate; converting alkyl 3-bromomethylbenzoate into alkyl 3-formylbenzoate; condensing alkyl 3-formylbenzoate with 7-Chioroquinaldine to give alkyl 3-[((7-Chloro-2-quinoliny)ethenyl)] benzoate; hydrolysing alkyl 3-[((7-Chloro- 2-quinolinyl)ethenyl)] benzoate to give 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoic acid; and reacting 3-[((7-Chloro-2-quinolinyl)ethenyl))benzoic acid with Potassium alkyl malonate to obtain a compound of structural formula VII'.
- R 1 is substituted or unsubstituted alkoxyl, carbonyl, alkyl, alkenyl, ring structure, or hydrogen, or halogen, or alcohol
- R 2 is substituted or unsubstituted alkoxyl, carbonyl, alkyl, alkenyl, ring structure, or a halogen, or alcohol
- R 3 is substituted or unsubstituted alkoxyl, carbonyl, akyl, alkenyl, ring structure, or hydrogen, or halogen or alcohol.
- Preferred compounds of the seventh aspect are those in which R 1 is a C1-C3 alcohol, R 2 is substituted or unsubstituted carbonyl; and R 3 is hydrogen. More preferably, Ri is CHO; and R 2 is carboxyl.
- Ri is methyl, R 2 is carboxyl; and R 3 is Hydrogen; or ,
- Ri is methyl, R 2 is COOR and R is lower alkyl or lower alkenyl and R 3 is Hydrogen; or
- Ri is a halogen substituted methyl
- R 2 is COOR and R is lower alkyl or lower alkenyl and R 3 is hydrogen; or
- Ri is substituted alkyl or alkenyl; R 2 is substituted carbonyl; and R 3 is hydrogen or lower alkyl.
- Ri is a compound of structural formula II and:
- R 2 is substituted lower alkyl carboxyl; R 3 is hydrogen or lower alkyl; R 4 is C1-C5 alkyl or alkenyl; and R 5 is halogen, hydroxy or lower alkyl.
- R 2 is COOR and R is hydrogen or lower alkyl, R 3 is hydrogen, R 4 is C2 alkenyl, and R 5 is halogen.
- R 2 is
- R 3 is hydrogen, R 4 is a 2 to 10 carbon-chain alkenyl group, R 5 is halogen and R 6 is halogen or hydroxyl.
- R 4 comprises a 2 carbon alkenyl group; and R 6 is hydroxyl.
- the product contains some dibromo derivative also.
- Benzoyl peroxide could be used as a radical initiator.
- Methyl 3-bromomethylbenzoate (220 g) was dissolved in an aqueous solution of acetic acid (1:1, 800 ml) and hexamine added (250 g, 1.8 mol) and heated at 60-65° for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice (3 Kg) under stirring. The solid precipitated was filtered, washed with water and dried under vacuum at room temperature.
- Methyl 3-formylbenzoate (90 g, 0.55 mol) and 7-chloroquinaldine (89 g, 0.5 mol) were dissolved in a mixture of acetic acid (100 ml), toluene (80 ml) and pyridine (40 ml) and refluxed for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and diluted with hexane (500 ml) under stirring. The precipitated solid was filtered, washed with hexane (50 ml) and dried under vacuum. Brown solid, 145 g (89%, yield)
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Abstract
A process for synthesizing a β- ketoester of formula (VII) which comprises: (a) converting 3-methylbenzoic acid into alkyl 3-methylbenzoate; (b) reacting 3 -methyl benzoate to form alkyl 3 -bromomethylbenzoate; (c)converting alkyl 3-bromo methyl benzoate into alkyl 3-formylbenzoate; (d) condensing alkyl 3-formyl benzoate with 7- Chioroquinaldine to give alkyl 3- [((7-Chloro-2-quinolinyl) ethenyl)]benzoate; (e) hydrolyzing alkyl 3 -[((7-Chloro-2-quinolinyl)ethenyl) benzoate to give 3-[((7- Chloro- 2-quinolinyl)ethenyl)]benzoic acid; and (f) reacting 3-[((7-Chloro-2-quinolinyI) ethenyjbenzoic acid with a malonate to obtain a compound of structural formula VII.
Description
"Process for and intermediates of leukotriene antagonists"
Technical Field: The present invention provides a novel method of producing Montelukast sodium and novel intermediates therefore.
Background of the invention:
Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. It has been found that antagonists to leukotrienes can perform valuable functions in the treatment or amelioration of certain disease states, particularly those associated with inflammation.
By way of example only, Montelukast sodium (structural formula VIII, below), is an important leukotriene antagonist and useful in the treatment of asthma and other related disorders.
VH
Several synthetic routes for leukotriene antagonists such as Montelukast sodium have been developed. In relation to Montelukast sodium, the -Keto ester (VH') is an important intermediate in these processes (WO 2006/021974 Al). In the past, the desired P-Keto ester (VH') has been obtained through a sequence of steps consisting of [1] the condensation of 7-chloroquinaldine and isophthalaldehyde in presence of acetic anhydride [2] the reaction of the resulting aldehyde with methyl magnesium halide to
produce a secondary alcohol [3] oxidation of the secondary alcohol to give an aromatic ketone and [4) reaction of the aromatic ketone with dialkylcarbonate.
However, the synthetic strategy of the condensation of 7-chioroquinaldine with isophthalaldehyde has a number of significant disadvantages which limit the utility of the synthesis. These include: the formation of a number of by-products and a relatively low yield (US 5,869,673). Further, prior methods use expensive reagents such as methyl magnesium halides, oxalyl halides. etc., making the economically inefficient.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the pRlor art forms part of the common general knowledge.
Summary of the invention:
According to a first aspect of the invention, there is provided a method of synthesizing a compound of formula VII:
According to a second aspect of the present invention, there is provided a method of synthesizing a compound of formula III
,methylbenzoate to form alkyl 3-bromomethylbenzoate. According to one preferred embodiment, 3-methylbenzoic acid reacts with an alcohol in the presence of a strong acid
(for example sulphuric acid) to form alkyl 3-methylbenzoate. Any suitable alcohol may be used, but preferably it is selected from one or more of methyl, ethyl, propyl, butyl or benzyl alcohol.
Bromination according to this aspect of the invention may be carried out in any suitable fashion. However, it has been found advantageous to carry it out with one or more of N- bromosuccinimide or l,3-Dibromo-5,5-dimethyl hydantoin and a suitable organic solvent.
The organic solvent is preferably selected from one or more of dichioromethane, chloroform, acetonitrile or carbon tetrachloride.
According to a third aspect of the invention, there is provided a method of synthesizing a compound of formula IV
IV comprising converting alkyl 3-bromomethylbenzoate into alkyl 3-formylbenzoate. Conversion into a formyl group may occur by any suitable means. According to one preferred embodiment, conversion is in the presence of one or more of hexamine or manganese dioxide and a suitable solvent. The solvent may be any suitable solvent, and preferably selected from one or more of acetic acid, aqueous acetic acid or water..
According to a fourth aspect of the present invention, there is provided a method of synthesizing a compound of formula V
comprising condensing alkyl 3-formylbenzoate with 7-Chioroquinaldine to give alkyl 3- [((7- Chloro-2-quinolinyethenyl)]benzoate. The condensation may be carried out in any suitable fashion. According to one preferred embodiment, it is carried out in the presence of a mixture selected from one or more of: (a) acetic anhydride, (b) acetic anhydride and toluene, (c) acetic anhydride and pyridine, (d) acetic anhydride and triethylamine or (e) acetic anhydride, pyridine and toluene. The condensation temperature may be any suitable temperature required for the reaction. Preferably it is maintained between 80- 15O0C and more particularly between 100-1300C.
According to a fifth aspect of the invention, there is provided a method of synthesizing a compound of general formula VI
VI comprising hydrolysing alkyl 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoate to give 3- [((7- Chloro-2-quinolinyl)ethenyl)]benzoic acid. According to one preferred embodiment, hydrolysis of the ester is carried out in the presence of one or more of aqueous sodium hydroxide, methanolic sodium hydroxide, sodium ethoxide, sodium methoxide or sodium tertiary amyloxide. In a still further preferred embodiment, the acid is treated with one or more of the thionyl chloride, thionyl chloride and triethylarnine. oxalyl chloride or DMF and POCI3 to form the corresponding acid chloride.
According to a sixth aspect of the invention, there is method of synthesizing a compound of formula VII
VU' converting 3-methylbenzoic acid into alkyl 3-methylbenzoate; reacting 3-methylbenzoate to form alkyl 3-bromomethylbenzoate; converting alkyl 3-bromomethylbenzoate into
alkyl 3-formylbenzoate; condensing alkyl 3-formylbenzoate with 7-Chioroquinaldine to give alkyl 3-[((7-Chloro-2-quinoliny)ethenyl)] benzoate; hydrolysing alkyl 3-[((7-Chloro- 2-quinolinyl)ethenyl)] benzoate to give 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoic acid; and reacting 3-[((7-Chloro-2-quinolinyl)ethenyl))benzoic acid with Potassium alkyl malonate to obtain a compound of structural formula VII'.
Scheme I (below) summarizes this particularly preferred embodiment.
Step 5
Scheme I
In a seventh aspect of the present invention, there are provided various intermediates for the synthesis of a leukotriene antagonist, the intermediates having the structural formula- I:
Preferred compounds of the seventh aspect are those in which R1 is a C1-C3 alcohol, R2 is substituted or unsubstituted carbonyl; and R3 is hydrogen. More preferably, Ri is CHO; and R2 is carboxyl.
According to an eighth aspect of the invention, there are provided intermediates having the structural formula I wherein:
Ri is methyl, R2 is carboxyl; and R3 is Hydrogen; or ,
Ri is methyl, R2 is COOR and R is lower alkyl or lower alkenyl and R3 is Hydrogen; or
Ri is a halogen substituted methyl; R2 is COOR and R is lower alkyl or lower alkenyl and R3 is hydrogen; or
According to a ninth aspect of the present invention, there are provided compounds having structural formula I, wherein:
Ri is substituted alkyl or alkenyl; R2 is substituted carbonyl; and R3 is hydrogen or lower alkyl. Preferably, Ri is a compound of structural formula II and:
R2 is substituted lower alkyl carboxyl; R3 is hydrogen or lower alkyl; R4 is C1-C5 alkyl or alkenyl; and R5 is halogen, hydroxy or lower alkyl. In another preferred compound, R2 is COOR and R is hydrogen or lower alkyl, R3 is hydrogen, R4 is C2 alkenyl, and R5 is halogen. In a still further preferred compound, R2 is
AA1,
R3 is hydrogen, R4 is a 2 to 10 carbon-chain alkenyl group, R5 is halogen and R6 is halogen or hydroxyl. In another preferred compound, R4 comprises a 2 carbon alkenyl group; and R6 is hydroxyl.
Throughout this specification (including any claims which follow), unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Detailed description of example embodiments:
It is convenient to describe the invention herein in relation to particularly preferred embodiments relating to production of montelukast sodium. However, it is to be appreciated that other constructions and arrangements are also considered as falling within the scope of the invention. Various modifications, alterations, variations and or additions to the construction and arrangements described herein are also considered as falling within the ambit and scope of the present invention.
Scheme II depicts the overall synthetic process of a preferred embodiment according to the present invention which relates to the synthesis of intermediates useful in synthesizing Montelukast.
1,3- Dibromo-5,5-dimethylhydantoin AIBN1 MDC
7-chloroquinaldine, Ac2O, Toluene Pyridine
VI
1) SOCl2
2) Pot Alkyl malonate Mgα2, CH3CN, Et3N
Scheme II
Example 1: Preparation of Methyl 3-methylbenzoate
Methanol (Excess) Cone H2SO4, Reflux, 15 h
To a solution of m- toluic acid (136 g, 1 mol) in methanol (800 ml) was added drop wise concentrated sulphuric acid (10 ml) under stirring at room temperature and heated under reflux for 15 h. After completion of the reaction (monitored by TLC), about 80% methanol was distilled off. The reaction mixture was diluted with water (800 ml) and extracted with dichloromethane twice (2 X 200 ml) and the combined organic layer was
washed with aqueous sodium bicarbonate (10%, 200 ml) solution followed by water. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed by distillation.
Colorless Liquid, 150 g (Quantitative yield)
Example 2: Preparation of Methyl 3-bromomethylbenzoate
To a solution of Methyl 3-methylbenzoate (150 g, I mol) and l,3-Dibromo-5,5-dimethyl hydantoin (DDH) (15O g, 0.52 mol) in dichloromethane (500 ml) was added AIBN (0.1 g, 0.0006 mol) at room temperature and heated under reflux for 1O h. AIBN in 0.1 g lots were added intermittently during reflux to complete the reaction. After completion of the reaction (monitored by TLC), the reaction mixture was poured into cold water (600 ml) and the organic layer was separated. The aqueous layer was extracted again with dichloromethane (200 ml). The combined organic layer was washed with water and dried over anhydrous sodium sulphate and the solvent was removed by distillation. Colorless liquid, 220 g (96 % yield)
Note: The product contains some dibromo derivative also. Benzoyl peroxide could be used as a radical initiator.
Example 3: Preparation of Methyl 3-formyIbenzoate
Hexaαane, Aq. Acetic Acid (1:1)
Reflux.6 h
Methyl 3-bromomethylbenzoate (220 g) was dissolved in an aqueous solution of acetic
acid (1:1, 800 ml) and hexamine added (250 g, 1.8 mol) and heated at 60-65° for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice (3 Kg) under stirring. The solid precipitated was filtered, washed with water and dried under vacuum at room temperature.
Cream colored solid, 130 g (83% yield)
Example 4: Preparation of Methyl 3-[((7-chIoro-2-quinoIinyI)ethenyI)]benzoate
Methyl 3-formylbenzoate (90 g, 0.55 mol) and 7-chloroquinaldine (89 g, 0.5 mol) were dissolved in a mixture of acetic acid (100 ml), toluene (80 ml) and pyridine (40 ml) and refluxed for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and diluted with hexane (500 ml) under stirring. The precipitated solid was filtered, washed with hexane (50 ml) and dried under vacuum. Brown solid, 145 g (89%, yield)
Example 5: Preparation of 3-[((7-chloro-2-quinoIinyI)ethenyl)]benzoic acid
Methyl 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoate (1 45g) was dissolved in a solution of sodium hydroxide (7Og in 200 ml of water and 200 ml of methanol) and refluxed for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice (0.5 Kg) under stirring. The reaction mixture was acidified slowly with concentrated HCI and the yellow colored solid precipitated was filtered, washed with water and dried under vacuum.
Light brown solid, 132 g (95% yield)
Example 6: Preparation of Ethyl [E]-3'-[((7-ehloro-2-quinoIinyl)ethenyI)phenyll-3- oxopropanoate
3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoic acid (40 g, 0.129 mol) was treated with excess thionyl chloride (161.5 g, 1.357 mol) portion wise in 30 mm at 10-150C followed by heating under reflux for 2 h. After completion of the reaction (monitored by TLC), thionyl chloride was distilled off under vacuum, completely. Toluene (100 ml) was added and stirred for 5 win. and toluene was distilled off to remove traces of thionyl chloride. The residue obtained was cooled to 150C and added acetonitrile (300 ml) followed by triethylamine (13g) and stirred the thick mass, 3-[7-Chloro-(2-quinolinylethenyl)]benzoyl chloride for 15 mm at room temperature.
To a cooled solution of potassium ethyl malonate (46.1 g, 0.27 mol) in acetonitrile (400 ml) at 10-150C under nitrogen was added triethylamine (41.8 g, 0.41 mol) followed by anhydrous MgC12 (30.7g, 0.32 mol) under stirring. The Reaction mixture was allowed to warm to 20- 250C and stirring was continued for 2 hr. The slurry obtained was cooled to
0-50C and added the acid chloride obtained above, quickly and the reaction mixture was kept overnight at 20- 250C. After completion of the reaction (monitored by TLC), acetonitrile was removed under vacuum, cooled to 10-150C and acidified with (aq. HCI,
13 %, 270 ml) by maintaining the temperature below 250C. The precipitate obtained was filtered and washed with water and dried under vacuum.
Yellow solid, 44 g (90% yield)
Claims
We claim:
I. A method of synthesizing a compound of formula VII
Comprising:
a. converting 3-methylbenzoic acid into alkyl 3-methylbenzoate; b. reacting 3 -methylbenzoate to form alkyl 3 -bromomethylbenzoate; c. converting alkyl 3-bromomethylbenzoate into alkyl 3-formylbenzoate; d. condensing alkyl 3-formylbenzoate with 7-Chioroquinaldine to give alkyl 3- [((7-Chloro-2-quinolinyl)ethenyl)]benzoate; e. hydrolyzing alkyl 3 -[((7-Chloro-2-quinolinyl)ethenyl) benzoate to give 3-
[((7- Chloro-2-quinolinyl)ethenyl)]benzoic acid; and f. reacting 3-[((7-Chloro-2-quinolinyI)etheny]benzoic acid with a malonate to obtain a compound of structural formula VII.
2. A method according to claim I, wherein 3-methylbenzoic acid reacts with an alcohol in the presence of a strong acid to form alkyl 3-methylbenzoate.
3. A method according to claim I wherein the strong acid is sulphuric acid.
4. A method according to claim 2, where in the alcohol is selected from one or more of methyl, ethyl, propyl, butyl or benzyl alcohol. J. A method according to claim 1, wherein bromination is carried out with one or more of N-bromosuccinimide or 1 ,3-Dibromo-5,
5-dimethyl hydantoin and a suitable organic solvent.
6. A method according to claim 4, wherein the organic solvent is selected from one or more of dichloromethane, chloroform, acetonitrile or carbon tetrachloride.
7. A method according to claim I, wherein the benzylic halide is converted into a formyl group by one or more of hexamine or manganese dioxide and a suitable solvent.
8. A method according to claim 6, wherein the solvent is selected from one or more of acetic acid, aqueous acetic acid or water.
9. A method according to claim 1 wherein condensation between 3-formyl benzoate and 7- chloroquinaldine is carried out in the presence of a mixture selected from one or more of: (a) acetic anhydride, (b) acetic anhydride and toluene, (c) acetic anhydride and pyridine, (d) acetic anhydride and triethylamine or (e) acetic anhydride, pyridine and toluene.
10. A method according to claim 8, wherein the temperature of the condensation is maintained between 80-1500C.
11. A method according to claim 8, wherein the temperature of the condensation is maintained between 100-1300C.
12. A method according to claim I wherein hydrolysis of the ester is carried out in the presence of one or more of aqueous sodium hydroxide, methanolic sodium hydroxide, sodium ethoxide, sodium methoxide or sodium tertiary amyloxide.
13. A method according to claim I wherein the acid is treated with one or more of the thionyl chloride, thionyl chloride and triethylamine, oxalyl chloride or DMF and POCI3 to form the corresponding acid chloride.
14. A method according to claim I wherein the malonate comprises one or more of potassium alkyl malonate or diethylmalonate and the reaction proceeds in the presence of a base to produce a β-Keto ester.
15. A method of synthesizing a compound of formula III
16. A method according to claim 15, wherein 3-methylbenzoic acid reacts with an alcohol in the presence of a strong acid to form alkyl 3-methylbenzoate.
17. A method according to claim 16, where in the alcohol is selected from one or more of methyl, ethyl, propyl, butyl or benzyl alcohol.
18. A method according to claim 14, wherein bromination is carried out with one or more of N-bromosuccinimide or 1 ,3-Dibromo-5,5-dimethyl hydantoin and a suitable organic solvent.
19. A method according to claim 18, wherein the organic solvent is selected from one or more of dichloromethane, chloroform, acetonitrile or carbon tetrachloride.
20. A method of synthesizing a compound of formula IV
21. A method according to claim 20, wherein the benzylic halide is converted into a formyl group by one or more of hexamine or manganese dioxide and a suitable solvent.
22. A method according to claim 21, wherein the solvent is selected from one or more of acetic acid, aqueous acetic acid or water.
23. A method of synthesizing a compound of formula V
comprising condensing alkyl 3-formylbenzoate with 7-Chloroquinaldine to [((7- Chloro-2-quinolinyl)ethenyl)]benzoate.
24. A method according to claim 23, wherein condensation is carried out in the presence of a mixture selected from one or more of: (a) acetic anhydride, (b) acetic anhydride and toluene, (c) acetic anhydride and pyridine, d) acetic anhydride and triethylamine or (e) acetic anhydride, pyridine and toluene.
25. A method according to claim 23, wherein the temperature of the condensation is maintained between 80-1500C.
26. A method according to claim 23, wherein the temperature of the condensation is maintained between 100-1300C,
27. A method of synthesizing a compound of general formula VI
28. A method according to claim 27, wherein hydrolysis of the ester is carried out in the presence of one or more of aqueous sodium hydroxide, methanolic sodium hydroxide, sodium ethoxide, sodium methoxide or sodium tertiary amyloxide.
29. A method according to claim 27, wherein the acid is treated with one or more of the thionyl chloride, thionyichioride and triethylamine, oxalylchloride or DMF and POCI3 to form the corresponding acid chloride.
30. A method of synthesizing a compound of formula VII
comprising reacting 3-[((7-Chloro-2-quinolinyl)ethenyl)benzoic acid with a malonate to obtain a compound of structural formula VII.
31. A method according to claim 30 wherein the malonate comprises one or more of potassium alkyl malonate or diethylmalonate and the reaction proceeds in the presence of a base to produce a β-Keto ester.
32. An intermediate for the synthesis of a leukotRlene antagonist, the intermediate having the structural formula I:
R1 is substituted or unsubstituted alkoxyl, carbonyl, alkyl, alkenyl, ring structure, or hydrogen, or halogen, or alcohol;
R2 is substituted or unsubstituted alkoxyl, carbonyl, alkyl, alkenyl, ring structure, or a halogen, or alcohol; and
R3 is substituted or unsubstituted alkoxyl, carbonyl, akyl, alkenyl, ring structure, or hydrogen, or halogen or alcohol.
33. An intermediate according to claim 32, wherein:
R1 is a Cl-C3 alcohol. R2 is substituted or unsubstituted carbonyl; and
R3 is hydrogen;
34. An intermediate according to claim 33, wherein:
R1 is CHO; and R2 is carboxyl
35. An intermediate according to claim 32 , wherein:
Ri is methyl;
R2 is carboxyl; and
R3 is Hydrogen.
36. An intermediate according to claim 32, wherein: R1 is methyl;
R2 is COOR and R is lower alkyl or lower alkenyl R3 is Hydrogen.
37. An intermediate according to claim 32, wherein: R1 is a halogen substituted methyl;
R2 is COOR and R is lower alkyl or lower alkenyl; and
R3 is hydrogen.
38. An intermediate according to claim 37, wherein the halogen OfR1 is bromo.
39. A compound having structural formula I, wherein:
R1 is substituted alkyl or alkenyl; R2 is substituted carbonyl; and R3 is hydrogen or lower alkyl.
40. A compound according to claim 39, wherein:
R1 is a compound of structural formula II
R2 is substituted lower alkyl carboxyl; R3 is hydrogen or lower alkyl;
R4 is C1-C5 alkyl or alkenyl; and
R5 is halogen, hydroxy or lower alkyl.
41. A compound according to claim 40, wherein:
R2 is COOR and R is hydrogen or lower alkyl R3 is hydrogen;
R4 is C2 alkenyl; and R5 is halogen.
42. A compound according to claim 40, wherein; R2 is
R.3 is hydrogen; R4 is a 2 to 10 carbon-chain alkenyl group;
Rs is halogen; and Rδ is halogen or hydroxyl.
43. A compound according to claim 40, wherein: R4 comprises a 2 carbon alkenyl group; and R6 is hydroxyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1710/CHE/2006 | 2006-09-19 | ||
| IN1710CH2006 | 2006-09-19 |
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| WO2008035379A2 true WO2008035379A2 (en) | 2008-03-27 |
| WO2008035379A3 WO2008035379A3 (en) | 2010-02-18 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IN2007/000414 Ceased WO2008035379A2 (en) | 2006-09-19 | 2007-09-14 | Process for and intermediates of leukotriene antagonists |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008035379A2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7812168B2 (en) | 2005-07-05 | 2010-10-12 | Teva Pharmaceutical Industries Ltd. | Purification of montelukast |
| CN101891649A (en) * | 2010-07-06 | 2010-11-24 | 荆州市腾飞化工有限公司 | Novel 3-cyano methyl benzoate preparing method |
| CN102617460A (en) * | 2012-03-29 | 2012-08-01 | 中国科学院上海有机化学研究所 | Compounding method of midbody required in compounding of montelukast sodium |
| WO2017060148A1 (en) | 2015-10-05 | 2017-04-13 | Basf Se | Pyridine derivatives for combating phytopathogenic fungi |
| WO2018065182A1 (en) | 2016-10-04 | 2018-04-12 | Basf Se | Reduced quinoline compounds as antifuni agents |
| WO2018134127A1 (en) | 2017-01-23 | 2018-07-26 | Basf Se | Fungicidal pyridine compounds |
| WO2019115343A1 (en) | 2017-12-15 | 2019-06-20 | Basf Se | Fungicidal mixture comprising substituted pyridines |
| US11064697B2 (en) | 2015-07-24 | 2021-07-20 | Basf Se | Pyridine compounds useful for combating phytopathogenic fungi |
| US11317628B2 (en) | 2015-09-03 | 2022-05-03 | BASF Agro B.V. | Microparticle compositions comprising saflufenacil |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006021974A1 (en) * | 2004-08-23 | 2006-03-02 | Morepen Laboratories Limited | A process for synthesizing diol (viii)-an intermediate of montelukast sodium |
| EP2094665A4 (en) * | 2006-11-06 | 2010-11-24 | Reddys Lab Ltd Dr | Preparation of montelukast and its salts |
| WO2009001374A2 (en) * | 2007-06-25 | 2008-12-31 | Aptuit Laurus Pvt Ltd | Preparation of ethyl-3'-[((7-chloro-2-quinolinyl)ethenyl)phenyl]-3-oxopropanoate, a key intermediate for montelukast sodium |
-
2007
- 2007-09-14 WO PCT/IN2007/000414 patent/WO2008035379A2/en not_active Ceased
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7812168B2 (en) | 2005-07-05 | 2010-10-12 | Teva Pharmaceutical Industries Ltd. | Purification of montelukast |
| CN101891649A (en) * | 2010-07-06 | 2010-11-24 | 荆州市腾飞化工有限公司 | Novel 3-cyano methyl benzoate preparing method |
| CN101891649B (en) * | 2010-07-06 | 2013-05-08 | 荆州市腾飞化工有限公司 | Novel 3-cyano methyl benzoate preparing method |
| CN102617460A (en) * | 2012-03-29 | 2012-08-01 | 中国科学院上海有机化学研究所 | Compounding method of midbody required in compounding of montelukast sodium |
| US11064697B2 (en) | 2015-07-24 | 2021-07-20 | Basf Se | Pyridine compounds useful for combating phytopathogenic fungi |
| US11317628B2 (en) | 2015-09-03 | 2022-05-03 | BASF Agro B.V. | Microparticle compositions comprising saflufenacil |
| WO2017060148A1 (en) | 2015-10-05 | 2017-04-13 | Basf Se | Pyridine derivatives for combating phytopathogenic fungi |
| WO2018065182A1 (en) | 2016-10-04 | 2018-04-12 | Basf Se | Reduced quinoline compounds as antifuni agents |
| WO2018134127A1 (en) | 2017-01-23 | 2018-07-26 | Basf Se | Fungicidal pyridine compounds |
| WO2019115343A1 (en) | 2017-12-15 | 2019-06-20 | Basf Se | Fungicidal mixture comprising substituted pyridines |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008035379A3 (en) | 2010-02-18 |
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