WO2006090409A1 - An improved process for the preparation of 5 - carboxyphthalide - Google Patents
An improved process for the preparation of 5 - carboxyphthalide Download PDFInfo
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- WO2006090409A1 WO2006090409A1 PCT/IN2005/000121 IN2005000121W WO2006090409A1 WO 2006090409 A1 WO2006090409 A1 WO 2006090409A1 IN 2005000121 W IN2005000121 W IN 2005000121W WO 2006090409 A1 WO2006090409 A1 WO 2006090409A1
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- carboxyphthalide
- terephthalic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
Definitions
- Citalopram may be prepared by the process described in U.S. Pat. No. 4,650,884, according to which 5-cyanophthalide is subjected to two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N 5 N- dimethylaminopropyl magnesium halogenide, respectively, and the resulting compound of the formula [C ]
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- Organic Chemistry (AREA)
- Furan Compounds (AREA)
Abstract
The invention disclosed in this applications relates to an improved process for the preparation of 5-carboxy phthalide useful as an intermediate for the preparation of citlopram which comprises adding terephthalic acid to Chloromethyl chlorosulphate , heating , adding water portion wise filtering , centrifuging and washing the resultant product with water.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF 5-CARBOXYPHTHALIDE FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 5- carboxyphthalide. The 5-carboxyphthalide prepared by the process of the present invention is, an isobenzofuran derivative namely l-Oxo-l,3-dihydro-5- isobenzofurancarboxylic acid represented by the formula [A] given below
5-carboxyphthalide is an useful intermediate for the preparation of several chemical compounds, particularly dyes, resins and drugs. In particular, 5- carboxyphthalide is an intermediate useful in the synthesis of Citalopram, a well- known antidepressant drug.
BACKGROUND OF THE INVENTION Citalopram having the formula [B] given below is a well-known antidepressant drug that has now been on the market for some years :
Citalopram may be prepared by the process described in U.S. Pat. No. 4,650,884, according to which 5-cyanophthalide is subjected to two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N5N- dimethylaminopropyl magnesium halogenide, respectively, and the resulting compound of the formula [C ]
Enantiomers of Citalopram may be prepared by the method described in U.S. Pat. No. 4,943,590, i.e. by separating the enantiomers of the intermediate of Formula [C] and performing enantioselective ring closure in order to obtain the desired enantiomer.
A method for the preparation of 5-cyanophthalide has previously been described in Bull. Soc. Sci. Bretagne, 1951, 26, 35 and in Levy and Stephen, J. Chem. Soc, 1931, 867. By this method, 5-aminophthalide is converted to the corresponding 5- cyanophthalide by diazotation followed by reaction with CuCN. 5-Aminophthalide was obtained from 4-aminophthalimide by a two-step reduction procedure.
The above method is not desirable in that a toxin and a heavy metal salt are involved, such as potassium cyanide and copper sulfide in the method . In
addition, synthesis of 5-aminophthalide requires a dangerous reaction of nitration of phthalimide (Organic Synthesis II, 459), and further, reduction to amino group by tin chloride and semi-reduction of phthalimide by zinc (J. Chem. Soc, 1931, 867), generating a waste heavy metal that is industrially undesirable.
Synthesis of certain alkyl- and phenylnitriles from acid chlorides is described in Tetrahedron Letters, 1982, 23, 14, 1505-1508, and in Tetrahedron, 1998, 54, 9281 Employing this general method 5-Cyanophthalide is prepared from 5- Carboxyphthalide on a commercial scale
It is also well known that 5-carboxyphthalide may be prepared by reduction of one of the carbonyl groups of trimellitic anhydride, which can occur by hydrogenation or, according to DE-2630927, by electrochemical reduction and the process is as follows.
The electrochemical reduction may be carried out at temperatures of from 10 to 95O0C and preferably at from 200 to500° C. The cathode(s) conveniently consist of a metal having adequately high hydrogen overvoltage (more negative than -0.5 volt) such as mercury, lead, cadmium or antimony. Lead has proved to be particularly suitable. The surface of the cathode may be structured to increase the active surfacearea. The anodes used may be made of the anode materials disclosed in the literature, such as graphite, manganese dioxide, precious metals, titanium doped with a precious metal oxideor, preferably, leaddioxide. The current density in the electrolysis may be for example from 1 to 30 A/dm2 and particularly from 3 to l5 A/dm2.
This method has the drawback of giving a 5-carboxyphthalide containing, as a byproduct, the 6 isomer in an amount, which can reach 10%. An impurity, which is present in such a percent, cannot be accepted if 5-carboxyphthalide must be used as an intermediate in the preparation of drugs and, in such a case, it must be removed or strongly reduced to a value not higher than 0.1%. The removal of the 6
isomer occurs by several crystallizations which lower the yield in final product considerably. It is also known that 5-carboxyphthalide may be prepared according to another method, described in U.S. Pat. No. 3,607,884. The method disclosed in the patent comprises reacting terephthalic acid with formaldehyde in liquid sulfur trioxide(60 %). This synthesis must be carried out very cautiously because it is highly exothermic .Nevertheless, the reaction mass remains in any case thick and pasty like material therefore, involves a difficult handling for the recovery of the end product. Whereby it is not suitable for the industrial scale-up owing to the problems connected to the use of liquid sulfur trioxide which is highly corrosive,hygroscopic and strong acidic compound in nature.
Furthermore, it is known that when a reaction mixture heated at 15O0C. for 2 hours in a sealed tube, gives good conversion rates (-50%) of terephthalic acid to 5-carboxyphthalide, the best conversion being achieved at a 60% of sulfur trioxide concentration. However, according to this method, 5-carboxy phthalide is not isolated because it is directly coverted in to methylester, and said conversion rate is calculated after esterifϊcation with methanol and determination of the 5-carboxy phthalide methyl ester thus obtained by gas chromatography.
US patent no 6403813 disclose processes for the preparation of 5-carboxy phthalide. , which comprises adding terephthalic acid to fuming sulfuric acid containing at least 20% of sulfur trioxide then adding formaldehyde to the mixture, heating the mixture at a temperature of 120-1450C and isolating 5- carboxyphthalide from the reaction mixture Reaction conditions like above is not suitable for the industrial scale because strong acidic conditions and highly corrosive,hygroscoρic nature of 20% sulfur trioxide handling is required.
US patent no 6458973 disclose processes for the preparation of 5-carboxy phthalide. , which comprises adding terephthalic acid to fuming sulfuric acid containing at least 20% of sulfur trioxide then adding 1,3,5-Trioxane to the
mixture, heating the mixture at a temperature of 120-1450C and isolating 5- carboxyphthalide from the reaction mixture
Reaction conditions like above is not suitable for the industrial scale because strong acidic conditions and highly corrosive,hygroscopic nature of 20% sulfur trioxide handling is required.
The antidepressant market is the largest segment of the total market for drugs to treat diseases in the central nervous system (CNS). In 2002, the antidepressant market accounted for 27% of the CNS market, and total antidepressant revenue worldwide was USD 17.1 billion in 2002. Measured by value, Citalopram market(USD 2.15 billion) increased by 30% from 2001 to 2002. (Source: IMS Health, IMS Dataview Q3 2003).
5-Carboxyphthalide is key intermediate of Citalopram and S-Citalopram. At present, no one is supplying commercial quantities. Current market size is -300 MT per annum of 5-Carboxyphthalide to produce required Citalopram and S- Citalopram..
Considering the importance of the drug Citalopram it is our intention to produce 5- Carboxyphthalide emfploying a simpler , cost effective, clean , having a neat reaction environmentally safe , easily controllable in process parameters and easy to scale-up for commercial production so that the important drug can be made available to the humanity at an affordable cost .
Therefore , the main objective of the present invention is to [provide an improved process for the preparation of 5-carboxy phthalide useful as an intermediate for the manufacture of Citalopram and S-Citalopram.
Another objective of the present invention is to provide an improved process for the preparation of 5-carboxy phthalide useful as an intermediate for the preparation of citlopram in high yields (>60% ) and high purity (>97%).
Yet another objective of the present invention is to provide an improved process for the preparation of 5-carboxy phthalide useful as an intermediate for the preparation of citlopram which is convenient , simple and economical
Still another objective of the present invention is to provide an improved process for the preparation of 5-carboxy phthalide useful as an intermediate for the preparation of citalopram which is safe and environmentally safe
Another objective of the present invention is to provide an improved process for the preparation of 5-carboxy phthalide useful as an intermediate for the preparation of citalopram in a one-pot procedure
Still another objective of the present invention is to provide an improved process for the preparation of 5-carboxy phthalide useful as an intermediate for the preparation of citalopram under easily controllable conditions, in an open and however not pressurized reactors and without any risk in handling the reaction mixtures.
Yet another objective of the present invention is to provide an improved process for the preparation of 5-carboxy phthalide useful as an intermediate for the preparation of citalopram which is industrially applicable
Accordingly the present invention provides an improved process for the preparation of 5-carboxy phthalide of the formula [A] given below
to Chloromethyl chlorosulphate of the formula [D]
O O CI— S— O CH2CI
and heating to a temperature in the range of 90 - 15O0C , cooling the reaction mixture to a temperature in the range of 20-25°C, adding water portion wise at a temperature in the range of 0-350C filtering , centrifuging the 5-Carboxy phthalide and washing the product with water to obtain 5-carboxyphthalide
According to a preferred embodiment of the invention, Chloromethyl chlorosulphate is used in an equimolecular amount in respect of terephthalic acid. Preferably the amount used may be in the range of 2.0-5.0 mol of CMCS/mol of terephthalic acid used .
The process may be carried out in practice by adding terephthalic acid to Chloromethyl chlorosulphate containing at least 90%, advantageously 95%, preferably 98% assay by titration and heated to a temperature in the range of 110-1300C, preferably at 120-13O0C for a period in the range of 3-4 hours.
The addition of water after cooling of the reactin , which produces exothermica, is preferably carried out at a temperature in the range of 30-350C . However, the control of the temperature may be limited to the initial period of the addition of 15- 25% of water, there after there is no exothermicity observed.
The reaction can be carried out using vacuum
The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the invention
EXAMPLE 1:
In a 2500-1 glass lined reactor, 250 Kg of Chloromethyl chlorosulphate charged under vacuum and good ventilation, under constant stirring, 200 Kg of terephthalic acid was added at a temperature of 330C . The reactor is heated to a temperature of t 1290C .for a period of 3 hours, Thereafter the mixture was cooled to 340CAt the end of this operation, 1250 Kg of water are added portionwise, whereby the temperature is maintained at 350C . by circulation of water through the glass lined reactor jacket of the reactor . The mixture is stirred for about 1 hour at a temperature of 330C, then the product formed was centrifuged , was well squeezed, abundantly washed with deionized water and dried to give 144 Kg .of 5-carboxyphthalide (HPLC) purity>97%. Yield 67% .
EXAMPLE 2:
In a 2500-1 glass lined reactor, 250 Kg of Chloromethyl chlorosulphate charged under constant stirring, 200 Kg of terephthalic acid was added at a temperature of 280C . The reactor is heated to a temperature oft 1280C .for a period of 3 hours, Thereafter the mixture was cooled to 350CAt the end of this operation, 1250 Kg
of water are added portionwise, whereby the temperature is maintained at 340C . by circulation of water through the glass lined reactor jacket of the reactor . The mixture is stirred for about 1 hour at a temperature of 390C, then the product formed was centrifuged , was well squeezed, abundantly washed with deionized water and dried under vacuum to give 142 Kg .of 5-carboxyphthalide (HPLC) purity>97%. Yield 66% .
EXAMPLE 3
In a 2500-1 glass lined reactor, 350 Kg of Chloromethyl chlorosulphate charged under constant stirring, 200 Kg of terephthalic acid was added at a temperature of 270C . The reactor is heated to a temperature oft 13O0C .for a period of 3 hours, Thereafter the mixture was cooled to 350CAt the end of this operation, 1850 Kg of water are added portionwise, whereby the temperature is maintained at 360C . by circulation of water through the glass lined reactor jacket of the reactor . The mixture is stirred for about 1 hour at a temperature of 350C, then the product formed was centrifuged , was well squeezed, abundantly washed with deionized water and dried to give 136 Kg .of 5-carboxyphthalide (HPLC) purity>96%. Yield 64% .
EXAMPLE 4
In a 2500-1 glass lined reactor, 450 Kg of Chloromethyl chlorosulphate charged under pressure ,constant stirring, 200 Kg of terephthalic acid was added at a temperature of 270C . The reactor is heated to a temperature oft 13O0C .for a period of 3 hours, Thereafter the mixture was cooled to 340CAt the end of this operation, 2250 Kg of water are added portionwise, whereby the temperature is maintained at 4O0C . by circulation of water through the glass lined reactor jacket of the reactor . The mixture is stirred for about 1 hour at a temperature of 380C, then the product formed was centrifuged , was well squeezed, abundantly washed with deionized water and dried in Tray drier to give 128 Kg .of 5-carboxyphthalide (HPLC) purity>94%. Yield 60% .
Advantages of the invention
• The process is simple and cost effective process.
• The process involves clean and neat reaction and having less pollution , thereby is a n environmentally safe .
• The reactions in the process are easily controllable in the industrial scale.
• The process produces 5 carboxy phthalate in a purity of 97% and yield of -65%.
• The process is applicable in an industrial scale
Claims
1. An improved process for the preparation of 5-carboxy phthalide of the formula [A] given below
useful as an intermediate for the preparation of citlopram having the formula B
to Chloromethyl chlorosulphate of the formula [D]
CI— S-O CH2CI
[D] and heating to a temperature in the range of 90 - 15O0C , cooling the reaction mixture to a temperature in the range of 20-250C, adding water portion wise at a temperature in the range of 0-35°C filtering , centrifuging the 5-Carboxy phthalide and washing the product with water to obtain 5-carboxyphthalide
2. An improved process as claimed in claim 1 wherein Chloromethyl chlorosulphate is used in an equimolecular amount in respect of terephthalic acid, preferably in the range of 2.0-5.0 mol of CMCS/mol of terephthalic acid used .
3. An improved process as claimed in claims 1 & 2 wherein the purity of Chloromethyl chlorosulphate CMCS used is of 98%., preferably 95%.
4. A process as claimed in claims 1 to 3 , wherein Terephthalic acid is added at a temperature of 20-400C.
5. A process as claimed in claims 1 to 4 wherein the reaction mixture is heated to a temperature in the range of 120 to 13O0C for a period in the range of 3-4 hours.
6. A process as claimed in claims 1 to 5 wherein the reaction mixture is heated under vacuum
7. A process as claimed in claims 1 to 5 wherein the process is carried out in a non-pressurized reactor
8. An improved process as claimed in claims 1 to 7 wherein the addition of water is carried out at a temperature in the range of 20 to 35 Deg C
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN182CHE2005 | 2005-02-28 | ||
| IN182CH2005 | 2005-02-28 |
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| Publication Number | Publication Date |
|---|---|
| WO2006090409A1 true WO2006090409A1 (en) | 2006-08-31 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/IN2005/000121 WO2006090409A1 (en) | 2005-02-28 | 2005-04-20 | An improved process for the preparation of 5 - carboxyphthalide |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3607884A (en) * | 1969-03-11 | 1971-09-21 | Mobil Oil Corp | Preparation of 5-carboxyphthalide in liquid sodium trioxide |
| GB1578989A (en) * | 1976-07-09 | 1980-11-12 | Basf Ag | Production of phthalide carboxylic acid-(5) |
| WO2001032643A1 (en) * | 1999-11-01 | 2001-05-10 | H. Lundbeck A/S | Method for the preparation of 5-carboxyphthalide |
| WO2001032642A1 (en) * | 1999-11-01 | 2001-05-10 | H. Lundbeck A/S | Method for the preparation of 5-carboxyphthalide |
| EP1118614A2 (en) * | 2000-01-18 | 2001-07-25 | Norpharma SpA | Process for the preparation of 5-carboxyphthalide |
| US6365747B1 (en) * | 1998-10-20 | 2002-04-02 | H. Lundbeck A/S | Method for the preparation of citalopram |
| WO2004083197A2 (en) * | 2003-03-21 | 2004-09-30 | H. Lundbeck A/S | Intermediates for the preparation of citalopram and escitalopram |
-
2005
- 2005-04-20 WO PCT/IN2005/000121 patent/WO2006090409A1/en not_active Application Discontinuation
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3607884A (en) * | 1969-03-11 | 1971-09-21 | Mobil Oil Corp | Preparation of 5-carboxyphthalide in liquid sodium trioxide |
| GB1578989A (en) * | 1976-07-09 | 1980-11-12 | Basf Ag | Production of phthalide carboxylic acid-(5) |
| US6365747B1 (en) * | 1998-10-20 | 2002-04-02 | H. Lundbeck A/S | Method for the preparation of citalopram |
| WO2001032643A1 (en) * | 1999-11-01 | 2001-05-10 | H. Lundbeck A/S | Method for the preparation of 5-carboxyphthalide |
| WO2001032642A1 (en) * | 1999-11-01 | 2001-05-10 | H. Lundbeck A/S | Method for the preparation of 5-carboxyphthalide |
| EP1118614A2 (en) * | 2000-01-18 | 2001-07-25 | Norpharma SpA | Process for the preparation of 5-carboxyphthalide |
| WO2004083197A2 (en) * | 2003-03-21 | 2004-09-30 | H. Lundbeck A/S | Intermediates for the preparation of citalopram and escitalopram |
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