KR20170048878A - New process for preparing Citalopram and Escitalopram - Google Patents
New process for preparing Citalopram and Escitalopram Download PDFInfo
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- KR20170048878A KR20170048878A KR1020150149519A KR20150149519A KR20170048878A KR 20170048878 A KR20170048878 A KR 20170048878A KR 1020150149519 A KR1020150149519 A KR 1020150149519A KR 20150149519 A KR20150149519 A KR 20150149519A KR 20170048878 A KR20170048878 A KR 20170048878A
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- 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
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Abstract
The present invention relates to a process for the preparation of citalopram which comprises the step of esterifying a compound of formula (3) with a compound of formula (4) to form a compound of formula (2) and cyclizing the compound in the presence of a base to form citalopram to provide:
[Chemical Formula 4]
(3)
(2)
Wherein X is a leaving group,
Y is selected from H or NO 2 , CF 3 , CN, and Cl.
Description
The present invention relates to a process for the production of 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile (S) - (+) - 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3 Dihydro-5-isobenzofurancarbonitrile (also known as escitalopram) and acid addition salts thereof:
[Chemical Formula 1]
[Formula 1a]
More specifically, the present invention provides a process for preparing citalopram or escitalopram through a novel ester intermediate compound.
Citalopram was first disclosed in U.S. Patent No. 4,136,193, and Esselatophilum was disclosed in U.S. Patent No. 4,943,590 (hereinafter referred to as 590 patent). Escitalopram is the active ingredient of the product citalopram, a racemic mixture of the R- and S-enantiomers, and is a valuable antidepressant of the selective serotonin reuptake inhibitor (SSRI) type. U.S. Patent No. 4,650,884 discloses a racemic diol which is cyclized in the presence of H 2 SO 4 to form citalopram represented by the following formula 1, namely 4- [4- (dimethylamino ) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) benzonitrile (see Scheme 1 below)
[Reaction Scheme 1]
590 patent discloses an enanthiomidiol compound represented by the following formula (3a), i.e., (S) - (-) - 4- (dimethylamino) -1- (4- fluorophenyl) Butyl] -3- (hydroxymethyl) -benzonitrile as a starting material to prepare escitalopram, a compound of formula (I). The process described in the '590 patent produces methanesulfonyl esters of formula 6 as intermediates which are readily degradable and are not isolated in the presence of a base but are directly cyclized to form escitalopram, Resulting in optical isomeric impurity formation in which the optical purity is reversed (Reaction Scheme 2 below): < RTI ID = 0.0 >
[Reaction Scheme 2]
Such prior art strategies include cyclization of the diol at high temperature under acidic conditions to give citalopram or derivatization with an ester derivative that is susceptible to degradation and cyclization in the presence of a base to give escitalopram Based. These conventional methods have the following disadvantages when increasing the size for industrial use:
The cyclization of the diol at elevated temperature under acidic conditions produces amides, acids, and by-products, leading to the formation of impure products.
The use of readily degradable esters which have been proven to produce escitalopram has the following problems. Firstly requires the use of a reactive reagent such as methane sulfonyl chloride, which can produce bismatesylate and thus cause the formation of undesirable impurities.
A second organic base such as triethylamine or pyridine is used as the proton eliminator and the undesirable decomposable ester of the tertiary alcohol group formed under the reaction conditions proceeds in an inconsistent manner leading to chirality disruption and impurity formation do.
Thirdly, it is sensitive to moisture and temperature and is easily decomposed. There is therefore a need for a more convenient and industrially available process for effectively producing citalopram and escitalopram.
According to WO 2006/021971 (hereinafter referred to as Patent No. 971), an enantiomeric diol compound of the formula (3a), namely (S) - (-) - 4- (dimethylamino) -1 - (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) -benzonitrile was reacted with 2,5-dichloronobenzene (Dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (2 -Nitro-4-chlorophenoxymethyl) -benzonitrile to prepare escitalopram (Reaction Scheme 3): < EMI ID =
[Reaction Scheme 3]
In the case of using the novel ether compound of the formula (7) of the '971 patent, the problem of chirality disarray due to the action of the unstable ester of the conventional 590 patent is overcome. However, in the production of the ether compound of the formula (7), potassium tertiary butoxide A long reaction time of 10 to 15 hours is required in the presence of a strong base. In this condition, it is difficult to suppress the progress of the subsequent intramolecular cyclization reaction. In order to prepare the ether compound of formula (7) in high purity, purification by column chromatography And noneconomical methods are used, for example, and there is a limit in industrial application.
The present invention relates to a process for producing citalopram and escitalopram in high purity and high yield by producing an ester derivative as an intermediate and cyclizing it to solve the disadvantages of the known technologies.
The present invention is intended to provide a production method most suitable for mass production and industrialization with remarkably shortened reaction time than the prior art.
The present invention
Esterifying a compound of formula (3) with a compound of formula (4) to form a compound of formula (2);
CLAIMS 1. A process for preparing a compound of formula (I), comprising cyclizing a compound of formula (2) in the presence of a base to form a compound of formula
To a process for preparing a compound represented by the formula (1).
[Chemical Formula 4]
(3)
(2)
[Chemical Formula 1]
Wherein X is a leaving group,
Y is selected from H or NO 2 , CF 3 , CN, and Cl.
The present invention also relates to novel intermediates represented by the above formula (2) or acid addition salts thereof.
The present invention also relates to a novel intermediate or a hydrochloride salt thereof represented by the following formula (5).
[Chemical Formula 5]
As described above, in the present invention, it is preferable to use 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- Methyl) benzonitrile as a starting material and via a novel intermediate compound represented by the general formula (2), the disadvantages of the conventional route through the unstable ester and ether type intermediates are drastically improved, Propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzofurancarbonitrile represented by the following formula:
In particular, in the present invention, the novel ester compound represented by the general formula (5), which is an intermediate in the preparation of escitalopram of enantiomer of citalopram, can be prepared by reacting the conventional easily degradable ester intermediate of formula (6) It is possible to inhibit the formation of unwanted escitalopram through the intramolecular cyclization reaction as compared with the compound, so that the ester compound represented by the general formula (5) can be isolated with high purity and high yield, The convenience can be guaranteed.
Further, in the synthesis of the ester compound represented by the general formula (5), the conventional ether compound requires a long reaction time of 10 to 15 hours, whereas the reaction can be completed in a short reaction time of 1 to 2 hours, Which leads to a reduction in the manufacturing cost, and ultimately, the production of escitalopram via the ester compound of the formula (5) is an economical and industrially improved production method as compared with the prior art.
Accordingly, the present invention is advantageous in that citalopram or escitalopram can be obtained in a high purity and a high yield in a short time on the entire process, making it the most suitable production method for mass production and industrialization.
The reaction according to the present invention will be described in more detail as follows.
By reacting the compound of formula (3) and the compound of formula (4) in the presence of a base, the compound of formula (2) can be obtained in the form of an acid addition salt.
Preferred examples of the compound represented by the formula (4)
The acid addition salts of the compounds of formula (2) can be prepared by reacting an acid such as an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like or a salt form of organic acid such as oxalic acid, citric acid, cinnamic acid, p-toluenesulfonic acid and the like to be.
The base used may be selected from alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or amine bases. The amine base may be selected from aliphatic or aromatic amines, cyclic or acyclic amines.
The acid addition salts of the novel intermediate compounds of formula (2) can be converted to the free base by treatment with a base and then cyclized to form citalopram or escitalopram.
The cyclization reaction may be carried out in any suitable solvent. Examples of solvents that can be used include bipolar aprotic solvents such as dimethyl sulfoxide; Ketone solvents such as methyl isobutyl ketone; Ether solvents such as dioxane; Ester solvents such as ethyl acetate and butyl acetate; Amide solvents such as dimethylformamide and dimethylacetamide; It is a nitrile solvent such as acetonitrile.
The reaction may be carried out in a suitable solvent with the base at a temperature ranging from ambient temperature to the reflux temperature of the selected solvent. The reaction may be terminated in 0.5 to 10 hours, preferably 0.5 to 3 hours, depending on the solvent and base selected.
The base used in converting the acid part of the compound of formula (2) into a free base and the base used in the cyclization reaction may be selected from alkali or alkaline earth metal hydroxides, carbonates or bicarbonates or amine bases. The amine base may be selected from aliphatic or aromatic amines, cyclic or acyclic amines.
The present invention will now be described in more detail with reference to the following examples, but the present invention is not limited thereto.
Example 1. (S) - (-) - 4- [4- ( Dimethylamino ) -1- (4- Fluorophenyl )-One- Hydroxy -1-butyl] -3- (4- Nitrobenzoyloxymethyl ) - Benzonitrile Of hydrochloride synthesis
(S) - (-) - 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) 186.71 mmol) was dissolved in 400 mL of methylene chloride, and 65 mL of triethylamine was injected. A mixed solution of 4-nitrobenzoyl chloride (224.05 mmol) and methylene chloride (100 mL) was slowly poured into the reaction at 30 ° C or lower, followed by stirring at room temperature for 2 hours. 600 mL of an aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by stirring to separate the layers. The separated organic layer was concentrated and 400 mL of acetone was added to dissolve the solution. The solution was cooled, and then 35% hydrochloric acid was injected to obtain (S) -4- [4- (dimethylamino) -1- Phenyl) -1-hydroxy-1-butyl] -3- (4-nitrobenzoyloxymethyl) -benzonitrile hydrochloride (yield: 91%).
Example 2. (S) - (-) - 4- [4- ( Dimethylamino ) -1- (4- Fluorophenyl )-One- Hydroxy -1-butyl] -3- (4- Chlorobenzoyloxymethyl ) - Benzonitrile Of hydrochloride synthesis
(S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] - Obtained the hydrochloride of 3- (4-chlorobenzoyloxymethyl) -benzonitrile (Yield: 80%).
Example 3. (S) - (-) - 4- [4- ( Dimethylamino ) -1- (4- Fluorophenyl )-One- Hydroxy -1-butyl] -3- (4- Cyanobenzoyloxymethyl ) - Benzonitrile Of hydrochloride synthesis
(S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] piperidine was obtained in the same manner as in Example 1, -3- (4-nitrobenzoyloxymethyl) -benzonitrile hydrochloride (yield: 77%).
Example 4. (S) - (-) - 4- [4- ( Dimethylamino ) -1- (4- Fluorophenyl )-One- Hydroxy -1-butyl] -3- (4- Trifluoromethylbenzoyloxymethyl ) - Benzonitrile Of hydrochloride synthesis
(S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-tert- butoxycarbonylamino- Butyl] -3- (4-nitrobenzoyloxymethyl) -benzonitrile hydrochloride (yield: 73%).
Example 5. (S) - (+) - 1- [3- ( dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isopropyl-benzofuran Synthesis of carbonitrile
(S) -4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- Chloride (164.78 mmol), 445 mL of ethyl acetate was poured, 890 mL of an aqueous solution of sodium hydrogen carbonate was poured, and the mixture was stirred to effect layer separation. The separated organic layer was concentrated, 250 mL of dimethylsulfoxide was injected and dissolved, and the temperature was raised to 90 캜. 48.93 g of potassium carbonate was added to the reaction mixture, followed by stirring at 100 DEG C for 2 hours. The reaction mixture was cooled to 20 DEG C, and then 330 mL of ethyl acetate and 745 mL of an aqueous sodium hydroxide solution were poured into the flask and stirred to effect layer separation. The separated organic layers were combined, washed with brine, and concentrated. To the concentrate residue was added oxalic acid to obtain (S) - (+) - 1- [3- (dimethylamino) propyl] -1- (4- fluorophenyl) -1,3-dihydro- Isobenzofurancarbonitrile oxalate (yield: 82%).
Comparative Example 1 Synthesis of ( S) - (+) - 1- [3- ( dimethylamino ) propyl] -1- (4- fluorophenyl ) -1,3- dahydroido -5 -isobenzofuran Synthesis of Carbonitrile 1
(S) - (-) - 4- [4- (dimethylamino) -1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (hydroxymethyl) 373.43 mmol) was dissolved in 600 mL of methylene chloride, and 156 mL of triethylamine was introduced. The reaction product is cooled to 5 DEG C or lower, 51.32 g of methanesulfonyl chloride is added dropwise at 5 DEG C or lower, and the mixture is stirred at 5 DEG C for 2 hours. 1000 mL of purified water is poured into the reaction mixture, followed by stirring to separate the layers. The separated organic layer was concentrated, and then an oxalic acid dihydrate was added thereto to obtain (S) - (+) - 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -Dihydro-5-isobenzofurancarbonitrile oxalate is obtained (yield: 65%).
Comparative Example 2. (S) - (+) - 1- [3- ( dimethylamino) propyl] -1- (4-fluorophenyl) -1, 3 is less than or equal to the draw-5-isopropyl-benzofuran Synthesis of carbonitrile 2
To a solution of (S) - (-) - 4- [4- (dimethylamino) -1- (4- fluorophenyl) -1- [hydroxy- Oxomethyl) -benzonitrile (16.35 mmol) in 10 ml of tetrahydrofuran was added 2.02 g of potassium tert-butoxide at 5 < 0 > C and stirred for 10 minutes. 3.14 g of 2,5-dichloronitrobenzene was added to the reaction at 5 DEG C and stirred at room temperature for 15 hours, the solvent was evaporated in vacuo, 40 ml of water was added, extracted with toluene and the toluene layer was washed with water And 10% sodium hydroxide solution and distilled to give an oily product which is purified by column chromatography on silica gel and ethyl acetate. The oily product was dissolved in isopropanol (IPA) at 30 ° C and then 2.0 ml of IPA-HCl was added, stirred, and the solvent was evaporated under vacuum and crystallized in IPA to give (S) - (- 1- (4-fluorophenyl) -1-hydroxy-1-butyl] -3- (2-nitro-4-chlorophenoxymethyl) -benzonitrile hydrochloride . To a solution of (S) - (-) - 4- [4- (dimethylamino) -1- (4- fluorophenyl) -1- To a solution of 4-chlorophenoxymethyl) -benzonitrile hydrochloride (15.06 mmol) was added 2.71 g of potassium carbonate and stirred for 30 minutes at 100 < 0 > C. (S) - (+) - 1- [3- (dimethylamino) propyl] - (3-methylpiperidin-4- ylmethyl) L- (4-fluorophenyl) -l, 3-dihydro-5-isobenzofurancarbonitrile oxalate. (Yield: 64%).
The following Table 1 compares the escitalophor oxalate prepared according to the method of the prior art using the methane sulfonyl ester derivative and the ether derivative and the method of Example 5:
In Comparative Example No. 1 of the above table, chiral purity was lowered due to the undesirable esterification reaction of the tertiary alcohol group of the methanesulfonyl ester intermediate represented by Chemical Formula 6, resulting in chiral chaos. (R -Isomer: 1.80%).
In Comparative Example 2, escitalopram was synthesized via the aryl ether intermediate represented by the above formula (7). As a result, the chiral disturbance was somewhat reduced (R-isomer: 0.15%), (Purity: 98.5%) was observed due to the use of butoxy potassium and the long reaction time of 15 hours.
On the other hand, in the case of Example 5, using the aryl ester intermediate represented by Chemical Formula 5, the reaction was carried out under mild reaction conditions using potassium carbonate and a high-purity eschar cigarette having a remarkably reduced chirality disarray (Purity: 99.5%, R-isomer: 0.03%).
Claims (4)
b) cyclizing the compound of formula 2 in the presence of a base to form a compound of formula 1 < RTI ID = 0.0 >
Method for preparing compound of formula (1)
[Chemical Formula 4]
(3)
(2)
[Chemical Formula 1]
Wherein X is a leaving group,
Y is selected from H or NO 2 , CF 3 , CN, and Cl.
(2)
In the above formula, X is a leaving group
Y is selected from H or NO 2 , CF 3 , CN, and Cl.
[Chemical Formula 5]
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020060011A1 (en) * | 2018-09-17 | 2020-03-26 | (주)유케이케미팜 | Novel preparation method for citalopram and escitalopram using carbonates |
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| ES2228274B1 (en) * | 2003-09-24 | 2006-06-01 | Astur Pharma, S.A. | CHEMIOENZYMATIC SYNTHESIS OF (+) - CITALOPRAM AND (-) - CITALOPRAM. |
| EP2141156A1 (en) | 2004-08-23 | 2010-01-06 | Sun Pharma Global FZE | Process for Preparation of Citalopram and Enantiomers |
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| WO2020060011A1 (en) * | 2018-09-17 | 2020-03-26 | (주)유케이케미팜 | Novel preparation method for citalopram and escitalopram using carbonates |
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