ITMI991486A1 - PROCESS FOR THE SYNTHESIS OF CITALOPRAM - Google Patents

Description

Patent application for industrial invention entitled:

"Process for the synthesis of citalopram"

FIELD OF THE INVENTION

The present invention is placed in the field of synthesis of derivatives with 1, 3-dihydroisobenzofuranic structure (phthalanes). An efficient process for the synthesis of 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1, 3-dihydro-5-isobenzofuranocarbonitrile (citalopram) is described.

FRONT TECHNIQUE

111 - [3- (dimethylamino) propyl] -1 - (4-fluorophenyl) -1, 3-dihydro-5-isobenzofuranocarbonitrile (citalopram) was first described in GB-A-1 526 331. This compound is a centrally acting serotonin reuptake inhibitor with marked antidepressant activity (Progr.Neuro-Psychopharmacol. & Biol.Psychiatr., 1982, 6, 277-295). In addition to antidepressant therapy, citalopram is used in the treatment of dementia and cerebrovascular disorders (EP-A-474580). Optically active enantiomers of citalopram have been described for the treatment of obesity and alcoholism.

The structure of citalopram is illustrated with (IV) in figure 2.

The synthetic approach most followed in the synthesis of citalopram is described in Figure 1 in which a phialide (A) is condensed with a reagent that carries a fluorophenyl group and with a reagent that carries a dimethiaminopropyl group; these condensations, normally carried out with Grinard reagents, are followed by the opening of the furan ring with the formation of the diol (B); from it the furan ring is restored by dehydration. The R group is a nitrile or a precursor group thereof which can be converted into nitrile by cyanination. The resulting product (C) [R = CN] is citalopram.

There are several works that follow the aforementioned synthetic approach. For example, the patent GB-A-1526 331 describes a synthesis process of citalopram in which the derivative (A) in which R = Br is converted into (B) by reaction with Grignard reagents. This is followed by dehydration with concentrated phosphoric acid with formation of the product (C), and the subsequent conversion of the Br group into CN by treatment with cuprous cyanide in dimethylformamide at reflux. In a variant of the process, initially only one of the two condensations is carried out, a reduction of the intermediate thus obtained is carried out, the ring is closed by dehydration, the Br group is converted into CN and finally the second alkylation is carried out, obtaining similarly citalopram.

These reactions involve rather low yields (of the order of 22%) as well as the use of cuprous cyanide (a toxic compound that requires considerable precautions of use) under drastic reaction conditions. The cyanination reaction involves wastewater that is difficult to dispose of due to the presence of heavy metals and cyanides themselves. The procedure is also very laborious since many washes of the organic reaction phase have to be carried out to obtain a product of acceptable quality. IN EP-A-171943 the above described scheme is proposed again, using as product (A) a 5-cyanophthalide, (R = CN); in this case the cuprous cyanide is used to obtain the product (A).

In another synthesis (WO-A-9819512) the substituent R in (A) is a primary amino group: the conversion of the amine into the CN group is obtained by diazotation followed by reaction with cyanides.

In WO-A-98-19513 the synthesis scheme described above is proposed again starting from a compound (A) in which R = alkoxycarbonyl. Although in this case the conversion of the R group into nitrile does not require the use of cyanides, it nevertheless involves a long series of reactions such as hydrolysis, formation of acyl halide, conversion into amine and dehydration, in order to transform the R group into the cyan.

The aforementioned reactions have the further disadvantage of starting from phthalides which have a high market cost, which negatively affects the general economy of these processes.

In view of the limitations set forth, none of the syntheses available up to now is totally satisfactory and therefore the need for efficient and low environmental impact processes for the synthesis of citalopram is still felt.

SUMMARY

A new process is described for the synthesis of citalopram characterized by the conversion of 1- (4'-fluorophenyl) 1-3- (di-methylaminopropyl) -5-bromophthalane into the corresponding 5-phthalan-aldehyde; the aldehyde is then reacted with a suitable hydroxylamine or hydrazine, and the product obtained is converted into citalopram. The process described allows to obtain citalopram in high yields, and does not involve the use of highly toxic reactants such as cuprous cyanide.

DESCRIPTION OF THE FIGURES

Figure 1: known synthesis scheme of citalopram

Figure 2: synthesis of citalopram starting from 1- (4'-fluorophenyl) -1- (3-dimethylaminopropyl) -5-bromophtha-lane (I)

Figure 3: synthesis of citalopram starting from terephthalic acid (VI)

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is a synthesis process of citalopram characterized by the following phases:

(i) conversion of 1- (4'-fluorophenyl) -1- (3-dimethylaminopropyl) -5-bromophthalane (I) into 1- (4'-fluorophenyl) 1-3- (dimethylaminopropyl) -5-phthalanaldehyde ( 11)

(ii) reaction of compound (II) with a reagent of NH2-X structure, where X is selected from -OH, -OCH3, -N (CH3) 2, -0S03H, with the formation of a compound of formula (III), where X has the above meanings.

(iii) conversion of compound (III) to citalopram (IV).

This process is illustrated in Figure 2:

The different steps of this process are detailed below.

Step (s)

The second step (i) of the process object of the invention consists in the conversion of 1 - (4'-fluorophenyl) -1 - (3-dimethylaminopropyl) -5-bromophthalane (I) into the corresponding 5-phthalanaldehyde (II)

step (i) first of all requires the reaction of compound (I) with activated magnesium, obtaining the corresponding Grignard reagent;

the Grignard reagent obtained has a structure corresponding to compound (I), in which the -Br in position 5 has been replaced by a -MgBr group.

The reaction mixture containing Grignard's reagent is then reacted with a substituted formamide, thus obtaining 5-phthalanaldehyde (II).

The compound (I) used in the present process is easily synthesized, such as e.g. described in GB-A-1 526331.

The activated magnesium to be used in this phase of the process can be obtained with conventional techniques, for example by reaction of metal magnesium in shavings with bromoethane in an ethereal solvent such as ethyl ether, tetrahydrofuran or 2-methyltetrahydrofuran, possibly in a mixture with toluene or similar solvents, at a temperature between 25 ° C and the reflux temperature of the mixture.

According to a preferred embodiment of the process in question, a solution of compound (I) in an organic solvent, for example tetrahydrofuran, is slowly added to the mixture of solvent and activated magnesium thus obtained (hereinafter referred to as "solution a"). (hereinafter referred to as "solution b") The temperature of the reaction mixture is preferably maintained between 40 ° C and 65 ° C.

In order to obtain high yields of the desired product, the following reaction conditions were particularly important:

Compound (I) is used in a weight ratio with respect to magnesium comprised between 5: 1 and 15: 1, preferably 7.5: 1;

■ the concentration of compound (I) in solution b is between 0.7M and 1.2M, preferably 1M;

■ the volume of solution a is between 40% and 60%, preferably 50%, with respect to the volume of solution b.

■ the time within which solution b is added is greater than 5 hours, and is preferably between 6 and 8 hours.

At this point, the Grignard reagent obtained is reacted with a substituted formamide, thus obtaining the compound (II)

The substituted formamides useful for the purposes of the present process are dimethylformamide, dipropylformamide, dibutylformamide, N-formyl-N-methyl-2-aminopyridine, trimethylformyl-ethylenediamine, N-formylpiperidine, N-formylmorpholine. Preferred is dimethylformamide.

The substituted formamide is used in a molar ratio of about 2: 1 with respect to compound (I). The temperature of the reaction mixture is between - 20 ° C and the reflux temperature, preferably between 15 ° C and 50 ° C, or more preferably between 20 ° C and 25 ° C.

The addition time is generally between 2 and 4 hours; preferably, after the addition, the mixture is left under stirring at room temperature for a further time equal to about 1-3 hours.

At the end are added toluene, water and possibly acid, for example glacial acetic acid. The aldehyde (II) is recovered from the reaction mixture by means of suitable washing.

The reaction conditions described above, in particular those relating to the use of solutions a and b, allow to minimize the formation of reaction by-products, in particular those obtained by etching the Grignard reagent on the acid sites in position 3 of the phthalane: competitiveness of these sites with respect to organometallic reagents is known for example from GB-A-1526331. All the reactions included in step (i) can be conveniently carried out in the same reactor, without the need to purify the intermediate products.

As for the aldehyde (II) obtained at the end of step (i), this can be purified before being subjected to the next step (ii). This purification is carried out with techniques known per se, such as those described in Org.Synth. 1955, Vol. 3, 701.

Aldehyde (II) as a product as such constitutes a further object of the present invention as it is a key intermediate of the process described here, which allows to obtain citalopram in high yields and without the use of highly toxic reagents such as cuprous cyanide. The simplicity and high yield of the aldehyde purification process further contribute to the efficiency of the process. The purification and analytical characterization of this product are described in the experimental part.

Step (ii)

In step (ii), the aldehyde (II) is reacted with the NH2-X compound (hydroxylamine or hydrazine), with the formation of compound (III) (oxime or hydrazone respectively). the specific meanings of X have been previously indicated.

Step (ii) takes place according to methods known per se (eg J. March, Advanced Organic Chemistry, IV ed., 1992, 367). The reaction takes place in a suitable organic such as for example toluene, dimethylacetamide, dimethylformamide, at a temperature between 20 ° C and the reflux temperature of the mixture, preferably between 20 ° C and 65 ° C. The reaction pH must be no less than 4: any pH greater than or equal to 4 is indifferently effective.

The molar ratios between the compound (II) and the NH2-X compound used in this reaction are comprised between 1: 1 and 3: 1, preferably being equal to about 2: 1.

The oxime (or hydrazone) (III) can possibly be purified before being subjected to the next step of the process: for example when using the NH2-X compound where X is -0S03H (hydroxylamine sulphonic), the purification takes place by extraction of the same in an aqueous alkaline environment.

Passage (III)

The second step (iii) of the process object of the invention consists in the conversion of the oxime (or hydrazone) of formula (III), into the corresponding cyanoderivative (IV), which is citalopram.

When starting from an oxime, the conversion is carried out by reaction with a concentrated acid or anhydride; preferred examples are concentrated acetic acid and acetic anhydride. The reaction is carried out at a temperature between 50 ° C and the reflux temperature in an organic solvent environment such as toluene. The molar ratios between the compound (II) and the acid are between 1: 1 and 1: 2.5.

When starting from a hydrazone, the conversion is carried out by catalyzed oxidation with techniques per se known, as described for example in Chem.Commun., 19, 2145-6, 1998, or Synthetic Commuti., 28, 24, 4577- 80, 1998. Examples of reactants used in the oxidation of hydrazone are methylrenium trioxide and hydrogen peroxide.

Citalopram is obtained in the form of oil, from which the pure product is easily crystallized, for example by dissolution in isopropanol and crystallization from it.

The ease of crystallization of the citalopram obtained in accordance with the present process constitutes a further advantageous element of the present invention.

The present invention relates to a further production process of citalopram. Similarly to the process described above, this variant involves the formation of aldehyde (II) and its conversion into citalopram according to steps (ii) and (iii) described above. According to this particular embodiment of the invention, however, the aldehyde (II) is not obtained starting from bromophthalane (I), but from a compound of formula (VI) (terephthalic acid) as illustrated in Figure 3, in which the steps ( g) and (h) correspond to the steps (ii) and (iii) described above.

The steps (a) - (h) of the process are described as follows:

(a) conversion of terephthalic acid (VI) into 5-phthalanecarboxylic acid (VII);

(b) halogenation of 5-phthalanecarboxylic acid (VII), with the formation of the corresponding acyl chloride (VIII);

(c) reduction of chloride (VIII), with the formation of 5-phthalanaldehyde (IX); (d) protection of 5-phthalanaldehyde by reaction with alcohols or glycols. (e) treatment of the protected 5-phthalanaldehyde (X) with suitable Grignard reagents, obtaining the alkylarylderivate (XI);

(f) deprotection and cyclization of the alkylaryl derivative (XI) in an acidic environment, with the formation of the corresponding cyclized aldehyde (II);

(g) reaction of aldehyde (II) with a reagent of NH2-X structure, where X is selected from -OH, -OCH3, -N (CH3) 2, -0S03H, with the formation of a compound of formula (III) , where X has the above meanings;

(h) conversion of compound (III) to citalopram (IV).

The synthetic scheme represented in figure 3 allows to obtain citalopram in high yields starting from terephthalic acid (VI), a product with great commercial availability and very low cost, moreover, the alkylaryl derivative (XI) does not require isolation, but is directly treatable with acids in accordance with step (f): these aspects of the process, in addition to the high yields found, help to create an effective, convenient and highly applicable process on an industrial scale.

The invention is now illustrated by means of the following experimental examples, which do not have a limiting function.

EXPERIMENTAL PART

1. Preparation of 1- (4'fuorofenyl-1-1 (3-dimethylaminopropyl) -5-phthalanaldelde

Synthesis of 1- (4'fluorophenyl) -1- (3-dimethiaminopropyl) -5-bromophthalane Grignard's reagent

In an inert atmosphere and under vigorous stirring, a suspension of 150 g (6.17 moles) of magnesium shavings in 1500 ml of tetrahydrofuran, is added at a temperature of 30-35X of 15 ml (21.9 g; 0.20 moles) of bromoethane. Once the magnesium has been activated, detected by spontaneous exothermic and foaming of the reaction mixture, at a temperature of 55 ° C an approximately 1 molar solution of 1125 g (2.98 moles) of 1- (4'-fluorophenyl) -1 begins to percolate. - (3-dimethylaminopropyl) -5-bromophthalane in 3000 ml of tetrahydrofuran in a time of 7 hours. The reaction mixture is spontaneously refluxed throughout the addition. The mixture containing the Grignard reagent thus obtained is used in the subsequent phase of the synthesis, after cooling to a temperature of about 20 ° C.

Formylation of the Grignard reagent of 1- (4'fluorophenyl) -1- (3-dimethylaminopmpil) -5-bromophthalane

The solution of Grignard's reagent previously prepared in tetrahydrofuran is added dropwise over 3 hours to 455 ml (430 g; 5.96 moles) of dimethylformamide. The temperature is maintained between 20 and 25 ° C. After the addition is completed, the reaction mixture is left under stirring at room temperature for about 3 hours. The mixture is then quenched with 4500 ml of toluene and 4500 ml of water, percolated in about 1 hour. A volume of 240 ml of glacial acetic acid is then added to the reaction mixture again, slowly and under continuous stirring. The heterogeneous mixture is heated to a temperature of about 55-60 ° C to allow a correct separation of the phases.

The organic phase is separated from the underlying aqueous phase at a temperature of 60 ° CC, and further washed with 3 aliquots of 1500 ml each of water. The toluene solution with a volume of about 5 liters containing about 1200 g of raw 1- (4’fluorophenyl) -1-1 (3-dimethylaminopropyl) -5-phthalanaldehyde, is used in the next phase of the process. An aliquot is taken and titrated by HPLC against an external standard for the determination of the yield (molar yield: 83%).

2. Purification of 1- (4'-fluorophenyl) -1-1 (3-dimethylaminopropyl) -5-phthalanaldelde (by forming a bisulfite adduct).

The previous toluene solution containing about 1200 g crude 1- (4'-fluorophenyl) -1 -1 (3-dimethylaminopropyl) -5-phthalanaldehyde, is added under vigorous stirring of an aqueous solution of 793 g (4.17 moles) of sodium metabisulphite in 1500 ml of water. The pH of the resulting aqueous phase is between 5 and 6 and is corrected between 4.5 and 5 by adding 450 ml of glacial acetic acid. The mixture is kept under vigorous stirring for about an hour and a half.

At the end of this phase the pH is corrected to values between 6.5 and 7 with 290 ml of aqueous sodium hydrate at 30%. The reaction mixture is left under vigorous stirring for about 15 minutes, at a temperature of 40 ° C. The stirring is then stopped and the phases are allowed to settle. The toluene phase is separated from the aqueous one, and discarded. The underlying aqueous phase is diluted with 4000 ml of water and further extracted with 5 aliquots of 1000 ml of toluene. At each extraction it is checked that the pH is between 6.5 and 7, otherwise it is corrected with aqueous sodium hydrate at 30%. Each single washing and separation of the phases is carried out at 40 ° C.

The aqueous phase thus obtained at the end of this cycle of extractions, is then corrected to a pH of not less than 9 with 700 ml of aqueous sodium hydrate at 10%, maintaining the temperature between 20 ° C and 30 ° C. 2000 ml of toluene are then added and the mixture obtained is stirred vigorously for at least 30 minutes. After this period it is checked that the pH of the aqueous phase is higher than 9, otherwise it is further corrected with 10% aqueous sodium hydrate. The aqueous phase is separated from the organic one and re-extracted twice with aliquots of 1000 ml each of toluene. Each extraction and separation of the phases is carried out at temperatures not lower than 40 ° C. The combined organic phases have a volume of approximately 4000 ml. A 50 ml aliquot of the organic phase is concentrated under reduced pressure, obtaining, after removal of the solvent, a dry residue equal to 23% by weight, consisting of a single pure product with ionization profile at mass spectrometry and with a spectrum <1> H -NMR according to the structure of 1- (4'-fluorophenyl) -1-1 (3-dimethylaminopropyl) -5-phthalanaldehyde.

The organic solution at the end of this phase of the synthesis containing 730 g of the pure product (80% molar yield from bromophthalane) is used without further purification in the subsequent phase of the synthesis.

’H-NMR in CDCL3 δ 9.97 (1H; s; 5-COH), from 7.80 to 6.94 (7H; m; aromatic protons); 5.20 (1H; d; J = 12.2; 3-Ha), 5.10 (1H; d; J = 12.2; 3-Hb); from 2.25 to 2.13 (2H; m; 3-CH2N); 2.11 (6H; s; NCH3); from 1.50 to 1.31 (4H; m; 1'-e 2'-CH2)

m / z ie 328 (MH) <+>; 298 (M-CHO) <+>; 241 (M-CH2CH2CH2 (NCH3) 2) <+>; 213 (m / z = 298-CH2CH2CH2 (NCH3) 2) <+>; 193 (m / z = 213-HF) <+>.

3. Preparation of oxime of 1- (4 <,> fiuorophenyl) -1> (dimethylaniniinoprop] 1) -5-phthalanaldehyde

The above toluene solution containing 200 g (0.61 moles) of 1- (4'-fluorophenyl) -1-1 (3-dimethylaminopropyl) -5-formyl phthalane pure, is added with 60 g (0.37 moles) of hydroxylamine sulfate. The mixture is heated to reflux and the pH is corrected to values between 4 and 5 with 70 ml of glacial acetic acid. After an hour of heating it cools down. A 10 ml aliquot of the aqueous phase is basified at a pH higher than about 9 with 10% soda and extracted with 10 ml of toluene. This small-volume concentrated toluene phase is analyzed by mass spectrometry providing an electron impact fragmentation and a 1H-NMR spectrum both in agreement with the oxime structure of 1- (4'-fluorophenyl) -1- (3-dimethylaminopropyl ) -5-phthalanaldehyde. The product has a purity of! 76%.

The organic phase of the reaction mixture is separated from the aqueous one and eliminated. The aqueous phase containing 202 g of pure product (molar yield; 97%) is used without further purification in the subsequent phase of the synthesis.

'H-NMR in CDCL3 δ 8.05 (1H; s; 5-CHNOH), from 7.51 to 6.94 (7H; m; aromatic protons), 5.16 (1H; d; J = 12.0, 3-Ηa), 5.13 (1H; d; J-12.0; 3-Hb), from 2.41 to 2.29 (2H; m; 3-CH2N); 2.23 (6H; s; NCH3); from 1.55 to 1.30 (4H; m; 1'- and 2'-CH2

m / z the 342 (M) <+>; 324 (M-H20) <+>; 256 (M-CH2CH2CH2 (NCH3) 2r; 239 (m / z = 256-OH) <+>.

4. Synthesis of 1 - (4'-fluorophenyl) -1 - (3-dimethylaminopropyl) -5 ftanancarbo-nitrile

To the above aqueous solution at pH 5 containing 200 g (0.59 moles) of oxime of 1- (4'fluorophenyl) -1- (3-dimethylaminopropyl) -5-phthalanaldehyde pure, 600 ml of toluene and 110 ml (120 g; 1.18 moles) of acetic anhydride. It is heated under reflux, observing contained foaming for not less than 3 hours. At the end of the reaction the mixture is allowed to cool down to a temperature of about 85 ° C and a volume of 200 ml of water is carefully percolated. At the end of the addition, the reaction mixture is allowed to cool spontaneously and then a solution of 460 ml of 30% sodium hydrate is added under vigorous stirring to a pH of 9-10. The organic phase is then washed with two aliquots of 200 ml each of water at a temperature of about 60 ° C. The organic phase is concentrated to a small volume at reduced pressure, obtaining a slowly solidifying oil weighing 253 g with anhydro-pontentiometric titre of 70%.

The oil obtained, equal to 250 g, is taken up with 750 ml of isopropanol and crystallized from this solvent to obtain the product, with a melting point of 93 ° C.

’H-NMR in CDCL3 δ 7.60 (1H; s; 4-H), from 7.52 to 6.98 (6H; m; aromatic protons); 5.25 (1H; d; J = 12.9 3-Ha), 5.15 (1H; d; J = 12.9; 3-Hb), 3.08 (2H; t; J = 7.5; 3'-CH2), 2.71 (6H; s ; NCH3, from 2.49 to 2.27 (2H; m; 1'-CH2), from 1.82 to 1.71 (2H; m; 2'-CH2)

m / z ie 324 (M) <+>; 238 (M-CH2CH2CH2 (NCH3) 2) <+>; 218 (m / z = 238-HFr. 5 Preparation of 1- (4fuorofenlty-1-1 (-dimethylaminopropyl) -Sphthalanaldehyde by reaction with butyllithium (Comparative example) To a solution of 40.5 g (0.107 mol) of 1- ( 4'fluorophenyl) -1- (3-dimethylaminopropyl) -5-bromophthalane in 135 ml of THF is percolated under vigorous stirring at a temperature between -3 ° C and 3 ° C a solution of 40 ml (0.108 moles) in heptane 2.7 molar butyllithium At the end of the addition, the reaction mixture is left under stirring at a temperature of 0-5 ° C for about one hour before percolating 8.5 ml (0.111 moles) of dimethylformamide.

The addition of dimethylformamide is strongly exothermic, the temperature must be maintained between 0 ° and 5 ° C throughout the addition. The reaction mixture is then stirred at a temperature of 5 ° C for about 30 minutes and then the temperature is allowed to rise spontaneously. When carrying out the first process control by gas chromatography after 30 minutes, the raw mixture contains about 4% of the phthalanaldehyde (II), 2% of the bromophthalane (I), while the remaining portion consists of 1- (4'fluorophenyl) - 1- (3-dimethylaminopropyl) -phthalane.

This example shows that not all organometallic reactants are suitable for effectively obtaining 1- (4'fuorophenyl) -1-1 (3-dimethylaminopropyl) -5-phthalanaldehyde. The choice of using the magnesium activated in step (i), and preferably in the reaction conditions indicated, are therefore decisive for the efficiency of this process.

Claims (15)

CLAIMS 1. Synthesis process of 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-5-isobenzovfuranocarbonitrile (citalopram), characterized by the following phases: (i) conversion of 1 - (4'-fluorophenyl) -1 - (3-dimethylaminopropyl) -5-bromophthalane (I) into 1- (4'-fluorophenyl) 1-3- (dimethylaminopropyl) -5-phthalanaldehyde ( II), said conversion being obtained by treating compound (I) with activated magnesium and, subsequently, with a substituted formamide; (ii) reaction of compound (II) with a reagent of NH2-X structure, where X is selected from -OH, -OCH3, -N (CH3) 2, -OSO3H, with the formation of a compound of formula (III), where X has the above meanings; (iii) conversion of compound (111) to citalopram (IV). 2. Process according to claim 1 wherein, in step (i), compound (I) is dissolved in an organic solvent ("solution b") and added to a mixture of activated magnesium in organic solvent ("solution a ") Process according to claim 2, wherein the compound (I) is used in a weight ratio with respect to magnesium comprised between 5: 1 and 15: 1, preferably 7.5: 1. 4. Process according to claim 2, where the concentration of compound (I) in solution b is comprised between 0.7M and 1.2M. 5. Process according to claim 2, where the volume of solution a is between 40% and 60% with respect to the volume of solution b. 6. Process according to claim 2, where the time within which solution b is added is greater than 5 hours. 7. Process according to claim 2, wherein: the compound (I) is used in a weight ratio with respect to the included magnesium equal to 7.5: 1; the concentration of compound (I) in solution b is 1M; the volume of solution a is 50% with respect to the volume of solution b; the time within which solution b is added is between 6 and 8 hours. 8. Process according to each of claims 1-7, wherein said substituted formamide is selected from dimethylformamide, N-formyl-N-methyl-2-aminopyridine, trimethylformyl-ethylenediamine, N-formylpiperidine, N-formylmorpholine. 9. Process according to each of claims 1-8, wherein said substituted formamide is used in a molar ratio equal to about 2: 1 with respect to compound (I). 10. Process according to each of claims 1-9, carried out continuously in the same reactor, without isolation and / or purification of intermediate products. 11. Process according to each of claims 1-10, where in step (ii) the molar ratios between the compound (II) and the NH2-X compound are between 1: 1 and 3: 1 Process according to each of claims 1-11, where compound (IIi) is an oxime and step (iii) is carried out by reaction with concentrated acetic acid or with acetic anhydride. 13. Process according to each of claims 1-11, where compound (III) is a hydrazone and step (iii) is carried out by oxidation with methylrenium trioxide and hydrogen peroxide. 14. Intermediate synthesis of citalopram of formula (II): 1- (4'-fluorophenyl) -1-1 (3-dimethylaminopropyl) -5-phthalanaldehyde. 15. Synthesis process of 1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1, 3-dihydro-5-isobenzo-furanocarbonitrile (citalopram) characterized by the following fast: (a) conversion of terephthalic acid (VI) into 5-phthalanecarboxylic acid (b) halogenation of 5-phthalanecarboxylic acid (VII), with the formation of the corresponding acyl chloride (VIII); (c) reduction of chloride (VIII), with formation of 5-ftatanaldehyde (IX); (d) protection of 5-phthalanaldehyde by reaction with alcohols or glycols. (e) treatment of the protected 5-phthalanaldehyde (X) with suitable Grignard reagents, obtaining the alkylaryl derivative (XI); (f) deprotection of the alkylaryl derivative (XI) in an acidic environment, with the formation of the corresponding cyclized aldehyde (II); (g) reaction of aldehyde (II) with a reagent of NH2-X structure, where X is selected from -OH, -OCH3, -N (CH3) 2, -0S03H, with the formation of a compound of formula (III) , where X has the above meanings; (h) conversion of compound (III) to citalopram (IV). (GER / pd)