JP2007505940A - New production method of biphenyl ether compounds - Google Patents

Abstract

The present invention is an improvement of the selective serotonin reuptake inhibitors 3-[(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide (L) or (D) tartrate (I). And an intermediate product in the production method.

Description

Detailed Description of the Invention

  The present invention relates to an improved process for the preparation of selective serotonin reuptake inhibitors 3-[(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide (L) or (D) tartrate. And an intermediate product in the production method.

  WO 01/72687 describes the preparation of 3-[(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide (L) tartrate (I). According to it, the compound reacts (i) 4- (methylmercapto) phenol (III) with 2-fluorobenzaldehyde (II) in the presence of potassium carbonate in a suitable solvent such as DMF; ii) performing a reductive amination of 2- [4- (methylsulfanyl) phenoxy] benzaldehyde (IV) with sodium triacetoxyborohydride and dimethylamine hydrochloride and then optionally forming the HCl salt of the product. (Iii) reacting N, N-dimethyl-N- {2- [4- (methylsulfanyl) phenoxy] benzyl} amine (V) with chlorosulfonic acid in dichloromethane; and (iv) 3-[(dimethyl Amino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonyl chloride (VI) in aqueous ammonia or ethanol It is produced by treating with ammonia in a solution to obtain (VII). Steps (iii) and (iv) may be integrated. The corresponding tartrate salt can be obtained by dissolving (VII) in an organic solvent, adding the appropriate tartaric acid, optionally cooling the solution and recovering the resulting crystals of (I).

  The whole procedure can be expressed as:

There are several problems with this route.
(A) Process step (i) is carried out under dilute reaction conditions, so that a large amount of waste solvent must be disposed of at the end of the reaction. Moreover, the reaction time is slowed down when the reaction is carried out on a large scale. Further, the reaction product compound (IV) is difficult to isolate. Since the compound has a low melting point (37-39 ° C.), it is not suitable for drying in a vacuum oven. Therefore, it is difficult to remove the solvent from the product at the end of the reaction. Isolation by crystallization is also hindered by this property.

  (B) The reductive amination of compound (IV), ie process step (ii), proceeds slowly, especially on a large scale, and can take up to one week to complete the reaction. This is a significant economic disadvantage. Furthermore, the yield is low and impurities are produced. Formation of by-products such as primary alcohol derivatives of compound (IV) further reduces the yield.

  (C) In process step (iii), chlorosulfonylation of compound (V) is carried out in dichloromethane solvent using a large excess of 97% chlorosulfonic acid (10 molar equivalents). Due to the detrimental nature of reagents and solvents, safe handling is difficult, especially on a large scale. In addition, excess reagents must be neutralized at the end of the reaction, generating a large amount of waste. Disposal of large amounts of dichloromethane is also expensive and harmful to the environment. In addition, several types of impurities are produced as by-products of this process step. These impurities inevitably bring to the next step of the procedure due to the high reactivity and physical form (sticky solid) of compound (VI), making effective isolation and purification difficult.

  (D) Since the purity of compound (VI) is moderate, process step (iv) has a low yield. Furthermore, a sulfonic acid derivative (IX) is formed as a by-product. Compound (IX) is difficult to separate from the desired product Compound (VII) because it is an impurity introduced from process step (iii).

  In summary, while this reaction procedure provides a reasonable route for the production of compounds of formula (I) on a laboratory scale, there is a robust process that is more applicable to the production of these compounds on an industrial scale. Clearly sought after.

  As a result, an improved synthesis of 3-[(dimethylamino) methyl] -4- [4- (methylsulfanyl) phenoxy] benzenesulfonamide (L) or (D) tartrate (I) that overcomes the above problems A method was developed.

  The whole procedure can be expressed as:

  In one embodiment of the invention, the compound of formula (IV) is a compound of formula (II) and (III), which is suitable in the presence of a base, under the conditions of process step (i), ie nucleophilic aromatic substitution. It can manufacture by making it react in an appropriate solvent.

  Suitable bases are carbonate bases such as potassium carbonate, sodium carbonate, cesium carbonate; butoxide bases such as potassium t-butoxide, lithium t-butoxide, sodium t-butoxide; hydroxide bases such as sodium hydroxide And organic bases such as pyridine and morpholine.

  Suitable solvents include polar aprotic solvents such as N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dioxane, acetonitrile and ethers.

The preferred base for the reaction is potassium carbonate and the preferred solvent is N, N-dimethylformamide.
Most preferably, the potassium carbonate has a small particle size (D ₉₀ <1000 μm).

  The resulting compound of formula (VIII) can be prepared by process step (vi) by reacting a compound of formula (IV) with a dimethylamine source and a suitable reducing agent, ie a reductive amination reaction. Where M is a suitable counter ion such as chloride ion, bromide ion, toluene sulfonate ion, benzene sulfonate ion, methane sulfonate ion, hydrogen sulfate ion, acetate ion or trifluoroacetate ion.

  Suitable sources of dimethylamine are dimethylamine, dimethylamine salts in the presence of bases (suitable salts are hydrochlorides and the like, suitable bases are triethylamine and the like); and N, N in the presence of acids or bases -Dimethylformamide (a suitable acid is formic acid and the like; a suitable base is triethylamine and the like).

  Suitable reducing agents are sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen gas in the presence of a catalyst, formic acid and formate, such as potassium formate and sodium formate.

In some cases, the addition of a Lewis acid such as titanium tetraisopropoxide may be beneficial.
Suitable solvents for the reaction are dichloromethane, tetrahydrofuran, tert-butyl methyl ether, ethanol, ethyl acetate, N, N-dimethylformamide and the like.

A preferred source of reducing agent is formic acid. In the case of formic acid, the required dimethylamine is produced by acid-mediated degradation of N, N-dimethylformamide.
N, N-dimethylformamide is a suitable solvent for the reaction.

The reaction is preferably carried out at an elevated temperature.
The intermediate tertiary amine product can then be isolated as a crystalline salt by reacting the amine with a suitable acid in the presence of a suitable solvent.

Suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid and trifluoroacetic acid.
Suitable acids are hydrochloric acid, sulfuric acid and methanesulfonic acid.

Suitable solvents are tert-butyl methyl ether and methyl ethyl ketone, which are used either alone, in combination or in the presence of some water.
Sulfuric acid is particularly preferred. The preferred production conditions are treatment with methyl ethyl ketone and sulfuric acid.

  Process steps 1 and 2 may be integrated. That is, the compound of formula (IV) is not isolated and purified. This is particularly advantageous because it makes isolation particularly difficult due to the low melting point of compound (IV).

  Thus, in one embodiment of the invention, the compound of formula (VIII) is obtained by reacting the compounds of formula (II) and (III) under the conditions of process step (i) and then reacting the crude reaction mixture with process step (vi ).

In this embodiment, suitable conditions for process step (i) are N, N-dimethylformamide as solvent and potassium carbonate as base.
Most preferably, the potassium carbonate has a small particle size (D ₉₀ <1000 μm).

In this embodiment, suitable conditions for process step (vi) are N, N-dimethylformamide as solvent and formic acid as reducing agent at elevated temperature.
According to another aspect of the present invention, the compound of formula (IX) is obtained by reacting a compound of formula (VIII) in the presence of a sulfonylating reagent in the presence of a suitable solvent, ie, sulfonylation. It can be produced by reaction.

Suitable sulfonylating reagents include chlorosulfonic acid, sulfuric acid and fuming sulfuric acid.
A preferred sulfonylating agent is chlorosulfonic acid (99%).
Suitable solvents include dichloromethane, chlorosulfonic acid, trifluoroacetic acid, methanesulfonic acid and sulfuric acid.

Suitable solvents are trifluoroacetic acid and methanesulfonic acid.
The most preferred conditions are chlorosulfonic acid (99%) and methanesulfonic acid or chlorosulfonic acid (99%) and trifluoroacetic acid.

The preferred reaction temperature is 0-5 ° C. when trifluoroacetic acid is the solvent. A suitable reaction temperature is 0 ° C. to room temperature when methanesulfonic acid is the solvent.
In accordance with yet another aspect of the present invention, the compound of formula (VII) is obtained by reacting the compound of formula (IX) with a chlorinating agent in a suitable solvent and then quenching the sulfonyl chloride intermediate with ammonia. It can be prepared by step (viii), ie the formation of a sulfonamide.

Suitable chlorinating agents include PCl ₅ , POCl ₃ , SOCl ₂ and (COCl) ₂ .
Suitable solvents include acetonitrile, propionitrile, toluene and ethyl acetate.

Suitable sources of ammonia include ammonia gas and a solution of ammonia gas in either an organic solvent or water.
Suitable conditions include treatment with phosphorus oxychloride in acetonitrile followed by aqueous ammonia.

The most preferred conditions include the addition of aqueous ammonia to a solution of the intermediate sulfonyl (VI) chloride followed by treatment with water.
In a further embodiment of the invention the resulting compound of formula (VII) may be treated with an absorbent to increase its purity. Suitable absorbents include activated carbon, resin and fuller's earth.

According to yet another aspect of the present invention, the compound of formula (I) can be prepared by process step (ix) by reacting the compound of formula (VII) with D or L tartaric acid in a solvent system.
Suitable solvent systems are isopropyl alcohol, isopropyl alcohol / water, ethanol, ethanol / water, methyl ethyl ketone, methyl ethyl ketone / water, methyl isobutyl ketone, methyl isobutyl ketone / water, acetone, acetone / water, and the like.

The most preferred conditions are (L) -tartaric acid water and methyl ethyl ketone as the solvent.
The formation of tartrate using the above solvent system results in an improved purity salt in an improved yield in a manner appropriate to the industrial scale.

The advantages of this new method can be summarized as follows.
i) The use of potassium carbonate with a particle size D ₉₀ <1000 μm reduces the reaction time required for process step (i) to reach completion when carried out on a large scale. Using this reagent, several kilos of reactions can be easily completed in less than 24 hours. This has significant economic benefits.

  ii) The use of N, N-dimethylformamide as both solvent and dimethylamine source in process step (vi) allows integration of process steps (i) and (vi). The integration of process steps (i) and (vi) avoids isolation of the low melting intermediate compound (IV) and also significantly reduces the volume of solvent required for these two transformations. Therefore, the reaction efficiency is increased because more product is produced from a smaller reaction volume.

iii) The use of formic acid as a reducing agent in process step (vi) is particularly advantageous for two reasons. First, since it is a liquid, it can be added to the reaction mixture in a controlled manner at the end of process step (i). Therefore, it is possible to safely manage the gas generation accompanying the pH change between the process steps (i) and (iv). Secondly, formic acid oxidation does not produce any chemical waste. CO ₂ is the only byproduct.

iv) The purity of compound (VIII) is increased by forming its suitable sulfate during process step (vi). This salt form is easily isolated from the reaction mixture at the end of the reaction.
v) Using 99% chlorosulfonic acid in process step (vii) (instead of 97% chlorosulfonic acid used in process step (iii)) reduces the amount of by-product produced by 50% Reduce more. Furthermore, since much less sulfonylating reagent is required compared to process step (iii), less chemical waste is disposed of at the end of the reaction. Furthermore, the solvent dichloromethane can be replaced with more environmentally friendly methanesulfonic acid or trifluoroacetic acid.

  vi) Compound (IX) is formed as a precipitate from process step (vii). The ability to isolate the product provides a valuable opportunity to purify the intermediate as needed at the midpoint of the reaction procedure. This allows greater control over purity during the manufacturing process.

  vii) Isolation of the reactive intermediate compound (VI) is avoided by process step (viii) which produces it in situ. The reaction conditions used in this step are mild compared to those in reaction step (iii), so that less impurities are produced and the purity of this intermediate is improved.

  viii) Subsequent quenching of this intermediate takes place in a new manner by adding aqueous ammonia to the reaction mixture, then water, and performing reflux in situ. A recognized industrial scale practice in the art is to add the reaction mixture to excess aqueous ammonia. This novel reverse mode addition method has the following advantages.

(A) Since the by-product sulfonic acid derivative (IX) is soluble in the reaction mixture, its removal from the product is facilitated.
(B) Since it is not necessary to transfer the slurry of intermediate compound (VI) to another reaction vessel, handling problems associated with its physical form are avoided.

(C) The reflux increases the solubility of the inorganic impurities in the reaction mixture and helps to separate them from the product. In addition, organic impurities are purged.
As a result of the above advantages, the yield of compound (VII) is increased.

ix) This new process is suitable for the production of large quantities of compound (I) on an industrial scale.
In a further aspect of the invention, there is provided compounds of formula (VIII) and (IX), wherein M is a suitable counter ion as described above.

  These compounds are particularly useful for synthesizing compounds of formula (I) by the method of the present invention.

Experimental The following abbreviations and definitions are used.
MEK Methyl ethyl ketone DMF N, N-dimethylformamide TBME Tertiary butyl methyl ether DMSO Dimethyl sulfoxide POCl ₃ Phosphorus oxychloride DCM Dichloromethane DMSO Dimethyl sulfoxide m / z Mass spectrum peak HPLC High performance liquid chromatography MS Mass spectrum NMR Nuclear magnetic resonance q Quadruple s singlet t triplet br broad TFA trifluoroacetic acid MSA methanesulfonic acid Kg kilogram L liter mL milliliter g gram CDCl ₃ deuterated chloroform powder X-ray diffraction (PXRD) pattern is theta-theta counter, automatic beam divergence slit, two Measured using a Siemens D5000 powder X-ray diffractometer equipped with a secondary monochromator and scintillation counter. It was. Irradiation with copper K-alpha 1 X-rays (wavelength = 1.05046 angstroms) filtered with a graphite monochromator (λ = 0.15405 nm) using an X-ray tube operated at 40 kV / 40 mA while rotating the specimen did. The main peaks (at an angle of 2θ) of the PXRD patterns of various solid forms are shown.

Melting points were measured using a Perkin Elmer DSC7 at a heating rate of 20 ° C./min or using a Buchi melting point B-545.
NMR spectra were obtained using a Varian Inova 300 MHz spectrometer by dissolving the sample in a suitable solvent.

  Mass spectra were obtained using an LC / MS system consisting of a 1100 series Hewlett Packard LC combined with a Micromass ZMD mass spectrometer.

N, N-dimethyl-2- [4- (methylthio) phenoxy] benzylamine hydrogensulfate

2-Fluorobenzaldehyde (38.0 Kg), 4- (methyl mercapto) phenol (43.8 Kg), potassium carbonate (46.6 Kg, particle size D ₉₀ <1000 μm) and DMF (171 L) are placed in a suitable reaction vessel, Heated to 110 ° C. for 24 hours. Once all 2-fluorobenzaldehyde was consumed (<3%, verified by HPLC), the reaction mixture was cooled to room temperature and treated with formic acid (169.1 Kg) over 30 minutes. The mixture was heated to 130 ° C. for a further 24 hours and then cooled to room temperature. Water (9.5 L) was added, followed by concentrated aqueous ammonia (152 L) to adjust the pH above 8.5. The mixture was extracted with TBME (114 L) and allowed to phase separate, then the lower aqueous phase was discarded. The TBME extract was diluted with MEK (114 L) to produce sulfate. The solution was cooled to 15 ° C. and concentrated sulfuric acid (30.6 Kg) was added while maintaining the temperature below 25 ° C. The mixture was then cooled to 20 ° C. and stirred overnight, finally cooled to 0-5 ° C. for 1 hour and the product collected by vacuum filtration. The filter cake was washed with MEK (76 L). The product was then dried overnight at 50 ° C. under vacuum. Yield = 81%

Melting point = 139-141 ° C.
3-[(Dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonic acid

The title compound can be prepared using either methanesulfonic acid (Method A) or trifluoroacetic acid (Method B) as a solvent.
Method A
Put methanesulfonic acid (17.66 L) in a suitable container, then add N, N-dimethyl-2- [4- (methylthio) phenoxy] benzylamine hydrogensulfate (7.85 Kg) to dissolve the mixture. Stir until room temperature. The reaction mixture was cooled to 0 ° C. and treated with chlorosulfonic acid (11.36 Kg) for 1 hour while maintaining the temperature below 5 ° C. The reaction was monitored by HPLC and the reaction was complete after 5 hours with <2% detection of starting material. In a separate container, water (70.65 Kg) was cooled to 5 ° C. The cooled reaction mixture was then quenched into chilled water while maintaining the temperature below 35 ° C. During quenching, a thick white precipitate was formed. Finally, the remaining reaction mixture was washed into quench water with methanesulfonic acid (2.91 Kg) and then water (7.85 Kg). The resulting slurry was stirred at room temperature overnight and then cooled to 0 ° C. for 1 hour. The product was filtered under reduced pressure and the cake was washed with water (15.7 L). The solid product was then stirred with water (78.5 L) at room temperature for 1 hour. The product was filtered under reduced pressure and the cake was washed with water (15.7 L). The material was then dried overnight at 50 ° C. under vacuum. Yield = 62%.

Method B
Place trifluoroacetic acid (138 mL) in a suitable container, then add N, N-dimethyl-2- [4- (methylthio) phenoxy] benzylamine hydrogensulfate (50 g) at −3 ° C. until the mixture dissolves. Stir with. The reaction mixture was maintained at −3 ° C. and treated with chlorosulfonic acid (36 mL) over 0.25 hours while maintaining the temperature below 6 ° C. Since 99% grade chlorosulfonic acid is used to minimize the formation of impurities during the reaction (compared to lower reagents), the resulting solid is isolated with high purity. The reaction was monitored by HPLC and the reaction was complete after 24 hours with <2% detection of starting material. Water (500 mL) was cooled to 2 ° C. in a separate container. The reaction mixture was then quenched into cooling water (over 2.5 minutes) while maintaining the temperature below 27 ° C. Rapid addition is necessary to keep the product in solution until the end of the addition. At the end of the addition, the product begins to precipitate slowly and maximum size crystals are observed. The reaction mixture was washed into the quenched mixture with trifluoroacetic acid (12 mL) and the slurry was stirred at 20 ° C. for 2.5 hours and then at 0 ° C. overnight. The product was filtered under reduced pressure.

Several options are available before drying to improve the quality of the material.
Option 1 solid product was stirred in water (250 mL) at room temperature for 0.5 h and then vacuum filtered. The solid was stirred in a 1: 1 acetonitrile / water mixture (250 mL) at 40 ° C. for 2 hours. The slurry was cooled to room temperature and filtered under reduced pressure after 1 hour. Reslurry with 1: 1 acetonitrile / water (250 mL) at 40 ° C. was repeated once more on the wet product and then dried overnight at 50 ° C. under vacuum. Yield = 54%.

Option 2 solid product was washed with water (2 × 50 mL). The solid was then stirred in a 1: 1 acetonitrile / water mixture (250 mL) at 60 ° C. for 1 hour. The slurry was cooled to room temperature and stirred at this temperature for 4 hours. The product was filtered under reduced pressure and then dried overnight at 50 ° C. under vacuum. Yield = 55%.

Option 3 The solid was then stirred in a 1: 1 acetonitrile / water mixture (250 mL) at 60 ° C. for 1 hour. The slurry was cooled to room temperature and stirred at this temperature for 4 hours. The product was filtered under reduced pressure and then dried overnight at 50 ° C. under vacuum. Yield = 58%.

  Additional reslurry or recrystallization may be performed as needed to further increase the purity of this major intermediate. Recrystallization significantly improves purity over reslurry. The process is outlined below.

  Acetonitrile (24.9 L), water (20.75 L) and 3-[(dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonic acid (4.15 Kg) are placed in a container and heated for 1 hour. Refluxed. The resulting solution was then cooled to room temperature over 3 hours and the slurry was stirred at that temperature overnight. The solid was collected by vacuum filtration and the cake was washed with a 1: 1 mixture of acetonitrile and water (4.15 L each). The material was then dried overnight at 50 ° C. under vacuum. Yield = 72%.

3-[(Dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonamide

Acetonitrile (60 mL) is placed in a container, 3-[(dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonic acid (10.0 g) is added, followed by POCl ₃ (2.9 mL). It was. The reaction mixture was heated to reflux (about 81 ° C.) for 2 hours. The reaction was monitored by HPLC and considered complete when the starting material was reduced to <2%. The reaction mixture was then cooled to −10 ° C. and treated with concentrated aqueous ammonia (60 mL) while maintaining the temperature below 20 ° C. The reaction mixture was then further treated with 40 ° C. water (60 mL). Any one hour heated reflux cycle may be used here. Then cool to room temperature. Any heating cycle allows a higher level of purge of process related impurities. The reaction mixture was stirred at room temperature overnight. The obtained solid was filtered under reduced pressure, and the filter cake was washed with water (20 mL) and then dried at 50 ° C. under vacuum overnight. Yield = 88%.

3-[(Dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonamide (R, R) tartrate

  For the preparation of 3-[(dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonamide (R, R) tartrate, the activated carbon is used in free form or in a solid supported form. There are two options depending on what you use.

Option 1
3-[(Dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonamide (10 g) was mixed with MEK (80 mL) at room temperature. The stirred mixture was heated to reflux (about 80 ° C.) for 15 minutes and then cooled to room temperature. The mixture was treated with activated carbon (20% w / w, Cuno'Pfizer Type A'2g). The suspension was stirred at room temperature for 15 minutes and then filtered while the carbon was washed with an additional amount of MEK (20 mL). This MEK solution was treated with a solution of (L) -tartaric acid (4.26 g) dissolved in water (13 mL) and MEK (13 mL) at room temperature for 10 minutes, and the resulting slurry was stirred at room temperature for 1 hour. . Next, the solid product was collected by filtration under reduced pressure, and the filter cake was washed with MEK (20 mL). The salt was dried at 50 ° C. under vacuum. Yield = 82%.

Option 2
3-[(Dimethylamino) methyl] -4- [4- (methylthio) phenoxy] benzenesulfonamide (31.65 Kg) was mixed with MEK (253.2 L) at room temperature. The stirred mixture was heated to reflux (about 80 ° C.) for 1 hour and then cooled to room temperature. The mixture was clarified by vacuum filtration. This solution was passed through a solid supported activated carbon cartridge (Cuno'R50Sp Pfizer Type A 'with 0.5 g / cm ² carbon surface area) at 10-12 L / min. The filter cake and then the solid support carbon cartridge were washed with MEK (95 L). This MEK solution was treated with a solution of (L) -tartaric acid (13.5 Kg) dissolved in water (41.0 L) and MEK (41.1 L) at room temperature for 20 minutes, and an additional amount of water (16 L The resulting slurry was stirred at room temperature for 3 hours. Next, the solid product was collected by filtration under reduced pressure, and the filter cake was washed with MEK (63.3 L). The salt was then dried at 50 ° C. under vacuum. Yield = 87%.

  The main peaks (at an angle of 2θ) of the PXRD pattern are as follows.

Claims (14)

Formula (I):

A compound of formula (VII):

A process comprising reacting a compound of the above with tartaric acid in a suitable solvent.   The process according to claim 1, wherein the solvent is methyl ethyl ketone and (L) form of tartaric acid is used. Formula (IX):

By reacting a compound of the formula with a suitable chlorinating agent in a suitable solvent to produce the sulfonyl chloride in situ; and then quenching the sulfonyl chloride by adding a suitable ammonia source to the reaction mixture. The process according to claim 1, further comprising the preparation of a compound of formula (VII). Formula (VIII):

The process according to claim 3, further comprising the preparation of a compound of formula (IX) by reacting a compound of (wherein M is a suitable counterion) and a suitable sulfonylating agent in a suitable solvent. .   The production method according to claim 4, wherein the solvent is methanesulfonic acid or trifluoroacetic acid, and M is a chloride ion, a hydrogen sulfate ion, or a methanesulfonic acid ion. Formula (IV):

The preparation of a compound of formula (VIII) by reacting a compound of formula (II) with a suitable source of dimethylamine in a suitable solvent in the presence of a suitable reducing agent and then treating the resulting amine with a suitable acid. The manufacturing method according to claim 4, further comprising:   The production method according to claim 6, wherein the reducing agent is formic acid and the solvent is N, N-dimethylformamide. Formula (II):

And a compound of formula (III):

The process according to claim 6, further comprising the preparation of a compound of formula (IV) by reacting a compound of formula (IV) in a suitable solvent in the presence of a suitable base. (I) the reaction of compounds (II) and (III) is carried out in N, N-dimethylformamide in the presence of a base;
(Ii) treating the resulting crude reaction mixture containing compound (IV) with formic acid and then reacting at elevated temperature;
(Iii) forming a salt of the resulting amine product by treatment with a suitable acid;
A process for producing a compound of formula (VIII) according to claim 8. Formula (VII):

A compound of formula (IX):

Reaction of the compound with a suitable chlorinating agent in a suitable solvent to produce a sulfonyl chloride in situ; and then quenching the sulfonyl chloride by adding a suitable source of ammonia to the reaction mixture. Manufacturing method including. Formula (IX):

A compound of formula (VIII):

A process comprising reacting a compound of (wherein M is a chloride ion, hydrogen sulfate ion, or methanesulfonate ion) and a suitable sulfonylating agent in methanesulfonic acid or trifluoroacetic acid as a solvent. . Formula (VIII):

(Wherein M is a suitable counter ion), wherein the formula (IV):

And a suitable source of dimethylamine in the presence of a suitable reducing agent in a suitable solvent and then treating the resulting amine with a suitable acid. Formula (IX):

Compound. Formula (VIII):

(Wherein, M is a hydrogen sulfate ion or a methanesulfonate ion).