Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
  • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
  • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
  • C07C323/20—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring

Definitions

• the present invention is concerned with an improved process for the preparation of the selective serotonin reuptake inhibitor 3-
• WO01/72687 describes the preparation of 3-[(Dimethylamino)methyl]-4-[4- (methylsulfanyl)phenoxy]benzenesulfonamide (L) tartrate (I) in which the compound is prepared by (i) reacting 4-(methylmercapto)phenol (III) with 2- fluorobenzaldehyde (II) in the presence of potassium carbonate in a suitable solvent such as DMF; (ii) carrying out a reductive amination of 2-[4-( ethylsulfanyl)phenoxy]benzaldehyde (IV) with Sodium triacetoxyborohydride and dimethylamine hydrochloride and then optionally forming the HCI salt of the product; (iii) reacting ⁇ /, ⁇ /-Dimethyl- ⁇ /- ⁇ 2-[4-(methylsulfanyl)phenoxy]benzyl ⁇ amine (V) with chlorosulfonic acid in dichloromethane; and (iv) treating 3-[(D
• Process step (i) is carried out under dilute reaction conditions, the result of which is that a large amount of waste solvent must be disposed of at the end of the reaction. Additionally, when the reaction is carried out on a large scale reaction times are slow. Furthermore, the product of the reaction, compound (IV), is difficult to isolate. It has a low melting point (37-39°C), and therefore the compound is not amenable to drying in a vacuum oven, which makes it difficult to remove the solvent from the product at the end of the reaction. Isolation by crystallisation is also hindered by this property. (b) The reductive amination of compound (IV), process step (ii), proceeds slowly, particularly on a larger scale where reactions can take up to 1 week to reach completion, this has significant economic disadvantages. Furthermore the yields are modest and impurities are generated. The generation of byproducts, such as the primary alcohol derivative of compound (IV), reduces the yield further.
• step (iii) the chlorosulfonylation of compound (V) is carried out using a large excess of 97% chlorosulfonic acid (10 molar equivalents) in the solvent dichloromethane.
• the hazardous nature of the reagent and solvent makes them difficult to handle safely, particularly on a large scale.
• the excess reagent must be neutralised at the end of the reaction generating a large amount of waste.
• the disposal of large volumes of dichloromethane is also expensive and harmful to the environment.
• several impurities are generated as by-products in this process step. These impurities have to be carried through to the next step of the sequence due to the highly reactive nature of compound (VI) and its physical form (a sticky solid), which render it difficult to isolate and purify effectively.
• process step (iv) Due to the moderate purity of compound (VI), process step (iv) is low yielding. Additionally, the sulfonic acid derivative (IX) is generated as a byproduct. Compound (IX) is difficult to separate from the desired product, compound (VII), as are the impurities carried through from process step (iii).
• compounds of formula (IV) may be prepared by reacting compounds of formula (II) and (III) under the conditions of process step (i), nucleophilic aromatic substitution, in the presence of a base in a suitable solvent.
• Suitable bases include carbonate bases such as potassium carbonate, sodium carbonate, caesium 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, dimethylsulfoxide, dioxan, acetonitrile and ethers.
• the preferred base for the reaction is potassium carbonate and the preferred solvent is N,N-dimethylformamide.
• the potassium carbonate is of small particle size (D 90 ⁇ 1000 microns).
• the resultant compounds of formula (VIII) may be prepared by process step (vi), a reductive amination reaction, by reacting compounds of formula (IV) with a dimethylamine source and a suitable-reducing agent; wherein M is a suitable counter-ion such as chloride, bromide, toluenesulfonate, benzenesulfonate, methane sulfonate, hydrogen sulfate, acetate or trfluororacetate.
• M is a suitable counter-ion such as chloride, bromide, toluenesulfonate, benzenesulfonate, methane sulfonate, hydrogen sulfate, acetate or trfluororacetate.
• Suitable sources of dimethylamine include dimethylamine, salts of dimethylamine in the presence of a base (a suitable salt would include hydrochloride, a suitable base would include triethylamine); and N,N- dimethylformamide in the presence of acid or base (a suitable acid would include formic acid; a suitable base would include triethylamine).
• Suitable reducing agents include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen gas in the presence of a catalyst, formic acid and formic acid salts such as potassium formate and sodium formate.
• a Lewis acid such as titanium tetra-iso-propoxide may be beneficial.
• Suitable solvents for the reaction include dichloromethane, tetrahydrofuran, tert-butylmethylether, ethanol, ethylacetate, N,N-dimethylformamide.
• the preferred source of reducing agent is formic acid wherein the required dimethylamine is generated by the acid-mediated degradation of N,N- dimethylformamide.
• N,N-dimethylformamide is the preferred solvent for the reaction.
• the reaction is preferably carried out at elevated temperature.
• the intermediate tertiary amine product may 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, toluene sulfonic acid, benzenesulfonic acid, acetic acid and trifluororacetic acid.
• Preferred acids are hydrochloric acid, sulfuric acid and methanesulfonic acid.
• Suitable solvents include tert-butylmethylether and methylethylketone, either alone, in combination or in the presence of some water.
• Sulfuric acid salts are particularly preferred. Preferred conditions for their preparation are treatment with methyl ethyl ketone and sulfuric acid. Process steps 1 and 2 may be combined, that is that compounds of formula (IV) are not isolated and purified. This is particularly advantageous as the low melting point of compound (IV) makes it particularly difficult to isolate.
• compounds of formula (VIII) may be prepared by reacting compounds of formula (II) and (III) under the conditions of process step (i), before treating the crude reaction mixture under the conditions of process step (vi).
• preferred conditions for process step (i) are N,N- dimethyformamide as solvent and potassium carbonate as base.
• the potassium carbonate is of small particle size (D go ⁇ 1000 microns).
• preferred conditions for process step (vi) are N,N- dimethylformamide as solvent and formic acid as reducing agent, at elevated temperature.
• Compounds of formula (IX) may be prepared by process step (vii), a sulfonylation reaction by reacting compounds of formula (VIII) in the presence of a sulfonylating reagent in the presence of a suitable solvent.
• Suitable sulfonylating reagents include chlorosulfonic acid, sulfuric acid and fuming sulfuric acid.
• the preferred sulfonylating agent is chlorosufonic acid (99%).
• Suitable solvents include dichloromethane, chlorosulfonic acid, trifluoroacetic acid, methanesulfonic acid and sulfuric acid. Preferred solvents are trifluoroacetic acid and methanesulfonic acid.
• chlorosulfonic acid 99%
• methanesulfonic acid 99%
• chlorosulfonic acid 99%
• trifluoroacetic acid 99%
• the preferred reaction temperature is between 0-5°C, when trifluoroacetic acid is the solvent.
• the preferred reaction temperature is 0°C to room temperature, when methansulfonic acid is the solvent.
• Compounds of formula (VII) may be prepared by process step (viii), formation of a sulfonamide by reacting compounds of formula (IX) with a chlorinating agent in a suitable solvent, before quenching the sulfonyl chloride intermediate with ammonia.
• Suitable chlorinating agents include PCI 5 , POCI 3 , SOCI 2 and (COCI) 2 .
• Suitable solvents include acetonitrile, propionitrile, toluene and ethylacetate.
• Suitable ammonia sources include ammonia gas and a solution of ammonia gas in either an organic solvent or water.
• Preferred conditions include Phosphorus oxychloride in acetonitrile followed by treatment with aqueous ammonia.
• Most preferred conditions encompass the addition of the aqueous ammonia to a solution of the intermediate sulfonylchloride (VI), followed by treatment with water.
• the resultant compound of formula (VII) may be treated with absorbents to enhance its purity. Suitable absorbents include activated charcoal, resins and Fuller's Earth.
• absorbents include activated charcoal, resins and Fuller's Earth.
• Compounds of formula (I) may be prepared by process step (ix), by reacting compounds of formula (VII) with D or L Tartaric acid in a solvent system.
• Suitable solvent systems include iso-propyl alcohol, iso-propyl alcohol /water, Ethanol, ethanol/water, methyl ethyl ketone, methyl ethyl ketone /water, methyl iso-butyl ketone, methyl iso-butyl ketone /water, acetone, acetone/water
• Most preferred conditions are aqueous (L)-Tartaric acid with methyl ethyl ketone as solvent.
• Formation of the tartrate salt using the above solvent system gives salts of improved purity in improved yield in a process suitable for an industrial scale.
• process step (vii) use of 99% chlorosufonic acid (instead of the 97% chlorosufonic acid used in process step (iii)) reduces the amount of by-products generated by more than 50%. Additionally far less sulfonylating reagent is required as compared to process step (iii), therefore there is less chemical waste to dispose of at the end of the reaction. Furthermore, the solvent dichloromethane can be replaced by the more environmentally benign methanesulfonic acid, or trifluoroactectic acid.
• Compound (IX) is formed as a precipitate from process step (vii).
• the ability to isolate this product provides a valuable opportunity to purify this intermediate, if necessary, at the mid-point of the reaction sequence. This allows greater control to be exercised with respect to purity during the process.
• reaction step (viii) The isolation of reactive intermediate compound (VI) is avoided by process step (viii) where it is generated in situ.
• the reaction conditions employed in this step are milder than those of reaction step (iii) and therefore fewer impurities are generated, improving the purity of the intermediate.
• NMR spectra were obtained using a Varian Inova 300 MHz spectrometer by dissolving the sample in an appropriate solvent.
• Mass spectra were obtained using a LC/MS system consisting of an 1100 series Hewlett Packard LC in combination with a Micromass ZMD mass spectrometer.
• 2-fluorobenzaldehyde (38.0 Kg), 4-(methylmercapto)phenol (43.8 Kg), potassium carbonate (46.6 Kg, with a particle size D 90 ⁇ 1000 microns) and DMF (171 L) were charged to a suitable reactor and heated to 110°C for 24 hours.
• the reaction mixture was cooled to room temperature, and treated with formic acid (169.1 Kg) over 30 mins.
• the mixture was heated to 130°C for a further 24 hours and then allowed to cool to room temperature. Water (9.5 L) was added followed by cone, aqueous ammonia (152 L) to adjust the pH to greater than 8.5.
• the mixture was extracted with TBME (114 L) and the phases allowed to separate, the lower aqueous phase was then discarded.
• To prepare the sulfate salt the TMBE extract was diluted with MEK (114 L). The solution was cooled to 15°C and concentrated sulphuric acid (30.6 Kg) was added keeping the temperature below 25°C. The mixture was then allowed to cool to 20°C and stirred overnight, finally the mixture was cooled to 0-5°C for 1 hour and the product collected by filtration at reduced pressure. The filter cake was washed with MEK (76 L). The product was then dried at 50°C under vacuum overnight.
• the title compound may be prepared either using methanesulfonic acid (method A) or trifluoroacetic acid (method B) as solvent.
• Option 2 The solid product was washed with water (2 x 50 mL).
• an additional reslurry or recrystallisation may be carried out if necessary.
• the recrystallisation improves purity to a greater extent than the reslurry and 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) was charged to a vessel and heated to reflux for 1 hour. The resultant solution was then cooled to room temperature over 3 hours and the slurry was stirred overnight at that temperature. The solid was collected by filtration at reduced pressure and the cake was washed with a 1 :1 mixture of acetonitrile and water (4.15 L of each). The material was then dried at 50°C under vacuum overnight.
• Acetonitrile 60 mL was charged to a vessel and 3-[(dimethylamino)methyl]- 4-[4-(methylthio)phenoxy]benzenesulfonic acid (10.0 g) was added followed by POCI 3 (2.9 mL).
• the reaction mixture was heated to reflux (approx. 81 °C) for 2 hours.
• the reaction was monitored by HPLC and was deemed to be complete when starting material was reduced to ⁇ 2%.
• the reaction mixture was then cooled to -10°C and treated with concentrated aqueous ammonia (60 mL) keeping the temperature below 20°C.
• the reaction mixture was then treated with further water (60 mL) at 40°C.
• an optional heat cycle to reflux for 1 hour can be used before cooling to room temperature.
• 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 (approx. 80°C) for 15 minutes and then cooled to room temperature. The mixture was treated with activated carbon (2O% w/w, 2 g of Cuno 'Pfizer Type A'). The suspension was stirred at room temperature for 15 minutes and then filtered washing the carbon with a further amount of MEK (20 mL).
• the MEK solution was treated with a solution of ( )-tartaric acid (13.5 Kg) dissolved in water (41.0 L) and MEK (41.1 L) at room temperature over 20 minutes, washing in with a further amount of water (16L) and the resultant slurry was stirred at room temperature for 3 hours.
• the solid product was then collected by filtration at reduced pressure and the filter cake was washed with MEK (63.3 L).
• the main peaks (in degrees 2 ⁇ ) of the PXRD pattern are as follows:

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• 2004
  • 2004-09-10 KR KR1020067005573A patent/KR20060070566A/ko not_active Application Discontinuation
  • 2004-09-10 EP EP04769377A patent/EP1667963A1/de not_active Withdrawn
  • 2004-09-10 JP JP2006527501A patent/JP2007505940A/ja active Pending
  • 2004-09-10 WO PCT/IB2004/002989 patent/WO2005028430A1/en not_active Application Discontinuation
  • 2004-09-10 CA CA002538115A patent/CA2538115A1/en not_active Abandoned
  • 2004-09-10 BR BRPI0414637-9A patent/BRPI0414637A/pt not_active IP Right Cessation
  • 2004-09-10 AU AU2004274245A patent/AU2004274245A1/en not_active Abandoned
  • 2004-09-17 TW TW093128270A patent/TWI247735B/zh not_active IP Right Cessation
  • 2004-09-21 AR ARP040103391A patent/AR045790A1/es unknown
• 2006
  • 2006-02-23 IL IL173902A patent/IL173902A0/en unknown

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