RU2114851C1 - METHOD OF PREPARING 7,7-DIOXIDE 5,6-DIHYDRO (S) -4- (ALKILAMINO)-(S)-6- ALKYL-4H- THIENO (2,3-b) THIOPYRAN - 2-SULFONAMIDE AND 7,7-DIOXIDE 5,6-DIHYDRO(S)-4- (ACYLAMIDO)-(S)-6-ALKYL-4H-THIENO (2,3-b)THIOPYRAN - Google Patents

Abstract

FIELD: pharmaceutical industry. SUBSTANCE: 7,7-dioxide 5,6-dihydro-4- (ethylamino)-6- methyl-5H- thieno (2,3-b) thiopyran sulfonamide is prepared by reacting 7,7-dioxide thieno (2,3-b) thiopyran hydroxyderivative with acetonitrile followed by addition of sulfonamide group to second position of heterocyclic system. The claimed method make it possible to carry out synthesis to retain molecule chirality. The above-mentioned compound is useful in pharmacology for regulating intra pressure. EFFECT: improved properties of the title compounds. 9 cl

Description

,
в которой R и R¹ обозначают низший алкил, в частности, дорзоламида, в котором R обозначает метил и R¹ обозначает метил. US патент 4797413 описывает новые ароматические сульфонамиды, применимые для лечения повышенного глазного давления, и их композиции.Modern therapy for the regulation of increased intraocular pressure (IOP) or increased eye pressure, which is believed to be a factor in the appearance and progression of glaucoma, usually consists in the use of various topical agents, which are divided into 4 categories: β-blockers, sympathomimetic agents, parasympathomimetic cholinesterase inhibitors and agents. Supplementary oral administration of a carbonic anhydrase inhibitor (CA1) is practiced when the side effects of the topical agents described above limit their use and / or adequate regulation (IOP) cannot be achieved. Active when orally administered, CA1 can detect serious side effects such as anorexia, gastrointestinal upset, and parasthesiasis. Therefore, an intensive and ongoing search was made for those active in the local administration of CA1 that did not detect such side effects due to the route of administration and the specificity of the target organ. This search led to the discovery of the class of compounds disclosed in Baldwin et al. (US Patent 4,797,413) of the general formula

,
in which R and R ¹ are lower alkyl, in particular dorzolamide, in which R is methyl and R ¹ is methyl. US patent 4,797,413 describes novel aromatic sulfonamides useful for treating high eye pressure and compositions thereof.

 The Ritter reaction is well known in the art and consists in treating an aliphatic hydroxyl with nitrile and a strong acid to form an amide.

Реакция проходит через образование иона карбония в месте присоединения -OH так, что если в исходном материале имеется хиральный центр, то хиральность теряется во время реакции и образуется рацемический продукт.

The reaction proceeds through the formation of a carbonium ion at the -OH attachment point so that if a chiral center is present in the starting material, then chirality is lost during the reaction and a racemic product is formed.

 In the invention, the Ritter reaction is used to introduce a nitrogen-containing group to the 4th position of the molecule, the starting material being the pure ethantiomer, and the chirality is unexpectedly preserved in the resulting product.

 This invention relates to a method for synthesizing a dorzolamide-type compound in high yield and high enantiomeric frequency. A key step in this new method is Ritter's reaction, with an unexpected and unpredictable tendency to go along while maintaining chirality.

 A new method of the invention can be depicted as shown in Scheme 1 (see end of text).

where R and R ¹ , the same or different, are C _1-3 alkyl.

Step A of Scheme 1 is a Ritter reaction or a modification thereof, comprising slowly adding an approximately 10-15 fold molar excess of a strong acid, such as concentrated sulfuric acid, or a mixture of concentrated sulfuric acid and fuming sulfuric acid to a stirred cold solution of 11 in nitrile of RCN structure, where R is C _1-3 alkyl, such as methyl, ethyl, propyl or isopropyl. The amount of water present during the Ritter reaction is critical for the optimal preservation of chirality and it varies (0.5-10%) depending on the acid used. Commercially available sulfuric acid can introduce too much water into the system and is reduced by adding fuming sulfuric acid. However, anhydrous acids, such as methanesulfonic, trifluoroacetic or boron trifluoride ether, require the addition of water to the reaction. Satisfactory temperatures are about -20 ^° C, especially -5 ^° C. After adding acid, the mixture is allowed to warm up spontaneously with stirring until the reaction is complete for about 12-18 hours. The reaction is stopped by adding the mixture to water, the acid is neutralized by adding a base such as sodium hydroxide, and the product is extracted with an organic solvent such as ethyl acetate.

Stage B involves sulfonylation of 111 by adding it to chilled chlorosulfonic acid or fuming sulfuric acid at approximately 0 ^° C. at such a rate as to maintain a temperature below approximately 20 ^° C. The resulting mixture is then heated at approximately 40-60 ^° C. until completion of the reaction for approximately 10-15 hours. This material is directly used in the next step.

Stage C, chlorination, is the slow addition of thionyl chloride to a cooled (15-25 ^o C) solution IV, followed by heating at about 40-60 ^o C for 4-8 hours

 The reaction is stopped by slowly adding the mixture to stirred chilled water, followed by collecting the product by filtration.

предусматривает медленное добавление

к охлажденному (-15 - 0^oC) раствору водного аммиака в THF при скорости, достаточной для поддержания температуры ниже приблизительно 0^oC с последующим перемешиванием при приблизительно 0^oC в течение приблизительно 0,5-2 ч. Продукт выделяют доведением pH до 3-5 концентрированной серной кислотой, отделением органических слоев, разбавлением водой и концентрированием, вызывающим кристаллизацию.Stage D, or amidation process to form sulfonamide

provides for slow addition

to a cooled (-15 - 0 ^o C) solution of aqueous ammonia in THF at a speed sufficient to maintain the temperature below about 0 ^o C, followed by stirring at about 0 ^o C for about 0.5-2 hours. The product is isolated by adjusting the pH to 3-5 concentrated sulfuric acid, separation of the organic layers, dilution with water and concentration, causing crystallization.

Stage E involves reducing the carbonylamide of compound VI by slowly adding a Lewis acid, such as boron trifluoride or aluminum chloride, or an anhydrous strong acid, such as methanesulfonic acid or trifluoroacetic acid, to a stirred suspension of VI and sodium borohydride in dry THF at approximately (-5) - (+5) ^o C, followed by stirring for about 4-6 hours at (-5) - (+5) ^o C, and then for about 12-18 hours at about 25-40 ^o C . Upon completion of the reaction, the reaction mixture is slow was added to a cooled dilute acid followed by isolation by standard methods, if desired. One skilled in the art will recognize that the above reaction with sodium borohydride in dry THF and an acid, such as boron trifluoride etherate or methanesulfonic acid, results in the formation of borane tetrahydrofuran during the formation of compound VII. Alternatively, compound VII can be prepared by reducing compound VI with borane-tetrahydrofuran or borane dimethyl sulfide, without using an acid.

 The maleate VIII salt is prepared by standard methods, converted to the crude salt I of hydrochloric acid and recrystallized to form pure I.

These reaction steps are illustrated by an example where R and R ^{1 are} both methyl.

 The product of the new method of the invention is a topically effective carbonic anhydrase inhibitor useful for treating high eye pressure. It is administered directly to the eye, usually in the form of a solution containing approximately 0.1-15 wt.% Of the compound, 1 or 2 drops 1-4 times a day.

Example 1. Stage A: Methodology for the reaction of Ritter with sulfuric acid
Concentrated sulfuric acid (18 M, 86 ml, 1) is slowly added to a mechanically stirred chilled (-5 ± 5 ^° C) solution of hydroxysulfone II (25.0 g, 0.114 mol: 98: 2 trans / cis) in acetonitrile (300 ml) , 52 mol) for 0.5 h, maintaining the internal temperature at -5 ± 5 ^o C.

The mixture is allowed to warm to 20 ± 5 ^o C and stirred at this temperature for 12 to 18 hours or until the reaction is complete (according to HPLC).

 Analysis procedure: An aliquot (0.1 ml) was diluted to 50.0 ml with water and then analyzed using the following HPLC method.

Device: Spectra Physics 8800
Column: 4.1 x 250 mm Uetrasphere C-8 (Altex inc.)
Eluent A: H ₂ O (0.1% (v / v) H ₃ PO ₄ )
Eluent B: MeCN
Isocratic Elution: 87:13 A: B for 7 min, then
Gradient Elution: 87:13 - 35:65 A: B for 14 minutes
Flow rate: 2.0 ml / min.

Temperature: 45 ^o C
Injection: 10.0 μl
Detection% UV (230 nm)
Retention time: Hydroxysulfone II (cis isomer) 6.0 min. Hydroxy sulfone II (trans isomer) 6.6 min. Acetamidosulfone III (cis isomer) 7.6 min. Acetamidosulfone III (trans isomer) 8.5 min.

 The reaction was considered complete when less than 1% hydroxysulfone II (US. Product of acetamidosulfone III) remained. At the end of the reaction, the trans / cis acetamidosulfone III ratio in the product was 92.4: 7.6.

After completion of the reaction, the reaction mixture was slowly added to a stirred, mechanically pre-cooled (0-5 ^° C) quenching mixture of ethyl acetate (1.7 L) and water (800 ml). At the same time, 50% (w / w) aqueous sodium hydroxide (185 ml) was added to the quenching mixture at such a rate that the pH was maintained between 3 and 5 and the internal temperature was kept below 25 ^o C. Then the pH was adjusted to 7 , 0 - 7.5 by the additional addition of sodium hydroxide and the mixture was stirred for 1 h at 30 ^o C. The mixture was filtered to remove sodium sulfate and the filter cake was washed with ethyl acetate (300 ml). The filtrate and the washing of the precipitate were combined and the mixture was separated into phases. The organic (upper) phases were combined and then concentrated in vacuo [10 mbar (1 • 10 ³ Pa), 50 ^° C] to a volume of 100 ml. Hexane (300 ml) was added slowly and the mixture was stirred for 1 h at 20 - 22 ^° C. The mixture was filtered and the filter cake was washed with hexane (1 layer volume). The product was dried in air, then dried in vacuum [100 mbar (1 • 10 ⁴ Pa) nitrogen stream, 30 - 35 ^o C] to constant weight.

 Yield: 31.0 g (95% purity according to HPLC, wt.%) Of crude acetamidosulfone III as a white solid. The crude product also contains a small amount of acetamide and sodium acetate.

¹ H-NMR: (DMSO - d ₆ ) δ 8.57 (broad d, 1H, J = 8.5 Hz), 8.53 (broad d, 1H, J = 11.7 Hz), 7, 96 (d, 1H, J = 5.0 Hz), 7.94 (d, 1H, J = 5.0 Hz), 7.03 (d, 1H, J = 5.0 Hz), 6.95 ( d, 1H, J = 5.0 Hz), 5.21 - 5.14 (m, 2H), 3.84 - 3.76 (m, 2H), 2.51 - 2.36 (m, 2H) 2.29 - 2.2 (m, 2H), 1.84 (s, 3H), 1.75 (s, 3H), 1.35 (d, 3H, J = 6.8 Hz), 1, 32 (d, 3H, J = 6.2 Hz).

HPLC: 93: 7 trans / cis (method described above)
Microanalysis: Analytically calculated for C ₁₀ H ₁₃ NO ₃ S ₂ :
C, 46.32; H, 5.05; N, 5.40; S, 24.73.

 Determined: C 46.41, H 4.94, N 5.34, S 24.55.

Stage A (Alternative): Methodology for the reaction of Ritter with sulfuric acid / fuming sulfuric acid
To a mechanically stirred chilled (-5 ± 5 ^° C) solution of hydroxysulfone 11 (10.0 g, 45.8 mmol, 98: 2 trans / cis) in acetonitrile (50 ml), concentrated sulfuric acid (18 M, 9, 0 ml, 162 mol), maintaining the internal temperature at 10 ^o C, followed by the addition of 30% fuming sulfuric acid (1.2 ml). The mixture was stirred for 2 hours at 15 - 20 ^° C, then for 3 hours at 20 - 22 ^° C (significant amounts of acetamide formed at temperatures above 25 ^° C). The progress of the reaction was observed using HPLC (the method is described in example 1). The reaction was considered complete when less than 1% of hydroxysulfone II (US. Product of acetamidosulfone III) remained. At the end of the reaction, the ratio of the trans / cis product of acetamidosulfone III was 93.5: 6.5. After completion of the reaction, the mixture was poured into ice (100 g) and the pH of the mixture was adjusted to 3.5-5.5 by slowly adding 50% aqueous sodium hydroxide (approximately 20 ml). The mixture was extracted with ethyl acetate (2 x 100 ml). The extracts were combined and washed with brine (1 x 50 ml). Then the solution was concentrated in vacuo [100 mbar (1 · 10 ⁴ Pa), 35 - 40 ^o C] to a volume of 20 ml. Ethyl acetate (100 ml) was added and the concentration was repeated (final volume 20 ml) to ensure complete removal of acetonitrile. Hexane (100 ml) was added slowly to the mixture, stirred for 2 hours at 20 - 22 ^° C (1 volume of the layer). The product was dried in air, then dried in vacuum [100 mbar (1 • 10 ⁴ Pa), nitrogen flow, 30 - 35 ^o C] to constant weight.

 Yield: 11.5 g (97%) of crude acetamidosulfone III as a white solid. In this case, the crude product does not contain acetamide and sodium acetate.

¹ H-NMR: consistent.

 HPLC: 93.5: 6.5 trans / cis (method described above).

Stage B: Sulfonylation Procedure
To mechanically stirred, cooled (0 ^° C.) chlorosulfonic acid (70 ml, 1.05 mol) was added crude acetamidosulfonamide III (29.7 g, 0.114 mol, 93: 7) in portions at a speed suitable to maintain an internal temperature of <20 ^o C. The dark sulfonylation reaction mixture was heated to 50 ^o C for 12 hours or until completion of the reaction according to HPLC. (Note: hydrochloric acid (0.114 mol) was released during the reaction.

 Analysis procedure: An aliquot (0.1 ml) was diluted to 100.0 ml with water and then analyzed according to the following HPLC method.

Device: Spectra Physics 88800 /
Column: 4.1 x 250 mm Ultrasphere C-8 (Altex Inc.)
Eluent A: H ₂ O (0.1% v / v H ₃ PO ₄ ).

Eluent B: MeC /
Gradient: 97: 3 - 35:65 A: B for 25 min.

 Flow rate: 2.0 ml / min.

Temperature: 45 ^o C.

 Injection: 10.0 μl.

 Retention time: Sulfonic acid IV (cis / trans isomers) 5.0 min. Acetamidosulfone III (cis isomer) 9.0 min. Acetamidosulfone III (trans isomer) 10.0 min.

 The sulfonylation reaction was considered complete when less than 1% acetamidosulfone III (US. Sulfonic acid IV) remained.

Stage C: Chlorosulfonylation Procedure
After the completion of the reaction of Step B, the mixture was cooled to 20 ^° C. Thionyl chloride (70 ml, 0.96 mol) was then added slowly at a rate that allowed the evolution of hydrogen chloride (0.114 mol) and sulfur dioxide (0.114 mol) to be controlled. After addition, the mixture was heated to 50 ^° C. for 6 hours or until completion of the reaction according to HPLC.

 Analysis procedure: An aliquot (0.1 ml) was diluted to 50.0 ml with acetonitrile and then immediately analyzed according to the HPLC method described above (to reduce the hydrolysis of sulfonyl chloride V).

 Retention time: Sulfonic acid IV (cis / trans isomers) 5.0 min. Sulfonyl chloride V (cis / trans isomers) 19 min.

The reaction was considered complete when less than 1% sulfonic acid IV (US. Product of sulfonyl chloride V) remained. After completion of the reaction, the mixture was cooled to 15 - 20 ^o C and then dosed slowly into intensively stirred water (1.4 L), pre-cooled to 0 - 5 ^o C, at a speed allowing to maintain the temperature <5 ^o C. (Note: internal the temperature should not exceed 5 ^o C to reduce the hydrolysis of the sulfonyl chloride product V). After adding about 10% of the reaction mixture, the quenched mixture can be cooled further to -5 ± 5 ^o C. During the quenching of the reaction, significant amounts of hydrochloric and sulfur dioxide are formed. The mixture was stirred for 1 h at 0-5 ^° C, filtered and the filtered precipitate was then washed with cold (5 ^° C) water (1 L). The filtered precipitate was well aspirated to remove as much water as possible.

 Yield: 68 g of crude sulfonyl chloride Y as a wet solid (about 40 wt.% Water), which was immediately used in the next step.

¹ H-NMR: (CDCl ₃ ) δ 7.74 (s, 1H), 8.07 (brd, J = 8.1 Hz), 5.45 - 5.35 (m, 1H), 3, 63 - 3.56 (m, 1H), 2.64 - 2.56 (m, 2H), 2.09 (s, 3H), 1.57 (d, 1H, J = 6.9 Hz).

Stage D: Amidation Procedure
To a mechanically stirred, cooled (-10 ± 5 ^° C) solution of concentrated aqueous ammonia (15 M, 43 ml), 0.65 mol) in tetrahydrofuran (THF, 300 ml), sulfonyl chloride Y (68 g wet, about 40 , 9 g, 0.114 mol) at a rate that maintains the internal temperature below 0 ^o C. After completion of the addition, the mixture was stirred at 0 - 5 ^o C for 1 h or until the reaction was completed according to HPLC.

 Analysis procedure: An aliquot (0.1 ml) was diluted to 50.0 ml with acetonitrile, and then immediately analyzed by the HPLC method described in example 3 (to reduce the hydrolysis of the starting material sulfonyl chloride V).

 Retention time: Acetamidosulfonamide VI (cis isomer) 9.0 min. Acetamidosulfonamide VI (trans isomer) 10.0 min. Sulfonyl chloride V (cis / trans isomer) 19 min.

The reaction was considered complete when less than 1% sulfonyl chloride V (US. Product of acetamidosulfonamide VI) remained. After completion of the reaction, the pH of the mixture was adjusted to 3-5 by adding dropwise concentrated sulfuric acid (18 M, approximately 12.2 ml, 0.218 mol), keeping the internal temperature below 20 ^° C. The mixture was allowed to settle and the layers were separated. The aqueous (lower) phase was extracted with THF (70 ml). Two organic layers were combined and then diluted with water (250 ml). The solution was then concentrated by distillation to a volume of 125 ml. During concentration, the product crystallized spontaneously. The suspension was diluted with water to a volume of 250 ml and the mixture was then stirred for 12-18 hours at 20-25 ^° C. The mixture was filtered and the filter cake was washed with water (150 ml). The product was dried in air, then dried in vacuum [100 mbar, 1 • 10 ⁴ Pa), nitrogen stream, 55 ^o C] to constant weight.

 Yield: 29.5 g (yield 76% of hydroxysulfone 11) of acetamidosulfonamide VI as a white crystalline solid.

 HPLC: 95: 5 trans / cis (method described above).

¹ H-NMR: (DMSO-d ₆ ) δ 8.65 (broad d, 1H, J = 9.5 Hz), 8.60 (broad d, 1H, J = 9.5 Hz), 8, 05 (br s. 4H), 7.42 (s, 1H), 7.31 (s, 1H), 5.32 - 5.15 (m, 2H), 4.10 - 3.80 (m, 2H), 2.53 - 2.41 (m, 2H), 2.34 - 2.18 (m, 2H), 1.91 (s, 3H), 1.87 (s, 3H), 1.37 (d, 3H, J = 7.0 Hz), 1.34 (d, 3H, J = 7.6 Hz).

Microanalysis: Analytically calculated for C ₁₀ H ₁₄ O ₅ N ₂ S ₃ :
C 35.49, H 4.17, N 8.28, S 28.42.

 Determined: C, 35.60; H, 4.04; N, 8.21; S, 28.40.

Stage E: Method of recovery through in situ formed borane
To a mechanically stirred, cooled (0 - 5 ^° C) suspension of acetamidosulfonamide VI (29.5 g, 87.1 mol, 95: 5 trans / cis) and sodium borohydride (16.9 g, 447 mmol) in dry THF (290 ml) was added undiluted boron trichloride etherate (8.13 M, 73 ml, 593 mmol) over 0.5 h, keeping the internal temperature below 5 ^o C. (Caution: hydrogen is formed during the reaction since sodium borohydride and / or Diborane reacts with sulfonamide protons). After complete addition, the mixture is stirred for 5 hours at 0-5 ^° C and then at 30-35 ^° C for 12-18 hours or until completion of the reaction according to HPLC.

 Analysis procedure: An aliquot (0.1 ml) was diluted to 50.0 ml with water and then analyzed by the HPLC method described in Example 3.

 Retention time: Aminosulfonamide VII (cis isomer) 4.5 min.

 Aminosulfonamide VII (trans isomer) 5.0 min; Acetamidosulfonamide VI (cis isomer) 9.0 min. Acetamidosulfonamide VI (trans isomer) 10.0 min. Amino-borane complex 14 - 20 min.

The reaction was considered complete when less than 1% acetamidosulfonamide VI (US. Aminosulfonamide VII) remained. After completion of the reaction, the reaction mixture was added slowly to a mechanically stirred, pre-cooled (0-5 ^° C) solution of 1 M aqueous sulfuric acid (400 ml) at such a rate as to maintain an internal temperature below 20 ^° C (caution: during reaction quenching hydrogen). The mixture was stirred for 2 hours at 20-25 ^° C or until hydrogen evolution ceased. The mixture was then concentrated by distillation (1 atm.) To a volume of 400 ml. The resulting aqueous solution was cooled to 10 ^° C. and the pH was carefully adjusted to 4-5 by adding dropwise 50% aqueous sodium hydroxide (e.g. 37 ml, 0.7 mol), maintaining the internal temperature below 20 ^° C. Ethyl acetate (600 ml) was added and The pH was further adjusted to 7.5-8.0 by the addition of saturated aqueous sodium bicarbonate (approximately 75 ml, 90 mmol). The mixture was filtered to remove sodium sulfate formed during the initial adjustment of the pH, and the filter cake was washed with ethyl acetate (100 ml). The filtrate and washing the precipitate were combined and the resulting mixture was separated into phases. The aqueous (lower) phase was extracted with ethyl acetate (100 ml). The organic layers were combined and then washed with brine (100 ml). This solution containing the crude product, aminosulfonamide VII (about 27.9 g), was used as such in the next step.

HPLC: 95: 5 trans / cis (method described above)
Stage F: Method for the formation of salts of maleic acid
A solution of aminosulfonamide VII in ethyl acetate (approximately 27.9 g, 86 mmol, 95: 5 trans / cis) from step 5 was concentrated by distillation (1 atm) (1.0133 x 10 ⁵ Pa) to a volume of 70 ml. Acetone (250 ml) was added and concentration was repeated to a volume of 70 ml. This operation was repeated, concentrating this time to a volume of 160 ml. Maleic acid (9.98 g, 86 mmol) was added. The mixture was stirred until the salt crystallized, and then was stirred for 12-18 hours at 20-22 ^° C. The mixture was filtered and the resulting precipitate was washed with acetone (1 layer volume). The product was dried in air, then dried in vacuum [100 mbar, (1 • 10 ⁴ Pa), nitrogen stream, 75 ^o C] to constant weight.

 Yield: 33.0 g (92%) of maleate VIII salt as a white crystalline solid.

HPLC: 99: 1 trans / cis (method described above)
¹ H-NMR: (DMSO - d ₅ ) δ 8.17 (br s, 2H), 7.81 (s, 1H), 6.05 (s, 2H), 4.61 (br s, 1H ), 4.08 - 4.00 (m, 1H), 3.24 - 3.14 (m, 1H), 3.06 - 2.93 (m, 1H), 2.7 - 2.45 (m , 2H), 1.39 (d, 3H, J = 6.7 Hz), 1.20 (t, 3H, J = 7.1 Hz).

Microanalysis: Analytically calculated for C ₁₄ H ₂₀ N ₂ O ₄ S ₃ :
C 38.17; H, 4.58; N, 6.39; S, 21.83.

 Determined: C, 38.19; H, 4.58; N, 6.29; S, 21.60.

Stage G: Method for obtaining the crude salt of hydrochloric acid
To a mechanically stirred mixture of ethyl acetate (250 ml) and saturated aqueous sodium bicarbonate (120 ml) was added the maleic acid VIII salt (33.0 g, 75 mmol 99: 1 trans / cis). The mixture was stirred at 20-25 ^° C until the solid was completely dissolved when the two phases became transparent. The mixture was allowed to settle and then the layers were separated. The aqueous (lower) phase was extracted with ethyl acetate (50 ml). The organic layers were combined and then washed with saturated aqueous sodium chloride (50 ml). Concentrated hydrochloric acid (12 M, 6.25 ml, 75 mmol) was slowly added to the well-mixed solution in ethyl acetate. During the addition, the product crystallized. The mixture was concentrated in vacuo (200 mbar (2 · 10 ⁴ Pa), replacing ethyl acetate as necessary, until the water content of the solution became less than 0.1 mg / ml in a volume of 150 ml. The mixture was cooled to 20 - 22 ^o C and then stirred for 12 to 18 hours at this temperature.The mixture was filtered and the filter cake was washed with ethyl acetate (2x55 ml). The product was dried in air, then dried in vacuum [100 mbar (1 · 10 ⁴ Pa) nitrogen flow, 45 - 50 ^o C] to constant weight.

 Yield: 26.4 g (98% yield, 64% total yield from hydroxysulfone 11) of the crude aminosulfonamide 1 hydrochloride as a white crystalline solid.

 HPLC: more than 99% (method described above).

Stage H: Recrystallization Procedure
A mechanically stirred suspension of the crude salt of aminosulfonamide 1 hydrochloride (26.4 g, 73 mmol) in water (70 ml) was heated at 90 - 95 ^° C until the solid was completely dissolved. To the hot solution was added activated carbon (Darco q ^®, 0,26 g) and the mixture was stirred for 15 min at 90 - 95 ^o C. The mixture was filtered hot (85 - 90 ^o C) through a well-washed layer of filter aid (Super Cel). The filtered precipitate was washed with boiling water (9 ml). The filtrate and the washing of the precipitate were combined and the product was allowed to crystallize by cooling a well-stirred solution to 60 ^° C. The mixture was stirred for 1 h at 60 ^° C. or until the product turned into a thermodynamically more stable hemihydrate crystalline form. The mixture was then slowly cooled to 3 ^° C. and then stirred for 1 hour at this temperature. The mixture was filtered by cold filtration using a mother liquor to rinse the precipitate. The product was dried in air, then dried in vacuum [100 mbar (1 • 10 ⁴ Pa), nitrogen flow, 45-50 ^o C] to constant weight.

 Yield: 24.2 g (92% yield, 59% total yield from hydroxysulfone 11) of the pure salt of aminosulfonamide 1 hydrochloride as a white crystalline solid.

HPLC: 99.9% (area) (254 nm); 99.6 wt.% Against the external standard; 99% (4.6) as an N-TFA derivative;
Specific rotation: / (α) _589/589 = -17,1 ^o C (c = 1,00, H ₂ O)
Mp: 238 ^o C (DS C, slope 2 ^o C / min.)
¹ H-NMR (DMSO - d ₆ ) δ 9.91 (br s, 1H), 9.63 (br s, 1H), 8.21 (s, 2H), 8.02 (s, 1H ), 4.68 (br s, 1H), 4.37 (m s, 2H), 3.19 (br s, 1H), 3.04 (br s, 1H), 2.80 ( d, 1H), 2.55 (m, 1H), 1.39 (d, 3H), 1.29 (d, 3H).

¹³ C-NMR: (DMSO - d ₆ ) δ 149.7 (s), 141.9 (s), 137.4 (s), 130.7 (s), 51.6 (s), 49.2 (s), 40.8 (s), 30.7 (s), 11.1 (s), 10.0 (s).

Microanalysis: Analytically calculated for C ₁₀ H ₁₇ N ₂ O ₄ S ₃ Cl:
C 33.28, H 4.75, N 7.76, S 26.66, Cl 9.84.

 Determined: C 33.33, H 4.70, N 7.67, S 26.60, Cl 9.77.

Claims (8)

1. The method of obtaining 7,7-dioxide 5,6-dihydro- (S) -4- (alkylamino) - (S) -6-alkyl-4H-thieno (2,3-b) thiopyran-2-sulfonamide of the General formula I

where R and R ^{1 are the} same or different and are C ₁ - C ₃ alkyl,
in optical form at C- ₆ and in crystalline form, preserving the trans-stereochemical ratio between the substituents C- ₄ and C- ₆ , or its hydrochloride salt, characterized in that a) a compound of general formula II

treated with nitrile formula
RCN
and strong acid so that the amount of water present, depending on the acid used, is in the range of 0.5 to 10.0 wt.%, with the formation of the compounds of General formula III

followed by b treating compound III with chlorosulfonic acid to form a compound of formula IV

treating compound IV with thionyl chloride to form a compound of formula V

d by treating compound V with ammonia to form a compound of formula VI

e treating compound VI with sodium borohydride and hydrocyanic acid or a borane-tetrahydrofuran or borane dimethyl sulfide complex to form a compound of formula I

f isolating compound I in free form or as a maleic acid salt VIII; g converting compound VIII to a hydrochloric acid salt I; and h purifying the hydrochloride of the compound of formula I. 2. The method according to claim 1, characterized in that R and R ¹ are methyl. 3. The method according to claim 1, characterized in that R is methyl and R ¹ is n-propyl. 4. The method of obtaining 7,7-dioxide 5,6-dihydro- (S) -4- (acylamino) - (S) -6-alkyl-4H-thieno (2,3-b) thiopyrin of the general formula III

in which chirality is fixed at C _-6 and the trans-stereochemical ratio between C _-4 and C _-6 substituents is maintained;
R and R ¹ are the same or different and are C ₁ -C ₃ alkyl,
characterized in that the compound of formula II

treated with nitrile formula
RCN
and strong mineral acid so that the amount of water present, depending on the acid used, is in the range of 0.5 to 10.0 wt.%. 5. The method according to claim 4, characterized in that R and R ¹ are methyl. 6. The method according to claim 4, characterized in that R is methyl and R ¹ is n-propyl.  7. The method according to p. 1, characterized in that the strong acid is concentrated sulfuric acid, a mixture of concentrated sulfuric acid and fuming sulfuric acid, methanesulfonic, trifluoroacetic acid, boron trichloride etherate or aluminum chloride and the amount of water present is 1 to 2 wt. % 8. The method according to claim 1, characterized in that the purification of the hydrochloride of the compound of structural formula I is carried out as follows: the crude hydrochloride of the compound of formula I is dissolved in an aqueous solution at about 90 - 95 ^° C, activated carbon is added, the mixture is stirred, the mixture is filtered through a layer filter aid, wash the filter cake with a hot aqueous solution, combine the filtrate and the filter cake, crystallize the hydrochloride of the compound of formula I while cooling the solution to about 1-5 ^° C, filter the mixture, collect and dry the precipitate.

Images