Title of Invention

"PROCESS FOR PRODUCING 2-AMINO-2-[2-[4-(3-BENZYLOXYPHENYLTHIO)-2-CHLOROPH ENYL]ETHYL]-1,3-PROPANEDIOL HYDROCHLORIDE AND HYDRATES THEREOF

Abstract

A process for the industrial production of 2-amino-2-[2-[4- (3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride (Compound I), an effective immunosuppressant. The process for producing 2-amino~2-[2- [4- {3-benzyloxyphenylthio)~2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride or a hydrate thereof includes the steps of reacting 4-(3~benzyloxyphenylthio)-2-chlorobenzaldehyde with ethyl diethylphosphonoacetate in a solvent in the presence of a base to form ethyl 3-[4 - (3-benzyloxypheny1thi o)-2-chlorophenyl]aerylate; reducing the resulting ethyl 3-[4-(3-henzyloxyphenylthio}-2-chlorophenyl]acrylate, followed by mesylat. ion, iodination and nitration, to form 1-benzyioxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benzene; forming 2 - 12- [ 4 - ( 3-benzyloxyphenylthio) -2-chlorophenyl ] ethyl ] -2-nitro- 1, 3-propanedio] using a formaldehyde solution; and reducing the resulting 2-[2-[4 -( 3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-I-, 3-propdnediol to form the desired product.

Full Text

DESCRIPTION PROCESS FOR PRODUCING 2-AMINO-2-[2-[4-(3-BENZYLOXYPHENYLTHIO)-2-CHLOROPHENYL]ETHYL]- 1,3-PROPANEDIOL HYDROCHLORIDE AND HYDRATES THEREOF, AND INTERMEDIATES IN THE PRODUCTION THEREOF TECHNICAL FIELD The present invention relates to a process for producing 2-amino-2- [2- [4 - ( 3-benzyloxyphenylthio) -2-chloropheny 1] ethyl] -1,3-propanediol hydrochloride (which may be referred to simply as "Compound 1,*' hereinafter), an effective- immunosuppressant that has little .side effects . The present; invention also relates to novel intermediates in the production of Compound I. BACKGROUND ART (Figure Removed) Compound I i :; a derivative of 2-amino-l, 3-propanediol that has a subst.j 1 ui ed di a rylsu 1 f ide structure and acts as a potent immuno.suppres.sanf. 'It. is a pharrnaceutically useful compound effective in the treatment of various diseases (including autoimmune diseases such as a rheumatoid arthritis, nephritis, gonarthrosis and systemic; lupus erythematosus, chronic inflammatory diseases such as Inflammatory bowel disease, and allergic diseases such as asthma and dermatitis) (The compound is described in Example 46 in Patent Document 1) . Even a production process of Compound I is specifically described in the International Publication Pamphlet of Patent Document 1 . Theprocess, however, is difficult to implement on an industrial scale and requires further improvements in many aspects, including operation, purification efficiency and yields of the product. There thus is a significant need for a practical process for t hr- industrial production of Compound I. Patent Document 1 W003/029205 pamphlet DISCLOSURE OK THF, INVENTION PROBLEMS TO BE SOLVED RY THE INVENTION Requirements for the industrial production of Compound I as a high quality pharmaceutical product include development of novel practical intermediates, elimination of the purification step by column chroinatoqraphy, improvements in the operation of the process and the yields and purity of the product, and reduction in the use of harmful solvent s MEANS FOR SOLVING THE PROBLEMS 0005] In t he coti r se of stud res t o find a way to meet these requirements, the present, inventors have found that novel compounds ethyl 3-[4-(3-benzyloxyphenylthio}-2-chlorophenyl]acrylate, 1 -benzyloxy- 3- f 3-chloro-4- (3-riitropropyl) phenylthio] benzene and ?.- [2- f 4- (3-benzyloxyphenylthio) -2-chlorophenyl] ethyl] -2-nitro-1, 3-propaned.iol can be used as intermediates in the production of Compound 1 and the use of these intermediates enables simple and industrially practical production of Compound I, It is this discovery that ultimately led to the present invention. Specifically, the present invention concerns the following: 1) A process for producing 2-ami no-2- [2 - [ I , 3-pr opaned i o i hydro-chloride or a hydrate thereof, comprising the steps of: reactinq 4- (3-benzyloxyphenylthio)-2-chlorobenzaldehyde with ethyl cJi.ethylphosphonoacetate in a solvent in the presence of a base to form ethyl 3-- [4- { 3-ben/yloxyphenyLthio) -2-chlorophenyl]acrylate; reducinq the resulting ethyl 3-- M- ( 3-benv.y.loxyphenyithio) -2-chlorophenyl] acrylate, followed by mesyiat. ion, iodination and nitration, to form i -berizy loxy ':) [ 3~c':h.! oro-'l - ( J-nitropropyl) pheny.1 thio] benzene; hydroxyniet hy.l at inq the resul ting I -benzy Loxy- 3- [ 3 -c:h lor o-'l - (' -ni t ropropyl) phenylthio j benzene with formaldehyde to iorrn 2-[2- [4- (3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1, 3-propanediol; and reducing the resulting 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol to form the desired product. 2) An intermediate in the production of 2-amino-2-|2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride or a hydrate thereof, comprising a novel compound ethyl 3-- [4- ( 3-berizyloxyphenylthio) -2-chlorophenyl] acrylate or a hydrate thereof. 3) An intermediate in the production of ,' -amino-2- i 2- [ 4 - ( 3 benzyloxypheny] thio) -2-chlorophenyl ]ethyl]-1 , J-propariodiol hydrochloride or a hydrate thereof, comprising a novel compound ibenzy loxy-3-*I3-chloro-4-(3-nitropropyl)phenylthio]benzene or a hydrate thereof. |0009] 4) An intermediate in the production of 1 -ami rio-2- [2 - [ 4 - (3-benzyloxyphenylthio) -2-chloropheny 11 ethyl 1 -1,3-propanedlol hydrochloride or a hydrate thereof, comprising a nie 1 compound 2 [2- [ A- ( 3-benzyloxyphenylthio) -2-chlorophenyl] ethyl] -2-nitro- 1,3-propanediol or a hydrate thereof. [ADVANTAGES OF THE INVENTION] Compounds of the present invention serving as raw materials, ethyl 3- [4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate, 1-benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benzene and ?-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3- propanedioi and their hydrates, are novel compounds that have never been described, nor has their usefulness ever been discussed. Each of ethyl 3- [4- ( 3-benzyloxyphenylthio)-2-ch Lorophenyl]acrylate, J-benzyloxy-i-[3-chloro-4-(3-nitropropyl)phenylthiojbenzene and 2- [2- [ 4- (3-benzy]oxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1 ,3-propanedio1 can serve as an intermediate in the production of Compound I and each allows stabl e and high yield practical production of Compound I with simple purification method. Thus, the use of the compound::; of the present Invention for the first time enables industrially production of Compound I. BEST MODE FOR CARRYING OUT THE PRESENT INVENTION The process of the present invention, which enables industrial scale product-ion of Compound 1, is carried out as follows (See also Scheme; .1 ) : Ethyl 3- [4 ( 3-ben/.yloxyphenylthio) -2-chlorophenyl] acrylate is reduced using bismuth trichloride and sodium borohydride. The reduced product is turtner reduced using potassium borohydride and lithium chloride. The resulting alcohol derivative is mesylatedby reacting with methanesulfonyl chloride. The mesylated product is iodinated with sodium iodide and then reacted with sodium nitrite to form i-benzy.ioxy-3- ( 3-chloro-4- ( 3-nitropropyl) phenylthio] benzene . This product is reacted with formaldehyde in the presence of a base to form 2- [2- [4- ( 3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol. Reducing this compound with palladium hydroxide-carbon gives Compound I. (Figure Removed) We now describe a process for obtaining the novel compounds of the present invention serving as raw materials, i.e., ethyl 3_ [4_ (3-benzyloxyphenylthio) -2-chlorophenyl] acrylate (3) , l-benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benzene (8) and 2- [2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro- 1, 3-propanedio] (9), and hydrates thereof. A mixture of 4-(3-benzy Loxyprienylthio)-2-chlorobenzaldehyde (1) and ethyl diethylphosphonoacetate (2) is stirred for 3 to 8 hours at 50 to BO°C in an organic solvent, such as dimethylformamide or dimethylsu.l.foxide, in the presence of a base, such as potassium bicarbonate, sodium bicarbonate, potassium carbonate or sodium carbonate. .Subsequently, the reaction mixture is chilled in an ice water bath whilo being stirred and water is added. The resulting crystals are collected by filtration and washed with aqueous 2 - p r o p a n o 1 to q i v e e t h y 1 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate (3) as crude crystals. This product is dissolved in ethyl acetate and the mixture •was washed with wafer. The organic layer is concentrated under reduced prossun- to obtain a pale yellow oil. To this product, acetone is added and the mixture is stirred while being chilled to form orysi air-; (Crystal seeds are added when necessary) . Water is then added arid the mixture is stirred while being chilled. The resulting crystals are collected by filtration and washed with acetone-water. The crystals are then dried at 40°C or below to give ethyl 3- [4- (3-benzyloxyphenylthio)-2-chlorophenyl]acrylate (3) or a hydrate thereof. Subsequently, ethyl 3- [4- (3-benzyloxyphenylthio)-2-chlorophenyl]acrylate (3) is dissolved in tetrahydrofuran or an alcohol, such as methanol and ethanol, or a mixture thereof. While the mixture is stirred at 30 to 40°C, bismuth trichloride and sodium borohydride are added. Additional, bismuth trichloride and sodium borohydride are added to complete ihe reduction. The product is treated to give a pale y stirred at 50 to 80°C for 3 to 5 hours. The product is treated to give a yellow oil. This oily product is dissolved in an organic solvent such as dimethylformamide, and phloroglucinol and sodium nitrite are added while the mixture is being stirred. Stirring is continued lor addit. Lonal 4 to 6 hours at 20 to 35°C. Subsequently, sodium thiosulfate pentahydrate in brine is added and the mixture is treated and purified to give l-benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benzene (8) or a hydrate thereof as a pale yellow oil. l-Benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benze ne (8) is dissolved in an organic solvent, such as acetonitrile and tet rahydj of uran . While the mixture is chilled in an ice bath, a formaldehyde solution is added and the reaction is allowed to proceed at 0 to 60 "C for I to 3 hours in the presence of a base, such as 1,B-diazabicyclo[5.4.0]undeca-7-ene, 1,5-diazabicycJ o [4 .3.0]non-5-ene, diazabicyclo[2.2.2]octane, trialkylamine, .sodium hydroxide and potassium hydroxide. Subsequently, the product is treated to give 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol (9> or a hydrate thereof. I'M)l7] 2- [ 2- [4- ( 5-is; nzyloxyphenylthio) -2-chlorophenyl] ethyl] -2-n U ro-1, 3-p.ropanr-d i."l (9) is reduced in an organic solvent such as ethanol in the presence of a catalyst such as palladium hydroxide-carbon at room temperature to 60°C under a hydrogen pressure of atmospheric pressure to 507 kPa. This gives 2-amino-2- [2- [4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol. This product is dissolved in an organic solvent, such as ethanol, 2-propanol and ethyl acetate, or a mixture thereof and is reacted with hydrochloric acid. This gives 2-amino-2- (.2- [4- ( 3-benzyloxyphenylthio) -2-chlorophenyl] ethyl] -1, 3-propanediol hydrochloride (Compound I). The above-described process enables simple production of Compound I in high yield and purity. [0018] T h e s t a r t i n g ma t e r i a 1 4- (3-benzyLoxyphenylthio) -2-chlorobenzaldehyde (I) can readily be obtained by converting commercially available 3-benzyloxyphenol (10) into n thiophenol derivative by dimethylthiocarbamate method (J. Org. Chem., 31, 3980 (1966).) and reacting the thiophenol derivative with commercially available 2-chloro-4-fluorobenzaldehyde (See Scheme II). As described above, the present invention provides an ef feet ive process for the industrial production of Compound I. [ [Examples ] The present invention will now be described with reference to specific examples, which are not intended to limit the scope of the invention in any way. (Reference Example 1] ( )-- (_3-BenzyloxyJ phenyldimethylthiocarbamate ( 11 ) A 60V; 3 odium hydride (19.9 g, 498 mmol) was slowly added to d .solution of 3-benzyloxyphenoJ (10) (83. 0 g, 415 mmol) in dehydrated diinethylu! foxide (DMSO) Mlb mL) while the solution wac water -cooled and stirred. The mixture was stirred for 30 mJ n . :Uibsecquent: 1 y , dimeldr/1 1 hiocarbamoyl chloride (61.5 g, 498 mmol) was slowly added while the mixture was water-cooled and stirred. The mixture wa.s then stirred at room temperature for 1.5 hours. Subsequently, the reaction mixture was slowly poured into ice water (2L) and was extracted with ethyl acetate twice (1.5 L and 500 mL) . The organic layers were combined, washed sequentially with water (2 L) and 28% brine (1L) and then dried over anhydrous sodium sulfate . The solvent, was evaporated and the residue was subjected to silica gel column chromatography (silica gel 60, 3 L, hexane: ethyl acetate 10 : 1 --> 5 : 1 ) to give 0- (3-benzyloxy) phenyldimethylthiocarbamate (2) as a pale yellow oil (107 g, 90%). 400MHz 'll-NMR (nDCl.3) 5; 3.32 (3H, s), 3.45 (3H, s), 5.04 (2H, s), 6.68-6.73 (2H, m),6.86-6.89 (1H, m) , 7.25-7.44 (6H, m) . HI-MS m/z; 287 (M1) . [ R e f e r e n c e E x a m p 1 e 2 ] 8(_3-BenzyLoxy) pheayldi methyl. thiocarbamate (12 ) O-(^-Benzyloxy)phenyIdimethylthiocarbamate (11) (100 g, 348 rnmol) was stirred for 1 hour at an internal temperature of 270 to 2B5°Cunder reduced pressure (4.53 kPa) . Subsequently, the mixture was allowed to cool at room temperature and diisopropyl ether (200 mL) was added at an internal temperature of 50°C. The mixture was .stirred at: room t emperature for crystallization . Diisopropyl ether (100 mL) was then -added and the mixture was stirred for 1 hour while being cooled in ice water. The resulting crystals were collected by filtration and washed with diisopropyl ether (50 mL) which had been cooled with ice. The wasiied product was then dried for 3 hours under reduced pressure to give S- (3-benzyloxy) phenyldimethylthiocarbamate (3) as white powdery crystals (79.3 g, 79%) . MP 68-69 °C 400 MHz 'H-NMR (CDC13) 6; 3.04 (3H, br s) , 3.09 (3H, br s), 5.05 (2H, s), 6.99-7.16 (3H, m) , 7.27-7.44 (6H, m) . El -MS m/z; 287 (M+) . [0023] [Reference Example 3] To S- -(3-benzyloxy) phenyldimethylthiocarbamate (12) (40.0 g, 139mmol), 2-propanol (160 mL), sodium hydroxide (22. 2 g, 556mmol) and purified wat.er (80 mL) were added and the mixture was refluxed tor 6 hours in an argon atmosphere. Subsequently, the mixture was stirred in ice water and 6 mol/L hydrochloric acid (120 mL) was added dropwise. Purified water (300 mL) was then added and the resulting crystals were collected by filtration. This product was washed with a 20"n aqueous 2-propanoL (300 mL) and the washed product was air-dried at room temperature for 2 days to give 3-benzyloxybenx.enethiol (4) as a pale yellow powdery crystals (30. 1 :.], 100%-) . 400 MHz 'H-NMR UV-DMSO) 5; 5.06 (2H, s), 5.41 (1H, s), 6.74-6.97 (3H, m) , 7.1-i ilH, t, J - 7.B Hz), 7.30-7.44 (5H, m) . [Reference Example 4] 4 (3-8B1riz3-L9xyp^lgn:YJi_thi0) ~2-chlorobenzaldehyde (1) 3-Benzyloxybenzenethiol (13) (75.0 g, 347 mmol) and 2-chloro--4-f1uorobenzaldehyde (55.0 g, 347 mmol) were dissolved in dimethylformamide (DMF) (350 mL) while the solution was being stirred. The solution was then placed in a water bath at 30 °C and potassium carbonate (62.3 g, 451 mmol) and dimethylformamide (25 mL) were added. This mixture was stirred for 30 min at an internal temperature of 40 to 42°C. Tap water (125 mL) was then added and the mixture was cooled in ice water. To the cooled mixture, additional tap water (625mL) was addeddropwisefor crystallization . The mixture was st i rred for 30 min and the resulting crystals were collected by filtration and washed with 10% aqueous 2-propanol (188 mi,). The moist crystals were dissolved in ethyl acetate (750 mL) and the solut ion was washed twice with tap water (375 mL x 2) . The organic layer was concentrated under reduced pressure and acetone (900 mL) was added to the resulting residue. Purified water (386 mL) was then added dropwise at an internal temperature of 23°C. The mixture- was stirred for 30 min and the resulting crystals were collected by filtration arid washed with 50% aqueous acetone (400 ml.9 . The washed crystals v.'ere air—dried overnight , Subseouent lv, the product was dried by blowing an air stream at 45°C for 1 hour. This gave 4- (3-benzy 1 oxyphenylth io) -2-ohlorobenzaldehyde (1) as a co Jo ties;; prism crystals (115 g, 94%). MP 58-59°C 400 MHz Hl-NMR (CDC13) 6; 5.07 (2H, s) , 7.04-7.14 (5H, m) , 7.31-7.43 (6H, m), 7.75 (1H, d, J = 8.3 Hz), 10.35 (1H, d, J = 0.7 Hz). El-MS m/z; 354(M+) . [Example L| ELhy11_3"l].1~_13-benzyloxyphenylthio) -2-chlorophenyl] acrylate (3) 4-(3-Benzyloxyphenylthio)-2-chlorobenzaldehyde (1) (115 g) (325mmol) and ethyl diethylphosphonoacetate (2) (94.6 g, 422mmol) were added to dimethylformamide (DMF) (518 mL). The mixture was stirred to dissolve the compounds. Potassium carbonate (58.3 g, 422 mmol) was then added and the mixture was stirred at an internal temperature of 70 to 73°C for 5.5 hours. While t he mixture was water-cooled and stirred at an internal temperature of 40°C, tap water (95 mL) was added and the mixture was further st ir red while being chilled. At an internal temperature of 10°C, water (5 mL) and crystal seeds were added and the formation of crystal:; was confirmed. Subsequently, tap water (936 mL) was t; lowly added dropwise and the mixture was stirred for 30 miri at in internal temperature of 3 to 10°C. The crystallized solid was co llected by filtration and washed with 10% aqueous 2-propano] (518 •uL) to obtain moist crystals as a crude product. This product was dissolved in ethyl acetate (806 mL) and the solution was washed I wice wilh water (-103 rnL) . The organic layer was concentrated under reduced pressure and the concentrate was dried for 30 min at an external temperature of 50 °C under reduced pressure to give a pale yellow oil. This product was dissolved in acetone (691 mL) . While the mixture was chilled and stirred, purified water (95 mL) and crystal seeds were added at an internal temperature of 5 to 10°C for crystallization. The mixture was further stirred for 5 min while being chilled. Subsequently, purified water (366 mL) was added dropwise and the mixture was stirred for 30 min at an internal temperature of 5 to 10°C. [0028] The crystallized solid was collected by filtration and was washed with '10", aqueous acetone (461 mL) (internal temperature = '1"C) .' The washed product was dried for 50 min under an air stream ;ind was subsequently air-dried at room temperature. The product was further dried at 38°C for 8 hours under an air stream. This qave Compound (3) as faint yellow granular crystals (136 g, 320 miriol, 98% yi eld ) . mp 45-47°C (hot plate method). Kl -MS in/z: ,'4 (iV ) 'H--NMR (TDCl ,,, '100 MHz) 5: 1.34 (3H, t, J = 7.1 Hz), 4.27 (2H, q, 4 --- 7.1 Hz), 5.05 (2H, s), 6.38 (1H, d, J - 16.1 Hz), 6.92-7.11 (41H, m) , 7.21-7.49 (8H, m) , 8.02 (1H, d, J - 15.9 Hz). Example .l--BezyJ:oxy-3- [ 3-chloro-4- (3-nitropropyl) phenylthio]benzene (8) Tetrahydrofuran (THF) (405 mL) and ethanol (405 mL) were added to ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate (3) (135 g, 318 mmol). While the mixture was stirred at an internal temperature of 35°C, bismuth trichloride (25.0 g, 79.4 mmol) was added, followed by slow addition of sodium borohydride (15.0 g, 397 mmol). The mixture was further stirred while being cooled and additional sodium borohydride (15.0 g, 397 mmol) was slowly added. The mixture was further stirred while being cooled. Additional bismuth trichloride (5.01 g, 15. 9 mmol) was then added at an internal temperature of 40°C, followed by addition of sodium borohydride (6. 01 g, 159 mmol ) and st.i rring for 55 min at an internal temperature of 40 to 46°C. While the reaction mixture was cooled and stirred, acetone (41 mL) was added at an internal temperature of 10°C and the mixture was stirred for 5 min. This was followed by addition of 810mL of 1 rnol/L hydrochloric acid adjusted to pH 1 and ethyl acetate mL) and stirring for 30 min. The resn] t. i nq bl ack solid in the reaction mixture was separated by iiltrat ion and washed with ethyl acetate (135 mL) . The organic Layer was sepai.ited and collected, and washed sequentially with 8 1 mol /L hycir ocd 1 or ic acid ( 405 mL) , a 5% aqueous sodium bicarbonate solution (405 mL) and 28% brine (405 mL) . The organic layer was concentrated under reduced pressure and was dried at an external temperature of 50°C for 30 min to give ethyl 3- [4- (3-benzyloxyphenylthio)-2-chlorophenyl]propionate (4 ) as a pale yellow oil (132 g, equivalent to 318 nunol). Without purification, Compound (4) was dissolved in tetrahydrofuran (THF) (949mL) . While the mixture was being stirred, potassiumborohydride (22.3 g, 413 mmol) and then lithium chloride (17.5 g, 413 mmol) were added at an internal temperature of 20°C and the mixture was stirred for 20 min. Subsequently, ethanol (47.5 mL) was added and the mixture was stirred for 1 hour at an internal temperature of 30 to 33°C and t hen for additional 40 min at an internal temperature of 44 to 45°C. Kthanol (23.7 mL) was then added and the mixture was stirred for additional 30 mi n at an internal temperature of 43 to 45°C to complete the reaction. While the reaction mixture was cooled and stirred, acetone (71.2 mL) and then water (475 mL) were added and the mixture was stirred for 1 hour while being cooled. Subsequently, 2 mol/L hydrochloric acid (217 mL, 434 mmol) and then ethyl acetate (475 mL) were added at an internal temperature of 26°C and the mixture was further stirred. The organic layer was separated and collected, and washed sequentially with a 5% aqueous sodium bicarbonate solution (475 mL) and 28% brine (475 mL) . The organic layer was then concentrated under reduced pressure and was dried at an external temperature of 50°C under reduced pressure for 1 hour. This gave 3- [4-(3-benzyloxyphenylthio)-2-chlorophenyl]propanol (5) (124 g, equivalent to 318 mmol) as a faint yellow oil. Without purification, Compound (5) was dissolved in ethyl acetate (1.22 L). Triethylamine (64.3 g, 635 mmol) was added and, while the mixture was being cooled and stirred, methanesulfonyl chloride (54.6 q, 477 mmol) was slowly added dropwise at an internal temperature of 6 to 15°C. The mixture was then stirred for 1 hour at an internal temperature of 5 to 15°C. Subsequently, tap water ( I .22 L) was added and the mixture was stirred for 20 min. 6 mol/L hydrochloric acid (26.3 mL, 158 mmoJ ) was then added and the organic Layer was separated arid collected. The organic layer was washed sequentially with a 2% aqueous sodium sulfate solution (1.22 L) and a 30% aqueous sodium sulfate solution (612 mL). The organic layer was then concentrated under reduced pi essure and the concentrate was dried under reduced pressure ;L an external, ternperat i.ire of 50 °C for 1 hour. This qave 3- [4- ( 3~bmzy loxypheny.l thio) - 2-ch 1 orophenyl ] propy 1 mothanesu 1 fonat ;• (6) as a pale yellow oil (150 g, equivalent to 318mmol) . Without purjfication, Compound (6) was dissolved in ethyl acetate (441 mL) and DMF (441 mL). While this mixture was being stirred, sodium iodide (61.9 g, 413 mmoL) was added and the mixture was stirred at an internal temperature of 62 to 65°C for 3 hours. While the mixture was cooled and stirred, an 8% aqueous sodium sulf ate solution (1.32L) and ethyl acetate (882mL) were added at an internal temperature of 30°C. The organic layer was separated and collected. The organic layer was washed by adding sodium thiosulfate pentahydrate (7. 35 g) in an 8% agueous sodiumsulfate solution (1.32 I.}. The organic layer was then washed with a 30% aqueous sodium sulfate solution (662 mL) and the organic layer was separated and collected. The collected organic layer was concentrated under reduced pressure and the concentrate was dried under reduced pressure al an external temperature of 50°C for 1 hour. This gave i-benzyloxy-V|3-chloro-4-(3-iodopropyl)phenylthio]benzene(7) as a ye I low oil (1. 60g, equivalent to 318 mmol) . Without purification, Compound (7) was dissolved in DMF (472 mL). While the mixture was being stir, red, phloroglucinol dihydrate (12.9 g, 79.4 mmol) and (hen sodium nitrite (28.5 q, 413 mol) were added and the mixture was stirred at an internal temperature of 29 to 32°C for 4 hours. After the mixture was cooled and stirred, sodium thiosulfate pontrthydLate 78. 9 g (318 mmol) in 5", brine (2.36 L) and ethyl acetate ( i . 57 L) wore added for extraction. The organic layer was separated and collected. The organic layer was washed with 5% brine (1.57 L) , then twice with a 5% aqueous sodium bicarbonate solution (1.57 L) and then with 28% brine (786 mL). Subsequently, the organic layer was concentrated under reduced pressure and the concentrate was dried at; an external temperature of 50°C for 15 min. The resulting oily residue was dissolved in toluene (157 mL) and the solution was concentrated under reduced pressure. 10039] To the concentrate, additional toluene (157 mL) was added and the solution was concentrated under reduced pressure. The concentrate was dried under reduced pressure at an external temperature of 50 °C for 30 min. This gave a brown oil (134 g) . This product was dissolved in toluene (236 mL) and the solution was subjected to silica gel column chromatography (silica gel = 393 g) using toluene as an eluant. The desired fractions were combined rind concentrated under reduced pressure. The concentrate was dried under reduced pressure at an external temperature of 50°C for 15 min. The result.ing oily residue was dissolved in ethyl acetate (157 mL) and the solution was concentrated under reduced pressure. Additional ethyl acetate (157 mL) was added and the solution was again concent rated under reduced pressure . The concentrate was then dried under reduced pressure at an external temperature of 50°C lor 30 min. This gave 1 -benzyioxy-- '3- | 3-chl oro-4- ( 3-nitropropyl) phenylthio] benzene ( 8 ) as a pale; yi.-Llow oil (72.4 g, 175 mmol, 55% yield). HI-MS m/z: 413 (M*) . 'H-NMR (CDC13, 400 MHz) 5: 2.32 (2H, quint., J= 7.1 Hz), 2.81 (2H, t, J - 7.3 Hz), 4.40 (2H, t, J = 7.1 Hz), 5.03 (2H, s), 6.89-6.98 (3H, m), 1. 11-7.41 (9H, m) . (Example 3] -2-chlorophenyl] ethyl] -2-nitro- ' L 3-propanedio 1 __(J))_ l-Benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benze ne (8) (72.3 q, 175 mmol) was dissolved in acetonitrile (217 ml) . While the soluti on was cooled and st i rred, a 37% formaldehyde solution (14. 5mL, 179mmol)was added. 1 ,8-diazabicyclo[5.4.0]undeca-7-ene (DBU) (2.6bq, 17. 5 mmol) was then slowly added dropwise at an internal temperature of 0 to 8°C and the mixture was stirred for 10 min. ,'Jubsequent 1 y, 37% formaldehyde solution (14.6 mL, 180 mmol) was added at: an internal temperature of 10°C or below and the mixture was stirred for 1.5 hours at an internal temperature of 2 to 3°C. To t. lie reaction mixture, 1 mol/L hydrochloric acid (17.5 mL) was added to adjust to pH 3 to 4 and the mixture was stirred for 15 min. The reaction mixture was then concentrated under reduced pressure. The resultinq oily residue was dissolved in ethanol (217 in!.,) and .' me;1./]. h"droohloric acid (108 mL) and the solution was ; t i rred at an irit ernal temperature of 45°C for 30 min. Subsequently, the read i HI mixture was concentrated under reduced pressure. To the resultinq oily residue, ethyl acetate (723 mL) and 2% brine (361 mL) were added for extraction and the organic layer was separated and collected. The organic Layer was washed sequentially with a 5% aqueous sodium bicarbonate solution (361 mL) and 2% brine (361 mL) and was concentrated under reduced pressure. The concentrate was dried under reduced pressure at an external pressure of 50°C for 15 min. To the resulting oily residue, methanol (72 mL) was added and the solution was concentrated under reduced pressure. Additional rnethanol (72 mL) was added and the solution was again concentrated under reduced pressure . The concentrate was then dried under reduced pressure at an external temperature of 50°C for 30 min to give a pale yei low oil (83.8 q). This product was dissolved in methanol (723 mL). While the solution was cooled and stirred, tap water (130 rnL) was added at an internal temperature of 5 to 10 °C to make the solution cloudy. Crystal seeds were then added to this solution. Once the formation of crystals was confirmed, the mixture was stirred for about 15 min and tap water (593 mL) was added dropwise while the mixture was being stirred. The mixture was cooled while being stirred and was further stirred for 1 hour at an internal temperature of 5 to 10o C. Subsequently, the mixture was left overnight at room 1 emperaturo . The crystallized solid was collected by filtration and was washed with 50% aqueous methanol (145 mL) . The resulting moist crystals were dried by blowing an air stream at room temperature and then blow ing an air stream at 30 °C for 16 hours. This gave Compound (9) as a faint, yellow powdery crystals (80.7 g, 170mmol, 98% yield) . rnp 69-70°C (hot plate method) . FAB-MS(positive) m/z: 473[M-H]+. 1H-NMR (CDCl.,, 400 MHz) 5: 2.12-2.17 (2H, m) , 2.54 (2H, t, J = 6.8 Hz), 2.65-2.69 (2H, m) , 4.08 (2H, dd, J=6.3, 12.2 Hz), 4.28 (2H, dd, J= 7,1, 12.5 Hz), 5.02 (2H, s), 6.88-6.96 (3H, m), 7.08-7.41 ('IfI, m) . [Kxample 'I] 0044] 2-Ami_no-2 - [2- [ 4 •- ( 3-berizyloxyphenylthio) -2-chlorophenyl ]ethyl ] -1 , 3_-pj;opa ned i q 1 hydj:ochlor ide (Compound I) 2 •- 2 - f 4 - { ^-B>3nzyloxyphenyl thio) -2-chlorophenyl ]ethyl]-2-n ii'ro-1,3 propanediol (9) (80.2 g, 169mmol) was dissolved in ethanol (802 mL) . After: the inside atmosphere was replaced with an inert gas atmosphere (arqon), 20%palLadiumhydroxide-carbon (61.5g (32.1 g dried product i) was added and the atmosphere was replaced with hydrogen. With a hydrogen balloon attached, the reaction mixture was vigorously stirred for 24 hours at an external temperature of The at mo.sphere was replaced with inert gas (argon) and the ttalysl was separated by filtration at an internal temperature of 30 °C. The remaining mixture was washed with 90% aqueous ethanol (401 mL) . The filtrate was concentrated under reduced pressure and the concentrate was then dried under reduced pressure at an external temperature of 50°C for 15 min. To this product, acetonitrile (80 mL) was added and the mixture was concent rated under reduced pressure . Additional acetonitrile (80 mL) was added and the mixture was again concentrated under reduced pressure . The concentrate was then dried under reduced pressure at an external temperature of 50 °C for 30 rrun. To the resulting residue, acetonitrile (401 mL) was added and the mixture was stirred at an internal temperature of 65 to 70°C for 30 mi n . The mixture was then allowed to cool while being stirred and then cooled while being stirred. Subsequently, the mixture was si irred at an internal temperature of 5 to 10°C for 30 min. The crystallized solid was collected by filtration, washed with acetonitriLe (160 mL, internal temperature = 1°C), and dried at room temper at ure to obtain crude crystals (44 . 9 g) . To this product, acetonit r i 1: (201 mL) was added and the mixture was stirred at an internal temperature of 65 to 70°C for 30 min. Subsequently, the mixture was a Hewed to cool while being stirred and was then stirred at an .internal temperature of 3 to 10°C for 1 hour. The crystallized sol i (1 was so j le-'t.ed by filtration and washed with acetonitrile (120 (iii,) (internal temperature = 2°C) . The washed product was dried under an air stream and further dried by blowing an air stream at 50°C for 3 hours. This resulted in a white powder (42.4 g) . To this product, acetonitrile (170 mL) and purified water (170 mL) were added and the mixture was stirred arid heated to dissolve the solid product. The solution was cooled while being stirred. This resulted in the formation of crystals at an internal temperature of 40°C. The mixture was further cooled while being stirred. The mixture was further stirred at an internal temperature of 3 to 10°C for I hour. The crystallized solid was eolleeted by f i it ration and washed with 50% aqueous acetonitrile (127 mL, internal temperature = 2°C) . The washed product was dried under an air stream for I hour. This product was further dried for 14 hour;; by blowing an air stream at 50°C to give white powdery crystal-, (38. 4 g). To this product (38.2 g) , ethanol (229 mL) was added and the mixture was stirred and heated to dissolve the solid product. The solution was filtrated and washed with ethanol (38 The filtrate was stirred while being heated and 6 mol/L hydrochloric: acid (15.8 mL, 94.8 mmol) was added at an internal lernperdfiire of 60°C (Crystallization was confirmed). This was followed by rjddition of ethyl acetate (535 mL) and stirring for 10 min at cin internal temperature of 50 to 58°C. Subsequently, the mixture was cooled while being stirred, and was further stirred for 1 hour, at an internal temperature of 1 to 10°C. The crystallized solid was collected by filtration and was washed with a mixture of ethanol (57 mL) and ethyl acetate (57 mL) . The washed product was dried under an air stream for 1 hour to obtain moist crystals, which were further dried for 15 hours by blowing an air stream at 60 °C. The dried product was crushed to obtain Compound I as white powdery crystals (38.3 g, 79.7 mmol, 47% yield). mp 158-160°C (hot plate method) . FAB-MS (positive) m/z: 444 [C24H26C1N03S +H] + . Elemental analysis: Calcd for C24H26C1N03S-HC1: C 60.00, H 5.66, N X.92; found: C 59.83, II 5.51, N 2.85. •'H-NMR (DMSO-CU, 400 MHZ) 5: 1.75-1.79 (2H, m), 2.71-2.75 (2H, m), 3.54 (4H, (i, J --= S.I Hz), 5.08 (2H, s), 5.42 (2H, t, J - 4.9 Hz), fo.88-7.00 (Hi, ni) , 7.23-7.41 (9H, m) , 7.93 (3H, br s). I N DU S T RIA L A P PI, IC A B1 LIT Y | 00491 The use ol any of the novel compounds of the present invention (i.e., ethyl 3[4- ( 3~bem"/loxyphenylthio) -2-chlorophenyl] acrylate, 1 --benzyl oxy- 3-[ 3-chloro-4- ( 3-nitropropyl) phenylthio] benzene and 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1 , 3-pr opaneci i o I ) as an intermediate in the production of Compound i, an effr-3t i'/e immunosuppressant, enables simple and industrially prad leal production of Compound I at high purity and stable yield. It. has thus been demonstrated that the present invention offers a way to provide high quality Compound I in high yield. The present invention establishes an industrially advantageous process for producing Compound I, an effective immunosuppressant. Compound 1 produced by the process of the present Invention can be used to as high purity and high quality pharmaceutical products. We claim: 1. A process for producing 2-amino-2-[2-[4-(3-benzyloxyphenyl"thio)-2-chlorophenyl] ethyl]-1, 3-propanediol hydrochloride or a hydrate thereof, comprising the steps of: reacting 4- (3-benzyloxyphenylthio)-2-chlorobenzaldehyde with ethyl diethylphosphonoacetate in a solvent in the presence of a base to form ethyl 3-[4- (3-benzyloxyphenylthio)-2-chlorophenyl] acrylate; reducing the resulting ethyl 3- [4- (3-benzyloxyphenylthio)-2-chlorophenyl]acrylate, followed by mesylation, iodination and nitration, to form l-benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio] benzene; hydroxymethylating the resulting l-benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benzene with formaldehyde to form 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-l,3-propanediol; and reducing the resulting 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol to form the desired product. 2. An intermediate in the production of 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl] ethyl]-1,3-propanediol hydrochloride or a hydrate thereof, comprising a novel compound ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate or a hydrate thereof. 3. An intermediate in the production of 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl] ethyl]-1,3-propanediol hydrochloride or a hydrate thereof, comprising a novel compound l-benzyloxy-3-[3-chloro-4-(3-nitropropyl)phenylthio]benzene or a hydrate thereof. 4. An intermediate in the production of 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl] ethyl]-1,3-propanediol hydrochloride or a hydrate thereof, comprising a novel compound 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol or a hydrate thereof. 5. A process for producing 2-amino-2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl] Ethyl]-1, 3-propanediol hydrochloride or a hydrate thereof, comprising the step of reducing 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyllethyl]-2- nitro-1, 3-propane-diol in the presence of a palladium catalyst. 6. The production process according to claim 5, wherein the palladium catalyst is a palladium hydroxide-carbon catalyst.

Documents:

3226-DELNP-2007-Abstract-(09-10-2012).pdf

3226-delnp-2007-abstract.pdf

3226-DELNP-2007-Claims-(09-10-2012).pdf

3226-DELNP-2007-Claims-(10-04-2012).pdf

3226-delnp-2007-Claims-(11-04-2013).pdf

3226-DELNP-2007-Claims-(14-03-2012).pdf

3226-delnp-2007-claims.pdf

3226-delnp-2007-Correspondence Others-(08-11-2013).pdf

3226-DELNP-2007-Correspondence Others-(10-04-2012).pdf

3226-delnp-2007-Correspondence Others-(11-04-2013).pdf

3226-DELNP-2007-Correspondence Others-(14-03-2012).pdf

3226-delnp-2007-Correspondence-others (18-04-2008).pdf

3226-delnp-2007-Correspondence-others (25-08-2011).pdf

3226-DELNP-2007-Correspondence-Others-(09-10-2012).pdf

3226-delnp-2007-Correspondence-Others-(17-07-2013).pdf

3226-delnp-2007-Correspondence-Others-(28-09-2012).pdf

3226-delnp-2007-correspondence-others.pdf

3226-delnp-2007-description (complete).pdf

3226-delnp-2007-form-1.pdf

3226-DELNP-2007-Form-13-(14-03-2012).pdf

3226-delnp-2007-Form-18 (18-04-2008).pdf

3226-delnp-2007-form-2.pdf

3226-delnp-2007-Form-3-(11-04-2013).pdf

3226-delnp-2007-Form-3-(17-07-2013).pdf

3226-delnp-2007-Form-3-(28-09-2012).pdf

3226-delnp-2007-form-3.pdf

3226-delnp-2007-form-5.pdf

3226-delnp-2007-pct-210.pdf

3226-delnp-2007-pct-301.pdf

3226-delnp-2007-pct-304.pdf

3226-delnp-2007-pct-308.pdf

3226-delnp-2007-Petition-137-(28-09-2012).pdf