Difamilast
PMDA Moizerto, JAPAN APPROVED 2021/9/27
ジファミラスト
ディファミラスト;
地法米司特
N-({2-[4-(difluoromethoxy)-3-(propan-2-yloxy)phenyl]-1,3- oxazol-4-yl}methyl)-2-ethoxybenzamide
OPA-15406
| Formula |
C23H24F2N2O5
|
|---|---|
| CAS |
937782-05-3
|
| Mol weight |
446.4439
|
MM 36; MM-36-Medimetriks-Pharmaceuticals; Moizerto; OPA-15406
| Efficacy |
Anti-inflammatory, Phosphodiesterase IV inhibitor
|
|---|---|
| Comment |
Treatment of atopic dermatitis
|
OriginatorOtsuka Pharmaceutical Development & Commercialization- DeveloperMedimetriks Pharmaceuticals; Otsuka Pharmaceutical Development & Commercialization
- ClassBenzamides; Nonsteroidal anti-inflammatories; Oxazoles; Skin disorder therapies
- Mechanism of ActionType 4 cyclic nucleotide phosphodiesterase inhibitors
- RegisteredAtopic dermatitis
- 27 Sep 2021Registered for Atopic dermatitis (In adolescents, In children, In adults) in Japan (Topical)
- 11 Nov 2020Otsuka Pharmaceutical completes a phase III trial in Atopic dermatitis (In children, In adolescents, In adults) in Japan (Topical) (NCT03961529)
- 28 Sep 2020Preregistration for Atopic dermatitis in Japan (In children, In adolescents, In adults) (Topical)
Difamilast is under investigation in clinical trial NCT01702181 (A Safety Study to Evaluate the Use and Effectiveness of a Topical Ointment to Treat Adults With Atopic Dermatitis).
PATENT
JP 2021059538
https://patentscope.wipo.int/search/en/detail.jsf?docId=JP322244172&_cid=P20-L1WXG6-04592-1
Patent Documents 1 and 2 report an oxazole compound having a specific inhibitory action on phosphodiesterase 4 (PDE4) and a method for producing the same. PDE4 is the predominant PDE in inflammatory cells, inhibition of PDE4 increases intracellular cAMP concentration, and the increase in this concentration downregulates the inflammatory response through regulation of the expression of TNF-α, IL-23, and other inflammatory cytokines. .. Elevated cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, it is considered that the oxazole compound is suitable for use as an anti-inflammatory agent. For example, it may be useful for controlling skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound having a specific inhibitory effect on PDE4 and can be efficiently absorbed into the skin. The contents of Patent Documents 1 to 3 are incorporated in the present specification by reference.
patcit 1 : International Publication No. 2007/058338 (Japanese Publication No. 2009-515872 )
patcit 2 : International Publication No. 2014/034958 (Japanese Publication No. 2015-528433 )
patcit 3 : International Publication No. 2017/115780
patcit 2 : International Publication No. 2014/034958 (Japanese Publication No. 2015-528433 )
patcit 3 : International Publication No. 2017/115780
[Synthesis of Oxazole Compound (Type A Crystal)]
Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007/088383).
Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (International Publication No. 2007/088383).
[0060]
化合物（５）データ
Ｎ−（｛２−［４−（ｄｉｆｌｕｏｒｏｍｅｔｈｏｘｙ）−３−ｉｓｏｐｒｏｐｏｘｙｐｈｅｎｙｌ］ｏｘａｚｏｌ−４−ｙｌ｝ｍｅｔｈｙｌ）−２−ｅｔｈｏｘｙｂｅｎｚａｍｉｄｅ
： ｗｈｉｔｅ ｐｏｗｄｅｒ．
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３）： δ ＝ ８．５６ （ｂｒ ｓ，
１Ｈ， ＮＨ）， ８．２３ （ｄｄ， Ｊ ＝ ７．６ Ｈｚ， １．６ Ｈｚ， １Ｈ， ＡｒＨ）， ７．６６ （ｓ， １Ｈ， ＡｒＨ）， ７．６３ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．５８ （ｄｄ， Ｊ ＝ ８．４ Ｈｚ， ２．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．４４−７．３９ （ｍ， １Ｈ， ＡｒＨ）， ７．２１ （ｄ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．０８−７．０４ （ｍ， １Ｈ， ＡｒＨ）， ６．９４ （ｄ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ， ＡｒＨ）， ６．６１ （ｔ， Ｊ ＝ ７５．２ Ｈｚ， １Ｈ， ＣＨＦ ２）， ４．６８ （ｓｅｐｔ， Ｊ ＝ ６．０ Ｈｚ， １Ｈ， ＣＨ）， ４．６２
（ｄ， Ｊ ＝ ６．０ Ｈｚ， ２Ｈ， ＣＨ ２）， ４．１７ （ｑ， Ｊ ＝ ６．９３， ２Ｈ， ＣＨ ２）， １．４８ （ｔ， Ｊ ＝ ７．２ Ｈｚ， ３Ｈ，
ＣＨ ３）， １．３９ （ｄ， Ｊ ＝ ５．６ Ｈｚ， ６Ｈ， ２ＣＨ ３）．
Ｎ−（｛２−［４−（ｄｉｆｌｕｏｒｏｍｅｔｈｏｘｙ）−３−ｉｓｏｐｒｏｐｏｘｙｐｈｅｎｙｌ］ｏｘａｚｏｌ−４−ｙｌ｝ｍｅｔｈｙｌ）−２−ｅｔｈｏｘｙｂｅｎｚａｍｉｄｅ
： ｗｈｉｔｅ ｐｏｗｄｅｒ．
１Ｈ ＮＭＲ （４００ ＭＨｚ， ＣＤＣｌ３）： δ ＝ ８．５６ （ｂｒ ｓ，
１Ｈ， ＮＨ）， ８．２３ （ｄｄ， Ｊ ＝ ７．６ Ｈｚ， １．６ Ｈｚ， １Ｈ， ＡｒＨ）， ７．６６ （ｓ， １Ｈ， ＡｒＨ）， ７．６３ （ｄ， Ｊ ＝ ２．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．５８ （ｄｄ， Ｊ ＝ ８．４ Ｈｚ， ２．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．４４−７．３９ （ｍ， １Ｈ， ＡｒＨ）， ７．２１ （ｄ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ， ＡｒＨ）， ７．０８−７．０４ （ｍ， １Ｈ， ＡｒＨ）， ６．９４ （ｄ， Ｊ ＝ ８．０ Ｈｚ， １Ｈ， ＡｒＨ）， ６．６１ （ｔ， Ｊ ＝ ７５．２ Ｈｚ， １Ｈ， ＣＨＦ ２）， ４．６８ （ｓｅｐｔ， Ｊ ＝ ６．０ Ｈｚ， １Ｈ， ＣＨ）， ４．６２
（ｄ， Ｊ ＝ ６．０ Ｈｚ， ２Ｈ， ＣＨ ２）， ４．１７ （ｑ， Ｊ ＝ ６．９３， ２Ｈ， ＣＨ ２）， １．４８ （ｔ， Ｊ ＝ ７．２ Ｈｚ， ３Ｈ，
ＣＨ ３）， １．３９ （ｄ， Ｊ ＝ ５．６ Ｈｚ， ６Ｈ， ２ＣＨ ３）．
[Preparation of B-type crystal 2]
Using the obtained B-type crystal as a seed crystal, it was examined to further prepare a B-type crystal. Specifically,
B-type crystals were prepared as follows according to the method described in Patent Document 3 (International Publication No. 2017/115780).
Using the obtained B-type crystal as a seed crystal, it was examined to further prepare a B-type crystal. Specifically,
B-type crystals were prepared as follows according to the method described in Patent Document 3 (International Publication No. 2017/115780).
[0072]
[Chem. 6]
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[0073]
Compound (1) 20.00 g (66.8 mmol) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate to cool the mixture, and 11.48 g (100 mmol) of methanesulfonyl chloride was introduced into the compound (1) at 10 to 30 ° C. Stir for hours. Subsequently, 17.41 g (200 mmol) of lithium bromide was added, and the mixture was stirred at 20 to 35 ° C. for 1 hour. 100 mL of water was added to the reaction solution to separate the layers, and the organic layer was concentrated under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve it, and the mixture was concentrated again under reduced pressure. 200 mL of N, N-dimethylformamide and 17.33 g (93.6 mmol) of phthalimide potassium were added to the concentrated residue, and the mixture was reacted at 75 to 85 ° C. for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals, and the precipitated crystals were collected by filtration and dried at 80 ° C. to obtain 27.20 g (yield 95.01%) of compound (3).
[0074]
[Chem. 7]
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[0075]
Compound (3) 20.00 g (46.7 mmol), 40 mL of a 40% aqueous methylamine solution, 40 mL of methanol, and 100 mL of water were mixed and reacted under reflux for 30 minutes. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75 ° C. to separate the liquids. A mixed solution of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted again to 65 to 75 ° C. to separate the liquids. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. Precipitated crystals were collected by filtration to obtain 27.58 g of wet crystals of compound (4).
[0076]
Wet crystals (46.7 mmol) of compound (4) were mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and the mixture was stirred at 20 to 30 ° C. for 1 hour. To the reaction solution, 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) were added, and 20 to 30 were added. The reaction was carried out at ° C. for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50 ° C. to separate the solutions. 60 mL of water and 6 mL of a 25%
aqueous sodium hydroxide solution were added to the organic layer, the temperature was adjusted again to 40 to 50 ° C., the liquid was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. Activated carbon was removed by filtration, washed with 12 mL of ethanol, the filtrate was cooled, and 10 mg of B-type crystals (seed crystals) were added to precipitate crystals. Precipitated crystals were collected by filtration and dried at 60 ° C. to obtain 18.38 g (yield 88.18%) of crystals of compound (5).
aqueous sodium hydroxide solution were added to the organic layer, the temperature was adjusted again to 40 to 50 ° C., the liquid was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. Activated carbon was removed by filtration, washed with 12 mL of ethanol, the filtrate was cooled, and 10 mg of B-type crystals (seed crystals) were added to precipitate crystals. Precipitated crystals were collected by filtration and dried at 60 ° C. to obtain 18.38 g (yield 88.18%) of crystals of compound (5).
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017115780
Production Example 1: Production 1 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.
Compound (3) was produced in accordance with the following reaction scheme.
[0146]
[Chem. 11]
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[0147]
10.00 g (55.5 mmol) of compound (1a) and 9.20 g (66.6 mmol) of potassium carbonate were added to 40 ml of N,N-dimethylformamide and 6 ml of water, and the mixture was stirred until exotherm subsided. 16.92 g (111 mmol) of sodium chlorodifluoroacetate was added thereto, and the mixture was reacted at 95 to 110°C for 3 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the solution was partitioned. 80 ml of water was added again to the organic layer, followed by partitioning. 3 ml of concentrated hydrochloric acid was added to the organic layer, and the mixture was stirred at 60 to 70°C for 30 minutes. 40 ml of water and 10 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the mixture was partitioned. 5.93 g (61.1 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 22.08 g (61.0 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at a temperature of 20°C or below. The mixture was reacted at 20°C or below for 15 minutes, and 10 ml of a 25% sodium hydroxide aqueous solution was added dropwise thereto at a temperature of 20°C or below, followed by pouring in 83.95 g (66.6 mmol) of a 10% sodium sulfite aqueous solution. Additionally, 2 ml of concentrated hydrochloric acid was added and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue to dissolve the residue, and 5 ml of concentrated hydrochloric acid was added dropwise thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 11.81 g (yield: 86.4%) of compound (3) as a white powder.
[0148]
1H-NMR (CDCl 3) δ: 7.70 (2H,dd,J = 6.4 Hz,2.0 Hz),7.22 (1H,d,J = 9.2 Hz),6.66 (1H,t,J = 74.8 Hz),4.66(1H,sept,J = 6.0 Hz),1.39 (6H,d,J = 6.0 Hz).
Production Example 2: Production 2 of Compound (3)
Compound (3) was produced in accordance with the following reaction scheme.
[0149]
[Chem. 12]
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[0150]
10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of potassium carbonate, and 8.50 g (69.1 mmol) of isopropyl bromide were added to 40 ml of N,N-dimethylformamide, and the mixture was reacted at 75 to 85°C for 2 hours. 80 ml of butyl acetate and 80 ml of water were added to the reaction solution, and the mixture was partitioned. 5.68 g (58.5 mmol) of sulfamic acid and 10 ml of water were added to the organic layer, and 21.15 g (58.5 mmol) of a 25% sodium chlorite aqueous solution was added dropwise thereto at 20°C or below, followed by reaction for 15 minutes. 10 ml of a 25% sodium hydroxide aqueous solution was added thereto at 20°C or below, and subsequently 80.41 g (63.8 mmol) of a 10% sodium sulfite aqueous solution was poured in. Additionally, 2 ml of concentrated hydrochloric acid was added, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25% sodium hydroxide aqueous solution were added to the concentrated residue, and the residue was dissolved, followed by dropwise addition of 5 ml of concentrated hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 12.09 g (yield: 92.4%) of compound (3) as a white powder.
[0151]
Production Example 3: Production of Compound (7)
Compound (7) was produced in accordance with the following reaction scheme.
Compound (7) was produced in accordance with the following reaction scheme.
[0152]
[Chem. 13]
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Production Example 4: Production of Compound (11)
Compound (11) was produced in accordance with the following reaction scheme.
Compound (11) was produced in accordance with the following reaction scheme.
[0160]
[Chem. 14]
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[0161]
Synthesis of Compound (9)
20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white powder.
20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) of N,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto and reacted at 20 to 35°C for 1 hour. 100 ml of water was added to the reaction solution, and the mixture was partitioned, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75 to 85°C for 1 hour. 200 ml of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a white powder.
[0162]
1H-NMR (DMSO-d 6) δ: 8.22 (1H,s),7.94-7.86 (4H,m),7.58 (1H,d,J = 2.0 Hz),7.52 (1H,dd,J = 8.8 Hz,2.4 Hz),7.30 (1H,d,J = 8.4 Hz),7.14 (1H,t,J = 74.2 Hz),4.78-4.69 (3H,m),1.30 (6H,d,J = 6.0 Hz).
[0163]
Synthesis of Compound (10)
15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, and reacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by partitioning. A mixture of 150 ml of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder.
15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40% methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, and reacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether (CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by partitioning. A mixture of 150 ml of water and 7.50 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by partitioning. 3.75 ml of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 11.95 g (yield: quant.) of compound (10) as a white powder.
[0164]
1H-NMR (DMSO-d 6) δ: 8.51 (3H,br-s),8.29 (1H,s),7.64 (1H,d,J = 2 Hz),7.59 (1H,dd,J = 8.0 Hz,1.6 Hz),7.37 (1H,d,J = 8.4 Hz),7.18 (1H,t,J = 74.0 Hz),4.72 (1H,sept,J = 6.1 Hz),4.03 (2H,s),1.33 (6H,d,J = 6.4 Hz).
[0165]
Synthesis of Compound (11)
13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder.
13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol) of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g (58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 54 ml of water and 5.4 ml of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by partitioning. 54 ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. 45 ml of ethanol, 18 ml of water, 5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 11 ml of ethanol. The filtrate was cooled, and a seed crystal was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 35°C, thereby obtaining 12.88 g (72.6%) of compound (11) as a white powder.
[0166]
1H-NMR (CDCl 3) δ: 8.56 (1H,br-s),8.23 (1H,dd,J = 7.6 Hz,1.6 Hz),7.66 (1H,s),7.63 (1H,d,J = 2.0 Hz),7.58 (1H,dd,J = 8.4 Hz,2.0 Hz),7.44-7.39 (1H,m),7.21 (1H,d,J = 8.0 Hz),7.08-7.04 (1H,mH),6.94 (1H,d,J = 8.0 Hz),6.61 (1H,t,J = 75.2 Hz),4.68 (1H,sept,J = 6.0 Hz),4.62 (2H,d,J = 6.0 Hz),4.17 (2H,q,J = 6.93),1.48 (3H,t,J = 7.2 Hz),1.39 (6H,d,J = 5.6 Hz).
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019194211
*DIPEA: Diisopropylethylamine, CPME: Cyclopentyl methyl ether,
DMF: N,N-dimethylformamide, 2-EBA: 2-Ethoxybenzoic acid,
WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
Type B Crystal Preparation 2
Analysis was conducted to further prepare the type B crystal using the obtained type B crystal as a seed crystal. More specifically, the type B crystal was prepared as follows, in accordance with the method disclosed in PTL 3 (WO2017/115780).
Analysis was conducted to further prepare the type B crystal using the obtained type B crystal as a seed crystal. More specifically, the type B crystal was prepared as follows, in accordance with the method disclosed in PTL 3 (WO2017/115780).
[0072]
[0073]
20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was added thereto, and the mixture was stirred at 20 to 35°C for 1 hour. 100 mL of water was added to the reaction solution, and the mixture was separated, followed by concentration of the organic layer under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue, and reacted at 75 to 85°C for 1 hour. 200 mL of water was added to the reaction solution to precipitate crystals. The precipitated crystals were collected by filtration and dried at 80°C, thereby obtaining 27.20 g (yield: 95.01%) of compound (3).
[0074]
[0075]
20.00 g (46.7 mmol) of compound (3), 40 mL of a 40% methylamine aqueous solution, 40 mL of methanol, and 100 mL of water were mixed and reacted for 30 minutes under reflux. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% sodium hydroxide aqueous solution were added to the reaction solution, and the temperature was adjusted to 65 to 75°C, followed by separation. A mixture of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65 to 75°C again, followed by separation. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, thereby obtaining 27.58 g of compound (4) as a wet crystal.
[0076]
The wet crystal (46.7 mmol) of compound (4) was mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and stirred at 20 to 30°C for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by separation. 60 mL of water and 6 mL of a 25% sodium hydroxide aqueous solution were added to the organic layer, and the temperature was adjusted to 40 to 50°C again. The mixture was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% sodium hydroxide aqueous solution, and 0.6 g of activated carbon were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated carbon was removed by filtration, and the filtrate was washed with 12 mL of ethanol. The filtrate was cooled, and 10 mg of the type B crystal (a seed crystal) was added thereto to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C, thereby obtaining 18.38 g (88.18%) of compound (5).
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/////////////Difamilast, JAPAN 2021, APPROVALS 2021, ジファミラスト , MM 36, MM-36-Medimetriks-Pharmaceuticals, Moizerto, OPA-15406, OPA 15406, 地法米司特
O=C(NCC1=COC(C2=CC=C(OC(F)F)C(OC(C)C)=C2)=N1)C3=CC=CC=C3OCC
INTrmediate No.CAS No.DIFAM-001177429-27-5DIFAM-00293652-48-3DIFAM-0031574285-26-9DIFAM-00470-23-5DIFAM-0051574285-28-1DIFAM-0061574285-30-5DIFAM-0071574285-32-7DIFAM-0081574285-36-1DIFAM-0091574285-38-3DIFAM-010DIFAM-0111574285-40-7DIFAM-0121574285-43-0DIFAM-013134-11-2Difamilast937782-05-3