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Copper histidinate

January 30, 2026 2:31 am / Leave a comment

Copper histidinate

CAS 12561-67-0 AND 13870-80-9

MF C₁₂H₁₆CuN₆O₄

FDA 2026, JAN/12/26, Zycubo, To treat Menkes disease, APPROVALS 2026, 9078K3MO9U, MN 88, CUTX 101

copper bis((2S)-2-amino-3-(1H-imidazol-5-yl)propanoate)

Copper histidinate, sold under the brand name Zycubo, is a medication used for the treatment of Menkes disease.^[1] Copper histidinate is a copper replacement therapy given by subcutaneous injection.^[1]^[2]

The most common side effects include infections, respiratory problems, seizures, vomiting, fever, anemia and injection site reactions.^[2]

Copper histidinate was approved for medical use in the United States in January 2026.^[2]

Medical uses

Copper histidinate is indicated for the treatment of Menkes disease in children.^[1]

Menkes disease is a neurodegenerative disorder caused by a genetic defect that impairs a child’s ability to absorb copper.^[2] The disease is characterized by seizures, failure to gain weight and grow, developmental delays, and intellectual disability.^[2] It leads to abnormalities of the vascular system, bladder, bowel, bones, muscles, and nervous system.^[2]

SYN

A275388 — Flores-Pulido AA, Jimenez-Perez VM, Garcia-Chong NR: Sintesis y uso de histidinato de cobre en ninos con enfermedad de Menkes en Mexico. Gac Med Mex. 2019;155(2):191-195. doi: 10.24875/GMM.18004310. [PubMed:31056589]

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US38595012&_cid=P22-ML09JO-91481-1

PAT

Copper amino acidate diimine nitrate compounds and their methyl derivatives and a process for preparing them

Publication Number: US-5576326-A

Priority Date: 1989-12-20

Grant Date: 1996-11-19

Wilson disease genePublication Number: CA-2108927-CPriority Date: 1993-09-21Grant Date: 2008-09-02
Wilson disease genePublication Number: CA-2106602-A1Priority Date: 1993-09-21
Wilson disease genePublication Number: WO-9508641-A1Priority Date: 1993-09-21
Process to obtain new mixed copper aminoacidate complexes from phenanthrolines and their alkyl derivatives to be used as anticancerigenic agentsPublication Number: EP-0434445-A2Priority Date: 1989-12-20
Method for producing a novel mixed copper amino acid complex used in anticancer drugsPublication Number: JP-H04316581-APriority Date: 1989-12-20METHOD FOR DETECTION OF BIOLOGICAL AGENTSPublication Number: EP-1097242-A4Priority Date: 1999-05-05
Method for detecting biological agentsPublication Number: US-2004023272-A1Priority Date: 1999-05-05
Method for detecting biological agentsPublication Number: WO-0066790-A1Priority Date: 1999-05-05
Method for detecting biological agentsPublication Number: EP-1097242-A1Priority Date: 1999-05-05
Process for producing nitrosonium ionsPublication Number: AU-773835-B2Priority Date: 1999-02-24Grant Date: 2004-06-10

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Side effects

The most common side effects include infections, respiratory problems, seizures, vomiting, fever, anemia and injection site reactions.^[2]

Society and culture

Legal status

Copper histidinate was approved for medical use in the United States in January 2026.^[2] The US Food and Drug Administration (FDA) granted the application for copper histidinate priority review, fast track, breakthrough therapy, and orphan drug designations.^[2] The FDA granted approval of Zycubo to Sentynl Therapeutics.^[2]

Names

Copper histidinate is the international nonproprietary name^[3] and the United States Adopted Name.^[4]

Copper histidinate is sold under the brand name Zycubo.^[5]

References

Sentynl Therapeutics (12 January 2026). “Zycubo (copper histidinate) for injection, for subcutaneous use” (PDF). Retrieved 15 January 2026.
“FDA Approves First Treatment for Children With Menkes Disease”. U.S. Food and Drug Administration (FDA) (Press release). 12 January 2026. Retrieved 15 January 2026. This article incorporates text from this source, which is in the public domain.
World Health Organization (2025). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 94”. WHO Drug Information. 39 (3). hdl:10665/383022.
“Copper histidinate”. American Medical Association. Retrieved 15 January 2026.
“Sentynl Therapeutics Inc. Announces FDA Approval of Zycubo (copper histidinate)”. Sentynl Therapeutics. 13 January 2026. Retrieved 15 January 2026 – via PR Newswire.

External links

Clinical trial number NCT00001262 for “Copper Histidine Therapy for Menkes Diseases” at ClinicalTrials.gov
Clinical trial number NCT00811785 for “Molecular Bases of Response to Copper Treatment in Menkes Disease, Related Phenotypes, and Unexplained Copper Deficiency” at ClinicalTrials.gov

Clinical data

Trade names	Zycubo
Other names	Copper(II) bis(histidinate)
AHFS/Drugs.com	zycubo
License data	US DailyMed: Copper histidinate
Routes of administration	Subcutaneous
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
IUPAC name
CAS Number	13870-80-9
PubChem CID	151722
DrugBank	DB32041
ChemSpider	133722
UNII	9078K3MO9U
KEGG	D13117
CompTox Dashboard (EPA)	DTXSID30154803
Chemical and physical data
Formula	C₁₂H₁₆CuN₆O₄
Molar mass	371.844 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

/////////////Copper histidinate, FDA 2026, JAN/12/26, Zycubo, To treat Menkes disease, APPROVALS 2026,
9078K3MO9U, 9078K3MO9U, MN 88, CUTX 101

Difamilast

April 17, 2022 2:45 am / Leave a comment

Difamilast (JAN/USAN).png

Difamilast

FDA 2026, APPROVALS 2026, difamilast, Adquey, 2/12/2026, To treat mild to moderate atopic dermatitis

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)

Fig. 1

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).

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019194211&_cid=P10-MLOK7B-25338-2

Synthesis of Oxazole Compound (Type A Crystal)
Compound (5) (white powder) was prepared in accordance with the method disclosed in Example 352 of PTL 1 (WO2007/058338).

SYN

https://www.chemicalbook.com/article/how-is-difamilast-synthesised.htm

Synthesis of difamilast commenced with the monobenzylated protocatechuic acid ethyl ester 15.1. Phenol 15.1 was first converted into the corresponding isopropyl ether, which was subsequently debenzylated under palladium-catalyzed hydrogenation conditions to generate the phenolic intermediate 15.3. Difluoromethylation of 15.3 was accomplished by introducing sodium chlorodifluoroacetate 15.4 in the presence of potassium carbonate at an elevated temperature. The decarboxylative C− O bond-forming reaction presumably proceeded via a difluorocarbene species. The difluoromethylated product was treated with acid followed by ester hydrolysis under a basic medium to furnish benzoic acid derivative 15.5. Benzoic acid 15.5 was subsequently transformed into benzamide 15.6 via a benzoyl imidazole intermediate. Condensation of benzamide 15.6 with 1-acetoxy-3-chloroacetone 15.7 produced an oxazole derivative, which was subsequently saponified and recrystallized from 50% aqueous MeOH to generate alcohol 15.8.

First, an activation−displacement process transformed alcohol 15.8 into bromide 15.9 via a mesylate intermediate. Alkyl bromide 15.9 was then treated with potassium phthalimide to incorporate the nitrogen center via an S_N2-type displacement. Methylamine-mediated phthalimide deprotection and subsequent salt formation produced amine 15.11 as a hydrochloride salt in 69% yield over 3 steps. Finally, hydrochloride salt 15.11 was treated with aqueous sodium bicarbonate to generate a free amine, which was subjected to amide bond formation with 2-ethoxybenzoic acid 15.12 to deliver difamilast after recrystallization from aqueous EtOH.

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

[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).

[0060]

化合物（５）データ
Ｎ−（｛２−［４−（ｄｉｆｌｕｏｒｏｍｅｔｈｏｘｙ）−３−ｉｓｏｐｒｏｐｏｘｙｐｈｅｎｙｌ］ｏｘａｚｏｌ−４−ｙｌ｝ｍｅｔｈｙｌ）−２−ｅｔｈｏｘｙｂｅｎｚａｍｉｄｅ
：ｗｈｉｔｅｐｏｗｄｅｒ．
^１ＨＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）： δ ＝８．５６（ｂｒｓ，
１Ｈ，ＮＨ），８．２３（ｄｄ，Ｊ＝７．６Ｈｚ，１．６Ｈｚ，１Ｈ，ＡｒＨ），７．６６（ｓ，１Ｈ，ＡｒＨ），７．６３（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ，ＡｒＨ），７．５８（ｄｄ，Ｊ＝８．４Ｈｚ，２．０Ｈｚ，１Ｈ，ＡｒＨ），７．４４−７．３９（ｍ，１Ｈ，ＡｒＨ），７．２１（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ，ＡｒＨ），７．０８−７．０４（ｍ，１Ｈ，ＡｒＨ），６．９４（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ，ＡｒＨ），６．６１（ｔ，Ｊ＝７５．２Ｈｚ，１Ｈ，ＣＨＦ _２），４．６８（ｓｅｐｔ，Ｊ＝６．０Ｈｚ，１Ｈ，ＣＨ），４．６２
（ｄ，Ｊ＝６．０Ｈｚ，２Ｈ，ＣＨ _２），４．１７（ｑ，Ｊ＝６．９３，２Ｈ，ＣＨ _２），１．４８（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ，
ＣＨ _３），１．３９（ｄ，Ｊ＝５．６Ｈｚ，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).

[0072]

[Chem. 6]

[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]

[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).

PATENT

[WO2007058338]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007058338&_cid=P10-MLOK7P-25609-1

Example 352

Using the compound obtained in Example 347 and 2-bromopropane, white powdery N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.

¹H-NMR (CDCl₃) δ: 8.57 (1H, br s), 8.24 (1H, dd, J = 7.5, 1.8 Hz), 7.67 (1H, s), 7.65-7.57 (2H, m), 7.46-7.40 (1H, m), 7.26-7.21 (1H, m), 7.08 (1H, t, J = 7.5 Hz), 6.95 (1H, d, J = 8.4 Hz), 6.63 (1H, t, J = 75 Hz), 4.74-4.62 (3H, m), 4.19 (2H, q, J = 6.9 Hz), 1.49 (3H, t, J = 6.9 Hz), 1.40 (6H, d, J = 6.3 Hz)

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.

[0146]

[Chem. 11]

[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]

[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.

[0152]

[Chem. 13]

Production Example 4: Production of Compound (11)
Compound (11) was produced in accordance with the following reaction scheme.

[0160]

[Chem. 14]

[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.

[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.

[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.

[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).

[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).

PATENT

WO2014034958A1

WO2007058338A2

WO2007058338A9

WO2007058338A3

US9181205B2

US2015239855A1

USRE46792E

US2020078340A1

US2017216260A1

US2019070151A1

US2009221586A1

US8637559B2

US2014100226A1

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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

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