Tigemocoxib

MF C15H14ClF3O3 MW 334.72

2H-1-Benzopyran-3-carboxylic acid, 6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-, (2S)-

(2S)-7-tert-butyl-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid

(2S)-7-tert-butyl-6-chloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid
cyclo-oxygenase 2 (COX-2) inhibitor, anti-inflammatory, SC-75416, SC 75416, C8D42HX4WH

CAS 215122-74-0

Originator: Pfizer Inc.

Tigemocoxib is a small molecule drug. The usage of the INN stem ‘-coxib’ in the name indicates that Tigemocoxib is a selective cyclo-oxygenase inhibitor. Tigemocoxib has a monoisotopic molecular weight of 334.06 Da.

Tigemocoxib (also known as SC-75416) is a selective cyclo-oxygenase 2 (COX-2) inhibitor and nonsteroidal anti-inflammatory drug (NSAID) designed for reducing pain and inflammation. Initially developed as an orally bioavailable clinical lead for treating acute, postoperative, and chronic inflammatory pain, it acts by targeting the COX-2 enzyme

SYN

Bioorganic & Medicinal Chemistry LettersPublication Date: 2010-12-01PMID: 20709553DOI: 10.1016/j.bmcl.2010.07.054

29b-(S) [PMID: 20709553]

PAT

WO2000037469

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO1998047890&_cid=P21-MMWULU-28679-1

EXAMPLE 68

(S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1- benzopyran-3-carboxylic acid To a solution of 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid (Example 8) (11.4 g, 34.1 mmol) and (S)-(-)-2-amino-3-phenyl-1-propanol (2.57 g, 17.00 mmol) was added n-heptane (200 mL) and the mixture set aside for 16 h. The resulting
suspension was filtered yielding a solid (3.8 g). This solid was recrystallized from 2-butanone (20 mL) and n-heptane (200 mL) yielding upon filtration a white solid (3.0 g).
This solid was dissolved in ethyl acetate (100 mL) and washed with 1 N hydrochloric acid (50 mL) and brine (2 × 50 mL), dried over MgSO₄ and concentrated in vacuo yielding a white solid. This solid was recrystallized from n-heptane yielding the title compound of high optical purity as a crystalline solid (1.7 g, 30%): mp 175.4-176.9 °C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (s, 1H), 7.52 (s, 1H), 7.12 (s,

1 H), 5.83 (q, 1H, J = 7.1 Hz), 1.48 (s, 9H). Anal. Calc’d for C₁₅H₁₄O₃F₃Cl : C, 53.83; H, 4.22; N, 0.0; Cl, 10.59. Found: C, 53.78; H, 4.20; N, 0.0; Cl, 10.65. This compound was determined to have an optical purity of greater than 90% ee. Chiral purity was determined as describe in Example 66.

EXAMPLE 8

6-Chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl- 2H-1-benzopyran-3-carboxylic acid

Step 1. Preparation of 4-tert-butylsalicylaldehyde.
A five liter three-neck round bottom flask equipped with overhead mechanical stirrer and condenser was charged with trifluoroacetic acid (2.4 L). A mixture of 3-tert-butylphenol (412 g, 2.8 mole) and HMTA (424 g, 3.0 mole) was added portion-wise causing an exotherm. With cooling, the temperature was maintained under 80 °C. The reaction was heated at 80 °C for one hour, then cooled, and water (2 L) added. After 0.5 hour additional water (4 L) was added and the mixture was extracted with ethyl acetate (6 L). The organic extract was washed with water and brine. The resulting organic phase was divided into 2 L volumes and each diluted with water (1 L), and solid NaHCO₃ added until the mixture was neutralized. The organic phases were isolated and combined, dried over MgSO₄, filtered and
concentrated in vacuo yielding an oil. This oil was
distilled at 95 °C (0.8 mm) yielding the desired
salicylaldehyde as an oil (272.9 g, 56 %) which was of sufficient purity to be used without further purification.

Step 2. Preparation of ethyl 7-(1,1-dimethylethyl)-2- (trifluoromethyl)-2H-1-benzopyran-3-carboxylate.
A one liter three-neck flask was charged with 4-tert-butylsalicylaldehyde (Step 1) (100.0 g, 0.56 mole),
dimethylformamide (110 mL), and potassium carbonate (79.9 g, 0.58 mole) causing the temperature of the mixture to rise to 40 °C. Ethyl 4,4,4-trifluorocrotonate (118.0 g, 0.70 mole) in dimethylformamide (110 mL) was added and the mixture heated to 60 °C at which time the reaction temperature rose to 70 °C. The reaction was cooled to 60 °C, maintained at 60

°C (with addedheating) for 8.5 hours and cooled to room temperature. Ethyl acetate (600 mL) and 3 N HCl (600 mL) were added, mixed, and the layers separated. The aqueous phase was extracted with ethyl acetate and the organic phases were combined. The combined organic phases were washed with brine-water (1:1), brine, dried over MgSO₄, filtered and concentrated in vacuo, yielding a semi-solid. Hexane (600 mL) was added with mixing and the mixture was filtered. The filtrate was washed with brine, dried over

MgSO₄, filtered and concentrated in vacuo yielding a solid. This solid was dissolved in hot ethanol (600 mL). Water (190 mL) was added which induced crystallization. Filtration of the mixture and drying of the product provided the desired ester as a crystalline solid (131.3 g, 71%): mp 91.0-94.9 °C. This material was of suitable purity to be used in subsequent steps without further purification.

Step 3. Preparation of ethyl 6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate.
A one liter three-neck flask equipped with mechanical stirrer and gas inlet tube was charged with the ester (Step 2) (100 g, 0.3 mole) and acetic acid (300 mL). While cooling (water bath) the reaction mixture, chlorine gas (37.6 g, 0.53 mole) was added which caused the temperature to rise to 48 °C. After stirring for two hours, the
reaction was cooled in an ice-water bath to 15 °C. Zinc powder (19.5 g, 0.3 mole) was added in one portion which caused the temperature to rise to 72 °C. After cooling to room temperature additional zinc powder (5.0 g, 0.08 mole) was added and the mixture was stirred for 0.5 hour longer. The crude mixture was filtered through diatomaceous earth and was concentrated in vacuo yielding an oil. The oil was dissolved in ethyl acetate (700 mL) washed with brine-water (1:1, 1 L) and brine (0.5 L). The resulting aqueous phase was extracted with ethyl acetate (700 mL). This ethyl acetate phase was washed with brine-water (1:1, 1 L) and brine (0.5 L). The combined organic phases were dried over

MgSO₄, filtered and concentrated in vacuo yielding the title compound as a yellow oil (116 g, 106 %). This material, which contained some entrained ethyl acetate, was of suitable purity to be used in subsequent steps without further purification.

Step 4. Preparation of 6-chloro-7-(1,1-dimethylethyl)-2- (trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.
To a solution of the ester (Step 3) (116 g,
0.3 mole) in methanol (500 mL) and tetrahydrofuran (500 mL) in a one liter flask was added aqueous
sodium hydroxide (2.5 N, 240 mL, 0.6 mole). After
stirring overnight, the pH of the solution was
adjusted to 1 with concentrated hydrochloric acid
and the solution was extracted with ethyl acetate.
The ethyl acetate phase was dried over MgSO₄,
filtered and concentrated in vacuo yielding a
solid. This solid was dissolved in hot ethanol
(500 mL). Water (500 mL) was added and upon
cooling to room temperature crystals formed which
were collected by vacuum filtration. The crystals
were washed with ethanol-water (3:7, 3 X 200 mL)
and dried providing the title acid as a
crystalline solid (91.6 g, 91 %) : mp 194.9-196.5
°C. ¹H NMR (acetone-d₆/300 MHz) 7.86 (s, 1H),
7.52 (s, 1H), 7.12 (s, 1H), 5.83 (q, 1H, J = 7.1
Hz), 1.48 (s, 9H). Anal. Calc’d for C₁₅H₁₄ClF₃O₃:
C, 53.83; H, 4.22; Cl, 10.59. Found: C, 53.92; H,
4.24; Cl, 10.50

REF

• The IUPHAR Guide to Immunopharmacology: connecting immunology and pharmacologyPublication Name: ImmunologyPublication Date: 2020-03-02PMCID: PMC7160657PMID: 32020584DOI: 10.1111/imm.13175
• Synthesis of Deuterated Benzopyran Derivatives as Selective COX-2 Inhibitors with Improved Pharmacokinetic PropertiesPublication Name: ACS Medicinal Chemistry LettersPublication Date: 2014-08-06PMCID: PMC4190635PMID: 25313331DOI: 10.1021/ml500299q
• Leukotrienes, But Not Angiotensin II, Are Involved in the Renal Effects Elicited by the Prolonged Cyclooxygenase-2 Inhibition When Sodium Intake Is LowPublication Name: Journal of Cardiovascular PharmacologyPublication Date: 2013-04PMID: 23288201DOI: 10.1097/fjc.0b013e31828399ae
• The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-lifePublication Name: Bioorganic & Medicinal Chemistry LettersPublication Date: 2010-12-01PMID: 20709553DOI: 10.1016/j.bmcl.2010.07.054
• Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitorsPublication Name: European Journal of PharmacologyPublication Date: 2008-06-24PMID: 18457826DOI: 10.1016/j.ejphar.2008.03.057
• Modeling and Simulation to Support Dose Selection and Clinical Development of SC-75416, a Selective COX-2 Inhibitor for the Treatment of Acute and Chronic Pain
• Publication Name: Clinical pharmacology and therapeutics
• Publication Date: 2007-09-19
• PMID: 17882158
• DOI: 10.1038/sj.clpt.6100374

PAT

• Substituted benzopyran derivatives for the treatment of inflammationPublication Number: EP-0977748-A1Priority Date: 1997-04-21
• Endothermic reaction apparatusPublication Number: NO-308725-B1Priority Date: 1993-06-16
• History of Transformed Benzofiran, their preparation and pharmacological preparations for the treatment of inflammation containing themPublication Number: IL-132296-APriority Date: 1997-04-21
• Substituted benzopyran derivatives for the treatment of inflammationPublication Number: KR-100538258-B1Priority Date: 1997-04-21Grant Date: 2006-01-12
• Substituted benzopyran derivatives for the treatmentPublication Number: US-6806288-B1Priority Date: 1997-04-21Grant Date: 2004-10-19
• Benzopyran derivatives with substituents for the treatment of inflammationPublication Number: JP-4577534-B2Priority Date: 1997-04-21Grant Date: 2010-11-10
• Substituted benzopyran derivatives for the treatment of inflammationPublication Number: KR-20010020152-APriority Date: 1997-04-21

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///////////tigemocoxib, ANAX, cyclo-oxygenase 2 (COX-2) inhibitor, anti-inflammatory, SC-75416, SC 75416, C8D42HX4WH