IMRECOXIB

 

Imrecoxib (Hengyang)

CHINA 2012  osteoarthritis

Imrecoxib was approved by China Food and Drug Administration (CFDA) on May 20, 2011. It was developed and marketed as 恒扬^® by HengRui Pharmaceuticals.

Imrecoxib is a selective COX-2 inhibitor indicated for treatment of osteoarthritis.

恒扬^® is available as tablet for oral use, containing 100 mg of free Imrecoxib, and the recommend dose is 100 mg twice daily.

Common name: Imrecoxib; BAP-909; BAP 909; BAP909
Trademarks: Hengyang
Molecular Formula: C21H23NO3S
CAS Registry Number: 395683-14-4
IUPAC Name: 4-(4-methane-sulfonyl-phenyl)-1-propyl-3-p-tolyl-1,5-dihydropyrrol-2-one
Molecular Weight: 369.48
SMILES: O=C1N(CCC)CC(C2=CC=C(S(=O)(C)=O)C=C2)=C1C3=CC=C(C)C=C3
Mechanism: COX-2 Inhibitor; Cyclooxygenase-2 Inhibitor
Activity: Treatment of Osteoarthritis; Analgesic; Antipyritic; Antiinflammatory Drug
Status: Launched 2011 (China)
Originator: HengRui

Drug Name：

Imrecoxib

Research Code：

BAP-909

Trade Name：

恒扬^®

MOA：

Selective cyclooxygenase-2 (COX-2) inhibitor

Indication：

Osteoarthritis (OA)

Status：

Approved

Company：

HengRui (Originator)

Sales：

ATC Code：

• CN

SYN

SYN

Imrecoxib Synthesis

Chin Chem Lett 2001, 12, 775-778 (also Ref 2. This route is quoted as industrial method in various texts)

CN104193664A (an improvement here as Br is replaced with Cl)

US7112605B2 (primary reference for synthesis routes)

Identification:

1H NMR (Estimated) for Imrecoxib

Experimental: ¹H-NMR (CDCl₃, TMS, 400MHz) 1.008 (3H, t, J = 7.2Hz), 1.701-1.756 (2H, m), 2.376 (3H, s), 3.078 (3H, s), 3.575 (2H, t, J = 7.2Hz), 4.317 (2H, s), 7. 175 (2H, d, J = 8.0Hz), 7.294 (2H, d, J = 8.0Hz), 7.505 (2H, t, J = 6.8Hz), 7.870 (2H, t, J = 6.8Hz)

Sideeffects:

Being a mild COX-2 inhibitor, it is expected not to cause any serious cardiovascular risks. Similarly, it should not have any serious gastrointestinal problems too, as it not a good inhibitor of COX-1. None of the reports though have listed any serious adverse event reported by patients in the clinical trials.

References:

1. Cheng, G. F.;et. al. Imrecoxib: A novel and selective cyclooxygenase 2 inhibitor with anti-inflammatory effect. Acta Pharmacol Sin 2004, 25(7), 927-931.
2. Zhang, F.;et. al.Method for preparing imrecoxib. CN102206178A
3. Chao, W.;et. al. Synthesis method of imrecoxib. CN104193664A
4. Bai, A. P.;et. al. Synthesis and in vitro Evaluation of a New Class of Novel Cyclooxygenase-2 Inhibitors: 3, 4-diaryl-3-pyrrolin-2 ones.Chin Chem Lett 2001, 12, 775-7785.
5. Guo, Z. Discovery of imrecoxib. Chin J New Drugs2012, 21, 223.
6. Guo, Z.;et. al. Sulfonyl-containing 3,4-diaryl-3-pyrrolin-2-ones, preparation method, and medical use thereof. US7112605B2

SYN

Imrecoxib (Hengyang)

Imrecoxib, a new non-steroid anti-inflammtory drug (NSAID), was launched in China with the trade name of Hengyang for the treatment of osteoarthritis in 2012. It was originally designed and synthesized by Guo and co-workers at the Institute of Materia Medica (IMM) of the Chinese Academy of Medical Sciences in collaboration with Hengrui Pharmaceuticals.88 Imrecoxib, which is a moderately selective COX-2 inhibitor (with IC50 values against COX-1 and COX-2 being 115 ± 28 and 18 ± 4 nM, respectively),89 is the subject of twwo synthetic routes reported across several publications.90–93

The most likely process-scale route to this drug is described in Scheme 15, 93 which began with 2-bromo-40 -(methylsulfonyl)-acetophenone (84) and p-tolylacetic acid (85) as starting materials. In the presence of base, a-bromoketone 84 was treated with acid 85 which resulted in lactone 86 in 72% yield across the two-step sequence. Exposure of lactone 86 with propylamine triggered a ring-opening-ring closing reaction, which resulted in imrecoxib (XIII) directly in 85% yield.93

 

88. Guo, Z. R. Chin. J. New Drugs 2012, 21, 223.

89. Chen, X. H.; Bai, J. Y.; Shen, F.; Bai, A. P.; Guo, Z. R.; Cheng, G. F. Acta Pharmacol. Sin. 2004, 25, 927.

90. Bai, A. P.; Guo, Z. R.; Hu, W. H.; Shen, F.; Cheng, G. F. Chin. Chem. Lett. 2001, 12, 775.

91. Guo, Z.; Cheng, G.; Chu, F.; Yang, G.; Xu, B. CN Patent 1134413 C, 2001.

92. Guo, Z.; Cheng, G.; Chu, F. US Patent 2004/0029951 A1, 2004.

93. Zhang, F. Y.; Shen, X. M.; Sun, P. Y. CN Patent 102206178 A, 2011

Patent

CN 111747879

PATENT

CN 111747874

CN 111747873

CN 110386891

CN 109553564

CN 109553563

CN 108997188

CN 108947884

CN 108912030

CN 108864003

CN 108707100

CN 107586268

CN 104193664

CN 102206178

CN 101774958

US 20040029951

PATENT

CN 109678775

https://patents.google.com/patent/CN102206178A/en

Ai Rui former times cloth (N-n-propyl-3-p-methylphenyl-4-is to methylsulfonyl phenyl-3-pyrrolidin-2-one) is the nonsteroidal anti-inflammatory drug that a kind of appropriateness suppresses COX-2; put down in writing the synthetic method of Ai Rui former times cloth in the prior art (US20040029951), may further comprise the steps:

1) is raw material with the methylsulfonyl methyl phenyl ketone, makes alpha-brominated methylsulfonyl methyl phenyl ketone through bromo;

2) sodium borohydride reduction of alpha-brominated methylsulfonyl methyl phenyl ketone obtains the Styrene oxide 98min. derivative;

3) reaction of Styrene oxide 98min. derivative and Tri N-Propyl Amine generates N-n-propyl-capable biology of beta-hydroxyphenyl ethamine;

4) tolyl-acetic acid and the reaction of excessive thionyl chloride are generated the methylbenzene Acetyl Chloride 98Min.;

5) methylbenzene Acetyl Chloride 98Min. and the capable biological respinse of N-n-propyl-beta-hydroxyphenyl ethamine are generated N-n-propyl-N-[2-hydroxyl-2-to the methylsulfonyl styroyl] phenylacetamide;

6) Jone ‘ s reagent or pyridine chromium trioxide oxidation N-n-propyl-N-[2-hydroxyl-2-are to the methylsulfonyl styroyl] phenylacetamide obtains the capable biology of oxo phenylacetamide;

7) the above-mentioned oxo phenylacetamide of condensation makes end product Ai Rui former times cloth under the alkaline medium effect.

Because existing preparation method’s route is longer, and relate to reduction, oxidation, steps such as acid amides coupling, solvent load is big, the cost height, particularly to use oxygenants such as Jone ‘ s reagent or pyridine chromium trioxide in the oxidation step, low and the product of this oxidation step productive rate is difficult for separation and purification, and is difficult to control because chromium metal residual quantity control criterion in bulk drug is extremely strict, thereby makes this preparation method be difficult to be applicable to scale operation.

Synthetic route 1

Step 1), preparation alpha-brominated methylsulfonyl methyl phenyl ketone (III)

51.0g 4-methylsulfonyl methyl phenyl ketone and 760mL acetic acid is added to has magnetic agitation, in three mouthfuls of glass flask of the 1000mL of thermometer and constant pressure funnel.Be heated to 40 ℃, beginning slowly drips 41.1g liquid bromine, after dripping, continues to stir 30 minutes at 40 ℃.Reaction solution 50 ℃ concentrate after, add entry, stir, filter, washing, oven dry obtains the thick product of 70.5g, adds ethyl acetate/normal hexane mixed solvent, reflux 1 hour, slowly be cooled to 25 ℃, filtering drying gets the alpha-brominated methylsulfonyl methyl phenyl ketone of 56.5g off-white color solid (III), yield 80.0%.

¹H-NMR(CDCl ₃，TMS，400MHz)：3.120(3H，s)，4.485(2H，s)，8.101(2H，dd，J＝2.0Hz)，8.191(2H，dd，J＝2.0Hz)

MS(M+1)：279.05

Step 2), prepare 4-(4-methylsulfonyl phenyl)-3-(4-aminomethyl phenyl)-2,5-dihydrofuran-2-ketone (II)

Experiment condition A

With the alpha-brominated methylsulfonyl methyl phenyl ketone of 44.3g (III), 24.0g 4-methylphenyl acetic acid and 600mL acetonitrile are added to and have magnetic agitation, in the 500mL there-necked flask of thermometer and constant pressure funnel.Be added dropwise to the 24.0mL triethylamine by constant pressure funnel, temperature is controlled at 25 ℃, after adding, continues to stir 1 hour.Add the 36.0mL triethylamine again, reaction solution is heated to 75 ℃, stirring reaction 18 hours.Cool to 25 ℃, concentrate, add ethyl acetate, washing, organic phase concentrates the back and adds ethyl acetate and ethanol, stirs, and filters and obtains 28.0g light yellow solid compound (II), yield 53.4%.

¹H-NMR(CDCl ₃，TMS)2.398(3H，s)，3.091(3H，s)，5.192(2H，s)，7.216(2H，d，J＝8.0Hz)，7.292(2H，d，J＝8.0Hz)，7.543(2H，d，J＝8.0Hz)，7.933(2H，d，J＝8.0Hz)

MS(M+1)：329.02

Similarly, compound (II) can prepare under experiment condition B, C, D.

Experiment condition B

With the alpha-brominated methylsulfonyl methyl phenyl ketone of 5.0g (III), 2.7g 4-methylphenyl acetic acid and 70mL acetonitrile are added to and have magnetic agitation, in the 100mL there-necked flask of thermometer and constant pressure funnel.Be added dropwise to the 2.3mL tetramethyl guanidine by constant pressure funnel, temperature is controlled at 20 ℃, after adding, continues to stir 1.5 hours.Add the 4.6mL tetramethyl guanidine again, 20 ℃ of stirring reactions 2 hours.Concentrate, add ethyl acetate, washing, organic phase concentrates the back and adds ethyl acetate and ethanol, stirs, and filters and obtains 2.5g light yellow solid compound (II), yield 42.0%.

Experiment condition C

With the alpha-brominated methylsulfonyl methyl phenyl ketone of 1.85g (III), 1.0g 4-methylphenyl acetic acid and 20mL ethanol are added to and have magnetic agitation, in the 50mL there-necked flask of thermometer and constant pressure funnel.Be added dropwise to the 1.0mL triethylamine by constant pressure funnel, temperature is controlled at 25 ℃, after adding, continues to stir 3 hours.Add the 2.0mL triethylamine again, 80 ℃ of stirring reactions 18 hours.Concentrate, add ethyl acetate, washing, organic phase concentrates the back and adds ethyl acetate and ethanol, stirs, and filters and obtains 0.83g light yellow solid compound (II), yield 38.1%.

Experiment condition D

With the alpha-brominated methylsulfonyl methyl phenyl ketone of 1.0g (III), 0.54g 4-methylphenyl acetic acid and 12mL acetonitrile are added to and have magnetic agitation, in the 50mL there-necked flask of thermometer and constant pressure funnel.Add 1.0g salt of wormwood, 25 ℃ were reacted 2 hours.50 ℃ of stirring reactions are 5 hours then.Concentrate, add ethyl acetate, washing, organic phase concentrates the back and adds ethyl acetate and ethanol, stirs, and filters and obtains 0.13g light yellow solid compound (II), yield 11%.

Step 3), preparation N-n-propyl-3-p-methylphenyl-4-are to methylsulfonyl phenyl-3-pyrrolidin-2-one (Ai Rui former times cloth (I))

Experiment condition A

With the 25.0mL Tri N-Propyl Amine, be added drop-wise in the 17.5mL acetic acid at 10 ℃, add the back and stir, in the Tri N-Propyl Amine acetate that generates, add 10.0g compound (II).Under the nitrogen protection, be heated to 160 ℃, stirring reaction 8 hours.Cool to 40 ℃, add methylene dichloride and water, standing demix.Organic phase concentrates in the residue of back and adds ethanol, and reflux cools to 25 ℃, filters, and oven dry obtains 8.2g white solid product compound (I), yield 72.8%.

¹H-NMR(CDCl ₃，TMS，400MHz)1.008(3H，t，J＝7.2Hz)，1.701-1.756(2H，m)，2.376(3H，s)，3.078(3H，s)，3.575(2H，t，J＝7.2Hz)，4.317(2H，s)，7.175(2H，d，J＝8.0Hz)，7.294(2H，d，J＝8.0Hz)，7.505(2H，t，J＝6.8Hz)，7.870(2H，t，J＝6.8Hz)

MS(M+1)：370.17

Similarly, compound (I) can prepare under experiment condition B, C, D.

Experiment condition B

2.9g Tri N-Propyl Amine hydrochloride and 1.0g compound (II) are mixed, under the nitrogen protection, be heated to 170 ℃, stirring reaction 2 hours.Cool to 40 ℃, add methylene dichloride and water, standing demix.Organic phase concentrates in the residue of back and adds ethanol, and reflux cools to 25 ℃, filters, and oven dry obtains 0.9g white solid product compound (I), yield 80.0%.

Experiment condition C

Digest compound (II) with 2.0,3 milliliters of Tri N-Propyl Amines, 1.75 gram Tri N-Propyl Amine hydrochlorides add in the tube sealing of nitrogen protections, are heated to 140 ℃, react 20 hours.Be cooled to room temperature, add methylene dichloride and water, standing demix.Organic phase concentrates in the residue of back and adds ethanol, and reflux cools to 25 ℃, filters, and oven dry obtains 1.8g white solid product compound (I), yield 80.0%.

Experiment condition D

With the 0.5mL Tri N-Propyl Amine, be added drop-wise in the 0.35mL acetic acid at 10 ℃, add the back and stir, in the Tri N-Propyl Amine acetate that generates, add 0.5g compound (II).Under the nitrogen protection, be heated to 120 ℃, stirring reaction 4 hours.Cool to 40 ℃, add methylene dichloride and water, standing demix.Obtain 0.14g compound (I) after organic phase is concentrated and purified, yield 24.2%.

PAPER

 Chinese Chemical Letters (2001), 12(9), 775-778.

PATENT

CN 110386891,

 

CLIP

For Chinese drugmaker Hengrui, R&D plans pan out

Ambitious program to launch innovative drugs starts to pay off for generics producerby Jean-François Tremblay

JULY 17, 2017 | APPEARED IN VOLUME 95, ISSUE 29

////////////////Imrecoxib, Hengyang, CHINA 2012,   osteoarthritis