Tegileridine

• YFJS8L4TGU
• CAS 2095345-66-5
• (9R)-N-((1S,4S)-4-Ethoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-9-(2-pyridinyl)-6-oxaspiro(4.5)decane-9-ethanamine
• 434.6 g/mol

WeightAverage: 434.624
Monoisotopic: 434.293328472

Chemical FormulaC₂₈H₃₈N₂O₂

(1S,4S)-4-ethoxy-N-[2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethyl]-1,2,3,4-tetrahydronaphthalen-1-amine

• (9R)-N-((1S,4S)-4-Ethoxy-1,2,3,4-tetrahydro-1-naphthalenyl)-9-(2-pyridinyl)-6-oxaspiro(4.5)decane-9-ethanamine
• (1S,4S)-4-Ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine
• (1S,4S)-4-Ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro(4.5)decane-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine

Tegileridine fumarate

CAS#2245827-85-2 (fumarate)

Chemical Formula: C32H42N2O6

Exact Mass: 550.3000

Molecular Weight: 550.70

CHINA 2025, APPROVALS 2025, AISUTE, Jiangsu Hengrui

Tegileridine is under investigation in clinical trial NCT06458400 (To Evaluate the Efficacy and Safety of Tegileridine and Oliceridine Injections in the Treatment of Postoperative Pain).

Tegileridine is a drug which acts as a μ-opioid receptor agonist. It is closely related to compounds such as oliceridine, TRV734, and SHR9352, and shares a similar profile as a biased agonist selective for activation of the G-protein signalling pathway over β-arrestin 2 recruitment.^[1]

In January 2024, tegileridine was approved in China for the treatment of moderate to severe pain after abdominal surgery.^[2]

SYN

CN107001347

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN203399246&_cid=P20-METU4Y-21400-1

SYN

WO 2017/063509

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017063509&_cid=P20-METU6J-22458-1

[0183]Examples 1 and 2 

[0184](S)-1-Ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydroquinolin-1-amine 1 

[0185](R)-1-ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydroquinolin-1-amine 2 

[0186]

[0187](R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4,5]decane-9-yl)acetaldehyde 1a (294 mg, 1.135 mmol, prepared by the method disclosed in patent application “WO2012129495”) and 1-ethyl-1,2,3,4-tetrahydroquinolin-4-amine 1b (200 mg, 1.135 mmol, prepared by the method disclosed in patent application “WO2014078454”) were dissolved in 15 mL of dichloromethane, stirred for 1 hour, and sodium triacetoxyborohydride (1.203 g, 5.675 mmol) was added and stirred for 16 hours. 20 mL of water was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain the title product, 1-ethyl-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydroquinolin-1-amine. Chiral preparation was performed (separation conditions: chiral preparative column Superchiral S-AD (Chiralway), 2 cm ID*25 cm, 5 um; mobile phase: CO 

₂ :methanol:diethanolamine=75:25:0.05, flow rate: 50 g/min). The corresponding fractions were collected and concentrated under reduced pressure to give the title products 1 (98 mg, brown oil) and 2 (95 mg, yellow solid). 

[0188]Example 1: 

[0189]MS m/z(ESI):420.3[M+1]； 

[0190]Chiral HPLC analysis: retention time 4.028 minutes, chiral purity: 99.7% (chromatographic column: Superchiral S-AD (Chiralway), 0.46 cm ID*15 cm, 5 μm; mobile phase: CO2: methanol: diethanolamine = 75:25:0.05 (v/v/v)) 

[0191]

¹H NMR(400MHz,DMSO-d ₆)δ8.54(s,1H),7.72(s,1H),7.45(d,1H),7.20(s,1H),6.95(s,1H),6.78(d,1H),6.52(d,1H),6.37(s,1H),3.60(br,2H),3.18-3.43(m,3H),2.99(m,1H),2.33-2.45(m,3H),1.77-1.99(m,3H),1.19-1.60(m,12H),1.00-1.06(m,4H),0.63(m,1H).

[0192]Example 2: 

[0193]MS m/z(ESI):420.3[M+1]； 

[0194]Chiral HPLC analysis: retention time 3.725 minutes, chiral purity: 99.8% (chromatographic column: Superchiral S-AD (Chiralway), 0.46 cm ID*15 cm, 5 μm; mobile phase: CO2: methanol: diethanolamine = 75:25:0.05 (v/v/v)) 

[0195]

¹H NMR(400MHz,DMSO-d ₆)δ8.53(s,1H),7.72(s,1H),7.46(d,1H),7.20(s,1H),6.97(s,1H),6.85(d,1H),6.54(d,1H),6.40(s,1H),3.61(br,2H),3.17-3.25(m,3H),3.00-3.01(m,1H),2.33-2.46(m,3H),1.78-1.97(m,3H),1.24-1.65(m,12H),1.01-1.06(m,4H),0.61(m,1H).

SYN

US11111236

https://patentscope.wipo.int/search/en/detail.jsf?docId=US306969245&_cid=P20-METUA8-25189-1

Embodiment 1: Preparation of (1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step One: Synthesis of Intermediate (D-1)

The compound represented by the formula (E1) (25 g), potassium hydroxide (22.4 g) and ethylene glycol (150 mL) were mixed and the resulting mixture was stirred at 150° C. for 16 hours, and then the reaction was stopped. The reaction solution was cooled to room temperature, diluted with water (150 mL) and extracted with dichloromethane (150 mL×2). The aqueous phase was adjusted to pH=6-7 with 3M hydrochloric acid and extracted with dichloromethane (200 mL×4). The combined organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (26.1 g, pale yellow oil) with a yield of 97.4% and a HPLC purity of 92%.

Step Two: Synthesis of Intermediate (D2-1)

The compound represented by the formula (D-1) (28 g) was dissolved in anhydrous ethanol (100 mL) and the temperature was raised to 50° C. The resolving agent S-phenylethylamine (6.2 g) was dissolved in anhydrous ethanol (100 mL) and the resulting S-phenylethylamine solution was added dropwise into the above solution at 50° C. The mixture was heated to reflux and stirred for 2 hours. Then the mixture was allowed to cool to 10° C. naturally, and solid was precipitated. The mixture was filtered, and the filter cake was washed to give the product (13 g, solid) with an enantiomeric excess (ee) value of 96.7%;

recrystallization: the obtained 13 g solid product was added to anhydrous ethanol (80 mL), heated to reflux and stirred for 6 hours. Then the mixture was naturally cooled to 10° C. and solid was precipitated. The mixture was filtered, the filter cake was washed and dried to give the product (10.6 g) with an ee value of 99.0%.

Step Three: Synthesis of Intermediate (D2)

KOH (2.18 g) was dissolved in water (120 mL), and then the compound represented by formula (D2-1) was dissolved in the solution. The mixture was extracted with dichloromethane (100 mL×3). The aqueous phase was adjusted to pH=6-7 with IN HCl solution and then extracted with dichloromethane (150 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the product (7 g) with a yield of 50% and an ee value of 99.4%.

MS m/z (ESI): 276.71 [M+H] +, 298.68 [M+Na] +.

1H NMR (400 MHz, CDCl 3) δ 8.50-8.51 (m, 1H), 7.73-7.77 (m, 1H), 7.51-7.53 (d, 1H), 7.21-7.24 (m, 1H), 3.73-3.84 (m, 2H), 2.78-2.81 (d, 1H), 2.58-2.63 (m, 1H), 2.53-2.56 (d, 1H), 2.39-2.43 (m, 1H), 1.98-2.02 (d, 1H), 1.87-1.94 (m, 1H), 1.76-1.80 (m, 1H), 1.61-1.65 (m, 1H), 1.39-1.58 (m, 4H), 1.14-1.19 (m, 1H), (m, 1H), (m, 1H).

Step Four: Synthesis of Intermediate (C2)

Dichloromethane (8.5 kg) was added to a reaction flask, and then the raw material (R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetic acid (350 g), N,O-dimethylhydroxylamine hydrochloride (148.8 g), EDCI (292.3 g) and DMAP (15.5 g) were added under stirring. After the resulting mixture was stirred for 15-25 minutes, DIPEA (492.4 g) was added. Then the mixture was stirred under argon protection at room temperature for 16-18 hours. A saturated ammonium chloride aqueous solution (2.8 kg) was added to the reaction solution, and the resulting mixture was stirred for 5-10 minutes and partitioned. The organic phase was washed with saturated ammonium chloride aqueous solution (2.8 kg×2) and saturated brine (2.7 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and then dichloromethane (2.5 kg) was added. The mixture was concentrated to dryness under reduced pressure to give an oil (372.03 g) with a yield of 92.0%.

MS m/z (ESI): 319.1 [M+H] +, 341.3 [M+Na] +.

1H NMR (400 MHz, CDCl 3) δ 8.50-8.51 (m, 1H), 7.66-7.71 (m, 1H), 7.43-7.45 (d, 1H), 7.15-7.18 (m, 1H), 3.63-3.66 (m, 2H), 3.47 (s, 3H), 2.86-2.88 (d, 3H), 2.62-2.65 (d, 1H), 2.50-2.57 (m, 1H), 2.36-2.39 (d, 1H), 1.96-2.00 (d, 1H), 1.80-1.86 (m, 1H), 1.68-1.72 (m, 1H), 1.48-1.55 (m, 1H), 1.31-1.46 (m, 4H), 1.03-1.07 (m, 1H), 0.63-0.71 (m, 1H).

Step Five: Synthesis of Intermediate (B2)

The compound represented by formula (C2) (334.4 g) was dissolved in toluene (2.2 kg) in a reaction flask. The solution was cooled to −45° C. to −35° C. and purged with argon, and then red aluminum (348.76 g) was added dropwise while maintaining the temperature between −45° C. to −35° C. After completion of the addition, the reaction solution was stirred at −45° C. to −35° C. for 3-4 hours, and then 10% citric acid aqueous solution (1 kg) was added to the reaction solution at −45° C. to −35° C. Then concentrated hydrochloric acid solution was added to adjust the pH to 2-3, followed by addition of ethyl acetate (1.8 kg). The mixture was stirred and allowed to stand to partition. The aqueous phase was adjusted to pH=11-13 with 5N sodium hydroxide solution, and then extracted with dichloromethane (3.3 kg×2). The combined dichloromethane phase was washed with saturated sodium chloride solution (2.7 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and then dichloromethane (3.3 kg) was added. The mixture was concentrated again under reduced pressure to give a pale red oil, which was directly used in the next step.

Step Six: Synthesis of the Compound Represented by Formula (III)

The above oil was added to a reaction flask, followed by addition of dichloromethane (8.5 kg) and the compound represented by formula (A1) (134.56 g). The resulting mixture was stirred for 2-3 hours, followed by addition of sodium triacetoxyborohydride (373.86 g). The mixture was stirred at room temperature for 16-18 hours, followed by addition of saturated sodium carbonate solution (2.66 kg). Then the mixture was adjusted to pH=11-13 by addition of 5N sodium hydroxide aqueous solution and partitioned. The organic phase was washed with saturated ammonium chloride aqueous solution (2.83 kg) and saturated sodium chloride aqueous solution (2.74 kg), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure, and then acetonitrile (120 g) was added. The mixture was stirred at room temperature for 16-18 hours to crystallize, and then filtered. The filter cake was dried to give the product (206.87 g) with a yield of 68.0%.

MS m/z (ESI): 435.3 [M+H] +.

1H NMR (400 MHz, CDCl 3) δ 9.74 (d, 1H), 9.58 (d, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 7.94 (d, 1H), 7.67 (d, 1H), 7.52 (d, 1H), 7.47 (t, 1H), 4.46-4.49 (m, 1H), 4.30-4.33 (m, 1H), 3.84-3.87 (m, 1H), 3.66-3.70 (m, 2H), 3.53-3.56 (m, 2H), 2.82-2.85 (d, 2H), 2.67 (s, 2H), 2.39-2.41 (m, 4H), 2.30-2.33 (m, 4H), 1.85 (s, 2H), 1.48-1.52 (m, 6H), 1.27 (m, 3H).

SYN

US20200054594A1

SYN

Tegileridine fumarate, developed by Jiangsu Hengrui Pharmaceuti
cals Co., Ltd., is a novel small-molecule analgesic that functions as a
complete opioid receptor agonist with relative selectivity for -opioid
receptors (MOR). It is marketed under the brand name Aisute. In 2024,
the NMPA approved Tegileridine fumarate injection for the treatment of moderate to severe pain following abdominal surgery. Tegileridine ex
erts its analgesic effects by activating MOR, leading to inhibition of
adenylate cyclase activity, decreased intracellular cAMP levels, and
subsequent modulation of ion channel conductance. This results in hy
perpolarization of neuronal membranes and reduced neuronal excit
ability, effectively alleviating pain. The clinical efficacy of Tegileridine
was evaluated in a Phase III randomized, double-blind, placebo-
controlled trial (NCT05012516) involving patients experiencing mod
erate to severe pain after abdominal surgery. The research indicated that
Tegileridine offered substantial alleviation of pain in contrast to the
placebo. It manifested a quick-acting property, and its analgesic effects
endured throughout the period of observation. In terms of toxicity,
Tegileridine was typically well-tolerated by the subjects. The most
frequently encountered adverse reactions were nausea, vomiting, and
dizziness, all of which were of mild to moderate intensity. Importantly,
Tegileridine exhibited a favorable safety profile with a lower incidence
of gastrointestinal adverse reactions compared to traditional MOR ag
onists, potentially offering an improved therapeutic window for post
operative pain management. The approval of Tegileridine provides a
new treatment option for patients suffering from moderate to severe
postoperative pain, particularly following abdominal surgeries,
addressing a significant clinical need in pain management [72,73].
The synthesis of Tegileridine fumarate, illustrated in Scheme 17,
begins with nucleophilic substitution reaction involving Tegi-001 to
yield Tegi-002 [74]. Tegi-002 is subsequently acidified to produce
Tegi-003. Finally, Tegi-003 undergoes reductive amination with
Tegi-004 to synthesize Tegileridine.

[72] S. Dhillon, Correction: tegileridine: first approval, Drugs 84 (2024) 1011.
[73] S. Dhillon, Tegileridine: first approval, Drugs 84 (2024) 717–720.
[74] X. Li, B. Feng, Y. Chen, T. Liu, F. He, M. He, W. Tao, P. Sun, Oxa Spiro Derivative
Useful in Treatment of Pain and pain-related Disease and Its Preparation, 2017.
CN107001347A.

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References

1.  WO 2017/063509, “Oxa spiro derivative, preparation method therefor, and applications thereof in medicines”, published 10 April 2018, assigned to Jiangsu Hengrui Medicine Company and Shanghai Hengrui Pharmaceutical Company Ltd .
2.  Dhillon S (June 2024). “Tegileridine: First Approval”. Drugs. 84 (6): 717–720. doi:10.1007/s40265-024-02033-4. PMID 38771484.

Clinical data
Trade names	艾苏特
Legal status
Legal status	Rx in China
Identifiers
IUPAC name
CAS Number	2095345-66-5
PubChem CID	129049969
UNII	YFJS8L4TGU
Chemical and physical data
Formula	C28H38N2O2
Molar mass	434.624 g·mol−1
3D model (JSmol)	Interactive image
SMILES
InChI

• New drugs approved by the NMPA in 2024: Synthesis and clinical applicationsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2025-07-05PMID: 40262297DOI: 10.1016/j.ejmech.2025.117643
• Tegileridine: First ApprovalPublication Name: DrugsPublication Date: 2024-05-21PMID: 38771484DOI: 10.1007/s40265-024-02033-4
• Study of the mass balance, biotransformation and safety of [14C]SHR8554, a novel μ-opioid receptor injection, in healthy Chinese subjectsPublication Name: Frontiers in PharmacologyPublication Date: 2023-09-14PMCID: PMC10538116PMID: 37781692DOI: 10.3389/fphar.2023.1231102

• Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: US-2018297988-A1Priority Date: 2015-10-15
• Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: WO-2017063509-A1Priority Date: 2015-10-15
• Oxaspiro derivatives, methods of their manufacture, and their application in pharmaceuticalsPublication Number: JP-6824502-B2Priority Date: 2015-10-15Grant Date: 2021-02-03
• Oxa spiro derivatives, their preparation, and their applications in medicinePublication Number: KR-102703513-B1Priority Date: 2015-10-15Grant Date: 2024-09-06

• Opioid Receptor (MOR) Agonist Salt, Its Fumarate Salt I Crystalline Form, and Process for Making SamePublication Number: JP-7153030-B6Priority Date: 2017-04-14Grant Date: 2023-07-24
• Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: EP-3354649-A1Priority Date: 2015-10-15
• Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: EP-3354649-B1Priority Date: 2015-10-15Grant Date: 2019-12-04
• Oxaspiro derivative, process for its production and its application in medicinePublication Number: JP-2018534257-APriority Date: 2015-10-15
• Oxa spiro derivative, preparation method therefor, and applications thereof in medicinesPublication Number: US-10442793-B2Priority Date: 2015-10-15Grant Date: 2019-10-15

////////////Tegileridine, CHINA 2025, APPROVALS 2025, AISUTE, Jiangsu Hengrui, YFJS8L4TGU, 2095345-66-5, Tegileridine FUMARATE