Ropivacaine

CAS No.84057-95-4 (Ropivacaine);

• Molecular FormulaC₁₇H₂₆N₂O
• Average mass274.401 Da

HCL SALT

Molecular Weight328.88, FormulaC17H26N2O • HCl • H2O

132112-35-7 (Ropivacaine HCl Monohydrate);

Chemical Name S-(-)-1-propyl-2′,6′-pipecoloxylidide hydrochloride monohydrate

Ropivacaine (rINN) /roʊˈpɪvəkeɪn/ is a local anaesthetic drug belonging to the amino amide group. The name ropivacaine refers to both the racemate and the marketed S–enantiomer. Ropivacaine hydrochloride is commonly marketed by AstraZeneca under the brand name Naropin.

Compound	Structure	Time to market	Application methods
Procaine		1904	Infiltration anesthesia, conduction anesthesia, subarachnoid anesthesia and epidural anesthesia
Chloroprocaine		1952	Infiltration anesthesia, epidural anesthesia and conduction anesthesia
Hydroxyprocaine		1960	Infiltration anesthesia
Tetracaine		1988	Conduction anesthesia, subarachnoid anesthesia and epidural anesthesia
Oxybuprocaine		1975	Topical anesthesia
Tutocaine		1976	Topical anesthesia and infiltration anesthesia
Butacaine		1976	Topical anesthesia and infiltration anesthesia
Dimethocaine		1938	Topical anesthesia and infiltration anesthesia
Thiocaine		Halt sales	Topical anesthesia and infiltration anesthesia
Lidocaine		1948	Conduction anesthesia and epidural anesthesia
Mepivacaine		1986	Infiltration anesthesia, conduction anesthesia, epidural anesthesia and topical anesthesia
Bupivacaine		2000	Infiltration anesthesia, conduction anesthesia and epidural anesthesia
Ropivacaine		1996	Infiltration anesthesia, conduction anesthesia and epidural anesthesia
Trimecaine		1965	Infiltration anesthesia, surface anesthesia and epidural anesthesia
Prilocaine		1993	Infiltration anesthesia, topical anesthesia and epidural anesthesia
Etidocaine		1976	Epidural anesthesia
Pyrrocaine		1964	Conduction anesthesia and epidural anesthesia
Butanilicaine		1982	Infiltration anesthesia and conduction anesthesia
Cinchocaine		1985	Topical anesthesia, subarachnoid anesthesia and epidural anesthesia
Articaine		2002	Infiltration anesthesia and subarachnoid anesthesia
Dyclonine		1956	Topical anesthesia
Falicaine		1957	Topical anesthesia
Quinisocaine		1957	Topical anesthesia
Pramocaine		1977	Topical anesthesia
Diperodon		1980	Topical anesthesia
Heptacaine		1984	Infiltration anesthesia

Syn

Synthesis Reference

Peter Jaksch, “Process for the preparation of ropivacaine hydrochloride monohydrate.” U.S. Patent US5959112, issued February, 1970.

US5959112

Route 1

Reference：1. US2799679A.

2. US4870086A.

Route 2

Reference：1. WO8500599A1.

https://patents.google.com/patent/WO1985000599A1/en

A large variety of N-alkyl-pipecolic acid amides have been synthesized. A number of these compounds have found use as local anesthetics, such as Mepivacaine, namely the racemate of N-methylpipecolic–acid-2,6-xylidide:

and Bupivacaine, namely the racemate of N-butylpipecolic- acid-2,6-xylidide:

References disclosing homologs of this series of compounds include U.S. Patent 2,799,679; British Patent 775,749; British Patent 775,750; British Patent 800,565; British Patent 824,542; British Patent 869,978; British Patent 949,729; U.S. Patent 4,110,331; and U.S. Patent 4,302,465.

There is a summary paper dealing with these types of anesthetics, and related compounds in a paper in Acta Che ica Scandinavica 11, (1957) No. 7 pp. 1183-1190 by Bo Thuresson af Ekenstam et al.

There is a discussion of the^“ effect of optical isomers in related compounds in J. Med. Chem., 14 (1971) pp. 891-892 entitled “Optical Isomers Of Mepivacaine And Bupivacaine” by Benjamin F. Tullar; Acta Pha m. Suecica, 8 (1971) pp. 361- 364 entitled “Some Physicochemical Properties Of The Racemates And The Optically Active Isomers Of Two Local Anaesthetic Compounds”, by . Friberger et al -.; Acta Pharmacol et Toxicol, 31 (1972). pp. 273-286 entitled “Toxicological And Local Anaesthetic Effects Of Optically Active Isomers Of Two Local Anaesthetic Compounds”, by G. Aberg; Annual Review Of Pharmacology, 9 (1969) pp. 5Q3-520 entitled “Duration Of Local Anaesthesia”, by F.P. Luduena and Acta Pharmacol, et Toxicol, 41 (1977). pp. 432-443 entitled “Studies On The Duration Of Local Anaesthesia: Structure/Activity Relationships In A Series Of Homologous Local Anaesthetics”, by G. Aberg et al.

Route 3

Reference：1. J. Labelled Compd. Rad. 1987, 24, 521-528.

Route 4

Reference：1. CN104003930A.

https://patents.google.com/patent/CN104003930A/en

Ropivacaine (Ropivacaine) is the long-acting local anesthetics of amide derivatives of Novel pure levo form of Astra drugmaker of Sweden listing in 1996, there is analgesia and anesthesia dual function, be widely used in nerve block anesthesia, local infiltration anesthesia and epidural anesthesia , be particularly useful for Postoperative Analgesia After and obstetrical analgesia.

On piperidine ring in ropivacaine structure, having a chiral carbon atom, is chipal compounds, and levoisomer is low compared with dextrorotatory isomer toxicity, and action effect is good.

Ropivacaine HCL is the hydrochloride of ropivacaine, and chemistry is by name: (-)-(S)-N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-carboxamide hydrochloride, molecular formula is C ₁₇ h ₂₆ n ₂ oHCl, structural formula:

At present, in prior art, the synthetic method of ropivacaine mainly contains:

Taking L-2-piperidine formyl chlorine as starting raw material, through phosphorus pentachloride or sulfur oxychloride acidylate, then with the condensation of 2,6-xylidine, and then react and obtain ropivacaine with n-propyl bromide.Although this method production technique is simple, reactions steps is also shorter, but commercially available L-2-piperidine carboxylic acid average price is 4～5 times of racemization Pipecolic Acid, raw materials cost is too high, and may there is racemization phenomenon in subsequent reactions process, affect optical purity of products, for example US Patent No. 4695576 and “Chinese Medicine magazine” o. 11th in 2012 “Ropivacaine HCL a synthetic” literary composition and Chinese patent CN201310041390.2 all adopt this kind of method.

“synthetic chemistry” the 14th the 4th phase of volume “Synthesis of Ropivacaine Hydrochloride by Triphosgene” in 2006 and Hunan University’s Master’s thesis “synthesising process research of Ropivacaine HCL and” disclose the synthetic method of another ropivacaine, the Pipecolic Acid that adopts inexpensive racemization is raw material, prepare Ropivacaine HCL through reactions such as amidation, alkylations, use triphosgene or thionyl chloride to prepare acyl chlorides, but triphosgene danger in the time of storage and aftertreatment is larger, is not suitable for suitability for industrialized production; And partial condition in the latter’s method (reagent that the pH separating as intermediate (I) and reagent, catalyzer and recrystallization are used etc.) haves much room for improvement,under its test conditions, be difficult to take into account high purity and high yield simultaneously, according to prior art, the separation of ropivacaine raceme is also not ideal.

The preparation method of embodiment 1, a kind of Ropivacaine HCL, comprises the steps:

(1) preparation of intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea

10.0g2-piperidine carboxylic acid, 160ml toluene are added in 500ml reaction flask.Pass into HCl gas, to pH2, be warming up to 48 ± 2 DEG C, add 1.5mlDMF, drip 11.2g (1.2 equivalent) sulfur oxychloride and 20ml toluene mixture liquid, drip and finish, be incubated 48 ± 2 DEG C of reaction 3h.Drip 2 of 4.0 equivalents, 6-xylidine and 20ml toluene mixture liquid, be incubated 58 ± 2 DEG C of reaction 3h.Filter, obtain yellow-green colour wet product 65g, dry to obtain gray solid 56g, solid is added in 280ml purified water, stir the molten reaction solution that obtains; 10%NaOH solution is slowly dropped in reaction solution, adjust pH to 4.5-5.0, use 100ml toluene wash , layering, retains water layer, continues to adjust pH to 9-10 with 10%NaOH solution, adds 100ml methylene dichloride.Layering, gets organic layer,and water layer continues to use 50ml dichloromethane extraction, merges organic layer, adds anhydrous sodium sulfate dehydration, 40 DEG C of concentrating under reduced pressure.Obtain pale yellow oily liquid body 15.5g, yield 86.2%, is intermediate (I) N-( 2,6-dimethyl benzene)-2-piperidyl urea.

(2) preparation of intermediate (II) N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide

Intermediate 15.5 g of (the I) Dissolved in 60mlDMF IS, ADDS 8.9gK ₂ cO _{. 3} , 8.2 g of drip (1.0 equivalent)-n-propyl bromide, and drip BE Finishing After Warming up to 78 ± 2 of DEG C, Insulation Reaction 2H; Ice Bath is down to room temperature, filters, and filtrate is added in 150ml frozen water, separates out a large amount of white solids, filter, dry, obtain white solid 17.4g, yield 95.0%, is intermediate (II) N-(2, 6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide.

(3) preparation of left-handed ropivacaine tartrate

17.4g intermediate (II) is dissolved in 100ml Virahol, heats up 40 DEG C and stir molten; Treat entirely moltenly, add successively 1.80g (0.1 equivalent) titanium isopropylate, 1.91g (0.2 equivalent) D-tartrate, be warming up to backflow, after solution clarification, continue reaction 2h; Be cooled to 30 DEG C of crystallizatioies, filter, 75 DEG C of oven dry, obtain white solid 8.7g, and yield 39.2% is left-handed ropivacaine tartrate; After testing, ropivacaine purity 99.02%, dextrorotatory isomer per-cent 0.98%.

(4) preparation of Ropivacaine HCL crude product

Left-handed 8.7g ropivacaine tartrate is joined in 50ml Virahol, be warming up to 50 DEG C, drip concentrated hydrochloric acid, surveying pH is 1～2, insulation reaction 2h.Be cooled to 0 DEG C of crystallization, separate out a large amount of white solids, filter, dry, obtain white solid 6.6g, yield 85.5%, is Ropivacaine HCL crude product.After testing, ropivacaine purity 99.11%, dextrorotatory isomer per-cent 0.89%.

(5) refining

6.6g crude product and 40ml dehydrated alcohol-concentrated hydrochloric acid mixed solution (20:1) are added in reaction flask, be heated to 50 DEG C and make to dissolve; Complete molten after, naturally cool to room temperature, ice-water bath is cooled to 0 DEG C, crystallization 2h; Filter, 5ml mixed solution washing for filter cake, obtains wet product, dries, and obtains white solid 6.0g, and yield 91.7%, is Ropivacaine HCL fine work.After testing, ropivacaine purity 99.91 %, dextrorotatory isomer per-cent 0.09%.

The preparation method of embodiment 2, a kind of Ropivacaine HCL

Step is as follows:

(1) preparation of intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea

100.0g2-piperidine carboxylic acid, 1600ml toluene are added in 3000ml reaction flask.Pass into HCl gas, to pH2 left and right, be warming up to 45～50 DEG C, add 15mlDMF, drip 111.5g (1.2 equivalent) sulfur oxychloride and 200ml toluene mixture liquid, drip and finish, be incubated 50-55 DEG C of reaction 3h.Drip 2 of 4.0 equivalents, 6-xylidine and 200ml toluene mixture liquid, be incubated 55～60 DEG C of reaction 2h.Filter, obtain the about 660g of yellow-green colour wet product, dry to obtain gray solid 545g, solid is added in 3000ml purified water, stir the molten reaction solution that obtains; 10%NaOH solution is slowly dropped in reaction solution, adjust pH to 4.5～5.0 , use 1000ml toluene wash, layering, retains water layer, continues to adjust pH to 9～10 with 10%NaOH solution, adds 1000ml methylene dichloride.Layering, gets organic layer,and water layer continues to use 750ml dichloromethane extraction, merges organic layer, adds anhydrous sodium sulfate dehydration, 40 DEG C of concentrating under reduced pressure.Obtain the about 151.8g of pale yellow oily liquid body, yield 84.5%, is intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea.

(2) preparation of intermediate (II) N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide

Intermediate 150.0 g (the I) Dissolved in 600mlDMF IS, ADDS 86.5gK ₂ cO _{. 3} , drip 95.4 g (1.2 equivalent)-n-propyl bromide, and drip BE Finishing After Warming up to 85 ~ 90 of DEG C, Insulation Reaction 2H; of Be Down to room temperature, filter, filtrate is added in 1500ml frozen water, separate out a large amount of white solids, filter, dry, obtain the about 167.6g of white solid, yield 94.6%, is intermediate (II) N-(2, 6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide.

(3) preparation of left-handed ropivacaine tartrate

160.0g intermediate (II) is dissolved in 1000ml Virahol, heats up 50 DEG C and stir molten; Treat entirely moltenly, add successively 16.58g (0.1 equivalent) titanium isopropylate, 43.8g (0.5 equivalent) D-tartrate, be warming up to backflow, after solution clarification, continue reaction 3h; Cooling, is down to 30-35 DEG C of crystallization, filters, and 75 DEG C of oven dry, obtain white solid 84.2g, and yield 41.3% is left-handed ropivacaine tartrate; After testing, ropivacaine purity 98.97%, dextrorotatory isomer per-cent 1.03%.

(4) preparation of Ropivacaine HCL crude product

Left-handed 80.0g ropivacaine tartrate is joined in 500ml Virahol, be warming up to 50 DEG C, drip concentrated hydrochloric acid, surveying pH is 1～2, insulation reaction 4h.Be cooled to 0～5 DEG C of crystallization, separate out a large amount of white solids, filter, dry, obtain the about 61.6g of white solid, yield 86.5%, is Ropivacaine HCL crude product.After testing, ropivacaine purity 99.07%, dextrorotatory isomer per-cent 0.93%.

(5) refining

60.0g crude product and 500ml dehydrated alcohol-concentrated hydrochloric acid mixed solution (20:1) are added in reaction flask, be heated to 50 DEG C and make to dissolve; Complete molten after, cooling crystallization, ice-water bath is cooled to 0-5 DEG C, crystallization 4h; Filter, a small amount of cold mixed solution washing for filter cake, obtains wet product, dries, and obtains white solid 55.6g, and yield 92.7%, is Ropivacaine HCL fine work.After testing, ropivacaine purity 99.87%, dextrorotatory isomer per-cent 0.13%.

The preparation method of embodiment 3, a kind of Ropivacaine HCL

Step is as follows:

(1) preparation of intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea

10.0g2-piperidine carboxylic acid, 160ml toluene are added in 500ml reaction flask.Pass into HCl gas, to pH3 left and right, be warming up to 48 ± 2 DEG C, add 1.5mlDMF, drip 9.3g (1.0 equivalent) sulfur oxychloride and 20ml toluene mixture liquid, drip and finish, be incubated 48 ± 2 DEG C of reaction 2h.Drip 2 of 4.0 equivalents, 6-xylidine and 20ml toluene mixture liquid, be incubated 58 ± 2 DEG C of reaction 3h.Filter, obtain yellow-green colour wet product 63.6g, dry to obtain gray solid 55g, solid is added in 280ml purified water, stir the molten reaction solution that obtains; 10%NaOH solution is slowly dropped in reaction solution, adjust pH to 4.5-5.0, use 100ml toluene wash, layering, retains water layer, continues to adjust pH to 9-10 with 10%NaOH solution, adds 100ml methylene dichloride.Layering, gets organic layer,and water layer continues to use 50ml dichloromethane extraction, merges organic layer, adds anhydrous sodium sulfate dehydration, 40 DEG C of concentrating under reduced pressure.Obtain the about 14.8g of pale yellow oily liquid body, yield 82.4%, is intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea.

(2) preparation of intermediate (II) N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide

Intermediate 14.8 g of (the I) Dissolved in 60mlDMF IS, ADDS 8.5gK ₂ cO _{. 3} , 7.8 g of drip (1.0 equivalent)-n-propyl bromide, and drip After Finishing of DEG BE Warming up to 75 C, Reaction Insulation 2H; IS Down Ice Bath to room temperature, filters, and filtrate is added in 150ml frozen water, separates out a large amount of white solids, filter, dry, obtain the about 16.0g of white solid, yield 91.5%, is intermediate (II) N-(2 ,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide.

(3) preparation of left-handed ropivacaine tartrate

15g intermediate (II) is dissolved in 100ml Virahol, heats up 40 DEG C and stir molten; Treat entirely moltenly, add successively 1.72g (0.1 equivalent) titanium isopropylate, 1.82g (0.2 equivalent) D-tartrate, be warming up to backflow , after solution clarification, continue reaction 1h; Be cooled to 32 DEG C of crystallizatioies, filter, 75 DEG C of oven dry, obtain white solid 7.5g, and yield 39.2% is left-handed ropivacaine tartrate; After testing, ropivacaine purity 98.92 %, dextrorotatory isomer per-cent 0.99%.

(4) preparation of Ropivacaine HCL crude product

Left-handed 7.5g ropivacaine tartrate is joined in 50ml Virahol, be warming up to 40 DEG C, drip concentrated hydrochloric acid, surveying pH is 1～2, insulation reaction 1h.Be cooled to 0 DEG C of crystallization, separate out a large amount of white solids, filter, dry, obtain the about 5.7g of white solid, yield 85.3%, is Ropivacaine HCL crude product.After testing, ropivacaine purity 99.12%, dextrorotatory isomer per-cent 0.96%.

(5) refining

5.7g crude product and 40ml dehydrated alcohol-concentrated hydrochloric acid mixed solution (20:1) are added in reaction flask, be heated to 50 DEG C and make to dissolve; Complete molten after, naturally cool to room temperature, ice-water bath is cooled to 0 DEG C, crystallization 2h; Filter, 10ml mixed solution washing for filter cake, obtains wet product, dries, and obtains white solid 5.5g, and yield 92.1%, is Ropivacaine HCL fine work.After testing, ropivacaine purity 99.92 %, dextrorotatory isomer per-cent 0.15%.

The preparation method of embodiment 4, a kind of Ropivacaine HCL

Step is as follows:

(1) preparation of intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea

10.0g2-piperidine carboxylic acid, 160ml toluene are added in 500ml reaction flask.Pass into HCl gas, to pH3 left and right, be warming up to 48 ± 2 DEG C, add 1.5mlDMF, drip 10.2g (1.1 equivalent) sulfur oxychloride and 20ml toluene mixture liquid, drip and finish, be incubated 48 ± 2 DEG C of reaction 6h.Drip 2 of 4.0 equivalents, 6-xylidine and 20ml toluene mixture liquid, be incubated 58 ± 2 DEG C of reaction 8h.Filter, obtain yellow-green colour wet product 64.2g, dry to obtain gray solid 55.6g, solid is added in 280ml purified water, stir the molten reaction solution that obtains; 10%NaOH solution is slowly dropped in reaction solution, adjust pH to 4.5-5.0 , use 100ml toluene wash, layering, retains water layer, continues to adjust pH to 9-10 with 10%NaOH solution, adds 100ml methylene dichloride.Layering, gets organic layer,and water layer continues to use 50ml dichloromethane extraction, merges organic layer, adds anhydrous sodium sulfate dehydration, 40 DEG C of concentrating under reduced pressure.Obtain the about 14.9g of pale yellow oily liquid body, yield 82.9%, is intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea.

(2) preparation of intermediate (II) N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide

Intermediate 14.9 g of (the I) Dissolved in 60mlDMF IS, ADDS 8.5gK ₂ cO _{. 3} , 7.8 g of drip (1.0 equivalent)-n-propyl bromide, and drip After Finishing of DEG BE Warming up to 75 C, Reaction Insulation 2H; IS Down Ice Bath to room temperature, filters, and filtrate is added in 150ml frozen water, separates out a large amount of white solids, filter, dry, obtain the about 16.1g of white solid, yield 92.0%, is intermediate (II) N-(2 ,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide.

(3) preparation of left-handed ropivacaine tartrate

15g intermediate (II) is dissolved in 100ml Virahol, heats up 60 DEG C and stir molten; Treat entirely moltenly, add successively 1.72g (0.1 equivalent) titanium isopropylate, 1.82g (0.2 equivalent) D-tartrate, be warming up to backflow , after solution clarification, continue reaction 4h; Be cooled to 30 DEG C of crystallizatioies, filter, 75 DEG C of oven dry, obtain white solid 7.6g, and yield 39.7% is left-handed ropivacaine tartrate; After testing, ropivacaine purity 99.01 %, dextrorotatory isomer per-cent 1.05%.

(4) preparation of Ropivacaine HCL crude product

Left-handed 7.6g ropivacaine tartrate is joined in 50ml Virahol, be warming up to 40 DEG C, drip concentrated hydrochloric acid, surveying pH is 1～2, insulation reaction 4h.Be cooled to 5 DEG C of crystallizatioies, separate out a large amount of white solids, filter, dry, obtain the about 5.7g of white solid, yield 85.3%, is Ropivacaine HCL crude product.After testing, ropivacaine purity 99.06%, dextrorotatory isomer per-cent 0.95%.

(5) refining

5.7g crude product and 40ml dehydrated alcohol-concentrated hydrochloric acid mixed solution (volume ratio 20:1) are added in reaction flask, be heated to 80 DEG C and make to dissolve; Complete molten after, naturally cool to room temperature, ice- water bath is cooled to 5 DEG C, crystallization 2h; Filter, 10ml mixed solution washing for filter cake, obtains wet product, dries, and obtains white solid 5.2g, and yield 91.2%, is Ropivacaine HCL fine work.After testing, ropivacaine purity 99.81%, dextrorotatory isomer per-cent 0.11%.

The optical isomer method for detecting purity of left-handed ropivacaine tartrate, Ropivacaine HCL crude product and the Ropivacaine HCL purified product obtaining in above-described 1-4 is: measure according to high performance liquid chromatography (annex VD), with alpha- acid glycoprotein post (AGP, 100mm × 4.0mm, 5 μ m are suitable for); Agilent-1260 type high performance liquid chromatograph; (get potassium primary phosphate 2.72g with Virahol-phosphate buffered saline buffer, the 800ml that adds water dissolves, regulating pH value with 0.1mol/L sodium hydroxide solution is 7.1, be diluted with water to 1000ml) be (10:90) moving phase, detection wavelength is: 210nm, column temperature: 30 DEG C, flow velocity 1.0ml/min, limit is: dextrorotatory isomer must not be greater than 0.5%.

PATENT

https://patents.google.com/patent/CN109503465A/en

The embodiment of 1 intermediate (-) of-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide

L- piperidinecarboxylic acid hydrochloride (30.00g, 0.18mol), toluene are sequentially added in three mouthfuls of reaction flasks of 500ml cleaning N,N-Dimethylformamide (1ml), thionyl chloride (25.85g, 0.2 2mol) is added in (300ml) , stirring.It finishes, is warming up to 50~55 DEG C insulation reaction 3 hours.Snubber device is added to vacuumize 1 hour.The toluene solution of 2,6- dimethylaniline is added dropwise (2,6- dimethylanilines (109.75g , 0.91mol) are mixed with toluene (60ml)).It finishes, 60 DEG C of insulation reaction 2.0h.Cooling It to 20~30 DEG C, is added purified water (300ml), water phase is collected in layering; Fresh toluene (300ml), 10% hydrogen-oxygen is added in water phase Change sodium regulation system pH=6- 7, water phase is collected in layering; Water phase 10% sodium hydroxide regulation system pH=11~12,room temperature Stirring 4 hours, filter, purified water (150ml) elute filter cake, filter cake in 60 DEG C of air dry ovens it is dry 35.88g (yield 85%, HPLC purity 94.023% is calculated by areas of peak normalization method) .

The purification of 2 intermediate (-) of-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide

1 gained intermediate (-) of embodiment-(2S)-N- (2,6- diformazan is sequentially added in three mouthfuls of reaction flasks of 100ml cleaning Base phenyl) piperidines -2- formamide (5.00g, 21.52mmol), ether (50ml), stir and are warming up to reflux, flow back insulated and stirred 1 Hour, it is cooled to room temperature, insulated and stirred 1 hour, is filtered, ether (10ml) elutes filter cake, and filter cake is dry in 50 DEG C of air dry ovens Dry 2 hours 2.66g (yield 53.2% calculates HPLC purity 99.837% by areas of peak normalization method), map is shown in attached drawing 1.

The purification of 3 intermediate (-) of-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide

1 gained intermediate (-) of embodiment-(2S)-N- (2,6- diformazan is sequentially added in three mouthfuls of reaction flasks of 100ml cleaning Base phenyl) piperidines -2- formamide (5.00g, 21.52mmol), isopropyl ether (50ml), stir and are warming up to reflux, reflux heat preservation is stirred It mixes 1 hour, is cooled to room temperature, insulated and stirred 1 hour, filters, isopropyl ether (10m l) elutes filter cake, and filter cake is dry in 50 DEG C of air blast Dry 2 hours 3.45g of dry case (yield 69.0% calculates HPLC purity 99.332% by areas of peak normalization method).Map is shown in attached Fig. 2.

The purification of 4 intermediate (-) of-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide

1 gained intermediate (-) of embodiment-(2S)-N- (2,6- diformazan is sequentially added in three mouthfuls of reaction flasks of 100ml cleaning Base phenyl) piperidines -2- formamide (5.00g, 21.52mmol), methyl tertiary butyl ether(MTBE) (50ml), stir and are warming up to reflux, flow back Insulated and stirred 1 hour, be cooled to room temperature, insulated and stirred 1 hour, filter, methyl tertiary butyl ether(MTBE) (10ml) elutes filter cake, filter cake in Dry 2 hours 4.75g (yield 95% calculates HPLC purity 99.709% by areas of peak normalization method) of 50 DEG C of air dry ovens, Map is shown in attached drawing 3.

5 intermediate (-) of embodiment-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide preparation and purification

A) the preparation of intermediate (-)-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide

L- piperidinecarboxylic acid hydrochloride (3kg, 18.1mol), toluene (30L) are added in 50L reaction kettle, N, N- is added in stirring Dimethylformamide (1L), thionyl chloride (2.59kg, 21.8mol). It finishes, is warming up to 50~55 DEG C of insulation reactions 3 hours. Snubber device is added to vacuumize 6 hours.Be added dropwise 2,6- dimethylaniline toluene solution (2,6- dimethylanilines (11kg, It 90.8mol) is mixed with toluene (6L)).It finishes, 60 DEG C of insulation reaction 2.0h. 20~30 DEG C are cooled to, is added purified water (30L), Water phase is collected in layering; Water phase is added fresh toluene (30L) , 10% sodium hydroxide regulation system pH=6-7, and water is collected in layering Phase; 10% sodium hydroxide regulation system pH=11~12 of water phase, are stirred at room temperature 4 hours, filter,purified water (15L) elution filter Cake, filter cake in 60 DEG C of air dry ovens it is dry 3.52kg (yield 84%, by areas of peak normalization method calculate HPLC purity 98.092%), map is shown in attached drawing 4.

B) the purification of intermediate (-)-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide

Intermediate (-)-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide (3. is sequentially added in 50L reaction kettle 5kg, 15.1mol), methyl tertiary butyl ether(MTBE) (35L), stirring is warming up to reflux, flows back insulated and stirred 1 hour, be cooled to room temperature, guarantor Temperature stirring 1 hour, filters, and methyl tertiary butyl ether(MTBE) (7L) elutes filter cake, and filter cake is in the dry 8 hours 3.3kg of 50 DEG C of air dry ovens (yield 94% calculates HPLC purity 99.889% by areas of peak normalization method), map is shown in attached drawing 5.

Literatures:
Navinta LLC Patent: US2006/276654 A1, 2006 ; Location in patent: Page/Page column 5 ;
Yield: ~82%

Literatures:
US2006/276654 A1, ; Page/Page column 5 ;
Yield: null

SYN

https://pubs.rsc.org/en/content/articlehtml/2019/ra/c9ra09287k

Ropivacaine is the S-enantiomer of an N-alkyl pipecoloxylidine derivative, which is the first local anesthetic with chiral activity, and is widely used in clinical infiltration anesthesia, conduction anesthesia and epidural anesthesia. It has a long of local anesthesia and analgesic effect. However, ropivacaine also has serious safety risks in clinical practice. When the concentration of ropivacaine in human blood is too high, it may cause toxicity to the cardiovascular and central nervous system, and even cause allergic reactions in some patients. Thus far, the mechanism of the effect of ropivacaine on local anesthesia is not clear. Ropivacaine is a multitarget drug that acts on the gamma-aminobutyric acid a receptor (GABAA-R) and N-methyl-D-aspartate acid receptor (NDMA-R). Sodium (Na⁺) channels are a key target of local anesthetics and these two receptors regulate sodium channels. Previous studies on the structural modification of ropivacaine mainly focused on the substitution of –CH₃ on the phenyl group or the substitution of –CH₂CH₂CH₃ on piperidine with different alkyl groups. In 2017, Wen L. et al.⁶⁹ reported the design and synthesis of ropivacaine analogues for local anesthesia. In the process of structural design, they used ropivacaine as the lead compound to design two series of compounds, 4a–4q (17 new substituted imines). In the first series of compounds, 4a–4i, different substituents were selected to replace –CH₂CH₂CH₃ on piperidine. In the second series of compounds, 4j–4q, the methyl groups were replaced by –CF₃ at the o-positions, m-positions and p-positions. Meanwhile, the –CH₂CH₂CH₃ on piperidine ring was also substituted and modified. The process for the synthesis of the target compounds is shown in Scheme 8. The synthetic route takes piperic acid (compound 1) as the starting material, hydrochloric acid and sulfoxide chloride as additives, and toluene as the reaction solvent to convert compound 1 into acyl chloride salt (compound 2). Compound 2 was then treated with substituted aniline and reacted at 58 °C for 5 h to form compounds 3a–3i and 3j–3q. Finally, bromoalkyl and hydrochloric acid were used to treat compounds 3a–3i and 3j–3q. Potassium carbonate (K₂CO₃) was used as an acid dressing agent and dimethylformamide (DMF) as the reaction solvent in N-alkylation reaction. The N-alkylation reaction lasted 10 h at 80 °C, and the salt reaction lasted 5 min at room temperature to obtain the final target compounds 4a–4q. The total yield of the target compounds ranged from 17.5% to 87.7%. The synthetic route has the advantages of mild reaction conditions, cheap reagents and simple operation. However, using this synthetic route, the total yield of some products is too low, and too low yield will bring great problems to the synthesis cost, which needs to be further optimized in follow-up work. In the evaluation of the local anesthesia effect, sciatic nerve block activity, infiltration anesthesia activity, corneal anesthesia activity and spinal cord anesthesia activity were used as evaluation indexes. Ropivacaine was used as a positive control substance to test the local anesthesia activity in vitro. Firstly, the local anesthesia effect of all the target compounds 4a–4q was screened by a sciatic nerve block test in toads in vitro (Table 6). The preliminary screening results in vitro showed that these compounds increased the blocking effect of the sciatic nerve on electrical stimulation, with ED₅₀ values ranging from 0.012 to 0.64 (positive control for ropivacaine was 0.013), with the highest activity shown by compound 4b. In terms of latent period, that of target compounds 4a–4q ranged from 27.7 to 59.4 min. Based on the results of the preliminary in vitro screening, compounds 4a, 4b, 4c, 4j and 4l were selected to test the efficacy of invasive anesthesia in guinea pigs. The results of the infiltration anesthesia test showed that the local anesthetic effect of compounds 4c and 4l was similar to that of the positive control ropivacaine, and the local anesthetic activity of other compounds was lower than that of the positive control. Furthermore, compounds 4a, 4b, 4c, 4j and 4l were used to test the local surface anesthesia effect of these compounds (Table 7). The results of the surface anesthesia test showed that compound 4l had a similar local anesthetic effect as the positive control ropivacaine, while the effect of the other compounds was poor in comparison with the positive control. Finally, compounds 4a, 4b, 4c, 4j and 4l were tested for spinal anesthesia in order to further study their local surface anesthesia effect. The experimental results showed that the ED₅₀ produced by compounds 4l and 4b was 5.02 and 7.87, respectively, while the effects of compounds 4a, 4c and 4j were poor. The evaluation of local anesthesia in vitro found that compound 4l had the best activity, and thus molecular docking of compound 4l and ropivacaine was conducted to further study its local anesthesia mechanism. The molecular docking results showed that compound 4l interacts with receptor proteins of VGSC, GABAA-R and NDMA-R, which may help optimize and predict the activity of these ropivacaine analogues as potential local anesthetics.

	Scheme 8 Reagents and conditions: (a) (i) HCl,PhCH3, r.t., 1 h; (ii) PhCH3, SOCl2, 55 °C, 1 h; (b) substituted anilines, 58 °C, 5 h; and (c) (i) RBr, K2CO3, DMF, 80 °C, 10 h; (ii) HCl, r.t., 5 min.

SYN

Prepn: A. F. Thuresson, C. Bovin, WO 8500599 (1985 to Apothekernes); H.-J. Federsel et al., Acta Chem. Scand. B41, 757 (1987).

CLIP

https://www.semanticscholar.org/paper/An-Efficient-and-Practical-Synthesis-of-Ropivacaine-Li-Meng/8d2f60efcf9ce74099dd5115e2fc6d6886c29387

Ropivacaine hydrochloride was synthesized from L-2-pipecolic acid by successive reaction with SOCl2 and 2,6-dimethylaniline at 40 °C under ultrasonic irradiation to yield L-N-(2,6-dimethylphenyl)piperidin-2-carboxamide (4), and 4 was reacted with 1-bromopropane at 50 °C for 1 h under ultrasonic irradiation. The effects of reaction solvent, temperature and time under ultrasonic irradiation were investigated. Compared with conventional methods, present procedures have the advantages in milder conditions, shorter reaction time and higher yields. The total yield was 67.5%, [α]25 D= – 6.6°(c = 2, H2O).

SYN

Ropivacaine (3.1.37) (Naropin) is the pure S(–)-enantiomer of propivacaine released for clinical use in 1996. It is a long-acting, well tolerated local anesthetic agent and first produced as a pure enantiomer. Its effects and mechanism of action are similar to other local anesthetics working via reversible inhibition of sodium ion influx in nerve fibers. It may be a preferred option among other drugs among this class of compounds because of its reduced CNS and cardiotoxic potential and its lower propensity for motor block in the management of postoperative pain and labor pain [48–58].

The synthesis of ropivacaine (3.1.37) was carried out starting with l-pipecolic acid (3.1.34), prepared by a resolution of (±)-pipecolic acid with (+)-tartaric acid, which was dissolved in acetyl chloride and converted to acid chloride (3.1.35) with phosphorus pentachloride. The obtained compound (3.1.35) dissolved in toluene a solution of 2,6-xylidine (3.1.28) dissolved in the mixture of equal volumes of acetone, and N-methyl-2-pyrrolidone was added at 70°C to give (+)-l-pipecolic acid-2,6-xylidide (3.1.36). Reaction of this compound with propyl bromide in presence of potassium carbonate in i-PrOH/H₂O gave the desired ropivacaine (3.1.37) [59] (Scheme 3.6).

Scheme 3.6. Synthesis of ropivacaine.

Another approach for the synthesis of ropivacaine (3.1.37) was proposed via a resolution of enantiomers of chiral pipecolic acid-2,6-xylidide [60].

SYN

Scheme 21. Generation of ‘cation pool’ and its applications.

Reproduced from Yoshida, J.; Suga, S.; Suzuki, S.; et al. J. Am. Chem. Soc. 1999, 121, 9546–9549, and Shankaraiah, N.; Pilli, R. A.; Santos, L. S. Tetrahedron Lett. 2008, 49, 5098–5100.

CLIP

Process R&D under the magnifying glass: Organization, business model, challenges, and scientific context

Hans-Jürgen Federsel, in Bioorganic & Medicinal Chemistry, 2010

The synthesis of ropivacaine is achieved in only three steps, as in the previous example, comprised of a resolution of a racemic, commercially available starting material (pipecoloxylidide) followed by an N-alkylation and the final precipitation of the product as its HCl salt.^14,24 Focusing on the middle step—the attachment of a propyl moiety onto the piperidine nitrogen—this reaction when developed in the laboratory and scaled up to maximum pilot plant volume (1000 L) behaved very well (Scheme 3). Thus, boiling the reaction mixture (reactants in a H₂O/organic solvent mixture in the presence of a solid inorganic base) for an extended period of time (6 h) at high temperature (100 °C), the transformation was considered complete once a sample of the process solution showed <1% of remaining starting material. In preparation for launch, the method that had been thoroughly investigated and tested over a number of years and proven reliable on scale up had to be validated in the authentic 4000 L production equipment. Much to our surprise (and shock) we, however, found that the reaction came to a complete stand still long before reaching the expected end point. With a large amount of un-reacted starting material (30–40%) we were facing a situation that had never occurred during the lengthy development phase and this put the whole project in a very critical state as we were not able to reproduce the manufacturing method.

Nmr

https://www.hindawi.com/journals/ijps/2019/1412737/

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History

Ropivacaine was developed after bupivacaine was noted to be associated with cardiac arrest, particularly in pregnant women. Ropivacaine was found to have less cardiotoxicity than bupivacaine in animal models.

Clinical use

Contraindications

Ropivacaine is contraindicated for intravenous regional anaesthesia (IVRA). However, new data suggested both ropivacaine (1.2-1.8 mg/kg in 40ml) and levobupivacaine (40 ml of 0.125% solution) be used, because they have less cardiovascular and central nervous system toxicity than racemic bupivacaine.^[1]

Adverse effects

Adverse drug reactions (ADRs) are rare when it is administered correctly. Most ADRs relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, however allergic reactions can rarely occur.

Systemic exposure to excessive quantities of ropivacaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. CNS effects may include CNS excitation (nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, seizures followed by depression (drowsiness, loss of consciousness), respiratory depression and apnea). Cardiovascular effects include hypotension, bradycardia, arrhythmias, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression.^[2]

Postarthroscopic glenohumeral chondrolysis

Ropivacaine is toxic to cartilage and their intra-articular infusions can lead to Postarthroscopic glenohumeral chondrolysis.^[3]

Treatment of overdose

As for bupivacaine, Celepid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anaesthetic overdose in animal experiments^[4] and in humans in a process called lipid rescue.^[5][6][7]

References

External links

• “Ropivacaine”. Drug Information Portal. U.S. National Library of Medicine.
• “Ropivacaine hydrochloride”. Drug Information Portal. U.S. National Library of Medicine.

Ropivacaine

Clinical data
Trade names	Naropin
AHFS/Drugs.com	Monograph
Pregnancy category	AU: B1
Routes of administration	Parenteral
ATC code	N01BB09 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)
Pharmacokinetic data
Bioavailability	87%–98% (epidural)
Metabolism	Liver (CYP1A2-mediated)
Elimination half-life	1.6–6 hours (varies with administration route)
Excretion	Kidney 86%
Identifiers
show IUPAC name
CAS Number	84057-95-4
PubChem CID	175805
IUPHAR/BPS	7602
DrugBank	DB00296
ChemSpider	153165
UNII	7IO5LYA57N
KEGG	D08490  as HCl: D04048
ChEBI	CHEBI:8890
ChEMBL	ChEMBL1077896
CompTox Dashboard (EPA)	DTXSID4040187
ECHA InfoCard	100.128.244
Chemical and physical data
Formula	C17H26N2O
Molar mass	274.408 g·mol−1
3D model (JSmol)	Interactive image
Melting point	144 to 146 °C (291 to 295 °F)
show SMILES
show InChI
(verify)

Patent

/////////////Ropivacaine, Anesthetic, ропивакаин , روبيفاكائين , 罗哌卡因 , DRopivacaine Hydrochloride Hydrate, LEA-103, NA-001, (-)-LEA-103

CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C