CN109438331A - A method of preparing Ropivacaine intermediate - Google Patents
A method of preparing Ropivacaine intermediate Download PDFInfo
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- CN109438331A CN109438331A CN201811100148.7A CN201811100148A CN109438331A CN 109438331 A CN109438331 A CN 109438331A CN 201811100148 A CN201811100148 A CN 201811100148A CN 109438331 A CN109438331 A CN 109438331A
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- CN
- China
- Prior art keywords
- ropivacaine
- piperidines
- preparing
- intermediate according
- phosphorus
- Prior art date
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- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 title claims abstract description 25
- 229960001549 ropivacaine Drugs 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 18
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000019253 formic acid Nutrition 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012190 activator Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 1
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000003053 piperidines Chemical class 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000007789 gas Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000008213 purified water Substances 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229960005015 local anesthetics Drugs 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003589 local anesthetic agent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- QCUYETTULZUEDY-UHFFFAOYSA-N N1=C(C=CC=C1)C(=O)O.N1CCNCC1 Chemical compound N1=C(C=CC=C1)C(=O)O.N1CCNCC1 QCUYETTULZUEDY-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960003150 bupivacaine Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- -1 oxalyl Chlorine Chemical compound 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The invention discloses a kind of methods for preparing Ropivacaine intermediate, L- piperidines -2- carboxylic acid hydrochloride is prepared by L- piperidines -2- formic acid, in the case of separation, S is directly directly prepared by L- piperidines -2- carboxylic acid hydrochloride and 2,6- dimethylaniline and phosphorus oxychloride single step reaction)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide, the intermediate of this method preparation simplifies technological operation, cost is reduced, yield is improved, is more suitable for scale industrialized production.
Description
Technical field
The invention belongs to chemosynthesis technical fields, and in particular to the preparation method of the intermediate of local anaesthetics Ropivacaine.
Background technique
Ropivacaine is single enantiomorph (S-shaped) long-acting local anesthetics of amide derivatives, mechanism of action and other local anaesthetics
It is identical, by inhibiting nerve cell sodium-ion channel, block nerves excitement and conduction.Since discovery long effective local anesthetic can induce the heart
It is dirty it is poly- stop after, people are seeking always fat-soluble lower, safer substitution drug.Ropivacaine is exactly such a
New-type long-acting local anesthetics of amide derivatives, acting duration is long, and has anesthesia and analgesic effect.
The product that Ropivacaine is replaced by the third position nitrogen-atoms of Bupivacaine piperidine ring by propyl is dissymmetrical structure
Single enantiotropy (single enantiomer), i.e. S- enantiotropy.It is pure levoform isomers, compared with right-spiral isomers poison
Low, the long action time of property.Its pharmacological characteristic is that cardiac toxic is humble, and it is more apparent to feel that retardance is separated with movement retardance, has
Outer vasoconstrictor effects of laing.Therefore the medicine is particularly suitable for Postoperative Analgesia After and obstetrical analgesia.
Chemical entitled (-)-(S)-N- (2,6- 3,5-dimethylphenyl) -1- propylpiperdine-of Ropivacaine (Ropivacaine)
2- formamide, its hydrochloride of clinical application or mesylate.The structural formula of Ropivacaine:
Ropivacaine is to obtain on the basis of Ropivacaine intermediate with bromopropane reaction.
The synthetic method of Ropivacaine intermediate specifically includes that United States Patent (USP) US4695576 discloses a kind of Ropivacaine
The synthetic method of intermediate first splits using piperidines -2- formic acid as starting material and synthesizes the method L- piperidines -2- formyl chloride again
It is acylated through Wu Lvization Lin for starting material, then be condensed with 2,6- dimethylaniline.Each step reaction intermediate requires to separate pure
Change, operating procedure is many and diverse, is unfavorable for producing in industry metaplasia.
United States Patent (USP) LS5777124 and US5959112 disclose a kind of synthetic method of Ropivacaine intermediate, with piperazine
Pyridine -2- formic acid is starting material, acylated through thionyl chloride, then is condensed with 2,6- dimethylaniline, is then split, then carry out subsequent
Reaction.This route higher cost, is equally unfavorable for industrial production.
Sieve is also reported in " synthesis chemistry " 2006 the 4th phase of volume 14 " triphosgene synthetic hydrochloric acid year piperazine cacaine " text
The synthetic method of piperazine cacaine intermediate, this method prepare acyl chlorides using triphosgene, and triphosgene has danger in storage and post-processing
It is dangerous, it is also not suitable for industrialized production.
Summary of the invention
The present invention is exactly to propose a kind of method for preparing Ropivacaine intermediate according to the above problem, this method preparation
Intermediate simplifies technological operation, reduces cost, improves yield, is more suitable for scale industrialized production.
In order to achieve the above objectives, The technical solution adopted by the invention is as follows: a kind of method for preparing Ropivacaine intermediate,
Specifically: L- piperidines -2- formic acid prepares L- piperidines -2- carboxylic acid hydrochloride in toluene, in the case of not having to separation, directly by L-
Piperidines -2- carboxylic acid hydrochloride and 2,6- dimethylaniline and phosphorus oxychloride single step reaction directly prepare S)-N- (2,6- dimethyl
Phenyl) piperidines -2- formamide, it is as follows to chemically react molecular formula:
Specifically, the method provided by the invention for preparing Ropivacaine, includes the following steps:
1) L- piperidines -2- formic acid is added into organic solvent, is passed through HCl gas to reaction solution at room temperature and reaches certain pH
Value；
2) in the case where not separating above-mentioned reaction solution, 2 6- dimethylanilines and trichlorine oxygen are directly added into reaction system
Phosphorus is warming up to and is stirred to react to complete.
Preferably, in the step (1), organic solvent is the halogenated hydrocarbons of C1-C4, DMF, toluene, NMP, acetone, acetic acid second
Ester, tetrahydrofuran, acetonitrile, dioxane or combinations thereof.
Preferably, in the step (1), pH value 2-5.
Preferably, in the step (2), activator is phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl
Chlorine.
Preparation method of the invention avoids the separation of each step intermediate, can directly obtain product Ropivacaine intermediate,
Greatly simplify technique, easy to operate, cost reduces, and yield improves, and yield is greater than 70%, is especially suitable for industrial production.
Specific embodiment
Embodiment 1
2.65gL- piperidines -2- formic acid is mixed with 13ml toluene, is stirred at room temperature down and is slowly passed through HCl gas until reaction solution
Then 2.42 gram of 2 6- dimethylaniline is added in pH=3,9.2g phosphorus oxychloride is then added dropwise, is added dropwise, and heats up 50 DEG C instead
6h is answered, end of reaction is cooled to 10 DEG C, and 13ml purified water is then added dropwise, PH=12 then is adjusted with 40% sodium hydroxide solution,
Then it is extracted 3 times with the ethyl acetate of 13ml, collects organic phase, concentration is spin-dried for, and white solid 3.6, yield are dried to obtain at 40 DEG C
77%, HPLC control are same point.
Embodiment 2
2.65gL- piperidines -2- formic acid is mixed with 13mlDMP, is stirred at room temperature down and is slowly passed through HCl gas until reaction solution
Then 2.42 gram of 2 6- dimethylaniline is added in pH=3,9.2g phosphorus oxychloride is then added dropwise, is added dropwise, and heats up 50 DEG C,
TLC control has product point generation, reacts 3h, and end of reaction is cooled to 10 DEG C, 26ml purified water is then added dropwise, then with 40%
Sodium hydroxide solution adjusts PH=5-6, is then extracted 3 times with the ethyl acetate of 13ml, collects water phase, molten with 40% sodium hydroxide
Liquid adjusts PH=12, then 0-5 DEG C of crystallization 3h, collection solid, chromatography post separation, and DCM: MeOH=10: 1, obtain white solid
0.72g, yield 15.4%, HPLC control are same point.
Embodiment 3
2.65gL- piperidines -2- formic acid is mixed with 13ml dioxane, is stirred at room temperature down and is slowly passed through HCl gas until anti-
Liquid pH=3 is answered, 2.42 grams of 26- dimethylanilines are then added, 9.2g phosphorus oxychloride is then added dropwise, is added dropwise, is heated up 50 DEG C,
TLC control has product point generation, reacts 12h, and end of reaction is cooled to 10 DEG C, and 13ml purified water is then added dropwise, then uses
40% sodium hydroxide solution adjusts PH=12, is then extracted 3 times with the ethyl acetate of 13ml, collects organic phase, and concentration is spin-dried for, and 40
White solid 3.6, yield 77% are dried to obtain at DEG C, HPLC control is same point.
Embodiment 4
2.65gL- piperidines -2- formic acid is mixed with 13ml dioxane, is stirred at room temperature down and is slowly passed through HCl gas until anti-
Liquid pH=3 is answered, 2.42 gram of 2 6- dimethylaniline is then added, 12.48g phosphorus pentachloride is then added dropwise, is added dropwise, heating 50
DEG C, TLC control has product point generation, reacts 6h, and end of reaction is cooled to 10 DEG C, and 13ml purified water is then added dropwise, then uses
40% sodium hydroxide solution adjusts PH=12, is then extracted 3 times with the ethyl acetate of 13ml, collects organic phase, and concentration is spin-dried for, and 40
White solid 2.5g, yield 53% are dried to obtain at DEG C, HPLC control is same point.
Embodiment 5
2.65gL- piperidines -2- formic acid is mixed with 13ml dioxane, is stirred at room temperature down and is slowly passed through HCl gas until anti-
Liquid pH=3 is answered, 2.42 grams of 26- dimethylanilines are then added, 12.48g thionyl chloride is then added dropwise, is added dropwise, heating 50
DEG C, TLC control has product point generation, reacts 36h, and end of reaction is cooled to 10 DEG C, and 13ml purified water is then added dropwise, then uses
40% sodium hydroxide solution adjusts PH=12, is then extracted 3 times with the ethyl acetate of 13ml, collects organic phase, and concentration is spin-dried for, and 40
White solid 1.88g, yield 40% are dried to obtain at DEG C.The above is only a preferred embodiment of the present invention, it is noted that right
For those skilled in the art, under the premise of not departing from technical principle of the invention, if can also make
Dry improvement and modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (5)
1. a kind of method for preparing Ropivacaine intermediate, which is characterized in that the molecular formula of its synthesis route is as follows:
2. a kind of method for preparing Ropivacaine intermediate according to right 1, which is characterized in that described to prepare Ropivacaine
The method of intermediate the following steps are included:
1) L- piperidines -2- formic acid is added into organic solvent, is passed through HCl gas to reaction solution at room temperature and reaches certain pH value；
2) in the case where not separating above-mentioned reaction solution, 2 6- dimethylanilines and phosphorus oxychloride are directly added into reaction system,
It is warming up to and is stirred to react to complete.
3. a kind of method for preparing Ropivacaine intermediate according to right 1, which is characterized in that in the step (1), have
Solvent is the halogenated hydrocarbons of C1-C4, DMF, toluene, NMP, acetone, ethyl acetate, tetrahydrofuran, acetonitrile, dioxane or its group
It closes.
4. a kind of method for preparing Ropivacaine intermediate according to right 1, which is characterized in that in the step (1), pH
Value is 2-5.
5. a kind of method for preparing Ropivacaine intermediate according to wooden fork benefit 1, which is characterized in that in the step (2),
Activator is phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811100148.7A CN109438331A (en) | 2018-09-20 | 2018-09-20 | A method of preparing Ropivacaine intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811100148.7A CN109438331A (en) | 2018-09-20 | 2018-09-20 | A method of preparing Ropivacaine intermediate |
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| CN109438331A true CN109438331A (en) | 2019-03-08 |
Family
ID=65532947
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| CN201811100148.7A Pending CN109438331A (en) | 2018-09-20 | 2018-09-20 | A method of preparing Ropivacaine intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110384698A (en) * | 2019-08-14 | 2019-10-29 | 牡丹江医学院 | A kind of anesthetic and its application suitable under color ultrasound guidance to brachial plexus nerve anesthesia |
| CN115057854A (en) * | 2022-04-19 | 2022-09-16 | 河北常山生化药业股份有限公司 | Preparation method of Alvatripopa maleate intermediate |
| CN115057810A (en) * | 2022-05-30 | 2022-09-16 | 山东科源制药股份有限公司 | Preparation method of ropivacaine hydrochloride intermediate |
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|---|---|---|---|---|
| US5777124A (en) * | 1994-10-25 | 1998-07-07 | Chiroscience Limited | Process for preparing levobupivacaine and analogues thereof |
| US20060276654A1 (en) * | 2005-06-06 | 2006-12-07 | Navinta Llc | Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom |
| CN102558030A (en) * | 2010-12-11 | 2012-07-11 | 山东方明药业股份有限公司 | Synthesis of 1-N-(2,6-dimethyl phenyl)-2-piperidinecarboxamide |
| CN103086954A (en) * | 2013-02-04 | 2013-05-08 | 山东省医药工业研究所 | Method for preparing ropivacaine |
| CN107325041A (en) * | 2017-06-20 | 2017-11-07 | 广州市桐晖药业有限公司 | A kind of preparation method of Ropivacaine HCL |
-
2018
- 2018-09-20 CN CN201811100148.7A patent/CN109438331A/en active Pending
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|---|---|---|---|---|
| US5777124A (en) * | 1994-10-25 | 1998-07-07 | Chiroscience Limited | Process for preparing levobupivacaine and analogues thereof |
| US20060276654A1 (en) * | 2005-06-06 | 2006-12-07 | Navinta Llc | Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom |
| CN102558030A (en) * | 2010-12-11 | 2012-07-11 | 山东方明药业股份有限公司 | Synthesis of 1-N-(2,6-dimethyl phenyl)-2-piperidinecarboxamide |
| CN103086954A (en) * | 2013-02-04 | 2013-05-08 | 山东省医药工业研究所 | Method for preparing ropivacaine |
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|---|
| 刘毅,等: "盐酸罗哌卡因的合成", 《中国医药工业杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110384698A (en) * | 2019-08-14 | 2019-10-29 | 牡丹江医学院 | A kind of anesthetic and its application suitable under color ultrasound guidance to brachial plexus nerve anesthesia |
| CN115057854A (en) * | 2022-04-19 | 2022-09-16 | 河北常山生化药业股份有限公司 | Preparation method of Alvatripopa maleate intermediate |
| CN115057810A (en) * | 2022-05-30 | 2022-09-16 | 山东科源制药股份有限公司 | Preparation method of ropivacaine hydrochloride intermediate |
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Application publication date: 20190308 |