CN105418489A - Synthesis method of bupivacaine - Google Patents
Synthesis method of bupivacaine Download PDFInfo
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- CN105418489A CN105418489A CN201610042790.9A CN201610042790A CN105418489A CN 105418489 A CN105418489 A CN 105418489A CN 201610042790 A CN201610042790 A CN 201610042790A CN 105418489 A CN105418489 A CN 105418489A
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- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960003150 bupivacaine Drugs 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title abstract 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 239000010410 layer Substances 0.000 claims abstract description 9
- 239000012044 organic layer Substances 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 238000010189 synthetic method Methods 0.000 claims description 11
- 230000031709 bromination Effects 0.000 claims description 7
- 238000005893 bromination reaction Methods 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- -1 dry filter Substances 0.000 claims description 4
- 238000010583 slow cooling Methods 0.000 claims description 4
- PMIGQXSPYSQKNR-UHFFFAOYSA-N 1,2-dimethylcyclohexa-2,4-dien-1-amine Chemical group CC1=CC=CCC1(C)N PMIGQXSPYSQKNR-UHFFFAOYSA-N 0.000 claims description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical class OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 239000003999 initiator Substances 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 abstract 1
- HXEACLLIILLPRG-YFKPBYRVSA-N L-pipecolic acid Chemical compound [O-]C(=O)[C@@H]1CCCC[NH2+]1 HXEACLLIILLPRG-YFKPBYRVSA-N 0.000 abstract 1
- 238000001816 cooling Methods 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- HXEACLLIILLPRG-RXMQYKEDSA-N l-pipecolic acid Natural products OC(=O)[C@H]1CCCCN1 HXEACLLIILLPRG-RXMQYKEDSA-N 0.000 abstract 1
- 230000000630 rising effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 5
- 239000003589 local anesthetic agent Substances 0.000 description 3
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002692 epidural anesthesia Methods 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- JBKVHLHDHHXQEQ-UHFFFAOYSA-N epsilon-caprolactam Chemical compound O=C1CCCCCN1 JBKVHLHDHHXQEQ-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010792 warming Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to a synthesis method of bupivacaine. The method comprises: adding 2 piperidinecarboxylicacid into aqueous alkali, dropwise adding Cbz and alkaline water, after finishing dropwise adding at normal temperature, reacting for 12 hours, after reaction, extracting with diethyl ether, washing a water layer to be weak-acid with 18% of diluted hydrochloric acid, extracting with the diethyl ether again, combining an diethyl ether layer, drying and filtering, and concentrating to obtain a dried product; adding the dried product into a DMF solvent, then adding a catalyst for reaction for 1 hour at normal temperature, then adding 2,6-dimethylaniline, reacting for 18hours at normal temperature, adding water and ethyl acetate for washing, taking an organic layer, drying and filtering, and concentrating to obtain a dried concentrated product; adding the dried concentrated product into a solvent, then adding a catalyst, pressurizing and introducing hydrogen, filtering after reaction and concentrating to obtain a dried product; adding the product in the above step into a solvent, dropwise adding bromo-n-butane at normal temperature, after dropwise adding, rising temperature to 80 DEG C for reacting for 12 hours, adding diluted hydrochloric acid, slowing cooling to normal temperature, and crystallizing, filtering and drying to obtain the product. The synthesis method has the advantages of higher yield, smaller pollution and low equipment requirement.
Description
Technical field
The present invention relates to bupivacaine production field, be specifically related to a kind of synthetic method of bupivacaine.
Background technology
The long-acting local anesthetics of amide derivatives of bupivacaine, is applicable to peripheral blockade, epidural anesthesia and ubarachnoid block.Its hydrochloride conventional is white crystalline powder, odorless, bitter.Local anesthetic action is better than lignocaine (about strong 4 times).Its 0.25% 0.5% solution causes the time of local anaesthesia to be generally 4 10 minutes, and 0.75% solution onset is than slightly fast.Add suprarenin with its 0.5% solution and make Epidural Block, effect can maintain 5 hours.Because this product concentration in blood is low, body accumulation is few, and acting duration is long, therefore is safer long effective local anesthetic.Existing bupivacaine synthetic method:
。
Existing methodical shortcoming: be starting raw material with hexanolactam through open loop, bromo, acyl chlorides, condensation, cyclization, refiningly to obtain finished product bupivacaine, and there is yield lower, seriously polluted, equipment corrosion resistant requires the shortcomings such as higher.
Summary of the invention
In order to solve the problem, the present invention proposes a kind of synthetic method of bupivacaine, rational technology, improve the yield of product, decreasing pollution, reduces the requirement to equipment.
A synthetic method for bupivacaine, is characterized in that following steps:
Step 1, upper protecting group: 2 piperidine carboxylic acids are added in alkali aqueous solution, drip Cbz and buck, the amount of Cbz is 1.2 ~ 2.0 times of weight ratios of starting raw material simultaneously; Buck is mineral alkali; Buck content is 5% ~ 15%; Alkali aqueous solution amount is 8 times of weight ratios; The amount dripped is the weight ratio of 2.5 times, and normal temperature dropwises, and reacts 12 hours, has reacted, and by extracted with diethyl ether, water layer 18% dilute hydrochloric acid washs to slightly acidic, then uses extracted with diethyl ether 3 times, combined ether layer, dry filter, concentrates and to obtain dry product;
Step 2, condensation: added in DMF solvent by the dry product of step 1, then add catalyst normal temperature and react 1 hour, then add 2,6-xylidine, normal-temperature reaction 18 hours, adds water and ethyl acetate washing, gets organic layer, dry, filter, and makes to obtain condenses dry product;
Step 3, hydrogenation goes protection:
Condenses dry product adds in solvent, then adds catalyzer, the logical hydrogen of pressurization, has reacted to refilter, concentratedly to obtain dry product; Catalyzer is palladium carbon, platinum carbon, Raney's nickel, and consumption is the weight ratio of 0.15 times; Solvent is methyl alcohol, ethanol, Virahol, and consumption is 4 times of weight ratios; Temperature of reaction is 50 ± 5 DEG C, reaction times 0.5-3 hour;
Step 4, then condensation: above walk product and add in solvent, normal temperature drips bromination of n-butane, and dropwise intensification 80 degree of reactions after 12 hours, add dilute hydrochloric acid, slow cooling is to normal temperature, and crystallization filtration drying obtains product.
The amount of the Cbz described in step 1 is 1.57 times of weight ratios of starting raw material; Buck is sodium hydroxide; Buck content is 10%.
Catalyzer described in step 1 is HATV, and consumption is 1.7 times of weight ratios of dry product, and solvent is 4.3 times of weight ratios; 1,6-xylidine is the weight ratio of 0.4 times.
Catalyzer described in step 3 is palladium carbon, and consumption is the weight ratio of 0.15 times; Solvent is methyl alcohol, and consumption is 4 times of weight ratios; Temperature of reaction is 50 ± 5 DEG C, 1 hour reaction times.
Solvent described in step 4 is DMF, and consumption is 10 times of weight ratios; Bromination of n-butane consumption is the weight ratio of 0.7 times; The consumption of dilute hydrochloric acid is 50 times of weight ratios of initiator, and content is 8%.
The synthetic chemistry reaction equation of bupivacaine is:
。
The advantage of present method is that yield is higher, and less pollution, equipment requirements is not high.
Embodiment
Protecting group on step 1(): add in alkali aqueous solution by 2 piperidine carboxylic acids, (amount of Cbz is 1.2 ~ 2.0 times of weight ratios of starting raw material, preferably 1.57 times of weight ratios for dropping Cbz and buck simultaneously; Buck is mineral alkali, preferred sodium hydroxide; Buck content is 5% ~ 15% preferably 10%; Alkali aqueous solution amount is 8 times of weight ratios; The amount dripped is the weight ratio of 2.5 times), normal temperature dropwises, and reacts 12 hours, has reacted, and by extracted with diethyl ether, water layer 18% dilute hydrochloric acid washs to slightly acidic, then uses extracted with diethyl ether 3 times, combined ether layer, dry filter, concentrates and to obtain dry product.
Step 2(condensation):
Step 1 dry product add in DMF solvent, then add catalyst normal temperature and react 1 hour, then add 2,6-xylidine, normal-temperature reaction 18 hours, add water and ethyl acetate washing, get organic layer, dry, filter, make to obtain condenses dry product.(catalyzer is HATV, and consumption is 1.7 times of weight ratios of dry product, and solvent is 4.3 times of weight ratios; 1,6-xylidine is the weight ratio of 0.4 times.）
Step 3(hydrogenation goes protection):
Condenses dry product adds in solvent, then adds catalyzer, the logical hydrogen of pressurization, has reacted to refilter, concentratedly to obtain dry product.(catalyzer is palladium carbon, platinum carbon, Raney's nickel, preferred palladium carbon, and consumption is the weight ratio of 0.15 times; Solvent is the alcohols such as methyl alcohol, ethanol, Virahol, particular methanol; Consumption is 4 times of weight ratios; Temperature of reaction is 50 ± 5 DEG C, reaction times 0.5-3 hour, and preferably 1 as a child.
Step 4(is condensation again):
Upper step product adds in solvent, and normal temperature drips bromination of n-butane, and dropwise intensification 80 degree of reactions after 12 hours, add dilute hydrochloric acid, slow cooling is to normal temperature, and crystallization filtration drying obtains product. and (solvent is DMF, and consumption is 10 times of weight ratios; Bromination of n-butane consumption is the weight ratio of 0.7 times; The consumption of dilute hydrochloric acid is 50 times of weight ratios of initiator, and content is 8%).
Embodiment 1:
Step 1: 10 grams of Pipecolic Acids are put into 250 milliliters of four-hole boiling flasks, add 80 gram of 10% aqueous sodium hydroxide solution, stirring and dissolving, slowly drips 15.7 grams of Cbz and 25 gram aqueous sodium hydroxide solutions simultaneously, dropwises normal-temperature reaction after 12 hours, get 100 grams of extracted with diethyl ether, water layer dilute hydrochloric acid neutralizes slightly acidic, then extracts 3 times, merges organic layer, filter by dried over mgso, concentration of organic layers obtains dry product 19.6 grams (single step yield 96.1%) again.
Step 2: get step dry product 2.3 grams and add in the reaction flask of 50 milliliters, add catalyzer HATV4 gram, 10 grams of DMF solvents, normal-temperature reaction 1 hour, then add 1 gram 2,6-xylidine, normal-temperature reaction 18 hours, has reacted rear use 50 grams of water and 500 grams of extraction into ethyl acetate, with 20 gram of 4% sodium hydroxide washing, after organic layer dry filter, concentration of organic layers obtains dry product 3.0 grams (single step yield 98.9%).
Step 3: get the dry product 3 grams that step obtains and add in autoclave, then add 100 grams of methyl alcohol, 0.5 gram of palladium carbon, under the pressure of 1.5 kilograms, temperature controls at 50 degree, and logical H-H reaction 30 minutes, reacts complete filtration, washing, concentrated, obtain dry product 1.75 grams (single step yield 92.1%).
Step 4: get step dry product 1.75 grams and add in the DMF solvent of 20 grams, normal temperature drips 1.2 grams of bromination of n-butane, dropwise and be warming up to 80 degree and react 12 hours, add the dilute hydrochloric acid of 100 gram 8% after completion of the reaction, slow cooling is to normal temperature, separate out solid, filtration drying obtains finished product 2.1 grams (single step yield is 80%).
Claims (6)
1. a synthetic method for bupivacaine, is characterized in that following steps:
Step 1, upper protecting group: 2 piperidine carboxylic acids are added in alkali aqueous solution, drip Cbz and buck, the amount of Cbz is 1.2 ~ 2.0 times of weight ratios of starting raw material simultaneously; Buck is mineral alkali; Buck content is 5% ~ 15%; Alkali aqueous solution amount is 8 times of weight ratios; The amount dripped is the weight ratio of 2.5 times, and normal temperature dropwises, and reacts 12 hours, has reacted, and by extracted with diethyl ether, water layer 18% dilute hydrochloric acid washs to slightly acidic, then uses extracted with diethyl ether 3 times, combined ether layer, dry filter, concentrates and to obtain dry product;
Step 2, condensation: added in DMF solvent by the dry product of step 1, then add catalyst normal temperature and react 1 hour, then add 2,6-xylidine, normal-temperature reaction 18 hours, adds water and ethyl acetate washing, gets organic layer, dry, filter, and makes to obtain condenses dry product;
Step 3, hydrogenation goes protection: condenses dry product adds in solvent, then adds catalyzer, the logical hydrogen of pressurization, has reacted to refilter, concentratedly to obtain dry product; Catalyzer is palladium carbon, platinum carbon, Raney's nickel, and consumption is the weight ratio of 0.15 times; Solvent is methyl alcohol, ethanol, Virahol, and consumption is 4 times of weight ratios; Temperature of reaction is 50 ± 5 DEG C, reaction times 0.5-3 hour;
Step 4, then condensation: above walk product and add in solvent, normal temperature drips bromination of n-butane, and dropwise intensification 80 degree of reactions after 12 hours, add dilute hydrochloric acid, slow cooling is to normal temperature, and crystallization filtration drying obtains product.
2. the synthetic method of a kind of bupivacaine according to claim 1, is characterized in that the amount of the Cbz described in step 1 is 1.57 times of weight ratios of starting raw material; Buck is sodium hydroxide; Buck content is 10%.
3. the synthetic method of a kind of bupivacaine according to claim 1, is characterized in that the catalyzer described in step 1 is HATV, and consumption is 1.7 times of weight ratios of dry product, and solvent is 4.3 times of weight ratios; 1,6-xylidine is the weight ratio of 0.4 times.
4. the synthetic method of a kind of bupivacaine according to claim 1, it is characterized in that the catalyzer described in step 3 is palladium carbon, consumption is the weight ratio of 0.15 times; Solvent is methyl alcohol, and consumption is 4 times of weight ratios; Temperature of reaction is 50 ± 5 DEG C, 1 hour reaction times.
5. the synthetic method of a kind of bupivacaine according to claim 1, is characterized in that the solvent described in step 4 is DMF, and consumption is 10 times of weight ratios; Bromination of n-butane consumption is the weight ratio of 0.7 times; The consumption of dilute hydrochloric acid is 50 times of weight ratios of initiator, and content is 8%.
6. the synthetic method of a kind of bupivacaine according to claim 1, the synthetic chemistry reaction equation of its feature bupivacaine is:
。
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| CN201610042790.9A CN105418489A (en) | 2016-01-22 | 2016-01-22 | Synthesis method of bupivacaine |
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| CN201610042790.9A CN105418489A (en) | 2016-01-22 | 2016-01-22 | Synthesis method of bupivacaine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117118A (en) * | 2016-07-11 | 2016-11-16 | 江苏天和制药有限公司 | A kind of preparation technology of bupivacaine hydrochloride |
| CN112939848A (en) * | 2021-02-25 | 2021-06-11 | 浙江工业大学 | Preparation method of bupivacaine and intermediate (S) -2-piperidinecarboxylic acid thereof |
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| WO1996012700A1 (en) * | 1994-10-25 | 1996-05-02 | Chiroscience Limited | Process for preparing levobupivacaine and analogues thereof |
| CN1295558A (en) * | 1998-04-03 | 2001-05-16 | 先进医药公司 | Novel local anesthetic compounds and uses |
| 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 |
-
2016
- 2016-01-22 CN CN201610042790.9A patent/CN105418489A/en active Pending
Patent Citations (4)
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| WO1996012700A1 (en) * | 1994-10-25 | 1996-05-02 | Chiroscience Limited | Process for preparing levobupivacaine and analogues thereof |
| CN1295558A (en) * | 1998-04-03 | 2001-05-16 | 先进医药公司 | Novel local anesthetic compounds and uses |
| 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 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117118A (en) * | 2016-07-11 | 2016-11-16 | 江苏天和制药有限公司 | A kind of preparation technology of bupivacaine hydrochloride |
| CN112939848A (en) * | 2021-02-25 | 2021-06-11 | 浙江工业大学 | Preparation method of bupivacaine and intermediate (S) -2-piperidinecarboxylic acid thereof |
| CN112939848B (en) * | 2021-02-25 | 2022-07-01 | 浙江工业大学 | A kind of preparation method of bupivacaine and its intermediate (S)-2-piperidinecarboxylic acid |
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Application publication date: 20160323 |