CN1827610A - Process for preparing 4-acyl substituted-2-methylpiperazines - Google Patents
Process for preparing 4-acyl substituted-2-methylpiperazines Download PDFInfo
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- CN1827610A CN1827610A CN 200610045802 CN200610045802A CN1827610A CN 1827610 A CN1827610 A CN 1827610A CN 200610045802 CN200610045802 CN 200610045802 CN 200610045802 A CN200610045802 A CN 200610045802A CN 1827610 A CN1827610 A CN 1827610A
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- methylpiperazine
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- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical group CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- BCXBBYDLRSJZTE-UHFFFAOYSA-N (3-methylpiperazin-1-yl)-phenylmethanone Chemical compound C1CNC(C)CN1C(=O)C1=CC=CC=C1 BCXBBYDLRSJZTE-UHFFFAOYSA-N 0.000 claims description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000007039 two-step reaction Methods 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 10
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 3
- 239000002360 explosive Substances 0.000 abstract description 3
- 230000003213 activating effect Effects 0.000 abstract description 2
- 150000004885 piperazines Chemical class 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 abstract 5
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000010961 commercial manufacture process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
- JOMNTHCQHJPVAZ-RXMQYKEDSA-N (2r)-2-methylpiperazine Chemical compound C[C@@H]1CNCCN1 JOMNTHCQHJPVAZ-RXMQYKEDSA-N 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- BAZLEIBBJFLUKK-UHFFFAOYSA-N 1-(3-methylpiperazin-1-yl)pentan-1-one Chemical compound CCCCC(=O)N1CCNC(C)C1 BAZLEIBBJFLUKK-UHFFFAOYSA-N 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000006480 benzoylation reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000003335 steric effect Effects 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940005605 valeric acid Drugs 0.000 description 2
- JOMNTHCQHJPVAZ-YFKPBYRVSA-N (2s)-2-methylpiperazine Chemical compound C[C@H]1CNCCN1 JOMNTHCQHJPVAZ-YFKPBYRVSA-N 0.000 description 1
- OKGPFTLYBPQBIX-CQSZACIVSA-N 1-[(2r)-4-benzoyl-2-methylpiperazin-1-yl]-2-(4-methoxy-1h-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione Chemical compound C1=2C(OC)=CC=NC=2NC=C1C(=O)C(=O)N([C@@H](C1)C)CCN1C(=O)C1=CC=CC=C1 OKGPFTLYBPQBIX-CQSZACIVSA-N 0.000 description 1
- YBTKGKVQEXAYEM-UHFFFAOYSA-N 2-bromopyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(Br)=C1 YBTKGKVQEXAYEM-UHFFFAOYSA-N 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- -1 methylpiperazine compound Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparation of selective monoacylated piperazine by N,N'-carbonyldiimidazole(CDI) activating carboxyl acid and especially to a method for preparation of 4-acylsubstitution-2-methylpiperazine compound by selectively monoacylating 4-nitrogen atom of 2-methylpiperazine ring.It is characterized in that it prepares carbonyl diimidazolederivant by the reaction of between N,N'-carbonyldiimidazole and carboxyl acid, and monoacylated 4-acylsubstitution-2-methylpiperazine compound is obtained by monoacylated condensation reaction between 2-methylpiperazine and the substances of the former step. In relation to the present technology, the said invention selects N,N'-carbonyldiimidazole which is cheap and easy for commercial manufacture as effective substitute agent of diethyl aluminium chloride, essentially removes potential safety hazard, avoids the explosive diethyl aluminium chloride, and is of simple operation and high reaction yield rate.
Description
Technical field
The present invention relates to use N; N ' phosphinylidyne diimidazole (CDI) activating carboxy acid prepares the method for the single acylated piperazine of selectivity, and especially the single acylation reaction of selectivity prepares the method for a kind of 4-acyl substituted-2-methylpiperazine compound on 4 nitrogen-atoms of 2-methylpiperazine ring.
Background technology
Conventional process for acylating according to techniques well known; without any regioselectivity; can only obtain two kinds of different single acylates on 1,4 nitrogen-atoms simultaneously, and the mixture of two acylates, and the product of two kinds of single acidylates can't effectively separate.
The 2-methylpiperazine compounds of the single acidylate of selectivity is a class chemosynthesis intermediate, is mainly used in the preparation of medicine, agricultural chemicals and dyestuff.For example, carry out clinical trial and having HIV-1 and suppress active compd B MS-378806, containing the benzoylation methylpiperazine in its structure. when preparing this intermediate, require the single benzoylation methylpiperazine of regioselectivity ring.In BMS-378806 synthetic, document J Med Chem.2003,46:4236-4239 adopts and costs an arm and a leg, and be difficult to buy, and inflammable and explosive diethyl aluminum chloride is as (R)-2-methylpiperazine and methyl benzoate selectivity list acidylate.Condensation reagent, by two the step successive reactions prepare 4-benzoyl-2-methylpiperazine.
The present invention has adopted cheap and easy to get and has been easy to the N of suitability for industrialized production; N ' phosphinylidyne diimidazole (CDI) is as the effectively alternative reagent of diethyl aluminum chloride; on two different sterically hindered nitrogen-atoms on the 2-methylpiperazine ring, carry out the single acylation reaction of selectivity by steric effect.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of methylpiperazine compound of single acidylate, particularly prepare the method for a kind of 4-acyl substituted-2-methylpiperazine compound.
Preparation method according to a kind of 4-acyl substituted of the present invention-2-methylpiperazine compound; it is characterized in that N; N ' phosphinylidyne diimidazole and carboxylic acid reaction are made the carbonyl dimidazoles derivative; carry out 4-acyl substituted-2-methylpiperazine compound that single acidylate condensation reaction generates single acidylate with the 2-methylpiperazine again
Wherein A represents phenyl, the tertiary butyl, 4-(1-tertiary butyloxycarbonyl phenylpiperidines) base, 4-(2-bromopyridine) base.
4-acyl substituted-2-methylpiperazine compound comprises the compound 1,2,3,4 of following structure.
According to the preparation method of a kind of 4-acyl substituted of the present invention-2-methylpiperazine compound, it is characterized in that 4-acyl substituted-2-methylpiperazine compound is 4-benzoyl-2-methylpiperazine.
Preparation method according to a kind of 4-acyl substituted of the present invention-2-methylpiperazine compound; it is characterized in that described 4-benzoyl-2-methylpiperazine molar ratio is N; N '-phosphinylidyne diimidazole: phenylformic acid: 2-methylpiperazine 1: 1-0.5: 1-0.5; described organic solvent is a tetrahydrofuran (THF); methylene dichloride, trichloromethane, its consumption are 10-30 times of 2-methylpiperazine quality; the temperature of reaction is 20-100 ℃, and the two-step reaction time was respectively 2-24 hour.
Preparation method according to a kind of 4-acyl substituted of the present invention-2-methylpiperazine compound; it is characterized in that it is solvent that described 4-benzoyl-2-methylpiperazine adopts tetrahydrofuran (THF); the temperature of reaction is 20-80 ℃; the two-step reaction time was respectively 2-15 hour; molar ratio is N, N ' phosphinylidyne diimidazole: phenylformic acid: 2-methylpiperazine 1: 1: 1.
According to method of the present invention, on two different sterically hindered nitrogen-atoms on the 2-methylpiperazine ring, carry out the single acylation reaction of selectivity by steric effect through experimental study.On 1 nitrogen-atoms of 2-methylpiperazine ring and 4 nitrogen-atoms, because that the existence of methyl produces is different sterically hindered, the product of reaction mainly is that the ratio of 4 N is big, or all is the product of 4 N.Select different carboxylic acids on the other hand, for example: acetate, positive valeric acid, PIVALIC ACID CRUDE (25), when phenylformic acid reacts as acylating reagent, acetate, positive valeric acid can obtain two kinds of different single acylates on 1,4 nitrogen-atoms simultaneously, and the mixture of two acylates; PIVALIC ACID CRUDE (25), phenylformic acid have the large space steric hindrance, all carry out acylation reaction on 4 nitrogen-atoms of 2-methylpiperazine ring.4-acyl substituted-2-methylpiperazine the compound of method preparation therefore of the present invention, the α bit space steric hindrance that is included in acyl group is equal to or greater than the analogue of phenyl, the tertiary butyl, pyridyl.
Preparation method of the present invention has used (R)-2-methylpiperazine, also can use its optical isomer (S)-2-methylpiperazine or enantiomorph 2-methylpiperazine as raw material.
Method of the present invention has compared with prior art been eliminated potential safety hazard from the source, has avoided inflammable and explosive diethyl aluminum chloride, and it is cheap and easy to get, easy to operate to have a raw material, and the reaction yield height is suitable for the characteristics of industrializing implementation.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
The extensively logical medication chemistry company limited of used instrument and reagent (R)-2-methylpiperazine among the embodiment, Nanjing; CDI, Suzhou U.S.A spend daily spices company limited; Phenylformic acid, Tianjin Da Mao chemical reagent factory; PIVALIC ACID CRUDE (25), worker company limited is deified by Wuan City China, and all the other reagent are commercially available chemically pure reagent.
Chemical structure testing tool: Bruker WM-300 nuclear magnetic resonance analyser; AppliedBioSystem Mariner API-3000 high resolution mass spec.
Embodiment 1
Synthesizing of 4-benzoyl-2-methylpiperazine
With phenylformic acid (2.5g 0.02mol) and N; N ' phosphinylidyne diimidazole (3.3g 0.02mol) was dissolved among the dry tetrahydrofuran 50mL reflux 3 hours; after adding (R)-2-methylpiperazine (2.0g0.02mol); continue reflux after 3 hours; reaction finishes; column chromatography purification reaction mixture (elutriant: ethyl acetate: methyl alcohol=4: 1) get product 4-benzoyl-2-methylpiperazine 1.6g, yield 40%.Low Resolution Mass Spectra (LCMS) M+1,205.1.H
1-NMR(300MHz，CD
3OD)：δ7.45(m，5H)，4.50(d，1H)，3.60(b，1H)，3.33-2.60(m，5H)，1.16-0.98(d，3H)。
Embodiment 2
Synthesizing of 4-valeryl-2-methylpiperazine
With PIVALIC ACID CRUDE (25) (0.02mol) and N; N ' phosphinylidyne diimidazole (0.02mol) was dissolved among the dry tetrahydrofuran 50mL reflux 3 hours; after adding (R)-2-methylpiperazine (0.02mol); continue reflux after 3 hours; reaction finishes; column chromatography purification reaction mixture (elutriant: ethyl acetate: methyl alcohol=4: 1) get product 4-valeryl-2-methylpiperazine, must measure 1.5g, yield 40%.Low Resolution Mass Spectra (LCMS) M+1:185.1.H
1-NMR(300MHz，CD
3OD)：4.32-4.24(m，2H)，3.00-2.92(m，2H)，2.76-2.65(m，2H)，2.59-2.51(m，1H)，1.26(s，9H)，1.09(d，3H)。
Embodiment 3
4-[4-(1-tertiary butyloxycarbonyl phenylpiperidines) formyl radical)]-2-methylpiperazine synthetic
(3.84g, 0.0166mol) and N, (3.769g 0.02324mol) adds in the exsiccant tetrahydrofuran (THF) (50mL) N ' phosphinylidyne diimidazole, and stirring at room is to dissolving with N-tertiary butyloxycarbonyl phenylpiperidines-4-carboxylic acid.Under the room temperature, and adding (R)-2-methylpiperazine in reaction solution (1.829g, 0.01826mol), room temperature continues to stir 24 hours, with the reaction solution concentrating under reduced pressure, its enriched material is leant on chromatography (ethanol: ethyl acetate=1: 5) get 3.4g thickness colourless liquid (3.4 gram), yield 65.4% through silica gel.Low Resolution Mass Spectra (LCMS) M+1=312.
Embodiment 4
4-[4-(2-bromopyridine) formyl radical)]-2-methylpiperazine synthetic
(5g, 0.02475mol) and N, (5.6188g 0.03465mol) adds in the exsiccant tetrahydrofuran (THF) (50mL) N ' phosphinylidyne diimidazole, and temperature rising reflux 4 hours is to material dissolution with 2-bromopyridine-4-carboxylic acid under the room temperature.Be back to room temperature, and adding (R)-2-methylpiperazine in reaction solution (2.6995g, 0.02723mol), stirring and refluxing reaction 20 hours, concentration of reaction solution is crossed post (ethanol: ethyl acetate=1: 5) get 4.9g thick liquid, yield 70%.
Claims (4)
1. the preparation method of one kind 4-acyl substituted-2-methylpiperazine compound; it is characterized in that N; N ' phosphinylidyne diimidazole and carboxylic acid reaction are made the carbonyl dimidazoles derivative, carry out 4-acyl substituted-2-methylpiperazine compound that single acidylate condensation reaction generates single acidylate with the 2-methylpiperazine again
Wherein A represents phenyl, the tertiary butyl, 4-(1-tertiary butyloxycarbonyl phenylpiperidines) base, 4-(2-bromopyridine) base.
2. the preparation method of 4 according to claim 1-acyl substituted-2-methylpiperazine compound is characterized in that 4-acyl substituted-2-methylpiperazine compound is 4-benzoyl-2-methylpiperazine.
The preparation method of 3 a kind of 4-acyl substituted according to claim 2-2-methylpiperazine compounds; it is characterized in that described 4-benzoyl-2-methylpiperazine molar ratio is N; N '-phosphinylidyne diimidazole: phenylformic acid: 2-methylpiperazine 1: 1-0.5: 1-0.5; described organic solvent is a tetrahydrofuran (THF); methylene dichloride, trichloromethane, its consumption are 10-30 times of 2-methylpiperazine quality; the temperature of reaction is 20-100 ℃, and the two-step reaction time was respectively 2-24 hour.
The preparation method of 4 a kind of 4-acyl substituted according to claim 2-2-methylpiperazine compounds; it is characterized in that it is solvent that described 4-benzoyl-2-methylpiperazine adopts tetrahydrofuran (THF); the temperature of reaction is 20-80 ℃; the two-step reaction time was respectively 2-15 hour; molar ratio is N, N ' phosphinylidyne diimidazole: phenylformic acid: 2-methylpiperazine 1: 1: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610045802XA CN100448849C (en) | 2006-02-02 | 2006-02-02 | Process for preparing 4-acyl substituted-2-methylpiperazines |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610045802XA CN100448849C (en) | 2006-02-02 | 2006-02-02 | Process for preparing 4-acyl substituted-2-methylpiperazines |
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| CN1827610A true CN1827610A (en) | 2006-09-06 |
| CN100448849C CN100448849C (en) | 2009-01-07 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012059048A1 (en) | 2010-11-03 | 2012-05-10 | 中国中化股份有限公司 | Pyrazole amide compound and use thereof |
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| US6239154B1 (en) * | 1996-03-08 | 2001-05-29 | Adolor Corporation | Kappa agonist compounds pharmaceutical formulations and method of prevention and treatment of pruritus therewith |
| DE19756036A1 (en) * | 1997-12-17 | 1999-06-24 | Merck Patent Gmbh | New indole amide derivatives |
| US7772227B2 (en) * | 2003-12-17 | 2010-08-10 | N.V. Organon | Tricyclic 1-[(indol-3-yl)carbonyl]piperazine derivatives as cannabinoid CB1 receptor agonists |
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Application publication date: 20060906 Assignee: Shenzhen China Associated Pharmaceutical Co., Ltd. Assignor: Shenzhen Tianming medical science and Technology Development Co Ltd Contract record no.: 2013440020223 Denomination of invention: Process for preparing 4-acyl substituted-2-methylpiperazines Granted publication date: 20090107 License type: Exclusive License Record date: 20130716 |
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Assignee: Shenzhen China Associated Pharmaceutical Co., Ltd. Assignor: Shenzhen Tianming medical science and Technology Development Co Ltd Contract record no.: 2013440020223 Date of cancellation: 20191218 |
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Application publication date: 20060906 Assignee: SHENZHEN ZHONGLIAN PHARMACEUTICAL Co.,Ltd. Assignor: Shenzhen Tianming medical science and Technology Development Co Ltd Contract record no.: X2020440020008 Denomination of invention: Process for preparing 4-acyl substituted-2-methylpiperazines Granted publication date: 20090107 License type: Exclusive License Record date: 20200316 |
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