CN100404516C - Process for preparing hexahydro pyridazine tricarboxylate - Google Patents
Process for preparing hexahydro pyridazine tricarboxylate Download PDFInfo
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- CN100404516C CN100404516C CNB2004100043107A CN200410004310A CN100404516C CN 100404516 C CN100404516 C CN 100404516C CN B2004100043107 A CNB2004100043107 A CN B2004100043107A CN 200410004310 A CN200410004310 A CN 200410004310A CN 100404516 C CN100404516 C CN 100404516C
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- magnesium
- general formula
- alkyl
- benzyl
- phenyl
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Abstract
The present invention discloses a method for preparing hexahydropyridazine tricarboxylic ester disclosed in the following general formula (I), which comprises the step of the reaction of 2, 5-bihalogeno valerate disclosed in the right general formula (II) and a hydrazine derivative disclosed in a general formula (III) under the existence of magnesium alkoxide and sodium hydride, wherein in the general formula (I), R<1> is C1 to C6 alkyl; R<2> is C1 to C6 alkyl, C1 to C6 alkylogen, substituted phenyl, allyl and benzyl or benzyl of which the phenyl part is substituted; in the general formula (II), X is Br or Cl; R<1> is defined according to R<1> in the general formula (I); in the general formula (III), R<2> is defined according to R<2> in the general formula (I). The compound in the general formula (I) of the present invention is a very important intermediate for the preparation of medicinal active molecules.
Description
Technical field
The present invention relates to the preparation method of hexahydro-pyridazine tricarboxylic ester, particularly in the presence of magnesium alkoxide and sodium hydride, prepare the method for hexahydro-pyridazine tricarboxylic ester.
Background technology
Hexahydro-pyridazine tricarboxylic acid and derivative thereof are very important intermediates for the synthetic of alpha-non-natural amino acid and peptide mimics.Prior art discloses the method for multiple synthetic hexahydro-pyridazine tricarboxylic acid and derivative thereof.Yet existing method needs a plurality of steps mostly, and used reagent is expensive, and the product productive rate is relatively low.
Summary of the invention
The purpose of this invention is to provide a kind of method that is prepared as follows the hexahydro-pyridazine tricarboxylic ester shown in the general formula (I):
This method comprises makes 2 shown in the following general formula (II), the step that 5-dihalo valerate reacts with the hydrazine derivative shown in the general formula (III) in the presence of magnesium alkoxide and sodium hydride:
CH
2X-CH
2-CH
2-CHX-COOR
1 (II)
R
2OCONH-NHCOOR
2 (III)
R in its formula of (I)
1Be C
1-6Alkyl, R
2Be C
1-6Alkyl, C
1-6The substituted benzyl of the phenyl of haloalkyl, replacement, allyl group, benzyl or phenyl moiety;
X is Br or Cl in its formula of (II), R
1Press as defined above;
R in its formula of (III)
2Press as defined above.
Term magnesium alkoxide used herein is to be often referred to C
1-6Alkoxyl magnesium is preferably C
1-4Alkoxyl magnesium.C
1-4Alkoxyl magnesium nail magnesium alkoxide, magnesium ethylate, magnesium propylate, magnesium isopropoxide, propyl carbinol magnesium, isobutyl magnesium alkoxide, sec-butyl alcohol magnesium or tert-butyl alcohol magnesium.Most preferred ethanol magnesium wherein.
Term C used herein
1-6Alkyl is meant straight chain or the branched-chain alkyl with 1～6 carbon atom.Preferred C
1-4Alkyl.Most preferable or ethyl.
Term C used herein
1-6Haloalkyl is meant straight chain or the branched-chain alkyl that contains one or more halogen atoms and have 1～6 carbon atom.Preferred C
1-4Haloalkyl.Trifluoromethyl most preferably.
The phenyl that replaces is meant by C
1-6Alkyl, C
1-6The phenyl that one or more substituting groups in haloalkyl, hydroxyl, nitro, the halogen atom replace.Preferred rubigan or to bromophenyl.
In preferred embodiments, adding has an amount of phase-transfer catalyst in the mixture of magnesium alkoxide and sodium hydride.
Method of the present invention is preferably carried out in aprotic solvent.The used aprotic solvent of the present invention is preferably selected from THF, DMSO, methyl tertiary butyl ether, Di Iso Propyl Ether, DMF, N-Methyl pyrrolidone, toluene or its mixture.
Method of the present invention is carried out under less than 0 ℃.
The compound of general formula (II) is preferably dibromide, it can use method preparation well known in the art, for example use W.A.J.STARMANS etc. at Tetrahedron 1998,54, disclosed method among the 4991-5004 by the δ-Wu Neizhi preparation, perhaps use R.Merchant etc. at J.Am.Chem.Soc.1927,49, disclosed method among the 1828-1831 by the preparation of 5-bromine valeric acid.
R wherein
2General formula (III) compound for methyl, ethyl or phenyl can obtain from commercial, for example obtains from Aldrich or Fluka.Perhaps can prepare by currently known methods, method described in for example following reference: L.A.Carpino and P.J.Crowely are at Organic Syntheses.Coll.Vol.V, in 160, J.M.Mellor and R.N.Pathirana be at J.Chem.Soc.Perkin Trans.11984, among the 753-759 and
With J.Ullrich at Chem.Ber.1959, disclosed method in 92,1478.
In a preferred embodiment of the invention, R
1And R
2Be C
1-4Alkyl.In a further preferred embodiment, R
2C preferably
1-4The benzyl of haloalkyl, benzyl or replacement.R
2Most preferably be trifluoromethyl-COOR
2Can be regarded as amino protecting group, it can prevent that amino participation reaction from can be removed again easily after the chemical reaction at other position of molecule is finished.For example, after required reaction is finished, can be at back hydrolysis hexahydro-pyridazine tricarboxylic ester in the presence of the alkali metal hydroxide and general-COOR
2Remove from nitrogen-atoms.And then can use souring method well known in the art that hexahydro-pyridazine tricarboxylic acid an alkali metal salt is changed into the hexahydro-pyridazine tricarboxylic acid.
Product of the present invention, promptly the compound of general formula (I) can use method well known in the art such as extraction, distillation or chromatography to separate and obtain.
General formula (I) compound is very important intermediate for preparation pharmaceutical activity molecule.
Compared with prior art, the present invention in the presence of magnesium alkoxide and sodium hydride by 2,5-dihalo valerate and hydrazine derivative cyclisation and make the hexahydro-pyridazine tricarboxylic ester, its product purity and reaction yield all are greatly improved.
Embodiment
The present invention will be described in more detail below in conjunction with embodiment.
Raw material embodiment
2, the preparation of 5-dibromo Valeric acid ethylester
In 2 hours with bromine (64.57g, purity 99%, 0.40mol) be added to temperature be 110-115 ℃ δ-Wu Neizhi (41.72g, purity 96%, 0.40mol) and PBr
3(2.20g, 0.008mol) under the liquid level of mixing solutions, wherein latter half needs to add more lentamente.After 60 minutes, solution is cooled to 0-5 ℃, adds again and contain the cold ethanol that 3.65g (0.10mol) does HCl gas.After the stirring at room 22 hours, remove second alcohol and water (also can use toluene or other solvent that is fit to remove the water-ethanol azeotrope) by underpressure distillation.(200ml) extracts thick product with ether, and (98ml 0.124mol) washs to remove any unreacted acid altogether with saturated sodium bicarbonate aqueous solution.After solvent was removed in vacuum-drying, crude product ester (92.27g, purity 69.6%, productive rate 55.8%) was 3: 1 60cm Vigreux post fractionation through reflux ratio, obtains 2 of 56.53g, 5-dibromo Valeric acid ethylester, boiling point: 97-98 ℃/1.8mbar, productive rate: 49.1%.
Preparation embodiment
Hexahydro-pyridazine-1,2, the preparation of 3-tricarboxylic acid ethyl ester
In 1 liter four-hole bottle, add magnesium ethylate 1.73g (0.025mol), sodium hydride 10.5g (0.25mol) and DMF 100ml, add 1.73g PCT again as phase-transfer catalyst, under less than 0 ℃ temperature stirring, drip by 1,2-hydrazono-ethyl dicarboxylate 19.4g (0.11ml, 99%) and the solution formed of DMF 100ml, drips off the back and continue reaction 2 hours.Then, keep less than dripping under 0 ℃ the temperature by 2, the solution that 5-dibromo Valeric acid ethylester 30.4g (0.1ml, 95%) and DMF 124ml form drips off the back and continues reaction 1 hour.Keep then dripping by KH down less than 15 ℃
2PO
4(9.6g) and the solution formed of water 250ml, layering.Water layer merges oil reservoir and extract layer with N-BUTYL ACETATE extraction (140ml * 2), water 140ml washing.Concentrating under reduced pressure obtains thick liquid product hexahydro-pyridazine-1,2, and (GC purity is 90.9% to 3-tricarboxylic acid ethyl ester 30.5g, and 0.092mol), productive rate is 88.5%.
Should be appreciated that embodiments of the invention only are for understanding the indefiniteness explanation that the present invention makes the present invention better.Those skilled in the art are not departing from the spirit and scope of the present invention and can make various modifications, replacement and change to the present invention, and these modifications, replacement and change still belong to protection scope of the present invention.
Claims (9)
1. method that is prepared as follows the hexahydro-pyridazine tricarboxylic ester shown in the general formula (I):
Described method comprises makes 2 shown in the following general formula (II), the step that 5-dihalo valerate reacts with the hydrazine derivative shown in the general formula (III) in the presence of magnesium alkoxide and sodium hydride:
CH
2X-CH
2-CH
2-CHX-COOR
1 (II)
R
2OCONH-NHCOOR
2 (III)
R in its formula of (I)
1Be C
1-6Alkyl, R
2Be C
1-6Alkyl, C
1-6The substituted benzyl of the phenyl of haloalkyl, replacement, allyl group, benzyl or phenyl moiety;
X is Br or Cl in its formula of (II), R
1Press as defined above;
R in its formula of (III)
2Press as defined above.
2. the method for claim 1, wherein said magnesium alkoxide is magnesium methylate, magnesium ethylate, magnesium propylate, magnesium isopropoxide, propyl carbinol magnesium, isobutyl magnesium alkoxide, sec-butyl alcohol magnesium or tert-butyl alcohol magnesium.
3. method as claimed in claim 1 or 2, wherein R
1Be C
1-4Alkyl.
4. method as claimed in claim 1 or 2, wherein R
1And R
2All be C
1-4Alkyl.
5. method as claimed in claim 1 or 2, wherein R
2Be C
1-4The benzyl of haloalkyl, benzyl or replacement.
6. the method for claim 1, the phenyl of wherein said replacement is meant by C
1-6Alkyl, C
1-6The phenyl that one or more substituting groups in haloalkyl, hydroxyl, nitro, the halogen atom replace.
7. method as claimed in claim 1 or 2, wherein adding in the mixture of magnesium alkoxide and sodium hydride has an amount of phase-transfer catalyst.
8. method as claimed in claim 1 or 2, wherein said being reflected in the aprotic solvent that is selected from THF, DMSO, methyl tertiary butyl ether, Di Iso Propyl Ether, DMF, N-Methyl pyrrolidone, toluene or its mixture carried out.
9. method as claimed in claim 1 or 2, wherein said being reflected under 0 ℃ carried out.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100043107A CN100404516C (en) | 2004-02-13 | 2004-02-13 | Process for preparing hexahydro pyridazine tricarboxylate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100043107A CN100404516C (en) | 2004-02-13 | 2004-02-13 | Process for preparing hexahydro pyridazine tricarboxylate |
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| Publication Number | Publication Date |
|---|---|
| CN1654458A CN1654458A (en) | 2005-08-17 |
| CN100404516C true CN100404516C (en) | 2008-07-23 |
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|---|---|---|---|
| CNB2004100043107A Expired - Fee Related CN100404516C (en) | 2004-02-13 | 2004-02-13 | Process for preparing hexahydro pyridazine tricarboxylate |
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| CN108675962A (en) * | 2018-07-04 | 2018-10-19 | 中昊(大连)化工研究设计院有限公司 | One-step method green syt phthalylhydrazine |
| CN111909077A (en) * | 2020-09-02 | 2020-11-10 | 南通大学 | 2- (1-bromocyclobutyl) pyridine and synthesis method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995021818A1 (en) * | 1994-02-08 | 1995-08-17 | Alcon Laboratories, Inc. | Novel process for preparation of clonidine derivatives |
| WO1999055724A1 (en) * | 1998-04-27 | 1999-11-04 | Hoechst Marion Roussel | NOVEL OCTAHYDRO-6,10-DIOXO-6H-PYRIDAZINO/1,2-a/ /1,2/DIAZEPIN-1-CARBOXYLIC ACID DERIVATIVES, PREPARATION METHOD AND USE FOR PREPARING THERAPEUTICALLY ACTIVE COMPOUNDS |
| US6177565B1 (en) * | 1998-08-19 | 2001-01-23 | Vertex Pharmaceuticals Inc. | Process for synthesizing piperazic acid |
| WO2001056997A1 (en) * | 2000-02-04 | 2001-08-09 | Lonza Ag | Process for preparing piperazic acid derivatives thereof |
-
2004
- 2004-02-13 CN CNB2004100043107A patent/CN100404516C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995021818A1 (en) * | 1994-02-08 | 1995-08-17 | Alcon Laboratories, Inc. | Novel process for preparation of clonidine derivatives |
| WO1999055724A1 (en) * | 1998-04-27 | 1999-11-04 | Hoechst Marion Roussel | NOVEL OCTAHYDRO-6,10-DIOXO-6H-PYRIDAZINO/1,2-a/ /1,2/DIAZEPIN-1-CARBOXYLIC ACID DERIVATIVES, PREPARATION METHOD AND USE FOR PREPARING THERAPEUTICALLY ACTIVE COMPOUNDS |
| US6177565B1 (en) * | 1998-08-19 | 2001-01-23 | Vertex Pharmaceuticals Inc. | Process for synthesizing piperazic acid |
| WO2001056997A1 (en) * | 2000-02-04 | 2001-08-09 | Lonza Ag | Process for preparing piperazic acid derivatives thereof |
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| CN1654458A (en) | 2005-08-17 |
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