CN85105098A - The preparation method of 4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone derivative - Google Patents
The preparation method of 4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone derivative Download PDFInfo
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Abstract
Preparation has the method for the 4-acetoxy-3-hydroxyethyl azacyclo fourth-2-ketone derivatives of logical formula II, R in the formula
1Be the protecting group of hydroxyl, this method comprises the 'beta '-lactam compounds that will have logical formula I in the presence of alkali, reacts the protecting group of removing N then with acetic anhydride in the organic solvent.R in the formula
1The same, R
2, R
3And R
4Be C
1To C
4Low alkyl group, phenyl or aralkyl, R are the protecting groups of N.4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone derivative is preparation Carbapenem beta-Lactam antibiotics (as thiophene adriamycin) and Penem beta-Lactam antibiotics useful as intermediates.
Description
The present invention relates to the preparation method of 4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone, this ketone has the hydroxyethyl that hydroxyl is protected on 3 carbon, and 4-ethyl acyloxy is arranged on 4 carbon.Know, 4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone derivative is preparation Carbapenem beta-Lactam antibiotics (as thiophene adriamycin) and Penem beta-Lactam antibiotics useful as intermediates (" Tetrahe-dronletters " that people such as reference such as Laide write, the 23rd volume, 2293 pages, nineteen eighty-two version, " Chem.Pharm.Bull. " the 29th volume of writing with people such as Yoshida, 2899 pages, version in 1981).
Beg till the present, the method of synthetic 4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone derivative is known, for example, and by synthetic (" Chem.Parm.Bull. " the 29th volume write with reference to people such as Yoshida of 6-amino-penicillanic acid, 2899 pages, version in 1981); By Threonine synthetic (" tetrahedron " the 39th volume of writing with reference to people such as Shiozaki, 2399 pages, nineteen eighty-three version); By aspartic acid synthetic (with reference to " Tetrahedronletters " that people such as Laider write, the 23rd volume, 2293 pages, nineteen eighty-two version), or the like.But these methods are more insufficient to be to have used industrial unwelcome heavy metal in order to introduce acetoxyl group on 4 carbon of beta-lactam nucleus, as mercuric acetate and lead tetraacetate.The present inventor has found the method by enol silicomethane ether and a kind of Novel ' beta '-lactam compounds of Sulfuryl chloride isocyanate prepared in reaction; this method has the protected hydroxyethyl of O-on the 3rd carbon; on 4 carbon the silicomethane ether is arranged, this method is applied for a patent.The present inventor also finds, adopts above-mentioned 'beta '-lactam compounds can prepare 4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone at an easy rate, and then has realized the present invention.
The invention provides the preparation method of 4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone with logical formula II:
R in the formula
1Be hydroxyl protecting group, the 'beta '-lactam compounds that will have logical formula I reacts the protecting group of removing N then with acetic anhydride in organic solvent in the presence of alkali.
R wherein
1Be hydroxyl protecting group, R
2, R
3, R
4Be C
1To C
4Low alkyl group, phenyl or aralkyl, R are the protecting groups of N.
Preparation with 'beta '-lactam compounds of logical formula I is to go up by the N at the 'beta '-lactam compounds with general formula (I ') to introduce substituent R,
R in the formula
1, R
2, R
3, R
4Definition the same.Disclosed as the inventor's application form (Japanese unexamined patent publication number 139797/1984), can easily be obtained having general formula (I '), the 'beta '-lactam compounds of disiloxanyl-is arranged on 4 carbon by following reactions steps:
Have logical formula I, the 'beta '-lactam compounds of the protecting group of band N can by with the 'beta '-lactam compounds of general formula (I ') and general formula be R-X(wherein the definition of R is the same, X is the fontanel element) reagent react obtain.General formula is that the example of R-X reagent has trialkyl silicomethane fontanel (tria-lkyl-sily halide), t-butyl dimethylsilane chlorine for example, sec.-propyl dimethylsilane chlorine, isobutyl-dimethylsilane chlorine, trimethyl silyl chlorine and similar compound, the alkoxyl group oxalyl chloride, aralkoxy oxalyl chloride or allyloxy oxalyl chloride, as
And similar compounds.T-butyl dimethylsilane chlorine is desirable especially, and t-butyl dimetylsilyl can be introduced as protecting group.
With 'beta '-lactam compounds (I ') (as triethylamine and imidazoles) in the presence of alkali, in solvent (as DMF or methylene dichloride), be the reagent react of R-X, eliminate hydrogenchloride, steam solvent then with general formula, extract and steam extraction solvent again, can access the compound of general formula (I).
On 3 carbon of logical formula I 'beta '-lactam compounds, for the R of hydroxyl
1O-protecting group example the trialkylsilkl of logical formula III is arranged:
R in the formula
5, R
6, R
7Be C
1To C
4Low alkyl group, as t-butyldimethylsilyl, triisopropyl silyl, sec.-propyl dimetylsilyl, and the isobutyl-dimetylsilyl, t-butyl, benzyl, trichlorine ethoxy carbonyl, uncle-butoxy carbonyl, P-nitro benzyloxycarbonyl, and similar compounds.Tert-butyl dimetylsilyl or sec.-propyl dimetylsilyl are desirable especially, and they are stable in reaction process, and can protect by the acid treatment selective removal.R in the logical formula I lactam compound
2, R
3, R
4Can be identical or different, and can be from C
1To C
4Low alkyl group in select, as methyl, ethyl, sec.-propyl, isobutyl-, the tertiary butyl, phenyl, benzyl or aralkyl such as P-nitrobenzyl, but R
2, R
3, R
4It preferably all is methyl.
With the logical formula I B-lactam thing of preparation as stated above in organic solvent and alkali in the presence of with acetic anhydride reaction,
(R in the formula
1, R
2, R
3, R
4With the definition of R such as above-mentioned.) the 4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone derivative of the general formula (II ') that said 'beta '-lactam compounds changed into need,
R in the formula
1The same with the definition of R, at this moment, alkali, solvent and temperature of reaction are the factors that influences productive rate.Reaction solvent can adopt the hydrocarbon or the aromatic hydrocarbon of fontanelization, and the hydrocarbon of fontanelization preferably is as methylene dichloride.Best alkali is dimethyl aminopyridine, also can be with itself and other alkali such as pyridine, and lutidine and picoline are used in combination.The alkali number that uses is molar 1 to 5 times of a logical formula I 'beta '-lactam compounds, and best 1 to 3 times, acetic anhydride is as introducing acetoxyl group reagent, and its usage quantity is molar 1 to 20 times of a logical formula I 'beta '-lactam compounds, preferably 3 to 15 times.
Dimethyl aminopyridine and acetic anhydride are added in the logical formula I 'beta '-lactam compounds, in the presence of organic solvent such as methylene dichloride, react, stir this mixture, temperature be-50 ℃ to room temperature, be preferably-30 ℃ to 5 ℃, reaction is carried out disappearing until logical formula I compound.Except that dimethyl aminopyridine,, then can improve productive rate if also add another kind of alkali such as pyridine or picoline.Reaction adds extraction solvent, as methylene dichloride or hexane after finishing in reaction mixture; add aqueous carbonic acid hydrogen sodium then, tell organic layer and wash it, again dehydration; steam organic solvent, obtain on 4 carbon, having the protected 'beta '-lactam compounds of N-of acetoxyl group.Resulting general formula (II ') compound can react, and removes the N-protected base.If necessary, this compound can be passed through silica gel chromatography.
When removing the N-protected base, require optionally only the N-protected base to be removed, and the O-protecting group of not removing hydroxyethyl on 3 carbon.For example, if the N-protected base is alkyl silyl such as tert-butyl dimetylsilyl, then preferably adopt tetrabutylammonium fluoride.With fontanel quaternary ammonium such as TBAC tetrabutylammonium chloride, the bromination tetrabutylammonium, tetramethylammonium chloride, Variquat B 200 is used in combination with Potassium monofluoride, also can produce the effect same with tetrabutylammonium fluoride, if make solvent with methyl alcohol, also can only use Potassium monofluoride.
The solvent that uses in eliminating reaction is tetrahydrofuran (THF) preferably, and acetonitrile or methylene dichloride are reflected at like this under stirring and the room temperature and carry out smoothly.Adopt acetate to make productive rate make moderate progress when removing protecting group.After reaction is finished, in reaction mixture, add extraction solvent,, add dilute alkaline soln then as ethyl acetate.Extract organic layer again, wash it with water, and dehydration, drying, last, the organic solvent steaming is removed out, obtain required compound-4-acetoxy-3-hydroxyethyl azetidin-2-ketone derivatives.4-acetoxy-3-hydroxyethyl nitrogen heterocyclic din-2-ketone derivative can or pass through silica gel column chromatography and purifying by crystallization from normal hexane or sherwood oil.
The embodiment of following indefinite will explain the present invention especially.Can make any change and improvement and be no more than the spirit and scope of the invention, this is that the people understands.
Embodiment 1
(3R, 4R)-the 4-acetoxy-3-[(R)-1-tert-butyl-dimethylsilane oxygen base ethyl]-preparation of nitrogen heterocyclic din-2-ketone.
Dissolving 1.0 gram (3R in 10mlDMF, 5R)-3-(1-t-butyldimethylsilyloxy base ethyl)-4-trimethylsiloxy nitrogen heterocyclic din-2-ketone, to wherein adding 0.89 gram triethylamine and 0.61 gram tert-butyldimethylsilyl chloride, this mixture was at room temperature stirred 9 hours.After reaction is finished, steam DMF under the decompression, add the 30ml hexane again.Use 2.5% solution in succession, and use dried over mgso, steam solvent then, obtain the thick product liquid of 1.24 grams.
1.0 gram aforesaid liquids are joined in the 5ml methylene dichloride, add 0.85 gram dimethyl aminopyridine and 1.1ml acetic anhydride again, the mixture that obtains at room temperature reacted 6 hours.Then reaction mixture is used 5% NaHCO in succession
3The aqueous solution, pH value are 3 aqueous hydrochloric acid and saturated salt solution washing, and use dried over mgso, steam solvent after, obtain 0.8 and restrain thick product liquid.With silica gel chromatography liquid (benzene: hexane=2: 1), obtain 0.5 the gram (3R, 4R, 5R)-4-acetoxyl group-1-(t-butyldimethylsilyl)-3-(1-t-butyldimethylsilyloxy base ethyl)-nitrogen heterocyclic din-2-ketone liquid.
In 2ml THF, add 0.5 gram aforesaid liquid, add 0.4 gram tetrabutylammonium fluoride and 0.17 gram acetate (in 2 milliliters of THF solution) again, at room temperature stirred this mixture then 30 minutes.Add the 20ml vinyl acetic monomer in reaction mixture after, reactant is used 5% NaHCO successively
3The aqueous solution and saturated salt solution washing, and use dried over mgso, steam solvent, obtain the required crystalline compounds of 0.30 gram.Silica gel chromatography (benzene: vinyl acetic monomer=6: 1), provide the required beta-lactam solid of 0.27 gram is passed through in the crystallization that obtains.
Fusing point: 107 ℃～108 ℃
[α]＝+50°（C＝0.5CHCl
3）
I
HNMR（90MHZ CDCl
3）δ，（ppm）
0.08（6H，S），0.84（9H，S），1.20（3H，d），
2.01（3H，S），3.04（1H，dd），4.12（1H，m），
5.76(1H, d) and 6.73(NH)
Embodiment 2
(3R, 4R)-the 4-acetoxy-3-[(R)-the 1-tertiary butyl-dimethylsilane oxygen base ethyl]-preparation of nitrogen heterocyclic din-2-ketone
With 1 gram (3R, 4R)-the 1-tertiary butyl-dimetylsilyl-3-[(R)-1-t-butyldimethylsilyloxy base ethyl]-4-trimethylsiloxy nitrogen heterocyclic din-2-ketone is dissolved in the 10ml methylene dichloride, again to wherein adding 0.85 gram dimethyl aminopyridine and 0.71 gram acetic anhydride.The mixture that obtains reacted 1 day down at 0 ℃.Reaction mixture is used 5% NaHCO after diluting with hexane in succession
3The aqueous solution, pH value are 4 aqueous hydrochloric acid and saturated salt solution washing, use sulphur magnesium dry reaction product then, steam solvent, obtain the thick product liquid of 0.85 gram.By silica gel column chromatography with this liquid purifying (hexane: ether=30: 1), obtain 0.40 gram (3R, 4R)-the 4-acetoxyl group-1-tertiary butyl-dimetylsilyl)-3-[(R)-1-t-butyldimethylsilyloxy base ethyl) the nitrogen heterocyclic din-2-ketone colourless liquid.
In the liquid that obtains, add 2ml THF, be incorporated in gram tetrabutylammonium fluoride of 0.26 among the 2ml THF and 0.12 gram acetic acid again, mixture was at room temperature stirred 30 minutes.Add after 20 milliliters of vinyl acetic monomers in reaction mixture, reaction product is used 5% NaHCO one by one
3The aqueous solution and saturated salt solution washing, and use dried over mgso.Steam solvent, obtain 0.29 gram solid.With the solid recrystallization in hexane that obtains, obtain the required colourless needle crystal of beta-lactam of 0.20 gram.
The character of this beta-lactam conforms to the numerical value shown in the example 1.
Embodiment 3
(3R, 4R)-the 4-acetoxy-3-[(R)-the 1-tertiary butyl-dimethylsilane oxygen base ethyl]-preparation of nitrogen heterocyclic din-2-ketone
With 1 gram (3R, 4R)-the 1-tertiary butyl-dimetylsilyl-3-[(R)-1-t-butyldimethylsilyloxy base ethyl]-4-trimethylsiloxy nitrogen heterocyclic din-2-ketone is dissolved in the 10ml methylene dichloride, again to wherein adding 0.85 gram dimethyl aminopyridine and 0.75 gram 2,6-lutidine and 1.42 gram acetic anhydrides, this mixture reacted 44 hours down at-15 ℃.Reaction mixture dilutes with ether, and uses 5% NaHCO one by one
3The aqueous solution, pH value are 4 aqueous hydrochloric acid and saturated salt solution washing, use the dried over mgso reaction product afterwards.Steam solvent, obtain the thick product liquid of 0.88 gram.By this liquid of silica gel chromatography (hexane: acetic acid=100: 1), obtain 0.58 gram (3R, 4R)-4-acetoxyl group-t-butyldimethylsilyl)-3-[(R)-1-t-butyldimethylsilyloxy base ethyl) nitrogen heterocyclic din-2-ketone liquid.
The liquid that obtains is dissolved among the 2ml THF, and 0.38 gram tetrabutylammonium fluoride in wherein being incorporated in 2ml THF and 0.17 gram acetic acid at room temperature stirred mixture 30 minutes again.In reaction mixture, add after the 20ml vinyl acetic monomer, use 5%NaHCO again
3The aqueous solution and saturated brine solution be the washing reaction product successively, and uses dried over mgso.Steam after the solvent, obtain 0.42 gram solid.The solid that obtains is passed through silica gel chromatography (hexane: ether=10: 3), obtain the required beta-lactam needle crystal of 0.39 gram.
The character of gained beta-lactam conforms to the numerical value shown in the example 1.
Embodiment 4
(3R, 4R)-the 4-acetoxy-3-[(R)-1-sec.-propyl dimethylsilane oxygen base ethyl]-preparation of nitrogen heterocyclic din-2-ketone
With 1.2 gram 3[(R)-1-sec.-propyl dimethylsilane oxygen base ethyl-4-trimethylsiloxy nitrogen heterocyclic din-2-ketone [(3R, 4R, 5R)-and type: (3S, 4S, 5R)-and type=5: 1] be dissolved in 12ml, among the DMF, to wherein adding 0.52 gram triethylamine and 0.79 gram tert-butyl dimethylsilane chlorine, mixture at room temperature stirred 9 hours again.After reaction is finished, steam DMF under the decompression, and to wherein adding the 30ml hexane.Reaction mixture is used 2.5%NaHCO successively
3The aqueous solution, pH value are 5 aqueous hydrochloric acid and saturated salt solution washing, and use dried over mgso, steam solvent afterwards, obtain the thick product liquid of 1.13 grams.
The liquid that 0.90 gram is obtained is added in the 10ml methylene dichloride, adds 0.79 gram dimethyl nitrogen yl pyridines and 0.61 milliliter of acetic anhydride again, and mixture reacted 16 hours down at 4 ℃.Use 5% NaHCO then successively
3Aqueous hydrochloric acid and saturated salt solution washing reaction mixture that the aqueous solution, pH value equal 5, and use dried over mgso.After steaming solvent, obtain the thick product liquid of 0.70 gram.By silica gel column chromatography (hexane: purifying gained liquid ether=100: 3) obtains 0.20 gram 4-acetoxyl group-1-t-butyldimethylsilyl)-3-(1-sec.-propyl dimethylsilane oxygen base ethyl) nitrogen heterocyclic din-2-ketone liquid.
The liquid that 0.2 gram is obtained joins among the 2ml THF, is incorporated in gram tetrabutylammonium fluoride of 0.13 among the 2ml THF and 0.03 gram acetic acid again.Mixture at room temperature stirred 30 minutes.The 60ml vinyl acetic monomer is being joined in the reaction mixture, is using the 5% NaHCO aqueous solution and saturated salt solution purging compound successively, and with dried over mgso it.Steam solvent, obtain the required thick product of 0.14 gram [(3R, 4R, 5R)-type: (3S, 4S, 5R)-type=5: 1].This product recrystallization in hexane, obtain 0.58 gram (3R, 4R, 5R)-the type white crystals.
1HNMR(90MHZ, CDCl
3) [(3R, 4R, 5R)-type]
δ（ppm）：0.04（6H，S），0.90（7H），1.23（3H，d），2.06（3H，S），3.13（1H，dd），4.13（1H，m），
5.76(1H, d) and 6.40(NH)
[α]
25 D＝+54.2°（C＝0.5，CHCl
3）
Fusing point: 92 ℃～94 ℃
Claims (11)
1, preparation has the method for the 4-acetoxy-3-hydroxyethyl azacyclo fourth-2-ketone derivatives of logical formula II,
R wherein
1Be hydroxyl protecting group, this method comprises the 'beta '-lactam compounds that will have general formula (I) in the presence of alkali, in organic solvent, react with acetic anhydride, and the protecting group of removing N then,
R in the formula
1Definition the same, R
2, R
3And R
4Be C
1To C
4Low alkyl group, phenyl or aralkyl, R are the protecting groups of N.
2, the method for claim 1, wherein R
1Be logical formula III:
R in the formula
5, R
6And R
7Be C
1To C
4Low alkyl group.
3, the method for claim 1, wherein R
1It is tertiary butyl methyl-silicane base.
4, the method for claim 1, wherein R
1It is the sec.-propyl dimetylsilyl.
5, the method for claim 1, wherein R is a tertiary butyl methyl-silicane base.
6, the method for claim 1, wherein R
2, R
3And R
4It is methyl.
7, the method for claim 1, wherein alkali is dimethyl aminopyridine.
8, the method for claim 1, wherein alkali comprises dimethyl aminopyridine and other alkali.
9, the method for claim 8, wherein other alkali is pyridine, picoline or lutidine.
10, the method for claim 1, organic solvent wherein are halogenated hydrocarbon.
11, preparation has the method for the 4-acetoxy-3-hydroxyethyl azacyclo fourth-2-ketone of logical formula II,
R wherein
1Be hydroxyl protecting group, this method comprises having the reaction of the compound of general formula (I ') and reagent (R is the protecting group of N, and X is a fontanelle atom) that general formula is R-X,
R in the formula
1The same, R
2, R
3And R
4Be C
1To C
4Low alkyl group, phenyl or aralkyl form the compound with logical formula I:
R in the formula
1, R
2, R
3And R
4The same, will lead to the formula I compound again in the presence of alkali, react the protecting group of removing N then with acetic anhydride in the organic solvent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4724/1985 | 1985-01-14 | ||
| JP60004724A JPS6118758A (en) | 1985-01-14 | 1985-01-14 | Preparation of 4-acetoxy-hydroxyethylacetidin-2-one derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85105098A true CN85105098A (en) | 1986-07-09 |
| CN1003514B CN1003514B (en) | 1989-03-08 |
Family
ID=11591837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN85105098.0A Expired CN1003514B (en) | 1985-01-14 | 1985-07-04 | Process for preparing 4-acetoxy-3-hydroxyethylazetizin-2-one derivatives |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS6118758A (en) |
| CN (1) | CN1003514B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007098651A1 (en) * | 2006-02-28 | 2007-09-07 | Tianjin Greenbio Material Co., Ltd | USAGE OF POLY-3-HYDROXYALKANOATES IN PREPARATION OF β-LACTAM COMPOUNDS |
| CN102491912A (en) * | 2011-12-28 | 2012-06-13 | 上海新先锋药业有限公司 | Synthesizing method of N-methoxyphenyl-N-(acetyl)methylamine |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0655717B2 (en) * | 1986-11-13 | 1994-07-27 | 鐘淵化学工業株式会社 | Process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative |
| JPH0830057B2 (en) * | 1986-04-30 | 1996-03-27 | 鐘淵化学工業株式会社 | Process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative |
| JPS6467A (en) * | 1987-02-20 | 1989-01-05 | Kanegafuchi Chem Ind Co Ltd | Production of 4-acetoxy-3-hydroxyethylazetidin-2-one derivative |
-
1985
- 1985-01-14 JP JP60004724A patent/JPS6118758A/en active Granted
- 1985-07-04 CN CN85105098.0A patent/CN1003514B/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007098651A1 (en) * | 2006-02-28 | 2007-09-07 | Tianjin Greenbio Material Co., Ltd | USAGE OF POLY-3-HYDROXYALKANOATES IN PREPARATION OF β-LACTAM COMPOUNDS |
| CN102491912A (en) * | 2011-12-28 | 2012-06-13 | 上海新先锋药业有限公司 | Synthesizing method of N-methoxyphenyl-N-(acetyl)methylamine |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6118758A (en) | 1986-01-27 |
| CN1003514B (en) | 1989-03-08 |
| JPH0479333B2 (en) | 1992-12-15 |
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