CN1911926A - Synthesis method of (4R,5R) -4, 5-bis (aminomethyl) -1, 3-dioxolane compound - Google Patents
Synthesis method of (4R,5R) -4, 5-bis (aminomethyl) -1, 3-dioxolane compound Download PDFInfo
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- CN1911926A CN1911926A CN200610041327.9A CN200610041327A CN1911926A CN 1911926 A CN1911926 A CN 1911926A CN 200610041327 A CN200610041327 A CN 200610041327A CN 1911926 A CN1911926 A CN 1911926A
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- dioxolane
- aminomethyl
- tartrate
- aldehyde
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- -1 (4R,5R) -4, 5-bis (aminomethyl) -1, 3-dioxolane compound Chemical class 0.000 title claims abstract description 19
- 238000001308 synthesis method Methods 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006722 reduction reaction Methods 0.000 claims abstract description 13
- 150000005690 diesters Chemical class 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 238000005907 ketalization reaction Methods 0.000 claims abstract description 4
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 42
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical class C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 35
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- 229910021529 ammonia Inorganic materials 0.000 claims description 15
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical group O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 14
- 150000002576 ketones Chemical class 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 235000002906 tartaric acid Nutrition 0.000 claims description 11
- 239000011975 tartaric acid Substances 0.000 claims description 11
- 150000001299 aldehydes Chemical class 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 claims description 8
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 8
- 230000035484 reaction time Effects 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 6
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- QXXRLUXAOFVOTE-UHFFFAOYSA-N 1,3-dioxolan-2-ylmethanamine Chemical class NCC1OCCO1 QXXRLUXAOFVOTE-UHFFFAOYSA-N 0.000 claims description 2
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims description 2
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical group FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- IVKNYMXGZKPFOJ-RFZPGFLSSA-N [(4r,5r)-5-(aminomethyl)-1,3-dioxolan-4-yl]methanamine Chemical class NC[C@H]1OCO[C@@H]1CN IVKNYMXGZKPFOJ-RFZPGFLSSA-N 0.000 abstract 1
- 239000003999 initiator Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- 239000002994 raw material Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a synthesis method of diamine compounds, in particular to a preparation method of (4R,5R) -4, 5-bis (aminomethyl) -1, 3-dioxolane compounds. The invention takes D-tartaric diester as an initiator, and is prepared by acetalation or ketalization, ammonolysis and reduction in sequence. The synthesis method disclosed by the invention is environment-friendly, simple in process and low in cost, and the average total yield is 61.2%.
Description
Technical field:
The present invention relates to a kind of synthetic method of diamine compounds, relate in particular to a kind of (4R, 5R)-4, two (aminomethyl)-1 of 5-, the preparation method of 3-dioxolane compounds.
Background technology:
Wherein R is that carbonatoms is 1～8 aliphatic alkyl, or carbonatoms is 6～9 aryl.Special when R is sec.-propyl I for (4R, 5R)-4,5-pair of (aminomethyl)-2-sec.-propyls-1, the 3-dioxolane is the important intermediate of synthesizing antineoplastic medicament platinum in heptan.Existing technology adopts following method preparation:
(J.Med.Chem, 1994,37,1471 such as Dae-Kee Kim; J.LabelledCompd.Radiopharm, 1994,34,157; J.Am.Chem.Soc, 1978,100,4865) having reported diester tartaric acid used with D-is raw material, and through synthetic obtaining of five steps, this method not only step is longer, and used hypertoxic explosive sodiumazide, total recovery is also lower, so to human body and the big cost height of environmental hazard.
Summary of the invention:
Technical problem to be solved by this invention is that prior art exists reactions steps to grow, total recovery is also lower, use poisonous raw material and cost than problems such as height in order to overcome, and a kind of environmental friendliness, technology is simple, cost is low (4R have been proposed, 5R)-4, two (aminomethyl)-1 of 5-, 3-dioxolane compounds synthetic preparation method.
The present invention is to realize by such technical scheme for reaching above purpose:
A kind of prepare general formula I (4R, 5R)-4, two (aminomethyl)-1 of 5-, the method for 3-dioxolane compounds,
Wherein R is that carbonatoms is 1～8 aliphatic alkyl, or carbonatoms is 6～9 aryl
Its preparation process comprises:
A). acetalation or ketalization: D-is diester tartaric acid used to add solvent with aldehydes or ketones, under the effect of catalyzer, react, then through extraction, washing, drying, distill acetal or ketal product;
B). ammonia is separated: above-mentioned acetal or ketal product controlled temperature and time in ammoniacal liquor are carried out ammonolysis reaction, filter then, dry ammonia hydrolysis products;
C). reduction: above-mentioned ammonia hydrolysis products adds reductive agent and carries out reduction reaction in organic solvent, extraction then, drying, underpressure distillation get (4R, 5R)-4,5-pair (aminomethyl)-1,3-dioxolane compounds.
Synthetic method of the present invention, its synthetic route is as follows:
Wherein said D-is diester tartaric acid used to be D-dimethyl tartrate, D-diethyl tartrate or D-dipropyl tartrate; Catalyzer in described acetalation or the ketal reaction is Vanadium Pentoxide in FLAKES or copper sulfate, and solvent is a toluene; Described reductive agent is lithium aluminum hydride or sodium borohydride.
Wherein said aldehydes or ketones is that carbonatoms is 1～8 alkanoic, ketone or phenyl aldehyde and the phenyl aldehyde of replacement; Preferably carbonatoms is that 1～8 alkanoic, ketone are propionic aldehyde, isobutyric aldehyde, cyclopentanone or pimelinketone, and the phenyl aldehyde of preferred phenyl aldehyde and replacement is p-Fluorobenzenecarboxaldehyde, o-chlorobenzaldehyde or p-tolyl aldehyde.
Wherein said steps A) in D-diester tartaric acid used with mol ratio aldehydes or ketones be 1: 1～1: 4, temperature of reaction is 20 ℃～100 ℃, the reaction times is 3h～20h; Step B) temperature of reaction is 50 ℃～100 ℃, and the reaction times is 2h～5h; Preferred steps A) in D-diester tartaric acid used with mol ratio aldehydes or ketones be 1: 1.5～1: 3. temperature of reaction is 60 ℃～70 ℃, and the reaction times is 3h～4h; Step B) temperature of reaction is 70 ℃～80 ℃, reaction times 4h～5h.
Wherein said step B) used ammoniacal liquor mass percentage concentration is 26%～28% in, and the consumption of ammoniacal liquor is 200ml～500ml/ mole acetal or ketal product.Described step C) used organic solvent is ether or tetrahydrofuran (THF); Step C) mol ratio of ammonia hydrolysis products and reductive agent is 1: 1.5～1: 3.
Raw material among the present invention is commercially available.Extract among the present invention, drying, processing condition such as underpressure distillation are with existing known technology.
Beneficial effect:
1) synthetic method of the present invention is the diester tartaric acid used and aldehydes or ketones condensation with D-earlier, and then separates with ammoniacal liquor ammonia, the Lithium Aluminium Hydride reduction, so operational path of the present invention is simple, cost is low, and is easy to operate, is fit to suitability for industrialized production;
2) with report that route is compared and avoided using hypertoxic explosive trinitride, environmental friendliness;
3) yield of the present invention reaches 36.4%-78.1%, and average yield reaches 61.2%; The yield that prior art adopted for five steps produced only is 22.4%.
Concrete implementation:
Embodiment 1:(4R, 5R)-4, two (the aminomethyl)-2-ethyls-1 of 5-, 3-dioxolane synthetic: with the D-dimethyl tartrate is starting raw material, makes through following step successively:
(1) acetalation, promptly 2,3-oxygen-propylidene-D-dimethyl tartrate synthetic:
D-dimethyl tartrate 17.8g, propionic aldehyde 8.7g, dry toluene 100ml, anhydrous cupric sulfate 4g is at 60 ℃ of stirring reaction 4h.Stop heating, be chilled to room temperature, tell organic layer, the sodium bicarbonate with 5% is washed till neutrality, with saturated common salt washing, washing, revolves and desolvates again, obtains 2,3-oxygen-propylidene-D-diethyl tartrate 16.7g, yield 76.7%.
(2) ammonia is separated, promptly (4R, 5R)-4, two (the methane amide)-2-ethyls-1 of 5-, 3-dioxolane synthetic:
Above-mentioned 2,3-oxygen-propylidene-D-dimethyl tartrate 21.8g puts in the three-necked bottle of 100m1, adds strong aqua 30ml, 70 ℃ of following stirring reactions have solid to separate out gradually, put into refrigerator behind the reaction 4h and are chilled to 0 ℃, filter, filter cake washs successively with a small amount of frozen water, ethanol.Put vacuum drying oven dry (4R, 5R)-4, two (the methane amide)-2-ethyls-1 of 5-, 3-dioxolane 16.2g, yield are 86.4%.
(3) reduction, promptly (4R, 5R)-4, two (the aminomethyl)-2-ethyls-1 of 5-, 3-dioxolane synthetic:
In the 100ml three-necked bottle, add the 8.4g sodium borohydride, 0.5g calcium chloride, 50ml exsiccant tetrahydrofuran (THF), stirring at room 2h, adding 18.8g (4R, 5R)-4, two (the acid amides)-2-ethyls-1 of 5-, 3-dioxolane.Back flow reaction 4h. cooling adds the 50ml ethyl acetate.50ml water.Separatory is told ethyl acetate layer.Anhydrous magnesium sulfate drying is spin-dried for solvent after the filtration.Obtain 8.8g (4R, 5R)-4, two (the aminomethyl)-2-ethyls-1 of 5-, 3-dioxolane, yield are 55.0%.
Embodiment 2:(4R, 5R)-4, two (the aminomethyl)-2-ethyls-1 of 5-, 3-dioxolane synthetic: with the D-dimethyl tartrate is starting raw material, makes through following step successively:
(1) acetalation, promptly 2,3-oxygen-propylidene-D-dimethyl tartrate synthetic:
D-dimethyl tartrate 17.8g, propionic aldehyde 8.7g, dry toluene 100ml, Vanadium Pentoxide in FLAKES 3.0g is at 20 ℃ of stirring reaction 20h.Tell organic layer, the sodium bicarbonate with 5% is washed till neutrality, with saturated common salt washing, washing, revolves and desolvates again, obtains 2,3-oxygen-propylidene-D-diethyl tartrate 9.5g, yield 43.5%.
(2) ammonia is separated, promptly (4R, 5R)-4, two (the methane amide)-2-ethyls-1 of 5-, 3-dioxolane synthetic:
Above-mentioned 2,3-oxygen-propylidene-D-dimethyl tartrate 21.8g puts in the three-necked bottle of 100ml, adds strong aqua 30ml, 50 ℃ of following stirring reactions have solid to separate out gradually, put into refrigerator behind the reaction 5h and are chilled to 0 ℃, filter, filter cake washs successively with a small amount of frozen water, ethanol.Put vacuum drying oven dry (4R, 5R)-4, two (the methane amide)-2-ethyls-1 of 5-, 3-dioxolane 14.1g, yield are 75.3%.
(3) reduction, promptly (4R, 5R)-4, two (the aminomethyl)-2-ethyls-1 of 5-, 3-dioxolane synthetic:
In the 100ml three-necked bottle, add the 6.8g lithium aluminum hydride, splash into exsiccant tetrahydrofuran (THF) 30ml, backflow 0.5h.Adding 18.8g (4R, 5R)-4, two (the acid amides)-2-ethyls-1 of 5-, the 3-dioxolane is dissolved in the solution of 20ml exsiccant THF.Back flow reaction 20h. slowly splashes into the 30ml ethyl acetate.Slowly splashing into 5ml water.Filter, filter cake washs with the 50ml ethyl acetate.Anhydrous magnesium sulfate drying is spin-dried for solvent after the filtration, obtain 14.7g (4R, 5R)-4, two (the aminomethyl)-2-ethyls-1 of 5-, 3-dioxolane, yield are 92.4%.
Embodiment 3:(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, 3-dioxolane synthetic: with the D-diethyl tartrate is starting raw material, makes through following step successively:
(1) acetalation, promptly 2,3-oxygen-isobutylidene-D-diethyl tartrate synthetic:
D-diethyl tartrate 20.6g, isobutyric aldehyde 14.4g, dry toluene 100ml, Vanadium Pentoxide in FLAKES 3.0g places the three-necked bottle of 500ml, at 100 ℃ of stirring reaction 3h.Be chilled to room temperature, tell organic layer, the sodium bicarbonate with 5% is washed till neutrality, with saturated common salt washing, washing, revolves and desolvates again, obtains 2,3-oxygen-isobutylidene-D-diethyl tartrate 23.7g, yield 91.3%.
(2) ammonia is separated, promptly (4R, 5R)-4, two (the methane amide)-2-sec.-propyls-1 of 5-, 3-dioxolane synthetic:
2,3-oxygen-isobutylidene-D-diethyl tartrate 26.0g puts in the three-necked bottle of 100ml, adds strong aqua 50ml, and 100 ℃ of reactions down have solid to separate out gradually, put into refrigerator behind the reaction 2h and are chilled to 0 ℃, filter, and filter cake washs successively with a small amount of frozen water, ethanol.Dried dry the getting of vacuum (4R, 5R)-4, two (the methane amide)-2-sec.-propyls-1 of 5-, 3-dioxolane 13.4g, yield are 66.3%.
(3) reduction, promptly (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, 3-dioxolane synthetic:
In the 100ml three-necked bottle, add the 5.1g lithium aluminum hydride, splash into exsiccant tetrahydrofuran (THF) 30ml, backflow 0.5h.Slowly splash into again 20.2g (4R, 5R)-4, two (the methane amide)-2-sec.-propyls-1 of 5-, the 3-dioxolane is dissolved in the solution of 20ml exsiccant THF.Drip and finish, back flow reaction 20h. cooling slowly splashes into the 30ml ethyl acetate.Slowly splashing into 5ml water.Filter, filter cake washs with the 50ml ethyl acetate.Anhydrous magnesium sulfate drying is spin-dried for solvent after the filtration, obtain (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, 3-dioxolane 13.6g, yield are 78.4%.
Embodiment 4:(4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, 3-dioxolane synthetic: with the D-diethyl tartrate is starting raw material, makes through following step successively:
(1) acetalation, promptly 2,3-oxygen-isobutylidene-D-diethyl tartrate synthetic:
D-diethyl tartrate 20.6g, isobutyric aldehyde 14.4g, dry toluene 100ml, Vanadium Pentoxide in FLAKES 3.0g places the three-necked bottle of 500ml, at 65 ℃ of stirring reaction 3.5h.Be chilled to room temperature, tell organic layer, the sodium bicarbonate with 5% is washed till neutrality, with saturated common salt washing, washing, revolves and desolvates again, obtains 2,3-oxygen-isobutylidene-D-diethyl tartrate 24.7g, yield 95.0%.
(2) ammonia is separated, promptly (4R, 5R)-4, two (the methane amide)-2-sec.-propyls-1 of 5-, 3-dioxolane synthetic:
2,3-oxygen-isobutylidene-D-diethyl tartrate 26.0g puts in the three-necked bottle of 100ml, adds strong aqua 50ml, and 80 ℃ of reactions down have solid to separate out gradually, put into refrigerator behind the reaction 5h and are chilled to 0 ℃, filter, and filter cake washs successively with a small amount of frozen water, ethanol.Dried dry the getting of vacuum (4R, 5R)-4, two (the methane amide)-2-sec.-propyls-1 of 5-, 3-dioxolane 18.1g, yield are 89.4%.
(3) reduction, promptly (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, 3-dioxolane synthetic:
In the 100ml three-necked bottle, add the 8.5g lithium aluminum hydride, splash into exsiccant tetrahydrofuran (THF) 30ml, backflow 0.5h.Slowly splash into again 20.2g (4R, 5R)-4, two (the methane amide)-2-sec.-propyls-1 of 5-, the 3-dioxolane is dissolved in the solution of 20ml exsiccant THF.Drip and finish, back flow reaction 20h. cooling slowly splashes into the 30ml ethyl acetate.Slowly splashing into 5ml water.Filter, filter cake washs with the 50ml ethyl acetate.Anhydrous magnesium sulfate drying is spin-dried for solvent after the filtration, obtain (4R, 5R)-4, two (the aminomethyl)-2-sec.-propyls-1 of 5-, 3-dioxolane 16.0g, yield are 92.0%.
Embodiment 5:(4R, 5R)-4, two (the aminomethyl)-2-phenyl-1 of 5-, 3-dioxolane synthetic: with the D-diethyl tartrate is starting raw material, makes through following step successively:
(1) acetalation, promptly 2,3-oxygen-benzylidene-D-dimethyl tartrate synthetic:
D-dimethyl tartrate 17.8g, phenyl aldehyde 10.6g dry toluene 60ml, Vanadium Pentoxide in FLAKES 3.0g places the three-necked bottle of 100ml, at 70 ℃ of stirring reaction 5h, tells organic layer, sodium bicarbonate with 5% is washed till neutrality, with saturated common salt washing, washing, revolve and desolvate again, obtain 23.5g 2,3-oxygen-benzylidene-D-dimethyl tartrate, yield 88.2%.
(2) ammonia is separated, promptly (4R, 5R)-4, two (the methane amide)-2-phenyl-1 of 5-, 3-dioxolane synthetic:
Above-mentioned 2,3-oxygen-benzylidene-D-dimethyl tartrate 26.6g puts in the three-necked bottle of 100ml, adds strong aqua 50ml, and 75 ℃ of reactions down have solid to separate out gradually, put into refrigerator behind the reaction 4h and are chilled to 0 ℃, filter, and filter cake washs successively with a small amount of frozen water, ethanol.Vacuum-drying get (4R, 5R)-4, two (the methane amide)-2-phenyl-1 of 5-, 3-dioxolane 18.9g, yield are 80.2%.
(3) reduction, promptly (4R, 5R)-4, two (the aminomethyl)-2-phenyl-1 of 5-, 3-dioxolane synthetic:
In the 100ml three-necked bottle, add the 6.8g lithium aluminum hydride, splash into exsiccant tetrahydrofuran (THF) 30ml, backflow 0.5h.slowly splash into 23.6g (4R, 5R)-4, two (the methane amide)-2-phenyl-1 of 5-, the 3-dioxolane is dissolved in the solution of 20ml exsiccant THF.Drip and finish, back flow reaction 20h. cooling slowly splashes into the 30ml ethyl acetate.Slowly splashing into 5ml water.Filter, filter cake washs with the 50ml ethyl acetate.Anhydrous magnesium sulfate drying is spin-dried for solvent after the filtration.Obtain (4R, 5R)-4, two (the aminomethyl)-2-phenyl-1 of 5-, 3-dioxolane 18.8g, yield are 90.4%.
Embodiment 6:(4R, 5R)-4, two (aminomethyl)-2 of 5-, 2-dimethyl-1,3-dioxolane synthetic: with the D-dipropyl tartrate is starting raw material, makes through following step successively:
(1) ketalization, promptly 2,3-oxygen-isopropylidene-D-dipropyl tartrate synthetic:
D-dipropyl tartrate 23.4g, acetone 14.5g dry toluene 100ml, Vanadium Pentoxide in FLAKES 3.0g places the three-necked bottle of 500ml, 70 ℃ of reaction 3h.Stop heating, be chilled to room temperature, tell organic layer, the sodium bicarbonate with 5% is washed till neutrality, with saturated common salt washing, washing, revolves and desolvates again, obtains 2,3-oxygen-isopropylidene-D-dimethyl tartrate 25.5g, yield 93.1%.
(2) ammonia is separated, promptly (4R, 5R)-4, two (methane amide)-2 of 5-, 2-dimethyl-1,3-dioxolane synthetic:
Above-mentioned 2,3-oxygen-isopropylidene-D-dipropyl tartrate 27.4g puts in the three-necked bottle of 100ml, adds strong aqua 50ml, 80 ℃ of reactions down have solid to separate out gradually, put into refrigerator behind the reaction 5h and are chilled to 0 ℃, filter, filter cake washs successively with a small amount of frozen water, ethanol.Vacuum-drying get (4R, 5R)-4, two (methane amide)-2 of 5-, 2-dimethyl-1,3-dioxolane 14.9g, yield are 79.3%.
(3) reduction, promptly (4R, 5R)-4, two (aminomethyl)-2 of 5-, 2-dimethyl-1,3-dioxolane synthetic:
In the 100ml three-necked bottle, add the 5.1g lithium aluminum hydride, splash into exsiccant tetrahydrofuran (THF) 30ml, backflow 0.5h.slowly splash into 18.8g (4R, 5R)-4, two (methane amide)-2 of 5-, 2-dimethyl-1, the 3-dioxolane is dissolved in the solution of 20ml exsiccant THF.Drip and finish, back flow reaction 20h. cooling slowly splashes into the 30ml ethyl acetate.Slowly splashing into 5ml water.Filter, filter cake washs with the 50ml ethyl acetate.Anhydrous magnesium sulfate drying is spin-dried for solvent after the filtration.Obtain (4R, 5R)-4, two (aminomethyl)-2 of 5-, 2-dimethyl-1,3-dioxolane 14.6g, yield are 91.3%.
The above is a specific embodiment of the present invention only; should be pointed out that for a person skilled in the art, can also make a lot of modification and improvement; as use different aldehydes or ketones and the diester tartaric acid used condensation of D-, the modification of all these classes and improvement all should be considered as protection scope of the present invention.
Claims (9)
1, a kind of preparation (4R, 5R)-4, two (aminomethyl)-1 of 5-, the method for 3-dioxolane compounds, its preparation process comprises:
A). acetalation or ketalization: D-is diester tartaric acid used to add solvent with aldehydes or ketones and reacts under the effect of catalyzer, then through extraction, washing, drying, distill acetal or ketal product;
B). ammonia is separated: above-mentioned acetal or ketal product controlled temperature and time in ammoniacal liquor are carried out ammonolysis reaction, filter then, dry ammonia hydrolysis products;
C). reduction: above-mentioned ammonia hydrolysis products adds reductive agent and carries out reduction reaction in organic solvent, extraction then, drying, underpressure distillation get (4R, 5R)-4,5-pair (aminomethyl)-1,3-dioxolane compounds.
2, method according to claim 1 is characterized in that described D-is diester tartaric acid used for D-dimethyl tartrate, D-diethyl tartrate or D-dipropyl tartrate.
3, method according to claim 1 is characterized in that catalyzer is Vanadium Pentoxide in FLAKES or copper sulfate in described acetalation or the ketal reaction, and solvent is a toluene; Reductive agent is lithium aluminum hydride or sodium borohydride in the described reduction reaction.
4, method according to claim 1 is characterized in that described aldehydes or ketones is that carbonatoms is 1～8 alkanoic, ketone or phenyl aldehyde and the phenyl aldehyde of replacement.
5, method according to claim 4, it is characterized in that described carbonatoms is that 1～8 alkanoic, ketone are propionic aldehyde, isobutyric aldehyde, cyclopentanone or pimelinketone, the phenyl aldehyde of described phenyl aldehyde and replacement is p-Fluorobenzenecarboxaldehyde, o-chlorobenzaldehyde or p-tolyl aldehyde.
6, method according to claim 1 is characterized in that described steps A) in D-diester tartaric acid used with mol ratio aldehydes or ketones be 1: 1～1: 4, temperature of reaction is 20 ℃～100 ℃, the reaction times is 3h～20h; Step B) temperature of reaction is 50 ℃～100 ℃, and the reaction times is 2h～5h.
7, method according to claim 6 is characterized in that described steps A) in D-diester tartaric acid used with mol ratio aldehydes or ketones be 1: 1.5～1: 3, temperature of reaction is 60 ℃～70 ℃, the reaction times is 3h～4h; Step B) temperature of reaction is 70 ℃～80 ℃, reaction times 4h～5h.
8, method according to claim 1 is characterized in that described step B) in used ammoniacal liquor mass percentage concentration be 26%～28%, the consumption of ammoniacal liquor is 200ml～500ml/ mole acetal or ketal product.
9, method according to claim 1 is characterized in that described step C) used organic solvent is ether or tetrahydrofuran (THF); Step C) mol ratio of ammonia hydrolysis products and reductive agent is 1: 1.5～1: 3.
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| CN101805323A (en) * | 2010-03-23 | 2010-08-18 | 深圳万乐药业有限公司 | Method for synthesizing diastereoisomer of Doranidazole intermediate |
| CN101245083B (en) * | 2008-03-18 | 2012-11-21 | 南京工业大学 | Platinum complex containing 1, 3-dioxolane structure and synthesis method and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101245083B (en) * | 2008-03-18 | 2012-11-21 | 南京工业大学 | Platinum complex containing 1, 3-dioxolane structure and synthesis method and application thereof |
| CN101805323A (en) * | 2010-03-23 | 2010-08-18 | 深圳万乐药业有限公司 | Method for synthesizing diastereoisomer of Doranidazole intermediate |
| CN101805323B (en) * | 2010-03-23 | 2012-09-26 | 深圳万乐药业有限公司 | Method for synthesizing diastereoisomer of Doranidazole intermediate |
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