CN101735285A - Preparation method of 1,2,5-O-triacyl-3-deoxy-alpha-D-xylofuranose - Google Patents
Preparation method of 1,2,5-O-triacyl-3-deoxy-alpha-D-xylofuranose Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 62
- 150000001875 compounds Chemical class 0.000 claims abstract description 136
- -1 m-chlorobenzoyl Chemical group 0.000 claims abstract description 48
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 167
- SRBFZHDQGSBBOR-IOVATXLUSA-N Xylose Natural products O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 12
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 12
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 125000003541 2-chlorobenzoyl group Chemical group ClC1=C(C(=O)*)C=CC=C1 0.000 abstract 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 abstract 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 abstract 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 abstract 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 80
- 238000001816 cooling Methods 0.000 description 80
- 239000002994 raw material Substances 0.000 description 44
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 40
- 239000012141 concentrate Substances 0.000 description 40
- 238000001035 drying Methods 0.000 description 40
- 238000003810 ethyl acetate extraction Methods 0.000 description 40
- 238000004128 high performance liquid chromatography Methods 0.000 description 40
- 239000007788 liquid Substances 0.000 description 40
- 239000012266 salt solution Substances 0.000 description 40
- 229920006395 saturated elastomer Polymers 0.000 description 40
- 229910000029 sodium carbonate Inorganic materials 0.000 description 40
- 235000002639 sodium chloride Nutrition 0.000 description 40
- 239000011780 sodium chloride Substances 0.000 description 40
- 239000000243 solution Substances 0.000 description 40
- 238000003756 stirring Methods 0.000 description 40
- 238000005406 washing Methods 0.000 description 40
- 229960003487 xylose Drugs 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- JAUFWTSSYRTLLB-UHFFFAOYSA-N (2-phenylacetyl) 2-phenylacetate Chemical compound C=1C=CC=CC=1CC(=O)OC(=O)CC1=CC=CC=C1 JAUFWTSSYRTLLB-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Natural products OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 3
- SRBFZHDQGSBBOR-LECHCGJUSA-N alpha-D-xylose Chemical compound O[C@@H]1CO[C@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-LECHCGJUSA-N 0.000 description 3
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- VJUPMOPLUQHMLE-UUOKFMHZSA-N 8-Bromoadenosine Chemical compound BrC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VJUPMOPLUQHMLE-UUOKFMHZSA-N 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 2
- FQGYCXFLEQVDJQ-UHFFFAOYSA-N mercury dicyanide Chemical compound N#C[Hg]C#N FQGYCXFLEQVDJQ-UHFFFAOYSA-N 0.000 description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 230000007096 poisonous effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- XAFPZGWLMZHFMS-UHFFFAOYSA-N [2-(3-chlorophenyl)acetyl] 2-(3-chlorophenyl)acetate Chemical compound ClC=1C=C(C=CC1)CC(=O)OC(CC1=CC(=CC=C1)Cl)=O XAFPZGWLMZHFMS-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentane carboxylic acid Natural products OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 1
- GRCAXSKSTZXYIK-UHFFFAOYSA-N cyclopentanecarbonyl cyclopentanecarboxylate Chemical compound C1CCCC1C(=O)OC(=O)C1CCCC1 GRCAXSKSTZXYIK-UHFFFAOYSA-N 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- DUCKXCGALKOSJF-UHFFFAOYSA-N pentanoyl pentanoate Chemical compound CCCCC(=O)OC(=O)CCCC DUCKXCGALKOSJF-UHFFFAOYSA-N 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of the 1,2,5-O-triacyl-3-deoxy-alpha-D-xylofuranose represented by the following formula (II). The preparation method comprises the following steps of: at the temperature of 10-40 DEG C, in the presence of 4-(N,N-dimethylamino)pyridine, reacting the compound represented by the following formula (I) with acid anhydride, adding concentrated sulfuric acid, and reacting at 0-60 DEG C to obtain the compound represented by the following formula (II). The method of the invention is simple and feasible, has relatively low cost, high yield, high purity, environmental friendliness and easy industrialization. R1 and R2 are independently methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, phenyl, benzyl, o-chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, o-bromobenzoyl, m-bromobenzoyl, p-bromobenzoyl, o-methoxybenzyl, m-methoxybenzyl, p-methoxybenzyl, o-nitrobenzyl, m-nitrobenzyl, p-nitrobenzyl, phenethyl, cyclopentyl or cyclohexyl.
Description
Technical field
The present invention relates to a kind of 1,2, the preparation method of 5-O-three acyl groups-3-deoxidation-α-D-furyl xylose.
Background technology
1,2,5-O-three acyl groups-3-deoxidation-α-D-furyl xylose (II) have following structural formula:
Wherein, R
1And R
2Alone be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, phenyl, phenmethyl, adjacent chlorophenylmethyl, a chlorophenylmethyl, to chlorophenylmethyl, adjacent Brombenzyl, a Brombenzyl, to Brombenzyl, O-methoxy phenmethyl, meta-methoxy phenmethyl, to mehtoxybenzyl, ortho-nitrophenyl methyl, m-nitro methyl, p-nitrophenyl methyl, styroyl, cyclopentyl or cyclohexyl.
This compound is the synthetic field of a medicine intermediate commonly used, particularly has a wide range of applications at the diagnostic medicine of the antibiotic of preparation treatment infectation of bacteria, anti-AIDS medicine, cancer etc.
Bibliographical information is relevant 1,2 so far, and the synthetic method of 5-O-three acyl groups-3-deoxidation-α-D-furyl xylose has two types, is respectively to be that feedstock production forms with wood sugar and adenosine.But up to the present do not obtain gratifying result yet.
By adenosine is that the synthetic method of starting raw material is as follows:
Document (Carbohydrate Research, 1974,32, p339) reported the debrominate under the mercury cyanide condition of bromo adenosine, carry out then acylation reaction generate corresponding 1,2,5-O-three acyl groups-3-deoxidation-α-D-furyl xylose.In this method, used debrominate reagent mercury cyanide toxicity is big, environmental pollution is strong, makes to be difficult to industrialization by this method aftertreatment cost height.
C.B.Reese people such as (Synthesis, 1983,304) has reported that the bromo adenosine is at Bu
3Debromination under the SnH/AIBN condition carries out acylation reaction then, and is synthetic corresponding 1,2,5-O-three acyl groups-3-deoxidation-α-D-furyl xylose.In present method, used debrominate reagent Bu
3SnH toxicity is big, environmental pollution is strong, makes to be difficult to carry out suitability for industrialized production by this method aftertreatment cost height.
C.B.Reese people such as (Synthesis, 1983,304) has reported and has adopted at CH
3OH and NH
3Carry out the hydrolysis reaction of deoxyadenosine compounds under the condition, but the operating equipment that this condition need seal, the technological operation complexity is difficult to carry out suitability for industrialized production.
The use wood sugar is the raw material that sets out, and synthetic method is:
C.Mathe (Carbohydrate Research, 2000,323; p226-229) etc. the people has reported use acetic acid/vitriol oil, and aceticanhydride/pyridine system discloses a kind of preparation 1 by two-step reaction is synthetic; 2-O-diacyl-5-O-benzoyl-3-deoxidation-α-D-furyl xylose, productive rate is 64%.
Be in the starting raw material synthetic method of setting out with the wood sugar, acetic acid/vitriol oil has been used in the reaction for preparing final compound, aceticanhydride/pyridine system, and carried out for two steps, also used poisonous and harmful reagent pyridine, and yield is lower, product purity is lower, not only be not suitable for the laboratory and prepare on a small scale, and be difficult to industrialization production.
Summary of the invention
Technical problem to be solved by this invention is in order to overcome existing preparation 1; 2; defective such as agents useful for same toxicity is big in the method for 5-O-three acyl groups-3-deoxidation-α-D-furyl xylose, environmental pollution is strong, processing cost is high, reaction or aftertreatment complexity, purifying products difficulty or more difficult industrialization and a kind of simple possible is provided, cost is lower, productive rate is higher, purity is very high, environmental friendliness and be easy to industrialized preparation 1; 2, the method for 5-O-three acyl groups-3-deoxidation-α-D-furyl xylose.
The present invention relates to a kind of suc as formula 1 shown in the II; 2; the preparation method of 5-O-three acyl groups-3-deoxidation-α-D-furyl xylose; it comprises the following steps: under-10 ℃～0 ℃ temperature; under the existence of 4-(N, N-dimethylamino) pyridine (DMAP), with compound shown by formula I and acid anhydrides effect; add the vitriol oil then and react for 0～60 ℃, get final product suc as formula the compound shown in the II in interior temperature.
Wherein, R
1And R
2Alone be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, phenyl, phenmethyl, adjacent chlorophenylmethyl, a chlorophenylmethyl, to chlorophenylmethyl, adjacent Brombenzyl, a Brombenzyl, to Brombenzyl, O-methoxy phenmethyl, meta-methoxy phenmethyl, to mehtoxybenzyl, ortho-nitrophenyl methyl, m-nitro methyl, p-nitrophenyl methyl, styroyl, cyclopentyl or cyclohexyl, preferable is methyl or phenyl.Among the present invention, R
1And R
2Preferable is identical group.
Among the present invention, the consumption of described acid anhydrides is preferable be the compound shown by formula I molar weight 1.0-3.0 doubly; The consumption of described 4-(N, N-dimethylamino) pyridine (DMAP) is preferable be compound shown by formula I molar weight 0.1-0.5 doubly.
The vitriol oil described in the present invention is meant the sulphuric acid soln of concentration (the concentration here is meant vitriolic mass percent in the sulphuric acid soln) more than or equal to 70%; That the concentration of the vitriol oil is preferable is mass percentage concentration 90-98%; The consumption of the described vitriol oil is preferable be compound shown by formula I molar weight 1.0-5.0 doubly.
Among the present invention, the speed of the described adding vitriol oil preferable with temperature in keeping 0 ℃ with under control; The Nei Wengengjia's of described reaction is 10～25 ℃; Till the time of reaction can the TLC detecting reactant runs out of, preferable was 1～10 hour, and better is 3～4 hours.
The preparation of Compound I can with reference to following document: C.Mathe (Carbohydrate Research, 2000,323, p226-229).
Raw material that the present invention is used and reagent are all commercially available to be got.
Positive progressive effect of the present invention is: with respect to existing preparation 1,2, and the method for 5-O-three acyl groups-3-deoxidation-α-D-furyl xylose, preparation method's simple possible of the present invention only needs single step reaction can make final compound.And yield is higher, reaches 60%～75%, and purity is very high, reaches 90.7%～95.0%.Its cost is lower, and is easy to industrialization, and it has avoided use poisonous and harmful reagent pyridine, and is environmentally friendly.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1 Compound I I (R
1=R
2=methyl) preparation
With Compound I (R
1=methyl) (0.1mol) adds in the 100ml reaction flask.(0 ℃) adds acetic anhydride (0.1mol), DMAP (0.01mol) under cooling.Drip the vitriol oil (0.1mol) of massfraction 90% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 3h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 72%, purity HPLC:94.7%.
Embodiment 2 Compound I I (R
1=R
2=methyl) preparation
With Compound I (R
1=methyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding acetic anhydride (0.2mol) under the cooling, DMAP (0.01mol) at cryosel.Drip the vitriol oil (0.2mol) of massfraction 90% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (25-30 ℃), stirring the 2h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 75%, HPLC:94.1%.
Embodiment 3 Compound I I (R
1=R
2=ethyl) preparation
With Compound I (R
1=ethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (5 ℃) adding propionic anhydride (0.15mol) under the cooling, DMAP (0.015mol) at cryosel.Drip the vitriol oil (0.2mol) of massfraction 95% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 4h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 70%, HPLC:92.6%.
Embodiment 4 Compound I I (R
1=R
2=propyl group) preparation
With Compound I (R
1=propyl group) (0.1mol) adds in the 100ml reaction flask.Bathe (5 ℃) adding butyryl oxide (0.2mol) under the cooling, DMAP (0.04mol) at cryosel.Drip the vitriol oil (0.25mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 4 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 68%, purity HPLC:90.7%.
Embodiment 5 Compound I I (R
1=R
2=sec.-propyl) preparation
With Compound I (R
1=sec.-propyl) (0.1mol) adds in the 100ml reaction flask.Bathe (5 ℃) adding isobutyric anhydride (0.15mol) under the cooling, DMAP (0.07mol) at cryosel.Drip the vitriol oil (0.3mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 4h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 71%, purity HPLC:94.3%.
Embodiment 6 Compound I I (R
1=R
2=the tertiary butyl) preparation
With Compound I (R
1=the tertiary butyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding PIVALIC ACID CRUDE (25) acid anhydride (0.15mol) under the cooling, DMAP (0.05mol) at cryosel.Drip the vitriol oil (0.25mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 60%, purity HPLC:95.0%.
Embodiment 7 Compound I I (R
1=R
2=phenyl) preparation
With Compound I (R
1=phenyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding benzoyl oxide (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:91.7%.
Embodiment 8 Compound I I (R
1=R
2=phenmethyl) preparation
With Compound I (R
1=phenmethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding phenylacetic anhydride (0.15mol) under the cooling, DMAP (0.2mol) at cryosel.Drip the vitriol oil (0.25mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:93.8%.
Embodiment 9 Compound I I (R
1=R
2=phenmethyl) preparation
With Compound I (R
1=phenmethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding phenylacetic anhydride (0.25mol) under the cooling, DMAP (0.03mol) at cryosel.Drip the vitriol oil (0.3mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 66%, purity HPLC:90.9%.
Embodiment 10 Compound I I (R
1=R
2=cyclopentyl) preparation
With Compound I (R
1=cyclopentyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding cyclopentyl formic anhydride (0.2mol) under the cooling, DMAP (0.04mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 69%, purity HPLC:94.0%.
Embodiment 11 Compound I I (R
1=R
2=cyclohexyl) preparation
With Compound I (R
1=cyclohexyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding hexahydrobenzoic acid acid anhydride (0.20mol) under the cooling, DMAP (0.05mol) at cryosel.Drip the vitriol oil (0.5mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control).After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 7h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:92.2%.
Embodiment 12 Compound I I (R
1=R
2=cyclohexyl) preparation
With Compound I (R
1=cyclohexyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding hexahydrobenzoic acid acid anhydride (0.30mol) under the cooling, DMAP (0.05mol) at cryosel.Drip the vitriol oil (0.5mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (10-20 ℃), stirring the 7h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:92.2%.
Embodiment 13 Compound I I (R
1=R
2=adjacent chlorophenylmethyl) preparation
With Compound I (R
1=adjacent chlorophenylmethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (20 ℃) adding o-chlorobenzene acetic acid acid anhydride (0.25mol) under the cooling, DMAP (0.03mol) at cryosel.Drip the vitriol oil (0.3mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (0-30 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 63%, purity HPLC:92.9%.
Embodiment 14 Compound I I (R
1=R
2=chlorophenylmethyl) preparation
With Compound I (R
1=chlorophenylmethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding m-chloro phenylacetic anhydride (0.25mol) under the cooling, DMAP (0.03mol) at cryosel.Drip the vitriol oil (0.3mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 66%, purity HPLC:90.9%.
Embodiment 15 Compound I I (R
1=R
2=adjacent Brombenzyl) preparation
With Compound I (R
1=adjacent Brombenzyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding adjacent bromo-acid acid anhydride (0.25mol) under the cooling, DMAP (0.03mol) at cryosel.Drip the vitriol oil (0.3mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 66%, purity HPLC:90.9%.
Embodiment 16 Compound I I (R
1=R
2=Brombenzyl) preparation
With Compound I (R
1=Brombenzyl) (0.1mol) adds in the 100ml reaction flask.Bromo-acid acid anhydride (0.25mol) between (20 ℃) add under the cryosel bath cooling, DMAP (0.03mol).Drip the vitriol oil (0.3mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to 60 ℃, stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 68%, purity HPLC:90.8%.
Embodiment 17 Compound I I (R
1=R
2=O-methoxy phenmethyl) preparation
With Compound I (R
1=O-methoxy phenmethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding O-methoxy phenylacetic anhydride (0.15mol) under the cooling, DMAP (0.2mol) at cryosel.Drip the vitriol oil (0.25mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to 50 ℃, stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:93.8%.
Embodiment 18 Compound I I (R
1=R
2=meta-methoxy phenmethyl) preparation
With Compound I (R
1=meta-methoxy phenmethyl) (0.1mol) adds in the 100ml reaction flask.(5 ℃～10 ℃) add meta-methoxy phenylacetic anhydride (0.15mol), DMAP (0.2mol) under the ice bath cooling.Drip the vitriol oil (0.25mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (0-20 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 60%, purity HPLC:92.8%.
Embodiment 19 Compound I I (R
1=R
2=ortho-nitrophenyl methyl) preparation
With Compound I (R
1=ortho-nitrophenyl methyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding o-Nitrophenylacetic acid acid anhydride (0.15mol) under the cooling, DMAP (0.2mol) at cryosel.Drip the vitriol oil (0.25mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 61%, purity HPLC:92.5%.
Embodiment 20 Compound I I (R
1=R
2=m-nitro methyl) preparation
With Compound I (R
1=m-nitro methyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding m nitrophenylacetic acid acid anhydride (0.15mol) under the cooling, DMAP (0.2mol) at cryosel.Drip the vitriol oil (0.25mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 60%, purity HPLC:93.5%.
Embodiment 21 Compound I I (R
1=methyl, R
2=phenyl) preparation
With Compound I (R
1=methyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding benzoyl oxide (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:91.7%.
Embodiment 22 Compound I I (R
1=ethyl, R
2=phenmethyl) preparation
With Compound I (R
1=ethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding phenylacetic anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 59%, purity HPLC:92.2%.
Embodiment 23 Compound I I (R
1=the tertiary butyl, R
2=adjacent chlorophenylmethyl) preparation
With Compound I (R
1=the tertiary butyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding o-chlorobenzene acetic acid acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:91.7%.
Embodiment 24 Compound I I (R
1=sec.-propyl, R
2=Brombenzyl) preparation
With Compound I (R
1=sec.-propyl) (0.1mol) adds in the 100ml reaction flask.Bromo-acid acid anhydride (0.25mol) between (10 ℃) add under the cryosel bath cooling, DMAP (0.1mol).Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, productive rate 62%, purity HPLC:93.2%.
Embodiment 25 Compound I I (R
1=propyl group, R
2=to mehtoxybenzyl) preparation
With Compound I (R
1=propyl group) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding homoanisic acid acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 61%, purity HPLC:91.8%.
Embodiment 26 Compound I I (R
1=butyl, R
2=p-nitrophenyl methyl) preparation
With Compound I (R
1=butyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding paranitrophenylacetic acid acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 61%, purity HPLC:91.5%.
Embodiment 27 Compound I I (R
1=propyl group, R
2=cyclohexyl) preparation
With Compound I (R
1=propyl group) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding hexahydrobenzoic acid acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 60%, purity HPLC:92.6%.
Embodiment 28 Compound I I (R
1=phenyl, R
2=ethyl) preparation
With Compound I (R
1=phenyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding propionic anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 61%, purity HPLC:93.8%.
Embodiment 29 Compound I I (R
1=phenmethyl, R
2=propyl group) preparation
With Compound I (R
1=phenmethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding butyryl oxide (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 63%, purity HPLC:93.7%.
Embodiment 30 Compound I I (R
1=chlorophenylmethyl, R
2=the tertiary butyl) preparation
With Compound I (R
1=chlorophenylmethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding PIVALIC ACID CRUDE (25) acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 63%, purity HPLC:93.2%.
Embodiment 31 Compound I I (R
1=adjacent Brombenzyl, R
2=sec.-propyl) preparation
With Compound I (R
1=adjacent Brombenzyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding isobutyric anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 66%, purity HPLC:93.4%.
Embodiment 32 Compound I I (R
1=to mehtoxybenzyl, R
2=butyl) preparation
With Compound I (R
1=to mehtoxybenzyl) (0.1mol) add in the 100ml reaction flask.Bathe (10 ℃) adding valeric anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:92.2%.
Embodiment 33 Compound I I (R
1=ortho-nitrophenyl methyl, R
2=propyl group) preparation
With Compound I (R
1=ortho-nitrophenyl methyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding butyryl oxide (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 60%, purity HPLC:92.4%.
Embodiment 34 Compound I I (R
1=cyclopentyl, R
2=methyl) preparation
With Compound I (R
1=cyclopentyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding diacetyl oxide (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 62%, purity HPLC:91.2%.
Embodiment 35 Compound I I (R
1=phenyl, R
2=phenmethyl) preparation
With Compound I (R
1=phenyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding phenylacetic anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 63%, purity HPLC:91.0%.
Embodiment 36 Compound I I (R
1=phenmethyl, R
2=adjacent chlorophenylmethyl) preparation
With Compound I (R
1=phenmethyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding o-chlorobenzene acetic acid acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 64%, purity HPLC:90.8%.
Embodiment 37 Compound I I (R
1=to chlorophenylmethyl, R
2=adjacent Brombenzyl) preparation
With Compound I (R
1=to chlorophenylmethyl) ((0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding adjacent bromo-acid acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 63%, purity HPLC:92.2%.
Embodiment 38 Compound I I (R
1=to Brombenzyl, R
2=meta-methoxy phenmethyl) preparation
With Compound I (R
1=to Brombenzyl) (0.1mol) add in the 100ml reaction flask.Bathe (10 ℃) adding meta-methoxy phenylacetic anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 65%, purity HPLC:94.2%.
Embodiment 39 Compound I I (R
1=to mehtoxybenzyl, R
2=ortho-nitrophenyl methyl) preparation
With Compound I (R
1=to mehtoxybenzyl) (0.1mol) add in the 100ml reaction flask.Bathe (10 ℃) adding o-Nitrophenylacetic acid acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 67%, purity HPLC:91.2%.
Embodiment 40 Compound I I (R
1=m-nitro methyl, R
2=cyclopentyl) preparation
With Compound I (R
1=m-nitro methyl) (0.1mol) adds in the 100ml reaction flask.Bathe (10 ℃) adding cyclopentanecarboxylic acid acid anhydride (0.25mol) under the cooling, DMAP (0.1mol) at cryosel.Drip the vitriol oil (0.4mol) of massfraction 98% then, rate of addition with temperature in keeping 0 ℃ with under control.After interior temperature slowly was raised to room temperature (20-25 ℃), stirring the 6h reaction, to follow the tracks of raw material reaction up to TLC complete, adds saturated aqueous common salt under the icy salt solution cooling in reaction solution, stirred 3 hours.Use ethyl acetate extraction then, pH is to 6.5-7.5 in the aqueous sodium carbonate washing, and drying concentrates and promptly gets target compound is light yellow liquid, and productive rate is 66%, purity HPLC:93.2%.
Claims (9)
1. one kind suc as formula 1 shown in the II, 2, the preparation method of 5-O-three acyl groups-3-deoxidation-α-D-furyl xylose, it is characterized in that comprising the following steps: under-10 ℃～0 ℃ temperature, under the existence of 4-(N, N-dimethylamino) pyridine, with compound shown by formula I and acid anhydrides effect, add the vitriol oil then and react for 0～60 ℃, get final product suc as formula the compound shown in the II in interior temperature;
Wherein, R
1And R
2Alone be methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, phenyl, phenmethyl, adjacent chlorophenylmethyl, a chlorophenylmethyl, to chlorophenylmethyl, adjacent Brombenzyl, a Brombenzyl, to Brombenzyl, O-methoxy phenmethyl, meta-methoxy phenmethyl, to mehtoxybenzyl, ortho-nitrophenyl methyl, m-nitro methyl, p-nitrophenyl methyl, styroyl, cyclopentyl or cyclohexyl.
2. preparation method as claimed in claim 1 is characterized in that: R
1And R
2Alone be methyl or phenyl.
3. preparation method as claimed in claim 1 is characterized in that: the consumption of described acid anhydrides is 1.0～3.0 times of compound shown by formula I molar weight.
4. preparation method as claimed in claim 1 is characterized in that: the consumption of described 4-(N, N-dimethylamino) pyridine is 0.1～0.5 times of molar weight of compound shown by formula I.
5. preparation method as claimed in claim 1 is characterized in that: the mass percentage concentration of the described vitriol oil is 90～98%.
6. preparation method as claimed in claim 1 is characterized in that: the consumption of the described vitriol oil is 1.0～5.0 times of molar weight of compound shown by formula I.
7. preparation method as claimed in claim 1 is characterized in that: the speed of the described adding vitriol oil with temperature in keeping 0 ℃ with under control.
8. preparation method as claimed in claim 1 is characterized in that: the interior temperature of described reaction is 10～25 ℃.
9. preparation method as claimed in claim 1 is characterized in that: till the time of described reaction runs out of with detecting reactant.
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|---|---|---|---|
| CN200810202865A CN101735285B (en) | 2008-11-18 | 2008-11-18 | Preparation method of 1,2,5-O-triacyl-3-deoxy-alpha-D-xylofuranose |
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| CN104402945A (en) * | 2014-11-27 | 2015-03-11 | 苏州乔纳森新材料科技有限公司 | Synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose |
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| CN101172989B (en) * | 2006-11-03 | 2012-06-06 | 上海睿智化学研究有限公司 | Method for producing 5-O-acetyl-3-deoxidization-1,2-isopropylidene-alpha-D-tetrol xylose and intermediate |
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| CN104402945A (en) * | 2014-11-27 | 2015-03-11 | 苏州乔纳森新材料科技有限公司 | Synthesis method for 3-deoxy-1,2-O-isopropylidene-D-xylofuranose |
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Address after: Building 3, No. 99 Lianhe North Road, Fengxian District, Shanghai, 2014 Patentee after: Shanghai Boteng Zhituo Pharmaceutical Technology Co.,Ltd. Address before: No. 99, Lianhe North Road, Fengxian District, Shanghai 201203 Patentee before: Kaihui Pharmaceutical (Shanghai) Co.,Ltd. |