CN102276511A - Synthetic method for 1-tert-butyloxycarbonyl-3-iodo-azetidine - Google Patents
Synthetic method for 1-tert-butyloxycarbonyl-3-iodo-azetidine Download PDFInfo
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Abstract
The invention provides a synthetic method for 1-tert-butyloxycarbonyl-3-iodo-azetidine. The method comprises the following steps: dissolving 1-tert-butyloxycarbonyl-3-hydroxyazetidine in toluene, adding a catalyst, and carrying out stirring for 20 to 30 min; adding drop by drop a toluene solution containing iodine into the obtained solution in the previous step at a temperature of 0 to 20 DEG C; heating the obtained solution in the previous step to a temperature of 100 to 110 DEG C for reaction for 1 hour to 4 hours, and detecting whether the reaction is completely finished by thin layer chromatography; removing toluene when the resultant reaction solution is cooled to room temperature, adding petroleum ether for refrigeration for 1 hour to 2 hours, filtering the mixture, and condensing the filtrate to obtain a yellow grease; carrying out reduced pressure distillation on the yellow grease, and collecting fractions in a range of 80 to 100 DEG C so as to obtain a colorless grease, i.e., 1-tert-butyloxycarbonyl-3-iodo-azetidine. The 1-tert-butyloxycarbonyl-3-iodo-azetidine prepared by the synthetic method provided in the invention has a high purity and high yield; cost for raw materials used in the method is low, little organic reagents are used, little pollution is produced, and environmental protection is obtained.
Description
Technical field
The present invention relates to the biological medicine technology field, relate in particular to the intermediate of a kind of medicine, agricultural chemicals and other chemical additives.
Background technology
1-tertbutyloxycarbonyl-3-iodine azetidine is the intermediate of a kind of very important medicine, agricultural chemicals and other chemical additives.But at present the technology of domestic synthetic 1-tertbutyloxycarbonyl-3-iodine azetidine is to be raw material with 1-tertbutyloxycarbonyl-3-hydroxy azetidine, Methanesulfonyl chloride in the elder generation, made in tens hours with potassiumiodide 150 ° of reactions in DMSO, the industrialization means are lower again, and production technique falls behind.Cause the productive rate of this synthesis technique low, the purity of synthetic 1-tertbutyloxycarbonyl-3-iodine azetidine is lower, and energy consumption is big, and raw materials cost is too high, pollutes more serious.
Summary of the invention
The technical problem to be solved in the present invention is the defective that overcomes prior art, and the synthetic method of a kind of productive rate height, 1-tertbutyloxycarbonyl-3-iodine azetidine that product purity is high is provided.
In order to solve the problems of the technologies described above, the invention provides following technical scheme:
The synthetic method of 1-tertbutyloxycarbonyl-3-iodine azetidine, the step of described synthetic method is:
(1) 1-tertbutyloxycarbonyl-3-hydroxy azetidine is dissolved in the toluene, adds catalyzer and stir 20-30min;
(2), in the solution of step (1) gained, drip the toluene solution of iodine at 0 ~ 20 ℃;
(3) solution to 100 ~ 110 of heating steps (2) gained ℃, reaction 1 ~ 4h, the tlc detection reaction is complete;
(4) reaction solution for the treatment of step (3) cools to room temperature, removes toluene, adds the freezing 1-2h of sherwood oil, filter, filtrate concentrate yellow oil;
(5) with the yellow oil underpressure distillation of step (4) gained, collect 80 ~ 100 ℃ of cuts, obtaining colorless oil is 1-tertbutyloxycarbonyl-3-iodine azetidine.
Further, the catalyzer in the described step (1) is triphenyl phosphorus and imidazoles; Wherein the ratio of the amount of substance of 1-tertbutyloxycarbonyl-3-hydroxy azetidine, triphenyl phosphorus and imidazoles is 1:1 ~ 2.2:1 ~ 3.
Further, the volume of toluene and the mass ratio of 1-tertbutyloxycarbonyl-3-hydroxy azetidine are 5-12:1 in the described step (1).When the volume unit of toluene was mL, the mass unit of 1-tertbutyloxycarbonyl-3-hydroxy azetidine was g; When the volume unit of toluene was L, the mass unit of 1-tertbutyloxycarbonyl-3-hydroxy azetidine was kg.
Further, the ratio of the amount of substance of iodine in the described step (2) and the 1-tertbutyloxycarbonyl-3-hydroxy azetidine in the step (1) is 1.3 ~ 2.2:1.
Further, the quality of iodine and the volume ratio of toluene are 1:3 ~ 20 in the described step (2).When the volume unit of toluene was mL, the mass unit of iodine was g; When the volume unit of toluene was L, the mass unit of iodine was kg.
Further, adding the volume of sherwood oil and the mass ratio of the 1-tertbutyloxycarbonyl-3-hydroxy azetidine in the step (1) in the described step (4) is 10-15:1.Wherein when the volume unit of sherwood oil was mL, the mass unit of 1-tertbutyloxycarbonyl-3-hydroxy azetidine was g; When the volume unit of sherwood oil was L, the mass unit of 1-tertbutyloxycarbonyl-3-hydroxy azetidine was kg.
Preferably, described step (1) adds catalyzer and stirs 20-30min for 1-tertbutyloxycarbonyl-3-hydroxy azetidine is dissolved in the toluene; Wherein catalyzer is triphenyl phosphorus and imidazoles; The ratio of the amount of substance of 1-tertbutyloxycarbonyl-3-hydroxy azetidine, triphenyl phosphorus and imidazoles is 1:1.5:2.5; The mass ratio of the volume of toluene and 1-tertbutyloxycarbonyl-3-hydroxy azetidine is 10:1.
Preferably, described step (2) is at 0 ~ 20 ℃, drips the toluene solution of iodine in the solution of step (1) gained; Wherein the ratio of the amount of substance of the 1-tertbutyloxycarbonyl-3-hydroxy azetidine in iodine and the step (1) is 2.2:1; The quality of iodine and the volume ratio of toluene are 1:5.
Preferably, adding the volume of sherwood oil and the mass ratio of the 1-tertbutyloxycarbonyl-3-hydroxy azetidine in the step (1) in the described step (4) is 10:1.
This synthetic method is specifically carried out according to the following steps:
In the toluene that the 1-tertbutyloxycarbonyl-the 3-hydroxy azetidine is dissolved in, add triphenyl phosphorus and imidazoles, under 0 ° ~ 20 ℃ of temperature, drip the toluene solution of iodine, be heated to 100-110 ℃ of reaction 1-4 hour, 80-100 ℃ of cut (10mmHg) got in underpressure distillation.
1-tertbutyloxycarbonyl-3-hydroxy azetidine that synthetic method of the present invention makes utilizes gas chromatography determination purity to be 98.6-99.2%, and purity is higher, and yield is 79-85%, and yield is higher.And raw materials cost is lower, uses organic reagent few, pollute little, environmental protection.
Embodiment
The used experiment reagent of embodiment is commercially available.
Reaction raw materials: 1-tertbutyloxycarbonyl-3-hydroxy azetidine, molecular formula: C
8H
15NO
3, outward appearance and proterties: white or light yellow plate crystal, molecular weight: 173.11.
Auxiliary material: triphenyl phosphorus, molecular formula: C
18H
15P, outward appearance and proterties: white or light yellow plate crystal.Molecular weight: 262.30, flash-point: 180 ℃/open cup, fusing point: 79～82 ℃, boiling point: 377 ℃, solvability: water insoluble, be slightly soluble in ethanol, be dissolved in benzene, acetone, tetracol phenixin, density: relative density (water=1) 1.32; Relative density (air=1) 9.0 white crystals, purity 99%.
Imidazoles, this product are white prismatic or plate crystal, in soluble in water, the alcohol, are slightly soluble in benzene, are insoluble in sherwood oil.Purity 99%.Molecular weight: 68.08.
Iodine, iodine are the atropurpureus crystal, purity 98%.Molecular weight: 254.
Embodiment 1
Test apparatus: 500 milliliters of three mouthfuls of reaction flasks, magnetic agitation, thermometer.
The synthetic method of 1-tertbutyloxycarbonyl-3-iodine azetidine, the step of synthetic method is:
(1) 3.35 gram 1-Boc-3-hydroxy azetidines are dissolved in 40 milliliters of toluene, add triphenyl phosphorus 10.14 grams, imidazoles 3.95 grams stirred 20 minutes.
(2) then iodine 7.36 grams are dissolved in 150 milliliters of toluene, reaction solution is advanced in 5 ℃ of droppings.
(3) ℃ reaction of the solution to 110 of heating steps (2) gained is back 1 hour, and the TLC detection reaction is complete.
(4) reaction solution for the treatment of step (3) cools to room temperature, spins off toluene, has in a large number to salt out, and adds 50 milliliters of freezing 2h of sherwood oil, filter, filtrate concentrate yellow oil crude product 5.1 grams, be 97.3% by gas Chromatographic Determination purity, yield is 93%.
(5) with the yellow oil underpressure distillation of step (4) gained, collect 80-100 ℃ of cut (10mmHg), obtaining colorless oil is 1-tertbutyloxycarbonyl-3-iodine azetidine 4.3 grams, is 98.6% by gas Chromatographic Determination purity, and yield is 79%.The nucleus magnetic hydrogen spectrum data of implementing the 1 1-tertbutyloxycarbonyl for preparing-3-iodine azetidine are:
1H-NMR (CDCl
3, 400MHZ) δ: 1.34 (s, 9H), 4.15 (m, 2H), 4.37 (m, 1H), 4.51 (m, 2H).
Embodiment 2
Laboratory apparatus: 500 milliliters of three mouthfuls of reaction flasks, magnetic agitation, thermometer.
The synthetic method of 1-tertbutyloxycarbonyl-3-iodine azetidine, the step of synthetic method is:
(1) 5 gram 1-Boc-3-hydroxy azetidines are dissolved in 60 milliliters of toluene, add triphenyl phosphorus 17 grams, imidazoles 6 grams stirred 30 minutes.
(2) then iodine 9.36 grams are dissolved in 150 milliliters of toluene, reaction solution is advanced in 5 ℃ of droppings.
(3) solution to the 100 ℃ afterreaction of heating steps (2) gained is 1 hour, and the TLC detection reaction is complete.
(4) reaction solution for the treatment of step (3) cools to room temperature, spins off toluene, has in a large number to salt out, and adds 75 milliliters of sherwood oils freezing 2 hours, filter, filtrate concentrate yellow oil crude product 7.36 grams, by gas Chromatographic Determination purity 98.3%, yield 90%.
(5) with the yellow oil underpressure distillation of step (4) gained, collect 80-100 ℃ of cut (10mmHg), obtaining colorless oil is 1-tertbutyloxycarbonyl-3-iodine azetidine 6.4 grams, is 99% by gas Chromatographic Determination purity, and yield is 79%.The nucleus magnetic hydrogen spectrum data of implementing the 2 1-tertbutyloxycarbonyl for preparing-3-iodine azetidines are:
1H-NMR (CDCl
3, 400MHZ) δ: 1.46 (s, 9H), 4.25 (m, 2H), 4.47 (m, 1H), 4.57 (m, 2H).
Embodiment 3
Laboratory apparatus: 1000 milliliters of three mouthfuls of reaction flasks, magnetic agitation, thermometer.
The synthetic method of 1-tertbutyloxycarbonyl-3-iodine azetidine, the step of synthetic method is:
(1) 33.5 gram 1-Boc-3-hydroxy azetidines are dissolved in 300 milliliters of toluene, add triphenyl phosphorus 105 grams, imidazoles 40 grams stirred 30 minutes.
(2) then iodine 75 grams are dissolved in 300 milliliters of toluene, reaction solution is advanced in 0 ℃ of dropping.
(3) ℃ reaction of the solution to 100 of heating steps (2) gained is 1 hour, and the TLC detection reaction is complete.
(4) reaction solution for the treatment of step (3) cools to room temperature, spins off toluene, has in a large number to salt out, and adds 335 milliliters of sherwood oils freezing 2 hours, filter, filtrate concentrate yellow oil crude product 49.8 grams, yield 91%.
(5) with the yellow oil underpressure distillation of step (4) gained, collect 80-100 ℃ of cut (10mmHg), obtaining colorless oil is 1-tertbutyloxycarbonyl-3-iodine azetidine 44.8 grams, is 99.2% by gas Chromatographic Determination purity, and yield is 82%.The nucleus magnetic hydrogen spectrum data of implementing the 3 1-tertbutyloxycarbonyl for preparing-3-iodine azetidines are:
1H-NMR (CDCl
3, 400MHZ) δ: 1.38 (s, 9H), 4.23 (m, 2H), 4.42 (m, 1H), 4.54 (m, 2H).
Embodiment 4
Laboratory apparatus: 20 liters of three mouthfuls of reaction flasks, mechanical stirring, thermometer.
The synthetic method of 1-tertbutyloxycarbonyl-3-iodine azetidine, the step of synthetic method is:
(1) 500 gram 1-Boc-3-hydroxy azetidines are dissolved in 2500 milliliters of toluene, add triphenyl phosphorus 1600 grams, imidazoles 600 grams stirred 30 minutes.
(2)Then iodine 1075 grams are dissolved in 5000 milliliters of toluene, reaction solution is advanced in 0 ℃ of dropping.
(3)The solution of step (2) gained is warmed up to 110 ℃ of reactions 4 hours, and the TLC detection reaction is complete.
(4)The reaction solution for the treatment of step (3) cools to room temperature, spins off toluene, has in a large number to salt out, and adds 5 liters of sherwood oils freezing 2 hours, filters, and filtrate concentrates to such an extent that yellow oil crude product 801 restrains, and is 90% by gas Chromatographic Determination purity, and yield is 98%.
(5) 80-100 ℃ of cut (10mmHg) collected in the yellow oil underpressure distillation of step (4) gained, getting colorless oil is 1-tertbutyloxycarbonyl-3-iodine azetidine 640 grams, is 99% by gas Chromatographic Determination purity, and yield is 79%.The nucleus magnetic hydrogen spectrum data of implementing-4 1-tertbutyloxycarbonyl for preparing-3-iodine azetidines are:
1H-NMR (CDCl
3, 400MHZ) δ: 1.37 (s, 9H), 4.13 (m, 2H), 4.33 (m, 1H), 4.49 (m, 2H).
Embodiment 5
Laboratory apparatus: 2 liters of three mouthfuls of reaction flasks, mechanical stirring, thermometer.
The synthetic method of 1-tertbutyloxycarbonyl-3-iodine azetidine, the step of synthetic method is:
(1) 100 gram 1-Boc-3-hydroxy azetidines are dissolved in 500 milliliters of toluene, add triphenyl phosphorus 151 grams, imidazoles 39.3 grams stirred 30 minutes.
(2)Then iodine 220 grams are dissolved in 660 milliliters of toluene, reaction solution is advanced in 10 ℃ of droppings.
(3)The solution of step (2) gained is warmed up to 105 ℃ of reactions 2 hours, and the TLC detection reaction is complete.
(4)The reaction solution for the treatment of step (3) cools to room temperature, spins off toluene, has in a large number to salt out, and adds 1 liter of sherwood oil freezing 1.5 hours, filters, and filtrate concentrates to such an extent that yellow oil crude product 160 restrains, and is 92% by gas Chromatographic Determination purity, and yield is 98%.
(5) 80-100 ℃ of cut (10mmHg) collected in the yellow oil underpressure distillation of step (4) gained, getting colorless oil is 1-tertbutyloxycarbonyl-3-iodine azetidine 130 grams, is 99% by gas Chromatographic Determination purity, and yield is 80%.The nucleus magnetic hydrogen spectrum data of implementing-5 1-tertbutyloxycarbonyl for preparing-3-iodine azetidines are:
1H-NMR (CDCl
3, 400MHZ) δ: 1.39 (s, 9H), 4.13 (m, 2H), 4.33 (m, 1H), 4.50 (m, 2H).
Embodiment 6
Laboratory apparatus: 5 liters of three mouthfuls of reaction flasks, mechanical stirring, thermometer.
The synthetic method of 1-tertbutyloxycarbonyl-3-iodine azetidine, the step of synthetic method is:
(1)100 gram 1-Boc-3-hydroxy azetidines are dissolved in 1000 milliliters of toluene, add triphenyl phosphorus 227 grams, imidazoles 98.3 grams stirred 25 minutes.
(2) then iodine 327 grams are dissolved in 1635 milliliters of toluene, reaction solution is advanced in 20 ℃ of droppings.
(3) solution with step (2) gained is warmed up to 110 ℃ of reactions 4 hours, and the TLC detection reaction is complete.
(4) reaction solution for the treatment of step (3) cools to room temperature, spins off toluene, has in a large number to salt out, and adds 1 liter of sherwood oil freezing 1 hour, filter, filtrate concentrate yellow oil crude product 161 grams, be 93% by gas Chromatographic Determination purity, yield is 99%.
(5) with the 80-100 ℃ of cut of yellow oil underpressure distillation (10mmHg) of step (4) gained, getting colorless oil is 1-tertbutyloxycarbonyl-3-iodine azetidine 138 grams, is 99% by gas Chromatographic Determination purity, and yield is 85%.The nucleus magnetic hydrogen spectrum data of implementing the 6 1-tertbutyloxycarbonyl for preparing-3-iodine azetidines are:
1H-NMR (CDCl
3, 400MHZ) δ: 1.43 (s, 9H), 4.18 (m, 2H), 4.35 (m, 1H), 4.48 (m, 2H).
Embodiment 1-6 is by synthetic method of the present invention, and the 1-tertbutyloxycarbonyl that makes-3-iodine azetidine utilizes vapor-phase chromatography to record purity and is respectively 98.6%, 99%, 99.2%, 99%, 99% and 99%, and mean value is 98.97%.Yield is respectively 79%, 79%, 82%, 79%, 80% and 85%, and mean value is 80.7%, and yield is higher.It should be noted that at last: the above only is the preferred embodiments of the present invention, be not limited to the present invention, although the present invention is had been described in detail with reference to previous embodiment, for a person skilled in the art, it still can be made amendment to the technical scheme that aforementioned each embodiment put down in writing, and perhaps part technical characterictic wherein is equal to replacement.Within the spirit and principles in the present invention all, any modification of being done, be equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (9)
1.1-the synthetic method of tertbutyloxycarbonyl-3-iodine azetidine is characterized in that the step of described synthetic method is:
(1) 1-tertbutyloxycarbonyl-3-hydroxy azetidine is dissolved in the toluene, adds catalyzer and stir 20-30min;
(2), in the solution of step (1) gained, drip the toluene solution of iodine at 0 ~ 20 ℃;
(3) solution to 100 ~ 110 of heating steps (2) gained ℃, reaction 1 ~ 4h, the tlc detection reaction is complete;
(4) reaction solution for the treatment of step (3) cools to room temperature, removes toluene, adds the freezing 1-2h of sherwood oil, filter, filtrate concentrate yellow oil;
(5) with the yellow oil underpressure distillation of step (4) gained, collect 80 ~ 100 ℃ of cuts, obtaining colorless oil is 1-tertbutyloxycarbonyl-3-iodine azetidine.
2. the synthetic method of 1-tertbutyloxycarbonyl according to claim 1-3-iodine azetidine is characterized in that: the catalyzer in the described step (1) is triphenyl phosphorus and imidazoles; Wherein the ratio of the amount of substance of 1-tertbutyloxycarbonyl-3-hydroxy azetidine, triphenyl phosphorus and imidazoles is 1:1 ~ 2.2:1 ~ 3.
3. the synthetic method of 1-tertbutyloxycarbonyl according to claim 1-3-iodine azetidine is characterized in that: the volume of toluene and the mass ratio of 1-tertbutyloxycarbonyl-3-hydroxy azetidine are 5-12:1 in the described step (1).
4. the synthetic method of 1-tertbutyloxycarbonyl according to claim 1-3-iodine azetidine is characterized in that: the ratio of the amount of substance of the 1-tertbutyloxycarbonyl-3-hydroxy azetidine in iodine in the described step (2) and the step (1) is 1.3 ~ 2.2:1.
5. the synthetic method of 1-tertbutyloxycarbonyl according to claim 1-3-iodine azetidine is characterized in that:
The quality of iodine and the volume ratio of toluene are 1:3 ~ 20 in the described step (2).
6. the synthetic method of 1-tertbutyloxycarbonyl according to claim 1-3-iodine azetidine is characterized in that:
The volume of adding sherwood oil and the mass ratio of the 1-tertbutyloxycarbonyl-3-hydroxy azetidine in the step (1) are 10-15:1 in the described step (4).
7. according to the synthetic method of claim 2 or 3 described 1-tertbutyloxycarbonyl-3-iodine azetidines, it is characterized in that: described step (1) adds catalyzer and stirs 20-30min for 1-tertbutyloxycarbonyl-3-hydroxy azetidine is dissolved in the toluene; Wherein catalyzer is triphenyl phosphorus and imidazoles; The ratio of the amount of substance of 1-tertbutyloxycarbonyl-3-hydroxy azetidine, triphenyl phosphorus and imidazoles is 1:1.5:2.5; The mass ratio of the volume of toluene and 1-tertbutyloxycarbonyl-3-hydroxy azetidine is 10:1.
8. according to the synthetic method of claim 4 or 5 described 1-tertbutyloxycarbonyl-3-iodine azetidines, it is characterized in that: described step (2) drips the toluene solution of iodine at 0 ~ 20 ℃ in the solution of step (1) gained; Wherein the ratio of the amount of substance of the 1-tertbutyloxycarbonyl-3-hydroxy azetidine in iodine and the step (1) is 2.2:1; The quality of iodine and the volume ratio of toluene are 1:5.
9. the synthetic method of 1-tertbutyloxycarbonyl according to claim 6-3-iodine azetidine is characterized in that:
The volume of adding sherwood oil and the mass ratio of the 1-tertbutyloxycarbonyl-3-hydroxy azetidine in the step (1) are 10:1 in the described step (4).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102432514A (en) * | 2011-12-26 | 2012-05-02 | 兰州博实生化科技有限责任公司 | Synthesis method of 1-tert-butyloxycarbonyl-3-fluoroazetidine |
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| EP1440709B1 (en) * | 1999-10-21 | 2007-12-05 | Pfizer Limited | Combinations comprising cGMP PDE5 inhibitors. |
| WO2010084767A1 (en) * | 2009-01-22 | 2010-07-29 | Raqualia Pharma Inc. | N-substituted saturated heterocyclic sulfone compounds with cb2 receptor agonistic activity |
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| EP1440709B1 (en) * | 1999-10-21 | 2007-12-05 | Pfizer Limited | Combinations comprising cGMP PDE5 inhibitors. |
| CN101039904A (en) * | 2004-10-14 | 2007-09-19 | 艾博特股份有限两合公司 | Heterocyclic compounds suitable for treating disorders that respond to modulation of the dopamine d3 receptor |
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| CN102432514A (en) * | 2011-12-26 | 2012-05-02 | 兰州博实生化科技有限责任公司 | Synthesis method of 1-tert-butyloxycarbonyl-3-fluoroazetidine |
| CN102432514B (en) * | 2011-12-26 | 2014-05-07 | 兰州博实生化科技有限责任公司 | Method for synthesizing 1-tert-butoxycarbonyl-3-fluoroazetidine |
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Application publication date: 20111214 |