CN106632333A - Preparation method of low-cost 8-chlorotheophylline - Google Patents
Preparation method of low-cost 8-chlorotheophylline Download PDFInfo
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- CN106632333A CN106632333A CN201611075120.3A CN201611075120A CN106632333A CN 106632333 A CN106632333 A CN 106632333A CN 201611075120 A CN201611075120 A CN 201611075120A CN 106632333 A CN106632333 A CN 106632333A
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- Prior art keywords
- stirring
- preparation
- chlorine
- chlorotheophyline
- centrifugation
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
Abstract
The invention discloses a preparation method of low-cost 8-chlorotheophylline. The preparation method of the low-cost 8-chlorotheophylline comprises the following steps: adding theophylline into a mixed solution of DMF and SOCl2, introducing chlorine to react, and crystallizing, washing and drying after the reaction to obtain the final product. According to the method, the target product is synthesized by taking the recyclable DMF as a solvent at one step and the finished product can be obtained by pulping with tap water, so that the cost is low, the pollution is low and the yield is high.
Description
Technical field
The present invention relates to a kind of chemical field, more particularly to a kind of preparation method of inexpensive 8-Chlorotheophyline.
Background technology
8-Chlorotheophyline is important pharmaceutical intermediate, for medicine intermediates such as synthesis material medicine diphenhydramines.Tradition system
Standby technique：By caffeine Jing chlorinations；Hydrolyze and obtain.In reaction pot, caffeine is added；With carbon tetrachloride-nitrobenzene (severe toxicity)
Mixed liquor is reaction dissolvent, and the crystalline flake of iodine makees catalyst, is warming up to less than 80 DEG C, leads to chlorine reaction 3 hours.It is warming up to 90-95
DEG C, logical chlorine more than about 5 hours, reactant liquor is clarified completely, obtains 7,8- dichloro caffeines.Add water, plus thermal distillation, clarify distillate
Till formaldehydeless taste.Freezing and crystallizing, rejection filter uses ethanol；Chloroform is washed successively, is dried, and obtains 8-Chlorotheophyline.The method has following lacking
Point：
1st, carbon tetrachloride-nitrobenzene mixed reaction solvent is hypertoxic solvent, big to human body and environmental hazard.
2nd, recycling design is aqueous, it is impossible to apply mechanically, high cost.
3rd, crude product needs to be washed with organic solvent ethanol and chloroform, and high cost, yield is low, unfriendly to environment.
In view of disadvantages described above, it is necessary to which the preparation method of 8-Chlorotheophyline is further studied.
The content of the invention
Based on the technical problem that background technology is present, the present invention proposes a kind of preparation method of inexpensive 8-Chlorotheophyline.
Technical scheme is as follows：
A kind of preparation method of inexpensive 8-Chlorotheophyline, comprises the following steps：
A, DMF and S0Cl is squeezed into a kettle.2, under opening stirring condition, theophylline is put into, begin to warm to after the end that feeds intake
62-68 DEG C, control temperature starts logical chlorine at 65-70 DEG C, and 5-7h leads to chlorine, and logical chlorine terminates 65-70 DEG C of insulation 2.5- of rear temperature control
3.5h, then arrange chlorine 0.8-1.2h；
B, finally reactant liquor is transferred in crystallization kettle starts crystallization, chilled brine is cooled to 5-10 DEG C of stirring 1.5-
2.5h, starts blowing centrifugation；
Crude product and running water obtained by C, centrifugation is added in beating kettle, and the control that heats up stirs insulation 1.5- at 75-80 DEG C
2.5h, while hot blowing centrifugation, drying, barrelling warehouse-in；
D, filtrate are cooled to 5-10 DEG C of stirring 1.5-2.5h, and theophylline is reclaimed in blowing centrifugation, drying.
Preferably, in described step A, using magnetic stirring apparatus, stirring frequency is 20-25Hz.
Preferably, in described step B, chilled brine cools the temperature to 6 DEG C.
The chemical equation of the present invention is as follows：
The invention has benefit that：The preparation method of the present invention, in DMF and S0Cl2Mixed solution in, add tea
Alkali, and chlorine reaction is passed through, reaction is crystallized after terminating, washed, drying obtains final product.The method is adopted can be with recycled
DMF be solvent, one-step synthesis target product, then with running water beating can finished product, low cost, pollute little, high income.
Specific embodiment
Embodiment 1：
A kind of preparation method of inexpensive 8-Chlorotheophyline, comprises the following steps：
1500L DMF and 3kg S0Cl are squeezed into A, first enamel reaction still2, under opening stirring (22.9Hz), put into 280kg tea
Alkali, begins to warm to 65 DEG C after the end that feeds intake, control temperature starts logical chlorine at 65-70 DEG C, and the logical chlorine 120kg of 6h, logical chlorine terminates
Afterwards 65-70 DEG C of temperature control is incubated 3h, then arranges chlorine 1h；
B, finally reactant liquor is transferred in crystallization kettle starts crystallization, chilled brine is cooled to 6 DEG C of stirring 2h, starts blowing
Centrifugation；
Crude product and 1500L running water obtained by C, centrifugation is added in beating kettle, and at 75-80 DEG C, stirring is protected for the control that heats up
Warm 2h, while hot blowing centrifugation, drying, barrelling warehouse-in；
D, filtrate are cooled to 8 DEG C of stirring 2h, and theophylline is reclaimed in blowing centrifugation, drying.Product yield 89.2%.
Embodiment 2：
A kind of preparation method of inexpensive 8-Chlorotheophyline, comprises the following steps：
1500L DMF and 3kg S0Cl are squeezed into A, first enamel reaction still2, under opening stirring (23.2Hz), put into 280kg tea
Alkali, begins to warm to 62 DEG C after the end that feeds intake, control temperature starts logical chlorine at 65-70 DEG C, and the logical chlorine 120kg of 5h, logical chlorine terminates
Afterwards 65-70 DEG C of temperature control is incubated 3.5h, then arranges chlorine 0.8h；
B, finally reactant liquor is transferred in crystallization kettle starts crystallization, chilled brine is cooled to 10 DEG C of stirring 1.5h, starts
Blowing is centrifuged；
Crude product and 1500L running water obtained by C, centrifugation is added in beating kettle, and at 75-80 DEG C, stirring is protected for the control that heats up
Warm 2.5h, while hot blowing centrifugation, drying, barrelling warehouse-in；
D, filtrate are cooled to 5 DEG C of stirring 1.5h, and theophylline is reclaimed in blowing centrifugation, drying.Product yield 88.5%.
Embodiment 3：
A kind of preparation method of inexpensive 8-Chlorotheophyline, comprises the following steps：
1500L DMF and 3kg S0Cl are squeezed into A, first enamel reaction still2, under opening stirring (21.2Hz), put into 280kg tea
Alkali, begins to warm to 65 DEG C after the end that feeds intake, control temperature starts logical chlorine at 65-70 DEG C, and the logical chlorine 120kg of 7h, logical chlorine terminates
Afterwards 65-70 DEG C of temperature control is incubated 2.5h, then arranges chlorine 1.2h；
B, finally reactant liquor is transferred in crystallization kettle starts crystallization, chilled brine is cooled to 5 DEG C of stirring 2.5h, starts to put
Material centrifugation；
Crude product and 1500L running water obtained by C, centrifugation is added in beating kettle, and at 75-80 DEG C, stirring is protected for the control that heats up
Warm 1.5h, while hot blowing centrifugation, drying, barrelling warehouse-in；
D, filtrate are cooled to 10 DEG C of stirring 2.5h, and theophylline is reclaimed in blowing centrifugation, drying.Product yield 88.4%.
Comparative example 1
The chilled brine in step B in embodiment 1 is down into temperature by reactant liquor to be adjusted, it is studied to final product
The impact of yield.
| Temperature DEG C | 4 | 5 | 6 | 8 | 10 | 12 |
| Yield % | 89.3 | 89.2 | 88.8 | 88.0 | 86.4 | 83.1 |
By above detection data it is recognised that the temperature of reactant liquor affects larger to yield, but temperature is down to less than 5 DEG C
Afterwards, then reduce temperature yield is just had no significant effect, therefore consider cost, optimized temperature is 5 DEG C.
This detection data is just for above-mentioned detection sample.
The above, the only present invention preferably specific embodiment, but protection scope of the present invention is not limited thereto,
Any those familiar with the art the invention discloses technical scope in, technology according to the present invention scheme and its
Inventive concept equivalent or change in addition, all should be included within the scope of the present invention.
Claims (3)
1. a kind of preparation method of inexpensive 8-Chlorotheophyline, it is characterised in that comprise the following steps：
A, DMF and S0Cl is squeezed into a kettle.2, under opening stirring condition, theophylline is put into, begin to warm to 62-68 after the end that feeds intake
DEG C, control temperature starts logical chlorine at 65-70 DEG C, and 5-7h leads to chlorine, and logical chlorine terminates 65-70 DEG C of insulation 2.5-3.5h of rear temperature control, then
Row chlorine 0.8-1.2h；
B, finally reactant liquor is transferred in crystallization kettle starts crystallization, chilled brine is cooled to 5-10 DEG C of stirring 1.5-2.5h, opens
Beginning blowing is centrifuged；
Crude product and running water obtained by C, centrifugation is added in beating kettle, and the control that heats up stirs insulation 1.5- at 75-80 DEG C
2.5h, while hot blowing centrifugation, drying, barrelling warehouse-in；
D, filtrate are cooled to 5-10 DEG C of stirring 1.5-2.5h, and theophylline is reclaimed in blowing centrifugation, drying.
2. the preparation method of low cost 8-Chlorotheophyline as claimed in claim 1, it is characterised in that in described step A, adopt
Magnetic stirring apparatus, stirring frequency is 20-25 Hz.
3. the preparation method of low cost 8-Chlorotheophyline as claimed in claim 1, it is characterised in that in described step B, freezing
Salt solution cools the temperature to 6 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611075120.3A CN106632333A (en) | 2016-11-30 | 2016-11-30 | Preparation method of low-cost 8-chlorotheophylline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611075120.3A CN106632333A (en) | 2016-11-30 | 2016-11-30 | Preparation method of low-cost 8-chlorotheophylline |
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| Publication Number | Publication Date |
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| CN106632333A true CN106632333A (en) | 2017-05-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611075120.3A Pending CN106632333A (en) | 2016-11-30 | 2016-11-30 | Preparation method of low-cost 8-chlorotheophylline |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2614105A (en) * | 1949-05-23 | 1952-10-14 | Mallinckrodt Chemical Works | Preparation of 8-chlorotheophylline |
| DE858455C (en) * | 1950-10-10 | 1952-12-08 | Byk Gulden Lomberg Chem Fab | Process for the production of neutral or weakly acidic solutions of substituted xanthines |
| US5773423A (en) * | 1993-07-13 | 1998-06-30 | The United States Of America As Represented By The Department Of Health And Human Services | A3 adenosine receptor agonists |
| CN100467470C (en) * | 2007-02-28 | 2009-03-11 | 吉林省舒兰合成药业股份有限公司 | Improved preparation process of 8-chlorotheophylline |
| CN102875553A (en) * | 2012-10-18 | 2013-01-16 | 江西隆莱生物制药有限公司 | Preparation process for 8-chlorotheophylline and intermediate 7,8-dichlorotheophylline thereof |
| CN103360394A (en) * | 2013-07-29 | 2013-10-23 | 上海万巷制药有限公司 | 8-chlorotheophylline preparation method |
-
2016
- 2016-11-30 CN CN201611075120.3A patent/CN106632333A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2614105A (en) * | 1949-05-23 | 1952-10-14 | Mallinckrodt Chemical Works | Preparation of 8-chlorotheophylline |
| DE858455C (en) * | 1950-10-10 | 1952-12-08 | Byk Gulden Lomberg Chem Fab | Process for the production of neutral or weakly acidic solutions of substituted xanthines |
| US5773423A (en) * | 1993-07-13 | 1998-06-30 | The United States Of America As Represented By The Department Of Health And Human Services | A3 adenosine receptor agonists |
| CN100467470C (en) * | 2007-02-28 | 2009-03-11 | 吉林省舒兰合成药业股份有限公司 | Improved preparation process of 8-chlorotheophylline |
| CN102875553A (en) * | 2012-10-18 | 2013-01-16 | 江西隆莱生物制药有限公司 | Preparation process for 8-chlorotheophylline and intermediate 7,8-dichlorotheophylline thereof |
| CN103360394A (en) * | 2013-07-29 | 2013-10-23 | 上海万巷制药有限公司 | 8-chlorotheophylline preparation method |
Non-Patent Citations (1)
| Title |
|---|
| KENNETH A. JACOBSON等: "Effect of Trifluoromethyl and Other Substituents on Activity of Xanthines at Adenosine Receptors", 《J. MED. CHEM.》 * |
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Application publication date: 20170510 |