CN101463033B - Method for synthesizing diprophylline - Google Patents
Method for synthesizing diprophylline Download PDFInfo
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- CN101463033B CN101463033B CN2009100736457A CN200910073645A CN101463033B CN 101463033 B CN101463033 B CN 101463033B CN 2009100736457 A CN2009100736457 A CN 2009100736457A CN 200910073645 A CN200910073645 A CN 200910073645A CN 101463033 B CN101463033 B CN 101463033B
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- synthetic method
- diprophylline
- propylene glycol
- theophylline
- reaction
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- KSCFJBIXMNOVSH-UHFFFAOYSA-N dyphylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)CO)C=N2 KSCFJBIXMNOVSH-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960002819 diprophylline Drugs 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims description 10
- 230000002194 synthesizing effect Effects 0.000 title 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000010189 synthetic method Methods 0.000 claims abstract description 14
- 229960000278 theophylline Drugs 0.000 claims abstract description 12
- 238000006482 condensation reaction Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- SSZWWUDQMAHNAQ-UHFFFAOYSA-N 3-chloropropane-1,2-diol Chemical compound OCC(O)CCl SSZWWUDQMAHNAQ-UHFFFAOYSA-N 0.000 claims 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- 239000003513 alkali Substances 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract 3
- JCERKCRUSDOWLT-UHFFFAOYSA-N 1-bromopropan-1-ol Chemical compound CCC(O)Br JCERKCRUSDOWLT-UHFFFAOYSA-N 0.000 abstract 1
- RZWHKKIXMPLQEM-UHFFFAOYSA-N 1-chloropropan-1-ol Chemical compound CCC(O)Cl RZWHKKIXMPLQEM-UHFFFAOYSA-N 0.000 abstract 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 12
- VZIQXGLTRZLBEX-UHFFFAOYSA-N 2-chloro-1-propanol Chemical compound CC(Cl)CO VZIQXGLTRZLBEX-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 3
- -1 bromopropyl alcohol Chemical compound 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 3
- 239000003610 charcoal Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229960003556 aminophylline Drugs 0.000 description 2
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001088 anti-asthma Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- KYHQZNGJUGFTGR-LURJTMIESA-N 7-[(2s)-2-hydroxypropyl]-1,3-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C[C@@H](O)C KYHQZNGJUGFTGR-LURJTMIESA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000009447 Cardiac Edema Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000010815 organic waste Substances 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 229960004767 proxyphylline Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new synthetic method of diprophylline. The new synthetic method is as follows: performing a condensation reaction on theophylline and chloropropanol or bromopropanol with the mol ratio of 1:0.6-3 by taking alkali carbonate as a condensing agent in an N,N-dimethylformamide solvent at the temperature of 80-130 DEG C for 0.5-3h. The new synthetic method can effectively improve the purity and the yield of a product and is favorable for environmental protection.
Description
Technical field
The present invention relates to the synthetic method of compound, specifically the synthetic method of diprophylline.
Background technology
Diprophylline (DiproPhyllinum) is the xanthine anti-asthmatic, has another name called dihydroxypropyltheophylline, proxyphylline, dihydroxypropyltheo-pylline, and its formal name used at school is 1,3-dimethyl-7-(2,3 dihydroxypropyl)-3,7-dihydro-1H-purine-2,6-diketone.Diprophylline is the derivative of theophylline, acts on similar to aminophylline.Its anti-asthmatic action with the dosage aminophylline slightly a little less than, but its few side effects, the intramuscular injection pain reaction is little, and is oral several non-stimulated to gi tract.Be usually used in bronchial asthma, asthmatic bronchitis and chronic emphysema etc., also can be used for stenocardia and cardiac edema etc.
At present, the synthetic method of diprophylline is generally carries out condensation reaction with theophylline and propylene chlorohydrin under strong alkaline condition, is that solvent generates crude product with the monohydroxy-alcohol, gets the finished product diprophylline through twice decolorizing with activated carbon recrystallization again.Normally in reactor, add earlier basicity during reaction and be about 20% ionic membrane caustic soda (granular sodium hydroxide), then theophylline and propylene chlorohydrin are stirred intensification with 1: 1.5 reaction than dropping in the reactor, after the back flow reaction one hour, boil off the moisture of generation, add an amount of ethanol again and the gac reflux decolour gets final product.The weak point that this method exists is: reaction system is the strong basicity environment, product purity and yield low (yield only is 65-70%), and can produce a large amount of waste water in the production process, the feature of environmental protection is poor.
Summary of the invention
Purpose of the present invention is exactly the synthetic method that a kind of new diprophylline will be provided, and it not only can effectively improve the purity and the yield of product, and helps environment protection.
The object of the present invention is achieved like this:
The synthetic method of diprophylline provided by the present invention is according to 1: 0.6～3 mol ratio with theophylline and propylene chlorohydrin or bromopropyl alcohol, at N, in the dinethylformamide solvent, be condensing agent with carbonic acid alkali, under 80～130 ℃ of conditions, carry out condensation reaction, 0.5～3 hour reaction times.
Carbonic acid alkali of the present invention can be selected yellow soda ash, sodium bicarbonate or salt of wormwood, saleratus.
For the further beneficial effect that improves the inventive method,
The present invention's preferred Anhydrous potassium carbonate of said carbonic acid alkali or anhydrous sodium carbonate;
Reactant theophylline and N, the weight ratio of dinethylformamide solvent preferred 1: 4～8;
Theophylline and propylene chlorohydrin or bromopropyl alcohol are when carrying out condensation reaction, and propylene chlorohydrin or bromopropyl alcohol join in the reaction solution in the dropping mode; The time of its dropping preferably was controlled at 20～60 minutes.
The inventive method is compared with former technology has following beneficial effect.
(1) former technological reaction system is a water, produces a large amount of organic waste waters, has brought immense pressure to environmental protection.The inventive method adopts the organic phase reaction, and reaction solvent can recycling, thereby has effectively reduced discharge of wastewater, meets the environmental protection theory.
(2) show after testing, adopt the residual 100～200ppm of being of propylene chlorohydrin in the former processing method products obtained therefrom; The propylene chlorohydrin residual quantity that adopts the inventive method products obtained therefrom is below 1.25ppm.
(3) its impurity of the diprophylline of former explained hereafter has 5 kinds, and the main peak area is about 80%; Its impurity of diprophylline that the inventive method is produced is kept to 4 kinds, and content diminishes, and the main peak area increases to 88～90%.
(4) the inventive method is brought up to product yield more than 85%, thereby has improved utilization ratio of raw materials.
In sum, the inventive method reaction conditions gentleness, easy and simple to handle, the yield height, prepared quality product height, and be easy to realize suitability for industrialized production.It provides a new diprophylline route of synthesis.
Embodiment:
Embodiment 1:
With theophylline 18 grams (100mmol), Anhydrous potassium carbonate 14.6 gram (101mmol) and N, dinethylformamide 85 grams add in the 250ml four-hole boiling flask successively, stirring is warming up to 90 ℃, and the slow propylene chlorohydrin 12.16 that drips restrains (110mmol) under this temperature, 20 minutes dropping time, insulation reaction is 30 minutes then.Heat leaches solid insoluble, and filtrate is carried out underpressure distillation.Add ethanol 100ml (95%) and 4 gram gacs this moment, the insulation 1 hour that refluxes, hot filtering charcoal, crystallisation by cooling diprophylline 21.5 grams that get product, yield 85%.
Embodiment 2:
With theophylline 27 grams (150mmol), Anhydrous potassium carbonate 21.9 gram (152mmol) and N, dinethylformamide 135 grams add in the 500ml four-hole boiling flask successively, stirring is warming up to 105 ℃, and the slow propylene chlorohydrin 30 that drips restrains (271.5mmol) under this temperature, 30 minutes dropping time, insulation reaction is 50 hours then.Heat leaches solid insoluble, and filtrate is carried out underpressure distillation.Add ethanol 150ml (95%) and 6 gram gacs this moment, the insulation 1 hour that refluxes, hot filtering charcoal, crystallisation by cooling diprophylline 34.29 grams that get product, yield 90%.
Embodiment 3:
Theophylline 30.6 grams, anhydrous sodium carbonate 24.8 are restrained, and N, dinethylformamide 153 grams add in the 500ml four-hole boiling flask successively, stir and be warming up to 120 ℃, and slow dripping bromine propyl alcohol 35 restrains under this temperature, and 25 minutes dropping time, insulation reaction is 30 minutes then.Heat leaches solid insoluble, and filtrate is carried out underpressure distillation.Add ethanol 200ml (95%) and 6.8 gram gacs this moment, the insulation 1 hour that refluxes, hot filtering charcoal, crystallisation by cooling diprophylline 38.0 grams that get product, yield 88%.
162～163 ℃ of the product fusing points that the foregoing description obtained, product structure turns out to be diprophylline with analyses such as ultimate analysis and UV, IR.
Claims (5)
1. the synthetic method of a diprophylline, it is characterized in that this method is with theophylline and 3-chloro-1,2-propylene glycol or 3-bromo-1, the 2-propylene glycol is according to 1: 0.6～3 mol ratio, at N, in the dinethylformamide solvent, be condensing agent with salt of wormwood, saleratus, yellow soda ash or sodium bicarbonate, under 80～130 ℃ of conditions, carry out condensation reaction, 0.5～3 hour reaction times.
2. synthetic method according to claim 1 is characterized in that described condensing agent is Anhydrous potassium carbonate or anhydrous sodium carbonate.
3. synthetic method according to claim 1 and 2 is characterized in that said theophylline and N, and the weight ratio of dinethylformamide solvent is 1: 4～8.
4. synthetic method according to claim 1 and 2 is characterized in that said theophylline and 3-chloro-1,2-propylene glycol or 3-bromo-1, the 2-propylene glycol is when carrying out condensation reaction, 3-chloro-1,2-propylene glycol or 3-bromo-1, the 2-propylene glycol joins in the reaction solution in the dropping mode.
5. synthetic method according to claim 4 is characterized in that its dropping time of said dropping was controlled at 20～60 minutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100736457A CN101463033B (en) | 2009-01-13 | 2009-01-13 | Method for synthesizing diprophylline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100736457A CN101463033B (en) | 2009-01-13 | 2009-01-13 | Method for synthesizing diprophylline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101463033A CN101463033A (en) | 2009-06-24 |
| CN101463033B true CN101463033B (en) | 2011-05-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100736457A Active CN101463033B (en) | 2009-01-13 | 2009-01-13 | Method for synthesizing diprophylline |
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| CN (1) | CN101463033B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104098567B (en) * | 2013-04-09 | 2017-07-28 | 中国医学科学院药物研究所 | Diprophylline crystalline substance II types material and preparation method and its pharmaceutical composition and purposes |
| CN110256434B (en) * | 2019-06-03 | 2020-11-10 | 上海万巷制药有限公司 | Method for preparing high-purity diprophylline |
| CN112110921A (en) * | 2020-07-02 | 2020-12-22 | 江苏顺丰化工有限公司 | Synthesis method of diprophylline |
-
2009
- 2009-01-13 CN CN2009100736457A patent/CN101463033B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| 李长华等.平喘镇咳药多索茶碱的合成.中国医药工业杂志.1995,26(9), * |
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| Publication number | Publication date |
|---|---|
| CN101463033A (en) | 2009-06-24 |
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Address after: 051430 No.62 Zhangju Road, Luancheng District, Shijiazhuang City, Hebei Province Patentee after: Shiyao Innovation Pharmaceutical Co.,Ltd. Country or region after: China Address before: 051430 No. 36 prosperous West Road, Luancheng County, Hebei, Shijiazhuang Patentee before: SHIJIAZHUANG PHARMACEUTICAL GROUP NEW NORWICH PHARMACEUTICAL CO.,LTD. Country or region before: China |
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