CN101456814A - Dexibuprofen guaiacol ester and preparation method thereof - Google Patents
Dexibuprofen guaiacol ester and preparation method thereof Download PDFInfo
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- CN101456814A CN101456814A CNA2007101925758A CN200710192575A CN101456814A CN 101456814 A CN101456814 A CN 101456814A CN A2007101925758 A CNA2007101925758 A CN A2007101925758A CN 200710192575 A CN200710192575 A CN 200710192575A CN 101456814 A CN101456814 A CN 101456814A
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- dexibuprofen
- methyl
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- guaiacol ester
- ibuprofen
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Abstract
The invention relates to a novel optical isomer compound of a formula (1), in particular to a dextroisomer of ibuprofen guaiacol ester. The invention also discloses a method for preparing the compound, a drug composition taking the compound as an active ingredient and application of the compound and the drug composition to the preparation of drugs of diminishing inflammation, effectively alleviating various pain or having effects of relieving fever of adults and/or children.
Description
Invention field
The invention belongs to the Western medicine invention field.The dextrorotatory isomer that relates to (1) compound that has structural formula, the preparation method of this compound, and the pharmaceutical composition that contains this compound.The compounds of this invention has anti-inflammatory, analgesic effect, can effectively alleviate various pain, the medicine that uses The compounds of this invention to make can be used for alleviating various pain, comprises arthritic acute attack stage or lasting arthralgia symptom, can also treat various soft tissue rheumatism pain.The medicine that uses compound of the present invention to make also has has refrigeration function to adult and/or children's heating.
The new compound of discussion of the present invention is the dextrorotatory isomer of compound Benflogin.
Background technology
Ibuprofen BP/EP is accepted by extensive patients as non-steroidal anti-inflammatory analgesic good medicine.But side effects such as the maldigestion that long-term prescription brings, stomach ulcer, hepatotoxicity also become the problem that vast medical worker seeks to solve.Went on the market a kind of by the research and development of Italian Angelini company in 1989 by Ibuprofen BP/EP and methyl catechol synthetic Benflogin, in the human intestines and stomach, do not degrade, but be decomposed into Ibuprofen BP/EP and methyl catechol after entering blood, still bring into play analgesic, analgesia, the antiinflammation of Ibuprofen BP/EP in vivo, reduce it simultaneously greatly to the stimulation of stomach and intestine and reduced hepatotoxicity.
Yet Benflogin is a kind of racemic mixture, promptly is that the left-handed Benflogin of non-active ingredient R (-) and the two kinds of isomer of activeconstituents S (+) Dexibuprofen guaiacol ester by equivalent mix.Benflogin can be used chemical formula (1) expression.By chemical structure as seen, Benflogin has a center that forms three-dimensional arrangement.(formula is represented with * in (1))
Formula (1)
Stereochemistry purity is very important in pharmaceutical field.Because each enantiomorph has different effects or different activity.A kind of enantiomorph of useful isomer may not have drug effect even may be harmful to.
Of the present invention to liking the dextrorotatory isomer of Benflogin, be called later on (+)-Benflogin.In order to reduce the toxic side effect of clinical medicine dose, raising drug effect, reduction raceme, the contriver is through continuous experimental study, by synthetic method, obtain the optical isomer of racemic modification Benflogin, i.e. dextrorotatory isomer (+)-Benflogin.
Summary of the invention
The invention provides a kind of new compound, be enantiomorph, be i.e. dextrorotatory isomer (+)-Benflogin with following structural formula.(center that forms three-dimensional arrangement is represented with * in following structural formula)
The compounds of this invention can prepare by following step:
(1), carry out acyl chloride reaction, obtain (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride by (S)-ibuprofen and acyl chlorinating agent.
Above-mentioned acyl chloride reaction carries out under 20～60 ℃ of temperature, and the reaction times was controlled at 2～3 hours.Employed acyl chlorinating agent can be sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or five chlorethoxyfos.
Above-mentioned acyl chloride reaction more preferably carries out under 33～45 ℃ of temperature.Temperature of reaction can be controlled by oil bath.Preferred acyl chlorinating agent is a sulfur oxychloride,
(2), in the presence of alkaline catalysts, methyl catechol and (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride carry out esterification and generate Dexibuprofen guaiacol ester.
In above-mentioned esterification, (+) Alpha-Methyl-4-of methyl catechol, step a gained (2-methyl-propyl) phenyllacetyl chloride, and suitable organic solvent carried out esterification 1～6 hour under the effect of catalyzer.Reaction system is washed with water until neutrality again, add siccative at last and carry out drying, decompression and solvent recovery, gained reaction solution carry out recrystallization or underpressure distillation promptly gets Dexibuprofen guaiacol ester.
The described organic solvent of above-mentioned esterification can be toluene, benzene, acetone, methylene dichloride, trichloromethane and normal hexane etc.Described alkaline catalysts can be mineral alkali such as oxyhydroxide or alkaline carbonate, as sodium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus etc.; Or organic bases such as pyridine, triethylamine, N, dinethylformamide or metal alkoxide are as sodium methylate or potassium tert.-butoxide etc.
Above-mentioned esterification is to cool off under the powerful mechanical stirring at ice-water bath to drip catalyzer.
The consumption of used (S)-ibuprofen and guaiacol ester is (S)-ibuprofen in molar ratio among above-mentioned steps a and the b: guaiacol ester=0.8～1.2:1.
Be the enantiomorph of Benflogin, Dexibuprofen guaiacol ester by the The compounds of this invention of above-mentioned preparation method's gained.This compound is colourless oil liquid at normal temperatures.The data of nucleus magnetic resonance are after measured:
1H-NMR (CDCl
3): δ 0.91 (d, 6H ,-CH
3, J=8.8Hz); 1.61 (d, 3H ,-CH
3, J=9.6Hz); 1.80-1.91 (m, 1H ,-CH-); 2.47 (d, 2H ,-CH
2-, J=9.6Hz); 3.70 (s, 2H ,-OCH
3-); 3.98 (q, 1H ,-CH-, J=9.6Hz); 6.86-6.95 (m, 3H, Ar-H); 7.12-7.18 (m, 3H, Ar-H); 7.33 (d, 2H, Ar-H, J=10.8Hz).
13C-NMR(CDCl
3)：18.67(-CH
3)；22.33(-CH
3)；30.15(-CH-)；44.93(-CH-)；45.00(-CH
2-)；5.63(-OCH
3)；112.42(Ar)；120.60(Ar)；122.57(Ar)；126.65(Ar)；127.35(Ar)；129.20(Ar)；137.40(Ar)；139.96(Ar)；140.49(Ar)；151.15(Ar)；172.72(-C＝O)。Measure its specific optical rotation and be [α]
D 20=+73 ° to+90 ° (c=30mg/ml, dehydrated alcohol).Detect through high performance liquid chromatography, the optical purity of products therefrom can reach 95% or more than.
The compounds of this invention can be used as medicine, but and per os or without oral administration, dosage is had nothing in common with each other because of pharmaceutical dosage form is different, concerning the adult, every day, 10～800mg was proper.
The formula of using in the inventive method (1) compound preferably uses with the form of suitable composition.As suitable composition, can enumerate all various compositions that are generally used for whole body or local application.In order to prepare the present composition, as activeconstituents and one or more pharmaceutically acceptable carrier thorough mixing, this carrier can be taked form miscellaneous with the The compounds of this invention of effective quantity, and this depends on the form of the desired preparation of medication.These compositions are preferably made the single dose form of suitable oral, rectal administration, percutaneous dosing or the injection of non-enteron aisle.As oral preparations etc.
During the oral administration administration, The compounds of this invention and conventional pharmaceutical excipient such as vehicle, disintegrating agent, tamanori, lubricant, antioxidant, Drug coating, tinting material, perfume compound, tensio-active agent etc. are mixed, be made into form administrations such as granule, capsule, tablet; Can injection liquid during non-oral administration, form administration such as infusion solution or suppository.When preparing above-mentioned preparation, can use conventional preparation technique.
The medicine that uses The compounds of this invention to make has anti-inflammatory, analgesic effect, can alleviate various pain, comprises arthritic acute attack stage or lasting arthralgia symptom, can also treat various soft tissue rheumatism pain.
The medicine that uses compound of the present invention to make also has has refrigeration function to adult and/or children's heating.
The Benflogin pharmacological action mainly is not degrade in the human intestines and stomach, but is decomposed into Ibuprofen BP/EP and methyl catechol after entering blood, still brings into play analgesic, analgesia, the antiinflammation of Ibuprofen BP/EP in vivo.During oral racemize Benflogin, although exist (-)-Ibuprofen BP/EP changes into the possibility of (+)-Ibuprofen BP/EP, but this transforms and is incomplete, be about (-)-Ibuprofen BP/EP of 60% and change into (+)-Ibuprofen BP/EP, and need single-minded enzyme be a kind of coenzyme A (COA), and need spended time.
As known from the above, The compounds of this invention (+)-Benflogin is for the racemize Benflogin, it is single enantiomer with pharmacologically active, thereby side effects such as the damage that Ibuprofen BP/EP causes, gastrointestinal reaction had both been overcome to liver, help the optimization of dosage again, can also reduce the possibility of bringing out genotoxic potential simultaneously.So The compounds of this invention has considerable market outlook and good social effect.
Embodiment
The following examples and example of formulations can illustrate in greater detail the present invention, but do not limit the present invention in any form.
Embodiment 1
The sulfur oxychloride that in 100ml exsiccant single port bottle, adds 20.5g (0.1mol) (S)-ibuprofen and 20ml, heating (controlled temperature is at 60 ℃) is stirred, and be back to no hydrogen chloride gas and produce, normal pressure boils off excessive sulfur oxychloride then, obtains faint yellow liquid 20.2g (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride with intense stimulus smell.In 100ml exsiccant single port bottle, add above-mentioned gained liquid 18g (0.08mol) (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride and 9ml (0.08mol) methyl catechol again, add the 60ml methylene dichloride, ice-water bath cools off and drips the 10ml triethylamine under the powerful mechanical stirring, and it is complete that TLC detects raw material methyl catechol primitive reaction.About 5 hours of reaction times.Reaction system washes with water earlier until neutrality, adds anhydrous sodium sulfate drying then, and decompression and solvent recovery gets oily liquids, and underpressure distillation obtains white needle-like crystals 13.4g The compounds of this invention again.[α]
D 20=+75.8 ° (c=30mg/ml, dehydrated alcohol).
Embodiment 2
In 50ml exsiccant single port bottle, add 10g (0.049mol) (S)-ibuprofen and 10ml phosphorus trichloride, heating (controlled temperature is at 30 ℃) stirring and refluxing does not produce to there being hydrogen chloride gas, normal pressure boils off excessive phosphorus trichloride then, obtains faint yellow liquid 8g (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride with intense stimulus smell.In 100ml exsiccant single port bottle, add above-mentioned gained liquid 6g (0.027mol) (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride and 3ml (0.027mol) methyl catechol again, add 30ml acetone, ice-water bath cools off Dropwise 5 % sodium hydroxide solution 40ml under the powerful mechanical stirring, and it is complete that TLC detects raw material methyl catechol primitive reaction.About 4 hours of reaction times.Reaction system washes with water earlier until neutrality, adds anhydrous sodium sulfate drying at last, and decompression and solvent recovery gets oily liquids, obtains white needle-like crystals 4.8g The compounds of this invention with the dehydrated alcohol recrystallization again.[α]
D 20=+76.5 ° (c=30mg/ml is in dehydrated alcohol).
Embodiment 3
In 50ml exsiccant single port bottle, add 10g (0.049mol) (S)-ibuprofen and 10ml sulfur oxychloride, 40 ℃ of oil bath temperature controls, stirring and refluxing does not also produce (about 2.5 hours) to there being hydrogen chloride gas, the excessive sulfur oxychloride of pressure reducing and steaming obtains faint yellow liquid 10.5g (96%) (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride with intense stimulus smell then.In 100ml exsiccant single port bottle, add 10g (0.045mol) above-mentioned gained liquid (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride and 5ml (0.045mol) methyl catechol again, add 40ml toluene, ice-water bath cools off Dropwise 5 ml pyridine (1.2equ) under the powerful mechanical stirring, and it is complete that TLC detects raw material methyl catechol primitive reaction.About 6 hours of reaction times.Reaction system washes with water earlier until neutrality, adds anhydrous sodium sulfate drying at last, and decompression and solvent recovery gets oily liquids, obtains white needle-like crystals 7.5g The compounds of this invention with the dehydrated alcohol recrystallization again.[α]
D 20=+81.2 ° (c=30mg/ml is in dehydrated alcohol).
The following examples explanation comprises the medicinal preparations by compound provided by the invention.
Example of formulations 1, soft capsule
Prepare soft capsule according to methods known in the art, every capsules contains following composition:
The compounds of this invention 50mg
Glycerine 0.2ml
Sorbyl alcohol 0.2ml
Vegetables oil 0.1ml
10%～30% oily wax mixture 0.2ml
Tween-80 100mg
Example of formulations 2, suppository
Prepare suppository according to methods known in the art, every piece contains following composition:
The compounds of this invention 200mg
Cocounut oil fat 1600mg
Example of formulations 3, syrup
Prepare syrup according to methods known in the art, every 10ml contains following composition:
The compounds of this invention 200mg
Sucrose 1500mg
Glycerine 1ml
Example of formulations 4, emulsifiable paste
Prepare emulsifiable paste according to methods known in the art, the per unit ointment contains following composition:
The compounds of this invention 100mg
White vaseline 280mg
Ethyl p-hydroxybenzoate 20mg
Stearic acid 150mg
Single stearic acid glycerine lipoprotein 100mg
Example of formulations 5, oral liquid
Prepare oral liquid according to methods known in the art, every 10ml oral liquid contains following composition:
The compounds of this invention 50mg
Sucrose 100mg
Sorbic Acid 15mg
1,2-propylene glycol 5ml
Polyoxyethylene glycol 3ml
Ethyl p-hydroxybenzoate 2mg
Example of formulations 6, oral drip-pill agent
Prepare pill according to methods known in the art, every oral drip-pill agent contains following composition:
The compounds of this invention 50mg
2 hydroxy propanoic acid 0.3ml
Polyoxyethylene glycol 1.5ml
Soluble saccharin 5mg
Cacao flavor 10mg
Claims (11)
1, Dexibuprofen guaiacol ester, it is the dextrorotatory isomer with compound Benflogin of following structural formula.
2, the preparation method of the described Dexibuprofen guaiacol ester of a kind of claim 1 is characterized in that this compound is by the following steps gained:
A, obtain (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride by the reaction of (S)-ibuprofen and acyl chlorinating agent;
B, in the presence of alkaline catalysts, methyl catechol and (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride carry out esterification and generate The compounds of this invention.
3, the preparation method of Dexibuprofen guaiacol ester according to claim 2, it is characterized in that (S)-ibuprofen and acyl chlorinating agent carry out acyl chloride reaction among the described step a under 20～60 ℃ of temperature, acyl chlorinating agent can be sulfur oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or five chlorethoxyfos.
4, the preparation method of Dexibuprofen guaiacol ester according to claim 2 is characterized in that (S)-ibuprofen and sulfur oxychloride carry out acyl chloride reaction among the described step a under 33～45 ℃ of temperature, and acyl chlorinating agent can be a sulfur oxychloride.
5, the preparation method of Dexibuprofen guaiacol ester according to claim 2, it is characterized in that (+) Alpha-Methyl-4-(2-methyl-propyl) phenyllacetyl chloride and the suitable organic solvent of methyl catechol among the described step b, step a gained, under the effect of catalyzer, carried out esterification 1～6 hour.Reaction system is washed with water until neutrality again, add siccative at last and carry out drying, decompression and solvent recovery, gained reaction solution carry out recrystallization or underpressure distillation promptly gets Dexibuprofen guaiacol ester.Wherein, described suitable organic solvent comprises toluene, benzene, acetone, methylene dichloride, trichloromethane or normal hexane etc.; Described alkaline catalysts comprises mineral alkali such as oxyhydroxide or alkaline carbonate, as sodium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate or saleratus etc.; Or organic bases such as pyridine, triethylamine, N, dinethylformamide or metal alkoxide are as sodium methylate or potassium tert.-butoxide etc.
6, the preparation method of Dexibuprofen guaiacol ester according to claim 2 is characterized in that the esterification among the described step b is to cool off under the powerful mechanical stirring at ice-water bath to drip catalyzer.
7, the preparation method of Dexibuprofen guaiacol ester according to claim 2 is characterized in that the consumption of used (S)-ibuprofen and guaiacol ester among described step a and the b is (S)-ibuprofen in molar ratio: guaiacol ester=0.8～1.2:1.
8, pharmaceutical composition wherein contains the described Dexibuprofen guaiacol ester of claim 1 as effective constituent, and contains conventional pharmaceutical carrier.
9, use the described compound of claim 1 as medicine.
10, the application of the described compound of claim 1 in preparation anti-inflammatory, analgesic medicine.
11, the described compound of claim 1 has application in the medicine of refrigeration function in preparation to adult and/or children heating.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101925758A CN101456814A (en) | 2007-12-11 | 2007-12-11 | Dexibuprofen guaiacol ester and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101925758A CN101456814A (en) | 2007-12-11 | 2007-12-11 | Dexibuprofen guaiacol ester and preparation method thereof |
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| CN101456814A true CN101456814A (en) | 2009-06-17 |
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| CNA2007101925758A Pending CN101456814A (en) | 2007-12-11 | 2007-12-11 | Dexibuprofen guaiacol ester and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013010400A1 (en) * | 2011-07-21 | 2013-01-24 | Hou Wenge | Compounds based on ibuprofen, preparation methods, uses and pharmaceutical preparation thereof |
| CN111138928A (en) * | 2020-01-10 | 2020-05-12 | 沈阳顺风新材料有限公司 | Efficient antibacterial environment-friendly coating and preparation method thereof |
| CN114380785A (en) * | 2021-07-19 | 2022-04-22 | 南京海融医药科技股份有限公司 | Ibuprofen derivative, preparation method and application |
-
2007
- 2007-12-11 CN CNA2007101925758A patent/CN101456814A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013010400A1 (en) * | 2011-07-21 | 2013-01-24 | Hou Wenge | Compounds based on ibuprofen, preparation methods, uses and pharmaceutical preparation thereof |
| CN111138928A (en) * | 2020-01-10 | 2020-05-12 | 沈阳顺风新材料有限公司 | Efficient antibacterial environment-friendly coating and preparation method thereof |
| CN114380785A (en) * | 2021-07-19 | 2022-04-22 | 南京海融医药科技股份有限公司 | Ibuprofen derivative, preparation method and application |
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Owner name: HUNAN JIUDIAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: ZHU ZHIHONG Effective date: 20121226 |
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Effective date of registration: 20121226 Address after: 410005, Hunan, Changsha province Furong Road, No. 368 BOBO world city CTA wealth center, 24 floor Applicant after: Hunan Jiudian Pharmaceutical Co., Ltd. Address before: 410004, Hunan, Changsha province Furong Road, No. 368 BOBO world city CTA wealth center, 24 floor Applicant before: Zhu Zhihong |
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Application publication date: 20090617 |