CN106748824A - A kind of new salbutamol drug salts salbutamol fumarate and preparation method thereof - Google Patents
A kind of new salbutamol drug salts salbutamol fumarate and preparation method thereof Download PDFInfo
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- CN106748824A CN106748824A CN201611046978.7A CN201611046978A CN106748824A CN 106748824 A CN106748824 A CN 106748824A CN 201611046978 A CN201611046978 A CN 201611046978A CN 106748824 A CN106748824 A CN 106748824A
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- Prior art keywords
- salbutamol
- fumarate
- preparation
- fumaric acid
- alcohol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
- C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/15—Fumaric acid
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of new salbutamol drug salts salbutamol fumarate and preparation method thereof.The novel substance exists in the form of salts, there is preferable stability, and solubility in aqueous improves a lot than former drugs salbutamol, with larger range of application.It, with salbutamol and fumaric acid as raw material, is 3 in ratio that the preparation method of this salt is:1~1：Under conditions of 2, the alcoholic solution of fumaric acid will be dissolved with and be slowly dropped in the alcoholic solution containing a certain amount of salbutamol, 3 ~ 4 h are heated to reflux afterwards, directly filtered, that is, obtain salbutamol fumarate, yield is more than 85%.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to salbutamol fumarate and preparation method thereof.
Technical background
Bronchial astehma is a kind of non-specific disease of air flue, is also a kind of most common chronic to human health threat
Disease.The current whole world at least 300,000,000 people above asthmatics, and just have 30,000,000 asthmatic patients in China, the incidence of disease is about
It is 1.3%.Though control of the salbutamol as a kind of air flue diastole agent for the treatment of bronchial disease to disease has certain treatment
Effect, but single salbutamol medicine can have some side effects to health, therefore salbutamol is done further
It is necessary to explore with research.
Salbutamol fumarate is such as shown in (I).
Entitled 1- (hydroxymethyl phenyl of 4 hydroxyl -3) -2- (the tertiary fourth amino) ethanol of salbutamol chemistry, also known as methoxyphenamini hydrochloridum, be
A kind of selective β 2 receptor agonist, at present, in the market is more to be existed in the form of its sulfate, next to that the shape of hydrochloride
Formula.
Fumaric acid has been related to the form appearance of medicine fumarate, such as fumaric acid at present as the acceptable acid of medicine
Ketotifen piece.
Any report about salbutamol fumarate is not seen also at present.
The content of the invention
Object of the present invention is to provide a kind of new salbutamol drug salts-salbutamol fumarate and its preparation
Method.
The preparation method of salbutamol fumarate is mainly realized by the following aspects in the present invention：
(1) it, with salbutamol and fumaric acid as raw material, is 3 in ratio that its preparation method is:1~1：Under conditions of 2, by rich horse
The alcoholic solution of acid is slowly dropped in the alcohol solution containing a certain amount of salbutamol, and 3~4h, direct mistake are heated to reflux afterwards
Filter, that is, obtain salbutamol fumarate.
In above-mentioned (1), alcohol used is methyl alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, ethylene glycol, glycerine.
In above-mentioned (1), the consumption of alcohols solvent used is 50~150mg solutes/g solvents.
The invention provides a kind of new salbutamol drug salts-salbutamol fumarate and preparation method thereof.And profit
With infrared spectrum (IR), proton nmr spectra (H1NMR), X-ray powder diffraction (XRD) experiment is entered to salbutamol fumarate
Row is characterized.
FTIR spectrum (FT-IR).
The FT-IR of salbutamol fumarate is obtained by Prestige-21 infrared spectrophotometers, and sample does background with KBr, red
External curve is shown in accompanying drawing 1.
Proton nmr spectra (H1-NMR)。
The hydrogen nuclear magnetic resonance spectrogram of salbutamol fumarate comes from the NMRs of Bruker AVANCE 500,000,000, and its figure is shown in
Accompanying drawing 2.
X-ray powder diffraction (XRD) method
The X-ray powder diffraction figure of salbutamol fumarate uses the X-ray powder of Philips X ' the Pert types equipped with Cu-Ka
Last diffractometer, powder diagram is shown in accompanying drawing 3.
The H of salbutamol fumarate1- NMR data is as follows：H1-NMR(D2O,500MHz):1.27 (s, 9H), 3.20-3.00
(m, 2H), 4.54 (s, 2H), 4.80 (dd, J=9.4,3.7Hz, 1H), 6.38 (s, 1H), 6.83 (d, J=8.3Hz, 1H),
7.15 (dd, J=8.4,2.4Hz, 1H), 7.23 (d, J=2.3Hz, 1H).
The X-ray powder diffraction instrument data of salbutamol fumarate are as follows：
Testing result
Peak list
Brief description of the drawings：
Fig. 1 is the molecular structure of salbutamol fumarate
Fig. 2 is the FT-IR curves of salbutamol fumarate
Fig. 3 is the H of salbutamol fumarate1- NMR curves
Fig. 4 is the XRD curves of salbutamol fumarate
Specific embodiment
By calculating yield of directly weighing, yield=actual product quality/theory product quality
Embodiment 1：
By the fumaric acid methanol solution containing 0.58g, the methyl alcohol containing salbutamol raw material 2.40g is added drop-wise under magnetic stirring
In solution, after being added dropwise completely, at 30 DEG C of bath temperature, continue magnetic agitation reaction 4h, sand is directly filtered and obtained after cooling
Butylamine alcohol fumarate white solid, yield is calculated after vacuum drying 24h, and yield is 87%.
Embodiment 2：
By the fumaric acid methanol solution containing 0.29g, the methyl alcohol containing salbutamol raw material 1.20g is added drop-wise under magnetic stirring
In solution, after being added dropwise completely, at 30 DEG C of bath temperature, continue magnetic agitation reaction 3h, sand is directly filtered and obtained after cooling
Butylamine alcohol fumarate white solid, yield is calculated after vacuum drying 24h, and yield is 85%.
Embodiment 3：
By the fumaric acid ethanol solution containing 1.16g, the ethanol containing salbutamol raw material 4.80g is added drop-wise under magnetic stirring
In solution, after being added dropwise completely, at 30 DEG C of bath temperature, continue magnetic agitation reaction 4h, sand is directly filtered and obtained after cooling
Butylamine alcohol fumarate white solid, yield is calculated after vacuum drying 24h, and yield is 88%.
Embodiment 4：
By the fumaric acid methanol solution containing 1.16g, the ethanol containing salbutamol raw material 5.80g is added drop-wise under magnetic stirring
In solution, after being added dropwise completely, at 30 DEG C of bath temperature, continue magnetic agitation reaction 3h, sand is directly filtered and obtained after cooling
Butylamine alcohol fumarate white solid, yield is calculated after vacuum drying 24h, and yield is 89%.
Claims (4)
1. salbutamol fumarate and preparation method thereof：
It is characterized in that being 3 in salbutamol and fumaric acid molar ratio:1~1：Under conditions of 2, the alcoholic solution of fumaric acid is delayed
Slowly it is added drop-wise in the alcoholic solution containing a certain amount of salbutamol, 3 ~ 4 h is heated to reflux afterwards, directly filter, that is, obtains Sha Ding
Amine alcohol fumarate.
2. the preparation method of the salbutamol fumarate is required according to claim 1, it is characterised in that by the alcohol of fumaric acid
Solution is slowly dropped in the alcoholic solution containing a certain amount of salbutamol, and directly filtering obtains target product.
3. the preparation method of the salbutamol fumarate is required according to claim 1, it is characterised in that alcohol used is first
Alcohol, ethanol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, ethylene glycol, glycerine.
4. the preparation method of the salbutamol fumarate is required according to claim 1 or 3, it is characterised in that alcohols used
Consumption is 50 ~ 150 mg solutes/g solvents.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611046978.7A CN106748824A (en) | 2016-11-21 | 2016-11-21 | A kind of new salbutamol drug salts salbutamol fumarate and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201611046978.7A CN106748824A (en) | 2016-11-21 | 2016-11-21 | A kind of new salbutamol drug salts salbutamol fumarate and preparation method thereof |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS176846B1 (en) * | 1975-08-05 | 1977-06-30 | ||
| WO1992011845A1 (en) * | 1991-01-03 | 1992-07-23 | Glaxo Canada Inc. | Method for production of solid pharmaceutical preparation |
| CN1051759C (en) * | 1990-09-11 | 2000-04-26 | 先灵公司 | Process for preparing albuterol, hemi-acetal, and hydrates of arylgyoxal intermediates thereof |
| CN1566076A (en) * | 2003-06-11 | 2005-01-19 | 新加坡纳米材料科技有限公司 | Synthetic method for superfine sulfuric acid and salbutamol |
| CN104356009A (en) * | 2014-10-22 | 2015-02-18 | 扬州市三药制药有限公司 | Production technology for synthetizing salbutamol sulphate |
| CN103951568B (en) * | 2014-05-19 | 2015-10-28 | 苏州弘森药业有限公司 | A kind of novel process of synthesizing salbutamol and vitriol thereof |
-
2016
- 2016-11-21 CN CN201611046978.7A patent/CN106748824A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS176846B1 (en) * | 1975-08-05 | 1977-06-30 | ||
| CN1051759C (en) * | 1990-09-11 | 2000-04-26 | 先灵公司 | Process for preparing albuterol, hemi-acetal, and hydrates of arylgyoxal intermediates thereof |
| WO1992011845A1 (en) * | 1991-01-03 | 1992-07-23 | Glaxo Canada Inc. | Method for production of solid pharmaceutical preparation |
| CN1566076A (en) * | 2003-06-11 | 2005-01-19 | 新加坡纳米材料科技有限公司 | Synthetic method for superfine sulfuric acid and salbutamol |
| CN103951568B (en) * | 2014-05-19 | 2015-10-28 | 苏州弘森药业有限公司 | A kind of novel process of synthesizing salbutamol and vitriol thereof |
| CN104356009A (en) * | 2014-10-22 | 2015-02-18 | 扬州市三药制药有限公司 | Production technology for synthetizing salbutamol sulphate |
Non-Patent Citations (1)
| Title |
|---|
| 陈芬儿，余红霞，万江陵，张珩，杨建设: "硫酸沙丁胺醇的合成研究Ⅰ", 《中国药物化学杂志》 * |
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Application publication date: 20170531 |