CN1824645A - Preparation method of demebeverine hydrochloride - Google Patents
Preparation method of demebeverine hydrochloride Download PDFInfo
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- CN1824645A CN1824645A CN 200610070907 CN200610070907A CN1824645A CN 1824645 A CN1824645 A CN 1824645A CN 200610070907 CN200610070907 CN 200610070907 CN 200610070907 A CN200610070907 A CN 200610070907A CN 1824645 A CN1824645 A CN 1824645A
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Abstract
The present invention relates to a preparation method of norfenefrine hydrochloride. Said preparation method includes the following steps: using m-hydroxybenzaldehyde as raw material, using sodium methylate or potassium hydroxide as alkali, making them and nitromethane implement addition reaction, then making catalytic hydrogenation reaction to reduce nitro-group, finally making hydrochlorination so as to obtain the target compound.
Description
Technical field
The present invention relates to a kind of preparation method of medicine Norfenefrine Hydrochloride.
Background technology
Norfenefrine Hydrochloride, or name Norfenefrine Hydrochloride, hydroxylphenylethyl alcohol amine hydrochlorate between formal name used at school, English name Norfenefrine Hydrochloride is adrenomimetic drug, is the medicine that a class and suprarenin similarly can make nervous excitation.Adrenoceptor divides two types of alpha-receptor and beta-receptors.Alpha-receptor mainly is present on the effector cell of blood vessels such as body of gland, skin, mucous membrane and internal organ.When the alpha-receptor excitation time, mainly show as mucocutaneous blood vessel and visceral vessel and shrink, make Peripheral resistance increase elevation of blood pressure.Medicine with excited alpha-receptor is used to raise blood pressure and antishock clinically.Clinical excited alpha-receptor, vasoconstriction, increase Peripheral resistance, the rising blood pressure of being used for of Norfenefrine Hydrochloride.
At present to the synthetic existing many reports of this compound.The earliest synthetic of Norfenefrine Hydrochloride sees nineteen forty-three U.S. Pat 2312916, it is raw material that patent adopts m-hydroxy acetophenone, obtain through bromination, vulkacit H amination, the reduction of palladium hydrocarbonize, this synthetic method yield is low, and the product that obtains is not easy purifying.
The patent that early stage also useful m-hydroxy acetophenone is a raw material through five, six-step process obtains Norfenefrine Hydrochloride, such as French Patent FR856296, German patent DE 913779, these routes are all oversize, thus total yield is very low, is about 20-30%.
It is that raw material obtains Norfenefrine Hydrochloride through the reaction of five steps that German patent DE 50627 adopts a m-Salicylic acid and a hydroxybenzoyl chloride, and total recovery is about 20-30%.
U.S. Pat 3966813 has been reported a kind of new synthetic method: the employing m-hydroxy acetophenone is a raw material, by obtaining oxime with the nitrite tert-butyl reaction, and then obtain Norfenefrine Hydrochloride by hydro-reduction, the total recovery of two-step reaction is at 70-80%, but thereby nitrite tert-butyl is owing to cost an arm and a leg and transport, use and exist safety issue to limit the application of this method on the synthetic hydrochloric acid norphenylephrine.
Summary of the invention
The object of the invention is, a kind of preparation method of medicine Norfenefrine Hydrochloride is provided.This method is raw material with the m-hydroxybenzaldehyde, is alkali with sodium methylate or potassium hydroxide, with itself and Nitromethane 99Min. addition, carries out catalytic hydrogenation then with the reduction nitro, carries out the salt acidifying at last, makes this target compound.Raw material of the present invention is easy to get, and synthetic route is succinctly convenient, is fit to scale operation.
The preparation method of Norfenefrine Hydrochloride of the present invention follows these steps to carry out:
A, with sodium methylate or potassium hydroxide is alkali, under 0 ℃, slowly be added dropwise to Nitromethane 99Min., temperature stirred 15-60 minute for 0 ℃, form light yellow negative ion suspension, after again m-hydroxybenzaldehyde being dissolved in Nitromethane 99Min. earlier, slowly drip in the suspension, rise to room temperature, stir, add the saturated ammonium chloride solution termination reaction, use the ethyl acetate extraction reaction solution, merge organic phase, use the saturated common salt water washing, through anhydrous sodium sulfate drying, obtain light yellow oil after concentrating, obtain light yellow solid intermediate product 3-(1-hydroxyl-2-nitro) ethylphenol through column chromatography purification, reaction formula is:
B, with intermediate product 3-(1-hydroxyl-2-nitro) ethylphenol, be dissolved in the anhydrous methanol, add palladium-carbon catalyst, room temperature atmospheric hydrogenation catalytic hydrogenation stirred 10-20 hour, passed through diatomite filtration, filtrate concentrating obtains crude product, crude product is dissolved in the dry ethyl acetate feeds dry hydrogen chloride gas, salify obtains the target compound Norfenefrine Hydrochloride.Reaction formula is:
Intermediate 2 target compounds 3
Embodiment
Embodiment 1:
In 50ml single port bottle, add 5ml methyl alcohol, add the 0.75g sodium Metal 99.5 after being cooled to 0 ℃, be stirred to dissolving and obtain sodium methylate, slowly be added dropwise to the 10ml Nitromethane 99Min. under 0 ℃, drip and finish, temperature stirred 15 minutes for 0 ℃, form light yellow negative ion suspension, with m-hydroxybenzaldehyde 1.0g, 8.2mmol is dissolved in earlier in the 10ml Nitromethane 99Min. again, slowly is added dropwise in the negative ion suspension, slowly rise to room temperature, stirring is spent the night, and adds the saturated ammonium chloride solution termination reaction, uses the ethyl acetate extraction reaction solution, merge organic phase, use the saturated common salt water washing,, obtain light yellow oil after concentrating through anhydrous sodium sulfate drying, obtain light yellow solid intermediate product 3-(1-hydroxyl-2-nitro) ethylphenol 1.104g through column chromatography purification, yield 73.6% is 79.3% based on the actual raw material yield that utilizes perhaps, and reclaims unreacted raw material 72mg.
In 25ml single port bottle, add intermediate product 3-(1-hydroxyl-2-nitro) ethylphenol 200mg, 1.09mmol, be dissolved in the 15ml anhydrous methanol, add the 20mg palladium-carbon catalyst, room temperature atmospheric hydrogenation catalytic hydrogenation, stirred 10 hours, by diatomite filtration, filtrate concentrating obtains crude product 158mg, yield 95%, crude product is dissolved in the dry ethyl acetate and feeds dry hydrogen chloride gas, and salify obtains the target compound Norfenefrine Hydrochloride.
Embodiment 2:
In 50ml single port bottle, add the 10ml Nitromethane 99Min., add 0.82g solid potassium hydroxide 0.82g after being cooled to 0 ℃ in batches, 20.5mmol, add the 2ml anhydrous methanol again, temperature stirred 60 minutes for 0 ℃, formed light yellow negative ion suspension, again with m-hydroxybenzaldehyde 1.0g, 8.2mmol be dissolved in earlier in the 10ml Nitromethane 99Min., slowly be added dropwise in the negative ion suspension, slowly rise to room temperature, stirring is spent the night, add the saturated ammonium chloride solution termination reaction, use the ethyl acetate extraction reaction solution, merge organic phase, use the saturated common salt water washing, through anhydrous sodium sulfate drying, obtain pale brown look oily matter after concentrating, obtain light yellow solid intermediate product 3-(1-hydroxyl-2-nitro) ethylphenol 1.06g, 70.1% through column chromatography purification, be 76.7% perhaps, and reclaim unreacted raw material 80mg based on the actual raw material yield that utilizes.
In 25ml single port bottle, add intermediate product 3-(1-hydroxyl-2-nitro) ethylphenol 200mg, 1.09mmol, be dissolved in the 15ml anhydrous methanol, add the 20mg palladium-carbon catalyst, room temperature atmospheric hydrogenation catalytic hydrogenation, stirred 20 hours, by diatomite filtration, filtrate concentrating obtains crude product 158mg, yield 95%, crude product is dissolved in the dry ethyl acetate and feeds dry hydrogen chloride gas, and salify obtains the target compound Norfenefrine Hydrochloride.
Claims (1)
1, a kind of preparation method of Norfenefrine Hydrochloride is characterized in that following these steps to carrying out:
A, with sodium methylate or potassium hydroxide is alkali, under 0 ℃, slowly be added dropwise to Nitromethane 99Min., temperature stirred 15-60 minute for 0 ℃, form light yellow negative ion suspension, after again m-hydroxybenzaldehyde being dissolved in Nitromethane 99Min. earlier, slowly be added dropwise in the suspension, rise to room temperature, stir, add the saturated ammonium chloride solution termination reaction, use the ethyl acetate extraction reaction solution, merge organic phase, use the saturated common salt water washing, through anhydrous sodium sulfate drying, obtain light yellow oil after concentrating, obtain light yellow solid intermediate product 3-(1-hydroxyl-2-nitro) ethylphenol through column chromatography purification, reaction formula is:
B, with intermediate product 3-(1-hydroxyl-2-nitro) ethylphenol, be dissolved in the anhydrous methanol, add palladium-carbon catalyst, room temperature atmospheric hydrogenation catalytic hydrogenation stirred 10-20 hour, passed through diatomite filtration, filtrate concentrating obtains crude product, crude product is dissolved in the dry ethyl acetate feeds dry hydrogen chloride gas, salify obtains the target compound Norfenefrine Hydrochloride.Reaction formula is:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100709070A CN100361962C (en) | 2006-03-22 | 2006-03-22 | Preparation method of demebeverine hydrochloride |
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| CNB2006100709070A CN100361962C (en) | 2006-03-22 | 2006-03-22 | Preparation method of demebeverine hydrochloride |
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| CN1824645A true CN1824645A (en) | 2006-08-30 |
| CN100361962C CN100361962C (en) | 2008-01-16 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102060719A (en) * | 2011-01-07 | 2011-05-18 | 天津市炜杰科技有限公司 | Method for preparing midodrine hydrochloride intermediate 1-(2,5-dimethoxy benzaldehyde)-2-aminoethanol |
| CN102234237A (en) * | 2010-04-22 | 2011-11-09 | 赤峰艾克制药科技股份有限公司 | Method for preparing L-phenylephrine hydrochloride |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966813A (en) * | 1971-06-21 | 1976-06-29 | Warner-Lambert Company | Process for the preparation of 1-(m- and p-hydroxyphenyl)-2-aminoethanol |
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2006
- 2006-03-22 CN CNB2006100709070A patent/CN100361962C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102234237A (en) * | 2010-04-22 | 2011-11-09 | 赤峰艾克制药科技股份有限公司 | Method for preparing L-phenylephrine hydrochloride |
| CN102234237B (en) * | 2010-04-22 | 2014-03-26 | 赤峰艾克制药科技股份有限公司 | Method for preparing L-phenylephrine hydrochloride |
| CN102060719A (en) * | 2011-01-07 | 2011-05-18 | 天津市炜杰科技有限公司 | Method for preparing midodrine hydrochloride intermediate 1-(2,5-dimethoxy benzaldehyde)-2-aminoethanol |
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| CN100361962C (en) | 2008-01-16 |
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Granted publication date: 20080116 Termination date: 20120322 |