CN106748835B - A kind of preparation method of stryphnonasal - Google Patents
A kind of preparation method of stryphnonasal Download PDFInfo
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- CN106748835B CN106748835B CN201710032415.0A CN201710032415A CN106748835B CN 106748835 B CN106748835 B CN 106748835B CN 201710032415 A CN201710032415 A CN 201710032415A CN 106748835 B CN106748835 B CN 106748835B
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- methylamine
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- adrenalone
- stryphnonasal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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Abstract
The present invention relates to a kind of preparation methods of stryphnonasal, and during preparing stryphnonasal using chloracetyl catechol and methylamine, control reaction carries out in alcoholic solution, and selects four butyl bromation amine or tetrabutylammonium iodide as phase transfer catalyst.Method of the present invention is carried out in alcoholic solution by controlling reaction, the abundant progress of reaction is promoted, while four butyl bromation amine or tetrabutylammonium iodide is added as phase transfer catalyst, accelerates reaction speed, the reaction time is shortened, the accumulation of impurity is reduced.Without purification, the stryphnonasal of high quality can be once prepared, provides the intermediate of high quality to prepare L- adrenaline.
Description
Technical field
The present invention relates to the technical field of organic synthesis of drug, and in particular to a kind of preparation method of stryphnonasal.
Background technique
The chemical name of stryphnonasal are as follows: 1- (3,4- dihydroxyphenyl) -2- methylamino acetophenone hydrochloride, is to prepare kidney
The intermediate of upper parathyrine.Domestic document is very few to the report of the synthesis technology of stryphnonasal.Due to stryphnonasal
For the intermediate for synthesizing adrenaline drug, it is necessary to its synthesis technology be studied and be optimized, to be conducive to industrial metaplasia
It produces.The molecular structural formula of adrenalone is as follows:
WO 2009/004593 reports adrenergic synthesis technology, and synthesizing adrenergic intermediate is not on kidney
Gland ketone, but benzyl adrenalone, then adrenaline is prepared by hydrogenation catalyst reaction.The structural formula of benzyl adrenalone is such as
Under:
Beam David, Wang Yueqiu are equal to the document that in August, 2014 is delivered, and " synthesis of (-)-noradrenaline bitartrate is ground
Study carefully " in describe the synthesis of hydrochloric acid noradrenaline ketone (chemical name are as follows: 4- (glycyl) -1,2- catechol hydrochloride)
Technique.The molecular structural formula of noradrenaline ketone is as follows:
Since the molecular structural formula of adrenalone is similar to the molecular structural formula of noradrenaline ketone, benzyl adrenalone,
Therefore the synthesis technology that noradrenaline ketone and benzyl base adrenalone can be used for reference according to composition principle, prepares adrenalone.
Summary of the invention
The object of the present invention is to provide a kind of preparation methods of the adrenalone of high-purity, high yield, include the following steps:
1) for the alcoholic solution of chloracetyl catechol and methylamine under the action of phase transfer catalyst, reaction generates adrenalone；
2) adrenalone is reacted with hydrochloric acid generates stryphnonasal.
Its reaction route is as follows:
Preferably, the phase transfer catalyst is quaternary ammonium salt substance；Preferably tetrabutylammonium bromide, tetrabutylammonium iodide
At least one of.
Preferably, the chloracetyl catechol, methylamine, phase transfer catalyst molar ratio be 1:(7~11): (0.015~
0.0.03).In reaction for ensure chloracetyl catechol can sufficiently fully reacting and reaction rate is fast, methylamine needs Excess quantities.First
Alcoholic solvent in the alcoholic solution of amine does not add solvent still further directly as the solvent of reaction system.
Preferably, the alcoholic solution of the methylamine is formulated using methanol and/or ethyl alcohol as solvent, it is preferable that the first
In the alcoholic solution of amine, the mass fraction of methylamine is 28~32%.Methylamine gas has dissolubility in methanol, second alcohol and water.City
There are two classes of aqueous solution of the alcoholic solution of methylamine and methylamine on field.Since the alcoholic solution of methylamine is in the reaction compared with the aqueous solution of methylamine
Reactivity is stronger, is more advantageous to the progress of reaction, reduces the generation of impurity, therefore the alcoholic solution of the preferred methylamine of the present invention.
Preferably, the reaction temperature in the step 1) is 20~40 DEG C, preferably 30 DEG C.If reaction temperature is excessively high, mistake
High temperature easily makes the methylamine in reaction solution volatilize, and reaction is caused to be difficult to carry out.If reaction temperature is too low, reaction is slow, when reaction
Between it is long, be also easy to produce impurity.Above-mentioned temperature range and reaction time both guarantee going on smoothly for reaction, it is also ensured that required reaction
Speed.
Preferably, the concrete operations of the step 2) are as follows: the adrenalone is entered to the mixing of alcohols solvent and hydrochloric acid
In solution, carry out into salt；Preferably, the alcohols solvent is methanol and/or ethyl alcohol.
Preferably, the ratio between amount of substance of the adrenalone and the hydrochloric acid is 1.1~1.3.
Preferably, in salification process, the pH for controlling reaction system is 2~3.
Preferably, it step 1) and 2) is carried out under the conditions of inert gas shielding.
Preferably, the method for the present invention includes following steps:
1) under inert gas shielding, the alcoholic solution of chloracetyl catechol and first ammonia is in phase transfer catalyst four butyl bromation amine
Or under the action of tetrabutylammonium iodide, adrenalone is generated in 20~40 DEG C of reactions；The chloracetyl catechol, methylamine, phase turn
The ratio between amount of substance of shifting catalyst is 1:(7~11): (0.015~0.0.03)；In the alcoholic solution of the methylamine, the matter of methylamine
Measuring score is 28~32%；
2) under inert gas shielding, the adrenalone is added dropwise in the mixed solution for entering alcohols solvent and hydrochloric acid, into
Row is crossed in kind at salt at salt, and the pH for controlling reaction system is 2~3 to get the adrenalin hydrochloride.
Method of the invention has the following beneficial effects:
Pure methylamine is replaced with the alcoholic solution of methylamine in this reaction system, is not added in reaction system other organic molten
Agent.Reactant does not select methylamine gas in this reaction system, and methylamine is selected to be dissolved in the alcoholic solution in alcohol, it is therefore an objective to increase anti-
It answers the contact area between material and avoids using the reaction side between gas phase (methylamine gas) and solid phase (chloracetyl catechol)
Formula, the latter are heterogeneous reaction and the carrier that must use gas, and reaction is difficult to carry out and has higher want to the airtightness of equipment
It asks.The reaction of the alcoholic solution and insoluble solid chloracetyl catechol of methylamine is also heterogeneous reaction system, but compared to gas-solid
Heterogeneous reaction is obviously more advantageous.But there are still sluggish disadvantages, and with the extension of reaction time, impurity gradually increases
Add.To shorten the reaction time, reduces the generation of impurity to the greatest extent, phase transfer catalyst is added in the reaction system.It is anti-to be directed to this
It answers, inventor has found that selection four butyl bromation amine or tetrabutylammonium iodide effect are preferable.Adrenalone is easily oxidized in air,
Especially when being reacted under contacting with air, reactant chloracetyl catechol, product adrenalone and impurity can be with
Oxidation causes the impurity generated when reaction more, and the content of principal component adrenalone is low, and impurity is more and miscellaneous.Therefore, for avoid compared with
Polymictic generation carries out reaction in the absence of oxygen.In short, method of the present invention, by control reaction in nothing
It is carried out under the conditions of oxygen, reduces the generation of side reaction, while four butyl bromation amine or tetrabutylammonium iodide is added as phase transfer
Catalyst accelerates reaction speed, shortens the reaction time, reduce the accumulation of impurity, it can be achieved that high yield high-purity salt
The preparation of sour adrenalone.
The present invention carries out methylamine reaction using chloracetyl catechol and methylamine and prepares stryphnonasal, is closed by determining
The reaction system and optimizing technology parameters of reason, be prepared the purity (HPLC normalization) of stryphnonasal crude product >=
99.0%, yield >=80.0%.
Effect of the invention, without purification, is realized in high yield with optimal reaction system and optimal technological parameter
The preparation of the stryphnonasal of high-purity.
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..
Embodiment 1
The present embodiment is related to a kind of preparation method of stryphnonasal, includes the following steps:
1) by chloracetyl catechol 10g (0.054mol), the ethanol solution 39g (containing methylamine 30%, 0.378mol) of methylamine
It is added in tri- mouthfuls of reaction flasks of 250ml together with tetrabutylammonium iodide 0.3g (0.0008mol), 30 DEG C of stirrings keep material uniform.
Whole logical nitrogen, reacts 6h at 30 DEG C of temperature after being passed through air 4 times in nitrogen displacement reaction flask, until reaction solution is grayish green
Color.Stop reaction, filtering obtains celadon solid, drains after washing the celadon solid with dehydrated alcohol, obtain adrenalone
Celadon earth tide product；
2) the celadon earth tide product of adrenalone are added to mixed solution (ethyl alcohol 30ml, the dense salt of ethyl alcohol and concentrated hydrochloric acid
Sour 9ml) salt-forming reaction is carried out, stirring adjusts pH=2~3 of reaction solution at any time, and reaction solution is muddy always.After stirring 0.5h, mistake
Filter, dehydrated alcohol washing obtain adrenalone hydrochloride salt as white crystal, 40 DEG C of air blast drying.
Weight 9.7g is received, molar yield 82.6%, measuring its purity by HPLC normalization method is 99.2%.
Embodiment 2
The present embodiment is related to a kind of preparation method of stryphnonasal, includes the following steps:
1) by chloracetyl catechol 10g (0.054mol), methylamine ethanol solution 61.3g (contain methylamine 30%,
It 0.594mol) is added in tri- mouthfuls of reaction flasks of 250ml together with tetrabutylammonium iodide 0.3g (0.0008mol), 30 DEG C of stirrings make
Material is uniform.Lead to nitrogen protection after being passed through air 4 times in nitrogen displacement reaction flask, reacts 4h at 30 DEG C of temperature.To reaction
Liquid is celadon.Stop reaction, filtering obtains celadon solid, drains, obtain after washing the celadon solid with dehydrated alcohol
Adrenalone；
2) the celadon earth tide product of adrenalone are added to mixed solution (ethyl alcohol 30ml, the dense salt of ethyl alcohol and concentrated hydrochloric acid
Sour 9ml) salt-forming reaction is carried out, the pH=2-3 of reaction solution is adjusted in stirring at any time, and reaction solution is muddy always.After stirring 0.5h, filtering,
Dehydrated alcohol washing obtains adrenalone hydrochloride salt as white crystal, 40 DEG C of air blast drying.
Weight 10.2g is received, molar yield 86.9%, measuring its purity by HPLC normalization method is 99.2%.
Embodiment 3
The present embodiment is related to a kind of preparation method of stryphnonasal, includes the following steps:
1) by chloracetyl catechol 10g (0.054mol), the ethanol solution 39g (containing methylamine 30%, 0.378mol) of methylamine
It is added in tri- mouthfuls of reaction flasks of 250ml together with tetrabutylammonium iodide 0.6g (0.0012mol), 40 DEG C of stirrings keep material uniform.
Lead to nitrogen protection after being passed through air 4 times in nitrogen displacement reaction flask, reacts 5h at 30 DEG C of heat preservation.It is celadon to reaction solution.
Stop reaction, filtering obtains celadon solid, drains after washing the celadon solid with dehydrated alcohol, obtain adrenalone；
2) the celadon earth tide product of adrenalone are added to mixed solution (ethyl alcohol 30ml, the dense salt of ethyl alcohol and concentrated hydrochloric acid
Sour 9ml) salt-forming reaction is carried out, the pH=2-3 of reaction solution is adjusted in stirring at any time, and reaction solution is muddy always.After stirring 0.5h, filtering,
Dehydrated alcohol washing obtains adrenalone hydrochloride salt as white crystal, 40 DEG C of air blast drying.
Weight 9.6g is received, molar yield 81.8%, measuring its purity by HPLC normalization method is 99.2%.
Embodiment 4
Compared with Example 1, difference is, using tetrabutylammonium bromide as phase transfer catalyst, the step 1)
Reaction needs 4.5h to complete, and the receipts weight 10.0g of products obtained therefrom, molar yield 85.2% measures its purity by HPLC normalization method
It is 99.3%.
Comparative example 1
Compared with Example 1, difference is, tetrabutylammonium iodide is not added during reaction；The step 1)
Reaction needs 18h to complete, and the receipts weight 6.8g of products obtained therefrom, molar yield 57.9%, measuring its purity by HPLC normalization method is
90.5%.
Comparative example 2
Compared with Example 1, difference be, using p-methyl benzenesulfonic acid as phase transfer catalyst, the step 1) it is anti-
16h should be needed to complete, the receipts weight 7.2g of products obtained therefrom, molar yield 61.4%, measuring its purity by HPLC normalization method is
92.6%.
Comparative example 3
Compared with Example 1, difference is, protects during reaction without anaerobic；The reaction of the step 1)
12h is needed to complete, the receipts weight 7.5g of products obtained therefrom, molar yield 63.9%, measuring its purity by HPLC normalization method is
94.8%.
Although above having used general explanation, specific embodiment and test, the present invention is made to retouch in detail
It states, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Range.
Claims (11)
1. a kind of preparation method of stryphnonasal, which comprises the steps of:
1) under the conditions of inert gas shielding, the alcoholic solution of chloracetyl catechol and methylamine is in phase transfer catalyst tetrabutyl phosphonium bromide
Under the action of at least one of ammonium, tetrabutylammonium iodide, reaction generates adrenalone；
2) under the conditions of inert gas shielding, the adrenalone is reacted with hydrochloric acid generates stryphnonasal.
2. preparation method according to claim 1, which is characterized in that the chloracetyl catechol, methylamine, phase transfer catalysis (PTC)
The molar ratio of agent is 1:(7 ~ 11): (0.015 ~ 0. 03).
3. preparation method according to claim 1, which is characterized in that the alcoholic solution of the methylamine is with methanol and/or second
Alcohol is formulated for solvent.
4. preparation method according to claim 3, which is characterized in that in the alcoholic solution of the methylamine, the quality point of methylamine
Number is 28 ~ 32%.
5. preparation method according to claim 1, which is characterized in that the reaction temperature in the step 1) is 20 ~ 40 DEG C.
6. preparation method according to claim 5, which is characterized in that the reaction temperature in the step 1) is 30 DEG C.
7. preparation method according to claim 1, which is characterized in that the concrete operations of the step 2 are as follows: by the kidney
Upper gland ketone enters in the mixed solution of alcohols solvent and hydrochloric acid, carries out into salt.
8. preparation method according to claim 7, which is characterized in that the alcohols solvent is methanol and/or ethyl alcohol.
9. preparation method according to claim 7, which is characterized in that the amount of the substance of the adrenalone and the hydrochloric acid
The ratio between be 1.1 ~ 1.3.
10. preparation method described according to claim 1 or 7 or 9, which is characterized in that in salification process, control reaction system
PH is 2 ~ 3.
11. preparation method according to claim 1, which comprises the steps of:
1) under inert gas shielding, the alcoholic solution of chloracetyl catechol and methylamine is in phase transfer catalyst four butyl bromation amine or four
Under the action of butyl ammonium iodide, adrenalone is generated in 20 ~ 40 DEG C of reactions；The chloracetyl catechol, methylamine, phase transfer catalysis (PTC)
The ratio between amount of substance of agent is 1:(7 ~ 11): (0.015 ~ 0.03)；In the alcoholic solution of the methylamine, the mass fraction of methylamine is 28
~32%；
2) under inert gas shielding, the adrenalone is added dropwise in the mixed solution for entering alcohols solvent and hydrochloric acid, carry out at
Salt, in salification process, the pH for controlling reaction system is 2 ~ 3 to get the stryphnonasal.
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| CN108047121B (en) * | 2017-11-24 | 2021-11-12 | 江苏慈星药业有限公司 | Production process of adrenal color hydrazone |
| CN116041194A (en) * | 2021-10-28 | 2023-05-02 | 武汉武药制药有限公司 | Synthesis method of norepinephrine hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3809714A (en) * | 1972-08-31 | 1974-05-07 | Interx Research Corp | Novel ester of ((methylamino)methyl) benzyl alcohol |
| WO2009004593A2 (en) * | 2007-07-03 | 2009-01-08 | Wockhardt Research Centre | Processes for the preparation of epinephrine |
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2017
- 2017-01-16 CN CN201710032415.0A patent/CN106748835B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3809714A (en) * | 1972-08-31 | 1974-05-07 | Interx Research Corp | Novel ester of ((methylamino)methyl) benzyl alcohol |
| WO2009004593A2 (en) * | 2007-07-03 | 2009-01-08 | Wockhardt Research Centre | Processes for the preparation of epinephrine |
Non-Patent Citations (1)
| Title |
|---|
| (-)-重酒石酸去甲肾上腺素的合成研究;梁大伟 等;《化工技术与开发》;20140831;第43卷(第8期);11-12 * |
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