CN106748835A - A kind of preparation method of stryphnonasal - Google Patents
A kind of preparation method of stryphnonasal Download PDFInfo
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- CN106748835A CN106748835A CN201710032415.0A CN201710032415A CN106748835A CN 106748835 A CN106748835 A CN 106748835A CN 201710032415 A CN201710032415 A CN 201710032415A CN 106748835 A CN106748835 A CN 106748835A
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- adrenalone
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- 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 method of stryphnonasal, during stryphnonasal is prepared using chloracetyl catechol and methylamine, control reaction is carried 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 by controlling reaction in alcoholic solution, fully carrying out for reaction is promoted, while adding four butyl bromation amine or tetrabutylammonium iodide as phase transfer catalyst, reaction speed is accelerated, the reaction time is shortened, the accumulation of impurity is reduced.Without refined, high-quality stryphnonasal can be once prepared, high-quality intermediate is provided to prepare L adrenaline.
Description
Technical field
The present invention relates to the technical field of organic synthesis of medicine, and in particular to a kind of preparation method of stryphnonasal.
Background technology
The chemical name of stryphnonasal is：1- (3,4- dihydroxyphenyl) -2- methylamino acetophenone hydrochlorides, are to prepare kidney
The intermediate of upper parathyrine.Domestic document is very few to the report of the synthesis technique of stryphnonasal.Due to stryphnonasal
To synthesize the intermediate of adrenaline medicine, it is necessary to its synthesis technique is studied and optimized, to be conducive to industrial metaplasia
Produce.The molecular structural formula of adrenalone is as follows：
WO 2009/004593 reports adrenergic synthesis technique, and its adrenergic intermediate of synthesis 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《The synthesis of (-)-noradrenaline bitartrate is ground
Study carefully》In describe hydrochloric acid noradrenaline ketone (chemistry it is entitled：4- (glycyl) -1,2- catechols hydrochloride) synthesis
Technique.The molecular structural formula of noradrenaline ketone is as follows：
Because the molecular structural formula of adrenalone is similar to the molecular structural formula of noradrenaline ketone, benzyl adrenalone,
Therefore the synthesis technique of noradrenaline ketone and benzyl base adrenalone can be used for reference according to composition principle, adrenalone is prepared.
The content of the invention
A kind of preparation method of adrenalone it is an object of the invention to provide high-purity, in high yield, comprises the following steps：
1) in the presence of phase transfer catalyst, reaction generates adrenalone to the alcoholic solution of chloracetyl catechol and methylamine；
2) adrenalone generates stryphnonasal with hydrochloric acid reaction.
Its reaction scheme is as follows：
Preferably, the phase transfer catalyst is quaternary ammonium salt material；Preferably TBAB, tetrabutylammonium iodide
In at least one.
Preferably, the chloracetyl catechol, methylamine, the mol ratio of phase transfer catalyst are 1：(7~11)：(0.015~
0.0.03).To ensure that chloracetyl catechol can fully react complete and reaction rate is fast in reaction, 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 with methyl alcohol and/or ethanol as solvent is formulated, it is preferable that the first
In the alcoholic solution of amine, the mass fraction of methylamine is 28~32%.Methylamine gas have dissolubility in methyl alcohol, second alcohol and water.City
There is the alcoholic solution of methylamine and the class of the aqueous solution two of methylamine on field.Because the alcoholic solution of methylamine is in the reaction compared with the aqueous solution of methylamine
Reactivity is stronger, is more beneficial for the alcoholic solution of the carrying out of reaction, the generation of reduction impurity, therefore the present invention preferably methylamine.
Preferably, the step 1) in reaction temperature be 20~40 DEG C, preferably 30 DEG C.If reaction temperature is too high, mistake
Temperature high easily makes the methylamine in reaction solution volatilize, and causes reaction to be difficult to.If reaction temperature is too low, reaction is slow, during reaction
Between it is long, be also easy to produce impurity.Said temperature scope and reaction time both ensure being smoothed out for reaction, it is also ensured that required reaction
Speed.
Preferably, the step 2) concrete operations be：The adrenalone is entered the mixing of alcohols solvent and hydrochloric acid
In solution, salt is carried out into；Preferably, the alcohols solvent is methyl alcohol and/or ethanol.
Preferably, the ratio between the adrenalone and amount of material of the hydrochloric acid are 1.1~1.3.
Preferably, in salification process, the pH for controlling reaction system is 2~3.
Preferably, step 1) and 2) carried out under the conditions of inert gas shielding.
Preferably, the method for the present invention comprises the 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 in the presence of tetrabutylammonium iodide, in 20~40 DEG C of reaction generation adrenalones；The chloracetyl catechol, methylamine, phase turn
The ratio between amount of material of shifting catalyst is 1：(7~11)：(0.015~0.0.03)；In the alcoholic solution of the methylamine, the matter of methylamine
Amount fraction is 28~32%；
2) under inert gas shielding, the adrenalone is added dropwise in the mixed solution for entering alcohols solvent and hydrochloric acid, is entered
Salt is gone into, is crossed into salt in planting, it is 2~3 to control the pH of reaction system, obtains final product the adrenalin hydrochloride.
The method of the present invention has the advantages that：
Pure methylamine is replaced with the alcoholic solution of methylamine in this reaction system, other is not added in reaction system organic molten
Agent.Reactant does not select methylamine gas in this reaction system, and the alcoholic solution in selecting methylamine to be dissolved in alcohol, it is therefore an objective to increase anti-
Answer the contact area between material and avoid using the reaction side between gas phase (methylamine gas) and solid phase (chloracetyl catechol)
Formula, the latter is heterogeneous reaction and must use the carrier of gas, and reaction be difficult to and the seal to equipment has higher wanting
Ask.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 substantially more advantageous.But sluggish shortcoming is still suffered from, with the extension in reaction time, impurity gradually increases
Plus.To shorten the reaction time, the generation of impurity is reduced as far as possible, phase transfer catalyst is added in reaction system.It is directed to this anti-
Should, inventor has found that selection four butyl bromation amine or tetrabutylammonium iodide effect are preferable.Adrenalone is easily oxidized in atmosphere,
Especially when being reacted under with air contact, reactant chloracetyl catechol, product adrenalone and impurity can be with
Oxidation, the impurity that produces is more when causing reaction, and the content of principal component adrenalone is low, and impurity is more and miscellaneous.Therefore, for avoid compared with
Polymictic generation, makes reaction carry out in the absence of oxygen.In a word, method of the present invention, by controlling reaction in nothing
Carried out under the conditions of oxygen, reduce the generation of side reaction, while adding four butyl bromation amine or tetrabutylammonium iodide as phase transfer
Catalyst, accelerates reaction speed, shortens the reaction time, reduces the accumulation of impurity, is capable of achieving the salt of high-purity in high yield
The preparation of sour adrenalone.
The present invention carries out methylamine reaction and prepares stryphnonasal using chloracetyl catechol and methylamine, by determining to close
The reaction system and optimizing technology parameters of reason, prepare the purity (HPLC normalization) of stryphnonasal crude product >=
99.0%, yield >=80.0%.
Effect of the invention is, with optimal reaction system and optimal technological parameter, without refined, to realize in high yield
The preparation of the stryphnonasal of high-purity.
Specific embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1
The present embodiment is related to a kind of preparation method of stryphnonasal, comprises the following steps：
1) by chloracetyl catechol 10g (0.054mol), the ethanol solution 39g (containing methylamine 30%, 0.378mol) of methylamine
It is added to together in tri- mouthfuls of reaction bulbs of 250ml with tetrabutylammonium iodide 0.3g (0.0008mol), 30 DEG C of stirrings make material uniform.
Whole logical nitrogen after the air 4 times in nitrogen displacement reaction bulb is passed through, 6h is reacted at 30 DEG C of temperature, be grayish green to reaction solution
Color.Stop reaction, filtering obtains celadon solid, with being drained after celadon solid described in absolute ethanol washing, obtains adrenalone
Celadon earth tide product；
2) the celadon earth tide product of adrenalone are added mixed solution (the ethanol 30ml, dense salt of ethanol and concentrated hydrochloric acid
Sour 9ml) salt-forming reaction is carried out, stir, pH=2~3 of reaction solution are adjusted at any time, reaction solution is muddy all the time.After stirring 0.5h, mistake
Filter, absolute ethanol washing obtains adrenalone hydrochloride salt as white crystal, 40 DEG C of air blast drying.
Receipts weight 9.7g, molar yield 82.6%, it is 99.2% to measure its purity by HPLC normalization methods.
Embodiment 2
The present embodiment is related to a kind of preparation method of stryphnonasal, comprises the following steps：
1) by chloracetyl catechol 10g (0.054mol), methylamine ethanol solution 61.3g (contain methylamine 30%,
0.594mol) it is added to together in tri- mouthfuls of reaction bulbs of 250ml with tetrabutylammonium iodide 0.3g (0.0008mol), 30 DEG C of stirrings make
Material is uniform.The air 4 times being passed through in nitrogen displacement reaction bulb leads to nitrogen protection afterwards, and 4h is reacted at 30 DEG C of temperature.To reaction
Liquid is celadon.Stop reaction, filtering obtains celadon solid, with being drained after celadon solid described in absolute ethanol washing, obtains
Adrenalone；
2) the celadon earth tide product of adrenalone are added mixed solution (the ethanol 30ml, dense salt of ethanol and concentrated hydrochloric acid
Sour 9ml) salt-forming reaction is carried out, stir, the pH=2-3 of reaction solution is adjusted at any time, reaction solution is muddy all the time.After stirring 0.5h, filtering,
Absolute ethanol washing, obtains adrenalone hydrochloride salt as white crystal, 40 DEG C of air blast drying.
Receipts weight 10.2g, molar yield 86.9%, it is 99.2% to measure its purity by HPLC normalization methods.
Embodiment 3
The present embodiment is related to a kind of preparation method of stryphnonasal, comprises the following steps：
1) by chloracetyl catechol 10g (0.054mol), the ethanol solution 39g (containing methylamine 30%, 0.378mol) of methylamine
It is added to together in tri- mouthfuls of reaction bulbs of 250ml with tetrabutylammonium iodide 0.6g (0.0012mol), 40 DEG C of stirrings make material uniform.
The air being passed through in nitrogen displacement reaction bulb leads to nitrogen protection 4 times afterwards, and 5h is reacted at 30 DEG C of insulation.It is celadon to reaction solution.
Stop reaction, filtering obtains celadon solid, with being drained after celadon solid described in absolute ethanol washing, obtains adrenalone；
2) the celadon earth tide product of adrenalone are added mixed solution (the ethanol 30ml, dense salt of ethanol and concentrated hydrochloric acid
Sour 9ml) salt-forming reaction is carried out, stir, the pH=2-3 of reaction solution is adjusted at any time, reaction solution is muddy all the time.After stirring 0.5h, filtering,
Absolute ethanol washing, obtains adrenalone hydrochloride salt as white crystal, 40 DEG C of air blast drying.
Receipts weight 9.6g, molar yield 81.8%, it is 99.2% to measure its purity by HPLC normalization methods.
Embodiment 4
Compared with Example 1, its difference is, using TBAB 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 methods
It is 99.3%.
Comparative example 1
Compared with Example 1, its difference is, without tetrabutylammonium iodide during reaction；The step 1)
Reaction needs 18h to complete, the receipts weight 6.8g of products obtained therefrom, molar yield 57.9%, and measuring its purity by HPLC normalization methods is
90.5%.
Comparative example 2
Compared with Example 1, its difference is, 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 methods is
92.6%.
Comparative example 3
Compared with Example 1, its difference is that anaerobic protection is not carried out during reaction；The step 1) reaction
12h is needed to complete, the receipts weight 7.5g of products obtained therefrom, molar yield 63.9%, measuring its purity by HPLC normalization methods is
94.8%.
Although above having used general explanation, specific embodiment and experiment, the present invention is made to retouch in detail
State, but on the basis of the present invention, it can be made some modifications or improvements, this is to those skilled in the art apparent
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, belong to claimed
Scope.
Claims (10)
1. a kind of preparation method of stryphnonasal, it is characterised in that comprise the following steps：
1) in the presence of phase transfer catalyst, reaction generates adrenalone to the alcoholic solution of chloracetyl catechol and methylamine；
2) adrenalone generates stryphnonasal with hydrochloric acid reaction.
2. preparation method according to claim 1, it is characterised in that the phase transfer catalyst is quaternary ammonium salt material；
At least one preferably in TBAB, tetrabutylammonium iodide.
3. the preparation method according to claim any one of 1-2, it is characterised in that the chloracetyl catechol, methylamine, phase
The mol ratio of transfer catalyst is 1：(7~11)：(0.015~0.0.03).
4. preparation method according to claim 1, it is characterised in that the alcoholic solution of the methylamine is with methyl alcohol and/or second
Alcohol is formulated for solvent, it is preferable that in the alcoholic solution of the methylamine, and the mass fraction of methylamine is 28~32%.
5. preparation method according to claim 1, it is characterised in that the step 1) in reaction temperature be 20~40
DEG C, preferably 30 DEG C.
6. preparation method according to claim 1, it is characterised in that the step 2) concrete operations be：By the kidney
Upper gland ketone enters in the mixed solution of alcohols solvent and hydrochloric acid, carries out into salt；Preferably, the alcohols solvent be methyl alcohol and/or
Ethanol.
7. preparation method according to claim 6, it is characterised in that the amount of the adrenalone and the material of the hydrochloric acid
The ratio between be 1.1~1.3.
8. the preparation method according to claim 1 or 6 or 7, it is characterised in that in salification process, control reaction system
PH is 2~3.
9. the preparation method according to any one of claim 1~8, it is characterised in that step 1) and 2) in inert gas
Carried out under protective condition.
10. preparation method according to claim 1, it is characterised in that comprise the 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 four
In the presence of butyl ammonium iodide, in 20~40 DEG C of reaction generation adrenalones；The chloracetyl catechol, methylamine, phase transfer are urged
The ratio between amount of material of agent is 1：(7~11)：(0.015~0.0.03)；In the alcoholic solution of the methylamine, the quality point of methylamine
Number is 28~32%；
2) under inert gas shielding, the adrenalone is added dropwise in the mixed solution for entering alcohols solvent and hydrochloric acid, is carried out into
Salt, crosses in planting into salt, and it is 2~3 to control the pH of reaction system, obtains final product the adrenalin hydrochloride.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047121A (en) * | 2017-11-24 | 2018-05-18 | 江苏慈星药业有限公司 | A kind of production technology of Adenaron |
| 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 |
-
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 |
|---|
| 梁大伟 等: "(-)-重酒石酸去甲肾上腺素的合成研究", 《化工技术与开发》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047121A (en) * | 2017-11-24 | 2018-05-18 | 江苏慈星药业有限公司 | A kind of production technology of Adenaron |
| 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 |
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| CN106748835B (en) | 2018-12-14 |
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