CN105198795B - A kind of preparation technology of lobeline hydrochloride - Google Patents
A kind of preparation technology of lobeline hydrochloride Download PDFInfo
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- CN105198795B CN105198795B CN201510659934.0A CN201510659934A CN105198795B CN 105198795 B CN105198795 B CN 105198795B CN 201510659934 A CN201510659934 A CN 201510659934A CN 105198795 B CN105198795 B CN 105198795B
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- Prior art keywords
- lobeline
- ethyl alcohol
- absolute ethyl
- mtbe
- butyl ether
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation technology of lobeline hydrochloride, comprise the following steps：Under stirring, room temperature condition sequentially adds left-handed lobeline, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) into reactor, is well mixed obtained mixture a；It is 10% ~ 25% ethanol solution of hydrogen chloride that mass percent concentration is added into mixture a, then starts to be slowly heated, and heating rate is 2 ~ 4 DEG C/min, stops heating when flowing back, 0.5 ~ 2h of insulation reaction, stops stirring；Then 0 ~ 5 DEG C is cooled to, 4 ~ 6h of crystallization, filters to obtain filter cake；Filter cake is respectively washed once with methyl tertiary butyl ether(MTBE) and absolute ethyl alcohol successively, rewinding；It is forced air drying at 45 ~ 60 DEG C in temperature, it is product to obtain white crystalline powder.Yield is the method increase, reduces cost, each index of product meets Chinese 2010 editions standards of pharmacopoeia and 2015 editions standards of pharmacopoeia.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation technology of lobeline hydrochloride.
Background technology
Lobeline hydrochloride is white crystals or particulate powder, odorless, bitter；The aqueous solution reacts in faintly acid.This product exists
It is readily soluble in ethanol or chloroform, dissolved in water.
Lobeline hydrochloride can optionally excited chemical receptor of carotid body, excited respiratory center, heavy dose of reflectingly
Also can directly excited respiratory center.Can stimulation of carotid sinus and chemoreceptor of aortic body（It is N1 acceptors）, reflectivity
Excited respiratory center and make accelerated breathing, but direct excitation is had no to respiratory center.Vagus nerve maincenter and blood vessel are transported
Dynamic maincenter also has reflexive excitation simultaneously；It is first excited to vegetative ganglia then to block.Asphyxia neonatorum, suction fiber crops
Liquor-saturated medicine and other central depressants suffocate as caused by morphine or barbitals poisoning, carbon monoxide and pneumonia, diphtheria etc. pass
Catch an illness caused respiratory failure.
Use salifying method at present：Using absolute ethyl alcohol system, left-handed lobeline alkali is added into salt.Yield 65% or so, production
The relevant material index of product is hardly consistent with Chinese 2010 editions pharmacopeia indexs.
The content of the invention
It is an object of the invention to provide a kind of preparation technology of lobeline hydrochloride, yield is the method increase, is reduced into
This, each index of product meets Chinese 2010 editions standards of pharmacopoeia and 2015 editions standards of pharmacopoeia.
A kind of preparation technology of lobeline hydrochloride, comprises the following steps：
（1）Under stirring, room temperature condition sequentially adds left-handed lobeline, absolute ethyl alcohol and methyl tertbutyl into reactor
Ether, it is well mixed obtained mixture a；The weight ratio of left-handed lobeline, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) is 1：（2~4）：（6~
12）；
（2）Under stirring, first to step（1）It is 10% ~ 25% chlorination that mass percent concentration is added in obtained mixture a
Hydrogen-ethanol solution, mass percent concentration are that the addition of 10% ~ 25% Hydrochlorine-Ethanol solution is the weight of left-handed lobeline
0.7 ~ 1.4 times, then start to be slowly heated, heating rate is 2 ~ 4 DEG C/min, stops heating when flowing back, and insulation is anti-
0.5 ~ 2h is answered, stops stirring；Then 0 ~ 5 DEG C is cooled to, 4 ~ 6h of crystallization, filters to obtain filter cake；
（3）By step（2）Obtained filter cake is respectively washed once with methyl tertiary butyl ether(MTBE) and absolute ethyl alcohol successively, rewinding；Yu Wen
Spend for forced air drying at 45 ~ 60 DEG C, it is product to obtain white crystalline powder.
Step（1）Described in left-handed lobeline, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) weight ratio be 1：2：6.
Step（1）Described in left-handed lobeline, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) weight ratio be 1：2：8.
Step（1）Described in left-handed lobeline, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) weight ratio be 1：2：12.
Step（2）Described in Hydrochlorine-Ethanol solution mass percent concentration be 20%.
Compared with prior art, the invention has the advantages that：
For the preparation technology of lobeline hydrochloride provided by the invention compared with conventional preparation techniques, yield improves more than 30%, has
Pass material list is miscellaneous, always miscellaneous reduction by 0.1%.Process is simple to operate, and product index meets 2010 editions and 2015 editions standards of pharmacopoeia,
Industrialized production can be carried out.
Embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This.
The raw material that following examples use is commercially available prod, and the left-handed lobeline of purchase has to comply with enterprises mark
It is accurate：Off-white color to light yellow solid, moisture must not exceed 0.5%, containing C22H26ClNO299.0% must not be less than, list is miscellaneous must not mistake
0.5%。
Comparative example
In the dry mouth reaction bulbs of 500mL tri-, left-handed lobeline 20g, absolute ethyl alcohol 140g are sequentially added, is added after stirring evenly
20% ethanol solution of hydrogen chloride 14g, starts to be slowly heated, and heating rate is 2 ~ 4 DEG C/min, stops heating when flowing back, and protects
Temperature reaction 1h；Then 0 DEG C is cooled to, crystallization 1h, filters to obtain filter cake, filter cake cooling absolute ethyl alcohol is washed once, rewinding；In temperature
For 45 ~ 60 DEG C, forced air drying 6h, white crystalline powder 14.4g is obtained, yield 64.9%, the relevant materials of HPLC are maximum single miscellaneous
0.17%, total miscellaneous 0.41%.
Embodiment 1
A kind of preparation technology of lobeline hydrochloride, comprises the following steps：
（1）Under stirring, room temperature condition sequentially adds left-handed lobeline 20g, absolute ethyl alcohol 40g and methyl- tert into reactor
Butyl ether 120g, it is well mixed obtained mixture a；
（2）Under stirring, first to step（1）It is 20% hydrogen chloride-second that mass percent concentration is added in obtained mixture a
Alcoholic solution 14g, then start to be slowly heated, heating rate is 2 ~ 4 DEG C/min, stops heating, insulation reaction when flowing back
1h, stop stirring；Then 0 ~ 5 DEG C is cooled to, 4 ~ 6h of crystallization, filters to obtain filter cake；
（3）By step（2）Obtained filter cake is respectively washed once with methyl tertiary butyl ether(MTBE) and absolute ethyl alcohol successively, rewinding；Yu Wen
Spend for forced air drying at 45 ~ 60 DEG C, it is product to obtain white crystalline powder.
The white crystalline powder 21.2g that the present embodiment obtains, yield 95.5%, the relevant materials of HPLC are maximum single miscellaneous
0.13%, total miscellaneous 0.28%.
Embodiment 2
A kind of preparation technology of lobeline hydrochloride, comprises the following steps：
（2）Under stirring, room temperature condition sequentially adds left-handed lobeline 20g, absolute ethyl alcohol 40g and methyl- tert into reactor
Butyl ether 160g, it is well mixed obtained mixture a；
（2）Under stirring, first to step（1）It is 20% hydrogen chloride-second that mass percent concentration is added in obtained mixture a
Alcoholic solution 14g, then start to be slowly heated, heating rate is 2 ~ 4 DEG C/min, stops heating, insulation reaction when flowing back
1h, stop stirring；Then 0 ~ 5 DEG C is cooled to, 4 ~ 6h of crystallization, filters to obtain filter cake；
（4）By step（2）Obtained filter cake is respectively washed once with methyl tertiary butyl ether(MTBE) and absolute ethyl alcohol successively, rewinding；Yu Wen
Spend for forced air drying at 45 ~ 60 DEG C, it is product to obtain white crystalline powder.
The white crystalline powder 21.3g that the present embodiment obtains, yield 95.9%, the relevant materials of HPLC are maximum single miscellaneous
0.12%, total miscellaneous 0.27%.
Embodiment 3
A kind of preparation technology of lobeline hydrochloride, comprises the following steps：
（3）Under stirring, room temperature condition sequentially adds left-handed lobeline 20g, absolute ethyl alcohol 40g and methyl- tert into reactor
Butyl ether 240g, it is well mixed obtained mixture a；
（2）Under stirring, first to step（1）It is 20% hydrogen chloride-second that mass percent concentration is added in obtained mixture a
Alcoholic solution 14g, then start to be slowly heated, heating rate is 2 ~ 4 DEG C/min, stops heating, insulation reaction when flowing back
1h, stop stirring；Then 0 ~ 5 DEG C is cooled to, 4 ~ 6h of crystallization, filters to obtain filter cake；
（5）By step（2）Obtained filter cake is respectively washed once with methyl tertiary butyl ether(MTBE) and absolute ethyl alcohol successively, rewinding；Yu Wen
Spend for forced air drying at 45 ~ 60 DEG C, it is product to obtain white crystalline powder.
The white crystalline powder 21.3g that the present embodiment obtains, yield 95.9%, the relevant materials of HPLC are maximum single miscellaneous
0.09%, total miscellaneous 0.29%.
Claims (5)
1. a kind of preparation technology of lobeline hydrochloride, it is characterised in that comprise the following steps：
（1）Under stirring, room temperature condition sequentially adds left-handed lobeline, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) into reactor, mixes
Close uniformly obtained mixture a；The weight ratio of left-handed lobeline, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) is 1：（2~4）：（6~12）；
（2）Under stirring, first to step（1）It is 10% ~ 25% hydrogen chloride-second that mass percent concentration is added in obtained mixture a
Alcoholic solution, mass percent concentration be 10% ~ 25% Hydrochlorine-Ethanol solution addition for left-handed lobeline weight 0.7 ~
1.4 times, then starting to be slowly heated, heating rate is 2 ~ 4 DEG C/min, stops heating up when flowing back, insulation reaction 0.5 ~
2h, stop stirring；Then 0 ~ 5 DEG C is cooled to, 4 ~ 6h of crystallization, filters to obtain filter cake；
（3）By step（2）Obtained filter cake is respectively washed once with methyl tertiary butyl ether(MTBE) and absolute ethyl alcohol successively, rewinding；It is in temperature
Forced air drying at 45 ~ 60 DEG C, it is product to obtain white crystalline powder.
2. the preparation technology of lobeline hydrochloride according to claim 1, it is characterised in that：Step（1）Described in left-handed Lip river
The weight ratio of Belling, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) is 1：2：6.
3. the preparation technology of lobeline hydrochloride according to claim 1, it is characterised in that：Step（1）Described in left-handed Lip river
The weight ratio of Belling, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) is 1：2：8.
4. the preparation technology of lobeline hydrochloride according to claim 1, it is characterised in that：Step（1）Described in left-handed Lip river
The weight ratio of Belling, absolute ethyl alcohol and methyl tertiary butyl ether(MTBE) is 1：2：12.
5. the preparation technology of lobeline hydrochloride according to claim 1, it is characterised in that：Step（2）Described in hydrogen chloride-
The mass percent concentration of ethanol solution is 20%.
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| CN201510659934.0A CN105198795B (en) | 2015-10-14 | 2015-10-14 | A kind of preparation technology of lobeline hydrochloride |
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| CN201510659934.0A CN105198795B (en) | 2015-10-14 | 2015-10-14 | A kind of preparation technology of lobeline hydrochloride |
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| CN105198795A CN105198795A (en) | 2015-12-30 |
| CN105198795B true CN105198795B (en) | 2017-11-21 |
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| CN113981020B (en) * | 2021-12-10 | 2024-09-10 | 江苏恒盛药业有限公司 | Method for synthesizing lobelin hydrochloride intermediate by enzyme catalytic chiral reduction |
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| DE102004034682A1 (en) * | 2004-07-17 | 2006-02-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Shortened process for the preparation of chiral lobeline |
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