CN105198795A - Preparation technique of lobeline hydrochloride - Google Patents
Preparation technique of lobeline hydrochloride Download PDFInfo
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- CN105198795A CN105198795A CN201510659934.0A CN201510659934A CN105198795A CN 105198795 A CN105198795 A CN 105198795A CN 201510659934 A CN201510659934 A CN 201510659934A CN 105198795 A CN105198795 A CN 105198795A
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- lobeline
- butyl ether
- handed
- dehydrated alcohol
- tertiary butyl
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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 invention relates to a preparation technique of lobeline hydrochloride, which comprises the following steps: sequentially adding levo-lobeline, anhydrous ethanol and methyl tert-butyl ether into a reactor at room temperature under stirring conditions, and uniformly mixing to obtain a mixture a; adding a 10-25 wt% hydrogen chloride-ethanol solution into the mixture a, starting slowly heating at the heating rate of 2-4 DEG C/minute, stopping heating when reflux appears, keeping the temperature to react for 0.5-2 hours, and stopping stirring; cooling to 0-5 DEG C, crystallizing for 4-6 hours, and filtering to obtain a filter cake; sequentially washing the filter cake with methyl tert-butyl ether and anhydrous ethanol, and collecting the material; and carrying out forced air drying at 45-60 DEG C to obtain the white crystalline powder product. The method enhances the yield and lowers the cost. Various indexes of the product conform to Chinese Pharmacopoeia 2010 Edition and Chinese Pharmacopoeia 2015 Edition.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of preparation technology of lobeline hydrochloride.
Background technology
Lobeline hydrochloride is white crystals or granulated powders, odorless, bitter; The aqueous solution is slightly acidic reaction.This product is easily molten in ethanol or chloroform, dissolves in water.
Lobeline hydrochloride can optionally excited chemical receptor of carotid body, reflectingly excited respiratory centre, and heavy dose also can direct excited respiratory centre.Can stimulation of carotid sinus and chemoreceptor of aortic body (being N1 acceptor), the reflectivity excited respiratory centre in ground and make accelerated breathing, but direct excitation be there is no to respiratory centre.Also there is reflexive excitation to vagus nerve maincenter and vasomotor center simultaneously; The first excitement of vegetative ganglia is then blocked.Asphyxia neonatorum, inhalation anesthetic and other central depressant are as suffocating of causing of morphine or barbitals poisoning, carbon monoxide and respiratory insufficiency that the transmissible disease such as pneumonia, diphtheria causes.
Current use salifying method: adopt dehydrated alcohol system, add left-handed lobeline alkali salify.Yield about 65%, the related substance index of product is difficult to meet China's 2010 editions pharmacopeia indexs.
Summary of the invention
The object of the present invention is to provide a kind of preparation technology of lobeline hydrochloride, the method increase yield, reduce costs, each index of product all meets China's 2010 editions standards of pharmacopoeia and 2015 editions standards of pharmacopoeia.
A preparation technology for lobeline hydrochloride, comprises the steps:
(1), under stirring, room temperature condition adds left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether successively in reactor, mixes obtained mixture a; The weight ratio of left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether is 1:(2 ~ 4): (6 ~ 12);
(2) under stirring, adding mass percent concentration in the mixture a first obtained to step (1) is 10% ~ 25% Hydrochlorine-Ethanol solution, 0.7 ~ 1.4 times of mass percent concentration to be the add-on of 10% ~ 25% Hydrochlorine-Ethanol solution the be weight of left-handed lobeline, then slow heating is started, temperature rise rate is 2 ~ 4 DEG C/min, stop when there is backflow heating up, insulation reaction 0.5 ~ 2h, stops stirring; Then be cooled to 0 ~ 5 DEG C, crystallization 4 ~ 6h, filter to obtain filter cake;
(3) filter cake step (2) obtained respectively is washed once with methyl tertiary butyl ether and dehydrated alcohol successively, rewinding; Forced air drying at temperature is 45 ~ 60 DEG C, obtains white crystalline powder and is product.
Described in step (1), the weight ratio of left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether is 1:2:6.
Described in step (1), the weight ratio of left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether is 1:2:8.
Described in step (1), the weight ratio of left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether is 1:2:12.
Described in step (2), the mass percent concentration of Hydrochlorine-Ethanol solution is 20%.
Compared with prior art, the present invention has following beneficial effect:
The preparation technology of lobeline hydrochloride provided by the invention is compared with conventional preparation techniques, and yield improves more than 30%, assorted, the total assorted reduction by 0.1% of related substance list.Processing method is simple to operate, and product index meets 2010 editions and 2015 editions standards of pharmacopoeia, can carry out suitability for industrialized production.
Embodiment
Below in conjunction with 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 adopt is commercially available prod, and the left-handed lobeline of purchase must meet enterprises standard: off-white color is to light yellow solid, and moisture must not more than 0.5%, containing C
22h
26clNO
2must not be less than 99.0%, list must not mix 0.5%.
comparative example
In 500mL tri-dry mouth reaction flask, add left-handed lobeline 20g, dehydrated alcohol 140g successively, add 20% ethanol solution of hydrogen chloride 14g after stirring evenly, start slowly to heat, temperature rise rate is 2 ~ 4 DEG C/min, stops heating up when there is backflow, insulation reaction 1h; Then be cooled to 0 DEG C, crystallization 1h, filter to obtain filter cake, filter cake is cooled dehydrated alcohol and wash once, rewinding; Be 45 ~ 60 DEG C in temperature, forced air drying 6h, obtains white crystalline powder 14.4g, the maximum list of yield 64.9%, HPLC related substance assorted 0.17%, and always assorted 0.41%.
embodiment 1
A preparation technology for lobeline hydrochloride, comprises the steps:
(1), under stirring, room temperature condition adds left-handed lobeline 20g, dehydrated alcohol 40g and methyl tertiary butyl ether 120g successively in reactor, mixes obtained mixture a;
(2), under stirring, adding mass percent concentration in the mixture a first obtained to step (1) is 20% Hydrochlorine-Ethanol solution 14g, then starts slow heating, temperature rise rate is 2 ~ 4 DEG C/min, stop when there is backflow heating up, insulation reaction 1h, stops stirring; Then be cooled to 0 ~ 5 DEG C, crystallization 4 ~ 6h, filter to obtain filter cake;
(3) filter cake step (2) obtained respectively is washed once with methyl tertiary butyl ether and dehydrated alcohol successively, rewinding; Forced air drying at temperature is 45 ~ 60 DEG C, obtains white crystalline powder and is product.
The white crystalline powder 21.2g that the present embodiment obtains, the maximum list of yield 95.5%, HPLC related substance assorted 0.13%, always mixes 0.28%.
embodiment 2
A preparation technology for lobeline hydrochloride, comprises the steps:
(2), under stirring, room temperature condition adds left-handed lobeline 20g, dehydrated alcohol 40g and methyl tertiary butyl ether 160g successively in reactor, mixes obtained mixture a;
(2), under stirring, adding mass percent concentration in the mixture a first obtained to step (1) is 20% Hydrochlorine-Ethanol solution 14g, then starts slow heating, temperature rise rate is 2 ~ 4 DEG C/min, stop when there is backflow heating up, insulation reaction 1h, stops stirring; Then be cooled to 0 ~ 5 DEG C, crystallization 4 ~ 6h, filter to obtain filter cake;
(4) filter cake step (2) obtained respectively is washed once with methyl tertiary butyl ether and dehydrated alcohol successively, rewinding; Forced air drying at temperature is 45 ~ 60 DEG C, obtains white crystalline powder and is product.
The white crystalline powder 21.3g that the present embodiment obtains, the maximum list of yield 95.9%, HPLC related substance assorted 0.12%, always mixes 0.27%.
embodiment 3
A preparation technology for lobeline hydrochloride, comprises the steps:
(3), under stirring, room temperature condition adds left-handed lobeline 20g, dehydrated alcohol 40g and methyl tertiary butyl ether 240g successively in reactor, mixes obtained mixture a;
(2), under stirring, adding mass percent concentration in the mixture a first obtained to step (1) is 20% Hydrochlorine-Ethanol solution 14g, then starts slow heating, temperature rise rate is 2 ~ 4 DEG C/min, stop when there is backflow heating up, insulation reaction 1h, stops stirring; Then be cooled to 0 ~ 5 DEG C, crystallization 4 ~ 6h, filter to obtain filter cake;
(5) filter cake step (2) obtained respectively is washed once with methyl tertiary butyl ether and dehydrated alcohol successively, rewinding; Forced air drying at temperature is 45 ~ 60 DEG C, obtains white crystalline powder and is product.
The white crystalline powder 21.3g that the present embodiment obtains, the maximum list of yield 95.9%, HPLC related substance assorted 0.09%, always mixes 0.29%.
Claims (5)
1. a preparation technology for lobeline hydrochloride, is characterized in that comprising the steps:
(1), under stirring, room temperature condition adds left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether successively in reactor, mixes obtained mixture a; The weight ratio of left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether is 1:(2 ~ 4): (6 ~ 12);
(2) under stirring, adding mass percent concentration in the mixture a first obtained to step (1) is 10% ~ 25% Hydrochlorine-Ethanol solution, 0.7 ~ 1.4 times of mass percent concentration to be the add-on of 10% ~ 25% Hydrochlorine-Ethanol solution the be weight of left-handed lobeline, then slow heating is started, temperature rise rate is 2 ~ 4 DEG C/min, stop when there is backflow heating up, insulation reaction 0.5 ~ 2h, stops stirring; Then be cooled to 0 ~ 5 DEG C, crystallization 4 ~ 6h, filter to obtain filter cake;
(3) filter cake step (2) obtained respectively is washed once with methyl tertiary butyl ether and dehydrated alcohol successively, rewinding; Forced air drying at temperature is 45 ~ 60 DEG C, obtains white crystalline powder and is product.
2. the preparation technology of lobeline hydrochloride according to claim 1, is characterized in that: described in step (1), the weight ratio of left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether is 1:2:6.
3. the preparation technology of lobeline hydrochloride according to claim 1, is characterized in that: described in step (1), the weight ratio of left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether is 1:2:8.
4. the preparation technology of lobeline hydrochloride according to claim 1, is characterized in that: described in step (1), the weight ratio of left-handed lobeline, dehydrated alcohol and methyl tertiary butyl ether is 1:2:12.
5. the preparation technology of lobeline hydrochloride according to claim 1, is characterized in that: described in step (2), the mass percent concentration of Hydrochlorine-Ethanol solution is 20%.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 true CN105198795A (en) | 2015-12-30 |
| CN105198795B CN105198795B (en) | 2017-11-21 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113981020A (en) * | 2021-12-10 | 2022-01-28 | 江苏恒盛药业有限公司 | Method for synthesizing lobeline hydrochloride intermediate by enzymatic chiral reduction |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014791A1 (en) * | 2004-07-17 | 2006-01-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for manufacturing of chiral lobelin |
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2015
- 2015-10-14 CN CN201510659934.0A patent/CN105198795B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014791A1 (en) * | 2004-07-17 | 2006-01-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for manufacturing of chiral lobelin |
Non-Patent Citations (2)
| Title |
|---|
| ROBERT CHÊNEVERT，ET AL.: "Synthesis of (-)-lobeline via enzymatic desymmetrization of lobelanidine", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| VLADIMIR B. BIRMAN，ET AL.: "Enantioselective Synthesis of Lobeline via Nonenzymatic Desymmetrization", 《ORGANIC LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113981020A (en) * | 2021-12-10 | 2022-01-28 | 江苏恒盛药业有限公司 | Method for synthesizing lobeline hydrochloride intermediate by enzymatic chiral reduction |
| 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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| Publication number | Publication date |
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| CN105198795B (en) | 2017-11-21 |
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