CN102557967A - Preparation method of ambroxol hydrochloride - Google Patents
Preparation method of ambroxol hydrochloride Download PDFInfo
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- CN102557967A CN102557967A CN2011104458655A CN201110445865A CN102557967A CN 102557967 A CN102557967 A CN 102557967A CN 2011104458655 A CN2011104458655 A CN 2011104458655A CN 201110445865 A CN201110445865 A CN 201110445865A CN 102557967 A CN102557967 A CN 102557967A
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Abstract
The invention relates to a preparation method of ambroxol hydrochloride. The preparation method comprises the steps of: directly obtaining a compound in formula (2) from simple intermediate 1,3-cyclohexadiene under the catalysis of palladium acetate, reacting with a compound in formula (3) to obtain a compound in formula (4), hydrolyzing the compound in the formula (4) in the presence of potassium carbonate, reducing by sodium borohydride, and carrying out salt forming with hydrochloric acid to obtain ambroxol hydrochloride. Therefore, synthesis of key intermediate trans-4-amino cyclohexanol in a common process is avoided and the separation of racemic products is avoided. The method is simple and feasible in operation, mild in conditions, mature in process and high in product yield and purity, and is suitable for industrialized mass production.
Description
Technical field
The present invention relates to the chemical pharmaceutical technical field, be specifically related to the synthetic of a kind of bulk drug, further relate to the novel method of synthetic hydrochloric acid Transbroncho.
Background technology
Ambroxol HCl is the active metabolite of bromhexine; Be widely used in assisting therapy clinically with the unusual excretory acute/chronic bronchitis of respiratory tract, bronchial asthma, the poverty-stricken disease in newborn respiration road and pulmonary surgery; Has hypotoxicity, advantages such as determined curative effect.The synthetic of Ambroxol HCl will be that main raw material carries out through the trans 4-Trans-4-Amino Cyclohexanol of key intermediate basically all at present.Since high-pressure hydrogenation and the optical resolution that when the trans 4-Trans-4-Amino Cyclohexanol of synthetic key intermediate, need use, and have bigger production risk, and the compound method that therefore is not suitable for traditional Ambroxol HCl is not suitable for industrialized production.
Summary of the invention
The objective of the invention is deficiency, a kind of preparation method of Ambroxol HCl of suitable industrialized production is provided to prior art.
The present invention is achieved in that a kind of preparation method of Ambroxol HCl, and it may further comprise the steps:
Step 1: formula (1) compound is at catalyzer lithium chloride (LiCl), Lithium Acetate (LiOAc), and palladium (Pa (OAc)), para benzoquinone (p-benzoquinone) adds acetate (HOAc-pentane) and reacts at ambient temperature and obtain formula (2) compound,
Step 2: formula (2) compound and formula (3) compound are at acetonitrile (CH
3CN) following reacting by heating, and reaction system reaches reflux state and obtains formula (4) compound,
Step 3: formula (4) compound is at salt of wormwood (K
2CO
3) obtain formula (5) compound under the hydrolysis,
Step 4: formula (5) compound is at Peng Qinghuana (NaBH
4) reduction under obtain formula (6) compound,
Step 5: formula (6) compound salify under hydrochloric acid (HCl) effect obtains formula (7) compound, promptly said Ambroxol HCl,
As the further improvement of such scheme, in step 1, add catalyst manganese dioxide again.Preferably, formula (1) compound and said Manganse Dioxide add at twice.
As the further improvement of such scheme, in step 1, formula (2) compound is at 95-105 ℃, underpressure distillation under the 1mm mercury column.
As the further improvement of such scheme, in step 3, hydrolysis temperature is a room temperature.
As the further improvement of such scheme, in step 4, said Peng Qinghuana (NaBH
4) can substitute by POTASSIUM BOROHYDRIDE 97MIN.
As the further improvement of such scheme, in step 5, said formula (7) compound water recrystallization is used activated carbon decolorizing.
The preparation method of said Ambroxol HCl directly obtains formula (2) compound by simple midbody 1 under the catalysis of palladium; Obtaining formula (4) compound with formula (3) compound reaction, the hydrolysis under salt of wormwood of formula (4) compound is synthesized and is obtained Ambroxol HCl after by sodium borohydride reduction and hydrochloric acid salify; Thereby avoided the synthetic of the trans 4-Trans-4-Amino Cyclohexanol of key intermediate in the ordinary process, avoided the fractionation of racemization product, operation is simple for method of the present invention; Mild condition; Technical maturity, yield and purity are higher, are fit to industrialized production.
Description of drawings
The preparing method's of the Ambroxol HCl that Fig. 1 provides for preferred embodiments of the present invention schema.
Embodiment
In order to make the object of the invention, technical scheme and advantage clearer,, the present invention is further elaborated below in conjunction with accompanying drawing and embodiment.Should be appreciated that specific embodiment described herein only in order to explanation the present invention, and be not used in qualification the present invention.
As shown in Figure 1, the preparation method of Ambroxol HCl may further comprise the steps.
Step 1: formula (1) compound is at catalyzer lithium chloride (LiCl), Lithium Acetate (LiOAc), and palladium (Pa (Oac)), para benzoquinone (p-benzoquinone) adds acetate (HOAc-pentane) and reacts at ambient temperature and obtain formula (2) compound,
Wherein, temperature of reaction is a room temperature, and solvent is a Skellysolve A.Raw material 1 (being formula (1) compound) and Manganse Dioxide add at twice, can obtain higher yield.At 95-105 ℃, underpressure distillation obtains formula (2) compound under the 1mm mercury column.
In this embodiment, with 5.1 gram (0.12mol) lithium chlorides, 12.2 gram (0.12mol) Lithium Acetates; 0.67 the palladium of gram (3mmol) and 12.9 gram (0.12mol) para benzoquinone add in 200 milliliters of acetate, are stirred to dissolving fully under the room temperature; The 1 that adds 300 milliliters of Skellysolve As and 4.82 grams (60mmol) subsequently stirs after 4 hours under the room temperature; The Manganse Dioxide that adds 2.87 grams (33mmol); Stir under the room temperature after 4 hours, continue to add Manganse Dioxide and 20 milliliters of acetate (33mmol) of 2.87 grams, vigorous stirring 30 minutes.In mixture, add 2.6 gram (60mmol), lithium chloride and 300 milliliters of pentanes, continue to add the 1 of 4.82 grams (60mmol); Stirred overnight under the room temperature; The saturated nacl aqueous solution that adds 70 milliliters is divided into after the stirring, and water filters the back with Skellysolve A extraction (2 * 300 milliliters).Merge organic phase water (2 * 120 milliliters), 120 milliliters of unsaturated carbonate calcium and saturated sodium-chloride washing are revolved after the dried over mgso and are done back underpressure distillation (95-105 ℃, the 1mm mercury column), obtain formula (2) compound of 14.6-15.6g (71-75% yield).
Step 2: formula (2) compound and formula (3) compound are at acetonitrile (CH
3CN) following reacting by heating, and reaction system reaches reflux state and obtains formula (4) compound,
Wherein, formula (2) compound and formula (3) compound are at acetonitrile (CH
3CN) reacting by heating under, reaction system must reach reflux state, just can obtain formula (4) compound.
In this embodiment, 8.37 gram formula (2) compounds (50mmol) and 20 gram formula (3) compounds (72mmol) are joined in 400 milliliters of acetonitriles, stirred 21 hours in the nitrogen protection refluxed.Added 5 gram solid sodium bicarbonate vigorous stirring 2 as a child.Cool to the ether after-filtration that adds 800 milliliters after the room temperature.Collect organic phase and revolve dried, with obtaining 18 gram yellow solid formula (4) compounds (90% yield) behind the ethyl alcohol recrystallization.
Step 3: formula (4) compound obtains formula (5) compound under salt of wormwood (K2CO3) hydrolysis,
Wherein, hydrolysis temperature is a room temperature.
In this embodiment, 18 gram formula (4) compounds (43mmol) and 6.17 are restrained the water that salt of wormwood (44.7mmol) join in 100 ml methanol and add 25 milliliters.After the stirring at room 6 hours, the reaction solution choosing is done.Add 100 milliliters of ETHYLE ACETATE.Water (2 * 20 milliliters) and saturated aqueous common salt (2 * 20 milliliters) washing, dried with revolving behind the anhydrous magnesium sulfate drying.Use ethyl alcohol recrystallization, obtain yellow solid formula (5) compound of 14.6 grams (90% yield).
Step 4: formula (5) compound is at Peng Qinghuana (NaBH
4) reduction under obtain formula (6) compound,
Wherein, Peng Qinghuana (NaBH
4) can substitute by POTASSIUM BOROHYDRIDE 97MIN, use potassium borohydride reduction, effect is the same.
In this embodiment, 14.6 gram formula (5) compounds (38.8mmol) and 1.77 gram Peng Qinghuanas (46.6mmol) are joined in 100 milliliters of ethanol stirring at room 24 hours.Add 10 ml waters, revolve dried.Add 100 milliliters and add 100 milliliters of ETHYLE ACETATE.Water (2 * 20 milliliters) and saturated aqueous common salt (2 * 20 milliliters) washing, dried with revolving behind the anhydrous magnesium sulfate drying.Use ethyl alcohol recrystallization, obtain yellow solid formula (6) compound of 13.2 grams (90% yield).
Step 5: formula (6) compound salify under hydrochloric acid (HCl) effect obtains formula (7) compound, promptly said Ambroxol HCl,
Wherein, formula (7) compound water recrystallization is used activated carbon decolorizing.
In this embodiment, 13.2 gram formula (6) compound dissolutions in 20 milliliters of acetone, are added 5 milliliters of concentrated hydrochloric acids.Stirred 4 hours, with solid filtering.Filter cake obtains faint yellow solid with oven dry behind 10 milliliters of washing with acetones 2 times.This solid water recrystallization is also used activated carbon decolorizing, obtains white solid formula (7) compound of 13 grams (90% yield).
In sum, the preparation method of Ambroxol HCl provided by the invention is directly by simple midbody 1; The 3-cyclohexadiene obtains formula (2) compound under the catalysis of palladium, obtaining formula (4) compound with formula (3) compound reaction, formula (4) compound under salt of wormwood hydrolysis after by sodium borohydride reduction and hydrochloric acid salify; Synthetic obtain Ambroxol HCl, thereby avoided the synthetic of the trans 4-Trans-4-Amino Cyclohexanol of key intermediate in the ordinary process, avoided the fractionation of racemization product; Operation is simple for method of the present invention, mild condition, technical maturity; Yield and purity are higher, are fit to industrialized production.
The foregoing description only is used for further specifying the preparation method of the present invention for a kind of Ambroxol HCl; But the present invention is not limited to embodiment; Every foundation technical spirit of the present invention all falls in the protection domain of technical scheme of the present invention any simple modification, equivalent variations and modification that above embodiment did.
Claims (7)
1. the preparation method of an Ambroxol HCl, it is characterized in that: it may further comprise the steps:
Step 1: formula (1) compound is at catalyzer lithium chloride (LiCl), Lithium Acetate (LiOAc), and palladium (Pa (OAc)), para benzoquinone (p-benzoquinone) adds acetate (HOAc-pentane) and reacts at ambient temperature and obtain formula (2) compound,
Step 2: formula (2) compound and formula (3) compound are at acetonitrile (CH
3CN) following reacting by heating, and reaction system reaches reflux state and obtains formula (4) compound,
Step 3: formula (4) compound is at salt of wormwood (K
2CO
3) obtain formula (5) compound under the hydrolysis,
Step 4: formula (5) compound is at Peng Qinghuana (NaBH
4) reduction under obtain formula (6) compound,
Step 5: formula (6) compound salify under hydrochloric acid (HCl) effect obtains formula (7) compound, promptly said Ambroxol HCl,
2. the preparation method of a kind of Ambroxol HCl according to claim 1 is characterized in that: in step 1, add catalyst manganese dioxide again.
3. the preparation method of a kind of Ambroxol HCl according to claim 2, it is characterized in that: formula (1) compound and said Manganse Dioxide add at twice.
4. the preparation method of a kind of Ambroxol HCl according to claim 1 is characterized in that: in step 1, formula (2) compound is at 95-105 ℃, underpressure distillation under the 1mm mercury column.
5. the preparation method of a kind of Ambroxol HCl according to claim 1, it is characterized in that: in step 3, hydrolysis temperature is a room temperature.
6. the preparation method of a kind of Ambroxol HCl according to claim 1 is characterized in that: in step 4, and said Peng Qinghuana (NaBH
4) can substitute by POTASSIUM BOROHYDRIDE 97MIN.
7. the preparation method of a kind of Ambroxol HCl according to claim 1, it is characterized in that: in step 5, said formula (7) compound water recrystallization is used activated carbon decolorizing, changes in quality to white solid from faint yellow solid.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964257A (en) * | 2012-11-24 | 2013-03-13 | 沈阳新马药业有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN103755577A (en) * | 2014-01-17 | 2014-04-30 | 浙江浙邦制药有限公司 | Method for recovering ambroxol base from ambroxol hydrochloride refined mother solution |
| CN104803860A (en) * | 2015-05-12 | 2015-07-29 | 山东罗欣药业集团股份有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN111072500A (en) * | 2019-11-15 | 2020-04-28 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of ambroxol hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11124369A (en) * | 1997-10-20 | 1999-05-11 | Sawai Pharmaceutical Co Ltd | New quinazoline derivative and its pharmaceutical use |
| CN1433396A (en) * | 1999-08-12 | 2003-07-30 | 尼科克斯公司 | Pharmaceutical compounds |
| US20050075386A1 (en) * | 2001-12-17 | 2005-04-07 | Heidi Sahagun-Krause | N-carbacycle monosubstituted indolocarbazoles as protein kinase inhibitors |
-
2011
- 2011-12-28 CN CN2011104458655A patent/CN102557967A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11124369A (en) * | 1997-10-20 | 1999-05-11 | Sawai Pharmaceutical Co Ltd | New quinazoline derivative and its pharmaceutical use |
| CN1433396A (en) * | 1999-08-12 | 2003-07-30 | 尼科克斯公司 | Pharmaceutical compounds |
| US20050075386A1 (en) * | 2001-12-17 | 2005-04-07 | Heidi Sahagun-Krause | N-carbacycle monosubstituted indolocarbazoles as protein kinase inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| ANNA L. E. LARSSON等: "Synthesis of chiral and achiral analogues of ambroxol via palladiumcatalysed Reaction", 《JOURNAL OF THE CHEMICAL SOCIETY》, no. 19, 31 December 1997 (1997-12-31) * |
| JAN-E. BäCKVALL等: "STEREOSELECTIVE 1,4-FUNCTIONALIZATIONS OF CONJUGATED DIENES: cis- AND trans-1-ACETOXY-4-(DICARBOMETHOXYMETHYL)-2-CYCLOHEXENE", 《ORGANIC SYNTHESES》, vol. 69, 31 December 1990 (1990-12-31), pages 38 - 1 * |
| 何永志等: "盐酸氨溴索合成工艺研究", 《天津药学》, vol. 16, no. 2, 30 April 2004 (2004-04-30) * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964257A (en) * | 2012-11-24 | 2013-03-13 | 沈阳新马药业有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN102964257B (en) * | 2012-11-24 | 2014-08-06 | 沈阳新马药业有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN103755577A (en) * | 2014-01-17 | 2014-04-30 | 浙江浙邦制药有限公司 | Method for recovering ambroxol base from ambroxol hydrochloride refined mother solution |
| CN103755577B (en) * | 2014-01-17 | 2015-11-18 | 浙江浙邦制药有限公司 | A kind of method reclaiming Transbroncho alkali from Ambroxol HCl refinement mother liquor |
| CN104803860A (en) * | 2015-05-12 | 2015-07-29 | 山东罗欣药业集团股份有限公司 | Ambroxol hydrochloride compound and medicine composition thereof |
| CN111072500A (en) * | 2019-11-15 | 2020-04-28 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of ambroxol hydrochloride |
| CN111072500B (en) * | 2019-11-15 | 2022-12-06 | 山东罗欣药业集团恒欣药业有限公司 | Preparation method of ambroxol hydrochloride |
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Application publication date: 20120711 |