CN102050748B - Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol - Google Patents
Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol Download PDFInfo
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Abstract
The invention relates to a method for preparing an expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol. Nitrobenzaldehyde and trans-4-amino cyclohexanol are subjected to the combination reaction of condensation, carbon and nitrogen double-bond hydrogenation and nitro reduction to prepare the trans-4-[(2-amino benzyl) amino]-cyclohexanol in a high-yield mode. The method has the advantages of reasonable process route design, simple and convenient process, high reaction yield, low raw material cost and no harsh reaction conditions and is easy for scale production.
Description
[technical field]
The present invention relates to medical manufacturing technology field, specifically, be a kind of expelling phlegm drugs Transbroncho key intermediate trans-the 4-[(2-aminobenzyl) amino]-new preparation process of hexalin.This intermediate directly carries out bromination reaction and namely gets Transbroncho.
[background technology]
Transbroncho (Ambroxol), chemical name: trans-4-[(2-amino-3, the 5-dibromo-benzyl) amino]-hexalin, U.S. chemical abstract registration number CAS:18683-91-5 has the following formula structure:
Transbroncho be by German Boehringer Ingelheim company in 1984 the medicine of exploitation listing at first, now be the expectorant commonly used of world many countries approval use.Transbroncho is the active metabolite of bromhexine, be widely used in acute/chronic bronchitis, bronchial asthma, the treatment of transient respiratory distress of the newborn disease and the assisting therapy of pulmonary surgery with the respiratory tract abnormal secretion clinically, it is low to have toxicity, advantages such as determined curative effect.Hydrochloride income version Chinese Pharmacopoeia in 2010 and 2009 editions British Pharmacopoeias of Transbroncho have a plurality of preparation varieties to use clinically.
The preparation method of relevant Transbroncho has many bibliographical informations both at home and abroad, as US 3536713, ES544292, ES 525701, ES 526526, ES2002438, (synthesizing of Ambroxol HCl such as CN 101337897, Yu Shuhai, Chinese Journal of Pharmaceuticals, 1996,27 (10): 435-437), (Study of synthesis method of the new drug Transbroncho that eliminates the phlegm such as thunder light is clear, China's pharmaceutical chemistry magazine, 2000,10 (3): 205-206), (Ambroxol HCl synthesising process research such as how to always cherish the memory of, the Tianjin pharmacy, 2004,16 (2): 5-6).
Jia Weiyuan (the Transbroncho graphical Synthetic Routes, Chinese Journal of Pharmaceuticals, 1995,26 (5): 235-237) relevant Transbroncho synthetic method is summarized as mainly contains three classes:
(1) with the Ortho Nitro Toluene or derivatives thereof be the first kind synthetic method of raw material, comprising:
(i) Ortho Nitro Toluene or derivatives thereof elder generation and trans-4-Trans-4-Amino Cyclohexanol condensation, and then carry out the synthetic route that the phenyl ring bromination prepares Transbroncho:
(ii) the Ortho Nitro Toluene or derivatives thereof carries out the synthetic route that condensation prepares Transbroncho with trans-4-Trans-4-Amino Cyclohexanol after finishing the phenyl ring bromination earlier again, wherein through 2-amino-3, the route (as CN 101337897 reported method) that 5-dibromobenzene formyl chloride prepares Transbroncho is needs use sodium borohydride or be expensive reagent such as hydrogen aluminium lithium usually:
(iii) the Ortho Nitro Toluene or derivatives thereof carries out single bromination of Ortho Nitro Toluene derivative earlier, prepares the synthetic route of Transbroncho again with trans-4-Trans-4-Amino Cyclohexanol condensation, bromination:
(2) with the isatoic anhydride be raw material, and the second class synthetic method for preparing Transbroncho after trans-4-Trans-4-Amino Cyclohexanol condensation again with Lithium Aluminium Hydride reduction, bromination:
(3) be raw material with the m-dibromobenzene carboxylic acid derivatives, with trans-4-Trans-4-Amino Cyclohexanol acetic ester condensation, prepare the 3rd class synthetic method of Transbroncho by taking off isoindoline ring, borane reduction again:
In addition, (synthesizing of Ambroxol HCl such as Yu Shuhai are arranged, Chinese Journal of Pharmaceuticals, 1996,27 (10): 435-437), thunder light waits the (Study of synthesis method of the new drug Transbroncho that eliminates the phlegm clearly, China's pharmaceutical chemistry magazine, 2000,10 (3): 205-206), watch and (Ambroxol HCl synthesising process research, Tianjin pharmacy such as always cherish the memory of, 2004,16 (2): 5-6) reported that with the 2-Aminobenzoate be raw material, through the phenyl ring bromination, with hydrazine hydrate ammonia solution, introduce the sulfonyloxy methyl diazanyl as leavings group with the Methanesulfonyl chloride amidation, with the condensation of trans 4-Trans-4-Amino Cyclohexanol, prepare the method for Transbroncho at last with sodium borohydride or catalytic hydrogenating reduction carbon-to-nitrogen double bon:
Can see that from the various synthetic routes of the Transbroncho of above-mentioned bibliographical information and method compound I is the most direct, the most important senior intermediate of preparation Transbroncho, can prepare Transbroncho by the direct bromination of I.Therefore, simple and effective prepares I just becomes the synthetic key issue of improvement Transbroncho, and this has great realistic meaning to adopting the green production technology, reduce the Transbroncho production cost, reducing environmental pollution.
The disclosed I preparation method of international literature mainly contains following several:
(1) von Johannes Keck (Synthese der Metaboliten Bisolvon, Liebigs Ann.Chem.1967,707:107-111) reported with the isatoic anhydride to be raw material, and obtained I through Lithium Aluminium Hydride reduction again after trans-4-Trans-4-Amino Cyclohexanol condensation, synthetic route is as follows:
This route uses expensive reagent LiAlH
4, two step yields only are 29.8%, the cost height is unsuitable for large-scale production.
(2) (Synthesis of chiral and achiral analogues of ambroxol via palladium-catelysed reactions such as A.L.E.Larsson, J.Chem.Soc., Perkin Trans.1,1997,2873-2877) reported with the synthetic I of following route:
This route steps is loaded down with trivial details, uses multiple expensive reagent, no using value.
(3) ES 544291 has reported with the o-Carboxynitrobenzene to be raw material, and obtains I through the reduction of deprotection, Lithium Aluminium Hydride again after trans-4-Trans-4-Amino Cyclohexanol acetic ester condensation:
This route reaction step is many, uses costliness to go back original reagent LiAlH
4, still be unfavorable for the mass-producing application.
Because the defective that exists in the I building-up process, invent the operational path of a low cost, preparation I simple to operation, to realize with green, mode large-scale production I is significant economically.
[summary of the invention]
The objective of the invention is to overcome the deficiencies in the prior art, the new preparation process of a kind of Transbroncho key intermediate I is provided.
Design of the present invention is: be that raw material and trans-4-Trans-4-Amino Cyclohexanol process condensation-carbon-to-nitrogen double bon hydrogenation-nitroreduction " are treated different things alike " to react and directly obtained trans-4-[(2-aminobenzyl with the Ortho Nitro Benzaldehyde) amino]-hexalin I.
The objective of the invention is to be achieved through the following technical solutions:
Consider that from the angle of synthesis technique and process compound I only needs a step bromination can prepare Transbroncho, is the intermediate of Transbroncho most critical.If the sieve of inventing a kind of I just, economic preparation route, just can open up the green of a Transbroncho, the economic route for preparing.
The synthetic route of I proposed by the invention, purpose are to overcome the defective that existing route steps is long, Atom economy is not good, the supplementary material cost is high, and the preparation method of a kind of low cost, high yield, I easy and simple to handle is provided; The synthetic route of I proposed by the invention was not all carried out description in disclosed document.
Operational path of the present invention is as follows:
A kind of prepare expelling phlegm drugs Transbroncho key intermediate trans-the 4-[(2-aminobenzyl) amino]-method of hexalin, its concrete steps are: Ortho Nitro Benzaldehyde and trans-4-Trans-4-Amino Cyclohexanol condensation obtain Schiff's base II, II directly carries out catalytic hydrogenating reduction with " treating different things alike " reaction formation then, obtains trans-4-[(2-aminobenzyl) amino]-hexalin I.
Specifically, the mol ratio of Ortho Nitro Benzaldehyde and trans-4-Trans-4-Amino Cyclohexanol is 1.0: 1.0～1.0: 2.5;
Can use catalyzer or not use catalyzer when preparation Schiff's base II, employed catalyzer can be organic bases, mineral alkali, organic acid, mineral acid;
Described hydrogenation catalyst is transition-metal catalyst when Schiff's base II reduces, the hydrogenating reduction catalyzer of deriving as Pd, Ni, Pt, Rh metal.
After reaction finishes, can reclaim excessive trans-4-Trans-4-Amino Cyclohexanol and hydrogenation catalyst, therefore, this synthesis route is the preparation method of a kind of green, economy.
Compared with prior art, positively effect of the present invention is:
(1) Process Route of the present invention is reasonable, and condensation, carbon-to-nitrogen double bon hydrogenation, nitroreduction are carried out " treating different things alike " reaction, and reaction process and simple to operation is a high efficiency reaction process;
(2) the present invention avoids the use of expensive auxiliary reagent by the direct synthetic product of raw material;
(3) hydrogenation catalyst can reclaim recycled, avoids using reductive agents such as expensive sodium borohydride, Lithium Aluminium Hydride;
(4) the present invention is easy and simple to handle, and the yield height does not have harsh reaction conditions, is suitable for large-scale production.
[embodiment]
Below provide a kind of preparation expelling phlegm drugs of the present invention Transbroncho key intermediate trans-the 4-[(2-aminobenzyl) amino]-embodiment of hexalin method.
Product I with thin-layer chromatography chromatogram (TLC), fusing point (mp), mass spectrum (MS) and proton nmr spectra (
1H NMR) structure of compound is proved conclusively in test.
Embodiment 1
With 150ml methyl alcohol, Ortho Nitro Benzaldehyde (10.0g, 66.2mmol), trans-4-Trans-4-Amino Cyclohexanol (11.4g, 99.0mmol), sodium methylate (0.2g, 3.7mmol) join in the autoclave pressure, stirring at room 2.5h, add 10% Pd/C catalyzer (0.5g) then, charge into hydrogen behind the nitrogen replacement air, stirring at room 8h under hydrogen pressure 0.2～0.3MPa.Opening autoclave pressure behind the nitrogen replacement hydrogen, the Pd/C catalyzer is reclaimed in filtering, reclaims solvent methanol, column chromatography for separation get product I be 13.9g (eluent: ethyl acetate/petroleum ether/triethylamine (v/v/v)=1/1/0.01), yield 95.3%, 93～94 ℃ of mp.Get by product 2-aminobenzyl alcohol 0.36g, yield 4.4%.Reclaim trans-4-Trans-4-Amino Cyclohexanol raw material 3.3g.
The spectroscopic data of product I:
EI-MS(m/z)：220[M
+]；
1H?NMR(500MHz，CDCl
3，ppm)，δ：1.12～1.17(m，2H，CH
2CHN)，1.25～1.36(m，4H，CH
2CHOH)，1.96～2.03(m，4H，CH
2，OH，NH)，2.48～2.51(m，1H，CHN)，3.5～4.8(brs，2H，ArNH
2)，3.60～3.66(m，1H，CHOH)，3.80(brs，2H，ArCH
2N)，6.65～6.69(m，2H，ArH)，7.00(t，1H，J＝7.1Hz，ArH)，7.08(td，1H，J
1＝7.6Hz，J
2＝1.2Hz，ArH)。
The spectroscopic data of by product 2-aminobenzyl alcohol:
EI-MS(m/z)：123[M
+]；
1H?NMR(500MHz，CDCl
3，ppm)，δ：3.28(brs，3H，NH
2，OH)，4.68(s，2H，CH
2)，6.70～6.74(m，2H，ArH)，7.08(d，1H，J＝7.2Hz，ArH)，7.14(t，1H，J＝7.2Hz，ArH)。
Embodiment 2
With 150ml methyl alcohol, Ortho Nitro Benzaldehyde (10.0g, 66.2mmol), trans-4-Trans-4-Amino Cyclohexanol (10.0g, 86.8mmol), sodium methylate (0.2g, 3.7mmol) join in the autoclave pressure, stirring at room 2.5h, add 10% Pd/C catalyzer (0.5g) then, charge into hydrogen behind the nitrogen replacement air, stirring at room 8h under hydrogen pressure 0.5～0.6MPa.Opening autoclave pressure behind the nitrogen replacement hydrogen, filtering Pd/C catalyzer reclaims solvent methanol, column chromatography for separation get product I be 13.8g (eluent: ethyl acetate/petroleum ether/triethylamine (v/v/v)=1/1/0.01), yield 94.6%.Get by product 2-aminobenzyl alcohol 0.30g, yield 3.7%; Get by product 2-aminotoluene 0.09g, yield 1.3%.Reclaim trans-4-Trans-4-Amino Cyclohexanol raw material 1.8g.
The spectroscopic data of product I is with embodiment 1.
The spectroscopic data of by product 2-aminobenzyl alcohol is with embodiment 1.
The spectroscopic data of by product 2-aminotoluene:
EI-MS(m/z)：107[M
+]；
1H?NMR(500MHz，CDCl
3，ppm)，δ：2.25(s，3H，CH
3)，3.74(s，2H，NH
2)，6.76(d，1H，J＝7.3Hz，ArH)，6.80(t，1H，J＝7.1Hz，ArH)，7.14(t，2H，J＝7.2Hz，ArH)。
Embodiment 3
With 150ml methyl alcohol, Ortho Nitro Benzaldehyde (10.0g, 66.2mmol), trans-4-Trans-4-Amino Cyclohexanol (10.0g, 86.8mmol), sodium methylate (0.2g, 3.7mmol) join in the autoclave pressure, stirring at room 2.5h, add Raney-Ni catalyzer (3.0g) then, charge into hydrogen behind the nitrogen replacement air, stirring at room 8h under hydrogen pressure 0.5～0.6MPa.Opening autoclave pressure behind the nitrogen replacement hydrogen, catalyzer is reclaimed in filtering, reclaims solvent methanol, column chromatography for separation get product I be 13.1g (eluent: ethyl acetate/petroleum ether/triethylamine (v/v/v)=1/1/0.01), yield 89.9%.Get by product 2-aminobenzyl alcohol 0.33g, yield 4.0%; Get by product 2-aminotoluene 0.11g; Yield 1.6%.Reclaim trans-4-Trans-4-Amino Cyclohexanol raw material 1.8g.
Embodiment 4
With 150ml methyl alcohol, Ortho Nitro Benzaldehyde (10.0g, 66.2mmol), trans-4-Trans-4-Amino Cyclohexanol (8.0g, 69.5mmol), sodium methylate (0.2g, 3.7mmol) join in the autoclave pressure, stirring at room 14h, add 10% Pd/C catalyzer (0.5g) then, charge into hydrogen behind the nitrogen replacement air, stirring at room 8h under hydrogen pressure 2.1～2.2MPa.Opening autoclave pressure behind the nitrogen replacement hydrogen, the Pd/C catalyzer is reclaimed in filtering, reclaims solvent methanol, column chromatography for separation get product I be 7.3g (eluent: ethyl acetate/petroleum ether/triethylamine (v/v/v)=1/1/0.01), yield 50.0%.Get by product 2-aminobenzyl alcohol 3.6g, yield 44.1%; Get by product 2-aminotoluene 0.30g, yield 4.2%.
Embodiment 5
With 150ml methyl alcohol, Ortho Nitro Benzaldehyde (10.0g, 66.2mmol), trans-4-Trans-4-Amino Cyclohexanol (9.0g, 78.1mmol), sodium methylate (0.2g, 3.7mmol) join in the autoclave pressure, stirring at room 8h, add 10% Pd/C catalyzer (0.5g) then, charge into hydrogen behind the nitrogen replacement air, stirring at room 8h under hydrogen pressure 2.1～2.2MPa.Opening autoclave pressure behind the nitrogen replacement hydrogen, the Pd/C catalyzer is reclaimed in filtering, reclaims solvent methanol, column chromatography for separation get product I be 11.0g (eluent: ethyl acetate/petroleum ether/triethylamine (v/v/v)=1/1/0.01), yield 75.4%.Get by product 2-aminobenzyl alcohol 1.7g, yield 20.8%; Get by product 2-aminotoluene 0.26g, yield 3.7%.
Embodiment 6
With 150ml methyl alcohol, Ortho Nitro Benzaldehyde (10.0g, 66.2mmol), trans-4-Trans-4-Amino Cyclohexanol (10.0g, 86.8mmol), sodium methylate (0.2g, 3.7mmol) join in the autoclave pressure, stirring at room 2.5h, add 10% Pd/C catalyzer (0.5g) then, charge into hydrogen behind the nitrogen replacement air, stirring at room 8h under hydrogen pressure 0.2～0.3MPa.To open autoclave pressure behind the nitrogen replacement hydrogen, the Pd/C catalyzer is reclaimed in filtering, reclaims solvent methanol, adds saturated aqueous common salt and separates out solid, and separating the dry product I of getting is 13.2g, yield 90.5%.
Embodiment 7
Synthetic Transbroncho
(10.0g 45.4mmol) is dissolved in the mixed solution of 80ml acetic acid and 20ml water composition compound I, and (14.9g, 93.1mmol), about 1h drips complete, again stirring at room 2h slowly to drip bromine under the stirring at room.Concentrating under reduced pressure is removed part water, and residuum transfers to alkalescence with the ammoniacal liquor of 2mol/L, and with the chloroform extraction organism, the reclaim under reduced pressure chloroform gets the Transbroncho crude product again, and is further refining, gets Transbroncho 14.7g, yield 85.7%.
The spectroscopic data of Transbroncho:
EI-MS(m/z)：376[M
+]；
1H?NMR(500MHz，CDCl
3，ppm)，δ：1.08～1.23(m，2H，CH
2)，1.22～1.52(m，5H，OH，NH，CH
2)，1.54～1.74(m，1H，CH
2)，1.91～2.09(m，4H，CH
2)，2.46(tt，1H，J
1＝10.6Hz，J
2＝3.5Hz，CHN)，3.62(tt，1H，J
1＝10.5Hz，J
2＝4.0Hz，CHOH)，3.78(brs，2H，ArCH
2N)，5.34(brs，2H，ArNH
2)，7.08(d，1H，J＝2.3Hz，ArH)，7.47(d，1H，J＝2.3Hz，ArH)。
Embodiment 8
Synthetic Transbroncho
(10.0g 45.4mmol) is dissolved in the chloroform solvent of 100ml compound I, and (7.6g, 47.5mmol), about 1h drips complete, drips 30% H more slowly to drip bromine under the stirring at room
2O
2(5.0ml, 49.0mmol), about 1h drips complete, again stirring at room 2h.The NaHSO of dropping 10%
3Solution 20ml stirs 0.5h, and residuum transfers to alkalescence with the ammoniacal liquor of 2mol/L, tells organic layer, and the reclaim under reduced pressure chloroform gets the Transbroncho crude product, and crude product is further refining, gets Transbroncho 14.3g, yield 83.3%.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, without departing from the inventive concept of the premise; can also make some improvements and modifications, these improvements and modifications also should be considered within the scope of protection of the present invention.
Claims (2)
- One kind prepare expelling phlegm drugs Transbroncho key intermediate trans-the 4-[(2-aminobenzyl) amino]-the hexalin method, it is characterized in that, Ortho Nitro Benzaldehyde and trans-4-Trans-4-Amino Cyclohexanol " are treated different things alike " to react through condensation-carbon-to-nitrogen double bon hydrogenation-nitroreduction and are directly made trans-4-[(2-aminobenzyl) amino]-hexalin, its synthetic route is:Its concrete steps are: Ortho Nitro Benzaldehyde and trans-4-Trans-4-Amino Cyclohexanol condensation obtain Schiff's base II, adopt sodium methylate as the catalyzer of the first step condensation; II directly carries out catalytic hydrogenating reduction with " treating different things alike " reaction formation then, adopts room temperature, and hydrogen pressure is the reducing process of 0.5-0.6Mpa; Obtain trans-4-[(2-aminobenzyl) amino]-hexalin Ι.
- A kind of preparation expelling phlegm drugs Transbroncho key intermediate as claimed in claim 1 trans-the 4-[(2-aminobenzyl) amino]-the hexalin method, it is characterized in that: the mol ratio of described Ortho Nitro Benzaldehyde and trans-4-Trans-4-Amino Cyclohexanol is 1.0:1.0～1.0:2.5.
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| CN 201010567715 CN102050748B (en) | 2010-11-29 | 2010-11-29 | Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol |
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| CN 201010567715 CN102050748B (en) | 2010-11-29 | 2010-11-29 | Method for preparing expectorant, namely ambroxol key intermediate trans-4-[(2-amino benzyl) amino]-cyclohexanol |
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| CN104788326B (en) * | 2015-05-13 | 2016-08-24 | 济南康和医药科技有限公司 | A kind of synthetic method of ambroxol hydrochloride |
| CN112745251B (en) | 2019-10-31 | 2023-10-27 | 华创合成制药股份有限公司 | Compound for treating phlegm and preparation method and application thereof |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES544291A0 (en) * | 1985-06-17 | 1986-01-16 | Lasa Lab | PROCEDURE FOR OBTAINING A HYDROXYCLOHE-XYLAMINE DERIVATIVE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS |
Family Cites Families (1)
| 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 |
-
2010
- 2010-11-29 CN CN 201010567715 patent/CN102050748B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES544291A0 (en) * | 1985-06-17 | 1986-01-16 | Lasa Lab | PROCEDURE FOR OBTAINING A HYDROXYCLOHE-XYLAMINE DERIVATIVE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS |
Non-Patent Citations (4)
| Title |
|---|
| Anna L. E. Larsson 等.Synthesis of chiral and achiral analogues of ambroxol via palladium-palladiumcatalysed reactions.《Journal of the American Chemical Society》.1997,第2873-2877页. |
| Synthesis of chiral and achiral analogues of ambroxol via palladium-palladiumcatalysed reactions;Anna L. E. Larsson 等;《Journal of the American Chemical Society》;19971231;第2873-2877页 * |
| 祛痰新药氨溴索的合成方法研究;雷光清等;《中国药物化学杂志》;20000930;第10卷(第3期);第205-206页 * |
| 雷光清等.祛痰新药氨溴索的合成方法研究.《中国药物化学杂志》.2000,第10卷(第3期),第205-206页. |
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