GB2239241A - Process for the preparation of N-(2-amino-3,5-dibromobenzyl)-trans-amino-cyclohexanol - Google Patents
Process for the preparation of N-(2-amino-3,5-dibromobenzyl)-trans-amino-cyclohexanol Download PDFInfo
- Publication number
- GB2239241A GB2239241A GB9027815A GB9027815A GB2239241A GB 2239241 A GB2239241 A GB 2239241A GB 9027815 A GB9027815 A GB 9027815A GB 9027815 A GB9027815 A GB 9027815A GB 2239241 A GB2239241 A GB 2239241A
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- United Kingdom
- Prior art keywords
- amino
- formula
- trans
- cyclohexanol
- acid
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 23
- 238000002360 preparation method Methods 0.000 title claims description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 claims abstract description 13
- RCPAZWISSAVDEA-UHFFFAOYSA-N 2-amino-3,5-dibromobenzaldehyde Chemical compound NC1=C(Br)C=C(Br)C=C1C=O RCPAZWISSAVDEA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 10
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 6
- 239000011707 mineral Substances 0.000 claims abstract description 6
- 230000001131 transforming effect Effects 0.000 claims abstract description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 10
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 229910052697 platinum Inorganic materials 0.000 claims description 5
- 239000002243 precursor Substances 0.000 claims description 5
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000003172 aldehyde group Chemical group 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 238000002955 isolation Methods 0.000 claims description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 15
- PACIGGABLPTEDO-XYPYZODXSA-N NC1=C(C=N[C@@H]2CC[C@H](CC2)O)C=C(C=C1Br)Br Chemical compound NC1=C(C=N[C@@H]2CC[C@H](CC2)O)C=C(C=C1Br)Br PACIGGABLPTEDO-XYPYZODXSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002262 Schiff base Substances 0.000 description 7
- 150000004753 Schiff bases Chemical class 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229960005174 ambroxol Drugs 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- -1 anthranilic acid ester Chemical class 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- IMLXLGZJLAOKJN-UHFFFAOYSA-N 4-aminocyclohexan-1-ol Chemical compound NC1CCC(O)CC1 IMLXLGZJLAOKJN-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- GOONVUGWFUNIJB-UHFFFAOYSA-N 2-amino-3,5-dibromobenzohydrazide Chemical compound NNC(=O)C1=CC(Br)=CC(Br)=C1N GOONVUGWFUNIJB-UHFFFAOYSA-N 0.000 description 1
- JBDGDEWWOUBZPM-UHFFFAOYSA-N 4-[(2-amino-3,5-dibromophenyl)methylamino]-1-cyclohexanol Chemical compound NC1=C(Br)C=C(Br)C=C1CNC1CCC(O)CC1 JBDGDEWWOUBZPM-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The compound of formula I <IMAGE> and pharmaceutically acceptable acid-addition salts thereof are prepared by reacting the 4-trans- (N-isopropylideneamino)-cyclohexanol of formula II <IMAGE> with 2-amino-3,5-dibromo-benzaldehyde of formula IV <IMAGE> optionally transforming the 2-amino-3,5-dibromobenzylidene-4-(trans-amino)-cyclohexanol of formula V <IMAGE> thus obtained into the acid-addition salt of formula VI <IMAGE> with the aid of a mineral acid, then reducing the same and isolating the acid-addition salt of N-(2-amino-3,5-dibromobenzyl)-trans-4-amino-cyclohexanol of formula I.
Description
Novel process for the preparation of N-(2-amino-3,5 dibromobenzyl)-trans-4-amino-cyclohexanol Technical field
The present invention relates to a novel process for the preparation of N-(2-amino-3,5-dibromobenzyl)-trans-4-amino- cyclohexanol of formula I
and pharmaceutically acceptable acid-addition salts thereof.
The compound of formula I is the basic material for the preparation of ambroxol, a known bronchosecretory agent.
Background art
The German published patent application No. 1,593,579 describes the preparation and pharmaceutical activity of ambroxol. Several processes are known in the art for the preparation of N-(2-amino-3, 5-dibromobenzyl)-trans-4-amino- cyclohexanol (DE 2,345,443, DE 2,402,577, DE 2,207,460, DE 2,311,637, DE 2,218,647, DE 2,223,193, DE 2,337,334, DE 2,337,363, DE 2,337,445, DE 2,338,408, ES 507,000, ES 508,642, ES 534,063, ES 544,291, ES 540,496, ES 525,701, ES 526,526, ES 544,292, ES 545,493), however only processes described in
Hungarian patent specification No. 165,758 and published European patent application No. 130,244 seem to be suitable for working on industrial scale.
Hungarian patent specification No. 165,758 describes the last steps of the synthesis of the product: N-(2-amino-3,5 dibromobenzylidene)-trans-4-amino-cyclohexanol is reduced with sodium borohydride with a yield of 91 %. The starting N-(2-amino 3, 5-dibromobenzylidene)-trans-4-amino-cyclohexanol is prepared from trans-4-amino-cyclohexanol and 2-amino-3,5-dibromobenzaldehyde but the yields are not reported.
According to published European patent application No.
130,244 anthranilic acid ester is transformed to 3,5-dibromo anthranilic acid ester, then 3,5-dibromo anthranilic acid hydrazide is prepared with the aid of hydrazine. This latter compound is reacted with a sulfohalide, thus the corresponding sulfonyl hydrazide is obtained which is transformed into a
Schiff-base (2-amino-3 , 5-dibromobenzylidene-4-trans-amino- cyclohexanol) with the aid of 4-trans-amino-cyclohexanol, finally ambroxol is prepared by reducing this latter compound.
According to the working examples the Schiff-base and ambroxol are obtained with a yield of 70 % and 80 %, respectively.
When the process is carried out in "one pot", the two last steps of the synthesis result in a common yield of 70 %.
When the process of Hungarian patent specification No.
165,758 or published European patent application No. 130,244 is carried out, sodium borohydride has to be used in high excess and it can be decomposed with the aid of a diluted acid at the end of the reaction. Then solutions comprising different boro compounds are obtained in high volume which are harmful to the nature and to the enviroment. They can be eliminated only by complicated and very expensive procedures.
Lithium aluminium hydride referred to in the claim is a very dangerous material which reacts with moisture in an explosion-like reaction. It can be treated only under very strict ensurance regulations, therefore its application on industrial scale is not desirable.
The preparation and quality (isomeric purity) of 4trans-amino-cyclohexanol are not referred to in the references.
The quality of ambroxol base or hydrochloric salt obtained as end-product is also not characterized by any data as the melting points and elemental analysis data do not give any information on the isomeric purity.
Summary of the invention
According to the present invention N-(2-amino-3,5 dibromobenzyl)-trans-4-amino-cyclohexanol of formula I and the pharmaceutically acceptable acid-addition salts thereof are prepared by reacting 4-trans-(N-isopropylideneamino)-cyclohexanol of formula II
with 2-amino-3,5-dibromo benzaldehyde of formula IV
optionally liberated from compound of formula III,
wherein A stands for a precursor group corresponding to the hydrogen atom of the aldehyde group, then, if desired, without isolation, optionally transforming the 2-amino-3,5-dibromobenzylidene-4-(trans-amino)-cyclohexanol of formula V
thus obtained into an acid-addition salt of formula VI
with the aid of a mineral acid, then reducing the same and isolating the acid-addition salt of N-(2-amino-3,5dibromobenzyl)-trans-4-amino-cyclohexanol of formula I.
Detailed description of the invention
In the process of the invention a 4-trans-(Nisopropylideneamino)-cyclohexanol of formula II is "transschiffed" with 2-amino-3,5-dibromo benzaldehyde of formula IV which is optionally liberated in situ from a compound of formula
III, wherein A is a precursor group corresponding to the hydrogen atom of the aldehyde group, i.e. the oxo-component of compound of formula II is changed to 2-amino-3,5-dibromo benzaldehyde.
If desired, the 2-amino-3,5-dibromobenzylidene-4-(transamino)-cyclohexanol of formula V thus obtained is optionally isolated, then optionally transformed into an acid-addition salt of formula VI, wherein X stands for an anion, then reduced and the thus-obtained acid-addition salt of compound of formula I is isolated.
The 4-trans-(N-isopropylideneamino)-cyclohexanol of formula II is a novel compound, it is prepared according to our co-pending patent application No. ... filed on 21st December 1990 and claiming priority from Hungarian No. 6744/89.
The 2-amino-3, 5-dibromobenzylidene-4-(trans-amino)-cyclo- hexanol of formula V can be prepared by reacting 4-trans-(Nisopropylideneamino)-cyclohexanol of formula II and 2-amino-3,5dibromo benzaldehyde of formula IV or the precursor of formula
III of compound of formula IV, wherein A is the same as defined hereinabove, in an inert solvent or solvent mixture, preferably at a temperature of 60 to 130 00. If 2-amino-3,5-dibromo benzaldehyde of formula IV is used as reactant, then preferably an inert polar solvent boiling under 100 OC, more preferably an aliphatic alcohol such as methanol, ethanol, isopropanol, etc., is used as solvent.
If the aldehyde-precursor of formula III is reacted in an inert higher-boiling solvent or solvent mixture, preferably in methylcellosolve, ethylene glycol, dimethyl formamide, a mixture of water and ethylene glycol, etc., then the process is carried out under basic conditions (preferably in the presence of sodium carbonate, potassium carbonate, sodium formiate, sodium hydroxide, etc.) preferably at a temperature over 100 OC, more preferably at a temperature of 120 to 130 00.
The 2-amino-3 , 5-dibromobenzylidene-4-(trans-amino)-cyclo- hexanol of formula V is recovered from the reaction mixture by cooling and/or by mixing with water. Optionally one can proceed by forming an acid-addition salt by adding a mineral acid in the presence of the solvent used in the reaction or in the presence of an other solvent, being miscible with the previous one, and isolating the N-(2-amino-3, 5-dibromobenzylidene)-trans-4-amino- cyclohexanol of formula VI in the form of an acid-addition, preferably hydrochloric, salt.
According to an especially preferred embodiment of forming the hydrochloric salt of the "Schiff-base" of formula VI, the 4-trans-(N-isopropylideneamino)-cyclohexanol of formula II is reacted with 2-amino-3,5-dibromo benzaldehyde of formula IV in a hydrochloric solvent.
The ambroxol of formula I is prepared from the hydrochloric salt of formula VI of the Schiff-base of formula V by reduction.
The modes of carrying out of the reduction, the last step of the synthesis, are highly limited by the bromine substituents being in the aromatic ring of the Schiff-base of formula V. It is known that there is possibility for carrying out the so-called "hydrohalogenating1, process during the reduction when the catalyst used for hydrogenation splits off the bromine atom(s) substituting the aromatic ring.
As to the possible catalyst, metal palladium (J. Org.
Chem. 41, 733 /1976/; Paul Rylander: Catalytic Hydrogenation in
Organic, Syntheses, Acad. Press, New York, 1979; Chem. Rev. 65, 51 /1965/) and Raney nickel (J.W. Wightower: Catalysis Vol. 2, 1073, Elsevier, New York, 1973; Chem. Ber. 91, 1376 /1958/;
Compt. Rend. 257, 3182 /1963/, Chem. Comm. 1968, 653) are known as causing dehalogenating side-reactions, but metal iron and zinc are also suitable for this reaction (Ber. dtsch. Chem. Ges. 31, 2153 /1898/; J. Org. Chem. 42, 835 /1977/).
The dehydrohalogenating character of alkaline borohydrides and lithium aluminium hydride is less known, but according to the prior art this undesired side-reaction may occur when these compounds are used for the hydrogenation of halogenated aryl compounds (Helv. Chim. Acta 51, 2090 /1968/;
Synthesis, 1975, 144; J. Am. Chem. Soc. 70, 3738 /1948/; Coll.
Cz. Chem. Comm. 34, 2782, 3110 /1969/).
Catalysts comprising metal palladium are not known as causing undesired dehalogenating reactions, thus they can preferably be used in the case of compounds which are optionally substituted - especially in their aryl moiety - by halogen atoms.
Thus the hydrochloric salt of the Schiff-base of formula
VI can be reduced in an inert solvent in the presence of metal platinum catalyst, preferably in ethanol or dimethyl formamide, with the aid of catalytically activated hydrogen.
Surprisingly it has been found that the metal platinum catalysts do not catalyze the reduction of the carbon-nitrogen double bond of azomethin (-CH=N-) character.
Simultaneously it has been also found that the presence of an acid, especially in case of metal platinum, preferably influences the catalytic effect and, depending on the quality and quantity of the acid, the effectiveness of the saturation of the double bond can be more and more enhanced.
When aliphatic or aromatic carboxylic acids are employed, the yield of the reaction is at most 50 %, while in the presence of a mineral acid, preferably in the presence of an equimolar amount of hydrochloric acid, the reduction results in a yield of almost 90 %.
It is known that azomethins (Schiff-bases) are formed in the course of a reversible reaction of amines and carbonyl compounds (such as aldehydes). The less basic the amine component, the more instable the products are. Thus they decompose due to the effect of diluted mineral acids or even in alcohol or acetic acid (Houben-Weyl: Methoden der Organischen
Chemie, Bd. VII/1, pages 458-460, Georg Thieme Verlag, Stuttgart, 1954; S. Patai: The Chemistry of the Carbon-Nitrogen Double Bond,
Interscience Publ., 1970, page 149).
Therefore it is surprising for a man skilled in the art that the hydrochloric salt of N-(2-amino-3,5-dibromobenzylidene)trans-4-amino-cyclohexanol of formula VI can be prepared and a compound to be readily treated is obtained.
The 4-trans-(N-isopropylideneamino)-cyclohexanol of formula II and the hydrochloric salt of N-(2-amino-3,5dibromobenzylidene)-trans-4-amino-cyclohexanol of formula VI are novel compounds which have not been described yet by the prior art.
The process of the invention has the following advantages:
- the novel 4-trans-(N-isopropylideneamino)-cyclohexanol of formula II is used as starting material which can be prepared without any cis-isomer contamination, thereby assuring the isomeric purity of the pharmaceutically active ingredient;
- the final step of the synthesis is the reduction of the hydrochloric salt of N-(2-amino-3, 5-dibromobenzylidene)-4-(trans- amino)-cyclohexanol, thus the reduction is more economical, it is unambiguously not harmful for the enviroment and results in a much purer product than the former reactions;
- the use of metal platinum as catalyst is very preferable as the reaction carried out under acidic conditions makes possible the industrial-scale reduction without the formation of undesired by-products;;
- the catalyst has to be used in a very small amount and it can be used in several consecutive reactions without loosing its activity and without a need of regeneration, contrary to other metal catalysts;
- the solvents used in the synthesis can be regenerated, thus they do not pollute the enviroment;
- the above-mentioned preferable route of reaction results in a significant savings in working power.
The invention is further illustrated by the following, non-limiting examples.
Example 1
Preparation of N-(2-amino-3 , 5-dibromobenzylidene)-trans- 4-amino-cyclohexanol
A mixture of 200 ml of ethylene glycol, 50 ml of water, 34.5 g (0.25 mole) of potassium carbonate and 20.17 g (0.13 mole) of 4-trans-(N-isopropylideneamino)-cyclohexanol are heated to a temperature of 120-1250C, then 48.4 g (0.125 mole) of N-(3,5 dibromoanthranoyl)-N,-methansulfonyl hydrazide are added within 5 minutes. The reaction mixture is kept at a temperature of 120-130 OC for 1 hour, then left to cool to room temperature. The precipitated crystals are filtered off and then washed with water. 39.5 g (84.1 %) of the aimed product are obtained.
Melting point: 123-1250C (after recrystallization from benzene)
Example 2
Preparation of the hydrochloric salt of N-(2-amino-3,5dibromobenzylidene)-trans-4-amino-cyclohexanol
To 80 ml of ethylene glycol heated to a temperature of 130 OC a mixture of 6.8 g (0.1 mole) of sodium formiate, 8.16 g (0.052 mole) of 4-trans-(N-isopropylideneamino)-cyclohexanol and 19.36 g (0.05 mole) of N-(3,5-dibromoanthranoyl)-N- methanesulfonyl hydrazide are added. The mixture is reacted for 1 hours at a temperature of 1300C, then cooled to room temperature and extracted with dry ethyl acetate. The phases are separated, then the ethyl acetate solution is filtered after purification with charcoal. The hydrochloride salt is precipitated by the addition of hydrochloric ethyl acetate.
13.2 g (63.9 %) of the aimed product are obtained.
Melting point: 218-2190C.
Example 3
Preparation of the hydrochloric salt of N-(2-amino-3,5dibromobenzylidene)-trans-4-amino-cyclohexanol
To 40 ml of ethylene glycol heated to a temperature of 120 OC a mixture of 3.45 g (0.025 mole) of potassium carbonate and 4.08 g (0.026 mole) of 4-trans-(N-isopropylideneamino)cyclohexanol is added, then 9.68 g (0.025 mole) of N-(3,5 dibromoanthranoyl)-N,-methanesulfonyl hydrazide are added to the reaction mixture under stirring. The mixture is reacted for 1 hour at a temperature of 120-1300C, then worked up as described in Example 2.
6.9 g (66.9 %) of the aimed product are obtained.
Melting point: 218-2190C.
Example 4
Preparation of the hydrochloric salt of N-(2-amino-3,5dibromobenzylidene)-trans-4-amino-cyclohexanol
To 50 ml of dimethyl formamide heated to a temperature of 130 OC a mixture of 6.9 g (0.05 mole) of potassium carbonate, 9.3 g (0.06 mole) of 4-trans-(N-isopropylideneamino)-cyclohexanol and 19.36 g (0.05 mole) of N-(3,5-dibromoanthranoyl)-Nmethanesulfonyl hydrazide are added. The mixture is reacted for 1 hour at a temperature of 1300C, then the formed white crystals are filtered off, the mother liquor is evaporated to half of its volume and hydrochloric ethyl acetate is added to the residue.
16.08 g (78 %) of the aimed product are obtained.
Melting point: 218-2190C.
Example 5
Preparation of the hydrochloric salt of N-(2-amino-3,5dibromobenzylidene)-trans-4-amino-cyclohexanol
To a solution of 650 ml of ethyl acetate and 79.55 g (0.21 mole) of N-(2-amino-3,5-dibromobenzylidene)-trans-4-aminocyclohexanol the ethyl acetate solution of an equimolar amount of hydrochloric acid is added dropwise under cooling with ice. The yellow crystals thus obtained are filtered off. 85 g (98.1 %) of the product according to Example 2 are obtained.
Melting point: 218-2190C.
Example 6
Preparation of the hydrochloric salt of N-(2-amino-3,5dibromobenzylidene)-trans-4-amino-cyclohexanol
20.17 g (0.13 mole) of 4-trans-(N-isopropylideneamino)cyclohexanol and 36.26 g (0.13 mole) of 2-amino-3,5 dibromobenzaldehyde are reacted in 120 ml of the ethyl acetate solution of equimolar amount of hydrochloric acid for 5 hours.
The precipitate thus obtained is filtered off. 46.7 g (87 %) of the yellow, crystalline product according to Example 2 are obtained.
Melting point: 218-2190C.
Example 7
Preparation of the hydrochloric salt of N-(2-amino-3,5 dibromobenzyl )-trans-4-amino-cyclohexanol 15 g (0.036 mole) of N-(2-amino-3,5-dibromobenzylidene)4-(trans-amino)-cyclohexanol hydrochloric salt are dissolved in 200 ml of dry ethanol, then 0.45 g of 5 % platinum-on-charcoal catalyst are added. The mixture is hydrogenated at a temperature of 20 OC under a pressure of 5 bar under stirring. After saturation the filtrate is evaporated, then recrystallized from 50 ml of water. 13 g (87.1 %) of the aimed product are obtained.
Melting point: 235 OC.
Claims (9)
1. A process for the preparation of N-(2-amino-3,5 dibromobenzyl)-trans-4-amino-cyclohexanol of formula I
and pharmaceutically acceptable acid-addition salts thereof, w h i c h c o m p r i s e s reacting the 4-trans-(Nisopropylideneamino)-cyclohexanol of formula II
with 2-amino-3,5-dibromo-benzaldehyde of formula IV
optionally liberated in situ from compound of formula III,
wherein A stands for a precursor group corresponding to the hydrogen atom of the aldehyde group, then, if desired, without isolation, optionally transforming the 2-amino-3,5-dibromobenzylidene-4-(trans-amino)-cyclohexanol of formula V
thus obtained into the acid-addition salt of formula VI
with the aid of a mineral acid, then reducing the same and isolating the acid-addition salt of the product of formula I.
2. A process as claimed in claim 1, w h i c h c o m p r i s e s hydrogenating N-(2-amino-3,5dibromobenzylidene)-4-(trans-amino)-cyclohexanol hydrochloride of formula VI in the presence of metal platinum catalyst.
3. A process as claimed in claim 1, w h i c h c o m p r i s e s reacting 4-trans-(N-isopropylideneamino)cyclohexanol of formula II with N-(3,5-dibromoanthranoyl)-N,- methansulfonyl hydrazide of formula III, wherein A stands for methansulfonyl hydrazinyl group, in a basic medium in inert solvent, preferably at a temperature over 1000C.
4. A process as claimed in claim 1, w h i c h c o m p r i s e s reacting 4-trans-(N-isopropylideneamino)cyclohexanol of formula II with N-(3,5-dibromoanthranoyl)-N'-4'- toluenesulfonyl hydrazide of formula III, wherein A stands for 4toluenesulfonyl hydrazinyl group, in a basic medium in an inert solvent at a temperature over 1000C.
5. Hydrochloric salt of N-(2-amino-3,5dibromobenzylidene)-4-(trans-amino)-cyclohexanol of formula VI.
6. A process as claimed in claim 1, wherein the compound of the general Formula V is formed by a process substantially as hereinbefore described in Example 1.
7. A process as claimed in claim 1, wherein the compound of the general Formula VI is formed by a process substantially as hereinbefore described in any one of Examples 2 to 6.
8. A process as claimed in claim 1, wherein the compound of the general Formula I is formed by a process substantially as hereinbefore described in Example 7.
9. The compound of the general Formula I and pharmaceutically acceptable acid addition salts thereof when made by a process as claimed in any one of claims 1 to 4 or 6 to 8.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU896745A HU207834B (en) | 1989-12-22 | 1989-12-22 | Process for producing n-/2-amino-3,5-dibromo-benzyl/-trans-4-amino-cyclohexanol |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9027815D0 GB9027815D0 (en) | 1991-02-13 |
| GB2239241A true GB2239241A (en) | 1991-06-26 |
| GB2239241B GB2239241B (en) | 1993-07-14 |
Family
ID=10971988
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9027815A Expired - Fee Related GB2239241B (en) | 1989-12-22 | 1990-12-21 | Novel process for the preparation of n-(2-amino-3,5-dibromobenzyl)-trans-4-amino-cyclohexanol |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPH04217943A (en) |
| AT (1) | AT400435B (en) |
| GB (1) | GB2239241B (en) |
| HU (1) | HU207834B (en) |
| IT (1) | IT1246049B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351720A (en) * | 2011-10-21 | 2012-02-15 | 南京理工大学 | Simple and efficient ambroxol synthesis method |
| 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 |
| CN109970579A (en) * | 2019-04-22 | 2019-07-05 | 浙江海洲制药有限公司 | A method of preparing ambroxol hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2218647A1 (en) * | 1972-04-18 | 1973-10-25 | Thomae Gmbh Dr K | Secretolytic n-(trans-4-hydroxycyclohexyl)-2-amino-3,5- - dibromobenzylamine prepn - by redn of n-(2-amino-3,5-dibromobenzylide |
| EP0130224A1 (en) * | 1983-06-29 | 1985-01-09 | LUDWIG HEUMANN & CO GMBH | Process for the preparation of 2-amino-3,5-dibromobenzyl amines |
-
1989
- 1989-12-22 HU HU896745A patent/HU207834B/en not_active IP Right Cessation
-
1990
- 1990-12-21 AT AT0261990A patent/AT400435B/en not_active IP Right Cessation
- 1990-12-21 IT IT02250790A patent/IT1246049B/en active IP Right Grant
- 1990-12-21 JP JP2412592A patent/JPH04217943A/en active Pending
- 1990-12-21 GB GB9027815A patent/GB2239241B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2218647A1 (en) * | 1972-04-18 | 1973-10-25 | Thomae Gmbh Dr K | Secretolytic n-(trans-4-hydroxycyclohexyl)-2-amino-3,5- - dibromobenzylamine prepn - by redn of n-(2-amino-3,5-dibromobenzylide |
| EP0130224A1 (en) * | 1983-06-29 | 1985-01-09 | LUDWIG HEUMANN & CO GMBH | Process for the preparation of 2-amino-3,5-dibromobenzyl amines |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351720A (en) * | 2011-10-21 | 2012-02-15 | 南京理工大学 | Simple and efficient ambroxol synthesis method |
| 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 |
| CN109970579A (en) * | 2019-04-22 | 2019-07-05 | 浙江海洲制药有限公司 | A method of preparing ambroxol hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| ATA261990A (en) | 1995-05-15 |
| IT9022507A1 (en) | 1992-06-21 |
| AT400435B (en) | 1995-12-27 |
| JPH04217943A (en) | 1992-08-07 |
| HU896745D0 (en) | 1990-03-28 |
| GB2239241B (en) | 1993-07-14 |
| HUT58274A (en) | 1992-02-28 |
| HU207834B (en) | 1993-06-28 |
| IT1246049B (en) | 1994-11-07 |
| GB9027815D0 (en) | 1991-02-13 |
| IT9022507A0 (en) | 1990-12-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19961221 |