CN110128339B - Synthetic method and intermediate for indacaterol and salt derivative thereof - Google Patents
Synthetic method and intermediate for indacaterol and salt derivative thereof Download PDFInfo
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- CN110128339B CN110128339B CN201910473479.3A CN201910473479A CN110128339B CN 110128339 B CN110128339 B CN 110128339B CN 201910473479 A CN201910473479 A CN 201910473479A CN 110128339 B CN110128339 B CN 110128339B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing indacaterol and salt derivatives thereof and an intermediate for synthesis. The method for synthesizing indacaterol takes a compound with a general formula IV and a compound with a formula V as raw materials, and obtains a compound with a formula I through amine alkylation and deprotection in one pot, wherein the reaction equation is as follows: wherein R is a silyl protecting group. According to the technical scheme provided by the invention, through carrying out Boc protection on amino, multi-alkylation on amino is ingeniously avoided, under the condition that both hydroxyl and amino are properly protected, alkylation reaction effectively avoids generation of byproducts, and deprotection of hydroxyl and amino can be directly carried out after alkylation reaction, so that multi-step reaction is completed in one reactor, the intermediate purification and separation process is saved, the reaction yield is improved to the greatest extent, and the production cost is reduced.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing indacaterol and salt derivatives thereof and an intermediate for synthesis.
Background
Indacaterol (Indacaterol), chemical name (R) -5- [2- (5, 6-diethylindan-2-ylamino) -1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one having the formula C24H28N2O3Structural formula I is as follows:
indacaterol is a long-acting β 2-adrenoceptor agonist. The indacaterol locally plays the role of a bronchodilator in the lung after inhalation, and is suitable for the maintenance treatment of adult Chronic Obstructive Pulmonary Disease (COPD) patients.
Indacaterol is prepared from 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine hydrochloride (compound of formula II) and
r-8- (benzylchloro) -5- (2-bromo-1-hydroxyethyl) quinolinone (compound of formula III) is obtained by amine alkylation. The specific synthetic process mainly comprises the following two steps:
in one aspect, a solution is provided in WO2005123684, specifically see the following reaction equation:
the route protects chiral hydroxyl by forming a three-membered ring, and then carries out ring opening and simultaneously carries out alkylation with amino amine, but the selectivity in the amine alkylation process is not ideal, and in addition, two quinolinones are connected to an amino group, so that the yield of the compound of the formula I is only 63.5%, and two main byproducts are generated and have similar properties with the target compound, thereby causing difficult separation, finally causing increased production cost and difficult quality control.
Secondly, another route is disclosed in US2016326118, and the reaction equation is as follows:
the chiral hydroxyl is protected by tert-butyldimethylsilane in the route, so that the problem of selectivity in the first route is solved, but the problem of controlling further reaction of amino cannot be solved, and the problems of low yield, difficulty in purification and high cost still exist.
Disclosure of Invention
The invention provides a method for synthesizing indacaterol and a salt derivative thereof and an intermediate for synthesis, which are used for solving the problems of more byproducts, low yield and difficult purification in the conventional indacaterol synthesis.
In order to solve the technical problems, the technical scheme of the invention is as follows: the method for synthesizing indacaterol uses a compound with a general formula IV of a silane protected compound with a formula II and 2-tert-butoxycarbonyl-amino- (5, 6-diethyl) indan, namely a compound with a formula V, as raw materials, and obtains a compound with a formula I through an amine alkylation and deprotection one-pot reaction, wherein the reaction equation is as follows:
wherein R is a silyl protecting group.
Alternatively, the silyl protecting group is selected from dimethyl tert-butylsilyl, trimethylsilyl or diphenyl tert-butylsilyl, preferably dimethyl tert-butylsilyl.
Optionally, the alkaline reagent in the amine alkylation reaction is potassium tert-butoxide or sodium tert-butoxide, the temperature of the system is controlled below 0 ℃, preferably-5 ℃ to 0 ℃ in the process of adding the alkaline reagent, and the reaction is stirred at normal temperature after the addition is finished.
Normal temperature means that the temperature (heating or cooling) of the system is not artificially controlled.
Alternatively, the reaction solvent in the amine alkylation reaction is selected from N, N-Dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).
Alternatively, the acidic reagent used for the deprotection reaction is selected from an inorganic acid selected from hydrochloric acid, sulfuric acid or nitric acid, or an organic acid selected from formic acid or acetic acid, and finally the corresponding salt derivative of indacaterol is obtained.
Alternatively, the feeding molar ratio of the compound of the general formula IV to the compound of the formula V is 1 (1-1.1).
The invention also provides a synthesis method of the indacaterol salt derivative, and the compound of formula I prepared by the synthesis method is added with acid in a solvent in a free state to form the corresponding salt derivative.
Optionally, the solvent is selected from dichloromethane, petroleum ether, ethyl acetate, n-butanol, isoamyl alcohol, diethyl ether or chloroform; the indacaterol salt derivative is a maleate derivative, a sulfate derivative, a hydrochloride derivative, a methanesulfonate derivative, a benzoate derivative, a formate derivative or a phosphate derivative.
The invention also provides an intermediate for synthesizing indacaterol, the chemical name of the intermediate is 2-tert-butyloxycarbonyl-amino- (5, 6-diethyl) indan, and the chemical formula of the intermediate is a compound shown in the formula V.
Alternatively, the compound of formula V is obtained by reacting 2-amino- (5, 6-diethyl) indan, i.e., a compound of formula II, with di-tert-butyl carbonate.
According to the technical scheme provided by the invention, the amino in the compound of the formula II is protected by Boc, so that polyalkylation on the amino is avoided ingeniously, the generation of byproducts is effectively avoided in the alkylation reaction under the condition that both hydroxyl and the amino are protected properly, and deprotection of the hydroxyl and the amino can be directly carried out after the alkylation reaction, so that the multi-step reaction is completed in one reactor, the intermediate purification and separation process is saved, the reaction yield is improved to the greatest extent, and the production cost is reduced.
Detailed Description
For the sake of understanding, the following examples are given to illustrate the synthesis of indacaterol and salt derivatives thereof and intermediates for the synthesis, and it is to be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
The reagents used in the following examples are all commercially available, with nuclear magnetic resonance data determined by Fourier 300, and mass spectra determined by GCMS 6800.
Example 1
Synthesis of 8-benzyloxy-5- ((R) -2-bromo-1- (tert-butyldimethylsilyl) oxy-ethyl) -1H-quinolin-2-one (Compound of formula IV)
Adding 50g of the compound of the formula III and 600mL of dichloromethane into a 1000mL three-necked bottle, stirring and dissolving at room temperature, adding 17g of triethylamine after dissolving, cooling to 0 ℃ in an ice bath, dropwise adding 24.8g of tert-butyldimethylsilyl chloride under stirring, and returning to normal temperature for reacting for 2-4 h after adding. After the reaction is finished, cooling to 0 ℃, slowly dropping 1N HCl solution with concentration, demixing, extracting water phase by 200ml dichloromethane, merging organic phases, drying, concentrating to obtain 78g of target compound with yield of 99.3%,
example 2
Synthesis of 2-tert-butoxycarbonyl-amino- (5, 6-diethyl) indan (compound of formula V)
Adding 40g of the compound II and 600ml of dichloromethane into a 1000ml three-necked bottle, stirring at room temperature, cooling to 0-5 ℃ in an ice bath, adding 37.6g of triethylamine under stirring, slowly dropwise adding 39.4g of di-tert-butyl carbonate, reacting after dropwise addition for about 0.5 hour under stirring at 0-5 ℃, pouring the reaction solution into 500ml of ice water for layering, extracting the water phase with 200ml of dichloromethane, combining the organic phases, drying, concentratingThe compound of formula V was condensed 49.1g, yield 96%. H1NMR(300MHz，CD3OD)ppm:7.20(s,2H),4.15(t,1H),2.90-3.15(m,4H),2.83(q,4H)，1.41(s,9H)，1.28(t,6H)；MS:290.4(M+)。
Example 3
Synthesis of (R) -5- [2- (5, 6-diethylindan-2-ylamino) -1-hydroxyethyl ] -8-benzyloxy-1H-quinolin-2-one hydrochloride (Compound hydrochloride of formula I)
48.8g (about 0.1mol) of the compound of the formula IV prepared in example 1 and 29g (about 0.1mol) of the compound of the formula V prepared in example 2 were put into a 1000ml three-necked flask, 500ml of DMF was added, 12.3g of potassium tert-butoxide was slowly added while stirring while cooling in an ice salt bath to-5 to 0 ℃ and the temperature was kept at 0 ℃ or lower. After the addition, the temperature is slowly restored to the normal temperature, after stirring for 4 hours, the reaction solution is poured into 1000mL of ice water, extraction is carried out for 2 times by using 300mL of ethyl acetate, organic phases are combined and concentrated to be dry, 500mL of absolute ethyl alcohol is added, 40mL of concentrated hydrochloric acid is added, stirring is carried out for 2 hours at room temperature, and suction filtration is carried out to obtain 45.67g of compound hydrochloride of the formula I, wherein the yield is 88%.
Example 4
(R) -5- [2- (5, 6-Diethylindan-2-ylamino) -1-hydroxyethyl ] -8-benzyloxy-1H-quinolin-2-one benzoate (Compound of formula I benzoate)
40g of the hydrochloride of the compound of the formula I prepared in example 3 and 400mL of ethyl acetate are added into a 1000mL three-necked flask, 1N potassium carbonate solution is added in portions under cooling of an ice water bath, the pH is adjusted to about 9, the aqueous phase is removed by liquid separation, 10.3g of benzoic acid is slowly added into the organic phase under stirring, the mixture is stirred for 2 hours for crystallization, the mixture is filtered, the mixture is rinsed for 2 times by 100mL of ethyl acetate, and the solid is dried to obtain 41.8g of the benzoate of the compound of the formula I with the yield of 90%.
Finally, it should be noted that: the above examples are only for illustrating the technical solutions of the present invention, and are not limited thereto. Although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: it is to be understood that modifications may be made to the technical solutions described in the foregoing embodiments, or some or all of the technical features may be equivalently replaced, and such modifications or replacements may not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (12)
1. The method for synthesizing indacaterol is characterized in that a compound shown in a formula I is obtained by taking a compound shown in a formula IV and a compound shown in a formula V as raw materials through amine alkylation and deprotection one-pot reaction, and the reaction equation is as follows:
wherein R is a silyl protecting group.
2. The synthetic method according to claim 1 wherein the silyl protecting group is selected from the group consisting of dimethyl tert-butylsilyl, trimethylsilyl and diphenyl tert-butylsilyl.
3. The synthetic method of claim 2 wherein the silyl protecting group is a dimethyl-t-butylsilyl group.
4. The synthesis method of claim 1, wherein the alkaline reagent in the amine alkylation reaction is potassium tert-butoxide or sodium tert-butoxide, the temperature of the system is controlled below 0 ℃ in the process of adding the alkaline reagent, and the reaction is stirred at normal temperature after the addition is finished.
5. The synthesis method according to claim 4, wherein the temperature of the system is controlled to be-5-0 ℃ during the process of adding the alkaline reagent.
6. The synthesis method according to claim 4, wherein the reaction solvent in the amine alkylation reaction is selected from N, N-dimethylformamide or dimethyl sulfoxide.
7. The synthesis method of claim 1, wherein the feeding molar ratio of the compound of the general formula IV to the compound of the formula V is 1 (1-1.1).
8. The synthesis method of claim 1, wherein the acidic reagent used for the deprotection reaction is selected from hydrochloric acid, sulfuric acid, nitric acid, formic acid or acetic acid.
9. The synthesis method of claim 1, wherein the compound of formula V is obtained by reacting a compound of formula II with di-tert-butyl carbonate, according to the following reaction equation:
10. a process for the synthesis of indacaterol salt derivatives, characterized in that a compound of formula I is first prepared according to any one of claims 1 to 6, and then the compound of formula I is added in the form of a free acid in a solvent to form the corresponding salt derivative.
11. The synthesis method according to claim 10, wherein the solvent is selected from dichloromethane, petroleum ether, ethyl acetate, n-butanol, isoamyl alcohol, diethyl ether or chloroform; the indacaterol salt derivative is selected from a maleate derivative, a sulfate derivative, a hydrochloride derivative, a methanesulfonate derivative, a benzoate derivative, a formate derivative or a phosphate derivative.
12. An intermediate for synthesizing indacaterol, which is characterized by having a chemical name of 2-tert-butoxycarbonyl-amino- (5, 6-diethyl) indan and has a chemical formula of a compound shown as a formula V:
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100363349C (en) * | 2003-02-28 | 2008-01-23 | 诺瓦提斯公司 | Process for preparing 5-'(r)-2-(5,6-diethyl-indian-2-ylamin o)-1-hydroxy-ethyl-8-hydroxy-(1h)-quinolin-2-one salt, useful as an adrenoceptor agonist |
| WO2014044566A1 (en) * | 2012-09-21 | 2014-03-27 | Crystal Pharma S.A.U. | Methods for the preparation of indacaterol and pharmaceutically acceptable salts thereof |
| WO2014154841A1 (en) * | 2013-03-27 | 2014-10-02 | Laboratorios Lesvi, S.L. | Process for the manufacture of (r)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-(1h)-quinolin-2-one |
| CN104744360A (en) * | 2013-12-26 | 2015-07-01 | 成都伊诺达博医药科技有限公司 | New method for synthesizing indacaterol |
| WO2017055506A1 (en) * | 2015-09-29 | 2017-04-06 | Laboratorios Lesvi, S.L. | Mixed solvate of (r)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl] -8-hydroxy-1h-quinolin-2-one l-tartrate |
| CN108409650A (en) * | 2018-02-09 | 2018-08-17 | 南京法恩化学有限公司 | A kind of preparation method of maleic acid datro |
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- 2019-05-31 CN CN201910473479.3A patent/CN110128339B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100363349C (en) * | 2003-02-28 | 2008-01-23 | 诺瓦提斯公司 | Process for preparing 5-'(r)-2-(5,6-diethyl-indian-2-ylamin o)-1-hydroxy-ethyl-8-hydroxy-(1h)-quinolin-2-one salt, useful as an adrenoceptor agonist |
| WO2014044566A1 (en) * | 2012-09-21 | 2014-03-27 | Crystal Pharma S.A.U. | Methods for the preparation of indacaterol and pharmaceutically acceptable salts thereof |
| WO2014154841A1 (en) * | 2013-03-27 | 2014-10-02 | Laboratorios Lesvi, S.L. | Process for the manufacture of (r)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-(1h)-quinolin-2-one |
| CN104744360A (en) * | 2013-12-26 | 2015-07-01 | 成都伊诺达博医药科技有限公司 | New method for synthesizing indacaterol |
| WO2017055506A1 (en) * | 2015-09-29 | 2017-04-06 | Laboratorios Lesvi, S.L. | Mixed solvate of (r)-5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl] -8-hydroxy-1h-quinolin-2-one l-tartrate |
| CN108409650A (en) * | 2018-02-09 | 2018-08-17 | 南京法恩化学有限公司 | A kind of preparation method of maleic acid datro |
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