CN110128339A - The synthetic method and synthesis intermediate of a kind of datro and its salt derivative - Google Patents
The synthetic method and synthesis intermediate of a kind of datro and its salt derivative Download PDFInfo
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- CN110128339A CN110128339A CN201910473479.3A CN201910473479A CN110128339A CN 110128339 A CN110128339 A CN 110128339A CN 201910473479 A CN201910473479 A CN 201910473479A CN 110128339 A CN110128339 A CN 110128339A
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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
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Abstract
The invention belongs to technical field of medicine synthesis, and in particular to the synthetic method and synthesis intermediate of a kind of datro and its salt derivative.The synthetic method of the datro obtains compound of formula I through amino-alkylation and deprotection one pot reaction using compound of Formula IV and Formula V compound as raw material, and reaction equation is as follows: where R is silylation protecting group.Technical solution provided by the invention is by carrying out Boc protection to amino; cleverly avoid more alkylations on amino; in the case where hydroxyl and amino all have appropriate protection; alkylated reaction effectively prevents the generation of by-product; and hydroxyl and amino deprotection can be directly carried out after alkylated reaction; multistep reaction is completed in a reactor, saves the process of intermediate purification separation, also improving reaction yield to the greatest extent reduces production cost.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to the synthetic method of a kind of datro and its salt derivative
With synthesis intermediate.
Background technique
Datro (Indacaterol), chemical name (R) -5- [2- (5,6- diethyl indane -2- base amino) -1-
Ethoxy] -8- hydroxyl -1H- quinoline-2-one, molecular formula C24H28N2O3, structural formula I is as follows:
Datro is a kind of long-acting beta-2-adrenoreceptor agonists.It is in intrapulmonary part after sucking datro
The effect of bronchodilator is played, the maintenance therapy of Adult chronic's obstructive disease of lung (COPD) patient is suitable for.
Datro be by 5,6- diethyl -2,3- dihydro -1H- indenes -2- amine hydrochlorate (Formula II compound) and
R-8- (benzyl chloride base) -5- (the bromo- 1- ethoxy of 2-) quinolinone (formula III compound) amino-alkylation obtains.It is specific to close
Mainly there are following two at process:
First, providing a kind of scheme in patent WO2005123684, it is specifically shown in following reaction equation:
The route is protected by forming three-membered ring come chiral hydroxyl, then while open loop with amino amine alkyl
Change, but the selectivity during amino-alkylation is not satisfactory, and two quinolinones in addition can be connected on amino, so that Formulas I chemical combination
The yield of object only has 63.5%, and two Main By products generated are close with target compound property, causes separation difficult,
Eventually lead to that increased production cost and quality is difficult to control.
Second, disclosing an other route in United States Patent (USP) US2016326118, reaction equation is as follows:
The route is protected by the chiral hydroxyl of t-butyldimethyl silane, overcomes selective in route one ask
Topic, but can not overcome the problems, such as that controlling amino further reacts, so that purification is difficult, and at high cost asks there are still yield is low
Topic.
Summary of the invention
The present invention provides a kind of datro and its synthetic methods and synthesis intermediate of salt derivative, to solve
The problem of it is more that there are by-products in datro synthesis at present, and yield is low, purification difficult.
In order to solve the above-mentioned technical problem, the technical scheme is that the synthetic method of the datro, with silicon
The compound of Formula IV and 2- t-butoxycarbonyl-amino-(5,6- diethyl) indane, that is, Formula V compound of alkane protection Formula II compound
Compound of formula I is obtained through amino-alkylation and deprotection one pot reaction for raw material, reaction equation is as follows:
Wherein, R is silylation protecting group.
Optionally, the silylation protecting group is selected from tert-butyldimethylsilane base, trimethyl silicane silylation or diphenyl
T-butylsilane base, preferably tert-butyldimethylsilane base.
Optionally, the amino-alkylation reaction neutral and alkali reagent is potassium tert-butoxide or sodium tert-butoxide, adds alkaline reagent mistake
Control system temperature is at 0 DEG C hereinafter, it is preferred that -5 DEG C -0 DEG C in journey, and stirring at normal temperature is reacted after addition.
Room temperature, which refers to, does not artificially carry out temperature (heating or cooling) control to system.
Optionally, the reaction dissolvent in the amino-alkylation reaction is selected from n,N-Dimethylformamide (DMF) or dimethyl
Sulfoxide (DMSO).
Optionally, acid reagent used in deprotection reaction is selected from inorganic acid or organic acid, and the inorganic acid is selected from hydrochloric acid, sulphur
Acid or nitric acid, the organic acid are selected from formic acid or acetic acid, and finally obtain the corresponding salt derivative of datro.
Optionally, the molar ratio of the compound of Formula IV and Formula V compound is 1:(1-1.1).
The present invention also provides the synthetic method of datro salt derivative, compound of formula I prepared by above-mentioned synthetic method,
Acid is added with free state in a solvent and forms corresponding salt derivative.
Optionally, the solvent is selected from methylene chloride, petroleum ether, ethyl acetate, n-butanol, isoamyl alcohol, ether or chloroform；
The datro salt derivative is maleate derivative, sulfate-derivatives, Hvdrochloride Derivatives, mesylate are derivative
Object, benzoate derivatives, formic acid salt derivative or phosphate derivative.
The present invention also provides a kind of intermediates for synthesizing datro, and its chemical name is 2- t-butoxycarbonyl-aminos-
(5,6- diethyl) indane, chemical formula are Formula V compound.
Optionally, the Formula V compound is by 2- amino-(5,6- diethyl) indane, that is, Formula II compound and dimethyl dicarbonate
Butyl ester reaction obtains.
Technical solution provided by the invention is cleverly avoided by carrying out Boc protection to the amino in Formula II compound
More alkylations on amino, in the case where hydroxyl and amino all have appropriate protection, alkylated reaction effectively prevents by-product
The generation of object, and hydroxyl and amino deprotection can be directly carried out after alkylated reaction, by multistep reaction in a reactor
Middle completion saves the process of intermediate purification separation, and also improving reaction yield to the greatest extent reduces production cost.
Specific embodiment
In order to make it easy to understand, illustrating the synthetic method of a kind of datro and its salt derivative below with reference to embodiment
With synthesis intermediate, it should be appreciated that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.
Agents useful for same is commercial goods in following embodiments, and wherein nuclear magnetic resonance data is measured by Fourier 300,
Middle mass spectrum is measured by GCMS6800.
Embodiment 1
8- benzyloxy -5- ((R) -2- bromo- 1- (t-Butyldimethylsilyl) oxygroup-ethyl) -1H- quinoline-2-one (formula IV
Compound) synthesis
Formula III compound 50g is added in 1000mL three-necked bottle, dissolution is stirred at room temperature, after dissolution in methylene chloride 600ml
Triethylamine 17g is added, ice bath is cooled to 0 DEG C, under stirring, and tert-butyl chloro-silicane 24.8g is added dropwise, finishes, and restores to normal
2~4h of temperature reaction.After reaction, it is cooled to 0 DEG C, it is 1N HCl solution, layering, water phase 200ml bis- that concentration, which is slowly added dropwise,
Chloromethanes extraction merges organic phase, dry, is concentrated to give target compound 78g, yield 99.3%,
Embodiment 2
The synthesis of 2- t-butoxycarbonyl-amino-(5,6- diethyl) indane (Formula V compound)
Formula II compound 40g is added in 1000ml three-necked bottle, methylene chloride 600ml is stirred at room temperature, and ice bath is cooled to 0
~5 DEG C, under stirring, triethylamine 37.6g is added, dimethyl dicarbonate butyl ester 39.4g is slowly added dropwise, drop finishes within about 0.5 hour, in 0~5 DEG C
Under be stirred to react 4 hours, reaction solution is poured into 500ml ice water and is layered, water phase with 200ml methylene chloride extract, merge it is organic
Phase, it is dry, it is concentrated to give Formula V compound 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+).
Embodiment 3
(R) -5- [2- (5,6- diethyl indane -2- base amino) -1- ethoxy] -8- benzyloxy -1H- quinoline-2-one
The synthesis of hydrochloride (compound of formula I hydrochloride)
Formula IV compound 48.8g (about 0.1mol) and the system of embodiment 2 prepared by embodiment 1 is added in 1000ml three-necked bottle
500ml DMF is added in standby Formula V compound 29g (about 0.1mol), and ice salt bath is cooled under -5~0 DEG C of stirring, is slowly added into uncle
Butanol potassium 12.3g, temperature are maintained at 0 DEG C or less.It adds and temperature is slowly restored to room temperature, after stirring 4 hours, by reaction solution
1000ml ice water is poured into, is extracted 2 times with ethyl acetate 300ml, merges organic phase concentration and does, dehydrated alcohol 500mL is added, is added
Concentrated hydrochloric acid 40mL stirs 2 hours at room temperature, filters to obtain compound of formula I hydrochloride 45.67g, yield 88%.
Embodiment 4
(R) -5- [2- (5,6- diethyl indane -2- base amino) -1- ethoxy] -8- benzyloxy -1H- quinoline-2-one
Benzoate (compound of formula I benzoate)
Compound of formula I hydrochloride 40g and 400ml ethyl acetate prepared by embodiment 3, ice are added in 1000ml three-necked bottle
Under water-bath cooling, 1N solution of potassium carbonate is added portionwise, adjusts pH about 9, liquid separation removes water phase, is slowly added into benzene under organic phase stirring
Formic acid 10.3g stirs 2 hours crystallizations, and filtering is eluted 2 times with 100mL ethyl acetate, and solid dries to obtain the benzene of compound of formula I
Formates 41.8g, yield 90%.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations.Although
Present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that: it still may be used
To modify to technical solution documented by previous embodiment, or some or all of the technical features are equal
Replacement, and these modifications or substitutions, the model for technical solution of various embodiments of the present invention that it does not separate the essence of the corresponding technical solution
It encloses.
Claims (10)
1. a kind of synthetic method of datro, which is characterized in that using compound of Formula IV and Formula V compound be raw material through amine alkane
Base and deprotection one pot reaction obtain compound of formula I, and reaction equation is as follows:
Wherein, R is silylation protecting group.
2. synthetic method according to claim 1, which is characterized in that the silylation protecting group is selected from dimethyl tertiary butyl silicon
Alkyl, trimethyl silicane silylation or diphenyl t-butylsilane base, preferably tert-butyldimethylsilane base.
3. synthetic method according to claim 1, which is characterized in that the amino-alkylation reaction neutral and alkali reagent is the tert-butyl alcohol
Potassium or sodium tert-butoxide add during alkaline reagent control system temperature at 0 DEG C hereinafter, it is preferred that -5 DEG C -0 DEG C, after addition
Stirring at normal temperature reaction.
4. synthetic method according to claim 3, which is characterized in that the reaction dissolvent in the amino-alkylation reaction is selected from N,
Dinethylformamide (DMF) or dimethyl sulfoxide (DMSO).
5. synthetic method according to claim 1, which is characterized in that the compound of Formula IV feeds intake with Formula V compound
Molar ratio is 1:(1-1.1).
6. synthetic method according to claim 1, which is characterized in that acid reagent used in the deprotection reaction is selected from salt
Acid, sulfuric acid, nitric acid, formic acid or acetic acid.
7. a kind of synthetic method of datro salt derivative, which is characterized in that the arbitrarily described synthetic method system of claim 1-6
Standby compound of formula I is added acid in a solvent with free state and forms corresponding salt derivative.
8. synthetic method according to claim 7, which is characterized in that the solvent is selected from methylene chloride, petroleum ether, acetic acid second
Ester, n-butanol, isoamyl alcohol, ether or chloroform；It is derivative that the datro salt derivative is selected from maleate derivative, sulfate
Object, Hvdrochloride Derivatives, methanesulfonate derivative, benzoate derivatives, formic acid salt derivative or phosphate derivative.
9. a kind of intermediate for synthesizing datro, which is characterized in that chemical name is 2- t-butoxycarbonyl-amino-(5,6- bis-
Ethyl) indane, chemical formula is Formula V compound:
10. intermediate according to claim 9, which is characterized in that react acquisition with dimethyl dicarbonate butyl ester by Formula II compound
, reaction equation is as follows:
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| CN201910473479.3A CN110128339B (en) | 2019-05-31 | 2019-05-31 | Synthetic method and intermediate for indacaterol and salt derivative thereof |
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| CN201910473479.3A CN110128339B (en) | 2019-05-31 | 2019-05-31 | Synthetic method and intermediate for indacaterol and salt derivative thereof |
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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 |
-
2019
- 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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