CN107337616A - A kind of synthetic method of KWD-2183 impurity F - Google Patents
A kind of synthetic method of KWD-2183 impurity F Download PDFInfo
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- CN107337616A CN107337616A CN201710571202.5A CN201710571202A CN107337616A CN 107337616 A CN107337616 A CN 107337616A CN 201710571202 A CN201710571202 A CN 201710571202A CN 107337616 A CN107337616 A CN 107337616A
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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
- C07C269/06—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 by reactions not involving the formation of carbamate groups
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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
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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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
- C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
- C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
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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 present invention relates to organic chemical synthesis field, more particularly to a kind of synthetic method of double (N, the N dimethyl carbamate) hydrochlorides of 5 (2 (tert-butylamino) acetyl group) 1,3 phenylenes.The present invention protects amine functional group from bambuterol, then hydroxyl is oxidized into carbonyl, and protection group is sloughed under last acid condition and obtains impurity F, while is transformed into the stable hydrochloride form of property.The invention overcomes the problem in terms of yield and purifying, breaks through conventional thought, has innovative well.
Description
Technical field
The present invention relates to organic chemical synthesis field, more particularly to a kind of 5- (2- (tert-butylamino) acetyl group) -1,
The synthetic method of 3-- phenylenes-bis- (N, N- dimethyl carbamate) hydrochloride.
Background technology
KWD-2183 is a kind of bronchodilators of super long effective, category third generation β2, adrenoceptor agonists,
For the double carbamate pro-drug of Terbutaline, the medicine hydrolyzes, is oxidized to Terbutaline and plays drug effect in vivo, and it is first
Cross metabolism and be significantly less than Terbutaline, absorb not by food effect, hear being up to during useful effect 24 hours.And Small side effects,
Convenient drug administration, to being easy to have very big medical value in the asthma patient that night or morning break out or aggravated, therefore it is considered as
A kind of preferable suppressing panting calming medicine.
Its entitled 1- [double-(3', 5'-N, N- diformazan of chemistry of KWD-2183 (Bambuterol Hydrochloride)
Carbamoyloxy group) phenyl] -2-N- t-butylaminoethyl hydrochlorides, the entitled Dimethylcarbamic acid 5- [2 of English
[(1,1-dimethyl) amino] 1-hydroxyethyl] -1,3-phenylene ester hydrochloride, CAS:
81732-46-9.The subsidiary of the Astra companies of Switzerland of Department of Pharmacy lists Draco companies nineteen ninety first in Switzerland.
5- (2- (tert-butylamino) acetyl group) -1,3-- phenylenes-bis- (N, N- dimethyl carbamate) are hydrochloric acid class cloth
One of contained impurity, referred to as KWD-2183 impurity F in special Luo Chengpin.Structural formula is as follows：
KWD-2183 impurity F is as the relevant material detection reference substance of KWD-2183, in KWD-2183
In terms of the quality control of bulk drug and its preparation, play the role of irreplaceable.
At present, rarer a kind of synthetic method specifically for KWD-2183 impurity F in the prior art.
The content of the invention
In view of the above the shortcomings that prior art, it is an object of the invention to provide a kind of 5- (2- (tert-butylamino)
Acetyl group) -1,3-- phenylenes-bis- (N, N- dimethyl carbamate) hydrochloride synthetic method, for solve in the prior art
The problem of.
In order to achieve the above objects and other related objects, the present invention adopts the following technical scheme that：
The first aspect of the present invention provides a kind of 5- (2- (tert-butylamino) acetyl group) -1,3-- phenylenes-bis- (N, N-
Dimethyl carbamate) hydrochloride synthetic method, comprise the following steps：
(1) compound of formula 1, under the conditions of existing for di-tert-butyl dicarbonate and alkali, the compound of production 2, reaction are reacted
Equation is as follows：
(2) compound of formula 2 reacts the compound of production 3 under the conditions of existing for catalyst, and reaction equation is as follows：
(3) compound of formula 3 reacts the compound of production 4 under the conditions of existing for hydrogen chloride, and reaction equation is as follows：
The synthesis of the compound of formula 1 belongs to prior art with preparation method, and those skilled in the art can be obtained by approach purchased in market
The compound of formula 1 is obtained, can also refer to existing method to prepare the compound of formula 1.
Preferably, in step (1), the mass ratio of the compound of formula 1 and di-tert-butyl dicarbonate usage amount is 1：(0.8~
1.2)。
Preferably, in step (1), the alkali is selected from any of triethylamine, diisopropylethylamine or a variety of.
Preferably, in step (1), the alkali and the mass ratio of the compound usage amount of formula 1 are (0.4~1.2)：1.
Preferably, in step (1), the reaction is carried out in organic solvent, and the organic solvent is selected from dichloromethane, three
Any of chloromethanes, acetonitrile are a variety of.
Those skilled in the art can determine the dosage of suitable organic solvent according to inventory.In some implementations of the present invention
In mode, the dosage of the organic solvent is the compound of 5~20ml/g formulas 1.
Preferably, in step (1), reaction temperature is 5~30 DEG C.
Those skilled in the art can determine the reaction time according to the process of reaction, and the various suitable inspections in this area can be used
Survey method monitors reaction process.
Preferably, in step (1), the post-processing approach of reaction is：Liquid separation extracts, and merges organic phase, and separation of solid and liquid is pure
Change, produce the compound of formula 2.
Those skilled in the art can select suitable organic solvent to be extracted according to the property of the target product of reaction
With precipitation target product.
Preferably, in step (2), the catalyst is selected from any of manganese dioxide, hydrogen peroxide or a variety of.
Those skilled in the art can be according to reaction system and the species of catalyst, the appropriate dosage for adjusting catalyst.It is preferred that
Ground, the catalyst and the mass ratio of the compound of formula 2 are (0.3~2.5)：1.
Preferably, in step (2), the reaction is carried out in organic solvent, and the organic solvent is selected from dichloromethane, three
Any of chloromethanes, 1,2- dichloroethanes are a variety of.
Those skilled in the art can determine the dosage of suitable organic solvent according to inventory.In some implementations of the present invention
In mode, the dosage of the organic solvent is the compound of 10~30ml/g formulas 2.
Preferably, in step (2), reaction temperature is 30~80 DEG C.
Those skilled in the art can determine the reaction time according to the process of reaction, and the various suitable inspections in this area can be used
Survey method monitors reaction process.
Preferably, in step (2), the post-processing approach of reaction is：Catalyst is removed, concentration, separation of solid and liquid, is purified, i.e.,
Obtain the compound of formula 3.
Preferably, in step (3), the mass ratio of the compound of formula 3 and hydrogen chloride usage amount is 1：(1.0~3.0).
Preferably, in step (3), the reaction is carried out in organic solvent, and the organic solvent is selected from ethyl acetate, first
Any of alcohol, ethanol are a variety of.
Those skilled in the art can determine the dosage of suitable organic solvent according to inventory.In some implementations of the present invention
In mode, the dosage of the organic solvent is the compound of 8~15ml/g formulas 3.
Preferably, in step (3), reaction temperature is -5~30 DEG C.
Those skilled in the art can determine the reaction time according to the process of reaction, and the various suitable inspections in this area can be used
Survey method monitors reaction process.
Preferably, in step (3), the post-processing approach of reaction is：Separation of solid and liquid, wash, dry, produce the compound of formula 4.
The second aspect of the present invention provides a kind of structural formula midbody compound as shown in Equation 2.
The second aspect of the present invention provides a kind of structural formula midbody compound as shown in Equation 3.
Compared with prior art, the present invention has the advantages that：
Temporarily non-document discloses report for the synthesis of the impurity.The synthesis of the impurity in itself has certain challenge.Because trip
It is very unstable from the impurity F under state, so synthesizing the impurity using conventional synthesis process can run into that yield is low, not easy purification etc.
It is difficult.The present invention protects amine functional group from bambuterol, then hydroxyl is oxidized into carbonyl, is taken off under last acid condition
Deprotection base obtains impurity F, while is transformed into the stable hydrochloride form of property.This group think the invention overcome yield and
Problem in terms of purifying, conventional thought is broken through, had innovative well.
Embodiment
Illustrate embodiments of the present invention below by way of specific instantiation, those skilled in the art can be by this specification
Disclosed content understands other advantages and effect of the present invention easily.The present invention can also pass through specific realities different in addition
The mode of applying is embodied or practiced, the various details in this specification can also be based on different viewpoints with application, without departing from
Various modifications or alterations are carried out under the spirit of the present invention.
It should be clear that in the following example not specifically dated process equipment or device using conventional equipment in the art or
Device.
In addition, it is to be understood that one or more method and steps mentioned in the present invention do not repel before and after the combination step
There can also be other method step or other method step can also be inserted between the step of these are specifically mentioned, unless separately
It is described；It should also be understood that the combination annexation between one or more equipment/devices mentioned in the present invention is not repelled
Can also have other equipment/device before and after the unit equipment/device or two equipment/devices specifically mentioning at these it
Between can also insert other equipment/device, unless otherwise indicated.Moreover, unless otherwise indicated, the numbering of various method steps is only
Differentiate the convenient tool of various method steps, rather than ordering or the enforceable model of the restriction present invention for limitation various method steps
Enclose, its relativeness is altered or modified, and in the case where changing technology contents without essence, when being also considered as, the present invention is enforceable
Category.
The compound 5- of 1 formula of embodiment 2 (2- ((tertbutyloxycarbonyl) (tert-butyl group) amino) -1- ethoxys) -1,3- phenylenes -
The synthesis and preparation of double (N, N- dimethyl carbamates)
Embodiment 1-1：
By 2.0 grams of compounds of formula 1 [5- (2- tert-butylaminos) -1- ethoxys) -1,3- phenylenes-bis- (N, N- diformazan ammonia
Carbamate)] it is dissolved in 20 milliliters of dichloromethane, add 2.4 grams (Boc)2O, 1.1 grams of triethylamines.After adding, stir at room temperature
Mix 4 hours.It is concentrated under reduced pressure and removes solvent, adds 30 milliliters of ethyl acetate and 20 milliliters of purified waters, extraction, aqueous phase is again with 20 milliliters
Ethyl acetate extracts once, merges organic phase, anhydrous sodium sulfate drying, filtering, is concentrated under reduced pressure to give crude product.By column chromatography
(eluant, eluent：Dichloromethane：Methanol=30:1) 900 milligrams of compounds of formula 2 [5- (2- ((tertbutyloxycarbonyl) (tert-butyl group) ammonia
Base) -1- ethoxys) -1,3- phenylenes-bis- (N, N- dimethyl carbamate)], yield 35.4%, purity 95%.
After being confirmed and characterized using prior art, the compound of gained formula 2 is [5- (2- ((tertbutyloxycarbonyl) (tertiary fourths
Base) amino) -1- ethoxys) -1,3- phenylenes-bis- (N, N- dimethyl carbamate)].
In embodiment 1-2~embodiment 1-5, the usage amount of the compound of formula 1, the usage amount of di-tert-butyl dicarbonate, alkali
Species, the usage amount of alkali, the species of solvent, the usage amount of solvent, reaction temperature are as shown in table 1, other reaction conditions with reality
Apply identical in a 1-1.The yield and content of product are specifically as shown in table 1.
Table 1
The compound 5- of 2 formula of embodiment 3 (2- ((tertbutyloxycarbonyl) (tert-butyl group) amino)-acetyl group) -1,3- phenylenes-bis-
The synthesis and preparation of (N, N- dimethyl carbamate)
Embodiment 2-1：
By 900 milligrams of compounds of formula 2 [5- (2- ((tertbutyloxycarbonyl) (tert-butyl group) amino) -1- ethoxys) -1,3- Asias benzene
Base-bis- (N, N- dimethyl carbamate)] all it is dissolved in 20 milliliters of dichloromethane, 1.0 grams of manganese dioxide are added, are heated to reflux
Reaction 4 hours.After being cooled to room temperature, manganese dioxide is filtered to remove, crude product is done to obtain in filtrate decompression concentration.Through column chromatography (eluant, eluent：
Ethyl acetate：Petroleum ether=1:2) 450 milligrams of compounds of formula 3 [5- (2- ((tertbutyloxycarbonyl) (tert-butyl group) amino)-second is obtained
Acyl group) -1,3- phenylenes-bis- (N, N- dimethyl carbamate)], yield 50.2%, purity 97%.
After being confirmed and characterized using prior art, the compound of gained formula 3 is [5- (2- ((tertbutyloxycarbonyl) (tertiary fourths
Base) amino)-acetyl group) -1,3- phenylenes-bis- (N, N- dimethyl carbamate)].
In embodiment 2-2~embodiment 2-5, the usage amount of the compound of formula 2, the species of catalyst, the usage amount of catalyst,
The species of solvent, the usage amount of solvent, reaction temperature are as shown in table 2, and other reaction conditions are identical with embodiment 2-1.Production
The yield and content of thing are specifically as shown in table 2.
Table 2
The compound 5- of 3 formula of embodiment 4 (2- (tert-butylamino) acetyl group) -1,3-- phenylenes-bis- (N, N- dimethylamino
Formic acid esters) hydrochloride synthesis and preparation
Embodiment 3-1：
By 450 milligrams of compounds of formula 3 [5- (2- ((tertbutyloxycarbonyl) (tert-butyl group) amino)-acetyl group) -1,3- Asias benzene
Base-bis- (N, N- dimethyl carbamate)] it is dissolved in 5 milliliters of ethyl acetate.Reaction system is cooled to 0-5 DEG C, is added dropwise 5 milliliters
4mol/L Hydrochloride/ethyl acetates.Ice bath is removed, is stirred 2 hours at room temperature, separates out solid, filtering, with a small amount of acetic acid second
Ester washs solid, and wet product obtains the 230 milligrams of compound of formula 4 [5- (2- (tert-butylamino) acetyl in 2 hours in 50 DEG C of vacuum drying
Base) -1,3-- phenylenes-bis- (N, N- dimethyl carbamate) hydrochloride], yield：59.2%, purity 99%.
The characterize data of the compound of formula 4 is as follows：
1H NMR(CDCl 3):δ9.15(s,2H),7.75(s,2H),7.38(s,1H),4.69-4.66(m,2H),3.07
(s,6H),2.93(s,6H),1.36(s,9H)。
It is the usage amount of the compound of formula 3, the usage amount of hydrogen chloride, the species of solvent, molten in embodiment 3-2~embodiment 3-5
Usage amount, the reaction temperature of agent are as shown in table 3, and other reaction conditions are identical with embodiment 3-1.The yield and content of product
It is specific as shown in table 3.
Table 3
In summary, the present invention effectively overcomes various shortcoming of the prior art and has high industrial utilization.
The above-described embodiments merely illustrate the principles and effects of the present invention, not for the limitation present invention.It is any ripe
Know the personage of this technology all can carry out modifications and changes under the spirit and scope without prejudice to the present invention to above-described embodiment.Cause
This, those of ordinary skill in the art is complete without departing from disclosed spirit and institute under technological thought such as
Into all equivalent modifications or change, should by the present invention claim be covered.
Claims (16)
1. a kind of 5- (2- (tert-butylamino) acetyl group) -1,3-- phenylenes-bis- (N, N- dimethyl carbamate) hydrochloride
Synthetic method, comprise the following steps：
(1) compound of formula 1, under the conditions of existing for di-tert-butyl dicarbonate and alkali, the compound of production 2, reactional equation are reacted
Formula is as follows：
(2) compound of formula 2 reacts the compound of production 3 under the conditions of existing for catalyst, and reaction equation is as follows：
(3) compound of formula 3 reacts the compound of production 4 under the conditions of existing for hydrogen chloride, and reaction equation is as follows：
2. synthetic method according to claim 1, it is characterised in that in step (1), the compound of formula 1 and two dimethyl dicarbonates
The mass ratio of butyl ester usage amount is 1：(0.8~1.2).
3. synthetic method according to claim 1, it is characterised in that in step (1), the alkali is selected from triethylamine, two different
Any of propylethylamine is a variety of.
4. synthetic method according to claim 1, it is characterised in that in step (1), the reaction is entered in organic solvent
OK, the organic solvent is selected from any of dichloromethane, triethylamine, acetonitrile or a variety of.
5. synthetic method according to claim 1, it is characterised in that in step (1), the post-processing approach of reaction is：Point
Liquid extracts, and merges organic phase, separation of solid and liquid, purifying, produces the compound of formula 2.
6. synthetic method according to claim 1, it is characterised in that in step (1), in addition to any in following characteristics
Item is multinomial：The alkali and the mass ratio of the compound usage amount of formula 1 are (0.4~1.2)：1；The dosage of the organic solvent is 5
The compound of~20ml/g formulas 1；Reaction temperature is 5~30 DEG C.
7. synthetic method according to claim 1, it is characterised in that in step (2), the catalyst is selected from titanium dioxide
Any of manganese, hydrogen peroxide are a variety of.
8. synthetic method according to claim 1, it is characterised in that in step (2), the reaction is entered in organic solvent
OK, the organic solvent is selected from any of dichloromethane, chloroform, 1,2- dichloroethanes or a variety of.
9. synthetic method according to claim 1, it is characterised in that in step (2), the post-processing approach of reaction is：Go
Except catalyst, concentration, separation of solid and liquid, purifying, the compound of formula 3 is produced.
10. synthetic method according to claim 1, it is characterised in that in step (2), in addition to appointing in following characteristics
It is one or more：The catalyst and the mass ratio of the compound of formula 2 are (0.3~2.5)：1；The dosage of the organic solvent is 10
The compound of~30ml/g formulas 2；Reaction temperature is 30~80 DEG C.
11. synthetic method according to claim 1, it is characterised in that in step (3), the compound of formula 3 uses with hydrogen chloride
The mass ratio of amount is 1：(1.0~3.0).
12. synthetic method according to claim 1, it is characterised in that in step (3), the reaction is in organic solvent
Carry out, the organic solvent is selected from any of ethyl acetate, methanol, ethanol or a variety of.
13. synthetic method according to claim 1, it is characterised in that in step (3), the post-processing approach of reaction is：Gu
Liquid separates, and washs, and dries, produces the compound of formula 4.
14. synthetic method according to claim 1, it is characterised in that in step (3), in addition to appointing in following characteristics
It is one or more：The dosage of the organic solvent is the compound of 8~15ml/g formulas 3；Reaction temperature is -5~30 DEG C.
A kind of 15. structural formula midbody compound as shown in Equation 2.
A kind of 16. structural formula midbody compound as shown in Equation 3.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539100A (en) * | 2021-11-05 | 2022-05-27 | 嘉实（湖南）医药科技有限公司 | Terbutaline derivative D and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20030085658A (en) * | 2002-04-30 | 2003-11-07 | 한올제약주식회사 | An improved synthetic method of bambuterol |
| CN101600701A (en) * | 2006-12-12 | 2009-12-09 | 惠氏公司 | Aryl sulfamide derivatives and its using method |
-
2017
- 2017-07-13 CN CN201710571202.5A patent/CN107337616A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20030085658A (en) * | 2002-04-30 | 2003-11-07 | 한올제약주식회사 | An improved synthetic method of bambuterol |
| CN101600701A (en) * | 2006-12-12 | 2009-12-09 | 惠氏公司 | Aryl sulfamide derivatives and its using method |
Non-Patent Citations (1)
| Title |
|---|
| 吴海虹等: "班布特罗的合成研究", 《合成化学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539100A (en) * | 2021-11-05 | 2022-05-27 | 嘉实（湖南）医药科技有限公司 | Terbutaline derivative D and preparation method and application thereof |
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