CN110143888A - The synthetic method of impurity in a kind of salmeterol bulk pharmaceutical chemicals - Google Patents
The synthetic method of impurity in a kind of salmeterol bulk pharmaceutical chemicals Download PDFInfo
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- CN110143888A CN110143888A CN201910430926.7A CN201910430926A CN110143888A CN 110143888 A CN110143888 A CN 110143888A CN 201910430926 A CN201910430926 A CN 201910430926A CN 110143888 A CN110143888 A CN 110143888A
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Abstract
The present invention provides a kind of synthetic method of impurity in salmeterol bulk pharmaceutical chemicals, and the synthetic method of the impurity includes: step 1: using SM1 and SM2 as starting material, being coupled by C-O, reaction obtains compound I；Step 2: the compound I hydrolysis in step 1 is generated into compound II；Step 3: the compound II in step 2 is hydrogenated into de- benzyl again and obtains compound III；Compound III reducing carbonyl in step 3 is obtained the impurity E P-ZD in salmeterol bulk pharmaceutical chemicals by step 4.It is starting material that the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals of the invention, which is by salmeterol intermediate, passes through four-step reaction, by simply post-processing, intermediate is even without purifying, directly synthesis pharmacopeia impurity E P-ZD, cost is substantially reduced, and improves production efficiency.
Description
Technical field
The invention belongs to medicinal chemistry arts, in particular to the synthetic method of impurity in a kind of salmeterol bulk pharmaceutical chemicals.
Background technique
Salmeterol is a kind of long-acting novel β with anti-inflammatory effect2Agonist has powerful inhibition lung loose thin
Born of the same parents discharge the effect of allergic reaction medium, can inhibit early stage and the late phase reaction of sucking antigen induced, reduce airway hyperreactivity；
It is mainly used for treating asthma (including Nocturnal and exercise-induced asthma), wheeze row bronchitis and Reversible airway obstruction.
The former quality standard ground is not achieved in the salmeterol bulk pharmaceutical chemicals quality of many producer's productions now, to solve bulk pharmaceutical chemicals
Problem of low quality needs to further investigate the related substance of bulk pharmaceutical chemicals；Key Quality of the related substance as bulk pharmaceutical chemicals
Parameter, impurity is as the important component in relation to substance, therefore impurity content directly affects stability of drug products, validity and peace
Quan Xing.
The impurity that salmeterol is embodied in European Pharmacopoeia has 7, including dimerization impurity E P-ZD, due to dimerization impurity
EP-ZD synthesis yield is low, purification difficult, and its reference substance price is excessively high, commercially will increase the research of bulk pharmaceutical chemicals
Cost, these factors are limited to the miscellaneous Quality Research of dimerization.
Summary of the invention
In view of the above-mentioned problems, the present invention provides a kind of synthetic method of impurity in salmeterol bulk pharmaceutical chemicals, the impurity tool
Just like following formula (1) structure:
The synthetic method of formula (1) impurity includes:
Step 1: using SM1 and SM2 as starting material, being coupled by C-O, and reaction obtains compound I；
Step 2: the compound I hydrolysis in step 1 is generated into compound II；
Step 3: the compound II in step 2 is hydrogenated into de- benzyl again and obtains compound III；
Compound III reducing carbonyl in step 3 is obtained the impurity E P-ZD in salmeterol bulk pharmaceutical chemicals by step 4.
Further, the reaction dissolvent in the step 1 includes one of DMF, DMSO, ethyl acetate, methylene chloride
Or it is a variety of；And the acid binding agent of the reaction includes potassium carbonate, sodium hydroxide, triethylamine, N, one of N diisopropylethylamine or
It is a variety of；The temperature of the reaction is 0~25 DEG C.
Further, the reaction dissolvent in the step 1 is DMF, and the acid binding agent of the reaction is potassium carbonate.
Further, the solvent of hydrolysis includes one of acetone, tetrahydrofuran, water or more in the step 2
Kind；The hydrolysing agent of the hydrolysis includes one of sulfuric acid, hydrochloric acid, sodium hydroxide, potassium carbonate or a variety of；The hydrolysis
The temperature of reaction is 50~65 DEG C.
Further, the solvent of the hydrolysis is tetrahydrofuran, and the hydrolysing agent of the hydrolysis is sulfuric acid.
Further, the hydrogenation in the step 3, which takes off benzyl, is reacted with hydrogen, the reaction dissolvent packet for hydrogenating de- benzyl
Include one of methanol, ethyl alcohol, ethyl acetate or a variety of；The catalyst of the hydrogenation debenzylation reaction includes palladium carbon, palladium dydroxide
One of carbon, Ranny Ni or a variety of；The temperature of the hydrogenation debenzylation reaction is 10~25 DEG C.
Further, the reaction dissolvent for hydrogenating de- benzyl is ethyl alcohol, and the catalyst of the hydrogenation debenzylation reaction is palladium carbon.
Further, the reducing agent of the reduction reaction in the step 4 includes sodium borohydride, triacetoxy boron hydride
One or more of sodium, sodium cyanoborohydride；The reaction temperature of the reduction reaction is 0~20 DEG C.
Further, the reducing agent of the reduction reaction in the step 4 is sodium borohydride.
It is starting material that the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals of the invention, which is by salmeterol intermediate,
By four-step reaction, by simply post-processing, intermediate makes into even without purifying, directly synthesis pharmacopeia impurity E P-ZD
Originally it substantially reduces, and improves production efficiency.
Other features and advantages of the present invention will be illustrated in the following description, also, partly becomes from specification
It obtains it is clear that understand through the implementation of the invention.The objectives and other advantages of the invention can be by specification, right
Pointed structure is achieved and obtained in claim and attached drawing.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is this hair
Bright some embodiments for those of ordinary skill in the art without creative efforts, can be with root
Other attached drawings are obtained according to these attached drawings.
Fig. 1 shows whole synthetic schemes according to an embodiment of the present invention；
Fig. 2 shows the synthetic schemes of SM2 according to an embodiment of the present invention.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
In attached drawing, technical solution in the embodiment of the present invention clearly and completely illustrated, it is clear that described embodiment is
A part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art
Every other embodiment obtained without making creative work, shall fall within the protection scope of the present invention.
The present invention provides a kind of synthetic method of impurity in salmeterol bulk pharmaceutical chemicals, and the impurity has such as following formula (1)
Structure:
Fig. 1 shows whole synthetic schemes according to an embodiment of the present invention；As shown in Figure 1,
The synthetic method of formula (1) impurity includes:
Step 1: using SM1 and SM2 as starting material, being coupled by C-O, and reaction obtains compound I；
Specifically, the reaction dissolvent of above-mentioned reaction includes DMF (dimethylformamide), DMSO (dimethyl sulfoxide), acetic acid
One of ethyl ester, methylene chloride are a variety of, but not limited to this；Preferably, the reaction dissolvent selects DMF；The reaction
Acid binding agent includes potassium carbonate, sodium hydroxide, triethylamine, N, one of N diisopropylethylamine or a variety of, but not limited to this；It is excellent
Choosing, the acid binding agent of the reaction is potassium carbonate；The temperature of the reaction is 0~25 DEG C.
Specifically, shown in the structural formula of the SM1 such as following formula (2):
Shown in the structural formula of the SM2 such as following formula (3):
Step 2: the compound I hydrolysis in step 1 is generated into compound II；
Specifically, the solvent of above-mentioned hydrolysis includes one or more of acetone, tetrahydrofuran, water, but unlimited
In this；Preferably, the solvent of the hydrolysis is tetrahydrofuran；The hydrolysing agent of the hydrolysis include sulfuric acid, hydrochloric acid,
One of sodium hydroxide, potassium carbonate are a variety of, but not limited to this；Preferably, the hydrolysing agent of the hydrolysis is sulfuric acid；
The temperature of the hydrolysis is 50~65 DEG C.
Step 3: the compound II in step 2 is hydrogenated into de- benzyl again and obtains compound III；
Specifically, the reaction dissolvent that above-mentioned hydrogenation takes off benzyl includes one of methanol, ethyl alcohol, ethyl acetate or a variety of, but
It is without being limited thereto；Preferably, the reaction dissolvent for hydrogenating de- benzyl is ethyl alcohol；The catalyst of above-mentioned hydrogenation debenzylation reaction includes palladium
One of carbon, hydroxide palladium carbon, Ranny Ni or a variety of, but not limited to this；Preferably, the catalysis of the hydrogenation debenzylation reaction
Agent is palladium carbon；The temperature of above-mentioned hydrogenation debenzylation reaction is 10~25 DEG C, and above-mentioned hydrogenation debenzylation reaction is to react synthesisization with hydrogen
Close object III.
It should be noted that Ranny Ni is Raney's nickel, it is one kind of catalyst；Ranny Ni is a kind of grid nickel,
Effectively enlarged surface product there can be acidity to promote to react, and main component is nickel.
Compound III reducing carbonyl in step 3 is obtained EP-ZD by step 4, i.e., miscellaneous in salmeterol bulk pharmaceutical chemicals
Matter.
Specifically, the reducing agent of above-mentioned reduction reaction includes sodium borohydride, sodium triacetoxy borohydride, cyano hydroboration
One or more of sodium, but not limited to this；Preferably, the reducing agent is sodium borohydride；The reaction of above-mentioned reduction reaction
Temperature is 0~20 DEG C.
Case study on implementation one
The synthesis of compound I:
Take three mouthfuls of reaction flasks of 1.0L, be added SM2 (39.0g, 77.4mmol, 1.0eq), and with the DMF of 200ml (N,
Dinethylformamide) it is dissolved, K is then added2CO3(12.8g, 92.9mmol, 1.2eq), and temperature is controlled 0~5
℃；SM1 (30.6g, 92.9mmol, 1.2eq) is taken, is dissolved with the DMF solution of 100ml, is then slowly dropped to three mouthfuls of reaction flasks
In, after being added dropwise, 15~20 DEG C are warming up to, reacts it at such a temperature 4~5 hours；TLC monitors reaction end (PE:EA
=2:1), after completion of the reaction, the ethyl acetate dilution of 350ml is added into reaction solution, the water washing that 500ml is added is primary, washes
After the completion of washing, the water for repeating to be added 500ml washed once again, and finally plus the saturated salt solution of 300ml washed once；Then make
With anhydrous sodium sulfate is dry, obtains grease crude product 66.5g after concentration.
The silica gel post separation of 200~300 mesh of crude product, dry column-packing, dry method loading, mobile phase be PE:EA=2:(1~
3) gradient elution is collected target components using LC-MS detection (liquid chromatography-mass spectrography detection), is concentrated under reduced pressure, obtains crocus oil
Shape object crude product 29.1g, yield 50.0%.
Wherein, TLC monitoring is thin-layer chromatography monitoring, is that the stationary phase that will be suitable for is coated on glass plate, plastics or aluminium substrate
On, form thin uniform layer；After point sample, expansion, according to Rf value (Rf) and suitable reference material resulting chromatogram by the same method
Rf value (Rf) compare, the method to carry out the identification of drug, determination of foreign matter or assay.In addition TLC is being carried out
When monitoring, the solvent ratio used is PE (petroleum ether): EA (ethyl acetate)=2:1.
The reaction equation of above-mentioned reaction are as follows:
Wherein the acid binding agent of above-mentioned reaction selects potassium carbonate (K2CO3)。
Case study on implementation two
The synthesis of compound II:
It in tri- mouthfuls of reaction flasks of 500mL, is added compound I (29.1g, 38.7mmol, 1eq), the tetrahydro of 300ml is then added
Furans dissolution.Under conditions of temperature is 20~30 DEG C, it is added 10% sulfuric acid solution (379.3g, 387mmol, 10eq).Charging
After the completion, 60~64 DEG C are warming up to, is reacted 14~15 hours at such a temperature, LCMS monitors (liquid chromatogram monitoring) fully reacting
Afterwards, cool down, removing solvent is concentrated under reduced pressure, obtain yellow oil crude product 19.8g, yield 76.7%.Due to compound II polarity
Greatly, it not easily passs through column chromatography and obtains sterling, therefore crude product is without further purification, direct plunge into and react in next step.
The reaction equation of above-mentioned reaction are as follows:
Wherein the hydrolysing agent of above-mentioned reaction selects sulfuric acid.
Case study on implementation three
The synthesis of compound III:
1L stand up reaction bottle is taken, is added compound II crude product (19.8g, 29.7mmol, 1eq), the second of 400ml is then added
Pure and mild 10% Pd/C (4.6g, water content 56.5%).In order to improve the security performance of reaction, first nitrogen displacement three times；And
Hydrogen displacement three times, is reacted for 24 hours under the conditions of 20~25 DEG C afterwards.After LCMS monitors fully reacting, replace into nitrogen, then mistake
Compound III crude product 10.2g, yield 59.6% are obtained after filter, filtrate concentration.It is acid strong since compound III polarity is big, hold
It is easily adsorbed on a silica gel column in pillar layer separation, therefore crude product is without further purification, direct plunges into and react in next step.
The reaction equation of above-mentioned reaction are as follows:
The wherein catalyst choice palladium carbon (Pd/C) of above-mentioned reaction.
Case study on implementation four
The synthesis of impurity E P-ZD in salmeterol bulk pharmaceutical chemicals:
It takes two mouthfuls of reaction flasks of 250mL, the anhydrous of compound III crude product (10.2g, 17.7mmol, 1eq) and 100ml is added
Then methanol is cooled to 0~5 DEG C；Then divide 4~5 times, sodium borohydride (2.7g, 70.8mmol, 4eq) gradually is added.After adding
20~25 DEG C are warming up to, is reacted 4 hours, LCMS monitors fully reacting.The saturated ammonium chloride solution quenching reaction of 20ml, mistake is added
Filter out insoluble matter.Filtrate extracts liquid separation with the methylene chloride of 200ml and the water of 100ml, receives to the organic phase after liquid separation
Collection, uses the methylene chloride of 200ml to extract the water layer after liquid separation again, in order to sufficiently extract the organic matter of water layer, utilizes again
The methylene chloride extraction of 200ml is primary, obtains organic phase extracted；Merge resulting organic phase twice, after reduced pressure, uses
Silica gel post separation, wet method dress post, dry method loading, mobile phase are DCM (methylene chloride): MeOH (methanol)=(0~10): 1.It collects
Target components obtain yellow oil crude product 8.0g using LC-MS detection (liquid chromatography-mass spectrography detection) after reduced pressure.It is yellow
Color grease crude product passes through preparation HPLC (high performance liquid chromatograph) purifying again, light yellow oil 0.9g is obtained after freeze-drying, instead
Total recovery 8.7% should be purified with preparation.LC-MS:[M+H]+(quasi-molecular ions)=580 (are LC-MS testing result, MS signal herein
Are as follows: molecular weight+1=580)
The reaction equation of above-mentioned reaction are as follows:
Illustratively, for the synthesis flow of starting material SM2, as shown in Figure 2.
(a) compound IV, compound V under alkaline condition, occur condensation reaction, obtain key intermediate VI；
(b) intermediate VI is hydrolyzed in acid condition, obtains intermediate SM2.
Specifically, in step a, compound IV, compound V be reacted in a solvent, wherein the solvent include ester,
One of ether, ketone, pure and mild nitrile or it is a variety of and they one of or it is a variety of with aromatic hydrocarbon, it is a kind of in aliphatic hydrocarbon, halogenated hydrocarbons
Or a variety of mixing, but not limited to this.Preferably, the reaction dissolvent is ethyl acetate, ether, tetrahydrofuran, petroleum ether, third
One of ketone, butanone, methanol, ethyl alcohol, acetonitrile and DMF or a variety of and they one of or it is a variety of with benzene, toluene, diformazan
One of benzene, ethane, hexamethylene, methylene chloride, chloroform or a variety of mixing.
Alkali in the step a includes NaOH, KOH, Na2CO3、NaHCO3、LiOH、Ba(OH)2, potassium tert-butoxide, the tert-butyl alcohol
Sodium, sodium methoxide, sodium ethoxide, pyridine, triethylamine, 2,6- lutidines, N, N- diisopropylethylamine etc. are one or more.It is preferred that
, the alkali in step a is Na2CO3、NaHCO3、LiOH、Ba(OH)2Etc. one or more.
The molar ratio of the compound IV and compound V are 1:(1~1.8), it is preferred that compound IV and compound V
Molar ratio be 1:1.5；The equivalent proportion of the compound IV and alkali are 1:(1.5~3), it is preferred that compound IV and alkali
Equivalent proportion is 1:2；Reaction temperature is -20 DEG C~60 DEG C, it is preferred that reaction temperature is -10 DEG C~40 DEG C；Reaction time is 12 small
When~18 hours.
Specifically, intermediate VI is hydrolyzed in acid condition in step b, hydrolysis carries out in a solvent；Described is molten
Agent is the alcohols solvents such as methanol, ethyl alcohol, isopropanol；The acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid；Preferably, acid is hydrochloric acid；
The equivalent proportion of the intermediate VI and acid are 1:(3~7), it is preferred that the equivalent proportion of intermediate VI and acid is 1:4.5, specifically
, acid is added dropwise into the solution of intermediate VI at -20 DEG C~30 DEG C, after being added dropwise to complete, keeps thermotonus of the same race, when reaction
Between be 2 hours~24 hours；After the reaction was completed, with lye regulation system pH to 8~9；Then isolated SM2.
Although the present invention is described in detail referring to the foregoing embodiments, those skilled in the art should manage
Solution: it is still possible to modify the technical solutions described in the foregoing embodiments, or to part of technical characteristic into
Row equivalent replacement；And these are modified or replaceed, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The spirit and scope of scheme.
Claims (9)
1. the synthetic method of impurity in a kind of salmeterol bulk pharmaceutical chemicals, the impurity has such as following formula (1) structure:
It is characterized in that, the synthetic method of formula (1) impurity includes:
Step 1: using SM1 and SM2 as starting material, being coupled by C-O, and reaction obtains compound I；
Step 2: the compound I hydrolysis in step 1 is generated into compound II；
Step 3: the compound II in step 2 is hydrogenated into de- benzyl again and obtains compound III；
Compound III reducing carbonyl in step 3 is obtained the impurity E P-ZD in salmeterol bulk pharmaceutical chemicals by step 4.
2. the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals according to claim 1, which is characterized in that the step 1
In reaction dissolvent include one of DMF, DMSO, ethyl acetate, methylene chloride or a variety of；And the acid binding agent packet of the reaction
Include potassium carbonate, sodium hydroxide, triethylamine, N, one of N diisopropylethylamine or a variety of；The temperature of the reaction is 0~25
℃。
3. the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals according to claim 2, which is characterized in that the step 1
In reaction dissolvent be DMF, the acid binding agent of the reaction is potassium carbonate.
4. the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals according to claim 1 to 3, which is characterized in that
The solvent of hydrolysis includes one or more of acetone, tetrahydrofuran, water in the step 2；The hydrolysis
Hydrolysing agent includes one of sulfuric acid, hydrochloric acid, sodium hydroxide, potassium carbonate or a variety of；The temperature of the hydrolysis be 50~
65℃。
5. the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals according to claim 4, which is characterized in that the hydrolysis is anti-
The solvent answered is tetrahydrofuran, and the hydrolysing agent of the hydrolysis is sulfuric acid.
6. the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals according to claim 1 to 3, which is characterized in that
Hydrogenation in the step 3, which takes off benzyl, is reacted with hydrogen, and the reaction dissolvent for hydrogenating de- benzyl includes methanol, ethyl alcohol, acetic acid second
One of ester is a variety of；The catalyst of the hydrogenation debenzylation reaction includes one of palladium carbon, hydroxide palladium carbon, RannyNi
Or it is a variety of；The temperature of the hydrogenation debenzylation reaction is 10~25 DEG C.
7. the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals according to claim 6, which is characterized in that the hydrogenation is de-
The reaction dissolvent of benzyl is ethyl alcohol, and the catalyst of the hydrogenation debenzylation reaction is palladium carbon.
8. the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals according to claim 1 to 3, which is characterized in that
The reducing agent of reduction reaction in the step 4 includes sodium borohydride, sodium triacetoxy borohydride, in sodium cyanoborohydride
One or more；The reaction temperature of the reduction reaction is 0~20 DEG C.
9. the synthetic method of impurity in salmeterol bulk pharmaceutical chemicals according to claim 8, which is characterized in that the step 4
In reduction reaction reducing agent be sodium borohydride.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884625A (en) * | 2016-05-10 | 2016-08-24 | 浙江工业大学 | synthetic method of R-salmeterol |
| CN108822065A (en) * | 2018-05-31 | 2018-11-16 | 四川农业大学 | A kind of benzopyrans compounds and its preparation method and application |
-
2019
- 2019-05-22 CN CN201910430926.7A patent/CN110143888A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884625A (en) * | 2016-05-10 | 2016-08-24 | 浙江工业大学 | synthetic method of R-salmeterol |
| CN108822065A (en) * | 2018-05-31 | 2018-11-16 | 四川农业大学 | A kind of benzopyrans compounds and its preparation method and application |
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Application publication date: 20190820 |