CN102718707A

CN102718707A - Hydroxychloroquine derivative and preparation method thereof

Info

Publication number: CN102718707A
Application number: CN2012102128320A
Authority: CN
Inventors: 郭亚兵; 张静; 张晓�; 杨波; 郭婷婷
Original assignee: WUHAN WUYAO TECHNOLOGY Co Ltd
Current assignee: WUHAN WUYAO TECHNOLOGY Co Ltd
Priority date: 2012-06-27
Filing date: 2012-06-27
Publication date: 2012-10-10

Abstract

The invention belongs to the field of pharmaceutical chemistry, and discloses a hydroxychloroquine derivative I, i.e. acetic acid . 2-[[4-[(7-chloroquinoline-4-radical) amino] pentyl] (ethyl) amino] ethyl ester, and a preparation method thereof. The hydroxychloroquine derivative I is a product of esterification of hydroxychloroquine with acetic acid, and is one of major impurities of hydroxychloroquine drugs and preparations thereof. The derivative I can be applied in analysis and detection of the purity of hydroxychloroquine and salts thereof and can also be applied in control of the quality of hydroxychloroquine and salts thereof. The invention also discloses a preparation method of impurities in hydroxychloroquine sulfate and application of reference samples of the prepared impurities in control of the quality of the hydroxychloroquine sulfate.

Description

Plaquenil verivate and preparation method thereof

Technical field

The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of Plaquenil derivative I, i.e. 2-[[4-[(7-chloro-4-quinolyl) amino] amyl group] ethylamino]-ETHYLE ACETATE, and preparation method thereof, and purposes.

Background technology

Hydroxychloroquine sulfate is a kind of antimalarial drug that can be used for the systemic lupus erythematous treatment, also is a kind of antirheumatic thing of uniqueness.In addition, Plaquenil also has photoprotection and reducing cholesterol effect.Recently some tests show that Plaquenil can reduce some untoward reaction of glucocorticosteroid.Plaquenil has good security and reliable curative effect, is applied to clinical just more and more widely.

The chemistry of Plaquenil derivative I is by name: 2-[[4-[(7-chloro-4-quinolyl) amino] amyl group] ethylamino]-ETHYLE ACETATE, and structure is following:

In carrying out the detection of hydroxychloroquine sulfate drug quality, find that compound I is present in hydroxychloroquine sulfate and the preparation thereof as impurity.

Through structural confirmation and mass analysis checking compound I is the impurity that side reaction produces in the hydroxychloroquine sulfate building-up process.

In carrying out the drug quality testing process, need highly purified impurity as reference substance, be used to control the quality of the medicine that possibly contain this impurity.Therefore, must synthesize highly purified known impurities compound.Compound I and compound method thereof are not appeared in the newspapers.

Therefore, the present invention has mainly solved the associated problem of Plaquenil derivative I preparation.

Summary of the invention

We find to contain 1 impurity in the hydroxychloroquine sulfate raw material in carrying out the quality examination process of hydroxychloroquine sulfate bulk drug and preparation, and are definite through scrutinizing, and find that in surprise this impurity is compound shown in the formula I.

The invention provides the preparation method of compound I.Compound I can be obtained by Plaquenil or Oxychloroquine salt and esterifying reagent reaction, and the preparation route is following:

Plaquenil (salt) compound I

The preparation method of compound I is:

(1) in Plaquenil or Plaquenil salt, adds esterifying reagent, stir reacting by heating;

(2) reaction is accomplished, and reaction solution to water, is added yellow soda ash and is adjusted to neutrality, uses dichloromethane extraction again, with the organic phase evaporate to dryness, under the room temperature, adds organic stirring solvent again, separates out solid, suction filtration;

(3) drying obtains bullion, can get the higher derivative I of purity after purified again.

Among the above-mentioned preparation method, acylating reagent is the mix reagent of acetate, diacetyl oxide or acetate, diacetyl oxide, and diacetyl oxide and mix reagent experiment effect are all good.

It is ETHYLE ACETATE, sherwood oil, acetone, normal hexane that solid is separated out with organic solvent, ethyl acetate etc.

Purification process is recrystallization simply, also can use column chromatography, or adopts the liquid phase separation preparation.Recrystallization solvent can be used methyl alcohol, ethanol, Virahol or methanol-water, ethanol water, isopropanol water etc.Also can adopt the preparation of column chromatography or liquid phase separation, its moving phase is methanol-water or acetonitrile water or degree or gradient elutions such as methyl alcohol, acetonitrile water, accepts the product flow point, is concentrated into dried product.We show in research, can obtain purity 99% above product, can be used to do quality approach fully.Can be used for impurity standard substance or impurity reference substance in the drug quality control.

We show that impurity HPLC peak position is consistent with our synthetic compound I liquid phase RT in the hydroxychloroquine sulfate bulk drug at research, and liquid matter molecular weight is consistent, and its compound I nuclear magnetic data ownership rationally.Therefore explain that synthetic compound I is the impurity in the hydroxychloroquine sulfate bulk drug, confirm that both molecular weight are consistent through LC-MS.

Compound I proton nmr spectra data: 1H NMR (CDCl3): δ 1.00-1.10 (6H, CH3), 2.01 (3H ,-CH3), 1.48-2.64 (2H ,-CH2-); 2.36 (2H ,-CH2-), 2.40 (2H ,-CH2-), 2.64 (2H ,-CH2-); (2.79 1H), 4.18 (2H ,-CH2-), 6.49-8.64 (5H).

Embodiment

The preparation method 1 of embodiment 1 compound I

In three mouthfuls of reaction flasks, add the 20g hydroxychloroquine sulfate, the 200mL diacetyl oxide stirs reflux; Reacted 10 hours, reaction is accomplished, and reaction solution is poured in the 500mL water, adds yellow soda ash and is adjusted to neutrality, uses dichloromethane extraction again; Organic phase is revolved dried, adds 100mL ETHYLE ACETATE in the resistates, and stirring at room 12h separates out a large amount of solids, suction filtration; Drying gets bullion, carries out recrystallization with the first alcohol and water again, is chilled to room temperature naturally, separates out a large amount of solids; Suction filtration, the dry off-white color solid 14.7g that gets is compound I, yield 65.3%, HPLC peak area normalization method content 99.4%.

The preparation method 2 of embodiment 2 compound I

In three mouthfuls of reaction flasks, add the 20g hydroxychloroquine sulfate, the 100mL diacetyl oxide, 100mL acetate stirs reflux; Reacted 10 hours, reaction is accomplished, and reaction solution is poured in the 500mL water, adds yellow soda ash and is adjusted to neutrality, uses dichloromethane extraction again; Organic phase is revolved dried, adds 100mL ETHYLE ACETATE in the resistates, and stirring at room 12h separates out a large amount of solids, suction filtration; Drying gets bullion, carries out recrystallization with the second alcohol and water again, is chilled to room temperature naturally, separates out a large amount of solids; Suction filtration, the dry off-white color solid 14.5g that gets is compound I, yield 64.4%, HPLC peak area normalization method content 99.1%.

Embodiment 3 different solids are separated out with solvent the preparation yield of compound I, the influence of quality

According to the preparation method 1 of compound I, select for use solid to separate out reagent and be respectively: ETHYLE ACETATE, acetone, sherwood oil, normal hexane, accomplish 4 experiments, obtain 4 samples, its yield, qualitative data sees the following form:

Sample	Select solvent for use	Output/g	Yield/%	Content/%
					1	ETHYLE ACETATE	14.7	65.3	99.4
2	Acetone	15.5	68.9	94.9
					3	Sherwood oil	15.0	66.7	98.4
4	Normal hexane	14.1	62.7	99.0

Conclusion: ETHYLE ACETATE is separated out reagent as solid, and yield, quality are best relatively.

The application of embodiment 4 compound I in the HPLC of hydroxychloroquine sulfate detects

The HPLC detection method of hydroxychloroquine sulfate:

Chromatographic column: Aglient Zorbax XDB-C8 4.6mm * 150mm5 μ m

Detect wavelength: 254nm

Sample size: 20 μ l

Flow velocity: 1.0ml/min

Chromatographic condition and system suitability test use octyl silane group silica gel to be weighting agent; With phosphate buffer solution (get potassium primary phosphate 2.72g, put (0.02mol/L) in the 1000ml water, add triethylamine 2ml, regulate pH to 8.0 ± 0.05 with 1mol/L Pottasium Hydroxide) is mobile phase A, and methyl alcohol is Mobile phase B, carries out gradient elution according to following table:

Time (minute)	A phase (V/V)	B phase (V/V)
			0-20	53→33	47→67
20-32 minute	33	67

The detection wavelength is 254nm.Number of theoretical plate calculates by the hydroxychloroquine sulfate peak should be not less than 2000.

Assay method is got these article in right amount, and precision is claimed fixed, adds the also quantitative dilution of diluent dissolving and processes the solution that contains 0.5mg among every 1ml, as need testing solution; It is an amount of that precision is measured need testing solution, adds the moving phase dilution and process the solution that every 1ml contains 5 μ g, as contrast solution.Precision is measured contrast solution 20 μ l, injects liquid chromatograph, regulates instrumental sensitivity, makes the peak height at principal constituent peak be about registering instrument full range 20%～25%, the record color atlas; Precision is measured need testing solution 20 μ l again, injection liquid chromatograph, 2 times of writing down color atlas to principal constituent peak RT.Thinner: A phase--B phase (53: 47).

Claims

1. Plaquenil derivative I, I is as shown in the formula shown in the i:

2. according to the said derivative I of claim 1, it is characterized in that: Plaquenil or its salt and esterifying reagent reaction make derivative I.

3. according to the said derivative I of claim 2, its preparation method is:

(2) reaction is accomplished, and reaction solution to water, is added yellow soda ash and is adjusted to neutrality, uses dichloromethane extraction again, organic phase is concentrated into dried, under the room temperature, adds organic stirring solvent again, separates out solid, suction filtration;

(3) drying obtains derivative I.

4. according to the said preparation method of claim 3, it is characterized in that: acylating reagent is the mix reagent of acetate, diacetyl oxide or acetate, diacetyl oxide.

5. according to the said preparation method of claim 4, it is characterized in that: it is ETHYLE ACETATE, sherwood oil, acetone, normal hexane, ether, normal heptane that solid is separated out with organic solvent.

6. according to the said Plaquenil derivative I of claim 1, it is characterized in that: derivative I is used for the quality control of Plaquenil and salt thereof.

7. according to the said Plaquenil derivative I of claim 1, it is characterized in that: derivative I is used for the quality control of Plaquenil Sulfate.

8. according to the said derivative I of claim 1, it is characterized in that: compound I is applied in the HPLC detection of hydroxychloroquine sulfate, and chromatographic condition is following:

Moving phase:

A phase: get 0.02mol/L potassium primary phosphate (being that 2.72gKH2PO4 puts in the 1000ml water), add triethylamine 2ml, regulate pH to 8.0 ± 0.05 with 1mol/L Pottasium Hydroxide;

B phase: methyl alcohol;

Thinner: A phase--B phase (53: 47);

Gradient elution:

Time The A phase The B phase 0 minute 53 47 20 minutes 33 67 32 minutes 33 67