CN102558156A - Preparation method of 5-losartan carbonate - Google Patents

Abstract

The invention provides a method for preparing a losartan derivative 5-losartan carbonate from 2-butyl-4-chloro-5-formoxyl-1-{[2'-2(1-H-tetrazole-5-yl)-biphenyl-4]-methyl} imidazole. According to the invention, the total yield of 5-losartan carbonate is 75.6%; and on the existing technology basis, the yield is further improved, cost is reduced, product purity is improved, maneuverability is increased. Thus, the method provided by the invention is suitable for industrial production.

Description

The preparation method of 5-carboxylic acid losartan

Technical field:

The present invention relates to a kind of verivate of antihypertensive drug losartan---the preparation method of 5-carboxylic acid losartan.

Background technology:

5-losartan carboxylate English name: 5-carboxylic acid metabolite, CAS#:124750-92-1; Molecular weight: 436.89, molecular formula: C ₂₂H ₂₁ClN ₆O ₂Chemical name is: chemistry 2-butyl by name-4-chloro-1-[2 '-(1H-tetrazolium-5-yl) 1,1 '-xenyl-methyl] imidazole-5-carboxylic acid; Be called for short EXP-3174.The 5-losartan carboxylate is as active metabolite in the human body of hypertension drug losartan, and its activity is 10-40 a times of losartan, and the transformation period of losartan is 1 hour, and the transformation period of EXP-3174 reaches 6-9 hour.

A series of imdazole derivatives is disclosed in patent EP0253310 at du pont company; Wherein code name is that the compound of DUP753 shows good hypotensive activity; And in the formal approval that obtains U.S. food and FAD (FDA) of nineteen ninety-five; Become the AngII receptor antagonist of first non-peptide class, i.e. Losartan Potassium.Disclose the 5-losartan carboxylate in the U.S. Pat 5138069, the antihypertensive activity of 5153197 pairs of 5-losartan carboxylates of U.S. Pat is described, and after the use that cooperates diuretic(s), the hyperpietic is had good result of treatment.

Based on good antihypertensive effect; 5-carboxylic acid losartan becomes the research and development object that many well-known medicines are looked forward to both at home and abroad; A lot of bibliographical informations about 5-carboxylic acid losartan preparation method are abroad arranged; Wherein patent WO2007095789 is the starting raw material raw material with the Losartan Potassium, behind potassium permanganate oxidation, obtains compound 5-carboxylic acid losartan; Patent CN200610096726 adds polar solvent such as DMF with losartan, and pyridine among the THF, under 5-80 ℃ condition, generates 5-carboxylic acid losartan behind the organic or inorganic reactant salt of adding permanganic acid; Patent documentation W02008076246 is as starting raw material equally with Losartan Potassium; As oxidising agent, and is catalyzer with chlorine ruthenium hydrate with sodium permanganate, and 0 ℃ of stirring reaction spends the night; Add Glyphosate 62 IPA Salt, phosphoric acid again, after simple purification, obtain the thick product of 5-carboxylic acid losartan; Document Tetrahedron Letter 44 (2003) 1149-1152 are starting raw material with the Losartan Potassium, via with the microwave exposure of activated manganese dioxide in water under the reaction, obtain 5-carboxylic acid losartan through chromatographic separation.

Above synthetic route all has earlier could oxidation prepare the limitation of losartan behind the generation losartan, and all is through crossing column purification, being unfavorable for industrial production.

Summary of the invention:

The objective of the invention is to overcome the deficiency of prior art; On the basis of existing technology; The preparation of 5-carboxylic acid losartan and purifying are proposed new technical scheme, and this scheme can be applicable to 2-butyl-4-chloro-5-formyl radical-1-{ [2 '-2 (1-H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles formula (3) is that starting raw material prepares desflurane.The present invention has further improved yield on existing technical foundation, reduce cost, and improves product purity, increases operability, is fit to suitability for industrialized production.Shown in synthetic route figure below of the present invention:

Starting raw material 2-butyl-4-chloro-5-formyl radical-1-{ [2 '-2 (1-H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles formula (3) but preparation referenced patent US5206374 and related art.

Detailed technology scheme of the present invention is following:

1. detritylation protection, adding formula (3) compound in the there-necked flask that reflux condensing tube and tap funnel are housed, an amount of Virahol; Mechanical stirring, heat temperature raising to 50 ℃, 0.5h drips 3.4N hydrochloric acid; The mol ratio of hydrochloric acid and raw material is 1: 1 to 3: 1, preferred 2.4: 1; Keeping temperature is 40 to 60 ℃, is preferably 50 ℃, stirring reaction, TLC (PE: EA=2: 1) follow the tracks of reaction process, show behind the 5h that the raw material primitive reaction finishes.Stop heating and stir the cooling hold over night., there is colourless transparent grain deposition at the bottle end, filters, and filtrating is poured in the big water gaging; Stir; Separate out white solid, get the white solid powder behind the filtering drying, get formula (2) 2-butyl-4-chloro-5-formyl radical-1-{ [2 '-2 (1-H-tetrazolium-5-yl)-biphenyl-4]-methyl the thick product of imidazoles; HPLC purity is 82.4%, yield 86%.Purity is 97% after ethyl alcohol recrystallization is refining, and total recovery is a yield 53%.153～155 ℃ of fusing points.

2. the oxidation of formula (2) compound, adding formula (2) compound and an amount of Virahol, heat temperature raising to 40 ℃ stirring in there-necked flask; Make the dissolving of compound 4 solids, be cooled to 5 ℃ again, add 30% hydrogen peroxide of 1.5 molar equivalents; In addition that the Textone of 1.5 molar equivalents is soluble in water; Under 5 ℃ of conditions the sodium chlorite solution who prepares is added there-necked flask in batches, (DCM: MeOH=10: 1) follow the tracks of reaction process, show behind the 5h to react does not have raw material to TLC basically.Stop to stir hold over night.Reaction solution is poured in the big water gaging, stirred and separate out, in suspension liquid, add the 10N/L sodium hydroxide solution, when PH is 13 with white solid; Liquid becomes clarification, filters and removes insoluble impurity, and agitation condition drips concentrated hydrochloric acid down fast, and the adularescent solid is separated out; Continue dropping and no longer disappear, filter until white solid, and the water flush cake, place oven drying to constant weight filter cake; Get white powder, get the thick product of 5-losartan carboxylate, HPLC purity 92%, bullion yield 88%.The refining back of ethyl alcohol recrystallization purity is 99.97%, and total recovery is 38%.

Further understand spirit of the present invention for ease, the embodiment once that is provided is merely the explanation of detail, is not limited to the content in claims of the present invention.HPLC representes performance liquid chromatography, and TLC representes thin-layer chromatography, and PE representes sherwood oil, and EA representes ETHYLE ACETATE, and DCM representes methylene dichloride, and MeOH representes methyl alcohol.

Embodiment

Embodiment one

2-butyl-4-chloro-5-formyl radical-1-{ [2 '-2 (1-H-tetrazolium-5-yl)-biphenyl-4]-methyl } preparation of imidazoles

Adding formula (3) compound in the 250ml there-necked flask that reflux condensing tube and tap funnel are housed (22.5g, 34.2mmol), Virahol (150ml); Mechanical stirring, heat temperature raising to 50 ℃, solid does not dissolve; 0.5h drip 3.4N hydrochloric acid (24ml), the solid dissolving, solution is yellow-green colour; Keeping temperature is 50 ℃ of stirring reactions, TLC (PE: EA=2: 1) follow the tracks of reaction process, show behind the 5h that the raw material primitive reaction finishes.Stop heating and stir the cooling hold over night., there is colourless transparent grain deposition at the bottle end, filters, and the solid particulate warp turns out to be trityl alcohol with the contrast of standard HPLC spectrogram.Filtrating is poured in the 500ml water, stir 0.5h, separate out white solid, get the white solid powder behind the filtering drying, warp turns out to be formula (2) compound with the contrast of standard HPLC spectrogram.Weigh the thick product of 15.0g, HPLC purity is 82.4%, yield 86%.This compound purity after ethyl alcohol recrystallization is refining is 97%, and total recovery is a yield 53%.153～155 ℃ of fusing points.

¹H?NMR(400MHz，DMSO-d ₆)δ：9.67(s，1H，)，7.69(d，1H，J＝8Hz)，7.65(t，1H，J＝8Hz)，7.56(t，1H，J＝8Hz)，7.52(d，1H，J＝8Hz)，7.11(d，2H，J＝8.5)，7.04(d，2H，J＝8.5Hz)，5.55(s，2H)，2.62(t，2H，J＝7Hz)，1.8-1.1(m，4H)，0.85(t，3H，J＝7Hz).

Embodiment two

The preparation of 5-carboxylic acid losartan

Adding compound 4 in the 100mL there-necked flask (3.0g, 6.93mmol), Virahol 50ml, heat temperature raising to 40 ℃ stirring makes the dissolving of compound 4 solids, is cooled to 5 ℃ again, adds 30% hydrogen peroxide (1.17ml).With in the Textone (1.84g) water-soluble (14.12ml), with add there-necked flask in the sodium chlorite solution 2h for preparing in batches, (DCM: MeOH=10: 1) follow the tracks of reaction process, show behind the 5h to react does not have raw material to TLC basically under 5 ℃ of conditions in addition.Stop to stir hold over night.Reaction solution is poured in the 500ml water, stirred the adularescent solid and separate out, in suspension liquid, add the 10N/L sodium hydroxide solution, when PH is 13; Liquid becomes clarification, filters and removes insoluble impurity, and filtrating is refunded beaker, and agitation condition drips concentrated hydrochloric acid down fast; Dissolved phenomenon again after can be observed the adularescent solid and separating out continues to drip and regulates PH to 1, and white solid no longer disappears, and filters; And the water flush cake, place 40 ℃ of oven dryings to constant weight filter cake, get white powder, turn out to be the 5-losartan carboxylate through the HPLC reference standards; Weigh to such an extent that 2.9 digest compound 5 thick products, HPLC purity 92%, bullion yield 88%.The refining back of ethyl alcohol recrystallization purity is 99.97%, and total recovery is 38%.125.2～128.5 ℃ of fusing points.

1H?NMR(500MHz，CDCl3)δ：7.71(d，1H，J＝8Hz)，7.68(t，1H，J＝8Hz)，7.57(t，1H，J＝8Hz)，7.54(d，1H，J＝8Hz)，7.10(d，2H，J＝8.5)，7.01(d，2H，J＝8.5Hz)，5.57(s，2H)，2.59(t，2H，J＝7Hz)，2.1-1.3(m，4H)，1.1(t，3H，J＝7Hz)

Claims (10)

1. a method for preparing the losartan verivate 5-carboxylic acid losartan of formula (1) comprises 2-butyl-4-chloro-5-formyl radical-1-{ [2 '-2 (1-H-tetrazolium-5-yl)-biphenyl-the 4]-methyl by formula (2) } imidazoles is as raw material, obtains 5-carboxylic acid losartan through oxidation:

2. according to the method for claim 1, choose Virahol as solvent.

3. according to the method for claim 1, choose hydrogen peroxide and Textone mixing solutions as oxidising agent, wherein the mol ratio of oxygenant Textone and raw material is 1.5: 1.

4. according to the method for claim 1, temperature of reaction is-5 to 15 ℃, and optimal reaction temperature is 5～10 ℃.

5. according to the method for claim 1, the reaction times is 10h.

6. according to the method for claim 1; The 2-butyl of its Chinese style (2)-4-chloro-5-formyl radical-1-{ [2 '-2 (1-H-tetrazolium-5-yl)-biphenyl-4]-methyl } imidazoles is by the 2-butyl-4-chloro-5-formyl radical-1-of formula (3) [2 '-(xenyl-4-of 1-trityl-tetrazole base-5-)] Methylimidazole, prepares through deprotection:

7. according to the method for claim 6, choose Virahol as solvent.

8. according to the method for claim 6, as deprotection agent, wherein the mol ratio of hydrochloric acid and raw material is 1: 1 to 3: 1, preferred 2.4: 1 with hydrochloric acid soln.

9. according to the method for claim 6, temperature of reaction is 40 to 60 ℃, is preferably 50 ℃.

10. according to the method for claim 6, the reaction times is 5h.