CN102786494A - Synthesis research and control method of ritonavir isomer impurities - Google Patents
Synthesis research and control method of ritonavir isomer impurities Download PDFInfo
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Abstract
The invention relates to a synthesis research and control method of ritonavir isomer impurities. According to the method, D-phenylalanine, L-phenylalanine and DL-phenylalanine are used as raw materials, N,O-benzylation, cyanidation and Grignard reaction are carried out, (2RS, 3RS, 5RS)-5-amino-2-dibenzyl amine-1,6-diphenyl-3-hexyl alcohol is prepared through reduction, the Bos protection is carried out, the palladium carbon catalysis is carried out for debenzylation, (2RS, 3RS, 5RS)-2,5-diamido-3-hydroxyl-1,6-(diphenyl hexane) (BDC) is prepared and is subjected to acidylation and Boc removal with (5-thiazolyl) methyl-(4-nitro) phenyl carbonate (NCT), and finally, the acylation is carried out with N-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] amino carbonyl]-L-valine (MTV) for preparing ritonavir chiral isomers. BDC is sequentially acylated with MTV and NCT for preparing ritonavir position isomer (impurity N), and basis is provided for researching substances relevant to ritonavir.
Description
Technical field
The invention belongs to the organic chemistry synthesis technical field, relate to the preparation method of agricultural chemicals and medicine intermediate, a kind of study on the synthesis and control method for preparing the ritonavir isomer impurities of saying so more specifically.
Background technology
Ritonavir (Ritonavir) structural formula is as follows; Its chemistry (2S by name; 3S, 5S)-5-(N-(((N-methyl-N-((2 '-sec.-propyl-4-thiazolyl) methyl) amino) carbonyl)-L-is valyl for N) amino)-2-(N-(5-thiazole) methoxycarbonyl) amino)-1,6-phenylbenzene-3-hydroxyl hexane; CAS:155213-65-7, it is the suppressor factor of HIV-1 proteolytic enzyme.Ritonavir is that white arrives filbert powder, and the metal bitter taste is arranged, and is soluble in methyl alcohol and ethanol, is slightly soluble in Virahol, is insoluble in water.Chemical formula is C
37H
48N
6O
5S
2, relative molecular weight is 720.95.Ritonavir is developed by Abbott company, and thereafter in Canada, Britain, Switzerland and several south american countries in succession ratify use first through the drugs approved by FDA listing in March, 1996, and preparation has capsule and oral liquid, is used for the early stage and progressive stage HIV-1 infection of treatment.
The ritonavir structural formula
Because ritonavir has four chiral centres, 16 isomer are just arranged, and four chiral centres are the S type as medicinal, therefore to the study on the synthesis of ritonavir isomer, and it is detected and control has important theory and actual value effectively.
Summary of the invention
The present invention relates to a kind of study on the synthesis and control method for preparing the ritonavir isomer impurities, is raw material with D-phenylalanine(Phe), L-phenylalanine(Phe), DL-phenylalanine(Phe), through N; O-benzylization, cyaniding, grignard reaction, reduction makes (2RS, 3RS; 5RS)-and 5-amino-2-dibenzyl amido-1,6-phenylbenzene-3-hexanol, Boc protection; Take off benzyl through the catalysis of palladium charcoal again and make (2RS; 3RS, 5RS)-2,5-diamino--3-hydroxyl-1; 6-phenylbenzene hexane (BDC) and (5-thiazolyl) methyl-(4-nitro) benzol carbonate (NCT) acidylate, take off Boc, final and N-[N-methyl-N-[(2-sec.-propyl-4-thiazolyl) methyl] aminocarboxyl]-L-Xie Ansuan (MTV) acidylate prepares the ritonavir chiral isomer; BDC prepares ritonavir positional isomers (impurity N) with MTV, NCT acidylate successively, for the research of ritonavir related substance provides foundation.
Ritonavir chiral isomer synthetic route of the present invention is following:
Ritonavir positional isomers synthetic route of the present invention is following:
Description of drawings:
Fig. 1, ritonavir USP standard mixt high-efficient liquid phase chromatogram
Fig. 2, ritonavir impurity N high-efficient liquid phase chromatogram
Fig. 3, ritonavir impurity O high-efficient liquid phase chromatogram
Fig. 4, ritonavir impurity Q high-efficient liquid phase chromatogram
Fig. 5, ritonavir impurity R high-efficient liquid phase chromatogram
Fig. 6, ritonavir impurity N, O, Q, R mixture high-efficient liquid phase chromatogram
The specific embodiment mode
Through following examples with better explanation the present invention.But the present invention does not receive the restriction of following embodiment.
N, N-two benzyl amino phenyl alanine benzyl esters (1) synthetic
In there-necked flask, add D-phenylalanine(Phe) 90.2g (546mmol), the mixed solvent of water/methyl alcohol (398ml/190ml) adds salt of wormwood 250g and Benzyl Chloride (216ml under stirring successively; 1.834mol), the about 8h of stirring reaction isolates organic layer under 90 ℃ of conditions; Add normal heptane (476ml) and water (216ml); Extraction, organic layer is washed once through first alcohol and water (1:1) 200ml, and organic layer is used anhydrous sodium sulfate drying.Filter, the filtrating evaporate to dryness obtains xanchromatic oily matter, directly next step reaction.
Embodiment 2
Synthesizing of 4-R-(N, the N-dibenzyl is amino)-3-oxo-5-phenyl-penta eyeball (2)
(16g 410mmol), adds THF (80mL) and normal heptane (160mL) again in bottle in there-necked flask, to add sodium amide; Reaction flask is put under-10 ℃, kept this temperature, add acetonitrile (15mL; 469mmol), stir 30min, slowly drip (1) (56g again; 129mmol), the solution of THF (40mL) and normal heptane 75 (mL), about 30min drips off.Detect with TLC that (ETHYLE ACETATE: sherwood oil=1:10), reaction finishes the Hydrocerol A cancellation with 25%, uses 25% sodium chloride aqueous solution (300mL) and 20% methanol aqueous solution (300mL) respectively to wash once successively to pH6-7 (about 200mL) organic layer.Organic layer is used anhydrous sodium sulfate drying again, filters, and filtrating is less than 50 ℃.Decompression and solvent recovery obtains faint yellow oily thing, uses ethyl alcohol recrystallization.Obtain faint yellow solid 22g, L-2mp 81.3-83.6 ℃; 94.2 ℃-95.6 ℃ of D-2mp.
Embodiment 3
2-is amino-(5-R-N, the N-dibenzyl is amino)-4 oxos-1, and 6-phenylbenzene-2-hexene (3) synthetic
((about 60min dropwises for 33g, 220mmol) anhydrous diethyl ether 100mL to drip the benzyl grignard reagent down at 0-5 ℃ for 20.3g, anhydrous THF (100mL) solution 55mmol) in there-necked flask, to add compound 2.Reaction is risen to room temperature, and the about 2-3h of stirring reaction detects (ETHYLE ACETATE: sherwood oil=1:5) with TLC; Reaction finishes, and reaction flask is put into frozen water, slowly drips 15% Hydrocerol A and is quenched to the solution layering; Branch vibration layer, organic layer are washed once with 10% sodium chloride aqueous solution again.There is organic layer to use anhydrous sodium sulfate drying, suction filtration, filtrate decompression concentrates, and obtains faint yellow oily thing, crosses silicagel column, obtains faint yellow solid 19.2g, L-3mp101.3-102.9; 99.8 ℃-101.0 ℃ of D-3mp.
Embodiment 4
(2S)-5-is amino-(2-N, the N-dibenzyl is amino)-3-hydroxyl-1,6-phenylbenzene hexane (4) synthetic
15g (3), THF 100mL, methylsulfonic acid 10mL, low temperature stirs 30min, adds Peng Qinghuana 30g in batches, slowly is warming up to room temperature; Stir 3h, use 6mol/L hydrochloric acid, the Peng Qinghuana of decomposing excessive is regulated pH to 7-8 with 30% sodium hydroxide, obtains organic layer, and water layer is used ethyl acetate extraction; Merge organic layer, anhydrous sodium sulfate drying, decompression and solvent recovery gets faint yellow oily thing, uses dissolve with methanol; Add Peng Qinghuana in batches, stirring at room 3h, decompression and solvent recovery adds water, uses dichloromethane extraction; Merge organic layer, washing and drying, concentrating under reduced pressure gets faint yellow oily thing 14g, directly gets into next step reaction.
Embodiment 5
(2S)-(2-N, N-dibenzyl amino)-3 (RS)-hydroxyl-5 (RS)-uncle's butyloxy formylamidos-1,6-phenylbenzene hexane (5) synthetic
Get the bullion L-414g that the step makes, add the dissolving of 100mL THF fully, join in the 500mL there-necked flask, add 150mL water, add 14.0g salt of wormwood again, the mechanical stirring dissolving.Get 21.8g two tertbutyloxycarbonyl acid anhydrides, with the dilution of 20mL THF, slowly be added drop-wise in the reaction system, the stirring at room reaction is spent the night.With twice of ethyl acetate extraction (100mL * 2), the saturated common salt water washing once, anhydrous sodium sulfate drying is crossed column separating purification (ETHYLE ACETATE: sherwood oil=1:20), draw four products, called after 5a, 5b, 5c, 5d respectively.During evaporate to dryness oily matter.
5a
1H-NMR(400MHz?CDCl
3)δppm:1.31-1.14(m,1H),1.38(s,9H),1.56-1.48(m,1H),2.71-2.59(m,2H),2.85-2.77(m,2H)),3.05(dd,1H,J＝14.9,6.0Hz),3.38(d,2H,J＝13.9Hz),3.65-3.55(m,1H),3.79(m,1H),3.92(d,2H,J＝13.9Hz),4.30(s,1H),4.80(brs,1H),7.32-7.09(m,20H);
5b
1H-NMR(400MHz?CDCl
3)δppm:1.42(s,9H),1.55-1.30(m,2H),2.75(d,2H,J=6.3Hz),2.95-2.85(m,2H),3.08-2.95(m,1H),3.68-3.58(m,4H),3.85-3.75(m,2H),4.15-4.00(m,1H),4.39(d,1H,J＝9.6Hz),7.35-7.05(m,20H);
5c
1H-NMR(400MHz?CDCl
3)δppm:1.40-1.28(m,1H),1.40(s,9H),1.95(ddd,1H,J＝13.4,2.4,2.4Hz),2.75-2.55(m,3H),3.10-2.85(m,3H),3.55(d,2H,J=15.0Hz),3.75-3.69(m,4H),4.98-4.84(m,1H),7.05-6.90(m,2H),7.38-7.08(m,18H);
5d
1H-NMR(400MHz?CDCl
3)δppm:0.95-0.87(m,1H),1.35(s,9H),1.85-1.71(m,1H),2.55(dd,2H,J＝15,9Hz),3.05-2.75(m,3H),3.40(d,2H,J＝15Hz),3.57(brs,1H),4.13-3.94(m,3H),4.25(s,1H),4.70(d,1H,J=9.0Hz),7.35-7.06(m,20H);
Embodiment 6
(2S, 3RS, 5RS)-and 2-amino-3-hydroxyl-uncle's 5-butyloxy formylamido-1, the synthetic logical method of 6-phenylbenzene hexane (6)
Get the 10g L-5 that the step makes, add 100mL methyl alcohol, dissolving adds 0.65g10%Pd/C fully; Use the nitrogen replacement air, use hydrogen exchange nitrogen again, hydrogenation to raw material is complete, filters; Reclaim Pd/C, the filtrating evaporate to dryness gets white solid 7.5g, mp125.8-126.2 ℃.
Embodiment 7
(2S, 3RS, 5RS)-(N-((5-thiazolyl) methoxycarbonyl) is amino-1,6-phenylbenzene 3-hydroxyl hexane (7) synthetic for uncle 5-butyloxy formylamido-2-
(20mmol, 1e.q) L-6 add 150mL ETHYLE ACETATE, and the mechanical stirring dissolving fully to get 7.5g; Adding 6.1g (22mmol, 1.1e.q) NCT is heated to back flow reaction, some plate (ETHYLE ACETATE: sherwood oil=1:4) monitor to reacting completely; Reacted completely in about 4 hours, and be cooled to room temperature, add 2g ammoniacal liquor, stirring at room 3h; Obtain organic layer, organic layer is used 5% solution of potassium carbonate, saturated common salt water washing, anhydrous sodium sulfate drying successively; Decompression and solvent recovery gets oily matter 8.5g, directly is used for next step reaction.
Embodiment 8
(2S, 3RS, 5RS)-(N-((5-thiazolyl) methoxycarbonyl) is amino-1,6-phenylbenzene 3-hydroxyl hexane (8) synthetic for 5-amino-2-
Get 8.5g L-7, adding 100mL acetic acid ethyl dissolution is complete, adds the 10mL concentrated hydrochloric acid again, refluxing and stirring 5h.Reaction solution has solid to occur, suction filtration, and filter cake washs with ETHYLE ACETATE; Get white solid, add in 50mL water and the 50mL ETHYLE ACETATE, using 5% sodium hydroxide solution to regulate pH is 8 ~ 9; Obtain organic phase, saturated common salt water washing, anhydrous sodium sulfate drying; Concentrate to remove desolvate 7.2g, directly be used for next step reaction.
2.2.6 ritonavir impurity R's is synthetic
(adding 100mL acetic acid ethyl dissolution is complete for 10mmol, 1e.q) L-8, and (10mmol, 1e.q) (stirring and dissolving is complete for 11mmol, 1.1e.q) MTV for HOBt and 3.4g to add 1.34g again to get 4.25g.(adding 10mL acetic acid ethyl dissolution is complete for 11mmol, 1.1e.q) DCC, joins then in the reaction system of front, and the stirring at room reaction is spent the night to get 2.2g.Filter, remove DCU, cross post (ETHYLE ACETATE: sherwood oil=2:1), get ritonavir impurity R 2.2g.mp:128.2-129.7℃;
1H-NMR(400MHz?DMSO-d
6)δppm:9.07(s,1H),7.81-7.85(m,2H),7.11-7.21(m,11H),6.97-7.00(d,J＝9.2H,1H),6.03-6.05(d,J＝8.4H,1H),5.10-5.18(m,2H),4.64-4.65(d,J＝5.6Hz,1H),4.40-4.51(q,2H),4.09(m,1H),3.91-3.95(m,1H),3.63(s,1H),3.54-3.56(m,1H),3.18-3.25(m,1H),2.88(s,3H),2.58-2.75(m,4H),1.75-1.81(m,1H),1.88-1.52(m,2H),1.27-1.29(ds,6H),0.62-0.66(m,6H)。
Embodiment 9
(2S, 3S, 5S)-2-(N-(((N-methyl-N-((2 '-sec.-propyl-4-thiazolyl) methyl) amino) carbonyl)-L-is valyl for N) amino)-uncle's 5-butyloxy formylamido-1,6-phenylbenzene-3-hydroxyl hexane (9) synthetic
(adding 150mL acetic acid ethyl dissolution is complete for 20mmol, 1e.q) BDC, and (20mmol, 1e.q) (stirring and dissolving is complete for 11mmol, 1.1e.q) MTV for HOBt and 6.8g to add 2.68g again to get 7.6g.(adding 20mL acetic acid ethyl dissolution is complete for 11mmol, 1.1e.q) DCC, joins then in the reaction system of front, and the stirring at room reaction is spent the night to get 4.4g.Filter, remove DCU, decompression and solvent recovery gets faint yellow oily thing 5.3g, gets portioned product, and column chromatography is used for nuclear-magnetism test, mp89.3-90.0 ℃;
1H-NMR (400MHz DMSO-d
6) δ ppm:7.73-7.45 (d, J=9.2Hz, 1H), 9.09-7.22 (m, 11H), 6.51-6.54 (d, J=8.8Hz, 1H); 6.12-6.14 (d, J=8.0Hz, 1H), 4.77-4.79 (d, J=5.6Hz, 1H), 4.38-4.51 (q, J=16.0Hz; 1H), 4.10 (s, 1H), 3.92-3.96 (m, 1H), 3.78 (s, 1H), 3.55-3.57 (m; 1H), 3.17-3.28 (m, 1H), 2.87 (s, 3H), 2.61-2.75 (m, 3H), 1.92-1.94 (m; 2H), 1.45-1.47 (m, 2H), 1.23-1.30 (m, 15H), 0.72-0.76 (m, 6H).
(2S, 3S, 5S)-2-(N-(((N-methyl-N-((2 '-sec.-propyl-4-thiazolyl) methyl) amino) carbonyl)-L-is valyl for N) amino)-5-is amino-1,6-phenylbenzene-3-hydroxyl hexane (10) synthetic
Getting the step makes L-94.8g, and it is complete to add the 80mL acetic acid ethyl dissolution, adds the 6mL concentrated hydrochloric acid again, refluxing and stirring 4h.Reaction solution has solid to occur, suction filtration, and filter cake washs with ETHYLE ACETATE; Get white solid, add in 50mL water and the 50mL ETHYLE ACETATE, using 5% sodium hydroxide solution to regulate pH is 8 ~ 9; Obtain organic phase, saturated common salt water washing, anhydrous sodium sulfate drying; Concentrate to remove desolvate 3.3g, directly be used for next step reaction.
Embodiment 11
Ritonavir impurity N's is synthetic
Get L-103.3g, add 150mL ETHYLE ACETATE, the mechanical stirring dissolving adds 2.7g NCT fully; Be heated to back flow reaction, (ETHYLE ACETATE: sherwood oil=2:1) monitoring reacted completely to reacting completely the some plate in about 4 hours, was cooled to room temperature; Add 2g ammoniacal liquor, continue to stir 1h, obtain organic layer, organic layer is used 5% solution of potassium carbonate, saturated common salt water washing successively; Anhydrous sodium sulfate drying, decompression and solvent recovery, column chromatographic isolation and purification gets 1.8g ritonavir impurity N.mp73.5-74.5℃;
1H-NMR(400MHz?DMSO-d
6)δppm:9.05(s,1H),7.84(s,1H),7.43-7.46(d,J＝9.2H,1H),7.07-7.20(m,12H),6.13-6.15(d,J＝8.4H,1H),5.11(m,2H),4.81-4.83(d,J＝5.6Hz,1H),4.38-4.51(q,2H),4.14(m,1H),3.92-3.96(m,1H),3.85(s,1H),3.54-3.56(m,1H),3.19-3.26(m,1H),2.87(s,3H),2.63-2.78(m,3H),1.90-1.95?(m,1H),1.48(m,2H),1.29-1.30(ds,6H),0.71-0.77(m,6H).
Embodiment 11
The detection of ritonavir related substance
0.03mol/l potassium dihydrogen phosphate: the 8.2g potassium primary phosphate added in the 2000mL water dissolve, mixing filters (make its can through the cellulose membrane of 0.45um)
Thinner: 0.03mol/L potassium primary phosphate and acetonitrile (1:1) are mixed, and filtration makes its cellulose membrane through 0.45um
Solution A: 0.03mol/L potassium dihydrogen phosphate-acetonitrile-THF-propyl carbinol (69:18:8:5)
Solution B: 0.03mol/l potassium phosphate solution-acetonitrile-THF-propyl carbinol (40:47:8:5) ritonavir characteristic standard solution-get ritonavir related substance mixture 50mg; It is fixed accurately to claim, puts in the 50ml measuring bottle, adds the thinner dissolving; Be settled to scale, shake up.
Standardized solution: precision is measured intermediate standard solution 5.0ml and is put in the 100ml measuring bottle, uses diluent, and constant volume shakes up.
Supply examination solution: take from each 10mg of system ritonavir related substance, accurate title is fixed, puts in the 50ml measuring bottle, adds the thinner dissolving, and constant volume shakes up.
System suitability test:
4.6mm * 15cm post, 3um Packing L26 detects wavelength 240nm, flow velocity 1.0ml/min, 60 ℃ of column temperatures.Program is following:
Concrete impurity color atlas is seen Figure of description
Being merely embodiments of the invention in sum, is not to be used for limiting practical range of the present invention.Be that all equivalences of doing according to the content of claim of the present invention change and modification, all should be technological category of the present invention.
Claims (7)
1. a study on the synthesis and a control method for preparing the ritonavir isomer impurities is characterized in that, comprises step:
A, be raw material with the phenylalanine(Phe), through N, O-benzylization, cyaniding, grignard reaction, reduction makes (2RS; 3RS, 5RS)-5-amino-2-dibenzyl amido-1,6-phenylbenzene-3-hexanol; The Boc protection is taken off benzyl through the catalysis of palladium charcoal again and is made (2RS, 3RS; 5RS)-2,5-diamino--3-hydroxyl-1,6-phenylbenzene hexane (BDC).
B, BDC and (5-thiazolyl) methyl-(4-nitro) benzol carbonate (NCT) acidylate, take off Boc, final and N-[N-methyl-N-[(2-sec.-propyl-4-thiazolyl) methyl] aminocarboxyl]-Xie Ansuan (MTV) acidylate prepares the ritonavir chiral isomer.
C, BDC prepare ritonavir positional isomers (impurity N) with MTV, NCT acidylate successively.
2. a kind of study on the synthesis and control method for preparing the ritonavir isomer impurities according to claim 1 is characterised in that: phenylalanine(Phe) is meant D-phenylalanine(Phe), L-phenylalanine(Phe), different ratios DL-phenylalanine(Phe) in the steps A.
3. a kind of study on the synthesis and control method for preparing the ritonavir isomer impurities according to claim 1 is characterised in that: in the steps A 2,5-diamino--3-hydroxyl-1, the structure of 8 isomer of 6-phenylbenzene hexane (BDC) as follows:
4. a kind of study on the synthesis and control method for preparing the ritonavir isomer impurities according to claim 1 is characterised in that: the BDC isomer is meant that single or two above optical isomers and NCT acidylate prepare the ritonavir midbody among step B, the C.
5. a kind of study on the synthesis and control method for preparing the ritonavir isomer impurities according to claim 1, be characterised in that: the MTV Xie Ansuan is meant D-Xie Ansuan, L-Xie Ansuan, different ratios DL-valine among step B, the C.
6. a kind of study on the synthesis and control method for preparing the ritonavir isomer impurities according to claim 1; Be characterised in that: the ritonavir chiral isomer comprises ritonavir chiral isomer impurity O, impurity Q, the impurity R that mentions in the USP pharmacopeia among the step B, and its structural formula is as follows.
7. a kind of study on the synthesis and control method for preparing the ritonavir isomer impurities according to claim 1; Be characterised in that: the ritonavir positional isomers comprises the ritonavir chiral isomer impurity N that mentions in the USP pharmacopeia among the step C, and its structural formula is following:
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| CN104311503A (en) * | 2014-11-03 | 2015-01-28 | 东北制药集团股份有限公司 | Method for preparing anti-HIV (human immunodeficiency virus) medicine ritonavir |
| CN111393329A (en) * | 2020-04-16 | 2020-07-10 | 安徽一帆香料有限公司 | Preparation method of ritonavir and lopinavir intermediate |
| CN114149382A (en) * | 2021-10-29 | 2022-03-08 | 乳源瑶族自治县东阳光生物科技有限公司 | Ritonavir impurity and preparation method thereof |
| CN115417829A (en) * | 2022-10-11 | 2022-12-02 | 武汉海特生物创新医药研究有限公司 | Preparation method of ritonavir enantiomer |
| CN115784936A (en) * | 2022-12-19 | 2023-03-14 | 启东东岳药业有限公司 | Preparation method of ritonavir key intermediate BDH |
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