CN104163787A - Preparation methods of Atazanavir and sulfate of Atazanavir - Google Patents
Preparation methods of Atazanavir and sulfate of Atazanavir Download PDFInfo
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- CN104163787A CN104163787A CN201410387631.3A CN201410387631A CN104163787A CN 104163787 A CN104163787 A CN 104163787A CN 201410387631 A CN201410387631 A CN 201410387631A CN 104163787 A CN104163787 A CN 104163787A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
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Abstract
The invention discloses preparation methods of Atazanavir and a sulfate of the Atazanavir. The preparation method of the Atazanavir comprises the following steps: 1) adding (a) and (b) into an alcohol solvent and reacting so as to obtain an intermediate shown in a formula (I); 2) dissolving the intermediate shown in the formula (I) in an fatty alcohol solvent, cooling, dropwise adding an alcoholic solution of hydrogen chloride and reacting so as to obtain an intermediate shown in a formula (II); 3) dissolving (c) in dichloromethane, cooling, reacting by adding a dehydrating agent, adding an organic alkali and the intermediate shown in the formula (II) and reacting so as to obtain an Atazanavir monomer shown in a formula (III). The Atazanavir monomer can be prepared into an Atazanavir sulfate shown in a formula (IV) according to a conventional method. The Atazanavir monomer has the advantages of high yield, less relevant impurity content, low preparation cost and the like, and can be used for preparing the Atazanavir sulfate with high purity and high yield. The structures of the Atazanavir monomer and the Atazanavir sulfate are as shown in the specification.
Description
Technical field
The present invention relates to the preparation method of a kind of Reyataz R and vitriol thereof, particularly relate to the preparation method of a kind of highly purified Reyataz R and vitriol thereof.
Background technology
Reyataz R (shown in (III)), it is the important source material for the preparation of sulfuric acid Reyataz R (Atazanavir Sulfate).
Sulfuric acid Reyataz R, commodity are called sharp Chinese mugwort appropriate (REYATAZ), are developed by Bristol-Myers Squibb Co. of the U.S., and go on the market in the U.S. in June, 2003 first, main and other antiretroviral drugs combination therapys HIV virus infection.Sulfuric acid Reyataz R is a kind of novel azepine peptide proteinoid enzyme inhibitors (PI), it is highly selective and the efficient inhibitor of HIV-1 proteolytic enzyme, by the cracking of blocking virus gap and gap-pol precursor polyprotein, thereby suppress the generation of virus structural protein reversed transcriptive enzyme, intergrase and proteolytic enzyme, the cell that HIV-1 is infected discharges noninfective jejune virion.
The molecular structure of sulfuric acid Reyataz R is as follows:
In existing synthesis technique, all exist with the synthesis yield of the intermediate shown in following formula (I) lower, and the intermediate shown in formula (II) is without separation and purification, cause the more shortcoming of foreign matter content of the free alkali shown in next step product formula (III), purifying difficulty is larger, make the yield of Reyataz R vitriol on the low side, production cost is higher.Wherein, in the intermediate shown in formula (I) synthetic adopt Virahols as reaction solvent (Organic Process Research and Development, 2002, P.323-328; EP2003120A1), only have 85% but reaction yield is the highest, large content of starting materials remains, and has increased the difficulty of purifying.The de-tertbutyloxycarbonyls (Boc) of hydrochloric acid solns that adopt in intermediate shown in formula (II) synthetic more, reaction solution is directly added drop-wise to (Organic Process Research and Development in next step condensation reaction, 2002, P.323-328; US2005/256202), make the purity of the intermediate shown in formula (II) lower, cause the product free alkali purity drop of next step condensation reaction, strengthen purifying and obtain difficulty, the yield that obtains high purity free alkali declines.
Summary of the invention
The invention provides the preparation method of a kind of Reyataz R and vitriol thereof.The method is by being optimized the synthesis technique of Reyataz R and vitriol bulk drug thereof, solve existing operational path productive rate low and produce more impurity, purifying products and cost compared with high-technology problem, improved quality and the purity of Reyataz R and vitriol bulk drug thereof.
The preparation method of Reyataz R of the present invention, its path is as follows:
For above-mentioned path, the preparation method of Reyataz R of the present invention, comprises the following steps:
1) by raw material 2-[4-(2-pyridyl) benzyl shown in formula (a)] raw material (1S)-1-(2R)-epoxy ethyl-2-styroyl t-butyl carbamate shown in-hydrazine carboxylic acid's tert-butyl ester and formula (b) is placed in alcoholic solvent, after reacting by heating, cooling, add water, separate out solid, filter, filter cake making beating, filter, intermediate---2-[(2S, 3S shown in formula (I) that must be refining)-3-[[(tert.-butoxy) carbonyl] amino]-2-hydroxy-4-phenyl butyl]-2-[[4-(2-pyridyl) phenyl] methyl] hydrazine carboxylic acid's tert-butyl ester;
2) by step 1) intermediate shown in gained formula (I) is dissolved in aliphatic alcohols solvent alcohol, be cooled to-5～5 DEG C, drip the alcoholic solution of hydrogenchloride, be warming up to 25～30 DEG C react after, in reaction solution, splash into organic solvent, separate out solid, filter, dry, obtain the intermediate shown in formula (II)---(2S, 3S)-3-amino-4-phenyl-1-{1-[4-(pyridine-2-yl) phenmethyl] diazanyl } hydrochloride of butane-2-alcohol;
3) the raw material N-methoxycarbonyl-S-Leucine shown in formula (c) and I-hydroxybenzotriazole (HOBt) are dissolved in methylene dichloride, be cooled to-10～0 DEG C, after adding dewatering agent to react, add organic bases and step 2) intermediate shown in the formula (II) that obtains, being warming up to 20～30 DEG C reacts, and after finishing, reaction filters, wash filtrate, be spin-dried for, solid is pulled an oar with ether, filter, obtain the Reyataz R monomer shown in formula (III);
Described step 1) in, the mol ratio of the raw material shown in the raw material shown in formula (a) and formula (b) is preferably 1:1～1:2; Alcoholic solvent is preferably one or more in n-propyl alcohol, Virahol, propyl carbinol, penta butanols, isopropylcarbinol or the trimethyl carbinol etc., more preferably penta butanols or the trimethyl carbinol; The amount ratio scope of the raw material shown in formula (a) and alcoholic solvent is preferably the raw material shown in 0.1g formula (a): the raw material shown in 1mL alcoholic solvent～1g formula (a): 1mL alcoholic solvent; The temperature of reacting by heating is preferably 75～90 DEG C (more preferably 80～85 DEG C), and the reaction times is preferably 16～30 hours, more preferably 16～24 hours;
Step 1) in, after reacting by heating, the raw material shown in formula (a) is carried out to HPLC detection, be less than 1.5% suc as formula the material content shown in (a), reaction system is carried out coolingly, wherein, cooled temperature is preferably 0～30 DEG C again;
Step 1) add water, the volume ratio of water and alcoholic solvent is preferably 1.2:1～3:1;
Step 1) filter cake making beating in, preferably with the aqueous solution of alcohol, filter cake is pulled an oar, wherein, this alcohol is preferably lower aliphatic alcohols, comprising: one or more in methyl alcohol, ethanol, Virahol etc.; The aqueous solution of particular methanol, wherein, the volume ratio of methyl alcohol and water is preferably 1:1.2～1:3; In addition, in filter cake making beating, the mass ratio of the aqueous solution of the intermediate shown in formula (I) and alcohol is 1:8～1:10, and the temperature in filter cake making beating is preferably 60～65 DEG C, and also can carry out coolingly to the system after making beating, cooled temperature is preferably 0～30 DEG C; The purity of the intermediate shown in formula (I) is 98.5%～99.5%.
Described step 2) in, aliphatic alcohols solvent alcohol can be selected from one or more in methyl alcohol, ethanol or Virahol; The mass ratio of the intermediate shown in formula (I) and aliphatic alcohols solvent alcohol is 1:0.5～1:5, is preferably 1:0.8;
Step 2) in, the alcohol in the alcoholic solution of hydrogenchloride is lower aliphatic alcohols, as being selected from a kind of or its mixture in methyl alcohol, ethanol etc.; Hydrogenchloride massfraction in the alcoholic solution of hydrogenchloride is 25～35%, and the consumption mol ratio of the intermediate shown in hydrogenchloride and formula (I) is 5:1～10:1 (referring to the equivalence ratio of hydrogenchloride with respect to formula (I));
Step 2) in, the time of reaction is preferably 8～24 hours; In addition, after reaction 8～24 hours, the intermediate shown in formula (I) is carried out to HPLC detection, be less than 1% suc as formula the intermediate content shown in (I), add again organic solvent;
Step 2) in, organic solvent can be selected from one or more in methylene dichloride, the tertiary ether of first, ethyl acetate or isopropyl ether etc.; The volume of organic solvent is 2～6 times of cumulative volume of alcohol in solution, is preferably 4 times.
Step 2) in, the purity of the intermediate shown in formula (II) can reach 99.0%～99.8%.
Described step 3) in, the consumption of I-hydroxybenzotriazole (HOBt) is preferably 1.0～3.0 equivalents; Dewatering agent is selected from N, N'-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) etc., and the consumption of dewatering agent is preferably 2～3.5 equivalents;
Step 3) in, add the time that dewatering agent reacts to be preferably 0.2～2 hour;
Step 3) in, organic bases is preferably one or more in diisopropylethylamine, triethylamine or pyridine etc., and the mol ratio of the intermediate shown in organic bases and formula (II) is preferably 1:4～1:7; The mol ratio of the raw material shown in the intermediate shown in formula (II) and formula (c) is preferably 1:2.2～1:2.5;
Step 3) in, being warming up to 20～30 DEG C and reacting, the reaction times is preferably 9～16 hours;
Step 3) in, in filtering after reaction finishes, the basis for estimation that reaction is finished can be: HPLC detection is carried out in sampling, when the intermediate content shown in formula (II) is lower than 0.1% time, finishes reaction.
Step 3) washing in, water (the 1/2-2 volume of solvent volume), saturated solution of sodium bicarbonate (1/3-1 of solvent volume) and sodium chloride saturated solution (1/3-1 of solvent volume) washing filtrate successively;
Step 3) in, ether is preferably one or more in ether, isopropyl ether or the tertiary ether of first etc., and the mass ratio of the Reyataz R monomer shown in ether and formula (III) is preferably 15mL ether: 1g Reyataz R monomer～25mL ether: 1g Reyataz R monomer; In addition, solid, with in ether making beating, is first warming up to 45～70 DEG C, stirs 2～6 hours, is then cooled to 0～30 DEG C.
Step 3) in, the purity of the Reyataz R monomer shown in formula (III) can reach 98.5%～99.5%.
In addition, above-mentioned Reyataz R monomer can be prepared by a conventional method to obtain Reyataz R vitriol, and concrete grammar is as follows:
In the Reyataz R monomer shown in formula obtained above (III), add acetone, be heated to after 50～60 DEG C, add aqueous sulfuric acid, stirring reaction, cooling, filter, obtain highly purified Reyataz R vitriol (compound shown in formula (IV)).
Wherein, the amount ratio of the Reyataz R monomer shown in formula (III) and acetone is preferably the Reyataz R monomer shown in 1g formula (III): the Reyataz R monomer shown in 10mL～1g formula (III): 15mL; The concentration of aqueous sulfuric acid is preferably 4～8mol/L, and the Reyataz R monomer shown in formula (III) and the mol ratio of sulfuric acid are preferably 1:1.05～1:1.2; The time of stirring reaction is preferably 1～2 hour, and cooled temperature is 0～30 DEG C.
The present invention is with existing with compared with synthesis technique, and tool has the following advantages:
1, in the intermediate shown in formula (I) is synthetic, owing to using the fatty alcohol of large steric hindrance can reduce side reaction and can accelerate speed of reaction and reduce product loss etc. by making beating such as methanol-water (volume ratio is 1:1.2-1:3) or ethanol water by improving temperature of reaction, can make the intermediate yield shown in synthesis type (I) can be 98%, higher more than 10% than the technique of having reported at present, and reduced the process of aftertreatment, and obtain the intermediate that purity is greater than 98.5%;
2,, in the preparation of the intermediate shown in formula (II), utilize the de-tertbutyloxycarbonyl of alcoholic solution of hydrogenchloride, thereby splashing into generation solid after organic solvent (as ethyl acetate), compared with prior art save time and the energy;
3, to the intermediate shown in formula (II) carried out separate and making beating purifying (effect: the one, make (II) solidify, be easy to purifying, be easy to feed intake; The 2nd, less (II) of little polar solvent making beating loss), obtain the product that purity is greater than 99%, greatly reduce to isolate in subsequent step the difficulty of straight product;
4, in the Reyataz R monomer shown in synthesis type (III), use the intermediate shown in highly purified formula (II), greatly reduce the content of impurity, reduce the number of times of purifying, reduce the loss of product, reduce production cost.
5, in the present invention, can obtain very highly purified Reyataz R vitriol by the Reyataz R monomer of above-mentioned preparation, the purity of Reyataz R vitriol can reach 99.5-99.9% (HPLC detection).
Therefore, the present invention has improved the yield of intermediate and has reduced cost, particularly to the intermediate salt hydrochlorate shown in formula (II) separate, purifying, and significantly reduced quantity and the limit (HPLC < 0.3%) of relative substance in intermediate (II).Thereby, with existing with compared with technology, Reyataz R monomer of the present invention has that yield is higher, relative substance content still less, the advantage such as preparation cost is lower, and can prepare the Reyataz R vitriol of high purity and high yield.Therefore, the present invention can be applicable to scale operation Reyataz R (comprising the intermediate of preparing Reyataz R) and Reyataz R vitriol bulk drug.
Embodiment
Following chemical reagent, if not otherwise specified, can be commercially produced product.
Synthesizing of intermediate shown in embodiment 1 formula (I)
In the there-necked flask of 500mL, add raw material 50.5g and the trimethyl carbinol 250mL shown in the intermediate 50.0g shown in formula (a), formula (b), oil bath is heated to 90 DEG C, along with heat solid is molten clear gradually, react after 3 hours, have gradually solid to separate out.Continue stirring reaction 18 hours, HPLC detection is carried out in sampling.
HPLC analytical procedure: chromatographic instrument: Dionex v3000DAD
Chromatographic column: Inertsil ODS-3
Chromatographic condition: acetonitrile: phosphate buffered saline buffer=70:30, wherein, phosphate buffered saline buffer is K
2hPO
3-KH
2pO
3damping fluid (0.02M K
2hPO
3with 0.02M KH
2pO
3)
Detect wavelength: UV210nm
Column temperature: 30 DEG C
Flow velocity: 1.5mL/min
Intermediate shown in formula (a) detects and is less than 1.5% through HPLC, can stop heating, cool to 30 DEG C, add 750mL water with constant pressure funnel, after dripping, continue to stir 0.5 hour, filter, filter cake is placed in 1L there-necked flask, and add 200mL methyl alcohol at this there-necked flask, be heated to after 60 DEG C, drip 400mL water, after dripping, continue to stir 0.5 hour, be cooled to 20 DEG C, filter yellowly or faint yellow solid, and through conventional structural identification method, confirmation is the intermediate shown in formula (I), the dry 92.5g that weighs to obtain, yield 98.40%, HPLC:98.97%.
The MS:563.4 (ESI, M+1) of product [intermediate shown in formula (I)].
Product [intermediate shown in formula (I)]
1h-NMR (400MHz, CDCl
3) δ 8.68 (d, J=4.6Hz, 1H), 7.94 (d, J=8.1Hz, 2H), 7.73 (m, 2H), 7.40 (d, J=8.1Hz, 2H), 7.22 (m, 4H), 7.16 (d, J=5.8Hz, 1H), 5.31 (bs, 1H), 5.11 (d, J=8.9Hz, 1H), 4.52 (s, 1H), 4.04 (d, J=13.8Hz, 1H), 3.91 (d, J=13.4Hz, 1H), 3.67 (d, J=7.9Hz, 1H), 3.57 (d, J=9.1Hz, 1H), 2.94 (d, J=6.7Hz, 2H), 2.83 (t, J=11.4Hz, 1H), 2.47 (m, 1H), 1.38 (s, 9H), 1.33 (s, 9H).
Synthesizing of intermediate shown in embodiment 2 formulas (II)
In 250mL there-necked flask, add intermediate and the 50mL methyl alcohol shown in formula (I) prepared by 50g embodiment 1, stir, be cooled to-5～5 DEG C, then, drip 69.4g methyl alcohol-hydrogen chloride solution (massfraction of hydrogenchloride is 25%), in dropping process, control temperature of reaction system at 0～5 DEG C, after dropwising, be warming up to 25～30 DEG C, reaction was stirred after 12 hours, HPLC detection is carried out in sampling, single Boc (tertbutyloxycarbonyl) by product is less than 1%, stop stirring, reaction solution is dropped in 400mL ethyl acetate, there is a large amount of solids to separate out, filter, and with ethyl acetate filter wash cake, dry, obtain solid 44.29g, and through conventional structural identification method, confirmation is the intermediate shown in formula (II), yield 98.0%, HPLC:99.2%.
The MS:363.3 (ESI, M+1) of product [intermediate shown in formula (II)].
Product [intermediate shown in formula (II)]
1h NMR (400MHz, D
2o) δ 8.65 (d, J=5.2Hz, 1H), 8.51 (td, J=8.1, 1.5Hz, 1H), 8.04 (d, J=8.2Hz, 1H), 7.92 (t, J=6.8Hz, 1H), 7.80 (d, J=8.3Hz, 2H), 7.65 (d, J=8.3Hz, 2H), 7.24 (t, J=7.3Hz, 2H), 7.18 (d, J=7.2Hz, 1H), 7.07 (d, J=7.1Hz, 2H), 4.22 (d, J=12.8Hz, 1H), 4.04 (m, 1H), 3.98 – 3.86 (m, 1H), 3.70 – 3.60 (m, 1H), 3.15 – 3.08 (m, 2H), 2.54 (m, 1H), 2.41 (m, 1H).
Synthesizing of intermediate shown in embodiment 3 formulas (II)
In 250mL there-necked flask, add intermediate and the 50mL methyl alcohol shown in formula (I) prepared by 50g embodiment 1, stir, be cooled to-5～5 DEG C, then, drip 46.3g methyl alcohol-hydrogen chloride solution (massfraction of hydrogenchloride is 35%), in dropping process, control temperature of reaction system at 0～5 DEG C, after dropwising, be warming up to 25～30 DEG C, reaction was stirred after 12 hours, HPLC detection is carried out in sampling, single Boc by product is less than 1%, stop stirring, reaction solution is dropped in 400mL ethyl acetate, there is a large amount of solids to separate out, filter, and with ethyl acetate filter wash cake, dry, obtain solid 44.75g, and through conventional structural identification method, confirmation is the intermediate shown in above-mentioned formula (II), yield 99.0%, HPLC:99.0%.
Synthesizing of intermediate shown in embodiment 4 formulas (II)
In 250mL there-necked flask, add intermediate and the 50mL ethanol shown in formula (I) prepared by 50g embodiment 1, stir, be cooled to-5～5 DEG C, then, drip 69.4g ethanol-hydrogen chloride solution (massfraction of hydrogenchloride is 25%), in dropping process, control temperature of reaction system at 0～5 DEG C, after dropwising, be warming up to 25～30 DEG C, reaction was stirred after 12 hours, HPLC detection is carried out in sampling, single Boc by product is less than 1%, stop stirring, reaction solution is dropped in 400mL ethyl acetate, there is a large amount of solids to separate out, filter, and with ethyl acetate filter wash cake, dry, obtain solid 44.79g, and through conventional structural identification method, confirmation is the intermediate shown in above-mentioned formula (II), yield 99.1%, HPLC:99.2%.
Synthesizing of intermediate shown in embodiment 5 formulas (III)
1L there-necked flask adds respectively the raw material shown in 45.88g formula (c) and 39.88g1-hydroxybenzotriazole (HOBT), add again 250mL methylene dichloride, be cooled to-10～0 DEG C, taking 56.54g dicyclohexylcarbodiimide (DCC) is dissolved in 250mL methylene dichloride, and join in constant pressure funnel, start to drip to reaction system the dichloromethane solution of DCC, after within 0.5 hour, dropwising, continue to stir 0.5 hour, then add successively the intermediate shown in the triethylamine of 65.06g and formula (II) prepared by 49.7g embodiment 2, temperature rise to 10 DEG C left and right, reaction is warming up to 25 DEG C of left and right, stir 16 hours, HPLC detection is carried out in sampling, raw material complete reaction is complete, stopped reaction, filter, filter cake is washed twice with 30mL methylene dichloride, filtrate washes with water respectively once, saturated sodium bicarbonate is washed twice, saturated sodium-chloride is washed once, anhydrous magnesium sulfate drying, filter, filtrate is spin-dried for, obtain yellow solid 78g.
Then, add 1200mL isopropyl ether, be heated to 55 DEG C, stir 2 hours, be cooled to 25 DEG C, filter, obtain filter cake, after oven dry, weigh, obtain light yellow solid 65.88g, and through conventional structural identification method, confirmation is the intermediate shown in formula (III), yield 95.42%, HPLC:99.74%.
The MS:704.5 (ESI, M+1) of product [intermediate shown in formula (III)].
Product [intermediate shown in formula (III)]
1h-NMR (400MHz, CDCl
3) δ 8.68 (d, J=4.2Hz, 1H), 7.93 (d, J=8.2Hz, 2H), 7.75 (td, J=7.7, 1.7Hz, 1H), 7.69 (d, J=7.9Hz, 1H), 7.42 (d, J=8.1Hz, 2H), 7.25 – 7.17 (m, 5H), 7.14 (m, 1H), 6.98 (s, 1H), 6.53 (d, J=8.8Hz, 1H), 5.39 (d, J=9.0Hz, 1H), 5.30 (d, J=5.7Hz, 1H), 4.92 (s, 1H), 4.13 – 4.00 (m, 2H), 3.95 (d, J=13.8Hz, 1H), 3.81 (d, J=8.4Hz, 1H), 3.66 (s, 3H), 3.63 (s, 3H), 2.94 (d, J=7.6Hz, 2H), 2.87 (m, 1H), 2.59 (d, J=10.3Hz, 1H), 1.97 (s, 3H), 0.86 (s, 9H), 0.77 (s, 9H).
Synthesizing of embodiment 6 Reyataz R vitriol
In 1L there-necked flask, add respectively intermediate and the 500mL acetone shown in formula (III) prepared by 50g embodiment 5, be warming up to 50 DEG C of left and right, the disposable 15.6mL of adding aqueous sulfuric acid (concentration of aqueous sulfuric acid is 5.0mol/L), continue to stir 1 hour, first naturally cool to room temperature, then, cryosel is bathed and is cooled to-5～5 DEG C of left and right, stir 0.5 hour, filter, twice of 50mL acetone drip washing for filter cake, filter cake is dried, obtain off-white color solid 50.8g, and through conventional structural identification method, confirmation is the compound shown in formula (IV), be Reyataz R vitriol, yield 89.60%, HPLC:99.8%.
The MS:704.5 (ESI, M+1) of product (Reyataz R vitriol).
Product (Reyataz R vitriol)
1h NMR (400MHz, DMSO) δ 9.17 (s, 1H), 8.81 (d, J=5.2Hz, 1H), 8.36 (t, J=7.7Hz, 1H), 8.22 (d, J=8.1Hz, 1H), 7.95 (d, J=8.0Hz, 2H), 7.80 – 7.73 (m, 1H), 7.56 (d, J=8.0Hz, 2H), 7.52 (d, J=6.8Hz, 1H), 7.20 (m, 4H), 7.16 – 7.11 (m, 1H), 6.94 (d, J=9.2Hz, 1H), 6.87 (d, J=9.2Hz, 1H), 4.04 (m, 3H), 3.84 (d, J=9.3Hz, 1H), 3.64 (m, 2H), 3.50 (d, J=11.9Hz, 6H), 2.86 – 2.67 (m, 4H), 0.77 (s, 9H), 0.63 (s, 9H).
Embodiment 7 contrast experiments---the preparation of the intermediate shown in above-mentioned formula (II)
In 250mL there-necked flask, add intermediate and the 150mL tetrahydrofuran (THF) shown in formula (I) prepared by 50g embodiment 1, stir, be cooled to-5～5 DEG C, then drip concentrated hydrochloric acid (massfraction 37%, 41mL), in dropping process, control temperature of reaction system at 0～5 DEG C, after dropwising, be warming up to 25～30 DEG C, reaction was stirred after 12 hours, sampling is carried out TLC (thin-layer chromatography) and is detected, after raw material reaction is complete, upper strata tetrahydrofuran (THF) inclines, water layer is used respectively twice of 100mL washed with dichloromethane, then under ice-water bath condition, drip 76mL triethylamine to water, keep temperature 0-10 DEG C, drip off and stir 30min, ice-water bath is preserved set aside for use (being the midbody solution shown in formula (II)).
Embodiment 8 contrast experiments---the preparation of the intermediate shown in above-mentioned formula (III)
1L there-necked flask adds respectively the raw material shown in 37g formula (c) and 33.7g1-hydroxybenzotriazole (HOBT), add again 100mL methylene dichloride, be cooled to-10～0 DEG C, separately taking 56.54g dicyclohexylcarbodiimide (DCC) is dissolved in 100mL methylene dichloride, and turned and joined in constant pressure funnel, start to drip to reaction system the dichloromethane solution of DCC, after within 0.5 hour, dropwising, continue to stir 0.5 hour, then drip the midbody solution shown in formula (II) prepared by embodiment 7, temperature maintains 5-15 DEG C, dropwise, reaction is warming up to 25 DEG C of left and right, stir 16 hours, HPLC detection is carried out in sampling, raw material complete reaction is complete, stopped reaction, filter, filter cake is washed twice with 30mL methylene dichloride, filtrate washes with water respectively once, saturated sodium bicarbonate is washed twice, saturated sodium-chloride is washed once, anhydrous magnesium sulfate drying, filter, filtrate is spin-dried for, obtain yellow solid 78g.
Then, add the mixed solution (isopropyl ether: ethanol=49:1, v/v) of 750mL isopropyl ether and ethanol, be heated to 55 DEG C, stir 2 hours, be cooled to 25 DEG C, filter, obtain filter cake, after oven dry, weigh, light yellow solid 52.7g through conventional structural identification method, confirmation is the intermediate (being Reyataz R monomer) shown in formula (III), yield 84.1%, HPLC:97.2%.
Hence one can see that, and the yield by the prepared Reyataz R monomer of method of the present invention and purity are apparently higher than contrast experiment.
Claims (10)
1. a preparation method for Reyataz R, is characterized in that, comprises the following steps:
1) raw material shown in the raw material shown in formula (a) and formula (b) is placed in to alcoholic solvent, after reacting by heating, cooling, add water, separate out solid, to filter, filter cake making beating, filters, and obtains the intermediate shown in formula (I);
2) by step 1) intermediate shown in gained formula (I) is dissolved in aliphatic alcohols solvent alcohol, after the alcoholic solution that drips hydrogenchloride reacts, in reaction solution, splashes into organic solvent, separate out solid, filter, dry, obtain the intermediate shown in formula (II);
3) raw material N-methoxycarbonyl-S-Leucine and I-hydroxybenzotriazole shown in formula (c) are dissolved in methylene dichloride, after adding dewatering agent to react, adding organic bases and step 2) intermediate shown in the formula (II) that obtains reacts, and after finishing, reaction filters, wash filtrate, is spin-dried for, and solid is pulled an oar with ether, filter, obtain the Reyataz R monomer shown in formula (III).
2. the method for claim 1, is characterized in that: described step 1) in, the mol ratio of the raw material shown in the raw material shown in formula (a) and formula (b) is 1:1～1:2;
Alcoholic solvent is one or more in n-propyl alcohol, propyl carbinol, penta butanols, isopropylcarbinol or the trimethyl carbinol, and the amount ratio scope of the raw material shown in formula (a) and alcoholic solvent is the raw material shown in 0.1g formula (a): the raw material shown in 1mL alcoholic solvent～1g formula (a): 1mL alcoholic solvent;
The temperature of reacting by heating is 75～90 DEG C, and the reaction times is 16～30 hours;
Step 1) add water, the volume ratio of water and alcoholic solvent is 1.2:1～3:1;
Step 1) filter cake making beating in, with the aqueous solution of alcohol, filter cake is pulled an oar, wherein, this alcohol comprises: one or more in methyl alcohol, ethanol, Virahol; The mass ratio of the aqueous solution of the intermediate shown in formula (I) and alcohol is 1:8～1:10, and the temperature in filter cake making beating is 60～65 DEG C, the system after making beating is carried out cooling, and cooled temperature is 0～30 DEG C.
3. the method for claim 1, is characterized in that: described step 1) in, alcoholic solvent is penta butanols or the trimethyl carbinol; The temperature of reacting by heating is 80～85 DEG C, and the reaction times is 16～24 hours;
Step 1) in, after reacting by heating, the raw material shown in formula (a) is carried out to HPLC detection, be less than 1.5% suc as formula the material content shown in (a), again reaction system is carried out coolingly, wherein, cooled temperature is 0～30 DEG C;
Step 1) filter cake making beating in, with the aqueous solution of methyl alcohol, filter cake is pulled an oar, wherein, the volume ratio of methyl alcohol and water is 1:1.2～1:3.
4. the method for claim 1, is characterized in that: described step 1) in, the purity of the intermediate shown in formula (I) is 98.5%～99.5%.
5. the method for claim 1, it is characterized in that: described step 2) in, by step 1) intermediate shown in gained formula (I) is dissolved in aliphatic alcohols solvent alcohol, is cooled to-5～5 DEG C, drips the alcoholic solution of hydrogenchloride, be warming up to 25～30 DEG C react after, in reaction solution, splash into organic solvent, separate out solid, filter, dry, obtain the intermediate shown in formula (II).
6. the method for claim 1, is characterized in that: described step 2) in, aliphatic alcohols solvent alcohol is selected from one or more in methyl alcohol, ethanol or Virahol;
The mass ratio of the intermediate shown in formula (I) and aliphatic alcohols solvent alcohol is 1:0.5～1:5;
Step 2) in, the alcohol in the alcoholic solution of hydrogenchloride is selected from a kind of or its mixture in methyl alcohol, ethanol; Hydrogenchloride massfraction in the alcoholic solution of hydrogenchloride is 25～35%, and the consumption mol ratio of the intermediate shown in hydrogenchloride and formula (I) is 5:1～10:1;
Step 2) in, the time of reaction is 8～24 hours;
Step 2) in, organic solvent is selected from one or more in methylene dichloride, the tertiary ether of first, ethyl acetate or isopropyl ether; The volume of organic solvent is 2～6 times of cumulative volume of alcohol in solution.
7. the method for claim 1, it is characterized in that: described step 2) in, after reaction, also the intermediate shown in formula (I) is carried out to HPLC detection, be less than 1% suc as formula the intermediate content shown in (I), add again organic solvent;
Step 2) in, the purity of the intermediate shown in formula (II) is 99.0%～99.8%.
8. the method for claim 1, it is characterized in that: described step 3) in, raw material N-methoxycarbonyl-S-Leucine and I-hydroxybenzotriazole shown in formula (c) are dissolved in methylene dichloride, be cooled to-10～0 DEG C, after adding dewatering agent to react, add organic bases and step 2) intermediate shown in the formula (II) that obtains, being warming up to 20～30 DEG C reacts, and after finishing, reaction filters, wash filtrate, is spin-dried for, and solid is pulled an oar with ether, filter, obtain the Reyataz R monomer shown in formula (III).
9. the method for claim 1, is characterized in that: described step 3) in, the consumption of I-hydroxybenzotriazole is 1.0～3.0 equivalents;
Dewatering agent is selected from N, N'-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, and the consumption of dewatering agent is 2～3.5 equivalents;
Step 3) in, adding the time that dewatering agent reacts is 0.2～2 hour;
Step 3) in, organic bases is one or more in diisopropylethylamine, triethylamine or pyridine, the mol ratio of the intermediate shown in organic bases and formula (II) is 1:4～1:7; The mol ratio of the raw material shown in the intermediate shown in formula (II) and formula (c) is 1:2.2～1:2.5;
Step 3) add organic bases and step 2) during the intermediate shown in the formula (II) that obtains reacts, the reaction times is 9～16 hours;
Step 3) washing in, water, saturated solution of sodium bicarbonate and sodium chloride saturated solution washing filtrate successively;
Step 3) in, ether is one or more in the tertiary ether of ether, isopropyl ether or first, the mass ratio of the Reyataz R monomer shown in ether and formula (III) is 15mL ether: 1g Reyataz R monomer～25mL ether: 1g Reyataz R monomer; With in ether making beating, be first warming up to 45～70 DEG C at solid, stir 2～6 hours, be then cooled to 0～30 DEG C.
10. the method for claim 1, it is characterized in that: described step 3) in after reaction finishes filter in, the basis for estimation that reaction is finished is: HPLC detection is carried out in sampling, when the intermediate content shown in formula (II) is lower than 0.1% time, finishes reaction;
The purity of the Reyataz R monomer shown in formula (III) is 98.5%～99.5%.
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| CN115215792A (en) * | 2022-06-27 | 2022-10-21 | 江西富祥药业股份有限公司 | Method for preparing atazanavir or sulfate thereof |
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