CN102911113B - A kind of preparation method of Reyataz R - Google Patents
A kind of preparation method of Reyataz R Download PDFInfo
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- CN102911113B CN102911113B CN201110223998.8A CN201110223998A CN102911113B CN 102911113 B CN102911113 B CN 102911113B CN 201110223998 A CN201110223998 A CN 201110223998A CN 102911113 B CN102911113 B CN 102911113B
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- reyataz
- phenyl
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- monomer
- pyridine
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- 108010019625 Atazanavir Sulfate Proteins 0.000 title claims abstract description 43
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 title claims abstract description 43
- 229940107904 reyataz Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000000178 monomer Substances 0.000 claims abstract description 21
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- OCBDXKCACMNHPJ-LLVKDONJSA-N (2S)-4-[amino(methyl)amino]-1-phenylbutan-2-amine Chemical class NN(C)CC[C@H](CC1=CC=CC=C1)N OCBDXKCACMNHPJ-LLVKDONJSA-N 0.000 claims abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 10
- -1 Triazole compounds Chemical class 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 150000001718 carbodiimides Chemical class 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000010168 coupling process Methods 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 231100000614 poison Toxicity 0.000 abstract 1
- 230000007096 poisonous effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 4
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229940043265 methyl isobutyl ketone Drugs 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000012805 post-processing Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000013517 stratification Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000383 hazardous chemical Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 235000010894 Artemisia argyi Nutrition 0.000 description 1
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 0 NNCC(C(Cc1ccccc1)C=NB1**1)O Chemical compound NNCC(C(Cc1ccccc1)C=NB1**1)O 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 244000030166 artemisia Species 0.000 description 1
- 229960003277 atazanavir Drugs 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to chemical and medicine industry field, be specifically related to a kind of preparation method of Reyataz R, reaction formula is as shown below.The present invention is using DEPBT as condensing agent, 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-diamino-6-phenyl-2-aza-hexanes and N-methoxycarbonyl-S-Leucine are obtained by reacting Reyataz R monomer in organic solvent.In existing document, the condensing agent of this reaction is commonly used as TPTU, carbodiimide class and the coupling of 124 Triazole compounds or is used alone carbodiimide compound, but these compounds are expensive, poisonous and pollute large.The DEPBT of the present invention's low price, safety and environmental protection, as condensing agent, provides that a kind of economically feasible, safety and environmental protection, yield are high, the segregative Reyataz R preparation method of product.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of Reyataz R.
Background technology
Reyataz R, English name Atazanavir, be by during the U.S. hundred Mei-Shi Guibao company develop open chain azepine intend peptide compounds, be a kind of novel HIV-1 proteinase inhibitor, chemical structure as shown in the formula shown in 1,
。
This product went on the market at US and European respectively on June 20th, 2003 and on March 2nd, 2004, and listing formulation Chinese traditional medicine composition is Reyataz R vitriol (trade(brand)name: sharp Chinese mugwort appropriate (Reyataz)).
The April 9 1997 patent US5849911(applying date of Novartis Co., Ltd of Switzerland application) embodiment 46 discloses Reyataz R and preparation method thereof, wherein a kind of Reyataz R preparation method for comprising the steps at first,
。
Formula 2 compound is at condensing agent O-(1,2-dihydro-2-oxygen-1-pyridyl)-N, N, N ', under N '-tetramethyl-Tetrafluoroboric acid (TPTU) effect, obtain formula 1 Reyataz R monomer with formula a compound N-(methoxycarbonyl)-(L)-Terleu condensation.But TPTU price is very expensive in the method, be difficult to obtain plant-scale supply, and its separation and Extraction step trivial operations, be not suitable for suitability for industrialized production.
WO9740029 also discloses this reaction, and open condensing agent can be carbodiimide class, as EDC.Carbodiimide class is conventional activator, but too high for its activation performance this reaction, and amino acid can be caused to produce racemization.For avoiding racemization, adopt carbodiimide class and the coupling of 124 Triazole compounds in this patent, 124 Triazole compounds used is HOBT.But HOBT belongs to the higher hazardous chemical of hazard level, dangerous code R5, R11, to be highly combustible and heating can set off an explosion, its transport, by strict supervision, be difficult to obtain, and the pollution of the method to environment is larger.
Thereafter there is different document as EP1930324, WO2009002829, WO2005108380 etc., use other carbodiimide compounds, as WSC, DCC, DIC etc. and HOBT coupling, there is as above defect equally.
WO2010146119 discloses the technique of alone DIC or DCC as condensing agent, and must not use HOBT, the relatively above process safety of this technique increases, but DIC and DCC still belongs to hazardous chemical, to eyes and skin irritant, have the danger of major injury eyes, and DIC belongs to extremely malicious chemical.
DEPBT, i.e. 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4-ketone, No. CAS is 165534-43-0, English 3-(Diethoxyphosphoryloxy)-1 by name, 2,3-benzotriazin-4 (3H)-one, U.S. Patent application US7834043(transferee: Abbott, the applying date: on December 9th, 2004) disclose DEPBT as the application of condensing agent for reacting as follows
Take DEPBT as condensing agent in this patent, react in THF and DIPEA, its yield is only 55%, and its separation and purification of products is complicated, needs to be separated with chromatography column, is unsuitable for suitability for industrialized production.
Therefore, be necessary that exploitation is a kind of simple to operate, economically feasible, of reduced contamination, safety and environmental protection, yield is high, is applicable to the preparation method of industrialized Reyataz R.
Summary of the invention
The present invention overcomes above-mentioned defect of the prior art, provides that a kind of economically feasible, safety and environmental protection, yield are high, the segregative Reyataz R preparation method of product.
The method is by 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-diamino-6-phenyl-2-aza-hexane and N-methoxycarbonyl-S-Leucine react under the existent condition of condensing agent DEPBT, obtain Reyataz R monomer, reaction formula is as follows:
。
Further, the preparation method of described Reyataz R monomer is: by 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-diamino-6-phenyl-2-aza-hexane is dissolved in organic solvent, add N-methoxycarbonyl-S-Leucine and DEPBT, stirring reaction obtains Reyataz R monomer.
Described organic solvent is the single solvent or the mixed solvent that are selected from tetrahydrofuran (THF), methylene dichloride, chloroform, butanone, triethylamine, N-methylmorpholine or methyl iso-butyl ketone (MIBK).Preferably, described organic solvent is the mixed solvent being selected from methylene dichloride, tetrahydrofuran (THF), N-methylmorpholine or triethylamine, more preferably, is methylene dichloride and N-methylmorpholine mixed solvent or tetrahydrofuran (THF) and triethylamine mixed solvent.Described reaction is carried out at 20 ~ 40 DEG C, preferably, carries out at 28 ~ 35 DEG C.
After above-mentioned reaction completes, Reyataz R monomer finished product can be obtained through post-processing step.Described post-processing step comprises: in reaction solution, drip alkali, and concentrating under reduced pressure adds recrystallisation solvent in debris, and decrease temperature crystalline after heating, obtains Reyataz R monomer.
Described alkali comprises: the aqueous solution of sodium hydroxide, sodium bicarbonate or sodium carbonate.
Described recrystallisation solvent comprises: the mixing solutions of water and methyl alcohol, ethanol, Virahol or ketones solvent, is preferably the mixing solutions of second alcohol and water.
Preferably, described post-processing step is: in reaction solution, drip alkali, stirs, stratification, organic layer washed with water, add ethanol, concentrating under reduced pressure, in debris, add second alcohol and water, be heated to 60 DEG C, slowly cool to about 0 DEG C, stir, suction filtration, dry material, obtain solid Reyataz R monomer.
Further; described formula 2 compound 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2; 5-diamino-6-phenyl-2-aza-hexane is obtained through deprotection reaction in organic solvent by formula 3 compound 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-bis-[(tertbutyloxycarbonyl) is amino]-6-phenyl-2-aza-hexane.Described protecting group is the tertbutyloxycarbonyl on amino.
Preferably, described 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2, the preparation method of 5-diamino-6-phenyl-2-aza-hexane can be: by 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2, 5-bis-[(tertbutyloxycarbonyl) is amino]-6-phenyl-2-aza-hexane mixes with organic solvent, in presence of an acid, insulation reaction after heating up, then lower the temperature, add alkali, stratification, organic layer obtains 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2 through concentrated, 5-diamino-6-phenyl-2-aza-hexane solid.
Wherein, described organic solvent is selected from the mixed solvent of one or more in tetrahydrofuran (THF), chloroform, butanone, methylene dichloride or methyl iso-butyl ketone (MIBK).
Described acid comprises sulfuric acid, hydrochloric acid, hydrogenchloride, trifluoroacetic acid, methylsulfonic acid, Phenylsulfonic acid or tosic acid.
Described alkali can be mineral alkali, as aqueous solution such as sodium hydroxide, sodium bicarbonate, sodium carbonate, or organic bases, as pyridine, N-methylmorpholine, triethylamine, diethylamine.
Further, Reyataz R monomer can prepare Reyataz R vitriol with strong sulfuric acid response, and preparation method is: dissolved in organic solvent by Zha Nawei monomer, add concentrated sulfuric acid solution, insulation reaction, cools to 0 ~ 5 DEG C, stirs and obtain Reyataz R vitriol.Described organic solvent is acetone, methyl tertiary butyl ether, methylene dichloride or Virahol etc.
The condensing agent of the present invention using DEPBT as synthesis Reyataz R monomer, relative to the synthesis technique of Reyataz R in prior art, there is following advantage: (1) DEPBT price is low, and reaction is without the need to other auxiliary materials, reaction conditions is gentle, to equipment and operational requirement relatively low, can carry out at 20 ~ 40 DEG C, effectively reduce cost; (2) DEPBT security is good, and the pollutent of generation is few, environmental friendliness; (3) simple to operate, do not need to activate carboxylic acid; (4) product yield is high, and easily separation and purification, be applicable to suitability for industrialized production.
Embodiment
In order to understand the present invention further, below in conjunction with embodiment, the preparation method to Reyataz R provided by the invention is described in detail.It is to be appreciated that these embodiments describe just for further describing feature of the present invention, instead of the restriction to the scope of the invention or the claims in the present invention scope.
embodiment 1:the preparation of 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-diamino-6-phenyl-2-aza-hexane
To in the reaction flask of cleaning, add 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2 of 11.25g (20mmol), in the methylene dichloride of 5-bis-[(tertbutyloxycarbonyl) is amino]-6-phenyl-2-aza-hexane and 45ml, drip 9.3g hydrochloric acid; Drip and finish, be warmed up to 40 ~ 45 DEG C of insulation about 3h; TLC analyzes tracking, reacts complete, is cooled to 25 DEG C, add 13.2gN-methylmorpholine, stir 1h at such a temperature, layering, organic over anhydrous dried over sodium sulfate 1 hour, filter, the a small amount of eluent solvent of filter cake, is evaporated to dry, obtains solid 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-diamino-6-phenyl-2-aza-hexane 6.87g, yield 95.2%.
embodiment 2:the preparation of Reyataz R monomer
To in the reaction flask of cleaning, add 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2 of 6.87g, 5-diamino-6-phenyl-2-aza-hexane, the methylene dichloride of 50ml and the N-methylmorpholine of 3.83g, add the N-methoxycarbonyl-S-Leucine of 4.16g (22mmol) and the DEPBT of 7.2g (24mmol) again, at 35 DEG C, stirring reaction 2h, TLC analyze and track to reaction end.Drip the sodium hydroxide 40ml of 2%, stir 0.5h, stratification, organic layers with water 2*40ml washs, and decompression removing methylene dichloride, adds 2*40ml ethanol, be evaporated to dry; In debris, add 45ml ethanol and 55ml water, be heated to 60 DEG C, slowly cooling to about 0 DEG C, stir 3h, suction filtration, the filter cake second alcohol and water (1:2) of 0 DEG C, mixed solution washs 2 times (40ml), drain, dry material, obtain solid Reyataz R monomer 11.28g.Yield: 84.1%
embodiment 3:the preparation of Reyataz R vitriol
At room temperature 25 DEG C, 70.5g Reyataz R monomer is dissolved in 700 acetone, under stirring, slowly drips the vitriol oil of the 40.4g of 5M, drip after finishing and be incubated 2h at such a temperature; Insulation terminates, and cools to 0 ~ 5 DEG C, stirs 2h.Suction filtration, filter cake, with after 150ml washing with acetone 2 times, dries to obtain product Reyataz R vitriol 76.3g, yield 95.4%.
embodiment 4:the preparation of 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-diamino-6-phenyl-2-aza-hexane
To in the reaction flask of cleaning, add 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2 of 225g (0.4mol), in the tetrahydrofuran (THF) of 5-bis-[(tertbutyloxycarbonyl) is amino]-6-phenyl-2-aza-hexane and 1000ml, drip 115.2g methylsulfonic acid; Drip and finish, be warmed up to backflow insulation about 2h, TLC analysis and follow the tracks of, react complete, add the triethylamine of 200g, stir 1h at such a temperature.Be cooled to 0 DEG C, filter, a small amount of eluent solvent of filter cake, merging filtrate and washings, reduce pressure dense to dry.Add the methylene dichloride of 1500ml, wash twice with water, use anhydrous sodium sulfate drying again, filter, the a small amount of washed with dichloromethane of filter cake, merging filtrate and washings, concentrating under reduced pressure is to doing to obtain 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-diamino-6-phenyl-2-aza-hexane 134.5g, yield 93%.
embodiment 5:the preparation of Reyataz R monomer
To in the reaction flask of cleaning, add 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2 of 134.5g, the DEPBT of the triethylamine of 5-diamino-6-phenyl-2-aza-hexane, 67.5g, the tetrahydrofuran (THF) of 1000ml, the N-methoxycarbonyl-S-Leucine of 83.3g (0.44mmol) and 150 (0.5mol), at 28 DEG C, stirring reaction 5h, TLC analyze and track to reaction end.Decompression removing tetrahydrofuran (THF), adds 2*40ml ethanol, and concentrating under reduced pressure is dry; In debris, add 400ml Virahol and 600ml water, be heated to backflow, slowly cooling to about 0 DEG C, stir 3h, suction filtration, the filter cake isopropyl alcohol and water (1:2) of 0 DEG C, drains, and dries material, obtains solid Reyataz R monomer 240g.Yield: 91.4%
embodiment 6:the preparation of Reyataz R vitriol
At room temperature 25 DEG C, 70.5g Reyataz R monomer is dissolved in 500ml Virahol, under stirring, slowly drips the vitriol oil of 40.4 of 5M, drip after finishing and be incubated 2h at such a temperature; Insulation terminates, and cools to 0 ~ 5 DEG C, stirs 2h.Suction filtration, a small amount of washed with isopropyl alcohol of filter cake, dries to obtain product Reyataz R vitriol 75g, yield 93.4%.
Claims (7)
1. the preparation method of a Reyataz R, it is characterized in that, 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-diamino-6-phenyl-2-aza-hexane and N-methoxycarbonyl-S-Leucine are in organic solvent, react under the existence of DEPBT, obtain Reyataz R monomer; Described organic solvent is methylene dichloride and N-methylmorpholine mixed solvent or tetrahydrofuran (THF) and triethylamine mixed solvent.
2. preparation method according to claim 1, is characterized in that, described reaction is carried out at 20-40 DEG C.
3. preparation method according to claim 1; wherein 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2; 5-diamino-6-phenyl-2-aza-hexane is obtained through deprotection reaction by 1-[4-(pyridine-2-base)-phenyl]-4 (S)-hydroxyl-5 (S)-2,5-bis-[(tertbutyloxycarbonyl) is amino]-6-phenyl-2-aza-hexane.
4. preparation method according to claim 1, wherein Reyataz R monomer can prepare Reyataz R vitriol further.
5. preparation method according to claim 1, is characterized in that, after described reaction completes, obtain Reyataz R monomer through following aftertreatment: in reaction solution, drip alkali, concentrating under reduced pressure, in debris, add recrystallisation solvent, decrease temperature crystalline after heating, obtains Reyataz R monomer.
6. preparation method according to claim 5, is characterized in that, described alkali is sodium hydroxide, sodium bicarbonate, sodium carbonate or its aqueous solution.
7. preparation method according to claim 5, is characterized in that, described recrystallisation solvent is the mixing solutions of water and methyl alcohol, ethanol, Virahol or ketones solvent.
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| CN104163787A (en) * | 2014-08-08 | 2014-11-26 | 山东威智医药工业有限公司 | Preparation methods of Atazanavir and sulfate of Atazanavir |
| CN105503705B (en) * | 2014-09-22 | 2019-06-25 | 浙江九洲药业股份有限公司 | A kind of atazanavir related substances and preparation method thereof |
| CN104356054B (en) * | 2014-09-30 | 2017-04-19 | 东北制药集团股份有限公司 | Method for preparing atazanavir monomer |
| CN106588755B (en) * | 2016-12-23 | 2019-09-13 | 东北制药集团股份有限公司 | A method of preparing anti-AIDS drug atazanavir monomer |
| CN107540603B (en) * | 2017-03-29 | 2018-09-21 | 南宁信肽生物技术有限责任公司 | The synthetic method of atazanavir |
| CN107245052A (en) * | 2017-06-21 | 2017-10-13 | 连云港杰瑞药业有限公司 | A kind of atazanavir preparation method |
| CN113603634B (en) * | 2021-08-06 | 2023-03-21 | 江苏八巨药业有限公司 | Preparation method of atazanavir intermediate |
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| CN101039954A (en) * | 2004-10-12 | 2007-09-19 | 弗·哈夫曼-拉罗切有限公司 | Solid phase peptide sythesis |
| CN1980666B (en) * | 2004-05-04 | 2011-03-30 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing atazanavir bisulfate and novel forms |
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| US20050148623A1 (en) * | 2003-12-11 | 2005-07-07 | Degoey David A. | HIV protease inhibiting compounds |
| CN1980666B (en) * | 2004-05-04 | 2011-03-30 | 布里斯托尔-迈尔斯斯奎布公司 | Process for preparing atazanavir bisulfate and novel forms |
| CN101039954A (en) * | 2004-10-12 | 2007-09-19 | 弗·哈夫曼-拉罗切有限公司 | Solid phase peptide sythesis |
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