CN103951677A - Preparation method of rifapentine - Google Patents
Preparation method of rifapentine Download PDFInfo
- Publication number
- CN103951677A CN103951677A CN201410098665.0A CN201410098665A CN103951677A CN 103951677 A CN103951677 A CN 103951677A CN 201410098665 A CN201410098665 A CN 201410098665A CN 103951677 A CN103951677 A CN 103951677A
- Authority
- CN
- China
- Prior art keywords
- rifapentine
- crystallization
- preparation
- washing
- recrystallisation solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960002599 rifapentine Drugs 0.000 title claims abstract description 60
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000005406 washing Methods 0.000 claims abstract description 41
- 238000002425 crystallisation Methods 0.000 claims abstract description 38
- 230000008025 crystallization Effects 0.000 claims abstract description 38
- 239000002904 solvent Substances 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- -1 dihydroxy methyl tert-butyl Chemical group 0.000 claims abstract description 13
- 238000000926 separation method Methods 0.000 claims abstract description 13
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- BTVYFIMKUHNOBZ-ZDHWWVNNSA-N Rifamycin S Natural products COC1C=COC2(C)Oc3c(C)c(O)c4C(=O)C(=CC(=O)c4c3C2=O)NC(=O)C(=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(=O)C)C1C)C BTVYFIMKUHNOBZ-ZDHWWVNNSA-N 0.000 claims abstract description 7
- BTVYFIMKUHNOBZ-ODRIEIDWSA-N Rifamycin S Chemical compound O=C1C(C(O)=C2C)=C3C(=O)C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O BTVYFIMKUHNOBZ-ODRIEIDWSA-N 0.000 claims abstract description 7
- 238000002791 soaking Methods 0.000 claims abstract description 7
- 239000000843 powder Substances 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 53
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 51
- 238000001953 recrystallisation Methods 0.000 claims description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000013078 crystal Substances 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 22
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 20
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 20
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 19
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 239000000047 product Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 12
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 claims description 12
- 235000010199 sorbic acid Nutrition 0.000 claims description 12
- 239000004334 sorbic acid Substances 0.000 claims description 12
- 229940075582 sorbic acid Drugs 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- 239000011718 vitamin C Substances 0.000 claims description 12
- 235000019154 vitamin C Nutrition 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000012043 crude product Substances 0.000 claims description 11
- 230000002829 reductive effect Effects 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 238000007654 immersion Methods 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000009413 insulation Methods 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 239000004202 carbamide Substances 0.000 claims description 5
- 235000013877 carbamide Nutrition 0.000 claims description 5
- 235000019253 formic acid Nutrition 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 239000000413 hydrolysate Substances 0.000 claims description 5
- 239000003999 initiator Substances 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 239000000498 cooling water Substances 0.000 claims description 3
- 239000006260 foam Substances 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000010899 nucleation Methods 0.000 claims description 3
- 230000006911 nucleation Effects 0.000 claims description 3
- 230000002269 spontaneous effect Effects 0.000 claims description 3
- 230000003068 static effect Effects 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 239000002245 particle Substances 0.000 abstract description 9
- 239000012535 impurity Substances 0.000 abstract description 8
- 238000001035 drying Methods 0.000 abstract description 5
- 239000003638 chemical reducing agent Substances 0.000 abstract 2
- QYHRIASMJNLWHJ-UHFFFAOYSA-N 4-cyclopentylpiperazin-1-amine Chemical compound C1CN(N)CCN1C1CCCC1 QYHRIASMJNLWHJ-UHFFFAOYSA-N 0.000 abstract 1
- 230000003064 anti-oxidating effect Effects 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 230000007547 defect Effects 0.000 abstract 1
- 238000002156 mixing Methods 0.000 abstract 1
- 238000007670 refining Methods 0.000 abstract 1
- 238000007142 ring opening reaction Methods 0.000 abstract 1
- 238000007873 sieving Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005119 centrifugation Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940062280 rifamycin sodium Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- YVOFSHPIJOYKSH-NLYBMVFSSA-M sodium rifomycin sv Chemical compound [Na+].OC1=C(C(O)=C2C)C3=C([O-])C=C1NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@H](C)[C@@H](OC)\C=C\O[C@@]1(C)OC2=C3C1=O YVOFSHPIJOYKSH-NLYBMVFSSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention discloses a preparation method of rifapentine, and the steps are as follows: rifamycin S is used as a starting material for reacting with dihydroxy methyl tert-butyl amine in a first organic solvent to convert into intermediate rifaoxazine; a catalyst and a reductant are added into a second organic solvent for hydrolysis ring opening of the intermediate rifaoxazine; a rifapentine solution is obtained by condensation of a rifaoxazine hydrolysis product and 1-amino-4-cyclopentyl piperazine; and a rifapentine finished product is obtained by filtration, segmented crystallization at multistage crystallization temperature, first separation, washing, second separation, drying, soaking, third separation, drip washing, spin drying, sieving, drying, and powder mixing refining processes of the rifapentine solution. The preparation method adopts the reductant which can play a role in anti oxidation; different crystallization temperature is adopted in the segmented crystallization process; and by combination with the adding of a crystallization solvent, the crystalline polymorph is uniform, the particles are uniform, the stability is good, and the defects of high impurity content and nonuniform particles of rifapentine processes in the prior art can be solved.
Description
Technical field
The present invention relates to medicine field, in particular to the preparation method of rifapentine.
Background technology
According to the record of data and patent documentation, at present, in disclosed medicine generated data storehouse, the operational path of rifapentine is as follows: the 3-aldehyde radical Rifamycin Sodium of 0.01ml is dissolved in tetrahydrofuran (THF), at room temperature adds 1-amino-4-cyclopentyl-based piperazine of 0.011mol.For reaction, thin layer is followed the tracks of, and disappears to raw material point.Boil off solvent, residuum re-crystallizing in ethyl acetate, obtains rifapentine, and yield is 55%, 179～180 DEG C of fusing points.This method adopts tetrahydrofuran (THF) as solvent, because tetrahydrofuran (THF) is easy to oxidation, easily aldehyde radical is oxidized to carboxyl, increases impurity, reduces productive rate.
Summary of the invention
The object of the present invention is to provide the preparation method of rifapentine, to solve the above problems.
Provide a kind of rifapentine preparation method in the embodiment of the present invention, comprised the following steps:
A. taking rifamycin-S as initiator, in the first organic solvent, react with dihydroxymethyl tert-butyl amine and be converted into intermediate profit good fortune oxazine;
B. in the second organic solvent, add catalyzer, reductive agent to make described intermediate Li Fu oxazine hydrolysis;
C. the hydrolysate of Li Fu oxazine and 1-amino-4-cyclopentyl-based piperazine are condensed into rifapentine solution;
D. to described rifapentine solution filter, the sectional type crystallization of multistage Tc, first separates, washing, second separates, dry, immersions, the 3rd separation, drip washing, dry, sieve, be dried, mix powder treating process and obtain rifapentine finished product.
In certain embodiments, be preferably, described the first organic solvent be following one or more: isopropyl acetate, ethyl acetate, DMF, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO).
In certain embodiments, be preferably, described the second organic solvent be following one or more: methyl alcohol, ethanol, Virahol, propyl carbinol; Catalyzer is one or both in S-WAT, sodium bicarbonate, sodium bisulfite, sodium carbonate, urea; Reductive agent is one or more in S-WAT, vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid.
In certain embodiments, be preferably, described sectional type crystallization comprises: first paragraph crystallization, and insulation, at 50-70 DEG C, drips fast recrystallisation solvent in the filtrate obtaining after described filtration, carries out thermostatical crystallization, enters second segment crystallization in the time of naked eyes visible crystals; Described second segment crystallization, reduces described recrystallisation solvent rate of addition, and stops insulation, and cooling, carries out spontaneous nucleation naturally, after a large amount of crystal are separated out, enters the 3rd section of crystallization; Described the 3rd section of crystallization, reduces recrystallisation solvent rate of addition, and described recrystallisation solvent drips rear with cooling water temperature, and batch type is cooled to 20 DEG C and stops stirring, leaving standstill after following.
In certain embodiments, be preferably, described recrystallisation solvent is one or both in the aqueous solution of formic acid, phosphoric acid, Glacial acetic acid, hydrochloric acid, Citric Acid, ethanol, VC.
In certain embodiments, be preferably, in described first paragraph crystallization, described recrystallisation solvent rate of addition is 100～200L/h; In described second segment crystallization, temperature is 18-35 DEG C, and described recrystallisation solvent rate of addition is 50～100L/h; Described the 3rd section of crystallization, temperature is below 20 DEG C, described recrystallisation solvent rate of addition is 10～50L/h.
In certain embodiments, be preferably, the working method of described batch type is: within every 30-60 minute, stir 5-10 minute; The described standing time is more than 2 hours.
In certain embodiments, be preferably, described washing is syllogic washing, and described syllogic washing comprises: first paragraph alcohol wash, to described the after a separation for solid crystal one or both in methyl alcohol, butanols, ethanol wash; Second segment washing, the more described solid crystal after to described first paragraph alcohol wash washs by purified water; The 3rd section of foam washing, the more described solid crystal after second segment washing is washed with one or more in the purification of aqueous solutions of S-WAT, sodium bisulfite, Sulfothiorine, Citric Acid, vitamins C, Sorbic Acid.
In certain embodiments, be preferably, described immersion is that two-section type is soaked, described two-section type is soaked and is comprised: first paragraph dynamic soaking, to dry a kind of or two kinds and above immersion the in S-WAT, vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid, purified water for crude product of described dried rifapentine, under the rotating speed of 50～100 revs/min, stir, soak 2～6 hours; Second segment static immersing, after dynamic soaking, stops stirring and soaks more than 1 hour again.
In certain embodiments, be preferably, described drip washing is that the described the 3rd solids ethanol separating is carried out to repeatedly drip washing.
The preparation method of the rifapentine that the embodiment of the present invention provides, compared with prior art, taking rifamycin-S as initiator, first make intermediate Li Fu oxazine, utilize the second organic solvent, catalyzer, reductive agent makes intermediate Li Fu oxazine hydrolysis, then hydrolysate and 1-amino-4-cyclopentyl-based piperazine are condensed into rifapentine solution, rifapentine solution is filtered, the sectional type crystallization of multistage Tc, first separates, adopt the multi-stage type washing of different solvents, second separates, dry, soak, the 3rd separates, drip washing, dry, sieve, dry, mixed powder treating process obtains rifapentine finished product.Wherein, adopt reductive agent can play oxidation resistant effect; Sectional type crystallization processes adopts different Tcs, and in conjunction with the dropping of recrystallisation solvent, can make xln crystal formation homogeneous, uniform particles, and good stability, has solved the shortcoming that in prior art rifapentine technique, foreign matter content is high, particle is inhomogeneous.
Embodiment
Below by specific embodiment, the present invention is described in further detail.
The embodiment of the present invention provides a kind of preparation method of rifapentine, comprises the following steps:
A. taking rifamycin-S as initiator, in the first organic solvent, react with dihydroxymethyl tert-butyl amine and be converted into intermediate profit good fortune oxazine;
B. in the second organic solvent, add catalyzer, reductive agent to make described intermediate Li Fu oxazine hydrolysis;
C. the hydrolysate of Li Fu oxazine and 1-amino-4-cyclopentyl-based piperazine are condensed into rifapentine solution;
D. to described rifapentine solution filter, the sectional type crystallization of multistage Tc, first separates, washing, second separates, dry, immersions, the 3rd separation, drip washing, dry, sieve, be dried, mix powder treating process and obtain rifapentine finished product.
Taking rifamycin-S as initiator, first make intermediate Li Fu oxazine, utilize the second organic solvent, catalyzer, reductive agent to make intermediate Li Fu oxazine hydrolysis, then hydrolysate and 1-amino-4-cyclopentyl-based piperazine are condensed into rifapentine solution, and the multi-stage type washing, second that rifapentine solution filters, the sectional type crystallization of multistage Tc, first separates, adopts different solvents is separated, dry, immersions, the 3rd separation, drip washing, dries, sieves, is dried, mixes powder treating process and obtain rifapentine finished product.Wherein, adopt reductive agent can play oxidation resistant effect; Sectional type crystallization processes adopts different Tcs, and in conjunction with the dropping of recrystallisation solvent, can make xln crystal formation homogeneous, uniform particles, and good stability, has solved the shortcoming that in prior art rifapentine technique, foreign matter content is high, particle is inhomogeneous.
Next, the present invention will describe the preparation method of this rifapentine in detail by some specific embodiments:
Step 101, preparation Li Fu oxazine;
The preparation method of this Li Fu oxazine can adopt preparation method of the prior art, such as:
1, get 1 kilogram of rifamycin-S, with the first organic solvent (isopropyl acetate, ethyl acetate, N, one or more in dinethylformamide, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO)) 1.0～8.0 liters, 0.15～1.5 kilogram of dihydroxymethyl tert-butyl amine reacts 1-5 hour under 50 ± 10 DEG C of conditions, and some plate determines whether reaction is complete.
2,, to adding a kind of in Citric Acid (or formic acid or phosphoric acid or Glacial acetic acid or hydrochloric acid) or two kinds 0.10～6.0 kilogram in reaction solution, 8.0～40.0 liters of purified water stir 1-6 hour.
3, centrifugation, dries.
Step 102, in the second organic solvent (one or more in methyl alcohol, ethanol, Virahol, propyl carbinol), utilize catalyzer (one or more in S-WAT, sodium bicarbonate, sodium bisulfite, sodium carbonate, urea), reductive agent (one or more in S-WAT, vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid) to be hydrolyzed to above-mentioned Li Fu oxazine, use sodium salt (one kind of multiple in S-WAT, sodium bicarbonate, sodium bisulfite, sodium hydroxide, SODIUM PHOSPHATE, MONOBASIC, sodium carbonate) regulation system PH simultaneously;
In specific embodiment, this step is: get 1 kilogram of the Li Fu oxazine that above-mentioned reaction obtains; Methyl alcohol, ethanol, Virahol, butanol solution 1.5-8.0 liter; S-WAT (sodium bicarbonate, sodium bisulfite, sodium carbonate, urea) 0.10-1.5 kilogram; A kind of or two kinds of 0.04-3.5 kilogram in S-WAT (or sodium bicarbonate or sodium bisulfite or sodium hydroxide or SODIUM PHOSPHATE, MONOBASIC or sodium carbonate); 0.035-2.5 kilogram of S-WAT (vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid) reacts 1-4.5 hour under 50-70 DEG C of condition, and some plate determines whether reaction is complete.
Wherein, methyl alcohol, ethanol, Virahol, butanol solution use as solvent; S-WAT (sodium bicarbonate, sodium bisulfite, sodium carbonate, urea) uses as catalyzer in this step, energy facilitation of hydrolysis; Sodium salt mainly plays the effect that regulates pH value, conventionally pH value is adjusted to 4-9.S-WAT (vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid), as reductive agent, plays antioxygenation.
Step 103, adds 1-amino-4-cyclopentyl-based piperazine to step 102 in the hydrating solution obtaining, carry out building-up reactions;
1-amino-4-cyclopentyl-based piperazine is side-chain structure, and its structural formula is:
Point plate determines whether reaction is complete.
Step 104, filters, and collects respectively filtrate, filter cake;
Step 105, carries out sectional type crystallization to filtrate;
This step is the important inventive point in rifapentine preparation method in the present invention, and product crystal formation is good, uniform particles, mobility are very good, can meet the auto-filling requirement of capsule completely.
Specifically comprise the steps:
Step 105-1 at the temperature of 50-70 DEG C, adds fast crystallization solution and purified water in described filtrate, stirs, and carries out thermostatical crystallization;
Recrystallisation solvent can select following one or more: formic acid, phosphoric acid, Glacial acetic acid, hydrochloric acid, Citric Acid, ethanol, VC.
In specific embodiment, operate by following: filtrate is incubated at 50-70 DEG C, and constantly stirs, in this reaction solution, comparatively fast drip 0.10～5.0 kilogram of recrystallisation solvent, 2.0～15.0 liters of purified water, rate of addition is controlled at 100～200L/h;
Step 105-2, in the time starting to form macroscopic crystal, reduces described recrystallisation solvent rate of addition, and stops insulation, and cooling, carries out spontaneous nucleation naturally.
This step temperature is controlled at 18-35 DEG C, and described recrystallisation solvent rate of addition is 50～100L/h;
In specific embodiment, operate by following: start, after crystallization, to stop insulation, allow feed liquid naturally be cooled to room temperature, reduce the rate of addition of recrystallisation solvent, rate of addition is controlled at 50～100L/h; And in 1-5 hour every 30-60 minute stir 5-10 minute.
Step 105-3, in the time having a large amount of crystal to occur, then reduces the rate of addition of recrystallisation solvent, and recrystallisation solvent dropwises that rear batch type, is cooled to below 20 DEG C with cooling water temperature, leaves standstill.
This step crystallization speed rate of addition is controlled at 10～50L/h, and the described intermittent alr mode stirring is: within every 30-60 minute, stir 5-10 minute, leave standstill as stopping and stirring more than 2 hours.
In specific embodiment, by following operation: stop stirring after starting to occur macroscopic crystal in mother liquor, naturally be cooled to room temperature, be cooled to below 20 DEG C by water quench, at 20 DEG C of following standing 5-15 hour.
It should be noted that, step 105 is sectional type crystallization processes, wherein, recrystallisation solvent adopts the dropping mode of three sections first quick and back slow, Tc control adopts insulation, cooling naturally, cold water to lower the temperature three sections, and this sectional type crystallization processes acts synergistically together with the recrystallisation solvent dripping first quick and back slow, can make xln crystal formation homogeneous, uniform particles, good stability.Solve the shortcoming that in prior art rifapentine technique, foreign matter content is high, particle is inhomogeneous.
Wherein, the addition manner of recrystallisation solvent, for first quick and back slow, added complete in 4-10 hour.Before adding recrystallisation solvent, whole system is undersaturated condition, and adding recrystallisation solvent object is to transfer system to state of saturation by undersaturated condition, and target product is separated out from solution.If drip too soon recrystallisation solvent, easily cause impurity to separate not exclusively, make to be mixed with too many impurity in target product, do not reach separation requirement.The operating method dripping first quick and back slow can be impelled nucleus homogeneous, and crystal formation is good, and impurity separates more abundant.
Step 106, mother liquor described in centrifugation, obtains solid crystal;
This step is the first separation; In specific embodiment, operate by following:
Above-mentioned mother liquor is put into whizzer and carry out centrifugation, discard upper strata liquid, lower floor's solid crystallized product is dried.
Step 107, washing, obtains washings;
The washing of this step is syllogic washing, and described syllogic washing comprises:
Step 107-1, first paragraph alcohol wash; To described after a separation methyl alcohol for solid crystal,
One or both in butanols, ethanol wash;
Step 107-2, second segment washing; Again by purified water after to described first paragraph alcohol wash
Described solid crystal washs;
Step 107-3, the 3rd section of foam washing; With one or more in the purification of aqueous solutions of S-WAT, sodium bisulfite, Sulfothiorine, Citric Acid, vitamins C, Sorbic Acid, described solid crystal after second segment washing is washed again.
Step 108, centrifugation soak solution, obtains the wet crude product of rifapentine;
Step 107-step 108, in specific embodiment, operates by following:
First use one or more in 20-80L formic acid (or Citric Acid or phosphoric acid or Glacial acetic acid or hydrochloric acid or ethanol), use again purified water 1.0～15.0L drip washing solid crystal 5-10 minute (twice), finally use the purification of aqueous solutions of 0.1%～5% S-WAT (vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid) to soak this crystallized product 10-150 minute, by centrifugal this soak solution 70-90 minute, discard supernatant liquid, take out from wet crude product in whizzer, obtain the wet crude product of rifapentine.
Step 109, is dried wet the described rifapentine obtaining crude product, obtains the dry crude product of rifapentine;
Dry condition is: at vacuum tightness≤-0.15Mpa, dry at temperature≤100 DEG C, and to weight loss on drying≤5.0～10.0%.
Step 110, soaks the dry crude product of rifapentine;
This step is soaked for two-section type and is soaked, and two-section type is soaked and comprised:
Step 110-1, first paragraph dynamic soaking;
To dry a kind of or two kinds and above immersion the in S-WAT, vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid, purified water for crude product of described dried rifapentine, under the rotating speed of 50～100 revs/min, stir, soak 2～6 hours;
Step 110-2, second segment static immersing;
After dynamic soaking, stop stirring and soak again more than 1 hour.
The immersion of step 110 is one of inventive point in rifapentine preparation of the present invention, by this step, can make foreign matter content greatly reduce, wherein single assorted average 0.2%(standard-required≤1.0%), average 0.5%(standard-required≤3.0% of total impurities) content reaches 99.0%(standard-required and is no less than 93.5%) more than, product is more stable, reaches more than 36 months.
In specific embodiment, operate by following:
Dry above-mentioned rifapentine crude product is soaked to 1-9 hour in S-WAT, sodium bisulfite, ethanol, sodium carbonate, sodium bicarbonate, biphosphate sodium water solution 2.5～10.0L, and constantly stir, under room temperature, leave standstill 1.5-20 hour, obtain the second soak solution.
Step 111, centrifugation;
This step is the 3rd separation, and the second soak solution described in centrifugation, obtains the first solids.
Step 112, drip washing;
Drip washing is that the described the 3rd solids by using industrial alcohol aqueous solution separating is carried out to repeatedly drip washing to described solids, obtains the second solids; Centrifugal to described the second solids, dry, sieve, obtain the wet fine work of rifapentine;
In specific embodiment, operate by following:
Above-mentioned the second soak solution is put into whizzer and separate, discard supernatant liquid, with 10-40L industrial alcohol drip washing two to three times, more centrifugal 50-70 minute, discard supernatant liquid, take out from wet crude product in whizzer, obtain the wet fine work of rifapentine.
Step 113, dry, the wet fine work of described rifapentine is dried to obtain to rifapentine;
Dry condition is: at vacuum tightness≤-0.15Mpa, dry at temperature≤100 DEG C, and to weight loss on drying≤5.0～10.0%.
Rifapentine provided by the invention is by the rifapentine good fluidity of the explained hereafter after optimizing, impurity level is low, and stability is high, and quality product has risen to a new level, through many batches of amplification trial productions continuously, the product key index of acquisition all reaches domestically leading level.
According to the national drug standards WS of State Food and Drug Administration
1---(X-305)---2004Z detects, wherein single assorted average 0.2%(standard-required≤1.0%), average 0.5%(standard-required≤3.0% of total impurities), content reaches 99.0%(standard-required and is no less than 93.5%) more than, product is more stable, reaches more than 36 months.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment of doing, be equal to replacement, improvement etc., within all should being included in protection scope of the present invention.
Claims (10)
1. a rifapentine preparation method, is characterized in that, comprises the following steps:
A. taking rifamycin-S as initiator, in the first organic solvent, react with dihydroxymethyl tert-butyl amine and be converted into intermediate profit good fortune oxazine;
B. in the second organic solvent, add catalyzer, reductive agent to make described intermediate Li Fu oxazine hydrolysis;
C. the hydrolysate of Li Fu oxazine and 1-amino-4-cyclopentyl-based piperazine are condensed into rifapentine solution;
D. to described rifapentine solution filter, the sectional type crystallization of multistage Tc, first separates, washing, second separates, dry, immersions, the 3rd separation, drip washing, dry, sieve, be dried, mix powder treating process and obtain rifapentine finished product.
2. according to the rifapentine preparation method described in claim 1, it is characterized in that, described the first organic solvent be following one or more: isopropyl acetate, ethyl acetate, DMF, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO).
3. according to the rifapentine preparation method described in claim 1, it is characterized in that, described the second organic solvent be following one or more: methyl alcohol, ethanol, Virahol, propyl carbinol; Catalyzer is one or both in S-WAT, sodium bicarbonate, sodium bisulfite, sodium carbonate, urea; Reductive agent is one or more in S-WAT, vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid.
4. according to the rifapentine preparation method described in claim 1, it is characterized in that, described sectional type crystallization comprises:
First paragraph crystallization, insulation, at 50-70 DEG C, drips fast recrystallisation solvent in the filtrate obtaining after described filtration, carries out thermostatical crystallization, enters second segment crystallization in the time of naked eyes visible crystals;
Described second segment crystallization, reduces described recrystallisation solvent rate of addition, and stops insulation, and cooling, carries out spontaneous nucleation naturally, after a large amount of crystal are separated out, enters the 3rd section of crystallization;
Described the 3rd section of crystallization, reduces recrystallisation solvent rate of addition, and described recrystallisation solvent drips rear with cooling water temperature, and batch type is cooled to 20 DEG C and stops stirring, leaving standstill after following.
5. according to the rifapentine preparation method described in claim 4, it is characterized in that, described recrystallisation solvent is one or both in the aqueous solution of formic acid, phosphoric acid, Glacial acetic acid, hydrochloric acid, Citric Acid, ethanol, VC.
6. according to the rifapentine preparation method described in claim 4, it is characterized in that, in described first paragraph crystallization, described recrystallisation solvent rate of addition is 100～200L/h; In described second segment crystallization, temperature is 18-35 DEG C, and described recrystallisation solvent rate of addition is 50～100L/h; Described the 3rd section of crystallization, temperature is below 20 DEG C, described recrystallisation solvent rate of addition is 10～50L/h.
7. according to the rifapentine preparation method described in claim 4, it is characterized in that, the working method of described batch type is: within every 30-60 minute, stir 5-10 minute; The described standing time is more than 2 hours.
8. according to the rifapentine preparation method described in claim 1-7 any one, it is characterized in that, described washing is syllogic washing, and described syllogic washing comprises:
First paragraph alcohol wash, to described after a separation for solid crystal one or both in methyl alcohol, butanols, ethanol wash;
Second segment washing, the more described solid crystal after to described first paragraph alcohol wash washs by purified water;
The 3rd section of foam washing, the more described solid crystal after second segment washing is washed with one or more in the purification of aqueous solutions of S-WAT, sodium bisulfite, Sulfothiorine, Citric Acid, vitamins C, Sorbic Acid.
9. according to the rifapentine preparation method described in claim 1-7 any one, it is characterized in that, described immersion is that two-section type is soaked, and described two-section type is soaked and comprised:
First paragraph dynamic soaking, to dry a kind of or two kinds and above immersion the in S-WAT, vitamins C, sodium bisulfite, Sulfothiorine, Citric Acid, Sorbic Acid, purified water for crude product of described dried rifapentine, under the rotating speed of 50～100 revs/min, stir, soak 2～6 hours;
Second segment static immersing, after dynamic soaking, stops stirring and soaks more than 1 hour again.
10. according to the rifapentine preparation method described in claim 1-7 any one, it is characterized in that, described drip washing is that the described the 3rd solids ethanol separating is carried out to repeatedly drip washing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410098665.0A CN103951677B (en) | 2014-03-17 | 2014-03-17 | The preparation method of rifapentine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410098665.0A CN103951677B (en) | 2014-03-17 | 2014-03-17 | The preparation method of rifapentine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103951677A true CN103951677A (en) | 2014-07-30 |
| CN103951677B CN103951677B (en) | 2016-04-06 |
Family
ID=51329053
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410098665.0A Active CN103951677B (en) | 2014-03-17 | 2014-03-17 | The preparation method of rifapentine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103951677B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018886A (en) * | 2019-12-20 | 2020-04-17 | 无锡福祈制药有限公司 | Preparation method of high-purity rifapentine |
| CN111848639A (en) * | 2020-07-09 | 2020-10-30 | 华东理工大学 | Process for synthesizing rifampicin |
| WO2022225384A1 (en) * | 2021-04-21 | 2022-10-27 | Interquim, S.A. De C.V. | Method for obtaining rifapentine with a new crystalline form |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3925366A (en) * | 1973-07-25 | 1975-12-09 | Archifar Ind Chim Trentino | 1,3-Oxazino(5,6-c)rifamycins and method for preparing the same |
| US4002752A (en) * | 1975-03-05 | 1977-01-11 | Gruppo Lepetit S.P.A. | Piperazinylimino rifamycins |
| US4562203A (en) * | 1983-03-24 | 1985-12-31 | Spa Societa Prodotti Antibiotici S.P.A. | Rifamycins derivatives and preparation and pharmaceutical compositions thereof |
| CN1654467A (en) * | 2004-02-11 | 2005-08-17 | 上海新先锋药业有限公司 | N-methyl benzothiazole lifumeisu and method for preparing same |
| CN101486716A (en) * | 2009-02-20 | 2009-07-22 | 薛荔 | Preparation of good quality benemicin |
-
2014
- 2014-03-17 CN CN201410098665.0A patent/CN103951677B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3925366A (en) * | 1973-07-25 | 1975-12-09 | Archifar Ind Chim Trentino | 1,3-Oxazino(5,6-c)rifamycins and method for preparing the same |
| US4002752A (en) * | 1975-03-05 | 1977-01-11 | Gruppo Lepetit S.P.A. | Piperazinylimino rifamycins |
| US4562203A (en) * | 1983-03-24 | 1985-12-31 | Spa Societa Prodotti Antibiotici S.P.A. | Rifamycins derivatives and preparation and pharmaceutical compositions thereof |
| CN1654467A (en) * | 2004-02-11 | 2005-08-17 | 上海新先锋药业有限公司 | N-methyl benzothiazole lifumeisu and method for preparing same |
| CN101486716A (en) * | 2009-02-20 | 2009-07-22 | 薛荔 | Preparation of good quality benemicin |
Non-Patent Citations (2)
| Title |
|---|
| PETER TRAXLER, ET AL.,: "Hypolipidemic Activity of Rifamycin Derivatives", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 黄莉等，: "体系pH值对利福霉素恶嗪环合反应的影响", 《辽宁化工》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111018886A (en) * | 2019-12-20 | 2020-04-17 | 无锡福祈制药有限公司 | Preparation method of high-purity rifapentine |
| CN111848639A (en) * | 2020-07-09 | 2020-10-30 | 华东理工大学 | Process for synthesizing rifampicin |
| WO2022225384A1 (en) * | 2021-04-21 | 2022-10-27 | Interquim, S.A. De C.V. | Method for obtaining rifapentine with a new crystalline form |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103951677B (en) | 2016-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102911036A (en) | Method for obtaining high pure dicarboxylic acid | |
| CN106278953A (en) | A kind of production method improving metformin hydrochloride purity | |
| CN103951677B (en) | The preparation method of rifapentine | |
| CN103804172B (en) | A kind of method improving organic acid production quality | |
| CN103420891B (en) | The synthetic method of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene | |
| CN104926709A (en) | L-tryptophan refining method | |
| CN102911228A (en) | Refining method and preparation method of erythromycin thiocyanate | |
| CN102146052B (en) | Method for preparing tryptophan | |
| CN106117038A (en) | A kind of technique using nisin waste water to produce calcium lactate | |
| CN110256238A (en) | A kind of refining methd of long-chain mixed dibasic acid | |
| CN102617461A (en) | Novel method for refining aripiprazole | |
| CN103483404B (en) | A kind of method of hesperidine of purifying from tangerine slag | |
| CN105001353A (en) | Refining optimization technology for crude heparin sodium | |
| CN102558042A (en) | 4-bromine-6-methylnicotinicacid and preparation method thereof | |
| CN106946676B (en) | Purification method of high-purity trichloroacetone for preparing folic acid | |
| CN111518119B (en) | Continuous amoxicillin crystallization process | |
| CN102295598B (en) | Crystallization method of vitamin B6 | |
| CN112125907B (en) | Vitamin B 2 Extraction method | |
| CN105111124B (en) | A kind of method for producing D tryptophans | |
| CN115094106B (en) | Preparation method of pullulan | |
| CN105037310B (en) | It is a kind of while extracting the technique of myricetin and dihydromyricetin | |
| CN113264822B (en) | Preparation method of disodium fumarate | |
| CN103044427B (en) | Refining and purification method of medical-grade adenine | |
| CN102584753A (en) | Processing method of low-turbidity vitamin C calcium | |
| CN102786605B (en) | A kind of dilution crystallization method of separation and purification polysaccharide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20140730 Assignee: Henan Hezhi Pharmaceutical Technology Co.,Ltd. Assignor: SICHUAN LONG MARCH PHARMACEUTICAL Co.,Ltd. Contract record no.: X2024980002170 Denomination of invention: Preparation method of rifampicin Granted publication date: 20160406 License type: Exclusive License Record date: 20240223 |
|
| EE01 | Entry into force of recordation of patent licensing contract |