CN102838534A - Preparation method of flupirtine maleate - Google Patents
Preparation method of flupirtine maleate Download PDFInfo
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- CN102838534A CN102838534A CN2012103817053A CN201210381705A CN102838534A CN 102838534 A CN102838534 A CN 102838534A CN 2012103817053 A CN2012103817053 A CN 2012103817053A CN 201210381705 A CN201210381705 A CN 201210381705A CN 102838534 A CN102838534 A CN 102838534A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- DPYIXBFZUMCMJM-BTJKTKAUSA-N (z)-but-2-enedioic acid;ethyl n-[2-amino-6-[(4-fluorophenyl)methylamino]pyridin-3-yl]carbamate Chemical compound OC(=O)\C=C/C(O)=O.N1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 DPYIXBFZUMCMJM-BTJKTKAUSA-N 0.000 title abstract description 4
- 229960001655 flupirtine maleate Drugs 0.000 title abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 75
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000003756 stirring Methods 0.000 claims description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 55
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 46
- JUUFBMODXQKSTD-UHFFFAOYSA-N N-[2-amino-6-[(4-fluorophenyl)methylamino]-3-pyridinyl]carbamic acid ethyl ester Chemical compound N1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 JUUFBMODXQKSTD-UHFFFAOYSA-N 0.000 claims description 40
- 229960003667 flupirtine Drugs 0.000 claims description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 26
- 239000012065 filter cake Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- 239000008213 purified water Substances 0.000 claims description 21
- 239000013078 crystal Substances 0.000 claims description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- 230000002829 reductive effect Effects 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 12
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 claims description 11
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 11
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 10
- WERABQRUGJIMKQ-UHFFFAOYSA-N 6-chloro-3-nitropyridin-2-amine Chemical compound NC1=NC(Cl)=CC=C1[N+]([O-])=O WERABQRUGJIMKQ-UHFFFAOYSA-N 0.000 claims description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 10
- 235000017550 sodium carbonate Nutrition 0.000 claims description 9
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000012546 transfer Methods 0.000 claims description 6
- 238000002386 leaching Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 241000628997 Flos Species 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 abstract description 7
- 238000006467 substitution reaction Methods 0.000 abstract description 7
- 238000005917 acylation reaction Methods 0.000 abstract description 6
- 238000007670 refining Methods 0.000 abstract description 6
- 238000012360 testing method Methods 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000000126 substance Substances 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000013461 design Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 150000003222 pyridines Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- -1 (4-fluorophenyl) methyl Chemical group 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical class C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000002349 favourable effect Effects 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- RDJILYVRVOTMTQ-UHFFFAOYSA-N 6-methoxy-3-nitropyridin-2-amine Chemical compound COC1=CC=C([N+]([O-])=O)C(N)=N1 RDJILYVRVOTMTQ-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- UUOLETYDNTVQDY-UHFFFAOYSA-N 2-chloro-3-nitropyridine Chemical class [O-][N+](=O)C1=CC=CN=C1Cl UUOLETYDNTVQDY-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 229940127315 Potassium Channel Openers Drugs 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 230000002950 deficient 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
- WBAZQELGBFQHPE-UHFFFAOYSA-N ethyl n-[2-amino-6-[(4-fluorophenyl)methylamino]pyridin-3-yl]carbamate;hydron;chloride Chemical compound Cl.N1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 WBAZQELGBFQHPE-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229940121367 non-opioid analgesics Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000004036 potassium channel stimulating agent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000010977 unit operation Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a novel preparation method of flupirtine maleate; the method mainly comprises steps of substitution reaction, reduction reaction, acylation reaction, salt forming reaction and refining. It is proved by small and medium scale tests that a novel process route and reaction process are achievable, technical parameters are stable, reproducibility is good and product quality is stable.
Description
Technical field
The invention belongs to the chemicals preparing technical field.Particularly, the present invention relates to the preparation method of toxilic acid flupirtine.
Background technology
The toxilic acid flupirtine is a kind of nonopioid analgesic that acts on cns; It is a kind of selectivity neuron potassium channel openers (Selective Neuronal Potassium Channel Opener; SNEPCO), have pain relieving, of flaccid muscles and neuroprotective three efficacy.Be mainly used in the treatment of various types of moderate acute pains, the pain and headache/migraine and the abdominal cramps etc. that cause like surgical operation, wound etc.
The English name of toxilic acid flupirtine is: Flupirtine Maleate, chemical name: 2-amino-6-[((4-fluorophenyl) methyl) amino] pyridine-3-urethanum PHENRAMINE MALEATE; Chemical abstracts (CAS) number: 75507-68-5; Molecular formula: C
15H
17FN
4O
2C
4H
4O
4Molecular weight: 420.39; Its structural formula is:
See that from structure the toxilic acid flupirtine is the molecule-type compound, by the verivate and the synthetic flupirtine that makes of pyridine derivate of benzene, flupirtine forms organic salt with toxilic acid again.Comprehensive relevant document, the synthetic route of toxilic acid flupirtine mainly contains two, and is existing that its main synthesis step division is following.
Route 1 (WO 98/47872A1): this route is with 2, and 6-two chloro-3-nitropyridines are raw material, through replacement, ammonification, high-pressure hydrogenation, acidylate, salify, process such as refining.Reaction formula is following:
。
Route 2 (US5959115A) is a starting raw material with 2-amino-3-nitro-6-methoxypyridine; Warp and NSC 158269 generation substitution reaction generate 2-amino-3-nitro-6-NSC 158269 yl pyridines, and yield is 95.2%; High-pressure hydrogenation reduction then; Filtration catalizer gets the flupirtine hydrochloride with Vinyl chloroformate generation acylation reaction again, and three step total recoverys are 53.3%.Reaction formula is following:
。
Route 1,2 starting raw materials are different, but comparatively speaking, route 1 easy control of reaction conditions, and 2-amino-3-nitro 6-chloropyridine is a kind of common chemical raw materials, buys easily on the market, can shorten reaction scheme like this.Route 2 three-step reactions, operational path is short, but raw material 2-amino-3-nitro-6-methoxypyridine expensive, hydrogenation, two step of acidylate yield have only 56.0%.
All disclose the preparation method of toxilic acid flupirtine among one Chinese patent application publication No. CN102241626A and the CN102260209A, but the preparation method in these two parts of applications is a laboratory scale, is not optimized to large-scale industrialization production.
In the present invention; The basis that our selected above-mentioned route 1 is developed for synthetic route is through the substitutability analysis of reacting phase system, chemical unit design, raw material and reagent, particularly through lab scale and pilot plant test; Proved that new operational path and reaction process are practical; Processing parameter is stable, favorable reproducibility, product with stable quality.
Summary of the invention
The preparation method of toxilic acid flupirtine of the present invention mainly comprises following five steps reaction.
The first step: substitution reaction
Main technologic parameters: 1, about 80 ℃ of temperature (80 ℃ ± 5 ℃), 2-amino-3-nitro-6-chloropyridine and NSC 158269 molar ratio 1.0:1.2; 2, about 4 hours (4 ± 0.5 hours) of backflow; 3, (60 ℃ ± 5 ℃) about vacuum-drying 6-8 hour about 60 ℃.
Second step: reduction reaction
Main technologic parameters: 1, about 80 ℃ of temperature (80 ℃ ± 5 ℃).
The 3rd step: acylation reaction
Main technologic parameters: 1, F1 and Vinyl chloroformate molar ratio 1.0:1.15-1.5; 2, temperature control is no more than 50 ℃, drips Vinyl chloroformate; 3, normal temperature drips the triethylamine neutralization.
The 4th step: salt-forming reaction
Main technologic parameters: 1,60 ℃ ± 5 ℃ following salifies; 2, water as solvent.
The 5th step: refining:
Main technologic parameters: in absolute ethyl alcohol, 65 ℃ ± 5 ℃ stirring and dissolving post crystallizations.
The chemical substance relevant information that relates in each step is as follows:
Midbody F1:2-amino-3-nitro-6-NSC 158269 yl pyridines;
Midbody F2:2,3-diamino--6-NSC 158269 yl pyridines;
Midbody F3: flupirtine.
Their chemical formula is respectively:
In one embodiment, the invention provides a kind of preparation method of toxilic acid flupirtine, may further comprise the steps:
(1) 2-amino-3-nitro-6-chloropyridine, yellow soda ash, absolute ethyl alcohol, pyridine and NSC 158269 80 ℃ ± 5 ℃ back flow reaction in first reaction vessel obtain midbody F1;
(2) midbody F1, absolute ethyl alcohol, Raney's nickel and Hydrazine Hydrate 80 80 ℃ ± 5 ℃ back flow reaction in second reaction vessel are reacted the after-filtration that finishes, and filtrating moves in the 3rd reaction vessel and removes solvent under reduced pressure to there not being distillate, obtains the midbody F2 of solid-like;
(3) absolute ethyl alcohol is added in said the 3rd reaction vessel, drip Vinyl chloroformate, temperature must not surpass 50 ℃ in the dropping process, drips triethylamine then, transfers pH to 7～8, removes solvent under reduced pressure to there not being distillate, gets the midbody F3 of solid-like; With
(4) purified water is added in said the 3rd reaction vessel, is warming up to 60 ℃ ± 5 ℃ dissolving midbody F3 under stirring, then the toxilic acid aqueous solution is joined in said the 3rd reaction vessel; Continue to stir, be cooled to the room temperature crystallization afterwards, filter; Collect filter cake, obtain toxilic acid flupirtine bullion.
In further embodiment, the preparation method of said toxilic acid flupirtine further comprises step:
(5) toxilic acid flupirtine bullion 65 ℃ ± 5 ℃ stirring and dissolving post crystallizations in absolute ethyl alcohol.
In further embodiment, said step (1) is:
2-amino-3-nitro-6-chloropyridine, yellow soda ash, absolute ethyl alcohol, pyridine are dropped in first reaction vessel, be heated with stirring to 80 ℃ ± 5 ℃, occur obviously refluxing; NSC 158269 slowly is added drop-wise in the reaction vessel,, stops heating 80 ℃ ± 5 ℃ stirring and refluxing reactions 4 ± 0.5 hours; Add purified water, be cooled to normal temperature (25 ℃ ± 5 ℃) under stirring, separate out yellow crystal; Filter, collect filter cake, with purified water washing leaching cake 2 times; 60 ℃ ± 5 ℃ vacuum-drying 6-8 hour, obtain midbody F1.
In further embodiment, said step (2) is:
Midbody F1, absolute ethyl alcohol and Raney's nickel are joined in second reaction vessel; Be heated with stirring to 80 ℃ ± 5 ℃; Drip Hydrazine Hydrate 80 after occurring refluxing, dropwise the back and stirred 1 ± 0.5 hour, filter; To filtrate to move in the 3rd reaction vessel removes solvent under reduced pressure to there not being distillate, obtains the midbody F2 of solid-like.
In further embodiment, said step (3) is:
Absolute ethyl alcohol is added in said the 3rd reaction vessel; Stir down and drip Vinyl chloroformate, temperature must not surpass 50 ℃ in the dropping process, drips off continued and stirs 2 ± 0.5 hours; Drip triethylamine then; Transfer pH to 7～8, stir and remove solvent after 30 ± 5 minutes under reduced pressure, get the midbody F3 of solid-like to there not being distillate.
In further embodiment, said step (4) is:
Purified water is added in said the 3rd reaction vessel, is warming up to 60 ℃ ± 5 ℃ dissolving midbody F3 under stirring, then the toxilic acid aqueous solution is joined in said the 3rd reaction vessel; Have solids to separate out, 60 ℃ ± 5 ℃ are continued down to stir 1 ± 0.5 hour, are cooled to room temperature and continued stirring and crystallizing 5-10 hour; Filter, with purified water washing, absolute ethanol washing; Collect filter cake, obtain toxilic acid flupirtine bullion.
In further embodiment, said step (5) is:
In the 4th reaction vessel, add absolute ethyl alcohol, add toxilic acid flupirtine bullion again, be heated to 65 ℃ ± 5 ℃ under stirring and dissolve to solid; Add gac, insulated and stirred 15-30 minute, heat filtered gac, and filtrating gets in the crystallizer after smart filter; Stir down and be cooled to stirring at room 1 hour, separate out floss after, be cooled to 0 ℃ ± 5 ℃, continuation stirring and crystallizing 5-10 hour; Filter, collect filter cake, behind the absolute ethanol washing filter cake with filter cake 60 ℃ ± 5 ℃ vacuum-drying 6-8 hour.
In further embodiment, the mol ratio of 2-amino in said step (1)-3-nitro-6-chloropyridine and NSC 158269 is 1.0:1.2-1.5, and is preferred, 1.0:1.2.
In further embodiment, in said step (2), the amount of the midbody F1 that uses according to step (2), the mol ratio of midbody F1 and Hydrazine Hydrate 80 is 1:4-8, preferably, and 1:4-6, preferred, 1:4-5.
In further embodiment, in said step (3), the amount of the midbody F1 that uses according to step (2), the mol ratio of midbody F1 and Vinyl chloroformate is 1:1.15-1.5.
In further embodiment, in said step (4), the amount of the midbody F1 that uses according to step (2), the mol ratio of midbody F1 and toxilic acid is 1:1.0-1.5.
In one embodiment, the invention provides a kind of preparation method of toxilic acid flupirtine, may further comprise the steps:
(1) 2-amino-3-nitro-6-chloropyridine, yellow soda ash, absolute ethyl alcohol, pyridine are dropped in first reaction vessel, be heated with stirring to 80 ℃ ± 5 ℃, occur obviously refluxing, slowly be added drop-wise to NSC 158269 in the reaction vessel; 80 ℃ ± 5 ℃ stirring and refluxing reactions 4 ± 0.5 hours, stop heating, add purified water, be cooled to normal temperature under stirring; Separate out yellow crystal, filter, collect filter cake; With purified water washing leaching cake 2 times, 60 ℃ ± 5 ℃ vacuum-drying 6-8 hour, obtain midbody F1;
(2) midbody F1, absolute ethyl alcohol and Raney's nickel are joined in second reaction vessel; Be heated with stirring to 80 ℃ ± 5 ℃; Drip Hydrazine Hydrate 80 after occurring refluxing, dropwise the back and stirred 1 ± 0.5 hour, filter; To filtrate to move in the 3rd reaction vessel removes solvent under reduced pressure to there not being distillate, obtains the midbody F2 of solid-like;
(3) absolute ethyl alcohol is added in said the 3rd reaction vessel; Stir down and drip Vinyl chloroformate, temperature must not surpass 50 ℃ in the dropping process, drips off continued and stirs 2 ± 0.5 hours; Drip triethylamine then; Transfer pH to 7～8, stir and remove solvent after 30 ± 5 minutes under reduced pressure, get the midbody F3 of solid-like to there not being distillate;
(4) purified water is added in said the 3rd reaction vessel, is warming up to 60 ℃ ± 5 ℃ dissolving midbody F3 under stirring, then the toxilic acid aqueous solution is joined in said the 3rd reaction vessel; Have solids to separate out, 60 ℃ ± 5 ℃ are continued down to stir 1 ± 0.5 hour, are cooled to room temperature and continued stirring and crystallizing 5-10 hour; Filter, with purified water washing, absolute ethanol washing; Collect filter cake, obtain toxilic acid flupirtine bullion; With
(5) in the 4th reaction vessel, add absolute ethyl alcohol, add toxilic acid flupirtine bullion again; Be heated to 65 ℃ ± 5 ℃ under stirring to the solid dissolving, add gac, insulated and stirred 15-30 minute; Heat filters gac, and filtrating gets in the crystallizer after smart filter, is cooled to stirring at room 1 hour under stirring; After separating out floss, be cooled to 0 ℃ ± 5 ℃, continued stirring and crystallizing 5-10 hour; Filter, collect filter cake, behind the absolute ethanol washing filter cake with filter cake 60 ℃ ± 5 ℃ vacuum-drying 6-8 hour.
Detailed description of the invention
One, operational path confirms
So the selected described route 1 of preamble is a synthetic route, and changes hydrogenation reduction process, uses safer and more effective Hydrazine Hydrate 80 to be reductive agent, this has shortened the reaction times greatly.Study on the synthesis route reaction formula is following:
In the synthesis technique of confirming, be raw material with 2-amino-3-nitro-6-chloropyridine, through replacement, reduction, acidylate, salify, flupirtine such as refining.The reaction that technology relates to mainly is a not homogeneous reaction of solid-liquid, and the raw material and the reagent of use have substitutability, and main chemical process flow has solid-separation, solid-liquid separation etc. Gu make the toxilic acid unit operation.To above characteristics, several kinds of factors below when process design, mainly considering.
(1) is directed against not homogeneous reaction
In synthesis technique; Midbody 2-amino-3-nitro-6-NSC 158269 yl pyridines (F1); 2,3-diamino--6-NSC 158269 yl pyridines (F2), flupirtine (F3) and the finished product toxilic acid flupirtine synthetic; Be not homogeneous reaction, when reactor design, taken into full account the state of the art of present chemical plant.
Midbody F1, F2's is synthetic, and reaction conditions is similar, requires to have backflow; Consider the synthetic continuity; We carry out synthetic, the neutralization reaction of midbody F3 in concentrating in the same reactor drum, this not only effectively solves flupirtine alkali and is prone to oxidized problem, and can save into alkali, neutral conversion unit; The HCl that has sharp aroma, the organic amine that particularly generate can better be dissolved in the mother liquor; Can reclaim then, operator's Working environment is improved, also reduce fixing
The input of assets.
When selective reaction medium, solvent, that emphasis uses is nontoxic, cheap, steady quality, the organism that can recycle.Midbody F1's is synthetic, and methyl alcohol, ethanol, Virahol etc. are according with process requirements all, but final safety non-toxic, the cheap ethanol selected; In the preparation of A crystal formation, also select ethanol to make solvent, mother liquor recycles after reclaiming.
(2) to the substitutability of raw material and reagent
As previously mentioned, except that solvent, medium, in the selection of raw material and reagent, also follow this thinking.In the alkali reagent that uses, caustic soda, Ke Xingjia, soda ash, triethylamine, diethylamine all can, except that irreplaceable, select the most cheap chemicals soda ash in the technology as far as possible, this not only reduces synthetic cost, more environmental protection eases off the pressure; In toxilic acid flupirtine synthetic; Make water, ethanol, methyl alcohol, Virahol all passable, but consider the synthetic cost, select water to make solvent at last; Not only reduce production costs greatly; But also find to remove the strong impurity of segment polarity in the technology, reach the ideal technology requirement, reduce the pressure of environmental protection.
The selection of reagent sees the following form
。
(3) chemical unit design
In the chemical unit that relates to, solid-liquid inhomogeneous reaction, solid-liquid separate and occupy main proportion, so when design, emphasis is considered the chemical plant of existing moulding, promptly mainly consider the chemical plant of GB standard.Main reaction kettle, separating device can reach processing requirement at present.
(4) product crystal formation research
According to relevant bibliographical information, the toxilic acid flupirtine has three kinds of crystal formations--and-A, B, S type, wherein the S type is called the solvent crystal formation again, because the A crystal formation has characteristics such as solubleness is good, bioavailability is high, finished product is stable, so require finished product A crystal formation content high.
In crystal formation research, we adopt different solvents such as absolute ethyl alcohol, methyl alcohol, sherwood oil, ETHYLE ACETATE, Virahol respectively, on processing condition respectively with temperature, whether stir be parameter.Experimental result shows, at sherwood oil, ETHYLE ACETATE because solubleness is little, so do not adopt this two solvents; Absolute ethyl alcohol, methyl alcohol, Virahol all can reach the crystal formation content requirement under various conditions; In all solvents, all need to stir.
Finally confirm with ethanol to be solvent, temperature is 65 ℃ ± 5 ℃ a crystal formation preparation condition.Following table has shown the result of crystal formation preparation condition research.
√ contains qualified A crystal formation; * A crystal formation content is defective.
In order to study different crystal forms character better,, find out the preparation method of pure A, B crystal formation also through the conversion crystallization condition.
Two, technical study is summed up
Through the substitutability analysis of reacting phase system, chemical unit design, raw material and reagent, particularly, proved that operational path and reaction process are practical through lab scale and pilot plant test, processing parameter is stable, favorable reproducibility, product with stable quality.
The important technical parameter result of study sees the following form:
Embodiment 1---the preparation experiment of toxilic acid flupirtine
(1) substitution reaction----midbody F1's is synthetic
I, charging capacity and proportioning
| Title | Kg | mol |
| 2-amino-3-nitro-6-chloropyridine | 5.0 | 28.9 |
| Absolute ethyl alcohol | 14.0 | -- |
| NSC 158269 | 4.3 | 34.4 |
| Yellow soda ash | 6.02 | -- |
| Pyridine | 0.85 | -- |
| Purified water | 34.0 | -- |
II, experimentation
2-amino-3-nitro-6-chloropyridine, yellow soda ash, absolute ethyl alcohol, pyridine are put in the exsiccant 211# reaction kettle, opened and stir and be heated to (80 ℃ ± 5 ℃) about 80 ℃, occur obviously refluxing; NSC 158269 slowly is added drop-wise in the reaction kettle, and after dropwising, (80 ℃ ± 5 ℃) stirring and refluxing was reacted about 4 hours about 80 ℃.
Stop heating, add the 34.0kg purified water, be cooled to normal temperature (25 ℃ ± 5 ℃) under stirring, have a large amount of yellow crystals to separate out.
Filter, collect filter cake, with an amount of purified water washing leaching cake 2 times, 60 ℃ vacuum-drying 6-8 hour.
Product: 6.8kg.
Yield scope: 85.0-95.0%.
III, midbody control
Outward appearance: middle this F1 is a yellow powder shape solid;
HPLC measures midbody F1 content>=95%, NSC 158269 limit≤0.5%.(normalization method).
(2) reduction reaction----midbody F2's is synthetic
I, charging capacity and proportioning
| Title | Kg | mol |
| Midbody F1 | 6.8 | 26 |
| 80% Hydrazine Hydrate 80 | 5.4 | 108 |
| Absolute ethyl alcohol | 51.0 | -- |
| Raney's nickel | 580.0g | -- |
II, operating process
The Raney's nickel of midbody F1, absolute ethyl alcohol and catalytic amount is joined in the 201# reaction kettle, open and stir, be warming up to (80 ℃ ± 5 ℃) about 80 ℃, drip Hydrazine Hydrate 80 (according to response situation, consumption is at 5.4-10.5kg) as early as possible after occurring refluxing.Stirred 1 ± 0.5 hour after dropwising, filter, will filtrate to move into removes solvent under reduced pressure to there not being distillate in the 210# reaction kettle, get the solid-like thing, after the TLC detection is errorless, drops into next step reaction.
III, midbody control
TLC detects: ETHYLE ACETATE: after launching in the developping agent of sherwood oil ≈ 1:1, and colour developing under ultraviolet 254nm.
Rf ≈ 0.6 is a target compound.
(3) acylation reaction----midbody F3's is synthetic
I, charging capacity and proportioning
| Title | Kg | mol |
| Midbody F2 | -- | -- |
| Vinyl chloroformate | 4.25 | 39.35 |
| Absolute ethyl alcohol | 38.0 | -- |
| Triethylamine | 3.1 | 30.7 |
II, operating process
Absolute ethyl alcohol 38kg is added in the 210# reaction kettle, stirs down and drip Vinyl chloroformate 4.25kg (according to response situation, consumption is at 3.25-4.25kg), temperature must not surpass 50 ℃ in the dropping process, drips off continued and stirs 2 hours.Drip triethylamine 3.1kg (actual amount is as the criterion with pH) then, transfer pH to 7～8, stir and remove solvent under reduced pressure to there not being distillate after 30 minutes.Get the solid-like thing, TLC detects errorless back and drops into next step reaction.
III, quality control
TLC detects
ETHYLE ACETATE: sherwood oil ≈ 4:1.
Rf ≈ 0.7 is a target compound.
(4) synthesizing of salt-forming reaction----toxilic acid flupirtine
I, charging capacity and proportioning
| Title | Kg | mol |
| Toxilic acid | 3.1 | 26.7 |
| Purified water | 120.0 | -- |
II, operating process
The 120.0kg purified water is added in the 210# reaction kettle, is warming up to 60 ℃ ± 5 ℃ under stirring; Other gets the 3.1kg toxilic acid and is dissolved in the 17kg purified water; Then the toxilic acid aqueous solution is joined in the 210# reaction kettle, have a large amount of solidss to separate out, 60 ℃ ± 5 ℃ are continued to stir 1h down; Be cooled to room temperature and continued stirring and crystallizing 5-10 hour, filter, wash with purified water; Absolute ethanol washing is collected filter cake, gets into next step rectification flow.
III, quality control
TLC detects: ETHYLE ACETATE: sherwood oil ≈ 4:1.Rf ≈ 0.7 is a target compound.
(5) preparation of refining----crystal form A
I, charging capacity and proportioning
| Title | Kg | mol |
| Absolute ethyl alcohol | 120.0 | -- |
| Toxilic acid | 0.17 | 1.47 |
| Gac | 0.68 | -- |
II, experimentation
In the 300L reaction kettle, add absolute ethyl alcohol 120kg, add the toxilic acid of toxilic acid flupirtine bullion and 170g again; Be heated to 65 ℃ ± 5 ℃ under stirring to the solid dissolving, add the 680.0g gac, insulated and stirred 15-30 minute; Heat filters gac, and filtrating gets in the clean area 500L crystallizer after smart filter, is cooled to stirring at room 1 hour under stirring; After separating out a large amount of flosss, be cooled to (0 ℃ ± 5 ℃) about 0 ℃, continued stirring and crystallizing 5-10 hour; Filter, collect filter cake, behind the absolute ethanol washing filter cake with about 60 ℃ of filter cakes (60 ℃ ± 5 ℃) vacuum-drying 6-8 hour.
Filter cake was pulverized the whole grain of 40 mesh sieves, weighing products packing warehouse-in.
III, quality control
Outward appearance: white crystal.
Fusing point: 172-176 ℃.
Embodiment 2---the control of committed step and making with extra care of product
The production of these article is divided into substitution reaction, reduction reaction, acylation reaction; Salify, in refining five steps, wherein substitution reaction can obtain solid product; The product of reduction reaction and acylation reaction is difficult for making solid in operation; And product is prone to oxidation, and it is refining that the bullion that salify makes is difficult for the later stage after because of drying, and a spot of water that contains in the bullion is to the not significantly influence of quality of finished product.In experimentation, our emphasis is temperature of reaction, the material feed ratio, and the reaction times is progressively found out relevant parameters as research object.
In synthesis technique, the product of substitution reaction is midbody F1 and can be separated preferably, and midbody F1 is the basic framework that forms the finished product toxilic acid flupirtine, and the quality of its quality not only influences the second step three step process.So F1 is confirmed as key intermediate and quality detection in addition.
When needed, midbody F1 is made with extra care.The process for purification of midbody F1 is following:
The process for purification of toxilic acid flupirtine the finished product is following:
Under 65 ℃ ± 5 ℃ toxilic acid flupirtine bullion is mixed with mass ratio 1:30-40 with absolute ethyl alcohol, bullion dissolves fully, adds the 680g gac again; Stirred 15-30 minute, filtered while hot is got filtrating; Stirring drops to room temperature; Be chilled to 0 ℃ of crystallization 5-10 hour again, cross the leaching filter cake, the filter cake oven dry is got final product.
Embodiment 3---and multiple batches of technical study and data thereof gather
Carried out a plurality of batches, the trial-production of different batch weights according to the described toxilic acid flupirtine of preamble preparation method, yield and quality product are studied, data are as shown in the table.Data show that compound method of the present invention is reliable and stable, can obtain highly purified product, and related substances is very low with maximum single assorted content simultaneously, and processing parameter is stable, favorable reproducibility, product with stable quality.
Claims (12)
1. the preparation method of a toxilic acid flupirtine may further comprise the steps:
(1) 2-amino-3-nitro-6-chloropyridine, yellow soda ash, absolute ethyl alcohol, pyridine and NSC 158269 80 ℃ ± 5 ℃ back flow reaction in first reaction vessel obtain midbody F1;
(2) midbody F1, absolute ethyl alcohol, Raney's nickel and Hydrazine Hydrate 80 80 ℃ ± 5 ℃ back flow reaction in second reaction vessel are reacted the after-filtration that finishes, and filtrating moves in the 3rd reaction vessel and removes solvent under reduced pressure to there not being distillate, obtains the midbody F2 of solid-like;
(3) absolute ethyl alcohol is added in said the 3rd reaction vessel, drip Vinyl chloroformate, temperature must not surpass 50 ℃ in the dropping process, drips triethylamine then, transfers pH to 7～8, removes solvent under reduced pressure to there not being distillate, gets the midbody F3 of solid-like; With
(4) purified water is added in said the 3rd reaction vessel, is warming up to 60 ℃ ± 5 ℃ dissolving midbody F3 under stirring, then the toxilic acid aqueous solution is joined in said the 3rd reaction vessel; Continue to stir, be cooled to the room temperature crystallization afterwards, filter; Collect filter cake, obtain toxilic acid flupirtine bullion.
2. according to the method for claim 1, further comprise step:
(5) toxilic acid flupirtine bullion 65 ℃ ± 5 ℃ stirring and dissolving post crystallizations in absolute ethyl alcohol.
3. according to the process of claim 1 wherein that said step (1) is:
2-amino-3-nitro-6-chloropyridine, yellow soda ash, absolute ethyl alcohol, pyridine are dropped in first reaction vessel, be heated with stirring to 80 ℃ ± 5 ℃, occur obviously refluxing, slowly be added drop-wise to NSC 158269 in the reaction vessel; 80 ℃ ± 5 ℃ stirring and refluxing reactions 4 ± 0.5 hours, stop heating, add purified water, be cooled to normal temperature under stirring; Separate out yellow crystal, filter, collect filter cake; With purified water washing leaching cake 2 times, 60 ℃ ± 5 ℃ vacuum-drying 6-8 hour, obtain midbody F1.
4. according to the process of claim 1 wherein that said step (2) is:
Midbody F1, absolute ethyl alcohol and Raney's nickel are joined in second reaction vessel; Be heated with stirring to 80 ℃ ± 5 ℃; Drip Hydrazine Hydrate 80 after occurring refluxing, dropwise the back and stirred 1 ± 0.5 hour, filter; To filtrate to move in the 3rd reaction vessel removes solvent under reduced pressure to there not being distillate, obtains the midbody F2 of solid-like.
5. according to the process of claim 1 wherein that said step (3) is:
Absolute ethyl alcohol is added in said the 3rd reaction vessel; Stir down and drip Vinyl chloroformate, temperature must not surpass 50 ℃ in the dropping process, drips off continued and stirs 2 ± 0.5 hours; Drip triethylamine then; Transfer pH to 7～8, stir and remove solvent after 30 ± 5 minutes under reduced pressure, get the midbody F3 of solid-like to there not being distillate.
6. according to the process of claim 1 wherein that said step (4) is:
Purified water is added in said the 3rd reaction vessel, is warming up to 60 ℃ ± 5 ℃ dissolving midbody F3 under stirring, then the toxilic acid aqueous solution is joined in said the 3rd reaction vessel; Have solids to separate out, 60 ℃ ± 5 ℃ are continued down to stir 1 ± 0.5 hour, are cooled to room temperature and continued stirring and crystallizing 5-10 hour; Filter, with purified water washing, absolute ethanol washing; Collect filter cake, obtain toxilic acid flupirtine bullion.
7. according to the method for claim 2, wherein said step (5) is:
In the 4th reaction vessel, add absolute ethyl alcohol, add toxilic acid flupirtine bullion again, be heated to 65 ℃ ± 5 ℃ under stirring and dissolve to solid; Add gac, insulated and stirred 15-30 minute, heat filtered gac, and filtrating gets in the crystallizer after smart filter; Stir down and be cooled to stirring at room 1 hour, separate out floss after, be cooled to 0 ℃ ± 5 ℃, continuation stirring and crystallizing 5-10 hour; Filter, collect filter cake, behind the absolute ethanol washing filter cake with filter cake 60 ℃ ± 5 ℃ vacuum-drying 6-8 hour.
8. according to the method for claim 1, the mol ratio of 2-amino in said step (1)-3-nitro-6-chloropyridine and NSC 158269 is 1.0:1.2-1.5, and is preferred, 1.0:1.2.
9. according to the method for claim 1, in said step (2), the amount of the midbody F1 that uses according to step (2), the mol ratio of midbody F1 and Hydrazine Hydrate 80 is 1:4-8, preferably, and 1:4-6, preferred, 1:4-5.
10. according to the method for claim 1, in said step (3), the amount of the midbody F1 that uses according to step (2), the mol ratio of midbody F1 and Vinyl chloroformate is 1:1.15-1.5.
11. according to the method for claim 1, in said step (4), the amount of the midbody F1 that uses according to step (2), the mol ratio of midbody F1 and toxilic acid is 1:1.0-1.5.
12. each the toxilic acid flupirtine of method preparation according to claim 1-11.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103086963A (en) * | 2013-01-29 | 2013-05-08 | 吉林修正药业新药开发有限公司 | Synthetic method of flupirtine maleate A-type crystal compound and midbody |
| CN103333103A (en) * | 2013-07-12 | 2013-10-02 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
| CN104817494A (en) * | 2015-04-22 | 2015-08-05 | 江苏海岸药业有限公司 | Method for synthesizing flupirtine maleate by use of one-pot process |
| CN106397313A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High efficient synthesis method of flupirtine maleate |
| CN109053562A (en) * | 2018-07-20 | 2018-12-21 | 四川青木制药有限公司 | A method of preparing the flupirtine maleate of the high heap density of A crystal form |
| CN109053563A (en) * | 2018-07-20 | 2018-12-21 | 四川青木制药有限公司 | A method of preparing hydrochloric acid Flupirtine |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103086963A (en) * | 2013-01-29 | 2013-05-08 | 吉林修正药业新药开发有限公司 | Synthetic method of flupirtine maleate A-type crystal compound and midbody |
| CN103333103A (en) * | 2013-07-12 | 2013-10-02 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
| CN103333103B (en) * | 2013-07-12 | 2015-07-22 | 南京正大天晴制药有限公司 | Method for preparing flupirtine maleate by one-pot method |
| CN104817494A (en) * | 2015-04-22 | 2015-08-05 | 江苏海岸药业有限公司 | Method for synthesizing flupirtine maleate by use of one-pot process |
| CN104817494B (en) * | 2015-04-22 | 2017-09-29 | 江苏海岸药业有限公司 | A kind of method of one pot process flupirtine maleate |
| CN106397313A (en) * | 2016-08-31 | 2017-02-15 | 安徽省润生医药股份有限公司 | High efficient synthesis method of flupirtine maleate |
| CN109053562A (en) * | 2018-07-20 | 2018-12-21 | 四川青木制药有限公司 | A method of preparing the flupirtine maleate of the high heap density of A crystal form |
| CN109053563A (en) * | 2018-07-20 | 2018-12-21 | 四川青木制药有限公司 | A method of preparing hydrochloric acid Flupirtine |
| CN109053563B (en) * | 2018-07-20 | 2022-03-29 | 四川青木制药有限公司 | Method for preparing flupirtine hydrochloride |
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