CN110950795A - N-ethylpyridine methylamine methanesulfonate crystal, preparation process and application thereof in preparation of tropicamide - Google Patents
N-ethylpyridine methylamine methanesulfonate crystal, preparation process and application thereof in preparation of tropicamide Download PDFInfo
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- CN110950795A CN110950795A CN201911189776.1A CN201911189776A CN110950795A CN 110950795 A CN110950795 A CN 110950795A CN 201911189776 A CN201911189776 A CN 201911189776A CN 110950795 A CN110950795 A CN 110950795A
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- ethylpyridine
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- 239000013078 crystal Substances 0.000 title claims abstract description 41
- BGDKAVGWHJFAGW-UHFFFAOYSA-N Tropicamide Chemical compound C=1C=CC=CC=1C(CO)C(=O)N(CC)CC1=CC=NC=C1 BGDKAVGWHJFAGW-UHFFFAOYSA-N 0.000 title claims abstract description 28
- GCPMLTJUGDGKRL-UHFFFAOYSA-N CS(=O)(=O)O.CN.C(C)N1CC=CC=C1 Chemical compound CS(=O)(=O)O.CN.C(C)N1CC=CC=C1 GCPMLTJUGDGKRL-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229960004791 tropicamide Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- MTGUXBIZQWFIPU-UHFFFAOYSA-N CN.C(C)N1CC=CC=C1 Chemical compound CN.C(C)N1CC=CC=C1 MTGUXBIZQWFIPU-UHFFFAOYSA-N 0.000 claims abstract description 39
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229940098779 methanesulfonic acid Drugs 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims abstract description 4
- 230000032683 aging Effects 0.000 claims abstract description 3
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 2
- 239000007858 starting material Substances 0.000 abstract description 18
- 238000000746 purification Methods 0.000 abstract description 12
- 150000003839 salts Chemical group 0.000 abstract description 11
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000002425 crystallisation Methods 0.000 abstract description 5
- 230000008025 crystallization Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- -1 tropine amide Chemical class 0.000 description 9
- XQJMXPAEFMWDOZ-UHFFFAOYSA-N 3exo-benzoyloxy-tropane Natural products CN1C(C2)CCC1CC2OC(=O)C1=CC=CC=C1 XQJMXPAEFMWDOZ-UHFFFAOYSA-N 0.000 description 7
- QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 description 7
- QIZDQFOVGFDBKW-DHBOJHSNSA-N Pseudotropine Natural products OC1C[C@@H]2[N+](C)[C@H](C1)CC2 QIZDQFOVGFDBKW-DHBOJHSNSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 150000002466 imines Chemical class 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 238000005265 energy consumption Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- AVCRYECOWDUKJB-ULKQDVFKSA-N 3alpha-Acetoxytropane Natural products O=C(OC1C[C@@H]2[N+](C)[C@H](C1)CC2)C AVCRYECOWDUKJB-ULKQDVFKSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- MDIDMOWWLBGYPG-MYJAWHEDSA-N O-acetyltropine Chemical compound C1[C@@H](OC(C)=O)C[C@H]2CC[C@@H]1N2C MDIDMOWWLBGYPG-MYJAWHEDSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229940126600 bulk drug product Drugs 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- BQSUUGOCTJVJIF-UHFFFAOYSA-N n-(pyridin-2-ylmethyl)ethanamine Chemical compound CCNCC1=CC=CC=N1 BQSUUGOCTJVJIF-UHFFFAOYSA-N 0.000 description 2
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- CYHOMWAPJJPNMW-JIGDXULJSA-N tropine Chemical compound C1[C@@H](O)C[C@H]2CC[C@@H]1N2C CYHOMWAPJJPNMW-JIGDXULJSA-N 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000001886 ciliary effect Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- FGYDHYCFHBSNPE-UHFFFAOYSA-N diethyl phenylmalonate Chemical compound CCOC(=O)C(C(=O)OCC)C1=CC=CC=C1 FGYDHYCFHBSNPE-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002637 mydriatic agent Substances 0.000 description 1
- 230000002911 mydriatic effect Effects 0.000 description 1
- MKTSSBCZDAXGGO-UHFFFAOYSA-N n-ethyl-n-methylpyridin-2-amine Chemical compound CCN(C)C1=CC=CC=N1 MKTSSBCZDAXGGO-UHFFFAOYSA-N 0.000 description 1
- CXGFWBPQQXZELI-UHFFFAOYSA-N n-ethylpyridin-2-amine Chemical compound CCNC1=CC=CC=N1 CXGFWBPQQXZELI-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- 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
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses an N-ethylpyridine methylamine mesylate crystal, a preparation process and an application thereof in preparation of tropicamide, wherein the mesylate of N-ethylpyridine methylamine is prepared from N-ethylpyridine methylamine and methanesulfonic acid, X-ray powder diffraction is used, and the crystal has diffraction peaks at about 9.49 degrees, 13.16 degrees, 16.18 degrees, 19.10 degrees, 20.54 degrees, 23.24 degrees, 26.96 degrees and 34.63 degrees. Dissolving N-ethylpyridine methylamine in organic solvent, and stirring at room temperature or under heating until the materials are completely dissolved; slowly adding acid, and crystallizing; preserving heat, aging, filtering and drying to obtain the tropicamide key starting material N-ethyl pyridine methylamine methanesulfonate crystal. The method has the advantages of simple operation, obvious purification effect, low content of impurities of salt forms and crystal forms obtained by crystallization preparation, high purity and contribution to industrial production.
Description
Technical Field
The invention relates to a mesylate crystal of N-ethylpyridine methylamine, a preparation process and application thereof in preparation of tropicamide, belonging to the technical field of medicine preparation.
Technical Field
Tropicamide is an anticholinergic, a parasympathetic inhibitory drug, a preferred mydriatic drug for fundus examination and diagnosis in the field of ophthalmology, and also has the effect of ciliary muscle anesthesia. In 1955, the medicament is firstly synthesized by Roche company and is mainly used as a compound preparation except for being used alone clinically. Tropicamide has many advantages such as rapid mydriasis and short recovery period compared with other mydriatic agents.
Physicochemical properties of tropicamide: the white crystal is powdery, bitter in taste, soluble in ethanol, chloroform and acetone, slightly soluble in water and insoluble in petroleum ether.
At present, the earliest synthetic method of tropine amide disclosed is the method reported by Siliva Dei et al (Life Sciences, Vol, 58, No.23, PP.2147-2153), which takes salicylic acid as a raw material, firstly acetylates to protect hydroxyl, then reacts with N-ethylpyridine methylamine, and finally obtains tropine amide through deacetylation protection, wherein the reaction route is shown as a reaction formula 1:
in 2017, Shanghai Tataceae technology Co., Ltd reports a synthetic route which takes diethyl phenylmalonate as a reaction raw material, reacts with N-ethylpyridine methylamine after two-step conversion, and finally, the tropine amide is synthesized by reduction, wherein the total yield is improved to 65%, and the synthetic route is shown as a formula 2:
both synthetic routes use N-ethylpyridine methylamine as the key starting material, with CAS numbers: 33403-97-3,
the molecular formula is: C8H12N 2: molecular weight: 136.20, having a chemical formula shown in formula 3:
the N-ethylpyridine methylamine is a light yellow oily liquid, the preparation process comprises the steps of carrying out condensation reaction on 4-pyridine formaldehyde and ethylamine to generate an imine intermediate 3, carrying out reduction reaction on the imine intermediate 3 through sodium borohydride to generate a crude product of the N-ethylpyridine methylamine, and carrying out further post-treatment and purification on the crude product to obtain an oily N-ethylpyridine methylamine product (shown in a formula 4).
At present, the industrialized post-treatment process is difficult to operate and purify and can only be purified by rectification, under 0.011atm, the boiling point of N-ethylpyridine methylamine is 103 ℃, under 0.005atm, the boiling point of the imine intermediate 3 is 87 ℃, the difference between the boiling points of the two materials is very small, the rectification and purification are difficult, the purification rate and the yield are not high, especially, the rectification energy consumption and the loss are large, and the cost is high; and N-ethylpyridine methylamine is an amine compound, is an organic base, is unstable after being stored for a long time, and is easily oxidized particularly during high-temperature rectification, so that the product purity is further reduced, and impurities are increased. Therefore, the commercial product prepared by the process usually contains more imine intermediates 3 and other related impurities, the purity is lower and generally does not exceed 95%, but as seen from the synthetic route of tropicamide, N-ethylpyridine methylamine is a key starting material of a key reaction step reported by a bulk drug product, and the quality and the purity of the N-ethylpyridine methylamine are directly related to the quality and the purity of the bulk drug product. Under the trend that the requirements of the current national policy on raw material medicines are more and more strict, the N-ethylpyridine methylamine with low purity hardly meets the market demand.
The oily N-ethylpyridine methylamine has high viscosity, and is difficult to transfer, split-package, store, transport and other operations, and the volatile unpleasant odor of organic amines is not friendly to workers in workshop operation, besides, the volatilized amine substances are easy to form smog urea derivative solids with carbon dioxide in the air, and the smog urea derivative solids are easy to block pipelines under the condition of airflow while polluting products, so that unnecessary accidents are caused, and therefore, the research and development of the high-purity, low-cost, and convenient-to-operate solidified N-ethylpyridine methylamine are significant and necessary;
the common purification method is crystallization, but N-ethylpyridine methylamine has a low melting point and is not suitable for crystallization, and the salt formation of the free base and acid is an effective means for solidification and purification considering that N-ethylpyridine methylamine is a free base per se. Therefore, the development of a salt forming method, which is simple in purification, better in stability and more environment-friendly, of the salt form of the starting material is a necessary trend.
Disclosure of Invention
The invention aims to provide mesylate of tropicamide key starting material N-ethylpyridine methylamine and a crystal form thereof, wherein N-ethylpyridine methylamine alkalescence is utilized to react with methanesulfonic acid to generate an N-ethylpyridine methylamine mesylate crystal with excellent stability, the crystal is a solid with good granularity, does not have unpleasant smell of organic amine which is volatile and is extremely unfriendly to workshop operators, does not have irritation of methanesulfonic acid, has good powder fluidity, is convenient to transfer, subpackage, store, transport and the like, and particularly does not generate smog solids which are easy to generate when liquid N-ethylpyridine methylamine is fed in a solid feeding process, further pollutes products and blocks pipelines, and the crystal is difficult to absorb moisture and is stable to store for a long time.
The N-ethylpyridine methylamine after salt formation has excellent impurity removal effect, the purity and yield of N-ethylpyridine methylamine methanesulfonate are high, as shown in an HPLC spectrogram in figure 1, the purity and yield of commercially available N-ethylpyridine methylamine (on figure 1) are higher than 10 at 254nm, the total product purity is less than 95.0%, the commercially available N-ethylpyridine methylamine contains more imine intermediates 3 and other organic impurities similar to the product structure, and the impurities are difficult to remove through conventional purification means and rectification, after the N-ethylpyridine methylamine is converted into the methanesulfonate, the purity of crystals (on figure 1) is higher than 99.95%, the purity is high, the impurity content is low, the product purification yield is higher than 95%, the purification of N-ethylpyridine methylamine after salt formation can greatly reduce energy consumption, the product purity is improved, the product cost is reduced, the competitiveness of the product is improved, and by controlling the quality and purity of key starting materials, the quality and purity of the raw material medicine of tropicamide can be effectively improved, so that the N-ethylpyridine methylamine mesylate is the optimal choice for purifying the N-ethylpyridine methylamine.
The invention also aims to provide a preparation process of the tropicamide key starting material N-ethylpyridine methylamine methanesulfonate crystal, which has the advantages of simple operation, no need of large energy consumption operation such as distillation and refining, room temperature availability of a stable crystal form, convenient operation and suitability for large-scale industrial production and preparation.
In order to achieve the purpose, the invention adopts the technical scheme that:
a tropicamide key starting material N-ethylpyridine methylamine mesylate is prepared by dissolving tropicamide key starting material N-ethylpyridine methylamine in an organic solvent, dropwise adding methanesulfonic acid, filtering and drying to obtain N-ethylpyridine methylamine mesylate, wherein the preparation route is shown as formula 5:
the structural formula of the obtained tropicamide key starting material N-ethylpyridine methylamine mesylate is shown as a formula 6:
a crystal of tropicamide key starting material N-ethylpyridine methanamine mesylate, which crystal has diffraction peaks at about 9.49 °, 13.16 °, 16.18 °, 19.10 °, 20.54 °, 23.24 °, 26.96 °, 34.63 ° using X-ray powder diffraction; further, using X-ray powder diffraction, said crystal has diffraction peaks at about 9.49 °, 13.16 °, 16.18 °, 17.88 °, 19.10 °, 20.54 °, 21.34 °, 23.24 °, 25.12 °, 26.96 °, 34.63 °; more specifically, a typical example of the crystal of tropicamide key starting material, N-ethylpyridine methylamine mesylate, of the present invention has an XRD pattern as shown in the following figure, which is characterized by table 1.
Table 1:
| 2-Theta | d(A) | Height | I％ | Area | I％ | FWHM |
| 6.550 | 13.4834 | 503 | 2.3 | 3106 | 1.7 | 0.176 |
| 8.888 | 9.9410 | 1085 | 4.9 | 9584 | 5.3 | 0.197 |
| 9.491 | 9.3112 | 21944 | 100.0 | 181745 | 100.0 | 0.141 |
| 12.134 | 7.2877 | 842 | 3.8 | 4823 | 2.7 | 0.125 |
| 13.163 | 6.7207 | 3227 | 14.7 | 27659 | 15.2 | 0.152 |
| 16.180 | 5.4736 | 9324 | 42.5 | 65592 | 36.1 | 0.120 |
| 17.879 | 4.9569 | 2008 | 9.2 | 16838 | 9.3 | 0.155 |
| 19.102 | 4.6423 | 1183 | 5.4 | 10299 | 5.7 | 0.176 |
| 19.635 | 4.5174 | 856 | 3.9 | 14552 | 8.0 | 0.382 |
| 20.544 | 4.3195 | 3600 | 16.4 | 26276 | 14.5 | 0.131 |
| 21.335 | 4.1613 | 1974 | 9.0 | 13481 | 7.4 | 0.134 |
| 21.851 | 4.0641 | 704 | 3.2 | 2528 | 1.4 | 0.099 |
| 22.395 | 3.9666 | 1088 | 5.0 | 7381 | 4.1 | 0.142 |
| 23.235 | 3.8251 | 781 | 3.6 | 22121 | 12.2 | 0.667 |
| 23.285 | 3.8169 | 958 | 4.4 | 6369 | 3.5 | 0.146 |
| 23.899 | 3.7203 | 1045 | 4.8 | 7952 | 4.4 | 0.172 |
| 24.481 | 3.6331 | 936 | 4.3 | 10099 | 5.6 | 0.261 |
| 25.122 | 3.5419 | 3244 | 14.8 | 40498 | 22.3 | 0.227 |
| 25.792 | 3.4513 | 799 | 3.6 | 5185 | 2.9 | 0.167 |
| 26.960 | 3.3044 | 1424 | 6.5 | 12870 | 7.1 | 0.175 |
| 28.811 | 3.0962 | 764 | 3.5 | 9373 | 5.2 | 0.268 |
| 30.018 | 2.9744 | 423 | 1.9 | 3328 | 1.8 | 0.232 |
| 30.767 | 2.9037 | 455 | 2.1 | 2836 | 1.6 | 0.172 |
| 32.684 | 2.7376 | 433 | 2.0 | 2556 | 1.4 | 0.159 |
| 33.310 | 2.6876 | 514 | 2.3 | 4796 | 2.6 | 0.235 |
| 34.633 | 2.5879 | 1358 | 6.2 | 14218 | 7.8 | 0.200 |
| 37.198 | 2.4151 | 318 | 1.4 | 1349 | 0.7 | 0.173 |
| 37.807 | 2.3776 | 764 | 3.5 | 5223 | 2.9 | 0.152 |
| 39.463 | 2.2815 | 295 | 1.3 | 1706 | 0.9 | 0.212 |
| 40.950 | 2.2021 | 490 | 2.2 | 2884 | 1.6 | 0.147 |
| 41.835 | 2.1575 | 488 | 2.2 | 2994 | 1.6 | 0.152 |
| 42.504 | 2.1251 | 302 | 1.4 | 2103 | 1.2 | 0.228 |
| 43.556 | 2.0762 | 268 | 1.2 | 1595 | 0.9 | 0.214 |
the preparation method of the tropicamide key starting material N-ethylpyridine methylamine methanesulfonate crystal comprises the following steps:
1) dissolving tropicamide key starting material N-ethylpyridine methylamine in an organic solvent, heating at room temperature or heating, and stirring until the material is completely dissolved;
2) slowly adding methanesulfonic acid, and crystallizing;
3) preserving heat, aging, filtering and drying to obtain the tropicamide key starting material N-ethyl pyridine methylamine methanesulfonate crystal.
The acid used is methanesulfonic acid, or a solution of methanesulfonic acid in an organic solvent.
The organic solvent is an alcohol or ester solvent and other organic solvents, including acetonitrile, dichloromethane and the like, and the alcohol is one or more of C1-C4 alcohols.
And (3) a crystallization process: adding N-ethylpyridylmethylamine into an organic solvent, stirring at room temperature (heating to clear if necessary), then dropwise adding methanesulfonic acid, precipitating solids, stirring for 1-5 hours (adding seed crystals and carrying out gradient cooling to 0[ ZZ1] if necessary), filtering, and leaching with a small amount of organic solvent. Drying to obtain N-ethylpyridine methylamine methanesulfonate crystal.
According to the invention, salt formation is carried out on the weak alkaline N-ethylpyridine methylamine and methanesulfonic acid, so that large-energy-consumption operation and loss such as distillation and purification are avoided, a mesylate crystal form of the tropicamide key starting material N-ethylpyridine methylamine is successfully developed, the crystal form is regular and uniform, the impurity content is low, the purity is good, the yield is high, the salt form is not easy to damp, the crystal form is stable after long-time storage, and the crystal form is characterized.
The salt form and the crystal form of the invention are reported for the first time.
Has the advantages that: the method for preparing the tropicamide key starting material N-ethylpyridine methylamine methanesulfonate crystal has the advantages of simple operation, obvious purification effect, low content of salt type and crystal type impurities obtained by crystallization preparation, high purity and contribution to industrial production.
Drawings
FIG. 1: HPLC spectra of N-ethylpyridyl methylamine mesylate and commercially available N-ethylpyridyl methylamine;
FIG. 2: an XRD spectrum of N-ethylpyridyl methylamine mesylate;
FIG. 3: HPLC chromatogram of N-ethylpyridine methylamine mesylate.
Detailed Description
The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention. The following example prepared the key starting material, N-ethylpyridylmethylamine mesylate, of tropicamide using the synthetic route shown in formula 7.
Example 1
Preparation of compound 1: adding 157.8g (1.4mol) of 4-pyridineformaldehyde and 2000mL of anhydrous ethanol into a 5000mL three-necked flask, stirring at room temperature to obtain a clear solution, controlling the temperature to be 0-10 ℃ by an ice-water bath, dropwise adding 214.6g (1.5mol) of 66% aqueous solution of ethylamine, finishing the dropwise addition, reacting for 1-2 hours, controlling the TLC point plate in a central manner, determining that the reaction is complete when the point of the raw material disappears, slowly adding 58.5g (1.5mol) of sodium borohydride in batches, finishing the addition, controlling the temperature to be 10-25 ℃, reacting for 1-2 hours, dropwise adding 300mL of purified water, stirring at room temperature overnight, controlling the TLC in a central manner, after the reaction is complete, carrying out vacuum concentration to remove the solvent, adding 2000mL of water, extracting with 2000mL of dichloromethane, washing the organic phase with 1500mL of saturated salt water, drying with anhydrous sodium sulfate, filtering, carrying out vacuum concentration on the filtrate to obtain 192.5g of dark yellow oily matter which, the crude product yield was 96.3%.
50.2g of the crude product was further distilled under reduced pressure to give 28.1g of a pale yellow oily substance as a pure N-ethylpyridinemethylamine product having a purity of 94.8% and a distillation yield of 56.2%.
Example 2
Preparation of compound 2: 4.03g (0.03mol) of pure N-ethylpyridine methylamine and 30mL of isopropanol are added into a 50mL three-necked bottle, a light yellow clear solution is obtained by stirring at room temperature, 3.41g (0.036mol) of methanesulfonic acid is slowly dripped, the mixture is stirred at room temperature for 1-5 hours, the filtration is carried out, a filter cake is washed by acetonitrile and dried in vacuum, and 6.32g of white crystals are obtained, the purity is 99.95 percent, and the yield is 92.0 percent.
Example 3
Preparation of compound 2: 4.02g (0.03mol) of pure N-ethylpyridine methylamine and 30mL of ethyl acetate are added into a 50mL three-necked flask, a light yellow clear solution is obtained by stirring at room temperature, 3.39g (0.036mol) of methanesulfonic acid is slowly dripped, the mixture is stirred at room temperature for 1-5 hours, the mixture is filtered, a filter cake is washed by acetonitrile and dried in vacuum, and 6.41g of white crystals with the purity of 99.52 percent and the yield of 93.3 percent are obtained, and the obtained crystals have the XRD pattern shown in figure 2 and have the characteristics shown in Table 1.
Example 4
Preparation of compound 2: adding 10.2g N-ethylpyridine methylamine crude product and 70mL acetonitrile into a 100mL three-necked bottle, stirring at room temperature for 1 hour, heating to 50 ℃ to obtain a yellow clear solution, slowly dropwise adding 8.1g of methanesulfonic acid, stirring for 1-5 hours, gradient cooling to room temperature, stirring for 1-3 hours, cooling to 0-5 ℃, stirring for 2-5 hours, filtering, washing a filter cake with methyl tert-butyl ether, and vacuum drying to obtain 14.2g of white crystals with the purity of 99.32%, wherein the yield is as follows: 83.3 percent.
Example 5
Preparation of tropicamide (compound 7): adding 20.4g (0.123mol) of tropine acid (compound 4) and 50mL of toluene into a 250mL three-necked bottle, heating to 50 ℃, adding 0.3g (0.003mol) of triethylamine, dropwise adding 19.0g (0.24mol) of acetyl chloride, reacting at 50 ℃ for 3 hours, dropwise adding 20.5g (0.17mol) of thionyl chloride, continuing to react for 5 hours, concentrating in vacuum to a small volume, adding 50mL of toluene, and cooling to room temperature; in another 500mL three-necked flask, 18.2g (0.134mol) of pure N-ethylpyridylamine (Compound 1),13.7g (0.136mol) of triethylamine and 100mL of toluene were placed, the mixture was cooled to 0 ℃, a solution of acetyltropine acid was added dropwise, the mixture was reacted at 0-10 ℃ overnight, 80mL of saturated saline was added and washed five times, 27g (0.23mol) of 31% hydrochloric acid was added to the organic phase, the mixture was heated to 90 ℃ and reacted overnight, the organic phase was separated, the mixture was washed with aqueous ammonia, dilute hydrochloric acid, saturated saline and purified water, the organic phase was concentrated under vacuum at 50 ℃, the concentrate was recrystallized from ethyl acetate/N-heptane, the cake was washed with N-heptane and dried under vacuum to obtain 26.5g of tropine amide with 98.8% purity and 75.9% yield.
Example 6
Preparation of tropicamide (compound 7): adding 11.6g (0.07mol) of tropine acid (compound 4) and 50mL of toluene into a 250mL three-necked bottle, heating to 50 ℃, adding 0.2g (0.002mol) of triethylamine, dropwise adding 11.0g (0.14mol) of acetyl chloride, reacting at 50 ℃ for 3 hours, dropwise adding 11.5g (0.10mol) of thionyl chloride, continuing to react for 5 hours, concentrating in vacuum to a small volume, adding 50mL of toluene, and cooling to room temperature; in another 500mL three-necked flask, 16.24g (0.07mol) of N-ethylpyridine methylamine methanesulfonate (Compound 2),7.05g (0.07mol) of triethylamine and 60mL of toluene were placed, the mixture was cooled to 0 ℃ and a solution of acetyltropine acid was added dropwise, the mixture was reacted at 0 to 10 ℃ overnight, 50mL of a saturated saline solution was added thereto and washed five times, 16.5g (0.14mol) of 31% hydrochloric acid was added to the organic phase, the mixture was heated to 90 ℃ and reacted overnight, the organic phase was separated, the separated liquid was washed with aqueous ammonia, dilute hydrochloric acid, a saturated saline solution and purified water, the organic phase was concentrated under vacuum at 50 ℃ and recrystallized from ethyl acetate/N-heptane, the cake was washed with N-heptane and dried under vacuum to obtain 17.5g of tropine amide with a purity of 99.4% and a yield of 88.2%.
Claims (9)
- N-ethylpyridine methylamine mesylate, which is characterized in that: the N-ethylpyridine methylamine mesylate is prepared from N-ethylpyridine methylamine and methanesulfonic acid, and has the following structural formula:。
- n-ethylpyridine methylamine mesylate crystals, which are characterized in that: using X-ray powder diffraction, the crystals had diffraction peaks at about 9.49 °, 13.16 °, 16.18 °, 19.10 °, 20.54 °, 23.24 °, 26.96 °, 34.63 °.
- 3. N-ethylpyridine methanamine methanesulfonate crystal according to claim 2, characterized in that: using X-ray powder diffraction, the crystal had diffraction peaks at about 9.49 °, 13.16 °, 16.18 °, 17.88 °, 19.10 °, 20.54 °, 21.34 °, 23.24 °, 25.12 °, 26.96 °, 34.63 °.
- 4. A process for producing N-ethylpyridine methylamine methanesulfonate crystal as claimed in claim 2 or 3, characterized in that:dissolving N-ethylpyridine methylamine in organic solvent, and stirring at room temperature or under heating until the materials are completely dissolved;slowly adding acid, and crystallizing;preserving heat, aging, filtering and drying to obtain the N-ethylpyridine methylamine mesylate crystal.
- 5. The process according to claim 4, characterized in that: the acid is methanesulfonic acid or a solution of methanesulfonic acid in an organic solvent.
- 6. The process according to claim 4, characterized in that: the organic solvent is an alcohol or ester solvent.
- 7. The process according to claim 4, characterized in that: the weight ratio of the N-ethylpyridine methylamine to the organic solvent is 1:2 to 1: 20.
- 8. The process according to claim 4, characterized in that: the dosage of the methanesulfonic acid is 0.5-1.5 mol equivalent of the N-ethylpyridine methylamine.
- 9. Use of the crystal of N-ethylpyridine methylamine mesylate according to any one of claims 1 to 3 for the preparation of tropicamide.
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| CN112592312A (en) * | 2020-12-23 | 2021-04-02 | 无锡济煜山禾药业股份有限公司 | Preparation method of tropicamide |
| KR102662895B1 (en) | 2022-01-04 | 2024-05-03 | 주식회사 한서켐 | Method for preparing high purity tropicamide |
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| GB728579A (en) * | 1952-10-24 | 1955-04-20 | Roche Products Ltd | Novel tropic acid n-substituted-n-(ª†-picolyl)-amides and process for the manufacture thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112592312A (en) * | 2020-12-23 | 2021-04-02 | 无锡济煜山禾药业股份有限公司 | Preparation method of tropicamide |
| KR102662895B1 (en) | 2022-01-04 | 2024-05-03 | 주식회사 한서켐 | Method for preparing high purity tropicamide |
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