CN115353465A - Synthesis method of neostigmine methylsulfate - Google Patents
Synthesis method of neostigmine methylsulfate Download PDFInfo
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- CN115353465A CN115353465A CN202211302439.0A CN202211302439A CN115353465A CN 115353465 A CN115353465 A CN 115353465A CN 202211302439 A CN202211302439 A CN 202211302439A CN 115353465 A CN115353465 A CN 115353465A
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- OSZNNLWOYWAHSS-UHFFFAOYSA-M neostigmine methyl sulfate Chemical compound COS([O-])(=O)=O.CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 OSZNNLWOYWAHSS-UHFFFAOYSA-M 0.000 title claims abstract description 9
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 229960002253 neostigmine methylsulfate Drugs 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 32
- 229940126214 compound 3 Drugs 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 229940125904 compound 1 Drugs 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 22
- 229940125782 compound 2 Drugs 0.000 claims description 20
- 229960002362 neostigmine Drugs 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 19
- 125000006239 protecting group Chemical group 0.000 claims description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 16
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 14
- 239000011230 binding agent Substances 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 claims description 7
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- -1 9-fluorenylmethyloxycarbonyl Chemical group 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 4
- 239000012022 methylating agents Substances 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000011987 methylation Effects 0.000 claims description 3
- 238000007069 methylation reaction Methods 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 239000002516 radical scavenger Substances 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 2
- 229940102396 methyl bromide Drugs 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- ALWKGYPQUAPLQC-UHFFFAOYSA-N neostigmine Chemical compound CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 ALWKGYPQUAPLQC-UHFFFAOYSA-N 0.000 claims 6
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000047 product Substances 0.000 description 40
- 238000001914 filtration Methods 0.000 description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- LULNWZDBKTWDGK-UHFFFAOYSA-M neostigmine bromide Chemical compound [Br-].CN(C)C(=O)OC1=CC=CC([N+](C)(C)C)=C1 LULNWZDBKTWDGK-UHFFFAOYSA-M 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 12
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical compound NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- 238000001291 vacuum drying Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 229940018563 3-aminophenol Drugs 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 229910017053 inorganic salt Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000009615 deamination Effects 0.000 description 2
- 238000006481 deamination reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- LKEQZFMJKLCAEA-UHFFFAOYSA-N (3-aminophenyl) n,n-dimethylcarbamate Chemical compound CN(C)C(=O)OC1=CC=CC(N)=C1 LKEQZFMJKLCAEA-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- 206010046555 Urinary retention Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940048961 cholinesterase Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000000718 cholinopositive effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-N methyl sulfate Chemical compound COS(O)(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001611 motor endplate Anatomy 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000003156 neuromuscular nondepolarizing agent Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- HJQNVUQTARSZDK-UHFFFAOYSA-N tert-butyl n-(3-hydroxyphenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(O)=C1 HJQNVUQTARSZDK-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/24—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfuric acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a synthesis method of neostigmine methosulfate, which comprises the following steps,the synthesis method has the advantages of simple process, short reaction time, high efficiency, high yield, mild reaction conditions and low cost, and is suitable for industrial productionAnd (4) large-scale production.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthesis method of neostigmine mesylate.
Background
Neostigmine mesylate is an injection of neostigmine. The indications are anticholinesterase drugs. Antagonize residual muscle relaxation effect of non-depolarizing muscle relaxants at the end of surgery, and can be used for myasthenia gravis, functional intestinal distention and urinary retention after surgery, etc. The product can inhibit cholinesterase activity to exert cholinomimetic effect, and can directly stimulate nicotinic receptor (N2 receptor) on skeletal muscle motor end plate. The medicine has the advantages of weak effect on gland, eye, cardiovascular and bronchial smooth muscle, capability of promoting gastric contraction and increasing gastric acid secretion on gastrointestinal smooth muscle, and capability of promoting peristalsis of small intestine and large intestine, especially colon, thereby preventing intestinal canal from relaxing and promoting intestinal contents to push downwards. It has strong exciting action on skeletal muscle but weak action on central nervous system.
The preparation process of neostigmine mesylate is reported IN indian patent IN1078MUM2014A, the route of which is briefly described below.
When two methyl groups on dimethyl sulfate are utilized on aniline in the reaction of step 1 in the scheme of the patent documents, the reaction is easy to stay in an intermediate state, namely a byproduct generated when one methyl group is on an amino group, the reaction is slow, quaternary ammonium salt is easy to generate at the end point of the reaction, the product yield is low, and the purification difficulty is high. In the 3 rd step of the route, alkali is not used as an acid-binding agent, the reaction is slow, and the by-product obtained after methylation of dimethyl sulfate is strong in acidity, so that problems such as hydrolysis of neostigmine methylsulfate and the like are easily caused. The method has the advantages of low reaction yield, high purification difficulty and high risk of subsequent industrial amplification.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a method for synthesizing neostigmine mesylate.
The application provides a preparation method of neostigmine mesylate, which comprises the following synthetic route:
the synthesis method has the advantages of simple process, short reaction time, high efficiency, high yield, mild reaction conditions and low cost, and is suitable for industrial scale-up production. The quality of the prepared neostigmine mesylate completely meets the requirements of pharmacopoeia, and the quality and the medication safety of the medicine can be ensured.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 1.
Fig. 2 is a carbon spectrum of compound 1.
FIG. 3 is a substance diagram of Compound 1.
FIG. 4 is a hydrogen spectrum of Compound 2.
Fig. 5 is a carbon spectrum of compound 2.
FIG. 6 is a substance diagram of Compound 2.
FIG. 7 is a hydrogen spectrum of Compound 3.
Fig. 8 is a carbon spectrum of compound 3.
FIG. 9 shows the substance pattern of Compound 3.
FIG. 10 is a hydrogen spectrum of Compound 4.
FIG. 11 is a carbon spectrum of Compound 4.
FIG. 12 is a substance diagram of Compound 4.
Detailed Description
In order to make the technical solution and advantages of the present invention more comprehensible, a detailed description is given below by way of specific examples.
In one aspect, the present application provides a method for preparing neostigmine mesylate, comprising the following synthetic route:
wherein PG is an amino protecting group;
reacting the compound 1 with dimethylamino formyl chloride, an acid-binding agent and a catalyst in the step 1 to obtain a compound 2;
in the step 2, a compound 2 is subjected to deamination Protecting Group (PG) to obtain a compound 3;
and (4) reacting the compound 3 with a methylation reagent and an acid-binding agent in the step (3) to obtain a compound 4.
In some embodiments, the PG is selected from the group consisting of alkoxycarbonyl protecting groups, acyl protecting groups, and alkyl protecting groups, such as benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc).
In some embodiments, the catalyst in step 1 is selected from one or more of 4-dimethylaminopyridine, pyridine, and imidazole.
In some embodiments, an acid is added to remove the protecting group in step 2, for example, the acid added is concentrated hydrochloric acid, ethanolic hydrogen chloride solution, ethyl acetate hydrogen chloride solution.
In some embodiments, the methylating agent in step 3 is selected from one or more of dimethyl sulfate, methyl iodide and methyl bromide.
In some embodiments, the method for preparing neostigmine mesylate comprises the following synthetic route:
wherein PG is tert-butyloxycarbonyl (Boc);
reacting the compound 1 with dimethylcarbamoyl chloride, an acid-binding agent and 4-dimethylaminopyridine in the step 1 to obtain a compound 2;
in the step 2, a compound 2 is subjected to deamination Protecting Group (PG) to obtain a compound 3;
and 3, reacting the compound 3 with dimethyl sulfate and an acid-binding agent to obtain a compound 4.
In some embodiments, the molar ratio of compound 1 to catalyst in step 1 is 1 (0.1-0.5), such as 1.
In some embodiments, the molar ratio of compound 1 to 4-dimethylaminopyridine in step 1 is 1 (0.1-0.5), such as 1.
In some embodiments, the molar ratio of compound 1 to acid scavenger in step 1 is 1: (1.0-2.0), for example 1: 1.0, 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6, 1: 1.7, 1: 1.8, 1: 1.9, 1: 2.0.
In some embodiments, the molar ratio of compound 2 to acid in step 2 is 1 (0.6-1.5), e.g., 1: 0.6, 1: 0.7, 1: 0.8, 1: 0.9, 1: 1.0, 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5.
In some embodiments, the reaction temperature in step 2 is 0-50 ℃, preferably 30 ℃.
In some embodiments, the molar ratio of compound 3 to methylating agent in step 3 is 1 (3.0-5.0), such as 1.
In some embodiments, the molar ratio of compound 3 to dimethyl sulfate in step 3 is 1 (3.0-5.0), such as 1.
In some embodiments, the molar ratio of compound 3 to acid scavenger in step 3 is 1: (2.0-4.0), such as 1.
In some embodiments, the reaction temperature in step 3 is 20 to 60 ℃, preferably 40 ℃.
In some embodiments, the acid-binding agent includes an organic or inorganic base, which is used to neutralize the acid generated in the reaction system and promote the forward reaction, and may be one or more selected from triethylamine, DIEA, pyridine, sodium acetate, sodium carbonate, potassium carbonate, and calcium carbonate.
In some embodiments, the acid-binding agent in step 1 is selected from bases capable of reacting with HCl generated in step 1, such as one or more of sodium carbonate, potassium carbonate, triethylamine, DIEA, pyridine, sodium acetate, calcium carbonate, preferably one or more of sodium carbonate, potassium carbonate, and triethylamine.
In some embodiments, the acid-binding agent in step 3 is selected from a base capable of reacting with sulfuric acid or methylsulfuric acid generated in step 3, such as one or more of sodium carbonate, potassium carbonate, calcium carbonate, triethylamine, DIEA, pyridine, and sodium acetate, preferably one or more of sodium carbonate, potassium carbonate, and calcium carbonate.
In some embodiments, the compound 1 is obtained by introducing an amino Protecting Group (PG) through m-aminophenol
In some embodiments, m-aminophenol is reacted with a BOC anhydride (di-tert-butyl dicarbonate) to provide compound 1.
In some embodiments, the molar ratio of m-aminophenol to BOC anhydride is 1 (1.0-1.5), such as 1: 1.0, 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5.
In some embodiments, the step 1 intermediate aminophenol is reacted with the BOC anhydride at a temperature of 30 to 70 ℃, preferably 50 ℃.
In some embodiments, the BOC anhydride is added dropwise into the reaction system in step 1.
Preparation of Compound 1 (tert-butyl 3-Hydroxyphenylcarbamate)
Example 1:
adding 50.0g (about 0.46 mol) of m-aminophenol and 250ml of ethyl acetate into a 1000ml reaction bottle, heating to 30 ℃, slowly adding 100.0g (about 0.46 mol) of BOC acid anhydride dropwise, keeping the temperature at 50 ℃ for reaction for 3 hours after the dropwise addition is finished, concentrating under reduced pressure by using a rotary evaporator to obtain an oily substance, adding 250ml of n-heptane, keeping the temperature at 50 ℃ for crystallization for 1 hour, cooling to room temperature, filtering to obtain a wet product of the compound 1, drying the wet product in vacuum at 50 ℃ for 4 hours to obtain 88.2g of the compound 1 totally, wherein the HPLC purity is more than 99.5%.
Example 2:
adding 50.0g (about 0.46 mol) of m-aminophenol and 250ml of ethyl acetate into a 1000ml reaction bottle, heating to 30 ℃, slowly adding 150.0g (about 0.69 mol) of BOC anhydride dropwise, keeping the temperature at 50 ℃ for reaction for 3 hours after the dropwise addition is finished, concentrating the mixture into oily matter under reduced pressure by using a rotary evaporator, adding 250ml of n-heptane, keeping the temperature at 50 ℃ for crystallization for 1 hour, cooling to room temperature, filtering to obtain a wet product of the compound 1, drying the wet product in vacuum at 50 ℃ for 4 hours to obtain 93.0g of the compound 1 totally, wherein the HPLC purity is more than 99.5%.
The hydrogen spectrogram, the carbon spectrogram and the related substance chart of the compound 1 prepared by the application are respectively shown in figures 1 to 3.
Preparation of compound 2 (3- ((tert-butoxycarbonyl) amino) phenyl dimethylcarbamate)
Example 3:
80.0g (about 0.38 mol) of the compound 1, 9.1g (about 0.076 mol) of 4-dimethylaminopyridine, 58.0g (about 0.57 mol) of triethylamine and 500ml of ethyl acetate are added into a 1000ml reaction bottle, the temperature is reduced to 10 ℃, 61.7g (about 0.57 mol) of dimethylcarbamoyl chloride is slowly dripped, the dripping is finished, the temperature is kept at 10 ℃ for reaction for 12 hours, the temperature is reduced to-10 ℃, white wet products are obtained by filtration, the wet products are beaten for 1 hour by 500ml of purified water, the wet products of the compound 2 are obtained by filtration, the wet products are placed at 50 ℃ for vacuum drying for 8 hours, the total 101.8g of the compound 1 is obtained, and the HPLC purity is more than 99.8 percent.
Example 4:
adding 80.0g (about 0.38 mol) of the compound 1, 9.1g (about 0.076 mol) of 4-dimethylaminopyridine, 58.0g (about 0.57 mol) of triethylamine and 500ml of ethyl acetate into a 1000ml reaction bottle, cooling to 10 ℃, slowly adding 61.7g (about 0.57 mol) of dimethylcarbamoyl chloride dropwise, keeping the temperature for 10 ℃ for reaction for 12 hours, cooling to 0 ℃, filtering to obtain a white wet product, pulping the wet product with 500ml of purified water for 1 hour, filtering to obtain a compound 2 wet product, placing the wet product at 50 ℃ for vacuum drying for 8 hours to obtain 91.2g of the compound 1 totally, wherein the HPLC purity is more than 99.8 percent.
Example 5:
adding 80.0g (about 0.38 mol) of compound 1, 9.1g (about 0.076 mol) of 4-dimethylaminopyridine, 30.4g (about 0.29 mol) of sodium carbonate and 500ml of ethyl acetate into a 1000ml reaction bottle, cooling to 10 ℃, slowly adding 61.7g (about 0.57 mol) of dimethylcarbamoyl chloride dropwise, keeping the temperature for 10 ℃ for reaction for 24 hours, cooling to-10 ℃, filtering to obtain a white wet product, pulping the wet product with 500ml of purified water for 1 hour, filtering to obtain a compound 2 wet product, placing the wet product at 50 ℃ for vacuum drying for 8 hours to obtain 95.2g of compound 1 totally, wherein the HPLC purity is more than 99.8%.
Example 6:
adding 80.0g (about 0.38 mol) of the compound 1, 9.1g of 4-dimethylaminopyridine (about 0.076 mol), 39.6g of potassium carbonate (about 0.29 mol) and 500ml of ethyl acetate into a 1000ml reaction bottle, cooling to 10 ℃, slowly adding 61.7g (about 0.57 mol) of dimethylcarbamoyl chloride dropwise, keeping the temperature for 10 ℃ for reaction for 24 hours, cooling to-10 ℃, filtering to obtain a white wet product, pulping the wet product for 1 hour by using 500ml of purified water, filtering to obtain a compound 2 wet product, placing the wet product at 50 ℃ for vacuum drying for 8 hours to obtain 75.5g of the compound 1 in total, wherein the HPLC purity is more than 99.8%.
The hydrogen spectrogram, the carbon spectrogram and the related substance chart of the compound 2 prepared by the application are respectively shown in figures 4-6.
Preparation of Compound 3 (3-aminophenyldimethylcarbamate)
Example 7:
a500 ml reaction flask was charged with 60.0g (about 0.21 mol) of Compound 2 and 300ml of ethyl acetate, heated to 30 ℃ and added with 36.0g of an ethanol solution of hydrogen chloride (concentration: 8 mol/L) dropwise, reacted at 30 ℃ for 6 hours, and then neutralized and separated with a 20% sodium carbonate solution. Separating out an organic phase, concentrating the organic phase into oily matter by using a rotary evaporator under reduced pressure, adding 300ml of n-heptane into the oily matter, crystallizing the oily matter for 1 hour, filtering the oily matter to obtain a wet product of the compound 3, placing the wet product at 50 ℃ and drying the wet product in vacuum for 4 hours to obtain the compound 3, wherein the total mass is 36.6g, and the HPLC purity is more than 99.9%.
Example 8:
adding 60.0g (about 0.21 mol) of compound 2 and 100ml of absolute ethyl alcohol into a 1000ml reaction bottle, heating to 30 ℃, dropwise adding 36.0g of hydrogen chloride ethanol solution (the concentration is 8 mol/L), reacting for 6 hours at the temperature of 30 ℃, and removing the ethanol by decompression and concentration by a rotary evaporator after the reaction is finished; 300ml of ethyl acetate was added, followed by neutralization with a 20% sodium carbonate solution and liquid separation. Separating out organic phase, concentrating under reduced pressure with rotary evaporator to obtain oily substance, adding 300ml n-heptane into oily substance, crystallizing for 1 hr, filtering to obtain wet product of compound 3, vacuum drying at 50 deg.C for 4 hr to obtain compound 3 with purity of over 99.9% by HPLC (35.6 g).
Example 9:
a1000 ml reaction flask was charged with 60.0g (about 0.21 mol) of Compound 2 and 300ml of ethyl acetate, heated to 30 ℃ and then added with 36.0g of concentrated hydrochloric acid dropwise, after completion of the reaction at 30 ℃ for 6 hours, the reaction mixture was neutralized with a 20% sodium carbonate solution and separated. Separating out organic phase, concentrating under reduced pressure by using a rotary evaporator to obtain oily substance, adding 300ml of n-heptane into the oily substance, crystallizing for 1 hour, filtering to obtain a wet product of the compound 3, placing the wet product at 50 ℃ and drying in vacuum for 4 hours to obtain the compound 3, wherein the total amount of 31.9g and the HPLC purity is more than 99.9%.
Example 10:
a1000 ml reaction flask was charged with 60.0g (about 0.21 mol) of Compound 2 and 100ml of ethyl acetate, the temperature was raised to 30 ℃ and 72.0g of ethyl acetate hydrochloride (concentration: 4 mol/L) was added dropwise thereto, and after completion of the reaction at 30 ℃ for 8 hours, the reaction was terminated and neutralized with a 20% sodium carbonate solution and separated. Separating out organic phase, concentrating under reduced pressure by using a rotary evaporator to obtain oily substance, adding 300ml of n-heptane into the oily substance, crystallizing for 1 hour, filtering to obtain a wet product of the compound 3, placing the wet product at 50 ℃ and drying in vacuum for 4 hours to obtain the compound 3, wherein the total amount of 36.9g and the HPLC purity is more than 99.9%.
The hydrogen spectrogram, the carbon spectrogram and the related substance chart of the compound 3 prepared by the application are respectively shown in figures 7 to 9.
Preparation of Compound 4 (neostigmine Methylsulfate)
Example 11:
a1000 ml reaction flask was charged with 30.0g (about 0.17 mol) of Compound 3, 35.3g (about 0.33 mol) of sodium carbonate, 150ml of acetonitrile, 63.0g (about 0.50 mol) of dimethyl sulfate was added dropwise at 20 ℃ and, after completion of the addition, the temperature was raised to 40 ℃ and the reaction was allowed to proceed for 6 hours. After the reaction is finished, inorganic salt is filtered out, the filtrate is decompressed and concentrated into oily matter by a rotary evaporator, 150ml of ethyl acetate is added for crystallization for 1 hour, wet product is obtained by filtration, the wet product is placed at 50 ℃ for vacuum drying for 4 hours, 50.6g of neostigmine mesylate is obtained, the HPLC purity is more than 99.9 percent, and the single impurity is less than 0.05 percent.
Example 12:
a1000 ml reaction flask was charged with 30.0g (about 0.17 mol) of Compound 3, 35.3g (about 0.33 mol) of sodium carbonate, 150ml of acetonitrile, 105.0.0g (about 0.83 mol) of dimethyl sulfate was added dropwise at 20 ℃ and, after completion of the addition, the temperature was raised to 40 ℃ and the reaction was allowed to proceed for 2 hours. After the reaction is finished, inorganic salt is filtered out, the filtrate is decompressed and concentrated into oily matter by a rotary evaporator, 150ml of ethyl acetate is added for crystallization for 1 hour, wet product is obtained by filtration, the wet product is placed at 50 ℃ for vacuum drying for 4 hours, 53.6g of neostigmine mesylate is obtained, the HPLC purity is more than 99.9 percent, and the single impurity is less than 0.05 percent.
Example 13:
a1000 ml reaction flask was charged with 30.0g (about 0.17 mol) of Compound 3, 35.3g (about 0.33 mol) of sodium carbonate, 150ml of acetone, 105.0.0g (about 0.83 mol) of dimethyl sulfate was added dropwise at 20 ℃ and, after completion of the addition, the temperature was raised to 40 ℃ and the reaction was allowed to proceed for 2 hours. After the reaction is finished, inorganic salt is filtered out, the filtrate is decompressed and concentrated into oily matter by a rotary evaporator, 150ml of ethyl acetate is added for crystallization for 1 hour, wet product is obtained after filtration, the wet product is placed at 50 ℃ for vacuum drying for 4 hours, 45.4g of neostigmine mesylate is obtained, the HPLC purity is 99.9 percent, and the single impurity is less than 0.05 percent.
Example 14:
a1000 ml reaction flask was charged with 30.0g (about 0.17 mol) of Compound 3, 46.0g (about 0.33 mol) of potassium carbonate, 150ml of acetonitrile, 105.0.0g (about 0.83 mol) of dimethyl sulfate was added dropwise at 20 ℃ and, after completion of the addition, the temperature was raised to 40 ℃ and the reaction was allowed to proceed for 2 hours. After the reaction is finished, inorganic salt is filtered out, the filtrate is decompressed and concentrated into oily matter by a rotary evaporator, 150ml of ethyl acetate is added for crystallization for 1 hour, wet product is obtained after filtration, the wet product is placed at 50 ℃ for vacuum drying for 4 hours, 52.7g of neostigmine mesylate is obtained, the HPLC purity is more than 99.9 percent, and the single impurity is less than 0.05 percent.
Example 15:
a1000 ml reaction flask was charged with 30.0g (about 0.17 mol) of Compound 3, 66.6g (about 0.67 mol) of calcium carbonate, 150ml of acetonitrile, 105.0.0g (about 0.83 mol) of dimethyl sulfate was added dropwise at 20 ℃ and, after completion of the addition, the temperature was raised to 40 ℃ and the reaction was allowed to proceed for 2 hours. After the reaction is finished, inorganic salt is filtered out, the filtrate is decompressed and concentrated into oily matter by a rotary evaporator, 150ml of ethyl acetate is added for crystallization for 1 hour, wet product is obtained after filtration, the wet product is placed at 50 ℃ for vacuum drying for 4 hours, 54.7g of neostigmine mesylate is obtained, the HPLC purity is more than 99.9 percent, and the single impurity is less than 0.05 percent.
The hydrogen spectrum, the carbon spectrum and the related substance map of the compound 4 prepared by the application are respectively shown in figures 10-12.
It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations encompassed by the claims. Various modifications and changes may also be made on the basis of the above embodiments without departing from the scope of the present disclosure. Likewise, various features of the above embodiments may also be combined in any combination to form additional embodiments of the invention that may not be explicitly described. Therefore, the above examples only represent some embodiments of the present invention, and do not limit the scope of the present invention.
Claims (10)
1. The preparation method of neostigmine mesylate is characterized by comprising the following synthetic route:
step 1: reacting the compound 1 with dimethylcarbamoyl chloride, an acid-binding agent and a catalyst to obtain a compound 2;
step 2: compound 2 is deaminated to form a compound 3;
and step 3: reacting the compound 3 with a methylation reagent and an acid-binding agent to obtain a compound 4;
the reaction equation is as follows:
wherein PG is an amino protecting group.
2. The process for producing neostigmine methosulfate according to claim 1,
the mol ratio of the compound 1 to the catalyst in the step 1 is 1 (1.0-2.0);
the mol ratio of the compound 1 to the 4-dimethylaminopyridine in the step 1 is 1 (0.1-0.5);
the molar ratio of the compound 1 to the acid-binding agent in the step 1 is 1 (1.0-2.0);
the mol ratio of the compound 3 to the methylating agent in the step 3 is 1 (3.0-5.0);
the molar ratio of the compound 3 to the acid binding agent in the step 3 is 1 (2.0-4.0).
3. A process for preparing neostigmine mesylate according to any one of claims 1 to 2, wherein the catalyst in step 1 is selected from the group consisting of 4-dimethylaminopyridine, pyridine and imidazole.
4. A process for the preparation of neostigmine methosulfate according to any one of claims 1-2, wherein the methylating agent in step 3 is selected from one or more of dimethyl sulfate, methyl iodide and methyl bromide.
5. A process for the preparation of neostigmine methosulfate according to any of claims 1-2, wherein the acid scavenger is selected from one or more of triethylamine, DIEA, pyridine, sodium acetate, sodium carbonate, potassium carbonate and calcium carbonate.
6. The method for preparing neostigmine mesylate according to claim 5, wherein the acid-binding agent in the step 1 is one or more selected from the group consisting of sodium carbonate, potassium carbonate and triethylamine.
7. The method for preparing neostigmine mesylate according to claim 5, wherein the acid-binding agent in the step 3 is one or more selected from sodium carbonate, potassium carbonate and calcium carbonate.
8. A process for the preparation of neostigmine mesylate according to any one of claims 1 to 2, wherein PG is selected from the group consisting of an alkoxycarbonyl protecting group, an acyl protecting group and an alkyl protecting group.
9. A process for preparing neostigmine methosulfate according to claim 8, wherein PG is selected from benzyloxycarbonyl, tert-butoxycarbonyl and 9-fluorenylmethyloxycarbonyl.
10. The method of preparing neostigmine mesylate according to claim 1, wherein an acid is added to remove a protecting group in step 2.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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RU2010130899A (en) * | 2010-07-23 | 2012-01-27 | Федеральное Государственное Учреждение "33 Центральный Научно-Исследовательский Испытательный Институт Министерства Обороны Российск | METHOD FOR PRODUCING NEOSTIGMINE METHYL SULPHATE AND NEOSTIGMINE IODIDE |
WO2017175238A1 (en) * | 2016-04-07 | 2017-10-12 | Neon Laboratories Limited | Highly chemoselective reactions in presence of aromatic amino groups |
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RU2010130899A (en) * | 2010-07-23 | 2012-01-27 | Федеральное Государственное Учреждение "33 Центральный Научно-Исследовательский Испытательный Институт Министерства Обороны Российск | METHOD FOR PRODUCING NEOSTIGMINE METHYL SULPHATE AND NEOSTIGMINE IODIDE |
WO2017175238A1 (en) * | 2016-04-07 | 2017-10-12 | Neon Laboratories Limited | Highly chemoselective reactions in presence of aromatic amino groups |
CN110950780A (en) * | 2019-12-13 | 2020-04-03 | 河南润弘制药股份有限公司 | Neostigmine methylsulfate-like compound, preparation method and application |
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