CN109912568A - A kind of acetal compound, preparation method and the usage - Google Patents
A kind of acetal compound, preparation method and the usage Download PDFInfo
- Publication number
- CN109912568A CN109912568A CN201910123745.XA CN201910123745A CN109912568A CN 109912568 A CN109912568 A CN 109912568A CN 201910123745 A CN201910123745 A CN 201910123745A CN 109912568 A CN109912568 A CN 109912568A
- Authority
- CN
- China
- Prior art keywords
- acetal compound
- preparation
- compound
- acetal
- nucleophilic substitution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 acetal compound Chemical class 0.000 title claims abstract description 167
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 title claims abstract description 100
- 238000002360 preparation method Methods 0.000 title claims abstract description 67
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 60
- 238000006482 condensation reaction Methods 0.000 claims abstract description 39
- 229950003825 vonoprazan Drugs 0.000 claims abstract description 27
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 claims abstract description 26
- 239000012535 impurity Substances 0.000 claims abstract description 19
- 238000002425 crystallisation Methods 0.000 claims abstract description 11
- 230000008025 crystallization Effects 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 71
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- 239000000203 mixture Substances 0.000 claims description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- 239000000047 product Substances 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 34
- 239000002253 acid Substances 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 27
- 239000011230 binding agent Substances 0.000 claims description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- 239000003208 petroleum Substances 0.000 claims description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 238000004809 thin layer chromatography Methods 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 14
- 239000007795 chemical reaction product Substances 0.000 claims description 11
- 230000000269 nucleophilic effect Effects 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 238000011160 research Methods 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 239000002798 polar solvent Substances 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000006073 displacement reaction Methods 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 231100000419 toxicity Toxicity 0.000 claims description 2
- 230000001988 toxicity Effects 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000005457 optimization Methods 0.000 abstract description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 90
- CZRHNFFNQJKGLW-UHFFFAOYSA-N 3-[2-(2-fluorophenyl)pyrrol-1-yl]sulfonylpyridine Chemical compound FC1=C(C=CC=C1)C1=CC=CN1S(=O)(=O)C=1C=NC=CC=1 CZRHNFFNQJKGLW-UHFFFAOYSA-N 0.000 description 32
- 239000003463 adsorbent Substances 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000012141 concentrate Substances 0.000 description 13
- 238000000926 separation method Methods 0.000 description 13
- 238000010792 warming Methods 0.000 description 13
- HOMDJHGZAAKUQV-UHFFFAOYSA-N 1-(propoxymethoxy)propane Chemical compound CCCOCOCCC HOMDJHGZAAKUQV-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 150000003233 pyrroles Chemical class 0.000 description 9
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- 206010011224 Cough Diseases 0.000 description 7
- 150000001241 acetals Chemical class 0.000 description 7
- 150000001299 aldehydes Chemical class 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 230000007674 genetic toxicity Effects 0.000 description 4
- 231100000025 genetic toxicology Toxicity 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229940126409 proton pump inhibitor Drugs 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- MQULPEUCGKEHEG-UHFFFAOYSA-N 5-(2-fluorophenyl)-1h-pyrrole-3-carbaldehyde Chemical compound FC1=CC=CC=C1C1=CC(C=O)=CN1 MQULPEUCGKEHEG-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 241001585714 Nola Species 0.000 description 3
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 3
- 108010083204 Proton Pumps Proteins 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 102000019057 Cytochrome P-450 CYP2C19 Human genes 0.000 description 2
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 2
- 206010063655 Erosive oesophagitis Diseases 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 229960003174 lansoprazole Drugs 0.000 description 2
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 208000010470 Ageusia Diseases 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the acetal compound impurity that drug field more particularly to a kind of Wo Nuolazan intermediate during preparing Vonoprazan fumarate generate, and preparation method thereof.The preparation method of the acetal compound specifically includes that nucleophilic substitution, forms nucleophilic substitution product, and and then cool down crystallization, and alkylol is then added and carries out condensation reaction, can the acetal compound.By choosing different nucleophilic substitution raw material and alkylol, it can be obtained by required acetal compound, preparation method of the invention is simple and efficient, preparation condition is mild, there is no rigors to reactor, the acetal compound that the present invention is prepared, which can be used for studying the performance of the acetal compound and provide data for optimization Vonoprazan fumarate preparation process, to be supported.
Description
Technical field
The invention belongs to drug fields, and in particular in a kind of Wo Nuolazan during preparing Vonoprazan fumarate
Mesosome generate acetal compound impurity, and preparation method thereof and separation method.
Background technique
Vonoprazan fumarate (TAK-438, Vonoprazan fumarate) is military field pharmacy and big tomb pharmacy cooperation
A kind of gastric antiacids object for the new oral released, suitable for erosive esophagitis, the treatment of gastric ulcer, duodenal ulcer,
As a kind of 3 class drugs, various countries not yet take in standards of pharmacopoeia at present.Vonoprazan fumarate belongs to potassium ion (K+) competitive sour
Retarding agent (P-CAB) is a kind of reversible proton pump inhibitor, after this product enters human body, secretes the last step of acid in parietal cell
Suddenly, by inhibiting potassium ion and H+-K+The combination of ATP enzyme (proton pump), terminates the secretion of gastric acid, reaches acid suppression effect, rich horse
Sour Wo Nuolazan has powerful, lasting gastric acid secretion inhibiting effect.Compared with traditional proton pump inhibitor Lansoprazole, have
Following advantage: (1) Wo Nuolazan is by competitive, the reversible K inhibited in proton pump+And work, clinical and animal is real
It tests and shows that fertile Nola praises than the action of PPI or H2 receptor blocker faster, the effect for increasing pH is stronger, can alleviate alimentary canal rapidly
Symptom, enzyme activity recovery after dissociation, adverse reaction is few, and several clinical tests confirm, Wo Nuolazan for erosive esophagitis,
Prevention and treatment taste-blindness rate, eradicate helicobacter pylori etc. as first-line treatment scheme and have significant therapeutic effect,
Curative effect is higher than Lansoprazole, and adverse reaction is small；(2) Wo Nuolazan lipophilicity is high, and dissociation constant is high, under acidic environment, is not required to
Acid activation is wanted, is worked at once, activation of the Wo Nuolazan to the inhibiting effect of proton pump without acid is entered in stomach with high concentration, first
Secondary administration just can generate maximum depression effect, and sustainable 24 hours, and Wo Nuolazan stablizes in acid, can increase in stomach rapidly
PH value plays acid suppression effect；(3) influence very little of the Wo Nuolazan to other enzymes influences small, safety to body physiological function
Good, more easy-tolerated, traditional PPI is metabolized by CYP2C19, and Wo Nuolazan is not metabolized by CYP2C19 mainly, drug effect and action agent
The difference measured in different patients is not significant, can preferably meet the personalized medicine scheme of patient.
There are many synthetic route of Vonoprazan fumarate, and wherein key intermediate Wo Nuolazan structure is as follows:
The step of wherein preparing key intermediate is as follows:
This step is reductive amination process, and reaction process is as follows:
Since protonic solvent can promote to react in reductive amination process, reaction dissolvent often uses alcohols solvent, as methanol,
Ethyl alcohol, isopropanol etc., due to substrate aldehyde containing carbonyl, can generate acetal impurities in this reaction process in reaction process.Acetal is miscellaneous
Matter is although unstable under acidic condition, but the technique once has impurity generation, during bringing into subsequent reactions or even band
Enter finished product, is a very big challenge for stability at later stage, because of the compound aldehyde-containing type substance after impurity decomposition thus,
It is studied according to genetic toxic impurities caution structure, which is genetic toxic impurities, miscellaneous for genetic toxicity
Matter is once brought into preparation, extremely stringent for the bound requirements of genetic toxic impurities, therefore this miscellaneous Quality Research is especially
It is important.
However, in the prior art not yet to generated impurity in related Vonoprazan fumarate preparation process, especially
The further investigation of acetals impurity, and the specific structure of the acetals impurity is not known, it is miscellaneous more to prepare the acetals without proposition
The preparation method of matter.For more in-depth study impurity structure, performance and pathology Journal of Sex Research, it is necessary to propose a kind of letter
The synthetic method being singly easy to get, more easily to obtain the target impurity, thus in Vonoprazan fumarate preparation process
Parameter optimization and purification & isolation provide reference frame.
Summary of the invention
It is an object of the invention to overcome the above-mentioned deficiency of the prior art, provide a kind of simple and easy to get, preparation process is simple
Convenient and the higher acetal compound of yield preparation method, in particular for being produced in Vonoprazan fumarate preparation process
Raw acetals impurity and preparation method thereof.
For achieving the above object, The technical solution adopted by the invention is as follows:
One aspect of the present invention provides generated acetal compound in a kind of Vonoprazan fumarate preparation process, described
The general structure of acetal compound is as follows:
In formula, X chooses one of F, Cl, Br, I；R1, R2Choose one of C1~C8 alkyl.
In Vonoprazan fumarate preparation process, due to using different synthesis routes, synthesis material and preparation
Parameter will be different, but be possible to generate acetal compound, and the further degradation meeting of the acetal compound
Therefore the drug effect for influencing subsequent reactions and final products seems particularly significant to the structural research of the acetal compound.
The acetal compound as represented by above-mentioned general formula (I), can be according to group X, R1, R2Difference, to choose difference
Reactant, to obtain the acetal compound of different structure formula, further to study specific acetal compound as rich horse
The performance of generated impurity and genetic toxicity mechanism in sour Wo Nuolazan preparation process.
Preferably, X F；R1, R2It is methyl, the molecular structural formula of the acetal compound are as follows:
Preferably, the acetal compound is separated by nucleophilic substitution-condensation reaction-thin layer chromatography
?.The preparation process is simple and convenient, and obtained acetal compound structure is clear, and component is single, and yield is higher.
Another aspect of the present invention provides a kind of preparation method of acetal compound, and described method includes following steps:
S1. it is anti-to carry out nucleophilic displacement of fluorine for the compound of general formula of molecular structure (II) and the compound of general formula of molecular structure (III)
It answers, obtains nucleophilic substitution product；
In formula, X1It is one of F, Cl, Br, I with X；
S2. the nucleophilic substitution product and alkylol carry out condensation reaction, obtain mixed containing condensation reaction products
Close object；
S3. the mixture containing condensation reaction products is separated, the acetal compound is obtained.
Preferably, the nucleophilic substitution in the step S1 carries out in polar solvent.It is further preferred that institute
Stating polar solvent is acetonitrile.
It preferably, further include cooling crystallization and filter operation, to obtain the institute of high-purity after the step S1
State nucleophilic substitution product.
Preferably, acetal compound is separated using thin layer chromatography in the step S3, and scrapes silica gel, process is molten
Agent dissolution, filtering are spin-dried for.
Preferably, the compound and the molecular structure of the general formula of molecular structure (II) in the step S1 are logical
The molar ratio of the compound of formula (III) is 1~10, preferably 1~5, more preferable 1~2.
Preferably, the reaction temperature of the step S1 is 20 DEG C~80 DEG C, preferably 20~60 DEG C.
Preferably, also contain acid binding agent in the step S1.It is further preferred that the acid binding agent be DMAP,
One or more of DIEA, natrium carbonicum calcinatum, Anhydrous potassium carbonate, triethylamine.
Preferably, the molar ratio of the acid binding agent and the compound of the general formula of molecular structure (III) is 1~10, excellent
Select 1~5, more preferable 1~3.
Preferably, the reaction condition of the step S2 are as follows: the alkylol and the nucleophilic substitution product
Volume mass ratio is 1~20 (mL/mg), preferably 1~10 (mL/mg).
Preferably, the step S2 reaction temperature is 20~60 DEG C, preferably 20~40 DEG C.
Preferably, the step S2 reaction time is 4~50h, preferably 4~for 24 hours.
Preferably, solvent used in the thin layer chromatography of the step S3 is the mixed of petroleum ether and ethyl acetate
Object is closed, and the volume ratio of petroleum ether and ethyl acetate is 1~10, more preferable 1~5.
Preferably, the X1 is Cl；The X is F；The alkylol is methanol.
The preparation method of acetal compound provided by the invention, preparation process is simple, and reaction raw materials are existing commercially availableization
Work raw material, cost is relatively low, and has no rigors to purity.Preparation step is less, by nucleophilic substitution and condensation reaction,
It can be prepared by target acetal compound, and separated after condensation reaction using thin layer chromatography, separation means are simple, are easy to
Operation, reaction product purity is higher, and no other by-products occur.Reaction condition provided by the invention is mild, is not necessarily to high temperature and pressure
Etc. unconventional equipment, no especial equipment requirements, preparation process is easy to industrialize, and low in cost, and entire reaction process safely may be used
Control.
Another aspect of the present invention provides a kind of impurity toxicity of acetal compound during preparing Vonoprazan fumarate
Purposes in research.
Acetal compound provided by the invention and preparation method thereof, by the structure and its property of studying the acetal compound
Can, and its catabolite is conducted further research, its genetic toxicity is studied, it can be more efficiently fertile to fumaric acid
The preparation process that Nola praises is monitored and adjusts, and to avoid occurring such acetal compound in reaction process, while avoiding this
Class acetal compound enters final products, brings injury for patient.
Detailed description of the invention
Fig. 1 is the flow chart of the preparation process of the acetal compound provided in the embodiment of the present invention；
Fig. 2 is the liquid chromatogram of acetal compound in embodiment 1；
Fig. 3 is the liquid chromatography-mass spectrography figure of acetal compound in embodiment 1.
Specific embodiment
In order to which technical problems, technical solutions and advantageous effects to be solved by the present invention are more clearly understood, below in conjunction with
Embodiment, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only used to explain
The present invention is not intended to limit the present invention.
On the one hand, the embodiment of the invention provides generated acetals in a kind of Vonoprazan fumarate preparation process
Object is closed, the general structure of the acetal compound is as follows:
In formula, X chooses one of F, Cl, Br, I；R1, R2Choose one of C1~C8 alkyl.
The acetal compound as represented by above-mentioned general formula (I), can be according to group X, the difference of R1, R2, to choose not
Same reactant, to obtain the acetal compound of different structure formula, further to study specific acetal compound as richness
The performance of generated impurity and genetic toxicity mechanism in horse acid Wo Nuolazan preparation process.Since existing fumaric acid is fertile
There are many preparation processes that Nola praises, and acetal compound produced during the preparation process passes through there is also various structures type
Specific targetedly analysis and research are carried out to the acetal compound of various structure types, are corresponding Vonoprazan fumarate
Preparation process improvement provide foundation.
Specifically, the concrete type of acetal compound includes but is not limited to following structural formula (IV)~(Ⅸ):
As long as on the basis of general formula (I), by selecting group X, R1, R2Concrete type, be formed by specific contracting
The structural formula of aldehyde compound belongs to the protection scope of acetal compound of the invention, due to different Vonoprazan fumarates
Preparation process formed in the structural formula of acetal compound be not quite similar, pass through transformation the group X, R1, R2Concrete kind
Type can form a series of acetal compounds, so that acetal compound is ground in the preparation process of abundant Vonoprazan fumarate
Study carefully range, greatly reduces the risk of such acetal compound residual in the final product.
On the other hand, as shown in Figure 1, the embodiment of the invention also provides a kind of preparation methods of acetal compound, including
Following steps:
S1. it is anti-to carry out nucleophilic displacement of fluorine for the compound of general formula of molecular structure (II) and the compound of general formula of molecular structure (III)
It answers, obtains nucleophilic substitution product, the general structure (Ⅹ) of institute's nucleophilic substitution product；
In formula, X1 and X2 are one of F, Cl, Br, I；R chooses one of H, C1~C4 alkyl；The nucleophilic takes
The generation reaction equation of reaction is as follows:
It should be noted that general formula of molecular structure (II) compound and general formula of molecular structure (III) compound usually from
Existing industrial chemicals market purchase gained is also possible to make by oneself and obtain as needed.The reactant of nucleophilic substitution includes
Compound, polar solvent and the acid binding agent of the compound of general formula of molecular structure (II), general formula of molecular structure (III), wherein pole
Property solvent for dissolving reactant and provide reacting environment, the optional example of polar solvent is acetonitrile.Acid binding agent generallys use weak
Alkali can be organic weak base, be also possible to inorganic weak bases, and the optional example of the weak base as acid binding agent includes DMAP, DIEA, nothing
Aqueous sodium carbonate, Anhydrous potassium carbonate, triethylamine, in the present embodiment, acid binding agent choose DMAP, DIEA, natrium carbonicum calcinatum, anhydrous carbon
One of sour potassium, triethylamine are a variety of, especially choose two kinds therein as acid binding agent, and limiting one such is to have
Machine weak base, another kind is inorganic weak bases, for example, DMAP and natrium carbonicum calcinatum, DMAP and Anhydrous potassium carbonate, triethylamine and anhydrous carbon
The compositions such as sour sodium, DIEA and Anhydrous potassium carbonate, as long as meeting a kind of is organic weak base, one kind is inorganic weak bases, without
Considered critical is done to the relative amount between both of composition.When the group that acid binding agent is a kind of organic weak base and inorganic weak bases
When closing object, due to the mutual synergistic effect of organic weak base and inorganic weak bases, the reaction of nucleophilic substitution can be significantly improved
Rate and reaction yield.
In the nucleophilic substitution of step S1, the compound and the molecular structure of the general formula of molecular structure (II) are logical
The molar ratio of the compound of formula (III) is 1~10, preferably 1~5, more preferable 1~2.Molar ratio is higher, be more conducive to reaction into
Row, but will cause the waste of the compound of general formula of molecular structure (II) simultaneously, therefore, by the change of the general formula of molecular structure (II)
The molar ratio for closing the compound of object and the general formula of molecular structure (III) is limited in 1~10, not only improves nucleophilic substitution
Efficient progress, be also unlikely to cause the excess waste of reaction raw materials.The acid binding agent and the general formula of molecular structure (III)
The molar ratio of compound is 1~10, preferably 1~5, more preferable 1~3.The reaction temperature of the nucleophilic substitution of the step S1
For 20 DEG C~80 DEG C, preferably 20~60 DEG C, the reaction rate of nucleophilic substitution can be made to reach within the said temperature range
Optimum state.
S2. the nucleophilic substitution product (Ⅹ) and alkylol carry out condensation reaction, obtain containing condensation reaction products
Mixture；The reaction equation of the condensation reaction is as follows:
It should be noted that condensation reaction carries out in the reactor for being able to carry out condensation reaction, in order to be more accurate
The reaction temperature of condensation reaction is controlled, condensation reaction can be in the tower reactor or double tube reactor for being equipped with intercooler
Middle progress, the embodiment of the present invention do not make restriction to condensation reactor, as long as can satisfy reaction needed for condensation reaction
Environment.
The condensation reaction of the step S2 can be places for a long time in same alkylol, at this point, R1And R2It is identical
, for the nucleophilic substitution product (Ⅹ) by being immersed in same alkylol for a long time, gradual condensation obtains acetalation
It closes object (I)；It is also possible to that condensation reaction occurs respectively in two kinds of alkylols, at this point, R1And R2It is different, the nucleophilic takes
For reaction product (Ⅹ) first in R1Level-one condensation reaction occurs in-OH solution, obtains intermediate product (Ⅹ I), then by intermediate product
Move to R2Second level condensation reaction occurs in-OH solution, obtains acetal compound (I).Alkylol and nucleophilic substitution product
(Ⅹ) condensation reaction can simply and easily obtain target product acetal compound (I) to the of less demanding of reaction condition,
In the process, the type of adjusting alkylol need to only be passed through, it will be able to the acetal compound (I) of different molecular structures is obtained, and
The reaction rate of condensation reaction, product yield etc. can be controlled by the content of control reaction temperature, reaction time and alkylol.
In an embodiment of the present invention, the reaction temperature of the step S2 is 20~60 DEG C, preferably 20~40 DEG C；When reaction
Between be 4~50h, preferably 4~for 24 hours；The volume mass ratio of the alkylol and the nucleophilic substitution product is 1~20 (mL/
Mg), preferably 1~10 (mL/mg).And condensation reaction stands for a long time preferably in same alkyl alcohol solution and be condensed instead
It answers, the preferred methanol of alkylol.
S3. the mixture containing condensation reaction products is separated, the acetal compound is obtained.
The lock out operation of the step S3 can be the general precipitation method, absorption method etc., in an embodiment of the present invention, excellent
Choosing is separated using thin layer chromatography, and the mixture containing condensation reaction products is carried out chromatography point using thin layer chromatography
From specifically, adsorbent and supporting agent are uniformly coated on supporter, as soon as being paved into very thin layer, chromatography is in the thin layer
Upper progress, then the adsorbent for being loaded with acetal compound is scraped off come, and and then, is carried out using the biggish solvent of polarity molten
Solution, elution finally are spin-dried for operating by filtering again, and acetal compound and adsorbent are separated, the acetal compound is obtained.
Preferably, silica gel, aluminium oxide can be selected in adsorbent；Glass plate or plastic plate can be selected in supporter；Polarity is biggish
Methanol, chloroform, ethyl alcohol can be selected in solvent.
Preferably, the solvent of thin layer chromatography is petroleum ether: ethyl acetate, and volume ratio is 1~10, more preferable 1~5.
It further, further include to parent obtained by the step S1 before the step S2 after the step S1
The separation and purification operation of core substitution reaction product.Specifically:
Solution after step S1 reaction is subjected to cooling processing, and was utilized after waiting crystallization complete with crystallization
Filter operation, which is realized, to be separated by solid-liquid separation, and obtained solid is the higher nucleophilic substitution product (Ⅹ) of purity.
Another aspect, the embodiment of the present invention also provide the purposes of above-mentioned acetal compound, especially by the research contracting
Aldehyde compound, the purposes of the preparation process of Lai Gaijin Vonoprazan fumarate.
The present invention successively carried out test of many times, now lifts A partial experiment result as reference, carries out to invention further
Detailed description, is described in detail combined with specific embodiments below.
Embodiment 1
Generated acetal compound in a kind of Vonoprazan fumarate preparation process, the knot of the acetal compound
Structure formula is as follows:
Acetal compound (IV) (5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrrole provided in this embodiment
Cough up -3- formaldehyde dimethylacetal) the preparation method comprises the following steps:
S1. nucleophilic substitution.Weigh commercially available -3 sulfonic acid chloride of 1mol pyridine and 1mol 5- (2- fluorophenyl) -1H- pyrrole
- 3- formaldehyde to be coughed up in appropriate acetonitrile solvent, and 1mol acid binding agent is added, acid binding agent is the composition of DMAP and natrium carbonicum calcinatum,
Above-mentioned material stirring is uniform, 60 DEG C are warming up to, heating rate is 1 DEG C/min, and 5h progress nucleophilic is kept the temperature after being warming up to 60 DEG C and is taken
Generation reaction.The reaction equation of the nucleophilic substitution is as follows:
Shown in reaction equation as above, the product of nucleophilic substitution is 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -
1H- pyrroles's -3- formaldehyde, 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde are still in second
In nitrile solvent.
And then, the mixture 3h after standing above-mentioned nucleophilic substitution, and it is made gradually to be cooled to room temperature, mixture
Crystallization can occur in temperature-fall period, form solidliquid mixture, be then filtered operation, the solid obtained after filtering is i.e.
For nucleophilic substitution product 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.Drying, weighing,
Conversion, obtains 0.83mol 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.
S2. condensation reaction.By above-mentioned 0.83mol 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3-
Formaldehyde is placed in reaction kettle, and methanol reagent, methanol and 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- is then added
The volume mass ratio of pyrroles's -3- formaldehyde is 20 (mL/mg), is gradually warmed up, and heating rate is 1 DEG C/min, is warming up to 60 DEG C of holdings
It is constant, it maintains for 24 hours until the reaction is complete, to generate 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde
Dimethylacetal.The reaction equation of the condensation reaction is as follows:
S3. it separates.Separation is contracted containing 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diformazan
The mixture of aldehyde.Separating step is carried out using thin layer chromatography, specifically: silica gel and supporting agent are uniformly coated on glass plate
On, as soon as being paved into very thin layer, chromatography carries out on the thin layer, using the composition of ethyl acetate and petroleum ether as expansion
The weight ratio of agent, petroleum ether and ethyl acetate is 1, then will be loaded with 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H-
The adsorbent of pyrroles's -3- formaldehyde dimethylacetal, which scrapes off, to come, and and then, is dissolved using chloroform as solvent, elution, finally
It is spin-dried for operating by filtering again, by 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dimethylacetal
It is separated with adsorbent, obtains the 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dimethylacetal.
Liquid chromatographic detection is carried out to gained concentrate, measures its 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -
The purity of 1H- pyrroles's -3- formaldehyde dimethylacetal.As shown in Figure 2.
Measure the test of 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dimethylacetal purity
Condition is as follows:
Chromatographic condition:
1, chromatographic column: Agilent ZORBAX SB-C18,5 μm, 4.6 × 250mm.
2, the preparation of mobile phase: mobile phase A: potassium dihydrogen phosphate 0.83g and dipotassium hydrogen phosphate 0.11g are taken, is dissolved in water simultaneously
It is diluted to 1000ml, with phosphorus acid for adjusting pH value to 3.0.
Mobile phase B: acetonitrile.
3, chromatographic condition: mobile phase: using phosphate solution as mobile phase A, using acetonitrile as Mobile phase B, according to the form below carries out ladder
Degree elution:
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 15 | 80 | 20 |
| 25 | 20 | 80 |
| 40 | 80 | 20 |
| 60 | 80 | 20 |
Detection wavelength: 225nm
Sample volume: 10 μ l
Flow velocity: 1.0ml/min
Column temperature: 30 DEG C
The preparation of reference substance solution: without related control product.
The preparation of test solution: it is appropriate that precision weighs this product, adds acetonitrile to make to dissolve in right amount, is made often with dilution in acetonitrile
Solution in 1ml containing about 1.0mg to get.
Measuring method: precision measures 10 μ l of test solution, injects liquid chromatograph, records chromatogram, principal component peak and phase
The peak-to-peak separating degree of adjacent impurity should meet the requirements, and test solution is calculated by area normalization method.
As a result: chromatography testing result data are as shown in table 1, and the purity for measuring main component is 98.14% or more.
Table 1: chromatography testing result data
Signal: DADl A, Sig=225,4Ref=off
| Serial number | Retention time min | Peak area | Peak height mAU | Peak area % | Tailing factor | The number of plates | Separating degree USP |
| 1 | 2.182 | 4.392 | 0.510 | 0.02 | 1.20 | 1.384 | |
| 2 | 2.383 | 45.411 | 8.522 | 0.20 | 1.99 | 6455 | |
| 3 | 4.123 | 7.761 | 1.138 | 0.03 | 1.18 | 7876 | 11.73 |
| 4 | 6.194 | 10.945 | 1.374 | 0.05 | 0.98 | 13874 | 10.53 |
| 5 | 6.562 | 4.825 | 0.497 | 0.02 | 0.89 | 10327 | 1.61 |
| 6 | 11.116 | 7.575 | 0.529 | 0.03 | 1.25 | 14143 | 16.24 |
| 7 | 12.171 | 21978.129 | 784.149 | 98.14 | 3.42 | 4180 | 1.87 |
| 8 | 16.311 | 127.906 | 6.834 | 0.57 | 1.04 | 17522 | 6.41 |
| 9 | 22.593 | 7.843 | 0.706 | 0.04 | 1.28 | 108161 | 17.03 |
| 10 | 24.657 | 8.153 | 0.585 | 0.04 | 0.97 | 63296 | 6.93 |
| 11 | 25.043 | 4.555 | 0.529 | 0.02 | 1.50 | 205579 | 1.41 |
| 12 | 25.445 | 7.152 | 0.853 | 0.03 | 0.86 | 223514 | 1.97 |
| 13 | 26.046 | 99.214 | 12.017 | 0.44 | 1.03 | 261057 | 2.92 |
| 14 | 27.335 | 17.072 | 1.524 | 0.08 | 1.51 | 158392 | 5.29 |
| 15 | 36.009 | 62.823 | 7.672 | 0.28 | 1.07 | 513005 | 35.64 |
Liquid chromatography-mass spectrography detection is carried out to gained concentrate.As shown in Figure 3.
Experimental condition is as follows:
Instrument model: Agilent 1200-6410
Chromatographic column: ACQUITY UPLC BEH C182.1*50mm, 1.7 μm
Column temperature: 35 DEG C
Sample volume: 5 μ L
Mobile phase A: 4mmol/L ammonium acetate aqueous formic acid；Mobile phase B: acetonitrile；
Flow velocity: 0.2mL/min；Gradient elution:
Parsing: the molecular formula of 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dimethylacetal
For C18H17FN2O4S molecular weight is 376.4 (M), measures molecular ion peak m/z 399.1 [M+Na]+。
As a result: the main component for showing gained concentrate is 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrrole
Cough up -3- formaldehyde dimethylacetal.
Embodiment 2
Generated acetal compound in a kind of Vonoprazan fumarate preparation process, the knot of the acetal compound
Structure formula is as follows:
Acetal compound (V) (5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrrole provided in this embodiment
Cough up -3- formaldehyde diethyl acetal) the preparation method comprises the following steps:
S1. nucleophilic substitution.Weigh commercially available -3 sulfonic acid chloride of 2mol pyridine and 1mol 5- (2- fluorophenyl) -1H- pyrrole
- 3- formaldehyde to be coughed up in appropriate acetonitrile solvent, and 3mol acid binding agent is added, acid binding agent is the composition of DIEA and Anhydrous potassium carbonate,
Above-mentioned material stirring is uniform, 80 DEG C are warming up to, heating rate is 1 DEG C/min, and 3h progress nucleophilic is kept the temperature after being warming up to 80 DEG C and is taken
Generation reaction.The reaction equation of the nucleophilic substitution is as follows:
Shown in reaction equation as above, the product of nucleophilic substitution is 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -
1H- pyrroles's -3- formaldehyde, 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde are still in second
In nitrile solvent.
And then, the mixture 5h after standing above-mentioned nucleophilic substitution, and it is made gradually to be cooled to room temperature, mixture
Crystallization can occur in temperature-fall period, form solidliquid mixture, be then filtered operation, the solid obtained after filtering is i.e.
For nucleophilic substitution product 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.Drying, weighing,
Conversion, obtains 0.85mol 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.
S2. condensation reaction.By above-mentioned 0.85mol 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3-
Formaldehyde is placed in reaction kettle, and ethanol reagent, ethyl alcohol and 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- is then added
The volume mass ratio of pyrroles's -3- formaldehyde is 10 (mL/mg), is gradually warmed up, and heating rate is 1 DEG C/min, is warming up to 40 DEG C of holdings
It is constant, it maintains 50h until the reaction is complete, generates 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde
Diethyl acetal.The reaction equation of the condensation reaction is as follows:
S3. it separates.Separation is contracted containing 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diethyl
The mixture of aldehyde.Separating step is carried out using thin layer chromatography, specifically: silica gel and supporting agent are uniformly coated on glass plate
On, as soon as being paved into very thin layer, chromatography carries out on the thin layer, using the composition of ethyl acetate and petroleum ether as expansion
The volume ratio of agent, ethyl acetate and petroleum ether is 1 ﹕ 5, then will be loaded with 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -
The adsorbent of 1H- pyrroles's -3- formaldehyde diethyl acetal, which scrapes off, to come, and and then, is dissolved using chloroform as solvent, elution,
It finally is spin-dried for operating by filtering again, by 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diethyl
Acetal and adsorbent separation, obtain the 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diethyl
Acetal.
Gained concentrate is detected, its 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles-is measured
The purity of 3- formaldehyde diethyl acetal.
Detected by liquid chromatography, testing conditions as embodiment 1, measure main component purity be 96% with
On.
It is detected by liquid chromatography-mass spectrometry, testing conditions measure as embodiment 1 the result shows that gained concentrate
Main component be 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diethyl acetal.
Embodiment 3
Generated acetal compound in a kind of Vonoprazan fumarate preparation process, the knot of the acetal compound
Structure formula is as follows:
Acetal compound (VI) (5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrrole provided in this embodiment
Cough up two propylal of -3- formaldehyde) the preparation method comprises the following steps:
S1. nucleophilic substitution.Weigh commercially available -3 sulfonic acid chloride of 5mol pyridine and 1mol 5- (2- fluorophenyl) -1H- pyrrole
- 3- formaldehyde is coughed up in appropriate acetonitrile solvent, and 5mol acid binding agent is added, acid binding agent is the combination of triethylamine and Anhydrous potassium carbonate
Object, above-mentioned material stirring is uniform, it maintains 20 DEG C of heat preservations and carries out nucleophilic substitution for 24 hours.The nucleophilic substitution it is anti-
Answer formula as follows:
Shown in reaction equation as above, the product of nucleophilic substitution is 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -
1H- pyrroles's -3- formaldehyde, 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde are still in second
In nitrile solvent.
And then, for 24 hours, crystallization can occur the mixture after standing above-mentioned nucleophilic substitution during standing for mixture
Phenomenon forms solidliquid mixture, is then filtered operation, the solid obtained after filtering is nucleophilic substitution product 5-
(2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.Drying is weighed, and conversion obtains 0.88mol 5-
(2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.
S2. condensation reaction.By above-mentioned 0.88mol 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3-
Formaldehyde is placed in reaction kettle, and propyl alcohol reagent, propyl alcohol and 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- is then added
The volume mass ratio of pyrroles's -3- formaldehyde is 20 (mL/mg), and temperature maintains 20 DEG C and remains unchanged, and maintains 50h until having reacted
Entirely, two propylal of 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde is generated.The condensation reaction
Reaction equation is as follows:
S3. it separates.Separation is contracted containing 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dipropyl
The mixture of aldehyde.Separating step is carried out using thin layer chromatography, specifically: silica gel and supporting agent are uniformly coated on glass plate
On, as soon as being paved into very thin layer, chromatography carries out on the thin layer, using the composition of ethyl acetate and petroleum ether as expansion
The volume ratio of agent, ethyl acetate and petroleum ether is 1 ﹕ 5, then will be loaded with 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -
The adsorbent of two propylal of 1H- pyrroles -3- formaldehyde, which scrapes off, to come, and and then, is dissolved using chloroform as solvent, elution,
It finally is spin-dried for operating by filtering again, by 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dipropyl
Acetal and adsorbent separation, obtain the 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dipropyl
Acetal.
Gained concentrate is detected, its 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles-is measured
The purity of two propylal of 3- formaldehyde.
Detected by liquid chromatography, testing conditions as embodiment 1, measure main component purity be 95% with
On.
It is detected by liquid chromatography-mass spectrometry, testing conditions measure as embodiment 1 the result shows that gained concentrate
Main component be two propylal of 5- (2- fluorophenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde.
Embodiment 4
Generated acetal compound in a kind of Vonoprazan fumarate preparation process, the knot of the acetal compound
Structure formula is as follows:
Acetal compound (VII) (5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrrole provided in this embodiment
Cough up -3- formaldehyde dimethylacetal) the preparation method comprises the following steps:
S1. nucleophilic substitution.Weigh commercially available -3 sulfonic acid chloride of 10mol pyridine and 1mol 5- (2- chlorphenyl) -1H- pyrrole
- 3- formaldehyde to be coughed up in appropriate acetonitrile solvent, and 1mol acid binding agent is added, acid binding agent is the composition of DMAP and natrium carbonicum calcinatum,
Above-mentioned material stirring is uniform, 60 DEG C are warming up to, heating rate is 1 DEG C/min, and 4h progress nucleophilic is kept the temperature after being warming up to 60 DEG C and is taken
Generation reaction.The reaction equation of the nucleophilic substitution is as follows:
Shown in reaction equation as above, the product of nucleophilic substitution is 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -
1H- pyrroles's -3- formaldehyde, 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde are still in second
In nitrile solvent.
And then, the mixture 3h after standing above-mentioned nucleophilic substitution, and it is made gradually to be cooled to room temperature, mixture
Crystallization can occur in temperature-fall period, form solidliquid mixture, be then filtered operation, the solid obtained after filtering is i.e.
For nucleophilic substitution product 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.Drying, weighing,
Conversion, obtains 0.86mol 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.
S2. condensation reaction.By above-mentioned 0.83mol 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3-
Formaldehyde is placed in reaction kettle, and methanol reagent, methanol and 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- is then added
The volume mass ratio of pyrroles's -3- formaldehyde is 10 (mL/mg), is gradually warmed up, and heating rate is 1 DEG C/min, is warming up to 60 DEG C of holdings
It is constant, it maintains 4h until the reaction is complete, generates 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde two
Dimethoxym ethane.The reaction equation of the condensation reaction is as follows:
S3. it separates.Separation is contracted containing 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diformazan
The mixture of aldehyde.Separating step is carried out using thin layer chromatography, specifically: silica gel and supporting agent are uniformly coated on glass plate
On, as soon as being paved into very thin layer, chromatography carries out on the thin layer, using the composition of ethyl acetate and petroleum ether as expansion
The volume ratio of agent, ethyl acetate and petroleum ether is 10, then will be loaded with 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -
The adsorbent of 1H- pyrroles's -3- formaldehyde dimethylacetal, which scrapes off, to come, and and then, is dissolved using chloroform as solvent, elution,
It finally is spin-dried for operating by filtering again, by 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diformazan
Acetal and adsorbent separation, obtain the 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diformazan
Acetal.
Gained concentrate is detected, its 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles-is measured
The purity of 3- formaldehyde dimethylacetal.
Detected by liquid chromatography, testing conditions as embodiment 1, measure main component purity be 98% with
On.
It is detected by liquid chromatography-mass spectrometry, testing conditions measure as embodiment 1 the result shows that gained concentrate
Main component be 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dimethylacetal.
Embodiment 5
Generated acetal compound in a kind of Vonoprazan fumarate preparation process, the knot of the acetal compound
Structure formula is as follows:
Acetal compound (VIII) (5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrrole provided in this embodiment
Cough up -3- formaldehyde diethyl acetal) the preparation method comprises the following steps:
S1. nucleophilic substitution.Weigh commercially available -3 sulfonic acid chloride of 5mol pyridine and 1mol 5- (2- chlorphenyl) -1H- pyrrole
- 3- formaldehyde to be coughed up in appropriate acetonitrile solvent, and 2mol acid binding agent is added, acid binding agent is the composition of DMAP and Anhydrous potassium carbonate,
Above-mentioned material stirring is uniform, 80 DEG C are warming up to, heating rate is 1 DEG C/min, and 5h progress nucleophilic is kept the temperature after being warming up to 80 DEG C and is taken
Generation reaction.The reaction equation of the nucleophilic substitution is as follows:
Shown in reaction equation as above, the product of nucleophilic substitution is 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -
1H- pyrroles's -3- formaldehyde, 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde are still in second
In nitrile solvent.
And then, the mixture 4h after standing above-mentioned nucleophilic substitution, and it is made gradually to be cooled to room temperature, mixture
Crystallization can occur in temperature-fall period, form solidliquid mixture, be then filtered operation, the solid obtained after filtering is i.e.
For nucleophilic substitution product 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.Drying, weighing,
Conversion, obtains 0.88mol 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.
S2. condensation reaction.By above-mentioned 0.88mol 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3-
Formaldehyde is placed in reaction kettle, and ethanol reagent, ethyl alcohol and 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- is then added
The volume mass ratio of pyrroles's -3- formaldehyde is 20 (mL/mg), is gradually warmed up, and heating rate is 1 DEG C/min, is warming up to 40 DEG C of holdings
It is constant, it maintains for 24 hours until the reaction is complete, to generate 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde
Diethyl acetal.The reaction equation of the condensation reaction is as follows:
S3. it separates.Separation is contracted containing 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diethyl
The mixture of aldehyde.Separating step is carried out using thin layer chromatography, specifically: silica gel and supporting agent are uniformly coated on glass plate
On, as soon as being paved into very thin layer, chromatography carries out on the thin layer, using the composition of ethyl acetate and petroleum ether as expansion
The volume ratio of agent, ethyl acetate and petroleum ether is 1, then will be loaded with 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H-
The adsorbent of pyrroles's -3- formaldehyde diethyl acetal, which scrapes off, to come, and and then, is dissolved using chloroform as solvent, elution, finally
It is spin-dried for operating by filtering again, by 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diethyl acetal
It is separated with adsorbent, obtains the 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diethyl acetal.
Gained concentrate is detected, its 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles-is measured
The purity of 3- formaldehyde diethyl acetal.
Detected by liquid chromatography, testing conditions as embodiment 1, measure main component purity be 97% with
On.
It is detected by liquid chromatography-mass spectrometry, testing conditions measure as embodiment 1 the result shows that gained concentrate
Main component be 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde diethyl acetal.
Embodiment 6
Generated acetal compound in a kind of Vonoprazan fumarate preparation process, the knot of the acetal compound
Structure formula is as follows:
Acetal compound (Ⅸ) (5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrrole provided in this embodiment
Cough up two propylal of -3- formaldehyde) the preparation method comprises the following steps:
S1. nucleophilic substitution.Weigh commercially available -3 sulfonic acid chloride of 10mol pyridine and 1mol 5- (2- chlorphenyl) -1H- pyrrole
- 3- formaldehyde is coughed up in appropriate acetonitrile solvent, and 3mol acid binding agent is added, acid binding agent is the combination of triethylamine and natrium carbonicum calcinatum
Object, above-mentioned material stirring is uniform, keep 20 DEG C of heat preservations to carry out nucleophilic substitution for 24 hours.The reaction of the nucleophilic substitution
Formula is as follows:
Shown in reaction equation as above, the product of nucleophilic substitution is 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -
1H- pyrroles's -3- formaldehyde, 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde are still in second
In nitrile solvent.
And then, crystallization can occur during standing for the mixture 10h after standing above-mentioned nucleophilic substitution, mixture
Phenomenon forms solidliquid mixture, is then filtered operation, the solid obtained after filtering is nucleophilic substitution product 5-
(2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.Drying is weighed, and conversion obtains 0.82mol 5-
(2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde.
S2. condensation reaction.By above-mentioned 0.82mol 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3-
Formaldehyde is placed in reaction kettle, and propyl alcohol reagent, propyl alcohol and 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- is then added
The volume mass ratio of pyrroles's -3- formaldehyde is 1 (mL/mg), is gradually warmed up, and heating rate is 1 DEG C/min, is warming up to 60 DEG C and keeps not
Become, maintains for 24 hours until the reaction is complete, to generate 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde two
Propylal.The reaction equation of the condensation reaction is as follows:
S3. it separates.Separation is contracted containing 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles's -3- formaldehyde dipropyl
The mixture of aldehyde.Separating step is carried out using thin layer chromatography, specifically: silica gel and supporting agent are uniformly coated on glass plate
On, as soon as being paved into very thin layer, chromatography carries out on the thin layer, using the composition of ethyl acetate and petroleum ether as expansion
The volume ratio of agent, ethyl acetate and petroleum ether is 1, then will be loaded with 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H-
The adsorbent of two propylal of pyrroles -3- formaldehyde, which scrapes off, to come, and and then, is dissolved using chloroform as solvent, elution, finally
It is spin-dried for operating by filtering again, by two propylal of 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde
It is separated with adsorbent, obtains two propylal of the 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde.
Gained concentrate is detected, its 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles-is measured
The purity of two propylal of 3- formaldehyde.
Detected by liquid chromatography, testing conditions as embodiment 1, measure main component purity be 96% with
On.
It is detected by liquid chromatography-mass spectrometry, testing conditions measure as embodiment 1 the result shows that gained concentrate
Main component be two propylal of 5- (2- chlorphenyl) -1- (pyridin-3-yl sulfonyl) -1H- pyrroles -3- formaldehyde.
By embodiment 1-6 it is found that the method that nucleophilic substitution-condensation reaction prepares acetal compound is simple and efficient,
Yield rate is higher, and by-product is less, and preparation condition is simple, and the requirement to reactor is lower, whole preparation process degree of controllability compared with
Height, designability are stronger.It can be by choosing the type of reaction product and the change response parameter of adaptability, so that it may easily
Expected acetal compound is obtained, for studying the performance of the acetal compound and to optimize Vonoprazan fumarate preparation
Technique provides data supporting.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (14)
1. a kind of acetal compound, which is characterized in that the general formula of molecular structure (I) of the acetal compound is as follows:
In formula, X chooses one of F, Cl, Br, I；R1, R2Choose one of C1~C8 alkyl.
2. a kind of acetal compound as described in claim 1, which is characterized in that the X is F, the R1And R2It is methyl.
3. a kind of acetal compound as described in claim 1, which is characterized in that the acetal compound is anti-by nucleophilic displacement of fluorine
Answer-condensation reaction-thin layer chromatography is isolated.
4. a kind of preparation method of acetal compound, which is characterized in that described method includes following steps:
S1. the compound of general formula of molecular structure (II) and the compound of general formula of molecular structure (III) carry out nucleophilic substitution, obtain
To nucleophilic substitution product；
In formula, X1It is one of F, Cl, Br, I with X；
S2. the nucleophilic substitution product and alkylol carry out condensation reaction, obtain the mixture containing condensation reaction products；
S3. the mixture containing condensation reaction products is separated, the acetal compound is obtained.
5. a kind of preparation method of acetal compound as claimed in claim 4, which is characterized in that
Nucleophilic substitution in step S1 carries out in polar solvent.
6. a kind of preparation method of acetal compound as claimed in claim 5, which is characterized in that
The polar solvent is acetonitrile.
7. a kind of preparation method of acetal compound as claimed in claim 4, which is characterized in that
It further include cooling crystallization and filter operation, to obtain the nucleophilic substitution of high-purity after the step S1
Product.
8. a kind of preparation method of acetal compound as claimed in claim 4, which is characterized in that
Acetal compound is separated using thin layer chromatography in the step S3, and scrapes silica gel, is dissolved by solvent, filtering rotation
It is dry.
9. a kind of preparation method of acetal compound as claimed in claim 4, which is characterized in that
The compound of the general formula of molecular structure (II) in the step S1 and the compound of the general formula of molecular structure (III)
Molar ratio be 1~10, preferably 1~5, more preferable 1~2；
And/or
The reaction temperature of the step S1 is 20 DEG C~80 DEG C, preferably 20~60 DEG C.
10. a kind of preparation method of acetal compound as claimed in claim 4, which is characterized in that
Also contain acid binding agent in the step S1, and
The acid binding agent is one or more of DMAP, DIEA, natrium carbonicum calcinatum, Anhydrous potassium carbonate, triethylamine；
And/or
The molar ratio of the acid binding agent and the compound of the general formula of molecular structure (III) is 1~10, preferably 1~5, more preferable 1
~3.
11. a kind of preparation method of acetal compound as claimed in claim 4, which is characterized in that
The reaction condition of the step S2 are as follows: the volume mass ratio of the alkylol and the nucleophilic substitution product is 1~
20 (mL/mg), preferably 1~10 (mL/mg)；
And/or
Reaction temperature is 20~60 DEG C, preferably 20~40 DEG C；
And/or
Reaction time is 4~50h, preferably 4~for 24 hours.
12. a kind of preparation method of acetal compound as claimed in claim 8, which is characterized in that
Solvent used in the thin layer chromatography of the step S3 be petroleum ether and ethyl acetate mixture, and petroleum ether and
The volume ratio of ethyl acetate is 1~10, preferably 1~5.
13. a kind of preparation method of acetal compound as described in claim 4-12 is any, which is characterized in that
The X1 is Cl；The X is F；The alkylol is methanol.
14. acetal compound a method according to any one of claims 1-3 or the acetal chemical combination as described in claim 4-12 is any
Purposes of the acetal compound prepared by object preparation method in impurity toxicity research during preparing Vonoprazan fumarate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910123745.XA CN109912568A (en) | 2019-02-19 | 2019-02-19 | A kind of acetal compound, preparation method and the usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910123745.XA CN109912568A (en) | 2019-02-19 | 2019-02-19 | A kind of acetal compound, preparation method and the usage |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109912568A true CN109912568A (en) | 2019-06-21 |
Family
ID=66961728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910123745.XA Pending CN109912568A (en) | 2019-02-19 | 2019-02-19 | A kind of acetal compound, preparation method and the usage |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109912568A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113390983A (en) * | 2021-05-26 | 2021-09-14 | 株洲千金药业股份有限公司 | Detection method for simultaneously determining 3 impurities in Voranolan fumarate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778286A (en) * | 2016-08-25 | 2018-03-09 | 成都弘达药业有限公司 | A kind of synthesis technique of Vonoprazan fumarate |
-
2019
- 2019-02-19 CN CN201910123745.XA patent/CN109912568A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107778286A (en) * | 2016-08-25 | 2018-03-09 | 成都弘达药业有限公司 | A kind of synthesis technique of Vonoprazan fumarate |
Non-Patent Citations (3)
| Title |
|---|
| M.E.EVANS: "Methyl 4,6-O-benzylidene-α- and -β-D-glucosides", 《CARBOHYDRATE RESEARCH》 * |
| TOORU KURODA ET AL.: "An Efficient Synthesis of Heterocyclic Analogs of 1-Arylnaphthalene Lignans", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
| 王乐平等主编: "《有机化学学习指南》", 28 February 2013 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113390983A (en) * | 2021-05-26 | 2021-09-14 | 株洲千金药业股份有限公司 | Detection method for simultaneously determining 3 impurities in Voranolan fumarate |
| CN113390983B (en) * | 2021-05-26 | 2022-06-07 | 株洲千金药业股份有限公司 | Detection method for simultaneously determining 3 impurities in Voranolan fumarate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018219967C1 (en) | Stable crystal form of tipiracil hydrochloride and crystallization method for the same | |
| ES2837431T3 (en) | Cystic fibrosis transmembrane conductance regulator modulators, pharmaceutical compositions, treatment methods, and processes for making the modulator | |
| DE69733478T2 (en) | ETHER-muscarinic antagonist | |
| CN106470975B (en) | The synthesis of polycyclic carbamoylpyridone compound | |
| CN109422752A (en) | One kind has inhibition and the active compound of bruton's tyrosine protein kinase B tk of degrading | |
| ES2982890T3 (en) | Muscarinic acetylcholine receptor antagonists M4 | |
| KR20070088485A (en) | Purification of cinacalcet | |
| EP1714965A1 (en) | Composition containing solifenacin succinate | |
| CN106146516B (en) | The preparation method of Buddhist nun's impurity of the drug is replaced according to Shandong | |
| CN109608436A (en) | Substituted methylformyl reagents and methods of using the same to improve the physicochemical and/or pharmacokinetic properties of compounds | |
| EP2807147A1 (en) | Phenyl methanesulfonamide derivatives useful as mgat - 2 inhibitors | |
| CN102702008B (en) | Agomelatine sulfuric acid composition and preparation method thereof | |
| CN106153798B (en) | It is a kind of to be used to analyze the purposes for doing reference standard about the HPLC methods and these impurity of material for Buddhist nun's preparation according to Shandong for Buddhist nun and according to Shandong | |
| EP1726304A1 (en) | Solifenacin-containing composition | |
| CN109912568A (en) | A kind of acetal compound, preparation method and the usage | |
| DE69216260T2 (en) | Piperidine derivatives | |
| CN106619636A (en) | Delafloxacin impurity compounds and preparation methods thereof | |
| CN103601673A (en) | Fluorinated derivatives of 3-hydroxypyridin-4-ones | |
| EP4450502A1 (en) | Azaindole derivative inhibiting h-pgds | |
| EP4091670A1 (en) | Crystal of imidazopyridinone compound or salt thereof | |
| CN110804026B (en) | Synthesis method of 1- (3- (3- (4-chlorphenyl) propoxy) propyl) piperidine hydrochloride | |
| CN115368355A (en) | Crystalline form of pyrazolo heteroaryl derivative | |
| CN104059082B (en) | Nitroimidazole heterocycle compound and the application in preparation treatment tubercular drugs thereof | |
| EP0117531B1 (en) | N-(3-trifluoromethyl phenyl)-n'-propargyl piperazine, method for its preparation and its use | |
| CN108409754A (en) | The Preparation method and use of Yi Dushaban oxidative degradation impurity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Li Jiahe Inventor after: Wang Rui Inventor after: Li Jing Inventor after: Wu Yanpeng Inventor after: Ge Zhimin Inventor after: Dai Xinmin Inventor before: Li Jiahe Inventor before: Wang Rui Inventor before: Li Jing Inventor before: Wu Yanpeng Inventor before: Ge Zhimin |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190621 |