CN114805317A - Preparation method of Tegolrazan - Google Patents
Preparation method of Tegolrazan Download PDFInfo
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- CN114805317A CN114805317A CN202210549838.0A CN202210549838A CN114805317A CN 114805317 A CN114805317 A CN 114805317A CN 202210549838 A CN202210549838 A CN 202210549838A CN 114805317 A CN114805317 A CN 114805317A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 13
- HGTYMLFMXKYIQW-ZETCQYMHSA-N (4s)-5,7-difluoro-3,4-dihydro-2h-chromen-4-ol Chemical compound FC1=CC(F)=C2[C@@H](O)CCOC2=C1 HGTYMLFMXKYIQW-ZETCQYMHSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 230000035484 reaction time Effects 0.000 claims description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 150000007514 bases Chemical class 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 10
- -1 3-bromo-4-amino-5-nitro-N, N-dimethylbenzamide Chemical compound 0.000 claims description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 8
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 7
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 6
- ZZNAYFWAXZJITH-UHFFFAOYSA-N 4-amino-3-nitrobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1[N+]([O-])=O ZZNAYFWAXZJITH-UHFFFAOYSA-N 0.000 claims description 6
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 6
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 6
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- JCSIZMVUEBODFZ-UHFFFAOYSA-N 4-amino-3-bromo-5-nitrobenzoic acid Chemical compound NC1=C(Br)C=C(C(O)=O)C=C1[N+]([O-])=O JCSIZMVUEBODFZ-UHFFFAOYSA-N 0.000 claims description 4
- LRVLIEIZJOKBQA-UHFFFAOYSA-N C(C1=CC=CC=C1)N1C(=NC2=C1C=C(C=C2O)C(=O)O)C Chemical compound C(C1=CC=CC=C1)N1C(=NC2=C1C=C(C=C2O)C(=O)O)C LRVLIEIZJOKBQA-UHFFFAOYSA-N 0.000 claims description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- POCWSMBLIUEXQA-UHFFFAOYSA-N 7-hydroxy-N,N,2-trimethyl-3H-benzimidazole-5-carboxamide Chemical compound C1=C(C2=C(C=C1C(=O)N(C)C)NC(=N2)C)O POCWSMBLIUEXQA-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000003541 multi-stage reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- CLIQCDHNPDMGSL-HNNXBMFYSA-N 7-[[(4s)-5,7-difluoro-3,4-dihydro-2h-chromen-4-yl]oxy]-n,n,2-trimethyl-3h-benzimidazole-5-carboxamide Chemical compound C1COC2=CC(F)=CC(F)=C2[C@H]1OC1=C(N=C(C)N2)C2=CC(C(=O)N(C)C)=C1 CLIQCDHNPDMGSL-HNNXBMFYSA-N 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 229950001401 tegoprazan Drugs 0.000 description 4
- UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 3
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention belongs to the technical field of raw material medicine synthesis, and discloses a preparation method of Tegolrazan. The invention adopts multi-step reaction to prepare 4-hydroxy-N, N, 2-trimethyl-1H-benzimidazole-6-formamide, and the obtained product is condensed with (S) -5, 7-difluoro-3, 4-dihydro-2H-chromene-4-ol in an alkaline compound and a solvent to obtain the Tegolazan. The method has the advantages of cheap and easily-obtained initial raw materials, high safety of reagents used in the reaction process, mild reaction conditions, high selectivity and simple reaction process, and is suitable for industrial synthesis of Tegolazan.
Description
Technical Field
The invention relates to the technical field of raw material medicine synthesis, in particular to a preparation method of Tegolrazan.
Background
Tegolazan, also known as tegorazan, Tegopracan, cj-12420, is a competitive potassium ion acid retarder (p-cab) and a hydrogen ion/potassium ion exchange atpase (h +/k + atpase) inhibitor, has quick response, can control the pH value of gastric juice for a long time, and is a medicament for treating gastroesophageal reflux disease and erosive esophagitis.
The chemical name of Tegoprazan (Tegopprazan) is(s) -4- ((5, 7-difluoro chroman-4-yl) oxy) -N, N, 2-trimethyl-1H-benzimidazole-6-formamide, and the chemical structure contains a benzimidazole structure and a chiral 5, 7-difluoro chroman-4-oxyl structure. The preparation of Tegolazan mainly relates to the preparation of (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol and the preparation of 4-hydroxy-N, N, 2-trimethyl-1H-benzimidazole-6-formamide and condensation reaction thereof. Patent CN101341149B discloses a preparation method of Tegoprazan, specifically, 4-hydroxy-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl ] -1H-benzo [ d ] imidazole-6-formamide and (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol are subjected to condensation reaction under the action of tributylphosphine/ADDP to prepare an intermediate of 4- [ ((4S) -5, 7-difluoro-3, 4-2H-chromen-4-yl) oxy ] -N, N, 2-trimethyl-1- [ (4-tolyl) sulfo ] -1H-benzo [ d ] imidazole-6-formamide, the latter removes the protecting group under the action of alkali to complete the preparation of Tegoprazan, based on the description of the above patent, the preparation of Tegoprazan mainly involves the condensation reaction of 4-hydroxy-N, N, 2-trimethyl-1- [ (4-tolyl) sulfonyl ] -1H-benzo [ d ] imidazole-6-formamide and (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, and the synthesis process involves the reaction of protecting group and protecting group removal, and has the disadvantages of complicated process, low yield and high cost.
Therefore, how to provide a synthetic method of the Tegolrazan with simple preparation process and high yield has important significance for the industrial development of the Tegolrazan.
Disclosure of Invention
The invention aims to provide a preparation method of Tegolrazan, which solves the defects of complicated process, low yield and high cost of the existing preparation process.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of Tegolazan, which comprises the following steps:
(1) reacting 4-amino-3-nitrobenzoic acid with bromine to give compound a 1: 3-bromo-4-amino-5-nitrobenzoic acid;
(2) reacting compound a1, trimethylacetyl chloride, an aqueous dimethylamine solution, and a basic compound to give compound a 2: 3-bromo-4-amino-5-nitro-N, N-dimethylbenzamide;
(3) reacting compound a2 with acetic anhydride to give compound A3: 3-bromo-4-acetylamino-5-nitro-N, N-dimethylbenzamide;
(4) reacting compound A3, an acidic compound, and a reducing agent to provide compound a 4: 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid;
(5) reacting compound a4, cuprous bromide, a basic compound, and a solvent to give compound a 5: 4-hydroxy-N, 2-trimethyl-1H-benzimidazole-6-carboxamide;
(6) reacting compound a5, (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, a basic compound, and tetrahydrofuran to give compound a 6: tegolrazan;
wherein the chemical structure of Tegolazan is as follows:
preferably, in the preparation method of tegolazan, the reaction temperature in the step (1) is 38-45 ℃; the reaction time is 20-26 h.
Preferably, in the preparation method of tegolazan, the reaction temperature in the step (2) is-10 to 0 ℃; the reaction time is 1-6 h; the basic compound is triethylamine.
Preferably, in the preparation method of tegolazan, the reaction temperature in the step (3) is 80-90 ℃; the reaction time is 1-2 h.
Preferably, in the preparation method of tegolazan, the reaction temperature in the step (4) is 50-75 ℃; the reaction time is 9-12 h; the acidic compound is sulfuric acid, acetic acid or hydrochloric acid; the reducing agent is metal reducing agent, sodium hydrosulfite or triethyl orthoformate.
Preferably, in the preparation method of tegolazan, the reaction temperature in the step (5) is 100-110 ℃; the reaction time is 6-9 h; the alkaline compound is sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the solvent is water.
Preferably, in the preparation method of tegolazan, the reaction temperature in the step (6) is-10 to 0 ℃; the reaction time is 1-3 h; the alkaline compound is potassium tert-butoxide, sodium ethoxide or sodium methoxide.
Through the technical scheme, compared with the prior art, the invention has the following beneficial effects:
the method has the advantages of cheap and easily-obtained initial raw materials, high safety of reagents used in the reaction process, mild reaction conditions, high selectivity and simple reaction process, and is suitable for industrial synthesis of Tegolazan.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
Fig. 1 is a nuclear magnetic hydrogen spectrum of tegolazan prepared in example 1.
Detailed Description
The invention provides a preparation method of Tegolazan, which comprises the following steps:
(1) dissolving 4-amino-3-nitrobenzoic acid in acetic acid, and adding bromine for reaction to obtain a compound A1: 3-bromo-4-amino-5-nitrobenzoic acid;
(2) dissolving a compound A1 in dichloromethane, adding an alkaline compound, stirring uniformly, adding trimethylacetyl chloride, reacting for a certain time, and adding a dimethylamine aqueous solution for reaction to obtain a compound A2: 3-bromo-4-amino-5-nitro-N, N-dimethylbenzamide;
(3) dissolving the compound A2 in acetic acid, and adding acetic anhydride to react to obtain the compound A3: 3-bromo-4-acetylamino-5-nitro-N, N-dimethylbenzamide;
(4) dissolving a compound A3 in dimethyl sulfoxide, adding a reducing agent, reacting for a certain time, and adding an acidic compound for reaction to obtain a compound A4: 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid;
(5) reacting compound a4, cuprous bromide, a basic compound, and a solvent to give compound a 5: 4-hydroxy-N, 2-trimethyl-1H-benzimidazole-6-carboxamide;
(6) reacting compound a5, (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, a basic compound, and tetrahydrofuran to give compound a 6: tegolrazan;
wherein the chemical structure of Tegolazan is as follows:
in the present invention, the molar ratio of 4-amino-3-nitrobenzoic acid to bromine in step (1) is preferably 1: 1-2, more preferably 1: 1.2 to 1.9, more preferably 1: 1.7.
in the present invention, the mass ratio of 4-amino-3-nitrobenzoic acid to acetic acid in step (1) is preferably 1: 20 to 22, and more preferably 1: 20.5 to 21.7, more preferably 1: 21.5.
in the invention, the reaction temperature in the step (1) is preferably 38-45 ℃, more preferably 39-43 ℃, and more preferably 41 ℃; the reaction time is preferably 20 to 26 hours, more preferably 21 to 25 hours, and even more preferably 24 hours.
In the present invention, the molar ratio of the compound a1, trimethylacetyl chloride, the basic compound and the aqueous dimethylamine solution in the step (2) is preferably 1: 1-2: 1-2: 6, more preferably 1: 1.1-1.8: 1.2-1.8: 6, more preferably 1: 1.6: 1.5: 6.
in the present invention, the concentration of the dimethylamine aqueous solution in step (2) is preferably 40 to 50%, more preferably 42 to 47%, and still more preferably 45%.
In the present invention, the mass ratio of the compound a1 to dichloromethane in the step (2) is preferably 1: 10 to 12, and more preferably 1: 10.2 to 11.3, more preferably 1: 10.7.
in the present invention, the basic compound in step (2) is preferably triethylamine.
In the invention, the reaction temperature after adding the trimethylacetyl chloride in the step (2) is preferably-10-0 ℃, more preferably-9-2 ℃, and more preferably-6 ℃; the reaction time is preferably 0.5 to 3 hours, more preferably 1.5 to 2.6 hours, and even more preferably 2 hours.
In the invention, the reaction temperature after adding dimethylamine aqueous solution in the step (2) is preferably-10-0 ℃, more preferably-8-3 ℃, and more preferably-5 ℃; the reaction time is preferably 0.5 to 3 hours, more preferably 1.5 to 3 hours, and still more preferably 3 hours.
In the present invention, the molar ratio of the compound a2 to acetic anhydride in the step (3) is preferably 1:1.5 to 4, more preferably 1:2.5 to 3.7, and still more preferably 1: 3.
In the present invention, the mass ratio of compound a2 to acetic acid in step (3) is preferably 1: 8-10, and more preferably 1: 8.4-9.6, more preferably 1: 9.
in the invention, the reaction temperature in the step (3) is preferably 80-90 ℃, more preferably 82-87 ℃, and more preferably 84 ℃; the reaction time is preferably 1 to 2 hours, more preferably 1.2 to 1.9 hours, and still more preferably 1.5 hours.
In the present invention, the molar ratio of compound a3, the acidic compound, and the reducing agent in step (4) is preferably 1: 1-2: 2-4, and more preferably 1: 1.1-1.8: 2.3 to 3.7, more preferably 1: 1.6: 3.
in the present invention, the mass ratio of compound a3 to dimethyl sulfoxide in step (4) is preferably 1: 4-5, and more preferably 1: 4.2 to 4.7, more preferably 1: 4.5.
in the present invention, the acidic compound in step (4) is preferably sulfuric acid, acetic acid or hydrochloric acid, more preferably sulfuric acid or hydrochloric acid, and still more preferably 1mol/L sulfuric acid.
In the present invention, the reducing agent in step (4) is preferably a metal-based reducing agent, sodium dithionite or triethyl orthoformate, more preferably sodium dithionite or triethyl orthoformate, and still more preferably sodium dithionite.
In the invention, the reaction temperature after adding the reducing agent in the step (4) is preferably 50-75 ℃, more preferably 52-71 ℃, and more preferably 65 ℃; the reaction time is preferably 1 to 2 hours, and more preferably 2 hours.
In the invention, the reaction temperature after the acidic compound is added in the step (4) is preferably 50-75 ℃, more preferably 53-70 ℃, and even more preferably 62 ℃; the reaction time is preferably 7 to 10 hours, more preferably 8 to 10 hours, and even more preferably 9 hours.
In the present invention, the molar ratio of compound a4, cuprous bromide and basic compound in step (5) is preferably 1: 0.1-0.5: 3-6, and more preferably 1: 0.2-0.4: 4-6, more preferably 1: 0.3: 5.
in the present invention, the basic compound in the step (5) is preferably sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, more preferably sodium hydroxide, potassium hydroxide or potassium tert-butoxide, and still more preferably sodium hydroxide.
In the present invention, the solvent in step (5) is preferably water.
In the invention, the reaction temperature in the step (5) is preferably 100-110 ℃, more preferably 102-107 ℃, and more preferably 105 ℃; the reaction time is preferably 6 to 9 hours, more preferably 7 to 9 hours, and even more preferably 8 hours.
In the present invention, the molar ratio of compound a5, (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, basic compound in step (6) is preferably 1: 1-1.5: 1 to 1.3, and more preferably 1: 1.1-1.4: 1.1 to 1.2, more preferably 1: 1.2: 1.1.
in the present invention, the mass-to-volume ratio of compound a5 to tetrahydrofuran in step (6) is preferably 1 g: 4-6 mL, more preferably 1 g: 4.2-5.8 mL, more preferably 1 g: 4.6 mL.
In the present invention, the basic compound in the step (6) is preferably potassium tert-butoxide, sodium ethoxide or sodium methoxide, more preferably potassium tert-butoxide, sodium ethoxide or sodium methoxide, and still more preferably potassium tert-butoxide.
In the invention, the reaction temperature in the step (6) is preferably-10-0 ℃, more preferably-8-1 ℃, and more preferably-5 ℃; the reaction time is preferably 1 to 3 hours, more preferably 1.5 to 3 hours, and even more preferably 2 hours.
In the present invention, the steps of filtration, recrystallization, washing, drying, or concentration in the preparation of the compounds a1 to a6 are not limited, and a method known to those skilled in the art may be used.
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The embodiment provides a preparation method of tegolazan, which comprises the following steps:
(1) 4-amino-3-nitrobenzoic acid (5g, 27.5mmol) was dissolved in 114g acetic acid, and bromine (8.76g, 54.9mmol) was added and reacted at 40 ℃ for 24h to give compound A1: 3-bromo-4-amino-5-nitrobenzoic acid;
(2) compound a1(6.88g, 26.3mmol) was dissolved in 73g dichloromethane, triethylamine (3.47g, 34.3mmol) was added, after stirring well, trimethylacetyl chloride (4.14g, 34.3mmol) was added, after reaction at 0 ℃ for 30min, 17.7g of 40% aqueous dimethylamine solution was added and reaction was carried out for 30min to give compound a 2: 3-bromo-4-amino-5-nitro-N, N-dimethylbenzamide;
(3) compound A2(7.28g, 25.3mmol) was dissolved in 61g of acetic acid, acetic anhydride (5.16g, 50.5mmol) was added and reacted at 85 ℃ for 1h to give compound A3: 3-bromo-4-acetylamino-5-nitro-N, N-dimethylbenzamide;
(4) compound A3(7.72g, 23.4mmol) was dissolved in 34g of dimethyl sulfoxide, sodium dithionite (8.14g, 46.8mmol) was added, reaction was carried out at 50 ℃ for 2h, then 5.69g of 30% hydrochloric acid was added, and reaction was carried out for 8h, giving compound A4: 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid;
(5) compound A4(6.14g, 21.7mmol) was dissolved in 30g of water, and sodium hydroxide (4.34g, 108.5mmol) and cuprous bromide (0.31g, 2.1mmol) were added and reacted at 100 ℃ for 8h to give compound A5: 4-hydroxy-N, 2-trimethyl-1H-benzimidazole-6-carboxamide;
(6) compound a5(4.38g, 20.0mmol), (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol (3.72g, 20.0mmol), potassium tert-butoxide (2.92g, 26.0mmol) in 20mL tetrahydrofuran at-5 ℃ for 2H gave compound a 6: the results of the nuclear magnetic hydrogen spectrum test of Tegolay are shown in figure 1.
Example 2
This example provides a process for the preparation of tegolazan, see in particular example 1, except that in step (5) compound a4 was used in an amount of 5.96g (21.1mmol) and cuprous bromide was used in an amount of 1.21g (8.44 mmol).
Example 3
This example provides a process for the preparation of tegolazan, see in particular example 1, except that in step (6) compound a5 was used in an amount of 4.25g (19.4mmol), (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol in an amount of 3.79g (20.4 mol).
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (7)
1. A preparation method of Tegolazan is characterized by comprising the following steps:
(1) reacting 4-amino-3-nitrobenzoic acid with bromine to give compound a 1: 3-bromo-4-amino-5-nitrobenzoic acid;
(2) reacting compound a1, trimethylacetyl chloride, an aqueous dimethylamine solution, and a basic compound to give compound a 2: 3-bromo-4-amino-5-nitro-N, N-dimethylbenzamide;
(3) reacting compound a2 with acetic anhydride to give compound A3: 3-bromo-4-acetylamino-5-nitro-N, N-dimethylbenzamide;
(4) reacting compound A3, an acidic compound, and a reducing agent to provide compound a 4: 1-benzyl-4-hydroxy-2-methyl-1H-benzimidazole-6-carboxylic acid;
(5) reacting compound a4, cuprous bromide, a basic compound, and a solvent to give compound a 5: 4-hydroxy-N, 2-trimethyl-1H-benzimidazole-6-carboxamide;
(6) reacting compound a5, (S) -5, 7-difluoro-3, 4-dihydro-2H-chromen-4-ol, a basic compound, and tetrahydrofuran to give compound a 6: tegolrazan;
wherein the chemical structure of Tegolazan is as follows:
2. the preparation method of tegolazan according to claim 1, wherein the reaction temperature in step (1) is 38-45 ℃; the reaction time is 20-26 h.
3. The method for preparing tegolrazan as claimed in claim 1 or 2, wherein the reaction temperature in the step (2) is-10 to 0 ℃; the reaction time is 1-6 h; the basic compound is triethylamine.
4. The method for preparing tegolazan according to claim 3, wherein the reaction temperature in step (3) is 80-90 ℃; the reaction time is 1-2 h.
5. The method for preparing Tegolazan according to claim 1, 2 or 4, wherein the reaction temperature in step (4) is 50-75 ℃; the reaction time is 9-12 h; the acidic compound is sulfuric acid, acetic acid or hydrochloric acid; the reducing agent is metal reducing agent, sodium hydrosulfite or triethyl orthoformate.
6. The method for preparing tegolrazan as claimed in claim 1 or 2, wherein the temperature of the reaction in the step (5) is 100-110 ℃; the reaction time is 6-9 h; the alkaline compound is sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the solvent is water.
7. The method for preparing tegolazan according to claim 6, wherein the reaction temperature in step (6) is-10 to 0 ℃; the reaction time is 1-3 h; the alkaline compound is potassium tert-butoxide, sodium ethoxide or sodium methoxide.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115536593A (en) * | 2022-10-28 | 2022-12-30 | 深圳市华先医药科技有限公司 | Scalable production method of 4-hydroxy-N, N, 2-trimethylbenzimidazole-6-formamide |
| CN115594639A (en) * | 2022-10-28 | 2023-01-13 | 深圳市华先医药科技有限公司（Cn） | Synthesis method of key intermediate of Tegolrazan |
| CN115894264A (en) * | 2022-12-09 | 2023-04-04 | 凤翔万生源医药科技有限公司 | Synthesis method of 4-amino-3-hydroxy toluic acid |
| WO2024045255A1 (en) * | 2022-08-30 | 2024-03-07 | 上海皓元医药股份有限公司 | Tegoprazan crystal form b and preparation method therefor |
| WO2024087157A1 (en) * | 2022-10-28 | 2024-05-02 | 深圳市华先医药科技有限公司 | Method for synthesizing key intermediate of tegoprazan |
| WO2024087155A1 (en) * | 2022-10-28 | 2024-05-02 | 深圳市华先医药科技有限公司 | Method for synthesizing 4-hydroxy-n,n,2-trimethylbenzimidazole-6-carboxamide |
| WO2024087156A1 (en) * | 2022-10-28 | 2024-05-02 | 深圳市华先医药科技有限公司 | Scalable production method for 4-hydroxy-n,n,2-trimethylbenzimidazole-6-carboxamide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007072146A1 (en) * | 2005-12-19 | 2007-06-28 | Pfizer Japan Inc. | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
| CN111303131A (en) * | 2020-03-19 | 2020-06-19 | 海门慧聚药业有限公司 | Tegoprazan (Tegoprazan) analogue and synthetic method thereof |
| CN112851646A (en) * | 2019-11-12 | 2021-05-28 | 中国医学科学院药物研究所 | Preparation method of Tegolrazan |
-
2022
- 2022-05-20 CN CN202210549838.0A patent/CN114805317A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007072146A1 (en) * | 2005-12-19 | 2007-06-28 | Pfizer Japan Inc. | Chromane substituted benzimidazoles and their use as acid pump inhibitors |
| CN112851646A (en) * | 2019-11-12 | 2021-05-28 | 中国医学科学院药物研究所 | Preparation method of Tegolrazan |
| CN111303131A (en) * | 2020-03-19 | 2020-06-19 | 海门慧聚药业有限公司 | Tegoprazan (Tegoprazan) analogue and synthetic method thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024045255A1 (en) * | 2022-08-30 | 2024-03-07 | 上海皓元医药股份有限公司 | Tegoprazan crystal form b and preparation method therefor |
| CN115536593A (en) * | 2022-10-28 | 2022-12-30 | 深圳市华先医药科技有限公司 | Scalable production method of 4-hydroxy-N, N, 2-trimethylbenzimidazole-6-formamide |
| CN115594639A (en) * | 2022-10-28 | 2023-01-13 | 深圳市华先医药科技有限公司（Cn） | Synthesis method of key intermediate of Tegolrazan |
| WO2024087157A1 (en) * | 2022-10-28 | 2024-05-02 | 深圳市华先医药科技有限公司 | Method for synthesizing key intermediate of tegoprazan |
| WO2024087155A1 (en) * | 2022-10-28 | 2024-05-02 | 深圳市华先医药科技有限公司 | Method for synthesizing 4-hydroxy-n,n,2-trimethylbenzimidazole-6-carboxamide |
| WO2024087156A1 (en) * | 2022-10-28 | 2024-05-02 | 深圳市华先医药科技有限公司 | Scalable production method for 4-hydroxy-n,n,2-trimethylbenzimidazole-6-carboxamide |
| CN115894264A (en) * | 2022-12-09 | 2023-04-04 | 凤翔万生源医药科技有限公司 | Synthesis method of 4-amino-3-hydroxy toluic acid |
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