CN104292209A - Novel method for preparing 2-(4-fluorophenyl) thiophene (compound V) - Google Patents
Novel method for preparing 2-(4-fluorophenyl) thiophene (compound V) Download PDFInfo
- Publication number
- CN104292209A CN104292209A CN201410461699.1A CN201410461699A CN104292209A CN 104292209 A CN104292209 A CN 104292209A CN 201410461699 A CN201410461699 A CN 201410461699A CN 104292209 A CN104292209 A CN 104292209A
- Authority
- CN
- China
- Prior art keywords
- thiophene
- fluoroaniline
- para
- fluorophenyl
- acid
- 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
- 238000000034 method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 title claims abstract description 20
- PURJRGMZIKXDMW-UHFFFAOYSA-N 2-(4-fluorophenyl)thiophene Chemical compound C1=CC(F)=CC=C1C1=CC=CS1 PURJRGMZIKXDMW-UHFFFAOYSA-N 0.000 title claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 51
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract description 50
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000003756 stirring Methods 0.000 claims abstract description 39
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 229930192474 thiophene Natural products 0.000 claims abstract description 25
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 239000003513 alkali Substances 0.000 claims abstract description 20
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 15
- 239000012954 diazonium Substances 0.000 claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000001989 diazonium salts Chemical class 0.000 claims abstract description 9
- -1 para-fluoroaniline diazonium salt Chemical class 0.000 claims abstract description 4
- 239000012044 organic layer Substances 0.000 claims abstract description 3
- 238000009413 insulation Methods 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- 238000000605 extraction Methods 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 14
- 239000002994 raw material Substances 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 238000004886 process control Methods 0.000 claims description 2
- 238000004821 distillation Methods 0.000 abstract description 15
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 5
- 238000005859 coupling reaction Methods 0.000 abstract description 5
- 238000001816 cooling Methods 0.000 abstract description 4
- 238000006193 diazotization reaction Methods 0.000 abstract description 3
- 238000001035 drying Methods 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229960001713 canagliflozin Drugs 0.000 description 3
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- OHOVBSAWJQSRDD-UHFFFAOYSA-N thiophen-2-yloxyboronic acid Chemical compound OB(O)OC1=CC=CS1 OHOVBSAWJQSRDD-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/12—Radicals substituted by halogen atoms or nitro or nitroso radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a novel method for preparing 2-(4-fluorophenyl) thiophene (a compound V). The method comprises the following steps: 1, adding para-fluoroaniline, alcohol, thiophene and copper powder into a reaction bottle, uniformly stirring, and cooling to 0-5 DEG C; adding a certain amount of acid, stirring and cooling to 0-5 DEG C; adding a certain amount of sodium nitrite, controlling the temperature to 0-5 DEG C in the adding process; insulating for 2 hours to obtain para-fluoroaniline diazonium salt; 2, intensively stirring the prepared diazonium salt, cooling to 0-5 DEG C, dripping alkali liquor into the diazonium salt, and strictly controlling the reaction temperature to 0-5 DEG C in the dripping process; insulating the reaction liquid for 5 hours at 0-5 DEG C; then distilling to reclaim solvent, extracting by chloroform, drying the solvent by distillation in an organic layer, and recrystallizing residues by methanol to obtain the final product 2-(4-fluorophenyl) thiophene. The method adopts diazotization and coupling reaction, is mild in reacting condition and low in operation requirement, and can realize industrial implementation easily.
Description
Technical field
The invention belongs to medicine intermediate manufacturing technology field, prepare the preparation of required key intermediate in the process of Novel diabetes medicine canagliflozin specifically, especially one prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V).
Background technology
Canagliflozin is a kind of newtype drug for the treatment of diabetes, and obtain U.S. FDA approval in March, 2013, its structural formula is for shown in I:
Patent WO2005012326 describes the preparation method of Compound I as shown in equation one:
Obtain compound IV by Compound II per and compound III condensation, then reduction obtains Compound I, i.e. Novel diabetes medicine canagliflozin.The general preparation method of its Compound II per used is:
Method shown in equation two to equation five, is described in detail in patent US20100099883.Be all first prepare key intermediate V, and then through acidylate, reduction, obtain Compound II per.Preparing in the method for V described, or use boric acid compound, or use Grignard reagent, is not that raw material is difficult to obtain, and is exactly that reaction process requires high, and has certain potential safety hazard.
Reactive mode represented by equation two, uses 2-thienyl boric acid, is the compound that business is difficult to obtain, and needs oneself to prepare, and preparation process needs the cold condition of-78 DEG C, and need use the valuable raw materials such as butyllithium.Not only reaction conditions is harsher, and part material is expensive, must increase manufacturing cost.
Reactive mode represented by equation three, uses 4-fluorobenzoic boric acid, although there is supply of commodities, expensive, and the finished product manufacturing cost can be made to increase.
Equation four and the reactive mode described by equation five, play the same tune on different musical instruments, and needs to use Grignard reagent, high to environmental requirement in the process of preparation, requires anaerobic waterless operation, is easy to cause security incident when operating not in place.In order to solve the problem existing for above technique, production method is extremely urgent more easily to find one.
Summary of the invention
The object of the invention is for the deficiencies in the prior art, provide one to prepare the novel method of 2-(4-fluorophenyl) thiophene (compound V).The present invention by para-fluoroaniline diazotization, and then and thiophene coupling, obtain key intermediate compound V, can Compound II per be obtained further across acidylate, reduction.
The technical solution adopted for the present invention to solve the technical problems is as follows:
Reaction formula of the present invention is as follows:
Preparation method of the present invention specifically comprises the steps:
Step 1. prepares diazonium salt:
In reaction flask, add para-fluoroaniline, alcohol, thiophene and copper powder, stir, be cooled to 0-5 DEG C, then add a certain amount of acid.Then stir and be cooled to 0-5 DEG C, add a certain amount of Sodium Nitrite, adition process control temperature 0-5 DEG C.Add rear insulation 2 hours, obtain para-fluoroaniline diazonium salt.
The consumption of described thiophene, its molar weight be the 1-10 of para-fluoroaniline molar weight doubly, as preferentially, the molar weight of described thiophene be the 3-5 of para-fluoroaniline molar weight doubly.
Described alcohol comprises propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol; As preferentially, described alcohol is Virahol;
The quality of described alcohol be the 0-10 of para-fluoroaniline quality in raw material doubly, as preferentially, the quality of described alcohol be the 1-2 of para-fluoroaniline quality in raw material doubly.
Described alcohol has certain water-soluble and fat-soluble as solvent, can promote dissolving each other of diazonium salt and thiophene, accelerated reaction is carried out.
The quality of described catalyst copper powder is the 0.5-20% of para-fluoroaniline quality in raw material, and as preferentially, the quality of described catalyzer copper is the 5-10% of para-fluoroaniline quality in raw material.
Described acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid; As preferentially, described acid is hydrochloric acid.
Described a certain amount of acid, the molar weight of its acid is 1.5-2.5 times of para-fluoroaniline molar weight; As preferentially, the molar weight of described acid is 2.05 times of para-fluoroaniline molar weight.
The molar weight of described a certain amount of Sodium Nitrite is identical with para-fluoroaniline molar weight.
Step 2. linked reaction:
By step 1 gained diazonium salt, vigorous stirring, is cooled to 0-5 DEG C, then drips a certain amount of alkali lye wherein, drips in 5-8 hour, and dropping process strictly controls temperature of reaction between 0-5 DEG C, adds the pH value of rear reaction solution between 6-8; And reaction solution is incubated 5 hours at 0-5 DEG C.Then distillating recovering solvent, chloroform extraction, organic layer solvent evaporated, obtains to obtain target product 2-(4-fluorophenyl) thiophene after residue recrystallizing methanol.
Its rotating speed of described vigorous stirring is at more than 600rmp;
Described a certain amount of alkali lye is the alkali lye of mass concentration 15%, and its consumption is 1/2nd of the mole number of acid in step 1.
The alcoholic solvent that step 2 uses by the present invention, reaction raw materials thiophene, catalyst copper powder start to add reactor cooling together with para-fluoroaniline in step 1 most, are conducive to ensureing that diazonium salt is in low-temperature condition all the time.
Beneficial effect of the present invention is as follows:
The present invention prepares compound V by the method for diazonium coupling, and reaction conditions milder used, operational requirement is low, is easy to industrializing implementation.The reaction used is diazotization, coupling, and operating environment is without particular requirement, easy and simple to handle, and equipment requirements is low, and two-step reaction can have been cooked different foods in one pot in same reactor.Specifically, the present invention is the diazonium salt first para-fluoroaniline being made para-fluoroaniline, and then and thiophene generation coupling, namely obtain target compound of the present invention.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment 1
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 50g (0.41mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 2g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 13g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H)。
Embodiment 2
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, propyl carbinol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 50g (0.41mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 2g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 11g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 3
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, propyl alcohol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 50g (0.41mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 2g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 8g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 4
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, isopropylcarbinol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 50g (0.41mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 2g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 10g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 5
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 160g (1.90mol), stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 37.5g (0.31mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 2g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 45g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 7g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 6
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 62.5g (0.51mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 1.12g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 80g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 10g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 7
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 224g, thiophene 2.0mol, stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 0.31mol, control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 2g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 13g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 8
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 50g (0.41mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 2.24g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 2g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 9
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 0.5mol, control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 0.112g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 9g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 10
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 0.2mol, stir and be cooled to 0-5 DEG C, drip concentrated hydrochloric acid 50g (0.41mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 4g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, within 5-8 hour, add, adjust reaction solution pH6-8.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 13g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 11
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip vitriol oil 40g (0.40mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 4g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, between measured reaction liquid pH value 6-8, about 5-8 hour adds.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 5g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 12
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip phosphatase 24 8g (0.41mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 4.48g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, between measured reaction liquid pH value 6-8, about 5-8 hour adds.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 6g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 13
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip acetic acid 24.8g (0.41mol), control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 4g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, between measured reaction liquid pH value 6-8, about 5-8 hour adds.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 6.2g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Embodiment 14
In 500ml flask, throw para-fluoroaniline 22.4g (0.20mol), water 10g, Virahol 25g, thiophene 53g (0.63mol), stir and be cooled to 0-5 DEG C, drip propionic acid 0.5mol, control below 5 DEG C.Add stirring and be cooled to 0-5 DEG C, add copper powder 4g, then drip Sodium Nitrite 14.4g and to add water the solution that 30g is made into, control below 5 DEG C.Add rear insulation 2 hours, drip 15% alkali lye and be about 60g, between measured reaction liquid pH value 6-8, about 5-8 hour adds.In 0-5 DEG C of insulation 5 hours after adding, distillation, adds 100ml chloroform extraction, solvent evaporated, recrystallizing methanol.Obtain product 6.2g.
1H-NMR(DMSO-d
6,400MHZ)δ7.67(t,2H),7.50(d,1H),7.44(d,1H),7.23(t,2H),7.12(d,1H).
Claims (9)
1. prepare a novel method for 2-(4-fluorophenyl) thiophene (compound V), it is characterized in that reaction formula is as follows:
Specifically comprise the steps:
Step 1. prepares diazonium salt:
In reaction flask, add para-fluoroaniline, alcohol, thiophene and copper powder, stir, be cooled to 0-5 DEG C, then add a certain amount of acid; Then stir and be cooled to 0-5 DEG C, add a certain amount of Sodium Nitrite, adition process control temperature 0-5 DEG C; Add rear insulation 2 hours, obtain para-fluoroaniline diazonium salt;
The consumption of described thiophene, its molar weight is 1-10 times of para-fluoroaniline molar weight;
Described alcohol comprises propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol; The quality of described alcohol is 0-10 times of para-fluoroaniline quality in raw material;
The quality of described catalyst copper powder is the 0.5-20% of para-fluoroaniline quality in raw material;
Described acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid; Described a certain amount of acid, the molar weight of its acid is 1.5-2.5 times of para-fluoroaniline molar weight;
The molar weight of described Sodium Nitrite is identical with para-fluoroaniline molar weight;
Step 2. linked reaction:
By step 1 gained diazonium salt, vigorous stirring, is cooled to 0-5 DEG C, then drips a certain amount of alkali lye wherein, drips in 5-8 hour, and dropping process strictly controls temperature of reaction between 0-5 DEG C, adds the pH value of rear reaction solution between 6-8; And reaction solution is incubated 5 hours at 0-5 DEG C; Then distillating recovering solvent, chloroform extraction, organic layer solvent evaporated, obtains to obtain target product 2-(4-fluorophenyl) thiophene after residue recrystallizing methanol.
2. one as claimed in claim 1 prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V), it is characterized in that the consumption of described thiophene, and its molar weight is 3-5 times of para-fluoroaniline molar weight.
3. one as claimed in claim 1 prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V), it is characterized in that described alcohol is Virahol.
4. one as claimed in claim 1 prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V), and the quality of the alcohol that it is characterized in that is 1-2 times of para-fluoroaniline quality in raw material.
5. one as claimed in claim 1 prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V), it is characterized in that the quality of described catalyzer copper is the 5-10% of para-fluoroaniline quality in raw material.
6. one as claimed in claim 1 prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V), it is characterized in that described acid is hydrochloric acid.
7. one as claimed in claim 1 prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V), it is characterized in that the molar weight of described acid is 2.05 times of para-fluoroaniline molar weight.
8. one as claimed in claim 1 prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V), it is characterized in that its rotating speed of described vigorous stirring is at more than 600rmp.
9. one as claimed in claim 1 prepares the novel method of 2-(4-fluorophenyl) thiophene (compound V), it is characterized in that its mass concentration of a certain amount of alkali lye described in step 2 is 15%, consumption is 1/2nd of the mole number of acid in step 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410461699.1A CN104292209A (en) | 2014-09-11 | 2014-09-11 | Novel method for preparing 2-(4-fluorophenyl) thiophene (compound V) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410461699.1A CN104292209A (en) | 2014-09-11 | 2014-09-11 | Novel method for preparing 2-(4-fluorophenyl) thiophene (compound V) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104292209A true CN104292209A (en) | 2015-01-21 |
Family
ID=52312197
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410461699.1A Pending CN104292209A (en) | 2014-09-11 | 2014-09-11 | Novel method for preparing 2-(4-fluorophenyl) thiophene (compound V) |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104292209A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106167480A (en) * | 2016-07-20 | 2016-11-30 | 浙江永太科技股份有限公司 | A kind of preparation method of canagliflozin intermediate 2 (4 fluorophenyl) thiophene |
| CN112125879A (en) * | 2020-09-29 | 2020-12-25 | 浙江永太科技股份有限公司 | Preparation method of canagliflozin intermediate 2- (4-fluorophenyl) thiophene |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829729A (en) * | 2003-08-01 | 2006-09-06 | 田边制药株式会社 | novel compound |
| CN102264714A (en) * | 2008-10-17 | 2011-11-30 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of sglt |
-
2014
- 2014-09-11 CN CN201410461699.1A patent/CN104292209A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1829729A (en) * | 2003-08-01 | 2006-09-06 | 田边制药株式会社 | novel compound |
| CN102264714A (en) * | 2008-10-17 | 2011-11-30 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of sglt |
Non-Patent Citations (2)
| Title |
|---|
| L.H.KLEMM ET AL.，: "Competitive Free Radical 4-Nitrophenylation of Pyridine and Thiophene", 《J. HETEROCYCLIC CHEM.》, vol. 28, 31 July 1991 (1991-07-31), pages 1153 - 1155 * |
| 南京大学化学系有机化学教研组: "《有机化学 下册》", 30 May 1962, article "重氮和偶氮化合物", pages: 412-413 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106167480A (en) * | 2016-07-20 | 2016-11-30 | 浙江永太科技股份有限公司 | A kind of preparation method of canagliflozin intermediate 2 (4 fluorophenyl) thiophene |
| CN112125879A (en) * | 2020-09-29 | 2020-12-25 | 浙江永太科技股份有限公司 | Preparation method of canagliflozin intermediate 2- (4-fluorophenyl) thiophene |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103864332B (en) | A kind of preparation method of collapse protection type naphthalene water reducer | |
| CN105254603A (en) | Synthetic technology of furan ammonium salt | |
| CN104004510B (en) | There is piezoluminescence and the luminous organic material and its synthetic method of aggregation-induced emission performance and application simultaneously | |
| CN105037139B (en) | A kind of 2 phenylpropionic acid preparation methods | |
| CN104292209A (en) | Novel method for preparing 2-(4-fluorophenyl) thiophene (compound V) | |
| CN106187709A (en) | A kind of preparation method of 1 hydroxyl pyrene | |
| CN102627627A (en) | Synthesis method of 2-thiophenecarboxaldehyde | |
| CN103922933A (en) | Preparation method of ethyl lactate | |
| CN101863912A (en) | Preparation method of cyclopropylboronic acid | |
| CN105601533B (en) | Industrial method for synthesizing O-chloropropene hydroxylamine by one-pot method | |
| CN106316892A (en) | Synthetic method of sodium houttuyfonate | |
| CN113024499A (en) | Green synthesis method of coumarin-3-carboxylic acid compounds | |
| CN102993156B (en) | Preparation method of aryl-substituted-naphthopyran photochromic compounds | |
| CN115304542B (en) | A kind of synthesis technology of 3-hydroxypyridine | |
| CN103012046A (en) | Method for extracting industrial naphthalene from coal tar | |
| CN101775029A (en) | Convenient synthesis method for alkyl substitution phenyloboricacid | |
| CN106478422A (en) | A kind of preparation method of paranitrophenylacetic acid | |
| CN105037127A (en) | Preparation method for ketoprofen | |
| CN102718785B (en) | The preparation method of aromatic ring boric acid | |
| CN101812061B (en) | Method for producing tetrahydroberineper from berberine hydrochloride | |
| CN102070426B (en) | Method for synthesizing flocumafen intermediate | |
| CN105085190A (en) | Preparing method of 2,6-difluoro-4-bromophenol | |
| CN107892665B (en) | Preparation method of N-ethyl-2-acetyl pyrrole | |
| CN103965160A (en) | Synthesis method of hydrogen sulfate clopidogrel intermediate derivative | |
| CN100360482C (en) | Method for preparing 1,3-dimethyladamantane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20150121 |