CN105175337A - Preparation method of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine - Google Patents
Preparation method of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine Download PDFInfo
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- CN105175337A CN105175337A CN201510576332.9A CN201510576332A CN105175337A CN 105175337 A CN105175337 A CN 105175337A CN 201510576332 A CN201510576332 A CN 201510576332A CN 105175337 A CN105175337 A CN 105175337A
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- piperazine
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- pyrazoles
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- FBCUUXMVVOANMV-UHFFFAOYSA-N 1-(5-methyl-2-phenylpyrazol-3-yl)piperazine Chemical compound C=1C=CC=CC=1N1N=C(C)C=C1N1CCNCC1 FBCUUXMVVOANMV-UHFFFAOYSA-N 0.000 title abstract 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 62
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940067157 phenylhydrazine Drugs 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- TWAMXSFTMXVREE-UHFFFAOYSA-N COC(CCC)=O.[S] Chemical compound COC(CCC)=O.[S] TWAMXSFTMXVREE-UHFFFAOYSA-N 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003880 polar aprotic solvent Substances 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical group 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000007171 acid catalysis Methods 0.000 abstract description 2
- -1 nitrogen-containing heterocyclic compounds Chemical class 0.000 abstract description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 abstract 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000009413 insulation Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 6
- 229950000034 teneligliptin Drugs 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 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 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 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 3
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 3
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 3
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 231100000004 severe toxicity Toxicity 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 2
- 239000002574 poison Substances 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 1
- FXBGZKSYEGBDSQ-UHFFFAOYSA-N CNCCN(C)CN Chemical compound CNCCN(C)CN FXBGZKSYEGBDSQ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to the technical field of drug intermediate synthesis, in particular to the technical field of nitrogen-containing heterocyclic compounds and specifically discloses a preparation method of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine. The method is used for preparing the 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl) piperazine by using 3-oxy-dithiomethyl butyrate, piperazine and phenylhydrazine as starting materials through nucleophilic substitution and cyclization under acid catalysis. The preparation method has the advantages that the use of highly toxic or expensive reagent is avoided, the reaction steps are short, the safety is good, the operation is simple and convenient and the method is suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to the preparing technical field of nitrogen-containing heterocycle compound.
Background technology
The structural formula of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine is as follows:
，
It has a wide range of applications in pharmaceutical chemistry and organic synthesis field, especially as a kind of important intermediate of teneligliptin.
Teneligliptin; English name: Teneligliptin; chemistry 3-[[(2S by name; 4S)-4-[4-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base)-1-piperazinyl]-2-pyrrolidyl] formyl radical] thiazolidine; commodity are called Tenelia, and structural formula is as follows:
This medicine is by Mitsubishi Tian Bianyu the or three company's joint study exploitation altogether.Teneligliptin in September, 2011 in the granted listing of Japan, clinically for the treatment of type-II diabetes.
At present, formula
the preparation method of compound mainly contains several as follows:
1) the patent WO2002/014271 of Mitsubishi of Yuan Yan company pharmacy discloses the preparation method of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, and its reaction formula is as follows:
The method yield is extremely low, is not suitable for carrying out industrialized amplification and produces.
2) patent WO2012/099915 discloses the preparation method using palladium acetate catalyst coupling.Its reaction formula is as follows:
Although the method avoids the condensation reagent using high poison, use expensive palladium catalyst, cost is very high.
3) the patent WO2012/165547 of Mitsubishi of Yuan Yan company pharmacy discloses the preparation method of another kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, the method for condensation reagent with the tetraphosphorus decasulfide of severe toxicity, is not suitable for carrying out industrialized amplification and produces.
4) patent CN103275010 discloses the preparation method that condensation reagents such as using Lawesson replaces the tetraphosphorus decasulfide of high poison.The condensation reagents such as Lawesson that the method uses are still expensive, and production cost is very high, are not suitable for carrying out industrialized amplification and produce.
Summary of the invention
The technical problem to be solved in the present invention is to provide the preparation method of a kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, do not use the reagent of severe toxicity or costliness, pollute few, yield is higher, cost is low, have that reactions steps is short, security good, advantage easy and simple to handle, be suitable for large-scale industrial production, the intermediate be particularly suited for as teneligliptin medicine synthesizes simultaneously.
For solving the problems of the technologies described above, the technical solution used in the present invention is: the preparation method of a kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, piperazine (formula III) and 3-oxygen-two sulphur methyl-butyrate (formula IV) are joined in polar aprotic solvent and reacts, gained reaction solution reacts under catalyst with phenylhydrazine (formula II) again, and products therefrom is purified through aftertreatment and obtained 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine (formula
); Its reaction formula is
。
Further, temperature of reaction is 70 ~ 80 DEG C.
Further, described polar aprotic solvent is methyl alcohol, ethanol, water or Virahol.
Further, described polar aprotic solvent is ethanol.
Further, described catalyzer is organic acid.
Further, described catalyzer is glacial acetic acid or tosic acid.
Further, the ratio of the amount of substance of described piperazine, 3-oxygen-two sulphur methyl-butyrate, phenylhydrazine is 1:(1.05 ~ 1.3): (1.05 ~ 1.3).
Further, the ratio of the amount of substance of described piperazine, 3-oxygen-two sulphur methyl-butyrate, phenylhydrazine is 1:1.1:1.1.
The beneficial effect adopting technique scheme to produce is:
1) the inventive method is prepared easy, and processing condition are reasonable, and pollute few, reaction yield is high;
2) the inventive method operational condition is easy to control, and catalytic reagent is easy to get, and reactions steps is short, and can obtain product by single step reaction, the cycle is short, and cost is low, is suitable for suitability for industrialized production, has larger implementary value and economic results in society.
Embodiment
The invention provides a kind of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine (formula
) preparation method, with 3-oxygen-two sulphur methyl-butyrate (formula IV), piperazine (formula III) and phenylhydrazine (formula II) for starting raw material, by nucleophilic substitution, cyclization under acid catalysis, can obtain Compound I.
Reaction formula is as follows:
The method overcome the shortcoming using severe toxicity or expensive reagent in prior art, cost is low, yield is high, is suitable for suitability for industrialized production, high financial profit.
Illustrate below and the present invention is described in further detail.
Embodiment 1
Ethanol 500ml is added in the 1L four-hole bottle of dried and clean, open stirring, add 50.0g(337mmol again) compound IV and 30.5g(354mmol) compound III, system is warming up to 70 ~ 80 DEG C of insulation 5h, again reaction system is cooled to 45 ~ 50 DEG C, adds phenylhydrazine 38.3g(354mmol), add glacial acetic acid 0.5g, system is warming up to again 70 ~ 80 DEG C of insulation reaction 2h, sampling tracks to and reacts completely.Reaction is finished, system is cooled to 40 ~ 45 DEG C, be evaporated to substantially without cut, system is cooled to 20 ~ 30 DEG C and adds tap water 300ml again, drip concentrated hydrochloric acid and regulate pH=2 ~ 3, aqueous phase uses Iso Butyl Acetate 200ml to extract 2 times, aqueous phase re-uses 30% sodium hydroxide and regulates pH to 10 ~ 11, off-white color solid is had to separate out, filter after system being cooled to 0 ~ 5 DEG C of insulation 1h and obtain 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine (formula I) crude product, second alcohol and water (1:8) recrystallizing and refining is used to obtain 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine white solid.Yield 82.5%.
H-NMR（300MHz，DMSO-D6）d1.87(3H,s),2.14(3H,m),2.72–2.74(8H,m),5.77(1H,m),7.26(1H,t),7.44(2H,t,J=7.8Hz),47.74(2H,d,J=7.8Hz)。
Embodiment 2
Ethanol 500ml is added in the 1L four-hole bottle of dried and clean, open stirring, add 50.0g(337mmol again) compound IV and 37.7g(438mmol) compound III, system is warming up to 70 ~ 80 DEG C of insulation 5h, again reaction system is cooled to 45 ~ 50 DEG C, adds phenylhydrazine 47.4g(438mmol), add glacial acetic acid 0.5g, system is warming up to 70 ~ 80 DEG C of insulation 2h, sampling tracks to and reacts completely.Reaction is finished, system is cooled to 40 ~ 45 DEG C, be evaporated to substantially without cut, system is cooled to 20 ~ 30 DEG C and adds tap water 300ml again, drip concentrated hydrochloric acid and regulate pH=2 ~ 3, aqueous phase uses Iso Butyl Acetate extraction (each 200ml, extract 2 times), aqueous phase re-uses 30% sodium hydroxide and regulates pH to 10 ~ 11, off-white color solid is separated out, filter after system being cooled to 0 ~ 5 DEG C of insulation 1h and obtain 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine (I) crude product, second alcohol and water (1:8) recrystallizing and refining is used to obtain 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine (I) white solid.Yield 85.1%.
H-NMR（300MHz，DMSO-D6）d1.87(3H,s),2.14(3H,m),2.72–2.74(8H,m),5.77(1H,m),7.26(1H,t),7.44(2H,t,J=7.8Hz),47.74(2H,d,J=7.8Hz)。
Embodiment 3
Ethanol 500ml is added in the 1L four-hole bottle of dried and clean, open stirring, add 50.0g(337mmol again) compound IV and 31.9g(371mmol) compound III, system is warming up to 70 ~ 80 DEG C of insulation 5h, again reaction system is cooled to 45 ~ 50 DEG C, adds phenylhydrazine 40.1g(371mmol), add glacial acetic acid 0.5g, system is warming up to 70 ~ 80 DEG C of insulation 2h, sampling tracks to and reacts completely.Reaction is finished, system is cooled to 40 ~ 45 DEG C, be evaporated to substantially without cut, system is cooled to 20 ~ 30 DEG C and adds tap water 300ml again, drip concentrated hydrochloric acid and regulate pH=2 ~ 3, aqueous phase uses Iso Butyl Acetate extraction, each 200ml, extract 2 times, aqueous phase re-uses 30% sodium hydroxide and regulates pH to 10 ~ 11, off-white color solid is separated out, filter after system being cooled to 0 ~ 5 DEG C of insulation 1h and obtain 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine (I) crude product, second alcohol and water (1:8) recrystallizing and refining is used to obtain 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine (formula I) white solid.Yield 86.2%.
H-NMR（300MHz，DMSO-D6）d1.87(3H,s),2.14(3H,m),2.72–2.74(8H,m),5.77(1H,m),7.26(1H,t),7.44(2H,t,J=7.8Hz),47.74(2H,d,J=7.8Hz)。
Application embodiment of the present invention method, compared to the method for patent WO2012/099915, obtained formula I product cost reduces about 30%.
Application embodiment of the present invention method, compared to the method for patent CN103275010, obtained formula I product cost reduces about 20%.
Claims (8)
1. the preparation method of 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, it is characterized in that: piperazine (formula III) and 3-oxygen-two sulphur methyl-butyrate (formula IV) are joined in polar aprotic solvent and reacts, gained reaction solution reacts under catalyst with phenylhydrazine (formula II) again, and products therefrom obtains 1-(3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine (formula through aftertreatment
); Its reaction formula is
。
2. the preparation method of a kind of 1-according to claim 1 (3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, is characterized in that temperature of reaction is 70 ~ 80 DEG C.
3. the preparation method of a kind of 1-according to claim 1 (3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, is characterized in that described polar aprotic solvent is methyl alcohol, ethanol, water or Virahol.
4. the preparation method of a kind of 1-according to claim 3 (3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, is characterized in that described polar aprotic solvent is ethanol.
5. the preparation method of a kind of 1-according to claim 1 (3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, is characterized in that described catalyzer is organic acid.
6. the preparation method of a kind of 1-according to claim 5 (3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, is characterized in that described catalyzer is glacial acetic acid or tosic acid.
7. the preparation method of a kind of 1-according to claim 1 (3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, is characterized in that the ratio of the amount of substance of described piperazine, 3-oxygen-two sulphur methyl-butyrate, phenylhydrazine is 1:(1.05 ~ 1.3): (1.05 ~ 1.3).
8. the preparation method of a kind of 1-according to claim 1 (3-methyl isophthalic acid-phenyl-1H-pyrazoles-5-base) piperazine, is characterized in that the ratio of the amount of substance of described piperazine, 3-oxygen-two sulphur methyl-butyrate, phenylhydrazine is 1:1.1:1.1.
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2015
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