WO2016045416A1 - 一种用于合成帕罗西汀的中间体及其制备方法和用途 - Google Patents
一种用于合成帕罗西汀的中间体及其制备方法和用途 Download PDFInfo
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- 0 *c1c(*)[n](C(C=Cc(cc2)ccc2F)=O)nc1* Chemical compound *c1c(*)[n](C(C=Cc(cc2)ccc2F)=O)nc1* 0.000 description 8
- SDXAWLJRERMRKF-UHFFFAOYSA-N Cc1cc(C)n[nH]1 Chemical compound Cc1cc(C)n[nH]1 SDXAWLJRERMRKF-UHFFFAOYSA-N 0.000 description 1
- TYBBZRMIEDZJDD-VMPITWQZSA-N Cc1cc(C)n[n]1C(/C=C/c(cc1)ccc1F)=O Chemical compound Cc1cc(C)n[n]1C(/C=C/c(cc1)ccc1F)=O TYBBZRMIEDZJDD-VMPITWQZSA-N 0.000 description 1
- ISMMYAZSUSYVQG-ZZXKWVIFSA-N OC(/C=C/c(cc1)ccc1F)=O Chemical compound OC(/C=C/c(cc1)ccc1F)=O ISMMYAZSUSYVQG-ZZXKWVIFSA-N 0.000 description 1
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- 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
- C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
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- C07C205/50—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
- C07C205/53—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
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- 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
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- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
- C07D405/06—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 carbon chain containing only aliphatic carbon atoms
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- the invention relates to the technical field of paroxetine, in particular to an intermediate of paroxetine, a preparation method thereof and use thereof.
- Paroxetine is indicated for the treatment of various types of depression, including depression with anxiety and reactive depression. Its chemical name is trans-(-)-3-[(1,3-benzodioxan-5-yl-oxy)methyl]-4-(4-fluorophenyl)piperidine, which has the following structure :
- the compound having the structure of the following formula III is a common intermediate for the synthesis of paroxetine.
- Tetrahedron: Asymmetry 22 (2011) 1-3 discloses the following method:
- the method provides a chiral amide (R)-3-(3-(4-fluorophenyl) propylene by reacting a chiral auxiliary (R)-4-phenyl-2-oxazolinone with p-fluorocinnamic acid.
- a chiral auxiliary (R)-4-phenyl-2-oxazolinone with p-fluorocinnamic acid.
- Sodium hydride, flammable and explosive requires harsh reaction conditions, does not utilize large-scale industrial production, and is repeatedly routed by a technician according to the method provided in the examples, and the obtained product has poor optical purity and low yield.
- the present invention provides the following technical solutions:
- R 2 , R 3 , R 4 are each independently hydrogen, C 1 -C 6 alkyl or C 6 -C 10 aryl;
- R 2 , R 3 , R 4 are each independently hydrogen, methyl, ethyl, propyl, phenyl, 4-methylphenyl, 3-methylphenyl.
- the compound of formula I is selected from the following structures:
- the present invention provides a process for the preparation of a compound of the formula III below,
- the compound of the formula I is reacted with the compound of the formula II in the presence of a complex of a chiral amine oxide L and a rare earth metal compound Ln(OTf) 3 in the presence of an organic base to obtain:
- R 1 is alkyl, phenyl or benzyl, preferably C 1 -C 6 alkyl, phenyl or benzyl;
- R 2 , R 3 , R 4 are each independently a C 1 -C 6 alkyl group or a C 6 -C 10 aryl group;
- the chiral amine oxide L has the following structure:
- the chiral amine oxide L is L-PiMe 2 having the following structure:
- R is 2,6-Me 2 C 6 H 3 .
- the Ln in the rare earth metal compound Ln(OTf) 3 is represented by a lanthanoid metal, and specifically may be La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb. , Lu.
- the rare earth metal compound Ln(OTf) 3 is yttrium triflate [Gd(OTf) 3 ], yttrium triflate [Ho(OTf) 3 ], ytterbium triflate [Yb] (OTf) 3 ], ytterbium triflate [Er(OTf) 3 ].
- the organic base is preferably an amine, specifically triethylamine, diisopropylethylamine, trimethylamine, tri-n-propylamine, tri-n-butylamine, dimethylaniline, diethylaniline, dimethylbenzyl Amine, diethylbenzylamine, 1,8-diazacyclo[5,4,0]undecene-7 (DBU).
- amine specifically triethylamine, diisopropylethylamine, trimethylamine, tri-n-propylamine, tri-n-butylamine, dimethylaniline, diethylaniline, dimethylbenzyl Amine, diethylbenzylamine, 1,8-diazacyclo[5,4,0]undecene-7 (DBU).
- the reaction solvent is selected from the group consisting of alkanes such as pentane, hexane, heptane, etc.; halogenated hydrocarbons such as dichloroethane, chloroform, etc.; aromatic hydrocarbons such as toluene, ethylbenzene, cumene; ethers , such as tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, etc., esters, such as ethyl acetate, isopropyl acetate, etc.;
- alkanes such as pentane, hexane, heptane, etc.
- halogenated hydrocarbons such as dichloroethane, chloroform, etc.
- aromatic hydrocarbons such as toluene, ethylbenzene, cumene
- ethers such as tetrahydrofuran, methyl tert-butyl
- the reaction temperature is preferably from 30 to 35 °C.
- the molar ratio of the compound of the formula I to L is preferably 1: (0.005 to 0.04), more preferably 1: (0.01 to 0.03).
- the molar ratio of the compound of the formula I to Ln(OTf) 3 is preferably 1: (0.005 to 0.04), more preferably 1: (0.01 to 0.03).
- the molar ratio of the compound of the formula I to the organic base is preferably 1: (1 to 4), more preferably 1: (1 to 2).
- the present invention provides a process for the preparation of a compound of formula I:
- R 2 , R 3 , R 4 have the same definitions as defined above.
- the dehydrating agent is preferably 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride (EDCI), 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate (HATU), dicyclohexylcarbodiimide (DCC), benzotriazol-1-yl-oxytripyrrolidinylphosphorus hexafluorophosphate PyBOP), etc.
- EDCI 1-ethyl-(3-dimethylaminopropyl)carbonyldiimide hydrochloride
- HATU 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate
- DCC dicyclohexylcarbodiimide
- the organic base is N-methylmorpholine, triethylamine, diisopropylethylamine, trimethylamine, tri-n-propylamine, tri-n-butylamine, dimethylaniline, diethylaniline, dimethylbenzylamine. , diethylbenzylamine or 1,8-diazacyclo[5,4,0]undecene-7 and the like.
- the reaction solvent is selected from the group consisting of alkanes such as pentane, hexane, heptane, etc.; halogenated hydrocarbons such as dichloroethane, chloroform, etc.; aromatic hydrocarbons such as toluene, ethylbenzene, cumene; ethers For example, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, etc., esters such as ethyl acetate, isopropyl acetate and the like.
- alkanes such as pentane, hexane, heptane, etc.
- halogenated hydrocarbons such as dichloroethane, chloroform, etc.
- aromatic hydrocarbons such as toluene, ethylbenzene, cumene
- ethers For example, tetrahydrofuran, methyl tert-butyl
- the reaction temperature of the reaction is from 20 ° C to reflux, preferably from 20 to 30 ° C.
- the molar ratio of the compound of the formula I to the dehydrating agent is preferably 1: (1 to 3), more preferably 1: (1 to 2).
- the molar ratio of the compound I to the organic base used in the preparation of the compound of the formula I is 1: (1 to 3), more preferably 1: (1 to 2).
- the present invention employs the following scheme to prepare a compound of formula I:
- the following compound of the formula IV is condensed with p-fluorocinnamic acid in the presence of a dehydrating agent and an organic base, and the resulting condensation product is concentrated and purified with an organic solvent to give the compound of the formula I.
- the solvent used in the purification process is one of hexane, heptane, petroleum ether, toluene, methyl tert-butyl ether (MTBE), ethyl acetate or a mixture of these;
- the preferred solvent for purification is Petroleum ether / ethyl acetate, heptane, hexane / ethyl acetate, or heptane / ethyl acetate, toluene, or MTBE.
- the conversion rate of the reaction raw material is high, and only the product obtained by the recrystallization operation can obtain a product with high yield and high optical purity, and thus has high industrial application value.
- Figure 1 is an HPLC chromatogram of the racemic control solution of the compound IIIa
- Example 3 is a hydrogen spectrum diagram of a compound of Ia prepared in accordance with Example 1.
- a pyrazole IV compound (30 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (30-45 mmol) were weighed sequentially into a 250 ml round bottom flask, N -Methylmorpholine (30-45 mmol) was added to 100-200 mL of dichloromethane to dissolve, then slowly add p-fluorocinnamic acid (30 mmol), react overnight, wash with water, concentrate and dry with petroleum ether / ethyl acetate (or g Crystallization of alkane, or hexane/ethyl acetate, or heptane/ethyl acetate, or toluene, or MTBE, affords 21-29 mmol of the pure fluorocinnamoylpyrazole compound III in a yield of 70-97%.
- EDCI 1-ethyl-(3-dimethylamin
- the compound of formula III can be prepared as follows:
- the metal catalyst Ln(OTf) 3 (0.01-0.03 mol), the chiral ligand L (0.02 mol), the fluorocinnamoylpyrazole III (0.2 mol), and the replacement of nitrogen three times were sequentially weighed. Adding 300 mL of dichloromethane to activate at 35 ° C for 10-30 min, sequentially adding monoamide II (0.2 mol) and Et 3 N (0.2-0.4 mol), and reacting at 30-50 ° C for 40-100 hours, the reaction solution is used. Wash with dilute hydrochloric acid, concentrate to dryness and crystallize from petroleum ether / ethyl acetate to give s.
- the metal catalyst Yb(OTf) 3 (0.02 mol), the chiral ligand L-PiMe 2 (0.02 mol), and the fluorocinnamoyl 3,5-dimethylpyrazole (0.2 mol) were weighed in order.
- nitrogen gas 3 times add 300mL dichloromethane to activate at 35 ° C for 20min, add monoamide (0.2mol) and Et 3 N (0.2mol), and react at 30-50 ° C for 60-80 hours, the reaction solution
- the organic layer was washed with dilute hydrochloric acid, concentrated and dried and purified from petroleum ether/ethyl acetate to give 51 g of catalyzed product.
- the yield was 87%
- HPLC purity was 94.65%, ee 99.12%
- the HPLC chromatogram of the product is shown in Fig. 2.
- Examples 3-10 are test data obtained by the same method as in Example 1:
- Examples 11-18 are test data obtained by the same method as in Example 2:
- Example 19 Test data obtained by the same procedure as in Example 2 using different catalysts L:
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Abstract
Description
Claims (10)
- 一种具有如下式III化合物的制备方法,由式I化合物与式II化合物在手性氧化胺L与稀土金属化合物Ln(OTf)3形成的络合物催化下,有机碱存在下进行反应制备得到:其中R1为烷基,苯基或苄基,优选为C1-C6的烷基,苯基或苄基;R2,R3,R4各自独立地为C1-C6的烷基或C6-C10芳基;所述的手性氧化胺L具有如下结构:其中n=1,2;R=Ph-,2,6-Me2C6H3-,2,6-Et2C6H3-,2,6-iPr2C6H3-,Ph2CH-;所述的稀土金属化合物Ln(OTf)3中的Ln表示为镧系金属,选自La,Ce,Pr,Nd,Pm,Sm, Eu,Gd,Tb,Dy,Ho,Er,Tm,Yb,Lu。
- 根据权利要求3所述的制备方法,其中所述有机碱为胺类。
- 根据权利要求3所述的制备方法,其中所述Ln(OTf)3为三氟甲磺酸钆[Gd(OTf)3]、三氟甲磺酸钬[Ho(OTf)3]、三氟甲磺酸镱[Yb(OTf)3]、三氟甲磺酸铒[Er(OTf)3]。
- 根据权利要求3所述的制备方法,其中所述有机碱为三乙胺,二异丙基乙胺,三甲胺,三正丙胺,三正丁胺,二甲基苯胺,二乙基苯胺,二甲基苄胺,二乙基苄胺或1,8-二氮杂环[5,4,0]十一烯-7。
- 根据权利要求3所述的制备方法,反应在溶剂戊烷、己烷、庚烷、二氯乙烷、氯仿、甲苯、乙苯、异丙苯、四氢呋喃、甲基叔丁基醚、2-甲基四氢呋喃、乙酸乙酯或乙酸异丙酯中进行。
- 根据权利要求8所述的制备方法,其中所述脱水剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐,2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、二环己基碳化二胺或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷。
- 根据权利要求8所述的制备方法,其中所述有机碱为N-甲基吗啉,三乙胺,二异丙基乙胺,三甲胺,三正丙胺,三正丁胺,二甲基苯胺,二乙基苯胺,二甲基苄胺,二乙基苄胺或1,8-二氮杂环[5,4,0]十一烯-7。
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EP15844676.5A EP3199526A4 (en) | 2014-09-22 | 2015-06-15 | Intermediate for use in synthesizing paroxetine, preparation method for the intermediate, and uses thereof |
US15/511,244 US9796675B1 (en) | 2014-09-22 | 2015-06-15 | Intermediate for synthesizing paroxetine, method for preparing the same, and uses thereof |
JP2017513185A JP2017529343A (ja) | 2014-09-22 | 2015-06-15 | パロキセチンを合成するための中間体およびその製造方法と用途 |
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CN201410486209.3 | 2014-09-22 | ||
CN201510291876.0A CN105418502B (zh) | 2014-09-22 | 2015-06-01 | 一种用于合成帕罗西汀的中间体及其制备方法和用途 |
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DE3680184D1 (de) * | 1985-08-10 | 1991-08-14 | Beecham Group Plc | Verfahren zur herstellung von arylpiperidincarbinol. |
WO2009005647A2 (en) * | 2007-06-27 | 2009-01-08 | Bioverdant, Inc. | Compounds and process to prepare chiral intermediates for synthesis of paroxetine |
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CN104262255A (zh) * | 2014-09-22 | 2015-01-07 | 四川大学 | 一种不对称催化合成γ-硝基吡唑酰胺化合物的方法 |
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SIBI, M.P. ET AL.: "Enantioselective Intermolecular Free Radical Conjugate Additions. Application of a Pyrazole Template", TETRAHEDRON LETTERS, vol. 38, no. 34, 31 December 1997 (1997-12-31), pages 5955 - 5958, XP004094160, DOI: doi:10.1016/S0040-4039(97)01353-1 * |
SOMAIAH, S. ET AL.: "An efficient and Stereoselective Synthesis of (3S, 4R)-(-)-trans-4-(4'-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine", TETRAHEDRON : ASYMMETRY, vol. 22, no. 1, 31 January 2011 (2011-01-31), pages 1 - 3, XP028144901, DOI: doi:10.1016/j.tetasy.2010.12.020 * |
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Publication number | Publication date |
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JP2017529343A (ja) | 2017-10-05 |
JP2017530956A (ja) | 2017-10-19 |
CN105985292B (zh) | 2019-05-10 |
CN105985292A (zh) | 2016-10-05 |
CN104262255A (zh) | 2015-01-07 |
US20170283380A1 (en) | 2017-10-05 |
US10464899B2 (en) | 2019-11-05 |
EP3199526A1 (en) | 2017-08-02 |
EP3199526A4 (en) | 2018-02-14 |
US9796675B1 (en) | 2017-10-24 |
EP3199525A1 (en) | 2017-08-02 |
CN105418502B (zh) | 2018-12-14 |
US20170291876A1 (en) | 2017-10-12 |
CN105418502A (zh) | 2016-03-23 |
EP3199525A4 (en) | 2018-02-14 |
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