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CN111533682B - Process for preparing paroxetine and analogues thereof - Google Patents

Process for preparing paroxetine and analogues thereof Download PDF

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CN111533682B
CN111533682B CN202010482067.9A CN202010482067A CN111533682B CN 111533682 B CN111533682 B CN 111533682B CN 202010482067 A CN202010482067 A CN 202010482067A CN 111533682 B CN111533682 B CN 111533682B
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paroxetine
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CN111533682A (en
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祖连锁
陈露
张智
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Tsinghua University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/98—Nitrogen atom
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
    • B01J31/0274—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 containing silicon
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    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
    • B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
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    • 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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Abstract

The invention provides a preparation method for synthesizing paroxetine and analogues thereof, and provides an intermediate compound for synthesizing paroxetine and analogues thereof:
Figure DDA0002516230530000011
the invention creatively adopts the steps of firstly constructing a chiral center, then being adjacent according to the position of two chiral centers to be constructed, and receiving a first chiral group Rb(e.g., 4-F-phenyl) steric hindrance, and the desired trans product is formed more efficiently without the use of a chiral catalyst during the reduction. With R being employed from the beginning of the reaction2NH-as an N-protecting group on the piperidine ring, avoiding the use of methyl protection leads to unavoidable demethylationThree toxic methyl-containing impurities are generated; the invention opens up a brand new reaction route for the synthesis of the paroxetine and the analogues thereof, and improves the yield and the chiral purity of the product; meanwhile, intermediates for synthesizing paroxetine and analogues thereof are enriched.

Description

Process for preparing paroxetine and analogues thereof
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of paroxetine and analogues thereof.
Background
Substituted piperidines having bimanual centers are often used for the treatment of depression and other diseases, for example, patent document CN1256692A describes in claim 1a compound having formula I and its pharmaceutically acceptable salts, and claim 13 describes the use of such compounds in the preparation of antidepressant drugs. CN1256692A the formula of the compound of formula I is as follows:
Figure BDA0002516230510000011
of the class of drugs that are on the market, the most successful is paroxetine. Paroxetine (parooxetine) is an antidepressant drug developed by Kurarin Schker (GSK) in the United states and approved for marketing in 1992, with a peak global sales of up to $ 33 billion. After the patent is over in 2006, a plurality of imitation medicines come into the market in China, the largest three of them are Zhejiang Huahai medicine industry, Zhejiang Hengjian medicine industry and Beijing Wansheng medicine industry, and the domestic sales in 2018 still have 9 hundred million yuan. The structural formula of paroxetine is as follows:
Figure BDA0002516230510000012
the piperidine ring of the drug has two adjacent chiral centers, and both asymmetric catalytic reaction and chiral resolution are difficult. The existing synthesis method of paroxetine generally comprises the steps of firstly synthesizing a racemate and then carrying out chiral resolution by using a resolving agent to establish a chiral center, wherein the synthesis route is shown as the following figure:
Figure BDA0002516230510000021
the heart of this reaction route is chiral resolution and protection of secondary amino groups with methyl groups. In the resolution, the first CN1096054A uses enzyme to assist resolution, the WO0146148a1 and the WO0129032a1 use (-) dibenzoyl tartrate as a resolving agent to resolve in a composite solvent such as methanol, acetone and toluene, the CN101974604A uses enzyme to resolve in an ionic liquid, and the yield of the above methods is about 40%.
The methyl group is introduced from the starting N-methylmalonic acid monoester in the preparation of compound 1, see paragraph 0005 of the specification of CN 104892491A. Since the secondary amino group participates in the reaction when the intermediate 3 is reacted to prepare the intermediate 4, the secondary amino group needs to be protected objectively, and other cheap raw materials are not found, and no attention is paid to the improvement of the position since the route is disclosed so far.
The existing synthesis method of paroxetine has the following problems:
1. due to N-CH3The bond energy between the two is high, so that violent reaction conditions cannot be used in order to avoid destroying C-O bonds in molecules, and the final step of demethylation cannot be completely reacted easily. The presence of N-CH in the final product3Wherein impurities II and B are described in chinese pharmacopoeia, impurities G is described in european pharmacopoeia, and impurities B is described in us pharmacopoeia. In particular, impurity II, which differs from the paroxetine molecule by only one methyl group, results in difficulty in removal, greatly increasing production costs.
Figure BDA0002516230510000031
2. In the second step, a chiral center is established by utilizing a traditional resolution mode, the compound 2 has two chiral centers, four chiral compounds with different configurations exist, and the resolved target product compound 3 is only one of the chiral compounds, so that although technical personnel exhaust various efforts in the last thirty years, the cost of a resolved solvent is only reduced, the yield can only reach about 40 percent at most, and the improvement is difficult in the future, so that the serious waste of resources is caused;
3. the reduction of the carbonyl group in the first amide step requires the use of strong reducing agents, such as Lithium Aluminum Hydride (LAH) and the like, which are relatively demanding to operate: low temperature and no water are required, and quenching is needed after reaction; but also generates a large amount of aluminum salt waste, and has large environmental protection pressure.
In view of the problems of the above routes, although it is very difficult to construct two chiral centers in a one-step reaction, and the skilled person has also tried chiral synthesis, the results are not ideal, for example, CN104892491A uses quinine and other groups as an assistant, and only the optical purity of the prepared intermediate 1 is improved, and then the intermediate still needs to be resolved; CN105418502A requires expensive rare earth metal catalyst and chiral auxiliary agent for generating two chiral centers at the same time, and the route still introduces N-CH3。
Based on the above problems of the existing methods for synthesizing paroxetine and analogues thereof, a brand new synthetic route needs to be designed, and the development of a preparation method of paroxetine and analogues thereof, which has few toxic impurities, high yield, mild conditions and low cost, is a technical problem to be solved urgently at present.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to overcome the defects of the synthesis method of paroxetine and analogues thereof in the prior art, so as to provide a preparation method of paroxetine and analogues thereof, a key intermediate used in the preparation method and a synthesis method of the intermediate.
Therefore, the invention provides the following technical scheme:
the invention provides a chiral center-containing piperidine compound of formula XI or IV, having the structure shown below:
Figure BDA0002516230510000041
wherein R isaIs selected from-COOR1or-CH2OR3；
R1Is selected from C1-8Straight or branched alkyl, C3-8A cycloalkyl group; preferably C1-4Straight or branched alkyl, C5-6Ring ofAn alkyl group; the alkyl or cycloalkyl group may be substituted by F, unsubstituted or by F, trifluoromethyl, C1-3Alkyl substituted phenyl; more preferred R1Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl or benzyl;
R2selected from unsubstituted or substituted 5-to 10-membered aryl, heteroaryl, preferably unsubstituted or substituted phenyl;
R3selected from H, C1-8Straight or branched alkyl, C3-8Any one of a cycloalkyl group, an unsubstituted or substituted 5-10 membered aryl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted benzyl group, preferably an unsubstituted or substituted phenyl group;
R2and R3By "substituted" in the definition of groups is meant that 1 to 5H on the group are selected from C1-4Alkyl, thioalkyl, alkoxy, fluoroalkyl, F, Cl, Br, hydroxyl, nitro, amino, methanesulfonyl, tetrahydronaphthyl or
Figure BDA0002516230510000051
Substitution;
Rbselected from unsubstituted or substituted by C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Fluoroalkyl, hydroxy, F, Cl, Br, methylthio or C6-10Aralkoxy substituted phenyl.
Further, R3Is composed of
Figure BDA0002516230510000052
Preferably, it is
Figure BDA0002516230510000053
Further, R2Is phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl or 3-bromophenyl.
Further, RbIs 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 3-nitrophenyl, 2-bromophenyl or 2-chloro-4-fluorophenylPreferably 4-fluorophenyl.
When Rb is p-fluorophenyl and R3 is H or
Figure BDA0002516230510000054
When compounds of formula XI or IV are intermediates in the synthesis of paroxetine.
Preferred examples of chiral center-containing piperidine compounds of formula XI or IV are the following compounds:
Figure BDA0002516230510000055
the invention further provides a preparation method for preparing the compound shown in the formula X by using the compound shown in the formula IV, which comprises the following steps:
Figure BDA0002516230510000061
step 1: the compound of formula IV is reduced to obtain a compound of formula VII,
step 2: further reduction of the compound of formula VII gives a compound of formula VIII,
and step 3: reaction of a compound of formula VIII to prepare a compound of formula IX,
and 4, step 4: removal of R from a Compound of formula IX2-NH-to give a compound of formula X,
the definition of the substituents appearing in the above compounds is the same as that of the chiral center-containing piperidine compounds of the formula XI or IV.
In step 1, a silane reducing agent is used, the reaction solvent can be an organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, etc., the reaction temperature is-20 to 30 ℃, the reaction is preferably carried out at room temperature (25 ℃), the reaction requires an acidic environment, and the reaction can be carried out by using trifluoroacetic acid, BF, etc3.Et2And O.
In step 2, borohydride or aluminum hydride, such as sodium borohydride or diisobutylaluminum hydride, is used as a reducing agent, and the reaction solvent may be an organic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, etc., and the reaction temperature is-20 to 30 ℃.
In step 3, one of the reactants may be activated first and then reacted, and the activation method may be methanesulfonic acid esterification or the like.
In the step 4, Zn/HAc conditions are adopted, and the reaction is carried out at room temperature.
The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following reaction steps:
Figure BDA0002516230510000071
step 1: firstly, a compound of a formula I and a compound of a formula II react to generate an alkenyl hydrazine intermediate V, wherein the structural formula of the intermediate compound V is as follows:
Figure BDA0002516230510000072
step 2: the intermediate V is not purified, and directly undergoes addition and cyclization reaction with the compound shown in the formula III under the action of a chiral catalyst to obtain a compound shown in the formula IV;
optionally, step 1 and step 2 may be accomplished using a one-pot process,
the definition of the substituents appearing in the above compounds is the same as that of the chiral center-containing piperidine compounds of the formula XI or IV.
In the step 1, reacting at room temperature, and using ethanol as a solvent;
in step 2, using an aprotic solvent, such as acetonitrile and toluene as a solvent, reacting under weak acidic conditions, providing a weak acidic environment can use an organic weak acid, such as benzoic acid;
further, the chiral catalyst has the following structure:
Figure BDA0002516230510000081
wherein R is4Is straight-chain or branched C1-4Alkyl groups of (a);
R5is unsubstituted or substituted 5-6 membered heteroaryl or phenyl which may be substituted by alkyl, alkoxy, fluoroalkyl, F or Cl having 1-4 carbon atoms, preferably R5Is phenyl; r4Is methyl, isopropyl or ethyl.
The present invention also provides a process for preparing a compound of formula VII using a compound of formula IV, comprising the steps of:
Figure BDA0002516230510000082
the compound of formula IV is reduced to obtain the compound of formula VII, the reaction does not need to use chiral catalyst, and the definition of the substituent group appearing in the compound is the same as that of the piperidine compound containing chiral center shown in formula XI or IV.
A process for preparing a compound of formula XI starting from a compound of formula IV comprising the steps of:
Figure BDA0002516230510000083
wherein: when R isaIs selected from-CH2OR3And R is3When the formula is H, the compound in the formula XI is a VIII compound,
when R isaIs selected from-CH2OR3And R is3Is C1-8Straight or branched alkyl, C3-8Any one of a cycloalkyl group, an unsubstituted or substituted 5-10 membered aryl group, an unsubstituted or substituted 5-10 membered heteroaryl group, an unsubstituted or substituted benzyl group, preferably an unsubstituted or substituted phenyl group; "substituted" means that 1 to 5H on the group are selected from C1-4Alkyl, thioalkyl, alkoxy, fluoroalkyl, F, Cl, Br, hydroxyl, nitro, amino, methanesulfonyl, tetrahydronaphthyl or
Figure BDA0002516230510000091
Substitution; in this case, the compound of formula XI is the compound of formula IX;
step 1: the compound of formula IV is reduced to obtain a compound of formula VII,
step 2: further reduction of the compound of formula VII gives a compound of formula VIII,
and optionally step 3: reaction of a compound of formula VIII to prepare a compound of formula IX,
r appearing in the above-mentioned compound1、R2And RbSubstituents as defined in any one of claims 1 to 4.
The present invention also provides paroxetine and analogues thereof of formula X prepared using a compound of formula IV, which is free of the following N-methylated impurities:
Figure BDA0002516230510000092
the technical scheme of the invention has the following advantages:
1. the technical problem solved by the invention is that the existing method for synthesizing paroxetine or analogues thereof needs to use a resolving agent for resolution when constructing a chiral center, so that the yield is low, and the resources are seriously wasted; meanwhile, because N on the piperidine ring is relatively active, a stable protecting group (-CH) needs to be introduced in the preparation process3) However, the protecting group (-CH)3) At the time of removal, due to N-CH3The bond energy between the two is high, so that severe reaction conditions cannot be used for avoiding damaging C-O bonds in molecules; this results in incomplete demethylation and the inevitable presence of three methyl-bearing toxic impurities (impurity II, impurity B and impurity G) in the final product, especially impurities II and B having a polarity similar to that of the desired paroxetine or the like, which makes removal difficult. The improvement of the existing method for synthesizing paroxetine and analogues thereof is only limited to the optimization of the two synthetic routes, and basically has no effect;
the invention departs from the synthesis idea of the prior art that either the resolution of a resolving agent or the simultaneous construction of two chiral centers is required, creatively adopts the steps of firstly constructing one chiral center and then constructing the chiral center according to the requirementAre positioned adjacent to each other and are subjected to a first chiral group Rb(e.g., 4-F-phenyl) steric hindrance, and the desired trans product is formed more efficiently without the use of a chiral catalyst during the reduction. With R being employed from the beginning of the reaction2NH-as N-protecting group on the piperidine ring, R is removed in contrast to demethylation2The NH-group reaction condition is milder, three toxic impurities containing methyl are fundamentally avoided, and the yield is high. In addition, the invention also avoids the use of strong reducing agent in the prior art, and has low operation requirement and low environmental protection pressure. Therefore, the invention opens up a brand new reaction route for the synthesis of the paroxetine and the analogues thereof, and improves the yield and the chiral purity of the product; meanwhile, intermediates for synthesizing paroxetine and analogues thereof are enriched.
2. The preparation method for synthesizing paroxetine and analogues thereof provided by the invention has the advantages of mild operation conditions, high yield, low cost, less toxic impurities, no generation of a large amount of solid wastes and contribution to industrial production.
3. The preparation method of the compound shown in the formula IV provided by the invention comprises the steps of firstly generating an alkenyl hydrazine intermediate by adopting propiolic acid ester substances shown in the formula I and hydrazine substances shown in the formula II
Figure BDA0002516230510000111
The intermediate is not required to be separated and purified, and is continuously subjected to addition and cyclization with the alpha, beta-unsaturated aldehyde compound shown in the formula III under the action of a chiral catalyst to generate a compound shown in the formula IV, wherein chiral carbon connected with-OH is partially racemized; and RbThe connected chiral carbon is in a single configuration (the ee value is 96-99 percent); by adopting the strategy of firstly constructing a chiral center, the subsequent reaction is not influenced, the chirality of the compound shown in the formula IV is relatively exclusive, and the utilization rate of raw materials is high.
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, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a chiral liquid phase diagram of compound B of example 1 of the present invention;
FIG. 2 is a chiral liquid phase diagram of Compound A of example 1 of the present invention;
FIG. 3 is a drawing of Compound A of example 1 of the present invention1HNMR；
FIG. 4 is a drawing of Compound B of example 1 of the present invention1HNMR；
FIG. 5 shows the VII-1 compound obtained in example 14 of the present invention1HNMR；
FIG. 6 is a drawing showing the preparation of VIII-1 compound obtained in example 16 of the present invention1HNMR；
FIG. 7 shows the preparation of a compound IX-1 according to example 18 of the present invention1HNMR；
FIG. 8 is a graph of paroxetine prepared according to example 19 of the present invention1HNMR。
Detailed Description
The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
All compounds defined in the present invention can be synthesized according to the preparation methods of the following examples.
The detection conditions of the chiral liquid phase chromatogram HPLC in each example are as follows:
a chiral column with a Chiralpak IC model is adopted, and a mobile phase is n-hexane: isopropanol 90: 10, isocratic elution, detection wavelength 254nm, flow rate 1.0ml/min, column temperature: at 25 ℃.
Example 1
This example provides a compound of formula IV, which is prepared according to the following equation:
Figure BDA0002516230510000121
adding 75mL of ethanol, methyl propiolate I-1(27.5mmol) and phenylhydrazine II-1(27.5mmol) into a reaction bottle in sequence, reacting for 4h at room temperature, concentrating to remove the ethanol, and then adding 75mL of acetonitrile, alpha, beta-unsaturated aldehyde III-1(33.0mmol), benzoic acid (2.75mmol) and catalyst VI-1(2.75mmol) into the concentrated solution in sequence; reacting at room temperature for 35h, concentrating the reaction solution after the reaction is finished, and purifying by silica gel column chromatography to obtain a product IV-1 with the yield of 89% and ee of 98%.
Wherein the ee value refers to the ee value of chiral carbon 1, and 1 chiral center is successfully constructed in the reaction. The chiral carbon 2 is divided into two configurations, so the reaction yields a mixture of trans and cis, in 89% overall yield. The configuration of the chiral carbon 2 has no influence on the subsequent synthesis of paroxetine and analogues thereof, because the hydroxyl group is reduced in the subsequent reaction. Therefore, the trans-and cis-products do not need to be separated in actual production.
Isolation of IV-1 from example 1 gave compounds A and B of the following configuration: the liquid phase and nuclear magnetic spectrum of compound B are shown in figures 1 and 4, and the liquid phase and nuclear magnetic spectrum of compound A are shown in figures 2 and 3, which are identified to indicate that the configuration of IV-1 is correct in the invention.
Figure BDA0002516230510000131
Of Compound A in IV-11H NMR(400MHz,CDCl3)δ：7.61(s,1H),7.25–7.20(m,2H),7.19–7.14(m,2H),6.96(t,J＝8.8Hz,2H),6.91(t,J＝7.2Hz,1H),6.75(d,J＝7.6Hz,2H),6.32(s,1H),4.65(td,J＝6.4,3.6Hz,1H),3.91(t,J＝6.4Hz,1H),3.58(d,J＝6.0Hz,1H),3.51(s,3H),2.20(dt,J＝13.6,6.4Hz,1H),2.10(ddd,J＝13.6,7.6,3.6Hz,1H)；
HRMS-ESI(m/z):[M+H]+343.1445。
Of compounds B in IV-11H NMR(400MHz,CDCl3)δ7.82(s,1H),7.34–7.24(m,4H),7.06–7.01(m,2H),6.93(t,J＝7.4Hz,1H),6.75(d,J＝7.7Hz,2H),6.37(s,1H),4.82(d,J＝10.3Hz,1H),4.12(d,J＝6.8Hz,1H),3.66(s,3H),2.54(dt,J＝14.3,2.1Hz,1H),2.36(ddd,J＝14.3,6.5,3.7Hz,1H),1.84(d,J＝10.3Hz,1H)；
HRMS-ESI(m/z):[M+H]+343.1445。
Example 2
Similar to example 1, the only difference is the chiral catalyst used, which in this example was:
Figure BDA0002516230510000141
the yield of the product IV-1 was 87% and the ee value was 97%.
Examples 3 to 13
Examples 3-13 were prepared identically to example 2, except that the substrates, compounds I, II and III, and the solvent added after the first concentration were different, as shown in Table 1 below.
TABLE 1 substrates and results of the reactions of examples 3-13
R1 R2 Rb Solvent(s) Yield% ee％ [M+H]+
Example 3 Me Ph 4-Cl-Ph Acetonitrile 99 98 359.1163
Example 4 Me Ph 4-Cl-Ph Toluene 81 99 359.1163
Example 5 Me Ph Ph Acetonitrile 99 97 325.1547
Example 6 Me Ph 4-OMe-Ph Acetonitrile 99 97 355.1658
Example 7 Me Ph 4-CF3-Ph Acetonitrile 96 97 393.1425
Example 8 Me Ph 3-Cl-Ph Acetonitrile 98 97 359.115
Example 9 Me Ph 3-NO2-Ph Acetonitrile 93 98 370.1403
Example 10 Me Ph 2-Cl-4-F-Ph Acetonitrile 93 98 377.1069
Example 11 Me 4-CF3-Ph 4-F-Ph Acetonitrile 80 96 --
Example 12 Me 3-Br-Ph 4-F-Ph Acetonitrile 86 96 --
Example 13 Et Ph 4-F-Ph Acetonitrile 90 96 --
Example 14
This example provides a compound of formula VII, which is prepared according to the following equation:
into the reaction flask were added 250mL of methylene chloride, IV-1(23.9mmol), triethylsilane (52.6mmol) and trifluoroacetic acid (52.6mmol) in this order. The reaction was carried out at room temperature for 24 hours. Washing the reaction solution after the reaction by saturated sodium bicarbonate aqueous solution, extracting by ethyl acetate, concentrating, purifying by silica gel column chromatography to obtain a product VII-1 with the yield of 75 percent,1h NMR is shown in FIG. 5.
Figure BDA0002516230510000151
VII-1 of1H NMR(400MHz,CDCl3)δ7.33–7.12(m,4H),7.06–6.95(m,2H),6.95–6.87(m,2H),6.82(s,1H),4.47(s,1H),3.43(s,4H),3.31(d,J＝8.8Hz,1H),3.07–2.92(m,1H),2.91–2.71(m,1H),2.55–2.26(m,2H),2.09–1.77(m,2H)；
HRMS-ESI(m/z):[M+H]+329.1666。
Example 15
This example is similar to example 14, except that BF was used3.Et2O instead of trifluoroacetic acid, gave VII-1 in 71% yield.
Example 16
This example provides a compound of formula VIII, which is prepared according to the following equation:
adding 0.5mL of tetrahydrofuran, 0.22mmol of sodium borohydride, 0.22mmol of lithium chloride and VII-1(0.03mmol) into a reaction bottle at room temperature in sequence; and then heating to 66 ℃ and reacting for 6 hours, and washing the reaction solution after the reaction is finished, extracting with ethyl acetate, concentrating, and purifying by silica gel column chromatography to obtain a product VIII-1 with the yield of 99%. Of VIII-11H NMR is shown in FIG. 6.
Figure BDA0002516230510000161
Of VIII-11H NMR(400MHz,CDCl3)δ：7.25–7.16(m,4H),7.02(t,J＝8.8Hz,2H),6.94(d,J＝7.6Hz,2H),6.81(t,J＝7.2Hz,1H),4.45(s,1H),3.51–3.44(m,1H),3.40(dt,J＝10.8,4.4Hz,1H),3.35–3.22(m,2H),2.40(td,J＝11.2,4.0Hz,1H),2.29(td,J＝10.8,2.0Hz,1H),2.21(t,J＝10.8Hz,1H),2.17–2.06(m,1H),1.96(qd,J＝12.4,3.2Hz,1H),1.86(dq,J＝13.2,4.0Hz,1H),1.13(t,J＝5.6Hz,1H)；
HRMS-ESI(m/z):[M+H]+301.1713。
Example 17
This example provides an alternative method for preparing compounds of formula VIII-1:
40mL of tetrahydrofuran, VII-1(8.0mmol) and diisobutylaluminum hydride (40.0mmol) were added to the reaction flask in this order at-20 ℃; the reaction was carried out at-20 ℃ for 20 min. After the reaction is finished, washing, filtering, concentrating and purifying the reaction solution by silica gel column chromatography to obtain the product VIII-1 with the yield of 99%.
Example 18
This example provides a compound of formula IX, which is prepared according to the following equation:
adding 10mL of dichloromethane, VIII-1(1.0mmol) and triethylamine (1.5mmol) into a reaction bottle in sequence at room temperature, then cooling to 0 ℃ and dropwise adding methanesulfonyl chloride (1.2 mmol); reacting at room temperature for 40min, washing the reaction solution after the reaction is finished with water, and concentrating to obtain a mesylate intermediate product. Dissolving the mesylate intermediate (1.0mmol) in 1mL DMSO, sequentially adding sesamol (1.5mmol) and potassium hydroxide (2.0mmol), reacting at room temperature for 3h, washing the reaction solution after the reaction is finished, extracting with ethyl acetate, concentrating, and purifying by silica gel column chromatography to obtain product IX-1 with yield of 88% of IX-11H NMR is shown in FIG. 7.
Figure BDA0002516230510000171
Of IX-11H NMR(400MHz,CDCl3)δ7.28–7.10(m,4H),7.03–6.89(m,4H),6.79(t,J＝6.8Hz,1H),6.59(d,J＝8.4Hz,1H),6.32(s,1H),6.10(d,J＝8.4Hz,1H),5.82(s,2H),4.45(s,1H),3.52(t,J＝9.2Hz,2H),3.47–3.37(m,1H),3.30(d,J＝10.4Hz,1H),2.57-2.45(m,1H),2.38–2.21(m,3H),2.05–1.90(m,1H),1.91–1.80(m,1H)；
HRMS-ESI(m/z):[M+H]+421.1915。
Example 19
This example provides a method for preparing paroxetine, which comprises the following reaction equation:
Figure BDA0002516230510000172
adding 0.5mL of acetic acid, 0.1mmol of IX-1(0.1mmol) and 0.5mmol of zinc powder into a reaction bottle in sequence at room temperature; and then reacting at room temperature for 6 hours, filtering the reaction solution after the reaction is finished by using diatomite, neutralizing by using a saturated sodium bicarbonate aqueous solution, extracting by using ethyl acetate, concentrating and purifying by using silica gel column chromatography to obtain the paroxetine product, wherein the yield is 98%. Process for preparation of paroxetine1H NMR is shown in FIG. 8.
Process for preparation of paroxetine1H NMR(400MHz,CDCl3)δ：7.16(dd,J＝8.0,5.6Hz,2H),6.96(t,J＝8.8Hz,2H),6.60(d,J＝8.8Hz,1H),6.32(d,J＝2.4Hz,1H),6.10(dd,J＝8.4,2.0Hz,1H),5.85(s,2H),4.98(bs,1H),3.60–3.48(m,2H),3.43(dd,J＝8.4,6.4Hz,1H),3.33(d,J＝8.4Hz,1H),2.90–2.74(m,2H),2.67(td,J＝11.2,4.0Hz,1H),2.30-2.14(m,1H),1.98-1.75(m,2H)；
HRMS-ESI(m/z):[M+H]+330.1513。
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.

Claims (6)

1. A chiral center-containing piperidine compound of formula XI or IV having the structure shown below:
Figure FDA0003308831510000011
wherein R isaIs selected from-COOR1、-CH2OH、
Figure FDA0003308831510000012
R1Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;
R2selected from phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl or 3-bromophenyl;
Rbselected from phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 3-nitrophenyl, 2-bromophenyl, 2-chloro-4-fluorophenyl.
2. A compound of claim 1, wherein R isbIs 4-fluorophenyl.
3. A process for preparing a compound of formula X using a compound of formula IV, comprising the steps of:
Figure FDA0003308831510000021
step 1: the compound of formula IV is reduced to obtain a compound of formula VII,
step 2: further reduction of the compound of formula VII gives a compound of formula VIII,
and step 3: reaction of a compound of formula VIII to prepare a compound of formula IX,
and 4, step 4: removal of R from a Compound of formula IX2-NH-to give a compound of formula X,
R3is H or
Figure FDA0003308831510000022
R appearing in the above-mentioned compound1、R2And RbSubstituents as defined in claim 1 or 2The above-mentioned processes are described.
4. A process for the preparation of a compound of formula IV, characterized in that the reaction steps are as follows:
Figure FDA0003308831510000023
step 1: firstly, a compound of a formula I and a compound of a formula II react to generate an alkenyl hydrazine intermediate V, wherein the structural formula of the intermediate compound V is as follows:
Figure FDA0003308831510000031
step 2: the intermediate V is not purified, and directly undergoes addition and cyclization reaction with the compound shown in the formula III under the action of a chiral catalyst to obtain a compound shown in the formula IV,
optionally, step 1 and step 2 may be accomplished using a one-pot process,
the substituents present in the above compounds are as defined in claim 1 or 2;
the chiral catalyst has the following structure:
Figure FDA0003308831510000032
wherein R is5Is phenyl; r4Is methyl, isopropyl or ethyl.
5. A process for preparing a compound of formula VII using a compound of formula IV, comprising the steps of:
Figure FDA0003308831510000033
reduction of a compound of formula IV to give a compound of formula VII, wherein the substituents present in said compound are as defined in claim 1 or 2.
6. A process for preparing a compound of formula XI starting from a compound of formula IV comprising the steps of:
Figure FDA0003308831510000041
wherein: when R isaIs selected from-CH2OR3And R is3When the formula is H, the compound in the formula XI is a VIII compound,
when R isaIs selected from-CH2OR3And R is3Is composed of
Figure FDA0003308831510000042
In this case, the compound of formula XI is the compound of formula IX;
step 1: the compound of formula IV is reduced to obtain a compound of formula VII,
step 2: further reduction of the compound of formula VII gives a compound of formula VIII,
and optionally step 3: reaction of a compound of formula VIII to prepare a compound of formula IX,
r appearing in the above-mentioned compound1、R2And RbSubstituents as defined in claim 1 or 2.
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