CN111533682A - Process for preparing paroxetine and analogues thereof - Google Patents

Process for preparing paroxetine and analogues thereof Download PDF

Info

Publication number
CN111533682A
CN111533682A CN202010482067.9A CN202010482067A CN111533682A CN 111533682 A CN111533682 A CN 111533682A CN 202010482067 A CN202010482067 A CN 202010482067A CN 111533682 A CN111533682 A CN 111533682A
Authority
CN
China
Prior art keywords
compound
formula
substituted
unsubstituted
group
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.)
Granted
Application number
CN202010482067.9A
Other languages
Chinese (zh)
Other versions
CN111533682B (en
Inventor
祖连锁
陈露
张智
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tsinghua University
Original Assignee
Tsinghua University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tsinghua University filed Critical Tsinghua University
Priority to CN202010482067.9A priority Critical patent/CN111533682B/en
Publication of CN111533682A publication Critical patent/CN111533682A/en
Application granted granted Critical
Publication of CN111533682B publication Critical patent/CN111533682B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 ofMethyl protection leads to the inevitable production of three toxic methyl-containing impurities upon demethylation; 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-mentioned routes, although it is very difficult to construct two chiral centers in a single-step reaction, the method is very difficultChiral synthesis attempts are also made by those skilled in the art, but the results are not ideal, for example, CN104892491A uses quinine and other groups as an aid, 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, C5-6Cycloalkyl groups of (a); 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-fluorophenyl, preferably 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 is needed or two chiral centers are needed to be constructed simultaneously, creatively adopts the steps of firstly constructing one chiral center, then adjacent to each other according to the positions of the 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 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 strong reducing agent in the prior artThe use of (3) has low operation requirement and small 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 α -unsaturated aldehyde compounds shown in formula III under the action of chiral catalysts to generate compounds shown in formula IV, wherein chiral carbon connected with-OH is partial racemization, and the chiral carbon is partial racemizationbThe 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)：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)7.82(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)7.33–7.12(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)：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)7.28–7.10(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; then reacting for 6h at room temperature, filtering the reaction solution after the reaction through diatomite, and saturating carbonic acidNeutralizing with sodium hydrogen solution, extracting with ethyl acetate, concentrating, and purifying with silica gel column chromatography to obtain paroxetine with yield of 98%. Process for preparation of paroxetine1H NMR is shown in FIG. 8.
Process for preparation of paroxetine1H NMR(400MHz,CDCl3)：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 (10)

1. A chiral center-containing piperidine compound of formula XI or IV having the structure shown below:
Figure FDA0002516230500000011
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, C5-6Cycloalkyl groups of (a); 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 FDA0002516230500000012
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.
2. A compound of claim 1, wherein R is3Is composed of
Figure FDA0002516230500000021
Preferably, it is
Figure FDA0002516230500000022
3. A compound according to claim 1 or 2, wherein R is2Is phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl or 3-bromophenyl.
4. A compound according to any one of claims 1 to 3, wherein R isbIs 4-fluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 3-chlorophenyl, 3-nitrophenyl, 2-bromophenyl or 2-chloro-4-fluoroPhenyl, preferably 4-fluorophenyl.
5. A process for preparing a compound of formula X using a compound of formula IV, comprising the steps of:
Figure FDA0002516230500000023
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 substituents present in the above compounds are as defined in any one of claims 1 to 4.
6. A process for the preparation of a compound of formula IV, characterized in that the reaction steps are as follows:
Figure FDA0002516230500000031
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 FDA0002516230500000032
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 any one of claims 1 to 4.
7. The method of claim 6, wherein the chiral catalyst has the following structure:
Figure FDA0002516230500000033
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.
8. A process for preparing a compound of formula VII using a compound of formula IV, comprising the steps of:
Figure FDA0002516230500000041
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 any one of claims 1-4.
9. A process for preparing a compound of formula XI starting from a compound of formula IV comprising the steps of:
Figure FDA0002516230500000042
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 on said group1-5H are selected from C1-4Alkyl, thioalkyl, alkoxy, fluoroalkyl, F, Cl, Br, hydroxyl, nitro, amino, methanesulfonyl, tetrahydronaphthyl or
Figure FDA0002516230500000051
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.
10. A compound of the formula X paroxetine and analogues thereof prepared according to the process of claim 5, which is free of the following N-methylated impurities:
Figure FDA0002516230500000052
CN202010482067.9A 2020-05-29 2020-05-29 Process for preparing paroxetine and analogues thereof Active CN111533682B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010482067.9A CN111533682B (en) 2020-05-29 2020-05-29 Process for preparing paroxetine and analogues thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010482067.9A CN111533682B (en) 2020-05-29 2020-05-29 Process for preparing paroxetine and analogues thereof

Publications (2)

Publication Number Publication Date
CN111533682A true CN111533682A (en) 2020-08-14
CN111533682B CN111533682B (en) 2022-03-01

Family

ID=71972362

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010482067.9A Active CN111533682B (en) 2020-05-29 2020-05-29 Process for preparing paroxetine and analogues thereof

Country Status (1)

Country Link
CN (1) CN111533682B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190496A2 (en) * 1984-12-13 1986-08-13 Beecham Group Plc Piperidine derivatives having a gastro-intestinal activity
WO2007072150A2 (en) * 2005-12-20 2007-06-28 Pfizer Products Inc. Piperidine derivatives
CN102414205A (en) * 2009-05-05 2012-04-11 弗·哈夫曼-拉罗切有限公司 Isoxazole-pyrazole derivatives
CN104039777A (en) * 2012-01-31 2014-09-10 卫材R&D管理有限公司 Paroxetine derivative
CN108025002A (en) * 2015-09-02 2018-05-11 特维娜有限公司 Delta opiate receptor modulating compound containing hexa-atomic aza heterocycles, it is used and preparation method

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190496A2 (en) * 1984-12-13 1986-08-13 Beecham Group Plc Piperidine derivatives having a gastro-intestinal activity
WO2007072150A2 (en) * 2005-12-20 2007-06-28 Pfizer Products Inc. Piperidine derivatives
CN102414205A (en) * 2009-05-05 2012-04-11 弗·哈夫曼-拉罗切有限公司 Isoxazole-pyrazole derivatives
CN104039777A (en) * 2012-01-31 2014-09-10 卫材R&D管理有限公司 Paroxetine derivative
CN108025002A (en) * 2015-09-02 2018-05-11 特维娜有限公司 Delta opiate receptor modulating compound containing hexa-atomic aza heterocycles, it is used and preparation method

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ARTUR NOOLE等: "Enantioselective Organocatalytic Aza-Ene-Type Domino Reaction Leading to 1,4-Dihydropyridines", 《THE JOURNAL OF ORGANIC CHEMISTRY》 *
BO HAN等: "Organocatalytic Asymmetric Inverse-Electron-Demand Aza-Diels-Alder Reaction of N-Sulfonyl-1-aza-1,3-butadienes and Aldehydes", 《ANGEW. CHEM. INT. ED.》 *
JIE-PING WAN等: "Enantioselective organocatalytic domino synthesis of tetrahydropyridin-2-ols", 《CHEM. COMMUN.》 *
JOSEPH G. CANNON: "Monomethyl Ether Derivatives of 7,8-Dihydroxy- and 8,9-Dihydroxy-4-n -propyl-l,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines as Possible Products of Metabolism by Catechol-O-methyltransferase", 《J. MED. CHEM.》 *
LU CHEN等: "Organocatalytic Hantzsch Type Reaction Using Aryl Hydrazines,Propiolic Acid Esters and Enals: Enantioselective Synthesis of Paroxetine", 《ADV. SYNTH. CATAL.》 *
RACHEL D. SLACK 等: "A Novel Bromine-Containing Paroxetine Analogue Provides Mechanistic Clues for Binding Ambiguity at the Central Primary Binding Site of the Serotonin Transporter", 《ACS CHEM. NEUROSCI.》 *

Also Published As

Publication number Publication date
CN111533682B (en) 2022-03-01

Similar Documents

Publication Publication Date Title
CN103333942B (en) A synthetic method for (R)-praziquantel
US10793570B2 (en) Methods and reagents for radiolabeling
JPH07309834A (en) Production of diarylprolinol enantiomerically pure
CN111171037A (en) Chiral spiro 3, 2' -pyrrolidine oxidation indole skeleton compound, preparation method and application thereof, intermediate and preparation method
WO2013020460A1 (en) Atazanavir preparation method
CN108675943A (en) The preparation method of one planting sand library Ba Qu key intermediates
CN114957078A (en) Preparation method of deuterated pharmaceutical intermediate
EP3156391A1 (en) Method for preparing sitagliptin intermediate via asymmetrical reduction method
CN111533682B (en) Process for preparing paroxetine and analogues thereof
EP2032561A2 (en) Dual molecules containing a peroxide derivative, their synthesis and therapeutic uses
CN107056681A (en) A kind of support method replaces the preparation method of cloth intermediate
CN112430208A (en) Preparation method of PF-06651600 intermediate
WO2021047566A1 (en) Preparation method for (r)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, derivative thereof and levo-praziquantel
US3907813A (en) Stereoisomeric forms of 4-anilino-3-methyl piperidines
CN109705014B (en) Novel chiral amine oxide ligand and preparation method thereof
JP2001270865A (en) Method for producing ethanesulfonylpiperidine derivative
Tayama et al. Resolution of nitrogen-centered chiral tetraalkylammonium salts: application to [1, 2] Stevens rearrangements with N-to-C chirality transmission
CN108997199B (en) Synthesis method of tofacitinib intermediate (3R,4R) -1-benzyl-N, 4-dimethylpiperidine-3-amine
CN111303188A (en) Novel oxoindole spiro-compound and preparation method thereof
CN105732613B (en) A kind of synthetic method of 9 demethyl (+) α dihydrotetrabenazineins
CN114736134B (en) (R) -beta-hydroxyaryl propionamide derivative and preparation method thereof
JP2006312626A (en) Method for producing optically active amino alcohol
CN113754715B (en) Optical selective process synthesis method of (5R) -5-hydroxyl triptolide
CN103755624B (en) A kind of synthetic method of piperidine derivative
JPH0550499B2 (en)

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant