CN104529854B - A kind of synthetic method of substituted azetidine class pharmaceutical intermediate compound - Google Patents

Abstract

The present invention provides a synthetic method of a substituted azetidine pharmaceutical intermediate compound shown in formula (I), The method comprises: in an organic solvent and in the presence of a catalyst, a base and a promoter, the compound of the formula (II) and the compound of the formula (III) react under an inert atmosphere to obtain the compound of the formula (I), Wherein, R ₁ is C ₁ -C ₆ alkyl, phenyl or naphthyl, and each group can be optionally substituted by C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy; R ₂ is diphenyl methyl (CHPh ₂ ), tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz); X is a halogen; the method of the present invention has good yield, thus has good industrial application prospect and potential.

Description

A kind of synthetic method of substituted azetidine pharmaceutical intermediate compound

technical field

The invention relates to a synthesis method of a nitrogen-containing heterocyclic compound, more specifically to a synthesis method of a substituted azetidine pharmaceutical intermediate compound, and belongs to the technical field of organic synthesis and pharmaceutical intermediates.

Background technique

Nitrogen-containing heterocyclic rings with small structures are ideal structural modules, which can be used to construct a variety of beneficial pharmaceutical compounds. Among them, azetidine compounds have become a class of structural components with great potential due to their suitable stability and molecular rigidity.

After years of research, many natural and synthetic pharmaceutical compounds contain azetidine structures. For example, the marketed drug calcium ion channel inhibitor-Azetidine is an effective pharmaceutical compound containing azetidine. In addition, azetidine has excellent functionality after having an aryl group substituted at the 3-position, and has been found to have high pharmacological activity.

It is precisely because of the excellent properties of this type of compound that the synthesis method of azetidine drug intermediates is of great significance in the field of pharmaceutical synthesis, and it has also become an important problem to be solved by pharmaceutical researchers.

After years of experimental research and technical research and development, the synthesis process of various azetidine compounds has been reported in the prior art, such as:

Matthew A.J.Duncton et al. ("Preparation of Aryloxetanes and Arylazeti dines by Use of an Alkyl-Aryl Suzuki Coupling", Organic Letters, 2008, 10, 3259-3262) reported the preparation of an aryl azetidine compound method. The method uses azetidin-3-yl and arylboronic acid as raw materials, and realizes the successful preparation of aryl azetidine through the Suzuki coupling reaction of the alkyl-aryl group induced by a nickel catalyst. The route is novel and practical, and can also be used in actual drug production.

Gary A.Molander et al. ("Reductive Cross-Coupling of Nonaromatic, Het erocyclic Bromides with Aryl and Heteroaryl Bromides", J.Org.Chem., 201 4,79,5771-5780) disclose a haloaryl and Reductive cross-coupling reaction of haloalkyl to form C-C bond method, this method is suitable for the reaction of non-aromatic, heterocyclic bromine and aryl or heteroaryl bromide, and does not require organometallic reagents, and has a very wide application prospect .

Daniel M.Allwood et al. ("Metal-Free Coupling of Saturated Heterocyclic Sulfonylhydrazones with Boronic Acids", J.Org.Chem., 2014,79,328-338) reported the synthesis of a novel aryl azetidine compound The preparation method adopts the reaction of 4-membered saturated heterocyclic p-methoxyphenylsulfonylhydrazone with aryl or heteroaryl boronic acid, and realizes the preparation of the target product under the catalysis of Cs ₂ CO ₃ , does not involve the use of metal catalysts, and is An effective method for synthesizing pharmaceutical intermediates.

As mentioned above, although researchers have provided a variety of synthesis methods for azetidine compounds, these methods often have some disadvantages, such as low material utilization, poor yield, and harsh reaction conditions.

Therefore, in order to overcome these problems that are unfavorable to industrial production, the development of a new preparation process for substituted azetidine compounds will have a profound impact on the synthesis of pharmaceutical intermediates or compounds.

In view of this, the present invention aims to provide a synthetic method for replacing azetidine compounds to achieve the purpose of improving material utilization and product yield, so that it can play its role in actual industrial production and reduce production Cost, to meet the synthesis needs.

Contents of the invention

Aiming at the above-mentioned many defects, the inventor, after devoting a lot of creative work, has developed a synthetic method for replacing azetidine pharmaceutical intermediate compounds after in-depth research. This method has a wide range of market application value .

Specifically, the present invention provides a method for synthesizing substituted azetidine pharmaceutical intermediate compounds represented by formula (I),

The method comprises: in an organic solvent and in the presence of a catalyst, a base and a promoter, the compound of the formula (II) and the compound of the formula (III) react under an inert atmosphere to obtain the compound of the formula (I),

Wherein, R ₁ is C ₁ -C ₆ alkyl, phenyl or naphthyl, and each group may be optionally substituted by C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

R ₂ is diphenylmethyl (CHPh ₂ ), tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz);

X is halogen.

In the method of the present invention, C ₁ -C ₆ alkyl refers to an alkyl group with 1-6 carbon atoms, which can be straight chain or branched, non-limiting examples can be methyl, ethyl Base, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc.

In the method of the present invention, a C ₁ -C ₆ alkoxy group refers to a group in which the above defined C ₁ -C ₆ alkyl group is linked to an oxygen atom.

In the method of the present invention, the halogen can be, for example, F, Cl, Br or I.

In the method of the present invention, in formulas (I) and (II), X may be located at the ortho or para position of the N atom.

In the method of the present invention, X in formula (II) and formula (III) is the same halogen, that is, X is the same halogen atom at the same time, preferably both are I.

In the method of the present invention, R ₁ can be, for example, p-tolyl, naphthalen-2-yl, methyl or m-methoxyphenyl.

In the method of the present invention, the catalyst is a copper compound, such as copper trifluoroacetylacetonate, copper acetylacetonate, copper acetate, copper trifluoromethanesulfonate, copper sulfate, cuprous trifluoromethanesulfonate, CuSCN, triphenylphosphine cuprous bromide (Cu(PPh ₃ )Br), bis(triphenylphosphine)cuprous nitrate (Cu(PPh ₃ ) ₂ NO ₃ ).

Among them, the catalyst is preferably triphenylphosphine cuprous bromide (Cu(PPh ₃ ) Br) or bis(triphenylphosphine) cuprous nitrate (Cu(PPh ₃ ) ₂ NO ₃ ), most preferably bis( Triphenylphosphine) cuprous nitrate (Cu(PPh ₃ ) ₂ NO ₃ ).

In the method of the present invention, the base is an organic base, such as various amines such as alcohol amines, alkylamines, etc., alkali metal alkoxides, etc., more specifically, such as diethanolamine, hexamethylene Tetramine, trimethylamine, triethylamine, DABCO (1,4-diazabicyclo[2.2.2]octane), sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, N,N- Diisopropylethylamine (DIPEA) and the like.

Among them, the base is preferably DABCO (1,4-diazabicyclo[2.2.2]octane), N,N-diisopropylethylamine (DIPEA) or hexamethylenetetramine, most preferably For DABCO (1,4-diazabicyclo [2.2.2] octane).

In the method of the present invention, the accelerator is a mixture of triethyloxonium tetrafluoroborate and AgBF ₄ , wherein the molar ratio of triethyloxonium tetrafluoroborate and AgBF is ₁ :0.1-0.3, such as 1:0.1, 1:0.2 or 1:0.3.

In the method of the present invention, the organic solvent is dimethylsulfoxide (DMSO), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), toluene, dichloromethane, chloroform , methanol, ethanol, isopropanol, etc., or any mixture of any of them.

Wherein, the amount of the organic solvent is not particularly limited, and those skilled in the art can properly determine it according to conventional technical means.

In the method of the present invention, the inert atmosphere may be nitrogen atmosphere or argon atmosphere, for example.

In the method of the present invention, the molar ratio of the compound of formula (II) to formula (III) is 1:1.5-2.5, such as 1:1.5, 1:2 or 1:2.5.

In the method of the present invention, the molar ratio of the compound of formula (II) to the catalyst is 1:0.04-0.1, such as 1:0.04, 1:0.06, 1:0.08 or 1:0.1.

In the method of the present invention, the molar ratio of the compound of formula (II) to the base is 1:0.5-1.5, such as 1:0.5, 1:1 or 1:1.5.

In the method of the present invention, the ratio of the molar weight of the compound of the formula (II) to the total molar weight of the promoter is 1:0.1-0.2, that is, the molar weight of the compound of the formula (II) and the triethyloxonium The ratio of the molar sum of tetrafluoroborate and AgBF ₄ is 1:0.1-0.2, for example, 1:0.1, 1:0.15 or 1:0.2.

In the method of the present invention, the reaction temperature is 80-120°C, non-limiting examples may be 80°C, 90°C, 100°C, 110°C or 120°C.

In the method of the present invention, the reaction time is 8-15 hours, such as 8 hours, 10 hours, 12 hours, 14 hours or 15 hours.

In the method of the present invention, the post-treatment after the reaction is completed is as follows: after the reaction is completed, add saturated brine to fully wash, separate the organic phase, then fully wash with deionized water, extract with ether, take the upper organic phase, and use Dry over anhydrous sodium sulfate, then concentrate under reduced pressure, and the residue is separated by silica gel column chromatography, wherein the eluent used for column chromatography separation is a mixture of chloroform and petroleum ether, and the volume ratio of the two is 1:2-4, that is, A compound of formula (III).

As mentioned above, the present invention adopts catalyst, base and accelerator system, and through suitable screening and selection of these components, substituted azetidine pharmaceutical intermediate compounds are obtained in high yield, with mild reaction, With the advantages of sufficient material utilization, it has a very broad prospect of large-scale production.

detailed description

The present invention will be described in detail below through specific examples, but the use and purpose of these exemplary embodiments are only used to exemplify the present invention, and do not constitute any form of any limitation to the actual protection scope of the present invention, nor will the present invention The scope of protection is limited to this.

Example 1

Add an appropriate amount of DMSO in the reaction vessel, pass into nitrogen purge until the atmosphere is a nitrogen atmosphere, then add 100mmol of the above formula (II) compound, 150mmol of the above formula (III) compound, 4mmol of bis(triphenylphosphine) cuprous nitrate, 50mmol DABCO and 10mmol accelerator (a mixture of 8mmol triethyloxonium tetrafluoroborate and 2mmol AgBF ₄ ) were heated to 80°C and reacted at this temperature for 15 hours.

After the reaction is complete, add saturated brine to wash fully, separate the organic phase, then wash fully with deionized water, extract with ether, take the upper organic phase, dry with anhydrous sodium sulfate, then concentrate under reduced pressure, and pass the residue through a silica gel column Chromatographic separation, wherein the eluent used in column chromatographic separation is a mixture of chloroform and petroleum ether, the volume ratio of which is 1:2, and the compound of formula (I) is obtained with a yield of 94.8%.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.44 (d, J = 7.3Hz, 4H), 7.26 (dd, J = 13.1, 5.4Hz, 4H), 7.15 (dd, J = 7.7, 5.8Hz, 4H ), 7.10 (d, J = 7.9Hz, 2H), 4.41 (s, 1H), 3.71-3.55 (m, 3H), 3.17 (t, J = 9.8Hz, 2H), 2.36 (s, 3H).

MS m/z: 313 (M+1,100).

Example 2

Add an appropriate amount of DMF in the reaction vessel, pass through nitrogen purging, until the atmosphere is a nitrogen atmosphere, then add 100mmol of the above formula (II) compound, 200mmol of the above formula (III) compound, 7mmol of bis(triphenylphosphine) cuprous nitrate, 100mmol DABCO and 15mmol accelerator (a mixture of 13mmol triethyloxonium tetrafluoroborate and 2mmol AgBF ₄ ), heated to 100°C and reacted at this temperature for 12 hours.

After the reaction is complete, add saturated brine to wash fully, separate the organic phase, then wash fully with deionized water, extract with ether, take the upper organic phase, dry with anhydrous sodium sulfate, then concentrate under reduced pressure, and pass the residue through a silica gel column Chromatographic separation, wherein the eluent used in column chromatographic separation is a mixture of chloroform and petroleum ether, the volume ratio of the two is 1:3, and the compound of formula (I) is obtained with a yield of 95.6%.

¹ H-NMR (400MHz, CDCl ₃ ,) δ: 7.83-7.74(m, 3H), 7.71(s, 1H), 7.45(qd, J=9.7, 3.5Hz, 3H), 4.40(m, J=8.7 Hz, 2H), 4.14-4.01 (m, 2H), 3.91 (tt, J=8.7, 6.0Hz, 1H), 1.45 (s, 9H).

MS m/z: 284 (M+1,100).

Example 3

Add an appropriate amount of toluene in the reaction vessel, pass into nitrogen purge until the atmosphere is a nitrogen atmosphere, then add 100mmol of the above formula (II) compound, 250mmol of the above formula (III) compound, 10mmol of bis(triphenylphosphine) cuprous nitrate, 150mmol DABCO and 20mmol accelerator (a mixture of 18mmol triethyloxonium tetrafluoroborate and 2mmol AgBF ₄ ), heated to 120°C and reacted at this temperature for 8 hours.

After the reaction is complete, add saturated brine to wash fully, separate the organic phase, then wash fully with deionized water, extract with ether, take the upper organic phase, dry with anhydrous sodium sulfate, then concentrate under reduced pressure, and pass the residue through a silica gel column Chromatographic separation, wherein the eluent used in column chromatographic separation is a mixture of chloroform and petroleum ether, the volume ratio of the two is 1:4, and the compound of formula (I) is obtained with a yield of 94.2%.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.33 (dd, J = 8.1, 1.0Hz, 4H), 7.24 (dd, J = 8.3, 6.8Hz, 4H), 7.22-7.11 (m, 2H), 4.24 (s,1H),3.34(dd,J=7.4Hz,2H),2.61(dd,J=7.3Hz,2H),2.56(tt,J=14.0,7.0Hz,1H),1.13(d,J= 6.6Hz, 3H).

MS m/z: 237 (M+1,100).

Example 4

Add an appropriate amount of isopropanol in the reaction vessel, pass into nitrogen purging until the atmosphere is a nitrogen atmosphere, then add 100mmol of the above formula (II) compound, 200mmol of the above formula (III) compound, 6mmol of bis (triphenylphosphine) nitrite Copper, 120mmol DABCO and 14mmol accelerator (a mixture of 10.5mmol triethyloxonium tetrafluoroborate and 3.5mmol AgBF ₄ ) were heated to 90°C and reacted at this temperature for 13 hours.

After the reaction is complete, add saturated brine to wash fully, separate the organic phase, then wash fully with deionized water, extract with ether, take the upper organic phase, dry with anhydrous sodium sulfate, then concentrate under reduced pressure, and pass the residue through a silica gel column Chromatographic separation, wherein the eluent used in column chromatographic separation is a mixture of chloroform and petroleum ether, the volume ratio of the two is 1:2, and the compound of formula (I) is obtained with a yield of 96.1%.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 7.46(d, J=7.2Hz, 4H), 7.24(t, J=8.0Hz, 4H), 7.21(t, J=8.0Hz, 1H), 7.14( dt,J=8.5,1.1Hz,2H),6.84-6.88(m,1H),6.77(dd,J=8.0,2.3Hz,2H),4.34(s,1H),3.74(s,3H),3.61 -3.65 (m, 1H), 3.62-3.66 (m, 2H), 3.17 (t, J=6.8Hz, 2H).

MS m/z: 329 (M+1,100).

Example 5-15

Except adopting different copper compound catalysts to replace bis(triphenylphosphine) cuprous nitrate, carry out embodiment 5-12 respectively in the same manner of embodiment 1-4, the result of catalyst used, corresponding relationship and product yield See Table 1 below.

Table 1: Effect of different catalysts

As can be seen from above Table 1 and Examples 1-4, in the copper compound catalyst, triphenylphosphine cuprous bromide (Cu(PPh ₃ ) Br) or bis(triphenylphosphine) cuprous nitrate (Cu(PPh _{3 )} ) ₂ NO ₃ ) has good catalytic performance, and bis(triphenylphosphine) cuprous nitrate has the best effect.

In order to investigate the catalyst effect of triphenylphosphine cuprous bromide (Cu(PPh ₃ ) Br), the catalysts in Examples 2-4 were replaced by triphenylphosphine cuprous bromide (Cu(PPh ₃ ) Br ), and carried out embodiment 13-15, but for convenience of comparison, the result of above-mentioned embodiment 5 is still listed together, and the results are shown in the following table 2:

Table 2: Effect of triphenylphosphine cuprous bromide

It can be seen that the catalytic effect of Cu(PPh ₃ )Br is weaker than that of bis(triphenylphosphine)cuprous nitrate, but still significantly higher than that of other copper compound catalysts.

Examples 16-24

Except that different bases were used instead of DABCO, Examples 16-24 were carried out in the same manner as in Examples 1-4, and the results of the bases used, corresponding relationships and product yields are shown in Table 3 below.

Table 3: Effect of different bases

As can be seen from Table 3 and Examples 1-4 above, DABCO (1,4-diazabicyclo[2.2.2]octane), N,N-diisopropylethylamine (DIPEA) or hexamethylene Tetramines have the best effect, among which DABCO has the best effect, while other bases all lead to a substantial reduction in yield, which may be closely related to the pKa value of the entire reaction system, and the inventor intends to conduct further in-depth research.

Examples 25-28

When the accelerator was omitted, Examples 25-28 were carried out in the same manner as in Examples 1-4, respectively, and the results of the corresponding relationship and product yield are shown in Table 4 below.

Table 4: Effect of Accelerators

It can be seen from the above table 4 and Examples 1-4 that the presence of the accelerator is crucial to the obtaining of high yield, and only the presence of the accelerator can obtain the high yield of the present invention.

Examples 29-36

Embodiment 29-32: except that the accelerator is replaced by triethyloxonium tetrafluoroborate (that is, the accelerator is only triethyloxonium tetrafluoroborate, the amount of which is the original The sum of the amount of the two components), carried out examples 29-32 in the same manner as examples 1-4 respectively.

Examples 33-36: except that the accelerator is replaced by the AgBF ₄ of the sum of the two moles (that is, the accelerator is only AgBF ₄ , and its amount is the sum of the amount of the original two components), respectively, with the same method as in Example Examples 33-36 were carried out in the same manner as 1-4.

The specific results are shown in Table 5 below.

Table 5: Effect of Components in Accelerator

As can be seen from the above table 5 and Examples 1-4, the good technical effect of the present invention can only be obtained by using a two-component accelerator, and when any component is omitted, the yield will be greatly reduced. This proves that the two can play an optimal synergistic effect with the catalyst, thereby achieving the best technical effect.

In summary, the present inventor has developed a synthetic method of a substituted azetidine pharmaceutical intermediate compound with good effects through a large number of creative experimental investigations. Through the appropriate selection/component of catalyst, base and accelerator, Thus, the target product was obtained in high yield, which is of great significance for the synthesis of high-quality drug intermediates.

It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the protection scope of the present invention. In addition, it should also be understood that after reading the technical content of the present invention, those skilled in the art can make various changes, modifications and/or variations to the present invention, and all these equivalent forms also fall within the appended claims of the present application. within the defined scope of protection.

Claims (7)

1. a synthetic method for substituted azetidine class pharmaceutical intermediate compound shown in formula (I),

Described method includes: in organic solvent, and in the presence of catalyst, alkali and accelerator, formula (II) compound and formula (III) compound react in an inert atmosphere, thus obtain formula (I) compound,

Wherein, R₁For C₁-C₆Alkyl, phenyl or naphthyl, and each group can be optionally by C₁-C₆Alkyl or C₁-C₆Alkoxyl replaces；

R₂For diphenyl methyl, tertbutyloxycarbonyl or benzyloxycarbonyl group；

X is halogen；

Described catalyst is double (triphenylphosphine) cuprous nitrates；

Described alkali is 1,4-diazabicylo [2.2.2] octane；

Described accelerator is triethyl group oxygen tetrafluoroborate and AgBF₄Mixture, wherein, triethyl group oxygen tetrafluoroborate and AgBF₄Mol ratio be 1:0.1-0.3.

2. synthetic method according to claim 1, it is characterized in that: described organic solvent is dimethyl sulfoxide (DMSO), oxolane, DMF, toluene, dichloromethane, chloroform, methyl alcohol, ethanol, any one or arbitrarily multiple mixtures in isopropanol.

3. synthetic method according to claim 1, it is characterised in that: described formula (II) compound is 1:1.5-2.5 with the mol ratio of formula (III).

4. synthetic method according to claim 1, it is characterised in that: described formula (II) compound is 1:0.04-0.1 with the mol ratio of catalyst.

5. synthetic method according to claim 1, it is characterised in that: described formula (II) compound is 1:0.5-1.5 with the mol ratio of alkali.

6. synthetic method according to claim 1, it is characterised in that: the mole of described formula (II) compound is 1:0.1-0.2 with the ratio of the integral molar quantity of accelerator.

7. the synthetic method according to any one of claim 1-6, it is characterised in that: reaction temperature is 80-120 DEG C, and the reaction time is 8-15 hour.