CN113999239A

CN113999239A - Method for synthesizing diaza-bridge compound

Info

Publication number: CN113999239A
Application number: CN202110793773.XA
Authority: CN
Inventors: 陆茜; 刘帅; 梁勇; 蔡佳明; 唐泉; 曾原
Original assignee: Shanghai Lingfu Pharmaceutical Research Co ltd
Current assignee: Shanghai Lingfu Pharmaceutical Research Co ltd
Priority date: 2021-07-14
Filing date: 2021-07-14
Publication date: 2022-02-01
Anticipated expiration: 2041-07-14
Also published as: CN113999239B

Abstract

The invention provides a synthesis method of a diaza-bridged compound, belonging to the field of organic synthesis. The reaction equation involved in the invention is as follows:

the reaction steps are as follows: step 1, compound 2 is reacted with NH₃Or NH₃Contacting the solution to obtain a reaction mixture; and 2, carrying out post-treatment on the reaction mixture to obtain the compound 1, wherein R is aryl, substituted aryl, alkyl or halogenated alkyl, and n is 1 or 2. The invention uses compound 2 and NH₃Is a raw material, so the process flow can be effectively shortened, the process cost is saved, and the reaction yield can be improved to a certain extent.

Description

Method for synthesizing diaza-bridge compound

Technical Field

The invention relates to the field of organic synthesis, in particular to a synthesis method of a diaza-bridged compound.

Background

The diaza-bridge compound is a very useful pharmaceutical intermediate, and there are a large number of drugs having fragments of the diaza-bridge compound, such as Selpercatinib (Compound I) developed by American Gift for the treatment of metastatic non-small cell lung cancer positive for transfection rearrangement gene fusion, a retinoic acid-related orphan nuclear receptor modulator (Compound II) developed by American Karlier, a drug for inhibiting type I11 β -hydroxysteroid dehydrogenase (Compound III) developed by American Pionel, and a drug for treating endometriosis (Compound IV) developed by Bayer AG in Germany, and so on.

According to literature reports, the medicines are directly or indirectly related to the compound 1a or 2a in the synthesis process.

In the prior art, the synthesis of compound 1a is as follows:

as is clear from the above reaction scheme, two steps are required from compound V to compound 1, and a large amount of o-nitrobenzenesulfonic acid is additionally produced, and the liberation of o-nitrotoluenesulfonic acid not only causes trouble in the post-treatment of the reaction, but also makes the whole reaction system acidic, which may cause the dropping of t-butyloxycarbonyl group to lower the reaction yield.

Further, the above route starts with the compound cis-2, however, the compound cis-2 generates a large amount of trans-side products during the synthesis process, and the cis-inverse ratio is about 1:1, which apparently results in a low yield. Because the cis-trans ratio of the product is low, the cis-trans products need to be analyzed by column chromatography subsequently, which also makes the production of the compound 1a difficult to process.

In the prior art, the synthesis of compound 2a is as follows:

from the above-mentioned route, it can be known that, in the synthesis process of the compound 2a, not only the harsh reaction conditions of 230 ℃ high temperature are required, but also the reduction reagent of Pd/C is required to be used repeatedly, the whole route is long, and the actual production process is not economical and environment-friendly.

In addition, this route also places certain requirements on the steric configuration of the starting reaction substrate compound VII, which further increases the cost of production.

Disclosure of Invention

The present invention has been made to solve the above problems, and an object of the present invention is to provide a method for synthesizing a diaza-bridged compound in a simplified step and in a high yield.

As used herein, the following definitions shall apply unless otherwise indicated. In addition, many of the groups defined herein may be optionally substituted. The list of substituents in the definitions is exemplary and should not be construed as limiting to the substituents defined elsewhere in the specification.

In this context, the term "alkyl" refers to a straight or branched hydrocarbon chain group free of unsaturation and having from one to ten carbon atoms, consisting only of carbon atoms and hydrogen atoms, which group is attached to the rest of the molecule via a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl and 1, 1-dimethylethyl (tert-butyl). The term "C1-10 alkyl" refers to an alkyl group as defined above having up to 10 carbon atoms.

As used herein, the term "aryl" refers to an aromatic group having 6 to 20 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, and the like.

As used herein, the term "substituted" refers to being substituted with any one or any combination of substituents, which may be the same or different and are independently selected from alkyl, hydroxy, halogen, carboxy, cyano, nitro, as the term "substituted aryl" may refer to p-methylphenyl, o-nitrophenyl, and the like.

As used herein, the term "halo", "halide" or alternatively "halogen" means fluorine, chlorine, bromine or iodine. The term "haloalkyl" is meant to include alkyl groups substituted with one or more halo groups or combinations thereof, such as trifluoromethyl and the like.

The term "contacting" as used herein is to be understood broadly and can be any means that enables at least two reactants to chemically react, for example, by mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed with stirring as necessary, and thus, the type of stirring is not particularly limited, and for example, mechanical stirring, that is, stirring under the action of a mechanical force may be used.

The invention provides a synthesis method of a diaza-bridge compound, which is characterized in that the reaction formula is as follows:

wherein R is aryl, substituted aryl, alkyl or haloalkyl, n is 1 or 2,

the reaction steps are as follows: step 1, compound 2 is reacted with NH₃Or NH₃Contacting the solution to obtain a reaction mixture; and 2, carrying out post-treatment on the reaction mixture to obtain the compound 1.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, in step 1, compound 2 is reacted with NH₃Or NH₃The solution is contacted in a reaction medium.

In the invention providedThe synthesis method of the aza-bridge compound can also have the following characteristics: wherein, in step 1, compound 2 is reacted with NH₃Or NH₃The solution contact method may be such that the compound 2 or a solution thereof is added to NH₃Or in solution, may also be NH₃Or NH₃Adding the solution to Compound 2 or a solution thereof, NH₃Or NH₃The solution may be ammonia gas, liquid ammonia, aqueous ammonia or an organic solution of ammonia.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, the reaction medium is non-alcohol liquid.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, the non-alcoholic liquid is any one or more of water, acetonitrile, DMF or tetrahydrofuran.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein R in the compound 2 is methyl or p-methylphenyl.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, in step 1, compound 2 is reacted with NH₃Or NH₃The solution is contacted at 25 ℃ to 80 ℃, preferably 30 ℃ to 70 ℃.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, in step 1, NH₃The solution is ammonia water with the concentration of 15 wt% -35 wt%, and preferably ammonia water with the concentration of 25 wt% -28 wt%.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, the post-treatment in the step 2 comprises the following steps: adding an extracting agent into the reaction mixture, extracting, taking an organic phase, washing with water, and recrystallizing to obtain the compound 1, wherein the recrystallizing agent used in the recrystallizing step is a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1 (8-20), preferably a mixed solution of ethyl acetate and petroleum ether with a volume ratio of 1 (8-11).

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein the structural formula of the compound 2 is

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, the reaction equation for preparing the compound 2 is as follows:

wherein R' is C1-C10 alkyl,

the method comprises the following steps: step a, contacting a compound 3 with benzylamine to obtain a compound 4; step b, contacting the compound 4 with an ester reducing agent to obtain a compound 5; step c, compound 5 is reacted sequentially or simultaneously with a benzyl removal agent and (Boc)₂O to give compound 6; and d, contacting the compound 6 with a sulfonylation reagent to obtain a compound 2, wherein the ester reducing agent is a reagent capable of reducing the ester into alcohol, and the reagent can consist of one compound or a plurality of compounds. In the present invention, the ester reducing agent is a reagent for reducing an ester group to a hydroxyl group, and may be a single metal complex hydrogen compound (such as lithium aluminum hydride), a composite reducing agent composed of a metal complex hydrogen compound and a Lewis acid (such as sodium borohydride/aluminum trichloride), or a sodium simple substance, the benzyl removing agent is a reagent for removing a benzyl group from a compound 5 without affecting other functional groups, the reagent may be composed of a compound such as trifluoroacetic acid, DDQ (2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone), ammonium ceric nitrate, or may be composed of a plurality of compounds such as H₂Pd/C, Na/liquid ammonia/t-butanol, etc., and the sulfonylating agent is a reagent capable of reacting with the compound 6 to form a sulfonic acid ester, and may be a sulfonyl chloride (RSO)₂Cl), sulfonyl bromide (RSO)₂Br), sulfonic anhydride

And the like.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: in the step a, the compound 3 is contacted with benzylamine in the presence of an acid-binding agent, wherein the acid-binding agent is one of di-isopropyl ethylamine or triethylamine or a mixture of the di-isopropyl ethylamine and the triethylamine.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, in the step a, the solvent is one or more of DMF, acetonitrile, toluene or tetrahydrofuran.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, in step a, after the compound 4 is contacted with the ester reducing agent, the post-treatment operation is further included, and the post-treatment operation comprises the following steps: adding an extracting agent into a reaction liquid obtained after the compound 4 is contacted with an ester reducing agent, extracting, taking an organic phase, introducing acid gas into the organic phase, controlling the temperature to be between 10 ℃ below zero and 10 ℃, stirring for 1 to 5 hours, filtering, taking a solid, and drying to obtain a compound 5.

In the method for synthesizing the diaza-bridge compound provided by the invention, the method can also have the following characteristics: wherein, the extractant is a mixed solution of toluene and water, and the volume ratio of toluene to water is preferably (1-3): (1-3), wherein the volume ratio of the extractant to the reaction stock solution is 1: (0.8-2), and the acid gas is hydrochloric acid gas.

Preparation of compound 2 the equation is:

wherein R' is C1-C10 alkyl,

the method comprises the following steps: step a, contacting a compound 7 with an aryl reducing agent to obtain a compound 8; step beta, contacting the compound 8 with an ester reducing agent to obtain a compound 9; step gamma, contacting the compound 9 with a sulfonylation reagent to obtain a compound 2, wherein the aryl reducing agent is a reagent for catalytic hydrogenation reduction of pyrrole to pyrrolidine, such as Pt/C/H₂，Cu/Al₂O₃Ruthenium catalysts, nickel catalysts, and the like; the ester reducing agent is a reagent for reducing an ester group into a hydroxyl group, and can be a single metal complex hydrogen compound (such as lithium aluminum hydride), a composite reducing agent (such as sodium borohydride/aluminum trichloride) consisting of the metal complex hydrogen compound and Lewis acid, and can also be a sodium simple substance; the sulfonylating agent is a reagent which can react with the compound 6 to form a sulfonic acid ester, and may be a sulfonyl chloride (RSO)₂Cl), sulfonyl bromide (RSO)₂Br), sulfonic anhydride

And the like.

Action and Effect of the invention

According to the invention, the diaza-bridge compound is synthesized by using the compound 2 and NH₃Or NH₃The solution is used as a raw material, so the method not only can effectively shorten the process flow and save the process cost, but also can improve the reaction yield to a certain extent.

Drawings

FIG. 1 is a gas phase diagram of 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane in example 1 of the present invention;

FIG. 2 is a nuclear magnetic spectrum of 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane in example 1 of the present invention;

FIG. 3 is a nuclear magnetic spectrum of cis-1-benzyl-2, 4-dialkoxycarbonyl azetidine of example 3 of the present invention; and

FIG. 4 is a nuclear magnetic spectrum of tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate in example 6 of the present invention.

Detailed Description

In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the invention is specifically described below by combining the embodiment and the attached drawings.

In the following examples, the conditions for HPLC detection were: c18 column, ultraviolet wavelength 210nm, column temperature 30 deg.C, flow rate 0.8mL/min, sample volume 10 u L, mobile phase 85 vol% of 0.3 wt% trifluoroacetic acid aqueous solution and 15 vol% acetonitrile.

In the following examples, the conditions for GC detection are: DB-624 capillary column (30mm × 0.32mm × 1.8 μm), split ratio of 20:1, carrier gas of nitrogen, gasification chamber temperature of 280 deg.C, detector temperature of 280 deg.C, temperature raising program of 60 deg.C, holding for 2min, and raising to 240 deg.C at 15 deg.C/min.

The starting materials in the examples which follow are, unless otherwise indicated, commercially available and chemically pure.

< example 1>

Synthesis of 6- (tert-butyloxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane

This example provides a method for the synthesis of 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane (compound 1a), according to the equation:

the reaction steps are as follows:

step 1, adding 5g (13.4mmol, prepared by the method of example 5) of the compound cis-2a into 15mL of acetonitrile, adding 50mL of 25 wt% -28 wt% concentrated ammonia water (commercially available, and not titrated before use), heating to 70 ℃, and stirring for reaction for 12 hours to obtain a reaction solution;

step 2, adding 20mL of dichloromethane into the reaction solution, stirring, extracting, taking an organic phase, washing the organic phase with water, adding 100mL of ethyl acetate/petroleum ether mixed solution for recrystallization, wherein the ethyl acetate/petroleum ether mixed solution is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:9, and obtaining 1.9g of compound 1a (namely 6- (tert-butyloxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane) as a white solid with a yield of 71.7%.

FIG. 1 is a gas phase diagram of 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane in example 1 of the present invention.

As shown in fig. 1, the GC purity of compound 1 was 94.8% and was put into the subsequent reaction without further purification.

FIG. 2 is a nuclear magnetic spectrum of 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane in example 1 of the present invention.

As shown in FIG. 2, the hydrogen spectrum of 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane (i.e., compound 1a) obtained in this example was consistent with that reported in the literature.

< example 2>

Screening of reaction conditions

In this example, reaction conditions were further selected based on example 1, and the reaction conditions and operations were the same as those in example 1 except for the conditions listed in the table, and the specific selected reaction conditions and the corresponding reaction results are shown in table 1.

TABLE 1 Synthesis reaction conditions screening Table for Compound 1a

Numbering	Solvent(s)	Reaction temperature	Yield of	Purity of
					1	DMF	70℃	65.5％	83.4％
2	Acetonitrile	30℃	51.2％	92.8％
					3	DMF	30℃	45.1％	81.4％
4	THF	70℃	57.2％	78.3％
					5	THF	30℃	43.3％	72.4％
6	Methanol	60℃	Trace amount of	-

As shown in table 1, the reaction proceeded smoothly when DMF, acetonitrile and tetrahydrofuran were used as the reaction solvent, but the target product could not be obtained when methanol was used as the solvent, probably because compound cis-2a and methanol were subjected to transesterification reaction, and the product after transesterification reaction was not reacted with ammonia water, and thus the target product could not be obtained either.

In addition, when the reaction temperature was 70 ℃, the yield of compound 1 was significantly increased compared to when the reaction temperature was 30 ℃. The purity of the product has a certain relation with the solvent, and when the solvent is acetonitrile, the purity of the product is obviously superior to that of DMF and THF.

< example 3>

Synthesis of cis-1-benzyl-2, 4-diethoxycarbonyl azetidine

This example provides a method for synthesizing cis-1-benzyl-2, 4-diethoxycarbonyl azetidine, the reaction equation is:

the method specifically comprises the following steps:

step 1, 10.0g (28.9mmol,1eq) of diethyl 2, 4-dibromoglutarate, 3.1g (28.9mmol,1eq) of benzylamine, 7.5g (58.0mmol,2eq) of diisopropylethylamine and 100mL of acetonitrile are added to a 250mL reaction flask, and the mixture is heated to 85 ℃ for reflux reaction for 5 hours to obtain a reaction stock solution. At this time, the reaction liquid was sampled and detected by HPLC, and the ratio of the cis-product to the trans-product in the reaction liquid was 60.6%: 12.3%, i.e. 4.9: 1.

And 2, concentrating the reaction stock solution to 20mL, adding an extracting agent consisting of 50mL of toluene and 50mL of water, extracting, and taking an organic phase. And (2) introducing hydrochloric acid gas into the organic phase until the pH value is 3, controlling the temperature to be 0 ℃, keeping stirring while introducing the hydrochloric acid gas, gradually separating out crystals from the organic phase in the stirring process, continuously controlling the temperature to be 0 ℃ after the pH value is adjusted, stirring for 2 hours, filtering, taking solids, and drying to obtain 5.82g of a target product, namely a white solid, wherein the yield is 69.2%, the purity of the liquid phase is 92.8%, and the target product can be directly put into the next reaction without further purification.

FIG. 3 is a nuclear magnetic spectrum of cis-1-benzyl-2, 4-dialkoxycarbonyl azetidine in an example of the present invention.

As shown in FIG. 3, it is consistent with the cis standard sample, and thus the product can be determined to be cis-1-benzyl-2, 4-diethoxycarbonylethetidine.

< comparative example >

Synthesis of cis-1-benzyl-2, 4-diethoxycarbonyl azetidine

The present comparative example provides a method for synthesizing cis-1-benzyl-2, 4-diethoxycarbonyl azetidine, and the reaction equation is as follows:

the method specifically comprises the following steps:

step 1, 10.0g (28.9mmol,1eq) of diethyl 2, 4-dibromoglutarate, 9.3g (86.7mmol,3eq) of benzylamine and 100mL of DMF were added to a 250mL reaction flask, and the mixture was heated to 85 ℃ to react for 5 hours to obtain a reaction stock solution. At this time, the reaction liquid was sampled and detected by HPLC, and the ratio of the cis-product to the trans-product in the reaction liquid was 31.6%: 37.6%, i.e. 1: 0.84.

Step 2, the reaction solution was concentrated to 20mL, and an extractant composed of 100mL of methylene chloride and 100mL of water was added to extract the reaction solution, and the organic phase was taken out. Since recrystallization cannot be performed due to a low cis-trans ratio, the organic phase was concentrated and subjected to column chromatography to obtain 1.86g of the target product as a yellow oily liquid with a yield of 22.1%.

< example 4>

Screening of reaction conditions

In this example, reaction conditions were further screened based on example 3, and specific screening conditions and corresponding experimental results are shown in table 2.

TABLE 2 screening Table for Synthesis reaction conditions of Compound cis-4a

Numbering	Acid-binding agent	Solvent(s)	Cis form: trans form	Yield of cis-product
					1	Diisopropylethylamine	DMF	3.96:1	56.3％
2	Diisopropylethylamine	Toluene	2.66:1	35.6％
					3	Diisopropylethylamine	Tetrahydrofuran (THF)^*	2.92:1	37.5％
4	Triethylamine	Acetonitrile	3.11:1	48.3％

^*The reaction temperature is 70 ℃ reflux

As shown in Table 2, when the acid-binding agent is diisopropylethylamine or triethylamine, the cis-trans ratio of the product is higher than that when benzylamine is used as the acid-binding agent (see the comparative example); the influence of the solvent on the cis-trans ratio is not very large, the yield of cis-products is between 30% and 50%, and the yield of DMF and acetonitrile can reach more than 40%.

< example 5>

Synthesis of Compound cis-2a

This example provides a method for the preparation of compound cis-2, according to the following equation:

the method comprises the following specific steps:

step 1, 10g of the compound cis-4a (34.3mmol, 1eq, prepared by the method of example 3) was dissolved in 200mL of anhydrous ether at 0 ℃ and 2.74g of LiAlH was added₄(72.0mmol, 2.1eq), reacting at 0 ℃ for 4h, then adding 20mL of water dropwise to quench the reaction, taking the organic phase, washing with saturated saline (100 mL. times.2 times), drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 5.69g of the compound cis-5 with a yield of 80%;

step 2, 5g of cis-5(24.1mmol,1eq) was dissolved in 120mL of ethanol, 0.9g of Pd/C (10%) was added, a hydrogen gas was introduced, the reaction was stirred at room temperature for 36 hours, and 7.9g of (Boc) was added₂O (36.2mmol,1.5eq) and 6.1g sodium bicarbonate (72.3 mmol,3eq) at room temperature for 12h, filtering with diatomaceous earth, drying the filtrate with anhydrous sodium sulfate, and concentrating under pressure to obtain 4.7g of compound cis-6 with a yield of 90%;

and step 3, dissolving 4g of the compound cis-6(18.4mmol, 1eq) in 100mL of dichloromethane, sequentially dropping 3.7g of triethylamine (36.8mmol, 2eq) and 5.1g of MsCl (44.2mmol, 2.4eq) in an ice-water bath, naturally returning to room temperature, reacting for 3h, adding 100mL of water for washing, decompressing and concentrating, adding 150mL of petroleum ether for pulping, filtering, taking a solid, and drying at 60 ℃ for 6h to obtain 5.9g of the compound cis-2a, wherein the yield is 86%.

< example 6>

Synthesis of Compound 3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

This example provides a method for synthesizing tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate, the reaction equation is:

the method comprises the following specific steps:

step 1, adding 5g (12.9mmol, prepared by the method of example 9) of the compound 2b into 15mL of acetonitrile, adding 50mL of 25 wt% -28 wt% concentrated ammonia water (commercially available, and not titrated before use), heating to 70 ℃, and stirring for reaction for 12 hours to obtain a reaction solution;

and 2, adding 20mL of dichloromethane into the reaction liquid, stirring, extracting, taking an organic phase, washing the organic phase with water, adding 100mL of ethyl acetate/petroleum ether mixed liquid for recrystallization, wherein the ethyl acetate/petroleum ether mixed liquid is a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:9, and obtaining 2.0g of compound 2b (namely 3, 8-diazabicyclo [3.2.1] octane-8-tert-butyl formate) which is a white-like solid, wherein the yield is 72.9%, the GC purity is 95.3%, and the compound can be put into subsequent reactions without further purification.

FIG. 4 is a nuclear magnetic spectrum of 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane in example 6 of the present invention.

As shown in FIG. 4, the hydrogen spectrum of tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (i.e., compound 1b) obtained in this example is consistent with that reported in the literature.

< example 7>

the method comprises the following specific steps:

step 1, add 5g of compound 2b (12.9mmol, prepared by the method of example 9) to 65mL of 0.5M ammonia in tetrahydrofuran, heat to 70 ℃ under reflux, stir to react for 12 hours to obtain a reaction solution;

and 2, adding 20mL of dichloromethane into the reaction liquid, stirring, extracting, taking an organic phase, washing the organic phase with water, adding 100mL of ethyl acetate/petroleum ether mixed liquid for recrystallization, wherein the ethyl acetate/petroleum ether mixed liquid is a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:9, and obtaining 1.60g of compound 2b (namely 3, 8-diazabicyclo [3.2.1] octane-8-tert-butyl formate) which is a white-like solid, wherein the yield is 58.4%, the GC purity is 92.5%, and the compound can be put into subsequent reactions without further purification.

< example 8>

In this example, reaction conditions were further selected based on example 6, and the reaction conditions and operations were the same as those in example 6 except for the conditions listed in the table, and the specific selected reaction conditions and the corresponding reaction results are shown in table 3.

TABLE 3 reaction conditions for Synthesis of Compound 1b screening Table

As is clear from table 3, similar to the synthesis of compound 1a, the reaction proceeded smoothly with DMF, acetonitrile or THF as the solvent, but the reaction did not proceed smoothly with methanol as the solvent. In addition, it is advantageous to increase the reaction temperature appropriately to improve the yield and purity of the reaction.

< example 9>

Synthesis of Compound 2b

This example provides a method for synthesizing compound 2b, the reaction equation is:

the method comprises the following specific steps:

step 1, dissolving 20g of compound 7b (70.6mmol, in this example, compound 7b, according to Donohoe T J, Headley C E, Cousins R, et al. Flexibilty in the partial reduction of 2, 5-disubstitated phenols: application to the synthesis of DMDP. [ J ] Organic Letters,2003,5(7): 999:. multidrug 1002. reported method synthesis) in 500mL of methanol, replacing nitrogen at room temperature, adding 6g of Pt/C (Pt content 10%), charging hydrogen to the reaction system with a partial pressure of 1atm, stirring and reacting for 8h at room temperature, filtering the filtrate with diatomaceous earth, taking the filtrate, evaporating the solvent to obtain 19.4g of compound 8b, yield 95.6%, and putting the mixture into the next step without further purification;

step 2, 4.8g LiAlH is added at 0 DEG C₄(126.3mmol,2.0eq) was dissolved in 200mL of anhydrous tetrahydrofuran solution to give LiAlH₄18g of the compound 8b (62.6mmol,1.0eq) was dissolved in 300mL of anhydrous tetrahydrofuran to obtain a tetrahydrofuran solution of the compound 8 b. Adding a tetrahydrofuran solution of the compound 8b to LiAlH under the protection of nitrogen₄Stirring the tetrahydrofuran solution for reaction for 20 hours at room temperature, adding 300mL of saturated ammonium chloride aqueous solution and 150mL of ethyl acetate to quench the reaction, extracting, taking an organic phase, washing the organic phase with 1MHCl aqueous solution (300mL multiplied by 3) and saturated saline solution (300mL multiplied by 1) respectively, drying the organic phase with anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain 12.4g of a compound 9, wherein the yield is 85.6 percent, and the compound is directly put into the next step without further purification;

step 3, 12g of compound 9(51.9mmol,1eq) was dissolved in 200mL of anhydrous tetrahydrofuran, 13.1g of triethylamine (129.8mmol, 2.5eq) was added, 13.1g of methanesulfonyl chloride (114.2mmol, 2.2eq) was added dropwise in an ice-water bath, the mixture was allowed to return to room temperature naturally, the reaction was stirred for 12 hours, and the mixture was washed with distilled water (300mL × 1), a 10 wt% aqueous solution of citric acid (300mL × 1), and a saturated saline solution (300mL × 1) in this order, an organic phase was taken out, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and recrystallized from a chloroform/n-heptane (v/v ═ 1:10) system to obtain 16.5g of compound 2b, yield 82.1%, liquid phase purity 98.3%, and the mixture was directly put into the subsequent reaction without further purification.

Effects and effects of the embodiments

According to the synthesis method of the diaza-bridge compound involved in the above embodiment, the compound 2a or the compound 2b and NH are used₃The method has the advantages of effectively shortening the process flow, saving the process cost and improving the reaction yield to a certain extent.

Furthermore, acetonitrile is used as a reaction solvent for the reaction of the compound 2a or the compound 2b and ammonia water, so that the product purity can be effectively improved while the yield is ensured, and the product can be directly subjected to the next reaction without further purification.

Further, since diisopropylethylamine or triethylamine is used as an acid-binding agent in the reaction for preparing cis-1-benzyl-2, 4-dialkoxycarbonyl azetidine (cis-4 a), and DMF or acetonitrile is used as a solvent, cis-1-benzyl-2, 4-dialkoxycarbonyl azetidine with a high cis-trans ratio can be obtained in a high yield.

Furthermore, the above embodiment develops a crystallization method suitable for the diaza-bridge compound on the basis of obtaining a product with a high cis-trans ratio, on one hand, column chromatography can be avoided, post-treatment operation is simplified, and product processing is possible, on the other hand, the final product is in a solid state by means of crystallization, and storage and transportation are convenient.

The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.

Claims

1. A method for synthesizing a diaza-bridged compound,

the reaction equation is:

wherein R is aryl, substituted aryl, alkyl or halogenated alkyl,

n is 1 or 2, and n is a linear,

the reaction steps are as follows:

step 1, compound 2 is reacted with NH₃Or NH₃Contacting the solution to obtain a reaction mixture;

and 2, carrying out post-treatment on the reaction mixture to obtain a compound 1.

2. The method of synthesizing the diaza-bridge compound according to claim 1, wherein:

wherein, in step 1, compound 2 is reacted with NH₃Or NH₃The solution is contacted in a reaction medium.

3. The method of synthesizing the diaza-bridge compound according to claim 2, wherein:

wherein, the reaction medium is non-alcohol liquid.

4. The method of synthesizing the diaza-bridge compound according to claim 3, wherein:

wherein, the non-alcoholic liquid is any one or more of water, acetonitrile, DMF or tetrahydrofuran.

5. The method of synthesizing the diaza-bridge compound according to claim 1, wherein:

wherein R in the compound 2 is methyl or p-methylphenyl.

6. The method for synthesizing the diaza-bridge compound according to claim 1,

wherein, in step 1, compound 2 is reacted with NH₃Or NH₃In solution inContact at 25-80 deg.c.

7. The method for synthesizing the diaza-bridge compound according to claim 1,

wherein, the post-treatment in the step 2 comprises the following steps:

adding an extracting agent into the reaction mixture, extracting, taking an organic phase, washing with water, and recrystallizing to obtain the compound 1.

8. The method for synthesizing the diaza-bridge compound according to claim 1,

wherein the structural formula of the compound 2 is

9. The method for synthesizing the diaza-bridge compound according to claim 8,

wherein, the reaction equation for preparing the compound 2 is as follows:

wherein R' is C1-C10 alkyl,

the method comprises the following steps:

step a, contacting a compound 3 with benzylamine to obtain a compound 4;

step b, contacting the compound 4 with an ester reducing agent to obtain a compound 5;

step c, compound 5 is reacted sequentially or simultaneously with a benzyl removal agent and (Boc)₂O to give compound 6;

step d, contacting compound 6 with a sulfonylating reagent to obtain compound 2.

10. The method for synthesizing the diaza-bridge compound according to claim 9,

in the step a, the compound 3 is contacted with benzylamine in the presence of an acid-binding agent, wherein the acid-binding agent is any one of diisopropylethylamine or triethylamine or a mixture of the diisopropylethylamine and the triethylamine.