WO2023216317A1 - Method for synthesizing nirmatrelvir intermediate - Google Patents

Abstract

Provided is a method for synthesizing a nirmatrelvir intermediate in formula (III), specifically comprising: (1) dissolving a compound represented by formula V in a solvent, and reacting with trifluoromethanesulfonic anhydride under an alkaline condition to give a compound represented by formula VI; and (2) adding DBU to the compound represented by formula VI for an elimination reaction to give a product represented by formula III. The method features cost-efficiency, a stable process, and a high purity and high yield of the synthesized product, and is suitable for industrial production.

Description

A kind of synthesis method of nematvir intermediate Technical field

The present invention relates to the field of synthesis technology, specifically a method for synthesizing nematvir intermediates.

Background technique

(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3,1,0]hexyl-2-carboxylate (compound represented by formula (I)) and its corresponding salt are Pfizer of the United States disclosed that it is an important intermediate of nirmatrelvir (PF-07321332, a compound represented by formula (II)), one of the components of its Covid-19 treatment drug Paxlovid. At present, patent CN114057627A discloses a new route synthesis method, in which the important raw material structure is formula (III):

The current synthesis method of formula III is as follows:

Patent US2008/0027262 reports using Boc-L-hydroxyproline methyl ester as raw material and directly eliminating it with T3P solution (ethyl acetate solution of 1-propyl cyclic phosphoric anhydride) to obtain the product, with a yield of 97% and an ee value of: 99%; however, T3P is expensive and the country controls dangerous goods, so this route has no industrial value.

Patent US2008/318923 reports the use of Boc-L-iodoproline methyl ester as the raw material and elimination with DBU to obtain the product, but there will be about 10-20% of the ectopically eliminated isomer (Formula IV), making it difficult to separate.

Patent CN109232612 reports that Boc-L-hydroxyproline methyl ester is used as raw material, Ms is added to the hydroxyl group first, and then the product is obtained by eliminating diphenyl diselenide and sodium borohydride. This method is complex to operate and the price of diphenyl diselenide is high. Difficult to use in industrialization.

In view of the various problems existing in the existing technical synthesis methods, such as complex operation, high cost, low purity and difficulty in industrialization, we are looking for a low-cost, stable process, high purity and yield of synthetic products, suitable for industrial production of nemat The synthesis method of Wei intermediate is very necessary.

Contents of the invention

In view of the problems existing in the prior art, the present invention provides a synthesis method of nematvir intermediate, which has low cost, stable process, high purity and yield of synthetic products, and is suitable for industrial production.

In order to achieve the above objects, the technical solutions adopted by the present invention are as follows:

The invention provides a synthesis method of nematvir intermediate, which includes the following steps:

(1) Dissolve formula V in a solvent and react with trifluoromethanesulfonic anhydride under alkaline conditions to obtain formula VI;

(2) Add DBU to Formula VI to eliminate the product of Formula III obtained by the reaction;

The reaction formula is as follows:

Among them, R1 is hydrogen, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, one of p-methoxybenzyl; R is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl one of them.

Further, the solvent in step (1) includes one of dichloromethane, 1,2-dichloroethane, chloroform, and tetrahydrofuran.

Further, the solvent is methylene chloride.

Further, the base in step (2) includes one or more of pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate, and sodium carbonate.

Further, the base is N,N-diisopropylethylamine.

Further, the molar ratio of formula V and trifluoromethanesulfonic anhydride described in step (1) is: 1:1.1-1.5.

Further, the weight ratio of formula V and solvent described in step (1) is: 1:5-10.

Further, the molar ratio of formula V and DBU in step (2) is: 1:1.1-1.5.

Further, step (1) specifically includes: dissolving Formula V in a solvent, adding a base, cooling, adding trifluoromethanesulfonic anhydride, reacting, adding water to stir, and separating the liquids to obtain the lower organic phase, washing, drying, and filtering, Obtain filtrate.

In some specific embodiments, step (1) specifically includes: adding Boc-L-hydroxyproline methyl ester to the reaction bottle and dissolving it in dichloromethane, adding DIPEA for cooling, and adding trifluoromethanesulfonic anhydride and dichloromethane. Mix to make a dilute solution, transfer to the dropping funnel, add the above dilute solution dropwise into the reaction system containing the raw materials, control the temperature to 0-10°C, continue the reaction after the dripping, and control the temperature (you can use TLC to monitor, high Potassium manganate develops color); after the reaction, add water, stir, and separate the liquids. The lower organic phase is washed with 1 mol/L dilute hydrochloric acid (50 mL), and then washed with 50 mL. The organic phase was dried by adding anhydrous sodium sulfate. Filter, and wash the filter cake with dichloromethane; combine the filtrate and use it directly for the next reaction.

In some preferred embodiments, step (1) specifically includes: adding 49g Boc-L-hydroxyproline methyl ester into the reaction bottle and dissolving it in 300mL methylene chloride, adding 31g of DIPEA and cooling to 0-10°C. Mix 62 grams of fluomethanesulfonic anhydride and 49 mL of methylene chloride to make a dilute solution. Transfer it to a dropping funnel. Add the above dilute solution dropwise to the reaction system containing the raw materials. Control the temperature to 0-10°C and continue after dripping. React for 1-2 hours, control the temperature to 0-10°C (you can use TLC to monitor and potassium permanganate to develop color); after the reaction, add 150mL of water, stir for 5-10 minutes, separate the liquids, and use 1mol/L for the lower organic phase. Wash with dilute hydrochloric acid (50 mL), and then wash with 50 mL. Add 49 grams of anhydrous sodium sulfate to the organic phase and dry for 0.5 hours. Filter, and wash the filter cake with 49 mL of methylene chloride; combine the filtrate and use it directly for the next reaction.

Further, step (2) specifically includes: adding DBU dropwise to the formula VI to react, continuing the reaction after the dropwise addition is completed, adding water, stirring, and liquid separation, and the obtained lower organic phase is washed, dried, filtered, and rinsed. After washing, the concentrated solution is concentrated to dryness to obtain the product of formula III.

In some specific embodiments, step (2) specifically includes: cooling the filtrate obtained in step (1), adding DBU dropwise, the reaction is exothermic, and controlling the reaction temperature to 0-10°C; continuing the reaction after dripping, and controlling the temperature to 0-10°C. 10°C (TLC can be used to monitor, and potassium permanganate can develop color); after the reaction is completed, add water, stir, and separate the liquids. The lower organic phase is washed with 1 mol/L dilute hydrochloric acid (50 mL), and then washed with 50 mL. The organic phase was dried over anhydrous sodium sulfate, filtered, rinsed, and the filtrate was concentrated to dryness to obtain an oily substance.

In some preferred embodiments, step (1) specifically includes: cooling the filtrate obtained in step (1) to 0-10°C, adding DBU (36.5 g) dropwise, the reaction is exothermic, and controlling the reaction temperature to 0-10°C; After the dripping, continue the reaction for 4-8 hours, and control the temperature to 0-10°C (you can use TLC to monitor and potassium permanganate to develop color); after the reaction is completed, add 150mL of water, stir for 5-10 minutes, separate the liquids, and use the lower organic phase. Wash with 1 mol/L dilute hydrochloric acid (50 mL), and then wash with 50 mL. The organic phase was dried over anhydrous sodium sulfate, filtered, rinsed, and the filtrate was concentrated to dryness to obtain an oily substance.

Further, the reaction temperatures in steps (1) and (2) are both 0-30°C; preferably 0-10°C.

The technical effects achieved by the present invention are:

Optimize and innovate a new route for the synthesis of nematvir intermediates so that they can be directly used in industrial production with low cost and stable and safe processes. The product purity reaches more than 95%, the ee value is >99%, the yield can reach 90%, and the content is more than 95%; it can be separated and purified without column chromatography and can be directly used in the next step of the reaction.

Description of the drawings

Figure 1 is a GC chart of the nematvir intermediate synthesized in the present invention.

Detailed ways

The following describes the embodiments of the present invention through specific examples. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments. Various details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

Before further describing the specific embodiments of the present invention, it should be understood that the protection scope of the present invention is not limited to the following specific specific embodiments; it should also be understood that the terms used in the embodiments of the present invention are for describing specific specific embodiments, It is not intended to limit the scope of the present invention.

When the examples give numerical ranges, it should be understood that, unless otherwise stated in the invention, the two endpoints of each numerical range and any value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It is worth noting that the raw materials used in the present invention are all common commercially available products, so their sources are not specifically limited.

Example 1

A method for synthesizing nematvir intermediates, including the following steps:

(1) Add 49g Boc-L-hydroxyproline methyl ester into the reaction bottle and dissolve it in 300mL dichloromethane, add 31g DIPEA and cool to 0-10°C; mix 62g trifluoromethanesulfonic anhydride and 49mL dichloromethane Mix to make a dilute solution, transfer to the dropping funnel, add the above dilute solution dropwise into the reaction system containing the raw materials, control the temperature to 0-10°C, continue the reaction for 1-2 hours after the dripping, control the temperature to 0-10 ℃ (TLC can be used to monitor, potassium permanganate color development); after the reaction is completed, add 150mL water, stir for 5-10 minutes, separate the liquids, and wash the lower organic phase with 1mol/L dilute hydrochloric acid (50mL), and then wash with 50mL . Add 49 grams of anhydrous sodium sulfate to the organic phase and dry for 0.5 hours. Filter, and wash the filter cake with 49 mL of methylene chloride; combine the filtrate and use it directly for the next reaction;

(2) Cool the filtrate in the previous step to 0-10°C, add DBU (36.5g) dropwise, the reaction will be exothermic, and control the reaction temperature to 0-10°C; continue the reaction for 4-8 hours after the dripping, and control the temperature to 0-10°C ( TLC can be used to monitor (potassium permanganate color development); after the reaction is completed, add 150 mL of water, stir for 5-10 minutes, separate the liquids, and wash the lower organic phase with 1 mol/L dilute hydrochloric acid (50 mL), and then wash with 50 mL. The organic phase was dried with anhydrous sodium sulfate, filtered, rinsed, and the filtrate was concentrated to dryness to obtain 41 g of oil, GC: 97.8%; yield 90.5%, content 95.3%, ee value 99.6%

The specific reaction formula is as follows:

The GC spectrum of the synthesized nematvir intermediate is shown in Figure 1. The corresponding peak number, retention time, area, height, etc. are specifically shown in the table below:

Table 1

Peak number	keep time	area	high	area(%)
1	8.508	3146	705	0.033
2	8.564	4916	715	0.051
3	9.352	2954	516	0.031
4	9.962	1577	181	0.016
5	10.985	1691	256	0.018
6	11.359	1565	178	0.016
7	11.592	5011	865	0.052
8	12.249	9446781	1627018	97.802

9	12.669	81638	6737	0.845
10	12.769	41649	5108	0.431
11	13.072	7291	1023	0.075
12	13.370	19190	2993	0.199
13	13.469	27836	6009	0.288
14	13.782	2688	438	0.028
15	14.504	1867	450	0.019
16	14.935	4332	629	0.045
17	15.476	4990	1285	0.052
total	-	9659121	1655108	100.000

Example 2

A method for synthesizing nematvir intermediates, including the following steps:

(1) Add 30g (2S,4R)-N-benzyloxycarbonyl-4-hydroxyproline methyl ester into the reaction bottle and dissolve it in 180mL methylene chloride, add 16.6g of DIPEA and cool to 0-10°C; Mix 34.8 grams of methanesulfonic anhydride and 30 mL of methylene chloride to make a dilute solution. Transfer it to a dropping funnel. Add the above dilute solution dropwise to the reaction system containing the raw materials. Control the temperature to 0-10°C and continue the reaction after the dripping. 1-2 hours, control the temperature to 0-10°C (you can use TLC to monitor and potassium permanganate to develop color); after the reaction is completed, add 150mL of water, stir for 5-10 minutes, separate the layers, and dilute the lower organic phase with 1mol/L Wash with hydrochloric acid (50 mL) and then with 50 mL. Add 30 grams of anhydrous sodium sulfate to the organic phase and dry for 0.5 hours. Filter, and wash the filter cake with 30 mL of methylene chloride; combine the filtrate and use it directly for the next reaction;

(2) Cool the filtrate in the previous step to 0-10°C, add DBU (19.6 g) dropwise, the reaction will be exothermic, and control the reaction temperature to 0-10°C; continue the reaction for 4-8 hours after the dripping, and control the temperature to 0-10°C ( TLC can be used to monitor (potassium permanganate color development); after the reaction is completed, add 150 mL of water, stir for 5-10 minutes, separate the liquids, and wash the lower organic phase with 1 mol/L dilute hydrochloric acid (50 mL), and then wash with 50 mL. The organic phase was dried over anhydrous sodium sulfate, filtered, rinsed, and the filtrate was concentrated to dryness to obtain 25.0 g of oil, GC: 98.2%; yield 90%, content 96.7%. ee value 99.8%

Example 3

A method for synthesizing nematvir intermediates, including the following steps:

(1) Add 50g Boc-L-hydroxyproline ethyl ester into the reaction bottle and dissolve it in 300mL dichloromethane, add 30g DIPEA and cool to 0-10°C; mix 59.8g trifluoromethanesulfonic anhydride and 50mL dichloromethane Mix to make a dilute solution, transfer to the dropping funnel, add the above dilute solution dropwise into the reaction system containing the raw materials, control the temperature to 0-10°C, continue the reaction for 1-2 hours after the dripping, control the temperature to 0-10 ℃ (TLC can be used to monitor, potassium permanganate color development); after the reaction is completed, add 150mL water, stir for 5-10 minutes, separate the liquids, and wash the lower organic phase with 1mol/L dilute hydrochloric acid (50mL), and then wash with 50mL . Add 50 grams of anhydrous sodium sulfate to the organic phase and dry for 0.5 hours. Filter, and wash the filter cake with 50 mL of methylene chloride; combine the filtrate and use it directly for the next reaction;

(2) Cool the filtrate in the previous step to 0-10°C, add DBU (35.2 g) dropwise, the reaction will be exothermic, and control the reaction temperature to 0-10°C; continue the reaction for 4-8 hours after the dripping, and control the temperature to 0-10°C ( TLC can be used to monitor (potassium permanganate color development); after the reaction is completed, add 150 mL of water, stir for 5-10 minutes, separate the liquids, and wash the lower organic phase with 1 mol/L dilute hydrochloric acid (50 mL), and then wash with 50 mL. The organic phase was dried with anhydrous sodium sulfate, filtered, rinsed, and the filtrate was concentrated to dryness to obtain 42.3g of oil, GC: 97.3%; yield 91.0%, content 95.1%, ee value 99.3%

Comparative example 1

The only difference between the synthesis method of nematvir intermediate and Example 1 is that methylsulfonyl chloride is used instead of trifluoromethanesulfonyl chloride; the result is that the GC purity is 96.3%, the yield is 92.3%, and the content is 95.7%, but The ee value is 15%, and the product is racemized.

Comparative example 2

The only difference between a synthesis method of nematvir intermediate and Example 1 is that the equivalent of triflate is 1.0eq; the equivalent of DBU is 1.0eq; the resulting GC purity is 83.2%, and the raw material Boc-L-hydroxy Proline methyl ester (V) remains at 5.6%; intermediate VI remains at 4.3%; the yield is 85.3%, the content is 84.2%, and the ee value is 99.6%.

Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, but does not limit the protection scope of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by those of ordinary skill in the art do not deviate from the scope of the present invention. The essence and scope of the technical solution of the invention.

Claims (10)

1. A method for synthesizing nematvir intermediates, which is characterized by comprising the following steps:

   (1) Dissolve formula V in a solvent and react with trifluoromethanesulfonic anhydride under alkaline conditions to obtain formula VI;

   (2) Add DBU to Formula VI to eliminate the product of Formula III obtained by the reaction;

   The reaction formula is as follows:

   

   Among them, R1 is one of hydrogen, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl and p-methoxybenzyl; R is hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl one of them.
2. The synthesis method according to claim 1, wherein the solvent in step (1) includes one of methylene chloride, 1,2-dichloroethane, chloroform, and tetrahydrofuran.
3. The synthesis method according to claim 2, characterized in that: the solvent is methylene chloride.
4. The synthesis method according to claim 1, characterized in that: the base in step (2) includes one of pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, or Various.
5. The synthesis method according to claim 4, characterized in that: the base is N, N-diisopropylethylamine.
6. The synthesis method according to claim 1, characterized in that: the weight ratio of formula V, solvent and trifluoromethanesulfonic anhydride in step (1) is: 1:1.1-1.5.
7. The synthesis method according to claim 1, characterized in that: the weight ratio of formula VI and DBU in step (2) is 1:1.1-1.5.
8. The synthesis method according to claim 1, characterized in that: step (1) specifically includes: dissolving formula V in a solvent, adding a base, cooling, adding trifluoromethanesulfonic anhydride, reacting, adding water, stirring, and liquid separation, Obtain the lower organic phase, wash, dry, and filter to obtain the filtrate.
9. The synthesis method according to claim 1, characterized in that step (2) specifically includes: adding DBU dropwise to the formula V for reaction, continuing the reaction after the dropwise addition, and after the reaction is completed, adding water, stirring, and liquid separation to obtain After the lower organic phase is washed, dried, filtered, and rinsed, the concentrated liquid is concentrated to dryness to obtain the product of Formula III.
10. The synthetic method according to claim 8 or 9, characterized in that: the temperatures of the reactions described in steps (1) and (2) are both 0-30°C; preferably 0-10°C.

Images