TW202330535A - Preparation method of DPP-IV inhibitor and key intermediate thereof - Google Patents

Abstract

The invention belongs to the technical field of drug synthesis, and relates to a preparation method of a DPP-IV inhibitor and a key intermediate thereof. Specifically, the key intermediate of the DPP-IV inhibitor is shown as a formula I. The preparation method of the key intermediate comprises the following steps: activating a compound B serving as an initial raw material, and reacting with a compound A to obtain the key intermediate of the DPP-IV inhibitor. The preparation method not only utilizes cheap and environment-friendly raw materials, but also solves various problems of product quality, purity, yield, safety, environmental protection, cost and the like, and is more suitable for industrialization and market requirements. On the basis, the invention also provides a new method and a new idea for preparing the novel DPP-IV inhibitor.

Description

A kind of preparation method of DPP-IV inhibitor and key intermediate thereof

The invention belongs to the technical field of drug synthesis, and relates to a DPP-IV inhibitor and its key intermediate (R)-4-((R)-8-methyl-3-(trifluoromethyl)-5,6-di Hydroimidazo[1,5-a]pyrazin-7(8H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate The preparation method of butyl ester.

(R)-4-((R)-8-Methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl) Tert-butyl-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate is a key intermediate in the synthesis of senagliptin, which can be deprotected to form Phosphate hydrate is the hypoglycemic drug Shengagliptin phosphate, which belongs to DPP-IV inhibitors.

For the above-mentioned key intermediates, CN103351391A discloses the synthetic route of compound 7, which uses 2-(tertiary butoxycarbonylamino)-3-(2,4,5-trifluorophenyl) propionic acid (compound 1) As the starting material, undergo the steps of sodium borohydride reduction, sulfonate formation, cyano substitution, acid hydrolysis, and re-protecting of the amine group to obtain 3-(tertiary butoxycarbonylamino)-4- (2,4,5-trifluorophenyl)butanoic acid (compound 5), and then with 8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1, 5-a] pyrazine reaction and obtain compound 7, concrete technique is as follows: .

Since there are two chiral carbon atoms in the structure of compound 7, the obtained compound 7 is actually a mixture, including four optical isomers, which requires chiral resolution to obtain RR type compound 11A, that is, the free base form Sheng Gliptin. It can be seen that this synthetic route requires relatively cumbersome resolution steps, which brings inconvenience to the post-treatment process, and the yield of this synthetic route is only 26%, which cannot meet the needs of large-scale production. Therefore, there is an urgent need to develop a new method for the preparation of DPP-IV inhibitors and key intermediates thereof.

In order to solve the above technical problems, the present invention provides a key intermediate (R)-4-((R)-8-methyl-3-(trifluoromethyl)-5,6-dihydro Imidazo[1,5-a]pyrazin-7(8H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate The ester method not only utilizes cheap and environmentally friendly raw materials, but also solves various problems such as product quality, purity, yield, safety, environmental protection and cost, and is completely suitable for industrialization and market demand. Meanwhile, based on the above method, the present invention also provides a method for preparing DPP-IV inhibitor based on the above key intermediate.

The technical scheme that the present invention adopts is as follows:

In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof; Among them, PG is selected from tertiary butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-(trimethylsilyl)ethoxycarbonyl , preferably tertiary butoxycarbonyl.

In a second aspect, the present invention provides a method for preparing a compound of formula I, which includes the following steps: in the presence of an organic solvent and a base, using compound B as a starting material, first activated, and then reacted with compound A; Among them, PG is selected from tertiary butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-(trimethylsilyl)ethoxycarbonyl , preferably tertiary butoxycarbonyl.

Further, in the above preparation method, the organic solvent is dichloromethane, chloroform or tetrahydrofuran, preferably dichloromethane.

Further, in the above preparation method, the base is an organic base.

Furthermore, in the above preparation method, the base is triethylamine, diisopropylethylamine or N-methylmorpholine, preferably N-methylmorpholine.

Further, in the above preparation method, the molar ratio of the compound B to the base is 1:1.2~1:1.7, preferably 1:1.3~1:1.65, more preferably 1:1.3.

Further, in the above preparation method, the mass ratio of the compound B to the base is 200-400:73-200, preferably 333.3:131.5.

Further, in the above preparation method, the activation is to react the compound B with an acyl chloride, and the acyl chloride is trimethylacetyl chloride (or pivalyl chloride), acetyl chloride or chloroformic acid Ethyl esters, preferably trimethylacetyl chloride.

Further, in the above preparation method, the molar ratio of the compound B to the acyl chloride is 1:0.9~1:1.4, preferably 1:0.92~1:1.38, more preferably 1:1.2.

Further, in the above preparation method, the mass ratio of the compound B to the acyl chloride is 200-400:67-200, preferably 333.3:144.7.

Further, in the above preparation method, the molar ratio of the compound A to the compound B is 0.9:1~1.3:1, preferably 1:1~1.22:1, more preferably 1:1.

Further, in the above preparation method, the mass ratio of the compound A to the compound B is 111~300:200~400, preferably 205.2:333.3.

Specifically, the above-mentioned preparation method comprises the following steps: 1) Dissolve compound B in an organic solvent, add alkali after cooling under stirring conditions, and then stir and mix the solution under natural heating conditions to obtain solution B; 2) Add acid chloride dropwise to the solution B obtained in step 1) under temperature control and stirring conditions, and then react under natural temperature rise conditions to obtain an activated mixed anhydride solution; 3) Dissolving compound A in an organic solvent to obtain solution A; 4) Add solution A obtained in step 3) dropwise to the activated mixed anhydride solution obtained in step 2) under temperature control and stirring conditions, and then react under natural heating conditions.

Preferably, in the above preparation method, the organic solvents in steps 1) and 3) are each independently dichloromethane, chloroform or tetrahydrofuran, preferably dichloromethane.

More preferably, in the above preparation method, the organic solvent in steps 1) and 3) is dichloromethane, chloroform or tetrahydrofuran, preferably dichloromethane.

Preferably, in the above preparation method, the mass ratio of the compound B to the organic solvent in step 1) is 200-400:4000-5000, preferably 333.3:4247.

Preferably, in the above preparation method, the base in step 1) is an organic base.

More preferably, in the above preparation method, the base in step 1) is triethylamine, diisopropylethylamine or N-methylmorpholine, preferably N-methylmorpholine.

Preferably, in the above preparation method, the molar ratio of the compound B to the base in step 1) is 1:1.2~1:1.7, preferably 1:1.3~1:1.65, more preferably 1:1.3.

Preferably, in the above preparation method, the mass ratio of the compound B to the base in step 1) is 200-400:73-200, preferably 333.3:131.5.

Preferably, in the above preparation method, the cooling target temperature in step 1) is -5~15°C, preferably 0°C.

Preferably, in the above preparation method, the target temperature of the heating in step 1) is 15-30°C, preferably 25°C.

Preferably, in the above preparation method, the reaction time in step 1) is 0.5~2h, preferably 1h.

Preferably, in the above preparation method, the acetyl chloride in step 2) is trimethyl acetyl chloride (or called pivalyl chloride), acetyl chloride or ethyl chloroformate, preferably trimethyl acetyl chloride.

Preferably, in the above preparation method, the molar ratio of the compound B in step 1) to the acyl chloride in step 2) is 1:0.9~1:1.4, preferably 1:0.92~1:1.38, more preferably 1:1.2.

Preferably, in the above preparation method, the mass ratio of the compound B in step 1) to the acyl chloride in step 2) is 200~400:67~200, preferably 333.3:144.7.

Preferably, in the above preparation method, the target temperature of the temperature control in step 2) is -5~15°C.

Preferably, in the above preparation method, the target temperature of the heating in step 2) is 15-30°C, preferably 25°C.

Preferably, in the above preparation method, the reaction time in step 2) is 1-5 hours, preferably 2 hours.

Preferably, in the above preparation method, the mass ratio of the compound A to the organic solvent in step 3) is 111-300:3000-5000, preferably 205.2:4247.

Preferably, in the above preparation method, the molar ratio of compound A in step 3) to compound B in step 1) is 0.9:1~1.3:1, preferably 1:1~1.22:1, more preferably 1:1.

Preferably, in the above preparation method, the mass ratio of compound A in step 3) to compound B in step 1) is 111~300:200~400, preferably 205.2:333.3.

Preferably, in the above preparation method, the target temperature of the temperature control in step 4) is -5~15°C.

Preferably, in the above preparation method, the target temperature of the heating in step 4) is 15-30°C, preferably 25°C.

Preferably, in the above preparation method, the reaction time in step 4) is 8-36 hours, preferably 16 hours.

Further, the above preparation method also includes the following steps: 5) Add lye to the reaction solution obtained in step 4) for alkaline washing, separate the liquids to obtain the organic phase, then add acid solution for pickling, separate the liquids to obtain the organic phase, finally add water for washing, and separate the liquids to obtain the organic phase followed by concentration.

Preferably, in the above preparation method, the lye in step 5) is an aqueous solution of alkali metal carbonate, bicarbonate or phosphate, preferably aqueous sodium bicarbonate, more preferably saturated aqueous sodium bicarbonate.

Preferably, in the above preparation method, the acid solution in step 5) is an aqueous solution of an ammonium salt of an inorganic strong acid, preferably an aqueous solution of ammonium chloride, more preferably a saturated aqueous solution of ammonium chloride.

Preferably, in the above preparation method, the mass ratio of the lye, acid and water in step 5) to the compound B in step 1) is 2667~5000:2667~5000:2667~5000:200~400 , preferably 4247:4247:4247:333.3.

Preferably, in the above preparation method, the concentration in step 5) is concentration under reduced pressure.

Furthermore, the above-mentioned preparation method also includes the following steps: 6) Beating the concentrate obtained in step 5) with a mixed organic solvent, then filtering and drying.

Preferably, in the above preparation method, the mixed organic solvent in step 6) is a mixture of alkanes and esters, preferably a mixture of n-heptane and ethyl acetate.

More preferably, in the above preparation method, the mass ratio of the alkane in step 6) to the ester and the compound B in step 1) is 533~1500:333~1000:200~400, preferably 1000:800:333.3 .

Preferably, in the above preparation method, the beating time in step 6) is 0.5~3h, preferably 1h.

Preferably, in the above preparation method, the drying temperature in step 6) is 25-100°C, preferably 60°C.

Preferably, in the above preparation method, the drying time in step 6) is 1-5 hours, preferably 3 hours.

In a third aspect, the present invention provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of hypoglycemic drugs.

Preferably, in the above use, the hypoglycemic agent is sengagliptin or a pharmaceutically acceptable salt thereof, preferably sengagliptin phosphate.

In a fourth aspect, the present invention provides a method for preparing sengagliptin phosphate, which includes the following steps: 1) Dissolving the compound of formula I in a solvent under stirring conditions, adding phosphoric acid thereto under reflux conditions, and the reaction ends Finally, the temperature of the system is lowered to room temperature; 2) Under stirring conditions, add alkali to the system, filter after the reaction is completed, and dry the filter cake after rinsing with eluent; Among them, PG is selected from tertiary butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-(trimethylsilyl)ethoxycarbonyl , preferably tertiary butoxycarbonyl.

Preferably, in the above preparation method, the solvent in step 1) is an aqueous solution of a lower alcohol, preferably an aqueous solution of isopropanol.

More preferably, in the above preparation method, the mass ratio of the lower alcohol, water and the compound of formula I is 181~406:231~517:231~517, preferably 380.424:484:484.

Preferably, in the above preparation method, the reflux time in step 1) is 2-5 hours, preferably 3 hours.

Preferably, in the above preparation method, the molar ratio of the compound of formula I to the phosphoric acid in step 1) is 1:2~1:6, preferably 1:3~1:5, more preferably 1:4.

Preferably, in the above preparation method, the mass ratio of the compound of formula I to the phosphoric acid in step 1) is 231-517:129-485, preferably 484:365.

Preferably, in the above preparation method, the base in step 2) is an inorganic base.

More preferably, in the above preparation method, the alkali in step 2) is alkali metal hydroxide, carbonate or bicarbonate, preferably alkali metal hydroxide, more preferably sodium hydroxide.

Preferably, in the above preparation method, the molar ratio of the compound of formula I in step 1) to the base in step 2) is 1:0.5~1:5, preferably 1:2.25~1:3.75, more preferably 1:3.

Preferably, in the above preparation method, the mass ratio of the compound of formula I in step 1) to the base in step 2) is 231~517:40~148, preferably 484:112.

Preferably, in the above preparation method, the reaction time in step 2) is 8-16 hours, preferably 14 hours.

Preferably, in the above preparation method, the eluent in step 2) is a lower alcohol, preferably isopropanol.

The present invention has following beneficial effects:

1. The present invention uses cheap and environmentally friendly raw materials to prepare the key intermediate of the DPP-IV inhibitor—(R)-4-((R)-8-methyl-3-(trifluoromethyl)-5, 6-Dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butan-2-ylamino Tertiary butyl formate solves various problems such as product quality, purity, yield, safety, environmental protection and cost at the same time, and is more suitable for industrialization and market demand.

2. The key intermediate preparation method of the present invention not only avoids the use of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide which is expensive, potentially genotoxic and difficult to remove in the previous process Condensing agents such as hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt), and avoid the final reaction caused by the disubstituted coupling impurities generated by 1-hydroxybenzotriazole (HOBt) and solvent dichloromethane The product quality is not high, the purity is low, and the yield is low, and it also avoids the hidden dangers of production safety and environmental protection pressure caused by the degradation product of the condensing agent containing a large amount of nitrogen, and has a stable reaction yield and a high compound purity.

3. The products obtained by using the key intermediate preparation method of the present invention can be further used to prepare DPP-IV inhibitors (such as senagliptin phosphate), which provides a new method and new method for the production of new DPP-4 inhibitors. train of thought.

Embodiments of the present invention will be described below, but the present invention is not limited thereto. Various changes can be made within the scope of the claimed protection of the invention, and the implementation modes and examples obtained by appropriately combining the technical means disclosed in the different implementation modes and examples also fall within the scope of the present invention.

Unless otherwise defined, the meanings of scientific and technical terms used in the present invention are the same as commonly understood by one of ordinary skill in the art to which this invention belongs.

In the present invention, the numerical range represented by "numerical value A~numerical value B" or "numerical value A-numerical value B" refers to the range including the numerical values A and B at the endpoints. In some embodiments, the above-mentioned numerical ranges also refer to including endpoint values A, B and ±10%, ±8%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5 % or ±0.1% error range.

In the present invention, the term "may" includes both meanings of performing certain processing and not performing certain processing. In the present invention, "optional" or "optionally" may mean that the next described event or situation may or may not occur, and that the description includes situations where the event occurs and situations where the event does not occur.

In the present invention, the terms "comprising", "having", "comprising" or "containing" may mean inclusive or open-ended and do not exclude additional, unrecited elements or method steps. At the same time, "comprising", "having", "including" or "comprising" can also mean enclosing, excluding additional, unrecited elements or method steps.

In the present invention, the term "about" may mean that a value includes the standard deviation of error of the device or method used to determine the value. The numerical ranges and parameters used to define the present invention are approximate numerical values, and the relevant numerical values in the specific examples have been presented here as precisely as possible. Any numerical values, however, inherently contain standard deviations resulting from the foregoing testing apparatus or methodology. Therefore, unless expressly stated otherwise, it should be understood that all ranges, numbers, values and percentages used herein are modified by "about". As used herein, "about" generally means that the actual value is within ±10%, ±5%, ±1%, or ±0.5% of a particular value or range.

＜Sengagliptin and its key intermediates＞

In the present invention, the term "Sengagliptin" refers to a drug used to prevent and/or treat diseases and/or conditions related to dipeptidyl peptidase IV (DPP-IV) (for example, diabetes mellitus, especially type II diabetes) with the chemical name (R)-3-amino-1-((R)-8-methyl-3-(trifluoromethyl)-5,6-dihydroimidazo[1, 5-a] Pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one.

In the present invention, the term "intermediate" refers to an intermediate product in the production of a certain product or a certain type of product; correspondingly, the term "key intermediate of sengagliptin" refers to a relatively important intermediate in the production process of sengagliptin. mid product.

In some embodiments, the key intermediate of senagliptin of the present invention may be a compound of formula I or a pharmaceutically acceptable salt thereof;

Among them, PG is a protecting group (protective group), selected from tertiary butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2 - Trichloroethoxycarbonyl (Troc) and 2-(trimethylsilyl)ethoxycarbonyl (Teoc).

In some specific embodiments, PG in the above-mentioned compound of formula I can be tertiary butoxycarbonyl (Boc), at this time, the compound of formula I is the compound of formula II; The compound of formula II or its pharmaceutically acceptable salt can also be the key intermediate of senagliptin in the present invention.

＜The preparation method of the key intermediate of senagliptin＞

In some embodiments, the above-mentioned compound of formula I can be prepared by the following method: in the presence of an organic solvent and a base, compound B is used as a starting material, first activated, and then reacted with compound A to obtain formula I as the target product compound; Among them, PG is selected from tertiary butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc ) and 2-(trimethylsilyl)ethoxycarbonyl (Teoc).

In some specific embodiments, PG in the above-mentioned compound of formula I can be tertiary butoxycarbonyl (Boc), at this moment, the compound of formula II can be prepared by the following method: in the presence of an organic solvent and a base, compound B' As the starting material, it is first activated, and then reacted with compound A to obtain the compound of formula II as the target product.

In some embodiments, the organic solvent in the above two methods can be dichloromethane (DCM), chloroform (TCM) or tetrahydrofuran (THF).

In some specific embodiments, the organic solvent in the above two methods can be dichloromethane (DCM).

In some embodiments, the base in the above two methods can be an organic base.

In some specific embodiments, the base in the above two methods can be triethylamine (TEA), diisopropylethylamine (DIPEA) or N-methylmorpholine (NMM).

In some more specific embodiments, the base in the above two methods can be N-methylmorpholine (NMM).

In some embodiments, the molar ratio of compound B or compound B' to the base in the above two methods can be about 1:1.2 to 1:1.7, for example, 1:1.2, 1:1.25, 1:1.3, 1 :1.35, 1:1.4, 1:1.45, 1:1.5, 1:1.55, 1:1.6, 1:1.65, 1:1.7 or other ratios.

In some specific embodiments, the molar ratio of compound B or compound B' and base in the above two methods can be about 1:1.3~1:1.65, for example, 1:1.3, 1:1.35, 1:1.4 , 1:1.45, 1:1.5, 1:1.55, 1:1.6, 1:1.65 or other ratios.

In some more specific embodiments, the molar ratio of compound B or compound B' and base in the above two methods can be about 1:1.3.

In some embodiments, the mass ratio of compound B or compound B' to the base in the above two methods can be about 200~400:73~200, for example, 200:73, 200:100, 200:150, 200: 200, 300:73, 300:100, 300:200, 400:73, 400:100, 400:150, 400:200 or other ratios.

In some specific embodiments, the mass ratio of compound B or compound B' to the base in the above two methods can be about 333.3:131.5.

In some embodiments, the activation in the above two methods is to react Compound B or Compound B' with an acyl chloride, which may be trimethylacetyl chloride, acetyl chloride or ethyl chloroformate.

In some specific embodiments, the acetyl chloride in the above two methods can be trimethyl acetyl chloride.

In some embodiments, the molar ratio of compound B or compound B' and acyl chloride in the above two methods can be about 1:0.9~1:1.4, for example, 1:0.9, 1:0.92, 1:0.95, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.35, 1:1.38, 1:1.4 or other ratios.

In some specific embodiments, the molar ratio of compound B or compound B' and acyl chloride in the above two methods can be about 1:0.92~1:1.38, for example, 1:0.92, 1:0.95, 1:0.92 1, 1:1.1, 1:1.2, 1:1.3, 1:1.35, 1:1.38 or other ratios.

In some more specific embodiments, the molar ratio of compound B or compound B' and acyl chloride in the above two methods can be about 1:1.2.

In some embodiments, the mass ratio of acyl chloride to compound B or compound B' in the above two methods can be about 67~200:200~400, for example, 67:200, 67:300, 67:350, 67 :400, 100:200, 100:300, 100:350, 100:400, 150:200, 150:300, 150:350, 150:400, 200:200, 200:300, 200:350, 200:400 or other ratios.

In some specific embodiments, the mass ratio of the acyl chloride and compound B or compound B' in the above two methods can be about 144.7:333.3.

In some embodiments, the molar ratio of compound A and compound B or compound B' in the above two methods can be about 0.9:1~1.3:1, for example, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or other ratios.

In some specific embodiments, the molar ratio of compound A and compound B or compound B' in the above two methods can be about 1:1 ~ 1.22:1, for example, 1:1, 1.1:1, 1.12: 1, 1.15:1, 1.18:1, 1.2:1, 1.22:1 or other ratios.

In some more specific embodiments, the molar ratio of compound A and compound B or compound B' in the above two methods can be about 1:1.

In some embodiments, the mass ratio of compound A to compound B or compound B' in the above two methods can be about 111~300:200~400, for example, 111:200, 111:300, 111:350, 111 :400, 200:200, 200:300, 200:350, 200:400, 250:200, 250:300, 250:350, 250:400, 300:200, 300:300, 300:350, 300:400 or other ratios.

In some specific embodiments, the mass ratio of compound A and compound B or compound B' in the above two methods can be about 205.2:333.3.

In the present invention, the compound of formula I or the compound of formula II as the key intermediate of senagliptin can also be prepared by the following method: 1) Dissolve compound B or compound B' in an organic solvent, add alkali after cooling under stirring conditions, and then stir and mix the solution under natural heating conditions to obtain solution B or solution B'; 2) Add acid chloride dropwise to solution B or solution B' obtained in step 1) under temperature control and stirring conditions, and then react under natural heating conditions to obtain an activated mixed anhydride solution; 3) Dissolving compound A in an organic solvent to obtain solution A; 4) Add solution A obtained in step 3) dropwise to the activated mixed anhydride solution obtained in step 2) under temperature control and stirring conditions, and then react under natural heating conditions.

In some embodiments, the organic solvents in steps 1) and 3) can be the same or different, for example, each independently dichloromethane (DCM), chloroform (TCM) or tetrahydrofuran (THF) .

In some specific embodiments, the organic solvent in steps 1) and 3) can be the same so that the entire reaction system is under relatively uniform and stable conditions, for example, dichloromethane (DCM), chloroform ( TCM) or tetrahydrofuran (THF).

In some more specific embodiments, the organic solvent in steps 1) and 3) can be dichloromethane (DCM) at the same time.

In some embodiments, the mass ratio of compound B or compound B' and organic solvent (for example, dichloromethane (DCM)) in step 1) can be about 200~400:4000~5000, for example, 200:4000, 200:4500, 200:5000, 300:4000, 300:4500, 300:5000, 400:4000, 400:4500, 400:5000 or other ratios.

In some specific embodiments, the mass ratio of compound B or compound B' to the organic solvent (for example, dichloromethane (DCM)) in step 1) may be about 333.3:4247.

In some embodiments, the base in step 1) can be an organic base.

In some specific embodiments, the base in step 1) can be triethylamine (TEA), diisopropylethylamine (DIPEA) or N-methylmorpholine (NMM).

In some more specific embodiments, the base in step 1) can be N-methylmorpholine (NMM).

In some embodiments, the molar ratio of compound B or compound B' and base (for example, N-methylmorpholine (NMM)) in step 1) may be about 1:1.2 to 1:1.7, for example, 1 :1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, 1:1.55, 1:1.6, 1:1.65, 1:1.7 or other ratios.

In some specific embodiments, the molar ratio of compound B or compound B' and base (for example, N-methylmorpholine (NMM)) in step 1) can be about 1:1.3~1:1.65, for example , 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, 1:1.55, 1:1.6, 1:1.65 or other ratios.

In some more specific embodiments, the molar ratio of compound B or compound B' and base (eg, N-methylmorpholine (NMM)) in step 1) may be about 1:1.3.

In some embodiments, the mass ratio of compound B or compound B' and base (for example, N-methylmorpholine (NMM)) in step 1) can be about 200~400:73~200, for example, 200: 73, 200:100, 200:150, 200:200, 300:73, 300:100, 300:150, 300:200, 400:73, 400:100, 400:150, 400:200 or other ratios.

In some specific embodiments, the mass ratio of compound B or compound B' to the base (for example, N-methylmorpholine (NMM)) in step 1) may be about 333.3:131.5.

In some embodiments, the target temperature for cooling in step 1) may be about -5°C to 15°C, for example, -5°C, 0°C, 5°C, 10°C, 15°C or other temperatures.

In some specific embodiments, the target temperature for cooling in step 1) may be about 0°C.

In some embodiments, the target temperature for heating in step 1) may be about 15-30°C, for example, 15°C, 20°C, 25°C, 30°C or other temperatures.

In some specific embodiments, the target temperature of heating in step 1) may be about 25°C.

In some embodiments, the reaction time in step 1) may be about 0.5~2h, for example, 0.5h, 1h, 1.5h, 2h or other time.

In some specific embodiments, the reaction time in step 1) may be about 1 h.

In some embodiments, the acetyl chloride in step 2) can be trimethyl acetyl chloride, acetyl chloride or ethyl chloroformate.

In some specific embodiments, the acyl chloride in step 2) can be trimethyl acetyl chloride.

In some embodiments, the molar ratio of compound B or compound B' in step 1) and acetyl chloride (for example, trimethylacetyl chloride) in step 2) can be about 1:0.9~1:1.4, For example, 1:0.9, 1:0.92, 1:0.95, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.35, 1:1.38, 1:1.4 or other ratios.

In some specific embodiments, the molar ratio of compound B or compound B' in step 1) and acyl chloride (for example, trimethylacetyl chloride) in step 2) can be about 1:0.92~1: 1.38, for example, 1:0.92, 1:0.95, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.35, 1:1.38 or other ratios.

In some more specific embodiments, the molar ratio of compound B or compound B' in step 1) to acyl chloride (eg, trimethylacetyl chloride) in step 2) may be about 1:1.2.

In some embodiments, the mass ratio of the acyl chloride (for example, trimethylacetyl chloride) in step 2) to the compound B or compound B' in step 1) can be about 67~200:200~400, for example , 67:200, 67:300, 67:350, 67:400, 100:200, 100:300, 100:350, 100:400, 150:200, 150:300, 150:350, 150:400, 200 :200, 200:300, 200:350, 200:400 or other ratios.

In some specific embodiments, the mass ratio of the acyl chloride (for example, trimethylacetyl chloride) in step 2) to compound B or compound B' in step 1) may be about 144.7:333.3.

In some embodiments, the target temperature for temperature control in step 2) may be about -5°C to 15°C, for example, -5°C, 0°C, 5°C, 10°C, 15°C or other temperatures.

In some specific embodiments, the target temperature of temperature control in step 2) may be about 0°C.

In some embodiments, the target temperature for heating in step 2) may be about 15-30°C, for example, 15°C, 20°C, 25°C, 30°C or other temperatures.

In some specific embodiments, the target temperature of heating in step 2) may be about 25°C.

In some embodiments, the reaction time in step 2) may be about 1~5h, for example, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h or other time.

In some specific embodiments, the reaction time in step 2) may be about 2 hours.

In some embodiments, the mass ratio of compound A and organic solvent (for example, dichloromethane (DCM)) in step 3) can be about 111~300:3000~5000, for example, 111:3000, 111:4000, 111:4500, 111:5000, 200:3000, 200:4000, 200:4500, 200:5000, 250:3000, 250:4000, 250:4500, 250:5000, 300:3000, 300:4000, 300: 4500, 300:5000 or other ratios.

In some specific embodiments, the mass ratio of compound A to the organic solvent (eg, dichloromethane (DCM)) in step 3) may be about 205.2:4247.

In some embodiments, the molar ratio of compound A in step 3) to compound B or compound B' in step 1) can be about 0.9:1~1.3:1, for example, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or other ratios.

In some specific embodiments, the molar ratio of compound A in step 3) to compound B or compound B' in step 1) can be about 1:1 to 1.22:1, for example, 1:1, 1.1: 1, 1.12:1, 1.15:1, 1.18:1, 1.2:1, 1.22:1 or other ratios.

In some more specific embodiments, the molar ratio of compound A in step 3) to compound B or compound B' in step 1) may be about 1:1.

In some embodiments, the mass ratio of compound A in step 3) to compound B or compound B' in step 1) can be about 111~300:200~400, for example, 111:200, 111:300, 111 :350, 111:400, 200:200, 200:300, 200:350, 200:400, 250:200, 250:300, 250:350, 250:400, 300:200, 300:300, 300:350 , 300:400 or other ratios.

In some specific embodiments, the mass ratio of compound A in step 3) to compound B or compound B' in step 1) may be about 205.2:333.3.

In some embodiments, the target temperature for temperature control in step 4) may be about -5°C to 15°C, for example, -5°C, 0°C, 5°C, 10°C, 15°C or other temperatures.

In some specific embodiments, the target temperature of temperature control in step 4) may be about 0°C.

In some embodiments, the target temperature for heating in step 4) may be about 15-30°C, for example, 15°C, 20°C, 25°C, 30°C or other temperatures.

In some specific embodiments, the target temperature of heating in step 4) may be about 25°C.

In some embodiments, the reaction time in step 4) may be about 8~36h, for example, 8h, 10h, 12h, 16h, 20h, 24h, 28h, 32h, 36h or other time.

In some specific embodiments, the reaction time in step 4) may be about 16 hours.

In the present invention, the preparation method of the above-mentioned compound of formula I or compound of formula II may also include the following steps: 5) Add lye to the reaction solution obtained in step 4) for alkaline washing, separate the liquids to obtain the organic phase, then add acid solution for pickling, separate the liquids to obtain the organic phase, finally add water for washing, and separate the liquids to obtain the organic phase followed by concentration.

In some embodiments, the lye in step 5) can be an aqueous solution of an alkali metal carbonate, bicarbonate or phosphate, for example, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate or potassium phosphate of aqueous solution.

In some specific embodiments, the lye in step 5) can be an aqueous solution of sodium bicarbonate.

In some more specific embodiments, the lye in step 5) can be a saturated aqueous solution of sodium bicarbonate.

In some embodiments, the acid solution in step 5) may be an aqueous solution of an ammonium salt of a strong inorganic acid, for example, an aqueous solution of ammonium chloride, ammonium sulfate or ammonium nitrate.

In some specific embodiments, the acid solution in step 5) may be an aqueous ammonium chloride solution.

In some more specific embodiments, the acid solution in step 5) can be a saturated ammonium chloride aqueous solution.

In some embodiments, the alkaline solution (eg, saturated aqueous sodium bicarbonate solution), acid solution (eg, saturated aqueous ammonium chloride solution) and water in step 5) and Compound B or Compound B' in step 1) The mass ratio can be about 2667~5000:2667~5000:2667~5000:200~400, for example, 2667:2667:2667:200, 2667:2667:2667:300, 2667:2667:2667:350, 2667: 2667:2667:400, 4000:4000:4000:200, 4000:4000:4000:300, 4000:4000:4000:350, 4000:4000:4000:400, 4500:4500:4500:200, 4500:4500: 4500:300, 4500:4500:4500:350, 4500:4500:4500:400, 5000:5000:5000:200, 5000:5000:5000:300, 5000:5000:5000:350, 5000:5000:5000: 400 or other ratios.

In some specific embodiments, the alkaline solution (for example, saturated aqueous sodium bicarbonate solution), acid solution (for example, saturated aqueous ammonium chloride solution) and water in step 5) and compound B or compound The mass ratio of B' may be about 4247:4247:4247:333.3.

In some embodiments, the concentration in step 5) is concentration under reduced pressure, for example, concentration under reduced pressure using a rotary evaporator.

In the present invention, the preparation method of the above-mentioned compound of formula I or compound of formula II may also include the following steps: 6) Beating the concentrate obtained in step 5) with a mixed organic solvent, then filtering and drying.

In some embodiments, the mixed organic solvent in step 6) can be a mixture of alkanes and esters, for example, n-hexane/ethyl acetate, n-heptane/ethyl acetate, n-octane/ethyl acetate, n-hexane/ Isopropyl acetate, n-heptane/isopropyl acetate or n-octane/isopropyl acetate.

In some specific embodiments, the mixed organic solvent in step 6) may be n-heptane/ethyl acetate, that is, a mixture of n-heptane and ethyl acetate.

In some embodiments, the mass ratio of the alkane (for example, n-heptane) in step 6) to the ester (for example, ethyl acetate) and the compound B or compound B' in step 1) can be about 533~1500: 333~1000:200~400, for example, 533:333:200, 533:333:400, 600:400:250, 800:500:300, 900:600:350, 900:700:350, 1000:800: 300, 1000:800:350, 1000:800:400, 1100:900:300, 1300:900:350, 1500:1000:200, 1500:1000:400 or other ratios.

In some specific embodiments, the mass ratio of the alkane (for example, n-heptane) in step 6) to the ester (for example, ethyl acetate) and the compound B or compound B' in step 1) can be about 1000: 800:333.3.

In some embodiments, the beating time in step 6) may be about 0.5~3h, for example, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h or other time.

In some specific embodiments, the beating time in step 6) may be about 1 hour.

In some embodiments, the drying temperature in step 6) can be about 25-100°C, for example, 25°C, 30°C, 35°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C , 100°C or other temperatures.

In some specific embodiments, the drying temperature in step 6) may be about 60°C.

In some embodiments, the drying time in step 6) may be about 1~5h, for example, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h or other times.

In some specific embodiments, the drying time in step 6) may be about 3 hours.

More specifically, in the present invention, the compound of formula II as the key intermediate of senagliptin can also be prepared by the following method: (i) Dissolve (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid (i.e. compound B') in dichloromethane (DCM) After cooling to 0°C under stirring, N-methylmorpholine (NMM) was added, the temperature was naturally raised to 25°C and the mixed solution was stirred for 1 hour to obtain solution B'; (ii) After cooling the temperature of solution B' obtained in step (i) to 0°C, add trimethylacetyl chloride dropwise to solution B' obtained in step (i) under stirring, during which the temperature is controlled, dropwise After the addition was completed, the temperature was naturally raised to 25°C and reacted for 2 hours to obtain an activated mixed anhydride solution; (iii) Dissolve (R)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine (Compound A) in In dichloromethane (DCM), solution A was obtained; (iv) After cooling the temperature of the solution A obtained in the step (iii) to 0°C, add the solution A obtained in the step (iii) dropwise to the activated mixed anhydride solution obtained in the step (ii) under stirring, During this period, the temperature was controlled, and after the dropwise addition was completed, the temperature was naturally raised to 25°C and reacted for 16 hours to obtain a reaction solution; (v) Add saturated aqueous sodium bicarbonate solution to the reaction solution obtained in step (iv), stir and stand for liquid separation, then add saturated ammonium chloride aqueous solution to the dichloromethane phase, stir and stand for liquid separation , then add water to the dichloromethane phase, stir and stand still for liquid separation, then concentrate the dichloromethane phase to obtain a concentrate; (vi) Using a mixed solvent of n-heptane and ethyl acetate, beat the concentrate obtained in step (v), then filter and dry to obtain the target product, which is the key intermediate of senagliptin of the formula II compound.

In some embodiments, (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid and dichloromethane (DCM ) mass ratio can be about 200~400:4000~5000, for example, 200:4000, 200:4500, 200:5000, 300:4000, 300:4500, 300:5000, 400:4000, 400:4500, 400 :5000 or other ratios.

In some specific embodiments, (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid and dichloromethane in step (i) (DCM) may have a mass ratio of about 333.3:4247.

In some embodiments, (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid and N-methylmorphine in step (i) The molar ratio of morphine (NMM) can be about 1:1.2~1:1.7, for example, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, 1 :1.55, 1:1.6, 1:1.65, 1:1.7 or other ratios.

In some specific embodiments, (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid and N-formaldehyde in step (i) The molar ratio of morphomorpholine (NMM) may be about 1:1.3.

In some embodiments, (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid and N-methylmorphine in step (i) The mass ratio of morphine (NMM) can be about 200~400:73~200, for example, 200:73, 200:100, 200:150, 200:200, 300:73, 300:100, 300:150, 300: 200, 400:73, 400:100, 400:150, 400:200 or other ratios.

In some specific embodiments, (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid and N-formaldehyde in step (i) The mass ratio of morphomorpholine (NMM) may be about 333.3:131.5.

In some embodiments, (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid in step (i) and The molar ratio of trimethylacetyl chloride can be about 1:0.9~1:1.4, for example, 1:0.9, 1:0.92, 1:0.95, 1:1, 1:1.1, 1:1.2, 1:1: 1.3, 1:1.35, 1:1.38, 1:1.4 or other ratios.

In some specific embodiments, (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acid in step (i) and step (ii ) in the trimethylacetyl chloride molar ratio may be about 1:1.2.

In some embodiments, trimethylacetyl chloride in step (ii) and (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5- The mass ratio of trifluorophenyl)butanoic acid can be about 67~200:200~400, for example, 67:200, 67:300, 67:350, 67:400, 100:200, 100:300, 100:350 , 100:400, 150:200, 150:300, 150:350, 150:400, 200:200, 200:300, 200:350, 200:400 or other ratios.

In some specific embodiments, trimethylacetyl chloride in step (ii) and (R)-3-(tertiary butoxycarbonylamino)-4-(2,4, The mass ratio of 5-trifluorophenyl)butanoic acid may be about 144.7:333.3.

In some embodiments, (R)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in step (iii) The mass ratio of oxazine and dichloromethane (DCM) can be about 111~300:3000~5000, for example, 111:3000, 111:4000, 111:4500, 111:5000, 200:3000, 200:4000, 200: 4500, 200:5000, 250:3000, 250:4000, 250:4500, 250:5000, 300:3000, 300:4000, 300:4500, 300:5000 or other ratios.

In some specific embodiments, (R)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a in step (iii) ] The mass ratio of pyrazine and dichloromethane (DCM) can be about 205.2:4247.

In some embodiments, (R)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in step (iii) The mol ratio of oxazine and (R)-3-(tertiary butoxycarbonylamino)-4-(2,4,5-trifluorophenyl) butanoic acid in step (i) can be about 0.9:1 ~1.3:1, eg, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or other ratios.

In some specific embodiments, (R)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a in step (iii) ] pyrazine and (R)-3-(the third butoxycarbonylamino group)-4-(2,4,5-trifluorophenyl) butyric acid mol ratio in step (i) can be about 1 :1.

In some embodiments, (R)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in step (iii) The mass ratio of (R)-3-(tertiary butoxycarbonylamino)-4-(2,4,5-trifluorophenyl) butanoic acid in the oxazine and step (i) can be about 111～300: 200~400, for example, 111:200, 111:300, 111:350, 111:400, 200:200, 200:300, 200:350, 200:400, 250:200, 250:300, 250:350, 250:400, 300:200, 300:300, 300:350, 300:400 or other ratios.

In some specific embodiments, (R)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a in step (iii) The mass ratio of ]pyrazine and (R)-3-(tertiary butoxycarbonylamino)-4-(2,4,5-trifluorophenyl) butanoic acid in step (i) can be about 205.2: 333.3.

In some embodiments, the saturated aqueous sodium bicarbonate solution, saturated ammonium chloride aqueous solution and water in step (v) and (R)-3-(tertiary butoxycarbonylamino)- in step (i) The mass ratio of 4-(2,4,5-trifluorophenyl)butanoic acid can be about 2667~5000:2667~5000:2667~5000:200~400, for example, 2667:2667:2667:200, 2667: 2667:2667:300, 2667:2667:2667:350, 2667:2667:2667:400, 4000:4000:4000:200, 4000:4000:4000:300, 4000:4000:4000:350, 4000:4000: 4000:400, 4500:4500:4500:200, 4500:4500:4500:300, 4500:4500:4500:350, 4500:4500:4500:400, 5000:5000:5000:200, 5000:5000:5000: 300, 5000:5000:5000:350, 5000:5000:5000:400 or other ratios.

In some specific embodiments, the saturated aqueous sodium bicarbonate solution, saturated ammonium chloride aqueous solution and water in step (v) and the (R)-3-(tertiary butoxycarbonylamino group in step (i) The mass ratio of )-4-(2,4,5-trifluorophenyl)butanoic acid may be about 4247:4247:4247:333.3.

In some embodiments, the concentration in step (v) is concentration under reduced pressure, for example, concentration under reduced pressure using a rotary evaporator.

In some embodiments, the n-heptane in step (vi) is combined with ethyl acetate and (R)-3-(tert-butoxycarbonylamino)-4-(2,4,5 - The mass ratio of trifluorophenyl)butanoic acid can be about 533~1500:333~1000:200~400, for example, 533:333:200, 533:333:400, 600:400:250, 800:500: 300, 900:600:350, 900:700:350, 1000:800:300, 1000:800:350, 1000:800:400, 1100:900:300, 1300:900:350, 1500:1000:200, 1500:1000:400 or other ratios.

In some specific embodiments, n-heptane in step (vi) is mixed with ethyl acetate and (R)-3-(tertiary butoxycarbonylamino)-4-(2,4 , The mass ratio of 5-trifluorophenyl)butanoic acid may be about 1000:800:333.3.

In some embodiments, the beating time in step (vi) may be about 0.5~3h, for example, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h or other time.

In some specific embodiments, the beating time in step (vi) may be about 1 hour.

In some embodiments, the drying temperature in step (vi) can be about 25-100°C, for example, 25°C, 30°C, 35°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C ℃, 100℃ or other temperature.

In some specific embodiments, the drying temperature in step (vi) may be about 60°C.

In some embodiments, the drying time in step (vi) may be about 1~5h, for example, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h or other times.

In some specific embodiments, the drying time in step (vi) may be about 3 hours.

＜Using key intermediates to prepare senagliptin or its pharmaceutically acceptable salt＞

In the present invention, the compound of formula I or compound of formula II, which is the key intermediate of senagliptin, can be used to prepare hypoglycemic drugs.

In some embodiments, the above-mentioned hypoglycemic agent may be a DPP-IV inhibitor.

In some specific embodiments, the above-mentioned hypoglycemic agent may be senagliptin or a pharmaceutically acceptable salt thereof.

In some more specific embodiments, the above-mentioned hypoglycemic agent may be senagliptin phosphate.

In some embodiments, the above-mentioned senagliptin phosphate can be prepared by using the compound of formula I as a raw material and by the following method: 1) Dissolving the compound of formula I in a solvent under stirring conditions, adding phosphoric acid thereto under reflux conditions, After the reaction is completed, the temperature of the system is lowered to room temperature; 2) Add alkali to the system under stirring conditions, filter after the reaction is completed, and dry the filter cake after rinsing with eluent; Among them, PG is selected from tertiary butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc ) and 2-(trimethylsilyl)ethoxycarbonyl (Teoc).

In some specific embodiments, the PG in the compound of formula I in the above method can be tertiary butoxycarbonyl (Boc), at this time, the compound of formula II can be used as a raw material and prepared by the following method: 1) under stirring conditions , dissolving the compound of formula II in a solvent, adding phosphoric acid to it under reflux conditions, and lowering the temperature of the system to room temperature after the reaction; 2) adding alkali to the system under stirring conditions, and filtering after the reaction , the filter cake was rinsed with eluent and then dried.

In some embodiments, the solvent in step 1) can be an aqueous solution of a lower alcohol, for example, an aqueous solution of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.

In some specific embodiments, the solvent in step 1) can be isopropanol aqueous solution.

Further, the mass ratio of lower alcohol (for example, isopropanol), water and the compound of formula I or compound of formula II may be 181~406:231~517:231~516.5.

Furthermore, the mass ratio of lower alcohol (for example, isopropanol), water and the compound of formula I or compound of formula II may be 380.424:484:484.

In some embodiments, the time of reflux in step 1) may be 2-5 hours.

In some specific embodiments, the reflux time in step 1) can be 3 hours.

In some embodiments, the molar ratio of the compound of formula I or compound of formula II and phosphoric acid in step 1) can be 1:2~1:6, for example, 1:2, 1:2.5, 1:3, 1: 3.5, 1:4, 1:4.5, 1:5, 1:6 or other ratios.

In some specific embodiments, the molar ratio of the compound of formula I or compound of formula II and phosphoric acid in step 1) can be 1:3~1:5, for example, 1:3, 1:3.5, 1:4, 1:5 or other ratios.

In some more specific embodiments, the molar ratio of the compound of formula I or compound of formula II to phosphoric acid in step 1) may be 1:4.

In some embodiments, the mass ratio of the compound of formula I or compound of formula II to phosphoric acid in step 1) can be 231~517:129~485.

In some specific embodiments, the mass ratio of the compound of formula I or compound of formula II to phosphoric acid in step 1) may be 484:365.

In some embodiments, the base in step 2) can be an inorganic base.

In some specific embodiments, the base in step 2) can be alkali metal hydroxide, carbonate, bicarbonate or phosphate.

In some specific embodiments, the base in step 2) can be an alkali metal hydroxide.

In some more specific embodiments, the base in step 2) can be sodium hydroxide.

In some embodiments, the molar ratio of the compound of formula I or compound of formula II in step 1) and the base (for example, sodium hydroxide) in step 2) can be 1:0.5~1:5, for example, 1: 0.5, 1:0.7, 1:0.9, 1:1, 1:2, 1:3, 1:4, 1:5 or other ratios.

In some specific embodiments, the molar ratio of the compound of formula I or compound of formula II in step 1) and the base (for example, sodium hydroxide) in step 2) can be 1:2.25~1:3.75, for example, 1:2.25, 1:2.5, 1:2.8, 1:3, 1:3.1, 1:3.3, 1:3.5, 1:3.7, 1:3.75 or other ratios.

In some more specific embodiments, the molar ratio of the compound of formula I or compound of formula II in step 1) and the base (eg, sodium hydroxide) in step 2) may be 1:3.

In some embodiments, the mass ratio of the compound of formula I or compound of formula II in step 1) to the base (for example, sodium hydroxide) in step 2) may be 231~517:40~148.

In some specific embodiments, the mass ratio of the compound of formula I or compound of formula II in step 1) to the base (eg, sodium hydroxide) in step 2) may be 484:112.

In some embodiments, the reaction time in step 2) may be 8-16 hours, for example, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours or other times.

In some specific embodiments, the reaction time in step 2) may be 14 hours.

In some embodiments, the eluent in step 2) can be a lower alcohol, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.

In some specific embodiments, the eluent in step 2) can be isopropanol.

The technical solutions of the present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. Unless otherwise stated, the instruments, consumables and reagents used in the following examples can be obtained through conventional commercial means.

Embodiment 1 : the preparation of compound 3

Compound 2 (333.3g, 1.0mol, 1eq) was dissolved in dichloromethane (DCM) (4247g), stirred and cooled to 0°C, N-methylmorpholine (NMM) (131.5g, 1.3mol, 1.3eq ), naturally heated to 25°C, stirred for 1 h; then cooled to 0°C, and trimethylacetyl chloride (144.7g, 1.2mol, 1.2eq) was added dropwise under stirring, and the temperature was controlled at -5~15°C. After the dropwise addition, the temperature was naturally raised to 25°C and reacted for 2 h to obtain an activated mixed anhydride solution.

Compound 1 (205.2g, 1.0mol, 1eq) was dissolved in dichloromethane (DCM) (4247g); the activated mixed anhydride solution was cooled to 0°C, and compound 1 in dichloromethane (DCM ) solution, the temperature was controlled at -5~15°C, after the dropwise addition was completed, the temperature was naturally raised to 25°C, and the reaction was carried out for 16 hours to obtain the reaction solution.

Add saturated aqueous sodium bicarbonate (4247g) to the reaction solution, stir for 30 min, let stand for 30 min, separate the liquids, discard the aqueous phase, then add saturated aqueous ammonium chloride (DCM) to the dichloromethane (DCM) phase 4247g), stirred for 30 min, stood still for 30 min, separated, discarded the water phase, then added water (4247g) to the dichloromethane (DCM) phase, stirred for 30 min, stood still for 30 min, separated, discarded The aqueous phase, and the dichloromethane (DCM) phase were concentrated under reduced pressure to give an off-white residue.

Add n-heptane (1000g)/ethyl acetate (800g) mixture to the residue, beat at 25°C for 1 h, filter, discard the filtrate, and dry the filter cake at 60°C for 3 h to obtain compound 3 (484g ), the yield was 93%, and the HPLC purity was >99%, reaching 99.860%. See Figure 1 for details.

Embodiment 2 : the preparation of compound 3

Compound 2 (33.3kg, 100.0mol, 1eq) was dissolved in dichloromethane (DCM) (400kg), stirred and cooled to 0°C, N-methylmorpholine (NMM) (13.2kg, 130.0mol, 1.3eq ), naturally heated to 25°C, stirred for 1 h; then cooled to 0°C, and trimethylacetyl chloride (14.5kg, 120.0mol, 1.2eq) was added dropwise under stirring, and the temperature was controlled at -5~15°C. After the dropwise addition, the temperature was naturally raised to 25°C and reacted for 2 h to obtain an activated mixed anhydride solution.

Compound 1 (20.5kg, 100.0mol, 1eq) was dissolved in dichloromethane (DCM) (300kg); the activated mixed anhydride solution was cooled to 0°C, and the dichloromethane (DCM ) solution, the temperature was controlled at -5~15°C, after the dropwise addition was completed, the temperature was naturally raised to 25°C, and the reaction was carried out for 16 hours to obtain the reaction solution.

Add saturated aqueous sodium bicarbonate (400 kg) to the reaction solution, stir for 30 min, let stand for 30 min, separate the liquids, discard the aqueous phase, then add saturated aqueous ammonium chloride (DCM) to the dichloromethane (DCM) phase 400kg), stirred for 30 min, stood still for 30 min, separated, discarded the water phase, then added water (400kg) to the dichloromethane (DCM) phase, stirred for 30 min, stood still for 30 min, separated, discarded The aqueous phase, and the dichloromethane (DCM) phase were concentrated under reduced pressure to give an off-white residue.

Add n-heptane (100kg)/ethyl acetate (80kg) mixture to the residue, beat at 25°C for 1 h, filter, discard the filtrate, and dry the filter cake at 60°C for 3 h to obtain compound 3 (47.3 kg), the yield was 91%, and the HPLC purity was >99%, reaching 99.601%. See Figure 3 for details.

Embodiment 3 : the preparation of compound 3

Compound 2 (200g, 0.6mol, 1eq) was dissolved in dichloromethane (DCM) (4000g), stirred and cooled to -5°C, N-methylmorpholine (NMM) (72.8g, 0.72mol, 1.2eq ), naturally warming up to 15°C, stirring for 0.5 h; then cooling to 0°C, adding trimethylacetyl chloride (66.5g, 0.55mol, 0.92eq) dropwise under stirring, and controlling the temperature at -5~15°C, After the dropwise addition, the temperature was naturally raised to 15°C and reacted for 1 h to obtain an activated mixed anhydride solution.

Compound 1 (110.7g, 0.54mol, 0.9eq) was dissolved in dichloromethane (DCM) (4000g); the activated mixed anhydride solution was cooled to 0°C, and compound 1 was added dropwise in dichloromethane ( DCM) solution, the temperature was controlled at -5~15°C, after the dropwise addition was completed, the temperature was naturally raised to 15°C, and reacted for 8 h to obtain the reaction solution.

Add saturated aqueous sodium bicarbonate (2666.7g) to the reaction solution, stir for 30 min, let stand for 30 min, separate the liquids, discard the aqueous phase, then add saturated aqueous ammonium chloride to the dichloromethane (DCM) phase (2666.7g), stirred for 30 min, stood still for 30 min, separated, discarded the water phase, then added water (2666.7g) to the dichloromethane (DCM) phase, stirred for 30 min, stood still for 30 min, separated , the aqueous phase was discarded, and the dichloromethane (DCM) phase was concentrated under reduced pressure to give an off-white residue.

Add n-heptane (533.3g)/ethyl acetate (333.3g) mixture to the residue, beat at 25°C for 0.5 h, filter, discard the filtrate, and dry the filter cake at 25°C for 5 h to obtain compound 3 (230.6g), the yield was 74%, and the HPLC purity was >99%, reaching 99.098%. See Figure 5 for details.

Embodiment 4 : the preparation of compound 3

Compound 2 (400g, 1.2mol, 1eq) was dissolved in dichloromethane (DCM) (5000g), stirred and cooled to 15°C, N-methylmorpholine (NMM) (200g, 1.98mol, 1.65eq) was added, Naturally raise the temperature to 30°C, stir and react for 2 h; then cool to 0°C, add trimethylacetyl chloride (200g, 1.66mol, 1.38eq) dropwise under stirring, control the temperature at -5~15°C, and complete the dropwise addition Afterwards, the temperature was naturally raised to 30°C and reacted for 5 h to obtain an activated mixed anhydride solution.

Compound 1 (300g, 1.46mol, 1.22eq) was dissolved in dichloromethane (DCM) (5000g); the activated mixed anhydride solution was cooled to 0°C, and compound 1 in dichloromethane (DCM ) solution, the temperature was controlled at -5~15°C, after the dropwise addition was completed, the temperature was naturally raised to 30°C, and the reaction was carried out for 36 hours to obtain the reaction solution.

Add saturated aqueous sodium bicarbonate (5000 g) to the reaction solution, stir for 30 min, let stand for 30 min, separate the liquids, discard the aqueous phase, then add saturated aqueous ammonium chloride (DCM) to the dichloromethane (DCM) phase 5000g), stirred for 30 min, stood still for 30 min, separated, discarded the water phase, then added water (5000g) to the dichloromethane (DCM) phase, stirred for 30 min, stood still for 30 min, separated, discarded The aqueous phase, and the dichloromethane (DCM) phase were concentrated under reduced pressure to give an off-white residue.

Add n-heptane (1500g)/ethyl acetate (1000g) mixture to the residue, beat at 25°C for 3 h, filter, discard the filtrate, and dry the filter cake at 100°C for 1 h to obtain compound 3 (516.5 g), the yield was 83%, and the HPLC purity was >93%, reaching 93.921%. See Figure 7 for details.

The liquid chromatography conditions used for reaction monitoring in Examples 1 to 4 are as follows: Sample solvent: methanol; Injection volume: 10 μl; Flow rate: 1.0ml/min; Instrument: LC-2010A Shimadzu high performance liquid chromatography; Detection Wavelength: 220nm and 254nm; Chromatographic column: Agilent TC-C18(2) 250mm*4.6mm*5μm (can be replaced by other C18 columns); Column temperature: 25°C; Mobile phase: Mobile phase A: acetonitrile; Mobile phase B : Sodium dihydrogen phosphate dihydrate aqueous solution (20nM/L); Gradient extraction procedure: time (min) A (%, v/v) B (%, v/v) 0.01 10 90 15 10 90 45 90 10 45.01 10 90 55 termination

Test example 1 : the comparative test of earlier stage technology and the preparation method among the present invention

In the initial stage of research and development of the present invention, it was tried to use (R)-3-(tertiary butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butyric acid as the starting material, EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride)/HOBt (1-hydroxybenzotriazole) and other condensing agents are activated, and then triethylamine, etc. It is a base, and it can be obtained by reacting with (R)-8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine. The specific process is as follows :

However, condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt) are expensive in this process , and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt) may introduce genotoxic impurities, and are not easy to Removal, leading to more stringent requirements on the residue limit of the final product. Simultaneously, 1-hydroxybenzotriazole (HOBt) reacts easily with solvent dichloromethane, produces the coupling impurity of two substitutions, causes the quality of final product not high, and purity is lower, and yield is low; Moreover, the degradation product of condensing agent It contains a large amount of nitrogen, which is neither safe nor environmentally friendly, and is not suitable for industrial production.

For this reason, the present invention further develops the preparation method in embodiment 1 to 4, and concrete technology is as follows:

Table 1. Comparison results of two production processes craft EIA genotoxic impurities total yield purity Production cycle cost Example 1 Less nitrogen-containing waste liquid No 93% 99.86% 1 week RMB 3700/kg Pre-process HOBt degrades nitrogenous waste liquid Both EDCI and HOBt will introduce 85% 87.00% 1 week RMB 7500/kg

As can be seen from Table 1, compared with the previous technology, the DPP-IV inhibitor key intermediate (i.e. (R)-4-((R)-8-methyl-3-(trifluoroform) prepared by the technology of the present invention Base)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)butane- tertiary butyl carbamate) has the following advantages: good purity, high yield, less environmental pollution, no introduction of genotoxic impurities, low cost, etc., and avoids complicated derivatization and resolution in CN103351391A The processing process is more suitable for industrial production.

Embodiment 5 : the preparation of compound 4

Under stirring, the compound 3 (484g, 0.93mol, 1eq) prepared in Example 1 was dissolved in water (484g) and isopropanol (380.424g), heated to reflux for 3 h, and 85.0 wt% phosphoric acid aqueous solution was added ( 429.308g, the amount of H ₃ PO ₄ : 364.912g, 3.72mol, 4eq), until the end of the reaction, down to room temperature.

Add 31.6 wt% sodium hydroxide aqueous solution (353.32g, NaOH dosage: 111.65g, 2.79mol, 3eq), react for 14 h, filter, rinse the filter cake with isopropanol (96.8g), drain it, and transfer it to a drum After drying in an air drying oven, compound 4 (473.9 g) was obtained with a yield of 95.0% and an HPLC purity of >99%, reaching 99.907%. See Figure 2 for details.

Embodiment 6 : the preparation of compound 4

Under stirring, the compound 3 (47.3kg, 90.9mol, 1eq) prepared in Example 2 was dissolved in water (47.3kg) and isopropanol (37.178kg), heated to reflux for 3 h, and 85.0 wt% phosphoric acid was added Aqueous solution (41.955kg, amount of H ₃ PO ₄ : 35.662kg, 363.9mol, 4eq), until the reaction is completed, down to room temperature.

Add 31.6 wt% sodium hydroxide aqueous solution (34.529kg, NaOH dosage: 10.911kg, 272.8mol, 3eq), react for 14 hours, filter, rinse the filter cake with isopropanol (9.46kg) and drain it, transfer it to a drum After drying in an air drying oven, Compound 4 (46.3kg) was obtained with a yield of 95.0% and an HPLC purity >99%, reaching 99.902%. See Figure 4 for details.

Embodiment 7 : the preparation of compound 4

Under stirring, the compound 3 (230.6g, 0.44mol, 1eq) prepared in Example 3 was dissolved in water (230.6g) and isopropanol (181.252g), heated to reflux for 2 h, and 85.0 wt% phosphoric acid was added Aqueous solution (152.2g, amount of H ₃ PO ₄ : 129.37g, 1.32mol, 3eq), until the reaction was completed, and cooled to room temperature.

Add 31.6 wt% sodium hydroxide aqueous solution (125.3g, NaOH dosage: 39.6g, 0.99mol, 2.25eq), react for 8 hours, filter, rinse the filter cake with isopropanol (46.12g) and drain it, transfer to Drying in a blast drying oven gave compound 4 (212.7g) with a yield of 89.5%, HPLC purity>93%, reaching 93.940%, see Figure 6 for details.

Embodiment 8 : the preparation of compound 4

Under stirring, the compound 3 (516.5g, 0.99mol, 1eq) prepared in Example 4 was dissolved in water (516.5g) and isopropanol (405.969g), heated to reflux for 5 h, and 85.0 wt% phosphoric acid was added Aqueous solution (570.7g, amount of H ₃ PO ₄ : 485.1g, 4.95mol, 5eq), until the reaction was completed, and cooled to room temperature.

Add 31.6 wt% sodium hydroxide aqueous solution (470g, NaOH dosage: 148.4g, 3.71mol, 3.75eq), react for 16 h, filter, rinse the filter cake with isopropanol (103.3g), drain it, and transfer it to a drum After drying in an air drying oven, Compound 4 (484.5 g) was obtained with a yield of 91.0% and an HPLC purity of >95%, reaching 95.994%. See Figure 8 for details.

The above-mentioned embodiments are only descriptions of the preferred implementation modes of the present invention, and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, those skilled in the art may make various modifications to the technical solutions of the present invention. and improvements, all should fall within the scope of protection determined by the scope of the patent application for the present invention.

Fig. 1 is the central control HPLC chromatogram of compound 3 in the embodiment 1 of the present invention; Fig. 2 is the central control HPLC chromatogram of compound 4 in the embodiment 5 of the present invention; Fig. 3 is the central control HPLC chromatogram of compound 3 in the embodiment 2 of the present invention; Fig. 4 is the central control HPLC chromatogram of compound 4 in the embodiment of the present invention 6; Fig. 5 is the central control HPLC chromatogram of compound 3 in the embodiment 3 of the present invention; Fig. 6 is the central control HPLC chromatogram of compound 4 in Example 7 of the present invention; Fig. 7 is the central control HPLC chromatogram of compound 3 in Example 4 of the present invention; Fig. 8 is the central control HPLC chromatogram of compound 4 in Example 8 of the present invention.

Claims (15)

A compound of formula I or a pharmaceutically acceptable salt thereof: Among them, PG is selected from tertiary butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-(trimethylsilyl)ethoxycarbonyl . A preparation method of a compound of formula I as described in claim 1, which comprises the following steps: in the presence of an organic solvent and a base, using compound B as a starting material, first activated, and then reacted with compound A; Among them, PG is selected from tertiary butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-(trimethylsilyl)ethoxycarbonyl . The preparation method as described in claim item 2, wherein, Described preparation method comprises the steps: 1) Dissolve compound B in an organic solvent, add alkali after cooling under stirring conditions, and then stir and mix the solution under natural heating conditions to obtain solution B; 2) Add acid chloride dropwise to the solution B obtained in step 1) under temperature control and stirring conditions, and then react under natural temperature rise conditions to obtain an activated mixed anhydride solution; 3) Dissolving compound A in an organic solvent to obtain solution A; 4) Add solution A obtained in step 3) dropwise to the activated mixed anhydride solution obtained in step 2) under temperature control and stirring conditions, and then react under natural heating conditions. The preparation method as described in claim item 3, wherein, The organic solvent described in step 1) is dichloromethane, chloroform or tetrahydrofuran; The base described in step 1) is an organic base; The molar ratio of the compound B and the base in step 1) is 1:1.2~1:1.7; The target temperature for cooling described in step 1) is -5~15°C; The target temperature for heating up in step 1) is 15-30°C; The reaction time in step 1) is 0.5~2h. The preparation method as described in claim item 3, wherein, The acyl chloride described in step 2) is trimethyl acetyl chloride, acetyl chloride or ethyl chloroformate; The molar ratio of the compound B described in step 1) to the acyl chloride described in step 2) is 1:0.9~1:1.4; The target temperature of the temperature control described in step 2) is -5~15°C; The target temperature for heating up in step 2) is 15-30°C; The reaction time in step 2) is 1~5h. The preparation method as described in claim item 3, wherein, The organic solvent described in step 3) is dichloromethane, chloroform or tetrahydrofuran; The molar ratio of compound A in step 3) to compound B in step 1) is 0.9:1-1.3:1. The preparation method as described in claim item 3, wherein, The target temperature of the temperature control described in step 4) is -5~15°C; The target temperature for heating up in step 4) is 15-30°C; The reaction time in step 4) is 8~36h. The preparation method as described in claim item 3, wherein, The preparation method also includes the steps of: 5) Add lye to the reaction solution obtained in step 4) for alkaline washing, separate the liquids to obtain the organic phase, then add acid solution for pickling, separate the liquids to obtain the organic phase, finally add water for washing, and separate the liquids to obtain the organic phase followed by concentration. The preparation method as described in claim item 8, wherein, The lye described in step 5) is an aqueous solution of alkali metal carbonate, bicarbonate or phosphate; The acid solution described in step 5) is an aqueous solution of ammonium salt of an inorganic strong acid. The preparation method as described in claim item 8, wherein, The preparation method also includes the steps of: 6) Beating the concentrate obtained in step 5) with a mixed organic solvent, then filtering and drying. The preparation method as described in claim item 10, wherein, The mixed organic solvent described in step 6) is a mixture of alkanes and esters; The beating time described in step 6) is 0.5~3h; The drying temperature in step 6) is 25-100° C., and the drying time is 1-5 hours. A use of the compound of formula I as described in Claim 1 or a pharmaceutically acceptable salt thereof in the preparation of hypoglycemic drugs. A preparation method of sengagliptin phosphate, which comprises the following steps: 1) Dissolving the compound of formula I as described in claim 1 in a solvent under stirring conditions, adding phosphoric acid thereto under reflux conditions, and after the reaction is completed Lower the temperature of the system to room temperature; 2) Add alkali to the system under stirring conditions, filter after the reaction is completed, and dry the filter cake after rinsing with eluent; Among them, PG is selected from tertiary butoxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2-(trimethylsilyl)ethoxycarbonyl . The preparation method as described in claim 13, wherein, The solvent described in step 1) is an aqueous solution of lower alcohol; The reflux time described in step 1) is 2 to 5 hours; The molar ratio of the compound of formula I to the phosphoric acid in step 1) is 1:2~1:6. The preparation method as described in claim 13, wherein, The alkali described in step 2) is an inorganic alkali; The molar ratio of the compound of formula I described in step 1) and the base described in step 2) is 1:0.5~1:5; The reaction time described in step 2) is 8~16h; The eluent described in step 2) is a lower alcohol.