1. A material combination system for catalyzing the reaction of PARP inhibitor intermediate, the structure of the intermediate is shown in formula (I),

the reaction of the material combination system comprises the following steps: reacting BG-10 with BG-5 in an organic solvent to obtain an intermediate represented by formula (I);

characterized in that the material combination system uses palladium catalyst [ Pd]And a cuprous salt, said palladium catalyst comprising at least Pd (dppf) Cl₂And Pd (dtbpf) Cl₂One or two of them; preferablySaid palladium catalyst comprising Pd (dppf) Cl₂(ii) a Or preferably, the palladium catalyst comprises Pd (dtbpf) Cl₂。

2. The material combination system of claim 1, wherein the palladium catalyst further comprises, optionally, Pd (PPh)₃)₂Cl₂Pd (dibenzylideneacetone) Cl₂(ii) a Or P (cyclohexyl)₃、PPh₃、BINAP、P(n-Bu)₃、P(t-Bu)₃One or more ligands of dtbpf, and/or Pd (OAc)₂、PdCl₂And the like, one or more palladium salts.

3. The material combination system of any one of claims 1-2, the organic solvent being selected from the group consisting of: dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), toluene, Tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), acetonitrile, dioxane, and any combination thereof; the cuprous salt is selected from cuprous iodide, cuprous bromide, cuprous chloride, cuprous acetate, cuprous trifluoromethanesulfonate and any combination thereof.

4. The material combination system according to any one of claims 1 to 3, wherein the mole ratio of BG-10 to BG-5 is 1: 0.8-1: 3; preferably 1: 0.9-1: 2; more preferably 1: 1 to 1: 1.5; even more preferably 1: 1.2-1: 1.4; and/or the mole ratio of BG-10 to the palladium catalyst is 1: 0.01-1: 0.1; preferably: 1: 0.05-1: 0.1; more preferably 1: 0.05-1: 0.08.

5. The material combination system of any one of claims 1-4, wherein the palladium catalyst is Pd (dPPf) Cl₂Or Pd (dtbpf) Cl₂(ii) a BG-10 and Pd (dppf) Cl₂The molar ratio of (A) to (B) is 1: 0.01-1: 0.1; preferably: 1: 0.05-1: 0.1; more preferably 1: 0.05-1: 0.08; preferably, BG-10 is reacted with Pd (dtbpf) Cl₂The molar ratio of (A) to (B) is 1: 0.01-1: 0.1; more preferably: 1: 0.05-1: 0.1; the most preferable ratio is 1: 0.05-1: 0.08.

6. The material combination system according to any one of claims 1 to 5, wherein the weight-to-volume ratio (M/V, g/mL) of BG-10 to the organic solvent is 1: 1 to 1: 10, preferably 1: 1 to 1: 6; more preferably 1: 2; 1: 3; 1: 4 and 1: 5; and/or the mole ratio of BG-10 to cuprous salt is 1: 0.01-1: 0.1; more preferably: 1: 0.05-1: 0.1; the most preferable ratio is 1: 0.06-1: 0.08.

7. The material combination system of any one of claims 1-6, wherein a basic material is also used in the reaction; the basic substance is selected from the group consisting of Diisopropylethylamine (DIPEA), Triethylamine (TEA), pyridine, Tetramethylguanidine (TMG), thiomorpholine (NMP), potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), and any combination thereof; more preferably selected from Diisopropylethylamine (DIPEA), cesium carbonate, triethylenediamine (DABCO), azabicyclo (DBU), Tetramethylguanidine (TMG), and any combination thereof; the mole ratio of BG-10 to the alkaline substance is 1: 0.5-1: 6; preferably 1: 0.8-1: 4; the most preferable ratio is 1: 1-1: 3.

8. The material combination system of any one of claims 1-7, wherein the reaction is carried out in a reaction kettle; more preferably, the reaction kettle is replaced by nitrogen; the reaction temperature is 50-100 ℃, preferably 60-85 ℃, more preferably 70-80 ℃, and most preferably 75-80 ℃; the reaction time is 1-48 hours, preferably 5-40 hours, and more preferably 12-30 hours; preferably, the temperature is reduced to 15-30 ℃ after the reaction, and preferably the temperature is reduced to room temperature.

9. The material combination system of any one of claims 1-8, a method of using the material combination system further comprising the step of preparing BG-5 free base: treating BG-5 salt with a base to obtain the free base of BG-5; preferably, this step is carried out in a mixed solution of n-heptane and water; preferably, the preparation of BG-5 free base comprises the steps of: the BG-5 salt is suspended in a mixed solvent of n-heptane and water, and an alkaline solution is added to the above mixed solution to perform a reaction, thereby obtaining the BG-5 free base.

10. The material combination system according to any one of claims 1-9, the method of use of the material combination system further comprising the steps of purification and recrystallization, preferably the recrystallization is performed in an alcohol solvent, preferably the recrystallization is performed in methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol; more preferably said recrystallization is carried out in methanol.

Background

WO2013/097225A1 discloses poly (ADP-ribosyl) transferase (PARPs) inhibitors and specifically compoundsI.e. (R) -2-fluoro-10 a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [ def]Cyclopenta [ a ]]Fluoren-4 (5H) -one, an inhibitor of poly Adenosine Diphosphate (ADP) ribose polymerase (PARP), which is highly selective for PARP-1/2 and effective in inhibiting proliferation of cell lines with BRCA1/2 mutations or other HR defects, significantly induces tumor regression in BRCA1 mutant breast cancer xenograft models at doses much lower than olaparib, has excellent DMPK properties and significant brain permeability. WO2017/032289A1 discloses (R) -2-fluoro-10 a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [ def]Cyclopenta [ a ]]A process for the large-scale synthesis of fluoren-4 (5H) -one, wherein,is an important intermediate in the preparation process of Pamiparib. In the large scale synthesis process disclosed in WO2017/032289a1,(BG-5) with(BG-10) in Pd (Ph)₃)₂Cl₂And Cul to form the intermediateI.e. (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester (BG-11), however when Pd (Ph) is used₃)₂Cl₂And Cul as a catalyst, there is a large amount of BG-10 that cannot complete the conversion, resulting in difficulty in purification and poor yield.

The inventors of the present invention have found, through a large number of inventive investigations, that Pd (dppf) Cl is used₂And cuprous salt is used as a catalyst, so that the problem of low conversion rate is solved, the reaction can be completed within 36 hours, only about 0.3 percent of BG-10 remains, and the conversion rate of BG-10 is greatly improved.

However, in the use of [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl₂) And cuprous salt is used as a catalyst, BG-10 generates partial racemization in the reaction process, and the chiral purity of the obtained product is only about 90 percent. Additional chemical resolution operations are required in subsequent steps to achieve the desired chiral purity of the downstream drug substance (not less than 98.5%), which results in increased production costs and material loss. On the basis, through screening of various catalysts and catalytic systems, the inventor of the invention more keenly finds that 1, 1' -bis (di-tert-butylphosphino) ferrocene palladium dichloride (Pd (dtbpf) Cl₂) And cuprous salt is used as a catalyst, so that the high reaction conversion rate of BG-10 can be ensured, and the chiral purity of the reaction liquid is controlled to be about 99.0 percent. After post-treatment and crystallization purification, the product with HPLC purity of more than 99.0% and chiral purity of more than 99.0% can be obtained, and the yield ranges from 65% to 85%.

Disclosure of Invention

The invention relates to a PARP inhibitor intermediate, in particular to a pamiprarib intermediateNamely (R) -2- (1- (2- (tert-butyloxy) -2-oxoethyl) -2-methylpyrrolidin-2-yl) -6-fluoro-1-tosyl-1H-indole-4-carboxylic acid methyl ester (i.e., BG-11), using a method comprising the steps of:

reacting BG-10 with BG-5 in an organic solvent to obtain BG-11;

the reaction is carried out using a palladium (Pd) catalyst and a cuprous salt,

the palladium catalyst at least comprises Pd (dppf) Cl₂And Pd (dtbpf) Cl₂One or two of them.

Preferably, the palladium catalyst comprises Pd (dtbpf) Cl₂。

Optionally, the palladium catalyst may also optionally comprise Pd (PPh)₃)₂Cl₂Pd (dibenzylideneacetone) Cl₂P (cyclohexyl)₃、PPh₃、BINAP、P(n-Bu)₃、P(t-Bu)₃One or more ligands of dtbpf, and/or Pd (OAc)₂、PdCl₂And any combination of one or more palladium salts.

Preferably, the palladium catalyst is Pd (dPPf) Cl₂。

More preferably, the palladium catalyst is Pd (dtbpf) Cl₂。

The cuprous salt may be selected from the group including, but not limited to, cuprous iodide, cuprous bromide, cuprous chloride, cuprous acetate, cuprous triflate, and any combination thereof.

Preferably, the organic solvent may be selected from the group including, but not limited to: dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), Dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), toluene, Tetrahydrofuran (THF), 2-methyltetrahydrofuran (MeTHF), acetonitrile, dioxane, and any combination thereof.

Preferably, the mole ratio of BG-10 to BG-5 is 1: 0.8-1: 3; preferably 1: 0.9-1: 2; more preferably 1: 1 to 1: 1.5; even more preferably 1: 1.2 to 1: 1.4.

Preferably, the mole ratio of BG-10 to the palladium catalyst is 1: 0.01-1: 0.1; preferably: 1: 0.05-1: 0.1; more preferably 1: 0.05-1: 0.08.

Preferably, BG-10 is reacted with Pd (dpPf) Cl₂The molar ratio of (A) to (B) is 1: 0.01-1: 0.1; preferably: 1: 0.05-1: 0.1; more preferably 1∶0.05～1∶0.08。

Preferably, BG-10 is reacted with Pd (dtbpf) Cl₂The molar ratio of (A) to (B) is 1: 0.01-1: 0.1; preferably: 1: 0.05-1: 0.1; more preferably 1: 0.05-1: 0.08.

Preferably, the weight-volume ratio (M/V, g/ml) of BG-10 to the organic solvent is 1: 1-1: 10, preferably 1: 1-1: 6; more preferably 1: 2; 1: 3; 1: 4 and 1: 5.

Preferably, the mole ratio of BG-10 to cuprous salt is 1: 0.01-1: 0.1; more preferably: 1: 0.05-1: 0.1; the most preferable ratio is 1: 0.05-1: 0.08.

Preferably, alkaline substances are also used in the material combination system. The basic material is selected from the group consisting of, but not limited to, Diisopropylethylamine (DIPEA), triethylamine, pyridine, tetramethylguanidine, azomethine morpholine, potassium carbonate, sodium carbonate, potassium phosphate, cesium carbonate, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), and any combination thereof; more preferably, the composition comprises a compound selected from the group consisting of diisopropylethylamine, cesium carbonate, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), tetramethylguanidine, and any combination thereof.

Preferably, the mole ratio of BG-10 to the alkaline substance is 1: 0.5-1: 6; preferably 1: 0.8-1: 4; the most preferable ratio is 1: 1-1: 3.

Preferably, the reaction of the material combination system is carried out in a reaction kettle. More preferably, the reaction kettle is replaced by nitrogen.

Preferably, the reaction temperature of the material combination system is 50-100 ℃, preferably 60-85 ℃, more preferably 70-80 ℃, and most preferably 75-80 ℃.

Preferably, the reaction time of the material combination system is 1-48 hours, preferably 5-40 hours, and more preferably 12-30 hours.

Preferably, after the material combination system is reacted, the temperature is reduced to 15-30 ℃, and preferably to room temperature.

Preferably, BG-5 is a free base.

The use method of the material combination system also comprises the step of preparing BG-5 free base: the BG-5 salt compound is treated with a base to obtain the free base of BG-5.

The base includes but is not limited to potassium hydroxide, sodium hydroxide, ammonia, sodium carbonate, sodium bicarbonate, potassium carbonate, ammonium bicarbonate.

Preferably, this step is carried out in a mixed solution of n-heptane and water. Preferably, the preparation of BG-5 free base comprises the steps of: suspending BG-5 salt in a mixed solvent of n-heptane and water, and adding an alkaline solution to the above mixed solution to carry out a reaction, thereby obtaining the BG-5 free base.

The specific operation of the reaction is as follows: stirring, reacting, standing for layering, collecting an organic phase, washing with water, and filtering to remove insoluble substances; the organic phase is concentrated and azeotropically dewatered, and N, N-Dimethylformamide (DMF) is added to continue to distill off the remaining N-heptane, yielding a DMF solution of BG-5 free base.

Preferably, the method for using the material combination system further comprises the steps of purification and recrystallization after the reaction.

The use method of the material combination system further comprises the step of recrystallizing the BG-11.

Preferably, said recrystallization is carried out in an alcoholic solvent. More preferably, the recrystallization is carried out in methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol. Even more preferably, said recrystallization is carried out in methanol.

The material combination system has stable production, good repeatability and high yield, does not need to carry out additional splitting operation in subsequent steps, saves the production cost in industrial mass production, and has good economic value.

Detailed Description

Experimental example-screening of catalyst

The following is intended to be illustrative and is intended to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should be accounted for within the knowledge of one skilled in the art. Unless otherwise specified, temperatures are in degrees Celsius.

The compounds BG-5 and BG-10 used hereinafter were synthesized according to the method disclosed in WO2017/032289A1, the entire content of which is incorporated herein by reference.

Experimental example 1

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reactor, then N, N-dimethylformamide (25 mL) was added, the reactor was purged with nitrogen, then cuprous iodide (0.746mmol, 0.06eq.) and Pd (dppf) Cl were added₂(0.746mmol, 0.06 eq.). Heating the reaction system to 75-80 ℃, and stirring for reaction for 15 hours. After the reaction is finished, cooling the reaction system to room temperature.

Wherein eq (equivalent) refers to the molar ratio of other substances based on the main raw material (set to 1eq.), and if the raw material Cul is 0.06eq, the molar ratio of the raw material Cul to the main raw material BG-10 is 0.06: 1.

The intermediate impurity BG-11A is generated when the reaction is in progress, and the impurity is one of important indexes needing to be monitored in a central control link. The experimental conversion rate was intermediately controlled using Agilent HPLC (high performance liquid chromatography), taking into account the content percentages of the raw material BG-10, the intermediate impurity BG-11A remaining in the reaction solution, and the product BG-11 (i.e. the intermediate control result). After 12-120 hours of reaction, cooling to below 50 ℃, taking about 0.2mL of reaction liquid, adding acetonitrile/water (volume ratio 8/2) for dissolution, and carrying out HPLC sample injection test. All chromatographic peaks above the limit of detection were integrated and the percentage of the corresponding compound HPLC peak area was read.

The chiral purity of BG-11 in the reaction solution was tested by HPLC using a chiral liquid chromatography column: reacting for a period of time, cooling to below 50 ℃, taking about 0.2ml of reaction liquid, adding ethanol for dissolving, adopting HPLC sample injection test loaded with a chiral liquid chromatographic column, integrating the product BG-11 and the corresponding isomer thereof, and calculating the percentage of the two respectively.

The control result is as follows: BG-10/BG-11A/BG-11 ═ 0.3%/0.8%/88.2%, chiral purity by HPLC was 90.1%.

In order to further improve the purity of BG-11, the following operations are still required: adding 30-50 g of methyl tert-butyl ether and 50-60 g of water, stirring, standing for layering, stirring the organic phase for a period of time, standing for layering, removing the water phase, and washing the organic phase with water. The organic phase was washed twice with 15-25 g of 10% aqueous thiourea solution and then filtered through silica gel. And (3) carrying out reduced pressure distillation on the filtrate, carrying out solvent replacement by using 10-30 g of n-heptane, adding 8-10 g of ethyl acetate to obtain an n-heptane/ethyl acetate solution of the BG-11 crude product, carrying out decolorization and secondary silica gel column treatment, concentrating the filtrate, and carrying out solvent replacement by using 10-15 g of ethyl acetate. The resulting solution of BG-11 in ethyl acetate (96% HPLC purity, 92.1% chiral purity, 68% yield) was used directly in the next step.

Experimental example 2

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (PPh) were added₃)₂Cl₂(0.746mmol, 0.06 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were carried out in the same manner as in example 1 to obtain the results of experiment 2, wherein BG-10/BG-11A/BG-11 ═ 31.6%/5.9%/50.4% and HPLC chiral purity was 97.1%.

Experimental example 3

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (dppf) Cl were added₂(0.746mmol, 0.06eq.) and PPh₃(1.491mmol，0.12 eq). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were carried out in the same manner as in example 1 to obtain the results of experiment 3, wherein BG-10/BG-11A/BG-11 was 0.1%/2.6%/81.1%, and HPLC chiral purity was 91.4%.

Experimental example 4

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (dPPf) Cl were added₂(0.249mmol, 0.02eq.) and Pd (PPh)₃)₂Cl₂(0.249mmol, 0.02 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 4 was obtained as follows: BG-10/BG-11A/BG-11 ═ 2.9%/2.1%/85.2%, chiral purity by HPLC 93.1%.

Experimental example 5

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (dibenzylideneacetone) Cl were added₂(Pd(dibenzalacetone)Cl₂) (0.746mmol, 0.06 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 5 was obtained as follows: BG-10/BG-11A/BG-11 ═ 92.7%/0%/0.5%, chiral purity by HPLC was not determined.

Experimental example 6

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to a reaction vessel followed by the addition of N, N-bisAnd 25ml of methyl formamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (PPh) were added₃)₄(0.746mmol, 0.06 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were carried out in the same manner as in example 1 to obtain the results of experiment 6, wherein BG-10/BG-11A/BG-11 ═ 46.9%/8.6%/26.6% and HPLC chiral purity was 98.8%.

Experimental example 7

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The autoclave was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (dtbpf) Cl were added₂(0.746mmol, 0.06 eq.)). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 7 was obtained as follows: BG-10/BG-11A/BG-11 ═ 2.6%/3.1%/82.6%, chiral purity by HPLC 99.0%.

Experimental example 8

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (OAc) were added₂(0.746mmol, 0.06eq.), P (cyclohexyl)₃(P(cyclohexyl)₃) (1.491mmol, 0.12 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 8 was obtained as follows: BG-10/BG-11A/BG-11 ═ 80.3%/2.6%/9.8%, chiral purity by HPLC 88.1%.

Experimental example 9

Compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 freeBase (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (OAc) were added₂(0.746mmol, 0.06eq.), BINAP (0.746mmol, 0.06 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 9 was obtained as follows: BG-10/BG-11A/BG-11 ═ 83.8%/2.1%/9.7%, chiral purity by HPLC 96.4%.

Experimental example 10

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (OAc) were added₂(0.746mmol，0.06eq.)，P(Bu)₃(1.491mmol, 0.12 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, the intermediate control and test were carried out in the same manner as in example 1 to obtain the intermediate control result of example 10, wherein BG-10/BG-11A/BG-11 is 90.4%/0%/1.0%, and the chiral purity of HPLC was not measured because the yield of BG-11 was too low.

Experimental example 11

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (OAc) were added₂(0.746mmol，0.06eq.)，PPh₃(1.491mmol, 0.12 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 11 was obtained as follows: BG-10/BG-11A/BG-11 ═ 39.5%/4.8%/43.1%, chiral purity by HPLC 96.0%.

Experimental example 12

Compound BG-10(5.0g, 1.491mmol, 0.12eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N,/N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (OAc) were added₂(0.746mmol, 0.06eq.), dtbpf (0.746mmol, 0.06 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 12 was obtained as follows: BG-10/BG-11A/BG-11 ═ 11.8%/0.8%/75.3%, chiral purity by HPLC 98.9%.

Experimental example 13

The compound BG-10(5.0g, 12.43mmol, 1eq.), BG-5 free base (14.91mmol, 1.2eq.) and tetramethylguanidine (37.29mmol, 3eq.) were added to the reaction vessel followed by 25mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.746mmol, 0.06eq.) and Pd (OAc) were added₂(0.746mmol，0.06eq.)，P(t-Bu)₃(0.746mmol, 0.06 eq.). The reaction system is heated to 75-80 ℃ and stirred for reaction for 15 hours. After the reaction is finished, the temperature is reduced to room temperature.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 13 was obtained as follows: BG-10/BG-11A/BG-11 ═ 27.9%/3.4%/59.2%, chiral purity by HPLC 99.0%.

Experimental example 14

The compound BG-10(1.0g, 2.49mmol, 1eq.), BG-5 free base (3.49mmol, 1.4eq.) and Diisopropylethylamine (DIPEA) (7.47mmol, 3eq.) were added to the reaction vessel followed by 4mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.149mmol, 0.06eq.) and Pd (OAc) were added₂(0.149mmol，0.06eq.)，P(t-Bu)₃HBF₄(0.149mmol, 0.06eq.) and reacted at 60 ℃ for 17 hours. The reaction system is heated to 80 ℃ and stirred for reaction for 48 hours. After the reaction is finished, sampling and carrying out central control measurementAnd (6) testing.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 14 was obtained as follows: BG-10/BG-11A/BG-11 ═ 31.65%/0%/50.66%.

Experimental example 15

The compound BG-10(1.0g, 2.49mmol, 1eq.), BG-5 free base (3.49mmol, 1.4eq.) and azabicyclo (DBU) (7.47mmol, 3eq.) were added to the reaction vessel followed by 4mL of N, N-dimethylformamide. The reaction vessel was purged with nitrogen, and then cuprous iodide (0.149mmol, 0.06eq.) and Pd (OAc) were added₂(0.149mmol，0.06eq.)，P(t-Bu)₃HBF₄(0.149mmol, 0.06eq.) and reacted at 60 ℃ for 17 hours. The reaction system is heated to 80 ℃ and stirred for reaction for 48 hours. After the reaction was completed, a sample was taken for central control testing.

Then, intermediate control and test were performed in the same manner as in experimental example 1, and the control result of experimental example 15 was obtained as follows: BG-10/BG-11A/BG-11 ═ 0%/1.41%/54.30%.

TABLE 1 results of catalyst screening

As can be seen from the screening results, when Pd (PPh) is used₃)₂Cl₂、Pd(dibenzalacetone)Cl₂And Pd (PPh)₃)₄、Pd(OAc)₂(using Pd (OAc)₂Used together with a phosphine ligand when used as a catalyst), etc., a large amount of BG-10 is present and cannot be converted into BG-11. Pd (PPh) was used as in Experimental example 2₃)₂Cl₂As a catalyst, 31.6% of BG-10 was not converted, and the controlled conversion of BG-10 was 50.4%. When Pd (dppf) Cl is used₂And/or Pd (dtbpf) Cl₂When used as a catalyst, the BG-10 medium-controlled conversion rate can be greatly improved, such as Pd (dppf) Cl used in experimental example 1 and example 3₂The balance of BG-10 was only 0.3% and 0.1%; using Pd (dtbpf) Cl₂The remaining amount of the catalyst BG-10 was only 2.6%.

Although it is used forUsing Pd (dppf) Cl₂When the catalyst is used as a catalyst, the conversion rate of BG-10 is high, but the chiral purity of the obtained BG-11 is only 90.1% (Experimental example 1), and the purity cannot be directly used for the next drug production, and the chiral purity needs to be improved by chemical resolution in the subsequent production steps.

And Pd (dtbpf) Cl is used₂The experimental example 7 as the catalyst has higher BG-10 conversion rate, the chiral purity of the reaction product BG-11 in the step can reach 99.0 percent, and the step of chemical resolution can be omitted, so that the production cost is reduced.

Example 1

64.0g of BG-5 salt (105mmol, 1.4eq.) was suspended in a mixed solvent composed of 150mL of n-heptane and 60mL of water to form a suspension, and the temperature of the suspension was lowered to 5 ℃. 23.4g of potassium hydroxide was dissolved in 75mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting an organic phase, washing the organic phase with water, and filtering to remove insoluble substances. The resulting organic phase was concentrated, azeotroped and water removed, then 60mL of N, N-Dimethylformamide (DMF) was added and the distillation continued to remove the remaining N-heptane to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction kettle and then 30.0g of BG-10(75mmol, 1.0eq.), 25.8g of tetramethylguanidine and 60mL of N, N-dimethylformamide were added. The autoclave was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added₂(4.5mmol, 0.060 eq.). The reaction was warmed to 80 ℃ and the reaction mixture was stirred for 22 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The organic phase is washed with 120-160 g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, supplementing 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Heating to dissolve the solid generated in the system, then cooling to 40 ℃, adding crystal seed BG-11 to induce crystallization, and slowly adding water to fully separate out the productThen, the temperature is reduced to 5 ℃. The solid is collected by filtration, washed by a methanol/water mixed solvent and dried in vacuum at 40-45 ℃ to obtain the product BG-11 (the HPLC purity is 99.8%, the chiral purity is 99.3%, and the control result is that BG-10/BG-11A/BG-11 is 0%/3.6%/81.3%, the raw material BG-10 is completely converted, the residual intermediate BG-11A is 3.6%, BG-11 is 81.3%, and the yield is 75.1%).

Example 2

64.0g of BG-5 salt (105mmol, 1.4eq.) was suspended in a mixed solvent consisting of 150mL of n-heptane and 45mL of water and cooled to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The resulting organic phase was concentrated to remove water azeotropically, then 90mL of N, N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction kettle and then 30.0g of BG-10(75mmol, 1.0eq.), 25.8g of tetramethylguanidine and 90mL of N, N-dimethylformamide were added. The autoclave was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added₂(4.5mmol, 0.060 eq.). The reaction system is heated to 80 ℃ and stirred for reaction for 24 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, supplementing 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating up the solid generated in the dissolution system, then cooling to 40-45 ℃ for crystallization, adding crystal seeds BG-11 for induced crystallization, slowly adding water to fully separate out the product, and then cooling to 5 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried in vacuo at 45 ℃ to give BG-11 (chiral purity 99.53%, yield 68.28%) as a product.

Example 3

Mixing 64.0g of BG-5The salt (105mmol, 1.4eq.) was suspended in a mixed solvent consisting of 150mL of n-heptane and 60mL of water and cooled to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The resulting organic phase was concentrated to remove water azeotropically, then 60mL of N, N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction kettle and then 30.0g of BG-10(75mmol, 1.0eq.), 25.8g of tetramethylguanidine and 60mL of N, N-dimethylformamide were added. The autoclave was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added₂(6.0mmol, 0.080 eq.). The reaction system was heated to 80 ℃ and stirred for 22 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, supplementing 150-180 q of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating up the solid generated in the dissolution system, cooling to 40-45 ℃ for crystallization, adding crystal seeds BG-11 for induced crystallization, slowly adding water to fully separate out the product, and cooling to 5 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried under vacuum at 45 ℃ to obtain BG-11 (chiral purity 99.43%, yield 76.98%).

Example 4

64.0g of BG-5 salt (105mmol, 1.4eq.) was suspended in a mixed solvent consisting of 150mL of n-heptane and 60mL of water and the temperature was reduced to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The organic phase is concentrated and azeotropically dewatered, then 60mL of N, N-Dimethylformamide (DMF) is added, and the remaining N-heptane is continuously distilled off to obtain BG-5 freeBase in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction kettle and then 30.0g of BG-10(75mmol, 1.0eq.), 25.8g of tetramethylguanidine and 60mL of N, N-dimethylformamide were added. The autoclave was purged with nitrogen, and then cuprous iodide (3.75mmol, 0.050eq.) and Pd (dtbpf) Cl were added₂(4.5mmol, 0.060 eq.). The reaction system was heated to 80 ℃ and stirred for 22 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, supplementing 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating up the solid generated in the dissolution system, then cooling to 40-45 ℃ for crystallization, adding crystal seeds BG-11 for induced crystallization, slowly adding water to fully separate out the product, and then cooling to 5 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried in vacuo at 45 ℃ to give BG-11 (chiral purity 99.50%, yield 69.93%).

Example 5

64.0g of BG-5 salt (105mmol, 1.4eq.) was suspended in a mixed solvent consisting of 150mL of n-heptane and 60mL of water and cooled to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The resulting organic phase was concentrated to remove water azeotropically, then 60mL of N, N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to give a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction kettle and then 30.0g of BG-10(75mmol, 1.0eq.), 25.8g of tetramethylguanidine and 60mL of N, N-dimethylformamide were added. The autoclave was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added₂(4.5mmol, 0.060 eq.). The reaction system is heated to 80 ℃ and stirred for reaction for 24 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butylEther and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, supplementing 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating up the solid generated in the dissolution system, then cooling to 40-45 ℃ for crystallization, adding crystal seeds BG-11 for induced crystallization, slowly adding water to fully separate out the product, and then cooling to 3 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried in vacuo at 45 ℃ to give BG-11 (chiral purity 99.32%, yield 75.01%) as a product.

Example 6

64.0g of BG-5 salt (105mmol, 1.4eq.) was suspended in a mixed solvent of 150mL of n-heptane and 60mL of water and cooled to 5 ℃. 23.4g of potassium hydroxide was dissolved in 120mL of water, added to the suspension, stirred for 2 hours, and then warmed to room temperature. Standing for phase separation, collecting organic phase, washing with water, and filtering to remove insoluble substances. The organic phase was concentrated to remove water azeotropically, then 60ml of N-Dimethylformamide (DMF) was added and the remaining N-heptane was distilled off to obtain a solution of BG-5 free base in N, N-dimethylformamide. The BG-5 solution was transferred to a reaction kettle and then 30.0g of BG-10(75mmol, 1.0eq.), 25.8g of tetramethylguanidine and 60mL of N, N-dimethylformamide were added. The autoclave was purged with nitrogen, and then cuprous iodide (4.5mmol, 0.060eq.) and Pd (dtbpf) Cl were added₂(4.5mmol, 0.060 eq.). The reaction system is heated to 80 ℃ and stirred for reaction for 24 hours. After the reaction is finished, cooling to room temperature, and then adding 200-250 g of methyl tert-butyl ether and 250-300 g of water. After stirring for a while, the mixture was allowed to stand to separate the aqueous phase and the organic phase was washed with water. The separated organic phase was washed with 120 to 160g of a mixed aqueous solution containing 5% thiourea and 5% sodium chloride, and then filtered through silica gel. And carrying out reduced pressure distillation on the filtrate, supplementing 150-180 g of n-heptane, and then filtering by using silica gel. The filtrate was distilled under reduced pressure, and then methanol was added for solvent exchange. Distilling the mixture, heating up the solid generated in the dissolution system, then cooling to 35-45 ℃ for crystallization, and addingSeed crystal BG-11 is added for induced crystallization, water is slowly added to fully separate out the product, and then the temperature is reduced to 5 ℃. The solid was collected by filtration, washed with a mixed solvent of methanol/water, and dried in vacuo at 45 ℃ to give BG-11 (chiral purity 99.35%, yield 67.69%).

It is noted that BG-11 seeds can be prepared according to any of the methods described in the examples (without the addition of seeds). The crystal form is prepared in small batches for the first time without crystal seeds, and the products in the previous batches can be used as the crystal seeds for subsequent preparation and production. The seeding is mainly used for better controlling the crystallization process, so that the product is stably separated out and prevented from being separated out. Seeding is not an essential operation, and crystallization can be carried out without seeding to obtain the required crystals.

The invention has been described in detail with respect to the general description, specific embodiments and experiments, and it is intended that all modifications and improvements made without departing from the spirit of the invention are within the scope of the invention as claimed. All cited references are incorporated by reference in their entirety into this application.