CN117486918A - Preparation method of naphthalene ring pinacol ester compound - Google Patents
Preparation method of naphthalene ring pinacol ester compound Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- -1 naphthalene ring pinacol ester compound Chemical class 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 39
- 239000002904 solvent Substances 0.000 claims abstract description 29
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims abstract description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 50
- 238000006243 chemical reaction Methods 0.000 claims description 45
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 20
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 20
- 235000011056 potassium acetate Nutrition 0.000 claims description 19
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000001953 recrystallisation Methods 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 15
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 11
- 239000007858 starting material Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 7
- 239000012043 crude product Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 8
- 239000000047 product Substances 0.000 description 29
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000003446 ligand Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002635 aromatic organic solvent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940124785 KRAS inhibitor Drugs 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- VBXDEEVJTYBRJJ-UHFFFAOYSA-N diboronic acid Chemical compound OBOBO VBXDEEVJTYBRJJ-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Abstract
The invention discloses a preparation method of a naphthalene ring pinacol ester compound. The invention provides a preparation method of a compound II, which comprises the following steps: in a solvent, in the presence of a base, tris (dibenzylideneacetone) dipalladium and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, compound I and pinacolato biborate react to obtain compound II. The preparation method of the naphthalene ring pinacol ester compound has the advantages of higher yield, less catalyst consumption and lower cost, and further has the advantage of simple and convenient post-treatment.
Description
Technical Field
The invention relates to the field of pharmaceutical chemical synthesis, in particular to a preparation method of a naphthalene ring pinacol ester compound.
Background
((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (structure shown as formula II) is an important class of molecular building blocks, and occupies an important position in drug development, particularly in KRAS inhibitors.
Patents WO2022015375A1, WO2022192790A1, WO2022262686A1 and WO2022192794A1 report methods for preparing compound II as shown in the following formulas.
The patent reports that the final product is obtained by taking active ester I, pinacol biborate as a raw material and 1,1' -bis-diphenylphosphine ferrocene palladium dichloride as a catalyst and purifying the catalyst through a high Wen Oulian column. However, the catalyst dosage is larger (10%), the product purity is low, and the product is not favorable for commercial supply of subsequent medicines due to separation and purification by a column, and is not suitable for industrial production.
The inventors have also repeated the preparation methods described in the above patents during the development, and have found that the yields described in the patents, in particular the methods described in WO2022262686A1, cannot be achieved, and that the yields can only be about 40% when the applicant repeats the experiments.
Therefore, there is a need to develop a process for the preparation of compound II suitable for industrial production.
Disclosure of Invention
The invention aims to solve the technical problems of lower yield, larger catalyst dosage and troublesome post-treatment in the prior art, and provides a preparation method of a naphthalene ring pinacol ester compound. The preparation method of the naphthalene ring pinacol ester compound has the advantages of higher yield, less catalyst consumption and lower cost, and further has the advantage of simple and convenient post-treatment.
The invention provides a preparation method of a compound II, which comprises the following steps: in a solvent, in the presence of alkali, tris (dibenzylideneacetone) dipalladium and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, carrying out a reaction of a compound I and pinacol biborate as shown in the following formula to obtain a compound II,
the solvent is selected from one or more of aromatic hydrocarbon organic solvents, amide organic solvents and ether organic solvents.
In a preferred embodiment, the solvent is an aromatic organic solvent.
In a preferred embodiment, the aromatic organic solvent is a benzene organic solvent, such as toluene.
In a preferred embodiment, the amide-based organic solvent is N, N-dimethylformamide.
In a preferred embodiment, the ether-based organic solvent is 1, 4-dioxane.
In a preferred embodiment, the molar volume ratio of said compound I to said solvent is (0.01-1) mmol/1 ml; for example, (0.1-0.3) mmol:1ml; for example, 0.19 mmol/1 ml.
In a preferred embodiment, the molar ratio of said pinacol ester of diboronic acid to said compound I is (1-3): 1, for example (1-1.5): 1, for example 1.3:1.
In a preferred embodiment, the molar ratio of said tris (dibenzylideneacetone) dipalladium to said compound I is (0.005-0.03): 1, for example (0.01-0.02): 1, for example 0.01:1 or 0.02:1.
In a preferred embodiment, the molar ratio of 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene to compound I is (0.01-0.05): 1, e.g. (0.02-0.04): 1, further e.g. 0.02:1 or 0.04:1.
In a preferred embodiment, the base is selected from one or more of potassium acetate, potassium carbonate and potassium phosphate, for example potassium acetate.
In a preferred embodiment, the molar ratio of base to compound I is (1-5): 1, e.g. 2.5-3.5): 1, e.g. 3.2:1.
In a preferred embodiment, the temperature of the reaction is from 80 ℃ to 150 ℃, such as from 100 ℃ to 120 ℃, and further such as 110 ℃.
The progress of the reaction can be detected using monitoring methods conventional in the art for such reactions (e.g., TLC or LC-MS) to either disappearance of compound I or no longer react as an endpoint of the reaction. The reaction time may be 5 to 15 hours, for example 8 to 12 hours, for example 10 hours.
In a preferred embodiment, the starting materials for the reaction consist of: the solvent, the compound I, the pinacol ester of biboronate, the base, the tris (dibenzylideneacetone) dipalladium and the 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene.
In a preferred embodiment, the starting materials for the reaction consist of: said toluene, said compound I, said pinacol ester of biboronate, said potassium acetate, said tris (dibenzylideneacetone) dipalladium, and said 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene;
the molar volume ratio of the compound I to the toluene is 0.19 mmol/1 ml;
the molar ratio of the pinacol ester of biboronate to the compound I is 1.3:1;
the molar ratio of the tris (dibenzylideneacetone) dipalladium to the compound I is 0.01:1;
the molar ratio of the 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene to the compound I is 0.02:1;
the molar ratio of potassium acetate to compound I was 3.2:1.
In a preferred embodiment, the starting materials for the reaction consist of: said toluene, said compound I, said pinacol ester of biboronate, said potassium acetate, said tris (dibenzylideneacetone) dipalladium, and said 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene;
the molar volume ratio of the compound I to the toluene is 0.19 mmol/1 ml;
the molar ratio of the pinacol ester of biboronate to the compound I is 1.3:1;
the molar ratio of the tris (dibenzylideneacetone) dipalladium to the compound I is 0.02:1;
the molar ratio of the 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene to the compound I is 0.04:1;
the molar ratio of potassium acetate to compound I was 3.2:1.
In a preferred embodiment, the preparation process further comprises a post-treatment, which is conventional in such reactions in the art, preferably the post-treatment comprises a recrystallization, preferably the recrystallization comprises the steps of: crystallizing the mixed solution consisting of the compound II and the solvent to obtain the compound II;
the crystallization temperature is-5 ℃;
the solvent is ethyl acetate, methanol, ethanol or isopropanol.
In a preferred embodiment, the crystallization temperature is 0 ℃.
In a preferred embodiment, the recrystallization is performed with the solvent being ethanol or isopropanol, such as ethanol.
In a preferred embodiment, the mixed solution is a saturated mixed solution in the recrystallization.
In a preferred embodiment, the temperature of the mixed solution in the recrystallization is 50 to 90 ℃, for example 65 to 80 ℃, and further for example 70 ℃ or 75 ℃.
In a preferred embodiment, the recrystallization comprises the steps of:
(I) Dissolving a compound II in a solvent at 50-90 ℃ to obtain the mixed solution;
(II) crystallizing the mixed solution in the step (I) to obtain a compound II.
In a preferred embodiment, in step (I), the temperature of dissolution is 65℃to 80℃such as 70℃or 75 ℃.
In a preferred embodiment, the post-treatment comprises the steps of: filtration, washing, concentration (e.g., concentration under reduced pressure), and recrystallization; the method of recrystallization is as described in any one of the present inventions.
In a preferred embodiment, the post-treatment comprises the steps of:
(a) Filtering, washing and concentrating the mixture obtained after the reaction is finished in sequence to obtain a crude product of the compound II;
(b) Dissolving a crude product of the compound II in a solvent at 50-90 ℃ to obtain a mixed solution; the solvent is ethyl acetate, methanol, ethanol or isopropanol;
(c) Crystallizing the mixed solution in the step (b) to obtain a compound II; the crystallization temperature is-5 ℃.
The invention provides a recrystallization method of a compound II, which comprises the following steps of crystallizing a mixed solution composed of the compound II and a solvent to obtain the compound II;
the crystallization temperature is-5 ℃;
the solvent is ethyl acetate, methanol, ethanol or isopropanol.
The operation and conditions of the recrystallization method of the compound II may also be as described in any one of the present inventions.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the preparation method of the naphthalene ring pinacol ester compound has the advantages of higher yield, less catalyst consumption and lower cost; furthermore, the preparation method of the naphthalene ring pinacol ester compound provided by the invention can adopt recrystallization for purification, so that the product purity is good, and the purification method is greatly simplified.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The synthetic route is shown in the following formula.
Example 1:
toluene (100 ml) was added to the reaction flask, compound I (10 g), pinacol diboronate (6 g), potassium acetate (5.8 g), tris (dibenzylideneacetone) dipalladium catalyst (0.17 g), ligand 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.22 g) was added, the temperature was raised to 110℃and the reaction was carried out for about 10 hours, TLC showed that the reaction of the starting materials was completed, and HPLC was monitoring the purity of the objective product of the reaction system to 88%.
Cooling, filtering to remove salt, washing an organic phase with water, concentrating the organic phase under reduced pressure, adding 20ml of absolute ethyl alcohol, heating to 70 ℃, dissolving the system, cooling to 0 ℃, precipitating solid, and filtering to obtain 8g of product. Yield: 83% the purity of the liquid phase detection product is 99%.
1 H-NMR(400MHz，CDCl 3 )δ7.66(dd，J＝9.0,5.7Hz,1H),7.50(d,J＝2.5Hz,1H),7.37(d,J＝2.6Hz,1H),7.24(t,J＝8.8Hz,1H),5.27(s,2H),3.49(s,3H),1.43(s,12H),1.16(s,21H)。
Example 2:
toluene (100 ml) was added to the reaction flask, compound I (10 g) was added, pinacol diboronate (6 g), potassium acetate (5.8 g) was added, tris (dibenzylideneacetone) dipalladium (0.34 g) was added, ligand 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.44 g) was added, the temperature was raised to 110℃and the reaction was carried out for about 10 hours, TLC showed that the reaction of the starting materials was completed, and HPLC was conducted to monitor the purity of the objective product of the reaction system.
Cooling, filtering to remove salt, washing an organic phase with water, concentrating the organic phase under reduced pressure, adding 20ml of absolute ethyl alcohol, heating to 70 ℃, dissolving the system, cooling to 0 ℃, precipitating solid, and filtering to obtain 8g of product. Yield: 83%, liquid phase detection product purity 99%.
The nuclear magnetic data of the target product are the same as those of the product in example 1.
Example 3:
toluene (100 ml) was added to the reaction flask, compound I (10 g) was added, pinacol diboronate (6 g), potassium acetate (5.8 g) was added, tris (dibenzylideneacetone) dipalladium (0.34 g) was added, ligand 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.44 g) was added, the temperature was raised to 110℃and the reaction was carried out for about 10 hours, TLC showed that the reaction of the starting materials was completed, and HPLC was conducted to monitor the purity of the objective product of the reaction system.
Cooling, filtering to remove salt, washing an organic phase with water, concentrating the organic phase under reduced pressure, adding 20ml of isopropanol, heating to 75 ℃, dissolving the system, cooling to 0 ℃, precipitating solid, and filtering to obtain 6g of product. Yield: 62%. The purity of the liquid phase detection product is 99 percent.
The nuclear magnetic data of the target product are the same as those of the product in example 1.
Example 4:
toluene (100 ml) was added to the reaction flask, compound I (10 g) was added, pinacol diboronate (6 g), potassium acetate (5.8 g) was added, tris (dibenzylideneacetone) dipalladium (0.34 g) was added, ligand 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.44 g) was added, the temperature was raised to 110℃and the reaction was carried out for about 10 hours, TLC showed that the reaction of the starting materials was completed, and HPLC was conducted to monitor the purity of the objective product of the reaction system.
Cooling, filtering to remove salt, washing the organic phase with water, concentrating the organic phase under reduced pressure, purifying the crude product by column chromatography, and purifying with ethyl acetate/n-heptane (1/100) as eluent to obtain 7.4g of product with purity of 97.9% and yield of 77%.
The nuclear magnetic data of the target product are the same as those of the product in example 1.
Comparative example 1:
toluene (100 ml) was added to the reaction flask, compound I (10 g) was added, pinacol diboronate (6 g) was added, potassium acetate (5.8 g), tris (dibenzylideneacetone) dipalladium (0.34 g) was added, ligand 1,1' -bis (diphenylphosphino) ferrocene (0.42 g) was added, the temperature was raised to 110℃for about 10 hours, TLC showed that the reaction of the starting material was completed, HPLC was monitored, the target product purity of the reaction system was 56%, and the crude product was purified by ethyl acetate/n-heptane (1/100) column chromatography to give 4.3g, purity was 97.6%, yield 45%.
The nuclear magnetic data of the target product are the same as those of the product in example 1.
Comparative example 2:
toluene (100 ml) was added to a reaction flask, compound I (10 g) was added, pinacol diboronate (6 g) and potassium acetate (5.8 g) were added, 1' -bis (di-t-butylphosphine) ferrocene ] palladium dichloride (0.24 g) was added, ligand 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (0.44 g) was added, the temperature was raised to 110℃and the reaction was carried out for about 10 hours, TLC showed that the reaction of the raw materials was completed, HPLC was conducted, the purity of the target product of the reaction system was 64%, and 5.2g was purified by column chromatography, with a yield of 55%.
The nuclear magnetic data of the target product are the same as those of the product in example 1.
Comparative example 3:
toluene (100 ml) was added to the reaction flask, compound I (10 g) was added, pinacol diboronate (6 g), potassium acetate (5.8 g) and 1, 1-bis (diphenylphosphine) ferrocene palladium dichloride (1.36 g,0.1 eq) were added, the temperature was raised to 110℃and the reaction was carried out for about 10 hours, TLC showed that the reaction was completed, HPLC was monitored, the purity of the target product of the reaction system was 51%, and the crude product was purified by ethyl acetate/n-heptane (1/100) column chromatography to give 4g, yield 42%.
The nuclear magnetic data of the target product are the same as those of the product in example 1.
Claims (10)
1. A process for the preparation of compound II, characterized in that it comprises the steps of: in a solvent, in the presence of alkali, tris (dibenzylideneacetone) dipalladium and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene, carrying out a reaction of a compound I and pinacol biborate as shown in the following formula to obtain a compound II,
the solvent is selected from one or more of aromatic hydrocarbon organic solvents, amide organic solvents and ether organic solvents.
2. A process for the preparation of compound II according to claim 1, characterized in that it satisfies one or more of the following conditions:
(1) The aromatic hydrocarbon organic solvent is benzene organic solvent;
(2) The amide organic solvent is N, N-dimethylformamide;
(3) The ether organic solvent is 1, 4-dioxane;
(4) The molar volume ratio of the compound I to the solvent is (0.01-1) mmol/1 ml;
(5) The mole ratio of the pinacol ester of the biboronate to the compound I is (1-3): 1;
(6) The molar ratio of the tris (dibenzylideneacetone) dipalladium to the compound I is (0.005-0.03) 1;
(7) The molar ratio of the 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene to the compound I is (0.01-0.05) 1;
(8) The alkali is selected from one or more of potassium acetate, potassium carbonate and potassium phosphate;
(9) The molar ratio of the base to the compound I is (1-5): 1;
(10) The temperature of the reaction is 80-150 ℃;
(11) The reaction time is 5-15h; and
(12) The preparation method further comprises post-treatment, wherein the post-treatment comprises recrystallization; the recrystallization includes the steps of: crystallizing the mixed solution consisting of the compound II and the solvent to obtain the compound II; the crystallization temperature is-5 ℃; the solvent is ethyl acetate, methanol, ethanol or isopropanol.
3. A process for the preparation of compound II according to claim 2, characterized in that it satisfies one or more of the following conditions:
(1) The aromatic hydrocarbon organic solvent is toluene;
(2) The molar volume ratio of the compound I to the solvent is (0.1-0.3) mmol/1 ml;
(3) The mole ratio of the pinacol ester of the biboronate to the compound I is (1-1.5): 1;
(4) The molar ratio of the tris (dibenzylideneacetone) dipalladium to the compound I is (0.01-0.02): 1;
(5) The molar ratio of the 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene to the compound I is (0.02-0.04) 1;
(6) The alkali is potassium acetate;
(7) The molar ratio of the base to the compound I is (2.5-3.5): 1;
(8) The temperature of the reaction is 100-120 ℃;
(9) The reaction time is 8-12h;
(10) In the recrystallization, the solvent is ethanol or isopropanol; such as ethanol;
(11) The crystallization temperature is 0 ℃; and
(12) In the recrystallization, the temperature of the mixed solution is 50 to 90 ℃, for example 65 to 80 ℃, and further, for example 70 ℃ or 75 ℃.
4. A process for the preparation of compound II according to claim 3, characterized in that it satisfies one or more of the following conditions:
(1) The molar volume ratio of the compound I to the solvent is 0.19 mmol/1 ml;
(2) The molar ratio of the pinacol ester of biboronate to the compound I is 1.3:1;
(3) The molar ratio of the tris (dibenzylideneacetone) dipalladium to the compound I is 0.01:1 or 0.02:1;
(4) The molar ratio of the 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene to the compound I is 0.02:1 or 0.04:1;
(5) The molar ratio of the base to the compound I is 3.2:1;
(6) The temperature of the reaction is 110 ℃;
(7) The reaction time is 10 hours; and
(8) The recrystallization includes the steps of:
(I) Dissolving a compound II in a solvent at 50-90 ℃ to obtain the mixed solution;
(II) crystallizing the mixed solution in the step (I) to obtain a compound II;
preferably, the temperature of dissolution is 65 ℃ to 80 ℃, such as 70 ℃ or 75 ℃.
5. The process for producing compound II according to claim 1, wherein the solvent is an aromatic hydrocarbon-based organic solvent.
6. A process for the preparation of compound II according to any one of claims 1 to 5, wherein the starting materials for the reaction consist of: the solvent, the compound I, the base, the tris (dibenzylideneacetone) dipalladium and the 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene.
7. The method of preparing compound II according to claim 6, wherein the method of preparing compound II is scheme 1 or scheme 2 below:
scheme 1: the raw materials of the reaction consist of the following substances: said toluene, said compound I, said pinacol ester of biboronate, said potassium acetate, said tris (dibenzylideneacetone) dipalladium, and said 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene;
the molar volume ratio of the compound I to the toluene is 0.19 mmol/1 ml;
the molar ratio of the pinacol ester of biboronate to the compound I is 1.3:1;
the molar ratio of the tris (dibenzylideneacetone) dipalladium to the compound I is 0.01:1;
the molar ratio of the 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene to the compound I is 0.02:1;
the molar ratio of the potassium acetate to the compound I is 3.2:1;
scheme 2: the raw materials of the reaction consist of the following substances: said toluene, said compound I, said pinacol ester of biboronate, said potassium acetate, said tris (dibenzylideneacetone) dipalladium, and said 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene;
the molar volume ratio of the compound I to the toluene is 0.19 mmol/1 ml;
the molar ratio of the pinacol ester of biboronate to the compound I is 1.3:1;
the molar ratio of the tris (dibenzylideneacetone) dipalladium to the compound I is 0.02:1;
the molar ratio of the 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene to the compound I is 0.04:1;
the molar ratio of potassium acetate to compound I was 3.2:1.
8. A process for the preparation of compound II according to any one of claims 2 to 4, wherein the post-treatment comprises the steps of: filtering, washing, concentrating and recrystallizing.
9. The process for the preparation of compound II according to claim 8, wherein the post-treatment comprises the steps of:
(a) Filtering, washing and concentrating the mixture obtained after the reaction is finished in sequence to obtain a crude product of the compound II;
(b) Dissolving a crude product of the compound II in a solvent at 50-90 ℃ to obtain a mixed solution; the solvent is ethyl acetate, methanol, ethanol or isopropanol;
(c) Crystallizing the mixed solution in the step (b) to obtain a compound II; the crystallization temperature is-5 ℃.
10. The recrystallization method of the compound II is characterized by comprising the following steps of crystallizing a mixed solution consisting of the compound II and a solvent to obtain the compound II; the crystallization temperature is-5 ℃; the solvent is ethyl acetate, methanol, ethanol or isopropanol;
the operation and conditions of the recrystallization process of compound II may also be as set forth in any one of claims 2-4.
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