CN116283828A - PARP1 inhibitor intermediate and preparation method and application thereof - Google Patents
PARP1 inhibitor intermediate and preparation method and application thereof Download PDFInfo
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- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 title claims abstract description 51
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a PARP1 inhibitor intermediate, and a preparation method and application thereof. Relates to the technical field of drug molecular design and drug synthesis. A PARP1 inhibitor intermediate comprising the structure:wherein R is 1 Selected from the group consisting of-Cl, -Br, -F, -I, -NO 2 and-NH 2 One of the following; wherein R is 2 Selected from benzyl, allyl, acetyl and (Boc) 2 At least one of O; wherein R is 3 One selected from-I, -Cl and-Br; wherein R is 4 Selected from C 1‑8 Alkyl, C 2‑8 Alkenyl, halogen substituted C 1‑8 At least one of an alkyl group, a nitrile group, a phenyl group, and a sulfonyl group. The PARP inhibitor can be used as a targeting drug to selectively kill BRCA mutant cells so as to play a role in killing tumors, and the PARP1 inhibitor intermediate of the invention is a key intermediate for synthesizing the PARP inhibitor and determines PARBased on the actual performance of the P inhibitor, the invention prepares a high-quality PARP1 inhibitor intermediate, which is favorable for PARP inhibitors with excellent activity of each layer.
Description
Technical Field
The invention relates to the technical fields of drug molecular design and drug synthesis, in particular to a PARP1 inhibitor intermediate and a preparation method and application thereof.
Background
Poly (ADP-ribose) polymerase (PARPs) is a ribozyme present in eukaryotic cells and is mainly involved in DNA repair, transcription, regulation and the like.
Among 18 members of the PARP family, PARP-1 has the highest intracellular content, and is most deeply studied, and ADP-ribose units are mainly catalyzed to transfer to nuclear receptor proteins by taking NAD+ as a substrate, so that a poly ADP-ribose polymer is formed, repair enzymes are guided to repair DNA gaps, and a key effect is played in a base excision repair path. In the current situation of extremely lack of high-quality targets in drug development at present, PARP-1 provides a few clinically verified anticancer targets for us.
Intermediates of different PARP1 inhibitors can synthesize active PARP1 inhibitors, and the prior PARP1 inhibitor intermediates still do not reach ideal performance. More importantly, the yield of the intermediate of the PARP1 inhibitor plays a decisive role in the yield of the PARP1 inhibitor, whereas the existing synthesis methods of the intermediate of the PARP1 inhibitor are not ideal.
Based on this, there is a need for a novel PARP1 inhibitor intermediate and a preparation method thereof, so as to promote the design, development and synthesis of more high-quality PARP1 inhibitors, promote the synthesis of PARP1 inhibitors with excellent activity, and promote the high-yield production of PARP1 inhibitors.
Disclosure of Invention
The first technical problem to be solved by the invention is as follows:
a PARP1 inhibitor intermediate is provided.
The second technical problem to be solved by the invention is as follows:
a process for preparing the PARP1 inhibitor intermediate is provided.
The third technical problem to be solved by the invention is:
use of said PARP1 inhibitor intermediate.
In order to solve the first technical problem, the invention adopts the following technical scheme:
a PARP1 inhibitor intermediate comprising the structure:
wherein R is 1 Selected from the group consisting of-Cl, -Br, -F, -I, -NO 2 and-NH 2 One of the following;
wherein R is 2 Selected from benzyl, allyl, acetyl and (Boc) 2 At least one of O;
wherein R is 3 One selected from-I, -Cl and-Br;
wherein R is 4 Selected from C 1-8 Alkyl, C 2-8 Alkenyl, halogen substituted C 1-8 At least one of an alkyl group, a nitrile group, a phenyl group, and a sulfonyl group.
According to the embodiments of the present invention, one of the technical solutions has at least one of the following advantages or beneficial effects:
the PARP inhibitor can be used as a targeting drug to selectively kill BRCA mutant cells so as to play a role in killing tumors, and the PARP1 inhibitor intermediate is a key intermediate for synthesizing the PARP inhibitor and determines the actual performance of the PARP inhibitor.
According to an embodiment of the invention, R 4 Selected from C 1-8 Alkyl, C 2-8 Alkenyl, halogen substituted C 1-8 At least one of the alkyl groups.
According to an embodiment of the invention, R 4 At least one selected from ethyl, propyl, butyl and isopropyl.
In order to solve the second technical problem, the invention adopts the following technical scheme:
a process for preparing the PARP1 inhibitor intermediate comprising the steps of:
s1, taking A0 as a starting material, and obtaining A1 through reaction;
S2A 1 is subjected to substitution reaction to obtain A2;
s3, mixing A2 with a first reducing agent, and reacting to obtain A3;
s4, mixing A3 with A3-1, and reacting to obtain A4;
s5, mixing A4 with Grubbs second generation catalyst, and carrying out catalytic reaction to obtain A5;
s6 mixing A5 with a composition containing R 2 Reacting the compounds of (2) to obtain A6;
s7, mixing A6 with a second reducing agent, and reacting to obtain A7;
s8, mixing A7 with iodine simple substance, and reacting to obtain the intermediate of the PARP1 inhibitor;
wherein R is 3 Selected from one of-Cl, -Br, -F and-I.
According to the embodiments of the present invention, one of the technical solutions has at least one of the following advantages or beneficial effects:
compared with the existing method, the preparation method of the PARP1 inhibitor intermediate has the advantages of easily obtained raw materials, high synthesis efficiency, extremely high yield and at least up to 95.98 percent.
According to an embodiment of the invention, the mass ratio of A0 to A1 is 80-100: :110-120..
According to an embodiment of the invention, the mass ratio of A0 to A1 is 99-100: :118-120..
According to an embodiment of the invention, the mass ratio of A1 to A2 is 100-120:70-80.
According to an embodiment of the invention, the mass ratio of A1 to A2 is 116-120:75-80.
According to an embodiment of the invention, the mass ratio of A2 to A3 is 60-79:50-60.
According to an embodiment of the invention, the mass ratio of A2 to A3 is 63-79:54-60.
According to an embodiment of the invention, the mass ratio of A3 to A4 is 20-30:8-10.
According to an embodiment of the invention, the mass ratio of A3 to A4 is 27-30:8-10.
According to an embodiment of the invention, the mass ratio of A4 to A5 is 5-10:5-12.
According to an embodiment of the invention, the mass ratio of A4 to A5 is 8-10:6-12.
According to an embodiment of the invention, the mass ratio of A5 to A6 is 2-10:3-12.
According to an embodiment of the invention, the mass ratio of A5 to A6 is 5-10:6-12.
According to an embodiment of the invention, the mass ratio of A6 to A7 is 2-10:3-6.
According to an embodiment of the invention, the mass ratio of A6 to A7 is 5-10:3-6.
According to an embodiment of the invention, the mass ratio of A7 to A8 (PARP 1 inhibitor intermediate) is 2-4:2-4.
According to an embodiment of the invention, the mass ratio of A7 to A8 (PARP 1 inhibitor intermediate) is 2-4:2-2.5.
According to an embodiment of the present invention, in step S1, the method further comprises the steps of: mixed concentrated HNO 3 Concentrated H 2 SO 4 And A0, obtaining A1 through reaction.
According to an embodiment of the present invention, in step S1, the method further comprises the steps of: collecting concentrated HNO 3 Cooling to 0-5 deg.c in a container, and dropping concentrated H 2 SO 4 After the dripping is finished, adding A0 in batches; after the reaction is completed, the reaction returns to normal temperature for 2 to 4 hours, the reaction solution is slowly dripped into ice water after the reaction is completed, and after the solid is separated out, the solution is filtered and leached to be neutral (pH is approximately equal to 6), the solid is dissolved by solvent, and saturated NaHCO is used 3 The organic phase is washed with solution, dried and concentrated to obtain A1.
According to one embodiment of the invention, in step S1, A0 is added in portions; after the addition, the reaction is carried out for 2 to 4 hours at normal temperature, specifically, the reaction time is selected from any one time or a section formed by any two times: 2h, 2.1h, 2.2h, 2.3h, 2.4h, 2.5h, 2.6h, 2.7h, 2.8h, 2.9h, 3.0h, 3.1h, 3.2h, 3.3h, 3.4h, 3.5h, 3.6h, 3.7h, 3.8h, 3.9h and 4.0h.
According to one embodiment of the invention, in step S1, the water is rinsed to a partial neutrality (ph≡6), where neutrality should be regarded as the presence of an adjustable pH interval, i.e. a pH value that the skilled person can choose from among this pH interval depending on the actual situation.
According to an embodiment of the present invention, the pH is at least selected from the pH range consisting of any one or both of the following pH values: 5.5, 5.6, 5.8, 6.0, 6.2, 6.4, 6.6, 6.8 and 7.0.
According to an embodiment of the present invention, in step S2, the method further comprises the steps of: mixing A1 with ethylene potassium trifluoroborate, and reacting to obtain A2.
According to an embodiment of the present invention, in step S2, the method further comprises the steps of: mixing A1, 4-dioxane, ethylene potassium trifluoroborate, TEA, water, dppf, pd (OAc) 2 Argon substitution and heating reaction overnight; extracting, drying, concentrating and purifying to obtain A2.
According to an embodiment of the present invention, in step S3, the method further comprises the steps of: mixing A2 with reduced iron powder and solvent, cooling to about 20 ℃, adding glacial acetic acid and concentrated hydrochloric acid, and reacting for 5-8h; cooling after reaction, regulating pH to 7-8, filtering, leaching, extracting, separating liquid, drying, concentrating and purifying to obtain A3.
According to one embodiment of the present invention, in step S3, glacial acetic acid and concentrated hydrochloric acid are added to react for 5 to 8 hours, specifically, the reaction time is selected from any one time or any two time intervals: 5.5h, 6.0h, 6.5h, 7.0h, 7.5h and 8.0h.
According to one embodiment of the present invention, step S4 further comprises a preparation method of A3-1, comprising the steps of: mixing 1, 4-diazabicyclo [2.2.2] octane-1, 4-diimmonium-1, 4-disulfonic acid and magnesium isopropenyl bromide, reacting, and adding a compound containing sulfonyl and halogen groups to obtain A3-1.
According to an embodiment of the present invention, in step S4, the method further comprises the steps of: mixing DABSO and THF, cooling to-50 to-40 ℃, adding magnesium isopropenyl bromide, controlling the temperature to-50 to-40 ℃, and reacting for 2-3h; cooling, dripping dilute hydrochloric acid for quenching, extracting, drying and concentrating; adding a solvent into the concentrated solution, carrying out water bath, dropwise adding a compound containing sulfonyl and halogen groups, reacting for 2 hours after the dropwise adding, extracting, drying and concentrating; adding solvent and A3 into the concentrated solution, water-bathing, dripping pyridine, and reacting overnight after dripping, wherein TLC monitoring reaction is advanced by one third; pouring the reaction liquid into a solvent, regulating the pH value to 4-5, extracting, drying, concentrating and purifying to obtain A4.
According to one embodiment of the present invention, in step S4, DABSO and THF are mixed and cooled to-50 to-40 ℃, specifically, the cooled temperature is selected from any one temperature or a temperature interval formed by any two temperatures: -50 ℃, -48 ℃, -46 ℃, -44 ℃, -42 ℃ and-40 ℃.
According to one embodiment of the present invention, in step S4, magnesium isopropenyl bromide is added, the temperature is controlled between-50 ℃ and-40 ℃, specifically, the temperature is selected from any one temperature or a temperature interval formed by any two temperatures: -50 ℃, -48 ℃, -46 ℃, -44 ℃, -42 ℃ and-40 ℃.
According to an embodiment of the present invention, in step S5, the method further comprises the steps of: under the protective atmosphere, mixing A4 with Grubbs second generation catalyst, heating to 40-50 ℃, and carrying out catalytic reaction to obtain A5.
According to one embodiment of the present invention, in step S5, mixing A4 with Grubbs second generation catalyst, heating to 40-50 ℃, specifically, the temperature after heating is selected from any one temperature or any two temperature ranges: 42 ℃, 44 ℃, 46 ℃, 48 ℃ and 50 ℃.
According to an embodiment of the present invention, in step S5, the method further comprises the steps of: mixing A4 with solvent, and heating to 40-60 deg.C under the protection of argon; slowly dripping a diluent of Grubbs 2nd catalyst, reacting for 2-4h after dripping, monitoring the residual 10% of the raw materials by LCMS, adding argon for replacement, reacting for 1.5-2h, monitoring the residual 2.1% of the raw materials by LCMS, and stopping the reaction; concentrating, pulping, and filtering to obtain A5.
According to one embodiment of the present invention, in step S5, A4 is mixed with a solvent, under the protection of argon, and the temperature is raised to 40-60 ℃, specifically, the temperature after the temperature is raised is selected from any one temperature or a temperature interval formed by any two temperatures: 42 ℃, 44 ℃, 46 ℃, 48 ℃, 50 ℃, 52 ℃, 54 ℃, 56 ℃, 58 ℃ and 60 ℃.
According to an embodiment of the present invention, in step S6, the method further comprises the steps of: mixing A5, carbonate-containing compound, containingR 2 And (3) reacting to obtain A6.
According to an embodiment of the present invention, in step S6, the method further comprises the steps of: mixing A5, carbonate-containing compound and solvent, and dropwise adding R under the protection of argon 2 After the dripping is finished, reacting for 4-6 hours, and completely reacting; extracting, drying, concentrating and purifying to obtain A6.
According to an embodiment of the present invention, in step S7, the method further comprises the steps of: mixing A6 and LiAlH at-10 to-15 DEG C 4 And (3) carrying out reaction to obtain A7.
According to one embodiment of the invention, in step S7, A6 is mixed with LiAlH at-10 to-15 DEG C 4 Specifically, the temperature may be selected and determined according to the actual situation. More specifically, the temperature is selected from a temperature interval consisting of any one or any two of the following temperatures: -10 ℃, -11 ℃, -12 ℃, -13 ℃, -14 ℃, -15 ℃.
According to an embodiment of the present invention, in step S7, the method further comprises the steps of: mixing A6 with solvent, argon protecting, cooling to-10 to-15 deg.C, and adding LiAlH in batches 4 Reacting for 2.5-5h after finishing adding; the reaction is complete; quenching, filtering, washing, concentrating and purifying to obtain 3A7.
According to one embodiment of the present invention, in step S7, A6 and a solvent are mixed, and the mixture is cooled to-10 to-15 ℃ under the protection of argon, and specifically, the temperature is selected and determined according to practical situations. More specifically, the temperature is selected from a temperature interval consisting of any one or any two of the following temperatures: -10 ℃, -11 ℃, -12 ℃, -13 ℃, -14 ℃ and-15 ℃.
According to one embodiment of the invention, in step S7, liAlH is added in portions 4 The reaction is carried out for 2.5 to 5 hours after the addition, specifically, the reaction time is selected from any one time or a section formed by any two times: 2.5h, 2.8h, 3.1h, 3.4h, 3.7h, 4.0h, 4.3h, 4.6h and 5.0h.
According to an embodiment of the present invention, in step S8, the method further comprises the steps of: mixing A7, an initiator, imidazole and iodine simple substance, and reacting to obtain the PARP1 inhibitor intermediate.
According to an embodiment of the present invention, in step S8, the method further comprises the steps of: mixing A7, initiator, imidazole and solvent, cooling to about 0deg.C, and dripping I 2 After dripping, reacting for 1-2h; the reaction is complete; adding sodium thiosulfate solid, extracting, drying, concentrating and purifying to obtain the PARP1 inhibitor intermediate.
According to one embodiment of the present invention, in step S8, I is added dropwise 2 After the dripping is finished, reacting for 1-2h, wherein the reaction time is selected from any one time or a section formed by any two times: 1.2h, 1.4h, 1.6h, 1.8h and 2.0h.
According to one embodiment of the invention, the addition of sodium thiosulfate solids can eliminate excess elemental iodine.
According to one embodiment of the present invention, a process for preparing the PARP1 inhibitor intermediate is routed as follows:
wherein, THF (tetrahydrofuran), DCM (dichloromethane), DMF (N, N-dimethylformamide), TEA (triethylamine), H 2 O (water), dioxane (1, 4-dioxane), meOH (acetic acid) as solvents, and in the present invention, the solvents may be replaced with common solvents as needed; wherein dppf (bis-diphenylphosphino ferrocene), pd (OAc) 2 As the catalyst, in the present invention, a suitable catalyst such as palladium metal complex such as tetraphenylphosphine palladium may be substituted as needed. Wherein PPh3 (triphenylphosphine) is an initiator, and in the present invention, the initiator may be replaced with a conventional initiator as required.
According to one embodiment of the present invention, in the process for preparing the PARP1 inhibitor intermediate, pyridine is added mainly as an acid binding agent.
According to an embodiment of the present invention, in the process for preparing the PARP1 inhibitor intermediate, pyridine may be replaced with other compounds having similar functions according to the actual situation, for example, pyridine may be replaced with at least one of triethylamine and diisopropylethylamine.
According to one embodiment of the present invention, in the process for preparing the PARP1 inhibitor intermediate, potassium carbonate is added mainly as an acid binding agent.
According to an embodiment of the present invention, in the method for preparing the PARP1 inhibitor intermediate, potassium carbonate may be replaced with an organic base or an inorganic base according to actual conditions. As one embodiment, the inorganic base may be sodium carbonate.
According to one embodiment of the present invention, a process for preparing the PARP1 inhibitor intermediate is routed as follows:
according to one embodiment of the invention, the process for preparing A3-3 is carried out as follows:
in another aspect, the invention also relates to the use of the PARP1 inhibitor intermediate for the preparation of PARP1 inhibitors. Including PARP1 inhibitor intermediates as described in the example of aspect 1 above. The application adopts all the technical schemes of the PARP1 inhibitor intermediate, so that the PARP1 inhibitor has at least all the beneficial effects brought by the technical schemes of the embodiment.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to fall within the scope of the invention.
In an embodiment, the term "alkyl" refers to a saturated hydrocarbon containing primary (positive) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof. Phrases containing this term, e.g., "C 1-8 Alkyl "refers to an alkyl group containing 1 to 8 carbon atoms. Suitable examples include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH), 2-propyl (i-Pr, i-propyl, -CH (CH) 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH) 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl (i-Bu, i-butyl, -CH) 2 CH(CH 3 ) 2 ) 2-butyl (s-Bu, s-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH) 3 ) 3), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) 1-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2Amyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 and octyl (- (CH) 2 ) 7 CH 3 )。
In an embodiment, "alkenyl" refers to a hydrocarbon comprising a normal carbon atom, a secondary carbon atom, a tertiary carbon atom, or a cyclic carbon atom having at least one unsaturated site, i.e., a carbon-carbon sp2 double bond. Phrases containing this term, e.g., "C 2-8 Alkenyl "refers to alkenyl groups containing 2 to 8 carbon atoms. Suitable examples include, but are not limited to: vinyl (-ch=ch) 2 ) Propenyl (-CH) 2 CH=CH 2 ) Cyclopentenyl (-C) 5 H 7 ) And 5-hexenyl (-CH) 2 CH 2 CH 2 CH 2 CH=CH 2 )。
In embodiments, halogen "or" halo "refers to F, cl, br or I.
In embodiments, "halo substituted" means that an optional amount of H at any optional position on the corresponding group is substituted with halo, e.g., fluoromethyl, including monofluoromethyl, difluoromethyl, trifluoromethyl.
The reagents, methods and apparatus employed in the present invention, unless otherwise specified, are all conventional in the art.
Examples
A PARP1 inhibitor intermediate comprising the structure:
the preparation of the PARP1 inhibitor intermediate comprises the following steps:
specifically, the preparation of the PARP1 inhibitor intermediate comprises the following steps:
step 1
Taking concentrated HNO at room temperature 3 (65%, 133.5g,13.7mol,3.2 eq) in a 1L three-necked flask, cooling the ice-water bath to 5 ℃ C., slowly adding concentrated H dropwise 2 SO 4 (98.3%, 213g,2.14mol,5.0 eq) after the addition, A0 (99.58 g,0.42mol,1.0 eq) was added in 5 portions; after the addition, the reaction is carried out for 2 hours at normal temperature, and TLC monitoring shows that the reaction is finished; slowly dripping the reaction solution into 1.5L ice water, precipitating a large amount of solid, filtering, leaching with water to neutrality (pH is about 6), dissolving the solid with 300ml EA, and dissolving the solid with saturated NaHCO 3 The EA phase was washed with solution, and the organic phase was dried and concentrated to give 118.5g of pale yellow solid A1 in 99.75% yield.
Wherein, the characterization data of A1 is as follows:
1 H-NMR(500MHz,CDCl 3 )δ8.854-8.53(d,J=6.6Hz,1H),7.59-7.58(d,J=9.3Hz,1H),3.98(s,3H)。
step 2
A1 (116.64 g, 0.319 mol,1 eq) was added to a 5L three-necked flask at room temperature followed by 1, 4-dioxane (2.1L), ethylene potassium trifluoroborate (62.72 g, 0.268 mol,1.1 eq), TEA (63.5 g, 0.6278 mol,1.5 eq), water (1.4L), dppf (35.41 g,0.0638mol,0.15 eq), pd (OAc) 2 (14.7 g,0.0645mol,0.15 eq), argon substitution, and heating to 80 ℃ for reaction overnight; the TCL monitors the completion of the reaction; 1L of water and 1L of EA are added for extraction and separation, the aqueous phase is extracted for 3 times by EA, the organic phases are combined, dried, concentrated and stirred by silica gel, and the mixture is purified by column chromatography to obtain 75.18g of yellow solid A2 with the yield of 79.6 percent.
Wherein, the characterization data of A2 is as follows:
1 H NMR(500MHz,CDCl 3 )δ8.62-8.61(d,J=6.5Hz,1H),7.39-7.37(d,J=10.9Hz,1H),7.26–7.20(dd,1H),5.87-5.84(d,J=17.2Hz,1H),5.66-5.64(d,J=11.0Hz,1H),3.98(s,3H)。
step 3
A2 (63.3 g,0.281mol,1.0 eq), reduced iron powder (78.5 g,1.405mol,5.0 eq) and methanol (1.35L, 25V) are added into a 5L three-necked flask in sequence at room temperature, the temperature is reduced to about 20 ℃, glacial acetic acid (158.25 ml, 2.5V) is added, concentrated hydrochloric acid (30%, 32ml, 0.5V) is slowly added dropwise, and RT reaction is carried out for 5h; TLC monitoring reaction is complete; cooling in ice water bath, slowly adding NaHCO 3 The solid is adjusted to pH 7-8, filtered, the filter cake is leached by EA, saturated saline water is added into the filtrate to extract and separate liquid, and the organic phase is dried, concentrated, mixed with silica gel and purified by column chromatography to obtain 54.85g yellow solid A3 with the yield of 90.3 percent.
Wherein, the characterization data of A3 is as follows:
m/z 196(M+H);
1 H NMR(500MHz,CDCl 3 )δ7.23-7.22(d,J=6.2Hz,1H),7.07-7.05(d,J=11.5Hz,1H),6.74-6.68(dd,J=17.4,11.1Hz,1H),5.74-5.71(d,J=17.4Hz,1H),5.47-5.45(d,J=11.1Hz,1H),3.90(s,3H)。
step 4
DABSO (33.6 g,0.14mol,1.0 eq) was added to a 2L three-necked flask at room temperature, THF (340 ml, 10V) was added, the temperature was reduced to-40℃and magnesium isopropenyl bromide (0.5M, 700ml,0.35mol,2.5 eq) was added dropwise, the temperature was controlled between-50 and-40℃and the reaction was resumed for 2h after the completion of the dropwise addition; cooling, dripping dilute hydrochloric acid (300 ml) for quenching, extracting with MTBE for 3 times, drying, concentrating; DCM (340 ml, 10V) was added to the concentrate, water-bath, sulfonyl chloride (45.3 g,0.335mol,2.4 eq) was added dropwise, reacted for 2h after the addition, then the reaction was added dropwise to ice water (300 ml), extracted 3 times with MTBE, dried, concentrated; DCM (340 ml, 10V) and A3 (27.3 g,0.14mol,1.0 eq) were added to the concentrate, water-bath, pyridine (33.2 g,0.42mol,3.0 eq) was added dropwise, after the addition, the reaction was allowed to proceed overnight, and TLC monitoring the reaction was one third advanced; the reaction solution was poured into 300ml of water, the pH was adjusted to 4 to 5 with dilute hydrochloric acid, extracted 3 times with DCM, dried, concentrated, stirred with silica gel and purified by column chromatography to give 8.2g of orange solid A4 with a yield of 19.6%.
Wherein, the characterization data of A4 is as follows:
m/z 300(M+H);
1 H NMR(500MHz,CDCl 3 )δ7.89-7.88(d,J=6.5Hz,1H),7.27–7.25(d,1H),6.98 -6.92(dd,J=17.3,11.1Hz,1H),6.44(s,1H),6.02(s,1H),5.84-5.80(d,J=17.4Hz,1H),5.68(s,1H),5.61-5.58(d,J=11.0Hz,1H),3.92(s,3H),2.13(s,3H)。
step 5
A4 (8.2 g,0.0274mol,1.0 eq) was added to a 2L single-necked flask at room temperature, DCM (1.2L, 150 v) was added, under argon protection, and the temperature was raised to 40 ℃; weighing Grubbs 2nd catalyst (1.64 g, 20%wt) and dissolving in 70ml DCM, slowly dripping a diluent of the Grubbs 2nd catalyst, reacting for 2 hours after dripping, monitoring the residual 10% of the raw material by LCMS, supplementing argon and replacing, reacting for 1.5 hours again, monitoring the residual 2.1% of the raw material by LCMS, and stopping the reaction; concentrated, slurried with DCM (10 ml) and n-heptane (50 ml) and filtered to give 6g of white solid A5 in 80.64%.
Wherein, the characterization data of A5 is as follows:
m/z 294(M+Na);
1 H NMR(500MHz,CDCl 3 )δ7.64-7.62(d,J=5.9Hz,1H),7.14-7.12(d,J=10.2Hz,1H),6.88(s,1H),3.96(s,3H),2.40(s,3H)。
step 6
A5 (5.8 g,0.0213mol,1.0 eq), potassium carbonate (5.91 g,0.0427mol,2.0 eq) and DMF (30 ml, 5V) were added to a 100ml single-necked flask at room temperature, under the protection of argon, p-methoxybenzyl chloride (3.68 g,0.0234mol,1.1 eq) was added dropwise, after the addition, the reaction was completed by TLC monitoring; the reaction solution was poured into 150ml of water, 100ml of EA was added to extract, the aqueous phase was extracted 2 times with EA, and the organic phases were combined, dried, concentrated, stirred with silica gel and purified by column chromatography to give 6g of white solid A6 in a yield of 71.145.
Wherein, the characterization data of A6 is as follows:
m/z 414(M+Na);
1 H NMR(500MHz,DMSO)δ7.84-7.83(d,J=6.0Hz,1H),7.55-7.53(d,J=10.9Hz,1H),7.29(s,1H),7.18-7.16(d,J=8.5Hz,2H),6.88-6.86(d,J=8.5Hz,2H),5.14(s,2H),3.86(s,3H),3.71(s,3H),2.34(s,3H)。
step 7
A6 (5.6 g,0.0143mol,1.0 eq) and THF (60 ml, 10V) were added at room temperature into a 100ml three-necked flask, cooled to-10℃under argon, and added in portions with LiAlH 4 (2.18 g,0.0572mol,4.0 eq) and 2.5h after addition; TLC monitoring reaction is complete; slowly dropwise adding 10ml of methanol for quenching, filtering with kieselguhr, washing a filter cake with EA, concentrating, stirring with silica gel, and purifying by column chromatography to obtain 3.3g of yellow solid A7 with the yield of 63.47%.
Wherein, the characterization data of A7 is as follows:
m/z 386(M+Na);
1 H NMR(500MHz,CDCl 3 )δ7.30-7.29(d,J=6.1Hz,1H),7.20-7.18(d,J=8.5Hz,2H),6.98-6.95(d,J=9.7Hz,1H),6.81-6.79(d,J=8.6Hz,2H),6.77(s,1H),5.05(s,2H),4.71(s,2H),3.76(s,3H),2.36(s,3H)。
step 8
A7 (2.0 g,0.0055mol,1.0 eq) and PPh were added at room temperature 3 (2.23 g,0.0083mol,1.5 eq), imidazole (0.75 g,0.01 mol,2.0 eq) and DCM (50 ml, 25V) were added to a 250ml three-necked flask, cooled to 0℃and weighed I 2 (2.1 g,0.0083mol,1.5 eq) was dissolved in 50ml DCM and I was slowly added dropwise 2 After dripping, reacting for 1h; TLC monitoring reaction is complete; the reaction solution was poured into 150ml of water, a small amount of sodium thiosulfate solid was added, and stirred until the organic phase became pale yellow in color, extracted 3 times with DCM, dried, concentrated, stirred with silica gel, and purified by column chromatography to give 2.5g of yellow solid A8 in a yield of 95.98%.
Wherein, the characterization data of A8 is as follows:
m/z 496(M+Na);
1 H NMR(500MHz,CDCl 3 )δ7.19-7.17(d,J=8.5Hz,2H),7.13-7.11(d,J=6.4Hz,1H),6.95-6.93(d,J=9.4Hz,1H),6.83-6.81(d,J=8.6Hz,2H),6.74(s,1H),5.02(s,2H),4.34(s,2H),3.76(d,J=7.5Hz,3H),2.35(s,3H)。
the foregoing is merely exemplary embodiments of the present invention and are not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention or direct or indirect application in the relevant art are intended to be included in the scope of the present invention.
Claims (10)
1. A PARP1 inhibitor intermediate, characterized in that: the structure comprises the following steps:
wherein R is 1 Selected from the group consisting of-Cl, -Br, -F, -I, -NO 2 and-NH 2 One of the following;
wherein R is 2 Selected from benzyl, allyl, acetyl and (Boc) 2 At least one of O;
wherein R is 3 One selected from-I, -Cl and-Br;
wherein R is 4 Selected from C 1-8 Alkyl group,C 2-8 Alkenyl, halogen substituted C 1-8 At least one of an alkyl group, a nitrile group, a phenyl group, and a sulfonyl group.
2. A process for preparing a PARP1 inhibitor intermediate according to claim 1, characterized in that: the method comprises the following steps:
s1, taking A0 as a starting material, and obtaining A1 through reaction;
S2A 1 is subjected to substitution reaction to obtain A2;
s3, mixing A2 with a first reducing agent, and reacting to obtain A3;
s4, mixing A3 with A3-1, and reacting to obtain A4;
s5, mixing A4 with Grubbs second generation catalyst, and carrying out catalytic reaction to obtain A5;
s6 mixing A5 with a composition containing R 2 Reacting the compounds of (2) to obtain A6;
s7, mixing A6 with a second reducing agent, and reacting to obtain A7;
s8, mixing A7 with iodine simple substance, and reacting to obtain the intermediate of the PARP1 inhibitor;
wherein R is 3 Selected from one of-Cl, -Br, -F and-I.
3. The method according to claim 2, characterized in that: in step S1, the method further includes the following steps: mixed concentrated HNO 3 Concentrated H 2 SO 4 And A0, obtaining A1 through reaction.
4. The method according to claim 2, characterized in that: in step S2, the method further includes the following steps: mixing A1 with ethylene potassium trifluoroborate, and reacting to obtain A2.
5. The method according to claim 2, characterized in that: in the step S4, the preparation method of A3-1 is also included, and comprises the following steps: mixing 1, 4-diazabicyclo [2.2.2] octane-1, 4-diimmonium-1, 4-disulfonic acid and magnesium isopropenyl bromide, reacting, and adding a compound containing sulfonyl and halogen groups to obtain A3-1.
6. The method according to claim 2, characterized in that: in step S5, the method further includes the following steps: under the protective atmosphere, mixing A4 with Grubbs second generation catalyst, heating to 40-50 ℃, and carrying out catalytic reaction to obtain A5.
7. The method according to claim 2, characterized in that: in step S6, the method further includes the steps of: mixing A5, carbonate-containing compound, R-containing 2 And (3) reacting to obtain A6.
8. The method according to claim 2, characterized in that: in step S7, the method further includes the steps of: mixing A6 and LiAlH at-10 to-15 DEG C 4 And (3) carrying out reaction to obtain A7.
9. The method according to claim 2, characterized in that: in step S8, the method further includes the steps of: mixing A7, an initiator, imidazole and iodine simple substance, and reacting to obtain the PARP1 inhibitor intermediate.
10. Use of a PARP1 inhibitor intermediate according to claim 1 for the preparation of a PARP1 inhibitor.
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