CN115636866A - Method for synthesizing bridged ring compound and intermediate thereof - Google Patents
Method for synthesizing bridged ring compound and intermediate thereof Download PDFInfo
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- CN115636866A CN115636866A CN202211330629.3A CN202211330629A CN115636866A CN 115636866 A CN115636866 A CN 115636866A CN 202211330629 A CN202211330629 A CN 202211330629A CN 115636866 A CN115636866 A CN 115636866A
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Abstract
The invention discloses a synthesis method of a bridged ring compound and an intermediate thereof. The invention provides a synthesis method of a bridged ring compound, which comprises the following steps of carrying out amidation reaction on a compound I and a compound SM-3 in a solvent in the presence of alkali to obtain a compound II; wherein R is + Is Na + 、K + Or Li + . The synthesis method of the bridged ring compound provided by the invention has one or more of the following advantages of easily available raw materials, high conversion rate, high product purity, high intermediate stability and simple and convenient post-treatment.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a method for synthesizing a bridged ring compound and an intermediate thereof.
Background
Nemadevir (Nirmatrelvir) is an inhibitor of 3CL pro, can be directly combined with the active site of the 3CL pro of the new coronavirus to inhibit the activity of the 3CL pro of the new coronavirus, thereby preventing the replication of the virus. It is an important drug in the compound antiviral drug Paxlovid (Paklovine) which is developed by the company Hurrill and consists of 2 kinds of tablets. The chemical structural formula of the important intermediate of the nemadefovir is shown as the following formula:
the synthetic process of the nemadevir is relatively fixed, and the synthetic route is mainly disclosed in the original patent WO2021/250648Al, and is specifically shown as the following formula:
the method comprises the steps of taking L-tert-leucine protected by Boc as a raw material, condensing with a cyclopropyl proline intermediate 1 in the presence of HATU to obtain a condensation product compound 3, hydrolyzing methyl ester to obtain an intermediate acid compound 4, removing a Boc protecting group to obtain an intermediate amino acid hydrochloride 5, and reacting with ethyl trifluoroacetate to obtain a compound 6, wherein the reaction is carried out for 4 steps. The reaction route is long, the yield is low, a large amount of tetrahydrofuran is needed when the compound 4 is synthesized, a large amount of hydrogen chloride 1,4-dioxane solution is needed when the compound 5 is synthesized, a large amount of waste liquid is generated by post-treatment, and the reaction process has poor controllability, unstable quality and great pollution to the environment.
The synthetic routes in patents CN114031543A and CN114605492A are shown as follows:
the reaction types in the two patent documents are condensation reactions, one is condensation agent N' N-carbonyl diimidazole, the other is active ester, the two synthetic methods are one-pot methods, the intermediate state and the active ester cannot be purified, the subsequent product purification pressure is large, and the final purification cost pressure is also large.
Disclosure of Invention
The invention aims to solve the technical problems of poor stability, difficult purification or higher purification cost of an intermediate in the prior art, and provides a method for synthesizing a bridged ring compound and the intermediate thereof. The synthesis method of the bridged ring compound provided by the invention has one or more of the following advantages of easily available raw materials, high conversion rate, high product purity, high intermediate stability and simple and convenient post-treatment.
The invention provides a preparation method of a compound II, which comprises the following steps of carrying out amidation reaction on a compound I and a compound SM-3 in a solvent in the presence of alkali to obtain the compound II;
wherein R is + Is Na + 、K + Or Li + 。
In the amidation reaction, the R + Preferably Na + 。
In the amidation reaction, the solvent is a solvent conventional in the art, and the solvent may be an amide solvent, preferably DMF and/or DMAC, and more preferably DMF.
In the amidation reaction, the mass ratio of the solvent to the compound I may be 1:1 to 5:1, preferably 2:1 to 4:1, and more preferably 2.85.
In the amidation reaction, the base can be an organic base and/or an inorganic base, and is preferably an organic base; the organic base is preferably triethylamine and/or DIPEA, and more preferably triethylamine; the inorganic base is preferably one or more of potassium carbonate, sodium hydroxide and potassium hydroxide, and more preferably sodium hydroxide.
In the amidation reaction, the molar ratio of the alkali to the compound I can be 1:1-3:1, preferably 2:1.
In the amidation reaction, the molar ratio of the compound SM-3 to the compound I can be 0.95 to 1.2, and is preferably 1:1.
In the amidation reaction, the reaction temperature of the amidation reaction may be-5 ℃ to 40 ℃, preferably 0 ℃ to 20 ℃, most preferably 5 ℃ to 15 ℃, for example 10 ℃.
The raw materials in the amidation reaction consist of the solvent, the base, the compound I and the compound SM-3.
In a certain embodiment, in the amidation reaction, the mass ratio of DMF to compound I is 2.85, the molar ratio of triethylamine to compound I is 2:1, and the molar ratio of compound SM-3 to compound I is 1:1.
The preparation method of the compound II further comprises the following steps that in a solvent, a compound SM-1 and N-hydroxysuccinimide undergo a condensation reaction shown in the following formula under the action of a condensing agent to obtain the compound I,
the condensation reaction in the present invention means a reaction in which two or more molecules of an organic compound emit simple molecules such as water to form a larger molecule, and the condensing agent is a reagent capable of initiating the condensation reaction.
In the condensation reaction, the condensing agent is a condensing agent conventional in the art, preferably, the condensing agent is one or more selected from EDCI, DCC, DIC and HOBT, and more preferably EDCI.
In the condensation reaction, the molar ratio of the condensing agent to the compound SM-1 can be 1:1-2:1, and is preferably 1.2.
In the condensation reaction, the solvent is a solvent which is conventional in the art, preferably an amide solvent and/or a nitrile solvent, and more preferably an amide solvent; the amide solvent is preferably DMF and/or DMAC, more preferably DMF; the nitrile solvent is preferably acetonitrile.
In the condensation reaction, the mass ratio of the solvent to the compound SM-1 can be 2:1-5:1, and is preferably 3.5.
In the condensation reaction, the molar ratio of the N-hydroxysuccinimide to the compound SM-1 can be 1:1-3:1, and is preferably 1.3.
In the condensation reaction, the reaction temperature of the condensation reaction can be 10-50 ℃, preferably 20-30 ℃, and most preferably 25 ℃.
The raw materials in the condensation reaction comprise the solvent, the compound SM-1, the N-hydroxysuccinimide and the condensing agent.
In one embodiment, in the condensation reaction, the mass ratio of DMF to compound SM-1 is 3.5, the molar ratio of EDCI to compound SM-1 is 1.2.
In the condensation reaction, the method also comprises the following post-treatment steps of crystallization, pulping, rinsing and drying after the condensation reaction is finished.
In the condensation reaction, the crystallization solvent can be water; the mass ratio of the crystallization solvent to the compound SM-1 can be 3.5.
In the condensation reaction, the temperature of crystallization can be 10-50 ℃, preferably 20-30 ℃ and most preferably 25 ℃.
In the condensation reaction, the pulping solvent can be water; the mass ratio of the slurried solvent to the compound SM-1 can be 1:1-10, preferably 5:1.
In the condensation reaction, the solvent for rinsing can be water; the mass ratio of the compound SM-1 in the rinsing solvent can be 1:1-5:1, and is preferably 1:1.
In the condensation reaction, the number of rinsing may be 1 to 3, preferably 1.
In the condensation reaction, the drying temperature can be 40-60 ℃, and preferably 50 ℃.
The invention also provides a preparation method of the compound II', which comprises the following steps,
(1) Preparing a compound II according to the preparation method of the compound II;
(2) Reacting the compound II obtained in the step (1) with acid to obtain a compound II',
in the step (1), the amidation reaction further comprises a dilution step after the amidation reaction is completed, and the diluted solvent is preferably water.
In the step (2), the acid can be an inorganic acid, preferably hydrochloric acid; the concentration of HCl in the hydrochloric acid is preferably 1N to 3N, and more preferably 2N.
In the step (2), after the reaction is finished, the pH value of the reaction system of the reaction can be more than or equal to 3 and less than or equal to 7, and preferably, the pH value of the reaction system is more than or equal to 4 and less than or equal to 6.
The raw materials in the preparation method of the compound II' comprise the solvent, the base, the compound I, the compound SM-3 and the acid.
In a certain embodiment, in the preparation method of the compound II', a mass ratio of the DMF to the compound I is 2.85.
The preparation method of the compound II' further comprises the following post-treatment steps: sequentially comprises extraction, washing, drying, concentration, crystallization, rinsing and drying.
The solvent for extraction can be an ester solvent, preferably isopropyl hypoacetate.
The number of extraction may be 1 to 5, preferably 2.
The solvent for washing may be a sodium chloride solution, preferably a saturated sodium chloride solution.
The number of washing may be 1 to 5, preferably 1.
The drying agent can be anhydrous sodium sulfate.
The concentration temperature can be 40-60 ℃, and preferably 50 ℃.
The temperature of the crystallization can be-5 ℃ to 5 ℃, and is preferably 0 ℃.
The solvent for rinsing can be an ester solvent, and isopropyl hypoacetate is preferred.
The drying temperature can be 40-60 ℃, and preferably 50 ℃.
The invention also provides a preparation method of the compound I, which comprises the following steps: in a solvent, a compound SM-1 and N-hydroxysuccinimide undergo a condensation reaction shown in the specification under the action of a condensing agent to obtain a compound I,
in the preparation method of the compound I, the reaction steps and the reaction conditions are as described above.
The invention provides a compound I, which is a compound I,
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the synthesis method of the bridged ring compound provided by the invention has one or more of the following advantages of easily available raw materials, high conversion rate, high product purity, high intermediate stability and simple and convenient post-treatment.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the invention thereto. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1: synthesis of Compound I
Controlling the temperature to be about 25 ℃, adding 101.30g of EDCI and 354.00g of DMF into a reaction bottle, adding 100.00g of compound SM-1 under the stirring state, and clarifying the reaction system; after the reaction is carried out for 1h under the condition of heat preservation, 66.10g of N-hydroxysuccinimide are added into a reaction bottle in batches, the reaction is carried out for 1h under the condition of heat preservation, 1050.00g of water is dripped into the reaction system, when half of the water is dripped, a large amount of white solids are separated out from the system, the dripping is continued to be completed, the heat preservation and crystallization are carried out for 1h, the filtration is carried out, and a filter cake is pulped once by 500.00g of water; filtration, rinsing the filter cake once with 100g of water and drying to constant weight at 50 ℃ gave compound I as a white solid, 130.28g, yield: 91.28% and HPLC purity 98.73%.
1H NMR(400MHz,DMSO-d6)，δ10.02(S,1H),δ4.68(S,1H),δ2.60(M,4H)，δ1.11(S,9H)；MS(ESI)(M/Z):[M+Na]+＝347.1.
Example 2: synthesis of Compounds II-1 and II
Controlling the temperature to be about 10 ℃, adding 24.00g of DMF, 4.60g of compound SM-3-1 (sodium salt) and 8.43g of compound I into a 250ml reaction bottle, stirring and dissolving, dropwise adding 5.26g of triethylamine, keeping the temperature and stirring for 21 hours, adding 80.00g of water system into the reaction system, clarifying, and adjusting the pH of the system to 4-6 by using 2N hydrochloric acid; extracting twice with 50.00 g/isopropyl acetate, merging organic phases, washing once with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating to 50.00g at 50 ℃, cooling to 0 ℃ for crystallization, filtering, rinsing filter cakes with 5.00g isopropyl acetate, and drying under reduced pressure at 50 ℃ for 12-18h to obtain 8.55g white solid with the yield of 90% and the purity of 99.5%.
1H NMR(400MHz,DMSO-d6),δ12.73(s,1H),δ9.43(d,1H),δ4.42(d,1H),δ4.13(s,1H),δ3.83(d,1H),δ3.70(d,1H),δ1.51(d,1H),δ1.41(d,1H),δ0.99(s,6H),δ0.98(s,9H)；MS(ESI)(M/Z):[M+Na]+＝387。
Claims (10)
1. A preparation method of a compound II comprises the following steps of carrying out amidation reaction on a compound I and a compound SM-3 in a solvent in the presence of a base to obtain a compound II;
wherein R is + Is Na + 、K + Or Li + 。
2. A process for the preparation of compounds II according to claim 1, characterized in that it satisfies one or more of the following conditions,
(1) Said R + Is Na + ；
(2) The solvent is an amide solvent, preferably DMF and/or DMAC, and more preferably DMF;
(3) The mass ratio of the solvent to the compound I is 1:1-5:1, preferably 2:1-4:1, and more preferably 2.85;
(4) The alkali is organic alkali and/or inorganic alkali, preferably organic alkali; the organic base is preferably triethylamine and/or DIPEA, and more preferably triethylamine; the inorganic base is preferably one or more of potassium carbonate, sodium hydroxide and potassium hydroxide, and is more preferably sodium hydroxide;
(5) The molar ratio of the alkali to the compound I is 1:1-3:1, preferably 2:1;
(6) The molar ratio of the compound SM-3 to the compound I is 0.95-1.2, preferably 1:1;
(7) The reaction temperature of the amidation reaction is-5 ℃ to 40 ℃, preferably 0 ℃ to 20 ℃, most preferably 5 ℃ to 15 ℃, for example 10 ℃;
(8) The raw material in the amidation reaction is composed of the solvent, the base, the compound I and the compound SM-3.
3. The method according to claim 2, wherein the mass ratio of DMF to compound I is 2.85:1, the molar ratio of triethylamine to compound I is 2:1, and the molar ratio of compound SM-3 to compound I is 1:1.
4. The process for preparing the compound II according to any one of claims 1 to 3, further comprising the step of subjecting the compound SM-1 and N-hydroxysuccinimide to a condensation reaction with a condensing agent in a solvent to obtain the compound I,
5. a process for the preparation of compounds II according to claim 4, characterized in that it satisfies one or more of the following conditions,
(1) In the condensation reaction, the condensing agent is selected from one or more of EDCI, DCC, DIC and HOBT, preferably EDCI;
(2) In the condensation reaction, the molar ratio of the condensing agent to the compound SM-1 is 1:1-2:1, preferably 1.2;
(3) In the condensation reaction, the solvent is an amide solvent and/or a nitrile solvent, preferably an amide solvent; the amide solvent is preferably DMF and/or DMAC, more preferably DMF; the nitrile solvent is preferably acetonitrile;
(4) In the condensation reaction, the mass ratio of the solvent to the compound SM-1 is 2:1-5:1, preferably 3.5;
(5) In the condensation reaction, the molar ratio of the N-hydroxysuccinimide to the compound SM-1 is 1:1-3:1, preferably 1.3;
(6) In the condensation reaction, the reaction temperature of the condensation reaction is 10-50 ℃, preferably 20-30 ℃, and most preferably 25 ℃;
(7) The raw materials in the condensation reaction consist of the solvent, the compound SM-1, the N-hydroxysuccinimide and the condensing agent;
(8) In the condensation reaction, the method also comprises the following post-treatment steps of crystallization, pulping, rinsing and drying after the condensation reaction is finished.
6. A process for the preparation of compounds II according to claim 5, characterized in that it satisfies one or more of the following conditions,
(1) In the condensation reaction, the mass ratio of the DMF to the compound SM-1 is 3.5;
(2) In the condensation reaction, the solvent for crystallization is water;
(3) In the condensation reaction, the mass ratio of the crystallization solvent to the compound SM-1 is 3.5 to 20;
(4) In the condensation reaction, the crystallization temperature is 10-50 ℃, preferably 20-30 ℃, and most preferably 25 ℃;
(5) In the condensation reaction, the pulping solvent is water;
(6) In the condensation reaction, the mass ratio of the slurried solvent to the compound SM-1 is 1:1-10, preferably 5:1;
(7) In the condensation reaction, the solvent for rinsing is water;
(8) In the condensation reaction, the mass ratio of the rinsed solvent to the compound SM-1 can be 1:1-5:1, and is preferably 1:1;
(9) In the condensation reaction, the rinsing times can be 1 to 3 times, and preferably 1 time;
(10) In the condensation reaction, the drying temperature is 40-60 ℃, preferably 50 ℃.
7. A process for the preparation of a compound II' comprising the steps of,
(1) A process for the preparation of compound II according to any one of claims 1 to 6, to give compound II;
(2) Reacting the compound II obtained in the step (1) with acid to obtain a compound II',
8. a process for the preparation of compounds II' according to claim 7, characterized in that it satisfies one or more of the following conditions,
(1) In the step (1), the amidation reaction further comprises a dilution step after the amidation reaction is finished, and the diluted solvent is preferably water;
(2) In the step (2), the acid is an inorganic acid, preferably hydrochloric acid; the concentration of HCl in the hydrochloric acid is preferably 1N-3N, and more preferably 2N;
(3) In the step (2), after the reaction is finished, the pH value of the reaction system of the reaction is more than or equal to 3 and less than or equal to 7, preferably, the pH value of the reaction system is more than or equal to 4 and less than or equal to 6;
(4) The raw materials in the preparation method of the compound II' consist of the solvent, the base, the compound I, the compound SM-3 and the acid;
(5) The preparation method of the compound II' further comprises the following post-treatment steps: sequentially extracting, washing, drying, concentrating, crystallizing, rinsing and drying; the solvent for extraction can be an ester solvent, preferably isopropyl hypoacetate; the extraction times are 1 to 5, preferably 2; the washing solvent can be a sodium chloride solution, and is preferably a saturated sodium chloride solution; the washing times are 1 to 5 times, preferably 1 time; the drying agent can be anhydrous sodium sulfate; the concentration temperature is 40-60 ℃, preferably 50 ℃; the crystallization temperature is-5 ℃ to 5 ℃, and 0 ℃ is preferred; the rinsing solvent can be an ester solvent, preferably isopropyl hypoacetate; the drying temperature is 40-60 ℃, preferably 50 ℃.
9. A process for the preparation of compound I, comprising the steps of: in a solvent, a compound SM-1 and N-hydroxysuccinimide undergo a condensation reaction shown in the specification under the action of a condensing agent to obtain a compound I,
the reaction steps and reaction conditions of the condensation reaction are as defined in any one of claims 4 to 6.
10. A process for preparing a compound I, which comprises reacting,
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