A method for preparing an important intermediate of pyrimidine-4(3H)-ketone heterocyclic compounds

Abstract

The application discloses a preparation method of an important intermediate of a pyrimidine-4(3H)-ketone heterocyclic compound shown in formula h, namely a preparation method of (3S,4S)-tert-butyl 4-((R)-1,1-dimethylethylsulfinamido)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate, which is synthesized through a series of reactions such as substitution, reduction, nucleophilic addition, reduction and deprotection, ring closure, oxidation and reductive amination and the like by taking L-methyl lactate as a raw material. In the application, red aluminum is used to replace lithium borohydride and tetrabutylammonium fluoride in the prior art, so that the problems of the risk caused by the use of lithium borohydride and the difficulty in post-treatment caused by the use of tetrabutylammonium fluoride in the prior art are overcome, the reaction steps are shortened, and the post-treatment operation is simplified.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to an industrial preparation method of (3S,4S)-tert-butyl4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ester, an important intermediate of pyrimidine-4(3H)-ketone heterocyclic compounds. Background Technology

[0002] SPH2 (Src Homology 2 domain-containing Phosphatase 2) is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 (Protein Tyrosine Phosphatase Nonreceptor type 11) gene. SPH2 contains two SH2 domains (Src Homology domain), one PTP domain (Protein Tyrosine Phosphatase), and a C-terminal tail. Under normal conditions, SPH2 is in a self-inhibitory conformation, where N-SH2 binds to PTP, blocking the substrate channel at the PTP catalytic site and thus inhibiting PTP activity. When SH2 binds to bisphosphonates (PTPs), the self-inhibitory interaction between SH2 and PTP is broken, exposing the PTP catalytic site and activating SPH2, which then catalyzes the dephosphorylation of tyrosine.

[0003] SPH2 is widely expressed and, as an oncogene, mediates the activation of various cancer cell signaling pathways, such as the RAS-ERK and PI3K-AKT pathways, promoting cancer cell survival and proliferation. Therefore, SPH2 activation is closely related to the development of various diseases, such as leukemia and breast cancer. SPH2 also plays an important role in the PD-1 and BTLA immune checkpoint channels, not only inhibiting T-cell activation but also promoting T-cell dysfunction. Therefore, SPH2 has attracted considerable attention as an anti-tumor target. However, due to the high protein sequence homology of the PTP catalytic site and the high hydrophilicity of the PTP catalytic pocket, SPH2 catalytic site inhibitors exhibit poor selectivity, poor cell permeability, and low bioavailability.

[0004] In existing technologies, some reagents used to synthesize this compound, such as lithium borohydride, are quite dangerous as they are hygroscopic and flammable; there is also tetrabutylammonium fluoride, which is very difficult to remove during post-processing. Summary of the Invention

[0005] To simplify post-processing, reduce reaction risks, and enable industrial production, this invention proposes for the first time an important intermediate for pyrimidine-4(3H)-ketone heterocyclic compounds, namely (3S,4S)-tert-butyl-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ester and its industrial synthesis method. This invention solves the problem of two dangerous reactions in existing technologies. This invention uses red aluminum to replace lithium borohydride and tetrabutylammonium fluoride in existing technologies, solving the risks associated with using lithium borohydride and the difficulties in post-processing associated with using tetrabutylammonium fluoride. This reduces reaction steps, increases reaction yield, lowers raw material costs, and facilitates scale-up production.

[0006] The (3S,4S)-tert-butyl-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ester proposed in this invention has the structure shown in formula h.

[0007]

[0008] The synthetic method proposed in this invention uses L-lactic acid methyl ester as a raw material and synthesizes (3S,4S)-tert-butyl4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ester through a series of reactions including substitution, reduction, nucleophilic addition, reduction and deprotection, cyclization, oxidation, and reductive amination. This invention simultaneously reduces the ester group and deprotects the group, and introduces a specific reducing agent. The optimized synthetic method proposed in this invention has advantages such as short reaction time, ease of operation, low risk, and suitability for industrial production. In particular, the use of red aluminum to replace lithium borohydride and tetrabutylammonium fluoride in the prior art solves the problems of risks associated with the use of lithium borohydride and post-processing difficulties associated with the use of tetrabutylammonium fluoride in the prior art.

[0009] The (3S,4S)-tert-butyl-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ester proposed in this invention is shown in formula h, and its synthetic route is shown in route (A) below.

[0010]

[0011] The industrial synthesis method of (3S,4S)-tert-butyl-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ester of formula h according to the present invention includes the following specific steps:

[0012] 1) In the first organic solvent, compound a reacts with TBSCl under the action of an acid-binding agent to give compound b;

[0013] 2) In the second organic solvent at low temperature, compound b is reduced to obtain compound c;

[0014] 3) In the third solvent, the nucleophile attacks compound c under the action of a base, and the reaction yields compound d;

[0015] 4) In the fourth organic solvent, the reducing agent reduces compound d while removing the protecting group to obtain compound e;

[0016] 5) In the fifth organic solvent, compound e undergoes cyclization under the action of NaH and TsCl to obtain compound f;

[0017] 6) In the sixth organic solvent and water, compound f undergoes an oxidation reaction under the action of an oxidizing agent to give compound g;

[0018] 7) In the seventh organic solvent, the imine bond formed by the compound of formula g and the amine under reflux is reduced to obtain the compound of formula h.

[0019] Specifically,

[0020] In step 1), the acid-binding agent is one or more of triethylamine, DIPEA, imidazole, pyridine, etc.; preferably, it is imidazole.

[0021] In step 1), the first organic solvent is dichloromethane.

[0022] In step 1), the molar ratio of the compound of formula a to the acid-binding agent is 1:(1-5); preferably, it is 1:1.1.

[0023] In step 1), the reaction temperature is 0-40℃; preferably, it is 10℃.

[0024] In step 2), the reducing agent is DIBALH.

[0025] In step 2), the reduction reaction temperature is -60 to -65°C; preferably, it is -65°C.

[0026] In step 2), the second organic solvent is dichloromethane.

[0027] In step 3), the base is LDA, which is prepared by reacting diisopropylamine and n-butyllithium.

[0028] In step 3), the third organic solvent is tetrahydrofuran.

[0029] In step 3), the specific reaction steps are as follows: add a THF solution of N-Boc-4-piperidinecarboxylate and a base, then add formula (c); after the reaction is completed, add a saturated ammonium chloride solution to the reaction solution and separate the liquids; extract the aqueous phase with ethyl acetate, combine the organic phases and concentrate to dryness; dissolve in ethyl acetate, wash with saturated brine, and dry with anhydrous sodium sulfate; filter and concentrate to dryness to obtain crude product which is directly used in the next reaction step.

[0030] In step 4), the reducing agent is red aluminum.

[0031] In step 4), the equivalent number of the reducing agent is selected from 2.0 eq to 6.0 eq; preferably, the equivalent number of red aluminum is 4.0 eq.

[0032] In step 4), the fourth organic solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, etc. Tetrahydrofuran is preferred.

[0033] In step 4), the reaction temperature is -10 to 50°C; preferably, it is 10°C.

[0034] In step 4), the reaction time is 1-5 hours; preferably, it is 3 hours.

[0035] In step 5), the cyclization reagent is a combination of sodium hydrogen and TsCl.

[0036] In step 5), the fifth organic solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, etc. Tetrahydrofuran is preferred.

[0037] In step 5), the molar ratio of the compound of formula e, TsCl and NaH is 1:(1-2):(2-8); preferably, it is 1:1:2.5.

[0038] The specific steps of step 5) are as follows: at a temperature of -10℃ to -20℃, the compound of formula e and TsCl are dissolved in the fifth solvent, and then added dropwise to the fifth solvent of NaH to complete the cyclization.

[0039] In step 6), the oxidant is selected from one of DMSO-SO3-Pyridine, DMSO-(COCl)2, TEMPO / sodium hypochlorite, and DMP; preferably, it is TEMPO / sodium hypochlorite.

[0040] In step 6), the sixth organic solvent is one or more selected from dichloromethane, 1,2-dichloroethane, tetrahydrofuran, etc., preferably dichloromethane.

[0041] In step 7), the reducing agent is selected from one or more of sodium borohydride, sodium triacetoxyborohydride, and sodium cyanoborohydride; preferably, sodium borohydride is the reducing agent.

[0042] In step 7), the temperature of the reduction reaction is -25℃ to -10℃, preferably -15℃.

[0043] In step 7), the seventh organic solvent is tetrahydrofuran.

[0044] The present invention also proposes a (3S,4S)-tert-butyl-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ester of formula (h) prepared according to the route (A).

[0045] The innovative and effective advantages of this invention include the following: the reduction method used in step 4) has significant advantages compared to existing reduction methods. For example, the use of red aluminum reduction avoids the use of lithium borohydride and tetrabutylammonium fluoride, solving the problems of lithium borohydride being flammable and expensive, and tetrabutylammonium fluoride being difficult to remove. Furthermore, by using red aluminum reduction and controlling the equivalent number of red aluminum, the TBS protecting group is removed while reducing the ester group to the hydroxyl group. This reduces one reaction step and simplifies post-reaction processing. Moreover, the reduction method used in step 7) also avoids the use of lithium borohydride. The synthesis method of this invention is simple to operate, shortens the operation steps, avoids the use of hazardous compounds (such as lithium borohydride and lithium aluminum hydride), and is conducive to industrial-scale production.

[0046] The table below shows the correspondence between abbreviations and full names used in this invention:

[0047] abbreviation Full name 1 DIBALH Diisobutylaluminum hydride 2 TBSCl tert-butyldimethylchlorosilane 3 TEMPO 2,2,6,6-Tetramethylpiperidine oxide 4 nBuLi n-Butyllithium 5 TsCl p-Toluenesulfonyl chloride 6 DIPEA N,N-Diisopropylethylamine 7 EA Ethyl acetate 8 THF Tetrahydrofuran 9 DCM dichloromethane Detailed Implementation

[0048] The invention will be further described in detail below with reference to specific embodiments. Except for the content specifically mentioned below, the processes, conditions, and experimental methods for implementing the invention are all common knowledge and general knowledge in the art, and the invention does not have any particular limitations.

[0049] The industrial synthesis of (3S,4S)-tert-butyl-4-((R)-1,1-dimethylethylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid ester of formula h according to the present invention is shown in the following route (A):

[0050]

[0051] Example 1

[0052] Synthesis of compound b:

[0053] Add L-methyl lactate (7 kg, 67.2 mol), imidazole and DCM (25 L, 3.5 V) to a 100 L reactor. After stirring until dissolved, purge with nitrogen. When the temperature drops to 10 °C, add TBSCl (11.1 kg, 73.9 mol) in batches. After the addition is complete, stir for half an hour. TLC detection shows that the reaction of the raw materials is complete.

[0054] Add ice water (1V) to the reaction mixture, stir, and separate the layers. Extract the aqueous phase using DCM (2V), and wash the combined organic phases once with water and once with saturated brine. Dry the mixture over anhydrous sodium sulfate, filter, and proceed directly to the next reaction step. ESI-MS: m / z = 219 (M+H) + correct.

[0055] Example 2

[0056] Synthesis of compound c:

[0057] Add a 30L solution of DCM for compound b synthesized in Example 1 of this invention to a 100L reactor, then add another 10-30L of DCM. Under nitrogen protection, lower the temperature to -65°C, and then add DIBALH (15.8kg, 27.5mol) dropwise, maintaining the temperature below -60°C. Stir for 1 hour after the addition is complete. TLC analysis confirms complete reaction of the reactants.

[0058] The reaction solution was added to a 2N aqueous sulfuric acid solution (2V), stirred for 2 hours, and then separated. The aqueous phase was extracted with DCM, and the organic phases were combined. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The receiving liquid was concentrated again to obtain 12.7 kg of colorless liquid. The two-step yield was approximately 100%. ESI-MS: m / z = 189 (M+H). + correct.

[0059] Example 3

[0060] Synthesis of compound d:

[0061] Diisopropylamine (66.3 mol) and THF (4V) were added to a 100L reactor. The reactor was purged with nitrogen three times, cooled to -20°C, and nBuLi (26.5L, 66.3 mol) was added dropwise while maintaining the temperature below -10°C. The mixture was stirred for 1 hour after the addition was complete. Next, a THF solution of N-Boc-4-piperidincarnate was added dropwise while maintaining the temperature below -10°C. The mixture was stirred for 1.5 hours after the addition was complete. Then, compound c synthesized in Example 2 of this invention was added dropwise while maintaining the temperature below -10°C. The mixture was stirred for 1 hour after the addition was complete. TLC analysis showed that the reaction proceeded completely.

[0062] A saturated ammonium chloride solution (2V) was added dropwise to the reaction mixture, and the mixture was stirred for 2 hours. The layers were separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were concentrated to dryness. The organic phase was then dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to dryness to give 30 kg of a brownish-yellow oily substance, with a yield of approximately 100%. ESI-MS: m / z = 446 (M+H). + correct.

[0063] Example 4

[0064] Synthesis of compound e:

[0065] Compound d (9.8 kg, 22 mol) synthesized in Example 3 of this invention and THF (4 V) were added to a 100 L reactor. The reactor was purged with nitrogen three times, cooled to -10 °C, and then 66 mol of red aluminum solution was added dropwise while maintaining the temperature below 10 °C. The mixture was stirred for 1 h after the addition was complete. TLC was used to confirm that the reaction of the raw materials was complete.

[0066] The reaction mixture was added to a 20% sodium chloride solution (2V), stirred for 2 hours, and then separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were concentrated to dryness. The solution was then dissolved in ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to dryness to give 11.7 kg of a yellow oily substance, yield 60%, ESI-MS: m / z = 290 (M+H). + correct.

[0067] Example 5

[0068] Synthesis of compound f:

[0069] Add 345g (8.5mol) NaH and 10V THF to a 50L reactor. Purge with nitrogen three times, cool to -15°C, and add dropwise a THF (4V) solution of compound e (1.0kg (3.4mol) synthesized in Example 4 of this invention. Bubbles are generated. Maintain the temperature below -5°C and stir for half an hour after the addition is complete. Then add dropwise a THF (3V) solution of TsCl (3.4mol). Bubbles are also generated. Stir for half an hour after the addition is complete, and TLC confirms that the reaction of the starting materials is complete.

[0070] The temperature was lowered to -20°C, and 100 ml of ammonium chloride aqueous solution was added dropwise, producing a large amount of gas. Then, 3 L of aqueous solution was added dropwise. After the addition was complete, the system became dilute, and no more bubbles were produced, indicating that the reaction had been quenched. Stirring was continued for 2 hours, and the mixture was allowed to stand and separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated to dryness, dissolved in DCM, and washed twice with water. This solution was used directly in the next reaction. ESI-MS: m / z = 272 (M+H) + correct.

[0071] Example 6

[0072] Synthesis of compound g:

[0073] Compound f (6.8 mol) synthesized in Example 5 of this invention, water (10 V), potassium bromide (0.36 mol), and DCM (15 V) were added to a 100 L reactor. The mixture was cooled to 0 °C, and TEMPO (0.14 mol) was added. Then, sodium hypochlorite aqueous solution (6 V) was added dropwise, with the temperature controlled below 5 °C. After the addition was complete, the mixture was stirred for half an hour. TLC was used to confirm that the reaction of the reactants was complete.

[0074] Sodium sulfite solid was added to the reaction solution until the system became colorless. Stirring was continued for 1 hour, followed by separation. The aqueous phase was extracted with DCM, and the combined organic phases were concentrated to dryness. Column chromatography yielded 7.6 kg of a yellow oily substance. The two-step yield was 70%. ESI-MS: m / z = 270 (M+H). + correct.

[0075] Example 7

[0076] Synthesis of compound h:

[0077] To a 100L reactor, add g (3.4 kg, 12.6 mol) of the compound synthesized in Example 6 of this invention, R-(+)-tert-butylsulfinamide (19 mol), tetraethyl titanate (50.4 mol) (for complexation and dehydration), and THF (10V). Heat under reflux for 12 hours. TLC analysis showed complete conversion of the raw materials to imine. Cool to -10°C and add methanol (1.3V). Then add sodium borohydride (3.3 mol) in batches, maintaining the temperature below -5°C. A large number of bubbles were generated. After the addition was complete, stir for half an hour. TLC analysis showed complete conversion of imine to amine.

[0078] The reaction solution was poured into a supersaturated ammonium chloride aqueous solution containing EA and ice. The mixture was stirred until it became a white, viscous liquid. Stirring continued for 1 hour, followed by separation. The upper organic phase was extracted, and the lower solid layer was filtered. The filter cake was washed twice with EA. The combined organic phases were concentrated to dryness and passed through a column chromatography column to obtain 3.7 kg of white solid, yield 35%. ESI-MS: m / z = 375 (M+H). + Correct. Both purity and EE value are greater than 98.0%.

[0079] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of the inventive concept are included in this invention and are protected by the appended claims.

Claims

1. A process for the synthesis of (3S,4S)-tert-butyl 4-((R)-1,1 -dimethylethyl sulfinamido)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate of formula h, characterized in that, The synthesis reaction comprises the following steps: 1) reacting a compound of formula a with TBSCl in a first organic solvent in the presence of an acid binding agent to obtain a compound of formula b; 2) reducing the compound of formula b at low temperature in a second organic solvent to obtain a compound of formula c; 3) reacting a nucleophile with the compound of formula c in the presence of a base in a third solvent to obtain a compound of formula d; 4) reducing the compound of formula d with a reducing agent in a fourth organic solvent to obtain a compound of formula e, wherein the reducing agent is red aluminum, and the TBS protecting group is removed while the ester group in formula (d) is reduced to a hydroxyl group, the number of equivalents of the reducing agent is selected from 2.0 eq to 6.0 eq, the reaction temperature is -10 to 50°C, and the reaction time is 1-5 h; 5) ring-closing the compound of formula e in the presence of NaH and TsCl in a fifth organic solvent to obtain a compound of formula f; 6) oxidizing the compound of formula f in the presence of an oxidizing agent in a sixth organic solvent and water to obtain a compound of formula g; 7) reducing the imine bond formed by refluxing the compound of formula g with an amine to obtain (3S,4S)-tert-butyl 4-((R)-1,1-dimethylethylsulfinamido)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate of formula h; The synthesis route of the compound of formula h is shown in route (A) as follows, In step 1), the acid binding agent is selected from one or more of triethylamine, DIPEA, imidazole, and pyridine; and / or, the first organic solvent is dichloromethane; the molar ratio of the compound of formula a to the acid binding agent is 1:(1-5); and the reaction temperature is 0-40°C.

2. The method of synthesis of claim 1, wherein, In step 2), the temperature of the reduction reaction is -60 to -65°C; and / or, the reducing agent for the reduction reaction is DIBALH; and / or, the second organic solvent is dichloromethane.

3. The method of synthesis of claim 1, wherein, In step 3), an ethyl N-Boc-4-piperidinecarboxylate THF solution and a base are added dropwise, and then the compound of formula (c) is added dropwise; after the reaction is completed, saturated ammonium chloride solution is added dropwise to the reaction solution, and the liquid is separated; the aqueous phase is extracted with ethyl acetate, the combined organic phase is concentrated and dried, then dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which is directly used in the next step.

4. The method of synthesis of claim 1, wherein, In step 3), the base is LDA, which is prepared by reacting diisopropylamine with n-butyllithium; and the third solvent is tetrahydrofuran.

5. The method of synthesis of claim 1, wherein, In step 4), the fourth organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

6. The method of synthesis of claim 1, wherein, ​ 7. The method of synthesis of claim 1, wherein, In the step 5), the compound of formula e and TsCl are dissolved in a fifth solvent at a temperature of -10°C to -20°C, and are added dropwise to NaH in the fifth solvent to complete the ring closure; and / or, the fifth organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene; and / or, the molar ratio of the compound of formula e, TsCl and NaH is 1:(1-2):(2-8).

8. The method of synthesis of claim 1, wherein, In the step 6), the oxidizing agent is selected from one of DMSO-SO3-Pyridine, DMSO-(COCl)2, TEMPO / sodium hypochlorite and DMP; and / or, the sixth organic solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran.

9. The method of synthesis of claim 1, wherein, In the step 7), the reducing agent is selected from one of sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride; and / or, the seventh organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, toluene; and / or, the temperature of the reaction is -25°C to -10°C.

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