A preparation method of a lung cancer treatment drug

Abstract

The application discloses a preparation method of a lung cancer treatment drug, adagrasib, which comprises the following steps: in step 1, 1-chloro-8-iodonaphthalene is subjected to C-N coupling reaction with 4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine to obtain 4-chloro-7-(8-chloronaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; in step 2, the product in step 1 is subjected to oxidation reaction to obtain 4-chloro-7-(8-chloronaphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine; and in step 3, the product in step 2 is subjected to docking reaction with [(2S)-1-methylpyrrolidin-2-yl]methanol, and then subjected to C-N coupling reaction with (S)-2-(1-(2-fluorovinylcarbonyl)piperazin-2-yl)acetonitrile to obtain adagrasib. The synthesis method of the adagrasib has the advantages of a short route, easy customization of starting materials, safe and simple operation, low cost and environmental friendliness, and the like, as compared with the prior art.

Description

Field of the invention

[0001] The present application belongs to the field of chemical drugs, and particularly relates to a new preparation method of a lung cancer treatment drug Adagrasib. BACKGROUND

[0002] Cancer is a major global public health problem, with lung cancer showing the fastest-growing incidence and mortality rates, making it one of the most common causes of cancer death worldwide. Lung cancer, also known as primary bronchogenic carcinoma, mainly includes small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer cases, and its most common cause is tobacco use. According to the latest global cancer data from the International Agency for Research on Cancer (IARC) of the World Health Organization, there were 9.96 million cancer deaths worldwide in 2020, with 1.8 million of them caused by lung cancer, far exceeding other cancer types. Studies have found RAS mutations in about one-third of human tumors. The RAS gene family includes three genes: NRAS, HRAS, and KRAS. RAS mutations mainly occur in the KRAS subtype. KRAS is a key mediator in the signaling cascade that promotes cell growth and proliferation and is the most common mutated oncogene in cancer, accounting for 85% of all RAS-related cancers. KRAS gene mutations are mainly concentrated at codons 12, 13, and 61, with mutations at codon 12 accounting for over 80%, including G12A, G12C, G12D, G12R, G12S, and G12V mutations. KRAS G12C mutations alone account for 44% of all KRAS mutations, and are most common in NSCLC, with an incidence of approximately 14%, and about 3% in colorectal carcinoma (CRC). Intracellularly, the protein encoded by KRAS transitions between inactive and activated states. KRAS is inactive when bound to guanosine diphosphate (GDP) and activated when bound to guanosine triphosphate (GTP), simultaneously activating downstream signaling pathways, including the MAPK and PI3K signaling pathways, which play important roles in promoting cell survival, proliferation, and cytokine release. This conversion process requires regulation by two types of factors. The first is the guanine nucleotide-exchange factor (GEF), which catalyzes the binding of KRAS to GTP, thereby activating the protein encoded by KRAS. The second is the GTPase-activating protein (GAP), which can hydrolyze GTP into GDP, thereby inhibiting the activity of KRAS.

[0003] Adagrasib is a RAS GTPase family inhibitor, which is used for treating adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring KRAS G12C mutation, who have previously received at least one systemic treatment. Adagrasib is an irreversible KRAS G12C inhibitor, which covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactivated state, thereby preventing downstream signaling without affecting wild-type KRAS protein. Adagrasib inhibits tumor cell growth and viability in cells harboring KRAS G12C mutation and leads to tumor regression in KRAS G12C mutant tumor xenograft models with minimal off-target activity. Adagrasib as a covalent inhibitor targeting KRAS G12C plays a complementary role in NSCLC treatment regimen, which has less adverse reactions, better tolerability, and is a potential NSCLC treatment drug.

[0004] Adagrasib, chemical name: {(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]-methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoropropyl-2-enyl)piperazin-2-yl}acetonitrile, molecular formula is C 32 H 35 ClFN7O2, relative molecular mass is 604.117, and its chemical structural formula is as follows:

[0005]

[0006] Adagrasib

[0007] The prior art document patent CN201880086849 reports that the synthetic route 1 of adagrasib is as follows:

[0008]

[0009] The route takes 7-benzyl-4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine, 2-[(2S)-piperazin-2-yl]acetonitrile, [(2S)-1-methylpyrrolidin-2-yl]methanol and 1-bromo-8-chlorodiazole as starting materials, first debenzylization, then Cbz protection of amino group to obtain 4-chloro-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylic acid benzyl ester; the intermediate reacts with docking to obtain 4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfanyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylic acid benzyl ester, which is oxidized to obtain 4-[(3S)-4-tert-butoxycarbonyl-3-(cyanomethyl)piperazin-1-yl]-2-methylsulfinyl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylic acid benzyl ester; then reacts with docking to obtain 4-[(3S)-4-tert-butoxycarbonyl-3-(oxymethyl)piperazin-1-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylic acid benzyl ester; after Cbz protection group is removed, it reacts with docking, and then Boc protection group is removed to obtain 2-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile, which finally reacts with 2-fluoroacrylic acid to obtain adagrasib. The reaction has 9 steps.

[0010] The prior art document Journal Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer (J. Med. Chem. 2020, 63, 13, 6679-6693) reports another synthetic route 2 of adagrasib as follows:

[0011]

[0012] The route takes 7-benzyl-2,4-dichloro-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine as a starting material, is subjected to methoxylation, and is subjected to docking reaction with [(2S)-1-methylpyrrolidin-2-yl]methanol, is subjected to debenzyl protection, and is subjected to docking reaction with 1-bromo-8-chloroquinoline to obtain an intermediate 4-methoxy-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine, the intermediate is subjected to demethylation, is subjected to hydroxyl activation into a triflate, is subjected to docking with 2-[(2S)-piperazin-2-yl]acetonitrile to generate 2-[4-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]piperazin-2-yl]acetonitrile, and finally is subjected to reaction with acrylic acid to obtain adagrasib, and the reaction has a total of 8 steps.

[0013] The above two routes for preparing adagrasib have a long route and a low yield. The precious palladium metal catalyst is used in the multi-step reaction, and the route 2 also uses the smelly reagent ethanethiol, and the environmental protection pressure is large.

[0014] The purpose of the present application is to provide a new method for preparing adagrasib from a compound of formula a, a compound of formula b, [(2S)-1-methylpyrrolidin-2-yl]methanol and (S)-2-(1-(2-fluorovinyl) piperazin-2-yl) acetonitrile through 4 steps, which has the advantages of a short route, easy customization of starting materials, safe and simple operation, low cost, environmental friendliness and the like.

[0015] Therefore, the present application helps to reduce the production cost of adagrasib, an lung cancer treatment drug, and alleviate the accessibility problem, so that Chinese adult patients with KRAS G12C mutation of locally advanced or metastatic non-small cell lung cancer (NSCLC) can benefit from it. SUMMARY

[0016] The purpose of the present application is to overcome the deficiencies of the prior art, provide a new preparation method of adagrasib, and the method is:

[0017]

[0018] Step 1, C-N coupling reaction of the compound of formula a with the compound of formula b to obtain an intermediate compound of formula c;

[0019] Step 2, the intermediate compound of formula c is subjected to oxidation reaction to obtain an intermediate compound of formula d;

[0020] Step 3, the intermediate compound of formula d is subjected to docking reaction with [(2S)-1-methylpyrrolidin-2-yl]methanol to obtain an intermediate compound of formula e;

[0021] Step 4, C-N coupling reaction of the intermediate compound of formula e with (S)-2-(1-(2-fluorovinyl) piperazin-2-yl)acetonitrile to obtain adagrasib;

[0022] wherein

[0023] X1 in the compound of formula a is selected from Br or I;

[0024] X2 in the compound of formula b, c, d is selected from Cl or Br.

[0025] The route of the present application is different from the synthetic route of adagrasib reported in the prior art documents patent CN201880086849 and journal Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer (J. Med. Chem. 2020, 63, 13, 6679-6693). The purpose of the present application is to provide a new method for preparing adagrasib from the compound of formula a, the compound of formula b, [(2S)-1-methylpyrrolidin-2-yl]methanol and (S)-2-(1-(2-fluorovinyl) piperazin-2-yl)acetonitrile through 4 steps of reaction, the docking order of each main structural fragment in the method is different from the prior art document, and the method has the advantages of short route, easy customization of starting materials, safe and simple operation, low cost, environmental friendliness and the like.

[0026] The feature of step 1 reaction of the present application is that C-N coupling reaction of the compound of formula a with the compound of formula b to obtain the intermediate compound of formula c, wherein the halogen in X1 in the compound of formula a and X2 in the compound of formula b is selected to be crucial, the halogen activity of X1 needs to be higher than that of X2, therefore X1 in the compound of formula a is selected from Br or I, and X2 in the compound of formula b is selected from Cl or Br. By over-dosing the compound of formula a and strictly controlling the reaction conditions, the by-product of the compound of formula b itself can be minimized, which is the most important invention of the present patent. In addition, the catalyst of the present reaction can be (trimethylammonium) pyridine 1-oxide and cesium carbonate catalytic system, or 2-dicyclohexylphosphine-2', 6'-diisopropoxy biphenyl (RuPhos), tris-dibenzaldehyde palladium (Pd2(dba)3) and cesium carbonate catalytic system, the former is more efficient and cheaper, and is preferred; the molar dosage ratio of the compound of formula b, the compound of formula a, (trimethylammonium) pyridine 1-oxide and cesium carbonate is 1:2-5:0.05-0.1:2-5, preferably 1:2.5-4:0.08-0.09:2.5-4, the reaction can proceed smoothly and the by-product is less.

[0027] The oxidant of the step 2 oxidation reaction of the present application is selected from meta-chloro-peroxy-benzoic acid, hydrogen peroxide or peroxy-benzoic acid, wherein meta-chloro-peroxy-benzoic acid is preferred due to its higher efficiency and less by-products. To avoid the conversion of sulfide into sulfone by excess oxidant, the amount of oxidant needs to be strictly controlled, the molar ratio of compound of formula c to oxidant is 1:0.9-1.1, preferably 1:0.95-1.05, and particularly preferably 1:1, which can avoid the generation of sulfone by-product. The group X2in the compound of formula c in step 2 of the present application is selected from Cl or Br, and the difference of the group has little effect on the reaction progress.

[0028] The intermediate compound of formula d in step 3 of the present application is reacted with [(2S)-1-methylpyrrolidin-2-yl]methanol to obtain the intermediate compound of formula e, wherein the halogen group in the compound of formula d may participate in the reaction to form by-products. When X2in the structure is bromine, the by-products of this step are slightly more, but the bromide is more reactive in step 4. In this step, the methylene sulfonyl group in the compound of formula d is more active than the chlorine structure in the structure, but it still needs to be controlled by the reaction conditions and purified by post-treatment to obtain the compound of formula e with high purity; the catalyst for the docking reaction is an organic base selected from potassium tert-butoxide, sodium tert-butoxide or sodium ethoxide, preferably potassium tert-butoxide or sodium tert-butoxide, wherein potassium tert-butoxide has the highest reaction efficiency and is preferred. The molar ratio of [(2S)-1-methylpyrrolidin-2-yl]methanol, compound of formula d, and organic base in step 3 is controlled to be 1:1-1.5:0.9-1.1, preferably 1:1.1-1.3:0.95-1.05, and in the dimethyl sulfoxide solvent reaction system, the dimethyl sulfoxide solution of [(2S)-1-methylpyrrolidin-2-yl]methanol and potassium tert-butoxide is added dropwise to the compound of formula e while controlling the temperature at 0-10℃, and the reaction is continued for 0.5h after the dropwise addition is completed. The above reaction conditions can reduce the by-products and obtain the compound of formula e with high purity by post-treatment and recrystallization.

[0029] The reaction of step 4 is characterized in that the high-purity intermediate compound of formula e is directly reacted with (S)-2-(1-(2-fluorovinyl) piperazin-2-yl) acetonitrile which has been docked with a 2-fluorovinyl structure fragment, which is different from the operation of the prior art documents which all adopt the last docking of 2-fluorovinyl to prepare adagrasib; the use of (S)-2-(1-(2-fluorovinyl) piperazin-2-yl) acetonitrile which has been docked with a 2-fluorovinyl structure fragment for the synthesis of adagrasib greatly improves the reaction efficiency, which is the biggest highlight of the present application, but this operation also brings some risks, because the stability of the 2-fluorovinyl structure fragment is slightly poor, and in the docking process of the intermediate compound of formula e and (S)-2-(1-(2-fluorovinyl) piperazin-2-yl) acetonitrile, 2-fluorovinyl may cause an increase in by-products, but fortunately, through reaction condition control and post-treatment refining, the adverse effects are effectively controlled, and high-purity adagrasib can still be obtained, and the advantages of this route design outweigh the disadvantages. In addition, when X2 in the compound of formula e is bromine, the reactivity is higher.

[0030] The docking reaction of step 4 is characterized in that an organic base needs to be added as a catalyst to ensure that the reaction proceeds smoothly, and the organic base is selected from triethylamine, N,N-diisopropylethylamine, N,N-diisopropylmethylamine, N,N-diethylmethylamine or N,N-diethylpropylamine, preferably the commonly used N,N-diisopropylethylamine or triethylamine, among which N,N-diisopropylethylamine is strongly basic, has a high boiling point and is relatively stable, and after salification, it is dissolved in an organic solvent and is preferred.

[0031] The molar feed ratio of the intermediate compound of formula e, (S)-2-(1-(2-fluorovinyl) piperazin-2-yl) acetonitrile and the organic base in the docking reaction of step 4 is 1:0.9-1.1:1-3, preferably 1:0.95-1.05:1.5-2.5, and particularly preferably 1:1:2, and the reaction is carried out in a water-free dimethylformamide solvent system at a temperature of 50-60°C for 7-8h, and the reaction can proceed smoothly with the least by-products.

[0032] The present application provides a new synthesis method of adagrasib which is short in route, high in yield and environmentally friendly, and has obvious advantages over the prior art documents and can benefit from it.

[0033] Specific implementation method:

[0034] The technical solutions in the embodiments of the present application will be described in detail below with reference to the embodiments of the present application, but the following embodiments are only used to understand the present application and cannot limit the present application, and the present application can be implemented in various different ways limited and covered by the claims.

[0035] The new synthesis method of adagrasyl and the advantages of the method will be further illustrated below in combination with Examples 1 and 10 of the present application.

[0036] Example 1: Synthesis method 1 of 4-chloro-7-(8-chloronaphthalen-1-yl)-2- (methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-I)

[0037]

[0038] The 1-chloro-8-iodonaphthalene (compound of formula a-I, 433 g, 1.5 mol), 4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula b-I, 108 g, 0.5 mol), cesium carbonate (326 g, 1 mol), catalyst 2-(trimethylamino)pyridine 1-oxide (9.25 g, 40 mmol) and solvent dimethylformamide 2 L were added into a three-necked flask, heated to 120-130 °C for 24 h, cooled to room temperature, 2.5 L of ethyl acetate and 2 L of water were added, the liquid was separated, the aqueous phase was extracted with 1.5 L of ethyl acetate again, the organic phase was washed with 1.5 L of saturated sodium chloride solution, the organic phase was added with 1.5 L of water and 375 ml of 2 mol / L hydrochloric acid solution, stirred and separated, 2 L of ethyl acetate was added to the aqueous phase, the pH was adjusted to 8-9 with 20% sodium carbonate solution under stirring, the liquid was separated, and the organic phase was washed with 1.5 L of water again; dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and recrystallized with ethyl acetate-n-hexane mixed solvent, and dried in an oven to obtain 4-chloro-7-(8-chloronaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-I, 143 g, yield 76%), Ms m / z 376.0 (M+1), NMR (400 MHz, CDCl3), δ 2.25 (s, 3H), 3.10 (t, 2H), 3.70 (t, 2H), 4.63 (s, 2H), 7.43-7.99 (m, 6H).

[0039] Example 2: Synthesis method 2 of 4-chloro-7-(8-chloronaphthalen-1-yl)-2- (methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-I)

[0040]

[0041] A three-necked flask was charged with 1-chloro-8-bromonaphthalene (compound of formula a-II, 96.0 g, 0.4 mol), 4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidine (compound of formula b-I, 21.6 g, 0.1 mol), cesium carbonate (97.7 g, 0.3 mol), copper iodide (0.95 g, 5 mmol) catalyst 2-(trimethylamino)pyridine 1-oxide (1.8 g, 8 mmol) and solvent dimethylformamide 400 ml, heated to 120-130 °C for 24 h, cooled to room temperature, added ethyl acetate 500 ml and 400 ml water, separated, the aqueous phase was extracted again with 300 ml ethyl acetate, the organic phase was washed with 300 ml saturated sodium chloride solution, the organic phase was added with 300 ml water and 2 mol / L hydrochloric acid solution 120 ml, stirred and separated, the aqueous phase was added with ethyl acetate 400 ml, stirred and pH was adjusted to 8-9 with 20% sodium carbonate solution, separated, the organic phase was washed again with 300 ml water; dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, the residue was recrystallized with ethyl acetate-n-hexane mixed solvent, dried in an oven to obtain 4-chloro-7-(8-chloronaphthalen-1-yl)-2-(methylthio)- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-I, 23.7 g, yield 63%).

[0042] Example 3: Process 3 for the synthesis of 4-chloro-7-(8-chloronaphthalen-1-yl)-2- (methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-I)

[0043]

[0044] Into a three-necked flask, 1-chloro-8-iodonaphthalene (compound of formula a-I, 86.6 g, 0.3 mol), 4-chloro-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula b-I, 21.6 g, 0.1 mol), cesium carbonate (97.7 g, 0.3 mol), catalyst 2-dicyclohexylphosphino-2',6'-d iisopropoxybiphenyl (RuPhos, 9.33 g, 20 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 9.2 g, 10 mmol) and solvent toluene 1 L were added under nitrogen atmosphere and heated to 90-100 °C for 10 h. Most of the solvent was concentrated, 600 ml of water and 600 ml of ethyl acetate were added to the residue, stirred and filtered. The filtrate was partitioned, the organic phase was washed with 600 ml of water and 120 ml of 2 mol / L hydrochloric acid solution, stirred and partitioned. To the aqueous phase, 400 ml of ethyl acetate was added, stirred and pH was adjusted to 8-9 with 20% sodium carbonate solution, partitioned and the organic phase was washed with 300 ml of water. It was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure and the residue was recrystallized from ethyl acetate-n-hexane mixture. It was dried in oven to obtain 4-chloro-7-(8-chloronaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-I, 20.7 g, yield 55%).

[0045] Example 4: Synthesis of 4-bromo-7-(8-chloronaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-II)

[0046]

[0047] To a three necked flask was added 1-chloro-8-iodonaphthalene (compound of formula a-I, 173.1 g, 0.6 mol), 4-bromo-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula b-II, 39.03 g, 0.15 mol), cesium carbonate (146.6 g, 0.45 mol), catalyst 2-(trimethylamino)pyridine 1-oxide (2.7 g, 12 mmol) and solvent dimethylformamide 600 ml, heated to 120-130 °C for 24 h, cooled to room temperature, added ethyl acetate 750 ml and water 600 ml, partitioned, aqueous phase was extracted again with ethyl acetate 450 ml, combined organic phase was washed with saturated sodium chloride solution 450 ml, organic phase was added with water 450 ml and 2 M hydrochloric acid solution 180 ml, stirred and partitioned, to the aqueous phase was added ethyl acetate 600 ml, pH was adjusted to 8-9 with 20% sodium carbonate solution with stirring, partitioned, organic phase was washed again with water 450 ml; dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, the residue was recrystallized from ethyl acetate-n-hexane mixture solvent, dried in oven to obtain 4-bromo-7-(8-chloronaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-II, 44.25 g, yield 70%), Ms m / z 420.0 (M+1).

[0048] Example 5: Synthesis of 4-chloro-7-(8-chloronaphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula d-I)

[0049]

[0050] To a three necked flask was added 1-chloro-8-iodonaphthalene (compound of formula a-I, 173.1 g, 0.6 mol), 4-bromo-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula b-II, 39.03 g, 0.15 mol), cesium carbonate (146.6 g, 0.45 mol), catalyst 2-(trimethylamino)pyridine 1-oxide (2.7 g, 12 mmol) and solvent dimethylformamide 600 ml, heated to 120-130 °C for 24 h, cooled to room temperature, added ethyl acetate 750 ml and water 600 ml, partitioned, aqueous phase was extracted again with ethyl acetate 450 ml, combined organic phase was washed with saturated sodium chloride solution 450 ml, organic phase was added with water 450 ml and 2 M hydrochloric acid solution 180 ml, stirred and partitioned, to the aqueous phase was added ethyl acetate 600 ml, pH was adjusted to 8-9 with 20% sodium carbonate solution with stirring, partitioned, organic phase was washed again with water 450 ml; dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, the residue was recrystallized from ethyl acetate-n-hexane mixture solvent, dried in oven to obtain 4-bromo-7-(8-chloronaphthalen-1-yl)-2-(methylthio)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula c-II, 44.25 g, yield 70%), Ms m / z 420.0 (M+1).

[0051] Example 6: Synthesis of 4-bromo-7-(8-chloronaphthalen-1-yl)-2- (methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula d-II)

[0052]

[0053] Compound of formula c-II (41.9 g, 0.1 mol) was dissolved in dichloromethane 200 ml. It was cooled to 0-5°C, m-chloroperoxybenzoic acid (17.2 g, 0.1 mol) was added, stirred at room temperature for 30 min, 10% Na2SO3 35 ml and water 200 ml were added, stirred and separated, the organic phase was concentrated to remove most of the solvent, the residue was added to n-hexane 100 ml and stirred to disperse, filtered, and the filter cake was dried to obtain 4-bromo-7-(8-chloronaphthalen-1-yl)-2- (methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (compound of formula d-II, 38.4 g, yield 88%), Ms m / z 436.0 (M+1).

[0054] Example 7: Synthesis of 4-chloro-[7-(8-chloro-1-naphthalenyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (compound of formula e-I)

[0055]

[0056] [(2S)-1 -methylpyrrolidin-2-yl]methanol (28.8 g, 0.25 mol) and potassium tert-butoxide (28.1 g, 0.25 mol) were dissolved in 150 ml of dimethylsulfoxide, and a cooled 4-chloro-7-(8-chloronaphthalen-1 -yl)-2-(methylsulfinyl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidine (Formula d-I, 98.1 g, 0.25 mol) in 350 ml of dimethylsulfoxide was added dropwise at 0-10°C, and the reaction was continued for 0.5 h while maintaining the temperature. 600 ml of water and 800 ml of dichloromethane were added, and the mixture was stirred and separated into layers. The aqueous layer was extracted with 500 ml of dichloromethane, and the combined organic layers were washed with 600 ml of water and 500 ml of saturated brine. The organic layer was dried over 50 g of anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was stirred with n-hexane, and the mixture was filtered. The filter cake was recrystallized from a mixture of anhydrous ethanol-n-hexane, and the product was dried to obtain 4-chloro-[7-(8-chloro-1 -naphthyl)-2-[[(2S)-1 -methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (Formula e-I compound, 86.8 g, 78.3% yield, 97.8% purity). Ms m / z 443.1 (M+1), NMR (400 MHz, CDC13), δ 1.74-1.90 (m, 3H), 1.95-2.03 (m, 1H), 2.33 (d, 1H), 2.46 (s, 3H), 2.55-2.71 (m, 2H), 2.80 (s, 2H), 3.11-3.19 (m, 1H), 3.39 (s, 2H), 4.06 (s, 2H), 4.32-4.44 (m, 2H), 7.15 (d, 1H), 7.43 (t, 1H), 7.55 (d, 1H), 7.60 (d, 1H), 7.82-7.91 (m, 1H).

[0057] Example 8: Synthesis of 4-bromo-[7-(8-chloro-1 -naphthyl)-2-[[(2S)-1 -methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (Formula e-II compound)

[0058]

[0059] [(2S)-1 -methylpyrrolidin-2-yl]methanol (7.7 g, 66.7 mmol) and potassium tert-butoxide (7.5 g, 66.7 mmol) were dissolved in 60 ml of dimethyl sulfoxide, and a cooled 150 ml dimethyl sulfoxide solution of 4-chloro-7-(8-chloronaphthalen-1 -yl)-2- (methylsulfinyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (formula d-II, 29.1 g, 66.7 mmol) was added dropwise while maintaining the temperature at 0-10°C. After the dropwise addition was completed, the reaction was continued for 0.5 h while maintaining the temperature, 200 ml of water and 300 ml of dichloromethane were added, and the mixture was stirred and separated into layers. The aqueous layer was extracted with 200 ml of dichloromethane, and the combined organic layers were washed with 200 ml of water and 200 ml of saturated brine. The organic layer was dried over 10 g of anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was stirred and dispersed in n-hexane, and the mixture was filtered. The filter cake was recrystallized twice from a mixture of anhydrous ethanol-n-hexane, and the product was dried to obtain 4-bromo-[7-(8-chloro-1 -naphthyl)-2-[[(2S)-1 -methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (compound of formula e-II, 19.4 g, 59.2% yield, 96.2% purity), Ms m / z 487.1 (M+1).

[0060] Example 9: Synthesis Method 1 of Adagrasib

[0061]

[0062] To a solution of 4-chloro-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (formula e-I, 66.5 g, 0.15 mol), (S)-2-(1-(2-fluorovinylidene)piperazin-2-yl)acetonitrile (29.6 g, 0.15 mol) and N,N-diisopropyl ethylamine (38.8 g, 0.3 mol) in dimethylformamide (400 ml) was added at 50-60 °C for 8 h. The reaction mixture was cooled to room temperature and water (500 ml) and ethyl acetate (700 ml) were added. The mixture was stirred and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (500 ml) and the combined organic phase was washed with water (500 ml) and saturated brine (400 ml). The organic phase was dried over anhydrous sodium sulfate (60 g) and the solvent was removed under reduced pressure. The residue was stirred in n-hexane and filtered. The filter cake was recrystallized from a mixture of anhydrous ethanol and n-hexane and then from anhydrous ethanol. The product was dried to give adagrasib (62.2 g, 68.6% yield, 98.8% purity). Ms m / z 604.2 (M+1), NMR (400 MHz, CDC13), δ 1.71-1.88 (m, 3H), 1.98-2.10 (m, 1H), 2.22-2.37 (m, 1H), 2.49 (d, 3H), 2.53-2.92 (m, 4H), 2.98-3.33 (m, 5H), 3.34-3.65 (m, 2H), 3.68-4.22 (m, 5H), 4.32-4.51 (m, 2H), 5.10 (s, 1H), 5.83 (d, 1H), 6.35-6.47 (m, 1H), 7.18-7.25 (m, 1H), 7.33-7.38 (m, 1H), 7.45 (t, 1H), 7.53 (d, 1H), 7.64 (t, 1H), 7.78 (d, 1H).

[0063] Example 10: Synthesis of adagrasib, method 2

[0064]

[0065] Into dimethylformamide (80 ml) was added 4-bromo-[7-(8-chloro-1-naphthyl)-2-[[(2S)-1- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine (formula e-II, 14.6 g, 30 mmol), (S)-2-(1-(2-fluorovinylidene)piperazin-2-yl)acetonitrile (5.9 g, 30 mmol) and N,N-diisopropylethylamine (7.8 g, 60 mmol), and the mixture was reacted at 50-60°C for 7 h. After cooling to room temperature, 100 ml of water and 140 ml of ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted with 100 ml of ethyl acetate, and the combined organic phase was washed with 100 ml of water and 80 ml of saturated brine. The organic phase was dried over 10 g of anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was stirred and dispersed in n-hexane, and the mixture was filtered. The filter cake was recrystallized from anhydrous ethanol, and the product was dried in an oven to obtain adagrasib (13.9 g, 76.9% yield, 99.1% purity), Ms m / z 604.2 (M+1).

[0066] Compared with the prior art document adagrasib synthesis route, the route of the present application is shorter, the yield is higher, and there is no use of noble metal catalyst, no harsh reaction conditions, and no use of odorant reagent, which is of great significance for the industrialization of adagrasib.

[0067] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing adagsibu, a drug for treating lung cancer, characterized in that, The method is as follows: Step 1: Compound a and compound b undergo a CN coupling reaction to obtain intermediate compound c; Step 2: The intermediate compound c undergoes an oxidation reaction to obtain the intermediate compound d; Step 3: The intermediate compound d is reacted with [(2S)-1-methylpyrrolidone-2-yl]methanol to obtain the intermediate compound e; Step 4: The intermediate compound e is coupled with (S)-2-(1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile via CN coupling to obtain adagxib; in In compound a, X1 is selected from Br or I; In compounds b, c, and d, X2 is selected from Cl or Br. The catalyst for the coupling reaction in step 1 is (trimethylamino)pyridine 1-oxide and cesium carbonate; the molar ratio of compound b, compound a, (trimethylamino)pyridine 1-oxide and cesium carbonate is 1:2~5:0.05~0.1:2~5.

2. The method for preparing adagsibu, a lung cancer treatment drug according to claim 1, is characterized in that, The method is as follows: The oxidant used in step 2 oxidation reaction is selected from m-chloroperoxybenzoic acid, hydrogen peroxide or peroxybenzoic acid. In step 2, the molar ratio of compound c to oxidant in the oxidation reaction is 1:0.9~1.

1.

3. The method for preparing adagsibu, a lung cancer treatment drug according to claim 2, is characterized in that, The method is as follows: The catalyst for the docking reaction in step 3 is an organic base, which is selected from potassium tert-butoxide, sodium tert-butoxide or sodium ethoxide. In step 3, the molar ratio of [(2S)-1-methylpyrrolidone-2-yl]methanol, compound d, and organic base is 1: 0.9~1.1: 0.9~1.

1.

4. The method for preparing adagsibu, a lung cancer treatment drug according to claim 3, is characterized in that, The method is as follows: The coupling reaction in step 4 requires the addition of an organic base as a catalyst. The organic base is selected from N,N-diisopropylethylamine, N,N-diisopropylmethylamine, N,N-diethylmethylamine, N,N-diethylpropylamine or triethylamine. In step 4, the molar ratio of compound e, (S)-2-(1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile, and organic base is 1:0.9~1.1:1~3.

5. The method for preparing adagxib, a lung cancer treatment drug according to claim 4, is characterized in that, In step 4, the molar ratio of compound e, (S)-2-(1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile, and organic base is 1:1:2.

Images