TW202333684A - The method of the preparation of fused multicyclic compounds - Google Patents

Abstract

The present invention discloses a process for preparing quinazoline compounds of Formula (I), particularly, a process manufacturing thereof on a multikilogram scale: wherein B, D, W, Z, R1, R2, and n are defined herein.

Description

Synthetic methods of fused polycyclic compounds

The present invention relates to a method for preparing quinazoline compounds of formula (I), especially a method for preparing on a kilogram scale.

Kinase inhibitors are a type of targeted anti-cancer drugs that block the function of overexpressed and/or mutated kinases. The United States Food and Drug Administration (US FDA) has approved inhibitors for approximately 20 kinases (Roskoski, Pharmacol . Res. 2020 , 152, 104609). Many kinase inhibitors have also been registered in clinical trials and are in different stages of drug development (Lightfoot et. al., ACS Med. Chem. Lett. 2018 , 10, 153-160).

U.S. Patent No. 9,006,252 discloses a series of quinazoline-based compounds as multiple kinase inhibitors, which have potent enzyme inhibition and cell activity against a variety of solid tumor cell lines, and are used intravenously in leukemia, colorectal cancer, and other cancers. In vivo efficacy in pancreatic cancer and pancreatic cancer xenograft mouse models. The synthetic route described consists of a seven-step reaction starting from commercially available 2-amino-4-fluorobenzoic acid, and can achieve milligram-level yields. However, attempts to scale up the synthesis to gram level resulted in a decrease in yield.

Several shortcomings were also discovered when scaling up the process, including: (1) Unstable yields in the chlorination and S _N Ar steps and the final dimethyl amination step increased the total synthesis cost. ; (2) Use of unsafe NaH/DMF reagent; and (3) Several purification steps require the use of column chromatography. If applied to pharmaceuticals, it is necessary to find alternative routes that are both safe and efficient to provide kilogram quantities of these compounds in high yields and easy purification steps.

As mentioned above, there is still a need to develop reliable and scalable synthetic pathways for quinazoline compounds. The present invention relates to methods for preparing compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein B is arylene or heteroarylene; D is alkyl, alkenyl ( alkenyl, alkynyl, aryl, monocyclic heteroaryl group, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycle Alkenyl (hetrocycloalkenyl); W and Z are each N or CR ^a , R ^a is hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl radical, heterocycloalkenyl alkoxy, halogen, alkoxy amino or alkoxy alkylamino; R ¹ and R ² are each hydrogen, halogen or - OA, wherein R ¹ and R ² are not hydrogen at the same time; A is alkylamino; n is 0, 1, 2, 3 or 4; the method includes reacting the compound of formula (II) with the compound of formula (III). In some preferred embodiments, the compound of formula (I) can be obtained by recrystallization from a solvent.

In certain embodiments, the method further comprises converting a compound of Formula (IV) to a compound of Formula (III). In some preferred embodiments, the compound of formula (III) can be obtained by recrystallization from a solvent.

In certain embodiments, the method further comprises reacting a compound of Formula (V) with a compound of Formula (VI) to form a compound of Formula (IV). In some preferred embodiments, the solid compound of formula (IV) is obtained by centrifugation.

In certain embodiments, the method also includes: converting a compound of formula (VI) into a compound of formula (VI). In some preferred embodiments, the reaction mixture uses liquid-liquid extraction to remove the compound of formula (VII) to obtain the compound of formula (VI). In some preferred embodiments, liquid-liquid extraction involves adding ETOAc to the reaction mixture to collect the compound of formula (VI) therefrom.

In some preferred embodiments, the method further comprises: reacting a compound of formula (VIII) with an alkanolamine to form a compound of formula (VII); wherein X and Y are each halogen or hydrogen, and X and Y are not simultaneously Hydrogen. In other specific embodiments, the alkanolamine is a compound of formula (IX), wherein A is ; wherein R ^b and R ^c are each hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; m is 2 , 3 or 4. In some preferred embodiments, m is 3 and both R ^b and R ^c are methyl. In some preferred embodiments, the solid compound of formula (VII) is obtained by centrifugation.

In some preferred embodiments, the method further comprises reacting a compound of formula (X) with formamidine acetate to form a compound of formula (VIII). In some preferred embodiments, the compound of formula (VIII) as a solid is obtained by centrifugation.

In some preferred embodiments, ^R2 is hydrogen.

In some preferred embodiments, B is phenyl or thiazolyl. In some other preferred embodiments, B is .

In some preferred embodiments, D is a 6-membered aryl or heteroaryl. In some other preferred embodiments, D is , , , , or .

In some preferred embodiments, R ² is hydrogen and A is , B is , D is , W and Z are both CR ^a , R ^a is hydrogen, n is 2, m is 3, and R ^b and R ^c are both methyl groups.

(I) (II) (III) (IV) (V) (VI) (VII) (VIII) (IX) (X)

In this specification, alkyl, alkenyl and alkynyl groups contain about 1-20 aliphatic carbon atoms. In certain embodiments, alkyl, alkenyl and alkynyl groups used in the present invention contain about 1-10 aliphatic carbon atoms. In still other embodiments, alkyl, alkenyl and alkynyl groups used in the present invention contain about 1-8 aliphatic carbon atoms. In still other embodiments, alkyl, alkenyl and alkynyl groups used in the present invention contain about 1-6 aliphatic carbon atoms. In some embodiments, alkyl, alkenyl and alkynyl groups used in the present invention contain about 1-4 carbon atoms. Therefore, exemplified aliphatic groups include, but are not limited to, methyl, ethyl, n-propyl (n-propyl), isopropyl (isopropyl), allyl (allyl), n-butyl (n- butyl), sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl ( isopentyl), tert-pentyl (tert-pentyl), n-hexyl (n-hexyl), sec-hexyl (sec-hexyl), etc., may have one or more substituents. Alkenyl, including but not limited to ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl -yl) etc. Typical alkynyl groups include but are not limited to ethynyl, 2-propynyl (propargyl), 1-propynyl, etc.

The term "cycloalkyl" in this specification refers to a cyclic alkyl group having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., as in aliphatic, hetero In the case of aliphatic (heteroaliphatic) or heterocyclic (heterocyclic), they can be optionally substituted. Similar usage also applies to other general categories (genus), such as "cycloalkenyl", "cycloalkynyl (cycloalkynyl)", etc.

Generally speaking, the term "aryl" refers to the aromatic moiety only and does not include moieties linked by an alkyl or heteroalkyl group. In certain embodiments of the present invention, "aryl" refers to a mono- or bicyclic carbocyclic system having one or two rings that satisfy the aromaticity criterion of Hückel's rule. , including but not limited to phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, etc.

Similarly, the term "heteroaryl" refers to a heterocyclic aromatic functional group, as described above, excluding moieties attached via an alkyl or heteroalkyl group. In certain embodiments of the invention, the term "heteroaryl" refers to a cyclic unsaturated group having about 5 to 10 ring atoms, one of which is selected from S, O and N; zero, one or Two ring atoms are additional heteroatoms independently selected from S, O and N; the remaining ring atoms are carbon, connected to the rest of the molecule through any ring atom as a free radical, such as pyridyl, pyridyl pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl , thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, etc.

Substituents for aryl and heteroaryl include, but are not limited to, any of the substituents mentioned above, those aliphatic fragments that can form stable compounds, or substituents described elsewhere in this disclosure.

The term alkoxy has been previously defined to mean an alkyl group attached to the main part of the molecule through an oxygen atom. In certain embodiments, alkyl groups contain about 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl group contains about 1-10 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-8 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-6 aliphatic carbon atoms. In still other embodiments, the alkyl group contains about 1-4 aliphatic carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butyl Oxygen (tert-butoxy), neopentoxy (neopentoxy) and n-hexoxy (n-hexoxy).

The term "alkylamino" refers to a group with the structure -N(R) ₂ , where each occurrence of R is either hydrogen, aliphatic, heteroaliphatic, aromatic or heteroaromatic Group groups, or R groups together form a heterocyclic group.

The terms "halo and halogen" as used herein refer to atoms selected from the group consisting of fluorine, chlorine, bromine and iodine.

The terms "alkyl", "alkenyl", "alkynyl", "heteroalkyl", "heteroalkenyl", "heteroalkynyl", etc. are used herein. Covers substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similar terms "heterocycloalkyl", "heterocycle" and the like include substituted and unsubstituted, as well as saturated and unsaturated groups. In addition, "cycloalkyl", "cycloalkenyl", "cycloalkynyl (cycloalkynyl)", "heterocycloalkyl", "heterocycloalkenyl", "heterocycle" used alone or as part of a larger moiety "Alkynyl (heterocycloalkynyl)", "aromatic", "heteroaromatic", "aryl", "heteroaryl", etc. also include substituted groups and unsubstituted groups.

The compounds of the present invention include the general description above and the examples specifically described herein, which are illustrated in part by the various classes, superordinate and subordinate features disclosed herein. The details of one or more embodiments within the invention are set forth in the description below. Other features, objects, and advantages of the invention will be disclosed in the description and claims.

Example compounds of the present invention are shown below: Compound 1 Compound 2 Compound 3 Compound 4 Compound 5 Compound 6 Compound 7 Compound 8 Compound 9 Compound 10

The previously described seven-step medicinal chemical synthesis route encountered some problems in the scale-up synthesis method, such as low yields, the generation of inseparable impurities, especially in the chlorination step, the use of dangerous reagents (NaH/DMF) and The troublesome column chromatography product purification step (Hsu, YC, et. al. Oncotarget 2016 , 7, 86239-86256.). Methods to solve the above problems are gradually presented in the following embodiment designs. Example 1 Condensation with formamidine to synthesize compound of formula (VIII)

The compound of formula (VIII) can be obtained by reacting the compound of formula (X) with formamidine (Scheme 1); wherein W and Z are each N or CR ^a , and R ^a is hydrogen, alkyl, alkenyl, alkynyl, aromatic base, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenylalkoxy, halogen, alkoxyamino or alkoxyalkylamino; where X and Y are each halogen or Hydrogen, X and Y are not hydrogen at the same time. Preferably, the solid compound of formula (VIII) can be collected by centrifugation. plan 1

For example, quinazolinone 2 is synthesized via the condensation of starting material 1 with formamidine acetate. The following three conditions were optimized for the reaction of 10.0 g of starting material 1 (Table 1). In this reaction system, the product 2 produced is insoluble in EtOH at room temperature, and the pure product can be removed by simple centrifugation. Table 1 Item Solvent Time(h) Temperature(℃) 3Yield (%) 1 without 12 120 63 2 DMSO 4 120 83 3 tOH 40 reflow 93

Unreacted starting material 1 was successfully removed in the work-up method. Once the reaction is complete, gradually reduce the temperature to approximately 10-15°C and stir for 4 hours. The precipitated product was centrifuged to obtain a filter cake, which was washed with cold ethanol and vacuum dried at 55°C for 24 hours to obtain compound 2 .

7-Fluoroquinazolin-4(3H)-one ( 2 ) . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.35 (brs, 1H), 8.16 (dd, J = 8.8, 6.4 Hz, 1H), 8.13 (s, 1H), 7.45 (dd, J = 10.4, 2.8 Hz, 1H), 7.39 (ddd, J = 8.4, 8.8, 2.4 Hz, 1H). ¹³ C NMR (100 MHz, DMSO-d ₆ ), δ 166.8- 164.3 (d, J = 249.3 Hz), 160.0, 150.9 (d, J = 13.0 Hz), 146.8, 128.9 (d, J = 10.7 Hz), 119.6, 115.2 (d, J = 23.7 Hz), 112.3 ( d, J = 21.4 Hz). HRMS (ESI) calcd for C ₈ H ₅ FN ₂ NaO [M + Na]: 187.0283; found 187.0283. Example 2 uses alkanolamine to perform S _N Ar reaction to obtain the formula ( VII) Compounds

The compound of formula (VII) can be obtained by reacting the compound of formula (VIII) with an alkanolamine under alkaline conditions (Scheme 2); wherein W and Z are each N or CR ^a , and R ^a is hydrogen, alkyl, alkenyl, Alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenylalkoxy, halogen, alkoxyamino or alkoxyalkylamino; R ¹ and R ² is each hydrogen, halogen or -OA, wherein R ¹ and R ² are not hydrogen at the same time; A is alkylamino; wherein X and Y are each halogen or hydrogen, and X and Y are not hydrogen at the same time. In some embodiments, the alkanolamine is a compound of formula (IX). Preferably, the solid compound of formula (VII) can be collected by centrifugation. Scenario 2

Taking the synthesis of compound 4 as an example, the following reaction conditions were set to optimize kilogram-scale synthesis (Table 2). The reaction can be carried out in pure 3-(dimethylamino)propan-1-ol ( 3 ), using KOH as the base, quenching the reaction with water, and then purifying it with ethyl acetate. (ethyl acetate) extraction, product 4 was isolated in high yield (88% isolated yield) at a scale of 10.0 g. Table 2 4 Item 2 (g) Solvent Temperature(℃) Scope(%) Purity(%) 1 10.0 DMSO 140 55 98.5 2 10.0 DMSO 125 83 98.1 3 20.0 without 120 73 98.4 4 560.0 without 120 79 99.1

Preferably, a special device (Reddy et. al., Org. Process Res. Dev. 2021 , 25, 817-830) can be used to perform long-term (3 days) using ethyl acetate or CH ₂ Cl ₂ Continuous aqueous extraction. Continuous extraction with ethyl acetate, without adding 6N hydrochloric acid to adjust the pH value of the reaction mixture (pH>10), can obtain products with relatively high yield and purity (after slurry purification treatment).

7-(3-(Dimethylamino)propoxy)quinazolin-4(3H)-one ( 4 ) . ¹ H-NMR (400 MHz, DMSOd ₆ ) δ 12.07 (brs, 1H), 8.04 (s, 1H), 8.00 ( d, J = 9.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 2H), 4.13 (t, J = 6.4 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H), 2.15 (s, 6H), 1.91- 1.84 (m, 2H). 13C-NMR (100 MHz, DMSO-d ₆ ), δ 163.2, 160.2, 150.9, 145.9, 127.4, 116.3, 115.9, 108.8, 66.3, 55.5, 45.1, 26.6. HRMS (ESI) calcd for C ₁₃ H ₁₈ N ₃ O ₂ [M + H]: 248.1399; found 248.1395. Example 3 Preparation of compound of formula (VI) by chlorination

Compounds of formula (VI) can be obtained by chlorinating compounds of formula (VII) (Scheme 3); wherein W and Z are each N or CR ^a , and R ^a is hydrogen, alkyl, alkenyl, alkynyl, aryl, mono Cyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenylalkoxy, halogen, alkoxyamino or alkoxyalkylamino; R ¹ and R ² are each hydrogen, halogen or -OA, where R ¹ and R ² are not hydrogen at the same time; A is alkylamino; n is 0, 1, 2, 3 or 4. Generally, POCl ₃ , SOCl ₂ , Cl ₂ can provide chloride. Preferably, a liquid-liquid phase extraction method can be used to remove the compound of formula (VII) from the reaction mixture to purify the compound of formula (VI). Some chlorination alternatives include bromination and the introduction of functional groups such as OTf, OSO ₂ CF ₃ , SOPh, SO ₂ Ph, SO ₂ Et or SOEt, which can set up good leaving groups for subsequent S _N Ar reactions. Option 3

To efficiently produce 5 , chlorination reactions using different solvents and reaction conditions were studied (Table 3). The completion of the reaction was monitored by HPLC by simultaneously detecting the disappearance of reactant 4 and the formation of product 5 . Product purity is affected by solvent and batch size. Because it was unstable during separation, the crude product 5 was directly carried out to the next step ( _SN Ar reaction) after work-up. table 3 HPLC (%) Item 4 (g) Temperature(℃) Solvent Time(h) 5 Impurities 1 0.7 70 Toluene 2.0 77.4 19.2 2 5.0 65 CH ₃ CN 2.0 93.9 2.7 3 20.0 65 CH ₃ CN 1.5 94.1 3.0 4 108.0 70 CH ₃ CN 1.5 90.2 5.4 5 164.0 80 CH ₃ CN 8.0 96.7 2.1 Example 4 Preparation of Compound (IV) via S _N Ar Reaction

Compounds of formula (VI) and compounds of formula (V) are reacted with S _N Ar to obtain compounds of formula (IV) (Scheme 4); where B is an arylene or heteroarylene group; W and Z are each N or CR ^a , R ^a is hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl alkoxy, halogen, alkoxy Amino or alkoxyalkylamino; R ¹ and R ² are each hydrogen, halogen or -OA, wherein R ¹ and R ² are not hydrogen at the same time; A is alkylamino; n is 0, 1, 2, 3 or 4. Preferably, the solid compound of formula (IV) can be collected by centrifugation.

Different types of bases and solvent conditions were tested for the S _N Ar displacement reaction of 5 and 6 (Table 4). There are still about 3% impurities in the product that need to be removed. Impurities can be successfully removed by washing product 7 with EtOAc/MeOH (10:1.5) mixture. Table 4 HPLC (%) Item 5 (g) base Solvent Temperature(℃) Time(h) 7 Impurities 1 0.60 t ₃ i-PrOH 80 2.5 83.0 8.9 2 0.60 t ₃ tOH 80 2.5 83.3 8.0 3 5.00 K ₂ CO ₃ DMF 70 2.0 72.4 9.7 4 3.30 K ₂ CO ₃ DMAC 70 2.5 75.1 12.2 5 3.34 DIPEA i-PrOH 80 3.0 79.1 11.3 6 0.50 DIPEA tOH 80 2.0 68.3 16.5 7 1.20 DIPEA CH ₃ CN 65 7.0 96.4 3.5 8 517.30 DIPEA CH ₃ CN 65 9.0 95.0 3.3

tert-Butyl(5-(2-((7-(3-(dimethylamino)propoxy)-quinazolin-4-yl)amino)ethyl)thiazol-2-yl) Carbamate ( 7 ) . 1 H-NMR (400 ^MHz , DMSO-d ₆ ) δ 11.16 (brs, 2H), 8.41 (s, 1H), 8.24 (t, J = 5.2 Hz, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.11 (dd, J = 9.2, 2.4 Hz, 2H), 7.07 (dd, J = 8.4, 2.4 Hz, 2H), 4.12 (t, J = 6.4 Hz, 2H), 3.70 (q, J = 12.8, 6.8 Hz, 2H), 3.06 ¹³ C-NMR (100 MHz, DMSO-d ₆ ) δ 161.7, 158.9, 158.3, 155.5, 152.7, 151.3, 134.9, 128.3, 124.2, 116.9, 109.1, 107.4, 80.8, 66.1, 55.5, 45. 1, 41.7, 27.8, 26.6, 25.7. HRMS (ESI) calcd for C ₂₃ H ₃₂ N ₆ NaO ₃ S [M + Na]: 495.2154; found 495.2679. Example 5 Removal of Boc group to obtain compound of formula (II)

Removing the Boc protecting group in the compound of formula (IV) under acidic conditions can give the compound of formula (II) (Scheme 5); where B is an arylene or heteroarylene group; W and Z are each N or CR ^a , R ^a is hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl alkoxy, halogen, alkoxyamino or Alkoxyalkylamino; R ¹ and R ² are each hydrogen, halogen or -OA, wherein R ¹ and R ² are not hydrogen at the same time; A is alkylamino; n is 0, 1, 2, 3 or 4. Preferably, the compound of formula (II) can be obtained by recrystallization from a solvent. Option 5

Take the synthesis of intermediate product 8 as an example. In order to make the product purity high enough on a batch scale, compound 7 as a TFA salt is reacted with TFA in dichloromethane at a temperature of about 40-45°C to remove the Boc protecting group, and 8 can be obtained. Isolating the pure product from the reaction mixture requires a robust recrystallization method, so a mixed solvent of MTBE (methyl tert-butyl ether) and MeOH was selected. Therefore, using the above reaction and work-up methods, the intermediate product 8 can be obtained with excellent yield (99%) and HPLC purity (98.2%) without column purification.

5-(2-((7-(3-(Dimethylamino)propoxy)quinazolin-4-yl)amino)ethyl)thiazol-2-amine ( 8 ). 1 HNMR ( ⁴⁰⁰ MHz, DMSO-d ₆ ) δ 9.98 ( brs, 1H), 9.83 (brs, 1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.38 (d, J = 9.6 Hz, 1H), 7.40 (dd, J = 9.2, 2.4 Hz, 1H ), 7.25 (d, J = 2.4 Hz, 1H), 7.04 (s, 1H), 4.24 (t, J = 6.0 Hz, 2H), 3.86 (q, J = 12.4, 6.4 Hz, 2H), 3.25 (brs , 2H), 3.03 (t, J = 6.4 Hz, 2H), 2.83 (s, 6H), 2.22-2.15 (m, 2H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ), δ 169.6, 163.6 , 160.1, 158.9 (q, J = 64.9, 32.8 Hz, C=O, trifluoroacetic acid), 151.4, 140.2, 125.7 (d, J = 98.4 Hz), 121.4 (CF ₃ , trifluoroacetic acid), 118.4 (d, J = 31.3 Hz), 115.3, 106.9, 101.2, 65.9, 53.9, 42.2, 41.8, 25.5, 23.6. HRMS (ESI) calcd for C ₁₈ H ₂₅ N ₆ OS [M + H]: 373.1810; found 373.1807. Example 6 Formation of urea bond to prepare compound (I)

The compound of formula (I) can be obtained by reacting the compound of formula (III) with the compound of formula (II) under alkaline conditions (Scheme 6); where B is an arylene or heteroarylene group; D is an alkyl or alkenyl group. base, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; W and Z are each N or CR ^a , R ^a is hydrogen, alkyl, Alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenylalkoxy, halogen, alkoxyamino or alkoxyalkylamino; R ¹ and R ² are each hydrogen, halogen or -OA, wherein R ¹ and R ² are not hydrogen at the same time; A is alkylamino; n is 0, 1, 2, 3 or 4. Preferably, the compound of formula (I) can be obtained by recrystallization from a solvent. Option 6

For example, in the coupling reaction to synthesize compound 10 , the reaction of intermediate product 8 and isocyanate (3-chlorophenyl isocyanate) ( 9 ) was carried out in DCM, and Et ₃ N was used as base. Solvent systems for generating urea bonds were screened as follows (Table 5). Use CH ₂ Cl ₂ /CH ₃ CN (1:1) mixed solvent to complete the reaction, and use CH ₃ CN and MeOH (1:1) mixed solution to recrystallize and separate. Compound 10 can be obtained in good yield. During the reaction, CH ₂ Cl ₂ /CH ₃ CN (1:1) solvent system can avoid the formation of glue. In addition, it was also found that the moisture content of the starting material needs to be reduced to a minimum so that 8 can be completely consumed in the reaction, thereby obtaining high-purity compound 10 . table 5 10 Item 8 (g) Solvent Time(h) Yield (%) Purity(%) 1 10.0 CH ₂ Cl ₂ 12 65.2 89.4 2 10.0 CH ₂ Cl ₂ /MeOH 12 66.0 96.5 3 16.6 CH ₂ Cl ₂ /CH ₃ CN 5 69.3 96.9 4 130.0 CH ₂ Cl ₂ /CH ₃ CN 5 92.9 97.7

1-(3-Chlorophenyl)-3-(5-(2-((7-(3-(dimethylamino)-propoxy)quinazolin-4-yl)amino)ethyl)thiazol-2-yl)urea ( 10 ). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (brs, 1H), 9.20 (brs, 1H), 8.41 (s, 1H), 8.25 (t, J = 5.6 Hz, 1H), 8.11 (d , J = 9.2 Hz, 1H), 7.70 (s, 1H), 7.33-7.28 (m, 2H), 7.11 (dd, J = 9.2, 3.2 Hz, 2H), 7.05 (m, 2H), 4.12 (t, J = 6.4 Hz, 2H), 3.72 (q, J = 12.8, 6.8 Hz, 2H), 3.07 (t, J = 7.2 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.15 (s, 6H), 1.92-1.85 (m, 2H). ¹³ C-NMR (100 MHz, DMSO-d ₆ ) δ 161.7, 159.2, 158.9, 155.6, 152.5, 151.3, 140.5, 133.2, 132.7, 130.4, 127.3 , 124.2, HRMS (ESI) calcd for C ₂₅ H ₂₈ ClN ₇ NaO ₂ S [M + Na]: 548.1611; found 548.15 98. Examples Total synthesis of compounds of formula (I) on a scale of 7 kilograms

Here, a practical, scale-up operation method that can produce compound 10 up to 3 kg is demonstrated. The optimized mass production method is to perform a six-step sequence reaction on a kilogram scale in a laboratory with kilogram scale facilities. All steps provide the product in solid form, and high purity products are obtained by centrifugation directly from the reaction mixture or by recrystallization from the solvent.

Put ethanol (70.0 kg) and 2-amino-4-fluorobenzoic acid ( 1 ) (9.70 kg, 62.52 mol, equivalent 1.0) into a 200.0 L glass-lined jacketed reactor (glass-lined jacketed reactor). The resulting reaction mixture was stirred at room temperature and formamidine acetate (13.13 kg, 125.04 moles, 2.0 equiv) was added in one portion. The reaction mixture was heated, refluxed and stirred for 2 days. When HPLC analysis shows that the remaining starting material 1 is less than 4%, gradually reduce the batch temperature to 10-15°C and maintain the temperature for 4 hours. While the internal temperature was maintained at 10-15°C, the compound began to precipitate. The reaction mixture was centrifuged and the filter cake was rinsed with ethanol (8.0 kg). The wet filter cake was vacuum dried in an oven at 55°C for 24 hours to obtain off-white solid compound 2 (9.17 kg, 89.4%), with a purity of 99.8% measured by HPLC.

Another 200.0 L glass-lined jacketed reactor was charged with 3-(dimethylamino)propan-1-ol ( 3 ) (31.62 kg, 306.59 mol, Equivalent 5.5) and powdered KOH (12.51 kg, 222.98 mol, Equivalent 4.0). The resulting reaction mixture was warmed to 120°C and stirred for 1 hour. Then, quinazolinone 2 (9.15 kg, 55.75 mol, equiv. 1.0) was added to the reactor at the same temperature. The reaction mixture was stirred at the same temperature for 8 hours; HPLC analysis showed that only 0.3% of 2 remained (Rt = 6.9 minutes). The reaction mixture was cooled to 15°C and _H2O (100.0 L) was added dropwise to the reactor over 1 hour, maintaining the internal temperature at 20-25°C. The resulting reaction mixture was continuously extracted with EtOAc (650.0 kg) in a liquid-liquid phase continuous extractor (Reddy et. al., Org. Process Res. Dev. 2021, 25, 817-830) for 3 days. Finally, the aqueous phase was extracted twice with a mixture of EtOAc (150.0 kg × 2) and EtOH (10.0 kg × 2); the combined organic phase was concentrated under vacuum at 50°C to a volume of approximately 55.0 L. The mixture was treated with EtOH (5.0 kg) and heated to 45°C for 1 h. The temperature of the solution was lowered to 15°C and maintained for about 2 hours to allow the product to precipitate. The mixture was centrifuged, the solids were collected, and the filter cake was washed with a mixture of EtOAc (4.9 kg) and EtOH (0.46 kg) to obtain 11.20 kg of wet cake. The wet filter cake was vacuum dried in a 45°C oven for 18 hours to obtain the target product 4 (9.22 kg, 66.9%) as a white solid with an HPLC purity of 98.5%.

Charge CH ₃ CN (7.8 kg) and 4 (1.64 kg, 6.63 mol, equivalent 1.0) into a 50.0 L glass-lined jacketed reactor at room temperature and stir. Additionally, POCl ₃ (2.03 kg, 13.26 mol, equiv. 2.0) was added to the reaction mixture over a period of 10 minutes while maintaining the batch temperature below 30 °C. The temperature was increased to approximately 80°C during 45 minutes (the reaction mixture was clear at 56°C) and maintained for 8 hours. Reaction completion was confirmed by HPLC showing that approximately 1% of unreacted starting material remained. The reaction was cooled to approximately 35°C over ₁ hour, _CH2Cl2 (46.0 kg) was added, and then transferred to a dropping tank. Transfer the reaction mixture in the drip tank to a 200.0 L reactor containing 12.5% K ₂ HPO ₄ quenching aqueous solution (97.4 kg) during 20 minutes and maintain the temperature at -5 to +5°C to achieve the target pH value 4-5. Then, 50% K ₂ CO ₃ aqueous solution (14.8 kg) was added to the reactor during 20 minutes, maintaining the temperature at 5-15 °C until the pH value was 9-10. The reaction mixture was stirred at approximately 15°C for 20 minutes and allowed to stand to separate. The organic layer was separated and the aqueous layer was washed again with _CH2Cl2 ( _46.0 kg). The combined organic phases were washed with 5% brine (33.0 kg) and dried over Na ₂ SO ₄ (6.6 kg) for 2 h. The reaction mixture was filtered and washed with CH ₂ Cl ₂ (13.0 kg). The purity of the filtrate was determined to be 96.7% by HPLC. Since the chlorinated product 5 is unstable, the above filtrate is directly used for the next reaction.

Compound 6 (1.45 kg, 5.97 mol, 0.9 equivalent) was added directly to filtrate 5 from the previous step. The reaction mixture was then concentrated in vacuo at 20°C to a volume of approximately 2.5 L and _CH3CN (8.2 kg) was added and concentrated to a volume of approximately 4.1 L. The reaction mixture was transferred to a 50.0 L reactor and CH ₃ CN (6.6 kg) and DIPEA (0.856 kg, 6.63 mol, equiv. 1.0) were added. The reaction mixture was heated to 55°C for 2 hours; the batch temperature was then increased to 65°C over a 30 minute period for 2 hours with continued stirring. . At this temperature another batch of compound 6 (0.161 kg, 0.663 mol, 0.1 equiv) was added to the reactor. The reaction temperature was raised to 75°C and stirred for 4 hours. The reaction mixture was sampled and analyzed by HPLC, and 3.5% of unreacted starting material 5 was detected. Then, MeOH (0.62 L) was added to the reactor while maintaining the temperature at approximately 65°C for 1 h. The reaction mixture was cooled to 20°C over 2 hours. The reaction mixture was stirred for about 5 hours and then centrifuged to obtain a crude filter cake, which was washed with a mixture of CH ₃ CN (7.0 kg) and MeOH (0.40 kg) to obtain 4.56 kg of wet cake of compound 7 , with an HPLC purity of 89.5%. A solution of EtOAc (6.32 kg) and MeOH (1.26 kg) and 4.56 kg of wet cake were placed in a 50L reactor and heated to 85°C for 12 hours. Then, the reaction temperature was cooled to 20°C over a period of 2.5 hours and maintained for 3 hours. The reaction mixture was centrifuged and the filter cake was washed with EtOAc (4.0 kg) to obtain 1.30 kg of product. The wet filter cake was vacuum dried in an oven at 50°C for 10 hours to obtain product 7 (1.22 kg, two-step yield 38.9%) as a light brown solid, with a purity of 96.8% measured by HPLC.

The 100.0 L jacketed reactor was vented with nitrogen and charged with compound 7 (4.00 kg, 8.46 mol, equivalent 1.0) and CH ₂ Cl ₂ (42.2 kg). Trifluoroacetic acid (15.20 kg, 132.88 mol, 15.7 eq.) was added dropwise to the reactor over a period of 1 hour while maintaining the reaction temperature below 30°C. The resulting reaction mixture was heated to 45°C and stirred at this temperature for approximately 6 hours. When HPLC analysis showed <1% of 7 remaining, the reaction was concentrated to approximately 10.0 L volume. Subsequently, MeOH (3.2 kg) and MTBE (12.0 kg) were added to the reactor and stirred at room temperature for about 6 h. The reaction mixture was filtered and the solid was washed with MTBE (12.0 kg). The wet filter cake was dried in a vacuum oven at 50°C for about 2 days to obtain 5.85 kg (~99%) of white solid 8 , with a purity of 98.2% measured by HPLC.

Pour nitrogen into the 200.0L jacketed reactor, add 8 (5.57 kg, 8.05 mol, equivalent 1.0), CH ₂ Cl ₂ (61.0 kg) and anhydrous CH ₃ CN (36.8 kg), and stir continuously at 32°C. Then, Et ₃ N (2.80 kg, 27.60 mol, equiv. 3.43) was added over 15 min at this temperature and stirred for 10 min. Next, 3-chlorophenyl isocyanate (2.06 kg, 13.44 mol, equivalent 1.67) was added at this temperature over a period of 5 minutes, and the reaction mixture was kept at about 35°C and stirred for about 4 hours; HPLC analysis determined that less than 0.07% of starting material 8 was unreacted. The reaction was cooled to 25°C for 1 hour, and the reaction mixture was recrystallized with CH ₃ CN (46.0 kg) and MeOH (36.8 kg) solvents, and centrifuged to obtain a cake-like product. The wet filter cake was vacuum dried in an oven at 50°C for at least 12 hours to obtain the final product 10 (3.04 kg, 71.8%) as a white solid with a purity of 97.8% and a single maximum impurity of about 0.6-0.7%. At , the purity was 97.2%.

Although a number of embodiments of the invention have been described, it will be apparent that the basic embodiments of this specification may be substituted and modified to provide other embodiments utilizing the compounds and methods of the invention. It is therefore to be understood that the scope of the invention will be defined by the appended claims rather than by the specific embodiments that have been expressed by way of example.

without.

without.

Claims (22)

A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, ; (I) Where B is arylene or heteroarylene; D is alkyl, alkenyl, alkynyl, aryl, monocyclic Monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; W and Z are each N or CR ^a , R ^a is hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenylalkoxy, halogen, alkoxyamino or alkyl Oxyalkylamino; R ¹ and R ² are each hydrogen, halogen or , wherein R ¹ and R ² are not hydrogen at the same time; A is an alkylamino group; n is 0, 1, 2, 3 or 4; and the method includes: reacting the compound of formula (II) with the compound of formula (III). (II) (III) The method of claim 1 further includes: converting the compound of formula (IV) into the compound of formula (III). (IV) The method of claim 2, further comprising: reacting the compound of formula (V) with the compound of formula (VI) to form the compound of formula (IV). (V) (VI) The method of claim 3 further includes: converting the compound of formula (VII) into the compound of formula (VI). (VII) The method of claim 4, further comprising: reacting a compound of formula (VIII) with an alkanolamine to form a compound of formula (VII); wherein X and Y are each halogen or hydrogen, and X and Y are not hydrogen at the same time. (VIII) The method of claim 5, wherein the alkanolamine is a compound of formula (IX) (IX) The method of claim 5 further includes: reacting the compound of formula (X) with formamidine acetate to form the compound of formula (VIII). (X) Such as the method of request item 6, where A is ;wherein R ^b and R ^c are each hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl; m is 2 , 3 or 4. Such as the method of claim 8, wherein m is 3, R ^b and R ^c are both methyl groups. The method of claim 1, wherein R ² is hydrogen. Such as the method of claim 1, wherein B is phenyl or thiazolyl. Such as the method of request item 11, where B is . The method of claim 1, wherein D is a 6-membered ring aryl group or heteroaryl group. Such as the method of request item 13, where D is , , , , or . The method of claim 1, wherein R ² is hydrogen and A is , B is , D is , W and Z are both CR ^a , R ^a is hydrogen, n is 2, m is 3, R ^b and R ^c are both methyl groups. The method of claim 1, wherein the compound of formula (I) is obtained by recrystallization from a solvent. The method of claim 2, wherein the compound of formula (III) is obtained by recrystallization from a solvent. The method of claim 3, wherein the compound of formula (IV) is obtained from the solid matter obtained by centrifugation. The method of claim 4, wherein the compound of formula (VI) is obtained by removing the compound of formula (VII) from the reaction mixture using liquid-liquid extraction. The method of claim 19, wherein the liquid-liquid phase extraction is performed by adding ETOAc to the reaction mixture and collecting the compound of formula (VI) therein. The method of claim 5, wherein the compound of formula (VII) is obtained from the solid matter obtained by centrifugation. The method of claim 7, wherein the compound of formula (VIII) is obtained from the solid matter obtained by centrifugation.