JP7416842B2 - Method for preparing fused polycyclic compounds - Google Patents

Description

Application of Article 30, Paragraph 2 of the Patent Act February 18, 2021 Org. Process Res. Dev. , 2021, Vol. 25, pp. Published at 817-830

The present invention relates to a method for preparing fused polycyclic compounds.

Kinase inhibitors are a class of targeted anti-cancer drugs that block overexpressed and/or mutant kinase function. The US FDA (US Food and Drug Administration) has approved several inhibitors that target approximately 20 kinases (Non-Patent Document 1). Furthermore, a large number of kinase inhibitors have been enrolled in clinical trials and are at different stages of drug development (Non-Patent Document 2).

US Pat. No. 5,001,001 describes the drug as a multi-kinase inhibitor with potent enzymatic and cellular activity in multiple solid tumor cell lines and in vivo efficacy in leukemia, colorectal and pancreatic xenograft mouse models when administered intravenously. discloses a series of quinazoline compounds. The reported synthetic route consisted of seven steps (milligram yield) from commercially available 2-amino-4-fluorobenzoic acid. However, scaling up to gram-scale synthesis resulted in decreased yields.

During scale-up synthesis, (i) variable yields during chlorination and S _N argon steps and final dimethyl amination step, increasing the total cost of synthesis, (ii) use of unsafe reagents NaH/DMF, and (iii) several drawbacks were also identified, including the need for several column chromatography purification steps. For pharmaceutical applications, it is necessary to seek alternative, safe, and efficient routes to provide kilograms of these compounds in high yields in easy-to-purify steps. .

U.S. Patent No. 9,006,252

Roskoski, Pharmacol. Res. 2020, 152, 104609 Lightfoot et. al., ACS Med. Chem. Lett. 2018, 10, 153-160

As mentioned above, there remains a need for the development of robust scale-up synthetic routes for quinazoline compounds.

A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein B is heteroarylene and D is alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group, W and Z are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenylalkoxy, halogen , an alkoxyamino group, or an alkoxyalkylamino group, and R ¹ and R ² are independently hydrogen, halogen or OA, where R ¹ and R ² are not both hydrogen. A is an alkylamino group. n is 0, 1, 2, 3 or 4 and relates to a method comprising reacting a compound of formula (II) with a compound of formula (III). In some preferred embodiments, the compound of formula (I) is recrystallized from a solvent.

In certain embodiments, the method further comprises converting the compound of formula (IV) to the compound of formula (III). In some preferred embodiments, the compound of formula (III) is recrystallized from a solvent.

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

In certain embodiments, the method further comprises converting the compound of formula (VII) to the compound of formula (VI). In some preferred embodiments, the compound of formula (VI) is provided by removing the compound of formula (VII) from the mixture using liquid-liquid extraction. In some preferred embodiments, liquid-liquid extraction is performed by adding ETOAc (ethyl acetate) to the mixture and collecting the compound of formula (VI) therein.

In certain embodiments, a process further comprising reacting a compound of formula (VIII) with an alkanolamine to produce a compound of formula (VII), wherein X and Y are independently Halogen or hydrogen, and both X and Y are not hydrogen. In certain other embodiments, the alkanolamine is a compound of formula (IX), where A is structure (1).

Here, R ^b and R ^c are independently hydrogen, alkyl, alkenyl, alkynyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl or heterocycloalkenyl group. m is 2, 3 or 4. In some preferred embodiments, m is 3 and each R ^b and R ^c is a methyl group. In some other preferred embodiments, the compound of formula (VII) is provided as a solid by centrifugation.

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

In some preferred embodiments, R ² is hydrogen.

In some preferred embodiments, B is a thiazolyl group. In some other preferred embodiments, B is structure (2).

In some preferred embodiments, D is a 6-membered aryl or heteroaryl group. In some other preferred embodiments, D is structure (3), structure (4), structure (5), structure (6), or structure (7).

In some preferred embodiments, R is hydrogen, A is structure (1), B ^is structure (2), D is structure (3), and W is Z is CR ^a , R ^a is hydrogen, n is 2, m is 3, and each R ^b and R ^c is a methyl group.

(definition)
In certain embodiments, the alkyl, alkenyl, and alkynyl groups used in the invention contain about 1-20 aliphatic carbon atoms. In certain other embodiments, the alkyl, alkenyl, and alkynyl groups used in the invention contain about 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups used in the invention contain about 1-8 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups used in the invention contain about 1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups used in the invention contain about 1-4 carbon atoms. Exemplary aliphatic groups are thus, for example, methyl, ethyl, n-propyl, isopropyl, aryl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert- It may itself have one or more substituents, including, but not limited to, pentyl, n-hexyl, sec-hexyl moieties, and the like. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl, and similar groups.

The term "cycloalkyl" as used herein specifically refers to cyclic alkyl groups having 3 to 7, preferably 3 to 10 carbon atoms. Suitable cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., which may be optionally substituted, such as in the case of aliphatic, heteroaliphatic or heterocyclic moieties. Not limited to these. Similar conventions apply to other common terms such as "cycloalkenyl", "cycloalkynyl", etc.

In general, the term "aryl" refers to an aromatic moiety as described above, except for those attached through an alkyl or heteroalkyl group. In certain embodiments of the invention, "aryl" refers to a monocyclic or bicyclic carbocyclic ring system having one or two rings that satisfy Huckel's rule for aromaticity, phenyl, Examples include, but are not limited to, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.

Similarly, the term "heteroaryl" refers to a heteroaromatic group as described above, except when attached through an alkyl or heteroalkyl group. In certain embodiments of the invention, the term "heteroaryl" as used herein refers to a cyclic unsaturated group having about 5 to about 10 ring atoms, one ring atom of which , S, O and N, zero, one or two ring atoms are additional heteroatoms independently selected from S, O and N, and the remaining ring atoms are e.g. , pyrazinyl, pyrimidinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, etc.

Substituents for aryl and heteroaryl groups include any of the substituents previously mentioned, i.e. those listed for aliphatic moieties or for other moieties as disclosed herein. including, but not limited to, resulting in the production of stable compounds.

The term "alkoxy," as used herein, refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. In certain embodiments, alkyl groups contain about 1-20 aliphatic carbon atoms. In certain other embodiments, alkyl groups contain about 1-10 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-8 aliphatic carbon atoms. In yet other embodiments, the alkyl group contains about 1-6 aliphatic carbon atoms. In yet 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-butoxy, neopentoxy, and n-hexoxy.

The term "alkylamino" refers to a group having the structure -N(R) ₂ , where each occurrence of R is independently hydrogen, or aliphatic, heteroaliphatic, aromatic or hetero The R groups may be aromatic or taken together to form a heterocyclic group.

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

As used herein, the terms "alkyl," "alkenyl," "alkynyl," "heteroalkyl," "heteroalkenyl," "heteroalkynyl" and the like include substituted and unsubstituted, saturated and unsaturated, and straight chain and branched groups. Similarly, the terms "heterocycloalkyl", "heterocycle" and the like include substituted and unsubstituted groups, as well as saturated and unsaturated groups. Additionally, the terms "cycloalkyl", "cycloalkenyl", "cycloalkynyl", "heterocycloalkyl", "heterocycloalkenyl", "heterocycloalkynyl", "aromatic", "heteroaromatic", "aryl" , "heteroaryl" and the like, used alone or as part of a larger moiety, include both substituted and unsubstituted groups.

Compounds of the invention are exemplified in part by the various classes, subgenera, and species disclosed herein, including those described generally above and specifically described herein. The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

Shown below are exemplary compounds of the invention.

A previously reported medicinal chemistry synthesis route with seven steps suffers from low yields, the formation of unseparable impurities especially in the chlorination step, the use of hazardous reagents (NaH/DMF), and the difficulty of product purification. Several problems were encountered during the scale-up synthesis, such as the laborious column chromatography step for ([Reference Non-Patent Document 1] Hsu, Y. C., et. al. Oncotarget 2016, 7, 86239-86256. ). A stepwise approach to overcome the above problems was planned in the following examples.

(Example 1)
(Synthesis of compound of formula (VIII) by condensation with formamidine)
Compounds of formula (VIII) can be obtained by reacting compounds of formula (X) with formamidine (Figure 1). In the formula, W and Z are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, heterocycloalkyl, heterocycloalkenylalkoxy, halogen, alkoxyamino, or alkoxyalkylamino group is N or CR ^a , R ^a . where X and Y are independently halogen or hydrogen, and both X and Y are not hydrogen. Preferably, the compound of formula (VIII) is provided as a solid by centrifugation.

As an example, compound 2, a quinazolinone, was synthesized from the starting material compound 1 by condensation with formamidine acetate. To optimize this reaction for a 10.0 g scale of starting compound 1, the following three conditions were studied (Table 1). In this reaction system, the obtained compound 2 was not soluble in EtOH at room temperature, facilitating easy isolation of the pure product by simple filtration.

The unreacted starting material Compound 1 could be successfully removed in the work-up step. Once the reaction was complete, the batch temperature was gradually lowered to about 10-15° C. and stirred for 4 hours. The precipitated product was centrifuged to yield a cake, rinsed with cold EtOH and dried under vacuum at 55° C. for 24 hours to yield compound 2.

7-fluoroquinazolin-4(3H)-one (product 2).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 12.35 (brs, 1H), 8.16 (dd, J = 8.8, 6.4Hz, 1H), 8.13 (s, 1H), 7.45 (dd, J=10.4, 2.8 ¹³ C NMR (100MHz, DMSO-d ₆ ), δ 166.8-164.3 (d, J=249.3Hz), 160.0, 150.9 ( HRMS (ESI) calcd for C ₈ H ₅ FN ₂ NaO [M + Na]: 187.0283; found 187.0283.

(Example 2)
(Formation of compound of formula (VII) by SNAr attack with alkanolamine)
Compounds of formula (VIII) can be obtained by reacting compounds of formula (VIII) with alkanolamines under basic conditions (Figure 2), where W and Z are independently hydrogen, alkyl , alkenyl, alkynyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkenyl, heterocycloalkenylalkoxy, halogen, alkoxyamino, or alkoxyalkylamino group. R ¹ and R ² are independently hydrogen, halogen, or OA, where R ¹ and R ² are both not hydrogen. A is an alkylamino group. X and Y are independently halogen or hydrogen, and both X and Y are not hydrogen. In some embodiments, the alkanolamine has Fomura (IX). Preferably, the compound of formula (VII) is provided as a solid by centrifugation.

Taking the synthesis of compound 4 as an example, reaction conditions were set to optimize for kilogram scale synthesis (Table 2). The reaction can proceed in pure 3-(dimethylamino)propan-1-ol (compound 3) using KOH as the base, the reaction is quenched with water, and then the product, compound 4, is treated with acetic acid. It was isolated in good yield (88% isolated yield) in a 10.0 g scale reaction by ethyl extraction.

Preferably, special equipment ([Reference _Non -Patent Document ₂ ] Reddy et. al., Org. Process Res. Dev. 2021, 25, 817-830) was used. Sequential extraction with EtOAc (ethyl acetate) without pH adjustment by adding 6N HCl to the reaction mixture (pH>10) yields the desired product in relatively good yield and purity (after slurry purification discard). Compound 4 is provided.

7-(3-(dimethylamino)propoxy)quinazolin-4(3H)-one (compound 4).
¹ H-NMR (400MHz, DMSOd ₆ ) δ 12.07 (brs, 1H), 8.04 (s, 1H), 8.00 (d, J=9.6 Hz, 1H), 7.08 (t, J=7.6Hz, 2H), 4.13 (t, J=6.4Hz, 2H), 2.37 (t, J=6.8Hz, 2H), 2.15 (s, 6H), 1.91-1.84 (m, 2H). ¹³ C-NMR (100MHz, 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)
(Production of compound of formula (VI) by chlorination)
Compounds of formula (VI) can be obtained by chlorination of compounds of formula (VII) (Figure 3), where W and Z are independently hydrogen, alkyl, alkenyl, alkynyl, alkynyl, aryl. , monocyclic heteroaryl, cycloalkenyl, heterocycloalkenylalkoxy, halogen, alkoxyamino, or alkoxyalkylamino group, N or CR ^a , R ^a , and R ¹ and R ² are independently hydrogen, halogen, or OA, where R ¹ and R ² are not both hydrogen. A is an alkylamino group. n is 0, 1, 2, 3, or 4. Typically, POCl ₃ , SOCl ₂ , Cl ₂ can be utilized as chloride donors. Preferably, the compound of formula (VI) is provided by removing the compound of formula (VII) from the reaction mixture using liquid-liquid extraction. Some alternatives to chlorination include bromination and introduction of OTf, OSO ₂ CF ₃ , SOPh, SO ₂ Ph, SO ₂ Et, SOEt, etc., with a good leaving group to follow the S _N Ar reaction. Set.

Chlorination reactions with different solvents and reaction conditions were investigated for efficient preparation of compound 5 (Table 3). Completion of the reaction was monitored using HPLC both by monitoring the disappearance of reactant Compound 4 and the formation of product Compound 5. Product purity was influenced by both reaction solvent and reaction batch size. The crude product, compound 5, was not stable upon isolation and was used directly in the next step (S _N argon reaction) after work-up.

(Example 4)
(Preparation of compound of formula (IV) by S _N argon reaction)
A compound of formula (IV) is a compound of formula (V) (Figure 4) and a compound of formula (VI) (wherein B is arylene or heteroarylene; W and Z are independently hydrogen, alkyl, alkenyl, N or CR A , R ^A is an alkynyl, alkynyl, ^aryl , monocyclic heteroaryl, cycloalkyl, heterocycloalkenylalkoxy, halogen, alkoxyamino, or alkoxyalkylamino group. R ¹ and R ² are independently is hydrogen, halogen, or OA, where both R ¹ and R ² are not hydrogen, A is an alkylamino group, and n is 0, 1, 2, 3, or 4). It can be obtained by performing an _Ar reaction between the compound and the compound of formula (VI). Preferably, the compound of formula (IV) is provided as a solid by centrifugation.

The S _N argon substitution reaction of Compound 5 and Compound 6 was tested using different base types and solvent conditions (Table 4). It was necessary to remove the approximately 3% level of impurities present in the final product. The use of EtOAc/MeOH (10:1.5) solvent mixture to wash the product compound 7 successfully removed the impurities.

t-Butyl (5-(2-(7-(3-(dimethylamino)propoxy)-quinazolin-4-yl)amino)ethyl)thiazol-2-yl)carbamate (Compound 7).
¹ H-NMR (400MHz, 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, 2.4Hz, 2H), 4.12 (t, J=6.4Hz, 2H), 3.70 (q, J=12.8, 6.8 Hz, 2H), 3.06 (t, J=6.8Hz, 2H), 2.38 (t, J=7.2Hz, 2H), 2.15 (s, 6H), 1.92-1.85 (m, 2H), 1.44 (s, 9H) ). ¹³ C-NMR (100MHz, 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 yields compound of formula (II))
Compounds of formula (II) can be obtained from compounds of formula (IV) by removing the Boc protecting group under acidic conditions (Figure 5), where B is arylene or heteroarylene. W and Z are independently hydrogen, alkyl, alkenyl, alkynyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, heterocycloalkenylalkoxy, halogen, alkoxyamino, or alkoxyalkylamino. R ¹ and R ² are independently hydrogen, halogen, or OA, where R ¹ and R ² are both not hydrogen. A is an alkylamino group. n is 0, 1, 2, 3, or 4. Preferably, the compound of formula (II) is recrystallized from a solvent.

The synthesis of intermediate Compound 8 was taken as an example. To obtain high purity on bulk scale, compound 7 was reacted with TFA in dichloromethane at about 40-45° C. to remove the Boc protecting group, yielding compound 8 as the TFA salt. Isolation of pure product from the reaction mixture required a robust recrystallization procedure using MTBE (methyl tert-butyl ether) and MeOH solvent mixture. As a result, using the above reaction and work-up method, the intermediate compound 8 was obtained in excellent yield (99%) and HPLC purity (98.2%) without the need for column purification. .

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

(Example 6)
(Urea bond formation to provide compound of formula (I))
Compounds of formula (I) can be obtained by reacting compounds of formula (III) with compounds of formula (II) under basic conditions (Figure 6), where B is arylene or heteroarylene; , D is an alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, heteroalkyl, cycloalkenyl, heteroalkenyl, heterocycloalkenyl, or heterocycloalkenyl group, and W and Z are independently hydrogen , alkyl, alkenyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenylalkoxy, halogen, alkoxyamino, or alkoxyalkylamino group, and R ¹ and R ² are independently hydrogen, halogen or OA, where R ¹ and R ² are not both hydrogen. n is 0, 1, 2, 3 or 4. Preferably, the compound of formula (I) is recrystallized from a solvent.

For example, compound 10 was synthesized using a coupling reaction between intermediate compound 8 and 3-chlorophenylisocyanate (compound 9) carried out in DCM using Et ₃ N as the base. Solvent systems were screened for urea bond formation (Table 5). Compound 10 was completed in good yield in a CH ₂ Cl ₂ /CH ₃ CN (1:1) solvent mixture and was isolated by recrystallization from a CH ₃ CN and MeOH (1:1) mixture. The CH ₂ Cl ₂ /CH ₃ CN (1:1) solvent system avoided sticky gel formation during the reaction process. Furthermore, it was found that the water content of the starting material needs to be kept to a minimum so that compound 8 can be completely consumed during the reaction in order to obtain compound 10 in high purity.

1-(3-chlorophenyl)-3-(5-(2-(7-(3-(dimethylamino)-propoxy)quinazolin-4-yl)amino)ethyl)thiazol-2-yl)urea (compound 10) ．．
¹ H-NMR (400MHz, DMSO-d ₆ ) δ 10.64 (brs, 1H), 9.20 (brs, 1H), 8.41 (s, 1H), 8.25 (t, J=5.6Hz, 1H), 8.11(d, J=9.2Hz, 1H), 7.70 (s, 1H), 7.33-7.28 (m, 2H), 7.11 (dd, J=9.2, 3.2Hz, 2H), 7.05 (m, 2H), 4.12(t, J =6.4Hz, 2H), 3.72(q, J=12.8, 6.8Hz, 2H), 3.07 (t, J=7.2Hz, 2H), 2.38 (t, J=7.2Hz, 2H), 2.15 (s, 6H) ), 1.92-1.85 (m, 2H). ¹³ C-NMR (100MHz, 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, 122.0, 117.8, 116.9, 109.1, 107.4, 66.0, 55.5, 45.1, 41.6, 26.6, 25.8. HRMS (ESI) calcd for C ₂₅ H ₂₈ ClN ₇ NaO ₂ S [M + Na]: 548.1611; found 548.1598.

(Example 7)
(Kilogram scale total synthesis of compounds of formula (I))
Here we demonstrate a practical and scale-up procedure that can be operated on a 3 kg scale for the production of compound 10. The optimized process manufacturing was performed on a multi-kilogram scale in a kilolab facility using a six-step reaction sequence. All steps provided the product as a solid and either centrifuged directly from the reaction mixture or recrystallized from the solvent to obtain the product in high purity.

A 200.0 L glass-lined jacketed reactor was charged with ethanol (70.0 kg) and 2-amino-4-fluorobenzoic acid (compound 1) (9.70 Kg, 62.52 moles, 1.0 equivalents). I entered. The resulting mixture was stirred at room temperature and then formamidine acetate (13.13 kg, 125.04 mol, 2.0 eq.) was added in one portion at the same temperature. The reaction mixture was heated to reflux and stirred for 2 days. When HPLC analysis showed less than 4% starting material Compound 1 remained, the batch temperature was gradually lowered to 10-15° C. and stirred at that temperature for 4 hours. The compound was precipitated, the mixture was centrifuged, and the cake was rinsed with ethanol (8.0 Kg) while maintaining the internal temperature at 10-15°C. The wet cake was dried in an oven under vacuum at 55° C. for 24 hours to yield compound 2 (9.17 kg, 89.4%) as an off-white solid with an HPLC purity of 99.8%.

In a separate 200.0 L glass-lined jacketed reactor were placed 3-(dimethylamino)propan-1-ol (compound 3) (31.62 kg, 306.59 mol, 5.5 eq) and powdered KOH (12.51 kg). , 222.98 mol, 4.0 eq). The resulting mixture was warmed to 120°C and stirred for 1 hour. The quinazolinone, Compound 2 (9.15 kg, 55.75 mol, 1.0 eq.) was then added to the reactor at that temperature. The reaction mixture was stirred at the same temperature for 8 hours. HPLC analysis showed only 0.3% of compound 2 remained (Rt=6.9 min). The mixture was cooled to 15°C, and H ₂ O (100.0 L) was added dropwise over 1 hour while keeping the internal temperature at 20-25°C. The obtained mixture was extracted with EtOAc (650.0 kg) using a liquid-liquid continuous extractor ([reprinted in reference non-patent document 2] Reddy et. al., Org. Process Res. Dev. 2021, 25, 817-830). It was extracted continuously for 3 days. Finally, the aqueous phase was extracted twice with a mixture of EtOAc (150.0 kg x 2) and EtOH (10.0 kg x 2), and the combined organic phases were heated under vacuum at 50 °C until the volume reached approximately 55.0 L. Concentrated. The mixture was treated with EtOH (5.0 kg) and heated at 45° C. for 1 hour. The solution temperature was lowered to 15° C. and held for about 2 hours to obtain precipitation of the product. The mixture was centrifuged, the solid collected, and the cake rinsed with a mixture of EtOAc (4.9 kg) and EtOH (0.46 kg) to yield 11.20 kg of wet cake. The wet cake was dried in an oven under vacuum at 45 °C for 18 h to yield the desired product, compound 4 (9.22 kg, 66.9%) as a white solid with HPLC purity of 98.5%. there were.

A 50.0 L glass-lined jacketed reactor was charged with CH ₃ CN (7.8 kg) and 4 (1.64 kg, 6.63 mol, 1.0 equiv) and stirred at room temperature. Additionally, POCl ₃ (2.03 kg, 13.26 moles, 2.0 equivalents) was added over 10 minutes while maintaining the temperature below 30°C. The temperature was increased to ˜80° C. over 45 minutes (reaction mixture became clear at 56° C.) and held for 8 hours. Completion of the reaction was confirmed by HPLC analysis, which showed approximately 1% unreacted starting material. The mixture was cooled to ~35°C over 1 hour, charged with CH ₂ Cl ₂ (46.0 kg), and transferred to a dropping tank. The inside of the dropping tank was transferred to a 12.5% K ₂ HPO ₄ quench aqueous solution (97.4 kg) in a 200.0 L reactor over 20 minutes, and maintained at -5 to +5°C to reach a target pH of 4 to 5. A 50% K ₂ CO ₃ aqueous solution (14.8 kg) was then charged to the reactor over 20 minutes at 5-15° C. to pH 9-10. The mixture was stirred at about 15° C. for 20 minutes, allowed to settle and the layers were separated. The organic layer was separated and the aqueous layer was washed again with CH ₂ Cl ₂ (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 hours. The filtrate was filtered and rinsed with CH ₂ Cl ₂ (13.0 kg) and the filtrate was sampled and found to be 96.7%. Due to the instability of chloro compound 5, the above filtrate was used directly in the next step.

The amine Compound 6 (1.45 kg, 5.97 mol, 0.9 eq.) was directly charged into the filtrate Compound 5 obtained in the previous step. Thereafter, the mixture was concentrated under reduced pressure at 20° C. to about 2.5 L, and then CH ₃ CN (8.2 kg) was added, and the mixture was concentrated to about 4.1 L. Transferred to a 50.0 L reactor and charged the reactor with CH ₃ CN (6.6 kg) and DIPEA (0.856 kg, 6.63 mol, 1.0 equiv). The mixture was heated to 55°C and held for 2 hours, then the batch temperature was increased to 65°C over 30 minutes and held with stirring for 2 hours. An additional amount of amine, Compound 6 (0.161 kg, 0.663 mol, 0.1) was charged to the reactor at that temperature. The reaction temperature was raised to 75°C and stirred for 4 hours. The reaction mixture was sampled by HPLC and 3.5% of unreacted starting material, compound 5, was detected. MeOH (0.62 L) was then added to the reactor and held for 1 hour while maintaining the temperature at approximately 65°C. The mixture was cooled to 20°C over 2 hours. The mixture was stirred for approximately 5 hours and then centrifuged to obtain a crude cake, which was washed with a mixture of CH ₃ CN (7.0 kg) and MeOH (0.40 kg) to give a wet cake with 89.5% HPLC purity. 4.56 kg of Compound 7 was obtained. A solution of EtOAc (6.32 kg) and MeOH (1.26 kg) and 4.56 kg of wet cake in a 50 L reactor was heated to 85° C. for 12 hours. The reaction temperature was then cooled to 20° C. over 2.5 hours and held for 3 hours. The mixture was centrifuged and the cake was rinsed with EtOAc (4.0 kg) to yield 1.30 kg of product. The wet cake was dried in an oven under vacuum at 50 °C for 10 h to give the product compound 7 (1.22 kg, 38.9% yield over two steps) with an HPLC purity of 96.8%. Obtained as a light brown solid with .

A 100.0 L jacketed reactor was purged with nitrogen and charged with Boc-amine Compound 7 (4.00 kg, 8.46 mol, 1.0 eq.) and CH ₂ Cl ₂ (42.2 kg). Trifluoroacetic acid (15.20 kg, 132.88 mol, 15.7 equivalents) was added dropwise to the reactor over 1 hour while maintaining the reaction temperature below 30°C. The resulting mixture was heated to 45°C and stirred at that temperature for about 6 hours. When HPLC analysis showed less than 1% of compound 7 remaining, the reaction was concentrated to approximately 10.0 L volume. Subsequently, MeOH (3.2 kg) and MTBE (12.0 kg) were charged into the reactor and stirred at room temperature for about 6 hours. The mixture was filtered and the resulting solid was washed with MTBE (12.0 kg). The wet cake was dried in a vacuum oven at 50° C. for about 2 days to yield 5.85 kg (about 99%) of compound 8 as a white solid with an HPLC purity of 98.2%.

Compound 8 (5.57 kg, 8.05 mol, 1.0 equivalent), CH ₂ Cl ₂ (61.0 kg), and dry CH ₃ CN were added to a 200.0 L jacketed reactor purged with nitrogen at 32° C. with stirring. (36.8 kg) was filled. Et ₃ N (2.80 kg, 27.60 mol, 3.43 eq.) was then added over 15 minutes at that temperature and stirred for 10 minutes. 3-chlorophenylisocyanate (2.06 kg, 13.44 mol, 1.67 eq.) was then added over 5 minutes at that temperature and the mixture was stirred for about 4 hours while maintaining the temperature at about 35°C. HPLC analysis determined that less than 0.07% of starting material Compound 8 remained unreacted. After cooling to 25° C. and holding for 1 hour, the product was caked by centrifugation and recrystallized from CH ₃ CN (46.0 kg) and MeOH (36.8 kg). The wet cake was dried in an oven under vacuum at 50° C. for 12 hours to yield the final product, compound 10 (3.04 kg, 71.8%) and the single largest impurity was up to 0.6-0.7%.

While a number of embodiments of the invention have been described, it will be obvious that the basic examples of the invention may be modified to provide other embodiments utilizing the compounds and methods of the invention. be. It will therefore be understood that the scope of the invention is defined by the appended claims rather than by the specific embodiments presented by way of example.

Claims (22)

A method for preparing a fused polycyclic compound for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:
In formula (I), B is heteroarylene,
In formula (I), D is an alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, or heterocycloalkenyl group,
In formula (I), W and Z are independently N or CR ^a , and R ^a is hydrogen, alkyl, alkenyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, a heterocycloalkenylalkoxy, halogen, alkoxyamino, or alkoxyalkylamino group,
In formula (I), R ¹ and R ² are independently hydrogen, halogen, or structure (X) in the formula, and R ¹ and R ² are not both hydrogen,
In the structure (X), A is an alkylamino group,
In formula (I), n is 0, 1, 2, 3, or 4, and in this case,
A method for preparing a fused polycyclic compound, comprising the step of reacting a compound of formula (II) with a compound of formula (III).

The method for preparing a fused polycyclic compound according to claim 1, further comprising the step of converting the compound of formula (IV) to the compound of formula (III).

3. The method for preparing a fused polycyclic compound according to claim 2, further comprising the step of reacting a compound of formula (V) with a compound of formula (VI) to produce a compound of formula (IV).

4. The method for preparing a fused polycyclic compound according to claim 3, further comprising the step of converting the compound of formula (VII) to the compound of formula (VI).

further comprising reacting a compound of formula (VIII) with an alkanolamine to produce a compound of formula (VII),
5. The method for preparing a fused polycyclic compound according to claim 4, wherein in formula (VIII), X and Y are independently halogen or hydrogen, and X and Y are not both hydrogen.

The method for preparing a fused polycyclic compound according to claim 5, wherein the alkanolamine is a compound of formula (IX).

6. The method for preparing a fused polycyclic compound according to claim 5, further comprising the step of reacting the compound of formula (X) with formamidine acetate to produce the compound of formula (VIII).

In formula (IX), A is structure (1) in the formula,
In the structure (1), R ^b and R ^c are independently hydrogen, alkyl, alkenyl, alkynyl, alkynyl, aryl, monocyclic heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, or heterocycloalkenyl group. and
7. The method for preparing a fused polycyclic compound according to claim 6, wherein in structure (1), m is 2, 3, or 4.

9. The method for preparing a fused polycyclic compound according to claim 8, wherein in structure (1), m is 3, and R ^b and R ^c are each a methyl group. The method for preparing a fused polycyclic compound according to claim 1, wherein in formula (I), ^R2 is hydrogen. The method for preparing a fused polycyclic compound according to claim 1, wherein in formula (I), B is a thiazolyl group . 12. The method for preparing a fused polycyclic compound according to claim 11, wherein B in formula (I) is structure (2).

The method for preparing a fused polycyclic compound according to claim 1, wherein in formula (I), D is a 6-membered aryl or heteroaryl group. 14. In formula (I), D is structure (3), structure (4), structure (5), structure (6), or structure (7), according to claim 13. A method for preparing a fused polycyclic compound.

In formula (I), R ² is H, A is structure (1), B is structure (2), D is structure (3), and W and Z are Preparation of a fused polycyclic compound according to claim 1, wherein each is CR ^a , R ^a is H, n is 2, m is 3, and R ^b and R ^c are each a methyl group. Method.

A process for preparing a fused polycyclic compound according to claim 1, wherein the compound of formula (I) is recrystallized from a solvent. 3. The method for preparing a fused polycyclic compound according to claim 2, wherein the compound of formula (III) is recrystallized from a solvent. 4. A process for preparing a fused polycyclic compound according to claim 3, wherein the compound of formula (IV) is provided as a solid by centrifugation. 5. A fused polycyclic compound according to claim 4, wherein the compound of formula (VI) is provided by removing the compound of formula (VII) from the mixture of compounds of formula (VII) using liquid-liquid extraction. Preparation method. The method for preparing a fused polycyclic compound according to claim 19, wherein the liquid-liquid extraction is performed by adding ETOAc (ethyl acetate) to the mixture and recovering the compound of formula (VI I ) therein. . 6. A process for preparing a fused polycyclic compound according to claim 5, wherein the compound of formula (VII) is provided as a solid by centrifugation. 8. A process for preparing a fused polycyclic compound according to claim 7, wherein the compound of formula (VIII) is provided as a solid by centrifugation.