Processes and intermediates for the preparation of spirocyclic KRAS inhibitors

Abstract

This invention relates to an efficient and enantioselective synthesis of spiro compounds of formula (1) as general intermediates, featuring highly selective asymmetric introduction of all-carbon quaternary centers and a highly efficient one-pot procedure for C2 extension to generate spiro structures. For all-carbon quaternary centers, the Tsuji-Trost asymmetric allylic alkylation (AAA) process was designed to develop a sustainable procedure with very low catalyst loading, thereby facilitating control of Pd content in the product under essentially solvent-free conditions. Furthermore, multiple synthetic transformations were carried out using this one-pot procedure in either a three-transformation sequence involving hydroboration-alkylation-Dieckmann condensation to compounds of formula (1) or a five-transformation sequence involving hydroboration-alkylation-Dieckmann condensation-saponification-decarboxylation to compounds of formula (9). JPEG2025537366000069.jpg3963

Description

[Technical Field]

[0001] The present invention relates to compounds and efficient and sustainable methods for the preliminary preparation of these compounds, which are useful as intermediates in the synthesis of KRAS inhibitors. [Background technology]

[0002] Spiro compounds of formula (1) [ka] (wherein R is defined hereinafter) is an intermediate in the class of annulated 2-amino-3-cyanothiophenes and derivatives of formula (2), described, for example, in WO 2023099624. Structurally, compound (1) contains a challenging spirocyclic ring system and an all-carbon quaternary chiral center, which poses challenges for synthetic chemists (Jens Christoffers, Angelika Baro, Quaternary Stereocenters, Challenges and Solutions for Organic Synthesis, 1 ed. WILEY-VCH, 2005), particularly when stereoselectively introduced, for example, by transition metal catalysis. [ka]

[0003] The compounds of formula (2) are used as KRAS inhibitors in pharmaceutical compositions and formulations containing such compounds, particularly as drugs for treating and / or preventing tumor diseases, such as cancer. This class of compounds has been found to have antitumor activity and is useful for suppressing uncontrolled cell proliferation resulting from malignant diseases. This antitumor activity is believed to result, inter alia, from the suppression of 12th-mutated KRAS, preferably G12D and G12V mutant KRAS, or the suppression of amplified wild-type KRAS. Advantageously, the compounds may be selective for specific KRAS mutants, preferably KRAS G12D and G12V, or may be effective against a group of KRAS mutants, including amplified wild-type KRAS. Because this class of compounds targets an unmet medical need in the oncology field, an efficient and scalable synthetic route that rapidly delivers kilogram quantities of the drug substance is of paramount importance. Previously reported synthetic routes have either been racemic, relying on chromatographic separation to obtain the enantiopure compound of formula (1) (see Tetrahedron Letters, 2003, 44, 3333), or have used chiral auxiliaries, as in J. Chem. Soc. Perkin Trans 1, 1994, 3441.

[0004] [ka] Therefore, our goal was to find an efficient and sustainable process that not only enantioselectively produces compounds of formula (1) as central intermediates, but also employs green chemistry principles to provide easy access to this class of pharmaceutically desirable compounds, formula (2). We focused specifically on one-pot procedures to reduce the number of reagents and solvents used, on the one hand, and the number of isolation and purification steps, on the other. Furthermore, flow photochemical reactors can also be advantageously used in sustainable manufacturing processes. Summary of the Invention

[0005] The present invention relates to an efficient and enantioselective process for spiro compounds of formula (1) as central building blocks of compounds of formula (2) including novel initial intermediates, wherein R is selected from the group consisting of linear, branched or cyclic alkyl groups and aryl groups, and combinations thereof, preferably in all the above definitions R has 1 to 12 carbon atoms or 1 to 6 carbon atoms, in particular R is an optionally substituted linear or branched alkyl C1-C12 or C1-C6 group, further in all the above definitions R is preferably a saturated and unsubstituted hydrocarbon group; preferably R is methyl or ethyl. In another aspect, the present invention relates to a short, three-step process for compound (1), wherein R is as defined above, that features a highly efficient one-pot procedure for the highly selective asymmetric introduction of an all-carbon quaternary center in step 1, carbonyl protection in step 2, and C2 elongation to generate the spiro structure in step 3. We found that the Tsuji-Trost asymmetric allylic alkylation (AAA) can prepare all-carbon quaternary centers at unexpectedly low catalyst loadings, which also facilitates control of the Pd content in the product under essentially solvent-free conditions. Furthermore, it has surprisingly been found that a one-pot procedure, meaning multiple synthetic transformations in one reaction vessel without purification, in the form of at least a three-transformation reaction sequence of hydroboration-alkylation-Dieckmann condensation, can be used for the C2 elongation and cyclization to the spiro compound of formula (1), which is the central intermediate in the process to the compound of formula (2). Furthermore, it has surprisingly been found that it is possible to carry out further transformations directly without isolating the product of the one-pot reaction, thereby converting the compound of formula (5) to the compound of formula (9) in a one-pot procedure involving a five-transformation reaction sequence of hydroboration-alkylation-Dieckmann condensation-saponification-decarboxylation. Furthermore, C2 elongation can be achieved directly and sustainably using photoredox-catalyzed radical hydroalkylation in a flow reactor. DETAILED DESCRIPTION OF THE INVENTION

[0006] The present invention relates to an efficient and enantioselective process for the preparation of spiro compounds of formula (1) as central building blocks of compounds of formula (2), wherein R is selected from the group consisting of linear, branched, or cyclic alkyl groups, and aryl groups, and combinations thereof, preferably, in all the above definitions, R has 1 to 12 carbon atoms or 1 to 6 carbon atoms, in particular, R is an optionally substituted linear or branched alkyl C1-C12 or C1-C6 group, and further, in all the above definitions, R is preferably a saturated and unsubstituted hydrocarbon group; preferably, R is methyl or ethyl. In another aspect, the present invention relates to a short, three-step process starting from commercially available starting materials and leading to compounds of formula (1), as shown in Scheme 1. Particular emphasis is placed not only on the highly efficient and straightforward approach to compounds of formula (1), but also on the sustainability of the sequence through the reduction of solvents and reagents required during the reaction, including the switch to environmentally friendly solvents and reagents. Furthermore, the use of additional solvents in isolation and purification is avoided, and waste is significantly reduced through the recycling of used solvents.

[0007] Step 1 introduces an all-carbon quaternary center via Tsuji-Trost asymmetric allylic alkylation (AAA), followed by carbonyl protection in step 2 and a one-pot hydroboration-alkylation-Dieckmann condensation (three transformations) sequence in step 3. [ka]

[0008] The Tsuji-Trost asymmetric allylic alkylation has been described in the literature using various Pd sources and chiral ligands to generate stereocenters, including all-carbon quaternary stereocenters (Chem. Rev. 2003, 103, 2921 and Org. Process Rec. Dev 2012, 16, 185). However, no scalable process for the required transformation has been reported in the literature (Adv. Synth. Catal. 2001, 343, 46). One aspect of the present invention is a scalable process for the introduction of quaternary stereocenters using green chemistry principles. Trost reported allylation conditions (J. Am. Chem. Soc 1997, 119, 7879), which were used as a starting point. In a ligand screen, the (S,S)-DACH-Ph ligand proved superior to other ligands tested. Compare Table 1.

[0009] [Table 1]

[0010] Furthermore, surprisingly, it was found that the Pd loading could be significantly reduced, up to 14 times less Pd was used, while maintaining good er and conversion rates, thus reducing Pd from 10,000 ppm to 700 ppm. In particular, the significant reduction in Pd loading has a strong impact on the management of residual Pd in ​​products, which is important because the heavy metal Pd in ​​pharmaceuticals must be strictly controlled. Furthermore, it has been surprisingly discovered that substantially solvent-free conditions requiring only 4 equivalents of solvent (Chem. Rev. 2007, 107, 2503-2545) lead to a shortened reaction time in the process. As the minimum amount of solvent, an organic solvent or a mixture of an organic solvent and water can be used. Examples of organic solvents are known to those skilled in the art, such as toluene or 2-Me-THF, preferably toluene. While water alone as a solvent does not lead to complete conversion, it has been surprisingly found that water is beneficial for complete conversion in an organic solvent. In the reaction, a molar ratio of water:Pd of 100:1 to 400:1 is preferably used, more preferably a molar ratio of water:Pd of 160:1 to 200:1. Higher concentrations shorten reaction times and allow Pd loadings to be reduced to less than 0.250 mol %, preferably less than 0.125 mol %, more preferably less than 0.05 mol %, and most preferably to around 0.035 mol %.

[0011] Surprisingly, it was found that temperatures around 10°C gave better conversion rates while maintaining good er, see Table 2. [Table 2] The base can be selected from commonly known nitrogen bases such as TMG, DBU, triethylamine, Hunig's base, pyridine, piperidine, morpholine, DABCO, etc., and it has been found that TMG is preferably used.

[0012] Preferably, TMG is used in an amount between 1.0 and 3.0 equivalents, more preferably between 1.5 and 2.5 equivalents, and most preferably approximately 2.0 equivalents. The allylation agent can be selected from a non-exhaustive list of allylic α-halogenated acetates such as allyl acetate, 2-chloroallyl acetate, allylic carbonates such as allyl methyl carbonate, allyl tert-butyl carbonate, allyl (2,2,2-trichloroethyl) carbonate, allyl benzyl carbonate, diallyl carbonate. Preferably, allyl acetate is used in the reaction.

[0013] Furthermore, no additional organic solvents for extraction are required during isolation, compared to the less safe diethyl ether used in the original Trost procedure, resulting in significantly less solvent waste to the environment than the original Trost procedure. In another aspect, it has been found that the ketal protection in step 2 can be carried out at ambient temperature using ethylene glycol as the reactant and solvent, thus avoiding the classical time-consuming azeotropic distillation in toluene at elevated temperatures, allowing the reaction of compound of formula (4) to give compound of formula (5) under ambient conditions. In another aspect, it has been found that step 3 can convert compounds of formula (5) directly to compounds of formula (1) via a one-pot hydroboration-alkylation-Dieckmann condensation (three transformation reactions) sequence, which very efficiently introduces C2 extension followed by cyclization to form spiro compounds of formula (1), as shown in Scheme 2 below.

[0014] [ka] Brown reported an ester synthesis based on hydroboration followed by alkylation over 50 years ago in J. Am. Chem. Soc 1969, 91, 2146. However, due to competing migrations of different B-alkyl bonds, yields were moderate, and for complete conversion, dihalogenated acetates were used, which gave the corresponding α-halogenated esters as products.

[0015] It has now been found that this can be overcome by careful selection of the reaction sequence and temperature profile. Sterically hindered boranes, such as 9-BBN, proved superior, and 9-BBN was used exclusively for the hydroboration reaction in the first transformation of the one-pot sequence. It has been found that as alkylating agents α-haloacetates can be used in which the halogen is selected from Cl, Br or I, preferably Cl. The acetates can be different alkyl or aryl esters as defined for R above, preferably benzyl, ethyl or methyl α-haloacetates. Furthermore, it has been found that at least one base is required for the alkylation reaction and the Dieckmann condensation reaction. The base for each transformation reaction can be selected from K0tBu, Na0tBu, KaOH, NaOH, LiOH, Li0tAmyl, Na0tAmyl, NHMDS, KHMDS, LHMDS, or LDA.

[0016] Additionally, it was surprisingly found that the one-pot procedure only yielded satisfactory results when NHMDS, KHMDS, or LHMDS was used for the alkylation and Dieckmann condensation. The use of LHMDS in excess of the stoichiometric amount for the alkylation of borane directly induces the Dieckmann condensation and forms the spiro compound by closing the second six-membered ring. The total amount of base used is between 3.0 and 6.0 equivalents, preferably between 3.1 and 4.0 equivalents, and more preferably approximately 3.3 equivalents. In another aspect of the present invention, it has been found that at this stage of the one-pot procedure, the product of the Dieckmann condensation, compound of formula (1), can be isolated as described above, or can be subjected to two further transformations without isolation or purification to react compound of formula (1) to compound of formula (9), as shown in Scheme 3 below.

[0017] [ka] It was found that adding aqueous base directly to (1) and raising the temperature resulted in saponification of the ester moiety of compound (1) followed by decarboxylation to give compound (9). Thus, five transformations can be carried out in one pot.

[0018] In another aspect, it has been found that the double bond of compounds of formula (5) can react in a radical hydroalkylation as described in JACS, 2021, 143, 11251, using a dual HAT (hydrogen atom transfer) catalysis with an electron-deficient / acidic CH, resulting in C2 extension of the unactivated double bond. Examples of electron-deficient CH include 1,3-dicarbonyl compounds, β-ketoesters, β-ketoamides, β-ketonitriles, cyanoacetates, and malonic acid diesters, and preferably malonic acid dialkyl esters and Meldrum's acid (25). As the solvent, trifluorotoluene, dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, and acetonitrile can be used, preferably acetonitrile. Commonly used photoredox catalysts are, for example, Ir or Ru complexes, whose reactivity depends on the redox potential of the metal center. However, heavy metal impurities are strictly regulated in pharmaceutical products due to toxicological concerns. Therefore, for toxicological, environmental, and economic reasons, metal-free photocatalysts have been tested to find sustainable options. Metal-free photocatalysts can be selected from a non-exhaustive list: 5CzBN (pentacarbazolylbenzonitrile), 4CzIPN (2,4,5,6-tetrakis(9H-carbazol-9-yl)isophthalonitrile), 3CzClIPN (2,4,6-tri(9H-carbazol-9-yl)-5-chloroisophthalonitrile), and 3DPAFIPN (2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile). The most preferred is the use of 4CzIPN (26).

[0019] Although disulfide-form thiol reagents have been described as H-atom donors, it was thought that switching to monomeric species might improve the reaction rate. Therefore, thiol reagents that are less likely to form disulfides, such as sterically hindered aromatic thiols, trialkylsilanethiols, and triarylsilanethiols, were tested, with triphenylsilanethiol being the most preferred. (27) Different borane catalysts of the type 3-quinuclidinol-borane can be utilized to generate the nucleophilic borane radical for the catalytic cycle, with 3-quinuclidinol-borane being the most preferred ( 28 ). In a further embodiment, the photochemical reaction can be carried out using a flow chemistry process. This has many advantages over the batch process previously described in Chem.Rev. 2016, 116, 17, 10276-10341, such as a larger surface area and easier temperature control in the photochemical reaction. The use of a flow reactor allows the reaction scale to be scaled up to the kilogram scale in the photoreaction. The use of a continuous flow process as a manufacturing process avoids multiple cleaning procedures, waiting times, and retention times, making it preferable from an economical and environmental standpoint.

[0020] The compound of formula (29) can be isolated as the direct product of photochemical hydroalkylation and further transformed, without further purification, via decarboxylative ring cleavage to the acid of formula (31) and its corresponding ester (7), which is also an intermediate in the one-pot reaction described above. Decarboxylative ring cleavage can be achieved in the crude product solution by adding CDI and increasing the temperature. The free acid moiety of the compound of formula (31) can be esterified to produce the compound of formula (7). Suitable reaction conditions for this transformation are known in the art.

[0021] [ka]

[0022] Under the conditions described above, compound 7 can be converted directly to compound 1 or to compound 9 in a one-pot reaction in three conversions. Surprisingly, it was found that no further adjustment of the reaction conditions from 7 to 9 was necessary. This highlights the robustness of the conversion, either in one pot from isolated 7, as in Scheme 5, or in the five-conversion one-pot sequence in Scheme 3 described above. [ka]

[0023] The compound of formula (9) can optionally be crystallized from heptane at low temperature to produce a crystalline product of excellent optical purity or can be used directly for further transformations. In another aspect, the present invention relates to an efficient, enantioselective and regioselective process for spiro compounds of formula (10) or (11) involving novel intermediates. [ka] It has been found that starting from either compounds of formula (1) or compounds of formula (9), it is possible to generate the corresponding different isoxazole regioisomers, which can be further converted to spiro compounds of formula (10) or (11), which on the one hand are densely functionalized compounds that can be selectively and efficiently converted to any desired compound of formula (2) in a highly convergent manner, and on the other hand are readily accessible in the synthetic process described above.

[0024] In one embodiment of the present invention, as shown in Scheme 4 below, starting from a compound of formula (9), a compound of formula (12) can be first C2-extended with ethyl oxalate to give a compound of formula (12), which can then be reacted with hydroxylamine without isolation to form a heteroaryl ring to give a compound of formula (13). The ester moiety of the compound of formula (13) can be further converted to a carboxamide moiety of a compound of formula (14) by treatment with ammonium hydroxide. Dehydration of the compound of formula (14) affords a compound of formula (15), characterized by a nitrile. The pyrimidine ring of a compound of formula (17) can then be formed by reaction with a nitrogen source and conversion of the unisolated amidine intermediate of formula (16) with malonic acid. The hydroxy group of the compound of formula (17) can be converted to a dichloride of formula (10). Such conversion reactions are known to those skilled in the art and include, inter alia, those described herein.

[0025] In another aspect, the present invention relates to the use of the compound of formula (10) as an intermediate in the synthesis of KRAS inhibitors, preferably ring-fused 2-amino-3-cyanothiophenes of formula (2) and derivatives. [ka]

[0026] In another embodiment of the present invention, shown in Scheme 5 below, starting from a compound of formula (1), an isoxazole heteroaryl ring is generated in a compound of formula (18a) by reaction with hydroxylamine. Compound (18a) is then reacted to introduce a triflate into a compound of formula (19). Carboxylation of the triflate of formula (19) provides a compound of formula (20) containing an ester moiety. The ester moiety can be further converted to a nitrile of formula (22) via a carboxamide of formula (20). The pyrimidine ring of a compound of formula (24) can then be formed by reaction with a nitrogen source and conversion of the unisolated amidine intermediate of formula (23) with a malonate. The hydroxy group of a compound of formula (24) can be converted to a dichloride of formula (11). Such conversion reactions are known to those skilled in the art and include, inter alia, those described herein.

[0027] In another aspect, the present invention relates to the use of compounds of formula (11) as intermediates in the synthesis of KRAS inhibitors, preferably annulated 2-amino-3-cyanothiophenes of formula (2) and derivatives. [ka]

[0028] Preferred Embodiments In one embodiment, the present invention provides a compound of formula (1) [ka] wherein R is selected from the group consisting of linear, branched, or cyclic alkyl groups, and aryl groups, and combinations thereof; preferably, in all the above definitions, R has 1 to 12 carbon atoms or 1 to 6 carbon atoms, in particular R is an optionally substituted linear or branched alkyl C1-C12 or C1-C6 group; further, in all the above definitions, R is preferably a saturated and unsubstituted hydrocarbon group; preferably, R is methyl or ethyl.

[0029] In another embodiment, the present invention provides a compound of formula (1) [ka] wherein R is as defined in the previous embodiment. A process for preparing a compound of formula (5) [ka] in a one-pot reaction.

[0030] In another embodiment, the present invention relates to a process according to the previous embodiment, wherein the one-pot sequence from the compound of formula (5) to the compound of formula (1) comprises at least three transformation reactions: hydroboration, alkylation, and Dieckmann condensation. In a further embodiment, the invention relates to a process according to the previous embodiment, wherein the hydroboration is carried out in the presence of 9-BBN. In a preferred embodiment, the present invention relates to a process according to the above embodiment, wherein 1.2 equivalents of 9-BBN are used. In a further embodiment, the invention relates to a process according to the previous embodiment, wherein the alkylation is carried out in the presence of an α-haloacetate ester, preferably an ethyl or methyl α-haloacetate ester. In a preferred embodiment, the α-haloacetic acid ester used is selected from Cl, Br or I, preferably Cl.

[0031] In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein each of the alkylation and condensation transformation reactions is carried out in the presence of at least one base, and different bases may be used for different transformation reactions. In a preferred embodiment, the present invention relates to a process according to the previous embodiment, wherein the base used in the hydroboration-alkylation-Dieckmann condensation sequence is selected from NHMDS, KHMDS or LHMDS, preferably LHMDS. In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the amount of base used is between 3.0 and 6.0 equivalents, preferably between 3.1 and 4.0 equivalents, more preferably approximately 3.3 equivalents.

[0032] In another embodiment, the present invention provides a compound of formula (1) [ka] wherein R is as defined in the previous embodiment. A process for preparing a compound of formula (5) [ka] in a photochemical reaction.

[0033] In a further embodiment, the invention relates to a process according to the previous embodiment, wherein the flow process is used for a photochemical reaction. In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the photochemical reaction uses 3-dicarbonyl compounds, β-ketoesters, β-ketoamides, β-ketonitriles, cyanoacetates, and malonic acid diesters, preferably, malonic acid dialkyl esters or Meldrum's acid are used. In a further embodiment, the present invention relates to the process according to the previous embodiment, wherein the photochemical reaction uses trifluorotoluene, dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, and acetonitrile as solvents, preferably acetonitrile. In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the photochemical reaction uses 5CzBN (penta-carbazolylbenzonitrile), 4CzIPN (2,4,5,6-tetrakis(9H-carbazol-9-yl)isophthalonitrile), 3CzClIPN (2,4,6-tri(9H-carbazol-9-yl)-5-chloroisophthalonitrile), or 3DPAFIPN (2,4,6-tris(diphenylamino)-5-fluoroisophthalonitrile), preferably 4CzIPN (26), as a photochemical catalyst.

[0034] In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the photochemical reaction uses a trialkyl or triaryl silanethiol, preferably triphenyl silanethiol. In a further embodiment, the photochemical reaction is carried out in the presence of 3-quinuclidinol-borane, preferably 3-quinuclidinol-borane (28). In a further embodiment, the present invention relates to a compound of formula (5) comprising a compound of formula (3) [ka] The process according to the previous embodiment relates to a process in which the compound is prepared from Preferably, compounds of formula (5) are prepared by asymmetric allylic alkylation of compounds of formula (3).

[0035] In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the asymmetric allylic alkylation of a compound of formula (3) uses less than 0.250 mol %, preferably less than 0.125 mol %, more preferably less than 0.050 mol %, and most preferably approximately 0.035 mol % of allylpalladium(II) chloride dimer. In a preferred embodiment, the present invention relates to a process according to the previous embodiment, wherein the asymmetric allylic alkylation of a compound of formula (3) uses (S,S)-DACH-Ph Trost ligand at a Pd / ligand ratio between 1.00:1.00 and 1.00:3.00, preferably between 1.00:1.07 and 1.00:1.20, and most preferably around 1.00:1.15. In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the asymmetric allylic alkylation of a compound of formula (3) uses toluene or MeTHF as a solvent, preferably toluene.

[0036] In a preferred embodiment, the present invention relates to a process according to the previous embodiment, wherein the asymmetric allylic alkylation of a compound of formula (3) uses toluene as the solvent, preferably using 4 equivalents of toluene. In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the asymmetric allylic alkylation of a compound of formula (3) uses between 1.0 and 3.0 equivalents of TMG, preferably between 1.5 and 2.5 equivalents, and most preferably approximately 2.0 equivalents of TMG. In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the asymmetric allylic alkylation of a compound of formula (3) is carried out at a reaction temperature between 5 and 20°C, most preferably between 10 and 15°C. In a further embodiment, the present invention relates to a process according to the previous embodiment, wherein the asymmetric allylic alkylation of a compound of formula (3) is carried out either under water-free conditions or in an organic solvent system having a molar ratio of water:Pd between 100:1 and 400:1, preferably between 160 and 200:1.

[0037] According to another embodiment, the present invention relates to a process according to the previous embodiment, wherein a compound of formula (5) is subjected to a one-pot sequence of five transformations, namely, hydroboration, alkylation, Dieckmann condensation, saponification, and decarboxylation, to give a compound of formula (9) as an isolated product. In another embodiment, the present invention provides a compound of formula (11) [ka] 1. A process for preparing a compound of formula (1) [ka] (wherein R is as defined above). The present invention relates to a process including:

[0038] The compound of formula (1) is produced according to any one of the above embodiments of the process of the invention. In a further embodiment, the present invention relates to a compound of formula (11) having the formula (24) [ka] The process according to the previous embodiment relates to a process in which

[0039] In a further embodiment, the present invention relates to a compound of formula (24) comprising a compound of formula (22) [ka] The process according to the previous embodiment relates to a process in which In a further embodiment, the present invention relates to a compound of formula (22) which is a compound of formula (21) [ka] The process according to the previous embodiment relates to a process in which

[0040] In a further embodiment, the present invention relates to a compound of formula (21) comprising a compound of formula (20) [ka] The process according to the previous embodiment relates to a process in which

[0041] In a further embodiment, the present invention relates to a compound of formula (20) comprising a compound of formula (19) [ka] The process according to the previous embodiment relates to a process in which

[0042] In a further embodiment, the present invention relates to a compound of formula (19) comprising a compound of formula (18a) [ka] The process according to the previous embodiment relates to a process in which

[0043] In a further embodiment, the present invention provides a compound of formula (18a) in its tautomeric form: [ka] The present invention relates to a process according to the above embodiment, wherein

[0044] In another embodiment, the present invention provides a compound of formula (10) [ka] which comprises as an intermediate a compound of formula (9) [ka] The present invention relates to a process including: The compound of formula (9) is produced according to one of the embodiments described above.

[0045] In a further embodiment, the present invention relates to a compound of formula (10) having the formula (17) [ka] The process according to the previous embodiment relates to a process in which In a further embodiment, the present invention relates to a compound of formula (17) which is a compound of formula (15) [ka] The process according to the previous embodiment relates to a process in which

[0046] In a further embodiment, the present invention relates to a compound of formula (15) comprising a compound of formula (14) [ka] The process according to the previous embodiment relates to a process in which In a further embodiment, the present invention relates to a compound of formula (14) comprising a compound of formula (13) [ka] The process according to the previous embodiment relates to a process in which

[0047] In a further embodiment, the present invention relates to a compound of formula (13) comprising a compound of formula (12) [ka] The process according to the previous embodiment relates to a process in which

[0048] In another embodiment, the present invention provides a compound of formula (10), a compound of formula (17), a compound of formula (15), a compound of formula (14), a compound of formula (13), and a compound of formula (12). [ka] The present invention relates to one of the compounds selected from:

[0049] In another embodiment, the present invention provides a compound of formula (11), a compound of formula (24), a compound of formula (22), a compound of formula (21), a compound of formula (20), a compound of formula (19), a compound of formula (18a), and a compound of formula (18b). [ka] The present invention relates to one of the compounds selected from:

[0050] In another embodiment, the present invention relates to a crystalline compound of formula (9), a crystalline compound of formula (15), a crystalline compound of formula (14), and a crystalline compound of formula (13). In another embodiment, the invention relates to the use of a compound of any of the previous embodiments as an intermediate in the synthesis of KRAS inhibitors, preferably ring-fused 2-amino-3-cyanothiophenes of formula (2) and derivatives. Terms and definitions used The term "alkyl" refers to a hydrocarbon moiety, including acyclic, saturated, branched or straight-chain hydrocarbon moieties, which may further be optionally substituted. The term "aryl" as used herein refers to a carbocyclic aromatic monocyclic group containing 6 carbon atoms, which may be further substituted.

[0051] As used herein, the term "substituted" means that one or more hydrogens on a designated atom are replaced with a group selected from the defined group of substituents, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. Similarly, the term "substituted" may be used in connection with a chemical moiety rather than a single atom, such as "substituted alkyl" or "substituted aryl." The one or more substituents may be fluorine, chlorine, bromine, NC-, F3C-, C 1-3 -Alkyl-, CH3-OC 1-3 -Alkylene-, C 1-3 -alkyl-O- and phenyl. Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or chemical name is intended to encompass tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of different proportions of separate enantiomers, mixtures of diastereomers, or mixtures of any of the aforementioned forms of such isomers and enantiomers, if they exist, and solvates thereof, such as hydrates.

[0052] In general, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, for example, by separation of corresponding mixtures, by use of stereochemically pure starting materials, and / or by stereoselective synthesis. The term "one-pot procedure" or "one-pot reaction" as used herein means carrying out multiple synthetic steps / transformations sequentially in one reaction vessel without purification by subjecting the reactants to sequential chemical reaction conditions in a single reactor. The term water:Pd molar ratio as used herein refers to the molar ratio of moles of water to moles of palladium, taking into account that the allylpalladium(II) chloride dimer contains 2 moles of Pd.

[0053] The term Pd / ligand ratio refers to the molar ratio of the active catalytic species formed in the reaction between the allylpalladium(II) chloride dimer and the (S,S)-DACH-Ph Trost ligand, taking into account that the dimer contains 2 moles of Pd. Abbreviations used herein [Table 3] JPEG2025537366000040.jpg249151 JPEG2025537366000041.jpg113162 [Example]

[0054] general Unless otherwise stated, all reactions are carried out with commercially available equipment using methods commonly used in chemical laboratories. Starting materials that are air- and / or moisture-sensitive are stored under protective gas, and the corresponding reactions and manipulations with them are carried out under protective gas (nitrogen or argon). When a compound is represented by both a structural formula and its nomenclature, the structural formula takes precedence in the event of a conflict.

[0055] Chromatography Thin layer chromatography is performed on pre-made silica gel 60 TLC plates on glass from Merck (with fluorescent indicator F-254). Analytical HPLC (reaction control) of intermediates and final compounds is carried out using columns from Waters (XBridge™ C18, 2.5 μm, 2.1×20 mm or XBridge™ C18, 2.5 μm, 2.1×30 mm or Aquity UPLC BEH C18, 1.7 μm, 2.1×50 mm), YMC (Triart C18, 3.0 μm, 2.0×30 mm) and Phenomenex (Luna C18, 5.0 μm, 2.0×30 mm).

[0056] HPLC Method I HPLC Agilent 1100 / 1200 system Detection signal 210 nm (bandwidth 10 nm, reference wavelength 500 nm) Column: Waters, Xbridge BEH C18, 2.5 μm, 4.6 x 100 mm column Column temperature: 30°C Eluent A: 0.1% (v / v) HClO4 in HPLC-grade water B: HPLC grade ACN Flow rate 1.2mL / min Gradient 0 min 20%B 10 minutes 65%B 12 minutes 80%B 14 minutes 90%B 15 minutes 90%B

[0057] HPLC method II HPLC Agilent 1100 / 1200 system Detection signal 210 nm (bandwidth 10 nm, reference wavelength 500 nm) Column: Waters, Xbridge BEH C18, 2.5 μm, 4.6 x 100 mm column Column temperature: 30°C Eluent A: 0.1% (v / v) HClO4 in HPLC-grade water B: HPLC grade ACN Flow rate 1.2mL / min Gradient 0 min 25%B 10 minutes 55%B 12 minutes 80%B 14 minutes 90%B 15 minutes 90%B

[0058] Chiral Method I: GC HP7890GC Column: CHIRALDEX G-TA, Catalog No. 73033AST, Column No.: 262953-01 (length: 30 m, inner diameter: 0.25 mm, film thickness: 0.12 μm) Detector FID Inlet split ratio = 50:1 Temperature 140℃ Carrier gas: Helium, constant flow, 1.5 ml / min Oven temperature: Initially 95°C, held for 5 minutes, increased to 160°C at a rate of 10°C / min and held for 10 minutes. Analysis time 21.5 minutes FID temperature 300℃ H2 flow rate 35mL / min Air flow rate: 400 mL / min Make-up flow rate: On, 20 mL / min Mode: Constant make-up and fuel flow

[0059] Chiral Method II: SFC Agilent 1260SFC System Detection signal 210 nm (bandwidth 10 nm, reference wavelength 500 nm) Column: Lux Cellulose-2, Phenomenex (4.6 x 100 mm, 5 μm particle size) Column temperature: 35°C Mobile Phase A: Extremely dry, CO2 (Air Gas UN1013) without a dip tube B:IPA Flow rate 2mL / min Gradient 0 min 1%B 3 minutes 3%B 8 minutes 50%B 9.5~10 minutes 1%B 10 minutes 1%B Pressure limit: 20~550bar

[0060] Chiral Method III: SFC Agilent 1260SFC System Detection signal 210 nm (bandwidth 10 nm, reference wavelength 500 nm) Column: ChiralPak IF (4.6 x 100 mm, 5 μm particle size) Column temperature: 35°C Mobile Phase A: Extremely dry CO2 (Air Gas UN1013) without a dip tube B:MeOH Flow rate 3mL / min Gradient 0 min 1% B 2 mL / min 0.05 min 1%B 3mL / min 1 min 3%B 3mL / min 6 minutes 30%B 3mL / min 11 minutes 30%B 3mL / min 11.5 minutes 1%B 3mL / min 11.95 min 1%B 2mL / min 12 minutes 1%B 2mL / min Pressure limit: 20~550bar

[0061] ( Example 1 ) [ka] A dry, clean reactor is charged with toluene (234 L) under nitrogen (Note: 2.5 V total toluene for this reaction). Water (1.56 kg, 85.5 mol, maintaining a 160:1 HO:Pd ratio) is added, followed by a nitrogen rinse of 1,1,3,3-tetramethylguanidine (175.5 kg, 1527.6 mol, 2.0 equiv.) through the charge line, followed by a toluene rinse (13 L). 3 (130.0 kg, 763.8 mol) is added under nitrogen, followed by a toluene rinse (13 L). Allyl acetate (98.8 kg, 992.9 mol, 1.3 equiv.) is added under nitrogen, followed by a toluene rinse (13 L). The mixture is cooled to 10° C. under stirring over 0.5 hours. The batch is degassed by sparging the solution with nitrogen for approximately 30 minutes. Add (S,S)-DACH-Ph Trost ligand (0.429 kg, 0.619 mol, 0.081 mol%) in degassed toluene (13 L) (Note: Maintain a Pd:ligand ratio of 1:1.15), followed by a rinse with degassed toluene (13 L). Add allylpalladium(II) chloride dimer (97.5 g, 0.267 mol, 0.035 mol%) in degassed toluene (13 L), followed by a rinse with degassed toluene (13 L). Hold the batch at 10-15 °C for at least 8 h. After the reaction is complete by HPLC, add a solution of N-acetyl-L-cysteine ​​(3.9 kg, 22.9 mol, 0.03 equiv.) in water (260 L) at <25 °C. Warm the resulting solution to 20-25 °C and hold at 20-25 °C for at least 1 h. After phase separation and discarding the bottom aqueous layer, 10% by weight of aqueous NH4Cl (260 L) is added. The mixture is stirred for 10 minutes, and the bottom aqueous layer is then drained. The organic phase is further washed with water (130 L). The organic layer is filtered through a very thin pad of Celite, and the reactor and Celite layer are rinsed with toluene (65 L). The filtrate is charged to a clean reactor, and the toluene is then distilled off under vacuum at 40-50 °C. The crude product is either used directly in the next step, or the product is poured into a container with a minimum amount of toluene (65 L) and stored at 20-23 °C. Typically, 150 kg of 4 is obtained as a pale yellow oil in 96% yield with an enantiomeric ratio of ≥ 90:10 (Chiral Method I). 1H NMR (500 MHz, CDCl3): δ 5.75 (ddt, J = 14.8, 9.4, 7.5 Hz, 1H), 5.06 - 5.00 (m, 2H), 4.19 (q, J = 7.1 Hz, 2H), 2.61 (dd, J = 13.9, 7.1 Hz, 1H), 2.51 - 2.43 (m, 3H), 2.33 (dd, J = 13.9, 7.9 Hz, 1H), 2.03 - 1.98 (m, 1H), 1.78 - 1.60 (m, 3H), 1.50 - 1.42 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 207.7, 171.6, 133.5, 118.4, 61.3, 61.0, 41.3, 39.4, 35.9, 27.7, 22.6, 14.3. ESI-MS: m / z 211 [M+H] + .

[0062] ( Example 2 )

Chem.

[0063] ( Example 3 ) [ka] To a dry, clean reactor under nitrogen, add 9-BBN (688.5 kg, 401 mol, 1.2 equiv.). Cool the solution to 0-5 °C to obtain a slurry. Add 5 (85.0 kg, 334.2 mol) from Step 2 at 0-5 °C and rinse with THF (40 L). Warm the mixture to 20-23 °C over 1 h and hold at 20-23 °C for at least 1 h. Then, cool the mixture to -45 to -40 °C and add methyl chloroacetate (69.6 kg, 1.3 equiv.) in one portion, followed by the dropwise addition of LiHMDS (909.5 kg, 1102.9 mol), maintaining the temperature below -35 °C. The batch is then warmed to 20-23 °C over 1 h and held at 20-23 °C for at least 18 h. Approximately 12-13 V of solvent is removed by distillation under vacuum with heating (35 °C). EtOH (255 kg) is added, followed by a solution of NaOH (13.4 kg) in HO (212.5 L). The mixture is heated under reflux (66-70°C) for at least 14 hours.

[0064] Approximately 5-6 V of solvent is then removed by distillation at reflux, the batch is cooled to 20-25 °C, and then filtered through a thin pad of Celite to remove insoluble material, rinsing with heptane (160 L). Approximately 5-6 V of solvent (or most of the residual THF and ethanol) is distilled off under vacuum at 40-50 °C. The batch is then cooled to 20-25 °C. Water (255 L) is then added, and the crude product is extracted twice with heptane (2364.8 kg). The combined heptane layers are washed once with water (85 L). After removing the solvent by distillation under vacuum at 40-50 °C, the crude product (52.7 kg, 87.5% by mass) is obtained as a yellow oil in 52.6% assay yield and with an enantiomeric ratio of ≥ 90:10 (Chiral Method II). The crude product 9 is used directly in the next step. 1H NMR (500 MHz, CDCl3): δ 4.01-3.82 (m, 4H), 2.50-2.44 (m, 1H), 2.382.34 (m, 1H), 2.28-2.22 (m, 1H), 2.11-2.05 (m, 1H), 2.01-1.95 (m, 1H), 1.92-1.86 (m, 1H), 1.81-1.58 (m, 6H), 1.54-1.43 (m, 3H), 1.27-1.18 (m, 1H). ESI-MS: m / z 225 [M+H] + .

[0065] ( Example 3a ) [ka] A clean reactor under a dry N2 atmosphere was charged with Meldrum's acid (25) (11.33 g, 78.64 mmol, 2 equiv.), borane 28 (0.78 g, 10 mol%), and acetonitrile (30 mL, 3 V). The mixture was then stirred to form a clear solution. 5 (10 g, 39.3 mmol, 1 equiv.) was then charged, followed by additional acetonitrile (5 mL, 0.5 V). Photocatalyst 26 (0.62 g, 0.79 mmol, 2 mol%) was then charged to the mixture, and the mixture was stirred until 26 was completely dissolved. Triphenylsilanethiol (27) (0.58 g, 1.97 mmol, 10 mol%) and acetonitrile (15 mL, 1.5 V) were then charged. The mixture was then stirred to form a yellow, homogeneous solution. The photochemical reaction is then carried out using a standard commercially available photoreactor or a custom-built reactor as described in the literature (Chem. Rev. 2022, 122, 2, 2752-2906). The photoreactor is preheated to 50 °C and the LED is turned on. The reaction mixture is then introduced into the flow photoreactor using a suitable metering pump, maintaining a residence time of 50 to 200 min. The product solution containing 29 is simultaneously collected. The crude product solution is used in the next step without purification. 29:1H NMR (500 MHz, CDCl3): δ 4.14-4.07 (m, 2H), 3.92-3.82 (m, 4H), 3.52 (t, 1H), 2.05-1.93 (m, 4H), 1.73 (d, 6H), 1.67-1.57 (m, 13C NMR (500MHz, CDCl3): δ 173.9, 165.4, 165.3, 110.9, 104.7, 64.7, 64.5, 60.4, 54.5, 45.8, 32.1, 31.1, 30.2, 28.4, 26.8, 26.7, 23.0, 21.7, 20.8, 14.1 ESI-MS: m / z 421 [M+Na] + .

[0066] ( Example 3b ) [ka] A clean reactor was charged with the crude solution of 29 (100 g, 40.7 mmol, 1 equiv.) produced by the flow process and imidazole (6.92 g, 101.6 mmol, 2.5 equiv.). The mixture was stirred at an internal temperature of 80-85 °C for 3.5 h. The reaction was cooled to 70 °C and water (100 mL, 1 V) was charged. The reaction temperature was maintained at an internal temperature of 65 °C for 3 h. The mixture was then stirred at 25 °C for an additional 16 h.

[0067] The reaction was worked up according to the following process: 4 M NaOH solution (50 mL, 200 mmol, 5 equiv.) was added and the mixture was stirred for 30 min. MTBE was added and the mixture was stirred. After phase separation, the methyl tert-butyl ether layer was removed and the aqueous layer was filtered through filter paper. The aqueous phase was added with 2 M HCl solution (5.2 V) to adjust the pH to between 3.5 and 5.0 while maintaining the internal temperature at 25 °C. EtOAc was added to the acidic aqueous mixture and the mixture was stirred. After phase separation, the EtOAc phase was collected. Concentration of EtOAc gave crude product 31, which was used directly in the next step. 31:1H NMR (500 MHz, CDCl3): δ 4.22-4.11 (m, 2H), 3.97-3.86 (m, 4H), 2.36 (t, 2H), 2.11-2.00 (m, 2H), 1.76-1.50 (m, 9H), 1.41-1.32 (m, 2H), 1.28-1.26 (t, 3H), 1.16-1.07 (m, 1H). 13C NMR (500MHz, CDCl3): δ 178.96, 174.04, 111.07, 64.77, 64.59, 60.35, 54.41, 33.69, 32.06, 30.68, 29.64, 25.17, 23.93, 23.11, 20.72, 14.25. ESI-MS 315 [M+H] +

[0068] A clean reactor under nitrogen is charged with CDI (8.67 g, 53.55 mmol, 1.5 equiv.), followed by toluene (22.4 mL, 2 V). In a separate mixing vessel, a solution of 31 (11.2 g, 35.63 mmol, 1 equiv.) is prepared in toluene (11.3 mL, 1 V). The solution of 31 in toluene is then slowly added to the reactor containing the CDI / toluene slurry. The mixture is heated to 55–60 °C for approximately 1 h. Ethanol is then charged (11.3 mL, 1 V), and the mixture is heated to 75–80 °C for 2 h. The reaction is cooled to 20–25 °C. The organic phase is washed with water (22.4 mL, 2 V), 1 M HCl (22.4 mL, 2 V), and then water (22.4 mL, 2 V). The organic phase is filtered through a pad of Celite. The filter is then rinsed with toluene (5.6 mL, 0.5 V). The toluene fractions are combined and distilled under vacuum at 30-60°C to give the desired product 7b in 92-95% yield. 7b:1H NMR (500 MHz, CDCl3): δ 4.25-4.05 (m, 4H), 3.95-3.86 (m, 4H), 2.30-2.26 (m, 2H), 2.06-1.98 (m, 2H), 1.75-1.48 (m, 9H), 1.40-1.22 (m, 8H), 1.14-1.02 (m, 1H).

[0069] ( Example 3c ) [ka] A dry, clean reactor containing LiHMDS (67.2 mL, 2.3 equiv., 1 M in THF) was cooled to -5 to 0 °C, and 7b (10.0 g, 1 equiv.) in THF was slowly charged while maintaining an internal temperature below 5 °C. The mixture was held at 5 °C for 30 min. EtOH (25 mL, 2.5 V) was charged, and the mixture was heated to 66 to 70 °C for 14 h. 5 to 6 V of solvent was then removed by vacuum distillation, and the remaining solution was filtered through a pad of Celite. The Celite pad was rinsed with MTBE (20 mL, 2 V). The organic solution was extracted with MTBE and water. The combined MTBE fractions were then filtered through a pad of Celite. After vacuum distillation at 30 to 60 °C, the desired product 9 was obtained in 90 to 95% yield. The analytical data were identical to those of 9 obtained in Example 3.

[0070] ( Example 4 ) [ka] A dry, clean reactor was charged with 9-BBN (387 mL, 193.5 mmol, 1.2 equiv., 0.5 M in THF) under nitrogen. The solution was cooled to 0–5°C to give a slurry. 5 (41.0 g, 161.2 mmol) was added at 0–5°C and rinsed in with THF (20.5 mL). The mixture was warmed to 20–23°C over 1 h and held at 20–23°C for at least 1 h. After the mixture was cooled to −45–−40°C, methyl chloroacetate was added in one portion, followed by the dropwise addition of LiHMDS (355 mL, 532.0 mmol, 3.3 equiv.), maintaining the temperature below −35°C. The batch was warmed to 20–23°C over 1 h and then held at 20–23°C for at least 18 h. The batch is then cooled to 5-10°C, and AcOH (30.4 mL, 3.3 equiv.) is added below 20°C, followed by water (41 mL) at below 20°C. AcOH (30.4 mL, 3.3 equiv.) is added below 20°C to reach a pH of approximately 6-7. Approximately 15-16 V of THF is removed under vacuum below 35°C. MTBE (246 mL) and water (205 mL) are added. After phase separation and discarding the bottom aqueous layer, the mixture is cooled to 0-5°C, and a solution of sodium percarbonate (37.2 g, 322.4 mmol, 2.0 equiv.) in water (320 mL) is added below 20°C. After 1 h at 20-23°C, 20% by weight sodium sulfite solution (31 mL) is added. After 15 min at 20-23°C, the bottom aqueous layer is separated and discarded. The organic layer was washed with 5% by weight ammonium chloride solution (123 mL) and water (328 mL). The organic layer was treated with 5% activated carbon for 30 min before filtering. After removing the solvent for about 4-5 V under vacuum at below 35 °C, crude product 1a (80% yield; [M+H] + =283) as an orange-brown oil.

[0071] ( Example 5 ) [ka] A reactor is charged with 1a (45.5 g, 161.2 mmol), ethanol (91.0 mL), NaOAc (39.7 g, 483.6 mmol, 3.0 equiv), water (45.5 mL), and NHOH·HCl (33.6 g, 483.6 mmol, 3.0 equiv). The mixture is heated at 73–78 °C for 16 h or more. After the batch is cooled to 20–23 °C, water (227.6 mL) is added over 0.5 h. MTBE (136.5 mL) is then added over 0.5 h, followed by heptane (113.8 mL) over 1 h. After 0.5 h at 20–23 °C, the solid is collected by filtration. The solid is washed successively with MTBE (45 mL) and water (91.0 mL). The solid is dried under vacuum to give the product 18a as an off-white solid (18.27 g, 93.2% by weight) in 40% yield. 1H NMR (500 MHz, DMSO-d6): δ 11.48 (br s, 1H), 4.04 (q, J = 6.0 Hz, 1H), 3.89-3.80 (m, 2H), 3.60 (q, J = 6.8 Hz, 1H), 2.10-1.95 (m, 2H), 1.92-1.76 (m, 4H), 1.69-1.39 (m, 8H). ESI-MS: m / z 266 [M+H] + .

[0072] ( Example 6 ) [ka] A clean reactor was charged with 18a (100.0 g, 376.9 mmol, 1.0 equiv.) and KPO (240.0 g, 1130.8 mmol, 3.0 equiv.) in water (499.0 g, 500.0 mL) and toluene (432.5 g, 500.0 mL). The biphasic mixture was stirred to mix thoroughly. After cooling the mixture to 0-5 °C, TfO (186.0 g, 110.9 mL, 659.6 mmol, 1.750 equiv.) was added over 2 h using a syringe pump at <5 °C. After phase separation, the organic layer was filtered through a pad of Celite with NaSO. After rinsing with toluene (50 mL), the crude product 19 (149.8 g, 100% yield) was used directly in the next step. 1H NMR (500 MHz, CDCl3): δ 3.95-3.91(m, 3H), 3.77-3.74 (m, 1H), 2.51-2.44 (m, 2H), 2.16-1.80 (m, 4H), 1.77-1.48 (m, 8H). ESI-MS: m / z 398 [M+H] + .

[0073] ( Example 7 ) [ka] A dry, clean autoclave reactor was charged with 19 (750 g, 1.89 mol, 1 equiv.), Pd(OAc)2 (8.48 g, 37.7 mmol, 0.02 equiv.), rac-BINAP (23.5 g, 37.7 mmol, 0.02 equiv.), 2-MeTHF (3 L), EtOH (870 g, 18.9 mol, 10 equiv.), and DIPEA (293 g, 2.26 mol, 1.2 equiv.). The reactor was purged twice with nitrogen (100 psi) and then twice with CO2 (100 psi). The reactor was pressurized to 200 psi with CO2 and heated at 55–60 °C for ≥12 h. The mixture was transferred to the reactor, and the autoclave reactor was rinsed with 2-MeTHF (0.75 L). The mixture was washed with water (3.75 L). After filtration through a thin pad of Celite, the solvent is removed by vacuum distillation to give crude product 20 (531.9 g, 87.7% yield), which is used in the next step without purification. 1H NMR (400 MHz, CDCl3): δ 4.38 (q, J = 7.1 Hz, 2H), 3.95-3.85 (m, 3H), 3.76-3.73 (m, 1H), 2.85 (dt, J = 17.5, 5.5 Hz, 1H), 2.64 (ddd, J = ESI-MS: m / z 322 [M+H] + .

[0074] ( Example 8 ) [ka] A dry, clean reactor was charged with 20 (482.0 g, 1.5 mol, 1 equiv.) and EtOH (3 V), and approximately 3 V was vacuum distilled to remove residual 2-MeTHF from the previous carbonylation step. EtOH (1.45 L) and NH4OH (1.93 L) were added. The mixture was held at 20-25 °C for ≥ 15 h. Water (1.69 L) was added over 30 min. After 30 min at 20-25 °C, the solid was collected and washed with 1:2 EtOH / water (0.96 L) and water (0.48 L). The solid was slurried in 1:1 MTBE / hexane (0.96 L) for 1 h. The solid is collected by filtration and dried under vacuum at 40-45 °C overnight to give product 21 (332.4 g, 75.8% yield, water content ≤ 0.5% based on Karl Fischer titration) as a brown solid. 1H NMR (500 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.78 (s, 1H), 3.94-3.72 (m, 4H), 2.78 (dt, J = 17.1, 5.0 Hz, 1H), 2.54-2.48 (m, 1H), 2.20-2.14 (m, 1H), 1.93-1.78 (m, 3H), 1.70-1.42 (m, 8H). ESI-MS: m / z 293 [M+H] + .

[0075] ( Example 9 ) [ka] A dry, clean reactor is charged with 21 (383 g, 86.7 wt%, 1.137 mol, 1 equiv.), MeCN (1.15 L), and pyridine (216 g, 0.19 L, 2.4 equiv.). After cooling the mixture to 0-5 °C, trifluoroacetic anhydride (287 g, 1.36 mol, 1.2 equiv.) is added below 5 °C. After 5 min at 0-5 °C, water (1.54 L) is added below 15 °C. The product is extracted with MTBE (1.92 L) and washed with 5% sodium bicarbonate solution (1.15 L). The organic layer is filtered through a silica gel pad (380 g) and rinsed with MTBE (0.58 L). After removing the solvent by distillation under vacuum, the product 22 (421.8 g, 97.8% yield) is obtained as an orange-brown oil. 1H NMR (500 MHz, CDCl3): δ 3.98-3.85 (m, 3H), 3.80-3.75 (m, 1H), 2.72 (dt, J = 17.0, 5.2 Hz, 1H), 2.60 (ddd, J = 17.0, 9.5, 5.8 Hz, 1H), 2.20-2.12 (m, 1H), 2.07-1.94 (m, 3H), 1.82-1.48 (m, 8H). ESI-MS: m / z 275 [M+H] + .

[0076] ( Example 10 ) [ka] A dry flask was charged with crude 22 (265 g, 72.3 wt%, 698.4 mmol) in MeOH (1590 mL) and a catalytic amount of NaOMe (8.0 mL, 25% in MeOH, 34.9 mmol). The mixture was stirred at room temperature for 1 h to achieve >99% conversion. Solid NH4Cl (52.0 g, 977.8 mmol, 1.4 equiv.) was added, and the resulting mixture was stirred at room temperature to achieve >95% conversion (if not, additional NH4Cl was added). Dimethyl malonate (168 g, 1047.7 mmol, 1.5 equiv.) was added at room temperature, followed by NaOMe (377 g, 25% in MeOH, 2.5 equiv.). The resulting mixture was heated to reflux for 4 h to achieve >95% conversion. After the mixture is cooled to 23°C, water (795 mL) is added, followed by the slow addition of 6N HCl (349 mL) below 20°C to reach a pH of approximately 3. MTBE (530 mL) is added to the slurry. After 1 h at room temperature, the solid is collected by filtration and washed with 3 V of water (796 mL) and MTBE (530 mL) to give product 24 (178 g) as an off-white solid in >98% A and 71% crude yield. The crude product is used directly in the next step. 1H NMR (500 MHz, CDCl3): δ 5.82 (s, 1H), 3.96-3.74 (m, 4H), 2.74-2.70 (m, 1H), 2.62-2.59 (m, 1H), 2.22-2.10 (m, 1H), 2.12-1.90 (m, 3H), 1.80-1.48 (m, 8H). ESI-MS: m / z 360 [M+H] + .

[0077] ( Example 11 ) [ka] A dry flask is charged with 24 (80.0 g, 253.7 mmol), DMAP (4.0 g), tetramethylammonium chloride (4.0 g), and POCl (400 mL). The mixture is heated at 80 °C for 1.5 h to achieve a concentration of >99%. POCl is removed under vacuum to give a thick, pale yellow slurry. MTBE (160 mL) is added. The mixture is then cooled to 5 °C. Water (800 mL) is slowly added. The resulting white slurry is stirred at 23 °C for 1 h. The solid is collected by filtration and then washed successively with water (480 mL) and MTBE (160 mL). After drying under vacuum at 60 °C overnight, 84.3 g of product 11 is isolated as a white solid with a purity of >99% and a yield of approximately 93%. 1H NMR (600 MHz, DMSO-d6): δ 8.05(s, 1H),2.96-2.91 (m, 1H), 2.76-2.69 (m, 2H), 2.53-2.48 (m, 2H), 2.37-2.34 (m, 1H), 1.97-1.96 (m, 2H), 1.88-1.82 (m, 4H), 1.70-1.61 (m,1H), 1.52-1.41(m, 1H). 13C NMR (125 MHz, DMSO-d6): δ 209.8, 164.3,161.4, 157.3, 155.7, 120.8, 120.2, 50.3, 38.1, 37.5, 31.0, 26.6, 20.7,19.9, 18.0. ESI-MS: m / z 353 [M+H] + .

[0078] ( Example 12 ) [ka] A dry, clean reactor is charged with LiHMDS (1 M in THF) (406.4 kg, 456.1 mol, 1.1 equiv). The solution is cooled to 0-5 °C, and crude 9 (93.0 kg, 414.6 mol) is added below 5 °C, followed by a THF (46.5 kg) rinse to aid transfer. After 30 min at 0-5 °C, diethyl oxalate (72.5 kg, 497.5 mol, 1.2 equiv) is added below 5 °C. The mixture is warmed to 20-25 °C over 1 h and then held at 20-25 °C for at least 3 h. After cooling the batch to 10-15°C, add a chilled HCl solution [prepared by adding acetyl chloride (73.6 kg, 932.9 mol, 2.25 equiv.) to EtOH (293.9 kg) at 0-5°C] to the batch at less than 25°C to achieve a final pH of approximately 6-7. Add solid NH2OH·HCl (28.8 kg, 414.4 mol, 1.05 equiv.) in one portion, and heat the resulting mixture to reflux at 66-70°C for 6-10 hours. Then, remove 5V of solvent by distillation at reflux at 66-70°C. Remove residual THF using EtOH (73.5 kg). Add water (372.0 kg) and EtOH (293.9 kg). After 3-6 hours at 70-75°C, cool the mixture to 30-35°C. Seed with 0.5-1% crystals of 13. After 2-4 hours at 30-35°C, heptane (63.2 kg) is added over 1 hour. After 60 minutes at 20-25°C, water (279.0 kg) is added over 4-6 hours. After 1 hour at 20-25°C, the solid is collected and washed with 1:2 EtOH / water (51.2 kg EtOH and 130.2 kg water), followed by two washes with heptane (63.2 kg). The solid is dried under vacuum under a stream of nitrogen to give product 13 (93.0 kg) in 65% yield. 1H NMR (500 MHz, CDCl3): δ 4.42 (q, J = 7.1 Hz, 2H), 2.73 (dt, J = 16.8, 5.1 Hz, 1H), 2.64 (dt, J = 14.3, 6.0 Hz, 1H), 2.60-2.51 (m, 2H), 2.43-2.30 (m, 2H), 2.09-1.96 (m, 3H), 1.91-1.81 (m, 3H), 1.76-1.67 (m, 1H), 1.65-1.58 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H). ESI-MS: m / z 278 [M+H] + .

[0079] ( Example 13 ) [ka] A dry, clean reactor was charged with 13 (72.0 kg, 259.6 mol), EtOH (56.9 kg), and NH4OH (aq) (280.8 kg). The mixture was held at 20-25 °C for 16 hours. Water (144.0 kg) was added over 30 minutes, and the slurry was then held at 20-25 °C for 30 minutes. The solid was collected by filtration and washed with 1:3 EtOH / water (28.5 kg EtOH and 108 kg water) followed by heptane (97.9 kg). After drying under vacuum at 23 °C for 1 hour, the solid was dried under vacuum at 50-55 °C overnight to give product 14 (61.4 kg, 87.2% yield, enantiomeric ratio ≥ 95:5 (at 254 nm), water content ≤ 0.5% by Karl Fischer titration).

[0080] A dry, clean reactor is charged with crude 14 (60.0 kg, 1.0 equiv.), 1,4-dioxane (240.0 kg), and activated carbon (3.0 kg, 5 wt%). The mixture is stirred at 55-65°C for 2-4 hours. After hot filtration (55-65°C), the filter cake is washed with 1,4-dioxane (33.0 kg). The filtrate is transferred to a clean reactor. The temperature is adjusted to 45-55°C and stirred at 45-55°C for 1-2 hours. Water (240.0 kg) is added over 2 hours. The temperature is adjusted to 45-55°C and stirred at 45-55°C for 1-2 hours. The mixture is cooled to 35-45°C and stirred at 35-45°C for 2-4 hours. Water (87.0 kg) is added over 4 hours. The mixture is cooled to 15–25°C and stirred at 15–25°C for 12–14 h. The solid is collected by centrifugation, washed with water (120.0 kg), and dried under vacuum at 50–55°C overnight to give product 14 (44.8 kg, 71% yield) as a pale yellow to off-white solid. 1H NMR (500 MHz, DMSO-d6): δ 7.99 (s, 1H), 7.71 (s, 1H), 2.80-2.69 (m, 1H), 2.60-2.53 (m, 1H), 2.50-2.42 (m, 1H), 2.40-2.28 (m, 2H), 2.26-2.18 (m, 1H), 2.05-1.70 (m, 7H), 1.48-1.39 (m, 1H). ESI-MS: m / z 249 [M+H] + .

[0081] ( Example 14 ) [ka] A dry, clean reactor was charged with 14 (40.0 kg, 161.1 mol), MeCN (96.0 kg), and pyridine (30.8 kg, 386.6 mol, 2.4 equiv). After cooling the mixture to 0-5 °C, TFAA (40.8 kg, 193.3 mol, 1.2 equiv) was added slowly below 5 °C. After 5 min at 0-5 °C, water (120.0 kg) was added over 30 min at 0-5 °C and seeded with 0.5% 15 crystals. After 15 min at 0-5 °C, water (120.0 kg) was added over 30 min. After 30 min at 0-5 °C, the solid was collected by filtration and washed with 1:3 MeCN / water (15.6 g acetonitrile and 60.0 kg water), followed by water (80.0 kg). The solid is dried under vacuum to give the crude product (33.0 kg, 93.6% yield) as a brown solid.

[0082] A dry, clean reactor is charged with crude 15 (32.5 kg, 1.0 equiv.) and MTBE (48.1 kg), and the slurry is stirred for 30 min at 20-25 °C. Heptane (132.6 kg) is added over 1 h. After 30 min at 20-25 °C, the solid is collected and dried under vacuum to give product 15 (26.6 kg, 82.0% yield) as a white solid with an enantiomeric ratio of >99:1 (254 nm, Chiral Method III) and a purity of >98% (220 nm). 1H NMR (500 MHz, DMSO-d6): δ 2.83-2.73 (m, 1H), 2.60-2.40 (m, 3H), 2.34-2.20 (m, 2H), 2.06-1.75 (m, 7H), 1.53-1.43 (m, 1H). ESI-MS: m / z 231 [M+H] + .

[0083] ( Example 15 ) [ka] To a stirred solution of 15 (25.0 g, 108.6 mmol, 1.0 equiv) in MeOH (150 mL), NaOMe (30% in MeOH, 4.89 g, 27.1 mmol, 0.25 equiv) was added, and the resulting mixture was stirred at room temperature for 2 h. Next, NHCl (6.39 g, 119.4 mmol, 1.1 equiv) was added, and the mixture was stirred at room temperature for 16 h. After complete conversion to the desired amidine, the mixture was filtered through a pad of Celite and concentrated. The residue was dissolved in DMF (125 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (32.3 g, 212.3 mmol, 2.1 equiv) and diethyl malonate (13.4 g, 101.1 mmol, 1.0 equiv) were added at 0 °C, and the resulting mixture was stirred at 90 °C for 16 h. After complete conversion, ice-cold water is added, the mixture is acidified with 1N HCl, and the precipitate is collected by filtration. The precipitate is dried under reduced pressure to give crude 17 ([M+H]=316), which is used in the next step without purification.

[0084] ( Example 16 ) [ka] 17 (10.0 g, 30.1 mmol, 1.0 equiv) and POCl3 (48.0 g, 310.0 mmol, 10.3 equiv) were combined at 0 °C and stirred for 5 min. DIPEA (8.2 g, 63.2 mmol, 2.1 equiv) was added, and the resulting mixture was stirred at 80 °C for 3 h. After complete conversion, ice-cold water (1 L) was slowly added to the mixture at 0 °C, after which the mixture was allowed to reach room temperature and stirred for 1 h. The precipitate was collected by filtration, washed with water and hexane, and dried under vacuum to give 10 ([M+H] = 352 / 354). The crude product was used in the next step without purification.

Claims

1. A compound of formula (1). 【Chemistry 1】 wherein R is selected from the group consisting of linear, branched, or cyclic alkyl groups, and aryl groups, and combinations thereof; preferably, in all the above definitions, R has 1 to 12 carbon atoms or 1 to 6 carbon atoms, in particular R is an optionally substituted linear or branched alkyl C1-C12 or C1-C6 group; further, in all the above definitions, R is preferably a saturated and unsubstituted hydrocarbon group; preferably R is methyl or ethyl.

2. The compound of formula (1) according to claim 1 【Chemistry 2】 A process for preparing a compound of formula (5) 【Transformation 3】 in a one-pot reaction.

3. 3. The process of claim 2, wherein the one-pot sequence from the compound of formula (5) to the compound of formula (1) comprises at least three transformation reactions: hydroboration, alkylation, and Dieckmann condensation.

4. 4. The process of claim 3, wherein the hydroboration is carried out in the presence of 9-BBN.

5. The process of claims 3-4, wherein the alkylation is carried out in the presence of an α-haloacetic acid ester.

6. The process according to claims 3 to 5, wherein each of the alkylation and condensation conversion reactions is carried out in the presence of at least one base.

7. The process according to claims 3 to 6, wherein the amount of base used is between 3.0 and 6.0 equivalents, preferably between 3.1 and 4.0 equivalents, more preferably around 3.3 equivalents.

8. The process of claims 2 to 7, wherein the compound of formula (5) is prepared by asymmetric allylic alkylation from a compound of formula (3). 【Chemistry 4】

9. 9. The process of claim 8, wherein the asymmetric allylic alkylation of a compound of formula (3) is carried out in the presence of less than 0.250 mol %, preferably less than 0.125 mol %, more preferably less than 0.050 mol %, and most preferably 0.035 mol % of allylpalladium(II) chloride dimer and (S,S)-DACH-Ph Trost ligand at a Pd / ligand ratio between 1.00:1.00 and 1.00:3.00, preferably between 1.00:1.07 and 1.00:1.20, and most preferably around 1.00:1.

15.

10. 10. The process according to claims 8 and 9, wherein the asymmetric allylic alkylation of (3) is carried out at a reaction temperature between 5 and 20°C, most preferably between 10 and 15°C.

11. A compound of formula (10) or (11), including a compound of formula (1) according to claim 1. 【Transformation 5】 A process for preparing

12. Compound of formula (10) 【Transformation 6】 which comprises as an intermediate a compound of formula (9) 【Transformation 7】 A process involving:

13. 13. The process of claim 12, wherein the compound of formula (9) is produced according to any one of claims 2 to 10, and the one-pot sequence of the compound of formula (5) has the compound of formula (9) as the isolated product and comprises five transformation reactions: hydroboration, alkylation, Dieckmann condensation, saponification, and decarboxylation.

14. A compound of formula (10) or (11). 【Transformation 8】

15. Use of the compound of formula (10) and / or the compound of formula (9) for the synthesis of fused 2-amino-3-cyanothiophenes and derivatives of formula (2).

16. Use of the compound of formula (1) and / or one of the compounds of formula (11) for the synthesis of fused 2-amino-3-cyanothiophenes of formula (2) and derivatives.

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