Methods of synthesizing substituted pyrrolopyrimidine compounds

Abstract

The present disclosure provides methods of synthesizing a compound of Formula I. The method includes an asymmetric transfer hydrogenation to produce an intermediate and then carrying forward the single or enriched enantiomer through the remainder of the synthesis of a compound of Formula I. Also disclosed is an alternative route for attaching the heterocyclic ring.

Description

PATENT 145688-005402 METHODS OF SYNTHESIZING SUBSTITUTED PYRROLOPYRIMIDINE COMPOUNDS Cross-Reference To Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 615,499 filed December 28, 2023, which is hereby incorporated by reference in its entirety for all purposes. Summary

[0002] The present disclosure includes embodiments directed to methods of synthesizing a compound of

[0003] The method includes an asymmetric transfer hydrogenation to produce an intermediate and then carrying forward the single or enriched enantiomer through the remainder of the synthesis of a compound of Formula I. Also disclosed is an alternative route to attaching the heterocyclic ring. Definitions

[0004] Before the present compositions and methods are described, it is to be understood that this invention is not limited to the particular processes, formulations, compositions, or methodologies described, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of embodiments herein which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of embodiments herein, the preferred methods, devices, and materials are now described. All publications mentioned herein are incorporated by reference in their entirety. Nothing herein is to be construed as an admission that embodiments herein are not entitled to antedate such disclosure by virtue of prior invention. -1- 1615709821.1PATENT 145688-005402

[0005] It must also be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise.

[0006] The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.

[0007] In embodiments or claims where the term “comprising” is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of” or “consisting essentially of.”

[0008] As used herein, the term “consists of” or “consisting of” means that the composition, formulation or the method includes only the elements, steps, or ingredients specifically recited in the particular claimed embodiment or claim.

[0009] As used herein, the term “consisting essentially of” or “consists essentially of” means that the composition, formulation or the method includes only the elements, steps or ingredients specifically recited in the particular claimed embodiment or claim and may optionally include additional elements, steps or ingredients that do not materially affect the basic and novel characteristics of the particular embodiment or claim. For example, the only active ingredient(s) in the formulation or method that treats the specified condition (e.g., nutrient depletion) is the specifically recited therapeutic(s) in the particular embodiment or claim.

[0010] As used herein, two embodiments are “mutually exclusive” when one is defined to be something which is different from the other. For example, an embodiment wherein two groups combine to form a cycloalkyl is mutually exclusive with an embodiment in which one group is ethyl the other group is hydrogen. Similarly, an embodiment wherein one group is CH2is mutually exclusive with an embodiment wherein the same group is NH.

[0011] When ranges of values are disclosed, and the notation “from n1 … to n2” or “between n1 … and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 μM (micromolar),” which is intended to include 1 μM, 3 μM, and everything in between to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.). -2- 1615709821.1PATENT 145688-005402

[0012] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean plus or minus 10% of the numerical value of the number with which it is being used. Therefore, about 50% means in the range of 45%-55%.

[0013] In embodiments or claims, “PG” is a protecting group.

[0014] In embodiments or claims, “X” is a halogen.

[0015] The term “chiral separation,” as used herein, refers to the separation of racemic compounds into their single or enriched enantiomers.

[0016] The term “substantially free” as used herein, is used interchangeably with, the term “substantially pure”, refers to a compound which is free from all other compounds within the limits of detection as measured by any means including nuclear magnetic resonance (NMR), gas chromatography / mass spectroscopy (GC / MS), or liquid chromatography / mass spectroscopy (LC / MS). In some embodiments, substantially free may be less than about 1.0%, less than about 0.5%, less than about 0.4%, less than about 0.3%, less than about 0.2%, less than about 0.1%, less than about 0.05%, or less than about 0.01%.

[0017] Also provided are embodiments wherein any embodiment herein may be combined with any one or more of the other embodiments, unless otherwise stated and provided the combination is not mutually exclusive. Brief Description of the Drawings

[0018] FIG.1 depicts a scheme of the reactor utilized in Example 5. Detailed Description

[0019] The present disclosure includes embodiments directed to methods of synthesizing a compound of Formula I, having the structure: F 1-((2S,5R)-5-((5-((R)-2,2- 4-yl)amino)-2-methylpiperidin-1--3- 1615709821.1PATENT 145688-005402

[0020] Scheme 1 outlines one route for synthesizing a compound of Formula I. The route features an asymmetric transfer hydrogenation of the difluorocyclopropene ring of CPD- 6 to arrive at CPD-07 and then carrying forward the single or enriched enantiomer through the remainder of the synthesis of a compound of Formula I. Scheme 2 depicts an alternative route of synthesizing CPD-11 from CPD-7. CPD-11 produced from the alternative route may be utilized in the route of Scheme 1 to synthesize a compound of Formula I.-4- 1615709821.1PATENT 145688-005402

[0023] Some embodiments of the present application describe a process for the preparation of compound ofcompound ; and (c) converting CPD-2 to Formula I.

[0024] In some embodiments of the forming of CPD-2, X1is selected from Cl, Br, or I.

[0025] In some embodiments of the forming of CPD-2, X1 is Cl.

[0026] In some embodiments of the forming of CPD-2, X2 is selected from Cl, Br, or I.

[0027] In some embodiments of the forming of CPD-2, X2 is I.

[0028] In some embodiments of the forming of CPD-2, the halogenating reagent is selected from N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-Dichloro- 5,5-dimethylhydantoin, or NaOCl.

[0029] In some embodiments of the forming of CPD-2, the halogenating reagent is N-iodosuccinimide. -5- 1615709821.1PATENT 145688-005402

[0030] In another embodiment of the process for the preparation of compound of Formula I, the process contacting the compound CPD-2 with a reagent anda base to form the compound .

[0031] In some embodiments of the forming of CPD-3, PG1 is selected from a 2- (trimethylsilyl)ethoxymethyl group, a tert-butyloxycarbonyl group, a p-methoxybenzyl group, a 4-toluenesulfonyl group, or a benzenesulfonyl group.

[0032] In some embodiments of the forming of CPD-3, the reagent is selected from 2-(trimethylsilyl)ethoxymethyl chloride, di-tert-butyloxycarbonate, p-methoxybenzyl chloride, 4-toluenesulfonyl chloride, or benzenesulfonyl chloride.

[0033] In some embodiments of the forming of CPD-3, the base is NaH.

[0034] In another embodiment of the process for the preparation of compound of Formula I, the process further comprises contacting the compound CPD-3 with a first catalyst,a second catalyst, a base,.

[0035] In some embodiments of the forming of CPD-4, PG2is a trimethylsilyl group.

[0036] In some embodiments of the forming of CPD-4, the first catalyst is PdCl2(PPh3)2.In some embodiments of the forming of CPD-4, wherein the second catalyst is CuI.

[0038] In some embodiments of the forming of CPD-4, the base is K3PO4.

[0039] In another embodiment of the process for the preparation of compound of Formula I, the process further comprises contacting the compound CPD-4 with a deprotection reagent to form the .-6- 1615709821.1PATENT 145688-005402

[0040] In some embodiments of the forming of CPD-5, the deprotection reagent is tetrabutylammonium fluoride.

[0041] In another embodiment of the process for the preparation of compound of Formula I, the process further comprises CPD-5 with a catalyst anda difluorocarbene reagent to form the compound .

[0042] In some embodiments of the forming of CPD-6, the catalyst is NaI.

[0043] In some embodiments of the forming of CPD-6, the difluorocarbene reagent is TMSCF3.

[0044] In another embodiment of the process for the preparation of compound of Formula I, the process further comprises contacting the compound CPD-6 with a catalyst, a hydrogen donor, and a base to form the compound

[0045] In some embodiments of the forming of CPD-7, the catalyst is selected from RuCl(p-cymene)[(S,S)-Ts-DPEN], RuCl[(R,R)-Ts-DPEN](mesitylene), RuCl[(S,S)-Teth- TsDpen], or Cu(OAc)2[(S,S)-PH-BPE].

[0046] In some embodiments of the forming of CPD-7, the catalyst is RuCl(p- cymene)[(S,S)-Ts-DPEN].

[0047] In some embodiments of the forming of CPD-7, the hydrogen donor is selected from isopropyl alcohol, formic acid, and methanol.

[0048] In some embodiments of the forming of CPD-7, the hydrogen donor is isopropyl alcohol.

[0049] In some embodiments of the forming of CPD-7, the base is NaOtBu.

[0050] In another embodiment of the process for the preparation of compound of Formula I, the process further comprises contacting the compound CPD-7 with a first acid then -7- 1615709821.1a first base followed by a second acid and a second base to form the compound .

[0051] In some embodiments of the forming of CPD-8, the first acid is trifluoroacetic acid.

[0052] In some embodiments of the forming of CPD-8, the first base is NH4OH.

[0053] In some embodiments of the forming of CPD-8, the second acid is HCl.

[0054] In some embodiments of the forming of CPD-8, the second base is Na2CO3.

[0055] In another embodiment of the process for the preparation of compound of Formula I, the process further comprises contacting the compound CPD-8 with

[0056] In some embodiments of the forming of CPD-10, PG3 is a benzyloxycarbonyl group.

[0057] In some embodiments of the forming of CPD-10, the halogen ion source is NaI.

[0058] In some embodiments of the forming of CPD-10, the base is KF. -8- 1615709821.1PATENT 145688-005402

[0059] In another embodiment of the process for the preparation of compound of Formula I, the the compound CPD-10 with an acid toform the compound .

[0060] In some embodiments of the forming of CPD-11, the acid is HCl or trifluoracetic acid.

[0062] In some embodiments of the forming of CPD-13, PG3is a benzyloxycarbonyl group.

[0063] In some embodiments of the forming of CPD-13, the halogen ion source is NaI.

[0064] In some embodiments of the forming of CPD-13, the base is KF.

[0065] In another embodiment of the process for the preparation of compound of Formula I, the process further comprises contacting the compound CPD-13 with an acid followed by a base to form the compound-9- 1615709821.1PATENT 145688-005402

[0066] In some embodiments of the forming of CPD-11, the acid is HCl or trifluoracetic acid.

[0067] In some embodiments of the forming of CPD-11, the base is NH3.

[0068] In another embodiment of the process for the preparation ofFormula I, the process further 11 withand a base to form the compound .

[0069] In some embodiments of the forming of CPD-12, X3 is selected from Cl, Br, or I.

[0070] In some embodiments of the forming of CPD-12, X3 is Cl.

[0071] In some embodiments of the forming of CPD-12, base is K3PO4.

[0072] In another embodiment of the process for the preparation of compound of Formula I, the process further comprises contacting the compound CPD-13 with a base to form the compound of Formula I.

[0073] In some embodiments of the forming of CPD-13, the base is NaOH.

[0074] Some embodiments of the present application relate to a compound, or a salt thereof, or a co-crystal thereof, selected from the group consisting of: -10- 1615709821.1SEM 4-chloro-5-(3,3-difluorocycloprop- 1-en-1-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H- d]pyrimidine , ,and . EXAMPLES

[0075] The compound of the present invention can be prepared using the methods illustrated in the experimental procedures detailed below. The starting materials used to prepare the compounds of the present invention are commercially available or can be prepared using routine methods known in the art. Solvents and reagents, whose synthetic preparations are not described below, can be purchased at Sigma-Aldrich or Fisher Scientific.

[0076] Representative procedures for the preparation of compounds of this disclosure are outlined below. Example 1: Preparation of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine

[0077] 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) and DMF (10V) were added to the reactor followed by NIS (1.2 eq) in portions at 20 ~ 30 °C. The reaction was warmed to 20 ~ 30 °C and stirred for 2 h. The reaction mixture was then poured into ice water (30V) at 5 ~ -11- 1615709821.1PATENT 145688-005402 10 °C and stirred for 30 min at 0 ~ 10 °C before filtering the mixture and rinsing the cake with ice water (5V). Example 2: Preparation of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]

[0078] NaH (2.0 eq) and THF (5V) were charged and then cooled to -2.~.3 °C, followed by addition of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq) in THF (22V) dropwise into the reaction mixture at 0 ~ 5 °C. The reaction was then stirred for 30 min at 0 ~ 5 °C. SEMCl (1.2 eq) was added dropwise into the reaction mixture at 0 ~ 5 °C. The reaction was then stirred for 2 h at 0 ~ 10 °C. The reaction mixture was quenched with acetic acid (4 eq) at 0 ~ 10 °C. Water (10V) and EtOAc (15V) were then added into the mixture. The organic layer was separated at 20 ~ 30 °C. The organic layer was concentrated to 2 ~ 3V under reduced pressure at below 40 °C. The organic layer was slurried with MeOH (2.0V) at 20 ~ 25 °C. The resulting suspension was filtered, and the cake was rinsed with MeOH (2.0V) then dried under vacuum. Example 3: Preparation of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-5- ((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine

[0079] 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine (1.0 eq), THF (10V), and purified water (2.2 eq) were charged at 15 ~ 25 °C -12- 1615709821.1PATENT 145688-005402 followed by the addition of K3PO4 (2.0 eq), CuI (0.05 eq), and PdCl2(PPh3)2 (0.75% eq) at 15 ~ 25 °C. The reaction was bubbled with N2 for 1 ~ 2 h followed by cooling to 10 ~ 15 °C. TMS-acetylene (1.5 eq) was added into the reaction mixture at 10 ~ 15 °C, and the reaction was stirred at 10 ~ 15 °C until reaction completion. The reaction mixture was stirred with 40% wt. sulfhydryl silica gel, and the organic phase was carried to Example 4 directly. MS (ESI) m / z 380.0 [M + H]+. Example 4: Preparation of 4-chloro-5-ethynyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]

[0080] 0.15 eq TBAF was added to the mixture resulting from Example 3, and the mixture was stirred until all of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-5- ((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine was consumed. 10% NH4Cl (5V) was then added to the mixture. The organic phase was separated and washed with another 10% NaCl (5V). The separated organic phase was switched with 5V HEP, and another 5V DCM was added.10% sulfhydryl silica gel and 10% wt silica gel were then added to the mixture and stirred for another 2 ~ 4 h. The slurry was filtered through a 0.5cm silica pad, and the cake was rinsed with another 5V DCM. The filtrate is concentrated to 2 ~ 3V, and another 5 V HEP is added to the mixture. After concentrating to 2 ~ 3V, the slurry was cooled to 0 and precipitation of 4-chloro-5-ethynyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine occurred which was then filtered and dried. MS (ESI) m / z 307.9 [M + H]+. Example 5: Preparation of 4-chloro-5-(3,3-difluorocycloprop-1-en-1-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine -13- 1615709821.1PATENT 145688-005402N SEMNSEM 4-chloro-5-ethynyl-7-((2- 4-chloro-5-(3,3- (trimethylsilyl)ethoxy)methyl) difluorocycloprop-1-en-1-yl)-7- -7H-pyrrolo[2,3-d]pyrimidine ((2-(trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine

[0081] The reaction of Example 5 was carried out in the reactor depicted in FIG.1.

[0082] TK-1 (Feed A) was charged with 4-chloro-5-ethynyl-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0 eq.), NaI (0.2 eq.), and THF (10V). TK-2 (Feed B) was charged with TMSCF3 (2.5 eq.) and THF (10V). PFR was heated to 90 ~ 110 °C. Pump 1 (P-1) was connected to Feed A, and Pump 2 (P-2) was connected to Feed B. The flow rate of P-1 was set at 0.61 g / min, and the flow rate of P-2 was set at 0.61 g / min. P-1 and P-2 were turned on simultaneously, back up 0.5 ~ 1.0 MPa pressure. The contents of P-1 and P-2 entered the PFR (residence time = 30min). The mixture was received in the receiver at 20 ~ 30 °C. The contents of the receiver were concentrated to 2~3V under reduced pressure at below 40 °C and subjected to Example 6 directly. MS (ESI) m / z 357.9 [M + H]+. Example 6: Preparation of (R)-4-chloro-5-(2,2-difluorocyclopropyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

[0083] NaOtBu and RuCl(p-cymene)[(S,S)-Ts-DPEN] were added to 2V THF in a reactor. 10V IPA was added dropwise followed by dropwise addition of 4-chloro-5-(3,3- difluorocycloprop-1-en-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d]pyrimidine in 2V THF solution. 1V DCM was used to rinse the pipeline and was added to -14- 1615709821.1PATENT 145688-005402 the reactor, and the reaction was continued at 15 ~ 25 . The reaction was quenched with 0.2 eq acetic acid. The solvent was switched with 10V isopropyl acetate. 0.5 eq 2- mercaptonicotinic acid and 2.2 eq NaOH in 5V water solution were added to the mixture before heating to 50 for another 2 h. The organic phase was separated, and then the isopropyl acetate was switched with 10V toluene. The organic phase was stirred with 50% wt silica gel and then passed through a 100% silica pad. An additional 10V toluene and 10V DCM was used to rinse the silica pad. 10% sulfhydryl gel and 20% silica gel treatment were used for the removal of Ru. After switching toluene with heptane, the product was crystallized at 0 ~ 10 . The cake was rinsed with 1V pre-chilled heptane giving the product as an off-white to yellow solid. 7: Alternative of 5-((R)-2,2- -N-((3R,6S)-6-

[0084] An alternative synthesis of 5-((R)-2,2-difluorocyclopropyl)-N-((3R,6S)-6- methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine was carried out as shown in the above reaction scheme. Example 8: Preparation of benzyl (2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2- methylpiperidine-1-carboxylate -15- 1615709821.1PATENT 005402 FNNKF, NaI, DMSO, 95~NSEM 100°C SEM (R)-4-chloro-5-(2,2- benzyl (2S,5R)-5-((5-((R)-2,2- difluorocyclopropyl)-7-((2- difluorocyclopropyl)-7-((2- (trimethylsilyl)ethoxy)methyl)- (trimethylsilyl)ethoxy)methyl)- 7H-pyrrolo[2,3-d]pyrimidine 7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-methylpiperidine-1- carboxylate

[0085] 1.2 eq benzyl (2S,5R)-5-amino-2-methylpiperidine-1-carboxylate mandelate salt, MTBE (7V), and purified water (7V) were added to the reactor followed by 5.23V of 2.5% NaOH solution at 0 ~ 10 . The mixture was stirred for 1 to 2 h until the solid was completely dissolved. The mixture was separated, and the organic layer was washed with purified water (2V). The organic phase was concentrated at T 40 under reduced pressure (P 0.08 MPa) until 1 – 2V remained. DMSO (5V) was added, and the mixture was concentrated to ~ 5V. The process was repeated until MTBE residual was NMT 5%. The mixture was cooled to 20 ~ 30 before charging 3.5 eq KF, 1.0 eq (R)-4-chloro-5-(2,2-difluorocyclopropyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine, and 0.1 eq NaI with stirring. The mixture was heated to 95 ~ 100oC (reference heating rate: 20 ~ 40oC / h). After 24 h, the mixture was sampled every 6 ~ 12 h for HPLC analysis until (R)-4-chloro-5-(2,2-difluorocyclopropyl)- 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine was NMT 5.0% or the difference between two consecutive samples was NMT 1%. The mixture was cooled to 20 ~ 30oC. Purified water (10V) and EA (5V) were added to the mixture, and NaHCO3was used to adjust the pH to 7 ~ 8. Stirring was continued for 10 ~ 20 min before settling and separating the layers. The aqueous phase was extracted with EA (5V). The combined organic phase was washed with purified water (10V) and was concentrated at T 40oC under reduced pressure (P -0.07 MPa) to 2~3V to afford the crude product solution. Methanol (1.5~2V) was added, and the mixture was concentrated. The process was repeated until the EA residual 1%. The product solution of benzyl (2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine- 1-carboxylate) in methanol was collected and analyzed for HPLC purity and HPLC assay or qNMR before proceeding to the next step. Yield: 84.3%; Assay by qNMR: 51.9%; Purity: 94.5%. -16- 1615709821.1PATENT 145688-005402 Example 9: Preparation of 5-((R)-2,2-difluorocyclopropyl)-N-((3R,6S)-6-

[0086] Benzyl (2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine- 1-carboxylate solution in methanol and concentrated. HCl aq. (7V) were charged to the reactor and heated to 30~40oC. After 12 h, the mixture was sampled every 2 ~ 4 h for HPLC analysis until the benzyl (2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine- 1-carboxylate was NMT 0.5%. The mixture was cooled to 15 ~ 25oC. Toluene (3V) was added to the mixture, and stirring was continued for 10 ~ 20 min before settling and separating the layers. The aqueous phase was extracted with toluene (3V) each time until the benzyl chloride residual was 0.1%, and the methyl chloride residual was 0.2%; the product is in the aqueous phase. 1.4-dioxane (5 V) was added, and the mixture was cooled to 0 ~ 5oC. Ammonium hydroxide (8V) was then added at 0 ~ 20oC. The reaction was continued at 20 ~ 30oC. After 12 h, the mixture was sampled every 2 ~ 4 h for HPLC analysis until the hydroxymethyl intermediate was NMT 0.5%. At 0 ~ 10oC, 6 M HCl aq. was added into the product aqueous phase to adjust the pH to 7 ~ 8. n-BuOH (10V*2) was charged into the mixture and stirred for 15 ~ 25 min before settling and separating the layers. The combined organic phase was then washed with 15% NaCl aq. (3V). The organic phase was concentrated under reduced pressure (P -0.08 MPa) until 2V remained. Toluene (10V) was added, and the mixture was concentrated under reduced pressure (P -0.08 MPa) until 5V remained. Toluene (5V) was added followed by concentration until n-BuOH was NMT 15%. The mixture was concentrated under reduced pressure (P -0.08 MPa) until 5V remained. Heptane (15V) was added dropwise, and the mixture was stirred for 1 h. The heptane solution was filtered, and the cake was washed with 1 ~ 2V heptane to obtain the product. The solid was dissolved into 3V H2O -17- 1615709821.1PATENT 145688-005402 to analyze for assay of 5-((R)-2,2-difluorocyclopropyl)-N-((3R,6S)-6-methylpiperidin-3-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-amine. Based on the corrected yield, the material is used in the next step. Yield: 85.6%; Assay by qNMR: 14.7%; Purity: 92.3%. Example 10: Preparation of 3-chloro-1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H- pyrrolo

[0087] 5-((R)-2,2-difluorocyclopropyl)-N-((3R,6S)-6-methylpiperidin-3-yl)-7H- pyrrolo[2,3-d]pyrimidin-4-amine in tetrahydrofuran, additional tetrahydrofuran, and purified water are added to a reactor and cooled to 0 to 10 °C. Potassium phosphate is added, and the mixture is stirred to obtain a clear solution.3-Chloropropionyl chloride is added to the mixture and stirred. After the reaction is complete, the mixture is settled into layers, and the aqueous phase is extracted with ethyl acetate. The organic phases are combined and washed with sodium chloride solution and purified water. The organic phase is concentrated, ethyl acetate is added, and the mixture is concentrated to remove tetrahydrofuran. The mixture is cooled, and n- heptane is added under stirring. The mixture is filtered, and the reactor wall is rinsed with n- heptane that is subsequently used to rinse the filter cake. The filter cake is dried under nitrogen to afford 3-chloro-1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)propan-1-one. The HPLC purity is the total of 3-chloro-1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)amino)-2-methylpiperidin-1-yl)propan-1-one and a small amount of 1-((2S,5R)-5-((5-((R)- 2,2-difluorocyclopropyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1- yl)prop-2-en-1-one that prematurely forms during the acylation reaction. Example 11: Preparation of 1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one -18- 1615709821.1PATENT 88-005402

[0088] 3-chloro-1-((2S,5R)-5-((5-((R)-2,2-difluorocyclopropyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)propan-1-one, tetrahydrofuran, and purified water are added to a reactor and cooled. Sodium hydroxide solution, which is prepared with sodium hydroxide and purified water, is added to the mixture and stirred. After the reaction is complete, the pH is adjusted to 7 to 8 using potassium dihydrogen phosphate solution. Ethyl acetate is added, and the mixture is stirred and separated. The aqueous phase is extracted with ethyl acetate. The combined organic phase is washed with sodium chloride and purified water. The organic phase is then concentrated until the residual tetrahydrofuran limit is met. The mixture is then filtered through a Nutsche filter containing a silica gel bed until the material is qualified. The combined filtrate is concentrated. Isopropanol charging and concentration are repeated until the residual ethyl acetate limit is met. Seed crystals of ATI-2138 are then added to the isopropanol solution, and it is stirred while the material crystallizes. n-Heptane is added to the mixture, and it is stirred. The mixture is filtered, rinsed with n-heptane, and the filter cake is vacuum-dried under nitrogen to afford the drug substance ATI-2138. If any criterion is not met, the filter cake is resubjected to the crystallization process. Drying continues until all residual solvent criteria are met.1H NMR (400 MHz, DMSO-d6) 11.54 (s, 1H), 8.11 (s, 1H), 7.01 (s, 1H), 6.77 (br s, 1H), 6.07 (d, J = 16.8 Hz, 1H), 5.95 (d, J = 8.0 Hz, 1H), 5.65 (d, J = 10.4 Hz, 1H), 4.77 (br s, 1H), 4.55 (br s, 1H), 4.32 (br s, 1H), 4.05 (br s, 1H), 3.36 (br s, 1H), 3.02 (br s, 1H), 1.92-2.13 (m, 1H), 1.65-1.98 (m, 4H), 1.19 (br s, 3H); MS (ES) m / z: 362.0 (M+H). -19- 1615709821.1

Claims

PATENT 145688-005402 CLAIMS What is claimed is:

1. A process for the preparation of compound of Formula I having the structure:comprising the steps of:(a) contacting the compound ,a halogenating reagent to form thecompound ; and (c) converting CPD-2 to Formula I.

2. The process according to claim 1, wherein X1 is selected from Cl, Br, or I.

3. The process according to claim 2, wherein X1 is Cl.

4. The process according to claim 1, wherein X2is selected from Cl, Br, or I.

5. The process according to claim 4, wherein X2is I.

6. The process according to claim 1, wherein the halogenating reagent is selected from N- chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-Dichloro-5,5- dimethylhydantoin, or NaOCl.

7. The process according to claim 6, wherein the halogenating reagent is N- iodosuccinimide. 1615709821.1PATENT 145688-005402 8. The process according to claim 1, further comprising contacting the compound CPD-2 with a reagent and a base to form the compound.

9. The process according to claim 8, wherein PG1 is selected from a 2- (trimethylsilyl)ethoxymethyl group, a tert-butyloxycarbonyl group, a p-methoxybenzyl group, a 4-toluenesulfonyl group, or a benzenesulfonyl group.

10. The process according to claim 8, wherein the reagent is selected from 2- (trimethylsilyl)ethoxymethyl chloride, di-tert-butyloxycarbonate, p-methoxybenzyl chloride, 4-toluenesulfonyl chloride, or benzenesulfonyl chloride.

11. The process according to claim 8, wherein the base is NaH.

12. The process according to claim 8, further comprising contacting the compound CPD-3with a first catalyst, a second catalyst, a base, andto form the compound.

13. The process according to claim 12, wherein PG2 is a trimethylsilyl group.

14. The process according to claim 12, wherein the first catalyst is PdCl2(PPh3)2.

15. The process according to claim 12, wherein the second catalyst is CuI.

16. The process according to claim 12, wherein the base is K3PO4. 1615709821.1PATENT 145688-005402 17. The process according to claim 12, further comprising contacting the compound CPD- 4 with a deprotection reagent to form the compound.

18. The process according to claim 17, wherein the deprotection reagent is tetrabutylammonium fluoride.

19. The process according to claim 17, further comprising contacting the compound CPD- 5 with a catalyst and a difluorocarbene reagent to form the compound.

20. The process according to claim 19, wherein the catalyst is NaI.

21. The process according to claim 19, wherein the difluorocarbene reagent is TMSCF3.

22. The process according to claim 19, further comprising contacting the compound CPD- 6 with a catalyst, a hydrogen donor, and a base to form the compound.

23. The process according to claim 22, wherein the catalyst is selected from RuCl(p- cymene)[(S,S)-Ts-DPEN], RuCl[(R,R)-Ts-DPEN](mesitylene), RuCl[(S,S)-Teth- TsDpen], or Cu(OAc)2[(S,S)-PH-BPE].

24. The process according to claim 22, wherein the catalyst is RuCl(p-cymene)[(S,S)-Ts- DPEN]. 1615709821.1PATENT 145688-005402 25. The process according to claim 22, wherein the hydrogen donor is selected from isopropyl alcohol, formic acid, and methanol.

26. The process according to claim 22, wherein the hydrogen donor is isopropyl alcohol.

27. The process according to claim 22, wherein the base is NaOtBu.

28. The process according to claim 22, further comprising contacting the compound CPD- 7 with a first acid then a first base followed by a second acid and a second base to formthe compound.

29. The process according to claim 28, wherein the first acid is trifluoroacetic acid.

30. The process according to claim 28, wherein the first base is NH4OH.

31. The process according to claim 28, wherein the second acid is HCl.

32. The process according to claim 28, wherein the second base is Na2CO3.

33. The process according to claim 28, further comprising contacting the compound CPD- a halogen ion source and a base to form the compound.

34. The process according to claim 33, PG3is a benzyloxycarbonyl group.

35. The process according to claim 33, wherein the halogen ion source is NaI. 1615709821.1PATENT 145688-005402 36. The process according to claim 33, wherein the base is KF.

37. The process according to claim 33, further comprising contacting the compound CPD-10 with an acid to form the compound.

38. The process according to claim 37, wherein the acid is HCl or trifluoracetic acid.

39. The process according to claim 22, further comprising contacting the compound CPD- a halogen ion source and a base to form the compound.

40. The process according to claim 39, PG3is a benzyloxycarbonyl group.

41. The process according to claim 39, wherein the halogen ion source is NaI.

42. The process according to claim 39, wherein the base is KF.

43. The process according to claim 39, further comprising contacting the compound CPD-13 with an acid followed by a base to form the compound .

44. The process according to claim 43, wherein the acid is HCl or trifluoracetic acid. 1615709821.1PATENT 145688-005402 45. The process according to claim 43, wherein the base is NH3.

46. The process according to claim 37 or claim 43, further comprising contacting the.

47. The process according to claim 46, wherein X3 is selected from Cl, Br, or I.

48. The process according to claim 47, wherein X3 is Cl.

49. The process according to claim 46, wherein the base is K3PO4.

50. The process according to claim 46, further comprising contacting the compound CPD- 13 with a base to form the compound of Formula I.

51. The process according to claim 50, wherein the base is NaOH.

52. A compound, or a salt thereof, or a co-crystal thereof, selected from the group consisting of: 1615709821.1PATENT 145688-0054024-chloro-5-(3,3-difluorocycloprop- 1-en-1-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H- ,pyrrolo[2,3-d]pyrimidine ,,. The compound of claim 52, or a salt thereof, or a co-crystal thereof, wherein the compound is:.

54. The compound of claim 52, or a salt thereof, or a co-crystal thereof, of claim 48 wherein the compound is:4-chloro-5-(3,3-difluorocycloprop- 1-en-1-yl)-7-((2- (trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidine .1615709821.1PATENT 145688-005402 55. The compound of claim 52, or a salt thereof, or a co-crystal thereof, of claim 48 wherein the compound is:.

56. The compound of claim 52, or a salt thereof, or a co-crystal thereof, of claim 48 wherein the compound is:. 1615709821.1

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