ACT-1014-6470 Kilogram-Scale Synthesis: N7-Selective Reductive Amination of an Unprotected Pyrazole, Subsequent N2 Alkylation, and Intramolecular Urea Formation

Introduction

In 2024, Reber and colleagues from the process research and development team at the Swiss biopharmaceutical company Idorsia Pharmaceuticals Ltd. (Idorsia) reported the kilogram-scale synthesis of ACT-1014-6470, an antagonist of complement C5a receptor 1 (C5aR1), in Organic Process Research & Development.[1] ACT-1014-6470 is the development code assigned to this candidate small molecule and refers to a defined chemical structure. The process comprises 11 synthetic steps, with a longest linear sequence of 6 steps and an overall yield of 42%, and more than 2.5 kg of ACT-1014-6470 was prepared cumulatively.[1]

ACT-1014-6470 contains a fused pyrazolo[3,4-d]pyrimidin-6-one scaffold, in which two ring nitrogens bear a 2-(trifluoromethyl)benzyl group and a 2,2-difluoropropyl group, respectively. The central structural challenge in the synthesis is how to install two different side chains selectively onto two different nitrogen atoms while also constructing the final fused cyclic urea scaffold.

Reber and colleagues adopted a sequence in which the side chains were installed first, followed by formation of the second ring. The exocyclic amino group of ethyl 3-amino-1H-pyrazole-4-carboxylate was first subjected to reductive amination to introduce the 2-(trifluoromethyl)benzyl group. The remaining pyrazole ring nitrogen was then N-alkylated with a 2,2-difluoropropyl group. Once the two N-substituent side chains had been established, the 4-position carboxylate ester was sequentially converted through hydrolysis, amidation, and amide reduction into a diamine precursor. Finally, intramolecular urea formation with 1,1′-carbonyldi(1,2,4-triazole) (CDT) generated the final fused pyrazolopyrimidinone scaffold.[1–3]

The overall structural transformation follows a continuous sequence:

Ethyl 3-amino-1H-pyrazole-4-carboxylate

→ Installation of 2-(trifluoromethyl)benzyl

→ Installation of 2,2-difluoropropyl

→ Conversion of the carboxylate ester into a diamine

→ CDT-mediated intramolecular urea formation

→ ACT-1014-6470

Both fluorinated N-substituent side chains are already attached to their respective nitrogen atoms before formation of the fused ring; the late-stage cyclization converts a precursor with the correct substitution pattern into the final pyrazolopyrimidinone scaffold.

1. The Two N-Substituent Side Chains and Cyclic Urea Scaffold of ACT-1014-6470

The core of ACT-1014-6470 is a pyrazolo[3,4-d]pyrimidin-6-one formed by fusion of a five-membered pyrazole ring with a six-membered ring containing a urea carbonyl.[2]

The three structural elements relevant to the synthetic sequence are:

Final Structure	Substituent or Structural Unit	Synthetic Origin
N7	2-(Trifluoromethyl)benzyl	Exocyclic amino group of 3-aminopyrazole
N2	2,2-Difluoropropyl	Pyrazole ring N
Six-membered cyclic urea	N–C(=O)–N	Formed by CDT-mediated ring closure of the diamine precursor

In the final product, the 2,2-difluoropropyl group is located at position 2, whereas the 2-(trifluoromethyl)benzyl group is located at position 7; this substitution pattern corresponds directly to the sequential structural changes of the synthetic intermediates.[2]

Installation of both N-substituent side chains occurs before formation of the second six-membered ring. At this stage, the molecule still consists primarily of a monocyclic 3-aminopyrazole. One target nitrogen is the exocyclic amino group at the 3-position, while the other is the N–H nitrogen of the pyrazole ring. Their different structures and reactivities allow the two side chains to be introduced in two separate steps.

2. Two Nitrogen-Containing Sites in 3-Aminopyrazole

2.1 The Exocyclic Amino Group and Pyrazole Ring Nitrogen Participate in Different Reactions

The starting material, ethyl 3-amino-1H-pyrazole-4-carboxylate, contains two nitrogen-containing sites that are directly involved in subsequent side-chain installation:

① The exocyclic amino group at the 3-position, –NH₂

② The N–H group in the pyrazole ring

The first side-chain installation occurs at the exocyclic amino group, whereas the second occurs at the pyrazole ring nitrogen. The two steps employ different types of C–N bond-forming reactions:

Reaction Site	Reaction Type	Side Chain Installed
Exocyclic –NH₂	Reductive amination	2-(Trifluoromethyl)benzyl
Pyrazole N–H	N-Alkylation	2,2-Difluoropropyl

This sequence establishes the positions of both side chains before formation of the fused ring and reduces the need for site-selective functionalization on the multi-nitrogen fused heterocycle at a later stage.

3. Installation of the 2-(Trifluoromethyl)benzyl Group by Reductive Amination

3.1 The Target N–Benzyl Bond Is Formed by Reductive Amination of an Aldehyde

The first fluorinated side chain is 2-(trifluoromethyl)benzyl. Its precursor is 2-(trifluoromethyl)benzaldehyde.

The target structure requires conversion of the following group in 3-aminopyrazole:

–NH₂

into:

–NH–CH₂–C₆H₄–CF₃

Reductive amination of the aldehyde directly accomplishes this transformation. The 3-aminopyrazole first forms a C–N linkage with 2-(trifluoromethyl)benzaldehyde, followed by reduction to give the benzyl-substituted secondary amine.

The overall structural transformation can be represented as:

Pyrazole–NH₂ + o-CF₃–C₆H₄–CHO

→ Pyrazole–NH–CH₂–C₆H₄–CF₃

The resulting product remains a monocyclic pyrazole. Its exocyclic amino group now bears the 2-(trifluoromethyl)benzyl substituent, while the pyrazole ring N–H remains available for further functionalization.[1,2]

3.2 Reductive Amination Conditions for Electron-Deficient Heterocyclic Amines

3-Aminopyrazole-4-carboxylates belong to the class of electron-deficient heterocyclic amines investigated by the Reber and Schäfer team. The reductive amination reactivity of these heterocyclic amines differs from that of conventional aliphatic amines.

In 2023, the same research team reported a reductive amination method applicable to electron-deficient heterocyclic amines, using triethylsilane (Et₃SiH) as the reducing agent and trifluoroacetic acid (TFA) as the acidic component. Reductive amination of these amines with aromatic and aliphatic aldehydes was carried out in refluxing dichloromethane. The method was demonstrated on a 750 g scale for one substrate combination, affording the corresponding product in 93% isolated yield.[3]

The 2024 ACT-1014-6470 process employed this type of Et₃SiH/TFA reductive amination to couple the 3-aminopyrazole starting material with 2-(trifluoromethyl)benzaldehyde.[1]

A key feature of this step is that unprotected ethyl 3-amino-1H-pyrazole-4-carboxylate is subjected directly to N7-selective reductive amination, installing the target benzyl substituent while retaining the pyrazole N2 position for subsequent 2,2-difluoropropylation.[1]

3.3 Structural State after Installation of the First Side Chain

After reductive amination, the molecule contains two clearly defined nitrogen-containing functionalities:

Exocyclic amino group:

–NH–CH₂–o-CF₃-phenyl

Pyrazole ring:

N–H

The first fluorinated side chain has now been installed, while the second reactive nitrogen remains available. The pyrazole N–H can therefore be used directly in the next step to install the second fluorinated side chain.

4. Installation of the 2,2-Difluoropropyl Group by Pyrazole N-Alkylation

4.1 Conversion of 2,2-Difluoropropanol into the Tosylate

The second fluorinated side chain is 2,2-difluoropropyl:

CH₃–CF₂–CH₂–

The hydroxyl group in its alcohol precursor, 2,2-difluoropropan-1-ol, is not suitable as a direct leaving group for N-alkylation. The route therefore first converts it into 2,2-difluoropropyl p-toluenesulfonate:

CH₃–CF₂–CH₂–OH

→ CH₃–CF₂–CH₂–O–SO₂–C₆H₄–CH₃

The tosylate group has good leaving-group ability, converting the terminal primary carbon into a reactive site suitable for nucleophilic substitution.[2]

4.2 Formation of the Second N–C Bond at the Pyrazole Ring Nitrogen

After completion of the first reductive amination step, the pyrazole ring still retains its N–H group.

The pyrazole nitrogen undergoes N-alkylation with 2,2-difluoropropyl p-toluenesulfonate:

Pyrazole–N–H

→ Pyrazole–N–CH₂–CF₂–CH₃

The product also retains the previously introduced 2-(trifluoromethyl)benzylamino group. Thus, the monocyclic pyrazole now contains two different fluorinated N-substituent side chains:[2]

① Exocyclic amino group: 2-(trifluoromethyl)benzyl

② Pyrazole ring N: 2,2-difluoropropyl

The N7 and N2 substitution patterns in the final ACT-1014-6470 are established by these two reactions, respectively.[1,2]

4.3 Completion of the Positioning of the Two N-Substituent Side Chains

At this stage, the 2-(trifluoromethyl)benzyl group at N7 and the 2,2-difluoropropyl group at N2 have both been positioned. The subsequent route shifts to functional-group transformations of the 4-position carboxylate ester and construction of the second six-membered ring.

5. From Carboxylate Ester to Diamine: Preparing the Second Nitrogen for Cyclic Urea Ring Closure

After installation of the two N-substituent side chains, the molecule still contains only the five-membered pyrazole ring. Formation of the final pyrazolopyrimidinone requires construction of a second cyclization-capable amine at the pyrazole 4-position, allowing it to form a six-membered cyclic urea together with the original substituted amino group at the 3-position.

This second amine is constructed from the ethyl carboxylate at the pyrazole 4-position through the sequential functional-group transformation carboxylate ester → carboxylic acid → amide → amine.

5.1 Ester Hydrolysis Provides the Site for Amide Formation

After installation of the two N-substituent side chains, the pyrazole intermediate still bears an ethyl carboxylate at the 4-position:

Pyrazole–CO₂Et

Hydrolysis gives the corresponding carboxylic acid:

Pyrazole–CO₂H

The two previously installed N-substituent side chains remain unchanged during this process.[1,2]

The carboxylic acid provides the site for incorporation of the piperidine amine module through amide formation in the next step.

5.2 Amide Formation Introduces the Piperidine Module

The carboxylic acid forms an amide with 1-(2-fluoro-6-methylphenyl)piperidin-4-amine:

Pyrazole–CO₂H

→ Pyrazole–C(O)–NH–piperidinyl

The piperidine module is thereby incorporated into the molecule, with the pyrazole 4-position and piperidine 4-position connected through an amide bond at this stage.[1,2]

5.3 Amide Reduction Generates the Amine Required for Ring Closure

The amide is then reduced to an amine:

–C(O)–NH– → –CH₂–NH–

This transformation retains the carbon atom originally present in the amide carbonyl while converting C=O into CH₂.

After reduction, the molecule contains the following functionalities at two adjacent positions of the pyrazole:

C3–NH–CH₂–o-CF₃-phenyl and C4–CH₂–NH–piperidinyl

Upon completion of this step, the molecule contains the two amine nitrogens required to form the six-membered cyclic urea.

Functional-Group Change at the 4-Position	Structural Role
–CO₂Et	Retains the site for subsequent construction
–CO₂H	Provides the site for amide formation
–C(O)NH–piperidinyl	Introduces the piperidine module
–CH₂NH–piperidinyl	Generates the amine capable of participating in ring closure

The pyrazole 4-position carboxylate ester therefore serves two functions in this route: attachment of the module and construction of the amine precursor required for ring closure.

6. CDT-Mediated Intramolecular Urea Formation Generates the Final Fused Scaffold

6.1 The Two Ring-Closing Nitrogens in the Diamine Precursor

The diamine precursor obtained after amide reduction contains the two nitrogen-containing sites required to form the second six-membered ring:

① A 2-(trifluoromethyl)benzyl-substituted amino group attached to the pyrazole 3-position;

② A piperidine-substituted amino group connected to the pyrazole 4-position through a methylene group.

Its local structure can be represented in simplified form as:

Pyrazole C3–NH–CH₂–o-CF₃-phenyl

Pyrazole C4–CH₂–NH–piperidinyl

The two amines are attached to the adjacent C3 and C4 positions of the pyrazole. The previously installed 2,2-difluoropropyl and 2-(trifluoromethyl)benzyl groups are already located at their required positions in the final structure. The final step must therefore establish a urea carbonyl linkage between these two amine nitrogens.[1,2]

6.2 CDT-Mediated Intramolecular Urea Formation

1,1′-Carbonyldi(1,2,4-triazole) (CDT) acts as a carbonyl-transfer reagent, promoting intramolecular urea formation of the diamine precursor and establishing an N–C(=O)–N linkage between the two amine nitrogens.[1]

The structural relationship of the reaction can be represented in simplified form as follows:

Two amine nitrogens within the same molecule:

Pyrazole C3–NH–benzyl

Pyrazole C4–CH₂–NH–piperidinyl

↓ CDT, intramolecular urea formation

The two amine nitrogens are linked through –C(=O)–

↓

Formation of a six-membered cyclic urea fused to the pyrazole ring

The two amines are anchored at the adjacent C3 and C4 positions of the pyrazole. After CDT establishes the carbonyl linkage between the two nitrogen atoms, the newly formed six-membered ring consists of pyrazole C3, pyrazole C4, the two amine nitrogens, the methylene group in the C4 side chain, and the newly introduced carbonyl carbon. The new ring shares the C3–C4 bond with the original pyrazole ring, generating the fused pyrazolo[3,4-d]pyrimidin-6-one scaffold of ACT-1014-6470.[1,2]

During ring closure, the two fluorinated N–C bonds established earlier remain unchanged: the exocyclic nitrogen bearing the 2-(trifluoromethyl)benzyl group becomes incorporated into the newly formed six-membered ring and becomes N7 in the final structure, whereas the 2,2-difluoropropyl group remains attached to the original pyrazole ring nitrogen, corresponding to N2 in the final product.[1,2]

6.3 CDT Cyclization Conditions and Kilogram-Scale Process Results

Reber and colleagues reported that CDT-mediated intramolecular urea formation can be carried out at room temperature without the addition of an external base. After completion of the reaction, aqueous workup and crystallization from ethanol afforded ACT-1014-6470 with an HPLC area-normalized purity of 99.4% a/a and an assay of 99% w/w.[1]

The overall process comprises 11 synthetic steps, with a longest linear sequence of 6 steps and an overall yield of 42%; the research team prepared more than 2.5 kg of ACT-1014-6470 cumulatively.[1]

CDT-mediated cyclization converts the diamine precursor into the final fused cyclic urea while retaining the two fluorinated N-substitution patterns established in the preceding steps.

7. Chemicals Related to the Kilogram-Scale Synthesis of ACT-1014-6470: Core Building Blocks, Key Transformation Reagents, Route-Development Reagents, and Process Media

Table 1. Core Structural and Side-Chain Building Blocks

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Pyrazole core starting material	6994-25-8	E121778	Ethyl 3-amino-4-pyrazolecarboxylate	≥98% (GC)	Unprotected 3-aminopyrazole core building block; the exocyclic amino group is used to introduce the 2-(trifluoromethyl)benzyl group, while the pyrazole ring nitrogen is retained for subsequent 2,2-difluoropropylation. It serves as the starting material for construction of the ACT-1014-6470 main scaffold.
N7 benzyl side-chain aldehyde building block	447-61-0	T102705	2-(Trifluoromethyl)benzaldehyde	≥98%	Provides the carbon source for the 2-(trifluoromethyl)benzyl group; undergoes reductive amination with the exocyclic amino group of 3-aminopyrazole to establish the benzyl substituent at the final N7 position.
N2 difluoropropyl side-chain precursor	33420-52-9	D169652	2,2-Difluoropropanol	≥95%	Alcohol precursor of the 2,2-difluoropropyl side chain; converted by tosylation into an activated alkylating reagent for subsequent functionalization of the pyrazole ring nitrogen.
N2 activated alkylating building block	1262400-01-0	D1037365	2,2-Difluoroprop-1-yl toluene-4-sulphonate	≥95%	Activated 2,2-difluoropropyl electrophilic building block; used for alkylation of the pyrazole ring nitrogen to establish the N–C bond between the final N2 position and the 2,2-difluoropropyl group.
Piperidine aryl module precursor	2646-91-5	D120651	2,3-Difluorobenzaldehyde	≥98%	Aryl precursor for the piperidine side chain; undergoes nucleophilic aromatic substitution with protected 4-aminopiperidine to construct a 2-fluoro-6-formyl arylpiperidine intermediate.
Piperidine nitrogen-containing module precursor	73874-95-0	N115469	4-Boc-Aminopiperidine	≥98%	Protected 4-aminopiperidine building block; the piperidine ring nitrogen participates in nucleophilic aromatic substitution, while the 4-amino group is protected with a tert-butoxycarbonyl group and is subsequently converted into the piperidine amine side chain of ACT-1014-6470.

Table 2. Key Bond-Forming and Functional-Group Transformation Reagents

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
N7 reductive amination—reducing agent	617-86-7	T106570	Triethylsilane (NSC 93579)	≥98%	Used with trifluoroacetic acid to form a reductive amination system for electron-deficient heterocyclic amines; used in the formation of the N-benzylated product from 3-aminopyrazole and 2-(trifluoromethyl)benzaldehyde, establishing the N7 side chain.
N7 reductive amination—acidic component	76-05-1	T433655	Trifluoroacetic acid (TFA)	Anhydrous, ≥99%	Acidic component of the triethylsilane reductive amination system; used in the reductive amination of electron-deficient 3-aminopyrazole with 2-(trifluoromethyl)benzaldehyde.
N2 side-chain activation—sulfonylation reagent	98-59-9	T104623	p-Toluenesulfonyl chloride (PTSC)	AR, ≥99%	Used to convert 2,2-difluoropropanol into 2,2-difluoropropyl p-toluenesulfonate, providing an activated difluoropropyl side chain for pyrazole N-alkylation.
Piperidine module—aldehyde reducing reagent	16940-66-2	S432207	Sodium borohydride (explosive precursor)	purum p.a., ≥96%	Used to reduce an aromatic aldehyde to a benzyl alcohol during construction of the piperidine side chain, generating the alcohol intermediate required for subsequent reductive transformation.
Diamine construction—amide reducing agent	13289-97-9	N138157	Borane–N,N-diethylaniline complex	≥98%	Used to reduce the piperidine-substituted amide, converting –C(O)NH– into –CH₂NH– and generating the diamine ring-closure precursor required for CDT-mediated intramolecular urea formation.
Cyclic urea ring closure—carbonyl-transfer reagent	41864-22-6	C113337	N,N′-Carbonyldi(1,2,4-triazole) (CDT)	≥96%	Carbonyl-transfer reagent for the final intramolecular urea formation; constructs the N–C(=O)–N unit between the two amine nitrogens, forming the fused six-membered cyclic urea of ACT-1014-6470.
Hydrolysis and basic workup	1310-73-2	S111498	Sodium hydroxide	GR, ≥96%	Used for carboxylate ester hydrolysis and related basification and aqueous workup operations.

Table 3. Reagents Related to the Early Protecting-Group Route and Reductive Amination Method Comparisons

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Early route—pyrazole protecting reagent	76513-69-4	T106619	2-(Trimethylsilyl)ethoxymethyl chloride (SEMCl)	≥95%	Used for SEM protection of the pyrazole nitrogen and subsequent functionalization of nitrogen-containing sites in an early ACT-1014-6470 synthetic route; applicable to comparison of site-control strategies between the protecting-group route and the 2024 unprotected 3-aminopyrazole route.
Reductive amination method comparison—reducing agent	25895-60-7	S105661	Sodium cyanoborohydride	≥95%	Literature comparator reducing agent for reductive amination of electron-deficient heterocyclic amines; can be used to compare reaction performance with the triethylsilane/trifluoroacetic acid system.
Route development—selective reductive amination reagent	56553-60-7	S106573	Sodium triacetoxyborohydride (STAB)	≥90%	Used for reductive amination of a pyrazole-4-carbaldehyde with the piperidine amine module in the early SEM-protected route, constructing a precursor for subsequent cyclization.
Early route—cyclic urea carbonyl-transfer reagent	530-62-1	C109315	N,N′-Carbonyldiimidazole (CDI)	≥99%	Used for intramolecular urea formation in an early ACT-1014-6470-related synthetic route, serving as a carbonyl-transfer reagent for construction of the cyclic urea.

Table 4. Process Solvents, Crystallization Media, and Acid-Treatment Reagents

Category	CAS No.	Aladdin Cat. No.	Name	Specification or Purity	Product Features and Applications
Reductive amination and cyclization solvent	75-09-2	D116144	Dichloromethane	AR, ≥99.5%, contains 50–150 ppm isoamylene as stabilizer	Used for triethylsilane/trifluoroacetic acid reductive amination and also as the reaction medium for CDT-mediated intramolecular urea formation; suitable for organic-phase reactions from low temperature to room temperature and for aqueous workup.
Polar aprotic process solvent	68-12-2	D119450	N,N-Dimethylformamide (DMF)	Anhydrous, ≥99.8%	Used for solutions related to 2,2-difluoropropyl p-toluenesulfonate and for the N-alkylation process; suitable for substitution reactions between primary sulfonate esters and nitrogen nucleophiles.
Hydrolysis and amide-assembly solvent	109-99-9	T1373933	Tetrahydrofuran (THF)	Ultra-dry, ≥99.9%, H₂O ≤50 ppm, containing 250 ppm BHT stabilizer	Used in aqueous/organic mixed systems related to carboxylate ester hydrolysis, amine salt treatment, and amide assembly, supporting process coupling between the pyrazole carboxylic acid and piperidine amine module.
Amide reduction solvent	108-88-3	T399633	Toluene (regulated precursor chemical)	Anhydrous, ≥99.8%	Used in the reaction system for reduction of the amide with the borane–N,N-diethylaniline complex to prepare the diamine ring-closure precursor; suitable for kilogram-scale amide reduction.
Crystallization and solvent-exchange medium	108-87-2	M119670	Methylcyclohexane (MCH)	Anhydrous, ≥99%	Used for crystallization, precipitation, and solvent exchange of piperidine and amide intermediates, supporting nonchromatographic isolation and solid separation of process intermediates.
Active pharmaceutical ingredient crystallization solvent	64-17-5	E329897	Ethanol	Moligand™, ≥99.7%	Used to crystallize ACT-1014-6470 after CDT-mediated cyclization and aqueous workup, enabling final active pharmaceutical ingredient isolation and purity control.
Salt formation and acid-treatment reagent	7647-01-0	H399545	Hydrochloric acid (regulated precursor chemical)	ACS, ≥37%	Used for salt formation and isolation of 1-(2-fluoro-6-methylphenyl)piperidin-4-amine hydrochloride, as well as in related acidic process conditions and cyclization-route development.

Note: The products listed above are representative Aladdin products related to scientific research. Specific applications should be determined according to product specifications, batch COAs, and the intended reaction or evaluation system. Additional product specifications, grades, and COA information can be searched on the Aladdin website using the product name/CAS number/catalog number.

References

[1] Reber S, Blumer N, Leuenberger D, Fleischer T, Renneberg D, Abele S, Schäfer G. Scalable Synthesis of C5aR1 Antagonist ACT-1014-6470 via N7-Selective Reductive Amination of an Unprotected Pyrazole Starting Material and Intramolecular Urea Formation with 1,1′-Carbonyl-di(1,2,4-triazol) (CDT). Organic Process Research & Development, 2024, 28(6): 2269–2283. DOI: 10.1021/acs.oprd.3c00492.

[2] Reber S, Blumer N, Leuenberger D, et al. Supporting Information for Scalable Synthesis of C5aR1 Antagonist ACT-1014-6470 via N7-Selective Reductive Amination of an Unprotected Pyrazole Starting Material and Intramolecular Urea Formation with 1,1′-Carbonyl-di(1,2,4-triazol) (CDT). Organic Process Research & Development, 2024, 28(6): 2269–2283. DOI: 10.1021/acs.oprd.3c00492.

[3] Schäfer G, Reber S, Ahmetovic M, Fleischer T, Leuenberger D, Blumer N, Udry M, Abele S. Robust and Scalable Reductive Amination Protocol for Electron-Poor Heterocyclic Amines Using Et₃SiH/TFA as Reducing Agent. Synthesis, 2023, 55(9): 1328–1336. DOI: 10.1055/a-1981-2727.

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