HK40112968A - Processes for the preparation of 1,2,3,5,6,7-hexahydro-s-indacene derivatives - Google Patents

Description

Method for preparing 1,2,3,5,6,7-hexahydro-s-dicyclopentadienebenzene derivatives

Technical Field

This invention relates to intermediates and methods for preparing 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-yl)carbamoyl)piperidine-4-sulfonamides and their salts. The invention further relates to 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienzophenyl-4-yl)carbamoyl)piperidine-4-sulfonamides and their salts prepared by such methods, and to related pharmaceutical compositions and their use for treating and preventing, particularly by means of NLRP3 inhibition, medical conditions and diseases.

Background Technology

1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-yl)carbamoyl)piperidine-4-sulfonamide is disclosed as an NLRP3 inhibitor in WO 2019/008025 A1 (see Example 6). However, there is a need for improved methods for the preparation of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienzophenyl-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts. Specifically, there is a need for efficient methods suitable for large-scale synthesis that, for example, avoid multiple complex and partially low-yield chemical steps and overall atom-inefficient synthesis.

There is also a need to provide 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide and its salts at higher yields compared to existing technologies, especially on a large scale. Furthermore, for large-scale industrial application, greener synthetic routes, reduced solvent waste, and improved safety are also of concern. This invention addresses the aforementioned problems. Moreover, this invention can be implemented using either batch or continuous methods.

Summary of the Invention

The present invention provides a method for preparing compound (C) or a salt thereof, comprising the step of contacting compound (A) with compound (B) in the presence of a solvent and a base to obtain compound (C) or a salt thereof.

Unless otherwise stated, any reference to an element is considered a reference to all isotopes of that element. Thus, for example, unless otherwise stated, any reference to hydrogen is considered to cover all isotopes of hydrogen, including deuterium and tritium.

Unless otherwise stated, any reference to a compound or group shall be regarded as a reference to all tautomers of that compound or group.

In one embodiment of the present invention, the solvent used to contact compound (A) with compound (B) is selected from toluene, anisole, cyclopentylmethyl ether, ethylbenzene, isopropyl acetate, isobutyl acetate, 2-methyltetrahydrofuran, water, tert-butanol, ethyl acetate, methyl acetate, xylene, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, tert-butylmethyl ether, N-methylpyrrolidone, N-ethylpyrrolidone, heptane, cyclohexane, acetone, or any combination thereof.

In another embodiment of the invention, the solvent used to contact compound (A) with compound (B) is selected from toluene, anisole, ethylbenzene and xylene.

In another embodiment of the invention, the solvent used to contact compound (A) with compound (B) is selected from 2-methyltetrahydrofuran and tetrahydrofuran.

In another embodiment of the invention, the solvent used to contact compound (A) with compound (B) is dimethyl sulfoxide.

In another embodiment of the invention, the solvent used to contact compound (A) with compound (B) is toluene, or a combination of toluene with water, tert-butanol, tetrahydrofuran, dimethyl sulfoxide, or acetonitrile.

In another embodiment of the invention, the solvent used to contact compound (A) with compound (B) is toluene and tetrahydrofuran.

In another embodiment of the invention, the base used to contact compound (A) with compound (B) is selected from potassium tert-butoxide, potassium hydroxide, or any other basic potassium salt.

In another embodiment of the invention, the base used to contact compound (A) with compound (B) is selected from potassium tert-butoxide or potassium hydroxide.

In another embodiment of the invention, the base used to contact compound (A) with compound (B) is potassium tert-butoxide.

One embodiment of the present invention provides a method for preparing a salt of compound (C), such as a cationic salt. Typically, the salt is pharmaceutically useful.

For the purposes of this invention, the “cationic salt” of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide is a salt formed between a protonated acid functional group (such as a urea proton) of a compound and a suitable cation by the loss of a proton. Suitable cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium, and ammonium. The salt can be a monosalt or a disalt. Preferably, the salt is a monolithium or dilithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, or an ammonium salt. More preferably, the salt is a monosodium or disodium salt, or a monopotassium or dipotassium salt. More preferably, the salt is a monopotassium or dipotassium salt, and even more preferably, the salt is a monopotassium salt.

Advantageously, when a cationic salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (C)) is required, the cation of the salt is provided by the conjugate acid of the base. For example, one embodiment of the first aspect of the present invention provides a method for preparing an alkali metal salt or alkaline earth metal salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienzobenzyl-4-yl)carbamoyl)piperidine-4-sulfonamide (C), the method comprising the step of contacting 1-ethyl-4-piperidinesulfonamide (A) with a 1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienzobenzyl derivative (B) or (B') in a solvent and in the presence of an alkali metal alkoxide or an alkaline earth metal alkoxide to obtain an alkali metal salt or alkaline earth metal salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienzobenzyl-4-yl)carbamoyl)piperidine-4-sulfonamide, wherein the alkali metal or alkaline earth metal of the salt is the same as the alkali metal or alkaline earth metal of the alkoxide. Typically in such embodiments, the alkali metal alkoxide or alkaline earth metal alkoxide is an alkali metal tert-butoxide or an alkaline earth metal tert-butoxide.

In one embodiment of the invention, the salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-yl)carbamoyl)piperidine-4-sulfonamide (C) is purified by recrystallization or reprecipitation. For example, the crude salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienzophenyl-4-yl)carbamoyl)piperidine-4-sulfonamide (C) can be dissolved in a first solvent to obtain a first mixture, which may optionally be filtered, and the salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienzophenyl-4-yl)carbamoyl)piperidine-4-sulfonamide (C) can be precipitated by adding a second solvent, optionally under cooling. Typically, the first solvent is a polar protic solvent, such as methanol. Typically, the second solvent is a polar aprotic solvent, such as acetonitrile.

Another aspect of the present invention provides a method for preparing compound (C) or a salt thereof, comprising the step of contacting compound (A) with compound (B) in the presence of a solvent and a base to obtain compound (C) or a salt thereof, wherein compound (B) is obtained from compound (D):

In one embodiment of the invention, an antisolvent separation compound (C) is used.

In another aspect of the invention, an antisolvent is used to separate the compound (C), wherein the antisolvent is selected from acetonitrile, any alcohol or water.

In one embodiment of the invention, a washing solvent is used to separate compound (C).

In another aspect of the invention, a washing solvent is used to separate compound (C), wherein the washing solvent is selected from tetrahydrofuran, toluene, dimethyl sulfoxide, or acetonitrile.

A second aspect of the invention provides 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4-sulfonamide (compound (C)) or a salt thereof, which is prepared by the method of the first aspect of the invention.

In one embodiment, a second aspect of the invention provides an alkali metal or alkaline earth metal salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienzylbenzo-4-yl)carbamoyl)-piperidine-4-sulfonamide. Typically, a second aspect of the invention provides a potassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienzylbenzo-4-yl)carbamoyl)-piperidine-4-sulfonamide. Most typically, a second aspect of the invention provides a monopotassium salt of 1-ethyl-N-((1,2,3,5,6,7-hexahydro-s-s-dicyclopentadienzylbenzo-4-yl)carbamoyl)-piperidine-4-sulfonamide.

In one embodiment of the invention, compound (B) is prepared by a method according to a third aspect of the invention.

A third aspect of the present invention provides a method for preparing compound (B), the method comprising the step of converting compound (D) into compound (B):

Therefore, in one embodiment of the third aspect of the present invention, a method for preparing compound (B) is provided, the method comprising the step of converting compound (D) into compound (B) using a reaction mixture of compound (D) with phosgene, triphosgene, carbonyl diimidazole or ditert-butyl dicarbonate in the presence of a base and a solvent.

In another embodiment of the third aspect of the invention, the solvent is selected from toluene, anisole, cyclopentylmethyl ether, ethylbenzene, isopropyl acetate, isobutyl acetate, 2-methyltetrahydrofuran, water, ethyl acetate, methyl acetate, xylene, tetrahydrofuran or dimethyl sulfoxide, acetonitrile, tert-butylmethyl ether, diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, N-methylpyrrolidone, N-ethylpyrrolidone, heptane, cyclohexane or any combination thereof, and the base is a tertiary amine, such as N,N-diisopropylethylamine, triethylamine or tributylamine, or the base is an inorganic base, such as potassium carbonate, potassium hydroxide or sodium carbonate.

In another embodiment of the third aspect of the invention, the solvent is selected from toluene, or a combination of toluene and water, acetonitrile, or tetrahydrofuran, and the base is selected from N,N-diisopropylethylamine, trimethylamine, tributylamine, potassium carbonate, potassium hydroxide, or sodium carbonate.

In another embodiment of the third aspect of the invention, the solvent is toluene and/or water, and the base is N,N-diisopropylethylamine, trimethylamine, or potassium carbonate.

In another embodiment of the third aspect of the invention, the solvent is toluene and the base is N,N-diisopropylethylamine or potassium carbonate.

In another embodiment of the third aspect of the invention, the solvent is toluene and the base is potassium carbonate.

In another embodiment of the third aspect of the invention, the solvent is toluene and the base is N,N-diisopropylethylamine.

Toluene and potassium carbonate, or toluene and N,N-diisopropylethylamine, offer advantages over the use of THF (tetrahydrofuran) and TEA (triethylamine), as previously used (EGGLER J F et al.: Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 45, No. 9, 2002, pp. 785-794, XP002264662), because the methods proposed above involve less post-treatment time and energy by eliminating the need for evaporation or silica gel filtration. Therefore, the method here is less intensive than previously reported methods.

In another embodiment of the third aspect of the invention, a method for preparing compound (B) is provided, the method comprising the step of converting compound (D) into compound (B), wherein the reaction mixture is washed with an aqueous solution to obtain compound (B) in an organic solvent.

One embodiment of the present invention provides a method for obtaining compound (C), wherein compound (B) is obtained according to a third aspect of the present invention.

One embodiment of the present invention provides a method for obtaining compound (C) according to a first aspect of the present invention, wherein compound (B) is obtained according to a third aspect of the present invention.

In one embodiment of the invention, compound (B) is prepared by batch or continuous methods.

In one embodiment of the invention, compound (B) is prepared in a continuous manner.

In one embodiment of the invention, the method for obtaining compounds (B) and (C) is cascaded.

The fourth aspect of the present invention provides compound (B):

In one embodiment of the third aspect of the invention, compound (D) is prepared by a method comprising the following steps:

The methods for preparing compound (D) are as described in WO 2020/079207 A1, the contents of which are incorporated herein by reference in their entirety.

In one embodiment, the method of the fifth aspect of the present invention is a method for preparing compound (A) or a salt thereof:

A fifth aspect of the present invention provides a method for preparing compound (A), the compound being prepared by a method comprising the following steps:

Where Cbz is carboxybenzyl/benzyloxycarbonyl, OMs is methanesulfonate, and SAc is acetylthio.

In an exemplary embodiment of the fifth aspect of the invention, reaction step (a) comprises contacting compound (1) with benzyl chloroformate to obtain N-carboxybenzyl-4-hydroxypiperidine compound (2):

Typically in such embodiments, compound (1) is contacted with benzyl chloroformate in the presence of a base and a solvent.

In an exemplary embodiment of the fifth aspect of the invention, reaction step (b) comprises contacting compound (2) with methanesulfonyl chloride to obtain compound (3):

Typically in such embodiments, compound (2) is contacted with methanesulfonyl chloride in the presence of a tertiary amine base (such as triethylamine) and a polar aprotic solvent (such as dichloromethane).

In an exemplary embodiment of the fifth aspect of the invention, reaction step (c) comprises contacting compound (3) with ^MeCOS in a solvent to obtain compound (4):

Typically in such embodiments, ^MeCOS is produced in situ via the reaction of MeCOSH with a base (such as cesium carbonate). Typically in such embodiments, the solvent is N,N-dimethylformamide.

In an exemplary embodiment of the fifth aspect of the invention, reaction step (d) comprises contacting compound (4) with a chlorinating agent to obtain compound (5):

Typically in such embodiments, the chlorinating agent is N-chlorosuccinimide. Typically in such embodiments, compound (4) is contacted with the chlorinating agent in the presence of acetic acid and water.

In an exemplary embodiment of the fifth aspect of the invention, reaction step (e) comprises contacting compound (5) with ammonia to obtain compound (6):

Typically in such embodiments, compound (5) is contacted with ammonia in the presence of a polar aprotic solvent such as dichloromethane.

In an exemplary embodiment of the fifth aspect of the invention, reaction step (f) includes contacting compound (6) with acetonitrile or acetaldehyde in the presence of a catalyst and hydrogen to obtain compound (A):

Typically in such embodiments, compound (6) is contacted with acetonitrile in the presence of a catalyst and hydrogen. Typically, the catalyst is a palladium catalyst, such as carbon-supported palladium hydroxide.

In one specific embodiment of the fifth aspect of the present invention, a method for preparing compound (A) or a salt thereof is provided:

Includes the following steps:

(a) Converting compound (1) into compound (2):

(b) Converting compound (2) into compound (3):

(c) Converting compound (3) into compound (4):

(d) Converting compound (4) into compound (5):

(e) Convert compound (5) into compound (6).

(f) and converting compound (6) into compound (A):

In one specific embodiment of the fifth aspect of the present invention, a method for preparing compound (A) or a salt thereof is provided, which is carried out via the following steps:

Where Cbz is carboxybenzyl/benzyloxycarbonyl, OMs is methanesulfonate, and SAc is acetylthio.

One embodiment of the present invention provides a method for obtaining compound (C), wherein compound (A) is obtained according to the fifth aspect of the present invention.

The compounds used and provided in this invention can be used both as free bases and as acid addition salts. For the purposes of this invention, the term "salt" in the compounds includes acid addition salts. Acid addition salts are preferably pharmaceutically acceptable and non-toxic addition salts of suitable acids, including but not limited to: inorganic acids such as hydrohalic acids (e.g., hydrofluoric acid, hydrochloric acid, hydrobromic acid, or hydroiodic acid) or other inorganic acids (e.g., nitric acid, perchloric acid, sulfuric acid, or phosphoric acid); or organic acids such as organic carboxylic acids (e.g., propionic acid, butyric acid, glycolic acid, lactic acid, mandelic acid, citric acid, acetic acid, benzoic acid, salicylic acid, succinic acid, malic acid or hydroxysuccinic acid, tartaric acid, fumaric acid, maleic acid, hydroxymaleic acid, viscous acid or galactopyric acid, gluconic acid, pantothenic acid, or dihydroxynaphthyl acid), organic sulfonic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2-naphthalenesulfonic acid, or camphorsulfonic acid) or amino acids (e.g., ornithine, glutamic acid, or aspartic acid). Acid addition salts can be monoacid addition salts, diacid addition salts, triacid addition salts, or polyacid addition salts. Preferred salts are hydrochloric acid addition salts, sulfuric acid addition salts, phosphoric acid addition salts, or organic acid addition salts. A preferred salt is a hydrochloric acid addition salt.

When the compounds of the present invention contain a quaternary ammonium group, the compound is typically used in its salt form. The counterion of the quaternary ammonium group can be any pharmaceutically acceptable, non-toxic counterion. Examples of suitable counterions include the conjugate base of a protonic acid discussed above with respect to acid addition salts.

The compounds used and provided in this invention can also be used in their free acid form and salt form. For the purposes of this invention, a "salt" of the compounds of this invention includes a salt formed between a protic acid functional group (such as a formic acid group or a urea group) of the compounds of this invention and a suitable cation. Suitable cations include, but are not limited to, lithium, sodium, potassium, magnesium, calcium, and ammonium. The salt can be a monosalt, disalt, trisalt, or multisalt. Preferably, the salt is a monolithium salt or dilithium salt, sodium salt, potassium salt, magnesium salt, calcium salt, or ammonium salt. More preferably, the salt is a monosodium salt or disodium salt, or a monopotassium salt or dipotassium salt.

Preferably, any salt is a non-toxic medicinal salt. However, other salts besides medicinal salts are also included in this invention because they can potentially serve as intermediates for purifying or preparing other salts such as medicinal salts, or for identifying, characterizing, or purifying free acids or bases.

The compounds and/or salts used and provided in this invention may be in the form of anhydrous or hydrated forms (e.g., hemihydrate, monohydrate, dihydrate, or trihydrate) or other solvates. Such other solvates can be formed using common organic solvents, including but not limited to alcohol solvents such as methanol, ethanol, or isopropanol.

The compounds, salts, and solvates used and provided in this invention may contain any stable isotopes, including but not limited to ^12C , ^13C , ^1H , ^2H (D), ^14N , ^15N , ^16O , ^17O , 18O, ^19F , and ^127I ; and any radioactive isotopes, including but not limited to ^11C , ^14C , ^3H (T), ^13N , ^15O , ^18F , ^123I , ^124I , ^125I , and ^{131I .}

Unless otherwise stated, the compounds, salts and solvates used and provided in this invention may be in any polymorphic or amorphous form.

A sixth aspect of the present invention provides a pharmaceutical composition comprising the compound (C) of the first aspect of the present invention and a pharmaceutical excipient.

The routine procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in “Aulton's Pharmaceuticals - The Design and Manufacture of Medicines”, M.E. Aulton and K.M.G. Taylor, Churchill Livingstone, Elsevier, 4th edition, 2013. Pharmaceutical excipients that can be used in the pharmaceutical compositions of the present invention, including adjuvants, diluents, or carriers, are those conventionally used in the field of pharmaceutical formulations.

The seventh aspect of the invention provides a compound (C) of the second aspect of the invention or a salt thereof, or a pharmaceutical composition of the sixth aspect of the invention, for use in a medicament and/or for treating or preventing a disease, ailment or condition.

Most notably, when compound (C) is used to treat or prevent diseases, ailments and conditions, compound (C) acts as an NLRP3 inhibitor.

In one implementation plan, the disease, disorder, or condition to be treated or prevented is selected from the following:

(i) Inflammation;

(ii) Autoimmune diseases;

(iii) Cancer;

(iv) Infection;

(v) Central nervous system diseases;

(vi) Metabolic diseases;

(vii) Cardiovascular diseases;

(viii) Respiratory diseases;

(ix) Liver diseases;

(x) Kidney disease;

(xi) Eye diseases;

(xii) Skin diseases;

(xiii) Lymphatic disorders;

(xiv) Mental disorder;

(xv) pain; and

(xvi) Any disease in which an individual has been identified as carrying a germline or somatic non-silent mutation in NLRP3.

Typically, the treatment or prevention of a disease, ailment, or condition includes administering to a subject the compound (C) of the second aspect of the present invention or a salt thereof, or the pharmaceutical composition of the sixth aspect of the present invention.

Any drug used in this invention can be administered orally, parenterally (including intravenously, subcutaneously, intramuscularly, intradermally, intratracheally, intraperitoneally, intra-articularly, intracranially, and epidurally), via airway (aerosol), rectum, vagina, or locally (including percutaneously, orally, via mucosally, and sublingually).

Typically, the chosen mode of application is the one most suitable for the disorder, disease, or symptom to be treated or prevented.

The eighth aspect of the present invention provides a method for inhibiting NLRP3, the method comprising using a compound (C) of the second aspect of the present invention or a salt thereof, or a pharmaceutical composition of the sixth aspect of the present invention to inhibit NLRP3.

To avoid doubt, to the extent possible, any embodiment of a given aspect of the invention may be combined with any other embodiment of the same aspect of the invention. Furthermore, to the extent possible, it should be understood that any preferred, typical, or optional embodiment of any aspect of the invention should also be considered as a preferred, typical, or optional embodiment of any other aspect of the invention.

Example

Unless otherwise stated, all solvents, reagents and compounds were purchased and used without further purification.

abbreviation

Cbz: Carboxybenzyl/Benzyloxycarbonyl

SAc: Acetyl thio group

GC: Gas Chromatography

HPLC: High Performance Liquid Chromatography

THF: Tetrahydrofuran

MTBE: Methyl tert-butyl ether

DCM: Dichloromethane

DMF: Dimethylformamide

TEA: Triethylamine

HDPE: High-density polyethylene

NMT: No more than

Vol: Volume

AKX reagent: AKX

%a/a: (Peak area under compound (a) / Peak area under compound (a) and all other components combined) x 100

Experimental methods

NMR method:

The NMR spectra were obtained on a Bruker AV 400MHz spectrometer (model: Advance IIID) operating at room temperature (25°C).

GC methods:

GC analysis was performed on one of the following machines: an Agilent 7890, 6890, or Agilent 6890N equipped with an ALS injector.

KF method:

Coulometric KF titration was performed using AKX reagent on a Mitsubishi CA-20 or Predicta OM1000.

Synthesis Example

1-Ethyl-4-piperidinesulfonamide (7)

1-Ethyl-4-piperidinesulfonamide (7) was prepared according to the reaction sequence shown in reaction scheme 1.

Scheme 1. Synthesis of 1-ethyl-4-piperidinesulfonamide (7)

Reaction Scheme 1 - Steps (a) and (b)

4-Hydroxypiperidine (1) (46.0 kg) was charged into the reactor at 25–30 °C. 1,4-Dioxane (226.0 L) was charged into the reactor at 25–30 °C. The reaction mixture was stirred for 5–10 minutes and then cooled to 15–20 °C. A 2N NaOH solution (prepared by mixing NaOH (18.4 kg) with cold purified water (230.0 L) in a separate reactor at 25–30 °C) was slowly charged into the reaction mixture at 15–25 °C. The reaction mixture was stirred for 5–10 minutes. A 50% benzyl chloroformate toluene solution (147.2 L) was slowly added into the reaction mixture over 1–2 hours. The temperature was raised to 25–30 °C and stirred for 1–2 hours.

Add purified water (230.0 L) to the reaction mixture and stir the reaction mixture at 25 to 30 °C for 10-15 min. Add MTBE (230.0 L) to the reactor at 30 to 35 °C. Stir the reaction mixture at 25 to 30 °C for 15-20 min and then let it stand for 20-30 min. Separate the organic layer (OL-1) and the aqueous layer (AL-1) into different containers and return AL-1 to the reactor. Add MTBE (230.0 L) to the reactor at 25 to 30 °C. Stir the reaction mixture at 25 to 30 °C for 15-20 min and then let it stand for 20-30 min. Separate the organic layer (OL-2) and the aqueous layer (AL-2) into different containers. Combine OL-1 and OL-2 and add them to the reactor at 25 to 30 °C. Add purified water (138.0 L) to the reactor at 25 to 30 °C. Stir the reaction mixture at 25 to 30°C for 15 to 20 minutes, and then let it stand for 20 to 30 minutes. Separate the aqueous layer (AL-3) from the organic layer (OL-3).

A 10% NaCl solution (prepared by adding NaCl (13.80 kg) to purified water (138.0 L) in a reactor with stirring at 25–30 °C) was added to OL-3 at 25–30 °C. The reaction mixture was stirred at 25–30 °C for 15–20 min and then allowed to stand for 20–30 min. The organic layer (OL-4) and the aqueous layer (AL-4) were separated into different containers. OL-4 was dried with sodium sulfate (23.0 kg). OL-4 was filtered through a Buchner funnel and washed with MTBE (46.0 L). OL-4 was downward distilled under vacuum (650 mmHg) at 40–45 °C to 46–92 L. The vacuum was released and DCM (138.0 L) was added to the mixture, and the mixture was co-distilled under vacuum at 35–40 °C to 46–92 L. The mixture was cooled to 25–30 °C and the vacuum was released. Add DCM (552.0 L) to the mixture at 25 to 30 °C and stir the mixture for 5 to 10 minutes. Cool the reaction mixture to 20 to 25 °C. Add TEA (127.8 L) at 20 to 25 °C. Cool the reaction mixture to -5 to 5 °C.

Slowly add methanesulfonyl chloride (67.62 kg) over 1-2 hours at -5 to 5°C. Raise the reaction mixture to 25 to 30°C and stir at 25 to 30°C for 1-2 hours.

Unwanted salts were filtered out, and the mixture was washed with DCM (92.0 L) at 25–30 °C and completely dried under vacuum at 25–30 °C. The filtrate was then loaded into the reactor at 25–30 °C. A 10% sodium bicarbonate solution (prepared by adding sodium bicarbonate (23.0 kg) to purified water (230.0 L) at 25–30 °C) was added to the filtrate at 25–30 °C. The reaction mixture was stirred at 25–30 °C for 15–20 minutes and then allowed to stand for 20–30 minutes. The organic layer (OL-5) and the aqueous layer (AL-5) were separated into different containers, and OL-5 was returned to the reactor at 25–30 °C.

Purified water (230.0 L) is added to the reactor at 25-30 °C. The reaction mixture is stirred at 25-30 °C for 15-20 minutes and then allowed to stand for 20-30 minutes. The organic layer (OL-6) and the aqueous layer (AL-6) are separated into different containers, and OL-6 is returned to the reactor at 25-30 °C. A 10% sodium chloride solution (prepared by adding sodium chloride (11.50 kg) to purified water (230.0 L) at 25-30 °C) is added to the reactor at 25-30 °C. The reaction mixture is stirred at 25-30 °C for 15-20 minutes and then allowed to stand for 20-30 minutes.

The organic layer (OL-7) and the aqueous layer (AL-7) were separated into different containers. OL-7 was dried with sodium sulfate (23.0 kg). OL-7 was filtered through a Buchner funnel and washed with DCM (46.0 L). OL-7 was downward distilled under vacuum (650 mmHg) at 40–45 °C to 46–92 L. The vacuum was released and ethyl acetate (92.0 L) was added to the mixture, which was then co-distilled under vacuum at 40–45 °C to 46–92 L. The mixture was cooled to 30–40 °C and the vacuum was released. Ethyl acetate (115.0 L) was added to the mixture at 30–40 °C, and the mixture was stirred at 30–35 °C for 10–15 minutes. Hexane (1150.0 L) was slowly added to the mixture at 30–35 °C, and the mixture was stirred at 25–30 °C for 2–3 hours. The solid was filtered under vacuum using a suction filter, washed with hexane (92.0 L) at 25 to 30 °C, and completely dried under vacuum at 25 to 30 °C. The solid material was then dried in a vacuum oven at 30 to 35 °C for 6 to 8 hours, and pulverized every 3 to 4 hours.

Final product: Benzyl 4-((Methylsulfonyl)oxy)piperidine-1-carboxylate

Grayish-white (solid)

Output: 121.87Kg

Yield: 85.5%

HPLC purity: 94.7%

¹ H NMR: (CDCl ₃ 400MHz): δ1.82-1.86(m,2H), δ1.96-1.97(m,2H), δ3.03(s,3H), δ3.41-3.45( m,2H)δ3.72-3.78(m,2H),δ4.88-4.92(m,1H)δ5.13(s,2H),δ7.26-7.37(m,5H)

Reaction Scheme 1 - Steps (c, d, e)

DMF was loaded into a clean and dry four-necked reactor (equipped with a mechanical stirrer, nitrogen inlet, heat bag, and reflux condenser) under a nitrogen atmosphere and heated to reflux at 60 to 65°C for 20 to 30 minutes. The temperature was then lowered to 25 to 30°C, the refluxed DMF was unloaded, and the reactor was dried under nitrogen and vacuum.

4-((methanesulfonyl)oxy)piperidine-1-carboxylic acid benzyl ester (3) (29.0 kg) was charged into the reactor at 25 to 30 °C. DMF (145.0 L) was also charged into the reactor at 25 to 30 °C. The reaction mixture was stirred for 5 to 10 minutes, cooled to 15 to 20 °C, and then allowed to stand for 20 to 30 minutes.

44.95 kg of cesium carbonate was added to the reactor at 15 to 25 °C. The reaction mixture was stirred for 5 to 10 minutes. 10.56 kg of thioacetic acid was added at 15 to 25 °C. The reaction mixture was heated to 45 to 50 °C and stirred for 24 hours.

Cool the reaction mixture to 25–30°C. Filter the unwanted salts through a Buchner funnel under vacuum at 25–30°C, wash with ethyl acetate (145.0 L), and completely dry under vacuum at 25–30°C. Return the filtrate to the reactor at 25–30°C and cool to 15–20°C. Add purified water (145.0 L) to the reactor at 15–25°C and stir the reaction mixture for 5–10 minutes. Add ethyl acetate (145.0 L) to the reactor at 25–30°C. Stir the reaction mixture at 25–30°C for 15–20 minutes and allow it to stand for 20–30 minutes.

The organic layer (OL-1) and the aqueous layer (AL-1) were separated into different containers. AL-1 was added to the reactor at 25 to 30°C. Ethyl acetate (145.0 L) was added at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 15 to 20 minutes and then allowed to stand for 20 to 30 minutes.

The organic layer (OL-2) and the aqueous layer (AL-2) were separated into different containers. OL-1 and OL-2 were then combined and loaded into the reactor at 25 to 30°C.

A 10% _NaHCO3 solution (prepared by adding sodium bicarbonate (14.50 kg) to purified water (145.0 L) at 25 to 30 °C and mixing thoroughly) was added to the reactor at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 15 to 20 minutes and allowed to stand for 20 to 30 minutes.

The organic layer (OL-3) and the aqueous layer (AL-3) were separated into different containers. OL-3 was added to the reactor at 25–30°C. A 10% NaCl solution (prepared by adding NaCl (14.50 kg) to purified water (145 L) at 25–30°C and mixing thoroughly) was added to the reactor at 25–30°C. The reaction mixture was stirred at 25–30°C for 15–20 minutes and allowed to stand for 20–30 minutes.

The organic layer (OL-4) and the aqueous layer (AL-4) were separated into different containers. OL-4 was dried with sodium sulfate (14.50 kg), filtered through a Buchner funnel, and washed with ethyl acetate (29.0 L). The filtrate was completely distilled in a reactor until no dripping occurred under vacuum (650 mmHg) at 45 to 50 °C. The vacuum was released, and the mixture was cooled to 25 to 30 °C.

Acetic acid (377.0 L) was charged into the reactor at 25–30 °C. The reaction mixture was stirred at 25–30 °C for 5–10 minutes. Purified water (37.7 L) was added at 25–30 °C. The reaction mixture was stirred at 25–30 °C for 5–10 minutes and then cooled to 17–25 °C. N-chlorosuccinimide (33.64 kg) was slowly added in portions over 1–2 hours at 18–25 °C. The reaction mixture was stirred at 25–30 °C for 1 hour.

Cool the reaction mixture to 15-20°C. Add purified water (377.0 L) to the reaction mixture at 15-20°C and stir the reaction mixture at 25-30°C for 5-10 minutes. Add DCM (145.0 L) to the reactor at 25-30°C. Stir the reaction mixture at 25-30°C for 10-15 minutes and let it stand for 20-30 minutes. Separate the organic layer (OL-5) and the aqueous layer (AL-5) into different containers. Add AL-5 to the reactor. Add DCM (145.0 L) to the reactor at 25-30°C. Stir the reaction mixture at 25-30°C for 10-15 minutes and let it stand for 20-30 minutes.

The organic layer (OL-6) and the aqueous layer (AL-6) were separated into different containers. OL-5 and OL-6 were combined and loaded into the reactor at 25 to 30°C. Purified water (145.0 L) was loaded into the reactor at 25 to 30°C. The reaction mixture was stirred at 25 to 30°C for 5 to 10 minutes and then allowed to stand for 25 to 30 minutes.

The organic layer (OL-7) and the aqueous layer (AL-7) were separated into different containers. OL-7 was loaded into the reactor. The first portion of a 2% sodium bicarbonate solution (prepared by adding sodium bicarbonate (8.70 kg) and purified water (435.0 L) and dividing it into three equal volumes) was loaded into the reactor at 25–30 °C. The reaction mixture was stirred at 25–30 °C for 5–10 minutes and allowed to stand for 25–30 minutes.

The organic layer (OL-8) and the aqueous layer (AL-8) are separated into different containers. OL-8 is then loaded into the reactor. The second portion of the above 2% sodium bicarbonate solution is loaded into the reactor at 25 to 30°C. The reaction mixture is stirred at 25 to 30°C for 5 to 10 minutes and then allowed to stand for 25 to 30 minutes.

The organic layer (OL-9) and the aqueous layer (AL-9) are separated into different containers. OL-9 is then loaded into the reactor. The third portion of the above 2% sodium bicarbonate solution is loaded into the reactor at 25 to 30°C. The reaction mixture is stirred at 25 to 30°C for 5 to 10 minutes and then allowed to stand for 25 to 30 minutes.

The organic layer (OL-10) and the aqueous layer (AL-10) were separated into different containers. OL-10 was dried with sodium sulfate (14.50 kg), filtered at 25 to 30 °C, and washed with DCM (29.0 L). The filtrate was then loaded into the reactor at 25 to 30 °C.

Cool the reaction mixture to -40 to -30°C and purge with ammonia for 2 to 3 hours. Raise the temperature to 25 to 30°C and stir at 25 to 30°C for 10 to 12 hours.

Unwanted salts were filtered off under vacuum at 25–30°C, washed with DCM (14.50 L), and completely dried. The filtrate was loaded into a clean and dry reactor at 25–30°C and dried with sodium sulfate (14.50 kg). The mixture was filtered off at 25–30°C and washed with DCM (14.50 L) to remove the sodium sulfate. The mixture was then loaded into a clean and dry reactor through a 0.2-micron filter cartridge and distilled downwards under vacuum at 35–40°C to 29–58 L.

Release the vacuum and cool the reaction mixture to 25-30°C. Charge ethyl acetate (58.0 L) into the reactor at 25-30°C and distill the mixture downwards under vacuum at 35-40°C to 29-58 L. Release the vacuum and cool the reaction mixture to 25-30°C. Charge ethyl acetate (72.5 L) into the reactor at 25-30°C and stir the mixture at 25-30°C for 30 min. Charge hexane (36.25 L) into the reactor at 25-30°C and stir the mixture at 25-30°C for 1-2 hours. Filter the solids under vacuum at 25-30°C, wash with hexane (58.0 L), and dry completely.

Output: 11.0Kg

Yield: 39.85%

HPLC purity: 90.5%

purification

Wet material (6) (53.95 kg) was charged into a clean and dry reactor at 25-30°C. DCM (580 L) was added at 25-30°C, and the mixture was stirred at 25-30°C for 5-10 minutes. Methanol (25.0 L) was added at 25-30°C, and the mixture was stirred at 25-30°C for 5-10 minutes. Neutral alumina (174.0 kg) was added at 25-30°C, and the mixture was stirred at 25-30°C for 1 hour. The neutral alumina was filtered at 25-30°C. The salt was washed with DCM (150.0 L). The filtrate was charged into a clean and dry reactor at 25-30°C. Hexane (1050 L) was added at 25-30°C, and the mixture was stirred at 25-30°C for 1-2 hours. The precipitate was filtered under vacuum at 25 to 30°C, washed with hexane (116.0 L), and completely dried. The wet material was dried under vacuum at 30 to 35°C for 6 to 8 hours, and pulverized every 3 hours.

Final product: 1-(benzyloxycarbonyl)-4-piperidinesulfonamide

White (solid powder)

Output: 41.60Kg

Yield: 41.80%

HPLC purity: 96.1%

¹ H NMR: (DMSO 400MHz): δ1.41-1.51(m,2H), δ1.99-2.01(m,2H), δ2.50-286(m,2H), δ3.022- 3.05(m,1H)δ4.08-4.11(m,2H),δ5.75(s,2H)δ6.78(s,2H),δ7.40-7.30(m,5H)

Reaction Scheme 1, Step (f)

1-(benzyloxycarbonyl)-4-piperidinesulfonamide (6) (21.85 kg) was loaded into a container and purged with nitrogen. Acetonitrile (excluding propionitrile) (109.8 kg) and purified water (65.0 L) were loaded into the container and the temperature was adjusted to 15-25°C. The container was purged three times with vacuum/nitrogen at 15-25°C, and then loaded with carbon-supported palladium hydroxide (20 wt%; 50% water) (0.455 kg). The container was purged three times with vacuum/nitrogen at 15-25°C. The container was then purged three times with vacuum/hydrogen at 15-25°C and maintained under a hydrogen atmosphere (approximately 1 bar absolute pressure). The reaction mixture was stirred until complete.

The container was purged three times with vacuum/nitrogen at 15 to 25°C, and then loaded with carbon-supported palladium hydroxide (20 wt%; 50% water) (2.265 kg) at 15 to 25°C. The container was then purged three times with vacuum/nitrogen at 15 to 25°C. The container was then purged three times with vacuum/hydrogen at 15 to 25°C and maintained under a hydrogen atmosphere (approximately 1 bar absolute pressure). The reaction mixture was stirred at 15 to 25°C until complete.

Stir the reaction mixture at 15 to 25°C until complete.

Once GC confirms the reaction is complete, the vessel is purged with nitrogen, and the reaction mixture is filtered through a 1 μm filter at 15–25 °C to remove the catalyst. The filter cake is washed twice with premixed purified water and acetonitrile at 15–25 °C.

The filtrate was loaded with decolorizing charcoal (activated) (4.40 kg) and stirred at 15–25 °C for at least 60 minutes (target 60–120 minutes). The mixture was then filtered through a 1 μm filter at 15–25 °C to remove the charcoal. The filter cake was washed twice with premixed purified water and acetonitrile at 15–25 °C. The filtrate was loaded with SiliaMetS thiols (40–63 μm, 4.515 kg) and stirred at 15–25 °C for at least 60 minutes (target 60–120 minutes). The mixture was then filtered through a 0.6 μm filter at 15–25 °C to remove the SiliaMetS thiols. The filter cake was washed twice with premixed purified water and acetonitrile at 15–25 °C.

The filtrate was transferred to a container and the temperature was adjusted to 50-60°C. The mixture was then concentrated under reduced pressure at 50-60°C to approximately 110 L. Next, 89.8 kg of n-butanol was added at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 110 L. Then, 86.9 kg of n-butanol was added at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 110 L. Finally, 88.4 kg of n-butanol was added at 50-60°C, and the mixture was concentrated under reduced pressure at 50-60°C to approximately 90 L.

Adjust the temperature to 15 to 25°C and add ethyl acetate (98.6 kg) at 15 to 25°C. Cool the reaction mixture to -2 to +2°C for at least 60 minutes (target 60 to 120 minutes). Stir the mixture at -2 to 2°C for at least 4 hours (target 4 to 6 hours). Filter the solids through a 20 μm filter cloth at -2 to 2°C and wash twice with ethyl acetate (38.1 kg and 39.9 kg) at -2 to 2°C.

The solid was dried under a nitrogen stream at up to 60°C until the n-butanol content was ≤0.5% w/w and the ethyl acetate content was ≤0.5% w/w (measured by ^1H NMR spectroscopy). The dry weight of the solid 1-ethyl-4-piperidinesulfonamide (7) was measured and analyzed by 1H NMR spectroscopy.

Final product: 1-Ethyl-4-piperidinesulfonamide

Output: 12.00Kg

Yield: 85%

GC purity: 99.7%

NMR purity: 98.7%

¹ H NMR: (DMSO)0.95(t),1.55(dq),1.80(app t),1.95(app d),2.30(q),2.75(m),2.90(app d)

1,2,3,5,6,7-Hexahydro-S-dicyclopentadienylphenyl-4-amine (12)

1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (12) was prepared according to the reaction sequence shown in reaction scheme 2.

Synthesis of Scheme 2.1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-amine (12)

Reaction Scheme 2 - Step (a)

DCM (385 L) and _AlCl3 (99.86 kg) were charged into a clean and dry glass-lined reactor at 25 to 30 °C under a nitrogen atmosphere. The reaction mixture was then cooled to -10 °C.

3-Chloropropionyl chloride (90.99 kg) was slowly added under a nitrogen atmosphere at -10 to -5 °C. The reaction mixture was then maintained at 10 °C under a nitrogen atmosphere for 30 minutes. Then, 2,3-dihydro-1H-indene (8) (77.00 kg) was slowly added to the reaction mixture under a nitrogen atmosphere at -10 to -5 °C.

The reaction mixture was kept at 10 to 15°C for 2 hours.

After the reaction is complete, the reaction mixture is slowly added to a 6N hydrochloric acid solution (prepared from water (308L) and concentrated hydrochloric acid (308L)) at 0 to 10°C. DCM (231L) is added, and the temperature of the reaction mixture is raised to 30 to 35°C. The reaction mixture is stirred at 30 to 35°C for 30 minutes and then allowed to stand at 30 to 35°C for 30 minutes. The layers are separated, and the organic layer (OL-1) is set aside. DCM (231L) is added to the aqueous layer at 25 to 30°C. The reaction mixture is stirred at 25 to 30°C for 30 minutes and then allowed to stand at 25 to 30°C for 30 minutes. The layers (aqueous layer (AL-1) and organic layer (OL-2)) are separated, and AL-1 is set aside. OL-1 and OL-2 are mixed at 25 to 30°C. Softened water (385L) is added to the combined organic layer. Stir the mixture at 25 to 30°C for 30 minutes and let it stand at 25 to 30°C for 30 minutes. Separate the layers (aqueous layer (AL-2) and organic layer (OL-3)) and set AL-2 aside.

A 10% saturated sodium bicarbonate solution (prepared from softened water (385 L) and sodium bicarbonate (38.5 kg)) was added to OL-3 at 25–30 °C. The reaction mixture was stirred at 25–30 °C for 30 minutes and then allowed to stand at 25–30 °C for 30 minutes. The layers (aqueous layer (AL-3) and organic layer (OL-4)) were separated, and AL-3 was set aside. OL-4 was dried over anhydrous _Na₂SO₄ (38.5 _kg ) and washed with anhydrous _Na₂SO₄ using DCM (150 _L ) at 25–30 °C.

Distill the solvent under vacuum at a temperature below 35 to 40°C until 5% remains. Add n-hexane (308 L) to the reaction mixture at 35 to 40°C and completely distill the solvent at 35 to 40°C until no condensation droplets form. Add n-hexane (150 L) to the reaction mixture at 35 to 40°C and cool the reaction mixture to 5 to 10°C and maintain it at 5 to 10°C for 30 minutes.

The solid product was filtered, washed with cooled hexane (77 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to obtain the product.

Final product: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)prop-1-one (9)

Output: 120.5Kg

Yield: 88.63%

HPLC purity: 99.3%

Moisture content: 0.09%

¹ H NMR: (500MHz, CDCl3): δ7.81(S,1H),7.76(d,1H),7.31(d,1H),3.93(t,2H),3.45(t,2H),2.97(t,4H),2.15(q,2H)

Reaction Scheme 2 - Steps (b) and (c)

Sulfuric acid (300.0 L) was charged into a 2.0 KL clean and dry glass-lined reactor at 25 to 30 °C. 3-chloro-1-(2,3-dihydro-1H-indene-5-yl)prop-1-one (9) (60.0 Kg) was added in portions at 25 to 30 °C, and the reaction mixture was maintained at 25 to 30 °C for 30 minutes. The reaction mixture was then slowly heated to 65 to 70 °C and maintained at 65 to 70 °C for 24 hours. The absence of 3-chloro-1-(2,3-dihydro-1H-indene-5-yl)prop-1-one (9) was confirmed by HPLC (limit: ≤1.0%).

The reaction mixture is then cooled to 0 to 5°C. Nitration mixture ^*1 is slowly added at 0 to 5°C, and the reaction mixture is maintained at 0 to 5°C for 1 hour. The reaction mixture is then kept at 0 to 5°C.

Softened water (900.0 L) was charged into a 2.0 KL clean and dry glass-lined reactor at 25 to 30 °C. The water was cooled to 0 to 5 °C. The reaction mixture was slowly added to the reactor at 0 to 5 °C. Toluene (480.0 L) was added and the temperature was raised to 30 to 35 °C. The reaction mixture was kept at 30 to 35 °C for 30 minutes and allowed to stand at 30 to 35 °C for 30 minutes. The reaction mixture was filtered through a bed (prepared with 6.0 Kg and 30.0 L of toluene). The bed was washed with 60.0 L of toluene. The solids were filtered off and dried for 30 minutes.

The reaction mixture was loaded into a clean and dry glass-lined reactor (2.0 KL). The reaction mixture was stirred at 30 to 35 °C for 30 minutes. The layers (aqueous layer (AL-1) and organic layer (OL-1)) were separated, and OL-1 was set aside. Toluene (60.0 L) was loaded into AL-1. The mixture was stirred at 35 to 40 °C for 30 minutes and allowed to stand at 35 to 40 °C for 30 minutes. The layers (aqueous layer (AL-2) and organic layer (OL-2)) were separated, and OL-2 was set aside. OL-1 and OL-2 were combined to form OL-3.

A 5% saturated sodium bicarbonate solution (prepared from softened water (300.0 L) and sodium bicarbonate (15.0 kg)) was slowly added to OL-3 at 30 to 35 °C. The reaction mixture was stirred at 35 to 40 °C for 30 minutes and then allowed to stand at 35 to 40 °C for 30 minutes. The reaction mixture was filtered through a bed (prepared from softened water (60.0 L) and 6.0 kg). The bed was washed with toluene (60.0 L).

The reaction mixture was loaded into a clean and dry glass-lined reactor with a capacity of 3.0 KL. The reaction mixture was stirred at 30 to 35 °C for 30 minutes. The layers (aqueous layer (AL-3) and organic layer (OL-4)) were separated and OL-4 was set aside.

Toluene (60.0 L) was added to AL-3. The layers (aqueous layer (AL-4) and organic layer (AL-5)) were separated, and AL-5 was set aside. AL-4 and AL-5 were combined to form AL-6. A brine solution was prepared from softened water (300.0 L) and sodium chloride (12.0 kg) at 25 to 30 °C. The reaction mixture was stirred at 30 to 35 °C for 30 min and allowed to stand at 30 to 35 °C for 30 min. The layers (aqueous layer (AL-5) and organic layer (OL-7)) were separated, and OL-7 was set aside. OL-7 was dried with anhydrous _Na₂SO₄ (9.0 kg) and washed with _toluene (30.0 _{L )} at 25 to 30 °C. The solvent was distilled under vacuum at a temperature below 40 to 45 °C until 5% remained. Methanol (60.0 L) was added to the reaction mixture at 40 to 45 °C and the mixture was reduced to 60 L of reactants.

Methanol (120.0 L) was added to the reaction mixture at 40 to 45 °C, and the reaction mixture was cooled to 5 to 10 °C and maintained at 5 to 10 °C for 30 minutes. The solid product was filtered, washed with cooled methanol (30.0 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to obtain the product.

*1: To prepare the nitration mixture, sulfuric acid (27.0 L) was charged into a clean and dry glass-lined reactor at 25 to 30 °C. The reaction mixture was cooled to 0 to 5 °C. Nitric acid (27.0 L) was slowly added at 0 to 5 °C, and the reaction mixture was maintained at 0 to 5 °C for 30 minutes to provide the nitration mixture.

Final products: 8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophen-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophen-1-one (11b)

Combined output (11a+11b): 38.87Kg

Portfolio return (11a+11b): 62.24%

Weight ratio (11a:11b): 9:1

HPLC purity: 95.9%

Moisture content: 0.19%

¹ H NMR: (500MHz, CDCl ₃ ): δ7.44(S,1H),2.21(m,2H),2.78(t,2H),3.02(m,4H),3.13(t,2H)

Reaction Scheme 2 - Step (d)

8-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophen-1-one (11a) and 4-nitro-1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophen-1-one (11b) (9:1 ratio; 27.0 kg) were loaded into a clean and dry 600 L pressure reactor at 25 to 30 °C.

Add methanol (270 L) at 25-30°C. Slowly add methanesulfonic acid (14.3 kg) at 25-30°C and maintain the reaction mixture for 30 minutes. Add 15% Pd(OH) _₂ slurry (60% wet) ^*2 .

The reaction mixture was degassed under vacuum and purged three times with an argon atmosphere (0.5 kg). The reaction mixture was then degassed under vacuum and purged three times with a hydrogen atmosphere (0.5 kg). Finally, the reaction mixture was stirred at room temperature under a hydrogen atmosphere (100 Psi) for 32 hours.

After the reaction is complete, the reaction mixture is cooled to 25 to 30°C. The reaction mixture is then degassed under vacuum and purged three times with a nitrogen atmosphere (0.5 kg).

The reaction mixture was filtered through a candy filter to remove Pd(OH) _₂ , then filtered through a microfilter and the bed was washed with methanol (54 L). 95% of the solvent was distilled off under vacuum at a temperature below 45–50 °C. Softened water (135 L) was added to the reaction mixture at 25–30 °C and maintained for 30 minutes. The reaction mixture was cooled to 5–10 °C. The pH was adjusted to approximately 9–10 with a 2N NaOH aqueous solution (prepared from NaOH (6.48 kg) and softened water (81 L)) and the reaction mixture was stirred for 30 minutes. Toluene (135 L) was then added to the reaction mixture and the mixture was stirred for 30 minutes. The reaction mixture was stirred for another 30 minutes while maintaining the temperature at 25–30 °C. The reaction mixture was allowed to stand for 30 minutes while maintaining the temperature at 25–30 °C.

The reaction mixture was filtered through a bed (prepared with 5.4 kg of toluene and 13.5 L of toluene). The bed was washed with 54 L of toluene.

Separate the layers (aqueous layer (AL-1) and organic layer (OL-1)) and set OL-1 aside. Add toluene (54 L) to AL-1 at 25 to 30 °C. Stir the reaction mixture at 25 to 30 °C for 30 minutes and allow it to stand at 25 to 30 °C for 30 minutes. Separate the layers (aqueous layer (AL-2) and organic layer (OL-2)) and set AL-2 aside. Add toluene (54 L) to AL-1 at 25 to 30 °C. Add a brine solution (prepared with softened water (135 L) and sodium chloride (54 kg)) to the combined organic layers (OL-1 and OL-2) at 25 to 30 °C. Stir the reaction mixture at 25 to 30 °C for 30 minutes and allow it to stand at 25 to 30 °C for 30 minutes.

Separate the layers (aqueous layer (AL-3) and organic layer (OL-3)) and set AL-3 aside. Add charcoal (1.3 kg) to OL-3 and raise the temperature to 35-40 °C and maintain it at 35-40 °C for 30 minutes. Filter the reaction mixture through a bed (prepared with (5.4 kg) and toluene (54 L)) at 35-40 °C. Wash the bed with toluene (54 L). Dry the organic layer _with anhydrous _Na₂SO₄ (13.5 kg). Wash _{the Na₂SO₄} with toluene (27 L).

Distill the solvent under vacuum at a temperature below 35 to 40°C until 5% remains. Add methanol (40.5 L) to the reaction mixture at 35 to 40°C and distill until 5% remains. Add methanol (97.2 L) and water (10.8 L) to the reaction mixture at 35 to 40°C. Heat the reaction mixture to 50 to 55°C, stir at 50 to 55°C for 1 hour, slowly cool to 0 to 5°C, and maintain at 0 to 5°C for 30 minutes.

The solid product was filtered and washed with cold methanol (13.5 L), and dried in a hot air oven at 40 to 45 °C for 6 hours to obtain the product.

*2: To prepare a 15% Pd(OH) ₂ slurry, carbon-supported 20% Pd(OH) ₂ (60% wet; 4.05 kg) was added to methanol (27 L).

Final product: 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-amine (12)

Output: 11.3Kg

Yield: 41.85%

HPLC purity: 98.1%

Moisture content: 0.10

¹ H NMR: (400MHz, DMSO-d ₆ ): δ6.38(S,1H), 4.45(S,2H), 2.75(t,4H), 2.58(t,4H), 1.98(t,4H).

Purification of 1,2,3,5,6,7-hexahydro-S-dicyclopentadienzylphenyl-4-amine (12) (A)

1,2,3,5,6,7-hexahydro-S-dicyclopentadienzylphenyl-4-amine (12) (54.5 kg) was charged into a clean and dry 250 L reactor at 25 to 30 °C. Toluene (27.2 L) was added at 25 to 30 °C, and the reaction mixture was stirred at 25 to 30 °C for 30 min. Methanol (163 L) was added to the reaction mixture at 25 to 30 °C. The reaction mixture was stirred at 25 to 30 °C for 30 min, cooled to -5 to 0 °C, and stirred at -5 to 0 °C for 30 min. The solid product was filtered, washed with cold methanol (54.5 L), and dried at 40 to 45 °C for 6 h.

Final product: 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzophenyl-4-amine (12)

Output: 40.5Kg

Yield: 74.31%

HPLC purity: 99.5%

Moisture content: 0.3%

¹ H NMR: (400MHz, DMSO-d ₆ ): δ6.33(s,1H), 4.53(s,2H), 2.72(t,4H), 2.57(t,4H), 1.98(t,4H).

1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)carbamoyl)piperidine-4- sulfonamide (potassium salt) (14)

Synthesis of reaction scheme 3(14):

1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine isocyanate (13) prepared in batches:

1,2,3,5,6,7-Hexahydro-S-dicyclopentadienzylphenyl-4-amine (12) (1.00 g, 1.00 equivalent) was dissolved in toluene (9.60 g) in a 50 mL reactor at 10–20 °C. N,N-Diisopropylethylamine (2.25 g, 3.00 equivalent) was added, followed by the addition of 20 wt% phosgene solution (4.28 g, 1.50 equivalent) over 3 minutes. The resulting suspension was further stirred at 10–20 °C for 30 minutes. The reaction mixture was washed with saturated _NaHCO3 solution (5.0 mL) and water (5.0 mL). The layers were separated to obtain a toluene solution (OL-1, about 20 mL, containing 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzylphenyl-4-amine isocyanate (12) (5.77 mmol)). The obtained solution OL-1 was used for the next step (coupling of dicyclopentadienzylphenyl-4-amine (12) with 1-ethyl-4-piperidinesulfonamide (7)) to produce (14) in about 80% of the total yield.

1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine-isocyanate was prepared by flow-through (13):

Preparation of feed solution:

Feed solution A: 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (12) (43.31 g) was dissolved in toluene (206.69 g) to obtain a 0.90 M solution.

Feed solution B: Dissolve potassium carbonate (103.5g) in water (950g) to obtain a 0.75M solution.

Feed A (0.70 mL/min, 1.10 equivalents), 20% w/w phosgene-toluene solution (0.45 mL/min, 1.50 equivalents), and feed B solution (2.35 mL/min, 3.10 equivalents) were simultaneously fed into reactor 1 (approximately 25 mL) at 0–10 °C (internal temperature). The residence time in reactor 1 was 5–10 min. The two-phase solution from reactor 1 was continuously pumped out and the layers were continuously separated to obtain an organic layer (OL-1) containing 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine isocyanate (13) and an aqueous layer (AL-1) directed to the waste. Organic layer OL-1 was collected over 81 min at steady state to obtain approximately 90 mL of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienylphenyl-4-amine (12) (51 mmol). The obtained solution OL-1 was used for the next step.

Coupling of dicyclopentadienylaniline-isocyanate (12) with 1-ethyl-4-piperidinesulfonamide (7):

1-Ethyl-4-piperidinesulfonamide (7) (8.88 g, 46 mmol, 1.0 equivalent) was loaded into a container. Tetrahydrofuran (62.52 g) was loaded into the container, and the mixture was adjusted to 20 to 25 °C. The mixture was stirred at 20 to 25 °C for at least 20 minutes until lumps disappeared and a homogeneous suspension was formed. Potassium tert-butoxide (1.05 M, 43.98 mL, 46 mmol) was loaded into the container over 90 to 120 minutes, the temperature was maintained at 20 to 25 °C, and the mixture was stirred at 20 to 25 °C for 2 to 4 hours to obtain a thick white suspension.

Organic layer OL-1 (51 mmol of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzylphenyl-4-amine isocyanate (13) in a batch or flow-through manner, approximately 90 mL, containing 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzylphenyl-4-amine (12)) was added to the resulting white toluene suspension over 2 hours while maintained at 20–25 °C. The reaction mixture quickly became a well-stirred suspension and, at the end of the addition, a slightly turbid brown solution. The reaction mixture was further stirred at 20–25 °C for 1–2 hours. The water content was analyzed by KF analysis, and the conversion of 1,2,3,5,6,7-hexahydro-s-dicyclopentadienzylphenyl-4-amine (typically >95%) was confirmed by LC/MS or HPLC analysis. Optionally, the mixture was clarified by filtration through a diatomaceous earth layer (G3 filter). Water (4.44 g, 0.5 V) was added dropwise to the reaction mixture over 2 hours at 25–40 °C. The solids began to crystallize at a water content of about 0.5–1 wt%. A suspension was formed at the end of the feeding. The reaction mixture was cooled to 0–5 °C (IT) over 1 hour and stirred further at 0–5 °C for 16 hours. The solids were filtered through a G3 filter and washed with a toluene/THF mixture (1/1, 44.4 mL by volume).

The solid was dried at up to 50 °C under a nitrogen flow of 10–20 mbar for 12 hours. The dried weight of the crude solid was measured, identified, and analyzed using ^1H NMR spectroscopy and HPLC.

Final product: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienzobenzo-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (14)

Output: Approximately 16.0g

Production: Approximately 80%

NMR purity: >97%

HPLC purity: >99%

1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienylbenzo-4-yl)-carbamoyl)piperidine-4- Recrystallization of sulfonamide (potassium salt) (14)

Crude 1-ethyl-N-((1,2,3,5,6,7-hexahydro-S-dicyclopentadienzobenzo-4-yl)carbamoyl)piperidine-4-sulfonamide (potassium salt) (14) (15.00 g) was added to the reaction vessel. Methanol (33.55 g), followed by acetonitrile (33.55 g), was added to the vessel, and the temperature was adjusted to 15 to 25 °C as needed, while stirring for 10 to 20 minutes (until a homogeneous, turbid solution free of solid lumps was formed). The solution was filtered through a 1 μm filter at 15 to 25 °C. The filter was washed with a methanol/acetonitrile mixture (7.59 g) at 15 to 25 °C, and acetonitrile (64.0 g) was further added, followed by seed crystals (0.138 g) of (14) in acetonitrile (approximately 1 g). A suspension was formed.

The solution was concentrated to approximately 122 mL at 25–35 °C. Acetonitrile (54.32 g) was added to the mixture, and the solution was concentrated to approximately 122 L at 25–35 °C. Acetonitrile (52.53 g) was added to the mixture, and the mixture was concentrated to approximately 122 mL at ≤35 °C. The residual methanol content of the mixture was analyzed. It was determined to be ≤0.3% w/w methanol by standard. Acetonitrile (53.45 g) was added to a container, and the temperature was adjusted to 15–25 °C. The slurry was aged at 15–25 °C for at least 1 hour (target 1–2 hours), and then filtered through a 20 μm cloth at 15–25 °C. The filter cake was washed twice with acetonitrile (43.39 g) at 15–25 °C. The solid was dried under a nitrogen stream at up to 50 °C, yielding 13.75 g (92%) of white solid.

Final product: 1-Ethyl-N-((1,2,3,5,6,7-hexahydro-s-dicyclopentadienzobenzo-4-yl)-carbamoyl)piperidine-4-sulfonamide (potassium salt) (14)

Output: 13.75g

Yield: 92%

HPLC purity: 99.7%.

Claims (26)

1. A method for preparing compound (C) or a salt thereof, the method comprising the step of contacting compound (A) with compound (B) in the presence of a solvent and a base to obtain compound (C) or a salt thereof. 2. The method according to claim 1, wherein the solvent used to contact compound (A) with compound (B) is selected from toluene, anisole, cyclopentyl methyl ether, ethylbenzene, isopropyl acetate, isobutyl acetate, 2-methyltetrahydrofuran, water, tert-butanol, ethyl acetate, methyl acetate, xylene, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, tert-butyl methyl ether, N-methylpyrrolidone, N-ethylpyrrolidone, heptane, cyclohexane, acetone, or any combination thereof. 3. The method according to claim 1 or 2, wherein the solvent used to contact compound (A) with compound (B) is toluene, or a combination of toluene with water, tert-butanol, tetrahydrofuran, dimethyl sulfoxide, or acetonitrile. 4. The method according to any one of claims 1 to 3, wherein the solvent used to contact compound (A) with compound (B) is toluene and tetrahydrofuran. 5. The method according to any one of claims 1 to 4, wherein the base used to contact compound (A) with compound (B) is selected from potassium tert-butoxide, potassium hydroxide, or any other basic potassium salt. 6. The method according to any one of claims 1 to 5, wherein the base used to contact compound (A) with compound (B) is selected from potassium tert-butoxide or potassium hydroxide. 7. The method according to any one of claims 1 to 6, wherein the base used to contact compound (A) with compound (B) is potassium tert-butoxide. 8. A method for preparing compound (B), wherein compound (D) is converted into compound (B): 9. The method according to claim 8, wherein, in the presence of a base and a solvent, compound (D) is converted to compound B using a reaction mixture of compound (D) with phosgene, triphosgene, carbonyl diimidazole or ditert-butyl dicarbonate. 10. The method of claim 9, wherein The solvent is selected from toluene, anisole, cyclopentyl methyl ether, ethylbenzene, isopropyl acetate, isobutyl acetate, 2-methyltetrahydrofuran, water, ethyl acetate, methyl acetate, xylene, tetrahydrofuran or dimethyl sulfoxide, acetonitrile, tert-butyl methyl ether, diethyl ether, dichloromethane, 1,2-dichloroethane, chloroform, N-methylpyrrolidone, N-ethylpyrrolidone, heptane, cyclohexane, or any combination thereof; and The base is a tertiary amine, such as N,N-diisopropylethylamine, triethylamine, or tributylamine, or the base is an inorganic base, such as potassium carbonate, potassium hydroxide, or sodium carbonate. 11. The method according to claim 9 or claim 10, wherein The solvent is selected from toluene, or a combination of toluene with water, acetonitrile, or tetrahydrofuran; and The base is selected from N,N-diisopropylethylamine, trimethylamine, tributylamine, potassium carbonate, potassium hydroxide, or sodium carbonate. 12. The method according to any one of claims 9 to 11, wherein the solvent is toluene and/or water, and the base is N,N-diisopropylethylamine, trimethylamine, or potassium carbonate. 13. The method according to any one of claims 9 to 12, wherein the solvent is toluene and the base is N,N-diisopropylethylamine or potassium carbonate. 14. The method according to any one of claims 8 to 13, wherein the reaction mixture is washed with an aqueous solution to obtain compound (B) in an organic solvent. 15. The method according to any one of claims 1 to 7, wherein compound (B) is prepared by the method according to any one of claims 8 to 14. 16. The method according to any one of claims 8 to 15, wherein compound (B) is prepared by batch or continuous methods. 17. The method according to any one of claims 8 to 15, wherein the method is performed in a continuous manner. 18. The method according to any one of claims 1 to 7, wherein an antisolvent is used to separate compound (C). 19. The method of claim 18, wherein the antisolvent is selected from acetonitrile, any alcohol, or water. 20. The method according to any one of claims 1 to 7, wherein a washing solvent is used to separate compound (C). 21. The method of claim 20, wherein the washing solvent is selected from tetrahydrofuran, toluene, dimethyl sulfoxide, or acetonitrile. 22. The method according to any one of claims 15 to 17, wherein the method for obtaining compound (B) and compound (C) is stacked. 23. A compound (C) or a salt thereof, prepared by the method according to any one of claims 1 to 7 or 18 to 22. 24. The method according to any one of claims 8 to 17, wherein compound (D) is prepared via the following steps: 25. The method according to any one of claims 1 to 7, or 18 to 22, or 24, wherein compound (A) is prepared via the following steps: Where Cbz is carboxybenzyl/benzyloxycarbonyl, OMs is methanesulfonate, and SAc is acetylthio. 26. A pharmaceutical composition comprising the compound (C) according to claim 23 or a salt thereof, and a pharmaceutical excipient.