WO2021106864A1 - Process for the preparation of producing pyrazolo[1,5-a] pyrimidine derivatives - Google Patents

Abstract

Processes and intermediates useful for producing pyrazolo[1,5-a] pyrimidine derivatives.

Description

[Title established by the ISA under Rule 37.2] PROCESS FOR THE PREPARATION OF PRODUCING PYRAZOLO[1,5-A] PYRIMIDINE DERIVATIVES

The present invention relates to processes useful for producing pyrazolo[1,5-a] pyrimidine derivatives such as 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid.

Protease-activated receptor (PAR) is a type of trimeric G protein-coupled seven-transmembrane receptor and belongs to the receptor family mediating the cell action of serine proteases. Four molecules PAR1, PAR2, PAR3 and PAR4 have been cloned so far.

Serine proteases cleave an extracellular amino-terminal peptide chain of the PAR molecule at a specific site and thus expose a new amino-terminal peptide chain having a receptor activation sequence consisting of 5 or 6 amino acid residues. The newly exposed amino-terminal peptide chain cleaved by a serine protease bonds as a chain-like ligand to the extracellular loop 2, which is the active site of PAR2 itself and thus activates PAR2. PAR2 is known to be activated by trypsin, tryptase, kallikrein (mainly kallikreins 2, 4, 5, 6, and 14), blood coagulation factor VIIa, blood coagulation factor Xa and the like, and also activated when a synthetic peptide consisting of 5 or 6 amino acids synthesized based on the receptor activation sequence enters exogenously.

PAR2 is widely distributed in vivo such as in blood vessels, prostate gland, small intestine, large intestine, liver, kidney, pancreas, stomach, lung, brain and skin and is known to be an aggravating factor in various diseases such as allergy.

US2018/0057499 discloses pyrazolo[1,5-a] pyrimidine compounds having a PAR2 inhibitory action. These pyrazolo[1,5-a] pyrimidine compounds are provided for the treatment of inflammatory skin disease including atopic dermatitis, contact dermatitis, skin eczema, psoriasis and dry skin dermatitis or inflammatory bowel disease including ulcerative colitis, Crohn’s disease or infectious enteritis.

There is an on-going need in the art for improved processes for producing pharmaceutical products such as the pyrazolo[1,5-a] pyrimidine compounds of US2018/0057499. The present invention provides improved methods for producing pyrazolo[1,5-a] pyrimidine derivatives such as 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid (referred to herein as compound X).

Data set out in US2018/0057499A1 demonstrates the use of compound X as an effective inhibitor of PAR2.

Compound X is produced by the coupling of two fragments, BB1 and D as illustrated below.

The present invention provides an improved process for the production of both the BB1 fragment and the fragment D. Hence, the invention provides an improved process for the production of compound X.

The first aspect of the invention therefore provides a process for the production of compound BB1, or a salt thereof, wherein:
(a) compound 4 is converted to compound 6a

wherein R¹ is a nitrogen protecting group selected from an amide protecting group or an amine protecting group;
wherein R^1a is an amide protecting group; and
wherein R² is selected from C₁-C₄ alkyl or benzyl;
(b) compound 6a is reacted in the presence of a base and a methylating agent to form compound 7a;

and
(c) compound 7a is deprotected to form BB1, or a salt thereof.

Examples of BB1 salts that may be prepared according to the process of the present invention include HCl, HBr, trifluoroacetate, formate, methanesulfonate, benzenesulfonate and para-toluenesulfonate salts. In one embodiment the salt is a HCl salt.

An embodiment of the first aspect provides a process wherein,
when R¹ is an amide protecting group, the N-atom and the R¹ group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide and when R¹ is an amine protecting group, it is selected from benzyl, α-methylbenzyl or para-methoxy benzyl;
R^1a is an amide protecting group, wherein the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide; and R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl.

A further embodiment of the first aspect provides a process wherein
when R¹ is an amide protecting group, the N-atom and the R¹ group form t-butyl carbamate and when R¹ is an amine protecting group it is benzyl;
R^1a is an amide protecting group, wherein the N-atom and the R^1a group form t-butyl carbamate; and R² is ethyl.

In one embodiment of the first aspect of the invention, the conversion of compound 4 to compound 6a as set out in step (a) above can be carried out by
(a) the asymmetric transfer hydrogenation of compound 4a to form a compound of formula 5a

wherein R^1a is an amide protecting group, where the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide and wherein R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl in the presence of a non-tethered Noyori catalyst and a hydrogen donor; and
(b) reacting compound 5a in the presence of a base to form compound 6a.

As the skilled person will appreciate, when an amide protecting group is for example t-butyl carbamate, the nitrogen atom of the piperidine ring will form part of the carbamate group. For example, where R^1a and the nitrogen atom (N-atom) to which it is attached is t-butyl carbamate, the compound of formula 5a will have the chemical structure.

As set out above, compound 5a is prepared in step (a) by the asymmetric transfer hydrogenation of compound 4a wherein R^1a is an amide protecting group, where the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide, and wherein R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl

in the presence of a non-tethered Noyori catalyst and a hydrogen donor.

Preferably, R^1a is an amide protecting group, where the N-atom and the R^1a group form a t-butyl carbamate group and R² is ethyl.

The conversion of compound 4a to compound 5a preferably produces compound 5a in an enantiomeric excess of the illustrated stereoisomer of greater than 40%, more preferably greater than 50%, more preferably greater than 60%, most preferably greater than 70%.

For the purposes of this invention, the non-tethered Noyori catalyst is preferably a Ru, Rh or Ir non-tethered Noyori catalyst, more preferably a Ru non-tethered Noyori catalyst. The catalyst can have the structure (I)

wherein A is methyl or a phenyl ring substituted with one or more of F or C₁-C₄ alkyl and wherein B is a phenyl ring optionally substituted with one or more C₁-C₄ alkyl; preferably wherein A is a phenyl ring substituted with one or more of F or Me and B is a phenyl ring optionally substituted with one or more of Me or isopropyl.

In the non-tethered Noyori catalyst, each C₁-C₄ group is preferably independently selected from methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.

For catalysts of the structure (I), the group A can be selected from the group consisting of

.

Alternatively, or in addition, group B can be selected from the group consisting of

.

Preferably, the group B is selected from the group consisting of

.

More specifically, the catalyst can be selected from one or more of RuCl (ρ-cymene) [(S,S)-Ts-DPEN], RuCl (ρ-cymene) [(S,S)-Fs-DPEN] or RuCl (mesitylene) [(S,S)-Ts-DPEN]. Preferably the catalyst is RuCl(ρ-cymene) [(S,S)-Fs-DPEN].

The catalyst can be provided in an amount of from 0.005 to 0.1 mol equivalents, for example in an amount of from 0.025 to 0.01 mol equivalents, in an amount of 0.05 to 0.01 mol equivalents. In particular, the catalyst can be provided in an amount of 0.005, 0.01, 0.025, 0.05 or 0.1 mol equivalents.

The process of the invention can be carried out at a temperature of from 20 to 50℃. For example, from 20 to 40℃, from 20 to 30℃, from 20 to 25℃. Preferably, the process is carried out at a temperature of from 20 to 25℃.

For the purposes of this invention, the hydrogen donor is not limiting but can be selected from formic acid and triethylamine or an alcohol selected from EtOH or IPA or sodium formate. Preferably, the hydrogen donor is formic acid and triethylamine.

Optionally, the hydrogen donor (for example, the formic acid and triethylamine) can be degassed (for example by sparging with nitrogen) prior to the process for the production of compound 5a. The process would then be carried out under an inert atmosphere (for example under nitrogen).

When the hydrogen donor is formic acid and triethylamine , the ratio of formic acid to triethylamine is from 5:2 to 1:2. For example, the ratio of formic acid to triethylamine can be 2:1 to 1:1 or 3:2 to 1:1. In particular the ratio of formic acid to triethylamine can be 5:2, 2:1, 3:2, 1:2 or 1:2, preferably 5:2.

For the purposes of this invention, the conversion of compound 4a to compound 5a may be carried out in the presence of an organic co-solvent which is selected from, PhMe, DCM, DMF, MTBE, THF, 1,4-dioxane, EtOAc, MeCN and IPA.

In a particular feature of the first aspect of the invention, compound 5a(i) is produced by the asymmetric transfer hydrogenation of compound 4a(i)

in the presence of RuCl(ρ-cymene)[(S,S)-Fs-DPEN] and formic acid and triethylamine, at a temperature of from 20 to 50℃, wherein RuCl(ρ-cymene)[(S,S)-Fs-DPEN] is provided in an amount of from 0.005 to 0.1 mol equivalents and where the ratio of formic acid to triethylamine is from 5:2 to 1:2.

In a second step of the process, compound 5a is converted into compound 6a using base. For the purposes of this invention, the base can be selected from one or more of potassium t-butoxide, sodium t-butoxide, sodium hydride, DBU or sodium methoxide, preferably potassium t-butoxide. The conversion can be carried out in an anhydrous solvent such as MTBE, THF, 2-methyl tetrahydrofuran, DME, or 1,4-dioxane, preferably THF. The conversion can be carried out at a temperature of from -10 to 40℃, preferably -5 to 0℃. The reaction can be carried out for 0.5-6h, preferably 1-2h.

The resulting compound 6a can be recrystallised. In particular, compound 6a can be dissolved in a solvent and then recrystallised by the addition of an anti-solvent optionally with cooling.

A suitable crystallisation solvent system includes a combination of a non-polar solvent and a polar solvent. Examples of suitable non-polar solvents include n-heptane and hexane. Examples of suitable polar solvents include MTBE, EtOAc or THF. Preferably, the crystallisation solvent system is n-heptane/MTBE. Crystallisation of compound 6a can involve heating of the system to a temperature as high as the boiling point of the solvent system and then slowly cooling the system to room temperature or to a temperature below room temperature such as about 0℃.

The recrystallised compound 6a is collected (for example by filtration). Preferably, compound 6a is recrystallised to produce a compound having an ee greater than 90%, more preferably greater than 95%.

In an alternative embodiment, the first aspect of the invention provides a process for the conversion of compound 4 into compound 6a comprising,
(a)converting compound 4b wherein the R^1b group is a benzyl group or a substituted benzyl group such as α-methylbenzyl or para-methoxybenzyl, and R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl, into a compound 6b;

(b) forming a chiral salt of compound 6b;
(c) resolving the chiral salt of compound 6b by recrystallisation and then desalting the chiral salt; and
(d) converting compound 6b to compound 6a

wherein R^1a is an amide protecting group, where the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide.

The group R^1b and the nitrogen atom of the piperidine ring can form a protected amine. For the purposes of this invention, the R^1b can be an unsubstituted benzyl group or a substituted benzyl group, such as α-methylbenzyl or ρ-methoxybenzyl.

Preferably, compound 6b is converted into a compound of formula 6a where R^1a and the N-atom form a t-butyl carbamate group by hydrogenation of compound 6b in the presence of a catalyst and di-tert-butyl dicarbonate.

The formation of compound 6b from compound 4b can be carried out in the presence of a reagent for example, an organoboron reducing agent such as K-Selectride, L-Selectride or N-Selectride to form lactone 6b. The formation of lactone 6b is preferably carried out in the presence of a solvent such as PhMe, DCM or THF, preferably THF. The lactone 6b formation can be carried out at a reaction temperature of from -78℃ to 30℃.

Enantiomerically enriched compound 6b is produced via a chiral salt. Reaction of compound 6b with an acid such as (2S,3S)-2,3-bis(benzoyloxy)succinic acid - forms a chiral salt. The chiral salt may be precipitated out in an organic/aqueous solvent system such as methyl acetate/water, EtOAc/water, methyl formate/water, ethyl formate/water, EtOAc/butanone, EtOAc/1-butanol, EtOAc/DCM, 1-butanol/PhMe, t-amyl alcohol/PhMe, MeCN/water, THF/water, MeOH/water, EtOH/water, IPA/water or IPA/water. Preferably the solvent system is MeOAc/water. The formation of the chiral salt can be carried out at a temperature of from 0 to 100℃. In particular, the reaction mixture is heated and then slowly cooled to facilitate crystallisation. The obtained chiral salt can be recrystallised from an organic/aqueous solvent system such as methyl acetate/water, EtOAc/water and EtOAc/1-butanol to further improve optical purity. Preferably the solvent system is methyl acetate/water.

The chiral salt is then desalted, for example by contact with a base, to produce enantiomerically enriched compound 6b. For this purpose, the base can be an aqueous solution of a base such as LiOH, NaOH, KOH, NaHCO₃, KHCO₃, Na₂CO₃, K₂CO_3, Cs₂CO₃, or K₃PO_4, preferably NaOH. The desalting of the chiral salt to yield enantiomerically enriched 6b can be carried out in an organic solvent, such as EtOAc, PhMe, MTBE or DCM, preferably EtOAc.

Compound 6b is then converted to compound 6a by removal of the protecting group R^1b and replacement with the protecting group R^1a. Where R^1a and the nitrogen atom to which it is attached is t-butyl carbamate, R^1b can be replaced with R^1a by a hydrogenation reaction of compound 6b in the presence of di-tert-butyl dicarbonate and a catalyst, preferably palladium on carbon.

The resulting compound 6a can be recrystallised to further increase the enantiomeric excess. For example, compound 6a can be dissolved in a solvent and then recrystallised by the addition of an anti-solvent optionally with cooling. The recrystallised compound 6a is collected, for example by filtration. Preferably, compound 6a is recrystallised to produce a compound having an ee greater than 90%, more preferably greater than 95%.

A suitable crystallisation solvent system would include a combination of a non-polar solvent and a polar solvent. Examples of suitable non-polar solvents include n-heptane and hexane. Examples of suitable polar solvents include MTBE, EtOAc or THF. Preferably, the crystallisation solvent system is n-heptane/MTBE. Crystallisation of compound 6a can involve heating of the system to a temperature as high as the boiling point of the solvent system and then slowly cooling the system to room temperature or to a temperature below room temperature such as about 0℃.

A second aspect of the invention provides a process for the production of compound 5a

wherein the R^1a is an amide protecting group, where the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide, and wherein R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl;
by the asymmetric transfer hydrogenation of compound 4a

in the presence of a non-tethered Noyori catalyst and a hydrogen donor.

The definition of the non-tethered Noyori catalyst, the amount of the catalyst, the process temperature and the hydrogen donor as set out for the conversion of compound 4a to compound 5a as described in the first aspect of the invention also apply to the conversion of compound 4a to compound 5a of the second aspect of the invention.

In particular, the process of the second aspect of the invention can be carried out in the presence of a catalyst which is selected from one or more of RuCl (ρ-cymene) [(S,S)-Ts-DPEN], RuCl (ρ-cymene) [(S,S)-Fs-DPEN] or RuCl(mesitylene)[(S,S)-Ts-DPEN]. Preferably, where the catalyst is RuCl (ρ-cymene) [(S,S)-Fs-DPEN].

The process of the second aspect of the invention particular provides the catalyst in an amount of from 0.005 to 0.1 mol equivalents.

The process of the second aspect of the invention is preferably carried out at a temperature of from 20 to 50 ℃.

The hydrogen donor is preferably selected from formic acid and triethylamine or an alcohol selected from EtOH or IPA and sodium formate. When the hydrogen donor is formic acid and triethylamine, the ratio of formic acid to triethylamine is from 5:2 to 1:2.

For the purposes of the second aspect of the invention, R^1a is preferably an amide protecting group, where the N-atom and the R^1a group form a t-butyl carbamate group and R² is ethyl.

The second aspect of the invention particularly relates to a process for the formation of compound 5a(i) by the asymmetric transfer hydrogenation of compound 4b(i), in the presence of RuCl(ρ-cymene)[(S,S)-Fs-DPEN] and formic acid and triethylamine, at a temperature of from 20 to 50 ℃, wherein RuCl(ρ-cymene)[(S,S)-Fs-DPEN] is provided in an amount of from 0.005 to 0.1 mol equivalents and where the ratio of formic acid to triethylamine is from 5:2 to 1:2.

A third aspect of the invention relates to the production of compound 4b.

A specific example of compound 4b, (compound 4b(i) wherein R^1b is benzyl and R² is ethyl) can be prepared via the reaction scheme below:

Compound 4b(i) is prepared in steps (b) and (c) by contacting compound 2b(i) with an acid, preferably HCl followed by heating of the reaction mixture with EtOH. Compound 2b(i) is prepared in step (a) by incubation of compound 1b(i) with a base such as Cs₂CO₃, in a solvent, such as MeCN and subsequent treatment with ethyl 2-bromoacetate.

Compound 4a can be prepared from compound 4b(i) by replacing the benzyl protecting group of compound 4b(i) with an oxycarbonyl group such that R^1a and the N-atom form a t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide protecting group.

In a preferred feature of the invention, the compound 4a is prepared from compound 4b(i) by the replacement of the benzyl protecting group with a Boc- protecting group by reaction of compound 4b(i) with di-tert-butyl dicarbonate in the presence of a catalyst, preferably palladium on carbon and hydrogen.

Compound 4b(i) can be converted into another compound 4b by replacing the benzyl protecting group with a substituted benzyl group selected from α-methylbenzyl or para-methoxybenzyl.

A fourth aspect of the invention provides a method for the production of BB1 from a compound 6a

wherein the R^1a is an amide protecting group, where the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide, preferably where the N-atom and the R^1a group form a group selected from t-butyl carbamate, wherein
(a) compound 6a is reacted in the presence of a base and a methylating agent to form compound 7a,

and
(b) compound 7a is deprotected to form BB1, or a salt thereof.

Step (a) requires reaction of the compound 6a to form compound 7a. Examples of a suitable methylating agent include MeI, or dimethyl sulfate, preferably MeI. Examples of a suitable base include one or more of LiOH, NaOH, KOH, Mg(OH)₂, or Ca(OH)₂, preferably KOH. Preferably, compound 6a is treated with a methylating agent and a base in the presence of an anhydrous solvent. Examples of a suitable anhydrous solvent include one or more of MTBE, THF, 2-methyl tetrahydrofuran, DME or 1,4-dioxane, preferably THF. The reaction mixture can be heated, for example at 50-100 ℃. The reaction can be carried out for a period of from 2 hours to one day.

The conditions required for the deprotection of the compound 7a will depend on the nature of the R^1a protecting group. Where R^1a is a Boc protecting group, removal of the Boc protecting group may be carried out by treatment with an acid solution in an organic solvent. The acid solution can be one or more of HCl, HBr, HI, H₂SO₄, or TFA. The organic solvent is preferable dioxane. In a particularly preferred feature of the invention, the deprotection of compound 7a is carried out using HCl in dioxane. The deprotection can be carried out at a temperature of from 0 ℃ to room temperature. The deprotection can be carried out for a period of from 30 min to 6 h. After concentration of the reaction mixture under reduced pressure, the residual salt can be directly used in subsequent amide coupling reactions.

The fifth aspect of the invention relates to a process for the production of a compound C,

said process comprising reaction of a compound of formula B

with a compound of formula

in the presence of a PdCl₂(PPh₃)₂ catalyst, a solvent and a base, at a temperature of from 40 to 100 ℃.

For the purposes of this invention, the base can be selected from K₃PO₄, CsF, KF, NaHCO₃, K₂CO₃, Cs₂CO₃ or Na₂CO₃, preferably Na₂CO_3. The solvent can be selected from water, THF, 1,4-dioxane, DMF, MeCN, PhMe and DME, preferably THF or a mixture of water and THF. The reaction is preferably carried out for a period of 6 to 16 hours.

The reaction can be carried out at a temperature of from 40 to 100 ℃, preferably at a temperature of from 40 to 80 ℃, more preferably at a temperature of from 40 to 60 ℃.

In a preferred feature of the fifth aspect of the invention, there is provided, a process for the production of a compound C, in the presence of a PdCl₂(PPh₃)₂ catalyst, THF and Na₂CO₃, at a temperature of from 40 to 60 ℃. The Na₂CO₃ according to this aspect may be aqueous Na₂CO₃.

Compound C can be used in a process for the formation of compound D,

said process comprising contacting compound C under conditions to hydrolyse the alkyl ester. In particular, compound C is treated with a base such as LiOH, KOH or NaOH, preferably LiOH. The hydrolysis reaction can be carried out in water or in a mixture of water and a miscible solvent, such as water and THF, MeOH, EtOH, IPA, 1,4-dioxane, tBuOH, DMF, DME and/or MeCN, preferably THF, MeOH and water.

In a preferred feature of the fifth aspect of the invention, compound C is hydrolysed in the presence of LiOH.H₂O.

The sixth aspect of the invention provides a process for the formation of compound X, said process comprising reacting a compound of formula BB1 or a salt thereof with a compound of formula D to form compound E and the subsequent deprotection of compound E to form compound X.

Conditions for the coupling of compounds D and BB1, and the conversion of compound E to form compound X are in accordance with those disclosed in US2018/0057499, the contents of which are incorporated herein by reference.

The reaction of the compound of formula BB1 with a compound of formula D can be carried out using the compound BB1 or a salt of BB1. In one embodiment the residual salt from the conversion of compound 7a to the compound BB1 may be used. For example, the compound of BB1 can be used as the hydrochloride salt.

For the purposes of this invention, the compound of formula BB1 or a salt thereof is produced according to the first aspect of the invention and/or the compound of formula D is produced according to the fifth aspect of the invention.

A further aspect of the present invention provides a compound of formula 5a(i) as described herein above. In one embodiment the compound of formula 5a(i) has an ee of greater than 40 %, preferably greater than 50%, more preferably greater than 60%, even more preferably greater than 70%.

A still further aspect of the present invention provides a compound 6a(i) as described herein above having an ee of greater 90%. In one embodiment the compound of formula 6a(i) has an ee greater than 95%, preferably greater than 98%, more preferably greater than 99%.

A still further aspect of the present invention provides a compound 7a(i) as described herein above. In one embodiment the compound of formula 7a(i) has an ee greater than 95%, preferably greater than 98%, more preferably greater than 99%.

A still further aspect of the present invention provides a compound 6b(i) as described herein above. In one embodiment the compound of formula 6b(i) has an ee greater than 50%, more preferably greater than 75%, even more preferably greater than 95%.

A still further aspect of the present invention provides a chiral salt of compound 6b(i). In one embodiment the chiral salt of compound 6b(i) is the (2S,3S)-2,3-bis(benzoyloxy)succinate salt.

For the purposes of this invention, all preferred features of a particular aspect of the invention can be applied to any other aspect of the invention.

FIG.1 shows an X-Ray Powder Diffraction (XRPD) diffractogram of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate (7b’).

The invention will now be illustrated by the following non-limiting examples.

Examples

General Methods
The chemical names for the compounds in the following examples were created based on the chemical structures using “E-Notebook 2014” version 13 (PerkinElmer Co., Ltd.).

In the case of compound 5a(i), the stereochemical descriptor represents the configuration of the major isomer.

A mixture of rotamers means a mixture of isomers having different conformations caused by intramolecular rotations around single bonds such as C-C, C-N or C-O.

Column chromatography was carried out using pre-packed silica gel cartridges on a Biotage(Registered trademark) Isolera Four(Registered trademark). The column, solvents and gradient used are described in the experimental details.

NMR Method
¹H NMR spectra were recorded at 25 ℃, using a Bruker AVIII (600 MHz) or Variant Inova (400 MHz) using a BBO double resonance broad band 5 mm probe. Chemical shifts are expressed in ppm relative to an internal standard, tetramethylsilane (ppm = 0.00). The following abbreviations have been used: br = broad signal, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet, or any combination thereof.

LCMS Methods
LCMS experiments to determine retention times (R_t) and associated mass ions were performed using one of the following methods:
Method A: Compounds were analysed using the following conditions: Experiments were performed on a Waters SQD mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector and ELSD detector. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses an Acquity CSH C18 1.7 μm 50 x 2.1 mm column, maintained at 40 ℃ and a 0.6 mL/min flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solvent B) for the first 0.2 min followed by a gradient up to 5% solvent A and 95% solvent B over the next 1.5 min. This was maintained for 0.5 min before returning to 95% solvent A and 5% solvent B over the next 0.05 min and maintained for 0.25 min. Total run time was 2.5 min.
Method B: Compounds were analysed using the following conditions: Experiments were performed on a Waters SQD mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector and ELSD detector. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses an Acquity BEH C18 1.7 μm 50 x 2.1 mm column, maintained at 40 ℃ and a 0.6 mL/min flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% MeCN containing 0.1% formic acid (solvent B) for the first 0.2 min followed by a gradient up to 5% solvent A and 95% solvent B over the next 1.5 min. This was maintained for 0.5 min before returning to 95% solvent A and 5% solvent B over the next 0.05 min and maintained for 0.25 min. Total run time was 2.5 min.

Chiral HPLC Methods
The ee determinations were carried out on a Shimadzu Chiral HPLC instrument using one of the following methods:
Method A: Compounds were analysed using a Daicel ChiralPak IE 5 μm 250 x 4.6 mm column, maintained at 30 ℃ and a 1 mL/min flow rate. 10 μL of the compound was injected as a 1 mg/mL solution in EtOH. The solvent system used was a 9:1 mixture of heptane/EtOH at an isocratic gradient for 20 min. UV analysis was carried out at 200 and 220 nm.
Method B: Compounds were analysed using a Daicel ChiralCel OB-H 5 μm 250 x 4.6 mm column, maintained at 35 ℃ and a 0.8 mL/min flow rate. 10 μL of the compound was injected as a 1 mg/mL solution in EtOH. The solvent system used was a 75:15:10 mixture of heptane/IPA/MeOH at an isocratic gradient for 20 min. UV analysis was carried out at 204 and 220 nm.
Method C: Compounds were analysed using a Daicel ChiralPak IC 5 μm 250 x 4.6 mm column, maintained at 30 ℃ and a 1 mL/min flow rate. 10 μL of the compound was injected as a 1 mg/mL solution in EtOH. The solvent system used was a 98:2 mixture of heptane/EtOH at an isocratic gradient for 20 min. UV analysis was carried out at 200 and 220 nm.
Method D: Compounds were analysed using a Daicel ChiralCel OJ-H 5 μm 250 x 4.6 mm column, maintained at 35 ℃ and a 1 mL/min flow rate. 5 μL of the compound was injected as a 1 mg/mL solution in MeOH. The solvent system used was a 5:8:87 mixture of MeOH/IPA/n-hexane at an isocratic gradient for 20 min. UV analysis was carried out at 220 nm.

Optical rotations
The optical rotation was measured on a DIP-1000 type polarimeter (JASCO) using a 100 mm path length microcell at 20 ℃. The measurement using Na D line was repeated five times and the mean value was used for calculation of specific rotation.

General Procedure for Asymmetric Transfer Hydrogenation and Optimisation of Reaction Conditions
Into a stirred mixture of tert-butyl 4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-1-carboxylate (4a(i)) (25-100 mg) and ruthenium catalyst (0.05 mol equivalents unless otherwise stated) in a nitrogen purged flask was added a preformed mixture (5:2 ratio unless otherwise stated) of formic acid and Et₃N (making final reaction concentration of 0.137 M unless otherwise stated). The mixture was stirred at RT (unless otherwise stated) for 17-21 h, diluted with DCM (20 mL), washed with saturated NaHCO₃ solution (20 mL), dried (Na₂SO₄), filtered, and then evaporated. The residue was purified by column chromatography (10 g KP-Sil, 0-80% EtOAc/cyclohexane) to give tert-butyl (3RS,4SR)-4-(2-ethoxy-2-oxoethyl)-3-hydroxypiperidine-1-carboxylate (5a(i)). The ee was determined by Chiral HPLC using Method A.

The reaction conditions used for the preparation of tert-butyl (3R,4S)-4-(2-ethoxy-2-oxoethyl)-3-hydroxypiperidine-1-carboxylate as described herein below in step 1 of the preparation of 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid were chosen on the basis of the results of the optimisation experiments.

Preparation of tert-butyl 4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-1-carboxylate (4a(i))
a) Preparation of ethyl 1-benzyl-4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-4-carboxylate (2b(i))
A mixture of ethyl N-benzylpiperid-3-one-4-carboxylate hydrochloride (1.00 g, 3.36 mmol) in EtOAc (25 mL) and saturated aqueous NaHCO₃ (25 mL) was stirred at RT for ～30 min until all solid dissolved. The aqueous layer was separated and extracted with EtOAc (25 mL), the combined organic extracts washed with saturated NaCl (20 mL), dried (Na₂SO₄), filtered and evaporated to provide ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (0.87 g) as a colourless oil.
To a solution of the product from above (0.87 g, 3.31 mmol) in anhydrous MeCN (20 mL) under nitrogen was added Cs₂CO₃ (2.16 g, 6.63 mmol). The mixture was cooled to -3 ℃ (internal temperature) and then ethyl 2-bromoacetate (0.37 mL, 3.31 mmol) was added dropwise over 2 min. After 5 min, the mixture was allowed to warm to RT and stirred for 1.5 h. The mixture was quenched with saturated aqueous NH₄Cl (20 mL), extracted with EtOAc (2 × 20 mL) and the combined organic extracts washed with saturated NaCl (20 mL), dried (Na₂SO₄), filtered, and evaporated to give the title compound (1.17 g). LCMS (Method A, ELSD): R_t 1.31 min, m/z 348 [M+H]⁺.

b) Preparation of ethyl 2-(1-benzyl-3-oxopiperidin-4-yl) acetate (4b(i))
A solution of ethyl 1-benzyl-4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-4-carboxylate (1.10 g, 3.18 mmol) in concentrated HCl (3.0 mL, 36.0 mmol) was stirred at 95 ℃ for 6 h and then left to cool to RT overnight. EtOH (11 mL) was added and the reaction was heated at 75 ℃ for 5.5 h. The mixture was cooled in an ice-water bath and adjusted to pH 7 by slow addition of 2 M aqueous Na₂CO₃ (～5.5 mL). The mixture was diluted with water (30 mL) and extracted with EtOAc (7 × 20 mL), adding a few drops of 2 M aqueous Na₂CO₃ to maintain the pH of the aqueous layer at 7-8. The combined organic extracts were washed with saturated NaCl solution (40 mL) dried (Na₂SO₄), filtered and evaporated to afford the title compound (0.66 g) as an orange-brown oil. LCMS (Method B, ELSD): R_t 0.90 min, m/z 276 [M+H]⁺.

c) Preparation of tert-butyl 4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-1-carboxylate (4a(i))
A solution of crude ethyl 2-(1-benzyl-3-oxopiperidin-4-yl)acetate (0.65 g, 2.35 mmol) and di-tert-butyl dicarbonate (0.57 g, 2.59 mmol) in EtOH (10 mL) was evacuated, back-filled with nitrogen and then palladium on carbon (10 wt. % loading dry basis, contains ～50% water) (0.100 g, 0.047 mmol) added. After a further three cycles of evacuation and refilling with nitrogen, the flask was evacuated and then refilled with hydrogen three times. Hydrogen was bubbled through the solution for 5 minutes and then the mixture stirred under hydrogen for 20 h. The mixture was filtered through Celite, washed with EtOAc and the filtrate evaporated. The residue was purified by column chromatography (50 g KP-Sil, 0-50% EtOAc/cyclohexane) to provide the title compound (0.25 g) as a pale yellow oil. LCMS (Method B, ELSD): R_t 1.48 min, m/z 308 [M+Na]⁺. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.27 (t, J=7.15 Hz, 3 H) 1.46 (s, 9 H) 1.68 - 1.77 (m, 1 H) 2.11 - 2.19 (m, 1 H) 2.34 (br dd, J=16.60, 6.51 Hz, 1 H) 2.81 (br dd, J=16.78, 5.23 Hz, 1 H) 2.84 - 2.92 (m, 1 H) 3.37 (br s, 1 H) 3.81 - 4.05 (m, 2 H) 4.09 - 4.22 (m, 3 H).

Process for the production of 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid (X)

2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl)acetic acid was prepared from tert-butyl (3R,4S)-4-(2-ethoxy-2-oxoethyl)-3-hydroxypiperidine-1-carboxylate prepared according to the present invention.

Step 1: Preparation of tert-butyl (3R,4S)-4-(2-ethoxy-2-oxoethyl)-3-hydroxypiperidine-1-carboxylate (5a(i))
To a stirred mixture of tert-butyl 4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-1-carboxylate (9.40 g, 32.9 mmol) and RuCl[(S,S)-FsDPEN](ρ-cymene) (0.235 g, 0.329 mmol) in a nitrogen purged flask was added a preformed mixture of formic acid (98 mL) and Et₃N (142 mL), prepared under nitrogen with cooling in an ice-water-salt bath. The mixture was stirred at RT for 4 d, diluted with DCM (500 mL) and water (500 mL) and the aqueous layer extracted with DCM (500 mL). The combined organic extracts were washed with saturated NaHCO₃ solution (250 mL), saturated NaCl (250 mL), dried (Na₂SO₄), filtered, and then evaporated. The residue was purified by column chromatography (340 g KP-Sil, 0-80% EtOAc/cyclohexane) to provide the title compound (7.15 g) as a pale yellow oil. LCMS (Method B, ELSD): R_t 1.38 min, m/z 310 [M+Na]⁺. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.26 (t, J=7.06 Hz, 3 H), 1.42 - 1.50 (m, 10 H), 1.52 - 1.61 (m, 1 H), 1.77 (br s, 1 H), 2.01 - 2.07 (m, 1 H), 2.28 (dd, J=15.86, 6.88 Hz, 1 H), 2.51 (dd, J=15.96, 7.34 Hz, 1 H), 2.77 (br t, J=11.37 Hz, 1 H), 2.93 (br d, J=12.84 Hz, 1 H), 3.84 (br s, 1 H), 3.96 - 4.08 (m, 1 H), 4.08 - 4.19 (m, 3 H). Chiral HPLC (Method A) R_t 11.7 min (major) 12.7 min (minor), 71.9% ee.

Step 2: Preparation of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate (6a(i))
To a stirred solution of tert-butyl (3R,4S)-4-(2-ethoxy-2-oxoethyl)-3-hydroxypiperidine-1-carboxylate (7.13 g, 24.8 mmol) in anhydrous THF (170 mL) under nitrogen at -2 ℃ (internal temp) was added dropwise, over 2 min, a 1 M THF solution of potassium tert-butoxide (2.48 mL, 2.48 mmol). The resulting solution was stirred at -2 ℃ for 85 min, diluted with EtOAc (200 mL), quenched with saturated NaHCO₃ (50 mL) and partitioned between saturated NaHCO₃ (400 mL) and EtOAc (200 mL), adding water (～50 mL) to dissolve solids. The aqueous layer was extracted with EtOAc (200 mL) and the combined organic extracts were washed with saturated NaCl (200 mL), dried (Na₂SO₄), filtered and evaporated to give the title compound (5.47 g) as a cream solid. This was dissolved in MTBE (135 mL) at 56 ℃ and n-heptane (90 mL) was added followed by a seed of homochiral tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c]pyridine-6(2H)-carboxylate and the mixture was stirred at 65 ℃ for 1 h. The resulting solution was allowed to cool slowly to RT overnight with stirring after adding more seeds of homochiral material. The mixture was cooled in an ice-water-salt bath for 1.5 h and the solid was collected by filtration, washed with ice-cold MTBE-heptane (3:2; 3 × ～15 mL) and dried in vacuo at 40 ℃ to give the title compound (4.04 g) as a colourless solid. Chiral HPLC (Method B) R_t 9.8 min (major), 8.3 min (minor), 86.3% ee.

The solid was stirred in MTBE (90 mL) at 56 ℃ to give almost complete dissolution and n-heptane (60 mL) was added. A seed of homochiral material was added and the mixture was stirred at 65 ℃ for 1 h before allowing to cool slowly to RT overnight with stirring. The mixture was cooled in an ice-water bath for 1 h and the solid was collected by filtration, washed with ice-cold MTBE-heptane (3:2; 3 × ～10 mL) and dried in vacuo at 40 ℃ to give the title compound (3.40 g) as a colourless solid. LCMS (Method B, ELSD): R_t 1.23 min, m/z 264 [M+Na]⁺. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.45 - 1.55 (m, 10 H), 1.77 - 1.82 (m, 1 H), 2.32 (dd, J=17.24, 2.38 Hz, 1 H), 2.57 (br s, 1 H), 2.71 (dd, J=17.15, 7.61 Hz, 1 H), 2.79 - 3.09 (m, 1 H), 3.20 - 3.42 (m, 1 H), 3.62 - 4.01 (m, 1 H), 4.07 - 4.28 (m, 1 H), 4.35 - 4.55 (m, 1 H). Chiral HPLC (Method B) R_t 9.8 min, >99.5% ee.

Step 3: Preparation of tert-butyl (3R,4S)-3-methoxy-4-(2-methoxy-2-oxoethyl) piperidine-1-carboxylate (7a(i))
To a stirred solution of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c]pyridine-6(2H)-carboxylate (3.38 g, 14.0 mmol) in anhydrous THF (70 mL) under nitrogen was added MeI (8.32 mL, 133 mmol) and then KOH (6.28 g, 112 mmol). The mixture was heated at 60 ℃ for 21 h and then partitioned between water (200 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (200 mL), the combined organic extracts were washed with saturated NaCl (100 mL), dried (Na₂SO₄), filtered and evaporated to provide the title compound (4.06 g) as a yellow oil. LCMS (Method B, ELSD): R_t 1.50 min, m/z 310 [M+Na]⁺. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.36 - 1.42 (m, 1 H), 1.46 (s, 9 H), 1.57 - 1.65 (m, 1 H), 2.04 - 2.11 (m, 1 H), 2.27 (br dd, J=15.86, 6.51 Hz, 1 H), 2.50 (dd, J=15.96, 7.34 Hz, 1 H), 2.68 - 2.86 (m, 2 H), 3.19 - 3.30 (m, 1 H), 3.34 (s, 3 H) 3.68 (s, 3 H), 3.87 - 4.17 (m, 1 H), 4.21 - 4.38 (m, 1 H). Chiral HPLC (Method C) R_t 12.3 min, >99.5% ee.

Step 4: Preparation of methyl 2-((3R,4S)-3-methoxypiperidin-4-yl) acetate hydrochloride (BB1.HCl)
To tert-butyl (3R,4S)-3-methoxy-4-(2-methoxy-2-oxoethyl) piperidine-1-carboxylate (4.06 g, 14.1 mmol) under nitrogen, cooled in an ice bath at -1 ℃ was added a 4 N solution of HCl in 1,4-dioxane (41 mL, 164 mmol) over 10 min and the solution was stirred at RT for 4.5 h. The solvent was evaporated at 30 ℃ and the residue was dried in vacuo at RT overnight to provide the title compound (3.62 g) as a yellow oil. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.66 - 1.71 (m, 1 H), 1.95 - 2.03 (m, 1 H), 2.11 - 2.19 (m, 1 H), 2.32 (dd, J=16.51, 6.42 Hz, 1 H), 2.56 (dd, J=16.41, 7.43 Hz, 1 H), 2.84 - 2.95 (m, 2 H), 3.42 - 3.49 (m, 4 H), 3.55 - 3.63 (m, 2 H), 3.69 (s, 3 H), 8.56 - 8.74 (m, 1 H), 10.22 (br s, 1 H).

Step 5: Preparation of ethyl 5-chloro-7-((2-fluoro-6-methylphenyl) amino) pyrazolo[1,5-a] pyrimidine-2-carboxylate
A solution of ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (WO 2011105628) (43.6 g, 168 mmol) and 2-fluoro-6-methylaniline (18.48 ml, 160 mmol) in anhydrous 1-methyl-2-pyrrolidinone (128 mL) under nitrogen was stirred at 97 ℃ for 17 h. The mixture was cooled to 50 ℃ and water was added dropwise until a cloudy solution persisted (ca. 43 mL) at which point the mixture was seeded with pure title compound. Additional water (～580 mL) was added slowly and the mixture was stirred at 50 ℃ for 2 h then cooled to RT. The solid was isolated by filtration, washed with water and dried in vacuo at 50 ℃ to give a cream solid (54.24 g). The solid was stirred in MeOH (800 mL) at reflux for 90 min then allowed to cool to RT. After 60 h the mixture was cooled to <0 ℃ and stirred for 1 h before the solid was collected by filtration. The resulting solid was washed with ice cold MeOH (2 × 25 mL) and dried in vacuo at 50 ℃ to provide the title compound (40.02 g) as a colourless solid. LCMS (Method B): R_t 1.71 min, m/z 349/351 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 1.36 (t, J=6.97 Hz, 3 H), 2.26 (s, 3 H), 4.41 (q, J=7.21 Hz, 2 H), 5.58 (br s, 1 H), 6.99 (br s, 1 H), 7.23 - 7.29 (m, 2 H), 7.41 (br d, J=5.87 Hz, 1 H), 10.33 (s, 1 H).

Step 6: Preparation of ethyl 5-chloro-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo[1,5-a] pyrimidine-2-carboxylate (B)
To a solution of ethyl 5-chloro-7-((2-fluoro-6-methylphenyl) amino) pyrazolo [1,5-a] pyrimidine-2-carboxylate (39.90 g, 114 mmol) in DMF (400 mL) was added Cs₂CO₃ (44.7 g, 137 mmol) then MeI (21.46 mL, 343 mmol) and the mixture was stirred at 40 ℃ (internal temperature) for 1 h. The mixture was allowed to cool to RT and diluted with water (1.5 L) with stirring, adding the first 500 mL over ～5 min before the bulk was added. The mixture was stirred for 30 min, the solid was collected by filtration, washed twice with water and dried in vacuo at 50 ℃ to provide the title compound (41.14 g) as a yellow solid. LCMS (Method B): R_t 1.77 min, m/z 363/365 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.37 (t, J=7.06 Hz, 3 H), 2.26 (s, 3 H), 3.83 (br s, 3 H), 4.36 (q, J=7.09 Hz, 2 H), 5.79 (br s, 1 H), 6.88 (s, 1 H), 7.04 (br t, J=8.60 Hz, 1 H), 7.12 (d, J=7.54 Hz, 1 H), 7.27 - 7.32 (m, 1 H).

Step 7: Preparation of ethyl 5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl)amino) pyrazolo[1,5-a] pyrimidine-2-carboxylate (C)
A solution of ethyl 5-chloro-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [1,5-a] pyrimidine-2-carboxylate (41.1 g, 113 mmol) in THF (600 mL) and water (140 mL) was sparged with nitrogen for 3 h then Na₂CO₃ (30.0 g, 283 mmol), (4-chloro-3,5-difluorophenyl)boronic acid (27.2 g, 142 mmol) and PdCl₂(PPh₃)₂ (3.98 g, 5.66 mmol) were added whilst sparging continued. The mixture was stirred at 60 ℃ for 6 h and allowed to stand at RT overnight. The mixture was re-warmed to 60 ℃ and water (700 mL) was added in one portion. The suspension was stirred vigorously at RT for 2 h, then the solid was collected by filtration and washed with water to afford a brown/grey solid, which was suspended in MeCN (700 mL), heated to 70 ℃ and stirred for 30 min, then cooled to 0 ℃ (internal temperature) in an ice/water/salt bath. The mixture was filtered and the solid was washed with ice cold MeCN (75 mL × 2) and dried in vacuo to afford the title compound (44.47 g) as a grey solid. LCMS (Method B): R_t 2.08 min, m/z 475/477 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃) δ ppm 1.38 (t, J=7.06 Hz, 3 H), 2.28 (s, 3 H), 3.88 (s, 3 H), 4.38 (q, J=7.09 Hz, 2 H), 6.14 (br s, 1 H), 7.02 (s, 1 H), 7.05 (t, J=8.98 Hz, 1 H), 7.15 (d, J=7.91 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.57 (br d, J=7.89 Hz, 2 H).

Step 8: Preparation of 5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [1,5-a] pyrimidine-2-carboxylic acid (D)
To a suspension of ethyl 5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo[1,5-a] pyrimidine-2-carboxylate (44.43 g, 93.563 mmol) in THF (900 mL) and MeOH (300 mL) was added water (300 mL) and lithium hydroxide monohydrate (11.78 g, 281 mmol) and the mixture was stirred at RT with a mechanical stirrer for 23 h. Water (800 mL) was added and the pH adjusted to ～4 using 2 N HCl (150 mL). The mixture was stirred for 3 h at RT and the resulting solid was collected by filtration, washed twice with water then dried in vacuo at 50 ℃ to provide the title compound (39.65 g) as a pale grey solid. LCMS (Method B): R_t 1.83 min, m/z 447/449 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 2.22 (s, 3 H), 3.59 (s, 3 H), 6.91 (s, 1 H), 7.06 (br t, J=9.06 Hz, 1 H), 7.15 (br d, J=7.70 Hz, 2 H), 7.25 - 7.30 (m, 1 H), 8.21 (br d, J=9.17 Hz, 2 H), 12.81 - 12.99 (m, 1 H).

Step 9: Preparation of methyl 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo[1,5-a] pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl) acetate (E)
To a suspension of 5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [1,5-a] pyrimidine-2-carboxylic acid (6.63 g, 14.8 mmol) and methyl 2-((3R,4S)-3-methoxypiperidin-4-yl) acetate hydrochloride (3.16 g, 14.1 mmol) in DMF (125 mL) at 0 ℃ was added HOBT (3.52 g, 18.4 mmol) then EDC.HCl (3.52 g, 18.4 mmol) and Et₃N (5.12 mL, 36.735 mmol). The mixture was stirred at 0 ℃ for 20 min then at RT for 20 h. The mixture was cooled to 0 ℃ and water (270 mL) was added slowly, followed by EtOAc (270 mL). The mixture was filtered through Celite and washed with further EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (250 mL). The combined organic extracts were treated with (R)-2-Amino-3-mercaptopropionic acid (8.56 g, 70.6 mmol) and 0.5 M aqueous NaOH (127 mL, 63.6 mmol) and stirred for 90 min. The layers were separated and the organic layer was washed with saturated NaHCO₃ solution (150 mL), saturated NaCl solution (150 mL), dried (Na₂SO₄), filtered, and evaporated to give the title compound (9.30 g) as a colourless foam. LCMS (Method B): R_t 1.90 min, m/z 616/618 [M+H]⁺. ¹H NMR (600 MHz, CDCl₃, mixture of rotamers) δ ppm 1.25 - 1.73 (m, 2 H), 2.05 - 2.95 (m, 9 H), 3.38 - 3.74 (m, 9 H), 4.10 - 4.95 (m, 2 H), 6.29-6.55 (m, 1 H), 6.89 - 7.25 (m, 4 H), 7.62 - 7.75 (m, 2 H).

Step 10: Preparation of 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl) amino) pyrazolo [1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl) acetic acid (X)
To a solution of methyl 2-((3R,4S)-1-(5-(4-chloro-3,5-difluorophenyl)-7-((2-fluoro-6-methylphenyl) (methyl)amino) pyrazolo [1,5-a]pyrimidine-2-carbonyl)-3-methoxypiperidin-4-yl) acetate (9.30 g, 15.1 mmol) in 1,4-dioxane (104 mL) at 10 ℃ was added a solution of LiOH monohydrate (1.11 g, 26.4 mmol) in water (52.2 mL) and the mixture was stirred at -2 to 0 ℃ for 2.5 h and then left at 2 ℃ overnight. The mixture was cooled to 0 ℃, adjusted to pH 4 with 2 N HCl (～13 mL) and extracted with 2-methyltetrahydrofuran (2 × 100 mL). The combined organic extracts were washed with saturated NaCl (70 mL), dried (Na₂SO₄), filtered, and evaporated. To the residue was added EtOAc (ca. 5 mL), the mixture sonicated for 5 mins, then diluted with cyclohexane/EtOAc (3:1, 100 mL) and cooled in an ice bath. The solid was collected by filtration, washed with cyclohexane/EtOAc (3:1, 3 × 20 mL) and then stirred in EtOAc (240 mL) at reflux for ～30 min. Cyclohexane (500 mL) was added and heating was continued for ～30 min before allowing to cool slowly to RT overnight. Additional cyclohexane (220 mL) was added and the mixture was cooled in an ice bath to -1 ℃. The solid was collected by filtration, washed with cyclohexane/EtOAc (3:1, 3 × ～10 mL) and dried in vacuo at 40 ℃. To this solid (8.35 g) was added MTBE (75 mL) and the mixture was stirred at RT for 24 h, filtered, washed with a small amount of MTBE and dried in vacuo at 40 ^oC to afford the title compound (7.56 g) as a colourless solid. LCMS (Method B): R_t 1.74 min, m/z 602/604 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD, mixture of rotamers) δ ppm 1.23 - 1.38 (m, 1 H), 1.48 - 1.60 (m, 1 H), 2.02 - 2.81 (m, 8 H), 2.98 - 3.67 (m, 7 H), 4.03 - 4.32 (m, 1 H), 4.36 - 4.56 (m, 1 H), 6.84 - 6.91 (m, 1 H), 6.95 - 7.35 (m, 4 H), 7.98 - 8.05 (m, 2 H). The CO₂H was not observed. [α]_D ²⁰ -108.5° (c = 2.00, DMSO).

Alternative preparation of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate (6a(i)) via chiral salt resolution

Step 1: Preparation of ethyl 1-benzyl-4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-4-carboxylate (2b(i))
A 22 L reactor equipped with a mechanic stirrer was charged with potassium t-butoxide (829 g, 7.39 mol) and THF (8.0 L). After dissolution of all the solid at ambient temperature, the mixture was cooled to 6 ℃ and treated with a solid ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride (1b(i)) (1.00 kg, 3.36 mol) portion wise over 15 min maintaining the internal temperature below 29 ℃. After cooling back to 4 ℃, the mixture was treated with ethyl bromoacetate (411 mL, 3.670 mol) maintaining the internal temperature below 10 ℃. The mixture was slowly warmed up to 18 ℃ over 5 h and stirred at rt for 24 h. After quenching the reaction with water (5 L), the mixture was extracted with EtOAc (12 L). The organic layer was washed with sat. NaHCO₃ (5 L) and with brine (8 L) and concentrated in vacuo to give the compound 2b(i) (1.095kg, 94%).
¹H NMR (400 MHz, CDCl₃) δ ppm 1.20 - 1.30 (m, 6H), 1.98 - 2.08 (m, 1H), 2.48 - 2.60 (m, 1H), 2.65 - 2.75 (m, 4H), 3.15 - 3.25 (m, 2H), 3.53 - 3.63 (m, 2H), 4.10 - 4.17 (m, 2H), 4.19 - 4.25 (m, 2H), 7.25 - 7.35 (m, 5H).

Step 2: Preparation of ethyl 2-(1-benzyl-3-oxopiperidin-4-yl) acetate (4b(i))
Ethyl 1-benzyl-4-(2-ethoxy-2-oxoethyl)-3-oxopiperidine-4-carboxylate (2b(i)) (1.079 kg, 3.106 mol) was charged into a 20 L reactor equipped with a mechanic stirrer, treated with conc. HCl (2.16 L, 25.9 mol), and heated to 95 ℃ for 6 h. After addition of EtOH (10.8 L), stirring was continued at 75 ℃ for additional 5 h. After cooling to 0 ℃, the mixture was basified to pH 10 with 3 N sodium hydroxide (6.25 L, 18.8 mol), and extracted twice with MTBE (14 L). The organic layers were combined, washed with sat. NaHCO₃ (10.8 L) and brine (10.8 L) and concentrated in vacuo. The residue was azeotroped twice with PhMe (2 L), loaded on a pad of silica gel (1.33 kg), and eluted with a 1:1 mixture of n-heptane and EtOAc (15 L). The eluent was concentrated in vacuo and azeotroped with THF (1 L) to give the compound 4b(i) (626 g, 70%).
¹H NMR (400 MHz, CDCl₃) δ 1.22 - 1.29 (m, 3H), 1.63 - 1.75 (m, 1H), 2.07 - 2.15 (m, 1H), 2.15 - 2.24 (m, 1H), 2.45 - 2.52 (m, 1H), 2.80 - 2.88 (m, 3H), 2.95 - 3.0 (m, 1H), 3.25 - 3.30 (m, 1H), 3.55 - 3.65 (m, 1H), 4.10 - 4.20 (m, 2H), 7.25 - 7.35 (m, 5H).

Step 3: Preparation of (+/-)-6-benzylhexahydrofuro[2,3-c] pyridin-2(3H)-one (6b(i))
A solution of ethyl 2-(1-benzyl-3-oxopiperidin-4-yl)acetate (4b(i)) (792 g, 2.88 mol) in THF (5.05 L) was cooled to -75 ℃ and treated with 1 M K-Selectride in THF (2.88 L, 2.88 mol) over 2 h maintaining the internal temperature below -70 ℃. After stirring at -75 ℃ for additional 1 h, the reaction was quenched with tBuOH (138 mL, 1.44 mmol). The mixture was warmed up to 0 ℃ and treated with water (7.92 L), EtOAc (1 L) and hydrogen peroxide (1.18 L, 11.5 mol). The mixture was extracted twice with EtOAc (16 L and 6 L). The organic layers were combined, sequentially washed with 10% sodium thiosulfate (6 L), sat. NaHCO₃ (7.9 L) and brine (7.9 L) and concentrated in vacuo. The residue was passed through a silica gel plug to give the racemic compound of 6b(i) (313.3 g, 47%).
¹H NMR (400 MHz, CDCl₃) δ 1.55 - 1.65 (m, 1H), 1.75 - 1.83 (m, 1H), 2.11 - 2.20 (m, 1H), 2.30 - 2.38 (m, 1H), 2.40 - 2.50 (m, 2H), 2.55 - 2.65 (m, 2H), 2.93 - 3.00 (m, 1H), 3.50 - 3.58 (m, 2H), 4.46 - 4.50 (m, 1H), 7.25 - 7.35 (m, 5H).

Step 4: Preparation of (3aS,7aR)-6-benzylhexahydrofuro[2,3-c] pyridin-2(3H)-one (2S,3S)-2,3-bis(benzoyloxy) succinate (8b(i))
A mixture of (+/-)-6-benzylhexahydrofuro [2,3-c] pyridin-2(3H)-one (6b(i)) (445.4 g, 1.93 mol) and (2S,3S)-2,3-bis(benzoyloxy) succinic acid (621 g, 1.73 mol) was dissolved in methyl acetate (13 L) and water (1.3 L). The mixture was heated to 60 ℃ for 10 min and cooled to 20 ℃ over 16 h (seeding with 100 mg of solid compound 8b(i) at 40 ℃). The resulting precipitate was filtered, rinsed with methyl acetate (1.5 L) and dried over N2 purge to give the compound 8b(i) (287.5 g, 55% ee).

The crystalline salt was suspended in water (300 mL) and methyl acetate (3000 mL) and heated to 60 ℃ for 2 h. The mixture was cooled to 45 ℃ over 1 h, stirred at 45 ℃ for 6 h and cooled to 20 ℃ over 8 h. The resulting precipitate was filtered, rinsed with methyl acetate (220 mL), and dried over N2 purge to give the compound 8b(i) (180g, 86% ee). The compound was recrystallized again by the same procedure from methyl acetate (700 mL) and water (70 mL) to give the compound 8b(i) (175 g, 15.4%).
¹H NMR (400 MHz, CDCl₃) δ 1.54 - 1.64 (m, 1H), 1.74 - 1.85 (m, 1H), 2.25 - 2.38 (m, 2H), 2.40 - 2.50 (m, 1H), 2.54 - 2.70 (m, 3H), 2.92 - 3.00 (m, 1H), 3.60 - 3.69 (m, 2H), 4.45 - 4.52 (m, 1H), 5.96 - 6.00 (m, 2H), 7.25 - 7.30 (m, 5H), 7.38 - 7.45 (m, 4H), 7.52 - 7.58 (m, 2H), 8.08 - 8.13 (m, 4H)
Chiral HPLC (Method D) R_t 15.6 min, 91%ee

Step 5: Preparation of (3aS,7aR)-6-benzylhexahydrofuro[2,3-c] pyridin-2(3H)-one (6b(i))
(3aS,7aR)-6-benzylhexahydrofuro[2,3-c]pyridin-2(3H)-one (2S,3S)-2,3-bis(benzoyloxy)succinate (8b(i)) (170 g, 288.3 mmol, 91%ee) was suspended in EtOAc (3386 mL) and water (270 mL) and then treated with 1 N sodium hydroxide (577 mL, 577 mmol). After stirring for 10 min, the organic layer was separated and washed with sat. NaHCO₃ (800 mL). The combined aqueous layer was back-extracted with EtOAc (1.7 L). The organic layers were combined, washed with brine (800 mL), and concentrated in vacuo to give the compound 6b(i) (65.03 g, 98%).
¹H NMR (400 MHz, CDCl₃) δ 1.55 - 1.65 (m, 1H), 1.75 - 1.83 (m, 1H), 2.12 - 2.20 (m, 1H), 2.30 - 2.38 (m, 1H), 2.40 - 2.50 (m, 2H), 2.55 - 2.65 (m, 2H), 2.94 - 3.00 (m, 1H), 3.50 - 3.59 (m, 2H), 4.46 - 4.51 (m, 1H), 7.25 - 7.35 (m, 5H).

Step 6: Preparation of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate (6a(i))
A solution of (3aS,7aR)-6-benzylhexahydrofuro[2,3-c]pyridin-2(3H)-one (6b(i)) (65.8 g, 284 mmol) in MeOH (753 mL) was treated with Boc anhydride (86 mL, 370 mmol) and 10% Pd on carbon (50% wet, 30.3 g, 14.2 mmol). The reaction mixture was purged with hydrogen gas and stirred under hydrogen gas (1.07 bar) for 1 d. After addition of Celite (95 g), the mixture was stirred at rt for 1 h, filtered through a short pad of silica gel (60 g) and Celite (90 g), and rinsed with MeOH (2.1 L). The filtrate was concentrated in vacuo and chased with EtOAc and n-heptane to give crude compound (86 g).

The crude product was dissolved in MTBE (263 mL), heated to 60 ℃, and treated with n-heptane (1053 mL). The mixture was stirred at 60 ℃ for 30 min, slowly cooled to rt and then to 0 ℃ and stirred at 0 ℃C for 1 h. The precipitate was filtered and rinsed with a 3:1 mixture of MTBE/n-heptane (150mL) and dried over N2 purge to give the compound 6a(i) (50.8 g, 74%).
¹H NMR (400 MHz, CDCl₃) δ 1.40 - 1.45 (s, 9H), 1.45 - 1.55 (m, 1H), 1.75 - 1.83 (m, 1H), 2.27 - 2. 35 (m, 1H), 2.50 - 2.60 (m, 1H), 2.65 - 2.75 (m, 1H), 2.80 - 3.00 (brs, 1H), 3.20 - 3.40 (m, 1H), 3.65 - 4.00 (m, 1H), 4.10 - 4.30 (brs, 1H), 4.35 - 4.55 (brs, 1H)
Chiral HPLC (Method D) R_t 8.4 min, 92% ee
tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c]pyridine-6(2H)-carboxylate (6a(i)) (62.6 g, 259 mmol, 92% ee) suspended in MTBE (778 mL) was heated up to reflux at 56 ℃ before n-heptane (518 mL) was added. The mixture was heated up to reflux again at 65 ℃. It was kept stirring at reflux for 3 h before it was allowed to cool down to 0 ℃. The precipitate was collected by filtration, rinsed with a 3:2 mixture of MTBE/n-heptane (230 mL), and dried over N₂ purge to give the compound 6a(i) (57.2 g, 91% recovery, 99% ee).
Chiral HPLC (Method D) R_t 8.4 min, 99% ee

X-ray diffraction data for a single crystal of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate (6a(i))
The structure of tert-butyl (3aS,7aR)-2-oxohexahydrofuro[2,3-c] pyridine-6(2H)-carboxylate 6a(i) obtained by X-ray diffraction as described below, is illustrated in Figure 1.
Experimental. Single colourless block-shaped crystals of compound 6a(i) were used. A suitable crystal (0.25×0.22×0.14) was selected and mounted on a nylon loop with paratone oil on a Bruker APEX-II CCD diffractometer. The crystal was kept at T = 173(2) K during data collection. Using Olex2 (Dolomanov et al., 2009), the structure was solved with the ShelXS (Sheldrick, 2008) structure solution program, using the Direct Methods solution method. The model was refined with version 2014/6 of XL (Sheldrick, 2008) using Least Squares minimisation.

Crystal Data. C₁₂H₁₉NO₄, M_r = 241.28, orthorhombic, P2₁2₁2₁ (No. 19), a= 8.6775(2)Å, b=11.0669(2)Å, c=13.1268(2)Å, α=β=γ= 90^°, V= 1260.61(4)ų, T=173(2)K, Z=4, Z =1, μ(CuK_α)=0.787,9537 reflections measured, 2371 unique (R_int = 0.0324) which were used in all calculations. The final wR₂ was 0.0793 (all data) and R₁ was 0.0305 (I > 2(I)).

Claims (31)

1. A process for the production of compound BB1, or a salt thereof, wherein:
   (a) compound 4 is converted to compound 6a
   

   

   wherein R¹ is a nitrogen protecting group selected from an amide protecting group or an amine protecting group;
   wherein R^1a is an amide protecting group; and
   wherein R² is selected from C₁-C₄ alkyl or benzyl;
   (b) compound 6a is reacted in the presence of a base and a methylating agent to form compound 7a;
   

   

   and
   (c) compound 7a is deprotected to form BB1, or a salt thereof.
   

   
2. A process according to claim 1 wherein,
   when R¹ is an amide protecting group, the N-atom and the R¹ group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide and when R¹ is an amine protecting group, it is selected from benzyl, α-methylbenzyl or para-methoxybenzyl;
   R^1a is an amide protecting group, wherein the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide; and
   R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl.
3. A process according to claim 1, wherein the conversion of compound 4a into compound 6a comprises:
   (a) the asymmetric transfer hydrogenation of compound 4a to form a compound of formula 5a
   

   

   wherein R^1a is an amide protecting group, where the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide;
   and wherein R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl;
   in the presence of a non-tethered Noyori catalyst and a hydrogen donor; and
   (b) reacting compound 5a in the presence of a base to form compound 6a.
   

   
4. A process for the production of compound 5a,
   

   

   wherein R^1a is an amide protecting group, where the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide; and
   wherein R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl;
   by the asymmetric transfer hydrogenation of compound 4a,
   

   

   in the presence of a non-tethered Noyori catalyst and a hydrogen donor.
5. The process of any one of claims 3 or 4 wherein the catalyst has the structure (I)
   

   

   wherein A is methyl or a phenyl ring substituted with one or more of F or C₁-C₄ alkyl and wherein B is a phenyl ring optionally substituted with one or more C₁-C₄ alkyl.
6. The process of claim 5 wherein group A is selected from the group consisting of
   

   

   .
7. The process of claim 5 or claim 6 where group B is selected from the group consisting of
   

   

   .
8. The process of any one of claims 5 to 7 wherein the catalyst is selected from one or more of RuCl(ρ-cymene)[(S,S)-Ts-DPEN], RuCl(ρ-cymene)[(S,S)-Fs-DPEN] or RuCl(mesitylene)[(S,S)-Ts-DPEN].
9. The process of any one of claims 5 to 7 wherein the catalyst is RuCl(ρ-cymene)[(S,S)-Fs-DPEN].
10. The process of any one of claims 5 to 9, wherein the catalyst is provided in an amount of from 0.005 to 0.1 mol equivalents.
11. The process of any one of claims 3 to 10, wherein the process is carried out at a temperature of from 20 to 50 ℃.
12. The process of any one of claims 3 to 11 wherein the hydrogen donor is selected from formic acid and triethylamine or an alcohol selected from EtOH or IPA and sodium formate.
13. The process of claim 12 wherein the hydrogen donor is formic acid and triethylamine and the ratio of formic acid to triethylamine is from 5:2 to 1:2.
14. The process of any one of claims 3 to 13, wherein R^1a is an amide protecting group, where the N-atom and the R^1a group form a t-butyl carbamate group and R² is ethyl.
15. A process for the formation of compound 5a(i) by the asymmetric transfer hydrogenation of compound 4a(i).
    

    
16. The process of any one of claims 3 to 15 wherein the process is carried out in the presence of an organic co-solvent which is selected from, PhMe, DCM, DMF, MTBE, THF, 1,4-dioxane, EtOAc, MeCN or IPA.
17. The process of claim 3 wherein compound 5a is prepared according to the process of any one of claims 13 and 14.
18. The process of any one of claim 3 or claims 5 to 17 wherein compound 6a is recrystallised to produce a compound having an ee greater than 95%.
19. The process according to claim 1 or claim 2, wherein the conversion of compound 4 to compound 6a comprises:
    (a) converting a compound 4b wherein the R^1b group is a benzyl group or a substituted benzyl group such as α-methylbenzyl or para-methoxybenzyl, and R² is selected from methyl, ethyl, isopropyl, t-butyl or benzyl, to a compound 6b;
    

    

    (b) forming a chiral salt of compound 6b;
    (c) resolving the chiral salt of compound 6b by recrystallisation and then desalting the chiral salt; and
    (d) converting compound 6b to compound 6a
    

    

    wherein R^1a is an amide protecting group, where the N-atom and the R^1a group form a group selected from t-butyl carbamate, benzyl carbamate, 9-fluorenylmethyl carbamate, acetamide or trifluoroacetamide.
20. The process of claim 19 wherein compound 6a is recrystallised to have an ee greater than 95%.
21. A process for the production of a compound C,
    

    

    said process comprising reaction of a compound of formula B
    

    

    with a compound of formula
    

    

    in the presence of a PdCl₂(PPh₃)₂ catalyst, a solvent and a base, at a temperature of from 40 to 100 ℃.
22. A process for the production of a compound C, according to claim 21 wherein the reaction of is in the presence of a PdCl₂(PPh₃)₂ catalyst, THF and Na₂CO₃, at a temperature of from 40 to 60 ℃.
23. A process for the formation of a compound of formula D,
    

    

    said process comprising contacting compound C as produced according to any one of claims 21 to 22 with a base selected from LiOH, KOH or NaOH.
24. A process for the formation of compound X, said process comprising reacting a compound of formula BB1 or a salt thereof as produced according to any one of claims 1 to 3, claims 5 to 14, or claims 16 to 20, with a compound of formula D to form compound E and the subsequent deprotection of compound E to form compound X.
    

    
25. A process for the formation of compound X, said process comprising reacting a compound of formula BB1 or a salt thereof with a compound of formula D as produced according to claim 23 to form compound E and the subsequent deprotection of compound E to form compound X.
    

    
26. A process for the formation of compound X, said process comprising reacting a compound of formula BB1 or a salt thereof as produced according to any claims 1 to 3, claims 5 to 14, or claims 16 to 20, with a compound of formula D as produced according to claim 23 to form compound E and the subsequent deprotection of compound E to form compound X.
    

    
27. A compound of formula 5a(i)
    

    
28. A compound of formula 5a(i) according to claim 26, having an ee of greater than 40 %.
29. A compound of formula 6a(i) having an ee of greater than 90%.
    

    
30. A compound of formula 7a(i).
    

    
31. A compound of formula 7a(i) according to claim 29, having an ee of greater than 90 %.
    
    

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