EP3810623A1

EP3810623A1 - A novel process for the preparation of sglt-2 inhibitors

Info

Publication number: EP3810623A1
Application number: EP19742290.0A
Authority: EP
Inventors: V. Theocharis KOFTIS; Thanos Andreou; Ioanna Georgopoulou; Efstratios Neokosmidis
Original assignee: Pharmathen SA
Current assignee: Pharmathen SA
Priority date: 2018-06-25
Filing date: 2019-06-21
Publication date: 2021-04-28
Also published as: WO2020001812A1

Abstract

The present invention relates to a novel process for the preparation of SGLT-2 inhibitors via addition of a hydroxymethylene group in an open chain intermediate, readily accessible from D-glucose.

Description

A NOVEL PROCESS FOR THE PREPARATION OF SGLT-2 INHIBITORS

TECHNICAL FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of SGLT-2 inhibitors. Such compounds have attracted a continuously growing interest, owed to their use in the treatment of diabetes.

BACKGROUND OF THE INVENTION

SGLT-2 inhibitors are a new and promising class of drugs utilized in diabetes treatment. Their distinguishing feature from previously known antidiabetic drugs is the biological pathway they are involved into. In particular, the sodium glucose transport proteins regulate the reabsorption of glucose from the nephron. Inhibition of SGLT proteins results in the excretion of glucose in the urine, leading in a reduction of blood glucose levels.

As a result, a considerable amount of effort and research has been focused on the discovery and synthesis of compounds possessing such inhibiting properties.

Patent application W02010023594A1 discloses the synthesis of such a SGLT-2 inhibitor, Ertugliflozin (Formula la), according to the scheme shown below. The starting material is prepared from D-glucose in 4 steps with 57% yield.

Scheme 1

This process features the introduction of the required hydroxymethyl group at the first steps of the synthetic route with the use of formaldehyde. The two-step transformation suffers from low yield (53%). The given process also employs the use of reagents unsuitable for industrial production, such as n-butyl lithium and trimethylaluminium. The process further requires the deprotection of three benzyl groups via catalytic hydrogenation with precious metals, raising the overall cost of the process. In addition, the method is hindered by the epimerization which occurs under the influence of n-butyl lithium, making tedious purifications unavoidable.

Another process for preparing compound of formula I is disclosed in Bernhardson D. et al 2014, “Development of an Early- Phase Bulk Enabling Route to Sodium- Dependent Glucose Cotransporter 2 Inhibitor Ertugliflozin” OPRD 18(57):57-65. This process alters the protection group strategy while maintaining a similar technique for inserting the extra hydroxymethyl group required. This strategy, although simple and attractive, has proved to be difficult to apply either to ring-closed structures or to open-chain structures (Bowles P. et al 2014, Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin. OPRD 2014 18(57):66- 81). As evident in scheme 2, the proposed route of synthesis has not solved the problem of low yield in the critical step of the hydroxymethylene group introduction, namely only 38% even under optimized conditions.

Scheme 2

Patent application WO2014159151A1 discloses another process for the preparation of compound of formula I. The starting material is tetra-O-benzyl-D-glucose.

Changing the approach, an open-chain intermediate is employed as substrate for the introduction of the hydroxymethyl group, since it proved difficult to do so in ring- closed derivatives with acceptable yields. The reaction yield improved to about 75% (as provided for individual step). However, this was only achieved with the replacement of p-formaldehyde with more expensive Grignard reagents, namely those derived from chloromethyldimethylisopropoxysilane or iodomethylpivalate. The first of those two requires one further step to liberate the diol, namely Tamao-Fleming oxidation conditions. It is disclosed in the cited literature that the presence of the amide limits the available options to appropriately chemo selective reagents.

Scheme 3

This process not only employs expensive reagents for the hydroxymethylene group introduction, but it further uses benzyl protecting groups, which requires the use of palladium catalyst. Overall this route suffers from the use of costly reagents.

In view of the above disadvantages there is still a need for a synthetic process towards compound of formula I, which is both efficient and more cost-effective in terms of reagents used therein. SUMMARY OF THE INVENTION

The present invention discloses a novel process for the preparation of compound of Formula I, comprising the introduction of a hydroxymethyl group into compound of formula II, thereby producing compound of formula III. Ar represents the moiety shown below, protecting groups PG1 and PG2 together form a first cyclic protecting group and protecting groups PG3 and PG4 form a second cyclic protecting group.

Scheme 4

General Definitions The term“hydroxyl protecting groups” refers to protecting groups suitable for the protection of the hydroxyl moiety, which is then defined as“protected hydroxyl group”. The definition includes both simple and cyclic protecting groups. Such groups are known in the art and are exemplified such as in Greene’s Protective Groups on Organic Synthesis 4^th Edition, John Wiley & Son, Peter G. M. Wuts, Theodora W. Greene, Print ISBN: 9780471697541. Preferred protecting groups are trltyl, benzyl, naphthyl, methoxybenzyl, p-nitrobenzyl, benzoyl, a substituted benzoyl, acetyl, a substituted acetyl, pivaloyl,trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, thexyldimethylsilyl, allyl, methoxymethyl, (2-methoxyethoxy)methyl, tetrahydropyranyl. Preferred cyclic hydroxyl protecting groups are ethylidene, isopropylidene, pentylidene, hexylidene, benzyline, p- methoxybenzylidene, naphthylidene, 4-phenylbenzylidene, methoxymethylene, ethoxymethylene, cyclic carbonate, l,3-(l,l,3,3-tetraisopropyl)disiloxanediyl, di-tert- butylsilylenediyl. Stereoisomers

Some compounds prepared according to the present invention exist as stereoisomers. The scope of the present invention involves the preparation of such compounds either as mixtures of stereoisomers, or as single stereoisomers. Optimal purification according to standard techniques, known to the skilled person, can afford each stereoisomer in a pure form, whenever this is preferred.

Bases

“Base” when used herein includes hydroxides or alkoxides, hydrides, or compounds such as amine and its derivatives, that accept protons in water or solvent. Thus, exemplary bases include, but are not limited to, alkali metal hydroxides and alkoxides (i.e., MOR, wherein M is an alkali metal such as potassium, lithium, or sodium, and R is hydrogen or alkyl, as defined above, more preferably where R is straight or branched chain Cl -5 alkyl, thus including, without limitation, potassium hydroxide, potassium tert-butoxide, potassium tert-pentoxide, sodium hydroxide, sodium tert- butoxide, lithium hydroxide, etc.); other hydroxides such as magnesium hydroxide (Mg(OH)₂) or calcium hydroxide (Ca(OH)₂), barium hydroxide (Ba(OH)₂); alkali metal hydrides (i.e., MH, wherein M is as defined above, thus including, without limitation, sodium, potassium, and lithium hydrides); alkylated disilazides, such as, for example, potassium hexamethyldisilazide and lithium hexamethyldisilazide; carbonates such as potassium carbonate (K₂C0₃), sodium carbonate (Na₂C0₃), potassium bicarbonate (KHC0₃), and sodium bicarbonate (NaHC0₃), alkyl ammonium hydroxides such as tetrabutyl ammonium hydroxide (TBAH) and so forth. Aqueous bases include metal hydroxides, for example, hydroxides of Group l/Group 2 metals such as Li, Na, K, Mg, Ca, etc. (e.g., aqueous LiOH, NaOH, KOH, etc.), alkyl ammonium hydroxides, and aqueous carbonates. Non-aqueous bases include but not limited to, amines and their derivatives, for example, trialkyl amine (e.g., Et₃N, diisopropylethyl amine, etc.), and aromatic amine (e.g., Ph-NH₂, PhN(Me)H, etc.); alkali metal alkoxides; alkali metal hydrides; alkylated disilazides; and non-aqueous carbonates. A“strong base” is a base that is completely dissociated in an aqueous solution.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention discloses a novel process for the preparation of compound of formula I, comprising: a) conversion of compound of formula II to compound of formula III, wherein Ar represents the moiety shown below, protecting groups PG1 and PG2 together form a first cyclic protecting group and protecting groups PG3 and PG4 together form a second cyclic protecting group, said cyclic protecting groups selected from cyclic acetals, cyclic ketals, cyclic ortho esters, cyclic carbonates and silyl derivatives and PG5 is a hydroxyl protecting group selected from alkyl and aryl ethers, silyl ethers, esters, carbonates, sulfonates; and

b) conversion of compound of formula III to compound of formula I.

The conversion of compound of formula II to compound of formula III is achieved by the addition of a hydroxymethylene group, followed by the reduction of the carbon which bears the aldehyde. The inventors surprisingly found that this reaction sequence can successfully be performed through the open-chain intermediate II, despite the sterically hindered nature of the substrate.

This conversion may conveniently be achieved in the presence of a formaldehyde source. The source of formaldehyde may be any source available to the skilled person either commercially or by using his common general knowledge and standard laboratory techniques. For example, p-formaldehyde or a solution of aldehyde, such as aqueous solution, may be used. The amount of formaldehyde should be excessive. Excess of formaldehyde promotes the reduction of the aldehyde carbon which leads to compound of formula III, in a Cannizzaro-type fashion.

The skilled person may realize the conversion of compound of formula II to compound of formula III by using other reagents as well. Any reagent that can deliver an equivalent of the hydroxymethylene group and bring about an aldol condensation may be suitable. Likewise, the subsequent reduction of the aldehyde carbon may be realized by creating appropriate Cannizzaro-type conditions.

The temperature of the reaction may be such that drives the reaction to completion. Preferably the reaction is performed at a temperature range from 25 °C to the boiling point of the solvent used in the reaction. More preferably, the reaction is performed at a temperature between 40 and 100 °C.

The reaction is performed in polar protic solvents, such as methanol and by using strong bases.

Compound of formula II may be isolated pursuant to standard techniques or it may be prepared shortly before and used without isolation in the reaction towards compound III. In a preferred embodiment compound II is not isolated.

Each pair of protecting groups PG1/PG2 and PG3/PG4 represents a cyclic protecting group. Accordingly, there are two cyclic protecting groups which are protecting 4 hydroxyl groups. Preferably, the cyclic protecting groups are selected from: ethylidene, isopropylidene, pentylidene, hexylidene, benzyline, p- methoxybenzylidene, naphthylidene, 4-phenylbenzylidene, methoxymethylene, ethoxymethylene, cyclic carbonate, l,3-(l,l,3,3-tetraisopropyl)disiloxanediyl, di-tert- butylsilylenediyl. More preferably, the cyclic protecting groups are selected from: ethylidene, isopropylidene, pentylidene, hexylidene, benzyline, p- methoxybenzylidene, 4-phenylbenzylidene. Even more preferably, the cyclic protecting groups are isopropylidene groups. According to a further embodiment, the present invention discloses a process for the preparation of compound of formula I as described above, wherein step b comprises: i) selectively deprotecting PG5 from compound of formula III to form compound of formula IV ;

ii) selectively oxidizing the secondary hydroxyl group of compound of formula IV to form compound of formula V ;

iii) deprotecting compound of formula V and effecting cyclization to form compound of formula I.

Scheme 5

The deprotection of protecting group PG5 according to step b-i may be performed in accordance with the nature of the group. Protecting group PG5 should be selected such that it can be removed in the presence of cyclic groups PG1/PG2 and PG3/PG4. Preferred hydroxyl protecting groups are alkyl and aryl ethers, silyl ethers, esters, carbonates, sulfonates. Preferably, protecting group PG5 is a silyl protecting group. Appropriate deprotection techniques are well known to the skilled person and can be found in textbooks as mentioned above. The conversion of compound of formula IV to compound of formula V according to step b-ii is performed by selective oxidation of the secondary (benzylic) hydroxyl group in the presence of two unprotected primary hydroxyls groups. A number of available techniques are disclosed in textbooks, such as March’s Advanced Organic Chemistry, M. B. Smith & J. March, John Wiley & Sons, 6^th edition, ISBN 13:978-0- 471-72091-1, Chapter 19-3.

Preferably, the selective oxidation is performed with manganese (II) oxide. The solvents of the reaction can be aprotic polar solvents, such as dichloromethane, tetrahydrofuran, 2-methyl-tetrahydrofuran, ethyl acetate, acetone, N,N- dimethylformamide, acetonitrile, dimethyl sulfoxide, or non-polar solvents, such as pentane, hexane, cyclohexane, benzene, toluene, chloroform, diethyl ether, chloroform, l,4-dioxane . Preferable is methylene chloride.

In a preferred embodiment excess of manganese (II) oxide is used, most preferably 10 equivalents.

The deprotection of protecting groups PG1-PG4 according to step b-iii may be performed in accordance with the nature of the group. The conditions employed for deprotection may also bring about the simultaneous cyclization of the deprotected intermediate towards compound of formula I. For example, when acidic conditions are used, this may lead to the deprotection of acid-labile protecting groups with simultaneous cyclization. Other conditions, suitable for the deprotection of protecting groups PG1-PG4 may also be employed, followed by the use of an appropriate reagent to promote the cyclization, as exemplified in prior art.

Scheme 6

Preferable are acidic conditions. Suitable reagents in this respect are trifluoroacetic acid, acetic acid, pyridinium p-toluenesulfonate (PPTS), hydrogen halides and their solutions, preferable, hydrogen chloride and its solutions, sulfuric acid and its solutions, acidic resins such as Amberlyst and Dowex resins. Suitable conditions for this step can be also found in widely used textbooks, such as Greene’s Protective Groups on Organic Synthesis 4^th Edition, John Wiley & Son, Peter G. M. Wuts, Theodora W. Greene, Print ISBN: 9780471697541.

According to still another embodiment, the present invention discloses a process for the preparation of compound of formula I as described in the previous embodiments, further comprising preparing compound of formula II by oxidation of compound of formula VI. Several methods for the oxidation of primary hydroxyl groups to aldehydes are available in prior art and exemplified in common textbooks (March’s Advanced Organic Chemistry, M. B. Smith & J. March, John Wiley & Sons, 6th edition, ISBN 13:978-0-471-72091-1, Chapter 19-3). Compound of formula II may be isolated or directly used in the next step of the process, as described in previous embodiments.

Preferably, the oxidation is performed under Swem conditions. Typical Swern conditions involve the use of dimethysulfoxide and oxalyl chloride and are well described in textbooks as mentioned above.

The skilled person may realize this oxidation by other means as well. The only important aspect is that the oxidation should not go beyond the aldehyde, i.e. the formation of carboxylix acid should be avoided.

Scheme 7 According to a further embodiment of the present invention, there is disclosed a process for the preparation of compound of formula I as described in the previous embodiments, further comprising preparation of compound of formula VI according to the following scheme.

Scheme 8

Compound of formula VIII is prepared from compound of formula VII by reaction with ArMgBr under standard Grigrard conditions. This reaction creates a new stereocenter and the product of the reaction may be a mixture of two diastereomers with respect to this stereocenter. Both of them, however, are equally useful within the process described herein, as this hydroxyl group is intended to be oxidized in the last steps of the process (see scheme 5). Therefore no separation of the diastereomers is required.

The benzylic hydroxyl group of compound of formula VIII is protected with protecting group PG5 to provide compound of formula IX under standard techniques available in textbook mentioned above. The nature of protecting group PG5 has been discussed above. It should be added that protecting group PG5 should be stable enough under conditions that remove protecting group PG6. Preferably, protecting group PG5 is a silyl protecting group. Thereafter, deprotection from PG6, performed according to the nature of the protecting group, converts compound of formula IX to compound of formula VI. Protecting group PG6 should be selected such that it can be removed in the presence of protecting groups PG1/PG2, PG3/PG4 and PG5. Preferably PG5 is an ester protecting group. According to yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula V, comprising the conversion of compound of formula II to compound of formula III as described in the previous embodiments.

According to a further embodiment of the present invention, there is provided a process for the preparation of compound of formula V as described above, further comprising conversion of compound of formula III to compound of formula IV and conversion of the latter to compound of formula V as described in previous embodiments.

According to another embodiment of the present invention, there is provided a process for the preparation of compound of formula IV, comprising the conversion of compound of formula II to compound of formula III as described in the previous embodiments.

According to a further embodiment of the present invention, there is provided a process for the preparation of compound of formula IV as described above, further comprising conversion of compound of formula III to compound of formula IV as described in previous embodiments.

According to yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula III, comprising the conversion of compound of formula II to compound of formula III as described in the previous embodiments.

According to still another embodiment of the present invention, there are provided novel compounds of formulae II, III, IV and V.

In a preferred embodiment of the present invention, protecting groups PG1/PG2 and PG3/PG4 are isopropylidene protecting groups and compounds of formulae III, IV and V are compounds of formulae Ilia’, IVa, Va.

In a more preferred embodiment of the present invention, protecting groups PG1/PG2 and PG3/PG4 are isopropylidene protecting groups and protecting group PG5 is a silyl protecting group. More preferably, PG5 is a TBS group and compounds of formulae II, III are respectively Ila and Ilia.

According to another embodiment of the present invention, there is provided the use of compounds of formulae II, Ila, Ila’, III, Ilia, Ilia’, IV, IVa, V or Va for the preparation of compound of formula I. In a preferred embodiment, there is provided the use of compounds of formulae III, Ilia, Ilia’, IV, IVa, V or Va for the preparation of compound of formula I.

EXAMPLES

Unless otherwise noted, the materials used in the examples are obtained from readily available commercial sources or synthesized by standard methods well known to the person skilled in the art.

Compound 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene can be prepared according to US20020137903A1. EXAMPLE 1: Preparation of 2,3:4,5-bis-G-( 1 -methylethylidene)-, diethyl dithioacetal D-Glucose, 6-benzoate Step a

D-Glucose diethyl dithioacetal (850 mg; 2.97 mmol) was dissolved in pyridine (30 ml) in a 100 ml round bottom flask and the mixture was cooled at 0 °C. Benzoyl bromide (420 mg; 2.97 mmol, leq) was then added and the resulting mixture was stirred for 3 h at 0 °C. Solvent was evaporated off and the residue was chromatographed on a silica gel column with PS/EA (5:1) as eluent to give 1 g of diethyl dithioacetal D-Glucose 6-benzoate as white crystals (86%). M.p. 114 °C, [a] _D = +47.2 (c 1.8, CHCl₃). IR (neat): 3681, 3479, 3175, 1697, 1454, 1333, 1265, 10,80,

1045 cm^-1. 1H-NMR (500 MHz, CDCl₃) d 8.07 (d, J = 7.7 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 4.67 (d, J = 11.3 Hz, 1H), 4.58 - 4.50 (m, 1H), 4.38 (s, 1H), 4.11 (d, J = 7.9 Hz, 2H), 3.83 (d, J = 5.6 Hz, 1H), 3.68 (d, J = 8.0 Hz, 1H), 2.81 - 2.61 (m, 5H), 1.28 (dt, J = 11.4, 5.6 Hz, 6H). ¹³C NMR (126 MHz, CDCl₃) d 167.22, 133.21, 129.76, 128.40, 75.03, 73.59, 70.54, 68.05, 66.65, 55.29, 25.89,

23.57, 14.61, 14.42.

Step b

To a solution of diethyl dithioacetal D-Glucose 6-benzoate (935 mg; 2.31 mmol) in acetone (23 ml), DMP (2.64 ml) and cone. H₂S0₄ (0.04 ml) were added and the mixture was stirred for 30 min at ambient temperature. The mixture was then placed in an ice bath and a few drops of Et3N and H20 (20 ml) were added before extracted with DCM (3 x 20 ml). The combined organic layers were dried over Na₂S0₄, the solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column with PS/EA (5:1) as eluent to give 850 mg of 2,3:4,5-bis-(9- isopropylidene-diethyl dithioacetal D-Glucose 6-benzoate as a colorless gel (76%). [a]D = +51.3 (c 1.8, CHCl₃). IR (neat) 3064, 2985, 1697, 1727, 1453, 1274, 1164 cm \ 1H NMR (500 MHz, CDCl₃) d 8.07 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H), 4.67 (d, J = 4.9 Hz, 1H), 4.61 - 4.54 (m, 2H), 4.48 (d, J = 6,8 Hz, 1H), 4.38 (dd, J = 7.8, 5.5 Hz, 1H), 4.20 (d, J = 7.8 Hz, 1H), 3.92 (d, J = 5.5 Hz, 1H), 2.83 - 2.66 (m, 4H), 1.53 (s, 3H), 1.41 (s, 9H), 1.26 (td, J = 7.4, 2.1 Hz, 6H). ¹³C NMR (500 MHz, CDCl₃) d 166.33, 129.76, 128.45, 110.02, 109.27, 79.71, 77.63, 75.21, 75.11, 64.40, 52.81, 27.37, 27.18, 26.98, 26.80, 26.69, 25.45, 25.29, 14.47, 14.28, 14.15.

EXAMPLE 2: Preparation of compound of formula Villa

2,3:4,5-bis-(9-isopropylidene-diethyl dithioacetal D-Glucose 6-benzoate (800 mg; 1.65 mmol) was dissolved in acetone (12 ml) and the mixture was cooled to -78 °C. NBS (640 mg, 3.3 mmol) was then added and the mixture was stirred for 30 min at the same temperature. Then, saturated aqueous NH₄Cl (10 ml) was added followed by extractions with DCM (3 x 15 ml). The combined organic layers were dried over Na₂S0₄, the solvent was evaporated off and the residue (compound of formula Vila) was filtered through a thin layer of silica gel and used in the next step as it was.

In a 10 ml round bottom flask, 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene (1.12 g; 3.46 mmol) was dissolved in dry THF (7 ml) and then Mg turns (83 mg; 3.46 mmol) and some granules I₂ were added. The mixture was refluxed for lh, and after discoloration of the mixture and consumption of all magnesium, the mixture was left at ambient temperature for 30 min. Subsequently, the organomagnesium compound prepared was added dropwise to compound of formula Vila (540 mg; 1.42 mmol) dissolved in dry THF (3 ml) at 0 °C. The mixture was stirred at 0 °C for another 1 h and then allowed to stir for 24 h at ambient temperature. The mixture was then placed in an ice bath and saturated aqueous NH₄Cl (10 ml) was added before extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na₂S0₄, the solvent was evaporated off and the residue was chromatographed on a silica gel column with PS/E A (12:1) as eluent to give 530 mg of a ca. 1: 1 mixture of diastereomeric mixture of compounds of formula Villa (58%) as a yellowish gel, which was used in the next step as it was.

EXAMPLE 3: Preparation of compound of formula IXa

The diastereomeric mixture of compounds of formula Villa (400 mg; 0,65 mmol) was dissolved in dry DCM (10 ml) in a dry 25 ml round-bottomed flask, and cooled at 0 °C. Then 2,6-lutidine (140 mg; 1.3 mmol, 2 eq) was added dropwise and immediately after TBSOTf (260 mg; 0.98 mmol, 1.5 eq) and catalytic amount of DMAP (5 mg). The mixture was stirred at 0 °C for 1 h and then allowed to stir for another 30 min at ambient temperature. The mixture was then placed in an ice bath and saturated aqueous NH4C1 (10 ml) was added before extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na2S04, the solvent was evaporated off and the residue was chromatographed on a silica gel column with PS/EA (15:1) as eluent to give 430 mg of a ca. 1:1 diastereomeric mixture of compounds of formula IXa as a colorless gel (92%). IR (neat) 3064, 3033, 1723, 1613, 1380, 1314 cm^-1. 1H NMR (500 MHz, CDCl₃) d 8.06 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 7.8 Hz, 2H), 7.56 (t, J = 7.4 Hz, 2H), 7.43 (dd, J = 16.8, 8.0 Hz, 4H), 7.30 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.17 - 7.09 (m, 4H), 7.04 (t, J = 8.6 Hz, 4H), 6.78 (dd, J = 11.3, 8.6 Hz, 4H), 4.86 (d, J = 4.9 Hz, 1H), 4.75 (s, 1H), 4.61 (dd, J = 11.4, 5.2 Hz, 1H), 4.48 - 4.30 (m, 5H), 4.25 (dd, J = 8.3, 4.9 Hz, 1H), 4.12 (d, J = 2.4 Hz, 2H), 4.05 - 3.90 (m, 9H), 3.86 (q, J = 6.9 Hz, 2H), 3.66 (dd, J = 12.0, 7.6 Hz, 2H), 1.49 (s, 3H), 1.47 (s, 3H), 1.38 - 1.30 (m, 16H), 1.21 (t, J = 4.9 Hz, 4H), 1.02 (s, 9H), 0.85 (s, 9H), 0.82 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H), -0.10 (s, 3H), -0.20 (s, 3H). ¹³C NMR (126 MHz, CDC13) d 166.27, 157.42, 140.20, 138.91, 138.57, 133.22, 132.98, 131.26, 130.21, 129.25, 129.01, 128.78, 128.32, 126.40, 125.63, 114.46, 109.61, 109.38, 108.81, 81.15, 79.49, 75.05, 74.95, 64.46, 63.33, 38.32, 27.43, 26.98, 26.75, 25.79, 25.30, 25.10, 20.37, 18.17, 14.83, -4.69, -4.71, -4.95, -5.09. MS: m/z 747 [M+Na]+). EXAMPLE 4: Preparation of compound of formula Via

The mixture of diastereomeric compounds of formula IXa (400 mg; 0.55 mmol) was dissolved in methanol in a 25 ml round bottom flask, and then K₂C0₃ (76 mg; 0.55 mmol) was added and the mixture was stirred for 12 h at ambient temperature. The mixture was then placed in an ice bath and saturated aqueous NH₄Cl (10 ml) was added before extraction with DCM (3 x 10 mL). The combined organic layers were dried over Na₂S0₄, solvent was evaporated off and the residue was chromatographed on a silica gel column with PS/E A (10: 1) as eluent to give 270 mg of a ca. 1: 1 diastereomeric mixture of compounds of formula Via as a colorless gel (78%). IR (neat) 3520, 2986, 1614, 1394, 1258 cm^-1. 1H NMR (500 MHz, CDCl₃) d 7.32 (dd, J = 8.1, 1.8 Hz, 2H), 7.12 (dd, J = 12.1, 6.1 Hz, 4H), 7.06 (dd, J = 8.7, 2.5 Hz, 4H), 6.81 (d, J = 8.6 Hz, 4H), 4.82 (d, J = 5.0 Hz, 1H), 4.78 (d, J = 4.8 Hz, 1H), 4.28 (dd, J = 8.2, 5.0 Hz, 1H), 4.21 - 4.13 (m, 2H), 4.01 -3.90 (m, 8H), 3.77-3.71 (m, 2H), 3.69 (d, J = 8.3 Hz, 1H), 3.64 (dd, J = 11.9, 5.0 Hz, 1H), 3.59 - 3.54 (m, 2H), 3.50 (d, J =

6.5 Hz, 1H), 1.46 (s, 3H), 1.44 - 1.36 (m, 16H), 1.26 (s, 3H), 1.13 (s, 6H), 0.84 (s, 6H), 0.83 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H), -0.10 (s, 3H), -0.17 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) d 157.45, 139.96, 139.03, 138.63, 133.29, 131.30, 129.79, 128.87, 126.49, 114.51, 109.75, 108.33, 108.11, 81.38, 80.02, 77.48, 77.43, 75.31, 75.26, 74.93, 74. 82, 74.68, 74.24, 74.17, 74.10, 74.02, 63.38, 61.68, 38.27, 27.07, 26.83,

26.43, 25.77, 25.38, 18.17, 14.85 , -4.70 , -490, -5.00. MS: m/z 643 [M+Na]⁺).

EXAMPLE 5: Preparation of compound of formula Ilia

Oxalyl chloride (0.095 ml; 1.14 mmol) was dissolved in dry DCM (2 ml) in a dry 25 ml round-bottomed flask, and cooled at -65 °C. In another dry flask, dry DMSO (0.1 ml) was dissolved in dry DCM( 0.6 ml) and the DMSO solution was added dropwise to the solution of oxalyl chloride at -65 °C, followed by stirring at this temperature for 10 min. Then, the mixture of compounds of formula Via (350 mg; 0.57 mmol) dissolved in dry DCM (1.3 ml) was added drop wise to the above mixture at -65 °C and the resulting mixture was stirred at the same temperature for 20 min before the slow addition of dry Et₃N (0.75 ml). Stirring was continued for another 30 min at -40 °C, and then the mixture was left for an additional 30 minutes at ambient temperature. Next, saturated aqueous NH₄Cl (10 ml) was added before extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na₂S0₄, solvent was evaporated off and the residue (compound of formula Ila) was used without further purification. This product was dissolved in methanol (15 ml), aqueous formaldehyde (2.3 ml) was added and the resulting mixture was heated to reflux. While kept refluxing an amount of K₂C0₃ (30 mg) was added every time at 20 min intervals until TLC showed complete consumption (about three hours). Then, the mixture was cooled to room temperature and saturated aqueous NH₄Cl (10 ml) was added, followed by extraction with DCM (3 x 15 ml). The combined organic layers were dried over Na₂S0₄, solvent was evaporated off and the residue was chromatographed on a silica gel column with PS/EA (5:1) as eluent to give 270 mg of a ca 1:1 diastereomeric mixture of compounds of formula Ilia as a colorless gel (73%). IR (neat) 3534, 2935, 2247, 1613, 1411, 1299 cm^-1. 1H NMR (500 MHz, CDCl₃) d 7.32 (d, J = 8.57 Hz, 2H), 7.13 (m, 4H), 7.09 (2 d, J = 8.6 Hz, 4H), 6.84 - 6.78 (d, J = 8.6 Hz, 4H), 4.88 - 4.82 (m, 2H), 4.37 (dd, J = 8.0, 5.0 Hz, 1H), 4.33 (d, J = 7.7 Hz, 1H), 4.27 (dd, J = 7.7, 4.2 Hz, 1H), 4.07 (d, J = 8 Hz, 1H), 4.05 - 3.96 (m, 10H), 3.89 (d, J = 8.0 Hz, 1H), 3.72 (d, J = 12.1 Hz, 1H), 3.68 - 3.62 (m, 2H), 3.53 (s, 2H), 3.48 (d, J = 5.3 Hz, 1H), 3.41 - 3.34 (m, 3H), 3.21 (s, 1H), 1.42 (m, 6H), 1.37 (s, 3H), 1.27 (s, 3H), 1.16 (s, 3H), 1.03 (s, 3H), 0.84 (s, 18H), 0.06 (s, 3H), 0.03 (s, 3H), -0.10 (s, 3H), -0.16 (s, 3H). ¹³CNMR : ¹³C NMR (126 MHz, CDCl₃) d 157.44, 139.64, 139.20, 138.74, 138.31, 133.42, 133.21, 131.22, 129.92, 129.70, 129.23, 128.87, 128.65, 126.53, 125.31, 114.50, 110.00, 109.80, 107.78, 107.33, 82.75, 81.62, 80.24, 76.58, 76.46, 74.14, 73.68, 73.34, 64.66, 63.36, 38.26, 27.77, 27.45, 27.16, 26.56, 26.06, 25.97, 25.94, 25.85, 25.75, 18.19, 18.18, 14.86, -4.77, -5.00. MS: m/z 673 [M+Na]⁺) EXAMPLE 6: Preparation of compound of formula IVa

A solution of 1M TBAF (0.225 ml; 0.225 mmol) was added dropwise to a solution of compound of formula Ilia (100 mg; 0.15 mmol) in dry THF (3 ml) at 0 °C and the resulting mixture was stirred at the same temperature for 2 h. Saturated aqueous NH₄Cl (10 ml) was added, followed by extraction with DCM (3 x 15 ml). The combined organic layers were dried over Na₂S0₄, solvent was evaporated off and the residue was chromatographed on a silica gel column with PS/EA (3:1) as eluent to give 55 mg of a ca. 1:1 diastereomeric mixture of compounds of formula IVa as a colorless gel (68%). IR (neat) 3534, 2835, 2247, 1613, 1355, 1299 cm^-1. 1H NMR (500 MHz, CDCI3) d 7.37 (dd, J = 8.0, 5.8 Hz, 2H), 7.24 - 7.13 (m, 4H), 7.10 (d, J = 8.5 Hz, 4H), 6.82 (d, J = 7.7 Hz, 4H), 5.02 (d, J = 3.7 Hz, 1H), 4.59 (d, J = 6.2 Hz, 1H), 4.44 - 4.34 (m, 2H), 4.24 (d, J = 8.0 Hz, 1H), 4.08 - 3.95 (m, 8H), 3.68 (dd, J = 12.1, 5.6 Hz, 2H), 3.44 (d, J = 7.5 Hz, 1H), 3.39 (dd, J = 11.5, 6.3 Hz, 4H), 3.09 (s, 1H), 2.85 (s, 1H), 1.48 - 1.43 (m, 10H), 1.42 - 1.36 (m, 11H), 1.25 (s, 2H), 1.12 (d, J

= 4.6 Hz, 2H), 1.05 (s, 3H). 13C NMR (126 MHz, CDC13) d 157.49, 157.47, 139.67, 139.59, 137.85, 137.02, 134.34, 133.67, 131.12, 130.99, 129.89, 129.82, 129.77,

129.62, 129.53, 128.07, 126.01, 124.74, 114.50, 110.58, 110.13, 107.73, 107.50,

82.62, 82.58, 81.17, 80.50, 76.26, 75.37, 74.69, 74.49, 72.71, 70.88, 64.60, 64.51, 63.38, 63.25, 38.33, 38.27, 27.76, 27.71, 27.46, 27.40, 26.12, 25.99, 25.97, 14.85.

MS: m/z 559 [M+Na]+).

EXAMPLE 7:

Compound of formula IVa (50 mg; 0.09 mmol) was dissolved in dry DCM (6 ml) in a dry 10 ml round-bottomed flask, Mn0₂ (93 mg; 10 equiv.) was then added at room temperature and the resulting mixture was stirred for 2 d at ambient temperature. Solids were removed by filtration through Celite, solvent was evaporated off and the residue was chromatographed on a silica gel column with PS/EA (1:1) as eluent to give compound of formula Va (35 mg) as a white gel (72%). IR (neat) 3681, 3569, 3200, 1700, 1454, 1312, 1265, 1089, 1045 cm^-1. 1H NMR (500 MHz, CDCl₃) d 7.91 (dd, J = 11.7, 8.2 Hz, 1H), 7.67 (d, J = 11.7 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.10 (d, J= 8.6 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.19 (d, J= 6.7 Hz, 1H), 4.82 (d, J = 6.7 Hz, 1H), 4.12 (s, 2H), 4.09 (d, J = 5.7 Hz, 2H), 4.01 - 3.98 (q, 2H), 3.81 - 3.68 (m, 4H), 3.55 (d, J = 12.1 Hz, 1H), 1.54 (s, 3H), 1.51 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H), 1.33 (s, 3H), 1.26 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) d 195.34, 157.63, 140.33, 139.84, 133.61, 131.96, 130.42, 129.88, 129.80, 128.72, 128.43, 114.58, 111.94, 108.27, 83.34, 79.72, 74.36, 64.33, 63.38, 63.34, 38.35, 29.68, 27.95, 26.69, 26.64, 26.12, 14.85. MS: m/z 557 [M+Na]⁺).

EXAMPLE 8:

Compound of formula Va (35 mg; 0.065 mmol) was added to a mixture of TFA/H₂0 (9:1) (2 ml) and the mixture was stirred for 1 h at ambient temperature. Volatiles were evaporated off under reduced pressure and aqueous 3M NaOH (aq) was added to the residue, followed by extractions with EA (3 x 10 mL). The combined organic layers were dried over Na₂S0₄, solvent was evaporated off and the residue was chromatographed on a silica gel column with DCM/MeOH (9:1) as eluent to give compound of formula I (27 mg) as white crystals (92%). %). [a]_D = +8.0 (c 0.5, MeOH). 1H NMR (500 MHz, MeOD) d 7.44 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.6 Hz, 2H), 4.14 (d, J = 7.5 Hz, 1H), 4.02 (s, 2H), 3.98 (q, J = 7.0 Hz, 2H), 3.83 (d, J = 12.5 Hz, 1H), 3.77 (d, J = 8.4 Hz, 1H), 3.67 (d, J = 12.4 Hz, 1H), 3.64 (d, J = 8.2 Hz, 1H), 3.58 (d, J = 7.5 Hz, 1H), 3.54 (d, J = 7.9 Hz, 1H), 1.35 (t, J = 7.0 Hz, 3H). ¹³C NMR (126 MHz, MeOD) d 157.41, 138.26, 137.11, 133.60, 131.35, 129.40, 129.35, 129.13, 129.02, 128.37, 125.72, 114.02, 108.15, 84.72, 77.93, 76.32, 71.76, 66.51, 63.00, 60.51, 37.85, 13.98. MS: m/z 437 [M+H]⁺).

Claims

1. A process for the preparation of compound of formula I, comprising:

a) conversion of compound of formula II to compound of formula III, wherein Ar represents the moiety shown below, protecting groups PG1 and PG2 together form a first cyclic protecting group and protecting groups PG3 and PG4 together form a second cyclic protecting group, said cyclic protecting groups selected from cyclic acetals, cyclic ketals, cyclic ortho esters, cyclic carbonates and silyl derivatives and PG5 is a hydroxyl protecting group selected from alkyl and aryl ethers, silyl ethers, esters, carbonates, sulfonates; and

b) conversion of compound of formula III to compound of formula I.

2. A process for the preparation of compound of formula I according to claim 1, wherein step a comprises the presence of a formaldehyde source.

3. A process according to claims 1 or 2, wherein step b comprises:

i) selectively deprotecting PG5 from compound of formula III to form compound of formula IV ;

4. A process according to any preceding claim, wherein compound of formula II is prepared by oxidation of compound of formula VI.

5. A process according to claim 4, wherein compound II is not isolated.

6. A process according to any preceding claim, wherein compound of formula VI is prepared according to the following scheme.

7. A process according to any preceding claim, wherein PG1/PG2 and PG3/PG4 are both isopropylidene groups.

8. A process according to claim 7, wherein PG5 is a silyl protecting group.

9. Compound of formula V per se.

10. Compound of formula IV per se.

11. Compound of formula III per se.

12. Compound of formula II per se.

13. Compounds according to claims 9-12, wherein PG1/PG2 and PG3/PG4 are both isopropylidene groups and compounds of formulae II, III, IV and V are compounds of formulae Ila’, Ilia’, IVa, Va.

14. Compounds according to claim 11 or 12, wherein protecting group PG5 is a TBS group and compounds of formulae II, III are compounds of formulae Ila and Ilia.

15. Use of compounds of formulae II, Ila, Ila’, III, Ilia, Ilia’, IV, IVa, V or Va for the preparation of compound of formula I.