WO2003080604A1 - Dihydroisoxazolyl substituted tetrahydrofuran coompounds as intermediates in the preparation of 2-(purin-9-yl) - tetrahydrofuran derivatives - Google Patents

Dihydroisoxazolyl substituted tetrahydrofuran coompounds as intermediates in the preparation of 2-(purin-9-yl) - tetrahydrofuran derivatives Download PDF

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WO2003080604A1
WO2003080604A1 PCT/EP2003/003028 EP0303028W WO03080604A1 WO 2003080604 A1 WO2003080604 A1 WO 2003080604A1 EP 0303028 W EP0303028 W EP 0303028W WO 03080604 A1 WO03080604 A1 WO 03080604A1
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range
integer
ethyl
formula
ethylamino
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PCT/EP2003/003028
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French (fr)
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Charles Edward Wade
Andrew Whitehead
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • isoxazole derived compounds were disclosed in international patent application number PCT/EP99/00503 (publication number: WO 99/38877) which are agonists of the adenosine 2a receptor. These compounds demonstrate anti- inflammatory properties capable of inhibiting leukocyte recruitment and activation, particularly of benefit in the treatment of inflammatory conditions such as asthma and chronic obstructive pulmonary disease (COPD).
  • PCT/EP99/00503 publication number: WO 99/38877
  • COPD chronic obstructive pulmonary disease
  • the method of forming the isoxazole group of the compounds disclosed in WO 99/38877 involves several complicated multi-step processes (detailed on pages 21 and 22 of WO 99/38877) which involve separate alkynylation and ring formation steps.
  • the inventors of the present invention have derived a synthetic route for preparing isoxazole derivatives which has the advantage of avoiding the need for separate alkynylation and ring formation steps, avoids the use of certain hazardous reagents and which utilises a novel intermediate.
  • CH CHCH 3 , isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH 3 , -(CH 2 ) q halogen, -(CH 2 ) h Y(CH 2 )iH, -(CH 2 ) k Z,
  • Z represents -COO(CH 2 ),H or -CON(CH 2 ) m H((CH 2 ) n H);
  • q represents an integer 0 to 3;
  • h represents an integer 0 to 2;
  • i represents an integer 0 to 2 such that h+i is in the range 0 to 3;
  • j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3;
  • k represents 0 or 1 ;
  • I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such thatk+u+v is in the range 0 to 1 ; L 1 and
  • L 2 represent hydroxy or a protected derivative thereof
  • L 3 represent a leaving group
  • Suitable leaving groups L 3 include hydroxyl, alkoxy (eg C ⁇ alkoxy such as methoxy), alkanoyloxy (eg C ⁇ alkanoyloxy such as acetyloxy), halogen (eg. chlorine) and benzoyloxy.
  • the hydroxy groups of L 1 and/or L 2 may for example be protected as alkyl (eg C ⁇ alkyl) ethers (eg as methoxy or ethoxy), alkyl (eg C h alky!) esters (eg as acetyloxy), benzoyl esters and together as acetals (eg C h alky! acetals) (eg as acetonide).
  • alkyl eg C ⁇ alkyl
  • ethers eg as methoxy or ethoxy
  • alkyl (eg C h alky!) esters eg as acetyloxy
  • benzoyl esters eg as acetals (eg C h alky! acetals) (eg as acetonide).
  • Step (i) typically comprises the use of a suitable acidic reagent eg. trifluoroacetic acid (TFA) in the presence of a suitable solvent, eg. water or paratoluene sulphonic acid (pTSA) in the presence of a suitable solvent eg methanol or methanol/water at a suitable temperature, eg. room temperature.
  • a suitable acidic reagent eg. trifluoroacetic acid (TFA) in the presence of a suitable solvent, eg. water or paratoluene sulphonic acid (pTSA) in the presence of a suitable solvent eg methanol or methanol/water at a suitable temperature, eg. room temperature.
  • TSA trifluoroacetic acid
  • pTSA paratoluene sulphonic acid
  • Step (i) may also be performed using camphorsulphonic acid (CSA).
  • CSA camphorsulphonic acid
  • This reagent performs the dehydration process and in general will not remove or alter the groups L 1 , L 2 and L 3 .
  • TFA or pTSA especially pTSA.
  • CH CHCH 3 , isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH 3 , -(CH 2 ) q halogen, -(CH 2 ) h Y(CH 2 )iH, -(CH 2 ) k Z,
  • Y represents O, S or NH(CH 2 )J
  • Z represents -COO(CH 2 ),H or -CON(CH 2 ) m H((CH 2 ) n H)
  • q represents an integer 0 to 3
  • h represents an integer 0 to 2
  • i represents an integer 0 to 2 such that h+i is in the range 0 to 3
  • j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3
  • k represents 0 or 1
  • I represents 1 or 2, such that k+ I is in the range 1 to 2
  • m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2
  • o represents an integer 0 to 3
  • L 1 and L 2 represent hydroxy or a protected derivative thereof
  • L 3 represent a leaving group
  • L 1 and L 2 represent hydroxy protected as the acetonide.
  • L 3 represents a methoxy group.
  • CH CHCH 3 , isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH 3 , -(CH 2 ) q halogen, -(CH 2 ) h Y(CH 2 )iH, -(CH 2 ) k Z,
  • Z represents -COO(CH 2 ),H or -CON(CH 2 ) m H((CH 2 ) n H);
  • q represents an integer 0 to 3;
  • h represents an integer 0 to 2;
  • i represents an integer 0 to 2 such that h+i is in the range 0 to 3;
  • j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3;
  • k represents 0 or 1 ;
  • I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such that k+u+v is in the range 0 to 1 ;
  • K represents a moiety which forms an ester, amide, halide or mixed anhydride derivative of the corresponding carboxylic acid eg -OC ⁇ e alkyl, -N(C-
  • N- pyrrolidinyl N-piperidinyl, N-morpholinyl, N-piperazinyl (optionally substituted by C ⁇ _ 6 alkyl or C ⁇ e alkanoyl), halogen (eg chlorine) or -COC ⁇ _ 6 alkyl (eg acetyl or propionyl); wherein aryl represents phenyl which is optionally substituted eg by one or more C-i.
  • L 1 and L 2 represent hydroxy or a protected derivative thereof
  • L 3 represent a leaving group
  • K represents a moiety which forms an amide derivative of the corresponding carboxylic acid, especially N-morpholinyl.
  • L 1 and L 2 represent a hydroxy group or a protected derivative thereof, and L 3 represents a methoxy group.
  • Step (ii) typically comprises the use of oxime (IV) together with a suitable proton abstracting reagent eg. n-butyl lithium in the presence of a suitable solvent, eg. tetrahydrofuran at a suitable temperature eg. less than 5°C.
  • a suitable proton abstracting reagent eg. n-butyl lithium
  • a suitable solvent eg. tetrahydrofuran at a suitable temperature eg. less than 5°C.
  • K represents -OH (i.e. the corresponding carboxylic acid) by conventional methods.
  • K represents N-morpholinyl
  • this compound may be prepared from the corresponding carboxylic acid by treatment with (COCI) 2 in an inert solvent eg dichloromethane preferably in the presence of a catalytic amount of pyridine, followed by treatment with morpholine.
  • the corresponding carboxylic acid compounds are known or may be prepared by known methods.
  • R 2 and R 3 independently represent a group selected from:
  • Y represents O, S or N(CH 2 ) j H;
  • Z represents -COO(CH 2 )
  • c, d and e independently represent an integer 0 to 3 provided that c + d + e is in the range 2 to 3; f represents 2 or 3 and g represents an integer 0 to 2; p represents 0 or 1 ; q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1 ;
  • I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such that k+u+v is in the range 0 to 1 ; R 4 and R 5 independently represent hydrogen, d-ealkyl, aryl, arylC ⁇ .
  • R 6 alkyl- or NR 4 R 5 together may represent pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl, N-d- ⁇ alkylpiperazinyl or 2-(1 -methyl-1 H-imidazol-4-yl)-;
  • R 6 represents -OH, -NH 2 , -NHCOCH 3 or halogen;
  • R 7 represents hydrogen, -d-ealkyl, -d.
  • X represents NR 7 , O, S, SO or SO 2 ;
  • aryl represents phenyl which is optionally substituted eg by one or more d. 6 alkyl or halogen groups;
  • L 1 and L 2 represent hydroxy or a protected derivative thereof; and L 3 represent a leaving group; and salts and solvates thereof.
  • the compound of formula (V) will be:
  • a particularly preferred compound of formula (V) is (2S,3S,4R,5R)-2-(3-Ethyl- isoxazol-5-yl)-5- ⁇ 6-(1 -ethyl-propylamino)-2-[2-(1 -methyl-1 H-imidazol-4-yl)- ethylamino]-purin-9-yl ⁇ -tetrahydro-furan-3,4-diol or a salt or solvate thereof.
  • a process for preparing compounds of formula (V) from compounds of formula (II) comprises:
  • R 1 , R 2 , R 3 , L 1 , L 2 , L 3 are as defined above, X 1 and X 2 represent halogen eg CI or F especially CI, L 4 and L 5 represent hydroxy or protected hydroxy (as per L 1 and L 2 ) and L 6 represents a leaving group (as per L 3 ).
  • Compounds of formula (VII) and (VIII) are preferably employed as derivatives in which the NH group of the purine is protected by a tetrahydro-2H-pyran-2-yl (THP) group since the reactions of steps (iii) and (iv) proceed at lower temperature and at higher efficiency than is the case with the unprotected compounds.
  • the compound of formula (IX) having the NH group of the purine protected by a tetrahydro-2H-pyran-2- yl group is preferably deprotected before reaction with the compound of formula (VI).
  • the compounds of formula (VII), (VIII) and (IX) (whether or not in the form of the THP protected derivative) may be employed in the form of acid addition salts.
  • Step (ii) is optional and is employed when it is necessary or convenient to change substituents L 1 , L 2 and/or L 3 .
  • L 4 and L 5 represent hydroxy protected as an alkyl (eg C ⁇ alkyl) ester (eg as acetyloxy) or a benzoyl ester.
  • the protecting groups give rise to an improved yield of the desired diastereoisomer in the reaction with (IX) relative to other protecting groups especially acetonide.
  • L 4 and L 5 represents acetyloxy.
  • L 6 has the same definition as L 4 and L 5 , and more preferably represents acetyloxy.
  • Step (i) is a dehydration step which typically comprises the use of a suitable acidic reagent eg. trifluoroacetic acid in the presence of a suitable solvent, eg. water at a suitable temperature, eg. room temperature.
  • a suitable acidic reagent eg. trifluoroacetic acid
  • a suitable solvent eg. water
  • a suitable temperature eg. room temperature.
  • Step (ii) is a reprotection step involving use of a suitable reagent, eg. acetic anhydride (wherein L 4 , L 5 and L 6 represent acetyloxy) optionally in the presence of a suitable base, eg. pyridine or a suitable acid, eg acetic acid at a suitable temperature, eg. room temperature.
  • a suitable reagent eg. acetic anhydride (wherein L 4 , L 5 and L 6 represent acetyloxy) optionally in the presence of a suitable base, eg. pyridine or a suitable acid, eg acetic acid at a suitable temperature, eg. room temperature.
  • Step (iii) typically comprises the use of a suitable base, eg. triethylamine and a suitable solvent, eg. n-propanol at a suitable temperature, eg. 95°C.
  • Step (iv) typically comprises the use of a suitable solvent, eg. ethylene glycol at a suitable temperature, eg. 135°C and optionally a suitable base eg KOH, which base will be required when the compound of formula (VIII) is employed as an acid addition salt.
  • Step (v) typically comprises the use of suitable reagents, eg trimethylsilyltrifluoromethanesulfonate (TMSOTf) optionally in the presence of N,O- bistrimethylsilylacetamide (BSA) or 1 ,8-diazabicyclo-[5,4,0]-undec-7-ene (DBU) at a suitable temperature, eg. 60 °C in the presence of a suitable solvent eg anhydrous acetonit le or ethyl acetate.
  • TMSOTf trimethylsilyltrifluoromethanesulfonate
  • BSA N,O- bistrimethylsilylacetamide
  • DBU 1 ,8-diazabicyclo-[5,4,0]-undec-7-ene
  • Step (vi) is a deprotection step which typically comprises the use of a suitable base, eg. potassium carbonate in the presence of a suitable solvent, eg. methanol at a suitable temperature, eg. room temperature.
  • a suitable base eg. potassium carbonate
  • a suitable solvent eg. methanol
  • the resulting milky suspension was allowed to warm to 0°C and a further aliquot of nBuLi (25ml, 1.8eq, 2.5M in hexanes) was added at such a rate as to maintain the reaction at 0°C.
  • the resulting bright yellow solution was cooled to -10°C and a solution of Intermediate 9 (10g, 35mmol) in THF (25ml) was added whilst maintaining the reaction at -10°C.
  • the solution was allowed to warm to 0°C and 5M HCI (33ml) was slowly added keeping the reaction at 0°C.
  • the mixture was allowed to warm to room temperature and the phases separated. The organics were washed with water (2 x 30ml) and then concentrated to ca. 30ml at atmospheric pressure.
  • Example 2 Acetic anhydride (20 mL) was added to a solution of Example 2 (2.64 g, 12.3 mmol) in pyridine (20 mL). The colourless solution was then stirred at room temperature for 1 hour 20 minutes. Water (50 mL) was added to the viscous colourless solution resulting in the evolution of heat, the solution was then extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO 4 ) and solvent removed under reduced pressure, followed by azeotroping with toluene (3 x 100 mL) to give the impure title compound. Purification of the title compound via column chromatography, eluting with 1 :1 EtOAc/cyclohexane yielded the title compound as a viscous light yellow oil (3.24 g, 9.49 mmol, 77%).
  • Trimethylsilyltrifluoromethanesulfonate (1.78g, 2.5eq) was added to a stirred suspension of Intermediate 8 (1.06g, 1eq) and Example 3 (1.2g, 1.1 eq) in ethyl acetate (8.5ml) at 0-5°C.
  • the mixture was heated at 55-60°C for 5.5 hours, cooled to 0-5°C and saturated sodium bicarbonate solution (9 ml) was added at ⁇ 10°C.
  • the layers were separated and the organic phase was washed with saturated sodium bicarbonate solution (2ml) and water (2 x 2ml) and evaporated to dryness to give the title compound as a pale orange foam (2.5g, quant.)
  • Example 1 5-[(3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4- d][1 ,3]dioxol-4-yl]-3-ethylisoxazole ( ⁇ )
  • Camphor sulphonic acid 94 mg, 0.41 mmol
  • Intermediate 4 2.33 g, 8.11 mmol
  • K 2 CO 3 100 mg
  • the mixture was then stirred ambient temperature for 1 hour, filtered and the solution concentrated under reduced pressure to yield the impure title compound as a light brown oil.
  • Trifluoroacetic acid 39 mL was added to a mixture of water (4.3 mL) and Intermediate 4 (3.94 g, 13.7 mmol), the resulting solution was then stirred at room temperature. After 3 hours 40 minutes the light yellow solution was concentrated under reduced pressure and the resulting residue azeotroped with toluene (2 x 50 mL) (most of the residue was insoluble in toluene) to yield the title compound (R6832/59/1) as a light brown oil.

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Abstract

Dihydroisoxazolyl substituted Tetrahydrofuran compounds as intermediates in the preparation of 2 (puxin-9-y1)-tetrahydrofuran derivatives A process for preparing a compound of formula (I) which comprises dehydration of a compound of formula (II) according to Step (i): wherein R1 represents methyl, ethyl, -CH=CP2, n-propyl, -CH2FH=CH2, -CH=CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclôpropylmethyl, cyclopropenylmethyl, -CH (OH) CH3, - (CH2) q halogen, - (CH 2) hY (CH2) iH, - (CH2) kZ, - (CH2)hCO(CH2)oH, - (CH2)rS (O) t (CH2) sH or - (CH 2 )kC( (CH2)uH)=NO(CH2)vH; wherein Y represents O, S or NH (CH2)j; Z represents -COO(CH2)1H or -CON (CH2)mH((CH2)nH); q represents an intégér 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1; 1 represents 1 or 2, such that k+ 1 is in the range 1 to 2; m and n independently represent an integer 0 to 2 such that k+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such that k+u+v is in the range O to 1; L1 and L2 represent hydroxy or a protected derivative' thereof; and L3 represent a leaving group.

Description

DIHYDROISOXAZOLYL SUBSTITUTED TETRAHYDROFURAN COMPOUNDS AS INTERMEDIATES IN THE PREPARATION OF 2- (PURIN-9-YL) -TETRAHYDROFURAN DERIVATIVES
A novel class of isoxazole derived compounds were disclosed in international patent application number PCT/EP99/00503 (publication number: WO 99/38877) which are agonists of the adenosine 2a receptor. These compounds demonstrate anti- inflammatory properties capable of inhibiting leukocyte recruitment and activation, particularly of benefit in the treatment of inflammatory conditions such as asthma and chronic obstructive pulmonary disease (COPD).
The method of forming the isoxazole group of the compounds disclosed in WO 99/38877 involves several complicated multi-step processes (detailed on pages 21 and 22 of WO 99/38877) which involve separate alkynylation and ring formation steps.
Surprisingly, the inventors of the present invention have derived a synthetic route for preparing isoxazole derivatives which has the advantage of avoiding the need for separate alkynylation and ring formation steps, avoids the use of certain hazardous reagents and which utilises a novel intermediate.
US 5,424,444 (Abbott Laboratories) discloses a dehydration process for the preparation of unrelated pyrrolidinyl derived compounds.
Thus, according to one aspect of the present invention we provide a process for preparing a compound of formula (I) which comprises dehydration of a compound of formula (II) according to step (i):
Figure imgf000002_0001
(II) (I) wherein R1 represents methyl, ethyl, -CH=CH2, n-propyl, -CH2CH=CH2,
CH=CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH3, -(CH2)qhalogen, -(CH2)hY(CH2)iH, -(CH2)kZ,
-(CH2)hCO(CH2)0H, -(CH2)rS(O)t(CH2)sH or -(CH2)kC((CH2)uH)=NO(CH2)vH; wherein Y represents O, S or NH(CH2)J;
Z represents -COO(CH2),H or -CON(CH2)mH((CH2)nH); q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1 ;
I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such thatk+u+v is in the range 0 to 1 ; L1 and
L2 represent hydroxy or a protected derivative thereof; and
L3 represent a leaving group.
Examples of suitable leaving groups L3 include hydroxyl, alkoxy (eg C^alkoxy such as methoxy), alkanoyloxy (eg C^alkanoyloxy such as acetyloxy), halogen (eg. chlorine) and benzoyloxy.
The hydroxy groups of L1 and/or L2 may for example be protected as alkyl (eg C^alkyl) ethers (eg as methoxy or ethoxy), alkyl (eg Chalky!) esters (eg as acetyloxy), benzoyl esters and together as acetals (eg Chalky! acetals) (eg as acetonide).
Preferably, R1 represents methyl, ethyl, n-propyl, CHOHCH3, CH2OH, CH=NOH, COOEt or bromine, especially methyl, ethyl or CH2OH, particularly ethyl.
Preferably, L and L2 represent hydroxy protected together as the acetonide. Preferably L3 represents a methoxy group. Step (i) typically comprises the use of a suitable acidic reagent eg. trifluoroacetic acid (TFA) in the presence of a suitable solvent, eg. water or paratoluene sulphonic acid (pTSA) in the presence of a suitable solvent eg methanol or methanol/water at a suitable temperature, eg. room temperature. These reagent are also capable of removing the protecting group L1 and L2 eg when they together represent acetonide, and are also capable of converting L3 to hydroxy, for example when L3 represents alkyloxy eg methoxy. Step (i) may also be performed using camphorsulphonic acid (CSA). This reagent performs the dehydration process and in general will not remove or alter the groups L1, L2 and L3. We prefer to use TFA or pTSA, especially pTSA.
It will be appreciated that compounds of formula (II) are new and represent an aspect of the present invention.
Thus, as a second aspect of the present invention we provide a compound of formula (II)
Figure imgf000004_0001
(II)
wherein R1 represents methyl, ethyl, -CH=CH2, n-propyl, -CH2CH=CH2,
CH=CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH3, -(CH2)qhalogen, -(CH2)hY(CH2)iH, -(CH2)kZ,
-(CH2)hCO(CH2)0H, -(CH2)rS(O),(CH2)sH or -(CH2)kC((CH2)uH)=NO(CH2)vH; wherein Y represents O, S or NH(CH2)J; Z represents -COO(CH2),H or -CON(CH2)mH((CH2)nH); q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1 ; I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such that k+u+v is in the range 0 to 1 ;
L1 and L2 represent hydroxy or a protected derivative thereof; and
L3 represent a leaving group.
Preferably, R1 represents methyl, ethyl, n-propyl, CHOHCH3, CH2OH, CH=NOH, COOEt or bromine, especially ethyl or CH2OH.
Preferably, L1 and L2 represent hydroxy protected as the acetonide. Preferably L3 represents a methoxy group.
Compounds of formula (II) may be prepared according to the following process:
Figure imgf000005_0001
wherein R1 represents methyl, ethyl, -CH=CH2, n-propyl, -CH2CH=CH2,
CH=CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH3, -(CH2)qhalogen, -(CH2)hY(CH2)iH, -(CH2)kZ,
-(CH2)hCO(CH2)0H, -(CH2)rS(O)»(CH2)sH or -(CH2)kC((CH2)uH)=NO(CH2)vH; wherein Y represents O, S or NH(CH2)J;
Z represents -COO(CH2),H or -CON(CH2)mH((CH2)nH); q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1 ;
I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such that k+u+v is in the range 0 to 1 ;
K represents a moiety which forms an ester, amide, halide or mixed anhydride derivative of the corresponding carboxylic acid eg -OC^e alkyl, -N(C-|.6 alkyl)2, -
NH(d.6 alkyl), -NH2, -N(aryl)2, -N(d.6 alkylaryl)2, -NH(C1.6 alkylaryl), -NHaryl, -N(aryl)(C1.6 alkyl), -N(C1.6 alkylarylXC-e alkyl), -N(d.6 alkylXOC^ alkyl), N- pyrrolidinyl, N-piperidinyl, N-morpholinyl, N-piperazinyl (optionally substituted by Cι_6 alkyl or C^e alkanoyl), halogen (eg chlorine) or -COCι_6 alkyl (eg acetyl or propionyl); wherein aryl represents phenyl which is optionally substituted eg by one or more C-i.
6alkyl or halogen groups; L1 and L2 represent hydroxy or a protected derivative thereof; and
L3 represent a leaving group.
Preferably, R1 represents methyl, ethyl, n-propyl, CHOHCH3, CH2OH, CH=NOH, COOEt or bromine, especially ethyl or CH2OH, particularly ethyl. Preferably, K represents a moiety which forms an amide derivative of the corresponding carboxylic acid, especially N-morpholinyl.
Preferably, L1 and L2 represent a hydroxy group or a protected derivative thereof, and L3 represents a methoxy group.
Step (ii) typically comprises the use of oxime (IV) together with a suitable proton abstracting reagent eg. n-butyl lithium in the presence of a suitable solvent, eg. tetrahydrofuran at a suitable temperature eg. less than 5°C.
Compounds of formula (III) may be prepared from corresponding compounds of formula (III) in which K represents -OH (i.e. the corresponding carboxylic acid) by conventional methods. For example when K represents N-morpholinyl, this compound may be prepared from the corresponding carboxylic acid by treatment with (COCI)2 in an inert solvent eg dichloromethane preferably in the presence of a catalytic amount of pyridine, followed by treatment with morpholine. The corresponding carboxylic acid compounds are known or may be prepared by known methods. As a further aspect of the present invention we provide the use of a compound of formula (II)
Figure imgf000007_0001
(II)
in the preparation of a compound of formula (V)
Figure imgf000007_0002
wherein R1 represents methyl, ethyl, -CH=CH2, n-propyl, -CH2CH=CH2, -CH=CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH3l -(CH2)qhalogen, -(CH2)hY(CH2)iH, -(CH2)kZ,
-(CH2)hCO(CH2)0H, -(CH2)rS(O)t(CH2)sH or -(CH2)kC((CH2)uH)=NO(CH2)vH;
R2 and R3 independently represent a group selected from:
(i) C3.8cycloalkyl-;
(ii) hydrogen; iii) aryl2CHCH2-;
Figure imgf000007_0003
(v) Chalky!-;
(vi) arylC^alkyl-;
(vii) R4R5N-C.,-6alkyl-; (viii) C1.6alkyl-CH(CH2OH)-;
(ix) arylC1.5alkyl-CH(CH2OH)-;
(x) arylC^alkyl-C(CH2OH)2-;
(xi) C3.8cycloalkyl independently substituted by one or more (e.g. 1 , 2 or 3)
-(CH2)PR6 groups; (xii) H2NC(=NH)NHC|.6alkyl-;
(xiii) a group of formula
Figure imgf000008_0001
or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl;
(xiv) -d-ealkyl-OH;
(xv) -d.shaloalkyl;
(xvi) a group of formula
Figure imgf000008_0002
(xvii) aryl; and
(xviii) -(CH2)fSO2NHg(C1^alkyl-)2.g or -(CH2)fSO2NHg(arylC1.4alkyl-)2.g ;
Y represents O, S or N(CH2)jH;
Z represents -COO(CH2)|H or -CON(CH2)mH((CH2)nH); a and b independently represent an integer 0 to 4 provided that a + b is in the range
3 to 5; c, d and e independently represent an integer 0 to 3 provided that c + d + e is in the range 2 to 3; f represents 2 or 3 and g represents an integer 0 to 2; p represents 0 or 1 ; q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1 ;
I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such that k+u+v is in the range 0 to 1 ; R4 and R5 independently represent hydrogen, d-ealkyl, aryl, arylCι.6alkyl- or NR4R5 together may represent pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl, N-d-βalkylpiperazinyl or 2-(1 -methyl-1 H-imidazol-4-yl)-; R6 represents -OH, -NH2, -NHCOCH3 or halogen; R7 represents hydrogen, -d-ealkyl, -d.6alkylaryl or -COd_6 alkyl; X represents NR7, O, S, SO or SO2; aryl represents phenyl which is optionally substituted eg by one or more d.6alkyl or halogen groups;
L1 and L2 represent hydroxy or a protected derivative thereof; and L3 represent a leaving group; and salts and solvates thereof.
Preferably, the compound of formula (V) will be:
(2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-{6-(1-ethyl-propylamino)-2-[2-(1-methyl- 1 H-imidazol-4-yl)-ethylamino]-purin-9-yl}-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-(1-ethyl-propylamino)-2-(2-piperidin-1-yl- ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2R,3R,4S,5S)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-phenethylamino-2-(2-piperidin-1-yl- ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; (2R,3R,4S,5S)-2-{6-(2,2-Diphenyl-ethylamino)-2-[2-(pyridin-2-ylamino)-ethylamino]- purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol;
(2R,3R,4S,5S)-2-[6-(2,2-Diphenyl-ethylamino)-2-(1S-hydroxymethyl-2-phenyl- ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; or
(2R,3R,4S,5S)-2-{6-(1 -Ethyl-propylamino)-2-[2-(1 -methyl-1 H-imidazol-4-yl)- ethylamino]-purin-9-yl}-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-Methyl-isoxazol-5-yl)-5-[6-(1-ethyl-propylamino)-2-(2-piperidin-1- yl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2R,3R,4S,5S)-2-{6-(2-Cyclohexyl-ethylamino)-2-[2-(1-methyl-1 H-imidazol-4-yl)- ethylamino]-purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; N-(4-{6-(2,2-Diphenyl-ethylamino)-9-[5S-(3-ethyl-isoxazol-5-yl)-3R,4S-dihydroxy- tetrahydro-furan-2R-yl]-9H-purin-2-ylamino}-cyclohexyl)-acetamide; or a salt or solvate of any one thereof.
A particularly preferred compound of formula (V) is (2S,3S,4R,5R)-2-(3-Ethyl- isoxazol-5-yl)-5-{6-(1 -ethyl-propylamino)-2-[2-(1 -methyl-1 H-imidazol-4-yl)- ethylamino]-purin-9-yl}-tetrahydro-furan-3,4-diol or a salt or solvate thereof. A process for preparing compounds of formula (V) from compounds of formula (II) comprises:
Figure imgf000010_0001
wherein R1, R2, R3, L1, L2, L3 are as defined above, X1 and X2 represent halogen eg CI or F especially CI, L4 and L5 represent hydroxy or protected hydroxy (as per L1 and L2) and L6 represents a leaving group (as per L3).
Compounds of formula (VII) and (VIII) are preferably employed as derivatives in which the NH group of the purine is protected by a tetrahydro-2H-pyran-2-yl (THP) group since the reactions of steps (iii) and (iv) proceed at lower temperature and at higher efficiency than is the case with the unprotected compounds. The compound of formula (IX) having the NH group of the purine protected by a tetrahydro-2H-pyran-2- yl group is preferably deprotected before reaction with the compound of formula (VI). The compounds of formula (VII), (VIII) and (IX) (whether or not in the form of the THP protected derivative) may be employed in the form of acid addition salts.
Step (ii) is optional and is employed when it is necessary or convenient to change substituents L1, L2 and/or L3. Preferably L4 and L5 represent hydroxy protected as an alkyl (eg C^alkyl) ester (eg as acetyloxy) or a benzoyl ester. The protecting groups give rise to an improved yield of the desired diastereoisomer in the reaction with (IX) relative to other protecting groups especially acetonide. Preferably L4 and L5 represents acetyloxy. Preferably L6 has the same definition as L4 and L5, and more preferably represents acetyloxy.
Step (i) is a dehydration step which typically comprises the use of a suitable acidic reagent eg. trifluoroacetic acid in the presence of a suitable solvent, eg. water at a suitable temperature, eg. room temperature.
Step (ii) is a reprotection step involving use of a suitable reagent, eg. acetic anhydride (wherein L4, L5 and L6 represent acetyloxy) optionally in the presence of a suitable base, eg. pyridine or a suitable acid, eg acetic acid at a suitable temperature, eg. room temperature.
Step (iii) typically comprises the use of a suitable base, eg. triethylamine and a suitable solvent, eg. n-propanol at a suitable temperature, eg. 95°C. Step (iv) typically comprises the use of a suitable solvent, eg. ethylene glycol at a suitable temperature, eg. 135°C and optionally a suitable base eg KOH, which base will be required when the compound of formula (VIII) is employed as an acid addition salt.
Step (v) typically comprises the use of suitable reagents, eg trimethylsilyltrifluoromethanesulfonate (TMSOTf) optionally in the presence of N,O- bistrimethylsilylacetamide (BSA) or 1 ,8-diazabicyclo-[5,4,0]-undec-7-ene (DBU) at a suitable temperature, eg. 60 °C in the presence of a suitable solvent eg anhydrous acetonit le or ethyl acetate. In this reaction either the alpha anomer or beta anomer for the orientation of L6 or a mixture of both may be employed.
Step (vi) is a deprotection step which typically comprises the use of a suitable base, eg. potassium carbonate in the presence of a suitable solvent, eg. methanol at a suitable temperature, eg. room temperature.
Thus in particular we provide a process for preparation of a compound of formula (X) which comprises reacting a compound of formula (VI) with a compound of formula (IX) as shown in the earlier scheme. We also provide a process which comprises further converting a compound of formula (X) to a compound of formula (V) as shown in the earlier scheme.
Compounds of formula (IV) and (VII) are either known or may be prepared according to known procedures.
The present invention is illustrated by the following non-limiting Examples:
Example Intermediates:
Intermediate 1 : 2-chloro-N6-(1-ethylpropyl)-9H-purin-2-amine
A stirred mixture of 2,6-dichloropurine (15.0g, 0.079mol), 1-ethylpropylamine (13.9ml, 0.110mol) and thethylamine (27.7ml, 0.198mol) in n-propanol (200ml) was heated to 95°C with stirring for 16 hours and then concentrated in vacuo. The residue was taken up in ethyl acetate (70ml) and washed with water (3x40ml) and then brine (40ml). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to leave the title compound (14.6g, 77%th, 99.3%a/a) as a pale yellow amorphous solid.
Intermediate 2: N6-1-ethylpropyl)-N2-(2-piperidin-1-ylethyl)-9H-purine-2,6- diamine
A stirred mixture of Intermediate 1 (11.8g, 0.049mmol) and 1-(2- aminoethyl)piperidine (17.1ml, 0.120mmol) in ethylene glycol (130ml) was heated to 135°C for 63 hours and then allowed to cool to room temperature. The mixture was diluted with ethyl acetate (75ml) and washed with water (800ml and 3x50ml). The aqueous phase was diluted with petrol (850ml) and thediaminopurine (13.9g, 85%th, 96.8%a/a) was collected by suction filtration. A sample was purified by column chromatography on silica using CH2CI2:MeOH:0.880 NH3 (93:7:1) to give the title compound as a pale blue foam.
Intermediate 3: Dimethyl 2,3-O-(1-methylethylidene)-beta-D- ribofuranosiduronate
Concentrated H2SO4 (5 mL) was added dropwise over 3 minutes to a solution of methyl 2,3-O-(1-methylethylidene)-β-D-ribofuranosiduronic acid (50 g, 230 mmol) in MeOH (500 mL). The colourless solution was stirred at room temperature for 3 hours then poured into saturated NaHCO3 (aq) (200 mL), resulting in a slight exotherm and the evolution of gas. The resulting white emulsion was then concentrated under reduced pressure to -300 mL, diluted with water (100 mL) and extracted with EtOAc (3 x 400 mL). The combined organic layers were then washed with brine (200 mL), dried (MgSO4) and solvent removed under reduced pressure to yield the impure title compound as a colourless oil.
Purification of the impure title compound was achieved via Biotage chromatography (800 g cartridge), eluting with 1:1 EtOAc/cyclohexane yielded the title compound as a colourless oil (35.0 g, 0.15 mmol, 66%).
Intermediate 4: 5-[(3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4- d][1 ,3]dioxol-4-yl]-3-ethyl-4,5-dihydroisoxazol-5-ol πBuLi (161 mL, 1.6 M in hexane) was added dropwise to a 0-5 °C solution of 2- butanone oxime (12.2 mL, 0.129 mmol) in THF (240 mL) over 1 % hours, initially resulting in a white precipitate, which became a cloudy light yellow solution after the addition was complete. An exotherm was observed during the addition of nBuLi, therefore the addition was carried out at a rate which maintained the internal temperature below 5 °C. The exotherm was greater during the addition of the first equivalent of nBuLi.
The reaction mixture was stirred at 0-5 °C for 1 hour then a solution oflntermediate 3 (20 g, 86.1 mmol) in THF (160 mL) was added over 20 minutes, maintaining the internal temperature below 5 °C. The cloudy light yellow solution was then removed from the cooling bath and allowed to warm to room temperature. After 4 hours 1M HCI (aq) (180 mL) was added to the light brown/orange opaque reaction mixture, resulting in an increase in internal temperature to 32 °C. The yellow mixture was stirred for 5 min, poured into saturated NaHCO3(aq) (60 mL) and extracted with EtOAc (1 x 200 mL & 2 x 300 mL). The combined organic layers were washed with saturated brine (300 mL) and concentrated under reduced pressure to yield the impure title compound (25.8 g).
Biotage chromatography of the impure title compound (800 g cartridge), eluting with 1:1 EtOAc/cyclohexane yielded the impure title compound as an amorphous white solid (12.6 g). This impure title compound was dissolved in EtOAc (40 mL) then cyclohexane (130 mL) was added and the light yellow solution stirred at room temperature, after 2 minutes fine needle like crystals began to form in the solution. The mixture was stirred for 2 % hours then the solid was isolated via filtration to yield the title compound as a white fine needle like solid (2.24 g). During the filtration more solid crystallised out of the filtrate, this was isolated via filtration to give the title compound as a fine needle like white solid (1.55 g). The filtrate was concentrated under reduced pressure to yield the title compound as a light brown oil which was dissolved in EtOAc (10 mL), followed by the addition of cyclohexane (50 mL). The solution was then cooled to 0-5 °C and stirred at this temperature for 1 hour. The resulting mixture was then filtered to yield the title compound as a fine needle like white solid (1.20 g). Total yield: 4.99 g, 17.0 mmol, 20%.
Intermediate 4: 5-[(3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4- d][1 ,3]dioxol-4-yl]-3-ethyl-4,5-dihydroisoxazol-5-ol (alternative method) 2-butanone oxime (6ml, 1.8eq) was taken into THF (100ml) and the solution was cooled to ca. -10°C. nBuLi (25ml, 1.8eq, 2.5M in hexanes) was added at such a rate as to maintain the reaction temperature at ca. -10°C. The resulting milky suspension was allowed to warm to 0°C and a further aliquot of nBuLi (25ml, 1.8eq, 2.5M in hexanes) was added at such a rate as to maintain the reaction at 0°C. The resulting bright yellow solution was cooled to -10°C and a solution of Intermediate 9 (10g, 35mmol) in THF (25ml) was added whilst maintaining the reaction at -10°C. The solution was allowed to warm to 0°C and 5M HCI (33ml) was slowly added keeping the reaction at 0°C. The mixture was allowed to warm to room temperature and the phases separated. The organics were washed with water (2 x 30ml) and then concentrated to ca. 30ml at atmospheric pressure. Isooctane (100ml) was added and the mixture was seeded and stirred at 65°C for 1 hour. The suspension was then cooled to 20°C and stirred overnight. The product is filtered, washed with THF:isooctane (2 x 20ml, 1:4) and dried in vacuo at 50°C to give the title compound as a white solid (6.0g, 60%th).
Intermediate s: (2S,3R,4R,5S)-2,4-bis(acetyloxy)-5-(3-ethylisoxazol-5- yl)tetrahydrofuran-3-yl acetate
Acetic anhydride (20 mL) was added to a solution of Example 2 (2.64 g, 12.3 mmol) in pyridine (20 mL). The colourless solution was then stirred at room temperature for 1 hour 20 minutes. Water (50 mL) was added to the viscous colourless solution resulting in the evolution of heat, the solution was then extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine (75 mL), dried (MgSO4) and solvent removed under reduced pressure, followed by azeotroping with toluene (3 x 100 mL) to give the impure title compound. Purification of the title compound via column chromatography, eluting with 1 :1 EtOAc/cyclohexane yielded the title compound as a viscous light yellow oil (3.24 g, 9.49 mmol, 77%).
Intermediate 6: (2R,3R,4R,5S)-4-(acetyloxy)-5-(3-ethylisoxazol-5-yl)-2-{6-[(1- ethylpropyl)amino]-2-[(2-piperidin-1-ylethyl)amino]-9H-purin-9-yl}tetrahydrofuran-3-yl acetate
Intermediate 2 (81 mg, 0.24 mmol) was added to a solution of Intermediate 5 (100mg, 0.29 mmol) in anhydrous acetonitrile (1.5 mL). BSA (0.11 mL, 0.43 mmol) was then added to the suspension and the mixture stirred at room temperature for 5 minutes, resulting in a colourless solution. TMSOTf (0.078 mL, 0.43 mmol) was then added and the solution heated to reflux. After 17 3 hours at reflux the brown solution was allowed to cool to room temperature, 10% K2CO3 (aq) (4 mL) was added and the resulting mixture extracted with EtOAc (3 x 10 mL). The combined organic layers were then washed with brine (10 mL), dried (MgSO4) and solvent removed under reduced pressure to yield the title compound (176 mg) as a light brown foam. Subsequent column chromatography, eluting with 5% MeOH/1 % 0.88 NH3(aq)/CH2Cl2 yielded the title compound (123 mg, 0.20 mmol, 84%) as an extremely viscous light brown oil.
Intermediate 7 : 2-chloro-/V-(1 -ethylpropyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6- amine
3-Pentylamine (97ml) was added over 5 minutes to a stirred slurry of Intermediate 11 (90.7g, 0.33mol) in IPA (272ml) at 25°C. Once the exotherm had subsided the mixture was heated to 50°C for 1 hour. Water (315 ml) was added over 12mins, the mixture was warmed to 55°C and then allowed to cool to 15°C. The slurry was filtered and the cake was washed with cold isopropanol-water (1 :2, 2 x 200ml) and sucked dry. The solid was dried in vacuo at 50°C to give the title compound (93.2g, 0.29mol, 87%th) as white prisms.
Intermediate 8: Λ/°-(1 -ethylpropyl)-Λ/2-[2-(1 -methyl-1 H-imidazol-4-yl)ethyl1-9H- purine-2,6-diamine
A slurry of Intermediate 7 (10g, 0.31 mol) and 1-methylhistamine (9.7g, 2.5eq) in ethylene glycol (15ml) was heated at 109°C for 71 hours and then allowed to cool to 30°C. The mixture was diluted with water (45ml), extracted with 3-pentanone (2 x 50ml) and then the combined organic extracts were extracted with 2M HCI (50ml). The aqueous layer was washed with 3-pentanone (40ml), basified to ca.pH11 with 5M NaOH and extracted with 3-pentanone (230ml) at ca.45°C. The organic layer was washed with water (2 x 40ml) and then ca. 3vols of solvent were removed by distillation. The solution (at 55°C) was seeded and then allowed to cool to 10°C. The mixture was filtered and then the cake was washed with cold 3-pentanone (2 x 30ml) and sucked dry. The solid was dried in vacuo at 55°C to give the title compound (7.9g, 0.24mol, 74%th) as white crystals.
Intermediate 9: 4-[1-O-methyl-2,3-O-(1-methylethylidene)-β-D- ribofuranuronoyl]morpholine
Pyridine (3.7ml, 0.05eq) was added to suspension of methyl 2,3-O-(1- methylethylidene)-β-D-ribofuranosiduronic acid (200g, 0.92mol) in dichloromethane (1.7L). The mixture was then heated to reflux and oxalyl chloride (80ml, 1.Oeq) was added over ca.1 hour. The solution is stirred at reflux for 3 hours before being cooled to 0°C. Morpholine (240ml) was added over ca.lhour keeping the temperature below 5°C. The mixture was warmed to 20°C and the layers separated. The organics are washed with 2.5M HCI (667ml), 10% KHCO3 (667ml) and then water (667ml). The organics were concentrated under reduced pressure to yield a orange/yellow oil, which solidified on standing and was dried in vacuo @50°C to give the title compound as a pale yellow solid (234g, 89%th).
Intermediate 10: (2R,3f?,4R,5S)-4-(acetyloxy)-5-(3-ethylisoxazol-5-yl)-2-(6-[(1 - ethylpropyl)amino]-2-{[2-(1 -methyl-1 H-imidazol-4-yl)ethyl]amino}-9H-purin-9- yl)tetrahydrofuran-3-yl acetate
Trimethylsilyltrifluoromethanesulfonate (1.78g, 2.5eq) was added to a stirred suspension of Intermediate 8 (1.06g, 1eq) and Example 3 (1.2g, 1.1 eq) in ethyl acetate (8.5ml) at 0-5°C. The mixture was heated at 55-60°C for 5.5 hours, cooled to 0-5°C and saturated sodium bicarbonate solution (9 ml) was added at <10°C. The layers were separated and the organic phase was washed with saturated sodium bicarbonate solution (2ml) and water (2 x 2ml) and evaporated to dryness to give the title compound as a pale orange foam (2.5g, quant.)
Intermediate 11 : 2,6-dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine 2,6-dichloropurine (1wt) and p-toluenesulphonic acid (0.01wt, 0.01eq) were suspended in ethyl acetate (2 vol). Dihydropyran (0.63 vol, 1.3eq) was added to the suspension and the reaction mixture heated to 50 °C. The reaction was held at 50 °C for 15 mins during which crystallisation occurred. N-Hexane (8 vol) was then added to the suspension over 15 mins whilst maintaining the vessel at 50 °C. Once the addition was complete, the slurry was cooled to 0 °C for 1 hr. The product was then filtered, washed with cold (0-5 °C) ethyl acetate/n-hexane (2x3 vols, 1:4) and dried in vacuo at 50°C to give the title compound, (yield 88%th) as a white solid.
Examples: Examples 1 , 2 and 3 are example preparations of compounds of formula (I). Examples 4 and 5 are example preparations of compounds of formula (V).
Example 1 : 5-[(3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4- d][1 ,3]dioxol-4-yl]-3-ethylisoxazole (±) Camphor sulphonic acid (94 mg, 0.41 mmol) was added to a mixture of Intermediate 4 (2.33 g, 8.11 mmol) in toluene (41 mL), the mixture was then heated to reflux. After 3 hours at reflux the light brown solution was allowed to cool to room temperature and K2CO3 (100 mg) was added. The mixture was then stirred ambient temperature for 1 hour, filtered and the solution concentrated under reduced pressure to yield the impure title compound as a light brown oil.
Purification of impure title compound via column chromatography, eluting with 40% EtOAc/cyclohexane yielded the title compound as a colourless oil which crystallised upon standing (1.94 g, 7.21 mmol, 89%).
Example 2: (3f?,4S,5S)-5-(3-ethylisoxazol-5-yl)tetrahydrofuran-2,3,4-thol
Trifluoroacetic acid (39 mL) was added to a mixture of water (4.3 mL) and Intermediate 4 (3.94 g, 13.7 mmol), the resulting solution was then stirred at room temperature. After 3 hours 40 minutes the light yellow solution was concentrated under reduced pressure and the resulting residue azeotroped with toluene (2 x 50 mL) (most of the residue was insoluble in toluene) to yield the title compound (R6832/59/1) as a light brown oil.
Column chromatography of the title compound, eluting with EtOAc yielded the desired title compound as a viscous colourless oil (2.69 g, 12.5 mmol, 91%).
Example 3: (2S,3f?,4f?)-4,5-bis(acetyloxy)-2-(3-ethylisoxazol-5-yl)tetrahydrofuran-3-yl acetate
Intermediate 4 (10g, 35mmol) and p-toluene sulphonic acid (0.66g, 0.1 eq) are taken into MeOH (100ml). Solvent was distilled off at atmospheric pressure and replaced with MeOH (4 x 20ml). The remaining solvent was removed in vacuo to give an oil which was dissolved in acetic acid (30ml) and warmed to 35°C. Acetic anhydride (11.5ml, 3.5 eq) was added and the solution was stirred at 35°C for 2 hours. The solution was then heated to 60°C and cone, sulphuric acid (1 drop) was added. The mixture was heated at 60°C for 2h, cooled to RT and water (100ml) was added. The mixture was extracted with ethyl acetate (100ml). The layers are separated and the aqueous phase was re-extracted with ethyl acetate (50ml). The organic extracts were combined, washed with saturated NaHCO3 (2 x 50ml) and then concentrated in vacuo to give the title compound as a brown oil (11.2g, 84%th)
Example 4: (2S,3S,4R,5R)-2-(3-ethylisoxazol-5-yl)-5-{6-[(1-ethylpropyl)amino]-2- [(2-piperidin-1-ylethyl)amino]-9H-purin-9-yl}tetrahydrofuran-3,4-diol K2CO3 (33 mg, 0.24 mmol) was added to a solution of Intermediate 6 (123 mg, 0.20 mmol) in MeOH (1.2 mL). The resulting suspension was then stirred at room temperature for 1 % hours then concentrated under reduced pressure -0.5 mL. Water (3 mL) was added and the mixture extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (5 mL), dried (MgSO4) and solvent removed under reduced pressure to yield the title compound (98 mg) as sticky light brown solid.
Column chromatography, eluting with 10% MeOH/1% 0.88 M NH3(aq) CH2Cl2 yielded the title compound (78 mg, 0.15 mmol, 75%) as light brown foam.
Example 5: (2S,3S,4R,5R)-2-(3-Ethylisoxazol-5-yl)-5-{6-(1 -ethyl-propylamino)-2-[2- (1 -methyl-1 H-imidazol-4-yl)ethyl]amino]-9H-purin-9-yl}-tetrahydro-furan-3,4-diol
Crude Intermediate 10 (2.5g) was dissolved in a mixture of methanol (5.3ml) and ethyl acetate (5.3ml) and potassium carbonate (250mg) was added. The mixture was heated at 40-45° for ca.1 hour. The solvent was evaporated off in vacuo and the residue was dissolved in ethyl acetate (20ml) and water (10ml). The layers were separated and the organic phase was washed with 10% brine. The organic phase was treated with charcoal which was removed by filtration through celite. The filtrate was evaporated in vacuo to give the title compound as a pale orange foam (1.6g, 82%th from Intermediate 8)
The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers but not to the exclusion of any other integer or step or group of integers or steps.
The above mentioned patents and patent applications are herein incorporated by reference

Claims

Claims
1. A process for preparing a compound of formula (I) which comprises dehydration of a compound of formula (II) according to Step (i):
Figure imgf000020_0001
(ID (I)
wherein R1 represents methyl, ethyl, -CH=CH2, n-propyl, -CH2CH=CH2,
CH=CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH3, -(CH2)qhalogen, -(CH2)hY(CH2)iH, -(CH2)kZ,
-(CH2)hCO(CH2)oH, -(CH2)rS(O)t(CH2)sH or -(CH2)kC((CH2)uH)=NO(CH2)vH; wherein Y represents O, S or NH(CH2)J;
Z represents -COO(CH2)|H or -CON(CH2)mH((CH2)nH); q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1 ;
I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such thatk+u+v is in the range 0 to 1; L1 and
L2 represent hydroxy or a protected derivative thereof; and L3 represent a leaving group.
2. A compound of formula (II)
Figure imgf000021_0001
(II)
wherein R1 represents methyl, ethyl, -CH=CH2, n-propyl, -CH2CH=CH2,
CH=CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH3, -(CH2)qhalogen, -(CH2) Y(CH2)iH, -(CH2)kZ,
-(CH2) CO(CH2)oH, -(CH2)rS(O)»(CH2)sH or -(CH2)kC((CH2)uH)=NO(CH2)vH; wherein Y represents O, S or NH(CH2)J;
Z represents -COO(CH2)|H or -CON(CH2)mH((CH2)nH); q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1 ;
I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such that k+u+v is in the range 0 to 1 ; L1 and
L2 represent hydroxy or a protected derivative thereof; and
L3 represent a leaving group.
3. Use of a compound of formula (II)
Figure imgf000022_0001
GO
in the preparation of a compound of formula (V)
Figure imgf000022_0002
wherein R1 represents methyl, ethyl, -CH=CH2, n-propyl, -CH2CH=CH2, -CH=CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, -CH(OH)CH3, -(CH2)qhalogen, -(CH2) Y(CH2)iH, -(CH2) Z, -(CH2)hCO(CH2)0H, -(CH2)rS(O)t(CH2)sH or -(CH2)kC((CH2)uH)=NO(CH2)vH; R2 and R3 independently represent a group selected from:
(i) C3.8cycloalkyl-;
(ϋ) hydrogen; iii) aryl2CHCH2-;
(iv) C3.8cycloalkylCι_6alkyl-;
(v) d-salkyl-;
(vi) aryld-ealkyl-;
(vii) R4R5N-d.6alkyl-;
(viii) d.6alkyl-CH(CH2OH)-;
(ix) aryld.5alkyl-CH(CH2OH)-;
Figure imgf000022_0003
(xi) C3.8cycloalkyl independently substituted by one or more (e.g. 1 , , 2 or 3) -(CH2)PR6 groups;
(xii) H2NC(=NH)NHd.6alkyl-;
(xiii) a group of formula
Figure imgf000023_0001
or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl; (xiv) -d_6alkyl-OH;
(xv) -d_8haloalkyl;
(xvi) a group of formula
Figure imgf000023_0002
(xvii) aryl; and
(xviii) -(CH2)fSO2NHg(C1.4alkyl-)2.g or -(CH2)ιSθ2NHB(arylCι^alkyl-)a<j ; Y represents O, S or NH(CH2)J;
Z represents -COO(CH2)|H or -CON(CH2)mH((CH2)nH); a and b independently represent an integer 0 to 4 provided that a + b is in the range
3 to 5; c, d and e independently represent an integer 0 to 3 provided that c + d + e is in the range 2 to 3; f represents 2 or 3 and g represents an integer 0 to 2; p represents 0 or 1 ; q represents an integer 0 to 3; h represents an integer 0 to 2; i represents an integer 0 to 2 such that h+i is in the range 0 to 3; j represents an integer 0 to 2 such that h+i+j is in the range 0 to 3; k represents 0 or 1 ;
I represents 1 or 2, such that k+ I is in the range 1 to 2; m and n independently represent an integer 0 to 2 such thatk+m+n is in the range 0 to 2; o represents an integer 0 to 2 such that h+o is in the range 0 to 2; r and s independently represent 1 or 2 such that r+s is in the range 2 to 3; t represents 1 or 2; u and v independently represent 0 or 1 such that k+u+v is in the range 0 to 1 ; R4 and R5 independently represent hydrogen, d.6alkyl, aryl, aryld.6alkyl- or NR4R5 together may represent pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl, N-d.6alkylpiperazinyl or 2-(1 -methyl-1 H-imidazol-4-yl)-;
R6 represents -OH, -NH2, -NHCOCH3 or halogen; R7 represents hydrogen, -d-ealkyl, -d_6alkylaryl or -COC|.6 alkyl; X represents NR7, O, S, SO or SO2; aryl represents phenyl which is optionally substituted eg by one or more d.6alkyl or halogen groups; L1 and L2 represent hydroxy or a protected derivative thereof; and L3 represent a leaving group, and salts and solvates thereof.
4. Use according to claim 3 wherein the compound of formula (V) is: (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-{6-(1-ethyl-propylamino)-2-[2-(1-methyl-
1 H-imidazol-4-yl)-ethylamino]-purin-9-yl}-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-(1-ethyl-propylamino)-2-(2-piperidin-1-yl- ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2R,3R,4S,5S)-2-(3-Ethyl-isoxazol-5-yl)-5-[6-phenethylamino-2-(2-piperidin-1-yl- ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2R,3R,4S,5S)-2-{6-(2,2-Diphenyl-ethylamino)-2-[2-(pyridin-2-ylamino)-ethylamino]- purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol;
(2R,3R,4S,5S)-2-[6-(2,2-Diphenyl-ethylamino)-2-(1S-hydroxymethyl-2-phenyl- ethylamino)-purin-9-yl]-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol; or (2R,3R,4S,5S)-2-{6-(1 -Ethyl-propylamino)-2-[2-(1 -methyl-1 H-imidazol-4-yl)- ethylamino]-purin-9-yl}-5-(3-hydroxymethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol;
(2S,3S,4R,5R)-2-(3-Methyl-isoxazol-5-yl)-5-[6-(1-ethyl-propylamino)-2-(2-piperidin-1- yl-ethylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol;
(2R,3R,4S,5S)-2-{6-(2-Cyclohexyl-ethylamino)-2-[2-(1-methyl-1 H-imidazol-4-yl)- ethylamino]-purin-9-yl}-5-(3-ethyl-isoxazol-5-yl)-tetrahydro-furan-3,4-diol;
N-(4-{6-(2,2-Diphenyl-ethylamino)-9-[5S-(3-ethyl-isoxazol-5-yl)-3R,4S-dihydroxy- tetrahydro-furan-2R-yl]-9H-purin-2-ylamino}-cyclohexyl)-acetamide; or a salt or solvate of any one thereof.
5. Use according to claim 4 wherein the compound of formula (V) is (2S,3S,4R,5R)-2-(3-Ethyl-isoxazol-5-yl)-5-{6-(1-ethyl-propylamino)-2-[2-(1-methyl- 1 H-imidazol-4-yl)-ethylamino]-puhn-9-yl}-tetrahydro-furan-3,4-diol or a salt or solvate thereof.
6. A process for preparing compounds of formula (V) from compounds of formula (II) which essentially comprises the following steps:
Figure imgf000025_0001
10 wherein R1, R2, R3, L1, L2, L3 are as defined in claim 1 , L4 and L5 represent hydroxy or protected hydroxy, L6 represents a leaving group; compounds of formula (IX) are optionally employed in the form of a derivative in which the NH group of the purine ring is protected by tetrahydro-2H-pyran-2-yl, and/or a salt thereof; and in which step (ii) is optional.
PCT/EP2003/003028 2002-03-21 2003-03-19 Dihydroisoxazolyl substituted tetrahydrofuran coompounds as intermediates in the preparation of 2-(purin-9-yl) - tetrahydrofuran derivatives WO2003080604A1 (en)

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