HK1168845B - Process for the preparation of (1s,4r)-2-oxa-3-azabicyclo[2.2.1]hept-5-enes - Google Patents

Description

Process for the manufacture of (1S,4R) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene

Technical Field

The invention relates to a method for producing enantiomerically enriched (1S,4R) -2-oxa-3-azabicyclo [2.2.1] hept-5-enes of formula (I),

wherein PG¹Is an amino protecting group.

The invention further relates to novel 5-O-protected (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene of formula (III),

wherein X is a halogen atom selected from fluorine, chlorine, bromine and iodine, PG²Is a hydroxy protecting group and PG³Is a 1, 2-diol protecting group.

Background

N-protected 2-oxa-3-azabicyclo [2.2.1] hept-5-enes are useful intermediates for the synthesis of various pharmaceutically active ingredients. See, for example, EP-A-0322242 and EP-A-0658539 for N-benzyloxycarbonyl derivatives. Although certain racemic compounds can be obtained relatively easily by the heterodiels Alder cycloaddition reaction of a nitroso compound such as benzyl nitrosoformate (obtainable, for example, by oxidation of benzyl N-hydroxy carbamate with periodate) with cyclopentadiene, no commercially viable method for the manufacture of enantiomerically pure or enantiomerically enriched compounds with a wide variety of possible protecting groups has been achieved.

Disclosure of Invention

It is therefore an object of the present invention to provide a process for the manufacture of enantiomerically enriched N-protected (1S,4R) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene using commercially available or at least readily available starting materials and allowing the synthesis of compounds with a variety of protecting groups.

Enantiomerically enriched (1S,4R) -2-oxa-3-azabicyclo [2.2.1] hept-5-enes of formula (I) have been found

Wherein PG¹Is an amino-protecting group, and is,

can be prepared by a method comprising the following steps:

(i) reacting a protected 1-C-nitroso-beta-D-ribofuranosyl halide of formula (II),

wherein

X is a halogen atom selected from fluorine, chlorine, bromine and iodine,

PG²is a hydroxy protecting group, and

PG³is a 1, 2-diol protecting group,

with cyclopentadiene to obtain (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene of formula (III),

x, PG therein²And PG³As defined above;

(ii) (ii) hydrolyzing the compound obtained in step (i) to obtain free (1S,4R) -2-oxa-3-azabicyclo [2.2.1]Hept-5-ene (I; PG)¹H) or the corresponding hydrohalide and the corresponding protected D-ribonolactone; and

(iii) introduction of amino protecting group PG¹。

This finding is quite surprising, since it has been found that the structurally related xylose-derived α -chloronitroso compound undergoes heterodiels-alder cycloaddition with both 1, 3-cyclohexadiene and 1, 3-cycloheptadiene, but does not produce any cycloaddition reaction products with cyclopentadiene (a. hall et al, chem. commun.1998, 2251-.

Suitable amino protecting groups PG¹Especially groups which form a carbamate moiety with an amino nitrogen, such as a simple alkoxycarbonyl group, especially methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, or a substituted methoxycarbonyl group, such as benzyloxycarbonyl (benzyloxycarbonyl) or (9-fluorenylmethoxy) carbonyl, wherein the phenyl or fluorenyl moiety is optionally substituted by one or more alkyl or halogen atoms. The carbamate-forming protecting groups are readily introduced by reacting the unprotected amino compound with the respective chloroformate. Other possible amino protecting groups are acyl groups such as acetyl or benzoyl, which can be introduced by reaction of the unprotected amino compound with the respective acyl chloride or anhydride; or benzyl, which can be introduced by reaction of the unprotected amino compound with benzyl chloride or benzyl bromide. Acetyl groups can also be introduced by reaction of unprotected amino compounds with ketenes.

Most preferred amino protecting group PG¹Is benzyloxycarbonyl, which can be introduced by reaction of the unprotected amino compound with benzyl chloroformate.

Hydroxy protecting group PG²May be any group which is not cleaved under the conditions of the process of the present invention or during the synthesis of the nitrosoribofuranosyl halide (II). Since the process of the present invention does not comprise PG²So PG is not required²Can be easily and/or selectively cleaved. Suitable hydroxy protecting groups are those that form ether (including silyl ethers) or ester (including carboxylate, carbonate, sulfonate, and alkyl or aryl carbamates) moieties with the hydroxy group at C-5 of the ribose molecule. The ether may be an alkyl ether, such as methyl ether or ethyl etherSubstituted methyl (e.g., methoxymethyl, benzyloxymethyl, or triphenylmethyl) ether; or silyl ethers such as trialkylsilyl (trimethylsilyl, triethylsilyl or triisopropylsilyl) ethers. Esters may be, for example, those of simple alkanoic or arenecarboxylic esters, such as acetates or benzoates; alkane sulfonates or arene sulfonates, such as methane sulfonate (methanesulfonate) or p-toluenesulfonate (toluenesulfonate); or N-aryl carbamates, such as N-phenyl carbamate. These and other protecting Groups and suitable methods of introduction are known to those skilled in the art or can be found in, for example, Greene's Protective Groups in Organic Synthesis, Peter G.M.Wuts and Theodora W.Greene, John Wiley&Sons, Hoboken, NJ in well-known textbooks and monographs.

Especially preferred hydroxy protecting group PG²Is triphenylmethyl (trityl) which may have one or more substituents on its phenyl group, such as C_1-4Alkyl groups or halogen atoms.

Suitable 1, 2-diol protecting groups include aldehyde or ketone derived groups which, together with the oxygen atoms (O-2 and O-3) and the adjacent carbon atoms (C-2 and C-3), form cyclic acetals or ketals. The protecting group may be introduced by direct reaction of the unprotected diol with an aliphatic or aromatic aldehyde or ketone, a cycloaliphatic ketone or ketone, or via acetalization or ketalization using a suitable open chain acetal or ketal such as dimethanol formal or 2, 2-dimethanol acetonide. These (trans) acetalization or ketalization reactions are usually catalyzed by acids. Examples of acetal-or ketal-forming 1, 2-diol protecting groups are methylene groups (introduced by reaction with formaldehyde or formal); ethylene (by reaction with acetaldehyde or its acetal); benzylidene (by reaction with benzaldehyde or its acetal); isopropylidene (by reaction with acetone or 2, 2-dimethanol acetonide); cyclopentylene (by reaction with cyclopentanone or 1, 1-dimethanol-cyclopentanone) and cyclohexylene (by reaction with cyclohexanone or 1, 1-dimethanol-cyclohexanone).

Other suitable 1, 2-diol protecting groups are groups which form cyclic orthoesters or cyclic carbonates. Examples of protecting groups forming cyclic orthoesters are methoxymethylene and ethoxymethylene (by reaction with trimethyl orthoformate and triethyl orthoformate, respectively) or 1-methoxyethylene (by reaction with trimethyl orthoacetate or 1, 1-dimethanol acetal). The cyclic carbonate group may be introduced by reacting a 1, 2-diol with phosgene, diphosgene (trichloromethyl chloroformate) or triphosgene (bis (trichloromethyl) carbonate).

In a particularly preferred embodiment, the 1, 2-diol protecting group PG³Is isopropylidene (═ C (CH)₃)₂)。

In a preferred embodiment, the substituent X is chlorine.

The cycloaddition reaction step (i) is preferably carried out in an inert solvent such as an aliphatic or aromatic hydrocarbon, a halogenated hydrocarbon, or an open-chain or cyclic ether. Non-limiting examples of such solvents are hexane, toluene, methylene chloride, tetrahydrofuran, methyl tert-butyl ether, and the like.

The cycloaddition reaction step (i) is preferably carried out at a temperature of from-100 ℃ to +40 ℃, preferably from-80 ℃ to 0 ℃ and most preferably about 78 ℃.

The reaction time of the cycloaddition reaction step (i) is typically in the range of several minutes to about one hour.

In a preferred embodiment, the three steps of the process of the invention (steps (i) to (III)) are carried out without isolation of the intermediate of formula III (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] as]Hept-5-ene, and/or unprotected (1S,4R) -2-oxa-3-azabicyclo [2.2.1]Hept-5-ene (formula I; PG)¹H) or a hydrohalide thereof having the formula,

wherein X is as defined above.

In a preferred embodiment, the 5-O-protected 1-C-nitroso-beta-D-ribofuranosyl halide of formula II used in step (i) is prepared by reacting a corresponding 5-O-protected D-furanosyl oxime of formula (IV)

Wherein PG²And PG³As defined above, with two equivalents of a hypohalite having the formula,

wherein X is chlorine, bromine or iodine, n is 1 or 2 and M is selected from the group consisting of alkali metals and alkaline earth metals, i.e. with hypohalites selected from the group consisting of alkali metal hypohalites and alkaline earth metal hypohalites. The 5-O-protected D-ribofuranose oxime (IV) may also be present as open-chain aldoxime or as a mixture of open-chain and said furanose. Although the prior art for the synthesis of 5-O-protected 1-C-nitroso-beta-D-ribofuranosyl halides and related compounds from the corresponding oximes involves two steps, namely an oxidation step on the corresponding oxyiminolactone (e.g. with periodate) and an oxidative halogenation step on the nitrosoribofuranosyl halide (e.g. with tert-butyl hypochlorite), it has been found that this conversion can be achieved in one process step using two equivalents of an inexpensive alkali or alkaline earth metal hypohalite as oxidant and halogenating agent.

Most preferably, sodium hypochlorite is used as the hypohalite for the conversion.

In another preferred embodiment, the 5-O-protected D-ribonolactone of formula (V) is formed during hydrolysis of the intermediate of formula III,

wherein PG²And PG³As defined above, it is recovered and converted via the hydroxyiminolactone to the protected 1-C-nitroso- β -D-ribofuranosyl halide of formula II, for example by reducing it to the corresponding protected D-ribofuranose, which is then reacted with hydroxylamine to obtain the corresponding oxime of formula IV, which is in turn reacted with the hypohalite as described above. When using this recycling method, the consumption of chiral auxiliary is minimal and theoretically only stoichiometric amounts of cyclopentadiene, hydroxylamine, sodium hypochlorite, reducing agents suitable for the reduction of lactones and amino-protecting groups PG are required¹A source.

The protected (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene of formula (III) is novel and is also an object of the present invention,

x, PG therein²And PG³As defined above.

In a preferred embodiment of (1S,4R) -3- (1-C-halo-. alpha. -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene of formula III, X is chlorine.

(1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] in the form of]In another preferred embodiment of hept-5-ene, PG²Is triphenylmethyl.

(1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] in the form of]In another preferred embodiment of hept-5-ene, PG³Is isopropylidene.

According to the process of the present invention, the desired enantiomerically enriched (1S,4R) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene (I) can be obtained in an enantiomeric excess (ee) of 80% or more, preferably 90% or more, and particularly preferably 95% or more.

Detailed Description

The following non-limiting examples will illustrate the process of the present invention and the process of making the novel intermediates.

Example 1

2, 3-0-isopropylidene-D-ribofuranose

Concentrated sulfuric acid (0.3mL) was added to a suspension of D-ribose (12.5g, 83mmol) in acetone (125 mL). The reaction mixture was stirred at room temperature for 90 minutes to obtain a clear solution, followed by neutralization with saturated aqueous sodium carbonate solution. Warp beamThe mixture was filtered and concentrated in vacuo.

Yield: 15.7g (. apprxeq.100%).

Example 2

2, 3-O-isopropylidene-5-O-trityl-ribofuranose

2, 3-O-isopropylidene-D-ribofuranose (15.7g, 83.1mmol) was dissolved in pyridine (100mL), and trityl chloride (27.8g, 0.1mol) was added. The mixture was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography using hexane/ethyl acetate (v: v ═ 4: 1) as eluent.

Yield: 32.3g (90%).

Example 3

2, 3-O-isopropylidene-5-O-trityl-ribofuranose

2, 3-O-isopropylidene-D-ribofuranose (20g, 105.2mmol) was dissolved in dichloromethane (200mL) at 0 ℃. Triethylamine (10.9g, 107.5mmol) and a catalytic amount of pyridine were added to the reaction mixture, followed by trityl chloride (27.8g, 0.1 mol). The mixture was stirred at 0 ℃ for 3 hours and further at room temperature for 12 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate (80mL) and the phases were separated. The organic phase was dehydrated over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The crude product was used in the next step without further purification.

Yield: 38.5g (85%).

Example 4

2, 3-O-isopropylidene-5-O-trityl-D-ribofuranoxime (IV; PG)²Trityl, PG³＝＝C(CH₃)₂)

Hydroxylamine hydrochloride (58g, 0.83mol) was added to a solution of 2, 3-O-isopropylidene-5-O-trityl-D-ribofuranose (30g, 0.69mol) in pyridine (200 mL). The mixture was stirred at room temperature for 3 hours, then water (250mL) and dichloromethane (250mL) were added and the phases were separated. The organic phase was dehydrated over anhydrous sodium sulfate, and filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography using hexane/ethyl acetate (v: v ═ 7: 3) as eluent.

Yield: 25.5g (82%).

Example 5

2, 3-O-isopropylidene-5-O-trityl-D-ribofuranoxime (IV; PG)²Trityl, PG³＝＝C(CH₃)₂)

To hydroxylamine hydrochloride (10.9g, 0.16mol) in ethanol (150mL) was added sodium bicarbonate (13.11g, 0.16 mol). The reaction mixture was stirred at room temperature until carbon dioxide ceased to precipitate. 2, 3-O-isopropylidene-5-O-trityl-D-ribofuranose (15g, 0.34mol) dissolved in ethanol (50mL) was then added and stirring was continued for 2 hours. The reaction mixture was then filtered through a short silica gel column (Plug of silica) and ethyl acetate (200mL) and water (200mL) were added. The organic phase was dehydrated over anhydrous sodium sulfate, and filtered, and the solvent was evaporated. The crude product was used in the next step without further purification.

Yield: 13.4g (86%).

Example 6

2, 3-O-isopropylidene-1-C-nitroso-5-O-trityl-beta-D-ribofuranosyl chloride (II, X ═ Cl, PG)²Arnethyl, PG³＝＝C(CH₃)₂)

Sodium hypochlorite (5 wt.% aqueous solution, 140mL, 0.92mol) was added dropwise to a solution of 2, 3-O-isopropylidene-5-O-trityl-D-ribofuranose oxime (25.5g, 0.57mol) in dichloromethane (150mL) with stirring at 0 ℃. After 30 minutes at 0 ℃, the reaction mixture was allowed to warm to room temperature and stirred for an additional 30 minutes. Water (50mL) was added and the phases separated. The organic phase was dehydrated over anhydrous sodium sulfate and filtered. The product was isolated by evaporation of the solvent.

Yield: 25g (88%).

Example 7

(1S,4R) -3-benzyloxycarbonyl-2-oxa-3-azabicyclo [2.2.1] hept-55-ene

(I，PG¹＝-COOCH₂C₆H₅)

2, 3-O-isopropylidene-1-C-nitroso-5-O-trityl-beta-D-ribofuranosyl chloride (1g, 1.96mmol) was dissolved in toluene or dichloromethane (10 mL). The solution was cooled to-78 ℃ and cyclopentadiene (1g, 14.6mmol) was added over 30 minutes with stirring. The reaction mixture was stirred at-78 ℃ for 1 hour and warmed to 0 ℃. Water (25mL) was added at 0 ℃ and the phases were separated. Methyl tert-butyl ether (5mL), benzyl chloroformate (350mg, 2.0mmol) and sodium hydroxide (25 wt.% aqueous solution, 800mg, 5mmol) were added and the resulting mixture was stirred at room temperature for 30 minutes. The phases were separated, the organic phase was washed with brine (5mL), dehydrated over anhydrous sodium sulfate and filtered. The product is isolated by evaporation of the solvent.

Yield: 89 percent

ee：96％。

When the reaction with cyclopentadiene was repeated at-20 ℃ and 0 ℃, the ee of the product was 88% and 82%, respectively.

Claims (14)

1. A process for the manufacture of enantiomerically enriched (1S,4R) -2-oxa-3-azabicyclo [2.2.1] hept-5-enes of formula (I),

wherein PG¹Is an amino-protecting group, and is,

which comprises the following steps:

(i) reacting a protected 1-C-nitroso-beta-D-ribofuranosyl halide of formula (II)

Wherein X is a halogen atom selected from fluorine, chlorine, bromine and iodine, PG²Is a hydroxy protecting group and PG³Is a 1, 2-diol protecting group, is reacted with cyclopentadiene to obtain (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] of formula (III)]Hept-5-ene

X, PG therein²And PG³As defined above;

(ii) (ii) hydrolyzing the compound obtained in step (i) to obtain free (1S,4R) -2-oxa-3-azabicyclo [2.2.1]Hept-5-ene (I; PG)¹H) or the corresponding hydrohalide and the corresponding 5-O-protected D-ribonolactone; and

(iii) introduction of the amino protecting group PG¹。

2. The method of claim 1, wherein the amino protecting group PG¹Is benzyloxycarbonyl and is prepared by reacting the (1S,4R) -2-oxa-3-azabicyclo [2.2.1]Hept-5-ene is introduced by reaction with benzyl chloroformate.

3. The process of claim 1 or 2, wherein X is chlorine.

4. The method of claim 1 or 2, wherein the 1, 2-diol protecting group PG³Is isopropylidene.

5. A process according to claim 1 or 2, wherein steps (i) to (III) are carried out without isolation of the intermediate of formula III or the free (1S,4R) -2-oxa-3-azabicyclo [2.2.1] ring]G-channel wine5-ene (I; PG)¹H) or a hydrohalide thereof.

6. The method of claim 1 or 2, wherein the compound is produced by the protected D-ribofuranose oxime tautomer of the corresponding formula (IV)

Wherein PG²Is a hydroxy protecting group and PG³Is a 1, 2-diol protecting group, is reacted with two equivalents of a hypohalite of the formula

Wherein X is chlorine, bromine or iodine, n is 1 or 2 and M is selected from the group consisting of alkali metals and alkaline earth metals, to produce a protected 1-C-nitroso-beta-D-ribofuranosyl halide of formula II.

7. The method of claim 6, wherein the hypohalite is sodium hypochlorite.

8. The process of claim 1 or 2, wherein the protected D-ribonolactone obtained in step (II) is recovered and converted to the protected 1-C-nitroso- β -D-ribofuranosyl halide (II).

9. The method of claim 1 or 2, wherein the hydroxyl protecting group PG²Is an optionally substituted triphenylmethyl group.

10. The method of claim 1 or 2, wherein the 1, 2-diol protecting group PG³Is isopropylidene.

11. (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene of formula (III),

wherein

X is a halogen atom selected from fluorine, chlorine, bromine and iodine,

PG²is a hydroxy protecting group, and

PG³is a 1, 2-diol protecting group.

12. The (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [2.2.1] hept-5-ene of claim 11 wherein X is chloro.

13. (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [ 2.2.1) as claimed in claim 11 or 12]Hept-5-ene, wherein PG²Is triphenylmethyl.

14. (1S,4R) -3- (1-C-halo- α -D-ribofuranosyl) -2-oxa-3-azabicyclo [ 2.2.1) as claimed in claim 11 or 12]Hept-5-ene, wherein PG³Is isopropylidene.