WO2017041228A1 - Method for preparing hexahydrofurofuranol derivative, intermediate thereof and preparation method thereof - Google Patents

Abstract

The present invention relates to the field of pharmaceutical synthesis, in particular to a method for preparing a hexahydrofurofuranol derivative, an intermediate thereof and a preparation method thereof. The preparation method uses a compound of formula A1 as an initial material, wherein R₁ and R₂ are the same or different alkyls, which differs from the initial material reported by the present patent documents, and the specific preparation method is different from that of the prior art patent documents; however, the preparation method can achieve the industrial production of a Darunavir key intermediate, (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-alcohol.

Description

Preparation method of hexahydrofuranfuranol derivative, intermediate thereof and preparation method thereof Technical field

The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of a hexahydrofuranfuranol derivative, an intermediate thereof and a preparation method thereof.

Background technique

A compound having the structure of the following formula Z is a chemical name of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol:

One of the derivatives of hexahydrofuranfuranol is an intermediate of the anti-AIDS drug darunavir.

The preparation method of the above (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol is provided in Chinese Patent Application No. 200580010400.X of Taibotek Pharmaceutical Co., Ltd., wherein the starting material is a compound of the formula (3) below,

The preparation method of the above (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol is provided in the Japanese Patent Application No. 200380109926.4 of Sumitomo Chemical Co., Ltd., wherein the starting material is as follows XIII compound,

Considering (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol is a preparation of darunavir For key intermediates, it is necessary to develop more preparation methods for this key intermediate. This requires research and development from different starting materials.

Summary of the invention

The method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol of the present invention starts from the selection of starting materials, and the research and development are different from the above-mentioned existing patent applications. The starting material is used to prepare a key intermediate of darunavir. The preparation method of the present invention provides another route suitable for industrialization for the preparation of the key intermediate of darunavir.

To achieve the technical object of the present invention, the present invention provides the following technical solutions:

The first aspect of the invention provides the following compound of formula B,

In particular, the following compound of formula B-1,

Wherein R ₁ , R ₂ are hydrogen, the same or different are carboxy protecting groups such as alkyl, substituted phenyl such as alkyl substituted phenyl, alkoxyalkyl substituted phenyl, nitroalkyl substituted Phenyl or silane group; PG is hydrogen or a hydroxy protecting group such as an alkyl group, an alkylsilyl group, an aryl group or the like.

The alkyl group is a C ₁ -C ₈ alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; the alkyl-substituted phenyl group is a benzyl group, a benzyl group, a trityl group; the alkoxyalkyl-substituted phenyl group is a p-methoxybenzyl group; the nitroalkyl-substituted phenyl group is a p-nitrobenzyl group, etc., preferably, Methyl, isopropyl, tert-butyl, benzyl; the alkyl silicon group is trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl; The aryl group is phenyl, furyl, thienyl, fluorenyl.

A second aspect of the invention provides the following compound of formula C,

In particular, the following compound of formula C1,

Wherein R ₂ has the same definition as defined in the compound of formula B above.

A third aspect of the invention provides the following compound of formula D,

In particular, the following compound of formula D-1,

The fourth aspect of the present invention provides a method for preparing a compound of the formula B and the formula B-1, wherein The compound of the formula B-1 is prepared by reacting a compound of the formula A1 with a compound of the formula A2, and the compound of the formula B is the same, and the compound of the formula A1 is adjusted to its racemate,

Wherein R ₁ , R ₂ , PG are the same as defined above, and X is a leaving group.

X may be a halogen atom, preferably an iodine atom, a bromine atom; a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a benzenesulfonyloxy group.

Specifically, a compound of the formula B-1 wherein the protecting group PG is a tert-butyl group is prepared,

Wherein R ₁ , R ₂ and X are the same as defined above.

Specifically, a compound of the formula B-1 wherein the protecting group PG is a trimethylsilyl group is prepared,

Wherein R ₁ , R ₂ and X are the same as defined above.

Specifically, a compound of the formula B-1 wherein the protecting group PG is a benzyl group is prepared,

Wherein R ₁ , R ₂ and X are the same as defined above.

Specifically, a compound of the formula B-1 wherein the protecting group PG is a diphenylmethyl group is prepared,

Wherein R ₁ , R ₂ and X are the same as defined above.

Among them, the compound of the formula B-1 wherein the protecting group is hydrogen can be prepared by deprotecting the protecting group to an alkyl group, a benzyl group or an alkylsilyl group. For example, the alkyl group is subjected to acid hydrolysis to a hydroxyl group, and the benzyl group and the diphenylmethyl group are deprotected to a hydroxyl group by palladium carbon, and the alkyl silicon group is deprotected to a hydroxyl group by an acid such as trifluoroacetic acid. The reaction for preparing the compound of the formula B-1 is carried out in the presence of a base. The base is an alkyl lithium or a compound of the following structure,

Wherein, L _1, L ₂ is alkyl, cycloalkyl, alkylsilyl, M being a metal atom such as lithium, potassium and sodium.

Specifically, the base is lithium diisopropylamide, lithium cyclohexylamide, hexamethyl Lithium silicon nitride, sodium hexamethyldisilazide, potassium hexamethyldisilazide or n-butyllithium.

Preferably, the base is lithium diisopropylamide.

The base is usually used in an amount of from 2.0 to 3.5 mol, preferably from 2.2 mol to 3.0 mol, per mol of the compound of the formula A1.

The reaction solvent is an ether solvent such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran or the like.

The reaction temperature is -78 ° C to 70 ° C, preferably -78 ° C to 0 ° C.

Wherein, the compound of the formula B-1 obtained by the reaction of the compound of the formula A1 with the compound of the formula A2 is mostly present in a compound of the following configuration,

Less in part in the form of its diastereomers,

A person skilled in the art can purify the compound of the formula B-1 by column chromatography or the like.

More preferably, however, it is directly used in the following reaction without purification to prepare a compound of formula C,

Wherein, since most of the compounds of the above formula B-1 exist in the following configuration,

After the reaction, the resulting compound of formula C also exists in the following configuration.

A small part exists in the following configuration,

Wherein, when R ₂ is hydrogen, the completion of the reaction may first pass through three processes of deprotection, post-cyclization, and hydrolysis, or may be hydrolysis first, then deprotection, re-cyclization, and It may be a process of first deprotecting, post-hydrolysis, and re-cyclization. That is, these three processes in any order.

The deprotecting reagent is acid or palladium carbon, and the cyclizing reagent may be an acid, wherein the acid is an inorganic acid or an organic acid; and the hydrolysis reagent is an inorganic base.

The inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is trifluoroacetic acid, and the inorganic base is sodium hydroxide, sodium carbonate or the like.

The preparation of the compound of the formula C of the present invention can also be carried out by reacting the compound of the formula A1 with the compound of the formula A2, and then subjecting it to a one-pot reaction of deprotection, cyclization and hydrolysis in any order.

The fifth aspect of the present invention provides a method for preparing a compound of the formula C1, an organic amine salt, wherein the organic amine reagent may be an amine having an active hydrogen such as a primary amine on nitrogen, or an amine having no active hydrogen on the nitrogen such as a tertiary amine. Amines, etc.

Specifically, the organic amine reagent may be dibenzylamine, benzylamine, dicyclohexylamine, cyclohexylamine, aniline, diethylamine, diisopropylamine, (S)-phenethylamine, diisopropylethylamine. Triethylamine, preferably dibenzylamine. The organic amine is usually used in an amount of from 0.5 to 1.5 mol, preferably from 0.8 to 1.3 mol, per mol of the compound of the formula C1.

The solvent is an alcohol solvent, a ketone solvent, an ether solvent, or an ester solvent. Preferably, It is an alcohol solvent, an ether solvent or a ketone solvent.

The alcohol solvent is methanol, ethanol, 2-propanol, 1-propanol, tert-butanol; the ketone solvent is methyl isobutyl ketone or acetone; and the ether solvent is methyl t-butyl Ether or diisopropyl ether; the ester solvent is ethyl acetate.

The formation of the organic amine salt can be carried out by heating to a temperature of usually 20 ° C to 100 ° C, preferably 50 ° C to 80 ° C, followed by cooling to a temperature of usually -20 ° C to 40 ° C, preferably -10 ° C to 25 ° C.

Generally, the recrystallization solvent is the same as the above reaction solvent, and is preferably a ketone solvent such as acetone.

After the formation of the organic amine salt, the compound of the formula C1 can be further obtained by a free step. However, it can also be used in the next reaction without being liberated.

The acid used in the free step is a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.

According to a sixth aspect of the present invention, there is provided a process for the preparation of a compound of the formula D-1, which is prepared from the above-mentioned compound of the formula C1 and an organic amine salt.

Of course, it is also possible to prepare a compound of the formula D after freely obtaining a compound of the formula C1.

Wherein, the acid binding agent is a tertiary amine such as triethylamine or diisopropylethylamine, and may also be pyridine.

Wherein the solvent is an ether solvent such as tetrahydrofuran or a halogenated alkane solvent such as dichloromethane.

The reaction temperature is from 0 ° C to 50 ° C.

A catalyst may optionally be added to the reaction, and the catalyst is 4-dimethylaminopyridine.

A seventh aspect of the invention provides a process for the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol from a compound of formula D-1. It is prepared from the compound of the formula D-1 by reduction and cyclization in two steps.

The reducing agent is an aluminum reagent such as lithium aluminum hydride, diisobutylaluminum hydride or sodium dihydrobis(2-methoxyethoxy)aluminate (red aluminum), tri-tert-butoxy aluminum hydride lithium.

The solvent for the reduction reaction is an ether solvent, a single solvent or a mixed solvent of a halogenated hydrocarbon or a hydrocarbon solvent.

The ether solvent is tetrahydrofuran; the halogenated hydrocarbon solvent is dichloromethane, chlorobenzene.

The cyclizing reagent is a mineral acid, an organic acid or an aqueous solution. The inorganic acid is hydrochloric acid, sulfuric acid; the organic acid is methanesulfonic acid, p-toluenesulfonic acid.

The solvent for the cyclization reaction is an ether solvent and an alcohol solvent.

A more preferred embodiment is the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol by a one-pot reaction of the compound of formula C1 and the organic amine salt.

Among them, the reaction solvent is preferably an ether solvent.

Another preferred embodiment is the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol by a one-pot reaction of a compound of formula C1.

Among them, the reaction solvent is preferably an ether solvent.

The invention prepares the key intermediate of darunavir (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol, starting from the compound of formula A1,

Wherein R ₁ and R ₂ are the same as defined above. This is different from the starting materials reported in the prior patent documents. The specific preparation method is also different from the prior patent documents, but the preparation method can industrially produce the key intermediate of darunavir.

detailed description

Example 1: Preparation of (3R)-diisopropyl-2-(2-(tert-butoxy)-ethyl)-3-hydroxyl

In a 250 ml four-necked flask equipped with a magnetic stirrer and a thermometer, under nitrogen protection, add 63 ml of LDA (2.1 eq) and 30 ml of THF, cool to -60 ° C to -70 ° C, and add isopropyl malate (13.1). g, 60mmol), control temperature does not exceed -60 ° C, drop, maintain internal temperature Stir for 30 min, slowly warm to -20 ° C, use for half an hour, then cool to -60 ° C ~ -70 ° C, add 2-iodoethyl tert-butyl ether (27.4 g, 2.0 eq) dropwise, stir and keep stirring for half an hour After that, the temperature was raised to -20 ° C and stirred overnight. The reaction system was added with 90 ml of water and 40 ml of ethyl acetate, and the mixture was stirred for 5 min, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (40 ml × 3). Part of the column was separated and identified as the target compound in a yield of 80%. Product spectrum data is as follows:

_{^{1 H NMR (400.2MHz, CDCl 3}} ) δ5.10 (1H, m), 5.01 (1H, m), 4.31 (1H, m), 3.54 (1H, d, J = 7.2Hz), 3.46 (2H, m ), 3.06 (1H, m), 2.13 (1H, m), 1.86 (1H, m), 1.29 (6H, d, J = 2.8 Hz), 1.27 (6H, d, J = 2.8 Hz), 1.18 (9H) , s);

¹³ C NMR (100.6 MHz, CDCl ₃ ) δ 172.8 (d, J = 8.8 Hz), 171.45 (d, J = 36.8 Hz), 72.83 (d, J = 5.9 Hz), 71.18 (d, J = 37.3 Hz) ), 69.48 (t, J = 8.2 Hz), 68.1 (d, J = 8.2 Hz), 58.88 (s), 45.67 ppm (s), 28.59 (s), 27.34 ppm (s), 21.58 ppm (s);

Mass spectrometry (ESI method) C ₁₆ H ₃₀ O ₆ (M) ⁺ calc.

Example 2: Preparation of (3R)-diethyl-2-(2-(tert-butoxy)-ethyl)-3-hydroxyl

In a 250 ml four-necked flask equipped with a magnetic stirrer and a thermometer, add 42 ml of LDA (2.1 eq) and 20 ml of THF under nitrogen, cool to -60 ° C to -70 ° C, and add ethyl malate (7.5 g). , 40mmol), control temperature does not exceed -60 ° C, drip, maintain internal temperature for 30min, slowly warm to -20 ° C, use half an hour, then cool to -60 ° C ~ -70 ° C, add 2-iodoethyl tert-Butyl ether (9.58 g, 2.0 eq) was added and stirred for half an hour, then warmed to -20 ° C and stirred overnight. The reaction system was added with 90 ml of water and 40 ml of ethyl acetate, and the mixture was stirred for 5 min, and the mixture was separated, and the aqueous layer was extracted with ethyl acetate (40 ml × 3). Partial separation of the column, determined as the target Compound, yield 60%. Product spectrum data is as follows:

_{^{1 H NMR (400.2MHz, CDCl 3}} ) δ4.30 (1H, m), 4.20 (2H, m), 4.11 (2H, m), 3.52 (1H, m), 3.49 (2H, m), 3.10 (1H m), 2.12 (1H, m), 1.88 (1H, m), 1.31 (6H, d, J = 2.8 Hz), 1.27 (6H, d, J = 2.8 Hz), 1.15 (9H, s).

Example 3: Preparation of (3R)-diisopropylmethyl-2-(2-(trimethylsiloxy)-ethyl)-3-hydroxyl

The compound of the formula B-1 whose protecting group is a trimethylsilyl group can be prepared according to the embodiment 1 or 2.

Example 4:

A compound of formula B-1 wherein the protecting group is benzyl can be prepared as in Example 1 or 2.

Example 5:

The compound of formula B-1 having a protecting group of hydrogen can be prepared by deprotection, and the product spectrum data is as follows:

_{^{1 H NMR (400.2MHz, CDCl 3}} ) δ5.14 (1H, m), 5.04 (1H, m), 4.53 (2H, m), 4.28 (1H, s), 3.22 (1H, m), 3.02 (1H , m), 2.60 (1H, m), 2.35 (1H, m), 1.29 (6H, m), 1.25 (6H, m);

Mass spectrum (ESI _{method) C 12 H 22 O 6 (} M) +, calcd 262.29. 263.2 measurements.

Example 6: Preparation of a compound of formula C

Add 300 mg of (3R)-diisopropyl-2-(2-(tert-butoxy)-ethyl)-3-hydroxyl and 1 ml of trifluoroacetic acid to a 50 ml two-necked flask and cool to -10 °C~- Stir at 5 ° C overnight, dilute the trifluoroacetic acid at low temperature, add sodium hydroxide aqueous solution and tetrahydrofuran, stir at room temperature for 6 hours, adjust pH to 2 with dilute hydrochloric acid, extract with ethyl acetate, evaporate the solvent, add toluene, and dry at atmospheric pressure. This operation was repeated twice to obtain 127 mg of a white solid in a yield of 80%. Product spectrum data is as follows:

¹ H NMR (400.2 MHz, DMSO-d ₆ ) δ 4.25 (3H, m), 3.13 (1H, m), 2.33 (1H, m), 2.13 (1H, m).

Mass spectrum (ESI _{method) C 6 H 8 O 5 (} M) -, calcd 160.1 159.1 measurements.

Example 7: Preparation of Compound C1 Dibenzylamine Salt of Formula C1

Add 3.2g of compound C and 30ml of methyl tert-butyl ether to a 100ml three-necked flask, add 3.96g of dibenzylamine dropwise, use about 30min, drip to 50 °C ~ 55 °C, keep warm for 3 hours, slowly cool down It was kept at 20 ° C for 2 hours, and then kept for 3 to 10 hours, and filtered to obtain 6.0 g of a white solid. The yield was 85%.

Example 8: Preparation of a compound of formula C1·dibenzylamine salt A one-pot reaction of (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-ol

Add 3.68 g of C1 compound · dibenzylamine salt and 30 ml of tetrahydrofuran to a 100 ml three-necked flask, cool to 0 ° C ~ 5 ° C, slowly add 0.9 g of triphosgene tetrahydrofuran solution, drip, heat for 3 hours, then slowly add red The aluminum was added dropwise, and further kept for 5 hours, acid-quenched, extracted with ethyl acetate, and evaporated to dryness to give the title compound.

Example 9

A one-pot reaction of the compound of formula C1 to prepare (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-ol was prepared as in Example 8.

Example 10: Preparation of a compound of formula D-1

Add 3.68 g of C1 compound · dibenzylamine salt and 30 ml of tetrahydrofuran to a 100 ml three-necked flask, cool to 0 ° C ~ 5 ° C, slowly add 0.9 g of triphosgene tetrahydrofuran solution, drop, incubate for 3 hours, evaporate the solvent, NMR The D-1 compound was detected.

Claims (20)

1. A compound having the formula B below:

   

   Wherein R ₁ , R ₂ are hydrogen, the same or different is a carboxy protecting group, the carboxy protecting group is an alkyl group, an alkylsilyl group or a substituted phenyl group; PG is a hydrogen or a hydroxy protecting group, and the hydroxy protecting group It is an alkyl group, an alkyl silicon group, and an aryl group.
2. The compound according to claim 1, further comprising an absolute stereo configuration of the compound of formula B-1 and an isomer thereof, or further a compound of formula B in a relative stereo configuration,

   

   Wherein R ₁ , R ₂ and PG are the same as defined in claim 1.
3. The compound according to claim 2, further a compound of the formula B-1 in its absolute stereo configuration,

   

   Wherein R ₁ , R ₂ and PG are the same as defined in claim 1.
4. The compound according to claim 1, 2 or 3, wherein R ₁ and R _{2 are the} same or different hydrogen, benzyl, methyl, ethyl, n-propyl, isopropyl or t-butyl; Is hydrogen, tert-butyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl, phenyl, diphenylmethyl, benzyl, furyl, Thienyl, fluorenyl.
5. An absolute stereoconfiguration of a compound of formula C and an isomer thereof, or further a compound of formula C in a relative stereo configuration,

   
6. The compound according to claim 5, further a compound of the formula C1 in its absolute stereo configuration,

   
7. a compound having the formula D below,

   
8. The compound according to claim 7, further comprising an absolute stereo configuration of the compound of formula D-1 and an isomer thereof, or further a compound of formula D in a relative stereo configuration,

   
9. The compound according to claim 8, further having its absolute stereo configuration as a compound of formula D-1,

   
10. A process for the preparation of a compound of the formula B, which is prepared by reacting a compound of the formula A1 with a compound of the formula A2,

    

    Wherein R ₁ , R ₂ , PG are the same as defined in claim 1, wherein X is a leaving group, the leaving group is a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, P-toluenesulfonyloxy, benzenesulfonyloxy.
11. The method according to claim 10, wherein X is an iodine atom, and R ₁ and R _{2 are the} same or different, methyl, ethyl, isopropyl, t-butyl, benzyl; The protecting group is tert-butyl, trimethylsilyl, benzyl, diphenylmethyl.
12. Process for the preparation of a compound of formula C, which is prepared from a compound of formula B by deprotection, cyclization and hydrolysis in any order,

    

    The R ₁ , R ₂ , PG are the same as defined in claim 1.
13. A process for the preparation of a compound of the formula C, which is prepared by reacting a compound of the formula A1 with a compound of the formula A2, optionally subjected to one-pot reaction of deprotection, cyclization and hydrolysis,

    
14. A method for preparing a compound of the formula C1, an organic amine salt, which is prepared by reacting a compound of the formula C with an organic amine which is free of primary amine or nitrogen on the nitrogen having active hydrogen. A tertiary amine of active hydrogen.
15. A method for producing a compound of the formula D-1, which is prepared by selectively reacting a compound of the formula C1 or a compound of the formula C1 with an organic amine salt under the conditions of a catalyst,

    
16. Process for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol, which is prepared by reduction and cyclization of a compound of formula D-1,

    
17. Process for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol, which is prepared by one-pot reaction of a compound of formula C1, an organic amine salt or a compound of formula C1 (3R , 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol,

    
18. The method according to claim 14, 15 or 17, wherein the organic amine is dibenzylamine, benzylamine, dicyclohexylamine, cyclohexylamine, aniline, diethylamine, diisopropylamine, (S ) - phenethylamine, diisopropylethylamine or triethylamine.
19. The production method according to claim 10 or 13, wherein the reaction of the A1 compound with the A2 compound is carried out in the presence of a base which is an alkyllithium or a compound having the following structure,

    

    Wherein, L ₁ , L ₂ are an alkyl group, a cycloalkyl group, a silicon-substituted alkyl group, and M is a metal atom, wherein the metal atom is lithium, potassium or sodium.
20. The preparation method according to claim 12 or 13, wherein the deprotecting agent is an acid or palladium carbon, the cyclizing agent is an organic acid or an inorganic acid; and the hydrolysis reagent is an inorganic base.