CN100410266C - Synthesizing process of podophyllotoxin phosphonate derivate - Google Patents

Abstract

The present invention relates to synthesis process of podophyllotoxin phosphate derivative. In the presence of tetrahalo methane, tertiary amine and 4-dimethylamido pyridine, podophyllotoxin derivative and phosphorous acid derivative are reacted for 1 hr. The present invention has simple operation, low production cost, short reaction period, high product yield and high product purity.

Description

The synthetic method of podophyllotoxin phosphonate derivate

Technical field:

The present invention relates to the synthetic method of podophyllotoxin phosphonate derivate.Be specifically related to podophyllotoxin derivative is carried out a kind of novel method of phosphorylated.

Background technology:

The phosphoric acid ester of podophyllotoxin derivative is the water-soluble antitumor drug of a class, and its structure is suc as formula shown in the I.

The common preparation method of the phosphoric acid ester of podophyllotoxin derivative is that the phenolic hydroxyl group with podophyllotoxin derivative (formula II) obtains after phosphorylated:

R in the formula ¹And R ²Multiple different substituting group can be arranged, obtain different derivatives.As work as R ¹Be methyl, R ², R ³, R ⁴When being hydrogen, be antitumor drug phosphoric acid Etoposide; R ¹Be the 2-thienyl, R ², R ³, R ⁴When being hydrogen, be antitumor drug phosphoric acid teniposide.

Owing in the glycosyl of podophyllotoxin molecule two hydroxyls are arranged, phosphating reaction also easily take place.Therefore, the phenolic hydroxyl group orientation of podophyllotoxin molecule being carried out phosphating reaction acquires a certain degree of difficulty.

English Patent 2207674 has been reported the preparation method of phosphoric acid Etoposide, and it is as Phosphation reagent with diphenyl phosphate chloride that this method is carried out the selectivity Phosphation.A disclosed example is that Etoposide and diphenyl phosphate chloride reaction generate the Etoposide diphenyl phosphate, gets etoposide phosphate through catalytic hydrogenation.This method has two big shortcomings: the one, and long reaction time needs nearly 100 hours; The 2nd, the cost height, the agents useful for same diphenyl phosphate chloride costs an arm and a leg.

The method of Chinese patent CN1189499A (on November 4th, 1993) is the hydroxyl protection of elder generation with glycosyl, carries out Phosphation again.Disclosed preparation method is that 4 '-demethyl table poison mortar toxin and the reacted product of dibenzyl phosphite generate intermediate with protected sugar again under Louis acid catalysis, obtains the phosphoric acid Etoposide through catalytic hydrogenation.This method needs protection sugar earlier, also needs the deprotection base, and complicated operation, preparation cost are also very high.

Summary of the invention:

The purpose of this invention is to provide the novel method that a kind of podophyllotoxin derivative (formula I) carries out phosphorylated, this method technology is simple, the reaction times is shorter, and cost is low than prior art.

Novel method provided by the invention is as described below:

Formula II compound is reacted with phosphorous acid derivative (formula III) in the presence of tetrahalomethanes, tertiary amine and phosphorylated catalyzer 4-dimethylamino pyridine; temperature of reaction is controlled at-10 ℃～-30 ℃; 30～60 minutes reaction times can obtain formula I compound, and reaction formula is as follows:

In the formula:

R ¹Be selected from the cycloalkyl, 2-furyl, 2-thienyl, the aromatic base of 6～10 carbon atoms, the aralkyl of 7～14 carbon atoms, the aralkenyl of 8～14 carbon atoms of the alkenyl of the alkyl of 1～10 carbon atom, 2～10 carbon atoms, 5～6 carbon atoms, wherein aromatic nucleus can also can have substituting group by unsubstituted, and its substituting group can be selected from substituting groups such as the alkoxyl group, hydroxyl, nitro, amido of the alkyl of halogen atom, 1～8 carbon atom, 1～8 carbon atom;

R ²Be selected from the alkyl of hydrogen or 1～8 carbon atom;

Perhaps, R ¹And R ²It is through the carbon atom connection and the cycloalkyl of 5～6 carbon atoms of formation;

X is oxygen or sulphur;

R ³And R ⁴It is respectively the alkyl of 1～5 carbon atom replacing of the alkyl that is selected from hydrogen, 1～5 carbon atom, halogen, the alkyl of 1～5 carbon atom that cyano group replaces, the cycloalkyl of 3～6 carbon atoms, the aromatic base of 6～10 carbon atoms, the aralkyl of 7～14 carbon atoms, wherein aromatic nucleus can unsubstituted or substituting group is arranged, and its substituting group is selected from alkyl, halogen, nitro; R ³And R ⁴Can be metallic element also, make formula I compound become salt, be preferably disodium salt, its structure be:

Perhaps

In above-mentioned reaction:

Reaction solvent can be selected the solubilized reactant and the solvent that can not participate in reacting, as acetonitrile, tetrahydrofuran (THF), ethyl acetate etc.;

Halogen is selected from fluorine, chlorine, bromine, iodine in the described tetrahalomethanes, can be the same or different, and consumption is preferably equivalent;

Described tertiary amine is selected from N, and N-diisopropylethylamine, triethylamine, consumption are preferably 2 equivalents

4-dimethylamino pyridine consumption is preferably 0.2 equivalent.

The consumption of phosphorous acid derivative (formula III) is preferably equivalent.

Method of the present invention has the following advantages:

1. simple to operate

1) do not need protection two hydroxyls on the sugar, one step of reaction carries out, and promptly is oriented in the phenolic hydroxyl group phosphorylated;

2) each reactant once adds and need not add in batches, operates easier;

2. cost is low

Phosphorus esterification reagent is di-substituted with the lower phosphorous acid of price, does not use the more expensive chlorine di(2-ethylhexyl)phosphate substitutive derivative of price, has reduced production cost;

3. shortened the reaction times greatly

Be reflected in 1 hour and finish, and English Patent 2207674 needs nearly 100 hours;

4. product yield height, purity height

Reaction yield is measured purity more than 90% up to 90% through high performance liquid phase form and aspect method.

Embodiment:

React the example that obtains the Etoposide phosphate dibenzyl ester by Etoposide and dibenzyl phosphite below, the present invention is elaborated.Gained Etoposide phosphate dibenzyl ester promptly obtains antitumor drug phosphoric acid Etoposide through hydrogenation.But it should be understood that present embodiment only is used to illustrate method of the present invention, does not limit the present invention.

Synthesizing of embodiment 1 phosphoric acid Etoposide

1) preparation Etoposide phosphate dibenzyl ester

Logical nitrogen adds the 30g Etoposide in 1 liter of three mouthfuls of reaction flask, and 600ml analytical pure acetonitrile cools to below-10 ℃ with cold salt bath under stirring, and adds CCl successively ₄25ml, N, N-diisopropylethylamine 20ml, 4-dimethylamino pyridine 1.2g is dripping the solution that dibenzyl phosphite 35g and 20ml acetonitrile are formed below-10 ℃, add the back-30 ℃ to-10 ℃ react disappear to the raw material Etoposide till, approximately need 1 hour.Reaction is poured reaction solution into 200ml 0.5M KH after finishing ₂PO ₄In the aqueous solution, with the extraction of 3 * 400ml ethyl ester, rare NaHCO ₃Be washed to neutrality, wash with water again, the anhydrous magnesium sulfate drying organic layer, 50 ℃ of water-bath vacuum concentration get crude product 45g to doing, and HPLC surveys content 90%, and is so purified that content can carry out next step reaction after 97%.

2) preparation phosphoric acid Etoposide

Make solvent with methyl alcohol, the Etoposide phosphate dibenzyl ester that preceding step reaction is obtained gets through the hydrogenation of normal temperature pressurized catalysis.The concrete operations step is as follows:

In the autoclave of clean dried, add Etoposide phosphate dibenzyl ester 39 grams after making with extra care, anhydrous methanol 390ml, 10%Pd/C 5g stirs, logical at normal temperatures H ₂Pressure 2～20 normal atmosphere carried out hydrogenation 2 to 10 hours, it is complete to detect raw material reaction through high performance liquid chromatography, stop hydrogenation, filter out catalyzer (can reuse), filtrate is concentrated into dried, and with 75 ℃ of hot anhydrous alcohol solution after-filtration, airtight being put in 60 ℃ of hot water baths left standstill slow cool overnight, filter crystal normal temperature P ₂O ₅Vacuum-drying gets colourless acicular crystal 28g, and greater than 99%, yield is greater than 80% through the HPLC detection level.147 ℃ of flavescence are decomposed.

Reaction formula is:

MS(FAB)669.1

¹HNMR(DMSO)

1.226(1H，d)2.852～2.923(1H，m)3.048(1H，t)

3.150(1H，dd)3.237(1H，m)3.349～3.293(2H，m)3.430(1H，m)

3.494(1H，t)3.588(6H，s)4.0645(1H，q)4.2265(2H，d)4.548(1H，d)

4.566(1H，d)4.7125(1H，q)4.936(1H，q)5.221(1H，bs)6.016(2H，s)

6.211(2H，s)6.526(1H，s)7.005(1H，s)

¹³CNMR(DMSO)

174.487?150.853?147.496?145.970?136.297?132.04?128.530?128.363

109.641?109.519?107.49?101.173?101.035?98.365?79.735?73.937?72.305

71.542?67.468?67.041?65.469?55.689?42.765?39.973?36.998?19.970

Claims (8)

1. the synthetic method of compound of Formula I in the presence of tetrahalomethanes, tertiary amine and 4-dimethylamino pyridine, is reacted formula II compound and formula III compound, and temperature of reaction is-10 ℃～-30 ℃, 30～60 minutes reaction times:

Formula II formula III formula I

In the formula:

R ¹Be selected from the cycloalkyl, 2-furyl, 2-thienyl, the aromatic base of 6～10 carbon atoms, the aralkyl of 7～14 carbon atoms, the aralkenyl of 8～14 carbon atoms of the alkenyl of the alkyl of 1～10 carbon atom, 2～10 carbon atoms, 5～6 carbon atoms, wherein aromatic nucleus can also can have substituting group by unsubstituted, and its substituting group can be selected from alkyl, the alkoxyl group of 1～8 carbon atom, hydroxyl, nitro, the amido of halogen atom, 1～8 carbon atom;

R ²Be selected from the alkyl of hydrogen or 1～8 carbon atom;

Perhaps, R ¹And R ²It is through the carbon atom connection and the cycloalkyl of 5～6 carbon atoms of formation;

X is oxygen or sulphur;

R ³And R ⁴Be selected from the alkyl of 1～5 carbon atom that the alkyl, halogen of hydrogen, 1～5 carbon atom replace respectively, the alkyl of 1～5 carbon atom that cyano group replaces, the cycloalkyl of 3～6 carbon atoms, the aromatic base of 6～10 carbon atoms, the aralkyl of 7～14 carbon atoms, wherein aromatic nucleus can unsubstituted or substituting group is arranged, and its substituting group is selected from alkyl, halogen, nitro; R ³And R ⁴It also can be metallic element.

2. the synthetic method of the described compound of Formula I of claim 1, wherein R ¹Be methyl or 2-thienyl, R ²Be hydrogen.

3. the synthetic method of the described compound of Formula I of claim 1, wherein R ³And R ⁴Be respectively hydrogen or benzyl.

4. the synthetic method of the described compound of Formula I of claim 1, wherein R ³And R ⁴Be respectively sodium.

5. the synthetic method of the described compound of Formula I of claim 1, wherein X is an oxygen.

6. the synthetic method of the described compound of Formula I of claim 1, halogen is selected from fluorine, chlorine, bromine, iodine in the described tetrahalomethanes; Halogen can be the same or different.

7. the synthetic method of the described compound of Formula I of arbitrary claim in the claim 1～6, used reaction solvent is selected from acetonitrile, tetrahydrofuran (THF) or ethyl acetate.

8. the synthetic method of the described compound of Formula I of arbitrary claim in the claim 1～6, described tertiary amine is selected from N, N-diisopropylethylamine, triethylamine.