JPH0395188A - Continuous production of dimer alkaloids - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a carcinostatic agent on an industrial scale at a low cost by reacting a specific compound with a hydride source in the presence of oxygen and an Fe<3+> ion source under specific condition. CONSTITUTION:The objective compound of formula II (one of R<4> and R<5> is hydroxy and the other is ethyl) is produced e.g. by continuously supplying (A) a solution produced by dissolving a compound of formula I (R<1> is H, lower alkyl or formyl; R<2> is lower alkoxycarbonyl or amido; R<3> is acetoxy or hydroxy) and oxygen in a solvent such as water, (B) a solution produced by dissolving 0.1-10,000 mol (based on 1mol of the compound of formula I) of an Fe<3+> ion source in water, etc., and adding 0.1-3mol (based on 1mol of the Fe<3+> ion source) of an oxalic acid ion source or malonic acid ion source, 0.1-100mol of an inorganic anion source and 0.01-10mol of a pyridine derivative to the Fe<3+> ion source solution and (C) an aqueous solution of a halide source (0.05-10mol per 1mol of Fe<3+>) such as sodium borohydroxide from a column and contacting the solutions with each other at -20 to +10 deg.C for 0.1sec to 60min.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (n) (wherein, l?, represents a hydrogen atom, a lower alkyl group, or a forel group, and R2 represents a lower alkoxycarbonyl group) (or represents an amide group, R3 represents an acetoxy group or a hydroxy group, and R4 and R represent one hydroxy group and the other ethyl group). .

Compound (II) produced according to the present invention has antitumor activity and is useful as a pharmaceutical, and representative compounds include vinblastine and leurocidine, which are useful as anticancer agents.

These representative compounds include R. ~R
, are shown in the combinations in Table 1.

Table 1 According to the present invention, anhydrovinblastine and its analogues represented by the general formula (I) (I) R.R. (wherein R, R2 and R3 have the same meanings as above) are used as starting materials, A new industrially advantageous continuous production method for producing dimeric alkaloids such as vinblastine and leulocidine represented by the above formula (II) by introducing 085 into the double bond of the raw material compound is provided.

[Conventional technology]

Conventionally, for example, anhydrovinplastin (AVLB)
For example, a method of preparing vinblastine (VLB), leurocidine (LEu), etc., which are useful as anticancer drugs, by chemical conversion of C. S. ChemCo
mmn1979. There is a method described in 583, but the yield of the target vinblastine (VLB) etc. is extremely low at 1 to 2%. Also, J. C. S. Chem Comm
n 1979, 257 and Phytochemis
tvy 26 (12), 3233 (1987) describes a method using #1 element, but it has drawbacks such as extremely low yield and long reaction time, and both are industrial production methods. There was a problem.

[Secret B to be Solved by the Invention] The present invention provides an industrially advantageous method for producing vinblastine, which is useful as an anticancer drug, in high yield by using the compound represented by (1) as a starting material. The purpose is to provide a method.

[Means for Solving the Problems] The present inventors have conducted various studies over a long period of time with the aim of establishing an industrially advantageous manufacturing method for dimeric alkaloids such as vinblastine useful as anticancer agents. First, a method for producing a dimeric alkaloid, which comprises reacting ``casalanthine and ndrin in the presence of Fe'', then allowing oxygen and a dicarboxylic acid or a derivative thereof to be present, and then reacting with a hydride source. '' and applied for a patent (Japanese Patent Application No. 198898-1983).

As a result of further research, it was found that anhydrovinblastine and its analogues represented by [I]
The OH group is introduced in good yield by contacting with a hydride source in the presence of hydride, and is easily converted to vinblastine and its analogues represented by formula (n). By coexisting a mixed substance of an and/or malonate ion source and one or more substances selected from an inorganic anion source, a pyridine derivative, and an amino acid, the yield is significantly improved; The present invention has been brought to fruition by discovering that the reaction proceeds with almost the same high yield even if the reaction raw materials and the order of addition of the coexisting botanicals are changed.

That is, the present invention provides r(1) general formula ([) (wherein R1 is a hydrogen atom or a lower alkyl group, a phoryl group, R2 is a lower alkoxycarponyl group or an amide group,
R3 represents an acetoxy group or a hydroxy group. ) and a hydride source with oxygen and Fe”
React in the presence of an ion source II) p. II R, R2 (wherein Rll R2 and R3 have the same meanings as above, and R4 and R, one is a hydroxy group and the other is an ethyl group) ), a hydride source, and an oxygen and Fe'゜ ion source in two or more solutions, and the two or more solutions are brought into continuous contact with each other. Continuous manufacturing method of

2. A sequence of dimeric alkaloids as described in 1 above, characterized in that a solution containing oxygen and the compound of formula (1), a solution containing a hydride source, and a solution containing a Fe'' ion source are brought into continuous contact. manufacturing method.

3. In two or more solutions brought into contact, an inorganic anion source,
A series of dimeric alkaloids as described in 1 or 2 above, characterized in that it contains one or more active ingredients selected from pyridine derivatives and amino acids and an oxalate ion source and/or malonate ion source. manufacturing method.

4. The compound of formula CHI) is vinplastine (wherein R+
= Gate e, Rz=COzMe, R3=OCOMe,
R4=Et, R, =OH).

5. The compound of formula (n) is leulocidine (wherein R=Me
, Rz=CO2Me, R3=OCMe+R4=O
H, Rs=Et), the method for continuously producing dimeric alkaloids according to any one of 1 to 3 above. ”.

In the continuous production method of dimeric alkaloids of the present invention, for example, two or more of the above-mentioned solutions are continuously fed into a reaction column from one inlet, contacted and mixed, and the reaction is completed while passing through the column. This can be carried out by an extremely simple operation in which the reaction mixture is continuously recovered from the other outlet.

In addition, in any of the solutions to be contacted and mixed in the present invention, one or more precepts selected from an inorganic anion source, a pyridine derivative, and an amino acid and an oxalate ion source and/or
By adding or a malonic acid ion source, the yield of the target compound can be significantly improved.

These additions are most preferably added to a solution containing a trivalent iron ion source, but are not limited to this, and may be added to any of two or more solutions brought into contact. The yield of the target compound is also improved in almost the same way.

However, additions of combinations that would rapidly decompose the hydride source should be avoided.

The trivalent iron source used may be any source that can dissolve in the reaction mixture and participate in the reaction. In the present invention, hydrochlorides, sulfates, and nitrates are particularly preferred. The amount of these additions is 0.1 to t o to the raw material.
ooo times the mole, preferably 1 to 2000 times.

As the oxalate ion source and malonic acid ion source to be added, any source may be used as long as it can be dissolved in the reaction mixture, but when adding free oxalic acid and malonic acid,
It is necessary to further add about an equivalent amount of a suitable base. Preferred examples of the oxalate ion source and malonate ion source include alkali ltL ammonium salts and alkylammonium salts such as Li salt, Na salt, and K salt.

The amount of these additions is 0.00% relative to trivalent iron. The amount is 1 to 3 times the mole, preferably 1 to 2 times the mole.

Any inorganic anion source may be used, but CO3"'
, PO43-, and other inorganic anions that would lead to the formation of insoluble iron salts are excluded. In the present invention, especially C
l-. Br-, do, so. In addition, the type of salt of the inorganic anion source may be any salt as long as it is soluble in the reaction solvent, but ammonium salts, alkyl anmonium salts, and alkali metal salts are particularly preferable. is 0.1 to 100 times mole, preferably 1 to 10 times mole, relative to trivalent iron.

The pyridine derivative may be any pyridine derivative, but pyridine, alkyl pyridines, α, α'-biviridine, and alkyl α, α'-biviridine are particularly preferred. The amount added is 0 for trivalent iron.
．． 01 to 10 times the molar amount is preferable.

As an amino acid, any amino acid may be used,
Although not particularly limited, low molecular weight amino acids such as glycine and N-methylglycine are generally preferred.

The oxygen may be oxygen or oxygen diluted with an inert gas, but air is usually preferred. It is preferable that the oxygen-containing gas be bubbled in advance into one of the solutions to be brought into contact so that it is appropriately dissolved.

Sodium borohydride as a hydride source? potassium borohydride, sodium cyanoborohydride,
Examples include amine complexes of borane. The amount of hydride source used is 0.05 to 10% relative to trivalent iron.
twice the mole, preferably 0. It is 1 to 1 times the mole.

Solvents used for this reaction include H20, methanol,
Alcohols such as ethanol, THF, 7-1! Examples include tonitrile, DMF, KanoSO, etc.

Further, a mixed solvent of two or more of these may also be used. Generally, 1110 alone or a mixed solvent of IhO and methanol are recommended.

The reaction temperature can be in a wide range from above the melting point of the reaction solvent to about 50°C, but is preferably -2°C.
0-10'C.

The contact time of the reaction solution is from 0.1 seconds to 60 minutes, preferably 1
It is from seconds to 10 minutes.

Although the reactor may be of any shape, a columnar reactor is particularly preferred.

〔Effect of the invention〕

According to the present invention, dimeric alkaloids such as vinblastine and leulocidine, which are useful as anticancer agents, can be produced industrially using anhydrovinblastine and its analogues as starting materials in significantly higher yields and with simpler operations compared to conventional methods. A continuous manufacturing method is provided for manufacturing to advantageous purposes.

Considering that vinblastine is a very expensive anticancer drug, the effects of the method of the present invention are very large.

〔Example〕

Next, the present invention will be explained in detail using examples.

However, the present invention is not limited to these Examples.

Example 1 Acihydrobinplasti 7 (AVLB) IQmg.
32 times molar FeCl to AVLB: +・611
zO, 2 for 5 equivalents of 2N-11CI Fe3+
twice the molar amount of (NH<)zCzOa, four times the molar amount of Nl14C
After dissolving 1 and 4 times the mole of glycine in 100 cc of water, air was bubbled at O''C for 30 minutes.This solution and 12.9 mg of NaBl{a were dissolved in 2 cc of water,
The liquid cooled to °C is introduced into the reaction ram and brought into contact with it,
After reacting by passing through the column for 1 minute, the reaction solution was poured into aqueous ammonia (25% aqueous ammonia diluted with water).

Extract this with AcOEt 100mffi three times,
It was dried under reduced pressure at 40°C or less and analyzed by liquid chromatography. The results showed that the conversion rate of AVLB was 67.5%, the yield of vinblastine (VLB) was 32%, and the yield of leulocidium 7 (LEU) was 67.5%.
The yield was 12%.

The analysis conditions for liquid chromatography are as follows.

Column: YMC Packed Column AM
-312 (S-5 120 AODS)} Container:
CH:lCN:0. OIM(NH4)zcOtaq=1
800:1200 Flow rate: lml/min Column temperature: 45°C Detection wavelength: 254nm ．． : VLB=12.8 minutes,
AVLB=42.1 min Example 2 AVLB nosulfate 2i. The procedure was carried out in exactly the same manner as in Example 1 except that 2 mg was used and 2N}1cI was not added. At the time of conversion, AVLB conversion rate was 67%, VLB yield was 3
3.5%, and the LED yield was 13%.

Examples 3 to 6 The same procedure as in Example 2 was carried out except that the amount of NaB}I4 was changed. The results are shown in Table 2.

Table 2 Table 3 Examples 9 to 10 Using 38 mg of A V L B with a contact time of about 6 seconds,
The same procedure as in Example 1 was carried out except that the amount of NaBH4 was changed.

The results are shown in Table 4.

Table 4 Examples 7-8 The same procedure as in Example 2 was carried out except that the amount of AVLB sulfate was doubled and the amount of NaBHs was changed. The results are shown in Table 3.

(Margins below this page) Example 11 The same procedure as in Example 1 was carried out except that 38 mg of AVLB was used, the amount of NaBHa was 34.4 mg, and the gas bubbling into the AVLB: liquid was changed from air to pure oxygen. At this time, AVLB conversion rate was 72.5%, vu yield was 27.5%, L
The Bu yield was 11%.

Example 12 NII. C.I.
The same procedure as in Example 2 was carried out, except that instead of trivalent iron, equivalent molar amount of α,α'-bipyridine was added. At this time, the AVLB conversion rate was 65%, the VLB yield was 36%, and the LE
The U yield was 9%.

Example 13 PeCl in AVLB sulfate solution in Example 5
3.6H20, (NHa)zCzOa, NH4CI, and glycine were prepared as separate 2 cc aqueous solutions, and this solution, AVLB sulfate solution, and NaBll4 solution were simultaneously and continuously introduced into the reaction ram. The same procedure as in Example 5 was carried out.

At this time, the conversion rate of 8 VLBs was 80%, the VLB yield was 31%, and the L
The EU yield was 12%.

Detonin Mitsui Petrochemical Industries Co., Ltd.

Claims (1)

[Claims] 1. General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc.▼... [I] (In the formula, R_1 is a hydrogen atom, a lower alkyl group, a formyl group, and R_2 is a lower alkoxy carbonyl group or amide group, R_3 represents an acetoxy group or hydroxy group) and a hydride source in the presence of oxygen and Fe^
3＾+ React in the presence of an ion source to form the formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ... [II] (In the formula, R_1, R_2 and R_3 have the same meaning as above, One of R_4 and R_5 is a hydroxy group and the other is an ethyl group) In the method for producing a compound represented by the formula [I] compound, a hydride source, oxygen and Fe^3^+ ion source, each component compound are included in two or more solutions, and the two or more
1. A method for continuously producing dimeric alkaloids, which comprises continuously bringing two or more kinds of solutions into contact with each other. 2. The method according to claim 1, wherein the solution containing oxygen and the compound of formula [I], the solution containing the hydride source, and the solution containing the Fe^3^+ ion source are brought into continuous contact. Continuous production method of mercury alkaloids. 3. One or more components selected from an inorganic anion source, a pyridine derivative, and an amino acid and an oxalate ion source and/or malon in one or more of the two or more solutions to be brought into contact with each other. 3. The method for continuously producing dimeric alkaloids according to claim 1 or 2, further comprising a source of acid ions. 4. The compound of formula [II] is vinblastine (wherein R_1
=Me, R_2=CO_2Me, R_3=OCMe,
4. The method for continuously producing dimeric alkaloids according to claim 1, wherein R_4=Et and R_5=OH. 5. The compound of formula [II] is leulocidine (wherein R_1=
Me, R_2=CO_2Me, R_3=OCOMe, R
The method for continuously producing dimeric alkaloids according to any one of claims 1 to 3, wherein _4=OH and R_5=Et.