CN101337900B - Method of synthesizing camptothecin-relating compounds - Google Patents
Method of synthesizing camptothecin-relating compounds Download PDFInfo
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- 0 C=CCC(*1)=C(*N=O)C=CC1O Chemical compound C=CCC(*1)=C(*N=O)C=CC1O 0.000 description 3
- IYYOBNRNXIHCBN-UHFFFAOYSA-N CC(C(CC(C1=CC(C2N=O)=C3COC2=O)C3=O)=C1N=O)=O Chemical compound CC(C(CC(C1=CC(C2N=O)=C3COC2=O)C3=O)=C1N=O)=O IYYOBNRNXIHCBN-UHFFFAOYSA-N 0.000 description 1
- DTKZGMJGXUHRMB-UHFFFAOYSA-N COC1NC([Si](C)(C)C)=CC(I)=C1CO Chemical compound COC1NC([Si](C)(C)C)=CC(I)=C1CO DTKZGMJGXUHRMB-UHFFFAOYSA-N 0.000 description 1
- NQKIFRSZGVLWSK-UHFFFAOYSA-N COc1c(C=O)c(I)cc([Si](C)(C)C)n1 Chemical compound COc1c(C=O)c(I)cc([Si](C)(C)C)n1 NQKIFRSZGVLWSK-UHFFFAOYSA-N 0.000 description 1
- VIAVPTSCPCVQCF-UHFFFAOYSA-N [O-][N+](C(CC1)=C(C=O)C=C1O)=O Chemical compound [O-][N+](C(CC1)=C(C=O)C=C1O)=O VIAVPTSCPCVQCF-UHFFFAOYSA-N 0.000 description 1
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Abstract
In order to effectively provide initial compound CPT of irinotecan hydrochloride and various camptothecinum derivatives through a practical total synthesis, the invention provides a method for effectively preparing 2'-amino-5'-(benzeneboronic)ethyl ketone homologous to AB-ring part of the framework of camptothecinum (CPT) and tricyclic ketone homologous to CDE-ring part and stably supplying CPT and the derivatives thereof.
Description
The application is to be dividing an application that February 21, Chinese Patent Application No. in 2002 are 02805323.0, denomination of invention is " synthetic method of camptothecin-relating compounds " applying date.
Technical field
The present invention relates to the synthetic method of camptothecin-relating compounds.In more detail, the present invention relates to and the preparation method of the synthetic relevant intermediate of the camptothecin with anti-tumor activity and the purposes of described intermediate, and relate to the complete synthesis of camptothecin.
Background technology
From China, the camptothecine (hereinafter referred to as CPT) of the separation such as the bark of original camplotheca acuminata (Camptotheca acuminata), root, fruit, leaf is the five rings alkaloid, and known its synthesizes and show anti-tumor activity by inhibition nucleic acid.On the other hand, in camptothecin derivative, reported side effect (the cancer とization Learn Treatment method 17 of inducing diarrhoea etc., p115-120,1990), also exist and cause the problem to Alimentary infringement, in order to reduce the purposes such as toxicity, reinforced effects, after tested various derivatives.
The present inventor has reported the compound alleviated than such CPT toxicity, water-soluble semi synthesis of derivatives 7-ethyl-10-[4-(1-piperidino-(1-position only)) of CPT-1-piperidino-(1-position only)] carbonyl oxygen base camptothecine hydrochloride trihydrate (hereinafter referred to as CPT-11), now it is widely used as to antitumour drug (general name: U 101440E).
Camptothecin as CPT-11 can carry out chemically modified by the CPT to obtaining from natural materials and obtain.
Yet, because the amount of the CPT obtained from natural materialss such as starting material camplotheca acuminatas is very low, along with the demand of useful derivative CPT-11 etc. increases, although taked the measure of the raw material supplies such as trees planting, can expect that the CPT supply of sufficient quantity is still very difficult.Although also tested by complete synthesis method for making, present situation is still not reach practical.
As the method for making by complete synthesis, knownly by following reaction formula, meaned, Shen, W. etc. through aminophenyl ethyl ketone and tricycle kentones
method (the J.Org. Chem.1993 of reaction, 58,611-617 " Concise Total Syntheses of dl-Camptothecinand Related Anticancer Drugs. "), but the method still exists step miscellaneous, and yield is not high yet, and problem that can only the synthesising racemation body.
On the other hand, although Curran, D.P. wait the method (Chem.Eur.J.1998 of the cascade free radical cyclization of aryl isonitrile by using following reaction formula to mean and iodo pyridone, 4, 67-83 " A General Synthetic Approach to the (20S)-CamptothecinFamily of Antitumor Agents by a Regiocontrolled Cascade RadicalCyclization of Aryl Isonitriles. ") carried out complete synthesis, but the yield that proposes cyclization is insufficient, must carry out the problem of the deprotection of protecting group after cyclisation.
In addition, although according to following mechanism, above-mentioned Curran, D.P. etc. have synthesized the iodo-2-methoxyl group of intermediate 4-in tricycle kentones part synthetic of CPT class-6-trimethyl silyl pyridine-3-formaldehyde,
Josien, H; Ko, S.-B.; Bom, D.; Curran, D.P.Chem Eur:J.1998,4, No.1,67. but this method makes dangerous the rising because needing a large amount of industrial inflammable t-BuLi of use, and require the reaction that temperature of reaction is-78 ℃, therefore can not enlarge in batches.In addition, owing to needing to carry out complicated temperature in reaction system integral body, control, so it is not the reaction system of industrial practicality.
Summary of the invention
The objective of the invention is the complete synthesis initial compounds CPT that U 101440E and various camptothecin derivatives are provided effectively by practicality, and the camptothecin of the synthetic important intermediate SN38 of U 101440E etc.Especially, the objective of the invention is to synthesize respectively the intermediate and the intermediate that is equivalent to the CDE loop section of the AB loop section that is equivalent to the camptothecin skeleton, and further with the synthetic camptothecin of these intermediates.
Embodiment
The inventor has carried out broad research to these situations, about the AB loop section, with compound (a) (5-hydroxyl-2-nitrobenzaldehyde):
As initial substance, 2 '-amino-the 5 '-hydroxypropiophenone that has effectively prepared the AB loop section that is equivalent to the CPT skeleton, thereby the means of CPT and derivative thereof have been found stably to provide, about the CDE loop section, with compound (k) (2-methoxyl group-6-trimethyl silyl pyridine (MTP)):
(in formula, TMS represents trimethyl silyl, the Me represent methylidene)
As initial substance, effectively prepared the tricycle kentones of the CDE loop section that is equivalent to the CPT skeleton, thereby found the stable means that CPT and derivative thereof are provided, by the proper combination of these means, set up the total synthesis method without the CPT class of natural materials, thereby completed the present invention.
That is to say, the present invention relates to basis
The preparation method of 2 ' of the AB loop section that is equivalent to the CPT skeleton of (in formula, R represents protecting group)-amino-5 '-hydroxypropiophenone, and preparation method's the total synthesis method of CPT class that has combined the tricycle kentones of the CDE loop section that is equivalent to the CPT skeleton, the preparation method of described tricycle kentones comprises the synthetic route Curran route (Josien based on known, H; Ko, S.B.; Bom, D.; Curran, D.P.Chem.Eur.J.1998,4 67-83) and Pharmacia& Upjohn route (P& hereinafter referred to as; The U route; Heneger, K.E.; Ashford, S, W.; Baughman, T.A.; Sih, J.C.; Gu, R.L.J.Org.Chem.1997,62,6588-6597) and the synthetic route set up
(in formula, TMS means trimethyl silyl, and Me means methyl, and Et means ethyl, and Pr means propyl group,
tbu means the tertiary butyl) improved and optimized, particularly by 2-methoxyl group-6-trimethyl silyl pyridine (compound (k)) or the synthetic iodo-2-methoxyl group of 3-formyl radical-4-of the iodo-2-methoxyl group of 3-methylol-4--6-trimethyl silyl pyridine (compound (v))-6-trimethyl silyl pyridine (compound (l)).In addition, because compound (v) is the by product generated from the process of the synthetic 3-(2-butylene oxygen methyl) of compound (the l)-iodo-2-methoxyl group of 4--6-trimethyl silyl pyridine (compound (m)), compound in said synthesis route (l) is described below.
In more detail, the present invention relates to the preparation method for the synthesis of 2 ' of camptothecin-amino-5 '-hydroxypropiophenone, wherein from compound (a):
Generate compound (b):
Generate compound (c) from compound (b):
Generate (d) from compound (c):
Generate compound (e) from compound (d):
It is characterized in that R may pass through catalytic reduction and the protecting group of deprotection.
The invention still further relates to aforesaid method, it is characterized in that may be by catalytic reduction the protecting group of deprotection be benzyl.
In addition, the present invention relates to aforesaid method, it is characterized in that described method comprises one or more following steps that are selected from:
(1) compound (a), benzyl reagent and alkali are mixed, and in solvent this mixture of heated and stirred and obtain the step of compound (b);
(2) obtain the step of compound (c) to dripping Grignard reagent in compound (b) under atmosphere of inert gases;
(3) compound (c) and oxygenant are mixed, and stir and the step of acquisition compound (d); And
(4) catalytic reduction compound (d) and obtain the step of compound (e).
In addition, the present invention relates to aforesaid method, wherein the solvent in step (1) is dimethyl formamide.
The invention still further relates to aforesaid method, wherein the Grignard reagent in step (2) is vinyl bromination magnesium.
In addition, the present invention relates to aforesaid method, wherein the oxygenant in step (3) is Jones reagent, Manganse Dioxide or TEMPO-(2,2,6,6-tetramethyl piperidine-1-oxygen)-clorox.
The invention still further relates to the compound that molecular formula (c ') means:
(in formula, Bn means benzyl).
In addition, the present invention relates to the compound of molecular formula (d '):
(in formula, Bn means).
The invention still further relates to the preparation method for the synthesis of 2 ' of camptothecin-amino-5 '-hydroxypropiophenone, wherein from compound (a):
The generation compound (c "):
Generate compound (d ") from compound (c "):
Generate compound (e) from compound (d "):
In addition, the present invention relates to aforesaid method, it is characterized in that described method comprises one or more following steps that are selected from:
(1) obtain the step of compound (c ") to dripping Grignard reagent in compound (a) under atmosphere of inert gases;
(2) compound (C ") and oxygenant are mixed, and stir and obtain the step of compound (d ");
(3) catalytic reduction compound (d ") and obtain the step of compound (e).
The invention still further relates to aforesaid method, wherein the Grignard reagent in step (1) is vinyl bromination magnesium.
In addition, the present invention relates to aforesaid method, wherein the oxygenant in step (2) is Jones reagent, Manganse Dioxide or TEMPO-clorox.
The invention still further relates to the purposes for the preparation of camptothecin by 2 ' of preceding method acquisition-amino-5 '-hydroxypropiophenone.
In addition, the present invention relates to the preparation method of camptothecin, described method comprises makes 2 '-amino-the 5 '-hydroxypropiophenone and the tricycle kentones reaction that obtain by preceding method.
The invention still further relates to the preparation method for the synthesis of the tricycle kentones of camptothecin, wherein from compound (k):
(in formula, TMS means trimethyl silyl, and Me means methyl), or compound (v):
(in formula, TMS means trimethyl silyl, and Me means methyl)
Generate compound (l):
(in formula, TMS means trimethyl silyl, and Me means methyl),
Generate compound (m) from compound (l):
(in formula, TMS means trimethyl silyl, and Me means methyl),
Generate compound (n) from compound (m):
(in formula, TMS means trimethyl silyl, and Me means methyl, and Et means ethyl),
Generate compound (o) from compound (n):
(in formula, TMS means trimethyl silyl, and Me means methyl, and Et means ethyl),
Generate compound (p) from compound (o):
(in formula, TMS means trimethyl silyl, and Me means methyl, and Et means ethyl),
Generate compound (q) from compound (p):
(in formula, Me means methyl, and Et means ethyl),
Generate compound (r) from compound (q):
(in formula, Me means methyl, and Et means ethyl, and Pr means propyl group),
Generate compound (s) from compound (r):
(in formula, Et means ethyl, and Pr means propyl group),
Generate compound (t) from compound (s):
(in formula, Et means ethyl,
tbu means the tertiary butyl),
Generate compound (h) from compound (t):
(in formula, Et means ethyl), it is characterized in that described method comprises one or more following steps that are selected from:
(1) compound (k), lithiation reagent, formylation reagent and iodination reagent are mixed and the step of acquisition compound (l);
(2) compound (l), crotyl alcohol, triethyl-silicane and acid are mixed, and under the condition without solvent this mixture of reaction and obtain the step of compound (m);
(3) by-product compounds (v) in step (2) and oxygenant and alkali mixed and obtain the step of compound (l);
(4) compound (m), palladium catalyst, alkali and phase-transfer catalyst are mixed, and in solvent this mixture of boiling reflux and obtain the step of compound (n);
(5) compound (n), osmium catalyst, co-oxidants, alkali and unsymmetrical reagent are mixed and the step of acquisition compound (o);
(6) compound (o), alkali and iodine are mixed, and in alcohol-water mixtures this mixture of boiling reflux and obtain the step of compound (p);
(7) compound (p) and desilylation iodination reagent are mixed and the step of acquisition compound (q);
(8) by compound (q), palladium catalyst and alkali are mixed, and under the carbon monoxide atmosphere in n-propyl alcohol this mixture of reaction and obtain the step of compound (r);
(9) by compound (r) and demethylation reagent mix, and at room temperature react this mixture and obtain the step of compound (s);
(10) compound of reaction (s) and obtain the step of compound (t) under the existence of tert-butyl acrylate and alkali.
In addition, the present invention relates to aforesaid method, wherein the lithiation reagent in step (1) is n-Butyl Lithium.
The invention still further relates to aforesaid method, wherein the temperature of reaction in step (1) is the constant temperature of-30～-40 ℃.
In addition, the present invention relates to aforesaid method, wherein the oxygenant in step (3) is the TEMPO-clorox.
The invention still further relates to aforesaid method, wherein the alkali in step (4) is salt of wormwood or DIPEA.
In addition, the present invention relates to aforesaid method, wherein the solvent in step (4) is tetrahydrofuran (THF) or diisopropyl ether-acetonitrile-water mixed solution.
The invention still further relates to aforesaid method, wherein the osmium catalyst in step (5) is the sour potassium of osmium (VI).
In addition, the present invention relates to aforesaid method, wherein, in step (6), for compound (o), iodine is 4 equivalents.
The invention still further relates to aforesaid method, wherein the desilylation iodination reagent in step (7) is iodo-trifluoroacetic acid silver or N-chlorosuccinimide-sodium iodide.
In addition, the present invention relates to aforesaid method, wherein by purification step, compound (q) is carried out to chemical purification, described purification step comprises:
The reaction product that will obtain by the step that generates compound (q) from compound (p) adds alkaline aqueous solution and the step stirred;
After adding organic solvent stirring, the step of removing organic layer; And
Make water layer become acidity, and by the step of organic solvent extraction.
The invention still further relates to aforesaid method, wherein alkaline aqueous solution is aqueous sodium hydroxide solution.
In addition, the present invention relates to aforesaid method, wherein organic solvent is chloroform.
The invention still further relates to aforesaid method, wherein by purification step, compound (q) is carried out to the optics purifying, described purification step comprises:
After the reaction product that will obtain by the step that generates compound (q) from compound (p) is dissolved in high polar solvent, the step of lamination low polar solvent; And
After filtering precipitate, under reduced pressure filtrate is concentrated into to dry step.
In addition, the present invention relates to aforesaid method, wherein high polar solvent is chloroform.
The invention still further relates to aforesaid method, wherein low polar solvent is normal hexane.
In addition, the present invention relates to aforesaid method, wherein the alkali in step (10) is salt of wormwood.
The invention still further relates to the tricycle kentones that obtained by the aforesaid method purposes for the preparation of camptothecin.
In addition, the present invention relates to the preparation method of camptothecin, described method comprises reacts the tricycle kentones and 2 ' that obtained by aforesaid method-amino-5 '-hydroxypropiophenone.
The invention still further relates to aforesaid method, wherein 2 '-amino-5 '-hydroxypropiophenone is 2 '-amino-the 5 '-hydroxypropiophenone obtained by aforesaid method.
In addition, the present invention relates to aforesaid method, wherein tricycle kentones and 2 '-amino-5 '-hydroxypropiophenone is mixed, and react this mixture under atmosphere of inert gases.
The present invention becomes possibility, and makes the complete synthesis practical possibility that becomes of CPT by 2 '-amino-the 5 '-hydroxypropiophenone that adopts these key elements to make effectively preparation be equivalent to the AB loop section of CPT skeleton.In addition, about the midbody compound in preparation method of the present invention (c ') and compound (d '), still there is no their synthetic reports, so they are useful new compounds in CPT is synthetic.
The present invention is by adopting these key elements, and the dissymmetric synthesis of compound that also makes practicably to be had the skeleton of the CDE loop section (tricycle kentones part) in the CPT skeleton becomes possibility.
Synthetic about the AB loop section of CPT skeleton (2 '-amino-5 '-hydroxypropiophenone), the preparation method of 2 '-amino-5 '-hydroxypropiophenone comprises one or more following steps:
(1) from the synthetic 5-benzyloxy of 5-hydroxyl-2-nitrobenzaldehyde (compound (a))-2-nitrobenzaldehyde (compound (b ')) step;
(2) from the synthetic 1-(5-benzyloxy-2-nitrophenols) of compound (b ')-2-propenyl-1-alcohol (compound (c ')) step;
(3) from the synthetic 1-(5-benzyloxy-2-nitrophenols) of compound (c ')-2-propenyl-1-ketone (compound (d ')) step; And
(4) from the step of synthetic 2 '-amino-the 5 '-hydroxypropiophenone (compound (e)) of compound (d ').
Typical synthetic route can be expressed as following synthetic route:
(in formula, R express possibility the protecting group of by catalytic reduction deprotection).
In the present invention; as long as R may pass through catalytic reduction and the protecting group of deprotection; to it, there is no particular limitation; typical example is benzyl, methoxybenzyl, 2; the benzylic ethers such as 6-dimethyl benzyl, 4-nitrobenzyl are protecting group, and the benzyl carbonic ether such as carbobenzoxy-(Cbz) is protecting group, especially; from the angle of reagent cost, it is suitable using benzyl.
In addition, as starter compound (a), can use the material synthetic by currently known methods, the material changed from similar compound chemistry, from the material of the separation such as various natural materialss, purifying, or the natural matter that contains compound (a).Also can use commercial reagent.
Below be described more specifically above-mentioned steps (1)～(4).
In step (1), compound (a) is dissolved or suspended in solvent, add benzyl reagent and alkali, heat and stir and obtain compound (b).
As solvent, can use DMF (DMF), methyl-sulphoxide, chloroform, acetonitrile, ethanol, water etc., especially, from solvability and reactive angle, DMF is preferred.
For compound (a), the usage quantity of DMF can, for more than 3 times or 3 times, be preferably the scope of 3～20 times of amounts.
As benzyl reagent, can use aptly any normally used benzyl reagent.The specific examples of benzyl reagent is benzyl chloride, bromotoluene, benzyl iodide, phenyldiazomethane, dimethyl benzyl etc., particularly can use aptly benzyl chloride.
The usage quantity of benzyl reagent can be modulated aptly according to reagent, for example, in the situation that the use benzyl chloride for compound (a), can be used 1～5 equivalent, preferably 1～2 equivalent.
As alkali, can use aptly any normally used alkali.The specific examples of alkali is salt of wormwood, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide etc., especially, can use aptly salt of wormwood.
The usage quantity of alkali can be modulated aptly according to reagent, for example, in the situation that use salt of wormwood for compound (a), is used 1～10 equivalent, preferably 1～4 equivalent.
Heating temperature, in the scope of 60～100 ℃, especially, is preferred in the scope of 60～80 ℃.
In addition, the reaction times, in the scope of 0.5～24 hour, especially, is preferred in the scope of 1～20 hour.
In step (2), by under atmosphere of inert gases, to dripping Grignard reagent in compound (b), obtaining compound (c).
As rare gas element, can use the rare gas class of any argon gas, helium, neon, Krypton, xenon, radon gas etc., or the low gas of nitrogen isoreactivity, especially, from the angle of cost, preferred helium and nitrogen.
As Grignard reagent, can use aptly any normally used Grignard reagent.The specific examples of Grignard reagent is vinyl bromination magnesium, vinyl chlorination magnesium, vinyl iodate magnesium etc., especially, can use aptly vinyl bromination magnesium.
The usage quantity of Grignard reagent can be modulated aptly according to reagent, for example, if vinyl bromination magnesium is 1～2 equivalent for compound (b), and preferred 1～1.5 equivalent.
Grignard reagent can be added drop-wise in the solution of compound (b), also can on the contrary the solution of compound (b) be added drop-wise in Grignard reagent, but in order to reduce reduced form by product (hereinafter referred to as compound (f))
(in formula, R express possibility the protecting group of by catalytic reduction deprotection), preferably be added drop-wise to Grignard reagent in the solution of compound (b).
The quantity of solvent of using about when reaction, for example, if tetrahydrofuran (THF) (hereinafter referred to as THF), its amount can be 10～100 times of amounts, especially, in order to reduce pure generation, is preferably 50～100 times of amounts.
Temperature of reaction preferably is no more than 10 ℃, especially, in order to reduce pure generation, is preferably-78～-40 ℃.
Reaction times is 0.1～3 hour, especially, is preferably 0.5～1 hour.
In step (3), by compound (c) and oxygenant are mixed, and stir and acquisition compound (d).
Oxygenant can be used any normally used oxygenant aptly.The example of this oxygenant is Manganse Dioxide, Dess-Martin reagent (Dess-Martin Periodinane), Jones reagent (Na
2cr
2o
7/ H
2sO
4), PCC, PDC, DMSO/ oxalyl chloride/triethylamine (Swern oxidation), TEMPO-clorox etc., especially, preferably use Manganse Dioxide, Dess-Martin reagent, Jones reagent and TEMPO-clorox.
Preferably just prepared by these oxygenants, for example, if Manganse Dioxide, can use aptly before use the Manganse Dioxide prepared from potassium permanganate and manganous sulfate before use.
The usage quantity of oxygenant can be according to reagent and modulation aptly, and for example, if Manganse Dioxide, for compound (c), its amount is 2～50 times of amounts, preferably 4～10 times of amounts.
As solvent, can use aptly such as chloroform, methylene dichloride, ethyl acetate, benzene, toluene etc., especially, be preferably chloroform and methylene dichloride.
The usage quantity of solvent is 5～50 times of amounts, is preferably 10～20 times of amounts.
Reaction times is 1～48 hour, especially, is preferably 1～18 hour.
In step (4), can obtain compound (e) by catalytic reduction compound (d).
As catalyst for reduction, can use aptly palladium-carbon, palladium hydroxide-carbon, rhodium-aluminum oxide etc., especially, be preferably palladium-carbon and palladium hydroxide-carbon.
For compound (d), the usage quantity of catalyst for reduction is 0.01～0.5 equivalent, is preferably 0.05～0.2 equivalent.
As solvent, can use aptly any normally used solvent, but, from deliquescent angle, ethyl acetate is preferred.
For compound (d), the usage quantity of solvent is 5～50 times of amounts, is preferably 10～20 times of amounts.
Reaction times in the scope of 0.1～24 hour, especially, preferably in the scope of 1～3 hour.
In addition, through above-mentioned steps (1) to step (4) synthetic compound (e) not, and can be from compound (a):
The generation compound (c "):
Generate compound (d ") from compound (c "):
Can generate compound (e) from compound (d "):
In this synthetic route, can obtain compound (c ") by under atmosphere of inert gases, Grignard reagent being added drop-wise in compound (a).In addition, can be by compound (c ") and oxygenant are mixed, and stir and acquisition compound (d "), can pass through catalytic reduction compound (d ") and obtain compound (e).Here identical with in above-mentioned steps (2) and step (3) of operable Grignard reagent and oxygenant.In this synthetic route, due to without protecting group, therefore can carry out easily the synthetic of AB loop section.
In addition, by compound (e) and the tricycle kentones reaction that step (4) or said synthesis route are obtained, camptothecin analogues can be prepared, as such tricycle kentones, for example compound (h) can be used:
Synthetic about the CDE loop section (tricycle kentones part) of CPT skeleton, carry out the preparation of tricycle kentones through following synthetic route.
In formula, TMS means trimethyl silyl, and Me means methyl, and Et means ethyl, and Pr means propyl group,
tbu means the tertiary butyl).
As the initial compounds compound (K) in said synthesis route, can use by aforesaid Curran route (Josien, H; Ko, S.B.; Bom, D.; Curran, D.P.Chem.Eur.J.1998,4,67-83) synthetic compound, the compound changed from similar compound chemistry, from the compound of various natural materialss separation, purifying, or the natural materials itself that contains compound (k).
The preferred synthetic method of the tricycle kentones in above-mentioned synthetic route comprises one or more in following 12 steps:
(1) the step of the synthetic iodo-2-methoxyl group of 4--6-trimethyl silyl-3-pyridylaldehyde (hereinafter referred to as compound (l)) from 2-methoxyl group-6-trimethyl silyl pyridine (hereinafter referred to as compound (k)), use n-Butyl Lithium as alkali, react under the constant temperature of-30～-40 ℃;
(2) the step of synthetic 3-(2-butylene oxygen the methyl)-iodo-2-methoxyl group of 4--6-trimethyl silyl pyridine (hereinafter referred to as compound (m)) from compound (l), do not use reaction solvent;
(3), the step of iodo-2-methoxyl group-6-trimethyl silyl pyridine (hereinafter referred to as compound (v)) synthetic compound (l) from 3-methylol-4-, use the TEMPO-clorox as oxygenant;
(4) synthesizing 4-ethyl-8-methoxyl group-6-trimethyl silyl-1H-pyrans [3 from compound (m), 4-c] in the step of pyridine (hereinafter referred to as compound (n)), use the mixed solution of diisopropyl ether, acetonitrile and water as reaction solvent, and use DIPEA as alkali;
(5) synthesizing (S)-4-ethyl-3 from compound (n), 4-dihydro-3, in the step of 4-dihydroxyl-8-methoxyl group-6-trimethyl silyl-1H-pyrans [3,4-c] pyridine (hereinafter referred to as compound (o)), use the sour potassium of osmium (VI) as osmium catalyst;
(6) synthesizing (S)-4-ethyl-3 from compound (o), 4-dihydro-4-hydroxyl-8-methoxyl group-6-trimethyl silyl-3-oxygen-1H-pyrans [3,4-c] in the step of pyridine (hereinafter referred to as compound (p)), use the iodine of 4 equivalents to carry out boiling reflux;
(7) synthesizing (S)-4-ethyl-3 from compound (p), the iodo-8-methoxyl group of 4-dihydro-4-hydroxyl-6--3-oxygen-1H-pyrans [3,4-c] in the step of pyridine (hereinafter referred to as compound (q)), be used in the N-chlorosuccinimide-sodium iodide in acetic acid;
(8) in the step of chemical purification compound (q), add the alkaline aqueous solution such as aqueous sodium hydroxide solution and make solution be alkalescence, with the organic solvent of chloroform etc., washed, then with organic solvent extractions such as chloroforms, be acid water layer;
(9) in the step of optics purifying compounds (q), compound (q) is dissolved in the high polar solvent of chloroform etc., carry out lamination with the low polar solvent of normal hexane etc., filter the throw out obtained concentrated filtrate;
(10) synthesizing (S)-4-ethyl-3 from compound (q), 4-dihydro-4-hydroxyl-8-methoxyl group-3-oxygen-1H-pyrans [3,4-c] in the step of pyridine-6-carboxylic acid propyl ester (hereinafter referred to as compound (r)), use palladium as palladium catalyst;
(11) synthesizing (S)-4-ethyl-3,4,7 from compound (r), 8-tetrahydrochysene-4-hydroxyl-3, in the step of 8-dioxy-1H-pyrans [3,4-c] pyridine-6-carboxylic acid propyl ester (hereinafter referred to as compound (s)), at room temperature reacted;
(12) synthesizing (S)-4-ethyl-3 from compound (s), 4,8,10-tetrahydrochysene-4,6-dihydroxyl-3,10-dioxy-1H-pyrans is [3,4-f] indolizine-7-carboxylic acid 1 also, in the step of 1-dimethyl ethyl ester (hereinafter referred to as compound (t)), use salt of wormwood to carry out the Michel addition reaction.
In addition, (13) from (S)-4-ethyl-7,8-dihydro-4-hydroxyl-1H-pyrans also [3,4-f] indolizine-3,6,10 (4H)-triketones (hereinafter referred to as compound (h)) and compound (e) obtain in the step of SN-38, by being reacted under atmosphere of inert gases, can obtain aptly SN-38.
Below will be specifically described above-mentioned 13 steps.
In (1), by compound (k) is dissolved in solvent, add lithiation reagent, formylation reagent and iodination reagent, and stir and acquisition compound (1).
As solvent, can use tetrahydrofuran (THF) (THF), diethyl ether, hexane, heptane etc., especially, from solvability and reactive angle, THF is preferred.
As lithiation reagent, can use aptly any normally used lithiation reagent.The specific examples of lithiation reagent is n-Butyl Lithium, s-butyl lithium, tert-butyl lithium, diisopropylamine lithium (LDA), two (trimethyl silyl) amido lithium (LiHMDS) etc., especially, from operation and reactive angle, can use aptly n-Butyl Lithium.
The usage quantity of lithiation reagent can be according to reagent and modulation aptly, and for example, in the situation that use n-Butyl Lithium, for compound (k), its consumption is 2～10 equivalents, preferably 2～5 equivalents.
The specific examples of formylation reagent is N-formyl radical-N, N ', and N '-trimethylammonium quadrol, DMF (DMF) etc., consider follow-up iodination reaction, can use aptly N-formyl radical-N, N ', N '-trimethylammonium quadrol.
About the usage quantity of formylation reagent, for example using N-formyl radical-N, N ', in the situation of N '-trimethylammonium quadrol, for compound (k), it is 1～10 equivalent, is preferably 1～3 equivalent.
As iodination reagent, can use iodine, N-iodosuccinimide (NIS) etc., especially, from cost and reactive angle, iodine is preferred.
For compound (k), the usage quantity of iodination reagent is 1～10 equivalent, is preferably 1～5 equivalent.
Temperature of reaction, in the scope of 0～-78 ℃, is preferably the constant temperature of-30～-40 ℃.
In (2), by crotyl alcohol, triethyl-silicane and acid are added in compound (l), and stir and acquisition compound (m) under the condition without solvent.
For compound (l), the usage quantity of crotyl alcohol is 1～10 equivalent, is preferably 2～5 equivalents.
For compound (l), the usage quantity of triethyl-silicane is 1～10 equivalent, is preferably 1～4 equivalent.
As acid, can use trifluoroacetic acid (TFA), sulfuric acid, methylsulfonic acid, hydrochloric acid etc., especially, from reactive angle, TFA is preferred.
About sour usage quantity, for example, in the situation that TFA, for compound (l), it is 1～15 equivalent, is preferably 5～10 equivalents.
In (3), be dissolved in solvent by the by-product compounds (v) by (2), and add oxygenant and alkali, stir and acquisition compound (l).
As solvent, can use aptly any normally used solvent.As this solvent, can enumerate methylene dichloride, chloroform, acetonitrile, toluene, normal hexane etc., especially, from reactive angle, toluene and normal hexane are preferred.
As oxygenant, can enumerate Manganse Dioxide, Dess-Martin reagent (Dess-MartinPeriodinane), Jones reagent (Na
2cr
2o
7/ H
2sO
4), PCC, PDC, DMSO-oxalyl chloride-triethylamine (Swern oxidation), TEMPO-hypochlorite, especially, be preferably the TEMPO-hypochlorite, more preferably the TEMPO-clorox.
About the usage quantity of oxygenant, for example, in the situation that the TEMPO-clorox, for compound (v), TEMPO is 0.001～0.1 equivalent, is preferably 0.005～0.02 equivalent.In addition, the consumption of clorox is 1～5 equivalent, is preferably 1～2 equivalent.
As alkali, can use aptly any normally used alkali.As this alkali, can enumerate sodium bicarbonate, sodium carbonate, salt of wormwood, calcium carbonate, sodium hydroxide, calcium hydroxide, triethylamine etc., especially, sodium bicarbonate is preferred.
About the usage quantity of alkali, for example, in the situation that sodium bicarbonate, for compound (v), the consumption of sodium bicarbonate is 1～10 equivalent, is preferably 2～4 equivalents.
Temperature of reaction is in the scope of-10～30 ℃, and especially, in order to suppress side reaction, it is preferably-10～10 ℃.
Reaction times is in the scope of 0.5～10 hour, preferably in the scope of 0.5～5 hour.
In (4), by compound (m) is dissolved in solvent, add palladium catalyst, alkali and phase-transfer catalyst, boiling reflux and obtain compound (n).
As solvent, can use acetonitrile, tetrahydrofuran (THF) (THF), diisopropyl ether (IPE), diethyl ether, toluene, water etc., especially, from reactive angle, acetonitrile, THF, IPE and water are preferred, more preferably THF or acetonitrile-IPE-water mixed liquid.
As palladium catalyst, can use aptly palladium, tetrakis triphenylphosphine palladium (o), dichloro-two (triphenylphosphine) palladium (II), Palladous chloride etc., especially, from reactive angle, palladium is preferred.
For compound (m), the usage quantity of palladium catalyst is 0.01～1 equivalent, is preferably 0.05～0.2 equivalent.
As alkali, can use aptly any normally used alkali.The example of this alkali is sodium carbonate, salt of wormwood, calcium carbonate, cesium carbonate, triethylamine (TEA), DIPEA (DIPEA), sodium hydroxide, potassium hydroxide etc., especially, can use aptly salt of wormwood and DIPEA.
About the usage quantity of alkali, for example, in the situation that DIPEA, for compound (m), its consumption is 1～20 equivalent, is preferably 5～10 equivalents.
As phase-transfer catalyst, can use aptly any normally used quaternary ammonium salt or crown ether, especially, the bromination tetrabutylammonium.
About the usage quantity of phase-transfer catalyst, for example, in the situation that the bromination tetrabutylammonium, for compound (m), its consumption is 0.1～3 equivalent, is preferably 0.5～1.5 equivalent.
In the situation that use THF, the reaction times is in the scope of 1～20 hour, preferably in the scope of 4～10 hours.In the situation that use acetonitrile-IPE-water mixed liquid, it is in the scope of 0.5～10 hour, preferably in the scope of 1～5 hour.
In (5), by compound (n) is dissolved in alcohol-water mixtures, add osmium catalyst, co-oxidants, asymmetric catalyst, alkali and amsacrine, stir and acquisition compound (o).
As alcohol, can enumerate methyl alcohol, ethanol, 1-propyl alcohol, Virahol (IPA), n-butyl alcohol, 2-butanols, the trimethyl carbinol etc., especially, from reactive angle, the trimethyl carbinol is preferred.
As osmium catalyst, can use aptly perosmic anhydride, the sour potassium of osmium (VI) etc., especially, from the angle of operation, the sour potassium of osmium (VI) is preferred.
For compound (n), the usage quantity of osmium catalyst is 0.001～0.1 equivalent, is preferably 0.002～0.01 equivalent.
As co-oxidants, can use aptly the sour potassium of six cyano group iron (III), 4-methylmorpholine N-oxide compound (NMO) etc., especially, from reactive angle, the sour potassium of six cyano group iron (III) is preferred.
About the usage quantity of co-oxidants, for example, in the situation that the sour potassium of six cyano group iron (III), for compound (n), its consumption is 1～10 equivalent, is preferably 2～5 equivalents.
As asymmetric catalyst, can enumerate (DHQD)
2pYR, (DHQD)
2pHAL, (DHQD)
2aQN etc., especially, from the angle of asymmetric yield, (DHQD)
2pYR is preferred.
About the usage quantity of asymmetric catalyst, for example, at (DHQD)
2in the situation of PYR, for compound (n), its consumption is 0.005～0.1 equivalent, is preferably 0.01～0.05 equivalent.
As alkali, can use sodium carbonate, salt of wormwood, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide etc., especially, from reactive angle, salt of wormwood is preferred.
About the usage quantity of alkali, for example, in the situation that salt of wormwood, for compound (n), its consumption is 1～20 equivalent, is preferably 4～10 equivalents.
For compound (n), the usage quantity of amsacrine is 0.1～5 equivalent, is preferably 0.5～2 equivalent.
Temperature of reaction, in the scope of-10～30 ℃, is preferably-10～10 ℃.
In (6), by compound (o) is dissolved in solvent, add alkali and iodine, boiling reflux and obtain compound (p).
As solvent, can enumerate methyl alcohol, ethanol, 1-propyl alcohol, Virahol (IPA), water etc., especially, from reactive angle, methanol-water mixture is preferred.
As alkali, can use aptly any normally used alkali.As this alkali, can enumerate sodium carbonate, salt of wormwood, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide etc., especially, calcium carbonate is preferred.
About the usage quantity of alkali, for example, in the situation that calcium carbonate, for compound (o), its consumption is 1～10 equivalent, is preferably 2～5 equivalents.
With respect to the amount of compound (o), the usage quantity of iodine is 1～10 equivalent, is preferably 3～5 equivalents.
Reaction times in the scope of 0.5～20 hour, more preferably 1～5 hour.
In (7), by compound (p) is dissolved in solvent, at iodo-Silver Trifluoroacetate (hereinafter referred to as I
2-CF
3cOOAg) or under N-chlorosuccinimide-sodium iodide (hereinafter referred to as NCS-NaI) react and acquisition compound (q).
As solvent, at I
2-CF
3in the situation of COOAg, methylene dichloride, tetracol phenixin, chloroform etc. are more suitable, and especially, methylene dichloride is preferred.In addition, in the situation that NCS-NaI can be used acetic acid, acetonitrile etc., especially, from reactive angle, acetic acid is preferred.
About I
2-CF
3the usage quantity of COOAg, for compound (p), I
2consumption be 1～10 equivalent, be preferably 2～4 equivalents.In addition, CF
3the consumption of COOAg is 1～10 equivalent, is preferably 2～4 equivalents.
About the usage quantity of NCS-NaI, for compound (p), the consumption of NCS is 1～20 equivalent, is preferably 5～8 equivalents.In addition, the consumption of NaI is 1～20 equivalent, is preferably 5～8 equivalents.
Using I
2-CF
3in the situation of COOAg, temperature during reaction is 10～60 ℃, is preferably 20～40 ℃.In addition, in the situation that use NCS-NaI, temperature of reaction is 20 ℃～boiling reflux temperature, is preferably 50～80 ℃.
Reaction times, in the scope of 5～48 hours, is preferably 15～24 hours.
In (8), by compound (q) with such as the basic solvents such as aqueous sodium hydroxide solution of 0.2N, add, stir and make compound (q) form lactone open loop body (compound (u)):
(in formula, Me means methyl, and Et means ethyl), it is dissolved in alkaline aqueous solution.When with this solution of organic solvent washing, the material of neutral～alkalescence shifts in organic layer.By after the organic layer separatory, with acid, make water layer be acid, and reclaim compound (q) with organic solvent extraction with good purity.
The alkali solvent, in the scope of 0.01～5N, is preferably 0.1～1N.0.2～0.5N more preferably.
As used alkali, can enumerate potassium hydroxide, calcium hydroxide, sodium hydroxide, salt of wormwood, sodium carbonate etc., especially, sodium hydroxide is preferred.
As organic solvent, can use aptly any normally used organic solvent.As this solvent, can enumerate methylene dichloride, chloroform, ethyl acetate, toluene, diethyl ether, diisopropyl ether etc., especially, methylene dichloride and chloroform are preferred.
As used acid, can enumerate hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, trifluoroacetic acid etc., especially, hydrochloric acid is preferred.
In (9), compound (q) is dissolved in high polar solvent, use the low polar solvent lamination, crystallization.Filtering for crystallizing, under reduced pressure concentrated filtrate is to dry.The crystallization obtained is racemic modification, and further the compound (q) of optics purifying obtains as residue.
As high polar solvent, can use chloroform, methylene dichloride, ethyl acetate, methyl alcohol, ethanol, propyl alcohol etc., especially, chloroform is preferred.
About used high polar solvent amount, for example, in the situation that chloroform, for 1g compound (q), it,, in the scope of 1～10ml, is preferably 3～6ml.
As low polar solvent, can enumerate normal hexane, normal heptane, diethyl ether etc., especially, normal hexane is preferred.
About high polar solvent: the ratio of low polar solvent, for example, in the situation that chloroform: normal hexane, it is preferably 2: 1～1: 2 in the scope of 10: 1～1: 20.
The temperature of crystallization operation preferably is no more than room temperature, more preferably no more than 5 ℃.
In (10), by compound (q) is dissolved in the 1-propyl alcohol, add palladium catalyst and alkali, under the CO (carbon monoxide converter) gas atmosphere, react and acquisition compound (r).
As palladium catalyst, can use aptly palladium, tetrakis triphenylphosphine palladium (o), dichloro-two (triphenylphosphine) palladium, Palladous chloride etc., especially, from reactive angle, palladium is preferred.
For compound (m), the usage quantity of palladium catalyst is 0.005～0.5 equivalent, is preferably 0.01～0.1 equivalent.
As alkali, can use aptly any normally used alkali.The example of this alkali is sodium carbonate, salt of wormwood, calcium carbonate, cesium carbonate, triethylamine (TEA), DIPEA (DIPEA), sodium hydroxide, potassium hydroxide etc., especially, can use aptly salt of wormwood.
About the usage quantity of alkali, for example, in the situation that salt of wormwood, for compound (m), its consumption is 1～20 equivalent, is preferably 4～10 equivalents.
Temperature of reaction is in the scope of 20 ℃～boiling reflux temperature, preferably in the scope of 50 ℃～boiling reflux temperature.
In (11), by compound (r) is dissolved in solvent, add demethylation reagent, at room temperature react and obtain compound (s).
As solvent, can use acetonitrile, chloroform, methylene dichloride, toluene etc., especially, acetonitrile is preferred.
As demethylation reagent, can enumerate trimethysilyl chloride-sodium iodide, iodo trimethyl silane, hydroiodic acid HI, Hydrogen bromide etc., especially, from reactive viewpoint, trimethysilyl chloride-sodium iodide is preferred.
About the usage quantity of demethylation reagent, for example, in the situation that trimethysilyl chloride-sodium iodide, for compound (r), its consumption, in the scope of 1～10 equivalent, is preferably 2～5 equivalents.
In (12), by compound (s) is dissolved in solvent, add alkali, under atmosphere of inert gases, stir.In the mixture that tert-butyl acrylate is dripped as obtains, under rare gas element, stir and acquisition compound (t).
As solvent, can use aptly methyl-sulphoxide (DMSO), DMF (DMF) etc., especially, from reactive angle, DMSO is preferred.
As alkali, can use salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide etc., especially, salt of wormwood is preferred.
About the usage quantity of alkali, for example, in the situation that salt of wormwood, for compound (s), it is 1～20 equivalent, is preferably 2～5 equivalents.
As rare gas element, can use the rare gas classes such as argon gas, helium, neon, Krypton, xenon, radon gas, or the low gas of nitrogen isoreactivity, especially, from the angle of cost, argon gas and nitrogen are preferred.
For compound (s), the usage quantity of tert-butyl acrylate is 1～20 equivalent, is preferably 8～12 equivalents.
Temperature of reaction, in the scope of 20～80 ℃, is preferably 40～60 ℃.
Reaction times is 5～48 hours, and especially, for the decomposition of the compound (t) that prevents from generating, temperature of reaction preferably is no more than 24 hours.
In (13), by compound (h) and compound (e) are dissolved in solvent, add acid, and under atmosphere of inert gases heated and stirred and obtain SN-38.
As solvent, can use aptly toluene, acetic acid etc., especially, toluene-acetic acid mixed solution is preferred.
As rare gas element, can use the rare gas such as argon gas, helium, neon, Krypton, xenon, radon gas, or the low gas of nitrogen isoreactivity, especially, from the angle of cost, argon gas and nitrogen are preferred.
As acid, can use toluenesulphonic acids, methylsulfonic acid, trifluoroacetic acid etc., especially, from reactive angle, toluenesulphonic acids is preferred.
About sour usage quantity, for example, in the situation that toluenesulphonic acids, for 1g compound (h), it is 1～100mg, is preferably 10～30mg.
For compound (h), the usage quantity of compound (e) is 1～3 equivalent, is preferably 1～1.5 equivalent.
Temperature of reaction is in the scope of 50 ℃～boiling reflux temperature, preferably in the scope of 80 ℃～boiling reflux temperature.
The present invention will be described in more detail by the following examples, but the invention is not restricted to these embodiment.
[embodiment 1] compound (b ') synthetic
In formula, Bn means benzyl.
38.5g (0.230mol) compound (a) is dissolved in 116mL DMF or acetone, add while stirring 33.4g (0.242mol under room temperature under argon atmosphere, 2.1 equivalent) salt of wormwood and 27.8mL (0.242mol, 1.05 equivalent) or 59.95mL (0.461mol, 2 equivalents) benzyl chloride.After interpolation, heating under 60 ℃, and vigorous stirring.Regularly confirm the residual quantity of compound (a), after 20 hours, after confirming the disappearance of compound (a), suction filtration.
The solid matter obtained with the washing of 116mL reaction solvent, merging filtrate and washings, under reduced pressure boil off solvent.After boiling off, in residue, add 300mL water, after stirring, the suction filtration throw out is also air-dry.After air-dry, will leach thing and be dissolved in the 170mL ethyl acetate, under agitation it be added in the 1L hexane.The solid that suction filtration is separated out, after the mixed solvent washing with 300mL ethyl acetate-hexane (1: 10), drying under reduced pressure.The amount of benzyl chloride is depended in preparation example 1 and 2 difference.In preparation example 3, acetone is used as to reaction solvent.
[table 1]
| Reaction solvent | The benzyl amount of reagent | Reaction times | Separation yield | |
| Preparation example 1 | DMF | 1.05 equivalent | 20 hours | 94％ |
| Preparation example 2 | DMF | 2.00 equivalent | 1 hour | 94％ |
| Preparation example 3 | Acetone | 2.00 equivalent | 18 hours | - |
-: do not reach detectability
As shown in table 1, in the situation that use the benzyl chloride (preparation example 1) of 1.05 equivalents, react on end of a period in 20 hours, yield is 94%.On the one hand, in the situation that use the benzyl chloride (preparation example 2) of 2.00 equivalents, react on end of a period in 1 hour, yield is 94%.The DMF amount is minimum is 3 times of amounts, otherwise separates out solid matter in reaction, makes to stir difficulty.On the other hand, while using acetone as reaction solvent, even reflux 18 hours, reaction is not carried out yet.The HPLC operational condition
Post: Inertsil ODS-2,5 μ m, 4.6mm ID * 250mm (GL Science production)
Near temperature: the constant temperature 40 ℃
Moving phase: water: acetonitrile mixed solution (1: 1)
Flow velocity: 1mL/ minute
Detect wavelength: 220nm
Synthetic (1) of [embodiment 2] compound (c ')
In formula, Bn means benzyl.
1.0g (3.89mmol) compound (b ') is dissolved in 20mL THF, dripped while stirring 5.84mL (5.84mmol, 1.5 equivalents) vinyl bromination magnesium THF solution (1.0M) under argon atmosphere in 15 minutes.Now the internal temperature of reaction solution is 3～10 ℃.Stir after 1 hour, reaction soln is under agitation joined in the aqueous ammonium chloride solution that 20mL is saturated.Then add 20mL ethyl acetate and 4mL hexane, each 20mL washing of the organic layer water of acquisition and saturated aqueous common salt, use the 3g dried over sodium sulfate, under reduced pressure boils off solvent, obtains reaction product A.
Under argon atmosphere, while stirring 20mL was added drop-wise in the vinyl bromination magnesium THF solution (1.0M) of 5.84mL under ice-cold as the THF solution of the compound of above-mentioned preparation (b ') in 15 minutes.Now the internal temperature of reaction solution is 3～10 ℃.Stir after 1 hour, reaction soln is under agitation added in the 20mL saturated aqueous ammonium chloride.Then add 20mL ethyl acetate and 4mL hexane, after each 20mL washing of the organic layer water obtained and saturated aqueous common salt, use the 3g dried over sodium sulfate, under reduced pressure boil off solvent, obtain reaction product B.
The reaction product A obtained and reaction product B are respectively by silica gel chromatography column purification (ethyl acetate: hexane=1: 20), from reaction product A, obtain preparation example 4, from reaction product B, obtain preparation example 5.
[table 2]
| The yield of compound (c ') | The yield of compound (f) (peak area %) | |
| Preparation example 4 | 84.0％ | 3.5％ |
| Preparation example 5 | 26.8％ | 11.3％ |
As shown in table 2, in the time of in the solution that Grignard reagent is added drop-wise to compound (b '), the generation of by-product compounds (f) is inhibited, and yield has raise 57%.
HPLC operational condition: reference example 1.
Synthetic (2) of [embodiment 3] compound (c ')
1.0g (3.89mmol) compound (b ') is dissolved in 10～100mL THF, dripped while stirring 5.84mL (5.84mmol, 1.5 equivalents) vinyl bromination magnesium THF solution (1.0M) under argon atmosphere in 15 minutes.Stir after 1 hour, reaction soln is under agitation joined in the 20mL saturated aqueous ammonium chloride.Then add 20mL ethyl acetate and 4 mL hexanes, each 20mL washing of the organic layer water obtained and saturated aqueous common salt, and use the 3g dried over sodium sulfate, and under reduced pressure boil off solvent, obtain reaction product.
By the reaction product that obtains by with embodiment 2 (preparation example 4 and 5) in same method purifying, obtain preparation example 6～preparation example 9.Preparation example 6 is to react and obtain by the quantity of solvent of 20 times of amounts under 20 ℃ of temperature of reaction, and preparation example 7～9th obtains by the quantity of solvent of 10 times of amounts, 40 times of amounts, 100 times of amounts respectively under 3 ℃.
[table 3]
| Temperature of reaction | Quantity of solvent | The yield (peak area %) of compound (c ') | The yield of compound (f) (peak area %) | |
| Preparation example 4 | 3℃ | 20 times of amounts | 84.0％ | 3.5％ |
| Preparation example 6 | 20℃ | 20 times of amounts | 68.7％ | 4.8％ |
| Preparation example 7 | 3℃ | 10 times of amounts | 81.1％ | 5.7％ |
| Preparation example 8 | 3℃ | 40 times of amounts | 88.6％ | 3.5％ |
| Preparation example 9 | 3℃ | 100 times of amounts | 90.2％ | 2.8％ |
As shown in table 3, by below 10 ℃ or 10 ℃, more preferably below 5 ℃ or 5 ℃, to be reacted, the generation of compound (f) is inhibited, and the yield of compound (C ') has also raise 15%.On the other hand, by the quantity of solvent (preparation example 9) of using 100 times of amounts, the generation of compound (f) is inhibited, and yield has also raise 6%.
HPLC operational condition: reference example 1.
Synthetic (1) of [embodiment 4] compound (d ')
In formula, Bn means benzyl.
(1) preparation of Manganse Dioxide:
Add 122g/150mL (0.506mol) five anhydrous manganeses and 117mL 40% aqueous sodium hydroxide solution in 96.0g/600mL (0.607mol) potassium permanganate solution under stirring at room.Stir after 18 hours, suction filtration water are washed.Air-dry obtained solid matter, obtain 91.2g Manganse Dioxide.
(2) compound (d ') is synthetic
2.00g (7.02mmol) compound (c ') is dissolved in 20mL chloroform, methylene dichloride or ethyl acetate, add while stirring 8.00g (4 times of amounts under 25 ℃ of conditions under argon atmosphere, 92.0mol, 13 equivalents) Manganse Dioxide prepared by aforesaid method, and vigorous stirring.After 15 hours, after confirming that raw material disappears, carry out suction filtration.The solid matter obtained with the washing of 20mL chloroform, merging filtrate and washings, under reduced pressure boil off solvent.Obtain preparation example 10～12.
[table 4]
| Reaction solvent | Reaction times | Raw material residual | Yield | |
| Preparation example 10 | Chloroform | 15 hours | - | 91％ |
| Preparation example 11 | Methylene dichloride | 3 hours | - | 79％ |
| Preparation example 12 | Ethyl acetate | 24 hours | 8％ | - |
-: do not reach detectability
As shown in table 4, by using chloroform or methylene dichloride as solvent, with high yield, synthesized compound (d '), especially, by using methylene dichloride, the reaction times can shorten more than 3 times or 3 times.On the other hand, in the situation that ethyl acetate, even after 24 hours, still residual have a compound (c ').
Synthetic (2) of [embodiment 5] compound (d ')
7.0g (3.5mmol) compound (c '), toluene (70mL), ethyl acetate (70mL), water (10mL) and 38.3mg (1mol%) TEMPO are mixed, drip 42mL aqueous sodium hypochlorite solution (available chlorine min.5.0% and sodium bicarbonate aqueous solution (7.1g sodium bicarbonate on ice-cold following vigorous stirring limit, 60mL water) (2～6 ℃, 55 minutes).After 5 minutes, raw material also has 0.4% (HPLC, peak area %).By the organic layer separatory, with KI/ aqueous potassium hydrogen sulfate washing (yellow → russet), with after saturated aqueous sodium thiosulfate and water washing, under reduced pressure boil off solvent, acquisition 6.4g compound (d ') (yield 91%, purity 92.6%).Get methanol-water for 3.0g (25: 1) recrystallization, obtain 2.3g (recrystallization yield 77%, the purity 95.2% that HPLC records).
HPLC operational condition: reference example 1.
Synthesizing of [embodiment 6] compounds (e)
In formula, Bn means benzyl.
1.84g (6.50mmol) compound (d ') is dissolved in the 37mL ethyl acetate, and under argon atmosphere, ice-cold stirring limit, limit adds 0.69g (0.65mmol, 10mol%) 10% palladium-charcoal.By mixture under atmosphere of hydrogen in 25 ℃ of vigorous stirring, regularly reclaimed.Filter the reaction solution obtained, boil off filtrate.Obtain preparation example 13～14.
[table 5]
| Reaction times | The yield of compound (e) | The yield of compound (g) (peak area %) | |
| Preparation example 13 | 0.1 hour | 71％ | 14％ |
| Preparation example 14 | 13 hours | 81％ | 0％ |
As shown in table 5, by the reaction more than 13 hours or 13 hours, the generation of by-product compounds (g) is inhibited, and the yield of compound (e) has raise 10%.
The HPLC operational condition
Post: Inertsil ODS-2,5 μ m, 4.6mm ID * 250mm (GL Science production)
Near temperature: the constant temperature 40 ℃
Moving phase: water: acetonitrile mixed solution (1: 1)
Flow velocity: 1mL/ minute
Detect wavelength: 254nm
[embodiment 7] 2 '-amino-5 '-hydroxypropiophenone complete synthesis
The preparation process that below shows 2 '-amino-5 '-hydroxypropiophenone (compound (e)).
(1) compound (b ') is synthetic
1.00g (5.98mmol) compound (a) is dissolved in 3mL DMF, add while stirring 0.87g (6.28mmol in room temperature under enclosing under the argon atmosphere room temperature, 2.1 equivalent) salt of wormwood and 0.72mL (6.28mmol, 1.05 equivalents) benzyl chloride.After interpolation, in 60 ℃ of heating, and vigorous stirring.Regularly confirm the residual quantity of compound (a), after 20 hours, after confirming the disappearance of compound (a), carry out suction filtration.After suction filtration, obtain solid matter.
By 3mL DMF washing for obtained solid matter, merging filtrate and washings, under reduced pressure boil off solvent.After boiling off, residue is added in 100mL water, after stirring, the suction filtration precipitate, and air-dry it.After air-dry, drying under reduced pressure (1mmHg, 20 ℃), acquisition 1.45g (yield 95%) faint yellow solid compound (b ').
The physical property such as NMR spectrum that below show compound (b ').
Compound (b '): 71～73 ℃ of mp
1H-NMR(400MHz，CDCl
3)：δ5.21(2H，s，PhCH
2O)，7.21(1H，dd，J＝2.8，9.3Hz)，7.35-7.44(6H，m)，8.16(1H，d，J＝9.3Hz)，10.48(1H，s，CHO)
IR(KBr)：1250，1333，1514，1589，1697cm
-1
EI-MS：m/z 257(M
+)。
(2) compound (c ') is synthetic
1.0g (3.89mmol) compound (b ') is dissolved in 20mL THF, under argon atmosphere, in the 15 minutes ice-cold stirring of inner edge limits, drips 5.84mL (5.84mmol, 1.5 equivalents) vinyl bromination magnesium THF solution (1.0M).Now the internal temperature of reaction solution is 3～10 ℃.Stir after 1 hour, reaction soln is under agitation added in saturated ammonium chloride solution.Then add 20mL ethyl acetate and 4mL hexane, the organic layer that each 20mL washing of water and saturated aqueous common salt obtains, use the 3g dried over sodium sulfate, under reduced pressure boils off solvent.
The reaction product obtained by silica gel chromatography (1.19g) (ethyl acetate: hexane=1: 20), acquisition 0.93g orange solids compound (c ') (yield 84%).
The physical property such as NMR spectrum that below show compound (c ').
Compound (c '): 60～63 ℃ of mp
1H-NMR(400MHz，CDCl
3)：δ5.15(2H，s，PhCH
2O)，5.22-5.26(1H，m)，5.39-5.44(1H，m)，5.90(1H，d，J＝5.1Hz)，6.06(1H，ddd，J＝5.1，10.5，15.6Hz)，6.94(1H，dd，J＝2.9，9.0Hz)，7.34(1H，d，J＝2.9Hz)，7.35-7.44(5H，m)，8.04(1H，d，J＝9.0Hz)
IR(KBr)：3298，1614，1582，1506，1292，1229cm
-1
EI-MS：m/z 285(M
+)。
(3) compound (d ') is synthetic
2.00g (7.02mmol) compound (c ') is dissolved in the 20mL chloroform, adds while stirring 8.00g (4 times of amounts, 92.0mmol, 13 equivalents) Manganse Dioxide under argon atmosphere under the condition of 25 ℃, and vigorous stirring.After 15 hours, after confirming the disappearance of raw material, carry out suction filtration.The solid matter obtained with the washing of 20mL chloroform, merging filtrate and washings, under reduced pressure boil off solvent, by silica gel chromatography residue (ethyl acetate: hexane=1: 20), obtain 1.88g white solid compound (d ') (yield 95%).
The physical property such as NMR spectrum that below show compound (d ').
Compound (d '): 84～85 ℃ of mp
1H-NMR(400MHz，CDCl
3)：δ5.17(2H，s，PhCH
2O)，5.83(1H，d，J＝17.7Hz)，6.01(1H，d，J＝10.6Hz)，6.62(1H，dd，J＝10.6， 17.7Hz)，6.91(1H，d，J＝2.7Hz)，7.10(1H，dd，J＝2.7，9.0Hz)，7.37-7.43(5H，m)，8.17(1H，d，J＝9.0Hz)
IR(KBr)：1686，1578，1506，1342，1244cm
-1
EI-MS：m/z 283(M
+)。
(4) compound (e) is synthetic
1.84g (6.50mmol) compound (d ') is dissolved in the 37mL ethyl acetate, on the following ice-cold stirring of argon atmosphere limit, adds 0.69g (0.65mmol, 10mol%) 10% palladium-charcoal.By mixture under atmosphere of hydrogen in 25 ℃ of vigorous stirring.After 13 hours, from obtained reaction solution, remove by filter catalyzer, boil off filtrate, obtain 0.87g (yield 81%, the purity 91.14% that HPLC records) orange solids crude product.
The reaction product obtained by silica gel chromatography (ethyl acetate: hexane=1: 10 → 1: 4), obtain 421mg yellow solid compound (e) (yield 84%, the purity 95.59% that HPLC records).
The physical property such as NMR spectrum that below show compound (e).
131～140 ℃ of compound (e): mp
1H-NMR(400MHz，CDCl
3)：δ1.20(3H，t，J＝7.2Hz)，2.93(2H，q，J＝7.2Hz)，6.59(1H，d，J＝8.8Hz)，6.88(1H，dd，J＝2.9，8.8Hz)，7.23(1H，d，J＝2.9Hz)
IR(KBr)：3379，3296，1670，1447，1194cm
-1
EI-MS：m/z 165(M
+)。
[embodiment 8] are without the synthesis method of the compound (e) of protecting group R
(1) from compound (a) synthetic compound (c ")
500mg (2.99mmo1) compound (a) is dissolved in 15mL THF, under argon atmosphere, in the about 5 minutes ice-cold stirring of inner edge limits, drips 7.5mL (7.5mmol, 2.5 equivalents) vinyl bromination magnesium THF solution (1.0M).Stir after 1 hour, ice-cold stirring limit, limit adds reaction mixture in 30mL 1mol/L hydrochloric acid.Then add 30mL ethyl acetate and 5mL hexane, the organic layer that each 50mL washing of water and saturated aqueous common salt obtains, use the 3g dried over sodium sulfate, under reduced pressure boils off solvent, obtains reaction product.
The reaction product obtained by silica gel chromatography (ethyl acetate: hexane=1: 10 → 1: 3), obtain the 541mg Huang to dark brown solid chemical compound (c ") (yield 93%).
Compound (c "):
1H-NMR(400MHz，CDCl
3)：δ5.22-5.26(1H，m)，5.35-5.40(1H，m)，5.90-5.92(1H，m)，6.06(1H，ddd，J＝5.2，10.5，15.6Hz)，6.83(1H，dd，J＝2.7，9.0Hz)，7.19(1H，d，J＝2.7Hz)，8.00(1H，d，J＝9.0Hz)。
(2) from compound (C ") synthetic compound (d ")
1.00g (5.13mmol) compound (c ") is dissolved in 8mL acetone, and ice-cold stirring limit, limit adds 3.0mL (5mmol, 1.5 equivalents) Jones reagent.Stir after 0.5 hour, in reaction mixture, add three ice cube sheets and the saturated sodium pyrosulfate aqueous solution of 5mL.Then add 50mL ethyl acetate and 5mL hexane, the organic layer that each 50mL washing of water and saturated aqueous common salt obtains, use the 5g dried over sodium sulfate, under reduced pressure boils off solvent, and acquisition 0.82g compound (d ") (yield 83%).
Compound (d "):
1H-NMR(400MHz，DMSO-d
6)：δ5.84(1H，d，J＝17.6Hz)，6.11(1H，d，J＝10.7Hz)，6.60(1H，dd，J＝10.7，17.7Hz)，6.75(1H，d，2.7Hz)，7.03(1H，dd，9.1Hz)，8.13(1H，d，J＝9.1Hz)，11.41(1H，s)。
(3) from compound (d ") synthetic compound (e)
100mg (0.513mmol) compound (d ") is dissolved in the 1mL ethyl acetate, on the following ice-cold stirring of argon atmosphere limit, adds 55mg (0.0513mmol, 10mol%) 10% palladium-charcoal, under atmosphere of hydrogen in stirring at room.Stir after 18 hours, remove by filter 10% palladium-charcoal, boil off the solvent in filtrate under decompression.
Obtain 64mg yellow solid compound (e) (yield 76%).
Synthesizing of [embodiment 9] SN38s (SN-38)
The compound (e) (0.36g, 2.14mmol) and the compound (h) (0.50g, 1.82mmol) that in embodiment 7, obtain are suspended in to acetic acid-toluene mixture liquid (AcOH-toluene; 1: 1,10mL) in, at room temperature add p-toluenesulphonic acids monohydrate (p-TsOHH
2o; 10mg), under nitrogen, in 100 ℃, stir 18 hours.Reaction solution is under reduced pressure concentrated, add toluene (10mL) in residue, then under reduced pressure concentrated.Add acetone (9mL) in residue, after stirring 2 hours, filter precipitate, the material obtained with acetone (2mL * 2) washing and filtering.Drying under reduced pressure, obtain brown solid SN-38 (0.63g, the purity 97.7% that HPLC records, yield 89%).
The HPLC operational condition:
Post: Inertsil ODS-2,4.6cm ID * 25cm (GL Science production)
Near temperature: the constant temperature 40 ℃
Flow velocity: 1mL/ minute
Moving phase: methyl alcohol: acetonitrile: the 10mM potassium primary phosphate mixes liquid (1: 1: 3)
Detect wavelength: 254nm
SN-38：
1H-NMR(400MHz，CDCl
3)：δ0.98(3H，t，J＝7Hz，CH
3)，1.38(3H，t，J＝7Hz，CH
3)，1.90(2H，q，J＝7Hz，CH
2)，3.08(2H，q，J＝7Hz，CH
2)，5.17(2H，s，CH
2O)，5.23(1H，d，J＝16Hz)，5.54(1H，d，J＝16Hz)，6.83(1H，d，J＝9Hz)，7.34-7.39(3H，m)。
[embodiment 10] 7-ethyl-10-[4-(1-piperidino-(1-position only))-1-piperidino-(1-position only)] carbonyl oxygen base camptothecine (SN-38B-11) synthetic
According to existing method (Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K.; Furuta, T.; Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T.Chem.Pharm.Bull.1991,39,1446) SN-38 (0.91g, 2.32mmol) synthetic from embodiment 9 obtain SN-38B-11 (1.22g, 2.08mmol, yield 89%, optical purity 99.8%ee).
Chirality HPLC operational condition
Post: DAICEL CHIRALCEL OD-H, 0.46cm ID * 25cm (# ODHOCE-AK031)
Guard column (Guard cartridge): DAICEL CHIRALCEL OD-H, 0.4cm ID * 1cm
Sample size: 10 μ g/10 μ L
Near temperature: the constant temperature 40 ℃
Flow velocity: 1mL/ minute
Moving phase: dimethylamine: normal hexane: alcohol mixeding liquid (1: 250: 250)
Detect wavelength: 254nm.
[embodiment 11] 7-ethyl-10-[4-(1-piperidino-(1-position only))-1-piperidino-(1-position only)] carbonyl oxygen base camptothecine hydrochloride trihydrate (CPT-11) synthetic
Add the hydrochloric acid (20mL, 2.0mmol) of 1/10N in the SN-38B-11 (1.00g, 1.7mmol) obtained to embodiment 10, by near 80 ℃, heating and dissolve, add acetonitrile (100mL), at room temperature stir and spend the night.Get precipitate, drying, moisture absorption, obtain yellow-white powder CPT-11 (0.95mg, yield 89.8%).
Synthetic (1) of [embodiment 12] compounds (l)
By use n-BuLi (n-Butyl Lithium) and N-formyl radical-N near-30 ℃ or-20 ℃; N '; N '-trimethylammonium quadrol, by compound (k) formylation, then carries out iodate and obtains compound (l) with n-BuLi and iodine near-30 ℃ or-20 ℃.
Pass into nitrogen in reaction vessel, by compound (k) (5.0g; 0.028mol) be dissolved in dry tetrahydrofuran (THF) (about 66mL), cooling near-30 ℃ or-20 ℃.Drip n-BuLi (1.6mol, hexane solution in obtained solution; 21.2mL, 0.034mol, 1.2 equivalents), in cooling lower stirring.Then add formylation reagent N-formyl radical-N, N ', N '-trimethylammonium quadrol (4.4g, 0.0034mol, 1.2 equivalents) stirs the mixture under cooling.
Drip n-BuLi (1.6mol, hexane solution in obtained mixture; 35mL, 0.05mol, 2 equivalents), and stir at the temperature described in table 6.Then drip dry tetrahydrofuran (THF) solution (19mL) of iodine (18.4g), stir the mixture.
Drop into aqueous solution of sodium bisulfite (12g/200mL) in obtained mixture, after stirring, reclaim organic layer (normal hexane), measured by the HPLC method.Result is as shown in table 6.The HPLC operational condition
Post: Capcell Pack ODS UG120,4.6mm ID * 150mm
Moving phase: 50mM KH
2pO
4-MeCN (9: 11)
Detect wavelength: 220nm
Flow velocity: about 1mL/ minute
Temperature: room temperature
[table 6]
| Formylation (℃) Annotate 1) | Reaction times (hour) | Iodate (℃) Annotate 1) | Reaction times (hour) | Compound (k) Annotate 3) | Compound (l) Annotate 3) | Yield (%) Annotate 4) | |
| Preparation example 15 | -48～-30 -32～-29 | 3.0 | Near-70～-65-75 | 0.3 | NT Annotate 5) | 67.8 | 70.6 |
| Preparation example 16 | Near-35～-28-35 | 1.0 | -30～-20 -35～-25 | 0.5 | 5.9 | 67.8 | 71.9 |
| Preparation example 17 | -20～-15 -20～-15 | 2.0 | -10～-5 -10～-5 | 0.5 | 6.2 | 70.5 | 66.7 |
| Preparation example 18 | -10～-5 -10～-5 | 3.0 | -10～0 -10～0 | 0.5 | 3.4 | 77.6 | 63.7 |
Annotate 1) above a line be the measured value of the internal temperature while dripping, below a line be the temperature range of the internal temperature while stirring
Annotate 2) preparation example 15: the result of the Production Example under the report condition
Annotate 3) peak area (%)
Notes 4) yield is for passing through the percentile scaled value of peak area (%) of HPLC method
Annotate 5) NT: undetermined
As shown in table 6, use n-BuLi as lithiation reagent, obtain the yield more than 60% or 60%.As shown in preparation example 16, under the constant temperature of-40 ℃～-30 ℃, can be reacted with the good yield more than 70% or 70%.
The purifying of [embodiment 13] compounds (l) (dilute hydrochloric acid washing)
Compound (k) (5.0g, 0.028mol) is dissolved in dry tetrahydrofuran (about 66mL), under near the constant temperature-35 ℃, is reacted similarly to Example 12.Reclaim the reaction mixture (normal hexane layer) obtained, use with the dilute hydrochloric acid of organic layer equivalent and washed.
After washing, with after anhydrous magnesium sulfate drying, filter organic layer, the part of filtrate, under the condition identical with embodiment 12, is measured by the HPLC method.Result is as shown in table 7.
[table 7] washs the result of the organic layer after each hexane layer with dilute hydrochloric acid
| Hexane layer Annotate 1)(mL) | Dilute hydrochloric acid (mol/L) | Residue amount (g) | Compound (k) Annotate 2) | MTPC Annotate 2,3) | Compound (l) Annotate 2) | The rate of recovery (%) |
| 25 | Annotate 4) - | 1.5 | 6.0 | 11.8 | 54.7 | - |
| 50 | 0.1 | 2.9 | 6.6 | 12.4 | 58.7 | 100 |
| 50 | 1.0 | 2.6 | 1.8 | 13.0 | 61.2 | 100 |
| 50 | 2.5 | 2.6 | 0.4 | 12.6 | 62.4 | 100 |
| 50 | 3.5 | 2.6 | 0.2 | 12.7 | 64.2 | 100 |
The hexane layer that notes 1) will obtain from reaction mixture is divided into 5 parts (25mL non-processor, 4 50mL are washed).
Annotate 2) peak area %
Annotate 3) MTPC:2-methoxyl group-6-trimethyl silyl pyridine-3-formaldehyde
Annotate 4) not washing
As shown in table 7, by dilute hydrochloric acid, wash, compound (k) almost all is removed.Especially, by with 1.0mol/L and the washing of the dilute hydrochloric acid more than 1.0mol/L, can obtain highly purified compound (l).On the other hand, reaction intermediate 2-methoxyl group-6-trimethyl silyl pyridine-3-formaldehyde (MTPC) almost is not removed.MTPC is the formylation intermediate of compound (k).
The purifying (dilute hydrochloric acid progressively washs) of [embodiment 14] compounds (l)
Compound (k) (5.0g, 0.028mol) is dissolved in dry tetrahydrofuran (about 66mL), under near the constant temperature-35 ℃, is reacted similarly to Example 12.Reclaim the reaction mixture (normal hexane layer) obtain, use with the dilute hydrochloric acid of the different concns as shown in table 8 of organic layer equivalent and progressively wash.
After washing, separate acid water layer, with the sodium carbonate neutralization, then use n-hexane extraction.With after the anhydrous magnesium sulfate drying organic layer, filter, under the condition identical with embodiment 12, measure the part of filtrate by the HPLC method.Result is as shown in table 8.
The order of [table 8] according to the form below (upper → under) respectively with the hexane layer after dilute hydrochloric acid washing aftertreatment, neutralize its water layer, by the result of hexane extraction organic layer
| Dilute hydrochloric acid (mol/L) | Residue (g) Annotate 1) | Compound (k) Annotate 2) | Compound (l) Annotate 2) | The rate of recovery (%) |
| Washing | - | NT Annotate 3) | NT | - |
| 0.1 | 0.40 | 21.9 | 10.7 | - |
| 0.1 | 0.04 | NT | NT | - |
| 1.0 | 0.21 | 67.0 | 13.7 | - |
| 2.5 | 0.28 | 71.0 | 3.0 | - |
| 5.0 | 0.54 | 18.0 | 4.0 | - |
| Residue after washing Annotate 4) | 7.27 | ND Annotate 5) | 77.9 | 98.3 |
Notes 1) washing of each dilute hydrochloric acid neutralizes with sodium carbonate, the mixture n-hexane extraction.Dry organic layer, filter, and then drying under reduced pressure filtrate is to dry
Annotate 2) HPLC (peak area %)
Annotate 3) undetermined
Annotate 4) residue of the hexane layer after washing progressively
Notes 5) do not reach detectability
As shown in table 8, by the dilute hydrochloric acid with different concns, progressively wash, obtained highly purified compound (l).
The purifying (passing through distillation purifying) of [embodiment 15] compounds (l)
Compound (k) (5.0g, 0.028mol) is dissolved in dry tetrahydrofuran (about 66mL), under near the constant temperature-35 ℃, is reacted similarly to Example 12.Reclaim the reaction mixture (normal hexane layer) obtain, under reduced pressure distill at (near degree of decompression: 0.35mmHg), the temperature of 81～99 ℃.After distillation, use silicagel column, with normal hexane, then with normal hexane-ethyl acetate mixed solution (50: 1) purifying residue, obtain purified product.
Obtained residue and purified product are measured by the HPLC method under the following conditions.Result is as shown in table 9.
The HPLC operational condition
Post: Capcell Pack ODS UG120,4.6mm ID * 150mm
Moving phase: 50mM KH
2pO
4-MeCN mixed solution (1: 1)
Detect wavelength: 220nm
Flow velocity: about 1mL/ minute
Temperature: room temperature
Result during the concentrating residues thing of the hexane layer of [table 9] distillation after aftertreatment
| Cut (g) | Compound (k) Annotate 1) | MTPC Annotate 1) | Compound (l) Annotate 1) | The rate of recovery (%) | |
| Thing before distillation | - | 3.6 | 13.5 | 71.5 | - |
| Partly-1 | 0.19 | 47.3 | 36.1 | 8.7 | - |
| Partly-2 | 1.16 | 8.9 | 53.7 | 28.8 | - |
| Trap | 1.17 | 70.3 | ND Annotate 2) | ND | - |
| The still residue | 5.13 | 0.3 | 3.1 | 89.9 | 75.9 |
| The column purification product Post 3) | - | - | 3.9 | 95 | - |
Annotate 1) peak area %
Annotate 2) do not detect: below detectability
Annotate 3) by silica gel chromatography final residue thing
As shown in table 9, almost removed whole MTPC by distillation.In addition, by silica gel chromatography, obtained the compound (l) of extreme high purity.On the other hand, because distillation at higher than this temperature is observed the painted of compound (l) and decomposes, thereby not preferred.
The purifying of [embodiment 16] compounds (l) (recovery of calculating with hydrochloride)
Compound (k) (5.0g, 0.028mol) is dissolved in to dry tetrahydrofuran (about 66mL).Under near the constant temperature-35 ℃, reacted similarly to Example 12.The reaction mixture that 10g is obtained is dissolved in the hydrochloric acid (10mL) of 10N, and at room temperature stirs.After stirring, filter and to obtain yellow precipitate, and with a small amount of 10N salt acid elution.After washing, it is dissolved in water (about 10mL), adds sodium bicarbonate that pH is reached approximately near 8, use n-hexane extraction, and vapourisation under reduced pressure is to dry.
Obtained residue, under the condition identical with embodiment 15, is measured by the HPLC method.Result is as shown in table 10.
[table 10] neutralizes the result of extraction to the hydrochloride in 10mol/L hydrochloric acid
| (g) Annotate 1) | Compound (k) Annotate 2) | MTP Annotate 2) | Compound (l) Annotate 2) | The rate of recovery (%) | |
| Before processing | 10 | - Annotate 3) | 16.9 | 61.8 | - |
| After processing | 6 | - | 3.3 | 90.0 | 87.4 |
Annotate 1) the residue amount
Annotate 2) peak area %
Annotate 3) undetermined
As shown in table 10, become the purification process of hydrochloride by making reactant, MTPC almost all is removed.
Compound (l): yellow oily material
1H-NMR(400MHz，CDCl
3)：δ0.30(9H，s)，4.05(3H，s)，7.67(1H，s)，10.19(1H，s)
EI-MS：m/z 335(M
+)。
Synthesizing of [embodiment 17] compounds (m)
In formula, TMS means trimethyl silyl, and Me means methyl.
Will be under nitrogen atmosphere, in 0～5 ℃ to compound (l) (20.00g, 56.0mmol, content 93.9%), triethyl-silicane (17.9mL, 112.0mmol, 2 equivalents) and in the mixed solution of crotyl alcohol (15.7mL, 184.8mmol, 3.3 equivalents) drip trifluoroacetic acid (28.5mL, 375.3mmol, 6.7 equivalent), stir 30 minutes, afterwards stir about 20 hours under room temperature.To Implantation acid sodium aqueous solution (20.8g is dissolved in 277mL water) and normal hexane (56mL) in reaction mixture, separate organic layer, by normal hexane (56mL) aqueous layer extracted.Merge organic layer and under reduced pressure be concentrated into dry.By silica gel column chromatography [silica gel: Fuji Silysia PSQ100B (approximately 4 times of weights of compound (l)), elutriant: n-hexane/ethyl acetate (73: 3)], residue is carried out to purifying, obtain table 11 (preparation example 20).Table 11 (preparation example 19) is method (Josien, the H. according to H.Josein etc.; Ko, S.B.; Bom, D.; Curran, D.P., Chem.Eur.J.1998,4,67-83, Curran, D.P.; Ko, S.B.; Josein, H., Angew.Chem.Int.Ed.Engl.1995,34,2683-2684) prepare.Under the condition of report, use methylene dichloride as reaction solvent.Without methylene dichloride the time, obtain the quality product (m) identical with yield.
[table 11]
The HPLC operational condition
Post: Intertsil ODS-2,5 μ m, 4.6mm I.D. * 250mm (GL Science production)
Near temperature: the constant temperature 40 ℃
Moving phase: acetonitrile/0.01mol/l potassium primary phosphate (5: 1)
Flow velocity: 1mL/ minute
Detect wavelength: 254nm.
Synthetic (2) of [embodiment 18] compounds (l)
In formula, TMS means trimethyl silyl, and Me means methyl.
To compound (v), (1.00g, purity 98.43% add TEMPO (2.3mg, 0.015mmol, 0.005 equivalent) and 7% (w/v) NaHCO in toluene 2.9mmol) (8.7mL) solution
3(6.98mL), cooling under 0～5 ℃ after, add aqueous sodium hypochlorite solution (available chlorine: minimum 5%, 4.5g, 3.0mmol, 1.05 equivalents), under 0～5 ℃, stir 2 hours.Add 10%Na in reaction solution
2sO
3(3.7mL, 2.9mmol) stirred after 30 minutes under 0～5 ℃, and the elimination insolubles, with toluene (1mL * 3) washing.By the organic layer separatory, water (10mL) washing, use anhydrous Na
2sO
4(2g) drying, filter, and then uses toluene wash, under reduced pressure is concentrated into dryly, obtains 0.93g (yield 87%) yellow oily compound (l), content 90.60% (by HPLC, recording (reference example 17)).
Synthetic (1) of [embodiment 19] compounds (n)
In formula, TMS means trimethyl silyl, and Me means methyl, and Et means ethyl.
Compound (m) (1.60g) is dissolved in the solvent shown in about 30mL table 12, adds 0.83g Tetrabutyl amonium bromide (Bu
4nBr), 0.71g salt of wormwood (K
2cO
3) and 57mg palladium (Pd (OAc)
2), reacted under the conditions shown in Table 12.To react mixed liquid placement and be cooled to room temperature, the normal hexane under injection 18mL is ice-cold.
By Celite pad elimination insolubles, with 6mL normal hexane washing 3 times.With 9mL water washing filtrate 2 times, use anhydrous sodium sulfate drying, and under reduced pressure concentrated.By silica gel column chromatography, purify residue with the mixed liquid (95: 5) of ethyl acetate hexane as elutriant, obtain preparation example 21～27.
The preparation example 21 of table 12 is method (Josien, the H. according to H.Hosien etc.; Ko, S.B.; Bom, D.; Curran, D.P., Chem.Eur.J.1998,4,67-83., Curran, D.P.; Ko, S.B.; Josien, H., Angew.Chem.Int.Ed.Engl.1995,34,2683-2684) prepare.Measure the interior type of obtained preparation example 21～27 and the amount of external form by HPLC.
[table 12]
DMF:N, dinethylformamide, MeCN: acetonitrile, THF: tetrahydrofuran (THF), than: the peak area of the peak area/external form of interior type (HPLC),
-: yield is not calculated
As shown in table 12, carry out boiling reflux by using THF as reaction solvent, the ratio of interior type and external form is approximately 7, and selectivity is improved (preparation example 25～27), and yield has also improved more than 10% or 10% than preparation example.
HPLC operational condition: reference example 17
Synthetic (2) of [embodiment 20] compounds (n)
By compound (m) (1.27g, 2.6mmol, content 78.7%) be dissolved in diisopropyl ether-acetonitrile-water mixed solution (4: 3: 1,20mL) in, add Tetrabutyl amonium bromide (0.82g under room temperature, 2.6mmol), N, N-diisopropylethylamine (3.48mL, 20.8mmol, 8 equivalents) and palladium (57 mg, 0.26mmol), boiling reflux 30 minutes.After being cooled to below 20 ℃ or 20 ℃ by reaction mixture, filtering, and wash with normal hexane (2.6mL * 3).Add normal hexane (10mL) and 10%Na in filtrate
2sO
3(16mL, 13.0mmol, 5 equivalents), by the organic layer separatory.With 1N HCl (16.4mL), then water (10mL * 2) washs organic layer.Under reduced pressure organic layer is concentrated into dryly, obtains brown oily compound (n) (0.83g, 2.325mmol, the content 73.34% that HPLC records, yield 91%, interior type/external form ratio: 10.6).
With preparation example 21, compare, its selectivity improves greatly, and yield has also improved 20%.
Synthesizing of [embodiment 21] compounds (o)
In formula, TMS represents trimethyl silyl, and Me means methyl, and Et means ethyl.
Add (DHQD) in the aqueous solution water (990mL) of six cyano group iron (III) (195.7g, 0.59mol), salt of wormwood (82.1g, 0.59mol) and amsacrine (37.7g, 0.40mol)
2pYR (4.36g, 4.95mmol) and two hydration potassium osmates (VI) (1.0mmol), stir 1 hour near 5 ℃.Add compound (n) (77.8g, 0.18mol, content 61.5%) in this solution, then stir 20 hours near 5 ℃.To the S-WAT (74.9g) that adds solid state in reaction solution, stir after 30 minutes, by Celite pad elimination insolubles near these 5 ℃.Wash insolubles (4 times, be total to 770mL) by ethyl acetate.The organic layer of separating filtrate, then by ethyl acetate (770mL) aqueous layer extracted.By the organic layer anhydrous sodium sulfate drying merged, filter, then under reduced pressure concentrated.By silica gel column chromatography [silica gel: Fuji Silysia PSQ100B (compound (n) approximately 3.5 times), elutriant: dichloromethane/ethyl acetate mixed solution (4: 1)] purifying residue, obtain russet solid chemical compound (o).
The result (preparation example 29) that obtains the situation of compound (p) is presented in table 13.
As shown in table 13, use than the low potassium osmate of perosmic anhydride (VIII) volatility and also obtain in equal result aspect yield and optical purity.
[table 13]
| Oxygenant | Yield (%) | Optical purity (%ee) | |
| Preparation example 28 | OsO 4 | 82～95 | 95.6～96.2 |
| Preparation example 29 | K 2OsO 4·2H 2O | 94 | 95.9 |
Preparation example 28 is according to method (Josein, the H. of H.Josien etc.; Ko, S.B.; Bom, D.; Curran, D.P., Chem.Eur.J.1998,4,67-83., Curran, D.P.; Ko, S.B.; Josein, H., Angew.Chem.Int.Ed.Engl.1995,34,2683-2684) preparation.
%ee: obtained compound (o) is changed into to compound (p) by the method for putting down in writing in embodiment 22, and its optical purity is measured by chirality HPLC method (reference example 22).
Synthesizing of [embodiment 22] compounds (p)
In formula, TMS means trimethyl silyl, and Me means methyl, and Et means ethyl.
70g compound (o) is dissolved in 1L methanol aqueous solution (10: 1), at room temperature adds the iodine of the amount of Table 12 and the calcium carbonate of 47.1g solid state, reacted under the conditions shown in Table 14.
Obtained reaction mixture is placed and is cooled to room temperature, add 1L 10% S-WAT and 1L chloroform, at room temperature stir 30 minutes, remove by filter insolubles.Separating filtrate, with 500mL chloroform extraction water layer.Organic layer after separating, washing, further with 500mL chloroform washing water layer.Merge organic layer and, by anhydrous acid sodium drying, filter, then under reduced pressure concentrated.
Similarly to Example 19, calculate the yield of the compound obtained, result is as shown in table 14.
As shown in table 14, by the iodine boiling reflux with 4 equivalents, reaction completes within reaction times of 1/9～1/10 of preparation example 30, and shows equal yield.
[table 14]
| Iodine (equivalent) | Temperature | Reaction times (hour) | Yield (%) | |
| Preparation example 30 | 9 | Room temperature | 48 | 86 |
| Preparation example 31 | 4 | Room temperature | 72 | 86 |
| Preparation example 32 | 4 | 40℃ | 48 | 88 |
| Preparation example 33 | 4 | 60℃ | 20 | 88 |
| Preparation example 34 | 4 | Boiling reflux | 5 | 84 |
Preparation example 30 is according to method (Josien, the H. of H.Josien etc.; Ko, S.B.; Bom, D.; Curran, D.P., Chem.Eur.J.1998,4,67-83, Curran, D.P.; Ko, S.B.; Josien, H., Angew.Chem.Int.Ed.Engl., 1995,34,2683-2684) preparation.
The HPLC operational condition:
Post: GL Science Inertsil ODS-2 (0.46cm φ * 25cm)
Sample size: 2 μ g/10 μ l
Temperature: 40 ℃
Flow velocity: 1mL/ minute
Moving phase: acetonitrile: 10mM potassium primary phosphate (5: 3)
Detect wavelength: 254nm
Chirality HPLC operational condition:
Post: DAICEL CHIRALCEL OD-H (#ODH0CE-AK031,0.46cm φ * 25cm)
Guard column: DAICEL CHIRALCEL OD-H (0.4cm φ * 1cm)
Sample size: 10 μ g/10 μ l
Temperature: the constant temperature of near room temperature
Flow velocity: 0.5mL/ minute
Moving phase: normal hexane: alcohol mixeding liquid (200: 1)
Detect wavelength: 254nm.
Synthesizing of [embodiment 23] compounds (q)
To solvent (about 400mL; Add the reagent in table in the solution of the compound (p) record in table 15), stirred at the time by obtained mixture in table and temperature.Add 1.7L 20% sodium carbonate, 1.0L 10% S-WAT and 550mL chloroform in reaction mixture, and stir.Separate organic layer, use 550mL chloroform extraction 2 times.The combined chloroform layer, use anhydrous sodium sulfate drying, filters, and will be evaporated to the compound (q) of doing and obtaining and carry out HPLC mensuration.Result is as shown in Table 15.
By at 65 ℃, in acetic acid, with NCS-NaI, fully carrying out this conversion (preparation example 39).Having reacted required time can significantly shorten, and the yield of compound under this condition (q) is than more than the comparative example 1 high 50% or 50% had been reported.
[table 15]
| Reaction solvent | Reagent | Equivalent | Temperature | Reaction times (hour) | Yield (%) | |
| Preparation example 35 | AcOH | NIS | 12 | 65℃ | 45.0 | 63 |
| Preparation example 36 | CH 2Cl 2 | I 2-CF 3CO 2Ag | 2 | Room temperature | 1716.5 | 97 |
| Preparation example 37 | AcOH | NCS-NaI | 6 | 65℃ | 16.0 | 95 |
| Preparation example 38 | AcOH | NCS-NaI | 6 | 65℃ | 15.0 | 93 |
| Preparation example 39 | AcOH | NCS-NaI | 6 | 65℃ | 15.0 | 94 |
| Comparative example 1 | X) | ICI | 4 | 0 ℃～room temperature | 48.0 | 45 |
X) methylene dichloride (CH
2cl
2): the mixed solvent of chloroform=3: 2,
ICI: iodine monochloride, NIS:N-iodo succinimide, NCS:N-chlorosuccinimide, Eq: the mol ratio of agents useful for same, yield: separation yield.
The purification process I of [embodiment 24] compounds (q)
The reaction mixture that contains compound (q) (purity 89.2% that HPLC records) obtained in 63g embodiment 23 is suspended in 150mL methyl alcohol, under agitation drips the aqueous sodium hydroxide solution of 0.2N and continue to stir 2 hours.With the 400mL chloroform, by basic solution washing 3 times, use the hydrochloric acid of 6N by pH regulator to 1～2, use 400mL chloroform extraction 3 times.By obtained chloroform layer anhydrous sodium sulfate drying, after filtration, dry by under reduced pressure being concentrated into, obtain compound (q) (purity 97.7% (peak area; HPLC operational condition: reference example 25)) (preparation example 40).
The purification process II of [embodiment 25] compounds (q)
The purified product that 50g is contained to the compound (q) obtained in embodiment 24 is dissolved in the 240mL chloroform, carries out lamination with the 400mL normal hexane, at room temperature standing 15 hours.The crystallization that filtration is separated out, filtrate under reduced pressure is concentrated into dry, obtains compound (q) (preparation example 41).
By present method, the compound (q) (preparation example 40, optical purity 93～96%) obtained in embodiment 24 is carried out to the optics purifying.The optical purity that the compound obtained (q) (preparation example 41) records by following chirality HPLC method is 99.7～99.9%.
The HPLC operational condition:
Post: Inertsil ODS-2,0.46cm I.D. * 25cm (GL Science production)
Near temperature: the constant temperature 40 ℃
Flow velocity: 1mL/ minute
Moving phase: (5: 3) of acetonitrile/10mM potassium primary phosphate
Detect wavelength: 254nm
Chirality HPLC operational condition:
Post: DAICEL CHIRALPAK AD-H (#ADH0CE-BC037,0.46cmID * 25cm)
Guard column: DAICEL CHIRALPAK AD-H (0.4cm ID * 1cm)
Near temperature: the about constant temperature 25 ℃
Flow velocity: 1mL/ minute
Moving phase: normal hexane: IPA mixed solution (25: 1)
Detect wavelength: 254nm.
The preparation method of [embodiment 26] compounds (r)
At room temperature, to compound (q) (42.8g, 0.10mol, content 84.5%) 1-propyl alcohol (490mL) solution in add palladium (1.34g, 6.0mmol) and salt of wormwood (24.7g, 0.18mol), degassed by decompression in reaction vessel, with nitrogen, replaced, more degassed by decompression, with the carbon monoxide displacement, under 60 ℃, stir 18 hours.Be cooled to room temperature, by Celite pad elimination insolubles, with ethyl acetate (300mL) washing.Add 1N hydrochloric acid (150mL) and saturated aqueous common salt (300mL) in filtrate, separate organic layer, add ethyl acetate (300mL) to be extracted.Merge organic layer, use anhydrous sodium sulfate drying, filter, then under reduced pressure be concentrated into dry.By silica gel column chromatography [silica gel: Fuji Silysia PSQ100B (approximately 3.5 times of weights of compound (r), elutriant: chloroform/methanol mixed solution (99: 1)) purifying residue, obtain brown oil compound (r) (30.3g, the content 73.4% that HPLC records, yield 70%).
The HPLC operational condition:
Post: GL Science Inertsil ODS-2 (0.46cm ID * 25cm)
Near temperature: the constant temperature 40 ℃
Flow velocity: 1mL/ minute
Moving phase: 10mM potassium primary phosphate: acetonitrile mixed solution (4: 3)
Detect wavelength: 254nm
The preparation method of [embodiment 27] compounds (s)
Under nitrogen atmosphere under shading, (r) (28.7g in room temperature to compound, 68.2mmol, content 73.4%) and sodium iodide (27.6g, 0.18mol) anhydrous acetonitrile (141mL) solution in add chloro trimethyl silyl (23.3mL, 0.18mmol), and stir 3 hours.Add 1N hydrochloric acid (8mL) in reaction mixture, then add 10% S-WAT (232mL), at room temperature stir 30 minutes.Be extracted with ethyl acetate mixed liquid, by the organic layer separatory, then under reduced pressure be concentrated into dryly, obtain compound (s) (22.3g, the content 85.6% that HPLC records (with reference to following), yield 95%).
The HPLC operational condition:
Post: Inertsil ODS-2,0.46cm I.D. * 25cm (GL Science production)
Near temperature: the constant temperature 40 ℃
Flow velocity: 1mL/ minute
Moving phase: 10mM potassium primary phosphate/acetonitrile (5: 2)
Detect wavelength: 254nm.
The preparation method of [embodiment 28] compounds (t)
0.50g compound (s) is dissolved in 7mL methyl-sulphoxide (hereinafter referred to as DMSO), adds 0.40g cesium carbonate (Cs under room temperature
2cO
3) or salt of wormwood (K
2cO
3), under argon atmospher, in 50 ℃, stir 20 minutes.Drip tert-butyl acrylate 2.1mL (1.8g) in mixture, stir 24 hours in 50 ℃ under argon atmospher.Add 10mL water and 1mL concentrated hydrochloric acid in ice-cold stirring downhill reaction mixture.With 7mL toluene-ethyl acetate mixed solution (4: 1) extraction mixture 4 times.Merge organic layer, with 5mL water washing 3 times, with after anhydrous sodium sulfate drying, filter, then vapourisation under reduced pressure, to dry, obtains preparation example 42 and preparation example 43.Analyze by HPLC (with reference to following) residue obtained.
Shown in table 16, in the situation that with cesium carbonate as alkali, the yield of compound (t) is 72% (preparation example 42), on the other hand, in the situation that with cheap salt of wormwood as alkali, yield and the preparation example 42 of compound (t) are equal.
[table 16]
The HPLC operational condition:
Post: Inertsil ODS-2,0.46cm I.D. * 25cm (GL Science production)
Near temperature: the constant temperature 40 ℃
Flow velocity: 1mL/ minute
Moving phase: 10mM potassium primary phosphate/acetonitrile (5: 2)
Detect wavelength: 254nm.
[embodiment 29] SN-38's is synthetic
By compound (h) (0.50g, 1.82mmol, content 96.6%) and the mixture of compound (e) (0.36g, 2.18mmol) at the nitrogen atmosphere low suspension at toluene-acetic acid mixed solution (1: 1,10mL), under room temperature, add p-TsOHH
2o (10mg), stir 7 hours in 90 ℃.Let cool to room temperature, under reduced pressure concentrated.Add toluene (10mL) in residue, and under reduced pressure after concentrated (this operation repetition 2 times to remove acetic acid), add acetone (9mL), under nitrogen atmosphere in stirring at room 30 minutes.Filter insolubles, with acetone (2mL * 2) washing, then drying under reduced pressure, obtain loess look solid SN-38 (0.63g, the purity 99.6% that HPLC records (reference example 9), yield 89.1%) (preparation example 45).
The preparation example 44 of table 17 is according to P& The method of U (Henegar, K.E.; Ashford, S.W.; Baughman, T.A.; Sih, J.C.; Gu, R.L., J.Org.Chem.1997,62,6588-6597) preparation.
Shown in table 17, by being reacted under atmosphere of inert gases, yield and purity are improved.
[table 17]
| Purity (%) | Yield (%) | ||
| Preparation example 44 | In air | 97.6 | 75 |
| Preparation example 45 | Nitrogen | 99.6 | 89 |
[embodiment 30] tricycle kentones complete synthesis
The preparation process that below shows tricycle kentones (compound (h)).
(1) compound (m) is synthetic
Under nitrogen atmosphere, in 0～5 ℃ to compound (l) (20.0g, 56.0mmol, 2 equivalents, content 93.9%), triethyl-silicane (17.9mL, 112mmol, 2 equivalents) and crotyl alcohol (15.7mL, 184.8mmol, 3.3 after dripping trifluoroacetic acid (28.5mL, 375.2mmol, 6.7 equivalents) in mixed solution equivalent), stir 30 minutes, afterwards stir about 20 hours under room temperature.To Implantation acid sodium aqueous solution (20.8g is dissolved in 277mL water) and normal hexane (56mL) in reaction mixture, separate organic layer, by normal hexane (57mL) aqueous layer extracted.The organic layer that extraction merges.By the organic layer of merging, under reduced pressure be concentrated into dry.By silica gel column chromatography [silica gel: Fuji Silysia PSQ100B (80g), elutriant: n-hexane/ethyl acetate (73: 3)] the purifying residue, remove by-product compounds (v) (4.95g from two, 14.68mmol, purity 98.43%, yield 26%), obtain yellow oily compound (m) (17.8g, the content 80.0% that HPLC records, yield 64%).
The NMR spectrum that below shows HPLC condition that assay is used and compound (m), compound (v).
HPLC operational condition: reference example 17
Compound (m):
1h-NMR (400MHz, CDCl
3): δ 0.24 (9H, s, TMS), 1.69 (3H, dd, J=1.0,6.1Hz ,=CHC
h 3 ), 3.85-4.05 (2H, m, OC
h 2 cH=), 3.93 (3H, s, CH
3o), 4.55 (2H, s, OCH
2), 5.55-5.83 (2H, m, CH=CH), 7.47 (1H, s)
Compound (v):
1h-NMR (400MHz, CDCl
3): δ 0.27 (9H, s, TMS), 2.45 (1H, t, J=6.8Hz, OH), 3.99 (3H, s, CH
3o), 4.79 (2H, d, J=6.8Hz, C
h 2 oH), 7.49 (1H, s).
(2) compound (n) is synthetic
By compound (m) (1.27g, 2.555mmol, content 78.73%) be dissolved in the mixed liquid of diisopropyl ether-acetonitrile-water (4: 3: 1,20mL), in room temperature, add Tetrabutyl amonium bromide (0.82g, 2.56mmol), N, N-diisopropyl ether ethamine (3.48mL, 2.555 * 8mol) and palladium (57mg, 0.26mmol), boiling reflux 30 minutes.Reaction mixture is cooled to below 20 ℃ or 20 ℃, filters, with normal hexane (10mL) washing.Add normal hexane (10mL) and 10%Na in filtrate
2sO
3(16mL, 113mmol, 5 equivalents), by the organic layer separatory.With 1N HCl (16.4mL), then water (10mL * 2) washs organic layer.Under reduced pressure organic layer is concentrated into dryly, obtains brown oily compound (n) (0.83g, 2.325mmol, the content 73.34% that HPLC records, yield 91%, interior type/external form: 10.6.
Below show HPLC condition that assay is used and the NMR spectrum of compound (n).
HPLC operational condition: reference example 17
Compound (n):
1h-NMR (400MHz, CDCl
3): δ 0.26 (9H, s, TMS), 1.12 (3H, t, J=7.3Hz, CH
2cH
3), 2.31 (2H, dq, J=1.0,7.3Hz, CH
2cH
3), 3.94 (3H, s, OCH
3), 5.00 (2H, s, OCH
2), 6.51 (1H, t, J=1.0Hz, OCH=), 6.83 (1H, s, aromatic ring-H).
(3) compound (o) is synthetic
Add (DHQD) in the aqueous solution (990mL) of six cyano group iron (III) sour potassium (195.7g, 0.59mol), salt of wormwood (82.1g, 0.59mol) and amsacrine (37.7g, 0.40mol)
2pYR (4.36g, 4.95mmol) and two hydration potassium osmates (VI) (0.99mmol), stir 1 hour near 5 ℃.Add compound (n) (77.8g, 0.18mol, content 61.5%) in this solution, then stir 20 hours near 5 ℃.
Add solid state S-WAT (74.9g) in reaction solution, stir 30 minutes near 5 ℃, by Celite pad elimination insolubles.Wash insolubles (4 times, be total to 770mL) by ethyl acetate.The organic layer of separating filtrate, then by ethyl acetate (770mL) aqueous layer extracted.Merge organic layer, use anhydrous sodium sulfate drying, filter, then under reduced pressure concentrated.By silica gel column chromatography [silica gel: Fuji Silysia PSQ100B (700g), elutriant: dichloromethane/ethyl acetate mixes liquid (4: 1)] purifying residue, obtain russet solid chemical compound (o).
(4) compound (p) is synthetic
By 70.2g compound (o) be dissolved in the mixed liquid of methanol-water (10: 1,1.0L) in, add solid iodine (183.7g, 0.72mol) and calcium carbonate (36.23g, 0.36mol) under room temperature, boiling reflux 5 hours.Reaction mixture is let cool to room temperature, add 10% S-WAT (1.0L) and chloroform (1.0L), at room temperature stir 15 minutes, filter insolubles, the material obtained with chloroform (0.5L) washing and filtering.
Separate organic layer, then by chloroform (0.5L) aqueous layer extracted.Merge organic layer, use anhydrous sodium sulfate drying, filter, under reduced pressure be concentrated into dryly, obtain russet oily mater compound (p) [53.6g, the content 80.4% that HPLC records, from the total recovery 81% of compound (m), chirality HPLC records 96.2%ee].
Below show HPLC condition that assay is used and the NMR spectrum of compound (p).
HPLC operational condition: reference example 22
Chirality HPLC operational condition: reference example 22
Compound (p):
1h-NMR (400MHz, CDCl
3): δ 0.28 (9H, s, TMS), 0.94 (3H, t, J=7.4Hz, CH
2c
h 3 ), 1.76 (2H, q, J=7.4Hz, C
h 2 cH
3), 3.61 (1H, s, OH), 3.98 (3H, s, OCH
3), 5.23 (1H, d, J=15.6Hz), 5.54 (1H, d, J=15.6Hz), 7.33 (1H, s, aromatic ring-H).
(5) compound (q) is synthetic
By compound (p) (50.2g, 0.14mol, content 80.4%, 96.2%ee) be dissolved in acetic acid (411mL), add solid N-chlorosuccinimide (107.36g under room temperature, 0.80mol) and sodium iodide (120.52g, 0.80mol), in approximately stirring 16 hours under 65 ℃.Let cool to room temperature, inject while stirring 20% sodium carbonate (1.7L), 10% S-WAT (1.0L) and chloroform (0.6L).Separate organic layer, then with chloroform (0.6L), water layer is extracted 2 times.Merge organic layer, use anhydrous sodium sulfate drying, filter, then under reduced pressure be concentrated into dry (crude product (q)).
(6) the purifying I of compound (q)
Residue (compound of crude product (q), the purity 89.2% that HPLC records) is suspended in methyl alcohol (150mL), under agitation is added drop-wise in 0.2N sodium hydroxide (0.40mol), at room temperature continue to stir 2 hours.By this alkali aqueous solution washing 3 times, separating water layer with chloroform (400mL), is 1～2 with 6N hydrochloric acid by pH regulator, with chloroform (400mL), extracts 3 times.Separate organic layer, use anhydrous sodium sulfate drying, filter, under reduced pressure be concentrated into dry ((q) of purge process, the purity that HPLC records: 97.7%).
(7) the purifying II of compound (q)
(q) of purge process is dissolved in chloroform (280mL) to lamination normal hexane (400mL), at room temperature standing 15 hours.The crystallization that filtration is separated out, filtrate under reduced pressure is concentrated into dry, acquisition dark brown tarring compound (q) (47.4g, 0.115mol, the content 84.5% that HPLC records, yield 86%, chirality HPLC records 99.7%ee).
The NMR spectrum and the specific optical rotation that below show HPLC condition, chirality HPLC condition and compound (q) that assay is used.
HPLC operational condition: reference example 22
Chirality HPLC operational condition: reference example 25
Compound (q):
1h-NMR (400MHz, CDCl
3): δ 0.94 (3H, t, J=7.3Hz, CH
2c
h 3 ), 1.75 (2H, q, J=7.3Hz, C
h 2 cH
3), 3.58 (1H, s, OH), 3.96 (3H, s, OCH
3), 5.16 (1H, d, J=15.6Hz), 5.47 (1H, d, J=15.6Hz), 7.59 (1H, s, aromatic ring-H)
[α]
D 20＝+51.3(c＝0.981，CHCl
3)。
(8) compound (r) is synthetic
At room temperature, to compound (q) (42.8g, 0.10mol, content 84.5%) 1-propanol solution (490mL) in add palladium (1.34g, 6.0mmol) and salt of wormwood (24.67g, 0.179mol), degassed by decompression in reaction vessel, and use argon replaces, then degassed by decompression again, with the carbon monoxide displacement, under 60 ℃, stir 4 hours.After letting cool and putting room temperature, by the Celite pad, filter insolubles, with ethyl acetate (300mL) washing.Add 1N hydrochloric acid (150mL) and saturated aqueous common salt (300mL) in filtrate, separate organic layer, then in water layer, add ethyl acetate (300mL) to be extracted.Merge organic layer, use anhydrous sodium sulfate drying, filter, then under reduced pressure be concentrated into dry.By silica gel column chromatography [silica gel: 200g, elutriant: chloroform: methyl alcohol mixes liquid (99: 1)] purifying residue, obtain brown oil materialization compound (r) (30.3g, 72.9mmol, the content 73.4% that HPLC records, yield 70%).
Below show HPLC condition that assay is used and the NMR spectrum of compound (r).
HPLC operational condition: reference example 26
Compound (r):
1h-NMR (400MHz, CDCl
3): δ 0.88 (3H, t, J=7.3Hz, CH
3), 1.04 (3H, t, J=7.3Hz, CH
3), 1.82 (4H, m, CH
2* 2), 3.69 (1H, s, OH), 4.09 (3H, s, OCH
3), 4.34 (2H, t, J=6.8Hz, CH
2), 5.31 (1H, d, J=16.3Hz), 5.61 (1H, d, J=16.3Hz), 7.94 (1H, s, aromatic ring-H).
(9) compound (s) is synthetic
Under nitrogen atmosphere under shading, (r) (28.7g in room temperature to compound, 68.2mmol, content 73.4%) and sodium iodide (27.6g, 0.184mol) anhydrous acetonitrile (141mL) solution in add chloro trimethyl silyl (23.3mL, 0.18mmol), and stir 3 hours.Add 1N hydrochloric acid (8mL) in the mixed liquid of reaction, then add 10% S-WAT (232mL), stir 30 minutes under room temperature.Be extracted with ethyl acetate mixed solution, by the organic layer separatory, then under reduced pressure be concentrated into dryly, obtain compound (s) (22.3g, 64.5mmol, the content 85.6% that HPLC (reference example 27) records, yield 95%).
Compound (s):
1h-NMR (400MHz, CDCl
3): δ 1.00 (3H, t, J=7.3Hz, CH
3), 1.02 (3H, t, J=7.3Hz, CH
3), 1.83 (4H, m, CH
2* 2), 3.75 (1H, s, OH), 4.35 (2H, t, J=6.8Hz, CH
2), 5.21 (1H, d, J=17.1Hz), 5.61 (1H, d, J=17.1Hz), 7.28 (1H, s, aromatic ring-H), 9.59 (1H, brs, OH).
(10) compound (t) is synthetic
At room temperature, in DMSO (7mL) solution of compound (s) (0.50g, 1.46mmol, content 86.6%), add salt of wormwood (0.40g, 2.92mmol), under argon atmosphere, stir 20 minutes in 50 ℃.Drip tert-butyl acrylate (2.1mL, 14.6mmol) in mixture, under argon atmosphere, stir 24 hours in 50 ℃.Add water (10mL) and concentrated hydrochloric acid (1mL) in ice-cold stirring downhill reaction mixture.With the mixed liquid of toluene-ethyl acetate (4: 1,7mL) by mixture extraction 4 times.Merge organic layer, water (5mL) washs 3 times, uses anhydrous sodium sulfate drying, filter, then under reduced pressure be concentrated into dry, acquisition tawny solid chemical compound (t) (0.55g 1.13mmol, the content 75.0% that HPLC (reference example 28) records, yield 77%).
Compound (t):
1h-NMR (400MHz, CDCl
3): δ 0.99 (3H, t, J=7.4Hz, CH
2c
h 3 ), 1.58 (9H, s, t-Bu), 1.83 (2H, m, C
h 2 cH
3), 4.68 (2H, s, CH
2), 5.25 (1H, d, J=17.8Hz), 5.69 (1H, d, J=17.8Hz), 7.01 (1H, s, aromatic ring-H).
(1) compound (h) is synthetic
Under argon atmosphere, under room temperature to compound (t) (1.02g, 1.84mmol, content 66.0%) add trifluoroacetic acid (1.7mL) in toluene solution (17mL), under argon atmosphere, in 110 ℃ of stirrings 100 minutes, and let cool to room temperature, under reduced pressure be concentrated into dry.Add methylene dichloride (50mL) in residue, by the Celite pad, filter insolubles.Add water (10mL) and separate organic layer in filtrate, then in water layer, adding methylene dichloride (20mL) to extract 3 times.Merge organic layer, use anhydrous sodium sulfate drying, filter, then under reduced pressure be concentrated into dry, obtain solid chemical compound (h) ((S)-4-ethyl-7,8-dihydro-4-hydroxyl-1H-pyrans is [3,4-f] indolizine-3,6 also, 10 (4H)-triketones) (0.46g, 1.41mmol, the content 80.7% that HPLC records, yield 77%).
Below show HPLC condition that assay is used and the NMR spectrum of compound (h).
Compound (h):
1h-NMR (400MHz, CDCl
3): δ 0.98 (3H, t, J=7.3Hz, CH
2c
h 3 ), 1.81 (2H, m, C
h 2 cH
3), 2.97 (2H, t, J=6.3Hz, C
h 2 cH
2), 3.64 (1H, s, OH), 4.34 (2H, m, CH
2c
h 2 ), 5.25 (1H, d, J=17.1Hz), 5.68 (1H, d, J=17.1Hz), 7.22 (1H, s, aromatic ring-H).
The HPLC operational condition:
Post: GL Science Inertsil ODS-2 (0.46cm ID * 25cm)
Near temperature: the constant temperature 40 ℃
Flow velocity: 1mL/ minute
Moving phase: 10mM potassium primary phosphate: methyl alcohol mixes liquid (4: 1)
Detect wavelength: 254nm.
Synthesizing of [embodiment 31] SN-38s (SN-38)
Compound (the h) (0.50g that embodiment 30 (11) are obtained, content 96.6%, 1.82mmol) and compound (e) (0.36g, 2.14mmol) be suspended in the mixed liquid of acetic acid-toluene (1: 1,10mL), at room temperature add a hydration tosic acid (p-TsOHH
2o, 10mg), under nitrogen atmosphere, in 100 ℃, stir 18 hours.After reaction solution is under reduced pressure concentrated, in residue, add toluene (10mL), then under reduced pressure concentrated.At room temperature in residue, add acetone (9mL), after stirring 2 hours, filter precipitate, the material obtained with acetone (2mL * 2) washing and filtering.Drying under reduced pressure, obtain brown solid (0.63g, the purity 97.7% that HPLC (reference example 9) records, yield 89%).
SN-38：
1H-NMR(400MHz，CDCl
3)：δ0.98(3H，t，J＝7Hz，CH
3)，1.38(3H，t，J＝7Hz，CH
3)，1.90(2H，q，J＝7Hz，CH
2)，3.08(2H，q，J＝7Hz，CH
2)，5.17(2H，s，CH
2O)，5.23(1H，d，J＝16Hz)，5.54(1H，d，J＝16Hz)，7.34-7.39(3H，m)，6.83(1H，d，J＝9Hz)。
[embodiment 32] 7-ethyl-10-[4-(1-piperidino-(1-position only))-1-piperidino-(1-position only)] carbonyl oxygen base camptothecine (SN-38B-11) synthetic
With the synthetic SN-38 (0.91g, 2.32mmol) obtained in embodiment 31, according to existing method (Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K.; Furuta, T.; Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T., Chem.Pharm.Bull., 1991,39,1446) synthetic SN-38B-11 (chirality HPLC (reference example 10) records 99.8%ee for 1.22g, yield 89%).
[embodiment 33] 7-ethyl-10-[4-(1-piperidino-(1-position only))-1-piperidino-(1-position only)] carbonyl oxygen base happiness hydrochloric acid tree alkali salt hydrochlorate trihydrate (CPT-11) synthetic
Hydrochloric acid (20mL) to adding 0.1N in the SN-38B-11 (1.00g, 1.7mmol) obtained in embodiment 32, make it to dissolve by near heating 80 ℃, adds acetonitrile (100mL), at room temperature stirs 15 hours.Filter precipitate, drying, moisture absorption, obtain yellow-white powder CPT-11 (0.95mg, yield 89.8%).
industrial applicibility
The synthetic method of the application of the invention, can, at short notice with 2 ' of high-recovery synthesis of high purity-amino-5 '-hydroxypropiophenone and tricycle kentones, by using them as intermediate, can effectively and practicably carry out the complete synthesis of CPT class.
Claims (12)
1. for the synthesis of the preparation method of 2 ' of camptothecin-amino-5 '-hydroxypropiophenone, wherein from compound (a):
Generate compound (b):
Generate compound (c) from compound (b):
Generate compound (d) from compound (c):
Generate compound (e) from compound (d):
It is characterized in that, R can pass through catalytic reduction and the protecting group of deprotection.
2. according to the method for claim 1, it is characterized in that, can be by catalytic reduction the protecting group of deprotection be benzyl.
3. according to the method for claim 1 or 2, it is characterized in that, described method comprises one or more following steps that are selected from:
(1) compound (a), benzyl reagent and alkali are mixed, and in solvent this mixture of heated and stirred and obtain the step of compound (b);
(2) obtain the step of compound (c) to dripping Grignard reagent in compound (b) under atmosphere of inert gases;
(3) compound (c) and oxygenant are mixed, and stir and the step of acquisition compound (d);
(4) catalytic reduction compound (d) and obtain the step of compound (e).
4. according to the method for claim 3, wherein, the solvent in step (1) is dimethyl formamide.
5. according to the method for claim 3, wherein, the Grignard reagent in step (2) is vinyl bromination magnesium.
6. according to the method for claim 3, wherein, the oxygenant in step (3) is Jones reagent, Manganse Dioxide or TEMPO-clorox.
7. for the synthesis of the preparation method of 2 ' of camptothecin-amino-5 '-hydroxypropiophenone, wherein from compound (a):
The generation compound (c "):
Generate compound (d ") from compound (c "):
Generate compound (e) from compound (d "):
8. according to the method for claim 7, it is characterized in that, described method comprises one or more following steps that are selected from:
(1) obtain the step of compound (c ") to dripping Grignard reagent in compound (a) under atmosphere of inert gases;
(2) compound (c ") and oxygenant are mixed, and stir and obtain the step of compound (d ");
(3) catalytic reduction compound (d ") and obtain the step of compound (e).
9. method according to Claim 8, wherein, the Grignard reagent in step (1) is vinyl bromination magnesium.
10. according to the method for claim 9, wherein, the oxygenant in step (2) is Jones reagent, Manganse Dioxide or TEMPO-clorox.
11.7-the preparation method of ethyl-10-hydroxycamptothecin, described method comprises that the method by any one of claim 1～10 obtains 2 '-amino-5 '-hydroxypropiophenone and makes obtained 2 '-amino-5 '-hydroxypropiophenone and (S)-4-ethyl-7,8-dihydro-4-hydroxyl-1H-pyrans also [3,4-f] indolizine-3,6,10 (4H)-tri-reactive ketones.
12. according to the method for claim 11, wherein, by (S)-4-ethyl-7,8-dihydro-4-hydroxyl-1H-pyrans is [3,4-f] indolizine-3,6 also, 10 (4H)-triketones and 2 '-amino-5 '-hydroxypropiophenone is mixed, and makes this mixture reaction under atmosphere of inert gases.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
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| JP200145430 | 2001-02-21 | ||
| JP2001-45430 | 2001-02-21 | ||
| JP2001045430 | 2001-02-21 | ||
| JP2001-309322 | 2001-10-05 | ||
| JP2001309322 | 2001-10-05 | ||
| JP2001309322 | 2001-10-05 |
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| CNB028053230A Division CN100408550C (en) | 2001-02-21 | 2002-02-21 | Method for synthesizing camptothecin-relating compounds |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5391745A (en) * | 1992-07-23 | 1995-02-21 | Sloan-Kettering Institute For Cancer Research | Methods of preparation of camptothecin analogs |
| CN1183414A (en) * | 1996-10-30 | 1998-06-03 | 田边制药株式会社 | S type 2 -substituted hydroxy-2 -indolidinylbutyric ester compounds and process for preparation thereof |
-
2002
- 2002-02-21 CN CN 200810146142 patent/CN101337900B/en not_active Expired - Fee Related
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- 2003-08-12 ZA ZA200306223A patent/ZA200306223B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5391745A (en) * | 1992-07-23 | 1995-02-21 | Sloan-Kettering Institute For Cancer Research | Methods of preparation of camptothecin analogs |
| CN1183414A (en) * | 1996-10-30 | 1998-06-03 | 田边制药株式会社 | S type 2 -substituted hydroxy-2 -indolidinylbutyric ester compounds and process for preparation thereof |
Non-Patent Citations (4)
| Title |
|---|
| Hubert Josien, et al..A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles.《Chemistry - A European Journal》.1998,第4卷(第1期),第67-83页. |
| Hubert Josien, et al..A General Synthetic Approach to the (20S)-Camptothecin Family of Antitumor Agents by a Regiocontrolled Cascade Radical Cyclization of Aryl Isonitriles.《Chemistry- A European Journal》.1998,第4卷(第1期),第67-83页. * |
| Kevin E. Henegar, et al..Practical Asymmetric Synthesis of (S)-4-Ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine- 3,6,10(4H)-trione, a Key Intermediate for the Synthesis of Irinotecan and Other Camptothecin Analogs.《J. Org. Chem.》.1997,第62卷(第19期),第6588-6597页. * |
| KevinE.Henegar et al..Practical Asymmetric Synthesis of (S)-4-Ethyl-7 |
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| CN101337900A (en) | 2009-01-07 |
| ZA200306223B (en) | 2004-06-03 |
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