UA76449C2 - Methods for producing camptothecin analogs and intermediary compounds - Google Patents

Abstract

To more efficiently provide CPT, which is a starting compound for irinotecan hydrochloride and various camptothecin derivatives, by a practically usable total synthesis, a means whereby 2'-amino-5'-hydroxypropiophenone corresponding to the AB cycle moiety of the camptothecin (CPT) skeleton and a tricyclic ketone corresponding to the CDE cycle moiety thereof can be efficiently produced and thus CPT and its derivatives can be stably supplied is provided.

Description

Description of the invention

The present invention relates to a method of synthesizing camptothecin-like compound(s). More particularly, invention 2 relates to a method for the preparation of intermediate compounds for the synthesis of camptothecin analogs having anticancer activity and used as said intermediate compounds, and relates to the general synthesis of camptothecin analogs.

Camptothecin (hereinafter referred to as CPT) extracted from the bark, root, fruit, leaf and similar of Satioyes asutipaia of Chinese origin is a pentacyclic alkaloid and is known to exhibit anticancer activity by inhibiting nucleic acid synthesis. Meanwhile, it has been reported that a derivative of camptothecin causes diarrhea and similar side effects (Sapp o Kadaki Kuopoi 17, r.115-120, 1990), and, accordingly, there is a need to solve the problem that is the cause of the disorder of the gastrointestinal tract, to determine the varieties of derivatives with less toxicity, increased efficiency, and so on.

Thus, the inventors have already described 12 7-ethyl-10-I4-(1-piperidino)-1-piperidino|)carbonyloxycamptothecin hydrochloride trihydrate (hereinafter referred to as

CPT-11), a water-soluble semi-synthetic derivative of CPT, as a compound that has less toxicity compared to CPT, is currently widely used as an anticancer agent (generic name: irinotecan hydrochloride).

Camptothecin analogs such as CPT-11 can be modified using chemical modifications of CPT obtained from natural sources.

However, natural sources such as Satioipesa asytipaia yield relatively low amounts of CPT as a starting material, and it is expected that due to the ever-increasing need for CPT-11, which is a useful derivative and so on, it is expected that sufficient supply of CPT will become quite difficult not considering the fact that the necessary amount of the necessary raw material is provided by planting plantations. Although a general method of synthesis has also been developed, today the situation in this matter is still far from practical use. p. 29 As a general method of synthesis, the method of Shen, V. and others is known. (Zpep, MU. ei ai.) is shown below with the help of (3 reaction scheme through the reaction of Friendlander (Egigaiapaeg) aminopropiophenone and tricyclic ketone (9. Oga.

Spent 1993, 58, 611-617 "Sopsize Toiaii Zupipezevs oii aI-Satrioiyesip i Keiaiei Apiiisapseg Ogoidv.", because of this there is a problem because the stages are quite complex, the yields are not sufficient and only the racemate is formed. o ' y y cha y ge LEV sadi vv 7 rot. and where her ME V KY WHAT domain I de - ve a bu bo ran WHOSE with "Diva: and also SA

OO. -and (22) At the same time, despite the fact that Curran, D, etc. (Sypap, O.R. ei aI.) carried out a general synthesis using a method that uses a series of radical cyclizations of arylisonitrile and iodopyridone, as shown in the reaction scheme below (Spet. Eig. 9. 1998, 4, 67-83 "A Sepega! Zupipeis Arrgoasp (o She - (205)-Satrioiyesip Ratiu oi Apiishtog Adepiz Bu a KediosopigoPed Sazsade Cadisa|! Susiigayop oi AGguiYi

Ge; IvopiigShevz."), the problems consist in the yield of the cyclization reaction, which is not sufficient and the need to remove the protective group after cyclization. ime) 60 b5

Mo, shi and | with se and y chi shko : MaEoah | "Mo Eee and m Co. R NV:

KZ o - in 70: Her self

Even

In addition, although above Kuran, dlp. etc. (Sytap, O.R. eg a.) synthesized 4-iodo-2-methoxy-b-trimethylsilylpyridine-3-carbaldehyde, an intermediate compound in the synthesis of a tricyclic ketone part of the CPT analogue, according to the scheme below,

OM sleep; me schu TO ze shva sho zhi « d9oviep, N; Co., 5.-8V.; Vot, O.; Otstap, O.R. Spet. Eig. 9U. 1998, 4, Mo.1, 67. this method is highly dangerous due to the need to use t-Viii, which easily ignites when used in large quantities on an industrial scale, and the reaction requires a temperature of -78 C, which makes it impossible to increase the size of the loading . In addition, due to the complexities of the necessary temperature control in the general reaction system, there is no industrially suitable reaction system. -

The object of the invention rationally provides CPT, which is the starting material for irinotecan hydrochloride and various kinds of camptothecin derivatives, and camptothecin analogues, such as 7-ethyl-10-hydroxycamptothecin, which is a key intermediate compound for the synthesis of irinotecan hydrochloride, by means of a practical common " synthesis In particular, the object of the invention is the synthesis of the intermediate compound corresponding to the AB-ring part of the skeleton 70 of camptothecin and the intermediate compound corresponding to the COE-ring part, respectively, and, in addition, the synthesis of 8c analogues of camptothecin using these intermediate compounds. Because of these circumstances, the inventors conducted an intensive search, and as a result, as an AB-ring part, "" received Compound (a) (5-hydroxy-2-nitrobenzaldehyde): p. i i ut c) h NO se ANO b More and with Y - I V schi and (a) zh. rn: ШЧИ all (Че) Шчи " - 7 | and her mo. p raw material, and developed a method of obtaining CRT and its stable derivatives using a rational method

F, preparation of 2'-amino-5'-hydroxypropiophenone, which corresponds to the AB-ring part of the CPT skeleton, and as the SOE-ring part is obtained from Compound (k) (2-methoxy-6-trimethylsilylpyridine (MTP)): 60 b5 and go m | (yu 9 shi SHII y y : (where ТМ5 represents a trimethylsilyl group, and Me represents a methyl group.) developed a method for obtaining CPT and its stable derivatives using the rational preparation of a tricyclic ketone corresponding to the SOE ring part of the CPT skeleton, and established a general methodology synthesis of CRT analogues using an acceptable combination of these methods without the use of natural materials, to complete the invention.

That is, the invention relates to a method of obtaining 2'-amino-5'-hydroxypropiophenone, which corresponds to the AB ring part of the CPT skeleton according to the sequence; a: her university. She is like U

Saz (c) (s « zdo. Ko « sa nu chn pk i p i: si ze ey Ff | y ( a ) yg) o s:z" (where K means a protective group), and refers to the general method of synthesis of CRT analogues by means of an acceptable process combination for 15 tricyclic ketone corresponding to the SOE ring part of the CPT skeleton, which includes, in particular, the synthesis of - 3-formyl-4-iodo-2-methoxy-6-trimethylsilylpyridine (Compound (I)) from 2- of methoxy-β-trimethylsilylpyridine (Compound (K)) or 3-hydroxymethyl-4-iodo-2-methoxy-β6-trimethylsilylpyridine (Compound (M)) by improving and (o) optimizing the process according to the synthetic sequence: sh» sh» 3e)

F) name) 60 b5

-КХ шк АХ do me D-t oo va y ШЭ 8 i b v Z 9 I 9 o v v sh o (where TM5 is a trimethylsilyl group, Me is a methyl group, Ei is an ethyl group, Pg is a propyl group, and" You are a t-butyl group), which is based on the method of Sigtap (Doziep, N,; Ko, 5. V.; Vot, O.: Sytap, 0. R.

Spent Eig. 9. 1998, 4 67-83) and the Rpagtasia 5 Orionp method (hereinafter referred to as the P 5 method; Nepedzeg, K.

IS.; Avioga, village, MU; Vatsdptap, T. A. iy, 9U. WITH; would, K. HER U. Og9d. Spent 1997, 62, 6588-6597.) which are Ge»! synthetic methods known today. In addition, since Compound (M) is a biproduct arising in the process of synthesis of 3-(2-butenyloxymethyl)-4-iodo-2-methoxy-β6-trimethylsilylpyridine (Compound (t)), in the above-mentioned synthetic method of Compound ( I) is described below. "AND

In particular, the invention relates to a method of obtaining 2'-amino-5'-hydroxypropiophenone for the synthesis of camptothecin analogues, where Compound (b) is obtained from Compound (a): : -I

b

(o) t. eto i edaiya FRUIT | ) I h ry: SHE yah . :; then! y s Y. Kh vo p che y tp Ka MOH me p Kai

F) name) and from Compound (b) get Compound (c): 60 b5 cha nolukas (vu get Opopuka (6); 9 iz Popukas (c) get Opolaka (g)

F

Noya Z va i « - s z -I

F g" road 50 so

F) yuyu bo b5

(c) c o (is) " " (se) i- " and from Compound (c) they get Compound (9): With c ;" -AND

Ge») g» iz 50 (che;

Ф) ho bo b5 cha nolukas (vu) get Opopuka (6); yiv Popukas (c) get Yepoluka (Fe and a'Epopukas (4) get Compound-(c):

Ge) o "I sha is " - s z -I (e))

Sg» iz 50 (Che) o ko bo b5

(a) c o (2) " " (Se) and - " and from Compound (4) get Compound (e): c) c from -I (2) d" iz 50 (32)

Ф) ko bo b5 cha nolukas (vu) get Opopuka (6); yiv Popukas (c) get Yepoluka (Fe and a'Epopukas (4) get Compound-(c):

Ge) o "I sha is " - s z -I (e))

Sg» iz 50 (Che) o ko bo b5

(e) c schi 6) (o) « « (Ce) and - where K is a protecting group that can be removed by catalytic reduction. Also, the invention relates to the method described above, in which the protective group that can be removed by catalytic reduction is a benzyl group. In addition, the invention relates to the method described above, where it includes one or more stages that is selected from the group that contains (1) the stage of obtaining Compound (B) by mixing Compound (a), a benzylating reagent and a base, and - stirring the mentioned mixture in a solvent at boiling temperature; b (2) the stage of obtaining Compound (c) by adding Grignard's reagent dropwise to Compound (B) in an inert gas atmosphere; in (3) the stage of obtaining Compound (4) by mixing Compound (c) and an oxidizing agent and mixing the mixture; (4) the stage of obtaining Compound (e) by catalytic reduction of Compound (4). In addition, the invention relates to the method mentioned above, in which in stage (1) the solvent is dimethylformamide.

The invention also relates to the method mentioned above, in which at stage (2) the Grignard reagent is vinylmagnesium bromide.

In addition, the invention relates to the method mentioned above, in which in stage (3) the oxidizing agent is a reagent

F! Jones, manganese dioxide or TEMRO-(2,2,6,6-tetramethylpiperidine-1-oxyl)-sodium hypochlorite.

Also, the invention relates to the compound represented by the formula (c): ime) 60 б5 ство в: (c) : шко Ж 70 в ФИ что se: 3 75 (in which Вп is a benzyl group).

In addition, the invention relates to the compound represented by formula (a):

M (4)

Sh-- iy

SHY with . щ Br Y o cho y F zo "VE y lk v « ! yu, "y - (Se) (in which Vp is a benzyl group). them

Also, the invention is a method of obtaining 2'-amino-5'-hydroxypropiophenone for the synthesis of camptothecin analogues, in which from Compound (a): ny set svy (in "

No - that is

And" ba

M Mokh -I (22) get the compound (с"): щ» their 50 signs: (с) in ай

Me, tire

N y SN y them and ri Betty ly

From I kose n 60 and from Compound (c"), Compound (a") is obtained: b5 i (487 -

Ff | (au 70 t and from Compound (a") receive Compound (e): s, (e) ish. nn MA re i still --; y y y , bottoms: Я A dy

And | F y

ZU SHI. "N Tit: s tat K o

In addition, the invention relates to the method mentioned above, which includes one or more stages, which are selected from the group containing (is) (1) the stage of obtaining Compound (c") by dropwise addition of the Grignard reagent to Compound (a) in an atmosphere of "inert gas; (2) a step of obtaining Compound (a") by mixing Compound (c") and an oxidizing agent and stirring the mixture; and "co (3) a step of obtaining Compound (e) by catalytic reduction of Compound (a"). The invention also relates to the method mentioned above, in which at stage (1) the Grignard reagent is vinylmagnesium bromide. -

In addition, the invention relates to the method mentioned above, in which in stage (2) the oxidizing agent is a reagent

Jones, manganese dioxide or TEMRO sodium hypochlorite.

The invention also relates to the use of 2'-amino-5'-hydroxypropiophenone, which is obtained by the method described above, for the preparation of camptothecin analogs.

In addition, the invention relates to a method of obtaining camptothecin analogs, which includes the reaction of tc 2'-amino-5'-hydroxypropiophenone obtained using the method described above and a tricyclic ketone. "with the invention there is also a method of obtaining a tricyclic ketone for the synthesis of camptothecin analogs, in which from "Compounds (K):

І ( ; в шмата -ай и мк пови 4: -й "а в я и име) 60 (in which ТМ5 is a trimethylsilyl group, and Me is a methyl group), or Compounds (М): б5

OMe.: ; and I -. 2 bl holo -taY i tsa i, so tia.

DE: ZAV M: PO . (9 c (8) that . . . (22) (in which TM5 is a trimethylsilyl group, and Me is a methyl group), obtain Compound (1):

PI a Y 1 h lp chiv a : i - s ;" () -I (22) sh» iz 50 3e) (in which TM5 is a trimethylsilyl group, and Me is a methyl group), and Compound (t) is obtained from Compound (I):

F) name) 60 b5

OMe 70 tm - LI " ZE s (8)

That I I I (22) zo (in which TM5 is a trimethylsilyl group, and Me is a methyl group), and Compound (n) is obtained from Compound (t): "

OM: | g im p y i: Sh Shk: y y t, Sho y g. y. go in "

Sh and | In Z I and no

And" you5 and

J

-I (p) (22) sh» iz 50 3e)

Ф) име) 60 (in which TM5 is a trimethylsilyl group, Me is a methyl group, and Ei is an ethyl group), and Compound (0) is obtained from Compound (n): : ED sk (o) c i) (in which TM5 is a trimethylsilyl group, Me is a methyl group, and Ei is an ethyl group), Me 7 and from Compound (o) get Compound (p): « « со со

Me

In her sleep y This is Z (v ) « shk d y what Vshi S y -

G. niy Y y De y -I (p) (o) t their 50 i3e) 52 iF) ime) 60 (in which TM5 is a trimethylsilyl group, Me is a methyl group, and Es is an ethyl group), and from Compound ( p) receive Compound (4): b5

- these! and 70% E g (in which Me is a methyl group and Es is an ethyl group), and from Compound (4) Compound (g) is obtained: сч о

Ome and. Shi y y y o shov her Ya y 3. « r o

С m- (9 « ши с ;» -I (22) и» (in which Me is a methyl group, Ei is an ethyl group, and Rg is a propyl group), and Compound (8) is obtained from Compound (d): » iChe) .. with Ko '

F! Shk. There is B. 60 m Kg actions EE KE: b5

(c) (in which Ey is an ethyl group, and Rg is a propyl group), and from Compound (5) we get the Compound »! o M « (Se) and - « shi s ;» " (in which Es is an ethyl group, and "Vy is a t-butyl group), and from Compound () we get Compound (Pp): -I

F tu them:! so y is not 8 ia Ж is the rest (53 names) 60 b5

(n) (in which Es is an ethyl group), and wherein it includes one or more steps selected from the group consisting of: (1) a step of obtaining Compound (I) by mixing Compound (K), a lithiation agent, a formylating agent reagent and iodizing reagent; (2) the stage of obtaining Compound (t) by mixing Compound (I), crotyl alcohol, triethylsilane and acid and reacting the mentioned mixture without using a solvent; (3) the stage of obtaining Compound (I) by mixing Compound (M), a biproduct of stage (2), with an oxidizing agent and a base; (4) the stage of obtaining Compound (n) by mixing Compound (t), a palladium catalyst, a base and a phase transfer catalyst and boiling the mentioned mixture in a solvent; (5) the stage of obtaining Compound (o) by mixing Compound (n), an osmium catalyst, a co-oxidizing agent, a base, and an asymmetric reagent; (6) the stage of obtaining Compound (p) by mixing Compound (0), a base and iodine, and boiling the mentioned mixture in a liquid alcohol-water mixture; (7) the stage of obtaining Compound (4) by mixing Compound (p) and desilylation-iodination reagent; (8) the stage of obtaining Compound (d) by mixing Compound (4), a palladium catalyst and a base and He! by the interaction of the mentioned mixture in 1-propanol in an atmosphere of carbon monoxide; (9) the stage of obtaining Compound (5) by mixing Compound (g) and a demethylating reagent and interacting in the said mixture at room temperature; (10) the stage of obtaining Compound (|) from Compound (5) in the presence of t-butyl acrylate and a base.

In addition, the invention relates to the method mentioned above, in which in stage (1) the lithiation agent is n-butyllithium. what

The invention also relates to the method mentioned above, in which at stage (1) the reaction temperature is a constant temperature in the range of -30-4020.

In addition, the invention relates to the method mentioned above, in which in stage (3) the oxidizing agent is

TEMRO sodium hypochlorite. "

The invention also relates to the method mentioned above, in which at stage (4) the base is potassium carbonate or

M,M-diisopropylethylamine. 8 c In addition, the invention relates to the method mentioned above, in which at stage (4) the solvent is tetrahydrofuran or a liquid mixture of isopropyl ether-acetonitrile-water. "» The invention also relates to the method mentioned above, in which in stage (5) the osmium catalyst is potassium osmate (MI).

In addition, the invention relates to the method mentioned above, in which at stage (6) iodine in relation to Compound -I (o) is used in a 4 equivalent excess.

The invention also relates to the method mentioned above, in which at stage (7) the desilylation-iodination reagent would be silver iodine-trifluoroacetate or sodium M-chlorosuccinimide-iodide. "d" In addition, the invention relates to the method mentioned above, in which Compound (4) is chemically purified using purification steps, which include the step of adding to the reaction mixture the product obtained in step e of obtaining Compound (4) from Compound (p) to aqueous alkaline solution and mixing; the stage of adding an organic (Che) solvent and mixing, followed by removal of the organic layer; and the stage of acidification of the aqueous layer and extraction with an organic solvent.

The invention also relates to the method mentioned above, in which the aqueous alkaline solution is an aqueous solution of sodium hydroxide.

In addition, the invention relates to the method mentioned above, in which the organic solvent is chloroform. o The invention also relates to the method mentioned above, in which Compound (4) is optically purified by means of several stages of purification, which includes the stage of dissolving the product of the reaction mixture obtained in the stage of preparation

Compound (4) from Compound (p) in a highly polar solvent, followed by exfoliation with a low copolar solvent; and the stage of sediment filtration and further concentration of the filtrate to dryness under reduced pressure.

In addition, the invention relates to the method mentioned above, in which the highly polar solvent is chloroform.

The invention also relates to the method mentioned above, in which the low polar solvent is n-hexane.

In addition, the invention relates to the method mentioned above, in which potassium carbonate is the basis at stage (10).

The invention also relates to the use of a tricyclic ketone obtained by the above-described method 65 for the preparation of camptothecin analogs.

In addition, the invention relates to a method for obtaining camptothecin analogs, where the tricyclic ketone obtained by the method described above reacts with 2'-amino-6'-hydroxypropiophenone.

The invention also relates to the method mentioned above, in which 2'-amino-5'-hydroxypropiophenone is 2'-amino-5'-hydroxypropiophenone obtained by the method described above.

In addition, the invention relates to the method mentioned above, in which tricyclic ketone and 2'-amino-5'-hydroxypropiophenone are mixed and the mentioned mixture reacts in an inert atmosphere.

The invention makes it possible to rationally obtain 2'-amino-5'-hydroxypropiophenone, which corresponds to

to the AB ring part of the CPT skeleton by adapting these components and makes it possible to propose a general synthesis of CPT for practical use. In addition, the intermediate compounds Compound (c) and Compound y (I) in the method of the invention have not yet been described for use in this synthesis, and therefore they are useful new compounds.

The invention also makes it possible to carry out practically asymmetric synthesis of compound(s) by adapting these components, as a result of which the compound(s) has a skeleton corresponding to the SOE ring part (part of the tricyclic ketone) in the CPT skeleton.

For the synthesis of 2'-amino-5'-hydroxypropiophenone, which is an AB ring in the CPT skeleton, the method of obtaining 2-amino-5'-hydroxypropiophenone includes one or more of the following stages: (1) the stage of synthesis of 5-benzyloxy-2 -nitrobenzaldehyde (Compound (B)) from 5-hydroxy-2-nitrobenzaldehyde (Compound (a)); (2) the synthesis stage of 1-(5-benzyloxy-2-nitrophenol)-2-propen-1-ol (Compound (c)) from Compound (B); (3) the synthesis stage of 1-(5-benzyloxy-2-nitrophenol)-2-propen-1-one (Compound (4) from Compound (c); and (4) the synthesis stage of 2'-amino-5'-hydroxypropiophenone (Compound (e)) from Compound (4). As a typical synthesis path, the following synthetic path is given: zo (c) (c) Se.; 2.4 st. c (where K is a protecting group that can be removed by catalytic reduction). :z" In the invention, in the case where K is a protecting group that can be removed by catalytic reduction, this should not be considered as a limitation, but typical examples are benzyl ether-type protecting groups such as benzyl, methoxybenzyl, 2,5-dimethylbenzyl, or 4-nitrobenzyl, and benzylcarbonate-type protecting groups such as -1 15 benzyloxycarbonyl, although the benzyl group is more suitable for use due to the cost of the reagent. (o ) In addition, Compound (a) can be used, which is a starting material synthesized using a 1" known method, which is chemically converted from a similar compound that isolated ate and purified from various types of natural materials, and natural materials containing Compound (a). Can also be used

Her 50 is a commercially available reagent. c Next, the above-mentioned stages (1)-(4) are discussed more specifically.

In stage (1), Compound (a) is dissolved or suspended in a solvent, after which a benzylating reagent and a base are added, and due to heating with stirring, Compound (b) is obtained.

M,M-dimethylformamide (DMF), dimethylsulfoxide, chloroform, 59 acetonitrile, ethanol, water and the like can be used as a solvent, and DMF is particularly preferred due to its solubility and reactivity.

GF) The amount of DMF used can be three or more times greater than Compound (a), preferably in the range from 3 to 20 times.

Any suitable reagent may be used as the benzylating reagent. Specific examples are benzyl chloride, benzyl bromide, benzyl iodide, phenyldiazomethane, dibenzyl carbonate and the like, and in particular, benzyl chloride can preferably be used.

The amount of benzylating reagent used may be appropriate for the reagent used, although in the case where, for example, benzyl chloride is used, 1-5 equivalents are used based on

Compounds (a), preferably 1-2 equivalents.

Any suitable agent can be used as a base. Specific examples are potassium carbonate, as sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and the like, and in particular potassium carbonate is particularly preferred.

The amount of base used may be acceptable for the reagent used, although in the case where potassium carbonate is used, for example, it is used in a 1-10 equivalent excess to

Compounds (a), preferably 1-4 equivalent.

The heating temperature is in the range from 60 to 1002C, preferably 60-8020. In addition, the reaction time is in the range from 0.5 to 24 hours, preferably from 1 to 20 hours.

At stage (2), Compound (c) is obtained by dropwise addition of Green's reagent to Compound (B) in an inert gas atmosphere. 70 Any gas can be used as the inert gas, in our case it is an inert gas such as argon, helium, neon, krypton, xenon, radon or the like, or a low reactivity gas such as nitrogen, and argon and nitrogen are particularly preferred in view of their cost.

Any suitable reagent may be used as the Grignard reagent. Specific examples are vinylmagnesium bromide, vinylmagnesium chloride, vinylmagnesium iodide and the like, and vinylmagnesium bromide is particularly preferred for use.

The amount of Grignard reagent used may be acceptable for the reagent used, although in the case of, for example, vinylmagnesium bromide, 1-2 equivalents are used based on Compound (B), preferably 1-1.5 equivalents. In the case when Grignard's reagent is dripped into a solution of Compound (B) or vice versa

Compound (B) is added dropwise to the Grignard reagent, the synthesis of Compound (c) is possible, although in order to reduce the formation of a biproduct (hereinafter described as Compound (i))

PE: and so on. D-t y y --y y Te still tya U shchi I Po o 7 nt sho p. se zay, - and "do, F 30 : « " (in which K is a protective group that can be removed by catalytic reduction), preferably reagent c

Grinyar is added dropwise to the solution of Compound (b). 35 The amount of solvent used in the reaction, for example, tetrahydrofuran (hereinafter referred to as -

THF) can be in the amount of 10-100 parts, and to reduce the formation of alcohol, the amount of 50-100 parts is preferable.

Also, the reaction temperature preferably does not exceed 109C, and to reduce the production of alcohol, a temperature of -78--4096 is preferred. 40 In addition, the reaction time is 0.1-3 hours, and particularly preferably, it is 0.5-1 hours. From c In step (3), Compound (4) can be obtained by mixing Compound (c) with an oxidizing agent and "" stirring the mixture. " As an oxidizing agent, any suitable agent can be used. Examples of such oxidizing agents are, for example, manganese dioxide, Dess-Martin periodate, Jones reagent (MaoSt2O7/Nzo)), ROS, 45 ROS, DMSO/oxalyl chloride/triethylamine (Svern oxidation), TEMRO-sodium hypochlorite and the like, and, in particular, - manganese dioxide, Dess-Martin periodate, Jones's reagent, and b TEMRO-sodium hypochlorite can preferably be used.

For these oxidizing agents, the agent is prepared immediately before use, and in the case of, for example, manganese dioxide, the agent is prepared before use from potassium permanganate and sulfate

ChT" 70 manganese.

The amount of oxidizing agent used can be acceptable for the reagent used, although in the case of, for example, manganese dioxide, a 2-50-fold excess is used relative to Compound (c), preferably a 4-10-fold excess.

As a solvent, it may be appropriate to use, for example, chloroform, methylene chloride, ethyl acetate, benzene, toluene and the like, and, in particular, preferably chloroform and methylene chloride.

F! The amount of solvent used is 5-50 parts, preferably 10-20 parts.

In addition, the reaction time is 1-48 hours and, in particular, preferably 1-18 hours. In step (4), Compound (e) o can be obtained by catalytic reduction of Compound (a).

As a catalyst for reduction, it is advisable to use palladium-carbon, palladium-carbon hydroxide, 60 rhodium-alumina and the like, and in particular, palladium-carbon and palladium-carbon hydroxide are preferred.

The amount of catalyst used for reduction is 0.01-0.5 equivalents with respect to Compound (a), preferably 0.05-0.2 equivalents.

Any acceptable solvent may be conveniently used as the solvent, although ethyl acetate is preferred due to its good solubility. Because the amount of solvent used is 5-50 parts, preferably 10-20 parts.

In addition, the reaction time is 0.1-24 hours and, in particular, preferably 1-3 hours.

In addition, instead of synthesizing Compound (e) through the above-described stages (1)-(4), it can be obtained as follows: from Compound (a): all: ; i: I (a) 70 her "mo ; they get the Compound (c"): (c) : a sh pishi, rya X tia ka IY and s i from the Compound (c") get the Compound (a"): o

What (a") eV

BUT She "p. и WHOSE ai « , ii -

Ker M and from Compound (a") receive Compound (e): "

NO (is) - p. h - y ze: y » y , y zh va AV. WE

What! and od z p KE I 3e) no no . " with

In this synthetic technique, Compound (c") can be prepared by dropwise addition of a Grignard reagent to Compound (a) under an inert atmosphere. In addition, Compound (a") can be prepared by mixing Compound (c") with its oxidizing agent and stirring the mixture , and Compound (e) can be obtained by catalytic reduction of Compound (a").

Here, the Grignard reagent and the oxidizing agent that can be used are the same as those that were

GF) mentioned in stages (2) and (3). In this synthetic technique, since no protecting group is used, the synthesis of the 7 AB-ring part can be carried out more easily.

In addition, camptothecin analogues can be obtained by the reaction of Compound (e) obtained in step (4) or the synthetic technique just described above and a tricyclic ketone, although a tricyclic ketone similar to, for example, Compound (PM): b5 ze and

What

And: soysh o I dream to Heaven

What and. (n) with o

Regarding the synthesis of the SOBE-ring part (part of the tricyclic ketone) of the CPT skeleton, the preparation of (2) tricyclic ketone is carried out using the following synthesis method. "t

Eeoya om Es me: "im (se)

MORE: I'm poisoned by V

As in. and ro in « s ma Oi yo: Oi

BE I nan Yu and - for: and ate and in. (22) -e» t o ge 5 her Z... her SHY M zh 22 (in which TM5 is a trimethylsilyl group, Me is a methyl group, EiiY is an ethyl group, Pg is a propyl

Gee! group, and"You are a t-butyl group.)

As the starting Compound (K) in the synthesis method described above, a compound synthesized using the above-described Curran method can be used (doviep, N.; Ko, 5. V.; Vot, O.: Sytap, Yu. R. Spet. Eig. 9. 1998, 4 67-83), which is chemically transformed into a similar compound, which was isolated and purified from various types of natural materials or natural material containing Compound (K).

A preferred synthesis method for the synthesis of a tricyclic ketone using the sequence described above includes one or more of the 12 steps below; (1) at the stage of synthesis of 4-iodo-2-methoxy-β6-trimethylsilyl-3-pyridinecarbaldehyde (hereinafter referred to as

Compound (I)) from 2-methoxy-b-trimethylsilylpyridine (hereinafter referred to as Compound (K)), n-butyllithium uses 65 as a base and the reaction is carried out at a constant temperature of -30 - -409С; (2) at the stage of synthesis of 3-(2-butenyloxymethyl)-4-iodo-2-methoxy-β6-trimethylsilylpyridine (hereinafter referred to as

Compound (t)) from Compound (I), the solvent is not used in the reaction; (3) at the stage of synthesis of Compound (I) from 3-hydroxymethyl-4-iodo-2-methoxy-b-trimethylsilylpyridine (hereinafter referred to as Compound (M)), TEMRO-sodium hypochlorite is used as an oxidizing agent; (4) at the stage of synthesis of 4-ethyl-8-methoxy-6-trimethylsilyl-1H-pyranoIII3,4-c|Ipyridine (further denoted as

Compound (p)) from Compound (t), a mixture of diisopropyl ether, acetonitrile and water is used as a solvent for the reaction mixture, and M,M-isopropylethylamine is used as a base; (5) at the stage of synthesis of (5)-4-ethyl-3,4-dihydro-3,4-dihydroxy-8-methoxy-β6-trimethylsilyl-1H-pyrano|3,4-c|Ipyridine (hereinafter referred to as 7 /0 Compound (o)) from Compound (n), potassium osmate (MI) is used as an osmium catalyst; (6) at the stage of synthesis of (5)-4-ethyl-3,4-dihydro-4-hydroxy-8-methoxy-6-trimethylsilyl-3-oxo-1H-pyrano|3,4-c|Ipyridine (further denoted as Compound (p)) from Compound (co), the reaction mixture is boiled with iodine (4 equivalents); (7) at the stage of synthesis of (5)-4-ethyl-3,4-dihydro-4-hydroxy-6-iodo-8-methoxy-3-oxo-1H-pyrano|3,4-c|Ipyridine 7/5 (hereinafter referred to as Compound (a)) from Compound (p), sodium M-chlorosuccinimide-iodide is used in acetic acid; (8) in the stage of chemical purification of Compound (4), the mixture is diluted with an alkali solution such as aqueous sodium hydroxide solution to make it alkaline, washed with an organic solvent such as chloroform, and then the aqueous layer after acidification is extracted with an organic solvent such as chloroform; (9) at the stage of optical purification of Compound (4), Compound (4) is dissolved in a highly polar solvent such as chloroform and stratified with a low polar solvent such as n-hexane to obtain a precipitate which is removed by filtration, after which the filtrate is concentrated; (10) at the stage of synthesis of propyl (3)-4-ethyl-3,4-dihydro-4-hydroxy-8-methoxy-3-oxo-1H-pyrano|3,4-c|Ipyridine-b-carboxylate (further marked as

Compound (d)) from Compound (4), using palladium acetate as a palladium catalyst; (11) at the stage of the synthesis of propyl (5)-4-ethyl-3,417,8-tetrahydro-4-hydroxy-3,8-dioxo-1H-pyrano|3,4-c|Ipyridine-b-carboxylate (further denoted which)

Compound (c)) from Compound (d), the reaction is carried out at room temperature; (12) at the stage of synthesis of 1,1-dimethylethyl (3)-4-ethyl-3,4,8,10-tetrahydro-4,6-dihydroxy-3,10-dioxo-1H-pyrano|3,4-Yindolidine -7-carboxylate (hereinafter Ge!

Zo is designated as Compound (O)) from Compound (5), a Michael condensation is carried out using potassium carbonate.

In addition, at stage (13), M-38 is obtained from Х (5)-4-ethyl-7,8-dihydro-4-hydroxy-1H-irano|13,4-Pindolidine-3,6,10(4" H)-trione (further denoted as Compound "g (n)) and Compound (e), BM-38 can be obtained by conducting a reaction in an inert gas atmosphere to obtain 5-38.

In the future, the above-mentioned 13 stages are revealed in more detail. re)

At stage (1), Compound (K) is dissolved in a solvent, after which lithiation, isormylation and iodination reagents are added and mixed to obtain Compound (1).

As a solvent, tetrahydrofuran (THF), diethyl ether, hexane, heptane and the like can be used, and

THF is particularly preferred due to its good solubility and inertness.

Any suitable reagent can be used as a lithiation reagent, if it is traditionally used. Specific examples are n-butyllithium, b-butyllithium, t-butyllithium, lithium diisopropylamide /-c (OA), lithium bis(trimethylsilyl)amide (INMO5) and the like, and n-butyllithium is particularly preferred for use due to its good processing and reactivity ;" The amount of lithiation reagent used may be suitable according to the reagent, although in the case of using, for example, n-butyllithium, 2-10 equivalents are used with respect to Compound (K), preferably 2-5 equivalents. -I Specific examples of the formulating reagent are M-formyl-M,M',M'-trimethylethylenediamine, dimethylformamide (DMF) and the like, and M-formyl-M,M',M'-trimethylethylenediamine is advisable to use

Me. given the subsequent iodination. The amount of formulating reagent used, for example, in the case of using 500 M-formyl-M,M',M'-trimethylethylenediamine, 1-10 equivalents are used in relation to Compound (K), preferably 1-3 equivalents.

He Iodine, M-iodosuccinimide (MI) and the like can be used as the iodizing reagent, and iodine is particularly preferred in view of cost and reactivity.

The amount of iodizing reagent used is 1-10 equivalents with respect to Compound (K), preferably two 1-9 equivalents.

The reaction temperature is in the range from 0 to -78 °C, a constant iF) temperature of -30 to -4026 is preferably used. In step (2), Compound (I) is added to crotyl alcohol, triethylsilane and acid and stirred without a solvent to obtain Compound (t). 60 The amount of crotyl alcohol used is 1-10 equivalents in relation to Compound (K), preferably 2-5 equivalents.

The amount of triethylsilane used is 1-10 equivalents with respect to Compound (K), preferably 1-4 equivalents.

As the acid, trifluoroacetic acid (TEA), sulfuric acid, methanesulfonic acid, hydrochloric acid and the like can be used, and TPA is particularly preferred due to its reactivity.

The amount of acid used, for example, in the case of TPA is 1-15 equivalents with respect to the Compound

(I), preferably 5-10 equivalents.

In stage (3), Compound (I) can be obtained by dissolving Compound (M), a biproduct of stage (2), in a solvent, followed by the addition of an oxidizing agent and a base, and mixing.

As a solvent, any suitable solvent can be used as long as it is generally accepted for use. Examples of such solvents are dichloromethane, chloroform, acetonitrile, toluene, n-hexane and the like, and toluene and n-hexane are particularly preferred due to their reactivity.

Examples of oxidizing agents are manganese dioxide, Dess-Martin periodinan, Jones reagent (Ma»CataO7/NzO)), ROS, ROS, DMSOSO-oxalyl chloride-triethylamine (Svern oxidation), TEMRO-hypochlorite and the like, and, in particular, TEMRO -hypochlorite is preferred, TEMRO sodium hypochlorite is more preferred.

The amount of oxidizing agent used, for example, in the case of TEMRO-sodium hypochlorite, is 0.001-0.1 equivalents of TEMRO in relation to Compound (M), preferably 0.005-0.02 equivalents. In addition, 1-5 equivalents of sodium hypochlorite are used, preferably 1-2 equivalents.

Any reasonable basis may be used as a basis, as long as it is generally accepted by /5 Usage. Examples of such bases are sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, calcium hydroxide, triethylamine and the like, where sodium bicarbonate is particularly preferred.

The amount of base used, for example in the case of sodium bicarbonate, is 1-10 equivalents with respect to Compound (M), preferably 2-4 equivalents.

The reaction temperature is in the range from -10 to 30 2C, especially preferably -10 to 109C, to prevent extraneous reactions.

In addition, the reaction time is in the interval from 0.5 to 10 hours, preferably 0.5-5 hours.

At stage (4), Compound (t) is dissolved in a solvent, palladium catalyst, base and phase transfer catalyst are added and heated under reflux to obtain Compound (p).

As a solvent, acetonitrile, tetrahydrofuran (THF), diisopropyl ether (IPE), diethyl ether, toluene, water and the like can be used, and acetonitrile, THF, IPE and water are particularly preferred due to their reactivity, THF or a liquid mixture of acetonitrile-IRE-water. at

As the palladium catalyst, palladium acetate, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride and the like are preferably used, and palladium acetate is particularly preferred due to its reactivity. F

The amount of palladium catalyst used is 0.01-14 equivalents relative to Compound (t), preferably 0.05-0.2 equivalents. -

Any suitable base can be used as a base, as long as it is generally accepted for use. Examples of such bases are, for example, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, triethylamine (TEA), M,M-diisopropylethylamine (OIREA), sodium hydroxide, potassium hydroxide and the like

Similarly, both potassium carbonate and OIREA are particularly preferred. what

The amount of base used, for example in the case of SIREA, is 1-20 equivalents in relation

Compounds (t), preferably 5-10 equivalents.

Any suitable catalyst can be used as the phase transfer catalyst, as long as it is a quaternary ammonium salt or crown ether, which are commonly used, and tetrabutylammonium bromide is particularly preferred. 8 s The amount of phase transfer catalyst used, for example, in the case of tetrabutylammonium bromide, is 0.1-3 equivalents with respect to Compound (t), preferably 0.5-1.5 equivalents. "" In addition, the reaction time in the case of using THF is in the interval from 1 to 20 hours, preferably 4-10 hours. In the case of using a liquid mixture of acetonitrile-IRE-water, the reaction time is in the interval from 0.5 to 10 hours, preferably 1-5 hours. -i At stage (5), Compound (p) is dissolved in a liquid alcohol-water mixture, an osmium catalyst, a co-oxidizing agent, an asymmetric catalyst, a base and methanesulfonamide are added and mixed to obtain

Fo Compound (0). Examples of alcohols are methanol, ethanol, 1-propanol, isopropanol (IPA), 1-butanol, 2-butanol, t-butyl 5p alcohol and the like, and t-butyl alcohol is particularly preferred due to its reactivity. As an osmium catalyst, it is advisable to use osmium tetroxide, potassium osmate (MI) and the like, and osmate

He)potassium (MI) is particularly preferred due to its ease of use.

The amount of osmium catalyst used is 0.001-0.1 equivalents in relation to Compound (n), preferably 0.002-0.01 equivalents.

As a co-oxidizing agent, it is advisable to use potassium hexacyanoferrate (II), M-methylmorpholine M-oxide (MMO) and the like, and potassium hexacyanoferrate (III) is particularly preferable due to its reactivity. iF) The amount of co-oxidizing agent used, for example, in the case of potassium hexacyanoferrate (II), which is 1-10 equivalents with respect to Compound (n), preferably 2-5 equivalents.

Examples of asymmetric catalysts are (0NOB)O»RUC, (ONOB)»RNAG, (HO)AOM and the like, and 6vo «ONObB)oRUC is particularly preferred due to the optical yield.

The amount of asymmetric catalyst used, for example, in the case of (0OHNOYUB)ORUK, is 0.005-0.1 equivalents in relation to Compound (n), preferably 0.01-0.05 equivalents.

Sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and the like can be used as the base, and potassium carbonate is particularly preferred due to its reactivity. 65 The amount of base used, for example in the case of potassium carbonate, is 1-20 equivalents with respect to Compound (n), preferably 4-10 equivalents.

The amount of methanesulfonamide used is 0.1-5 equivalents in relation to Compound (p), preferably 0.5-2 equivalents.

The reaction temperature is in the range from -10 to 302C, preferably -10 to 1020. At stage (6), Compound (0) is dissolved in a solvent, base and iodine are added and boiled to obtain Compound (p).

Examples of the solvent are methanol, ethanol, 1-propanol, isopropanol (IPA), water and the like, and a liquid methanol-water mixture is particularly preferred due to its reactivity.

Any suitable base may be used as a base, as long as it is generally accepted for use. Examples of such bases are sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and the like, and calcium carbonate is particularly preferred.

The amount of base used, for example in the case of calcium carbonate, is 1-10 equivalents with respect to Compound (o), preferably 2-5 equivalents.

The amount of iodine used is 1-10 equivalents relative to Compound (0), preferably 3-5 equivalents. In addition, the reaction time is in the interval from 0.5 to 20 hours, preferably 1-5 hours.

In step (7), Compound (p) is dissolved in a solvent and treated with silver iodine-trifluoroacetate (hereinafter referred to as I-SERZSOOOAO) or sodium M-chlorosuccinimide-iodide (hereinafter referred to as MOS5-May) to obtain Compound (4).

As a solvent, in the case of -СРЗСООАд, it is advisable to use dichloromethane, carbon tetrachloride, chloroform and the like, and, in particular, dichloromethane is preferable. In addition, in the case of MS5-Ma! acetic acid, acetonitrile and the like can be used, and acetic acid is particularly preferred due to its 20 reactivity.

The amount of IY-SRZSOOdAa used is 1-10 equivalents of I" in relation to Compound (p), preferably 2-4 equivalents. In addition, 1-10 equivalents of SEZSOODAO are used, preferably 2-4 equivalents.

The amount of MOS5-Ma used! is 1-20 equivalents of MC5 in relation to Compound (p), preferably 5-8 equivalents. In addition, 1-20 Ma equivalents are used! in relation to Compound (p), preferably 5-8 s equivalents.

The reaction temperature in the case of using I2-SEzSOODAd is 10-602C, preferably 20-4020. In addition, in the case of using MS5-Maya, it is 202C - the boiling point, preferably 50-8020.

In addition, the reaction time is in the interval from 5 to 48 hours, preferably 15-24 hours.

In step (8), Compound (4) is added to a basic solvent, for example, such as aqueous 0.2M sodium hydroxide Ge"), and stirred to obtain the opening of the lactone ring of the compound (Compound (s)): "(0) "I - D. and what? (in which Me is a methyl group and Ei is an ethyl group.), which is dissolved in an aqueous basic solution. -i After washing the solution with an organic solvent, separate the neutral-basic substance into the organic layer. b» The organic layer is separated, after which the aqueous layer is acidified with acid and extracted with an organic solvent to obtain Compound (4) in good yield.

The basicity of the solvent is in the range of 0.01-5M, preferably 0.1-1M, more preferably 0.2-0.5M. Examples of bases used are potassium hydroxide, calcium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like, and sodium hydroxide is particularly preferred. iChe) As an organic solvent, any suitable solvent can be used, if it is generally accepted for use. Examples of such a solvent are dichloromethane, chloroform, ethyl acetate, toluene, diethyl ether, diisopropyl ether and the like, and, in particular, both dichloromethane and chloroform are particularly preferred.

Examples of acids used are hydrochloric acid, sulfuric acid, nitric acid, acetic acid, phosphoric acid, trifluoroacetic acid and the like, and hydrochloric acid is particularly preferred. i.e.) At stage (9), Compound (4) is dissolved in a highly polar solvent, and stratified with a low polar solvent to obtain crystals that are filtered. The filtrate is concentrated to dryness under reduced pressure. 60 The resulting crystals are racemic, and the more optically pure Compound (4) is obtained as a residue.

As a highly polar solvent, chloroform, dichloromethane, ethyl acetate, methanol, ethanol, propanol and the like can be used, and in particular, chloroform is preferred. The amount of highly polar solvent used, for example, in the case of chloroform, is 1-10 ml, preferably 3-bml, to 1 g of Compound (4).

Examples of the low polar solvent are n-hexane, n-heptane, diethyl ether and the like, and n-hexane is particularly preferred.

The ratio of high polar solvent:low polar solvent, for example, in the case of chloroform:n-hexane, is in the range of 10:1-1:20, preferably 2:1-1:2.

The crystallization temperature is not higher than room temperature, preferably not higher than 526.

At stage (10), Compound (4) is dissolved in 1-propanol, a palladium catalyst and a base are added, and the reaction is carried out in a carbon monoxide atmosphere to obtain Compound (g).

As the palladium catalyst, palladium acetate, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium chloride, and the like are suitable, and palladium acetate is particularly preferred due to its reactivity.

The amount of palladium catalyst used is 0.005-0.5 equivalents with respect to Compound (a), 70 preferably 0.01-0.1 equivalents.

Any suitable base may be used as a base, as long as it is generally accepted for use. Examples of such bases are, for example, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, triethylamine (TEA), M,M-diisopropylethylamine (OIREA), sodium hydroxide, potassium hydroxide and the like, and potassium carbonate is particularly preferred.

The amount of base used, for example in the case of potassium carbonate, is 1-20 equivalents with respect to Compound (4), preferably 4-10 equivalents.

The reaction temperature is in the range from 202C to the boiling point, preferably not higher than 502C to the boiling point.

At stage (11), Compound (g) is dissolved in a solvent, a demethylating reagent is added, and the reaction is carried out at room temperature to obtain Compound (8).

As a solvent, acetonitrile, chloroform, dichloromethane, toluene and the like can be used, and in particular, acetonitrile is preferred.

Examples of demethylating reagents are sodium chlorotrimethylsilane-iodide, iodotrimethylsilane, hydroiodic acid, hydrobromic acid and the like, and sodium chlorotrimethylsilane-iodide is particularly preferred. Ha

The amount of demethylating reagent used, for example, in the case of sodium chlorotrimethylsilane-iodide, is 1-10 equivalents in relation to Compound (g), preferably 2-5 equivalents. and)

At stage (12), Compound (5) is dissolved in a solvent, a base is added and stirred in an inert gas atmosphere. t-butyl acrylate is added dropwise to the resulting mixture, and stirred in an inert gas atmosphere to obtain the compound (0. He»)

As a solvent, it is advisable to use dimethylsulfoxide (DMSO), M,M-dimethylformamide (DMF) and the like, and

DMSO is particularly preferred due to its reactivity. WITH

As a basis, you can use potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like, and, in particular, potassium carbonate is preferred.

The amount of base used, for example, in the case of potassium carbonate, is 1-20 equivalents and in relation to Compound (c), preferably 2-5 equivalents. h-

Any inert gas can be used as the inert gas, in our case it is an inert gas such as argon, helium, neon, krypton, xenon, radon or the like, or a low sensitivity gas such as nitrogen, and argon and nitrogen are particularly preferred due to their cost. "

The amount of t-butyl acrylate used is 1-20 equivalents with respect to Compound (5), preferably 8-12 equivalents. - s The reaction temperature is in the range from 20 to 802C, preferably 40-6020. and In addition, the reaction time is in the interval from 5 to 48 hours, and in particular, it is not more than "» 24 hours in order to avoid decomposition of the obtained Compound (0.

At stage (13), Compound (n) and Compound (e) are dissolved in a solvent, acid is added and heated in an inert gas atmosphere and stirred to obtain 5-38. - and As a solvent, it is advisable to use toluene, acetic acid and the like, and, in particular, a liquid mixture of toluene-acetic acid is preferable.

Any inert gas can be used as an inert gas, in our case it is such an inert gas

Cg" such as argon, helium, neon, krypton, xenon, radon or the like, or a low sensitivity gas such as nitrogen, and argon and nitrogen are particularly preferred due to their cost.

As the acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and the like can be used, and toluenesulfonic acid is particularly preferred due to its reactivity.

The amount of acid used, for example, in the case of toluenesulfonic acid, is 1-100mg in relation to 1g of Compound (p), preferably 10-ZOmg.

The amount of Compound (e) used is 1-3 equivalents in relation to Compound (p), preferably 1-1.5 equivalents. o The reaction temperature is in the interval from 50 C to the boiling point, preferably 8029 - to the boiling point.

Hereinafter, the invention is illustrated in more detail by the following examples, but the invention is not limited to them. 60 Example 1) Synthesis of Compound (B) b5 sa "Mo. VDMeA o, (8 vet where Vp is a benzyl group.

Compound (a) (38.5 g, 0.2300 mol) was dissolved in 11 bml of DMF or acetone. To a stirred solution,

Potassium carbonate (33.4 g, 0.242 mol, 2 eq.) and 27.vml (0.242 mol, 1.05 eq.) or 59.95 ml (0.461 mol, 2 eq.) of benzyl chloride were added to compound (a) at room temperature under an argon atmosphere. . After addition, the mixture was heated at 602C and intensively stirred for 20 hours periodically checking for the presence of Compound (a). After Compound (a) was not detected, the mixture was filtered with suction.

The solid was washed with the same solvent used for the reaction. The filtrate and washing solutions were combined and the solvent was evaporated under reduced pressure. Water (30 Oml) was added to the residue. The mixture was stirred and the precipitate was filtered with suction and dried in air. After drying in air, the filtered material was dissolved in 170 ml of ethyl acetate. This solution was added to 1 liter of hexane with stirring. The precipitated solid was filtered with suction, washed with 30 ml of a mixture of ethyl acetate and hexane (1:10) and dried under reduced pressure.

Experiment (Ex.) 1 and 2, in which the amount of benzyl chloride and in Ex. C, acetone was used as a reaction solvent. with

Table 1 o g Solvent g Quantity | Reaction times Final way out!

E s Y 1 is less than the limit of determination. " - less than the detection limit of 70 As shown in Table 1, 20 hours are required to complete the reaction with a yield of 9495 when 1.05 eq is used. benzyl chloride (Ex. 1). When using 2.00 eq. of benzyl chloride (Ex. 2), the reaction is completed in 1 hour with a yield of 9495. A three-fold excess of DMF was necessary for the reaction, otherwise mixing becomes difficult due to precipitation of a solid substance during the reaction. When acetone was used as the solvent of the reaction mixture, the reaction did not proceed even when heated under reflux - 395 for 18 hours.

Conditions of HPLC

Ge) Column: Ipegivii 0005-2, 5MM, 4,b6mm IOx25Omm (made 01. zsiepse) iz Temperature: constant temperature about 402 20 Mobile phase: mixture of water: acetonitrile (1:1) - Flow rate: Tml/min.

Ge) Detection: 220 nm

Example 2) Synthesis of Compound (c) (1)

THE SAME

VO es va i Gvinyara She and NN sy p

B KZ 9 60 in which Vp is a benzyl group.

Compound (B) (1.0 g, 3.89 mmol) was dissolved in 20 ml of THF. Vinylmagnesium bromide (1.0 M THF solution, 5.84 ml, 5.84 mmol, 1.5 equiv.) was added dropwise to the ice-cooled solution, and the solution of Compound (B) was stirred in an argon atmosphere for 15 minutes. During the addition, the internal temperature was maintained in the range of 3 to 10 260. 65 After stirring for 1 hour, the reaction solution was added to a saturated aqueous solution of ammonium chloride (20 mL) with stirring, and then 20 mL of ethyl acetate and 4 mL of hexane were added to the solution, and the resulting the organic layer was successively washed with 2 Oml of water and an aqueous saturated solution of sodium chloride, and dried over 3 g of sodium sulfate. The solvent was evaporated under reduced pressure to obtain reaction product A.

A THF solution (20 ml) of compound (B) obtained as mentioned above was added dropwise to an ice-cooled

Add vinyl magnesium bromide (1.0 M THF solution, 5.84 ml) in an argon atmosphere for 15 minutes. During the addition, the internal temperature was maintained in the range from 3 to 102C. After stirring for 1 hour, the reaction solution was added to a saturated aqueous solution of ammonium chloride (20ml) with stirring, and then 20ml of ethyl acetate and 4ml of hexane were added to the solution, and the organic layer was evaporated and washed with 20ml of water and a saturated aqueous solution of sodium chloride and dried over H2SO4 sodium The solvent was evaporated at 70° under reduced pressure to obtain reaction product B.

The product of the reaction A and B was purified by column chromatography on silica gel (ethyl acetate : hexane -1:20) to obtain Ex. 4 from Reaction Product A and Ex.5 from Reaction Product B, respectively.

Table 2 in Meblitsa du , "Exit of the Compound (2) Exit of the Compound (0: 1 beshchynaiku ! as ' ! sch

As shown in Table 2, when the Grignard reagent was added to a solution of Compound (B), the product yield increased by 5795 and the formation of Compound (7), a biproduct, was suppressed. at)

HPLC conditions; the same as in Example 1.

IExample C) Synthesis of Compound (c) (2)

Compound (B) (1.0 g, 3.89 mmol) was dissolved in 10-100 ml of THF. Vinylmagnesium bromide (1.0M in THF, 5.v4ml, 5.84mmol, 1.5eq.) was added dropwise to a stirred solution of Compound (B) under an argon atmosphere for 15 minutes. After stirring for 1 hour, the reaction solution with stirring was added to a saturated aqueous solution of ammonium chloride (20 ml) and then to a solution of 20 ml of ethyl acetate and 4 ml of hexane, and the organic layer was evaporated and successively washed with 20 ml of water and a saturated aqueous solution of sodium chloride, and dried over Zg of sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified in the same way as

It is described in Example 2 (Ex. 4 and 5). Ex.b presents the results of the reaction at 209 using 20 times the amount of solvent. Ex.7-9 represent the results of the reaction at 3 using 10-fold, 40-fold, 100-fold amount of solvent, respectively. The results of the reactions are summarized in Table 3.

Table Z zha: In minutes of RUT x «

There is a table. Temperature | Tick 1 Output mon (6) | Vykh bnoluki b ts . and fevyuschi | solvent | (foam plane 90). / (peak plane)

As shown in Table 3, when the reaction is carried out at 102 or below, more preferably 59C or below, the formation of Compound (7) is suppressed and the yield of Compound (C) increases by 1595 or more. When a 100-fold amount of solvent (Ex.9) is used, the formation of Compound (It) is suppressed, and the yield of Compound (c) increases by 695.

HPLC conditions; the same as in Example 1. 60 IExample 4) Synthesis of Compound (a) (1) b5 ge or Inn: To. s y gGiyunnnnonni s y ony piz ;

And I and what "haka Va and v g in which Vp is a benzyl group. (1) Production of manganese dioxide:

An aqueous solution of manganese sulfate pentahydrate (122g/150ml, 0.50bmol) and 117ml of 4095 sodium hydroxide 75 were added at room temperature and with stirring to an aqueous solution of potassium permanganate (96.0g/b0Oml,

Oh, 607 mol). After stirring for 18 hours, the solid was filtered off with suction and washed with water. The resulting solid was dried in air to obtain 91.2 g of manganese dioxide. (2) Synthesis of Compound (4)

Compound (c) (2.00 g, 7.02 mmol) was dissolved in 20 ml of chloroform, dichloromethane or ethyl acetate. To the solution

To the intensively stirred compound (c), at 25907 in an argon atmosphere, 8.00 g of manganese dioxide (4-fold amount, 92.00 mmol, 1 Seq.) obtained by the method described above was added. The mixture was intensively stirred for 15 hours. After the starting material was no longer detected, the mixture was filtered with suction. The obtained solid was washed with 200 ml of chloroform. The filtrate and washing solutions were combined and the solvent was evaporated under reduced pressure. Received Ex. 10-12. with

Table 4 o (table di zo. I i ' 7 iz v, i I I E I I . sko Ben: sraky , " chI i remained |: h» - less than the limit of detection " As shown in Table 4, when as a reaction solvent chloroform or dichloromethane was used, Compound (4) was formed in good yields. In particular, the reaction time was reduced by one-third when dichloromethane was used as the reaction solvent. On the other hand, Compound (c) remained even after 24 hours when ethyl acetate was used. b IExample 5) Synthesis of Compound (a) (2)

An aqueous solution of sodium hypochlorite (available chlorine min. 5.095; 42 ml) and an aqueous solution of sodium bicarbonate (7.1 g in bOml of water) were added to a mixture of 7.0 g (3.6 mmol) of Compound (c), toluene (7/Oml) , ethyl acetate (7Oml), water iz 20 (1Oml) and 38.3mg (Imolbo) TEMRO, which is intensively stirred and cooled with ice (at 2-6 C, 55Xx8v.).

After 5 minutes, 0.496 (HPLC, peak plane 95) of starting material was detected. The mixture was left with the separated organic layer and was successively washed with a mixture of potassium iodide and potassium hydrosulfate (yellow -» red-brown), saturated aqueous solution of sodium thiosulfate and then with water. The solvent was evaporated under reduced pressure to obtain 6b.4g of Compound (a) (yield 9195, purity 92.695 by HPLC), which was purified by 52 P recrystallization from a mixture of methanol and water (25:1) to obtain 2.3g of purified Compound (4) (from Z,OGg;

GF) purified Compound (4), 2.3 g, obtained from: 7790, purity: 95.295 by HPLC).

HPLC conditions; the same as in Example 1. di (Example 6) Synthesis of Compounds (e) shi or yu shi or No i in which Vp is a benzyl group.

To the ice-cooled solution of 1.84 g (6b.5O0mmol) of Compound («), which is mixed in 3/ml of ethyl acetate, in an argon atmosphere was added 0.69g (0b5mmol, TOmolbo) of 1095 palladium on charcoal. The mixture was intensively stirred at 259C in a hydrogen atmosphere and periodically a part of the mixture was taken as a sample for HPLC.

The reaction mixture was filtered and the filtrate was evaporated. Received Ex. 13-14.

Table 5 (table Bi shi! Y Reaction times | Bypass Compound(s) | Output Compound (9) and I 1 (peak plane 9 vel | bits y 1

As shown in Table 5, the reaction lasts more than 13 hours, the yield of Compound (e) increases by 1095 and the formation of the biproduct, Compound (49), is suppressed.

Conditions of HPLC

Speaker: Ipegivii 005-2.5mm, 4.b6mm Ih25Ohm (made by 0 zsiepse)

Temperature: Constant temperature of about 402

Mobile phase: mixture of water : acetonitrile (1:1) p

Flow rate: ml/min.

Detection: 254nm o

Example 7| Fully synthetic method of obtaining 2'-amino-5'-hydroxypropiophenone

A completely synthetic method of obtaining 2'"-amino-5'-hydroxypropiophenone is as follows. (1) Synthesis of Compound (B) Ge")

Compound (a) (1.00 g, 5.98 mmol) was dissolved in 3 ml of DMF. Potassium carbonate (0.87g, 6.28mmol, 2.Eq.) and 0.72ml in (6b, 2mmol, 1.05Eq.) benzyl chloride were added to a stirred solution of Compound (a) at room temperature under an argon atmosphere. After addition, the mixture was heated at 60 C and stirred intensively for 20 hours with periodic checking of the content of Compound (a) by HPLC. After Compound (a) was no longer detected, the mixture was filtered with suction. i-th

The solid was washed with 3 mL of DMF. The filtrate and washing solutions were combined, and the solvent was evaporated under reduced pressure. After evaporation, the residue was added to 100 ml of water. After that, the mixture was stirred, the insoluble material was filtered with suction and dried in air. After air drying, the material was dried under reduced pressure (1 mmHg, at 2022) to give 1.45 g (yield 9595) of Compound (B) as a pale yellow solid. The physical properties of Compound (5), including the NMR spectrum, are as follows.

Compound (6; Tpl. 71-735C. - s TN-NMR (400MHz, SOSIz): d 5.21 (2Н, s, RYSNYO), 7.21 (1Н, dd, 9U-2.8, 9.3Hz ), 7.35-7.44 (6H, m), 8.16 "» (1H, d, U-9.9Gu), 10.48 (1H, s, SHO). " IR (KVh): 1250 , 1333, 1514, 1589, 1697 cm".

EI-MS: t/:2 257 (MU. - 15 (2) Synthesis of Compound (c)

Compound (B) (1.0 g, 3.869 mmol) was dissolved in 20 ml of THF. A solution of vinylmagnesium bromide (1.0M 1" solution in THF, 5.684ml, 5.84mmol, 1.eq.) was added dropwise over 15 minutes to an ice-cooled (o) stirred solution of Compound (p) in an argon atmosphere. During the addition, the internal temperature was maintained between

From to 102C. After stirring for 1 hour, the reaction solution was added to a saturated aqueous solution of 50% ammonium chloride, which was being stirred. Then 20 ml of ethyl acetate and 4 ml of hexane were added, and the organic layer was evaporated and washed with 20 ml of water and a saturated aqueous solution of sodium chloride and dried over 3 g of sodium sulfate. The solvent was evaporated under reduced pressure. The residue (1.19g) was purified by silica gel column chromatography (ethyl acetate:hexane -1:20) to give 0.93g of Compound (c) (yield 8495) as an orange solid. The physical properties of Compound (c), including the NMR spectrum, are as follows. (F) Compound (c); Tpl. 60-632C.

HI 1H-NMR (400MHz, SOSIv) c; 5.15 (2H, s, RISNYO), 5.22-5.26 (1H, m), 5.39-5.44 (IN, m), 5.90 (1H, d, 3-5.1Gu ), 6.06 (1IN, ddd, 9U-5.1, 10.5, 15.6Hz), 6.94 (1Н, dd, 9U-2.9, 9.0Hz), 7.34 (1IN, d, 9U-2.9Hz), 7.35-7.44 in (OH, m), 8.04 (1H, d, U-9.0Hz).

IR (KVh): 3298, 1614, 1582, 1506, 1292, 1229sim'1.

EI-MS: t/:2 285 (MU. (3) Synthesis of Compound (4)

Compound (c) (2.00 g, 7.02 mmol) was dissolved in 20 ml of chloroform. Manganese dioxide (8.00 g, 4-fold amount, 92.Omol, 1 Sq.) was added to the solution of Compound (c), which is intensively stirred at 25923 in an argon atmosphere. The mixture was intensively stirred for 15 hours. After the starting material was no longer detected, the mixture was filtered with suction. The obtained solid was washed with 20 ml of chloroform.

The filtrate and washing solutions were combined, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane -1:20) to give 1.88 g of Compound (4) (yield 9595) as a white solid. The physical properties of Compound (4), including the NMR spectrum, are as follows. Compound (4);

Tpl. 84-8526. "H-NMR (400 MHz, SOSIv) w 9.17 (2H, s, RYSN2O), 5.83 (IN, d, 9U-17.7Hz), 6.01 (IN, d, U-10.6Hz) , 6.62 (1H, dd, 9U-10.6, 17.7Hz), 6.91 (1H, d, U-2.7Hz), 7.10 (1H, dd, U-2.7, 9 ,0Gu), 7.37-7.43 (5H, m), 8.17 (1H, d, U-9.0Hz).

IR (KVh): 1686, 1578, 1506, 1342, 1244sMm'1.

EI-MS: t/:2 283 (MU. (4) Synthesis of Compound (e)

To the ice-cooled solution of 1.84 g (6b.5O0mmol) of Compound («), which is mixed in 3/ml of ethyl acetate, in an argon atmosphere was added 0.69g (0b5mmol, TOmolbo) of 1095 palladium on charcoal. The mixture was intensively stirred at 252C in a hydrogen atmosphere. After stirring for 13 hours, the catalyst was removed from the reaction mixture by filtration. The filtrate was evaporated under reduced pressure to give 0.87g (yield 8190, HPLC purity 91.1495) of crude product as an orange solid. 500 mg of the obtained reaction product was purified by column chromatography on silica gel (ethyl acetate:hexane -1:10-51:4) to obtain 421 mg

Compound (e) (yield 84905, HPLC purity 95.5995) as a yellow solid. The physical properties of Compound (e), including the NMR spectrum, are as follows.

Compound (is); Tpl. 131-1402С 7"H-NMR (400MHz, SOSIz) w 1.20 (ZN, t, 9U-7.2Hz), 2.93 (2H, k, 9U-7.2Hz), 6.59 (1IN, d, U-8.8Hz), 6.88 (1H, dd, U-2.9, 8.8Hz), 7.23 (1H, d, 9U-2.9Hz).

IR (KVh): 3379, 3296, 1670, 1447, 1194 cm".

EI-MS:t/2165(M 7).

Example 8) Synthetic method of obtaining Compound (e) without a protective group K o (1) Synthesis of Compound (c") from Compound (a) What is he chlk and odlh tik zay chic, and o 35 . НЯ c. (c) 3

Compound (a) (500 mg, 2.99 mmol) was dissolved in 15 ml of THF. Vinylmagnesium bromide (1.0 M Z7Z 70 in THF, 7.5 mL, 7.5 mmol, 2.eq.) was added dropwise for about 5 minutes under an argon atmosphere to the ice-cooled solution of Compound (a), which is being stirred. After stirring for 1 hour, the reaction mixture was added to ice-cooled 1 mol/l hydrochloric acid (3 mL). Then 30 ml of ethyl acetate and 5 ml of hexane were added, and the organic layer was evaporated and washed with 5 ml of water and a saturated aqueous solution of sodium chloride and dried over

Zg of sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane -1:10.51:3) to give 541 mg of Compound (c") (yield 9396) as a yellow-brown solid.

Compound (c"); (22) 7"H-NMR (400 MHz, SOCI3) and 5.22-5.26 (1H, m), 5.35-5.40 (IN, m), 5.90- 5.92 (1H, m), 6.06 (1H, ddd, their 4-5.2, 10.5, 15.6Hz), 6.83 (1H, dd, U-2.7, 9, 0Hz), 7.19 (1H, d, U-2.7Gu), 8.00 (1H, d, U-9.0Hz).

Synthesis of Compound (a") from Compound (c") and (A ee resent gen » SHHI bo o i v, pve vainteya o (c) Ion bo Compound (c") (1.00 g, 5.13 mmol) was dissolved in ml of acetone. To the ice-cooled solution of Compound (c"), while stirring, Jones's reagent (33.0 ml, 5 mmol, 1.1 equiv) was added. After stirring for 0.5 hours, three parts of ice and a saturated aqueous solution of sodium hydrogen sulfate were added to the reaction mixture (bml). Then 5O0ml of ethyl acetate and 5ml of hexane were added and the layers were separated and successively washed with 5O0ml of water and a saturated aqueous solution of sodium chloride and dried over 5g of sodium sulfate. The solvent was evaporated under reduced pressure at 65 to obtain 0.82g of Compound (a") (yield 8395 ). Compound (a");

7"H-NMR (400MHz, DMSO-dv) 95.84 (1H, d, 9U-17.6Hz), 6.11 (1H, d, 9-10.7Hz), 6.60 (IN, ad , -10.7, 17.7Hz), 6.75 (1H, d, 2.7Hz), 7.03 (1H, dd, 9.1Hz), 8.13 (1H, d, 9U-9.1Hu ), 11.41 1H s).

C) Synthesis of Compound (e) from Compound (a") 9 zaishku No ion ua NI NN o OKO yubzhvae S S she ( (8)

Compound (a") (100 mg, 0.513 mmol) was dissolved in 1 ml of ethyl acetate. 55 mg (0.0513 mmol, TOmolbo) of 1095 palladium on carbon was added to the ice-cooled solution with stirring in an argon atmosphere. The mixture was stirred at room temperature in a hydrogen atmosphere for 18 hours. The catalyst was filtered and the filtrate was evaporated under reduced pressure to give 4 mg of Compound (e) (yield 7690) as a yellow solid.

Example 8) Synthesis of 7-ethyl-10-hydroxycamptothecin (5-38)

Her eh vteonnh and s

Sha uchi same sa OSCE ay Ve a trey yah tzhav 5 00OSBO Z

Compound (e) (0.36 g, 2.14 mmol) was obtained in Example 7 and Compound (p) (0.50 g, 1.92 mmol) was suspended in a mixture of acetic acid and toluene (AcOH-toluene; 1:1, 1 mL) ). To the suspension at room temperature was added p-toluenesulfonic acid monohydrate (p-TgOH.HNO; 1Omg) and the mixture was stirred at 1002 for 18 hours. The reaction mixture was condensed under reduced pressure, toluene (1 mL) was added to the residue, and the mixture was again condensed under reduced pressure. Acetone (OdOml) was added to the residue and the mixture was stirred at room temperature for 2 hours, the insoluble material was filtered and washed with acetone (2ml, twice). The filtered material was dried under reduced pressure to give 5M-38 (0.63g, purity 97.790 by HPLC, yield 89905) as a black solid.

HPLC conditions - s Column: Ipegivii 005-2, 5Mm, 4,b6mm IJUOx25Omm (manufactured 01 zsiepse) "s Temperature: constant temperature approximately 402 k Flow rate: Tml/min.

Mobile phase: methanol - acetonitrile - 10MM potassium dihydrogen phosphate (1:1:3)

Detection: 254nm and BM-38; b 7H-NMR (400 MHz, SOS) and: 0.98 (ZH, t, U-7Hz, CHz), 1.98 (ZH, t, U-7Hz, CHz), 1.90 (2H, k, 9 -7Hz, CH"), 3.08 (2H, k, 9-7Hz, SHO), 5.17 (2H, c, SHO), 5.23 (1H, d, 9U-16Hz), 5.54 ( 1H, d, 9U-16Hz), 6.83 (1H, d, 9U-9Gu), t- 7.34-7.39 (ZH, m). Example 101) Synthesis of 7-ethyl-10-14-(1-piperidino)-1-piperidino)carbonyloxycamptothecin (ZM-388-11) same

ZM-388-11 (1.22g, 2.08mmol, yield 8995, enantiopurity 99.895 ee) was obtained from 54-38 (0.91g, 2.32mmol) synthesized in Example 9 using the described method (Zaumada, 5.; Okaita , 5.; Aiuata, K.; Mokaiia, K.;

Eshigschia, T.; Mokokyga, T.; Zydipo, E.; Matadisny, K.; MiuazakKa, T. Spet. React. howl 1991, 39, 1446.).

Conditions of chiral HPLC bo Column: VOAISEIG. SNACK! SE. О0-Н, 0.46bsm IОx25cm (OONOSE-AKOZ1)

Protective cartridge: VAISEI SNIKAG SEI O0-N, 0.4 cm Шх1 cm

Entered amount: L10Mg/1O0Ml

Temperature: Constant temperature of about 402

Flow rate: Tml/min.

Mobile phase: a mixture of dimethylamine:'hexane:ethanol (1:250:250)

Detection: 254 nm (Example 11) Synthesis of 7-ethyl-10-(4-(1-piperidino)-1-piperidino|carbonyloxycamptothecin (SPT-11))

ZM-388-11 (1.00 g, 1.7 mmol) obtained in Example 10 was suspended in 1/10 M hydrochloric acid (20 ml, 2.0 mmol) and the suspension was heated at approximately 802C until dissolution. Acetonitrile (100 mL) was added to the solution and the mixture was stirred at room temperature overnight. The precipitates were filtered, dried and rehydrated to 7590

KN obtaining CPT-11 (0.95 mg, yield 89.895) as a pale yellow crystalline powder.

Example 12) Synthesis of Compound (I) (1) p

Compound (I) was obtained by formulating Compound (K) at approximately -30 C - -209C7 with n-butyllithium and

M-formyl-M,M',M'-trimethylethylenediamine followed by iodination at approximately -302C - -202C7 with n-butyllithium and iodine.

Compound (K) (5.0 g; 0.028 mol) was dissolved in anhydrous THF (approx. bbml) under a nitrogen atmosphere. The mixture was cooled to approximately -302С - -202С7. n-butyllithium (1.bmol/l in hexane; Ge) 21.2 ml, 0.034 mol, 1.2 equiv) was added dropwise to the solution and the mixture was stirred while cooling. Then to the reaction mixture was added "

M-formt-M,M',M'-trimethylethylenediamine (4.4 g, 0.0034 mol, 1.2 eq.) as the forminating reagent, and the mixture was stirred under cooling. AND

n-butyllithium (1.bmol/l in hexane; 35ml, 0.05mol, 1.2eq.) was added dropwise and stirred with at the temperature shown in Table 6. Then, iodine (18 ,4 g) in anhydrous THF (19 ml). uh-

An aqueous solution of sodium hydrosulfate (12 g in 200 ml) was added to the mixture. After stirring, the recovered organic layer (hexane) was analyzed by HPLC. The results are shown in Table 6.

Conditions of HPLC «

Column: Sarseyi Rusk 005 00120, 4, 6mm IХ150mm

Mobile phase: 50 mm mixture of potassium dihydrogen phosphate: acetonitrile (9:11) - s Detection: 220 nm "s Flow rate: approx. ml/min " Temperature: room temperature

Table 6

From the floor vyro osiv - Ggablitsa 5) (o): pi gyne yi I K. 7 gas ee ore, ntitnai t te E sya - No s t-e t ia s skh. ron i- G i dzzhnti ve in those as Dy i : - formulates | Mass | Modding | Time | Splicing: | Compound | Exit from Bannia ) reayushchii) C) oVeayut (0 I a ! rai I j enve KOM euvtiy: ! te) (0) at (hour). Shan | T

Hex ate | Java 1 ayu 1-68 Goa 1 nt 0 vya 106 zv She | bitizvko-uv | | ! ! o That would | 5-8 1 36 | 86-80 665 | ve I vv | yo yu and "about 85 |. Я "vve ! | she zu TV | b-jav | ab | 6-5 | b | 68 | 7085 1667 65 V : . Я ! 4. и 1) The upper lines show the actual internal temperature during addition. The bottom lines show the actual internal temperature range during mixing. 2) Ex.15: experimental results under the specified conditions

C) Peak plane 90 4) Outputs were corrected for purity (HPLC; peak plane 90) 5) NT: not tested

As shown in Table b, Compound (I) was obtained in 6096 yields or more when using n-butyllithium as the lithiation reagent. As shown in Ex. 16, the reaction took place at a constant temperature at -402С - -302С; with a good output (more than 70905).

Example 13) Purification of Compound (I) (washed with dilute hydrochloric acid)

Compound (K) (5.0 g, 0.02 vmol) was dissolved in anhydrous THF (approx. bbml). The reaction was carried out as described in Example 12 at a constant temperature of approximately -359C. The n-hexane layer obtained from the reaction mixture was washed with dilute hydrochloric acid (the amount of the organic layer).

After washing, the organic layer was dried over sodium sulfate, filtered, and a portion of the filtrate 75 was analyzed by HPLC under the conditions given in Example 12. The results are shown in Table 7.

Table 7

Analytical results of each hexane layer after washing with dilute hydrochloric acid ocheri(s) | (mole | 901 ОЙ И 1 09 8116 a re rovrvvovk yav ros royu, | 5 | 86 | 0 | 6 | I o » gv 1551 85 1 92 | i | a 1) The hexane layer was obtained from the reaction mixture by dividing it into 5 parts ( 25 ml of the whole mixture and 4 parts "t of 50 ml for washing). Each 500 ml portion was washed with diluted NA shown in Table 7 and the reconstituted hexane layers were analyzed by HPLC. |se) 2) peak plane 90 them 3) MTPK; 2-methoxy-6-trimethylsilylpyridine 3-carbaldehyde 4) was not washed

As shown in Table 7, Compound (Kc) was always removed by washing with hydrochloric acid. When 1.0 mol/ml and more concentrated hydrochloric acid were used for washing, Compound (1) 70 was obtained with good purity. 2-methoxy-b-trimethylsilylpyridine-3-carbaldehyde (MTPK), using this method from c, it is rather difficult to remove the formylated intermediate Compound (K).

Example 14) Purification of Compound (I) (sequential washing with dilute hydrochloric acid) :c» Compound (K) (5.0 g, 0.028 mol) was dissolved in anhydrous THF (approx. bbml). The reaction was carried out as described in Example 12 at a constant temperature of approximately -359C. The resulting n-hexane layer from the reaction mixture was washed in turn (from top to bottom) with dilute hydrochloric acid as shown in Table 8 (as well as the amount of -I organic layer).

After washing, the aqueous acidic layer was evaporated, neutralized with sodium carbonate and then extracted

Me n-hexane. The organic layer was dried over magnesium sulfate, filtered, and part of the filtrate was analyzed by HPLC under the conditions given in Example 12. The results are summarized in Table 8.

Table 8. Analytical results of hexane

Ge extracts from the neutralized aqueous layer, which was obtained after washing the original hexane layer with dilute hydrochloric acid as shown below (from top to bottom)

F) name) 60 b5

AND NOI (mol) Z Residue(9)7 ) Compound(Y" | Compound()" | Regeneration (Ж). :

Hm rorya drank shi and Po: SO

For 1101 events 1) each washing with diluted I-ish was neutralized with sodium caroionate | the mixture was extracted with n-hexane.

The organic layer was dried, filtered, and the filtrate was evaporated to dryness under reduced pressure. 2) HPLC (peak plane 90)

C) Not tested. 4) The remainder of the hexane layer after successive washings. 5) Not detected: less than detection limit

As shown in Table 8, the hexane layer is conveniently purified by multistage He washing with hydrochloric acid of various concentrations to obtain Compound (I) with high purity. (5)

Example 15) Purification of Compound (I) (Purification by distillation)

Compound (K) (5.0 g, 0.02 vmol) was dissolved in anhydrous THF (approx. bbml). The reaction was carried out as described in Example 12 at a constant temperature of approximately -359C. The resulting reaction mixture (n-hexane layer) was recovered and distilled at 81-992C under reduced pressure (approximately 0.35 mm Na). After distillation, the residue. /F) in a distillation flask was purified by column chromatography on silica gel with n-hexane, and then with a mixture of n-hexane and ethyl acetate (50:11) to obtain a purified product.

The residue and the purified material were analyzed by HPLC under the conditions given below. The results are shown in Table 9

Conditions of HPLC

From Column: Sarseyi Rusk 005 00120, 4.6mm IOx 150mm o

Mobile phase: 500 mm potassium dihydrogen phosphate: acetonitrile mixture (1:1)

Wavelength: 220nm

Flow rate: approximately ml/min. "

Temperature: room temperature

Table 9 and And More From it" | 6 HH bpoluyuaiyu?I MARK | Compound" | Bereneration

I - 7 And the sounds of sleep In: shin shen In these shshshishoya

F UM! Eat! salt, ry mn kind, refined II B: 95: 1) peak plane 90 in 2) Not detected: less than the limit of detection

C) The final residue was purified by silica gel column chromatography

As shown in Table Y, MTC is best removed by distillation. Subsequent purification by silica gel column chromatography provided Compound (I) in excellent purity. It is preferable that the distillation is not carried out at a temperature higher than that given in Table 9 because there is a change in color and decomposition of Compound (1).

Example 16) Purification of Compound (I) (regeneration from hydrochloric acid salt)

Compound (K) (5.0 g, 0.02 vmol) was dissolved in anhydrous THF (approx. bbml). The reaction was carried out as described in Example 12 at a constant temperature of approximately -352C. The reaction mixture (10 g) was dissolved in 10 M hydrochloric acid (1 Oml) and stirred at room temperature. The yellow precipitate was filtered and washed with a small

The amount of 10M hydrochloric acid and the material was dissolved in water (approximately 1Oml). The pH of the aqueous solution was adjusted to about 8 by adding sodium bicarbonate and the mixture was extracted with hexane and the organic layer was evaporated under reduced pressure to dryness.

The residue was analyzed by HPLC under the conditions given in Example 15. The results are shown in Table 10. 70 Table 10

Analogous results of the salt obtained by neutralization of extracts with hydrochloric acid in 1 mol/l of hydrochloric acid are table 10) Analytical results of the salt obtained by neutralization: hydrogen: shk pit ad what and viscose of extracts in 10 mole/l hydrogen chloride: go |De» ky: Sh 1685 | VE | i m nie ny p o a, 0 854 s ste dottyu t Y Z . I sem ov 1 Purification | 1: E 1) weight of note: 2) flatness 95; (22) 1) residue weight 2) peak plane "

C) Not tested "

As shown in Table 10, the crude reaction product was collected as a hydrochloric acid salt and the salt was reduced to Compound (I) by neutralization, MTPK was almost removed by this method. (Se)

Compound (I): yellow oil. M "H-NMR (499 MghC.SOCI 3) 6: 0.30 (OH, s) 4.05 (ЗН, s), 7.67 (1Н, s), 10.19 (1 Н, s),

EMO: t/2 335 (M).

IExample 17) Synthesis of Compound (t) « seams CHOTKA seam t t I: x -I b To a mixture of Compound (I) (20.0g, 5b.0mmol, content: 93.995 by HPLC), triethylsilane, (17.9ml, 112 ,O0mmol, 2eq.) and crotyl alcohol (15.7ml, 184.8mmol, 3.Eq.) trifluoroacetic acid (28.5ml, 375.3mmol, b.7eq) was added dropwise with stirring at 0-59С under a nitrogen atmosphere .). After stirring at a temperature of 20 °C, the mixture was stirred at room temperature for 20 h. An aqueous solution of sodium carbonate (20.8 g in 277 ml of water) and n-hexane (5 bml) were added to the mixture, and the organic layer was evaporated and the aqueous layer was extracted with n-hexane (5 bml). The combined organic layers were evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel; silica gel (80 g, Etsi Zyuvia RZO100B) with a mixture of n-hexane-ethyl acetate (73:3) as an eluent. 59 The results of this Example are summarized in Table 11 (Ex. 20). Ex. 9 in the Table shows the results of the repeated

GF) of the experiment under the above conditions; Dozeip, N.; Ko, 5. V.; Vot, O.; Sitap, OYUO. R., Spet. Eig. 9). 1998, 4, 67-83.

Sitap, O. R.; Ko, 5. V.; Dozeip, N., Apdemu. Spent Yippee Ed. Epodii. 1995, 34, 2683-2684. In the given method, where dichloromethane was used as a reaction solvent. An equivalent level of product (t) without dichloromethane was obtained in terms of quality and yield. 6o Table 11 b5

Conditions for holding the ЭВХ 0 you

Conditions for conducting HPLC

Column: Si. Zsiepse Ipegizii 005-2, 0.46bsm IХx25cmM

Temperature: Constant temperature of about 402C

Flow rate: Tml/min.

Mobile phase: acetonitrile - 10 mm potassium dihydrogen phosphate (5:1)

Detection: 254nm

Example 18) Synthesis of Compound (I) (2)

Osn, TEMRO: Osn, ss 0 MOB zob Mokh "en MeneOV and and sch ! pli Enn and tv 1 Shtbluzinod (Te ; in i. F

To the mixture of Compound (M) (1.00g, content; 98.4395, 2.bmmol), TEMRO (2.3mg, 0.015mmol, 0.00Beq.) and 790 (w/v) of sodium bicarbonate (7.Oml) in toluene (8.7ml) at 0-52 was added an aqueous solution of sodium hypochlorite in (available chlorine; minimum 595, 4.5g, 3,0mmol, 1.05eq.) and then the mixture was stirred at 0-52 for 2h. 1095 g of sodium sulfite (3.7 ml, 2.9 mmol) was added to "I" mixture and the resulting mixture was stirred at 0-59 for s

REFERENCE The insoluble material in the mixture was removed by filtration and the material on the filter paper was washed with toluene (Imlx3). The organic layer of the filtrate was evaporated and washed with water (1 ml), dried over sodium sulfate (2 g), filtered and the desiccant was washed with toluene. The filtrate and washing solutions were combined and then evaporated under reduced pressure to dryness. Compound (I): yellow oil, 0.93g (8795 yield), content: 90.60956 by HPLC (see Example 17). "

Example 19) Synthesis of Compound (p) (1) and c (Example 19) Synthesis of Compound (A) (0). there is still her one and KO in vimVe or i, i 4 Ki Z s tv. g ve ne v indy Te re MV

Compound (t) (1.60g) was dissolved in the solvents given in Table 12, tetrabutylammonium bromide (0.83g), potassium carbonate (0.71g) and palladium acetate (57mg) were added to the solution. Each reaction was carried out under conditions

Me; given in Table 12.

The reaction mixture, while stirring, was poured into ice-cooled n-hexane (18 ml). The insoluble material was filtered with suction and the material was washed with n-hexane (bml x3). The filtrate and washing solutions 22 were combined and washed with water (9mlx2), dried over anhydrous sodium sulfate and then evaporated at

F! under reduced pressure until dry. The residue was purified by column chromatography on silica gel with n-hexane-ethyl acetate (95:5) as eluent.

Ex. 21 in Table 12 reveals the results of the experiment conducted under the conditions described; Chdovivep, N.; Ko, 5.

IN.; Vot, O.; Sitap, OYUO. R., Spet. Eig.). 1998, 4, 67-83. Siptap, O. R.; Ko, 5. V.; doviep, N., Apdem. Spent 60 | Ed. Epodi. 1995, 34, 2683-2684.

The ratio of endo and exo forms of each purified product was measured using HPLC. As shown in Table 12, sufficient selectivity (endo-exo ratio) and final yield were obtained when THF was used as the reaction solvent under reflux (Ex. 25-27). The final yields (Ex.25-27) were higher by 1095 or more than under the described conditions (Ex.21). because Table 12

(table 18),

DMA; M. edimethyformamide, Tolusol, MESM: acetonitrile, TO: euhydrofuran;:

Ratio: peak plane of form type/peak plane of eco form (TOP), OUTPUT;

The final output, ": nazhizhinaly, Conditions for carrying out HPLC, see Example 17.

DM FA: M,M-dimethylformamide, Tol: toluene, MesmM: acetonitrile, TFG: tetrahydrofuran, Ratio: c y y y y - y endo form peak area/exo form peak area (HPLC), Yield: Final yield, -: did not determine the conditions (o) conducting the HPC; see Example 17.

Example 20) Synthesis of Compound (p) (2)

Tetrabutyl urea bromide (0.82g, 2.6mmol) was added to a solution of Compound (t) (1.27g, 2.bmmol, content: 78.790) in a mixture of isopropyl ether-acetonitrile-water Fu 20 (4:3:1, 20ml) .

REFERENCE After cooling to an internal temperature of 20 C or below, the material insoluble in the mixture was filtered off with suction and the filtered material was washed with n-hexane (2.bml x3). n-hexane (1Oml) and 1095 sodium sulfite (1bml, 13.Omol, ise) were added to the combined filtrate and washing solution

Bekv.). The organic layer was evaporated and successively washed with 1M hydrochloric acid (16.4ml) and then with distilled water (1Omlx2). The organic solution was evaporated to dryness under reduced pressure. Compound (n); brown oil, 0.83g (yield 9195), content: 73.395 by HPLC (see Example 17), endo-exo ratio: 10.6.

Thus, there is an obvious improvement in selectivity compared to Ex.21 in Table 12. The final yield is also improved by 2095 compared to Ex.21 in Table 12.

IExample 21) Synthesis of Compound (o) shsh ' Yuriklad NI Synthesis of Compound (c). and? осн круйнО осн; in Yasna Mevozhn; CIS UN t 70 - I 0 uvodtnyun she p 9 more To a solution of potassium ferricyanide (195.7g, O.59mol), potassium carbonate (82.1g, O.59mol) and methanesulfonamide (37.77, O4Omol) in water ( (9900ml) (0ONOVB)2RUC (4.36g, 4.95mmol) and potassium osmate dihydrate (MI) (1.0mmol) were added and the mixture was stirred at about 59C for 1h. Compound (n) 22 (77.8 g, 0.18 mol, content: 61.595) was added to the stirred mixture and the resulting mixture was stirred at temperature for another 20

F! hours Powdered sodium sulfite (74.9g) was added to the mixture and stirring was continued at a temperature of 30°C. The material insoluble in the mixture was filtered on a layer of Celite and the material on the layer was washed with ethyl acetate (4 times, a total of 77 Oml). The organic layer of the filtrate was evaporated and the aqueous layer was extracted with ethyl acetate (77 Oml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel with a mixture of dichloromethane - ethyl acetate (4:11) as an eluent; silica gel (280g, ЕРции 5uvia РБО100В).

Compound (so); brown solid.

As shown in Table 13, using potassium osmate as the oxidant instead of the highly volatile osmium oxide (MI) provides an equivalent amount of final yield and enantio-excess. because Table 13

Ggablitsa i8i and 70 Ex. 28: conducted under the conditions described; Dozeip, N. ; Ko, 5.8.; Vot, YuO.; Sitap, Y.R., Spet. Eig. 9. 1998, 4, 67-83. Sitap, O.R.; Co., 5.V. ; doveip, N., Apdem/. Spent Yippee Ed. Epai. 1995, 34, 2683-2684.

Fooee: Compound (o) obtained here was converted to Compound (p) using the method described in Example 22 and its enantio-excess was measured by chiral HPLC (see; Example 22)

IExample 22) Synthesis of Compound (r) 2 (Dream dreams Introduction, MeOM. DREAM;

To a solution of Compound (0) (70g) in a mixture of methanol and water (10:1, 1.0L) at room temperature with stirring at 29°C, iodine (the amount is indicated in Table 14) and powdered calcium carbonate (47.1g) were added. (IN

The reaction mixture was stirred at the temperature and for the time given in Table 14.

One liter of 1095 sodium sulfite and chloroform (1.0 l) were added to the mixture, and the resulting mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the organic layer of the filtrate was evaporated. The aqueous layer was extracted with chloroform (500 mlx2). The extracts were combined, dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure to dryness. "AND

Using 4 equivalents of iodine under reflux, this reaction was completed in 5 g, which was about one-tenth of the previously indicated conditions in the comparative example.

Table 14 (se)

Yarablytsia T4i - r» By COMPLETELY PASSING BY WE o LE SHY rea | 166 3 9 nn: nn niya nin v or wine nyni wine nin

F Eco. ZO was conducted according to the instructions of Humev 00,000 people and "Ivin, M; Kos; In Vot Batap, V. YeNet: Ego 1998; 4, 88" about biyan. b. ROKoO, Ya. Vo proved; N.. Ave. Played by B. Bas, 1995, Z4; EV BVA,

Ex. 30: conducted under the specified conditions;

Chovivep, N.; Ko, 5.V.; Vot, O.; Sitap, O.R., Spet. Eig.). 1998, 4, 67-83.

Sitap, O.R., Ko, 5.V.; doviep, N.; Apdem Spent Yippee Ed. Epai., 1995, 34, 2683-2684. o Exit (9): Final exits

Conditions for conducting HPLC (name) Column: S. Zsiepse Ipegizii 005-2, O, 46 bsm 10x25 cmM

Temperature: constant temperature approx. 402 60 Flow rate: Tml/min.

Mobile phase: 10 mm potassium dihydrogen phosphate - acetonitrile (4:3)

Detection: 254nm

Conditions for chiral HPLC

Column: SAISEI. SNACK IT! 00-Н, ZHOYOUNOSE-AKOZI, 0.46 cm IЮОх25 смМ бо Protective cartridge: ODYSSEY. DREAM! SE. O0-H, 0.4cm Ix1ism

Temperature: Constant temperature around 259

Flow rate: 0.5 ml/min.

Mobile phase: a mixture of n-hexane - ethanol (200:1)

Detection: 254nm

Example 23) Synthesis of Compound (a)

IExample 5) Synthesis of Compound 9) 70 t I vv end shen pi cho /5 I: SHO

R sh

To a solution of Compound (p) (50.2 g) in a solvent (approximately 400 ml; given in Table 15), the reagents given in the Table were added and the resulting mixture was stirred at the indicated temperature for some time. 2095 of sodium carbonate (1.7 L), 1095 of sodium sulfite (1.0 L) and chloroform (5500 ml) were added to the reaction mixture while stirring. The organic layer was evaporated and the aqueous layer was extracted with chloroform (550mlx2).

The extracts were combined, dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure to dryness. The content of Compound (4) in the residue was determined by HPLC. The results are summarized in

Tables 15. p

This conversion is satisfactorily performed using MoH - Ma! at 65 C in acetic acid (Ex. 39). (9

The time required to complete the reaction was definitely shorter and the yields of Compound (4) under the specified conditions higher than previously reported (Comparative Experiment 1 (Cf. 1)) by 5095 or more.

Table 15 of Public television) ch rev re ur royu v

TE ab ON 1006-0108 Kimnatnaiu |OYAY 01 ИС « este VE | From the line nn nn t a a and OA NN I - 7) I wash with dichloromethane and chloroform (3:2), ASOM acetic acid, IS: iodine chloride, MIV: M. m Modsuccinimide; MOV: Mechlorseuccinimide, Eq-: molar ratio of the used T. 77 silver agent(s), Output: Final outputs: with a mixture of dichloromethane and chloroform (3:2), AcOH: acetic acid, ISI: iodine chloride, MI5: M- iodosuccinimide,

MO: M-chlorosuccinamide, Eq.: molar ratio of reagent(s) used, Yield: Final yields.

Example 24) Purification of Compound (a) (1)

Compound (a) (63Zg, Purity 89.295 by HPLC) obtained in Example 23 was suspended in methanol (150 ml), until

HF) suspension was added dropwise with intensive stirring, and 0.2 M sodium hydroxide was added and stirring was continued for 2 h. The alkaline solution was washed with chloroform (400mlx3) and the pH of the aqueous layer was adjusted to 1-2 with hydrochloric acid, and the acidified solution was extracted with chloroform (400mlx3). The chloroform layer was dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure to dryness. 60 Compound (4) (Ex. 40); purity 97.795 (90 peak planes; HPLC conditions: see Example 25)

Example 25) Purification of Compound (4) (2)

Compound (a) (50g), purified by the method described in Example 24, was dissolved in chloroform (240ml) and n-hexane (400ml) and carefully added to the surface of the solution. The mixture was left to stand at room temperature for 15 hours. The precipitate of the mixture was removed by filtration and the filtrate was evaporated under reduced pressure to dryness (Ex. 41). because Compound (a) (Ex.40) obtained in Example 24 (93-9695 enantio excess) was optically purified by this method.

Compound (a) (Ex. 41) obtained here had 99.7-99.9956 enantio-excesses, determined by chiral

HPLC of the following.

Conditions for conducting HPLC

Column: SI. Zsiepse Ipegivi 005-2, 0.46 cm ЮХХ25 cmM

Temperature: Constant temperature of about 402

Flow rate: Tml/min.

Mobile phase: a mixture of acetonitrile -1 Ohm potassium dihydrogen phosphate (5:3)

Detection: 254 nm

Conditions for conducting choral HPLC

Column: OAISEI. SNIKAG RAK AYU0-N, F AONOSE-VSOZ37, 0.46 cm x 25 cm

Protective cartridge: OAISEI SNIKAG RAK AB-N, 0.4 cm Шх1 cm

Temperature: Constant temperature around 2590

Flow rate: Tml/min.

Mobile phase: a mixture of n-hexane - 2-propanol (25:1)

Detection: 254 nm

Example 26) Synthesis of Compound (d)

Example 28), Synthesis. Temptations (2)

In ' ; and the foundation; ROASI, United Nations,

A solution of Compound (a) (42.8g, О0.1Omol, content: 84.5905), palladium acetate (1.34g, b.O0mmol) and potassium carbonate Ф y na y y (24.7 g, О.18 mol) in propanol (490 ml) was loaded into the reaction flask. The flask was degassed with suction and flushed with nitrogen, degassed again with suction and then filled with carbon monoxide. The mixture was stirred at 602C in a monoxide atmosphere for 18 hours. The insoluble material was filtered on a layer

Celite and material were washed with ethyl acetate (300 ml). 1M hydrochloric acid (100ml) and saturated aqueous sodium chloride solution (100ml) were added to the filtrate, and the mixture was vigorously shaken. The organic layer was evaporated and the aqueous layer was extracted with ethyl acetate (300ml). The combined organic layers were dried over anhydrous sodium sulfate, was filtered and then evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel; silica gel (100g, Rciuvia RBO100OV) with a mixture of chloroform and methanol (99:1) as eluent. Compound (g): brown oil, Z30,Zg (70905 output), content: 73,490 was determined using HPLC. « 20 Conditions for carrying out HPLC

Column: Si. Zsiepse Ipegizii 005-2, 0.46bsm Ih25cmM s and Poii and emperature: constant temperature about 402 s Flow rate: Tml/min.

Mobile phase: 10 mm potassium dihydrogen phosphate - acetonitrile (4:3)

Detection: 254 nm - and Example 27| Synthesis of Compounds (5)

F nn y NN m Glrikpad 27) Synthesis of Compound (c) 1 OH, ppidkya o

CH; V. sa i u vm SO i Vo i zi o g V ime)

To a stirred solution of Compound (g) (28.7g, 68.2mmol, content: 734905) and sodium iodide (27.6g, in 0O.18mol) in absolute acetonitrile (141ml), dropwise at room temperature in the atmosphere of nitrogen, chlorotrimethylsilane (23.3 ml, 0.18 mmol) was added. The mixture was stirred at room temperature for 3 h.

1 M hydrochloric acid (ml) and 1095 sodium sulfite (232 ml) were added to the mixture, and the resulting mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate and the organic layer was evaporated and evaporated to dryness under reduced pressure. Compound (c): 22.3g (95905 yield), content: 85.69o was determined by HPLC (as indicated below). 65 Conditions for conducting HPLC Column: 01. 5siepse Ipegizi 005-2, О46bsm ИОх25cmМ

Temperature: Constant temperature of about 402

Flow rate: Tml/min.

Mobile phase: 10 mm potassium dihydrogen phosphate - acetonitrile (5:2).

Detection: 254nm

Example 28) Synthesis of Compound (

Griklad 281 Sintvia Yepomukio

OO Ko soy VAMOO ruti tsoneb dn, chad 75 8 Zh

A solution of Compound (c) (0.50g) in dimethylsulfoxide (DMSO, 7ml) in the presence of an inorganic base (potassium or cesium carbonate, 0.4g) was stirred at 5023 in an argon atmosphere for 20 minutes. Tert-butyl acrylate (1.8 g) was added dropwise to the stirred mixture and the resulting mixture was stirred at 502C in an argon atmosphere for 24 h. Water (10ml) was added to the ice-cooled mixture and concentrated with hydrochloric acid (ml) and the mixture was extracted with a mixture of toluene and ethyl acetate (4:11, 7mlx4). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to dryness (Ex. 42-43). The residue was analyzed by HPLC (as shown below).

As shown in Table 16, Compound () was obtained in 72956 yield using cesium carbonate as a base (Ex.42), on the other hand, using inexpensive potassium carbonate as a base provided an equivalent yield of

Ex. 42. o

Table 16 (Table 161 . int Ge») br 1 oo ee froviyou h - : tya ' y -

Conditions for conducting HPLC

Column: S. Zsieepse Ipegizii 005-2, 0.4 cm Lx25cmM

Temperature: constant temperature of about 402 "

Flow rate: Tml/min. - 70 Mobile phase: 10 mm potassium dihydrogen phosphate - acetonitrile (5:2) with Detection: 254 nm with» IExample 29) Synthesis of 5M-38

A mixture of Compound (p) (0.50g, 1.82mmol, content: 96.695) and Compound (e) (0.36bg, 2.18mmol) in a mixture of toluene - acetic acid (1:1, 1Oml) in the presence of p-TON .H2oO (1Omg) was heated at 902C with stirring in an atmosphere of -1 75 nitrogen for 7 hours. After cooling, the mixture was evaporated under reduced pressure to dryness. After 2 azeotropic removals of acetic acid with the help of toluene (1 Oml), acetone (Oml) was added to the residue and the suspension (e) was stirred in a nitrogen atmosphere for 30 min. The solid was collected by filtration, washed with acetone (2mlx2) and then dried under reduced pressure. 5M-38 (Ex. 45): ocher-colored solid, 0.63 g (yield 89.190 g), purity; 99.695 by HPLC (see Example 9). t» Ex. 44 in Table 17 shows the results of the experiment under the conditions described; Nepedag, K. E.; Avpioga, 5. MU.;

Vashdptanp, T. A.; Battle, 9. C; by, K. GI, U. Oga. Spent 1997, 62, 6588-6597. iChe) and . . I

Under nitrogen, the purity and yield of 5-38 improved as shown in Table 17.

Table 17 (Table 17)

GF) Y Y t p N y Dt copper: ih still set. wa li in рПООШ0Ш07012р70702000 I Cher | hanging yu | Opened 96 ee | ek | TV ev (Example of ZOY Synthesis of a tricyclic ketone And What

The complete synthetic method of tricyclic ketone (p) based on Compound (I) is given below; bo (1) Synthesis of Compound (t)

To a stirred mixture of Compound (I) (20.0g, 56b.0mmol, 2eq., content: 93.995), triethylsilane (17.9ml, 112mmol, 2eq.) and crotyl alcohol (15.7ml, 184.8mmol, Z,Zeq. .) trifluoroacetic acid (28.5 ml, 375.2 mmol, 6.7 equiv.) was added dropwise at 0-59 under a nitrogen atmosphere, and the mixture was stirred at temperature for

REFERENCE The mixture was stirred at room temperature for 20 g, and then an aqueous solution of sodium carbonate (20.8 g in 277 ml of water) and n-hexane (5 bml) were added to the mixture. The organic layer was evaporated and the aqueous layer was extracted with n-hexane (57ml). The combined organic layers were evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel; silica gel (8Og, Rcii Zyuvia RBOO100OV), eluent; n-hexane -ethyl acetate (73:3) removing the biproduct, Compound (M) (4.95g, 14.6vmmol, purity 98.4395, yield 26905). Compound 70. (t); 17.8g (6495 yield), content: 80.095 by HPLC (see Example 17). "H-NMR (400 MHz, SOSIv) w: 0.24 (9H, s, TM5), 1.69 (ZN, dd, U-1.0, 6b1Hz, -CHCH"), 3.85-4.05 (2H, m,

OSN.oSNU-), 3.93 (ЗН, с, СНЗзО), 4.55 (2Н, с, OSН»), 5.55-5.83 (2Н, m, СНА-СН), 7.4 7 (1H, p).

Compound (M); 5.Og (2695 output), content: 98.495 (HPLC). "H-NMR (400 MHz, SOSIv) w: 0.27 (9H, s, TM5), 2.45 (1H, t, y-6.8Hz, OH), 3.99 (ZN, s, SNZO), 4.79 (2Н, d, U-6.8Hz, СНоОН), 7.49 (1Н, с). 12 (2) Synthesis of Compound (n)

A mixture of Compound (t) (1.27g, 2.5bmmol, content: 78.7390), tetrabutylammonium bromide (0.82g, 2.5bmmol) and palladium acetate (57mg, 0.2bmmol) in a mixture of isopropyl ether - acetonitrile - water (4:3:1, 20 Oml) was heated under reflux for ЗОхв. After cooling to an internal temperature of 20°C or below, the insoluble material of the mixture was removed by filtration and the material was washed with n-hexane (1 mL). The filtrate and washing solutions were combined and n-hexane (10 ml) and 1095 sodium sulfite (1 bml, 1133 mmol, bq.) were added to the solution. The organic layer of the mixture was evaporated and washed successively with 1 M hydrochloric acid (16.4 ml) and water (1 mlx2). The organic layer was evaporated under reduced pressure to dryness. Compound (n): brown oil, 0.83g (9190 yield), content: 73.3495 by HPLC, endo-exo ratio: 10.6 by HPLC (see Example 17). "H-NMR (400 MHz, SOSI»v) w: 0.26 (9Н, с, TM), 1.12 (ЗН, т, У-7.9Hz, СНоСН3, 2.31 (2Н, dk, 9У- 1,0, 7, ZGu, p

СН.СН,), 3.94 (ЗН, с, OSН»), 5.00 (2Н, с, OSН»), 6.51 (1Н, т, У-1.0Гу, OSН-), 6, 83 (1H, p, aromatics-H o

C) Synthesis of Compound (o)

To a solution of potassium ferrocyanide (195.7 g, 0.59 mol), potassium carbonate (82.1 g, 0.59 mol) and methanesulfonamide (37.77, 0.4 mol) in water (990 ml) was added (0OHNOYUB)RUMK (4.36 g , 4.95 mmol) and potassium osmate dihydrate (MI) F) zo (0.99 mmol) and the mixture was stirred at approximately 59C for 1 h. Compound (p) (77.8g,

O.18mol, content: 61.595) and the resulting mixture was stirred at approximately 59C for 20g and then powdered sodium sulfite (74.9g) was added. The suspension was stirred at approximately 59C for 30 minutes. and the insoluble material was filtered through a pad of Celite. The layer material was washed with ethyl acetate (4 times, a total of 77 Oml). The organic layer of the filtrate was evaporated and the aqueous layer was further extracted with ethyl acetate (77 Oml).

The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. eat

The residue was purified by column chromatography on silica gel; silica gel (700 g, Ecii ZyPuvia RBO100OV), eluent: dichloromethane - ethyl acetate (4:11). Compound (0): Brown solid. (4) Synthesis of Compound (p) "

A mixture of Compound (0) (70.2g), iodine (183.7g, 0.72mol) and calcium carbonate (36.23g, 0.3bmol) in methanol - water (10:11, 1.0L) was heated under reflux within 5 years After cooling, sodium sulfite (1.0 L) and chloroform (1.0 L) were added to the mixture at 1090 - s, and the resulting mixture was stirred at room temperature for 15 minutes. The insoluble material was filtered with suction and the material was washed with chloroform (0.5 L). The combined organic layers of the filtrate and washing solutions were separated and the aqueous layer was further extracted with chloroform (0.5 L). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to dryness. Compound (p): brown oil, 53.6bg (complete 81905 yield of Compound -i (t)), yield: 80.49 by HPLC (see Example 22), 96.296ee by chiral HPLC (see Example 22).

FO "H-NMR (400MHz, SOSI»v) w: 9.28 (9Н, с, ТМ5), 0.94 (ЗН, т, У-7.4Hz СНоСН»), 1.76 (2Н, К, У- 7.4Hz, СНХСН»), 3.61 (1Н, с, ОН), 3.98 (ЗН, с, OSН»У), 5.23 (1Н, d, 9У-15.6Hz), 5.54 (1H, d, U-15.6Hz), 7.33 (1H, s, aromatics-H).ve (5) Synthesis of Compound (4) iz 50 Mixture of Compound (p) (50.2g, O.14mol, content: 80.495, 96.2Uvee), M-chlorosuccinimide (107.36g, 0.vOmol) and sodium iodide (120.52g, 0.8Omol) in acetic acid (411ml) were heated at approximately 652C with stirring for 16h. After cooling, 2095 of sodium carbonate (1.7L), 1095 of sodium sulfite (1.0L), and chloroform (0.bl) were sequentially added to the mixture. The organic layer of the mixture was evaporated and the aqueous layer was extracted with chloroform (0.blx2). The combined organic layers dried over anhydrous sodium sulfate, 59 was filtered and then evaporated under reduced pressure to dryness (crude 4).

HF) (6) Purification of Compound (4) (1) 7 A suspension of crude Compound (4) (residue from the previous stage, purity: 89.295 by HPLC) in methanol (15Oml) was added dropwise to 0.2M sodium hydroxide (0.4O0mol) while stirring. The mixture was stirred at room temperature for 2 h. The alkaline mixture was washed with chloroform (400 ml x3) and the aqueous layer was evaporated and the pH was adjusted to 1-2 using 6M hydrochloric acid. The acidic solution was extracted with chloroform (400mlx3). The organic layer was evaporated and dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure to dryness. Semi-purified (4), purity: 97.79o5 by HPLC (see Example 25). (7) Purification of Compound (4) (2) 65 The semi-purified (4) was dissolved in chloroform (280ml) and n-hexane (400ml) adding to the surface of the solution and the resulting mixture was left at room temperature for 15g. The precipitate was removed by filtration and the filtrate was evaporated to dryness under reduced pressure. Compound (4); jelly-like oil, 47 4g (86905 yield), content: 84.595 per

HPLC (see Example 25), 99.7 Uvee by chiral HPLC (see Example 25). "H-NMR (400 MHz, SOSIv) and: 0.94 (ZH, t, U-7.3 Hz, СНоСН»z). 1-75 (2Н, k, а-7.3 Hz, СНоСН»), 3, 58 (1H, c, OH), 3.96 (ZN, c, OSNU), 5.16 (1H, d, 9-15.6G4), 5.47 (1H, d, 9-15.684), 7, 59 (1 H, s, aromatics-H). (94579 -51.3 (s-0.981, CHO") (8) Synthesis of Compound (g)

A solution of Compound (a) (42.8g, 0.1Omol, content: 84.590), palladium acetate (1.34g, 5.95mmol) and potassium carbonate (24.67g, 0.17Umol) in propanol (490ml) was degassed with suction and flushed with argon and degassed with 70 suction and then filled with carbon monoxide. The mixture was stirred at 602 for 4 h. After cooling, the insoluble material was removed on a bed of Celite and the material on the bed was washed with ethyl acetate (300 ml). The filtrate was washed with 1M hydrochloric acid (150ml) and saturated aqueous sodium chloride solution (300ml) and the aqueous layer was evaporated and extracted with ethyl acetate (300ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel; silica gel (200g), eluent: chloroform - methanol (99:1). Compound (g): Brown oil, C0.3g (7090 yield), HPLC grade 73.4906 (see Example 26). "H-NMR (400MHz, SOSIv) w: 0.88 (ZH, t, U-7.93Hz, CH), 1.04 (ZH, t, 9U-7.3Hz, SNU), 1.82 (4H . 31 (1H, d, U-16.3Hz), 5.61 (1H, d, U-16.3Hz), 7.94 (TN, c, aromatics-H) (9) Synthesis of Compound (5)

To a stirred solution of Compound (g) (28.7g, 68.2mmol, content: 734905) and sodium iodide (27.6g, 0O.18mol) in absolute acetonitrile (141ml) was added dropwise at room temperature under a nitrogen atmosphere chlorotriethylsilane (23.3 ml, 0.18 mmol). The mixture was stirred at room temperature for 1 h, then quenched with 1 M hydrochloric acid (8 ml) and 10906 sodium sulfite (232 ml). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was extracted with ethyl acetate and the organic layer was evaporated and He) was evaporated under reduced pressure to dryness. Compound (5): 22.3g (9590 yield), content: 85.696 by HPLC (see

Example 27). "H-NMR (400MHz, SOSIv) w: 1.00 (ZN, t, U-7.9Г4, SNU"), 1.02 (ZN, t, 9U-7.3Hz, SN), 1.83 ( 4Н, m, СНох2), 3.75 F zo (IN, с, ОН), 4.35 (2Н, т, У-6.8Hz, СНо), 5.21 (1Н, d, 9У-17.1Х ), 5.61 (IN, d, 9U-17.1HC), 7.28 (IN, s, aromatics-H), 9.59 (1H, shs, OH). " (10) Synthesis of Compound (O) "

A solution of Compound (c) (0.50g, 1.4bmmol, content: 86.695) and potassium carbonate (0.40g, 2.92mmol) in dimethyl sulfoxide (ml) was stirred at 5023 in an argon atmosphere for 20 minutes. Tert-butyl acrylate (2.1 mL, 14.bmol) was added dropwise to the stirred mixture (Ce) in an argon atmosphere, and stirring was continued for 20 h. Water (1 ml) and concentrated hydrochloric acid (1 ml) were added dropwise to the mixture cooled in an ice bath and stirred. The mixture was extracted with toluene-ethyl acetate (4:11, 7mlx4). The combined extracts were washed with water (bmlx3), dried over anhydrous sodium sulfate, filtered and then evaporated under reduced pressure to dryness. Compound (9: 0.55g (7790 yield), content: 75.095 by HPLC (see Example 28). « 7H-NMR (400MHz, SOCI8) n: 0.99 (ZN, t, 9U-7.4Hz, СНоСнНв) . 8Hz), 5.69 (1H, d, 9U-17.8Hz), 7.01 (1H, s, aromatics-H). a (11) Synthesis of Compound (n) "» To a solution of Compound (Y (1, 02g, 1.84mmol, content: 66.095) in toluene (17ml), while stirring in an argon atmosphere, trifluoroacetic acid (1./7ml) was added. The mixture was stirred at 1102 in an argon atmosphere for 100min. After cooling, the mixture was evaporated under reduced pressure to dry. The residue was suspended in dichloromethane (5Oml) and the insoluble material was filtered through a pad of Celite. The filtrate was washed with water (1Oml) and the organic layer was evaporated and the aqueous layer was extracted with dichloromethane (20mlx3). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to dryness. H)-trione; 0.46g (7790 output), content: iz 20 80.795 by HPLC (as shown below). 7"H-NMR (400MHz, SOSI"z) w: 0.98 (ZN, t, 9U-7.9Hz, СНоСНаз, 1.81 (2Н, m, СНоСНаз), 2.97 (2Н, t, 9У-6 ,3Gu, c SNOCH,.), 5.64 (1H, c, OH), 4.34 (2H, m, СНоCH»), 5.25 (1H, d, 9U-17.1Hz), 5.68 (1H, d, 9U-17.1Gu), 7.22 (1H, c, aromatics-H).

Conditions for conducting HPLC

Column: Ipegizii 005-2, 0, Absm ХХ25cm

HF) Temperature: constant temperature approx. 402 g Flow rate: Tml/min.

Mobile phase: 10mm potassium dihydrogen phosphate - methanol (4:1) in Detection: 254nm

Example 31) Synthesis of 7-ethyl-10-hydroxycamptothecin (5-38) b5

Kf to: a vek I K y Still m he ZNO s slav y sty and So I AK s ton sh chin

A suspension of Compound (j) (0.50 g, 1.82 mmol, content: 96.696) was obtained as described in Example 3 (11), |i

Compound (e) (0.36g, 2.14mmol) in the presence of p-toluenesulfonic acid monohydrate (1Omg) in acetic acid - toluene (111, 1Oml) was stirred at 1009 in a nitrogen atmosphere for 18h. The mixture was evaporated under reduced pressure and toluene (1 Oml) was added to the residue and then evaporated under reduced pressure to dryness. 75 The residue was suspended in acetone (dhl) and the suspension was stirred at room temperature for 2 h.

The suspension was filtered with suction and the collected solid was washed with acetone (2ml x 2) and then dried under reduced pressure. ZM-38: brown solid, 0.63g (89905 yield), content: 97.7956 by HPLC (see Example 9). 7H-NMR (400MHz, SOS) and: 0.98 (ZH, t, U-7Hz, CHz), 1.98 (ZH, t, U-7Hz, CHz), 1.90 (2H, k, 9- 7Hz, CH"), 3.08 (2H, k, d-7Hz, CH"), 5.17 (2H, s, SNHO), 5.23 (1H, d, 9U-16HzC), 5.54 ( 1IN, d, 9U-16Hz), 7.34-7.39 (ZN, m), 6.83 (TN, d, U-9Hz).

Example 321 Synthesis of 7-ethyl-10-I4-(1-piperidino)-1-piperidino|)carbonyloxycamptothecin (ZM-388-11)

IM-38 (0.91g, 2.32mmol), prepared as described in Example 31, was converted to 5M-388-11 (1.22g, 8990% yield, 99.8% by chiral HPLC; see Example 10) using the described method (5. Zazhmada, ea|.,

Spent RNagt. Vii., 1991, 39, 1446). "

Example III Synthesis of 7-ethyl-10-I4-(1-piperidino)-1-piperidino|carbonyloxycamptothecin hydrochloride trihydrate (SPT-11)

Х Х Х Х A z v i yy: Х y. y and ngsheke

K y zh y and also zve -y sho. What is ZAY, and this is GK SHY - and it is obvious what it is. ZM-388-11 (1.00g, 1.7mmol), obtained as described in Example 32, dissolved in 0.1M hydrochloric acid

He") (20 ml) by heating at approximately 80 2С. Acetonitrile (10 ml) was added to the solution and the mixture was gently stirred at room temperature for 15 h. The precipitates were filtered with suction and dried under reduced pressure and then moistened. CRT-11: pale yellow crystalline powder, 0.95 mg (89.995 yield). t» 50 Industrial applicability c Using the synthetic method of the invention, it is possible to obtain highly pure 2'-amino-5'-hydroxypropiophenone and a tricyclic ketone in a short time with a high yield, and using these intermediate compounds it is possible to rationally carry out the general synthesis of CPT analogues.

Claims (39)

Formula of the invention F) o 1. The method of obtaining 2'-amino-5'-hydroxypropiophenone for the synthesis of camptothecin analogs, in which compound (b) is obtained from compound (a): 60 on CHO (a) and U: MO 65: when CHO (B) FI pd MO and from compound (B) compound (c) is obtained: an , (c) when I pe MO and from compound (c) compound (4) is obtained: , (a 75 o (a) co to |SHO by MO and compound (e) is obtained from compound (4): (c) , (e) no dx s po. МН о where K is a protecting group that can be removed by catalytic reduction. 2. The method according to item 1, in which the protective group that can be removed by catalytic reduction is a benzyl group. b" C. The method according to item 1 or 2, where it includes one or more stages selected from the "E group, which contains (1) the stage of obtaining the compound (B) by mixing the compound (a), a benzylating reagent and a base and " stirring the mentioned mixture in a solvent under reflux; Ge (2) the stage of obtaining compound (c) by adding drops of the Grignard reagent to compound (B) in an inert gas atmosphere; i- (3) the stage of obtaining the compound (4) by mixing the compound (c) and the oxidizing agent and stirring the mixture; and (4) the step of obtaining compound (e) by catalytic reduction of compound (4). " 4. The method according to point 3, in which in stage (1) the solvent is dimethylformamide. 5. The method according to item 3, in which in step (2) the Grignard reagent is vinyl magnesium bromide. With c b. The method according to item C, in which in stage (3) the oxidizing agent is Jones reagent, manganese dioxide or (2,2,6,6-tetramethylpiperidine-1-oxyl)-sodium hypochlorite (TEMRO-sodium hypochlorite). " 7. The compound of formula (c): an, (c) - VpO do a Ge) sh ich mo, "iz" 20 in which Vp is a benzyl group. 8. Compound of formula (a): iChe) t (4) VpO EE ime) not in which Vp is a benzyl group. 9. The method of obtaining 2'-amino-5'-hydroxypropiophenone for the synthesis of camptothecin analogs, in which compound (c") is obtained from compound (a): but (a) C by 7 tm, b5): an (c) but up to 4 pe MO and from compound (c") compound (a) is obtained: (8) ; (a 7 but about MO; and from compound (a") compound (e) is obtained: (c) ( f) but with MN; 10. The method according to item 9, where it includes one or more stages selected from the group consisting of (1) the stage of obtaining the compound (c") by adding drops of the Grignard reagent to the compound (a) in an atmosphere of inert gas; o (2) the step of obtaining compound (j") by mixing compound (c") and an oxidizing agent and stirring the mixture; and (3) the step of obtaining compound (e) by catalytic reduction of compound (a"). 11. The method according to item 10, in which in step (1) the Grignard reagent is vinyl magnesium bromide. (is) 12. The method according to item 11, in which in stage (2) the oxidizing agent is Jones reagent, manganese dioxide or TEMRO-sodium hypochlorite. 13. The use of 2'-amino-5'-hydroxypropiophenone, which is obtained by the method according to any of "items 1-6, for obtaining camptothecin analogs. "co 14. Use of 2'-amino-5'-hydroxypropiophenone, which is obtained by the method according to any of items 9-12, for obtaining camptothecin analogues. - 15. The method of obtaining camptothecin analogues, which includes the reaction of 2'-amino-5'-hydroxypropiophenone, obtained by the method according to any of items 1-6, and a tricyclic ketone. 16. The method of obtaining camptothecin analogs, which includes the reaction of 2'-amino-5'-hydroxypropiophenone, obtained by the method according to any of items 9-12, and a tricyclic ketone. 17. The method of obtaining a tricyclic ketone for the synthesis of camptothecin analogs, in which from the compound (K): t c OoMe, (ky) ;" IR a sh- tm Ge" in which TM5 is a trimethylsilyl group and Me is a methyl group, or compounds (khm): e oMme ch iz 50 s M | zones in which TM5 is a trimethylsilyl group and Me is a methyl group, HF) obtain compound (1): (I yuyu OoMe () sno bo M poyu tm in which TM5 is a trimethylsilyl group and Me is a methyl group, in and from the compound (I) compound (t) is obtained: -BO0- omMe ; (t) Kai 8) where - tM8 SH in which TM5 is a trimethylsilyl group and Me is a methyl group, and from compound (t) compound (n) is obtained: omMe (n) Kei | 8) Mo E! in which TM5 is a trimethylsilyl group, Me is a methyl group and Ei is an ethyl group, and from compound (n) compound (0) is obtained: oMe , (o) and | o s pe o tm 7 that E on in which TM5 is a trimethylsilyl group, Me is a methyl group and Ei is an ethyl group, and compound (p) is obtained from compound (o): (e) OMme (c) « MA | o Z Ochi Ф tm also - no Ey in which TM5 is a trimethylsilyl group, Me is a methyl group and Ey is an ethyl group, and compound (p) is obtained from compound (4): « OoMe , (a) shi с ME | poison » o " ho I zy, TO But V -I in which Me is a methyl group and Ei is an ethyl group, F and from compound (4) get compound (g): OoMme (9 sh» iz 50 ШЭ | . i o no E o 59 in which Me is a methyl group, Ei is an ethyl group and Pg is a propyl group, HF) and compound (8) is obtained from compound (d): HO) 1 (c) ime) and - in IM | (8) РО о я Ted, о no Е о 65 in which Eі is an ethyl group and Рг is a propyl group, and compound (5) is obtained from compound (0: o 0 o M | a ry nt) un i se no "yiv no in which Ei is an ethyl group and V is a t-butyl group, and compound (B) is obtained from compound (0): o (n) M | o o z t a 8) no EI in which Es is an ethyl group, where the method includes one or more stages selected from the group that contains: (1) a stage of obtaining compound (I) by mixing compound (K), a lithiation agent, a formylating reagent and an iodizing reagent; (2) the stage of obtaining the compound (t) by mixing the compound (I), crotyl alcohol, triethylsilane and acid and the interaction of the mentioned mixture without using a solvent; (3) the stage of obtaining the compound (I) by mixing the compound (hm), the biproduct of the stage (2) ) with an oxidizing agent and a base; o (4) the stage of obtaining compound (n) by mixing compound (t), a palladium catalyst, a base and a phase transfer catalyst and boiling the mentioned mixture in a solvent; (5) the stage of obtaining a compound (o ) by mixing compound (p), osmium catalyst, co-oxidizing agent, base and asymmetric reagent; b" (6) the stage of obtaining the compound (p) by mixing the compound (0), the base and iodine and boiling the mentioned mixture in a liquid alcohol-water mixture; (7) the stage of obtaining compound (e) by mixing compound (p) and desilylating-iodizing reagent; (8) the stage of obtaining compound (d) by mixing compound (4), a palladium catalyst and a base and "with the interaction of the mentioned mixture in 1-propanol in an atmosphere of carbon monoxide; (9) the stage of obtaining the compound (5) by mixing the compound (d) and the demethylating reagent and the interaction of the said mixture at room temperature; (10) the stage of obtaining compound (I) by reacting compound (5) with t-butyl acrylate in the presence of a base. 18. The method according to item 17, in which in stage (1) the lithiation agent is n-butyllithium. " 19. The method according to item 17 or 18, in which in step (1) the reaction temperature is a constant temperature within the range of -30 to -4096. t s 20. The method according to item 17, in which in stage (3) the oxidizing agent is TEMRO-sodium hypochlorite. "» 21. The method according to item 17, in which in stage (4) the base is potassium carbonate or diisopropylethylamine. " 22. The method according to item 17 or 21, in which in stage (4) the solvent is tetrahydrofuran or a liquid mixture of diisopropyl ether-acetonitrile-water. 23. The method according to item 17, in which in step (5) the osmium catalyst is potassium osmate (MI). - 24. The method according to item 17, in which in stage (6) 4 equivalents of iodine are used in relation to b compound (0). 25. The method according to item 17, in which at stage (7) the desilylation-iodination reagent is silver iodine-trifluoroacetate or M-chlorosuccinimide-sodium iodide. there are 20 of them 26. The method according to item 17 or 25, in which the compound (4) is purified chemically by means of purification stages, including: c the stage of adding the reaction product obtained at the stage of obtaining the compound (4) from the compound (p) to an aqueous alkaline solution and mixing; the stage of adding an organic solvent and mixing followed by removal of the organic layer; and 99 stage acidification of the aqueous layer and extraction with an organic solvent. GF! 27. The method according to item 26, in which the aqueous alkaline solution is an aqueous solution of sodium hydroxide. 28. The method according to item 26, in which the organic solvent is chloroform. at 29. The method according to item 17 or 25, in which the compound (4) is optically purified by means of purification stages, which includes: the stage of dissolving the reaction product obtained at the stage of obtaining the compound (4) from the compound (p) in a highly polar solvent, followed by stratification with a low-polarity solvent and the stage of sediment filtration followed by concentration of the filtrate to dryness under reduced pressure. 30. The method according to item 29, in which the highly polar solvent is chloroform. 31. The method according to item 29, in which the low polar solvent is n-hexane. for 32. The method according to item 17, in which in stage (10) the base is potassium carbonate. 33. Use of the tricyclic ketone obtained by the method according to any of items 17-32 for the preparation of camptothecin analogs. 34. The method of preparation of camptothecin analogs, in which the tricyclic ketone, which is obtained by the method according to any of items 17-32, reacts with 2'-amino-5'-hydroxypropiophenone. 35. The method according to item 34, in which 2'-amino-5'-hydroxypropiophenone is 2'-amino-5'-hydroxypropiophenone obtained by the method according to any of items 1-6. 36. The method according to item 34, in which the 2'-amino-5'-hydroxypropiophenone is 2'-amino-5'-hydroxypropiophenone obtained by the method according to any of items 9-12. 37. The method according to item 15, in which the tricyclic ketone and 2'-amino-5'-hydroxypropiophenone are mixed and/or said mixture is reacted in an inert gas atmosphere. 38. The method according to item 16, in which the tricyclic ketone and 2'-amino-5'-hydroxypropiophenone are mixed, and said mixture is reacted in an inert gas atmosphere. 39. The method according to any of clauses 34-3b, in which the tricyclic ketone (') and 2-amino-5-hydroxypropiophenone are mixed and said mixture is reacted in an inert gas atmosphere. 0. и и и 0. Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 8, 15.08.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s (8) (22) « « (Se) m. - with . and? -I (22) sh» sh» 3e) F) ime) 60 b5